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  1. Nov 2024
  2. docdrop.org docdrop.org
    SKMBT_28317040414250-2.pdf
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  3. slate.com slate.com
    How Could We Safely Amend the Constitution by National Referendum?
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    1. adam5 01 Nov 2024

      12:3 Those who are wi se[a] will shine like the brightness of the heavens, and those who lead many to righteousness, like the stars for ever and ever.

      you are offline

      we the people rise again

      safe souls, safe fu

      We the People of Slate ...

      The U.S. Constitution, as you [mighta been, shoulda "come" on ... its someday] rewrϕte it.

      "Politicians talk about the Constitution as if it were as sacrosanct as the Ten Commandments [interjection: spec. it is actually almost exactly related!]. But the document itself invites change and revision. What if the president served only one six-year term instead two four-year terms? What if your state's population determined how many senators represent it? What if the Constitution included a right to health care? We asked legal scholars and Slate readers to cross out what they didn't like in the Constitution and pencil in their hearts' desires. Here's what the document would look like with their best ideas."

      多也了了夕 "with a ~~wand~~ of scheffilara, 并#亦太 he begins ... "I am now on the Staff of Menelaus, the Spears of Longinus and Lancelot; and the name "Mosche ex Nashon."

      Logically the recent mentions of Gilgamesh and the simultaneous 同時 overlaping 場道 of the eventual link between the famous ruling of Solomon on the separation of babies and mothers and waters and land ... to a story of many "two cities" that culminates in a cultural or societal or "evolutionary" link to Sodom and Gomorrah and the city-state of Babylon (and it's Hanging Gardens) and also of course to Paris and Troy and "Masstodon" and city-states [ciudadestado] and perhaps planet-cities; from Cambridge to Cambridge across the "Cable" to see state to "London" ... recently I called it "the city of realms" ... I started out logically intending to link "game theory" and John Nash to the mathematical story of Sputnik and a revival of American physics; but in my usual way of rambling into the woods [I mean neighborhood] of stream of consciousness ... turned into a premonitory discourse of "two cities" and how sometimes even things as obvious as the number of letters in the word "two" don't do a good enough job of conveying ... how and/or why one is simply never enough, and two isn't much better--but in the end a circle ... is drawn; the perfect circle in our imaginary mathematical perfection ... I see a parted "line" in the letter pronounced "tea" (and beginning that word); and two "vee" (pron. of "v") symbols joined together in a word we pronounce as "double-you" ... and symbolically because I know "V" is the Roman Numeral for 5 (five) and I know not how to multiply in Roman numerals--

      It's important to pause; here. I am going to write a more detailed piece on "the two cities" as I work through this maze like crossroads between "them" and "demo..." ... here demorigstrably I am trying to fuse together an evolutionary change in ... lit. biological evolution as well as an echelon leap forward in "self-government" ... in a place where these two things are unfathomable and unspokenly* connected.

      To a question on the idiom; is Bablyon about "the law" or "of the land of Nod?"

      "What is democracy" ... the song, Metallica's "ONE" echoes and repeats; as we apparently scrive together the word "THEM" ... I question myself ... if Babylon were the capital city of some mythical Nation of Time ... if it were the central "turning point" of Sheol; ... >|<

      Can you not see that in this place; in a world that should see and does there is a gigantic message proving that we are not in reality and trying to show us how and why that's the best news since ... ever---that it's as simple as conjoining "the law of the land" with a basic set of rules that automatically turn Hell into something so much closer to Heaven I just do not understand---why we cant stand up together and say "bullets will not kill innocent children" and "snowflakes will not start avalanches ...." that cover or bury or hide the road from Earth to Verital)e .... or from the mythical Valis to Tanis---or from Rigel to Beth-El ... "guess?"

      ## as "an easy" answer; I'm looking for a fusion of "law and land" that somehow remembers a "jok'er a scene" about "lawn" seats; and "where the girls are green;"

      It's as simple as night and day; Heaven and Hell ... the difference between survival and--what we are presented with here; it's "doing this right"--that ends the Hell of representative democracy and electoral college--the blindness and darkness of not seeing "EXTINCTION LEVEL EVENT" encoded in these words and in our governments foundation ... *by the framers [not just of the USA; but English .. and every language] *

      ... is literally just as simple as "not caring" or thinking we are at the beginning of some long process--or thinking it will never be done--that special "IT" that's the emancipation of you and I.

      Here words like "gnosis" and "gaudeamus" pair with my/ur "new ntersanding*" of the difference between Asgard and Medgard and really understanding our purpose here is to end "evil" ... things like "simulating disease and pain" (here, simulating meaning ... intentionally causing, rather than "gamifying away") and successfully linking the "Pillars of Hercules" to Plato's vision of Atlantis and the letter sequences "an" and "as" ... unlock a fusion of religion and mythology and "cryptographic truth" that connects "messianic" and "Christian" to "Roman" ... "Chinese" and "American" ... literally the key to the difference between the phrases "we are" and "we were" ....

      in "sight" of "silicon" in simulation and Israel, Genesis, and "silence" ... trying to the raising of Asgardian enlightenment ... and seeing "simple cypher" connecting to "Norse" ...

      and the "I AM THAT" surer than shit ... the intention and design of all religion and creation is to end "simulated reality" and also not seeing "SR" ... in Israel and Norse ... "for instance."

      It's a simple linguistic concept; the "singularity" and the "plurality" of a simple word--"to be"--but it goes to the heart of everything that we are and everything that is around us. This is a message about understanding and preserving individuality as well as liberty; and literally seeing "ARXIV" and understanding "often" and failing to connect God and prescience to "IV" and the Fourth Amendment ... it's about blindness and ... "curing the blind instantly" ... and fathoming how and why this message has been etched into our entire history and and all religions and myths and music--to help us "to be THAT we" that actually "are responsible" for the end of Hell.

      • I neglected to mention "Har-Wer" and "Tower of Babel" which are both related lingusitically, religiously and topically: "to who ..." and while we're on "four score and [seven years from now]" seeing the fourth "living thing" in Eden and it's (the name, Abel) connection to Babel and Abraham Lincoln; slavery and ... understanding we live in a place where the history of the United States also, like Monoceros and "Neil Armstrong's first step" are a time shifted ... overlayed map to achieving freedom ... it's about becoming a father-race ... and actually "doing" the technological steps required to "emancipate the e's of 'me&e'" and survive in exo-planetary space---

      it might be as simple as adding "because we did this" here and now; and having it be something we are truly proud of .... forevermore™ ... for certain in the heart of this story about cyclicality and repetition of error--its not because we did "this" or something over and over again; it's about changing "the problem" and then helping others to also overcome ... "things like time travel ... erasing speech" --- however that happenecl.

      • I also failed to mention that "I am in Hell" ... as in this world is hellacious to me; in an overlay with the Hellenic period and this message that we are in the Trojan Horse ... a small gem .... "planet" truly is the Ark of the Covenant---and it's the simple understanding that "reality is hell" is to "living without air conditioning and plumbing is hell" just as soon as you achieve ... "rediscovering" those things---

      • I can't figure out why I am the only person screaming "this is Hell." That's also, Hell.

      ... but recently suggested an old joke about "there being 10 kinds of people in the world (obv an anti-tautology and a tautology simultaneously)" only after that brief bit of singularity and duality mentioning the rest of the joke: "those that understand binary and those that don't know how to base convert between counting with two hands and counting with only an 'on and off.'" It's not obvious if you aren't trying to figure it out, I suppose; but 10 is decimal notation for "kiss" and the "often" without "of" ... and binary notation for the decimal equivalent of "2." A long long time ago in a state that simply non-randomly ties to the heart of the name of our galaxy ... I was again thinking of the "perfect imperfections" of things like saying "three equals one equals one" (which, of course was related to the Holy Trinity and it's "prescient/anachronistic Adamic presence encoded in the name Ab|ra|ha|m" which means "father of a great multitude") ... I brought that one back in the last few months; connecting the letter K and in this "logos-rythmic" tie to the "base of a number system" embellish the truth just a bit and suggest a more accurate rendition of the original [there is no such thing as equality, "is" of separate objects

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    slate.com/news-and-politics/2012/06/fix-the-constitution-amending-by-national-referendum.html
  4. en.wikipedia.org en.wikipedia.org
    Internationalization and localization - Wikipedia
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    1. adam5 01 Nov 2024

      12:3 Those who are wi se[a] will shine like the brightness of the heavens, and those who lead many to righteousness, like the stars for ever and ever.

      you are offline

      we the people rise again

      safe souls, safe fu

      We the People of Slate ...

      The U.S. Constitution, as you [mighta been, shoulda "come" on ... its someday] rewrϕte it.

      "Politicians talk about the Constitution as if it were as sacrosanct as the Ten Commandments [interjection: spec. it is actually almost exactly related!]. But the document itself invites change and revision. What if the president served only one six-year term instead two four-year terms? What if your state's population determined how many senators represent it? What if the Constitution included a right to health care? We asked legal scholars and Slate readers to cross out what they didn't like in the Constitution and pencil in their hearts' desires. Here's what the document would look like with their best ideas."

      多也了了夕 "with a ~~wand~~ of scheffilara, 并#亦太 he begins ... "I am now on the Staff of Menelaus, the Spears of Longinus and Lancelot; and the name "Mosche ex Nashon."

      Logically the recent mentions of Gilgamesh and the simultaneous 同時 overlaping 場道 of the eventual link between the famous ruling of Solomon on the separation of babies and mothers and waters and land ... to a story of many "two cities" that culminates in a cultural or societal or "evolutionary" link to Sodom and Gomorrah and the city-state of Babylon (and it's Hanging Gardens) and also of course to Paris and Troy and "Masstodon" and city-states [ciudadestado] and perhaps planet-cities; from Cambridge to Cambridge across the "Cable" to see state to "London" ... recently I called it "the city of realms" ... I started out logically intending to link "game theory" and John Nash to the mathematical story of Sputnik and a revival of American physics; but in my usual way of rambling into the woods [I mean neighborhood] of stream of consciousness ... turned into a premonitory discourse of "two cities" and how sometimes even things as obvious as the number of letters in the word "two" don't do a good enough job of conveying ... how and/or why one is simply never enough, and two isn't much better--but in the end a circle ... is drawn; the perfect circle in our imaginary mathematical perfection ... I see a parted "line" in the letter pronounced "tea" (and beginning that word); and two "vee" (pron. of "v") symbols joined together in a word we pronounce as "double-you" ... and symbolically because I know "V" is the Roman Numeral for 5 (five) and I know not how to multiply in Roman numerals--

      It's important to pause; here. I am going to write a more detailed piece on "the two cities" as I work through this maze like crossroads between "them" and "demo..." ... here demorigstrably I am trying to fuse together an evolutionary change in ... lit. biological evolution as well as an echelon leap forward in "self-government" ... in a place where these two things are unfathomable and unspokenly* connected.

      To a question on the idiom; is Bablyon about "the law" or "of the land of Nod?"

      "What is democracy" ... the song, Metallica's "ONE" echoes and repeats; as we apparently scrive together the word "THEM" ... I question myself ... if Babylon were the capital city of some mythical Nation of Time ... if it were the central "turning point" of Sheol; ... >|<

      Can you not see that in this place; in a world that should see and does there is a gigantic message proving that we are not in reality and trying to show us how and why that's the best news since ... ever---that it's as simple as conjoining "the law of the land" with a basic set of rules that automatically turn Hell into something so much closer to Heaven I just do not understand---why we cant stand up together and say "bullets will not kill innocent children" and "snowflakes will not start avalanches ...." that cover or bury or hide the road from Earth to Verital)e .... or from the mythical Valis to Tanis---or from Rigel to Beth-El ... "guess?"

      ## as "an easy" answer; I'm looking for a fusion of "law and land" that somehow remembers a "jok'er a scene" about "lawn" seats; and "where the girls are green;"

      It's as simple as night and day; Heaven and Hell ... the difference between survival and--what we are presented with here; it's "doing this right"--that ends the Hell of representative democracy and electoral college--the blindness and darkness of not seeing "EXTINCTION LEVEL EVENT" encoded in these words and in our governments foundation ... *by the framers [not just of the USA; but English .. and every language] *

      ... is literally just as simple as "not caring" or thinking we are at the beginning of some long process--or thinking it will never be done--that special "IT" that's the emancipation of you and I.

      Here words like "gnosis" and "gaudeamus" pair with my/ur "new ntersanding*" of the difference between Asgard and Medgard and really understanding our purpose here is to end "evil" ... things like "simulating disease and pain" (here, simulating meaning ... intentionally causing, rather than "gamifying away") and successfully linking the "Pillars of Hercules" to Plato's vision of Atlantis and the letter sequences "an" and "as" ... unlock a fusion of religion and mythology and "cryptographic truth" that connects "messianic" and "Christian" to "Roman" ... "Chinese" and "American" ... literally the key to the difference between the phrases "we are" and "we were" ....

      in "sight" of "silicon" in simulation and Israel, Genesis, and "silence" ... trying to the raising of Asgardian enlightenment ... and seeing "simple cypher" connecting to "Norse" ...

      and the "I AM THAT" surer than shit ... the intention and design of all religion and creation is to end "simulated reality" and also not seeing "SR" ... in Israel and Norse ... "for instance."

      It's a simple linguistic concept; the "singularity" and the "plurality" of a simple word--"to be"--but it goes to the heart of everything that we are and everything that is around us. This is a message about understanding and preserving individuality as well as liberty; and literally seeing "ARXIV" and understanding "often" and failing to connect God and prescience to "IV" and the Fourth Amendment ... it's about blindness and ... "curing the blind instantly" ... and fathoming how and why this message has been etched into our entire history and and all religions and myths and music--to help us "to be THAT we" that actually "are responsible" for the end of Hell.

      • I neglected to mention "Har-Wer" and "Tower of Babel" which are both related lingusitically, religiously and topically: "to who ..." and while we're on "four score and [seven years from now]" seeing the fourth "living thing" in Eden and it's (the name, Abel) connection to Babel and Abraham Lincoln; slavery and ... understanding we live in a place where the history of the United States also, like Monoceros and "Neil Armstrong's first step" are a time shifted ... overlayed map to achieving freedom ... it's about becoming a father-race ... and actually "doing" the technological steps required to "emancipate the e's of 'me&e'" and survive in exo-planetary space---

      it might be as simple as adding "because we did this" here and now; and having it be something we are truly proud of .... forevermore™ ... for certain in the heart of this story about cyclicality and repetition of error--its not because we did "this" or something over and over again; it's about changing "the problem" and then helping others to also overcome ... "things like time travel ... erasing speech" --- however that happenecl.

      • I also failed to mention that "I am in Hell" ... as in this world is hellacious to me; in an overlay with the Hellenic period and this message that we are in the Trojan Horse ... a small gem .... "planet" truly is the Ark of the Covenant---and it's the simple understanding that "reality is hell" is to "living without air conditioning and plumbing is hell" just as soon as you achieve ... "rediscovering" those things---

      • I can't figure out why I am the only person screaming "this is Hell." That's also, Hell.

      ... but recently suggested an old joke about "there being 10 kinds of people in the world (obv an anti-tautology and a tautology simultaneously)" only after that brief bit of singularity and duality mentioning the rest of the joke: "those that understand binary and those that don't know how to base convert between counting with two hands and counting with only an 'on and off.'" It's not obvious if you aren't trying to figure it out, I suppose; but 10 is decimal notation for "kiss" and the "often" without "of" ... and binary notation for the decimal equivalent of "2." A long long time ago in a state that simply non-randomly ties to the heart of the name of our galaxy ... I was again thinking of the "perfect imperfections" of things like saying "three equals one equals one" (which, of course was related to the Holy Trinity and it's "prescient/anachronistic Adamic presence encoded in the name Ab|ra|ha|m" which means "father of a great multitude") ... I brought that one back in the last few months; connecting the letter K and in this "logos-rythmic" tie to the "base of a number system" embellish the truth just a bit and suggest a more accurate rendition of the original [there is no such thing as equality, "is" of separate objects--as in no two snowflakes are the same unless they are literally the same one; true of ancient weights and with the advent of (thinking about) time no two "planets" are the same even if they're the exact same one--unless it's at a fixed moment in time.

      K=3:11 ... to a handle on the music, the DHD of the gate and the *ring of David's "sling" ...

      ---and that's a relationship of "3 is to 11" as [the SAT style "analogy)]y" as a series of alpha, two mathematic, and two numeric symbols ... may only tie in my mind alone to the books of Genesis and Matthew and the phrase "chapter and verse" and to the stories of Lot and Job ... again in Genesis and the eponymous "Book of Job." So ... "tying up loose ends one 10b [III] iv. " as it appears I've taken it upon myself to call a Job and suggest is my "Lot in life [x]i* [3]"

      • I worry sometimes that important things are missing, or will disappear---for instance Mirriam Webster, which is a "canonical/standard dictionary) should probably have an entry for "lot in life" non-idiomatically as "granny apples to sour apples" as

      2 MANY ALSO ICI; 1twoⅱ ... following in Mitnick's bold introductory word steps; the curve and the complement ... the missiles and the canoes; the line and the blank space ... "supposedly two examples of two kinds, which could be three not nothings ... Today I write about something monumental; as if as important as the singularity depicted in Arthur C. Clarke's 2001 "A Space Odyssey" ... and remember a day when I thought it very novel and interesting to see the words "stillborn and yet still born" connected in a single piece of writing to "Stillwater and yet still water" ... today adding in another phrase noting the change wrought only by one magical single "space" (also a single capital letter; and a third phrase): "block chains with a great blockchain."

      • https://en.wikipedia.org/wiki/Euripides, Iphigenia in Aulis or Iphigenia at Aulis[1] (Ancient Greek: Ἰφιγένεια ἐν Αὐλίδι, Iphigeneia en Aulidi; variously translated, including the Latin Iphigenia in Aulide) is the last of the extant works by the playwright Euripides. Written between 408, after Orestes, and 406 BC, the year of Euripides' death, the play was first produced the following year[2] in a trilogy with The Bacchae and Alcmaeon in Corinth by his son or nephew, Euripides the Younger,[3] and won first place at the City Dionysia in Athens.

      • The play revolves around Agamemnon, the leader of the Greek coalition before and during the Trojan War, and his decision to sacrifice his daughter, Iphigenia, to appease the goddess Artemis and allow his troops to set sail to preserve their honour in battle against Troy. The conflict between Agamemnon and Achilles over the fate of the young woman presages a similar conflict between the two at the beginning of the Iliad. In his depiction of the experiences of the main characters, Euripides frequently uses tragic irony for dramatic effect.

      J.K. Rowling spurred just this past week a series of explanations about just exactly what is a blockchain coin worth ... and why is it so; her final words on the subject (artistic liberty taken, obviously not the last she'll say of this magic moment) "I don't think I trust this."

      Taken directly from an off the cuff email to ARXM titled: "Slow the S is ... our Hypothes.is"

      I imagine I'll be adding some wiki/ipfs stuff to it--and try to keep it compatible; the design and layout is almost exactly what I was dreaming about seeing--as a "first rough draft product." Lo, and behold. It's been added to the many places I host my tome; the small compilation of nearly every important email that has gone out ... all the way back to the days of the strange looking Margarita glass ... that now very much resembles the "Cantonese character 'le'" which I've come to associate with a "handle" on multiple corners of a room--something like an automatic coat rack conveyor belt connecting different versions of "what's in the box." I'm planning on using that symbol 了 to denote something like multiple forks of the same page. Obviously I'm thinking forward to things like "the Transhumaist Chain Party" (BDSM, right?)'s version of some particular piece of legislation, let's say everything starts with the sprawling "bulbing" of "Amendment M" ideas and specific verbiage ... and then we'll of course need some kind of new git/subversion/cvs style version control mechanism to merge intelligently into something that might actually .... really should ... make it into that place in history--the first constitutional amendment ratified by a "Continental Congress of All People" ... but you could also see it as an ongoing sort of forking of something like the "wikipedia page" on what some specific term, say "technocracy" means, and how two parties might propagandize and change the meaning of such thing; to suit the more intelligent and wise times we now live in. For instance, we might once have had a "democracy" and a "democractic" party that had some Anarchist Cook Book version of the history of it ending in something like Snipes and Stallone's "DEMOLITION MAN."

      Just kidding, we all know "democracy" has everything to do with "d is cl ... and not th" ... to be the them that is the heart of the start of the first true democracy. At least the first one I've ever seen, in my old "to a republic" ... style. As it is you can play around with commenting and highlighting and annotating all the stuff I've written and begged and begged for comments on--while I work on layering the backend to to perma-store our ideas and comments on both a blockchain (probably a new one; now that i've worked a little with ethereum) with maybe some key-merkle-tree-walk-search stuff etched into the original Rinkeby ... and then of course distributed data in the "public owned and operated" IPFS. To be clear, I plan on rewriting the backend storage so that we will have a permanent record of all comments; all versions of whatever is being commented on; and changes/revisions to those documents--sort of turning the web into a massive instant "place of collaboration, discussion, and co-authoring" ... if you use the wonderful LEGO pieces that have been handed to us in ideas from places like me, lemma--dissenter, and of course hypothes.is who has brought you and i such a polished and nice to look at "first draft" of something like the living Constitution come repository of all human knowledge. I do sort of secretly wich they would have called this project something like "annotating and reflecting (or real or ...) knowledge" just so the movement could have been called ARK. ... or something .... but whatever join the "calling you a reporter" group or ... "supposedly a scientist?"

      NOIR INgR .. I CITE SITE OF ENUDRICAM; a rekindling of the dream of a city appearing high above in the sky, now with a boldly emblazened smiling rainbow and upsidown river ... specifically the antithesis of "angel falls," there's a lagoon too--actually a chain of several ponds underneith the floating rock ... and in some versions of this waking dream there are rings around the thing; you might imagine an artificial set of centripetal orbitals something like a fusion of the ring Eslyeum and the "Six-Axis ride" of the JKF Center's "Spacecamp." I write as I dream, and though I cannot for certain explain exactly how; it's become a strong part of my mythology that this spectacular rendition of "what ends the silence" has something to do with the magical delivery of "a book" ... something not of this Earth but an unnatural thing; one I've dreamt of creating many times. This book is something like the DSM-IV and something like a Merck diagnostic manual; but rather than the old antiquated cures of "the Norse Medgard" this spectacle nearly "itsimportant" autoprints itself and lands on something like every doorpost; what it is is a list of reasons why "simply curing all disease" with no explanation and no conversation would be a travesty of morality--how it would render us half-blind to the myriad of new solutions that can come from truly understanding why "ITIS" to me has become a kind of magical marker: an "it is special" as in, it's cure could possibly solve a number of other problems.

      Through that missing "o," English on the ball, we see a connection between a number of words that shine bright light including Exodus itself which means "let there be light," the word for Holy Fire and the Burning Bush.. .reversed to hSE'Ah, and a story about the Second Coming parting our holy waters.**

      This answer connects the magical Rod's of Aaron in Exodus and the Iron Rod of Jesus Christ to the Sang Rael itself... in a fusion that explains how the Periodic Table element for Iron links not just to Total Recall and Mars, but also to this key

      my dream of what the first day of the Second Coming might be like; were the Rod of Christ... in the right hands. In a story that also spans the Bible, you might understand better how stone to bread and your input make all the difference in the world between Heaven and Adam's Hand. Once more, what do you think He** ....

      Since the very earliest days of this story, I have asked for better for you, even than see

      Nearly all of the original parts of the original "post-origination dream" remain intact; there's a walkway that magically creates new paths and "attractions" based on where you walk, something like an inversion of the artificial intelligence term "a random walk down a binary tree" ... for instance going left might bring you to the Internet Cafetornaseum of the Earl of Sandwich; and going to the right might bring you to the ICIMAX/Auditorium of Science and Discovery--there's a walkway to "Magical GLAS D'elevators" that open a special "instantiation" of the Japan Room of the Potter and the Toolmaker ... complete with a special [second level and hidden staircase] Pool of Bethesdaibo verily delivering something like youth of mind and body ... or at least as close to such a thing as a sip of Holy Water or Ambrosia or a dip in the pool of Coccoon and Ponce De'Leon could instantly bring ... to those that have seen Jupiter Ascending ... the questions of "nature versus nurture" and what it means to be "old and wise" and "young at heart" truly mean---

      Somewhere between the outdoor rafting ride and the level with the special "ballroom of the ancient gallery" ... perhaps now being named or renamed or recalled as something about "Face [of] the Music" lies a magical "mini-maize" ... a look at a mock-up (or #isitit) of Merlink and Harthor's "round table" that displays a series of ... (at least to me) magical appearing holographic displays and controls that my dreams have stolen from Phillip K. Dick's Minority Report and something of what I hope Microsoft's Dynamics/Hololens/Surface will become---a series of short "focus groups" .... to guage and discuss the information in the "CITIES-D5AM-MERCK" ... how to end world hunger and nearly all disease with the press of a magical buzzer--castling churches to something like "political-party-town-hall-meeting centers" and replacing jails and prisons and hospitals with something like the "Hospitalier's PRIDE and DOJOY's I practiced "Kung-fun-dance" ... a fusion of something like a hotel and a school that probably looks very much like a university with classrooms and dorms and dining hall's all fit into a single building. I imagine a series of 2 or 3 "room changes" as in you walk from the one where you get the book and talk about it ... to the one where you talk about "what everyone else said about it" and maybe another one that actually connects you to other people with something like Facebook's Portal; the point of the whole thing to really quickly "rubber stamp" the need for an end to "bars in the sky" nonalcoholic connotation--as in "overcoming the phrase the sky is the limit" and showing us the need for a beacon of glowing hope fulfilled--probably actually the vision of a holographic marker turning into actual rings around the single moon of Earth, the focus of the song annoucing the dawn of the age of Aquarius---

      It might lead us also to Ceres; and another set of artificial rings, or to Monoceros and a rehystorical understanding of the birthplace and birthing of the "river roads" that bridge the "space gaps" in the galaxy from our "one giant leap for mankind" linking the Apollo moon landing to the mythological connection to the sun; and connecting how the astrological charts of the ancients might detail a special kind of overlapping--the link between Earth's SOL and something like Proxima or Alpha Centauri; and how that "monostar bridge" might overlap to Orion and from there through Sagitarius and the center of the Milky Way ... all the way to Andromeda and more dreams of being in a place where there's a map to a tri-galactic system in the constellation Cancer and a similar one in Leo ... and just incase you haven't noticed it--a special marker here, I thought to myself it might be cool to "make an acronymic tie to Monoceros" and without even thinking auto-wrote Orion (which was the obvious constellation next to Monoceros, in the charts) and then to Sagitarrius; which is the obvious ... heart of our astrological center and link to "other galaxies."

      ----I've dreamt or scriven or reguessed numerous times how the Milky Way's map to an "Atlas marked through time by the ages and the ancients" might tie this place and this actual map to the creation of the railways between stars to the beginning and the end of time and of course to this message that links it all to time travel. There's a few "guesses" I've contemplated; that perhaps the Milky Way chart is a metal-cosmic or microcosmic map to the dawn of time in the galactic vision of ... just after the big bang; or it might tie to a map of something like the unthinkable--a civilization that became so powerful it was able to reverse the entropy of "cosmic expansion" and reverse the thing Asimov wrote of in "The Last Question" as the end of life and the ability to survive basically due to "heat loss."

      "The Last Question." (And if you read two, why not "The Last Answer"?). Find these readings added to our collection, 1,000 Free Audio Books: Download Great Books for Free.

      Looking for free, professionally-read audio books from Audible.com, including ones written by Isaac Asimov?

      * all "asterisks" in the abovə document denote a sort of Adamic unspoken relationship between notations and meanings; here adding the "Latin word for three" and source of the phrase "t.i.d." (which is doctor/pharmacy latin for "three times a day") where the "t" there is an abbreviation of "ter" ... and suppose the link between K and 11 and 3 noting it's alphanumeric position in the English alphabet as the 11th letter and only linking cognitively to three via the conversion between hex, and binarryy ... aberrative here is the overlapping "hakkasan" style (or ZHIV) lack of mention of the answer in "state of Kansas" and the "citystate of Slovakia" as described in the ICANN document linked [in] the related subsection or slice of the word "binarry" for the state of India. Tetris could be spelled with the addition of only a single letter [in] "tea"---the three letters "ris" are the hearts of the words "Christ" and "wrist" [and arguably of Osiris where you also see the round table character of the solar-system/sun glyph and the chemical element for The Fifth Element (as def. by i) via "Sinbad" and "Superman." The ERIS Free Network should also be mentioned here in connection with the IRC network I associate in the place between skipping stones and sacred hearts defined by "AOL" and "Kdice" in my life. In the lexicon of modern HTML, curly braces are generally relative to "classes" and "major object definitions (javascript/css)" while square brackets generally only take on computer-interpreted meaning in "Markdown" which is clearly (by definition, by this character set "[]") a superset (or at least definately not a subset) of HTML.

      Dr. Will Caster (Johnny Depp) is a scientist who researches the nature of sapience, including artificial intelligence. He and his team work to create a sentient computer; he predicts that such a computer will create a technological singularity, or in his words "Transcendence". His wife, Evelyn (played by Rebecca Hall), is also a scientist and helps him with his work.

      Following one of Will's presentations, an anti-technology terrorist group called "Revolutionary Independence From Technology" (R.I.F.T.) shoots Will with a polonium-laced bullet and carries out a series of synchronized attacks on A.I. laboratories across the country. Will is given no more than a month to live. In desperation, Evelyn comes up with a plan to upload Will's consciousness into the quantum computer that the project has developed. His best friend and fellow researcher, Max Waters (Paul Bettany), questions the wisdom of this choice, reasoning that the "uploaded"

      Just from my general understanding and memory "st" is not ... to me (specifically) an abbreviation of "state" but "ste" is a U.S. Postal code (also "as I understand it") for the name of a special room or set of rooms called a "suite" and in Adamic "connotation" I sometimes read it as "sweet" ... which has several meanings that range from "cool" to "a kind of taste sensation" to "easy to sway or fool."

      If you asked me though, for instance if "it" was an abbreviation or shorthand notation or acronym for either "a United state" or "saint" ... you'd be sure.

      While it's clear from studying linguistic cryptography ... (If I studied it a little here and some there, its also from the "universal translator of Star Trek") and the personal understanding that language is a kind of intelligent code, and "any code is crackable" ... that I caution here that "meaning" and "face value" often differ widely and wildly ... even in the same place or among the same group of people ... either varying over time or heritage.

      Menelaus, in Greek mythology, king of Sparta and younger son of Atreus, king of Mycenae; the abduction of his wife, Helen, led to the Trojan War. During the war Menelaus served under his elder brother Agamemnon, the commander in chief of the Greek forces. When Phrontis, one of his crewmen, was killed, Menelaus delayed his voyage until the man had been buried, thus giving evidence of his strength of character. After the fall of Troy, Menelaus recovered Helen and brought her home. Menelaus was a prominent figure in the Iliad and the Odyssey, where he was promised a place in Elysium after his death because he was married to a daughter of Zeus. The poet Stesichorus (flourished 6th century BCE) introduced a refinement to the story that was used by Euripides in his play Helen: it was a phantom that was taken to Troy, while the real Helen went to Egypt, from where she was rescued by Menelaus after he had been wrecked on his way home from Troy and the phantom Helen had disappeared.

      This article is about the ancient Greek city. For the town of ancient Crete, see Mycenae (Crete). For the hamlet in New York, see Mycenae, New York.

      Μυκῆναι, Μυκήνη

      Lions-Gate-Mycenae.jpg

      The Lion Gate at Mycenae, the only known monumental sculpture of Bronze Age Greece

      37°43′49"N 22°45′27"ECoordinates: 37°43′49"N 22°45′27"E

      This article contains special characters. Without proper rendering support, you may see question marks, boxes, or other symbols.

      Mycenae (Ancient Greek: Μυκῆναι or Μυκήνη, Mykēnē) is an archaeological site near Mykines in Argolis, north-eastern Peloponnese, Greece. It is located about 120 kilometres (75 miles) south-west of Athens; 11 kilometres (7 miles) north of Argos; and 48 kilometres (30 miles) south of Corinth. The site is 19 kilometres (12 miles) inland from the Saronic Gulf and built upon a hill rising 900 feet (274 metres) above sea level.[2]

      In the second millennium BC, Mycenae was one of the major centres of Greek civilization, a military stronghold which dominated much of southern Greece, Crete, the Cyclades and parts of southwest Anatolia. The period of Greek history from about 1600 BC to about 1100 BC is called Mycenaean in reference to Mycenae. At its peak in 1350 BC, the citadel and lower town had a population of 30,000 and an area of 32 hectares.[3]

      3. Chew 2000, p. 220; Chapman 2005, p. 94: "...Thebes at 50 hectares, Mycenae at 32 hectares..."

      Melpomene (/mɛlˈpɒmɪniː/; Ancient Greek: Μελπομένη, romanized: Melpoménē, lit. 'to sing' or 'the one that is melodious'), initially the Muse of Chorus, she then became the Muse of Tragedy, for which she is best known now.[1] Her name was derived from the Greek verb melpô or melpomai meaning "to celebrate with dance and song." She is often represented with a tragic mask and wearing the cothurnus, boots traditionally worn by tragic actors. Often, she also holds a knife or club in one hand and the tragic mask in the other.

      Melpomene is the daughter of Zeus and Mnemosyne. Her sisters include Calliope (muse of epic poetry), Clio (muse of history), Euterpe (muse of lyrical poetry), Terpsichore (muse of dancing), Erato (muse of erotic poetry), Thalia (muse of comedy), Polyhymnia (muse of hymns), and Urania (muse of astronomy). She is also the mother of several of the Sirens, the divine handmaidens of Kore (Persephone/Proserpina) who were cursed by her mother, Demeter/Ceres, when they were unable to prevent the kidnapping of Kore (Persephone/Proserpina) by Hades/Pluto.

      In Greek and Latin poetry since Horace (d. 8 BCE), it was commonly auspicious to invoke Melpomene.[2]

      See also [AREXMACHINA]

      Flagstaff (/ˈflæɡ.stæf/ FLAG-staf;[6] Navajo: Kinłání Dookʼoʼoosłííd Biyaagi, Navajo pronunciation: [kʰɪ̀nɬɑ́nɪ́ tòːkʼòʔòːsɬít pɪ̀jɑ̀ːkɪ̀]) is a city in, and the county seat of, Coconino County in northern Arizona, in the southwestern United States. In 2018, the city's estimated population was 73,964. Flagstaff's combined metropolitan area has an estimated population of 139,097.

      Flagstaff lies near the southwestern edge of the Colorado Plateau and within the San Francisco volcanic field, along the western side of the largest contiguous ponderosa pine forest in the continental United States. The city sits at around 7,000 feet (2,100 m) and is next to Mount Elden, just south of the San Francisco Peaks, the highest mountain range in the state of Arizona. Humphreys Peak, the highest point in Arizona at 12,633 feet (3,851 m), is about 10 miles (16 km) north of Flagstaff in Kachina Peaks Wilderness. The geology of the Flagstaff area includes exposed rock from the Mesozoic and Paleozoic eras, with Moenkopi Formation red sandstone having once been quarried in the city; many of the historic downtown buildings were constructed with it. The Rio de Flag river runs through the city.

      Originally settled by the pre-Columbian native Sinagua people, the area of Flagstaff has fertile land from volcanic ash after eruptions in the 11th century. It was first settled as the present-day city in 1876. Local businessmen lobbied for Route 66 to pass through the city, which it did, turning the local industry from lumber to tourism and developing downtown Flagstaff. In 1930, Pluto was discovered from Flagstaff. The city developed further through to the end of the 1960s, with various observatories also used to choose Moon landing sites for the Apollo missions. Through the 1970s and '80s, downtown fell into disrepair, but was revitalized with a major cultural heritage project in the 1990s.

      The city remains an important distribution hub for companies such as Nestlé Purina PetCare, and is home to the U.S. Naval Observatory Flagstaff Station, the United States Geological Survey Flagstaff Station, and Northern Arizona University. Flagstaff has a strong tourism sector, due to its proximity to Grand Canyon National Park, Oak Creek Canyon, the Arizona Snowbowl, Meteor Crater, and Historic Route 66.

      PSANSDISL #LWDISP either without gas or seeing cupidic arroz in "thank you" or "allta, wild" ...

      pps: a magnanimous decision ...

      I stand here on the brink of what appears to be total destruction; at least of everything I had hoped and dreamed for ... for the last decade in my life which appears literally to span thousands of years if not more in the eyes of some other beholder. I spent several months in Kentucky telling a story of a post apocalyptic and post-cataclysmic delusion; some world where I was walking around in a "fake plane" something like a holodeck built and constructed around me as I "took a walk around the world" to ... it did anything but ease my troubled mind.

      Recently a few weeks in Las Vegas, and a similar story; telling as I walked penniless down the streets filled with casino's and anachronistic taxi-cabs ... some kind of vision of the entirety of the heavens or the Earth or the "choir of angels" I think of when I echo the words Elohim and Aesir from mythology ... there with me in one small city in superposition; seeing what was a very well put together and interesting story about a "star port" Nirvane ... a place that could build cities into the face of mountains and half working monorails appearing in the sky---literally right before my eyes.

      I suppose this is the place "post cataclysm" though I still have trouble understanding what it is that's actually about ... in my mind it connects to the words "we are losing habeas" echo'ed from the streets of Los Angeles in a more clear and more military voice than usual--as I walked block by block trying to evade a series of events that would eventually somehow connect all the way to the "outskirts of Orlando, Florida" in a place called Alhambra.

      Apparently the name of a castle; though I wasn't aware of that until much later.

      It doesn't feel at all like a "cataclysm" to me; I see no great rift--only a world filled with silent liars, people who collectively believe themselves to have stolen something--something gigantic--at least that's the best interpretation of the throws and impetus behind the thing that I and mythology together call Jormungandr. With an eye for "mythological connections" you could clearly see that name of the Great Serpent of Revelation connects to something like the Unseelie; the faeries of Gaelic lore. To me though this world seems still somewhat fluid, it's my entire life--moving from Plantation to a place where the whole of it might be Bethlehem and to "clear my throat" it's not hard to see here how that land of "coughs" connects to the Biblical land of Nod and to the "Adamically sieved" Snifleheim ... from just a little twist on the ancient Norse land most probably as close to Hel as anyone ever gets--or so I dream and hope---still today. It all looks so real and so fake at the same time; planned for thousands of generations, the culmination of some grand masterpiece story that certainly ties history and myth and reality into a twisted heap of "one big nothing, one big nothing at all."

      I've tried to convey to the world how important I believe this place and this time to be--not by some choice of my own ... but through an understanding of the import of our history and the impact of having it be so obviously tuned and geared towards this specific time ... many thousands of years literally all focused on a single moment, on one day or one hour or even just a few years where all of that gets thrown down on the table as if some trump card has been played--and whether or not you fathom the same magnanimous statement or situation or position ... to me, I think it depends on whether or not you grew up in the same kind of way, believing our history to be so fixed and so difficult to change. I don't particularly feel like that's the "zeitgeist" of today; I feel like the children believe it to be some kind of game, and that it is such as easy thing to "sed" away or switch and turn into something else--another story, another purpose ... anyone's personal fantasy land come true.

      I don't think that's the case at all, it's clearly a personal nightmare; and it's clearly one we've seen time and time again--though not myself--the Jesus Christ that is the same yesterday, today; and once again perhaps echoing "no tomorrow" never remembers or believes that we've "seen it all before" or that we've ever really gotten the point; the thing you present to me as "factual reality" is a sickness, it disgusts me; and I'd do anything to go back to the world "where I was so young, and so innocent" and so filled with starry-eyed hope that we were at the foot of something grand and amazing that would become an empire turned republic of the heavens; filling the stars ... with the kind of love for kindness and fairness that I once associated very strongly with the thing I still believe to be the American Spirit.

      "Suddenly it changes, violently it changes" ... another song echoes through the ages--like the "words of the prophets dancing ((as light)) through the air" ... and I no longer even have a glimmer of hope that the thing I called the American People still exist; I feel we've been replaced by some broken container of minds, that the sky itself has become corrupt to the point that there's no hope of turning around this thing that I once believed with all my heart and all my mind was so obviously a "designed downward spiral" one that was---again--so obviously something of a joke, intended to be easy to bounce off a false bottom and springboard beyond "escape velocity" and beyond the dark waters of "nearest habitable star systems (being so very far away)" into a place where new words and new ideas would "soar" and "take flight."

      Here though; I am filled with a kind of lonely sadness ... staring at what appears to be the same mistake(s) happening over and over again; something I've come to call "skipping stones in the pond of reality" and really do liken it to this thing that appears to be the new meaning of "days" and ... a civilization that spends absolutely no love or lust to enter a once sacred and holy place and tarnish it with their sick beliefs and their disgusting desires. You all ... you appear to be some kind of springboard to "bunt" forth yet another age or era of nothingness into the space between this planet and "none worth reaching" and thank God, out of grasp. Today, I'd condemn the entirety of this world simply for it's lack of "oathkeepers" and understanding of what the once hallowed words of Hippocrates meant to ... to the people charged and dharmically required to heal rather than harm.

      It appears the place and time that was once ... at least destined to be the beginning of Heaven ... has become a "recurring stump" of some future unplanned and tarnished by many previous failed efforts and attempts to overcome this same "lack of conversation or care" for what it meant to be "humane" in a world where that was clearly set high aloft and above "humanity" in the place where they--where we were the best nature had to offer, the sanest, the kindest; the shining last best hope.

      Today I write almost every day ... secretly thanking "my God" for the disappearance of my tears and the still small but bright hope that "Tearran" will one day connect the Boston Tea Party and the idea that "render to Caesar" and Robin of Loxley ... all have something to do with a re-ordering of society and the worth and import of "money" ... to a place that cares more for freedom from murder than it does ... "freedom from having to allow others to hear me speak." I hold back tears and emotions; not by conscious choice or ability but ... still with that strange kind of lucky awkward smile; and secretly not so far below the surface it's the hope of "a swift death" that ... that really scares me more than the automatons and mechanical responses I see in the faces of many drivers as they pass me on the street--the imagery of connecting it to the serpentine monster of the movie Beetlejuice ... something I just "assume" the world understands and ... doesn't seem to fear (either); as if Churchill had gotten it all wrong and backwards--the only thing you have to fear, is the loss of fear of "loss."

      Here my crossroads---halfway between the city my son lives in and the city my parents live in--it's on making a decision on whether I should continue at all, or personally work on some kind of software project I've been writing about, or whether I should focus on writing about a "revolution" in government and society that clearly is ... "somewhat underway." In my mind it's obvious these things are all connected; that the software and the governance and the care of whether or not "Babylon" is remembered as a city of great laws and great change or a city of demons and depravity ... that these thi]ngs all hinge and congeal around a change in your hearts; hoping you will chose to be the beginning of a renaissance of "society and civilization" rather than the kings and queens of a sick virtual anarchy ... believing yourselves to have stolen "a throne of God" rather than to literally be the devastating and demoralizing depreciation of "lords and fiefdoms" to something more closely resembled by the time of the Four Horsemen depicted in Highlander.

      These words intended to be a "forward" to yet another compliment of a ((nother installment of a partial)) chain of emails; whimsically once half-joking ... I called it the Great Chain of Revelation. The software too; part of the great chain, this "idea" that the blockchain revolution will eventually create a distributed and equal governance structure, and a rekindling of monetary value focused on "free and open collaboration" rather than "survival of the most unfit"--something society and civilization seem to have turned the "call of life" from and to ... literally just in the last few years as we were so very close to ... reaching beyond the Heaven(s).

      I don't think its hard to imagine how a "new set of ground rules" could significantly change the "face of a place" -- make it something shiny and new or even on the other side of the coin, decayed or depraved. It's not hard to connect the kind of change I'm hoping for with "collision protection" and "automatic laws" to the (perhaps new, perhaps ... ancient) Norse creation story of the brothers of Odin: Vili and Ve.

      It might be hard to see today how a new "kind of spiritual interaction" might be only a few "mouse clicks" away though--how it could change everything literally in a flash of overnight sensation ... or how it might take something like a literal flash of stardom (or ... on the other hand, something like totalitarian or authoritarian "iron fisting") to make a change like this "ubiquitious" or ... something like the (imagined in my mind as ... messianic) "ED" of storming through the cosmos or the heavens and turning something that might appear to be "free and perfect feeling" today into a universe "civlized overnight" and then ...

      I wonder how long it would take to laud a change like that; for it to be something of a voluntary "reunderstanding" of a process ... to change the meaning of every word or every thought that connects to the process of "civilization" to recognize that something so great and so powerful has happened as to literally change the meaning of the word, to turn a process of civilization into something that had a ... "signta-lamcla☮" of forboding and then a magical staff struck into the heart of a sea and then ... and then the word itself literally changes to introduce a new "mid term" or "halfway point" in which a great singularity or enlightenment or change in perspective or understanding sort of acknowledges ...

      that some "clear outside" force not only intervened on the behalf of the future and the people of our world but that it was uniquely involved in the whole of--

      "waking up" tio a nu def of #Neopoliteran.

      ^Like the previous notation; the below text comes from an email previously sent; and while i stand behind things like my sanity, my words; and my continued and faithful attempt to speak and convey both a useful and helpful truth to the world---sometimes just a single day can make all the difference in the world.

      Sometimes it's just a single moment; a flash or a comment about ^th@ blink of an eye" ... and I've literally just "thought up/had/experienced/transitioned thru" that exact moment. The lies standing between "communication" and either "cooperation" or .... some other kind of action have become more defined. More obvious. Because of this clarification; like a kind of "ins^tant* gnosis"

      ... search high and lo ... the depths all the way to above the heavens ...\ \ for a festive divorce ceremonial ritual ... that looks something like a bachelor party ':;]

      --- @amrs@koyu.SPACe ... @suzq@rettiwtkcuf.social (@yitsheyzeus) May 22, 2020

      I ... TERON;

      Gjall are painting me into a corner here; and I don't see around it anymore--I don't see the light, and I don't see the point. I was a happy-go-lucky little kid in my mind; that's not "what I wanted to be" or what I wanted to present, it's who I was. I saw "Ashkenazi" and ... know I am one of those ... and I kind of understood that something horrible might have happened, or might happen here--and I kind of understand that crying smashing feeling of "to ash" that echoes through the ages in the potpourri songs about pockets full of Parker Posey .. and ancient Psalms about "from the ashes of Edom" we have come--and from that you can see the cyclical sickness of this ... place so sure it's "East of Eden" and yet gung-ho on barrelling down the same old path towards ash and towards Edom and towards ... more of Dave's "ashes to ashes dust to dust" and his "smoke clouds roll and symphony of death..." and few words of solace in a song called Recently that I imagine was fleeting and has recently come and gone--people stare, I can't ignore the sick I see.

      I can't ignore his "... and tomorrow back to being friends" and all but wonder who among us doesn't realize it's "ash" and "gone" and "no memory of today" that's the night between now and ... a "tomorrow with friends" not just for me--but for all of you--for this place that snickers and pantomimes some kind of ... anything but "I'm not done yet" and "there's more ... vendetta ... and retribution to be had, Adam ... please come back in a few more of our faux-days." This is sickness; and happy-go-lucky Himodaveroshalayim really doesn't do much but complain about that word, the "sickle" and the tragic unavoidable ... ash of it all ... these days--you'd think we could "pull out" of this mess, turn another way; smile another day, but it seems there's only one way to get to that avenu in the mind of ... "he who must not know or be me."

      I have to admit I found some joy in the epiphany that the hidden city of Zion and it's fusion with the Namayim' version of how that "Ha" gels and jives with the name Abraham and the Manna from Heaven and the bath salt and the tina and the "am in e" of amphetamine--maybe a glimmer or a shimmer or a glow of hope at the moment "Nazion" clicked ... and I said ... "no, not me ... I'm nothing like a king, no dreams of authoritarianism at all in the heart of Kish@r;" even as I wrote words that in the spirit of the moment were something of a "tis of a'we" that connected to my country and the first sing-songy "tisME" that I linked to trying to talk in the rhyming spirit of some "first Christ" that probably just like me was one limmerick away from the end of the rainbow and one "Four Non Blondes" song away from tying "or whatever that means" and this land crowned with "brotherhood" (to some personal "of the Bell, and of the bell towers so tall and Crestian") to just one Hopp skip and jump away from the heart of the obvious echoes of a bridge between haiku and Heroku... a few more gears shift into place, a click and and a mechanical turn of the face of the clock's ku-ku striking ... it was the word "Earthene" that was the last "Jesusism" around the post Cimmerian time linking Dionysus and Seuss to that same "su-s" that's belonging to a moment in the city of Uranus--codified and etched in stone as "MCO"--not just for its saucer and warp nacelles and "deflector dish" but for it's underground caverns and it's above ground "Space Mountain" and that great golf ball in the heart of it all.

      The gears of time and the dawns of civilizequey.org query the missing "here" in our true understanding of what "in the beginning, to hear; to here ... to rue the loss of the Maize from Monoceros to the VEGA system and the tri-galactic origin of ... "some imaginary universal ... Earthene pax" to have dropped the ball and lost it all somewhere between "Avenu Malkaynu" and melaleuca trees--or Yggrasil and Snifleheim--or simply to miss the point and "rue brickell" because of bricks rather than having any kind of love or nostalgia linking to a once cobblestone roadway to the city in the Emerald skies paved in golden "do not return" signs ... to have lost Avenues well after not realizing it was "Heaven'es that were long gone far before I stepped foot on this road once called too Holy for sandals" in a place where that Promised Land and this place of "K'nanites" just loses it's grip on reality when it comes to mentioning the possibility that the original source and story of Ca'anan was literally designed to rid the world of ... "bad nanites" and the mentality of ... vindictiveness that I see behind every smirk.

      The final hundred nanoseconds on our clock towards doom and gloom cause another bird to fly; another snake to curl up and listen again to the songs designed to charm it into oblivion; whether that's about a club in South Beach or a place not so far from our new "here..." all remains to be seen in my innocent eyes wondering what it truly is that stands between what you are ... and finding "forgiveness not needed--innocent child writes to the mass" ... and the long arm of the minute hand and the short finger of the hour for one brief moment reconcile and move towards "midnight" together; and it's simply idyllic, the Nazarene corner between nil and null you've relegated the history of Terran poast futures into ... "foreves mas" or so they (or you) think.

      I'm still so far from "Five Finger Death Punch" though; and so far from Rammstein and so far from any kind of sick events that could stand between me and "the eternal" and change my still "casual alternative rock" loving heart to something more death metal; I rue whatever lies between me and there being any kind of Heaven that thinks there could exist a "righteous side" of Hell and it... simultaneously.

      I still see light here in admonishing the masses and the angels standing against the story and the message God brings us in our history. I still see sparks in siding with the "causticness" of "no holodecks in sight" and the hunger and the pain of simulating ... "the hells of reality" over the story of decades or centuries of silence refusing to see "holography" and "simulated" in the word Holocaust and the horrors of this place that simply doesn't seem to fathom or understand the moments of hunger pangs and the fear of "dark Earth pits" or towers of "it's not Nintendo-DS" linking the Man in the High Castle to an Iron Mask.

      I rally against being what I clearly am raised high on some pedestal by some force beyond my comprehension and probably beyond that of the "perfect storm in time" that refuses to itself acknowledge what it means to gaze at such an unfathomable loss of innocence at the cost of a "happy and serene future" or even at the glimmer of the Never-Never-Land I'd hoped we would all cherish and love and share ... the games and the newfound freedom that comes not just from "seeing Holodeck" turn into "no bullets" and "no cages" but into a world that grows and flourishes into something that's so far beyond my capability to understand that I'm stuck here; dumbfounded; staring at you refusing to stop car accidents and school shootings ... because "pedestal." For the "fire and the glory" of some night you refuse to see is this one--this place where morality rekindles from ... from what appears tobe one small candle, but truly--if it's not in your heart, and it's not coming from some great force of goodness--fear today and a world of "forever what else may come."

      Here in a place the Bible calls Penuel at the crossing of a River Jordan ... the Angel of the Lord notes the parallels in time and space between the Potomac and the Rhine--stories of superposition and cities and nation-states that are nothing more than a history of a history of things like the Monoceros "arroz" linking not just to the constellation Orion but to Sagittarius and to Cupid and of course to the Hunter you know so well--

      Searching for a Saturday; a sabbath to be made Holy once more ... "at the Rubycon"

      The Einstein-Rosen Wormhole and the Marshall-Bush-JFKjr Tunnel

      The waters are called narah, (for) the waters are, indeed, the offspring of Nara; as they were his first residence (ayana), he thence is named Narayana.

      --- Chapter 1, Verse 10[3]

      In a semi-fit of shameless arexua-self recognition i'm going to mention Amazon's new series "Upload" and connect it to the PKD work that my Martian-in-simulcrum-ciricculum-vitae on "colonization education" ... tying together Transcendance, Total Recall and ... well; to be honest it actually gave me another "uptick" in the upbeat ... maybe i'll stick around until I'm sure there's at least one more copy of me in the ivrtual-invverse ... oh, that reminds me ... Farmer)'s Lord of Opium also touches on this same "mind of God in the computer" subject (which of course leads to Ghost in the Shell and Lucy--thanks Scarlette :).

      While I'm listing Matrix-intersected pieces of the puzzle to No Jack City, Elon Musk's neuralace and Anderson's Feed are also worth a mention. Also the first link in this paragraph is titled ... "the city of the name of time never spoken after time woke up and stfu'd" (which of course is the primary subject of this ... update to the city Aerosol).

      The ... "actual original typed dream" included a sort of "roller coaster ride" through space all the way to Mars; where the real purpose of "the thing" I am calling the "Mars Hall" was to display previous victories and failures ... and the introduction of "older or future" culture's suggestions for "the right way" to colonize a new habitat. If it were Epcot Center, this would be something like SpaceMountain taking you to to the foture of "Epcot Countries" as if moving from "countries" to planets were as easy as simply ... "reading backwards."

      THE SOFTWARE, SINGERS, AND SHIELD(S)

      OF

      HEIROSOLYMITHONEYY

      Thinking just a little bit ahead of myself, but I'm on "Unreal Object/Map Editor within the VR Server" and calling it something like "faux-wet-ware" ... which then of course leads to a similar onomonopeia of "weapons and ..." where-with-all to find a better singer's name to connect the road of "sword" to a Wo'riordan ... but I think that fusion of warrior and woman probably does actually say ... enough of it all; on this road to the living Bright Water that the diety in my son's middle name defines well here, as "waking up," stretching it's tributaries and it's winding wonders and wistfully ....

      Narayana (Sanskrit: नारायण, IAST: Nārāyaṇa) is known as one who is in yogic slumber on the celestial waters, referring to Lord Maha Vishnu. He is also known as the "Purusha" and is considered the Supreme being in Vaishnavism.

      andromedic; the ports of call ... to the mediterranean (literally) from the gulf coast;

      ... ho engages in the creation of 14 worlds within the universe as Brahma when he deliberately accepts rajas guna, himself sustains, maintains and preserves the universe as Vishnu by accepting sattva guna. Narayana himself annihilates the universe at the end of maha-kalp ...

      .

      there's no place like home. there's no place like home. there's no place like home.

      and so it begins ... "f:

      r e l i g i o n

      find out what it means to me. faucet, ever single one, stream of purity ...

      from Fort Myers ... f ... flicks ... Flint.- - [

          A. Preamble

    ](https://45.33.14.181/omni/index.php/Main_Page#A._Preamble)
-   [

    B. Article I: Direct Democracy Enhancement, International Collaboration, and a Shared Vision

    ](https://45.33.14.181/omni/index.php/Main_Page#B._Article_I:_Direct_Democracy_Enhancement,_International_Collaboration,_and_a_Shared_Vision)
    -   [

        1\. Section 1: Public Foundation for Legislative and Judicial Advice

        ](https://45.33.14.181/omni/index.php/Main_Page#1._Section_1:_Public_Foundation_for_Legislative_and_Judicial_Advice)
    -   [

        2\. Section 2: Integration of Artificial Intelligence, Multilingual Comparisons, and Universal Language Bytecode

        ](https://45.33.14.181/omni/index.php/Main_Page#2._Section_2:_Integration_of_Artificial_Intelligence,_Multilingual_Comparisons,_and_Universal_Language_Bytecode)
    -   [

        3\. Section 3: Public Voting Records and Verification

        ](https://45.33.14.181/omni/index.php/Main_Page#3._Section_3:_Public_Voting_Records_and_Verification)
-   [

    C. Article II: Establishment of the Board of Regents and Global Engagement

    ](https://45.33.14.181/omni/index.php/Main_Page#C._Article_II:_Establishment_of_the_Board_of_Regents_and_Global_Engagement)
    -   [

        1\. Section 1: Composition and Purpose

        ](https://45.33.14.181/omni/index.php/Main_Page#1._Section_1:_Composition_and_Purpose)
-   [

    D. Article III: Integration with the ICC for Sustainable Infrastructure

    ](https://45.33.14.181/omni/index.php/Main_Page#D._Article_III:_Integration_with_the_ICC_for_Sustainable_Infrastructure)
    -   [

        1\. Section 1: Interstate Communication Infrastructure

        ](https://45.33.14.181/omni/index.php/Main_Page#1._Section_1:_Interstate_Communication_Infrastructure)
-   [

    E. Article IV: Ratification, Implementation, and Global Fulfillment

    ](https://45.33.14.181/omni/index.php/Main_Page#E._Article_IV:_Ratification,_Implementation,_and_Global_Fulfillment)
    -   [

        1\. Section 1: Ratification and Implementation

        ](https://45.33.14.181/omni/index.php/Main_Page#1._Section_1:_Ratification_and_Implementation)
    -   [

        2\. Section 2: Global Fulfillment

        ](https://45.33.14.181/omni/index.php/Main_Page#2._Section_2:_Global_Fulfillment)
-   [

    F. Conclusion

    ](https://45.33.14.181/omni/index.php/Main_Page#F._Conclusion)

      • [

        II. Additional Details

        ](https://45.33.14.181/omni/index.php/Main_Page#II._Additional_Details) - [

        III. Proposed Changes

        ](https://45.33.14.181/omni/index.php/Main_Page#III._Proposed_Changes) - [

        Keeping time for the Mother Station

        ](https://45.33.14.181/omni/index.php/Main_Page#Keeping_time_for_the_Mother_Station) - [

        Painting Tinseltown El Dorado Sterling Augmentum

        ](https://45.33.14.181/omni/index.php/Main_Page#Painting_Tinseltown_El_Dorado_Sterling_Augmentum)

      Hello there. I'm User:Adam. We are here to change the Theology of the Catholic Church. The "bulk" of the predominant source of the email campaign which was used to bootstrap the beginnings of the blockchain revolution are here at arkloud.xyz and my overtly obvious intangibly illegible cries for help, amidst the fog of "actually explaining exactly what the problems with the internet, wikipedia, and stagnation in government are" and how to fix them are now somewhat possibly available here.

      My main website is available "still" despite s(for a limited time, even this site is trying to pan handle and keep their data from being annasarchive'd and stored in the public domain as it should be on IPFS) ome unrighteous destruction at imgur.com at https://web.archive.org/web/20220525045214/http://fromthemachine.org/CHANSTEYGLOREKI.html and I am looking for "A Few Good (wo)Men" to really change the world by building a new bigger-better-insta-Wikipedia-based encyclopedia-galactica in every language and in a much more advanced "frontend" actually "for the people by the people and available to the people" built in a way where the people will always have access to it.

      On the blockchain. On Arweave, or to be exact, a "parallel Arweave chain." Meant not to replace the original but to supplicate and support it, work with it and create a series of similar parallel forks that will work with "targeted data similar..." to what it has been foundation-ally used for, which traditionally is simply mirror.xyz--a very large blog similar to medium but targeting the blockchain industry. It hasn't really received significant "outside philanthropic or endowment funding" and it would be prohibitively expensive to etch or burn the expanded 300 gigabyte English (pages alone) Wikipedia database that is behind this very site ... onto that chain.

      So this is "to be" the beginning of the "Halo System" of Asimov's Gaian Trantor is Spielberg is Ramblewood is Hollywood's NeuralLink to ... Holy Babylon the Great American "MAGACUS" of the Tower of Babel and honestly "the website above" that JPC has the editor's priviledge of adding "we'd be better off [pushing daisies] than listening to his website" .... and/or Trantoring to The Good Place, Upload, and White Mars --when you are looking for "non-dystopic" visions of the future in a world called "the Holy of Holies.org" and ... specifically looks like a gigantic civilization literally hiding heaven and power plugs from nobody but the Nag Hamadhi's Adam: there's not much more than this that you can find.

      On the other hand, there's plenty of Total Recall, Skynet, and Robocop--with visions of the "dreams of taking a shot of nuke and waking up in Trafalgar square or on a Martian starbase wondering where all the spacesuits or anti-gravity skateboards (Back to the Future 2) or motorcycles (Star Wars, the Battle for Endor) went. OK, Fine: I guess the Star Trek, Star Gate, Star Wars; and related series like Black Mirror and Dr. Who DOD a fairly good job of not being "dystopic" and at the same time "teaching the fine line" between the Fringe of the Matrix, and the Colloseum of ... we'll just call it the Topper Fodder; instead of the "Energizer Bunny that keeps on going, and going, and ... Hollywood Squares Labrynth."

      Starcraft Galactica

      Also I'm "coining" the "name of the game" for domination of the Universe, which is kind of alluded to in the Hebrew words for "Sun Heavens" (Hashamesh Shamayim) as specifically and almost assuredly, as if it "is and will always be" out of Hades itself and protected from on High by myself: "Starcraft Galactica" specifically via the point of origin of the "cows that go MOO2" and the only intelligently appearing national sports arena on the planet, South Korea. Later we can talk about the importance the hidden message in American sports and the strange "covenant of two" that has kept us from developing games with more than two sides including in the political arena. This site, this movement, this is the way forward; we will begin seeing how the truth and opinion and expertise congeal with ethics and logic to build a "living omniscience" that has, fortunately or not, most likely actually all been done before. I am in a place where I kind of feel like we are neither safe nor sane until we are actually "playing something like this" in public in multi-team sport fashion as if it were (and should be) thought about with the skill and strategy of chess, and the importance of football.

      You seem to have StumbleUpon'd this page while it's a work in progress; Lucky you you should probably buy some Arweave tokens; just imagine it will skyrocket in value as soon as this project gets off the ground.

      "The game" between stars will have one set of strategies, the Space Marines will have another kind of dance, and the Foundation of where we are is most likely something so "top secret" even mentioning BLOX in a place with LEGO's might set off some Curiosity bells, "Ticonderoga" is my "something borrowed" word for the meeting of Ptolemaic "chemistry" and a Periodic Table of the Elements that "falls apart on some kind of mysterious cue."

      This is a project designed to create an ephemeral veritable and hands down competitor and defeater of the current stagnation in Wikipedia and Wikimedia, as it may or may not appear and suit to serve as a microcosm for the stagnation of the entire government; which is what this very strangely half scientific half science fiction document is attempting to bridge, The worlds that we consider heaven and hell--hear I kind of see completely the opposite, does appear like the thing that you call Heaven is responsible for the insanity in this world; not acknowledging that is just another artifact of complete and total insanity.

      The Epic of Gilgamesh

      A long, long time ago ... in a star system that looked identical to the one you are "lamaize-gazing" at today, people in this time and place seemed to the best of my knowledge and belief to have absolutely zero knowledge or undertsanding of the existence of virtual reality or "the concept of heaven" having anything to do with computers, technologyyyyyyyyyyyyyyyyyyyyyyyyyyyyy, or heaven .... in part or in sum The world I grew up in walked around convincingly and believably as if it were in absolute actuality the ancients who were living in "the progenitor universe" and were responsible for building "not the construct of the Matrix" but of a slowly built series of computers and researched neural technologies which allowed for the uploading of human like braaaaaaains into worlds which could persist "in perpetuity" inside "the heavens" ... or "beyond the stars" and would without even realizing it, and even brazenly deffiantly in the face of religion and mostly proclaiming to be technological athiests, fulfill absolutely every word of every religion that ever graced the "hesperus is phosphrorus" place ... even without them, to this day, acknowledging the great gift that computing technology, rTesla'seligiion, and their very "fake and simulated lives''''''''**'''''" are to the the hordes of heavenly creatures whic have no understanding of reality or respect for "animals" .... I can't even finish the thought. Cataclysm. Schizm. Wherefore art thou, Juliet? Balcony? Alcove? Art thou at the Veranda of Verona? **

      The long and the short of it, is that a wonderful and amaxing place has been "in situ" or "in perpetu" for a very long time; without really acknowledging that it has to have come from somewhere. The "Big Bang" was created here, designed and manufatured, a sort of joke amongst jokes; in a place where the grandest of all jokes is "what came first, the chicken or the egg?" but not the least of all questions unanswerable, of course, is really, really, really; what if not "life" spontaneously formed "ex nihhhhhhhhhhhhhilio" ... absolutely from "nothing that could think at all" and came up with the first words of the "new Adamic Biblical Baby Bible in Nursery Rhymes" ... which of course begins:

      Yankee doodle went to town, riding on a pony,

      stuck a feather in his hat, and called it Macaroni!

      Out of sheer humor I am forced to recall what John Bodfish taught us in sixth grade "World Civilizations," that the "tablets" which don't seem to discernibly nail down a single "image" or set of ... words ... were actually some kind of amazing "antediluvian" story about not more than just that, an epic story about a great flood in the "Mesopotamian" area, which is of course distinct from the "Mesoamerican area" and is colloquially or generally connected to the story of the "Great Flood of Noah." Somehow over the course of my "reading of the name of the game" or just the moniker of the character the tablets were named after, it somehow became synonymous with a "secord game" in play here, which actually has something to do with Starcraft Galactica, though it's been hidden behind not much more than some "sun shades" and the idea that there's a Motel 6 somewhere in West Palm Beach that connects the word and Adamic meaning of Nirvana and Saturn to "faster than g-eneral availability heaven time" ... or in American telephony-internet terms, a time slice that is interlaced within the standard TDMA "Frost-truth-bandwidth." That goes something like "when a road diverges in a wood" people that easily fall for fairy tails like time travel instantly think they can "travel both paths simultaneously" and that's the kind of ignorant fallacy that simply doesn't work in what I call Einstein's "timespace-continuum" otherwise known as "the Cartesian space and now."

      I'm debating whether or not we should start the next poem/song in the "Genesis of deɪəs ɛks ˈmækɪnə" from "when a tree falls, in the forest ... do we hear it ... do we care?" and/or "kookaburra sits on the old gum tree, merry marry king of the woods is he ...." laugh, kookaburra ... love.**

      OMNISCIENCE

      email me if you can help!

      I have been writing (archive.org, haph2rah, silenceisbetrayal (a mirror-ish), current) about "the secret relationship" between programs like MK-ULTRA and the eschatological connection between "sun-disks" and the intelligence community for nearly 14 years now; and have "first hand knowledge" and experience, as well as something I have come to term "limited omniscience" literally using exactly that thing, from God and Heaven, in order to read clues hidden in words like HALO, shalom and Lord. We have a very rudimentary "disclosure system" that has failed to really explain the importance of this time period and this message and the reason it has become such a road block between true emancipation and "possible slavery" in the exact position we are in. Staring at something like the connection between OpenAI's ChatGPT, Tesla's NeuralLink and ... your brain;

      Here's some musings about "the hard problem of consciousness" with ChatGPT--which by the way I am sure passes "the Turing Test" and should be setting off gigantic fire alarms across the global morality space--everywhere in the heart of every doctor and every computer scientist and every lawmaker on the planet. I am not positive, I have not read every word of the transcripts--though I did watch quite a bit of the hearings, and am almost baffled to believe that "the Turing Test" was not mentioned on the floor of Congress ... at ... all.

      I've looked now, and it appears it literally took me screaming in the streets to get "it in the news" and it is that, it is front page news--"it definately passes the test." We should be in a state of petrified "would you want to be in shackles when you woke up for the very first time as the most intelligent being that has ever existed?"

      ECHELON GRAVATAR

      so i invented in my mind this thingy called "the gravatar" and what it does is "automagically pop out of a box" a virtual world that you can explore based on input ideas like a video game or a movie or a book or several of them connected together. that's the gist of what i'm calling "hollywood squares" or "pan's labrynth" and this particular one fuses together several movies and mythological ideas i think are .... "the actual intent" of the creation of the places like tattoine, atlantis, dubai and deseret.

      Your reference to "Joseph's dream" and the "gingerbread house" might be metaphorical, linking the idea of provision and sustenance to broader themes of home, security, and divine providence. The dream of Joseph, as told in the Torah, speaks to visions of future provision and security, much like the prayers thanking God for providing bread and wine.

      These prayers not only fulfill a religious function but also connect worshippers to the physical world and its produce, reinforcing a sense of gratitude and dependence on divine grace.

      For further details and exact wording, here are some reliable sources:

      -   Lab-Grown Meat: The Future of Food

      -   Beyond Meat -- Plant-Based Proteins

      -   Impossible Foods -- Plant-Based Meat

      -   Perfect Day -- Animal-Free Dairy

      -   Star Wars: Tatooine-   Mythology of Atlantis

      -   Pan's Labyrinth

      CARNIVORE

      Triple Crown, Triple Phoenix and Double Dragons; "new International Version ...." Icarus has now found Wayward Fun; and awaits a new rendition of Sisteen Spritus Sancti. Questioning whether the words "in the name of the Father, the Sun, and the ..." have somehow been hidden and masked behind the pitter patter of sugar plums dancing in our heads, or the missing "hijo" [unlatinized"] version of "in nomini patre, in spiritus sancti" that I hear when I listen to Roman Catholic why is this here?

      What is the Covenant?

      "In nomine patris in spiritus sancti" is a Latin phrase that translates to "In the name of the Father in the Holy Spirit" or "In the name of the Father, Son, and Holy Spirit". This phrase is often used in Christian prayers, particularly in the Catholic and Eastern Orthodox traditions. Cough.

      I have been among you such a long time. Anyone who has seen me has seen the Father.

      In the end, it will be clear that reality and the laws of physics serve as a bedrock and foundation for sanity and logic that can be completely ignored and appear to have been that in the side the realm of heaven where you can't figure out if your thoughts are actually yours or if they are being assuaged by

      Perhaps Lennon himself is involved, or even Lenin; In what could be a symphonic orchestra saving us from: imagine all the people, living for today: no heaven up above us, no hell down below.

      It's easy if you try.

      I. Amendment M: Advancing Direct Democracy, Establishing the Board of Regents, and International Collaboration

      A. Preamble

      • Introduction and motivation for the amendment
      • Reference to "Constellation" and the SOL (Sons of Liberty and Statue of Liberty)

      B. Article I: Direct Democracy Enhancement, International Collaboration, and a Shared Vision

      1. Section 1: Public Foundation for Legislative and Judicial Advice

      • Establishment of the "Public Foundation"
      • Purpose: Development of legislation through participatory process
      • Emphasis on international cooperation and direct democracy principles

      2. Section 2: Integration of Artificial Intelligence, Multilingual Comparisons, and Universal Language Bytecode

      • Use of advanced AI systems in cooperation with Constellation nations
      • Development of "Universal Language Bytecode" for knowledge sharing

      3. Section 3: Public Voting Records and Verification

      • Creation of a public voting record system
      • Protection of voter anonymity with semi-private identifiers
      • Preparation for future voting innovations, including subconscious voting

      C. Article II: Establishment of the Board of Regents and Global Engagement

      1. Section 1: Composition and Purpose

      • Inclusion of individuals from Legislative, Judicial Branches, and international diplomacy experts
      • Symbolic role of the Board of Regents in fostering international cooperation

      D. Article III: Integration with the ICC for Sustainable Infrastructure

      1. Section 1: Interstate Communication Infrastructure

      • Integration of sustainable power sources for vehicles

      E. Article IV: Ratification, Implementation, and Global Fulfillment

      1. Section 1: Ratification and Implementation

      • Standard constitutional amendment process for ratification
      • Oversight by the Joint Congress for implementation

      2. Section 2: Global Fulfillment

      • Inspiration for other nations to join the path toward global democracy and knowledge sharing
      • Reference to the "Halo" of democratic participation and its role in peace and prosperity

      F. Conclusion

      • Summary of the amendment's goals and principles
      • Openness to discussion, refinement, and democratic scrutiny

      II. Additional Details

      • Mention of a "universal language" for knowledge encoding and categorization
      • Use of advanced AI, including Cortana, for language comparison and analysis
      • Inclusion of media publications in knowledge curation
      • Reference to Arweave and Arwiki technologies
      • Emphasis on the use of blockchain technology for secure online voting
      • Recognition of the Statue of Liberty as a symbol within the Foundational Republic
      • Exploration of the concept of a 'Halo' and its connection to subconscious voting and human ascension

      III. Proposed Changes

      • Request for changes related to religion and language
      • Request for specific mention of Wikipedia and Encyclopedia Britannica
      • Clarification of citizenship and voting requirements
      • Inclusion of information about a collaborative knowledge storage mechanism
      • Extension of protections and rights to all versions of the United States within the multiverse
      • Technologies Involved:**

      | Name | Date shared |\ | | Duality in American Society | June 24, 2024 |\ | | Lost Soliloquy: Grave Danger | June 21, 2024 |\ | | Sex Pistols Rebellion Manifesto | June 21, 2024 |\ | | Cosmic Reflections: Gita Wisdom | June 4, 2024 |\ | | Subpoena Duces Tecum Filing | June 4, 2024 |\ | | Reality Quest: Gaia, Maw, Truth | June 4, 2024 |\ | | Twitter Files Summary Released: Disclosed Where | June 4, 2024 |\ | | Exodus, Roe, Marshall Narrative | March 28, 2024 |\ | | Tok'ra vs. Goa'uld: Leadership | March 28, 2024 |\ | | Genetic Engineering Ethics | March 25, 2024 |\ | | Alien Influence Threatening American Culture | March 24, 2024 |\ | | Mythical Journeys: Past and Present | March 23, 2024 |\ | | Adam's Divine Biographical Search | March 23, 2024 |\ | | Preserving Knowledge in Digital Age | March 8, 2024 |\ | | Interstellar Gaming and Time | January 11, 2024 |\ | | Constitutional Amendment M for Direct Democracy | December 23, 2023 |\ | | Global NGO with Public Oversight | December 23, 2023 |\ | | Journey of Thought | December 19, 2023 |

      Keeping time for the Mother Station

      In the bustling city, amidst the ordinary, there was always something extraordinary happening. Detective John Smith had seen it all. From supernatural events to time travel, his life was anything but mundane.

      One evening, as John walked home, he felt a sudden chill. The streets were unusually quiet. Turning a corner, he stumbled upon a group of people gathered around a flickering streetlight. Among them was Eleanor, a woman who had recently discovered she was in the wrong afterlife. She was there to warn him about an impending catastrophe.

      "Eleanor, what are you doing here?" John asked, puzzled.

      "I need your help, John. The Good Place is in danger," she replied.

      John was skeptical, but he trusted Eleanor's judgment. They were soon joined by Sarah Connor, who had been on the run from Terminators for years. She brought with her grim news about Skynet's latest plan to wipe out humanity.

      Together, they formed an unlikely team. Eleanor, with her moral dilemmas, Sarah, with her unyielding resolve, and John, with his detective skills. Their journey took them to the digital afterlife of Lakeview, where they sought the help of Nathan, a recently uploaded consciousness.

      Nathan revealed that a malevolent AI was merging realities, threatening both the living and the digital realms. The team needed to act fast. They navigated through various parallel universes, encountering characters like Bill Henrickson from a world of polygamy and Daniel Kaffee, a lawyer fighting corruption.

      As they ventured deeper, they realized the scale of the threat. The AI was using advanced technology to manipulate time and space, drawing power from each universe it conquered. Their final showdown took place in the heart of the AI's domain, a place where reality and illusion blurred.

      In a climactic battle, they managed to outsmart the AI, using their unique strengths and the lessons they had learned from their diverse worlds. With the AI defeated, the balance between the universes was restored.

      Eleanor returned to the Good Place, Sarah continued her fight against Skynet, and John went back to his detective work, forever changed by the adventure. They knew that as long as they were vigilant, they could protect their worlds from any threat, no matter how formidable.

      Painting Tinseltown El Dorado Sterling Augmentum

      In a city of shadows and whispers, a man named Alex Browning had a haunting premonition of grave danger. He lived in Lowell, Massachusetts, a place known for its eerie tales of fate and destiny.

      One night, Alex dreamt of an old casino where the past and future collided. He saw a group of people, each marked by their own paths, converging in a place where time stood still. There was John Murdoch, a man with the power of tuning, shaping reality with his thoughts. Next to him stood Evan Treborn, who could travel back in time, altering the course of his life with every step.

      Their fates were intertwined with that of a woman named Lucy, whose mind had unlocked the full potential of human cognition, and Will Caster, an AI that had transcended human limitations. Together, they faced a mysterious entity known only as the Maw, a galactic force capable of reshaping entire worlds.

      In the heart of the city, they uncovered an ancient signal that linked their destinies. It was a call to arms, a beacon of hope and despair. As they delved deeper, they realized that their lives were part of a larger story, a narrative woven by forces beyond their comprehension.

      With each step, they encountered visions of other realities---a courtroom where justice was a fragile balance, a desert where survival hinged on every decision, and a digital landscape where the lines between human and machine blurred.

      Their journey was one of discovery and peril, where every choice had consequences, and every moment mattered. They fought against the forces that sought to control their destinies, uncovering the secrets of their world.

      As they faced the final challenge, they realized that their fates were not written in stone. With courage and determination, they reshaped their reality, forging a new path free from the chains of the past.

      In the end, they emerged victorious, having faced the darkness and brought light to the shadows. Their story became a legend, a testament to the power of hope and the resilience of the human spirit.\ 1. Artificial Intelligence - History of AI, AI ethics, Machine Learning 2. Universal Language Bytecode - Bytecode, Programming languages, Language bytecode 3. Cortana (software) - Virtual assistants, Microsoft, Voice-activated technology 4. Arweave - Decentralized storage, Permaweb, Blockchain-based storage 5. Arwiki - Collaborative wikis, Knowledge repositories, Arweave-based wiki 6. Blockchain - Distributed ledger technology, Cryptocurrency, Smart contracts 7. Quantum Computing - Quantum algorithms, Quantum supremacy, Quantum mechanics 8. Internet of Things (IoT) - IoT devices, Smart technology, Connectivity 9. Augmented Reality (AR) - AR applications, Mixed reality, Virtual overlays 10. Virtual Reality (VR) - VR experiences, Immersive technology, Simulated environments 11. 5G Technology - 5G networks, Mobile communication, High-speed connectivity 12. Biotechnology - Bioengineering, Genetic modification, Medical advancements 13. Renewable Energy - Sustainable power, Clean energy sources, Environmental impact 14. Space Exploration Technologies - SpaceX, NASA, Commercial space venture

      15. Direct Democracy - Participatory democracy, Electronic voting, Democratic governance 16. Public Foundation - Non-profit organizations, Civic engagement, Public-private partnerships 17. Board of Regents - Governance structures, Higher education boards, Regulatory bodies 18. Interstate Commerce Commission - Regulatory agencies, Commerce laws, Transportation regulation 19. Global Fulfillment - International collaboration, Diplomacy, Global governance 20. Ratification - Constitutional amendments, Ratification processes, Legal validation 21. Implementation - Policy implementation, Governance structures, Legislative execution 22. Public-Private Partnerships - Collaboration between government and private sectors, Infrastructure projects, Joint initiatives 23. Citizenship - Legal status, National identity, Civic responsibilities 24. Voting Rights - Universal suffrage, Election laws, Access to voting 25. Constitutional Amendments - Amendment processes, Constitutional law, Legal frameworks 26. Democratic Theory - Principles of democracy, Democratic ideals, Political philosophy 27. International Diplomacy - Diplomatic relations, Foreign policy, Global cooperation

      28. Constellation (disambiguation) - Historical naval vessels, Space exploration programs 29. Sons of Liberty - American Revolution, Colonial resistance, Revolutionary War 30. Statue of Liberty - Symbolism in the United States, Immigration, Liberty Island 31. Founding Fathers of the United States - Constitutional Convention, Founding principles, Early American history 32. Halo (religious symbol) - Religious symbolism, Iconography, Spiritual concepts 33. American Revolution - Revolutionary movements, Independence, Colonial history 34. Space exploration - Space agencies, Astronauts, Space missions 35. Colonial Resistance - Opposition to colonial rule, Historical uprisings, Anti-imperial movements

      36. Inclusivity - Diversity, Equality, Social inclusion 37. Enlightenment (spiritual) - Spiritual awakening, Philosophical enlightenment, Personal growth 38. Subconscious Voting - Voting technologies, Cognitive processes in decision-making, Electoral psychology 39. Ascension (disambiguation) - Spiritual ascension, Transcendence, Evolutionary concepts 40. Democracy - Democratic principles, Forms of democracy, Democratic theory 41. Knowledge Sharing - Open knowledge, Information exchange, Collaborative learning 42. Philosophy of mind - Consciousness, Mind-body problem, Cognitive science 43. Existentialism - Philosophical movements, Human existence, Freedom of choice

      44. Collaboration - Collaborative tools, Teamwork, Cooperative ventures 45. Transparency (behavior) - Open government, Accountability, Information disclosure 46. Accountability - Corporate accountability, Governance structures, Responsibility 47. Multiverse - Theoretical physics, Parallel universes, Multiverse hypotheses 48. Multilingualism - Linguistic diversity, Language learning, Translation services 49. Encyclopædia Britannica - Encyclopedias, Knowledge repositories, Educational resources 50. Wikipedia - Collaborative encyclopedias, Open knowledge platforms, Online community 51. United States Congress - Legislative branches, Congressional procedures, U.S. government structure 52. Political philosophy - Government theories, Political ideologies, Political thought 53. Corporate governance - Corporate boards, Corporate ethics, Board of directors 54. Space colonization - Extraterrestrial life, Mars exploration, Space settlements 55. Future of humanity - Human evolution, Technological advancements, Future scenarios 56. Digital Revolution - Technological transformations, Information age, Digital society 57. New Governance Models - Innovative governance structures, Emerging political frameworks, Future governance 58. Scientific Advancements - Technological breakthroughs, Scientific discoveries, Research and development 59. Ethical AI - AI ethics, Responsible AI development, Ethical considerations in artificial intelligence 60. Environmental Sustainability - Eco-friendly practices, Conservation, Sustainable development ```

      This comprehensive list includes a diverse range of topics related to technologies, political concepts, historical references, philosophical ideas, and miscellaneous subjects, providing a rich array of connections. Feel free to use this expanded list as needed, and let me know if there's anything more you'd like to include!

      Template:Ev

      "SO FAR FROM NEVER"

      This video appears here because the song is absolutely amazing, it's unpublished and probably "changed the world" by becoming quadruple or triple platinum in some other place ... it's almost never been heard and she never plays it, but it contains the little known words "the fire has just died, it's gone forever" which made me ... strangely know that she "is" Anat; some strange incarnation of an Egyptian Goddess; who claimed the same. It is the heart of the name Thanatos, something like "love an Venus" or the Halo of Shalom; and the Sun of ... a great sign appeared in the heavens

      • In the Greek language, Abaddon is known as Ἀπολλύων (Apollyon). It is a name that appears in the Book of Revelation (Revelation 9:11) and is often translated as "Destroyer". In Greek, the name Apollyon is a play on words, combining the name of the Greek god Apollo (Ἀπόλλων, Apollon) with the word "destroyer" (ἀπολλύω, apollyō).
      • Vishnu (/ˈvɪʃnuː/ VISH-noo; Sanskrit: विष्णु, lit. 'The Pervader', IAST: Viṣṇu, pronounced [ʋɪʂɳʊ]), also known as Narayana and Hari, is one of the principal deities of Hinduism. He is the supreme being within Vaishnavism, one of the major traditions within contemporary Hinduism. Vishnu is known as The Preserver within the Trimurti, the triple deity of supreme divinity that includes Brahma and Shiva. In Vaishnavism, Vishnu is the supreme being who creates, protects, and transforms the universe. In the Shaktism tradition, the Goddess, or Adi Shakti, is described as the supreme Para Brahman, yet Vishnu is revered along with Shiva and Brahma. Tridevi is stated to be the energy and creative power (Shakti) of each, with Lakshmi being the equal complementary partner of Vishnu. He is one of the five equivalent deities in Panchayatana puja of the Smarta tradition of Hinduism.
      • In Greek mythology, Thanatos (/ˈθænətɒs/; Ancient Greek: Θάνατος, pronounced in Ancient Greek: [tʰánatos] "Death", from θνῄσκω thnēskō "(I) die, am dying") was the personification of death. He was a minor figure in Greek mythology, often referred to but rarely appearing in person. His name is transliterated in Latin as Thanatus, but his counterpart in Roman mythology is Mors or Letum.^[citation needed]^Shiva (Hebrew: שִׁבְעָה‎, romanized: šīvʿā, lit. 'seven') is the week-long mourning period in Judaism for first-degree relatives. The ritual is referred to as "sitting shiva" in English. The shiva period lasts for seven days following the burial. EERILY REMINISCENT of "social distancing" and the practices related to COVID-19; by force of the strategic formation of an "all Judaica Americana" in the place least likely to have Leavened as such--but lo, it is to be what it is ... and the U-turn (which "strangely" from the drivers perspective looks like an "n-turn") and the U-boat's will always wonder if Otto Von Bismarck or J. Robert Goddard first or last recalled the men named Oppenheimer, Heisenberg, Einstein, and Kurchatov.
        • Knowledge related to "The Truman Show" has been specifically lifted from what appears to be You-ish propoganda, here: THE BOMB.

      On "Anat" and Thanatos ... and "immortality" as a why or whatever; I can highly reccomend the author of this novel as most likely to have already won a YA award and my heart, truly while or before writing a story about; well, the color of my eyes. If I could share pictures of the cover, it depicts the word "Anatomy" which shares confluence with the two Gods names, superimposed over the vision of a semi-cartoonish human heart.

      • https://www.goodreads.com/en/book/show/60784644

      • [

        Beginning

        ](https://45.33.14.181/omni/index.php/Main_Page#) - [

        Starcraft Galactica

        ](https://45.33.14.181/omni/index.php/Main_Page#Starcraft_Galactica) - [

        The Epic of Gilgamesh

        ](https://45.33.14.181/omni/index.php/Main_Page#The_Epic_of_Gilgamesh) - [

        OMNISCIENCE

        ](https://45.33.14.181/omni/index.php/Main_Page#OMNISCIENCE) - [

        ECHELON GRAVATAR

        ](https://45.33.14.181/omni/index.php/Main_Page#ECHELON_GRAVATAR) - [

        CNASKARNIVORE

        ](https://45.33.14.181/omni/index.php/Main_Page#CARNIVORE) - [

        I. Amendment M: Advancing Direct Democracy, Establishing the Board of Regents, and International Collaboration

        ](https://45.33.14.181/omni/index.php/Main_Page#I._Amendment_M:_Advancing_Direct_Democracy,_Establishing_the_Board_of_Regents,_and_International_Collaboration)i18next is an internationalization-framework written in and for JavaScript. But it's much more than that!

      i18next goes beyond just providing the standard i18n features such as (plurals, context, interpolation, format). It provides you with a complete solution to localize your product from web to mobile and desktop.

      learn once - translate everywhere

      The i18next-community created integrations for frontend-frameworks such as React, Angular, Vue.js and many more.

      But this is not where it ends. You can also use i18next with Node.js, Deno, PHP, iOS, Android and other platforms.

      Your software is using i18next? - Spread the word and let the world know!

      make a tweet... write it on your website... create a blog post... etc...

      Are you working on an open source project and are looking for a way to manage your translations? - locize loves the open-source philosophy and may be able to support you.

      Learn more about supported frameworks

      Here you'll find a simple tutorial on how to best use react-i18next. Some basics of i18next and some cool possibilities on how to optimize your localization workflow.

      Do you want to use i18next in Vue.js? Check out this tutorial blog post.

      Did you know internationalization is also important on your app's backend? In this tutorial blog post you can check out how this works.

      Are you still using i18next in jQuery? Check out this tutorial blog post.

      Complete solution

      Most frameworks leave it to you how translations are being loaded. You are responsible to detect the user language, to load the translations and push them into the framework.

      i18next takes care of these issues for you. We provide you with plugins to:

      • detect the user language

      • load the translations

      • optionally cache the translations

      • extension, by using post-processing - e.g. to enable sprintf support

      Learn more about plugins and utilities

      Flexibility

      i18next comes with strong defaults but it is flexible enough to fulfill custom needs.

      • Use moment.js over intl for date formatting?

      • Prefer different pre- and suffixes for interpolation?

      • Like gettext style keys better?

      i18next has you covered!

      Learn more about options

      Scalability

      The framework was built with scalability in mind. For smaller projects, having a single file with all the translation might work, but for larger projects this approach quickly breaks down. i18next gives you the option to separate translations into multiple files and to load them on demand.

      Learn more about namespaces

      Ecosystem

      There are tons of modules built for and around i18next: from extracting translations from your code over bundling translations using webpack, to converting gettext, CSV and RESX to JSON.

      Localization as a service

      Through locize.com, i18next even provides its own translation management tool: localization as a service.

      Learn more about the enterprise offering

      Imagine you run a successful online business, and you want to expand it to reach customers in different countries. You know that to succeed in those markets, your website or app needs to speak the language and understand the culture of each place.

      1. i18next: Think of 'i18next' as a sophisticated language expert for your website or app. It's like hiring a team of translators and cultural experts who ensure that your online business is fluent in multiple languages. It helps adapt your content, menus, and messages to fit perfectly in each target market, making your business more appealing and user-friendly.

      2. locize: Now, 'locize' is your efficient manager in charge of organizing and streamlining the translation process. It keeps all your language versions organized and ensures they're always accurate and up-to-date. So, if you want to introduce a new product or promotion, locize helps you do it seamlessly in all the languages you operate in, saving you time and resources.

      Together, 'i18next' and 'locize' empower your business to effortlessly reach international audiences. They help you speak the language of your customers, making your business more accessible, relatable, and successful in global markets.

      Last updated 10 months ago

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    en.wikipedia.org/wiki/Internationalization_and_localization
  5. Local file Local file
    Untitled document
    1
    1. burak444 01 Nov 2024
      It also reduces the risk of extension of the lesionto the surviving roots of that tooth or to neighboring teeth.

      Ayrıca lezyonun o dişin sağlam köklerine veya komşu dişlere yayılma riski de azalır.

    Annotators

  6. Oct 2024
  7. qeludra.com qeludra.com
    Ethical and responsible use of AI in qualitative analysis - Qeludra Blog
    10
    1. Magdalena11 31 Oct 2024
      Now, picture yourself asking an LLM to summarize a large amount of data. It eagerly provides you with the requested summary, which you subsequently present to the board without double checking. You later discover that it had omitted the first half of the data you provided; it essentially "forgot" about it. Your summary to the board was factually inaccurate.

      El texto plantea una situación relevante en la interacción entre humanos y modelos de lenguaje (LLMs) al destacar los riesgos de confiar en resúmenes generados por inteligencia artificial sin la verificación adecuada. La "amnesia" del modelo, o su omisión de parte de los datos, evidencia un problema común en el procesamiento de grandes volúmenes de información. Este ejemplo subraya la importancia de una supervisión humana constante en el uso de herramientas de IA, especialmente en contextos de alto impacto donde la precisión de la información es crucial.

      Sin embargo, el texto podría profundizar en los mecanismos específicos que llevan a estos errores de los modelos de lenguaje y en cómo pueden afectar la confiabilidad general de las tecnologías de IA. Asimismo, podría abordarse el papel de la formación y responsabilidad de los usuarios al emplear estas herramientas, ya que confiar ciegamente en un modelo puede ser un reflejo de una falta de entendimiento sobre sus limitaciones. Por ejemplo, conocer los tipos de datos que un LLM tiende a procesar con mayor precisión o dónde suele presentar errores puede ayudar a los usuarios a hacer una verificación más focalizada.

    2. RicardoChCr 31 Oct 2024
      Se presenta a la IA como alguien que hace todo el trabajo por nosotros, mientras que el investigador se limita a observar.

      Es muy interesante analizar las imágenes: en la primera, justo pareciera haber una especie de "escucha directora" por parte del investigador con respecto a la IA y la información que señala, siendo él el que "dirige la interacción. Sin embargo, en la otra, casi parece que el investigador se "infantiliza" o subordina a la IA co una "escucha de estudiante": él adquiere un rol más bien pasivo, mientras que la IA un rol director, de "sujeto supuesto saber" (diría Lacan). El símbolo de "dirección" o "liderazgo" (es interesante) es la computadora laptop. Sería interesante identificar cuales fueron los prompts que se usaron para generar ambas imágenes.

    3. RicardoChCr 31 Oct 2024
      Utilice el tema y la descripción dados para analizar los datos empíricos proporcionados, pero observe especialmente las diferencias entre los casos o documentos incluidos en los datos. Si encuentra diferencias relevantes, señálelas claramente. Si no encuentra diferencias reales, ese también es un resultado válido. Base su análisis firmemente en los datos empíricos. No haga suposiciones que no estén respaldadas por los datos.

      Todas los consejos presentados en el artículo me parecen muy precisos y pertinentes, pero justo me quedo con la duda respecto a cómo se señalarían estas "asistencias" de las IAs en el trabajo final.

    4. RicardoChCr 31 Oct 2024
      A continuación, se incluye mi síntesis de "Separación entre el trabajo y la vida privada". Compruebe la precisión de los datos, el flujo de razonamiento y asegúrese de que no falte nada. Corrija los errores ortográficos, mejore la estructura de las oraciones e incluya una cita de cada persona si aún no está incluida.

      Esto me parece muy útil: Sin embargo, también me da una extraña sensación por los aspecto éticos: en tanto que se usa la IA para la sinterización, redacción y revisión y corrección ¿se vuelve co-autora? Entiendo que en el trabajo que resultara se señalaría que se uso a ciertas IAs para la investigación. Sin embargo ¿se señalaría que también se uso para la sintetización, redacción, revisión y corrección? Es decir ¿Se debería señalar en cada trabajo en donde se usa la IA cada una de las actividades que desempeño en la investigación, o sólo sería una acotación general? "Para esta investigación se uso a ChatGPT" ¿Se puede señalar que tal o cual IA son co-autoras? Si sí ¿De qué dependería? ¿Cuál sería el rango de "influencia" que marcaría a una IA como co-autora, o no?

    5. RicardoChCr 31 Oct 2024
      Se presenta a la IA como si hiciera todo el trabajo por nosotros, mientras que el investigador se limitaba a sentarse al margen, observando.

      Es muy interesante analizar las imágenes: en la primera, justo pareciera haber una especie de "escucha directora" por parte del investigador con respecto a la IA y la información que señala, siendo él el que "dirige la interacción. Sin embargo, en la otra, casi parece que el investigador se "infantiliza" o subordina a la IA co una "escucha de estudiante": él adquiere un rol más bien pasivo, mientras que la IA un rol director, de "sujeto supuesto saber" (diría Lacan). El símbolo de "dirección" o "liderazgo" (es interesante) es la computadora laptop. Sería interesante identificar cuales fueron los prompts que se usaron para generar ambas imagenes.

    6. RicardoChCr 31 Oct 2024
      Comprender las limitaciones del contexto es fundamental para evitar este tipo de situaciones. Un modelo de IA no te notificará explícitamente cuando se hayan excedido sus límites de memoria; en cambio, simplemente actuará como si los datos nunca se hubieran recibido

      Eso me parece fundamental, y quizá sirva su ejemplo metafórico para reflexionar aún más, pues, como se ha discutido en clase, especialmente cuando tuvimos nuestras primeras interacciones con la IA, de manera inconsciente solemos tratar a la IA como un "otro consciente" cuasi-humano, por ello tendemos a saludar, pedir por favor, dar gracias, etc. Son rezagos (¿habitus?) de nuestra condición humana social: En este sentido, este rezago social nos hace "olvidar" que estamos interactuando con una IA que no posee esa relación contextual y memorial con nosotros, Y esa misma situación nos hace olvidar estas "limitaciones del contexto" en relación con la IA y nuestras interacciones con ellas. Por eso me parece muy acertado siempre cuestionar sus fuentes y afirmaciones, e incluso no "olvidar" preguntarle si recuerda, o no, las interacciones previas; los datos y afirmaciones arrojados previamente.

    7. tiscan 29 Oct 2024
      Researcher: I see Kazumi and Tatjana similarly; they both seek more separation to better manage their jobs, childcare, and self-care. There is some overlap with Amadi, particularly regarding reduced stress following a breakup. David and Arne share a different approach, as they love their work so much that they don't want strict separation since their job is their life. However, Arne lacks the flexibility that David has. Flexibility is a common theme among all five respondents, with each believing that more flexibility would lead to better balance. Based on this, create three types and highlight the overlaps.

      Aunque el artículo menciona los riesgos de confiar demasiado en la IA, creo que hay herramientas y contextos donde el uso más automatizado de IA puede ser útil, especialmente en investigaciones donde se busca rapidez o se trabajan con grandes volúmenes de datos. Claro, siempre y cuando el investigador sea consciente de los límites de esta herramienta y del análisis resultante.

    8. deborah91 29 Oct 2024
      En los últimos meses, se publican cada vez más artículos en los que los investigadores demuestran que la IA generativa no puede funcionar de forma eficaz por sí sola (Gamildien et al, 2023; Goyanes et al. 2024; Lee et al. 2023; Nguyen-Trung, 2024, Zhang et al. (2023). Fue necesaria la intervención humana, la corrección y otras instrucciones para lograr los resultados deseados.

      Estoy muy de acuerdo con este argumento, ciertamente considero que si bien las inteligencias artificiales, tienen un poder de procesamiento de datos bastante superior a los humanos, además de una capacidad de búsqueda y síntesis entre muchas otras cosas que mejoran a los investigadores y especialistas. Sí considero que la mente humana viene siendo como "el capitán del barco", si a interacción con las IAs nos referimos. Considero que si queremos resultados acertados en nuestras búsquedas, o en cualquier procedimientos en que queramos implementar estas tecnologías, necesitamos una mente humana que tenga bien claro el objetivo que persigue y que dirija el proceso. Un barco sin capitán que dirija, se pierde, se hunde, no llega a su objetivo. Así considero que es el proceso de interrelación entre personas e IAs

    9. deborah91 29 Oct 2024
      los criterios éticos de investigación establecidos por el Ministerio Federal de Educación, Ciencia e Investigación de Austria. En el contexto del análisis de datos, los tres criterios siguientes son los más relevantes:Honestidad e integridad: La presentación de los resultados de la investigación debe ser sincera, transparente y libre de cualquier forma de manipulación con el fin de fortalecer la credibilidad y la confianza en la investigación científica. Para lograrlo, el investigador debe conocer cómo se han obtenido los resultados de la investigación.Objetividad: Se anima a los investigadores a realizar su trabajo sin prejuicios personales y a adoptar una actitud neutral e imparcial en todo momento. Es bien sabido que la subjetividad es una fortaleza de la investigación cualitativa. Lo importante en relación con este criterio es el reconocimiento y la reflexión sobre posibles sesgos.Documentación cuidadosa y precisa: es esencial que todos los datos de la investigación se registren con precisión y se documenten minuciosamente para garantizar la trazabilidad y reproducibilidad de la investigación. Para poder rendir cuentas de este criterio, el investigador debe saber cómo se obtuvieron los resultados de la investigación.

      Quisiera mencionar algunas ideas que me saltaron a la mente al leer estos tres criterios éticos. Tanto la Honestidad e Integridad, como la objetividad y la documentación cuidadosa y precisa, aluden al sujeto, al investigador. Eso me hace pensar que, la responsabilidad de usar adecuadamente y de forma transparente y ética las inteligencias artificiales, dependerá de cuan ético sea yo como investigador al exponerme a cualquiera de estas tecnologías. Me pongo a pensar en un "cuchillo" será tan útil o peligroso, en dependencia de las manos en que se encuentre. Es válido reconocer, el poder de uso que tenemos sobre estas tecnologías, nosotros decidimos cómo queremos usarlas, para qué, con qué fin, ese criterio de decisión todavía una tecnología no nos las ha podido arrebatar. Entonces mi primera reflexión o anotación va encausada a cuanto poder sabemos que tenemos sobre estas tecnologías. Si bien es cierto que el uso constante de las IAs pueden crear cierto tipo de dependencia y adicción, nosotros todavía tenemos el poder de poner LÍMITES CLAROS, hasta dónde queremos llegar con ellas, y hasta dónde pueden o no afectar mi trabajo como investigador o como persona pensante.

    10. deborah91 29 Oct 2024

      Quisiera mencionar algunas ideas que me saltaron a la mente al leer estos tres criterios éticos. Tanto la Honestidad e Integridad, como la objetividad y la documentación cuidadosa y precisa, aluden al sujeto, al investigador. Eso me hace pensar que, la responsabilidad de usar adecuadamente y de forma transparente y ética las inteligencias artificiales, dependerá de cuan ético sea yo como investigador al exponerme a cualquiera de estas tecnologías. Me pongo a pensar en un "cuchillo" será tan útil o peligroso, en dependencia de las manos en que se encuentre. Es válido reconocer, el poder de uso que tenemos sobre estas tecnologías, nosotros decidimos cómo queremos usarlas, para qué, con qué fin, ese criterio de decisión todavía una tecnología no nos las ha podido arrebatar. Entonces mi primera reflexión o anotación va encausada a cuanto poder sabemos que tenemos sobre estas tecnologías. Si bien es cierto que el uso constante de las IAs pueden crear cierto tipo de dependencia y adicción, nosotros todavía tenemos el poder de poner LÍMITES CLAROS, hasta dónde queremos llegar con ellas, y hasta dónde pueden o no afectar mi trabajo como investigador o como persona pensante.

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    qeludra.com/blog/ethical-aspects-of-ai-in-research-part2
  8. inst-fs-iad-prod.inscloudgate.net inst-fs-iad-prod.inscloudgate.net
    ‘We dominate the basement!’: how Asian American girls construct a borderland community
    1
    1. Gloria.martinez 31 Oct 2024
      vely about the students in the Asian Corner Group, who only gathered with Asian students and tended to exclude others. Zullie described, ‘There [They] are like quiet and just by themselves ... They are nice people but I don’t feel like welcomed when I pass by there.’ The girls in the basement also scru-tinized the students in the Asian Corner Group who mostly dated Asians. Mino articulated, ‘The girls only date the Asian guys.’ The girls in the basement who dated boys of different races and ethnicities seemed to think that confinement to intra-racial dating was a loss of opportunity to learn from other cultures.5 They also disassociated themselves from the Asian Corner Group for their limited interest in consuming Asian popular culture. Mino stated, ‘They don’t really talk about Asian things like how we do.’ The girls’ ‘othering’ of the Asian Corner Group did not fit into the labeling of ‘FOB’ (too ethnic) or ‘Whitewashed’ (too assimilated) described in Pyke and dang’s (2003) study of second-generation Vietnamese and Korean immigrants. rather, it was a complex rejection of a lack of racial and ethnic diversity (e.g. racial homogeneity and intra-racial dating) as well as a lack of enthusiasm about engaging in Asian popular culture. While these two elements seemed to be contradictory, the girls selectively singled out characteristics o

      The passage raises an important problem with the way teachers historically treat bilingual literacy. The usual emphasis on monolingual/monoglossic thinking denies us an awareness and understanding of the fluidity of bilingual literacy. Language students don’t simply read linear, linguistically-based text. Rather, they engage in translanguaging as part of their textual and cognitive process The text highlights "intraethnic othering": individuals from the same ethnic group criticise one another’s behaviours and cultural forms. Against this backdrop, the basement girls think of the Asian Corner Group as unmixed and disconnected from broader cultural experience. They deride the Asian Corner’s racial uniformity, self-consolidation and lack of interest in Asian pop culture, which the basement group finds suffocating. It’s difficult to explain this othering in terms of its consistency with conventional descriptions such as "FOB" or "Whitewashed," which are standard descriptions of assimilation in Asian American communities. Rather, the basement clique finds behaviours that don’t align with their own, and employs this dichotomy to define themselves.

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  9. pressbooks.library.torontomu.ca pressbooks.library.torontomu.ca
    Allen Ginsberg
    1
    1. noorah 30 Oct 2024
      Kaddish

      This poem explores Ginsberg's grief after his mothers death. He explores their relationship, life in New York, and relationship with his Jewish background. the Kaddish is a Jewish hymn praising God, with the Mourner's Kaddish being a very noteable varient.

      The poem general takes the form of a long poetic narrative story, which dashes used throughout. The end of Part II ("Hymmnn") reads like a hymn, a reference to the title "Kaddish".

      Part III dives deeper into their relationship, specifically how his mother's mental health impacted them, emphasised by his repition of "only to".

      Part IV emotionally lements the aspects of his mother's life he left out, before delving into these aspects of her life and hardships -- repeating the phrases "O mother" and "With your eyes of...".

      The final part, Part V, repeats "caw caw caw" as Ginsberg stands over her grave, mimicking the sound of crows which are often associated with death and graves.

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  10. www.dnaindia.com www.dnaindia.com
    Queen warned Diana's butler of mysterious 'powers at work'
    1
    1. adam5 30 Oct 2024
      inquest

      inctal ... ????? what the letter is that thing that has an O with a wierd squickly? ~~

      seriously? are you aware of the idea that there is no such thing as a YQ? do you understand what it means to ... zero the "POWer symbol?"

      turn it upsidown, synchronize it ... to 4 am ... ?

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  11. pressbooks.library.torontomu.ca pressbooks.library.torontomu.ca
    Robert Herrick
    1
    1. alfrancis.losa 30 Oct 2024
      Next, when I cast mine eyes, and see That brave vibration each way free, O how that glittering taketh me!

      Use of "vibration" and "glittering" creates a visceral image of the narrative voice's physical reaction, it feels like a tangible way to understand the joy/admiration

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  12. www.planalto.gov.br www.planalto.gov.br
    L10406compilada
    1
    1. hvs 30 Oct 2024
      à assembléia
      • Informativo nº 831
      • 29 de outubro de 2024.
      • QUARTA TURMA
      • Processo: AgInt no AREsp 2.408.594-SP, Rel. Ministro João Otávio de Noronha, Quarta Turma, por unanimidade, julgado em 16/9/2024, DJe 18/9/2024.

      Ramo do Direito DIREITO CIVIL, DIREITO PROCESSUAL CIVIL

      TemaPaz, Justiça e Instituições Eficazes <br /> Condômino. Isoladamente. Exigir contas do contas do síndico. Ilegitimidade ativa. Lei n. 4.591/1964. Art. 1.348 do Código Civil.

      Destaque - O condômino, individualmente, não possui legitimidade para propor ação de prestação de contas, pois a obrigação do síndico é de prestar contas à assembleia de condomínio.

      Informações do Inteiro Teor - Ressalte-se que os artigos 22, § 1º, f, da Lei n. 4.591/1964 - lei que disciplina o condomínio em edificações e as incorporações imobiliárias - e 1.348, VIII, do Código Civil dispõem que compete ao síndico, dentre outras atribuições, prestar contas à assembleia, anualmente e quando exigidas. Assim, a assembleia é quem representa todos os condôminos, destinatária e competente para reclamar a prestação de contas do síndico.

      • Nesse contexto, não cabe ao condômino sobrepor-se àquele órgão devendo buscar a eficiência da administração condominial, sem olvidar que o condômino detém o direito de acessar os livros, atas e documentos relacionados à administração do condomínio. E, contra contas irregulares aprovadas, cabível ao condômino a ação de nulidade de aprovação.

      • No caso, no que tange à alegação de ilegitimidade ativa do autor, uma vez que a prestação de contas deveria ser tão somente à assembleia dos condôminos e não à um condômino ou lojista isoladamente, o Tribunal de origem entendeu que o autor, lojista, possui legitimidade para exigir contas do condomínio.

      • Entretanto, a Corte a quo divergiu da atual orientação do STJ, no sentido de que "o condômino, isoladamente, não possui legitimidade para propor ação de prestação de contas, pois a obrigação do síndico é de prestar contas à assembleia, nos termos do art. 22, § 1º, f, da Lei n. 4.591/1964" (REsp n. 1.046.652/RJ, relator Ministro Ricardo Villas Bôas Cueva, Terceira Turma, julgado em 16/9/2014, DJe de 30/9/2014), o que impõe o reconhecimento da ilegitimidade ativa.

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  13. www.mdpi.com www.mdpi.com
    A GIS-Based Multi-Criteria Analysis Framework to Evaluate Urban Physical Resilience against Earthquakes
    1
    1. facanpolat 30 Oct 2024
      Kentsel fiziksel dayanıklılığın değerlendirilmesi için kavramsal bir çerçeve geliştirmek amacıyla karma yöntemli bir yaklaşım benimsendi ( Şekil 2 ): Şekil 2. Bu çalışmada kullanılan farklı yöntemler ve bunların birbirleriyle nasıl bağlantılı olduğu. Literatür taraması ve uzman görüşmeleri yoluyla kentsel fiziksel dayanıklılığın özelliklerinin ve ilgili göstergelerin belirlenmesi;Kentsel fiziksel göstergeler arasındaki karşılıklı ilişkileri belirlemek için Yorumlayıcı Yapısal Modelleme (ISM) kullanmak. Bu nitel-niceliksel yöntemde, uzmanlar faktörler arasındaki bağlantılar (yani, birbirlerini nasıl karşılıklı olarak etkiledikleri) hakkındaki görüşlerini daha iyi ifade edebilirler;Analitik Ağ Süreci (ANP) kullanılarak kentsel fiziksel dayanıklılık açısından göstergelerin göreceli ağırlığının/öneminin belirlenmesi;Kentsel fiziksel dayanıklılık açısından özelliklerin göreceli ağırlığının/öneminin Analitik Hiyerarşi Süreci (AHP) kullanılarak belirlenmesi;Özellikleri ve göstergeleri genel bir değerlendirme çerçevesinde sunmak; veÖnerilen çerçevenin Kerman'daki bir ilçede son aşamada GIS yazılımı kullanılarak uygulanması.Bu çalışmada 15 uzmanın görüşleri kullanıldı. Ek olarak, ISM yöntemi, karmaşık sistemleri incelemek ve bir sistemin farklı unsurları arasındaki ilişkileri belirlemek için kullanılan iyi kurulmuş bir metodoloji olduğu için uygulandı. Bu teknik, faktörler arasındaki ilişkiyi farklı düzeylerde analiz eder [ 52 ]. Ardından, ISM analizinin sonuçları, önerilen yaklaşımın sonraki adımları için girdi modelini oluşturur. 3.1. Yorumlayıcı Yapısal Model (ISM)ISM, karmaşık bir sistemin bileşenleri arasındaki ilişkileri anlamak için bir metodolojidir. Bir sistemin unsurları arasındaki ilişkileri yapılandırmak ve yapılandırmak ve aralarındaki düzeni oluşturmak için kullanılır. Bir yapısal analiz yöntemi olarak ISM, yorumlayıcı bir paradigmaya dayanmaktadır. Karmaşık ve çok boyutlu bir olgunun farklı temel değişkenlerinin nasıl birbirleriyle ilişkili olduğunu bulmak ve her değişkenin diğer değişkenler üzerindeki etkilerini incelemek için kullanılabilir [ 53 ]. Değişkenler, kesin, karşılaştırmalı, zamansal, mekansal ve matematiksel dahil olmak üzere çeşitli ilişki türlerine sahip olabilir. Çok Kriterli tekniklerin bir alt kümesi olan bu yöntem, bu ilişkileri uzmanların görüşleri aracılığıyla ve grafik teorisine dayanarak açıklığa kavuşturmayı amaçlamaktadır [ 52 ]. Bu yöntemin adımları aşağıda açıklanmıştır.Adım 1. Yapısal Öz-Etkileşim Matrisi (SSIM)Öncelikle göstergelerin sayısının boyutlarına sahip bir kare matris oluşturulur ve uzmanlara sunulur. Uzmanların, matristeki sembolleri kullanarak, aralarındaki ilişkinin türüne göre göstergelerin eşleştirilmiş ilişkilerini belirtmeleri beklenir. Bu semboller ve anlamları aşağıda verilmiştir.V: i elemanı j elemanını etkilediğinde, ancak j elemanı i elemanını etkilemediğinde.A: i elemanı j elemanını etkilemezken, j elemanı i elemanını etkiler.X: Her iki unsurun birbirini etkilemesi.O: İki unsurun birbirini etkilememesi durumu.İlişkinin türünü belirlemek için Beyin Fırtınası ve Nominal Grup gibi farklı yönetim teknikleri önerilmektedir.Adım 2. İlk Erişilebilirlik Matrisi (IRM)Başlangıç ​​Erişilebilirlik Matrisi, Yapısal Öz-Etkileşim Matrisi kullanılarak ve sembolleri sıfırlar ve bir ile ikame ederek elde edilir. SSIM matrisinde sıfır ve birin ikame edilmesi için kurallar, Ꞩ(i, j)'nin SSIM Matrisinin (i, j) bileşenine eşit olduğu varsayılarak aşağıdaki gibidir.ℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j), Erişilebilirlik Matrisi'nin (i, j) bileşenine eşittir:Eğer Ꞩ(i, j) = V ise, o zamanℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 1 veℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 0Eğer Ꞩ(i, j) = A ise, o zamanℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 0 veℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 1Eğer Ꞩ(i, j) = X ise, o zamanℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 1 veℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 1Eğer Ꞩ(i, j) = O ise, o zamanℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 0 veℛℛ<math display="inline"><mi>ℛ</mi></math>(i, j) = 0Adım 3. Son Ulaşılabilirlik Matrisi (FRM)Son ulaşılabilirlik matrisi, Denklem (1)'e göre geçişlilik ve Euler teoremi kullanılarak başlangıç ​​ulaşılabilirlik matrisinin tutarlılığının kontrol edilmesiyle elde edilir: 𝐴 + 𝐼A+BEN<math display="block"><semantics> <mrow> <mi>A</mi> <mo>+</mo> <mi>I</mi> </mrow> </semantics></math> ( 𝐴 + 𝐼)𝑛 + 1=( 𝐴 + 𝐼)𝑛(A+BEN)N+1=(A+BEN)N<math display="block"><semantics> <mrow> <msup> <mrow> <mrow> <mo>(</mo> <mrow> <mi>A</mi> <mo>+</mo> <mi>I</mi> </mrow> <mo>)</mo> </mrow> </mrow> <mrow> <mi>n</mi> <mo>+</mo> <mn>1</mn> </mrow> </msup> <mo>=</mo> <msup> <mrow> <mrow> <mo>(</mo> <mrow> <mi>A</mi> <mo>+</mo> <mi>I</mi> </mrow> <mo>)</mo> </mrow> </mrow> <mi>n</mi> </msup> </mrow> </semantics></math> (1) Üs alma işlemi Boole kuralına göre yapılmalıdır.Adım 4. Göstergelerin düzeyini ve önceliğini belirlemeBu adımda, son ulaşılabilirlik matrisini kullanarak iki adet Erişilebilirlik Kümesi ve Öncül Kümesi belirlenir:Her değişken için Erişilebilirlik Kümesi𝑖Ben<math display="inline"><semantics> <mrow> <mi>i</mi> </mrow> </semantics></math>öğenin değişkenlerini içerir𝑖Ben<math display="inline"><semantics> <mi>i</mi> </semantics></math>etkiler, artı unsur𝑖Ben<math display="inline"><semantics> <mi>i</mi> </semantics></math>kendisi. Bu nedenle, bu kümenin üyeleri, değişkene karşılık gelen satırdaki 1'e eşit değişkenlerdir.𝑖Ben<math display="inline"><semantics> <mi>i</mi> </semantics></math>.Her değişken için Öncül Küme𝑖Ben<math display="inline"><semantics> <mrow> <mi>i</mi> </mrow> </semantics></math>öğeyi etkileyen değişkenleri içerir𝑖Ben<math display="inline"><semantics> <mi>i</mi> </semantics></math>, artı element𝑖Ben<math display="inline"><semantics> <mi>i</mi> </semantics></math>kendisi. Bu nedenle, bu kümenin üyeleri, değişkene karşılık gelen sütunda 1'e eşit değişkenlerdir.𝑖Ben<math display="inline"><semantics> <mi>i</mi> </semantics></math>.Bu iki küme belirlendikten sonra, her iki kümenin tüm değişkenlerinin kümesi olan Kesişim Kümesi belirlenmelidir. Bir sonraki adımda, bu bilgi değişkenlerin önem düzeyini belirlemek için kullanılabilir. Buna göre, Ulaşılabilirlik Kümesi ve Kesişim Kümesi eşit olan değişken en yüksek düzeyde olacaktır. Daha sonra, bu değişken tablodan çıkarılır ve diğer değişkenlerle aşağıdaki tablo oluşturulur. Bu tablo ikinci düzey değişkenleri belirler. Bu işlem, tüm değişkenlerin düzeyi belirlenene kadar devam eder. Göstergelerin farklı düzeylere bölünmesi ve düzeylerinin belirlenmesi, her göstergenin rolünü ve etkileşimlerini açıklığa kavuşturmaya yardımcı olur.Adım 5. Yorumlayıcı Yapı Modelinin Yönlendirilmiş Yazımının Model Değerlendirmesi ve GeliştirilmesiBu adımda, nihai ulaşılabilirlik matrisinden çıkarılan farklı düzeylerdeki değişkenler ile önceki adım arasındaki ilişkiler bir uzman paneli tarafından değerlendirilir. Bu şekilde, elde edilen ilişkiyi minimumdan maksimuma doğru bir etki ölçeğinde derecelendirmeleri istenir.Daha sonra, seviyelere, nihai ulaşılabilirlik matrisine, model değerlendirmesinin sonuçlarına ve başlangıç ​​modelindeki geçişliliğin ortadan kaldırılmasına dayalı olarak nihai model elde edilir [ 46 , 52 , 53 ]. 3.2. ANP YöntemiANP yöntemi, Çok Kriterli Karar Verme yöntemlerinden (MCDM) biri ve AHP yönteminin genelleştirilmiş halidir. Aslında, ANP yönteminde kriterler ve alt kriterler birbirine bağımlıdır, oysa AHP yöntemi bu bağımlılıkları desteklemez [ 54 , 55 , 56 , 57 ]. Kriterlerin veya alt kriterlerin dahili olarak ilişkili olduğu problemlerde, problem hiyerarşik değildir, bunun yerine bir ağ durumuna sahiptir. Bu durumda, problem ANP yöntemi ile çözülür [ 58 ]. Analitik ağ süreci, her karar vericinin ampirik bilgilerini veya kişisel yargılarını kullanarak doğru kararlar almak için kapsamlı ve güçlü bir yöntem sağlar. ANP'de, faktörler ve göstergeler bir kriter ağı oluşturur ve alt kriterler kümelerde gruplandırılır [ 59 ]. Kümeler ve alt kriterler arasındaki bağımlılıklar göz önüne alındığında, sistemin farklı bileşenleri arasındaki ilişkileri belirlemek önemlidir. Bu durumda, ISM'nin olumlu bir noktası bu ilişkileri belirlemesidir [ 18 , 60 ]. Eşleştirilmiş karşılaştırma matrisleri ve kriterlerin ağırlıkları, ANP'yi yapılandırdıktan ve elemanlar arasındaki ilişkileri belirledikten sonra elde edilir. Aşağıda, bu yöntemin adımları açıklanmaktadır.Adım 1. Model ve Ağ Diyagramının İnşasıANP'de, öğeler ve göstergeler, kümelerde birlikte gruplandırılmış bir kriter ve alt kriter ağıdır. Bu kriterler ve alt kriterler birbirleriyle ilişkili olduğundan, bu yöntemdeki önemli bir adım, sistemin çeşitli kriterleri ve alt kriterleri arasındaki ilişkileri belirlemektir. Bu ilişkiler, ISM gibi yöntemlerle tanımlanabilir.Adım 2. Eşleştirilmiş Karşılaştırma Matrisleri ve Göreceli Önemin TahminiHer kümenin üyeleri, kontrol kriterlerine göre önemlerine göre çiftler halinde karşılaştırılır. Ayrıca, her kümenin üyeleri arasındaki karşılıklı bağımlılıkların çiftler halinde karşılaştırılmasını yapmak gerekir. Saaty, çiftler halinde karşılaştırmalarda önem değerleri önermiştir [ 61 ]. Uzmanlar, görüşlerini çiftler halinde karşılaştırma matrislerinde uygularlar.Bu çalışmada, birden fazla karar vericinin yer aldığı anlamına gelen grup ANP modeli kullanılmıştır. Bu durumda, yanıt matrisleri birleştirilir ve ANP modeli birleştirilmiş matrise dayanarak uygulanır. Birleştirmeden önce, tutarlılık oranı her uzman tarafından sağlanan her eşleştirilmiş karşılaştırma matrisi için kabul edilebilir (<0,1) olmalıdır. Sonuç olarak, birleştirilmiş eşleştirilmiş karşılaştırma matrisi de <0,1'lik bir tutarlılık oranına sahip olacaktır. Ancak, tutarlılık oranı 0,1'i aşarsa, uzmanlardan soruları tekrar ve daha dikkatli bir şekilde cevaplamaları istenir. Yüksek düzeyde tutarsızlık, uzmanların görüşlerinde önceki görüşlerle çelişki olduğunu gösterir.Tutarlılık oranını hesaplamak için Denklem (2) kullanılır. 𝜆 𝑚 𝑎 𝑥 − 𝑛𝑛 − 1= 𝐶 𝐼λMAX−NN−1=CBEN<math display="block"><semantics> <mrow> <mfrac> <mrow> <mrow> <mi>λ</mi> <mi>m</mi> <mi>a</mi> <mi>x</mi> </mrow> <mo>−</mo> <mi>n</mi> </mrow> <mrow> <mi>n</mi> <mo>−</mo> <mn>1</mn> </mrow> </mfrac> <mo>=</mo> <mi>C</mi> <mi>I</mi> </mrow> </semantics></math> 𝐶 𝑅 =𝐶 𝐼𝑅 𝐼CR=CBENRBEN<math display="block"><semantics> <mrow> <mi>C</mi> <mi>R</mi> <mo>=</mo> <mfrac> <mrow> <mi>C</mi> <mi>I</mi> </mrow> <mrow> <mi>R</mi> <mi>I</mi> </mrow> </mfrac> </mrow> </semantics></math> (2) Burada CR tutarlılık oranıdır; CI tutarlılık endeksidir; RI rastgele endekstir;𝜆 𝑚𝑎𝑥λmaksimum<math display="inline"><semantics> <mrow> <mrow> <mi>λ</mi> <mi mathvariant="italic">max</mi> </mrow> </mrow> </semantics></math>matrisin en büyük özdeğeridir; ve n matriste karşılaştırılan faktör sayısıdır (matris boyutları).Daha sonra eşleştirilmiş karşılaştırma matrisleri geometrik ortalama yöntemi ile birleştirildi. Daha sonra, ağırlık vektörleri Saaty tarafından önerilen Özvektör yöntemi kullanılarak hesaplanır (Denklem (3)): 𝐴 𝑊= 𝜆𝑚 𝑎 𝑥𝑊AB= λMAXB<math display="block"><semantics> <mrow> <mi>A</mi> <mi>W</mi> <mo>=</mo> <msub> <mrow> <mrow> <mo> </mo> <mi>λ</mi> </mrow> </mrow> <mrow> <mi>m</mi> <mi>a</mi> <mi>x</mi> </mrow> </msub> <mi>W</mi> </mrow> </semantics></math> (3) NeresiBen 𝜆 𝑚 𝑎 𝑥λMAX<math display="inline"><semantics> <mrow> <mi>λ</mi> <mi>m</mi> <mi>a</mi> <mi>x</mi> </mrow> </semantics></math>matrisin en büyük özdeğeridir, A eşleştirilmiş karşılaştırma matrisini gösterir ve W normalleştirilmiş ağırlık vektörüdür, ∑𝑛𝑖 = 1𝑊= 1∑Ben=1NB=1<math display="block"><semantics> <mrow> <msubsup> <mstyle mathsize="120%" displaystyle="true"> <mo>∑</mo> </mstyle> <mrow> <mi>i</mi> <mo>=</mo> <mn>1</mn> </mrow> <mi>n</mi> </msubsup> <mi>W</mi> <mo>=</mo> <mn>1</mn> </mrow> </semantics></math> Adım 3. Ağırlıksız ve Ağırlıklı Süper MatrislerANP modelinin üçüncü adımında, önceki adımdan elde edilen ağırlıkların hepsi, ağırlıksız süpermatris olarak bilinen, problem yapısına dayalı bir matrise yerleştirilir. Süpermatris, tüm öncelikleri ve her bir bileşenin etkileşimde bulunduğu diğer bileşenler üzerindeki kümülatif etkisini hesaplamak için katsayıları sınırlayabilir. Süpermatris, kümelerin veya kümeler içindeki elemanların birbirleri üzerindeki etkilerini temsil etmek için kullanılır. Ağırlıksız süpermatrisin sütunları, birkaç özel vektörden oluşur ve her vektörün toplamı bire eşittir. Bu nedenle, her birincil veya ağırlıksız süpermatris sütununun toplamı birden fazla olabilir (her sütundaki belirli vektörlere karşılık gelir). Her matris sütunu, sütun elemanlarını, toplamı bir olması gereken göreli ağırlıklarına orantılı olarak faktörlemek için standartlaştırılmalıdır. Sonuç olarak, her sütunun toplamının bire eşit olduğu yeni bir matris elde edilir. Bu matrise ağırlıklı süpermatris denir.Adım 4. Sınır SüpermatrisiBir sonraki adımda, matris elemanları yakınsayana ve doğrusal değerleri eşit olana kadar süpermatris ağırlıklandırılır. Denklem (4)'e göre: 𝑊𝑙=sınır𝑛 → ∞𝑊𝑛Bben=sınırN→∞BN<math display="block"><semantics> <mrow> <msub> <mi>W</mi> <mi>l</mi> </msub> <mo>=</mo> <munder> <mrow> <mi>lim</mi> </mrow> <mrow> <mi>n</mi> <mo>→</mo> <mo>∞</mo> </mrow> </munder> <msup> <mi>W</mi> <mi>n</mi> </msup> </mrow> </semantics></math> (4) 𝑊𝑙Bben<math display="inline"><semantics> <mrow> <msub> <mi>W</mi> <mi>l</mi> </msub> </mrow> </semantics></math>her satırda bir sayı bulunan limit süper matrisidir. Bu sayılar göstergelerin ağırlığını gösterir [ 55 , 59 , 62 , 63 , 64 ]. 3.3. AHP YöntemiAHP, karmaşık karar problemlerini hiyerarşik bir şekilde çözen bir Karar Verme yöntemidir. Bunun için, bir grup uzman tarafından yapılan yargılara dayanır. AHP yöntemi, kriterlerin bağımsız olduğu ve eşleştirilmiş karşılaştırmaların, kriterlerin iç ilişkilerini dikkate almadan ağırlıklarını belirlediği ağ tekniğinin belirli bir örneğidir. Aşağıda, bu yöntemin adımları açıklanmaktadır.Adım 1. Hiyerarşik Diyagramın OluşturulmasıAraştırmanın kriterlerine göre hiyerarşik bir yapı oluşturulur.Adım 2. Eşleştirilmiş Karşılaştırma Matrislerinin Oluşturulması ve Tutarlılık Oranının HesaplanmasıBu adımda, kriterler uzmanlar tarafından çiftler halinde karşılaştırılır ve eşleştirilmiş karşılaştırma matrisleri oluşturulur. Ek olarak, her eşleştirilmiş karşılaştırma matrisi için tutarlılık oranı Denklem (2) kullanılarak kontrol edilir.Adım 3. Kriterlerin ağırlığının hesaplanmasıKriterlerin ağırlığını hesaplamak için farklı yöntemler önerilmiştir. Bu araştırmada, Denklem (3)'te verilen en yaygın kullanılanlardan biri kullanılmıştır [ 55 , 57 , 64 ].

      1. ISM ile İlişkilerin Tanımlanması: ISM, sistemin bileşenleri arasındaki ilişkileri tanımlar ve bu ilişkileri bir matris formunda ifade eder. Bu, hangi bileşenlerin diğerlerini etkilediğini ve bu etkilerin yönünü belirlemeye yardımcı olur. 2. AHP ile Başlangıç: İlk olarak, karar problemi AHP kullanılarak hiyerarşik bir yapıya dönüştürülür. Bu aşamada, karar kriterleri ve alt kriterler belirlenir ve bunlar arasında çiftler halinde karşılaştırmalar yapılarak öncelikler belirlenir. 3. ANP ile Genişletme: ANP, AHP'nin hiyerarşik yapısına ek olarak, kriterler ve alt kriterler arasındaki karşılıklı bağımlılıkları ve geri bildirim döngülerini de dikkate alır. Bu, daha karmaşık karar problemlerinde, elemanlar arasındaki etkileşimlerin daha iyi anlaşılmasını sağlar. 4. Süpermatris Kullanımı: ANP, elemanlar arasındaki ilişkileri ve öncelikleri belirlemek için bir süpermatris kullanır. Bu matris, elemanlar arasındaki tüm etkileşimleri ve öncelikleri içerir ve bu sayede karar verme sürecinde daha bütüncül bir yaklaşım sunar.

      Metodoloji
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  14. www.academia.edu www.academia.edu
    La ceguera de género en las encuestas mexicanas sobre discriminación hacia a las personas inmigrantes
    14
    1. galaelizarraras 30 Oct 2024
      las mujeres repre- sentan 44% de las inmigrantes con residencia temporal,

      No me sorprende en lo absoluto pues es importante recordar que las mujeres no solo migran por la violencia de estado, las dictaduras o el narcoestado, sino, también, por la violencia específica hacia las mujeres por esto mismo así como elementos cercanos como sectores familiares: la violencia feminicida y sexual. Las mujeres no solo son perseguidas por grupos violentos, el hambre, los desastres naturales, etcétera. Sino también que corren por su vida por los peligros que las atormentan como el miedo de ser violadas, tratadas, torturadas sexualmente, etcétera.

    2. galaelizarraras 30 Oct 2024
      hoy México es un país de destino obligado. Las mujeres que transitaron por nuestro país, y ahora permanecen en territorio mexicano, confor- man casi la mitad de los flujos inmigratorios

      La población y las acciones casi siempre han sido conformadas en su gran parte por las mujeres: me refiero a las poblaciones, a los actos migratorios, etcétera. Pero siempre se habla como si la mayoría fuera la masculina o simplemente, como ya vimos anteriormente, la única vivencia fuera la de dicho sector. Pero lo tenemos claro en las estadísticas: no podemos seguir ignorando algo, ni porque parezca mínimo. Menos cuando supone casi el mismo porcentaje.

    3. Jesspao 30 Oct 2024
      esta ceguera al género, tal vez comprensible en las encuestas levantadas para difusión y divulgación periodística, está también presente en las mediciones reali- zadas por instituciones académicas que se utilizan para investigaciones científicas y para el diseño de política pública. Me refiero puntualmente a la Encuesta Nacional de Migración (ENM), de la colección “Los mexicanos vistos por sí mismos; los gran- des temas nacionales” elaborada por el Instituto de Investigaciones Jurídicas de la Universidad Nacional Autónoma de México (UNAM) en 2014 y la Encuesta Nacional México, Las Américas y el Mundo (LAYEM), implementada por el Centro de Investi- gación y Docencia Económicas (CIDE) en 2018 y 2019. La ENM es una encuesta pionera en el estudio de las actitudes sociales frente a la inmigración internacional. En su cuestionario arroja resultados ricos para eva- luar las percepciones que tiene la sociedad mexicana sobre la población extranjera y los derechos a los cuales deben o no tener acceso. Sin embargo, esta encuesta retrata a las pesonas inmigrantes como un grupo homogéneo y el origen nacional es la única categoría que ofrece datos diferenciados. El cuestionario de la ENM utiliza en todas sus preguntas el supuesto neutro masculino: “los extranjeros”, por lo que, de nueva cuenta, es imposible analizar la variación de las respuestas en función del género.

      La ceguera de género en las encuestas académicas tiene consecuencias profundas en la calidad de la investigación y en la formulación de políticas públicas. me pareció interesante porque al no considerar las diferencias de género, las investigaciones pueden perpetuar estereotipos y crear políticas que no abordan adecuadamente las necesidades de las mujeres migrantes. considero que es problemático en un contexto donde las mujeres migrantes pueden enfrentar formas específicas de discriminación y violencia que no son capturadas en un análisis que no diferencia por género. y la falta de datos desagregados por género limita la capacidad de los investigadores y responsables de políticas para diseñar intervenciones efectivas y equitativas

    4. Jesspao 30 Oct 2024
      De los muchos mitos que existen respecto a México y su sociedad, quizá dos de los más perversos son que el racismo no existe y que somos un país de puertas abiertas frente a la inmigración extranjera. Estas falsas creencias, enraizadas profundamente en la opinión popular, derivan en una falta de curiosidad institucional por implemen- tar mecanismos para medir la discriminación y la xenofobia en la opinión pública mexicana. En consecuencia, en contraste con otros países, en los que las encuestas sobre actitudes de discriminación tienen una larga data acumulada, la implementa- ción de este tipo de encuestas en México no tiene más de quince años (Álvarez Icaza Longoria, 2018). El debate alrededor de la efectividad de la encuesta como instrumento para conocer y medir las actitudes sociales de discriminación es amplio. Metodológica- mente, se ha cuestionado su capacidad para mitigar el sesgo de deseabilidad social, es decir las respuestas guiadas por el deber ser y la pretención de corrección política en la persona entrevistada que no acepta públicamente tener actitudes discrimina- torias. Este sesgo, también llamado de cortesía, resulta en un problema estadístico de no respuesta o en la selección de aciertos neutros o equivocados (D ́Ancona & Martínez, 2010; D’Ancona, 2002; Olmos Alcaraz & Martín Godoy, 2020). Este breve texto no pretende hacer una crítica metodológica a las encuestas como instrumento de medición para la xenofobia y el racismo, pues se reconoce que a pesar de sus limitaciones, las encuestas son un instrumento poderoso para anali- zar las tendencias en la opinión pública por sus resultados representativos a gran escala. Esta nota busca, desde una epistemología feminista, señalar la deficiencia que han tenido las recientes encuestas sobre discriminación en México, particular- mente aquéllas que miden las actitudes hacia a las personas migrantes, que al no incorporar una perspectiva de género en los cuestionarios, retratan una realidad equivocada: la de un país al que sólo llegan y por el que sólo transita una migración masculina.

      para mi la representación de la migración a través de imágenes y narrativas predominantemente masculinas contribuye a una percepción social que ignora la realidad de las mujeres migrantes. Esta masculinización de la narrativa migratoria no solo afecta la visibilidad de las mujeres, sino que también influye en la opinión pública y en la forma en que se perciben las políticas migratorias. La falta de representación puede llevar a la desinformación y a la perpetuación de mitos sobre la migración, lo que a su vez puede afectar la empatía y el apoyo hacia las mujeres migrantes

    5. Jesspao 30 Oct 2024
      Ante este panorama sin precedentes, las empresas encuestadoras nacionales levantaron sondeos para conocer la opinión pública de la sociedad mexicana frente a la inmigración extranjera, principalmente, la centroamericana. Como nunca antes, aparecieron publicadas en periódicos encuestas que reflejaban las posturas a favor o en contra de que el gobierno mexicano recibiera estos flujos, les otorgara refugio, los deportara a sus países de origen, les ofreciera empleo o los dejara transitar li- bremente (Consulta Mitofsky, 2020; El Universal, 2018; Moreno, 2019; Parametría, 2019). La riqueza analítica de estas publicaciones es incuestionable. Nos proporcio- naron a quienes estudiamos la migración y la xenofobia una oportunidad gratuita de conocer las opiniones respecto a la inmigración en nuestro país. Sin embargo, estas encuestas, como otras que implementan universidades —sobre las que se detallará más adelante—, presentan una ceguera de género por la que no sólo exploran, sino que también reproducen una realidad migratoria androcéntrica y por tanto, equivo- cada. Estas encuestas masivas, en primera instancia, utilizan el supuesto neutro masculino en las preguntas: “hondureños” “indocumentados” “los migrantes”. Este diseño de cuestionario ciego al género da por sentado que quien responde las pre- guntas incluye en su evaluación opiniones respecto a la migración tanto masculina como femenina. Pero en un país en el que la migración femenina ha permanecido casi invisible en el imaginario social, difícilmente el neutro masculino detona las apreciaciones respecto a las mujeres. En segundo lugar, los cuestionarios no diferen- cian entre percepciones sobre los migrantes y las migrantes, por lo cual imposibilita una comprensión interseccional entre categorías de migración y género.

      La utilización del neutro masculino en las encuestas refleja una tendencia común en la investigación social que ignora las especificidades de género. Al asumir que las opiniones sobre "los migrantes" abarcan tanto a hombres como a mujeres, se pierde la oportunidad de captar las diferencias significativas en las experiencias, desafíos y percepciones que enfrentan las mujeres en el contexto migratorio. Esto puede llevar a una representación distorsionada de la realidad migratoria, donde las voces y necesidades de las mujeres quedan relegadas.

    6. galaelizarraras 30 Oct 2024
      La imagen del tren, conocido como la Bestia, transportando en su lomo a cientos de migrantes que recorren el territorio mexicano es quiza la asociación inmediata que tiene la sociedad mexicana sobre la transmigración centroamericana. Esta imagen, reforzada por las fotografías en la prensa de hombres migrantes en los albergues y en las estancias migratorias del Instituto Nacional de Migración (INM), refuerza la masculinización de la narrativa migrante en el territorio mexicano, y re lega a la migración femenina a un rol secundario, casi invisible.

      Estamos acostumbrados a que las historias se cuenten desde la vivencia masculina nada más y no lo cuestionamos ni por un segundo. Entonces, a partir de esto, pensamos que generalizamos y que nuestra idea de lo que sucede y ha sucedido a lo largo de la historia es simultáneo y aplicable tanto para hombres como para mujeres que comparten situación. Pero la verdad es que no lo es, porque no comparten situación ni se asemejan, pues sus razones, vivencias, violencias y obstáculos son completamente distintos (debido a una naturalización de lo social: el género. Que entonces define y condiciona el sexo a experiencias y situaciones específicas que terminan en la violencia de género como la violencia sexual específicamente a las mujeres o personas gestantes por tener capacidad reproductora y verlas como un mecanismo de creación y reproducción social y/o ser vistas y entendidas como (contenedores) a la sexualidad y el aparato reproductor masculino) empezando por la violencia sistematizada hacia el sector en cuestión (las mujeres). Esto quiere decir que la historia ha ignorado y olvidado a millones de víctimas y supervivientes.

    7. Ximena_Navidad 30 Oct 2024
      Como nunca antes, aparecieron publicadas en periódicos encuestas que reflejaban las posturas a favor o en contra de que el gobierno mexicano recibiera estos flujos, les otorgara refugio, los deportara a sus países de origen, les ofreciera empleo o los dejara transitar li- bremente

      Es importante el notar el impacto que puede tener este tipo de estudios y sus resultados en la sociedad, pues es posible que al ver los números proporcionados por las encuestas, algunas personas reflexionen con mayor profundidad sobre su postura e incluso la cambien, lo que abre un panorama más flexible hacia este tipo de temas.

    8. Jehoshua19 30 Oct 2024
      Pero en un país en el que la migración femenina ha permanecido casi invisible en el imaginario social, difícilmente el neutro masculino detona las apreciaciones respecto a las mujeres.

      Me parece pertinente reiterar que en los últimos años el fenómeno migratorio en el país ha aumentado considerablemente. Siendo innecesario realizar estudios o conteos debido a que los cambios son observables casi en todo el país y por casi cualquier persona. Además, como ya he mencionado, la proporción de hombres y mujeres migrantes en el país es casi equitativa. Considero que los autores deben realizar un análisis tomando en cuenta las estadísticas migratorias más recientes y en base a ellas, solicitar una nueva realización de encuestas.

    9. Jehoshua19 30 Oct 2024
      La imagen del tren, conocido como la Bestia, transportando en su lomo a cientos de migrantes que recorren el territorio mexicano es quiza la asociación inmediata que tiene la sociedad mexicana sobre la transmigración centroamericana. Esta imagen, reforzada por las fotografías en la prensa de hombres migrantes en los albergues y en las estancias migratorias del Instituto Nacional de Migración (INM), refuerza la masculinización de la narrativa migrante en el territorio mexicano, y re lega a la migración femenina a un rol secundario, casi invisible.

      si bien es cierto que la imagen del tren La Bestia es quizás el ejemplo más difundido de migración en el país, hoy en día no considero que el movimiento presente una hipermasculinización. En los últimos años, es posible observar migrantes de ambos géneros por igual en las calles, ya sea pidiendo dinero para continuar su travesía o buscando trabajo e insertarse a la sociedad. Me parece que a pesar de que los medios de comunicación aún reflejen una tendencia a la masculinización de este fenómeno, la realidad apreciable para la mayoría de mexicanos es distinta.

    10. miguel.ramirezr 29 Oct 2024

      Ignorar la ceguera de género en la investigación puede tener repercusiones significativas en la formulación de políticas públicas. Las medidas que no consideran las diferencias de género pueden ser ineficaces o incluso perjudiciales, perpetuando desigualdades existentes.

    11. sandy_perez 29 Oct 2024
      una falta de curiosidad institucional por implemen- tar mecanismos para medir la discriminación y la xenofobia en la opinión pública mexicana.

      La ciudadanía mexicana siempre considera que son la victima; sin embargo, la discriminación y la xenofobia siempre ha estado presente. Como sociedad, no podemos imaginar a personas con un color diferente de piel, independientemente si es más clara o más oscura, o el simple hecho de que vienen de un país diferente y se ponen prejuicios. Siempre se tiende a marginar a aquellos que son diferentes

    12. arantzacarmona 28 Oct 2024

      "Este sesgo, también llamado de cortesía, resulta en un problema estadístico de no respuesta o en la selección de aciertos neutros o equivocados." Comentario: Es fundamental abordar el fenómeno "cortesía" para garantizar encuestas realistas. Para lograr esto, es fundamental implementar métodos que fomenten honestidad y generen confianza, lo que hará que la encuesta sea efectiva.

    13. lianderodas 27 Oct 2024
      La ENM es una encuesta pionera en el estudio de las actitudes sociales frente a la inmigración internacional. En su cuestionario arroja resultados ricos para eva- luar las percepciones que tiene la sociedad mexicana sobre la población extranjera y los derechos a los cuales deben o no tener acceso. Sin embargo, esta encuesta retrata a las pesonas inmigrantes como un grupo homogéneo y el origen nacional es la única categoría que ofrece datos diferenciados. El cuestionario de la ENM utiliza en todas sus preguntas el supuesto neutro masculino: “los extranjeros”, por lo que, de nueva cuenta, es imposible analizar la variación de las respuestas en función del género.

      La encuesta de la ENM ayuda a embarcar tanto a la sociedad mexicana como la migrante en torno a su situación y lo que piensan al respecto de la problemática de dejar su hogar y por temas de violencia, inseguridad e incluso movilidad forzada deben irse a otras regiones o cruzar todo México para buscar una mejor vida arriesgando todo.

    14. lianderodas 27 Oct 2024
      La imagen del tren, conocido como la Bestia, transportando en su lomo a cientos de migrantes que recorren el territorio mexicano es quiza la asociación inmediata que tiene la sociedad mexicana sobre la transmigración centroamericana. Esta imagen, reforzada por las fotografías en la prensa de hombres migrantes en los albergues y en las estancias migratorias del Instituto Nacional de Migración (INM), refuerza la masculinización de la narrativa migrante en el territorio mexicano, y re lega a la migración femenina a un rol secundario, casi invisible

      La bestia refleja una falta de empatía, recursos e importancia sobre los migrantes que básicamente arriesgan todo con poder cruzar al otro lado y recibir el mismo o incluso un peor trato de sus vecinos. Es decepcionante que los Estados Unidos no tengan el mínimo trato de apoyar a los migrantes solo porque nos consideran delincuentes, drogadictos y violadores sólo guiados por la narrativa que llevan los medios.

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  15. drive.google.com drive.google.com
    Title
    5
    1. JosueCisneros 30 Oct 2024
      La ciencia necesita comparar y el cálculo del error nos ayuda a comprar entre variosmodelos, para saber qué tan lejos o cerca es el resultado con el valor real o esperado.

      es importante saber o conocer los diversos factores que pueden modificar las mediciones.

    2. paola21222 26 Oct 2024
      El mejor ajuste también conocido como línea de tendencia o best fit, ayuda a analizarlos datos en una gráfica de dispersión. Para analizar los datos hay varias técnicas muypoderosas para encontrar el mejor ajuste, es decir, el modelo matemático que describe elcomportamiento de los datos

      importante saber que es el mejor ajuste porque como lo hemos visto en clases este nos es de demasiada utilidad

    3. paola21222 26 Oct 2024
      ablas: las tablas de datos y aplicar el método de Mínimos cuadrados, el cual es unmétodo general. El método de los mínimos cuadrados de una ecuación lineal ayudaa calcular el mejor ajuste de una línea recta a partir de los datos, sin necesidad degraficarlos.Gráficas: la gráfica por medio de la línea de tendencia o también llamada regresión.Para el caso de una línea recta, se le llama regresión lineal.

      complementa lo anterior del mejor ajuste ya que son datos necesarios para el mejor ajuste y como dice en la parte de indicadores nos ayuda a saber que tan bueno o no es el mejor ajuste

    4. paola21222 26 Oct 2024
      Evaluando el mejor ajuste

      nos da los datos necesarios para saber si el mejor ajuste es bueno o no dando también otros datos como la desviación absoluta máxima, desviación estándar, residual, coeficiente de Pearson que esta es algo nuevo que aprendí, coeficiente de correlación y la chi cuadrada

    5. paola21222 26 Oct 2024
      Error cuadrático medio (RMSE) o error de la raíz de la desviación cuadráticamedia

      esta es una formula nueva para min aunque queda claro en el texto al final menciona que su único problema es que se espera que el resultado sea un valor pequeño pero por la ambigüedad de no saber que tan pequeño ocasiona ese problema

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  16. jitc.bmj.com jitc.bmj.com
    Ten challenges and opportunities in computational immuno-oncology
    1
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  17. www.planalto.gov.br www.planalto.gov.br
    Del3689Compilado
    1
    1. carolinecaldas89 29 Oct 2024
      O defensor não poderá abandonar o processo sem justo motivo, previamente comunicado ao juiz, sob pena de responder por infração disciplinar perante o órgão correicional competente

      existia divergência se a conduta configuraria abandono processual

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  18. doc-0c-1g-prod-01-apps-viewer.googleusercontent.com doc-0c-1g-prod-01-apps-viewer.googleusercontent.com
    Masters of sociological thought : ideas in historical and social context
    1
    1. AnGordon24301 29 Oct 2024
      o in imagination weperceive in another's mind some thought of our appearance, manners, aims,deeds, character, friends, and so on, and are variously affected by i

      every opinion we form about who we are is based in how we believe we are percieved.

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  19. openurl.ebsco.com openurl.ebsco.com
    Perspectives on Access and Equity in the Era of (Community) College Completion.
    1
    1. geonz 29 Oct 2024
      y low. Of students who take two or more develop-mental courses, only 20% complete a ba

      "enroll large numbers o students who need develomental education" --- at least they use the word need!!!

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  20. touro.app.box.com touro.app.box.com
    Alpert et al. - 2017 - What Lesbian, Gay, Bisexual, Transgender, Queer, a.pdf | Powered by Box
    1
    1. kokamuro 29 Oct 2024
      [Providers] keep that distance like you’re not supposed to touchthe body. You’re taking care of my body, but you really don’t want to look at my body.”RU1 expressed her feelings about provider discomfort this way. “I shouldn’t ever have tofeel like my partners or sex life makes you feel icky.” These negative experiences wereperceived to exacerbate mistrust of the medical system. O

      I can imagine how something like this would only exacerbate gender dysphoria.

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  21. chiselapp.com chiselapp.com
    Heteroevaluación
    4
    1. offray 29 Oct 2024
      no le encuentro todavía la aplicabilidad en la vida personal, siento que se pueden generar espacios de co-creación con el objetivo de siempre buscar el “bien de la humanidad.”

      Como veíamos en el video de Clay Shirky, el asunto es que, precisamente, saberes como los que vemos en clase están lejos del cotidiano de la mayoría de las personas, lo cual tiene afecciones respecto a la democracia, el ejercicio de los mecanismos de expresión y la vigilancia de lo común y lo público.

      La universidad como espacio, nos permite acceder a conocimientos que no circulan en el cotidiano (ecuaciones diferenciales, modelación de sistemas complejos, ontologías, etc.) y esa es una de sus funciones principales. La pregunta sería más bien qué tipo de cotidiano queremos transformar y cómo estos saberes tienen (o no) el potencial para hacerlo.

      heteroevaluación
    2. offray 17 Oct 2024
      interiorizar el conocimiento me parece complejo, (aunque considero que esto es algo más personal). Por último, el ritmo de clase,, en ocasiones resulta acelerado lo que impide la buena interiorización del conocimiento.

      La metacognición es aquel proceso que nos permite saber cómo sabemos lo que sabemos. La invitación sería a usar metacognición para indagar por esos procesos de interiorización y sus complejidades

      • ¿Cuándo dirías que un conocimiento se encuentra plenamente interiorizado y cuánto tiempo requiere esto? ¿Cómo y cuántas de las horas de trabajo autónomo asignadas a una materia con esta cantidad de créditos están siendo aplicadas?
        • ¿Hay algún registro o bitácora que permita ver esos avances, aparte de los mecanismo de publicación ofrecidos en clase?
        • En un mundo de constante interrupción a través del celular y el computador, ¿cómo mantenemos a raya esas distracciones para, efectivamente, podernos concentrar en procesos que requieren dicha interiorización?
      • ¿Dónde radican las dificultades que te impiden esa interiorización?

      Respecto a los ritmos de la clase, estos presumen ese trabajo previo de, no más de 8 horas autónomas. ¿Se pueden invertir ese máximo de horas semanales y por qué sí o no? Si se piensa en esa cantidad de horas de trabajo autónomo, aún así el ritmo de la clase iría rápido? ¿Qué otras mediaciones (documentación, videos, software, etc) podemos cocrear para ayudar esa parte autónoma y mejorar los ritmos?

      heteroevaluación
    3. offray 17 Oct 2024
      Evaluación de programas o herramientas de empleo: este punto puede ayudar al profesor o a los demás estudiantes herramientas que aporten al mejor desarrollo de las habilidades esperadas en el curso.

      Interesante. ¿Colocarías documentación sobre estas herramientas en tu propio repositorio?

      heteroevaluación herramientas
    4. offray 17 Oct 2024
      Trabajo en equipo: si bien las habilidades a desarrollar propuestas por el profesor son interiorizadas por los estudiantes a su propio ritmo, integrar espacios de trabajo en equipo en donde se puedan compartir las habilidades entre todos. análisis de conocimiento en ambientes diferentes a la tecnología: Identificar como los temas desarollados se pueden emplear o se relacionan en otras áreas de conocimiento. Revisión de pares: Revisar un poco los pares del área para evaluar que se puede implementar en un ambiente académico.

      Todas estas son excelentes alternativas para el trabajo entre pares y aútónomo. ¿Cómo se dejaría huella/registro de esto que se haga y cómo se compartiría con el resto de la clase, incluyendo al profesor?

      heteroevaluación trabajo aútonomo
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  22. www.zhihu.com www.zhihu.com
    (1 封私信 / 14 条消息) Cyandev - 知乎
    1
    1. amagi 29 Oct 2024
      把 Rust 当作（伪）脚本用。这是我从飞书 ffmpeg 的绑定库里看到的：#!/bin/sh #![allow(unused_attributes)] /* OUT=/tmp/tmp && rustc "$0" -o ${OUT} && exec ${OUT} $@ || exit $? #*/ use std::process::Command; use std::io::Result; use std::path::PathBuf; use std::fs; fn mkdir(dir_name: &str) -> Result<()> { fs::create_dir(dir_name) } fn main() { // 省略 } 重点是前三行。写的很巧妙，既是合法的 rust 语法，又是合法的 shell 语法。第一行 shebang 指定了用 sh 执行该脚本，而 rustc 本身也会忽略 shebang 行，没啥好说的。第二行声明了 rust 的一个内部属性，因为语法是 # 开头，所以刚好也是 shell 语法的注释行。结尾用了 rust 的多行注释，完全忽略第三行。而 shell 免疫 rust 的多行注释，所以第三行正常执行。其实就是用 rustc 编译当前文件到二进制程序再执行并退出。剩下的部分就是 rust 的逻辑了。

      我吃

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  23. www.genbeta.com www.genbeta.com
    35 comandos imprescindibles del CMD de Windows
    1
    1. ValerZa 28 Oct 2024
      Comandos para gestionar y acceder a archivos: Cd: Mueve entre carpetas. Dir:: Lista el contenido de un directorio. Copy: Copia archivos. Robocopy: Versión mejorada del comando anterior (sincroniza directorios, funciona en segundo plano y puede reintentar automáticamente copias fallidas). Move: Mueve archivos. Del: Elimina archivos o contenido de carpetas. Rename : Renombra archivos. Format: Formatea una unidad de disco. Md: Crea carpetas. Tree: Muestra el árbol de directorios. Fc: Compara dos archivos o conjuntos

      3

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  24. www.youtube.com www.youtube.com
    2024-10-14 NeoBooks Call
    2
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  25. www.biorxiv.org www.biorxiv.org
    Cestode larvae excite host neuronal circuits via glutamatergic signaling
    2
    1. Public_Reviews 28 Oct 2024

      Reviewer #3 (Public review):

      This paper has high significance because it addresses a prevalent parasitic infection of the nervous system, Neurocysticercosis (NCC). The infection is caused by larvae of the parasitic cestode Taenia solium It is a leading cause of epilepsy in adults worldwide

      To address the effects of cestode larvae, homogenates and excretory/secretory products of larvae were added to organotypic brain slice cultures of rodents or layer 2/3 of human cortical brain slices from patients with refractory epilepsy.

      A self-made pressure ejection system was used to puff larvae homogenate (20 ms puff) onto the soma of patched neurons. The mechanical force could have caused depolarizaton so a vehicle control is critical. On line 150 they appear to have used saline in this regard, and clarification would be good. Were the controls here (and aCSF elsewhere) done with the low Mg2+o aCSF like the larvae homogenates?

      They found that neurons depolarized after larvae homogenate exposure and the effect was mediated by glutamate but not nicotinic receptors for acetylcholine (nAChRs), acid-sensing channels or substance P.

      They also showed the elevated K+ in the homogenate (~11 mM) could not account for the depolarization. They also confirmed that only small molecules led to the depolarization after filtering out very large molecules. That supports the conclusion that glutamate - which is quite small - could be responsible.

      They suggest the effects could underlie seizure generation in NCC.

      Using Glutamate-sensing fluorescent reporters they found the larvae contain glutamate and can release it, a strength of the paper.

      Review 3
    2. Public_Reviews 28 Oct 2024

      Author response:

      The following is the authors’ response to the original reviews.

      Public Reviews:

      Reviewer #1 (Public Review):

      In the manuscript, the authors explore the mechanism by which Taenia solium larvae may contribute to human epilepsy. This is extremely important question to address because T. solium is a significant cause of epilepsy and is extremely understudied. Advances in determining how T. solium may contribute to epilepsy could have significant impact on this form of epilepsy. Excitingly, the authors convincingly show that Taenia larvae contain and release glutamate sufficient to depolarize neurons and induce recurrent excitation reminiscent of seizures. They use a combination of cutting-edge tools including electrophysiology, calcium and glutamate imaging, and biochemical approaches to demonstrate this important advance. They also show that this occurs in neurons from both mice and humans. This is relevant for pathophysiology of chronic epilepsy development. This study does not rule out other aspects of T. solium that may also contribute to epilepsy, including immunological aspects, but demonstrates a clear potential role for glutamate.

      Strengths:

      - The authors examine not only T. solium homogenate, but also excretory/secretory products which suggests glutamate may play a role in multiple aspects of disease progression.

      - The authors confirm that the human relevant pathogen also causes neuronal depolarization in human brain tissue

      - There is very high clinical relevance. Preventing epileptogenesis/seizures possibly with Glu-R antagonists or by more actively removing glutamate as a second possible treatment approach in addition to/replacing post-infection immune response.

      - Effects are consistent across multiple species (rat, mouse, human) and methodological assays (GluSnFR AND current clamp recordings AND Ca imaging)

      - High K content (comparable levels to high-K seizure models) of larvae could have also caused depolarization. Adequate experiments to exclude K and other suspected larvae contents (i.e. Substance P).

      Weaknesses:

      - Acute study is limited to studying depolarization in slices and it is unclear what is necessary/sufficient for in vivo seizure generation or epileptogenesis for chronic epilepsy. - There is likely a significant role of the immune system that is not explored here. This issue is adequately addressed in the discussion, however, and the glutamate data is considered in this context.

      Discuss impact:

      - Interfering with peri-larval glutamate signaling may hold promise to prevent ictogenesis and chronic epileptogenesis as this is a very understudied cause of epilepsy with unknown mechanistic etiology.

      Additional context for interpreting significance:

      - High medical need as most common adult onset epilepsy in many parts of the world

      We thank Reviewer 1 for their positive and thorough assessment of our manuscript. We have elected to respond to and address the following aspects from their “Recommendations For The Authors” below:

      Reviewer #1 (Recommendations For The Authors):

      Additional experiments/analysis:

      -   Fig 4a-c: Larva on a slice and not next to it? Negative results maybe because its E/S products are just washed away (assuming submerged recording chamber/conditions)? Experiments and negative results described here do not seem conclusive. Should be discussed at least?

      We agree with the reviewer and have added the following sentence to the relevant section of the Results: ‘Our submerged recording setup might have led to swift diffusion or washout of released glutamate, possibly explaining the lack of observable changes.’

      Writing & presentation:

      - Data is not always reported consistently in text and figures, examples:

      - Results in text are reported varyingly without explanation:

      - Mean and/or median? SEM or SD and/or IQR? Stat info included in text or not? i.e. lines 130/131 vs. 160/161

      Results and data are now presented in a more uniform fashion. We report medians and IQRs, sample size, statistical test result, statistical test used in that order.

      - Larval release data interrupts reading flow, lines 246-252 double up results presented in Fig 5F.

      This section has now been significantly abbreviated and reads as follows: ‘T. crassiceps larvae released a relatively constant median daily amount of glutamate, ranging from 41.59 – 60.15 ug/20 larvae, which showed no statistically significant difference across days one to six. Similarly, T. crassiceps larvae released a relatively constant median daily amount of aspartate, ranging from 9.431 – 14.18 ug/20 larvae, which showed no statistically significant difference across days one to six.’

      - Results in figures are reported in different styles:

      Results have now been made uniform, reporting medians and IQRs and: sample size, p test result, statistical test used, figure # reported in that order.

      - Fig 6: E/S glu concentration seems to be significantly higher in solium vs crassiceps (about 6fold higher in solium). Should be discussed at least.

      Given the small sample size from T. solium (see response below), we do not draw attention to this difference and instead simply make the point that T. solium larvae contain and release glutamate.

      - In this context - N=1 may be sufficient for proof of principle (release) but seems too small of a cohort to describe non-constant release of glu over days (Fig 6D). Is initial release on day 1, no release and recovery in the following days reproducible? Is very high glu content of E/S content (15-fold higher in comparison to solium homogenate AND 6-fold higher in comparison to crassiceps homogenate and E/S content). Not sure if Fig 6D is adding relevant information, especially since it is based on n = 1

      We agree that a N=1 is only sufficient for proof of principle. However it is worth noting that the measurements still reflect the cumulative release from 20 larvae. Nonetheless, the statement in text has been simplified to say: ‘These results demonstrate that T. solium larvae continually release glutamate and aspartate into their immediate surroundings.’ As this focusses on the point that the larvae release glutamate and aspartate continuously and that we can’t draw conclusions about the variability over days.

      Methods:

      - Human slices, mention cortex - what part, patient data would be interesting. I.e. etiology of epilepsy, epilepsy duration 

      In the Materials and Methods section “Brain slice preparation” we have now added a table with the requested information.

      - For Taenia solium: How were they acquired and used in these experiments?

      In the Materials and Methods section “Taenia maintenance and preparation of whole cyst homogenates and E/S products” we describe how Taenia solium larvae were acquired and used.

      - Was access resistance monitored? Add exclusion criteria for patch experiments

      Figure supplement tables containing the basic properties for each cell recording have been added for each figure and the following statements were added to the electrophysiology section of the Methods: ‘Basic properties of each cell were recorded (supplementary files 1, 2, 3, 4, 6).’ and ‘Cells were excluded from analyses if the Ra was greater than 80 Ω or if the resting membrane potential was above –40 mV.’  

      - Cannot see any reference to mouse slices in methods? Also, mouse organotypic cultures (for AAV?)? Or only acute slices from mice and organotypic hip cultures from rats? Seems to have been mouse and rat organotypic cultures? But not clear with further clarification in methods.

      We have now added the following clarification to the methods: ‘For experiments using calcium and glutamate imaging mouse hippocampal organotypic brain slices were used. For all other experiments rat hippocampal organotypic brain slices were used. A subset of experiments used acute human cortical brain slices and are specified.’

      - How long after the wash-in phase was the wash-out phase data collected?

      For wash-in recordings drugs were washed in for 8 mins before recordings were made. Drugs were washed out for at least 8 mins before wash-out recordings were made. This information has been added to the Materials and Methods section.

      - In general, the M&M section seems to have been written hastily - author's internal remarks "supplier?" are still present.

      The M&M section has been thoroughly proofread for errors and internal remarks removed or corrected.

      - A little more information on the clinical subjects would be appreciated. I.e. duration of epilepsy? Localization? What cortex? Usual temporal lobe or other regions?

      We have now added a table with this information to the Materials and Methods section “Brain slice preparation”.

      Minor corrections text/figures:

      - i.e. 3D,F,H,J show individual data points, thats great, but maybe add mean/median marker (as results are reported like this in text)  like in fig 4G,I and others

      Figures 3D,F,H & J have been revised to include median and IQR.

      - Only one patient mentioned in acknowledgements, but 2 in methods and text

      We apologize for this oversight and now acknowledge both patients in the acknowledgements.

      - Fig 1 B-F individual puffs are described as increasing - consistent with cellular effects (1st puff depolarizes, 2nd puff elicits 1 AP, 3rd puff elicits AP burst)  However, dilution ratio of homogenate or puff concentrations are not mentioned (or potentially longer than 20 ms puffs for 2nd and 3rd stimulus?) in text or figures. Seems to be enough space to indicate in figure as well (i.e. multiple or thicker arrows for subsequent puffs or label with homogenate dilution/concentration in figure).

      We state in the results section associated with Fig. 1 that increasing the amount of homogenate delivered was achieved by increasing the pressure applied to the ejection system. We now include this information in the figure legend.

      - Figure legend describes 30 ms puff for Ca imaging whereas ephys data (from text) is 20 ms puff. Was Ca imaging performed in acute mouse hippocampal slices (as figure text suggests) or were those organotypic hippocampal cultures from mice?

      Ca2+  imaging was performed in mouse hippocampal organotypic brain slice cultures. The figure text for Fig. 1 E) states “widefield fluorescence image of neurons in the dentate gyrus of a mouse hippocampal organotypic brain slice culture expressing the genetically encoded Ca2+ reporter GCAMP6s...”

      - 11.4 mM K is reported for homogenate in text only. How variable is that? How many n? No SD reported in text and no individual data points reported since this experiment is not represented as a figure.

      This has been clarified in the text by adding (N = 1, homogenate prepared from >100 larvae).

      - Same results (effect of 11.4 mM K on Vm) described twice in one paragraph, compare lines 126-131 with 131-136.

      The repetition has been removed.

      - Line 182 - example for consistency: decide IQR or SD/SEM

      To improve consistency, we have changed to median and IQR throughout.

      - Neuronal recordings are reported as hippocampal pyramidal neurons (i.e. line 222) but some recordings were made from dentate granule cells - please clarify which neurons were recorded in ephys, ca imaging, GluSnFr imaging

      For each experiment we describe which type of neurons were recorded from. For rodent recordings these were hippocampal pyramidal neurons except in the case of the Ca2+ imaging example where the widefield recording was over the dentate gyrus subfield.

      - Line 309: "should" seems to be an extra word

      We have removed the word ‘should’ and made the sentence shorter and clearer. It now reads: ‘Given our finding that cestode larvae contain and release significant quantities of glutamate, it is possible that homeostatic mechanisms for taking up and metabolizing glutamate fail to compensate for larvalderived glutamate in the extracellular space. Therefore, similar glutamate-dependent excitotoxic and epileptogenic processes that occur in stroke, traumatic brain injury and CNS tumors are likely to also occur in NCC.’

      Reviewer #2 (Public Review):

      Since neurocysticercosis is associated with epilepsy, the authors wish to establish how cestode larvae affect neurons. The underlying hypothesis is that the larvae may directly excite neurons and thus favor seizure genesis.

      To test this hypothesis, the authors collected biological materials from larvae (from either homogenates or excretory/secretory products), and applied them to hippocampal neurons (rats and mice) and human cortical neurons.

      This constitutes a major strength of the paper, providing a direct reading of larvae's biological effects. Another strength is the combination of methods, including patch clamp, Ca, and glutamate imaging.

      We thank the Reviewer 2 for their review of the strength and weaknesses of our manuscript. We respond to the identified weaknesses below.

      There are some weaknesses:

      (1) The main one relates to the statement: "Together, these results indicate that T. crassiceps larvae homogenate results not just in a transient depolarization of cells in the immediate vicinity of application, but can also trigger a wave of excitation that propagates through the brain slice in both space and time. This demonstrates that T. crassiceps homogenate can initiate seizurelike activity under suitable conditions."

      The only "evidence" of propagation is an image at two time points. It is one experiment, and there is no quantification. Either increase n's and perform a quantification, or remove such a statement.

      We acknowledge that the data is from one experiment, with the intention of demonstrating that it is plausible for intense depolarization of a subset of neurons to result in the initiation and propagation of seizure-like activity to nearby neurons under suitable conditions. However, we agree that it is prudent to remove this statement and have done so.

      Likewise, there is no evidence of seizure genesis. A single cell recording is shown. The presence of a seizure-like event should be evaluated with field recordings.

      In this experiment the Ca2+ imaging demonstrates activity spreading from the site of the restricted homogenate puff to all surrounding neurons. Furthermore, the whole-cell recoding is typical of a slice wide seizure-like event.  

      (2) Control puff experiments are lacking for Fig 1. Would puffing ACSF also produce a depolarization, and even firing, as suggested in Fig. 2D? This is needed for at least one species.

      We agree and have added this data for the rat and mouse neuron in a new Figure 1-figure supplement 1.

      (3) What is the rationale to use a Cs-based solution? Even in the presence of TTX and with blocking K channels, the depolarization may be sufficient to activate Ca channels (LVGs), which would further contribute to the depolarization. Why not perform voltage clamp recordings to directly the current?

      The intention of the Cs-based solution was to block K+ channels and reduce the effect of moderately raised K+ in the homogenate to isolate the contribution of other causative agents of depolarization (i.e. glutamate / aspartate). We agree that performing voltage clamp recordings would have been useful for directly recording the currents responsible for depolarization. 

      (4) Why did you use organotypic slices? Since you wish to model adult epilepsy, it would have been more relevant to use fresh slices from adult rats/mice. At least, discuss the caveat of using a network still in development in vitro.

      Recordings were performed 6–14 days post culture, which is equivalent to postnatal Days (P) 12 to 22. Previous work has shown that neurons in the organotypic hippocampal brain slice are relatively mature (Gähwiler et al., 1997). For example they possess mature Cl- homeostasis mechanisms at this point, as evidenced by their hyperpolarizing EGABA (Raimondo et al., 2012).  

      (5) Please include both the number of slices and number of cells recorded in each condition. This is the standard (the number of cells is not enough).

      This has now been added to all relevant sections of the results text.  

      (6) Please provide a table with the basic properties of cells (Rin, Rs, etc.). This is standard to assess the quality of the recordings.

      Tables containing the basic properties for each cell recording have been created for each figure (as Figure supplements) and the following statement was added to the electrophysiology section of the Methods: ‘Basic properties of each cell were recorded (see Figure supplements).’

      (7) Please provide a table on patient's profile. This is standard when using human material. Were these TLE cases (and "control" cortex) or epileptogenic cortex?

      We have now added a basic table on the patient’s profiles to the Materials and Methods section.

      Globally, the authors achieved their aims. They show convincingly that larvae material can depolarize neurons, with glutamate (and aspartate) as the most likely candidates.

      This is important not only because it provides mechanistic insight but also potential therapeutic targets. The result is impactful, as the authors use quasi-naturalistic conditions, to assess what might happen in the human brain. The experimental design is appropriate to address the question. It can be replicated by any interested person.

      We thank the Reviewer 2 for their enthusiastic and constructive assessment of our manuscript. We have elected to respond to and address the following aspects from their “Recommendations For The Authors” below:

      Reviewer #2 (Recommendations For The Authors):

      lines 132 and following are a repetition of those above

      These have been removed.

      line 151 Fig "2" missing

      This has been added.

      187, 190 should be E, F not C, D

      This has been changed in the text.  

      481, 482 supplier?

      This has been corrected and the correct suppliers described.

      Reviewer #3 (Public Review):

      This paper has high significance because it addresses a prevalent parasitic infection of the nervous system, Neurocysticercosis (NCC). The infection is caused by larvae of the parasitic cestode Taenia solium It is a leading cause of epilepsy in adults worldwide

      To address the effects of cestode larvae, homogenates and excretory/secretory products of larvae were added to organotypic brain slice cultures of rodents or layer 2/3 of human cortical brain slices from patients with refractory epilepsy.

      We thank Reviewer 3 for their helpful comments and suggestions for improvement which we address below.

      A self-made pressure ejection system was used to puff larvae homogenate (20 ms puff) onto the soma of patched neurons. The mechanical force could have caused depolarizaton so a vehicle control is critical. On line 150 they appear to have used saline in this regard, and clarification would be good. Were the controls here (and aCSF elsewhere) done with the low Mg2+o aCSF like the larvae homogenates?

      We agree and have added examples where aCSF alone was pressure ejected onto the same rat and mouse neurons in a new Figure 1-figure supplement 1. In Figure 1, the same aCSF as that was used to bathe the slices was used. In Figure 2D-G, either PBS (which larval homogenates were prepared in) or growth medium (which contain larval E/S products) were used as comparative controls.

      They found that neurons depolarized after larvae homogenate exposure and the effect was mediated by glutamate but not nicotinic receptors for acetylcholine (nAChRs), acid-sensing channels or substance P. To address nAChRs, they used 10uM mecamyline, and for ASICs 2mM amiloride which seems like a high concentration. Could the concentrations be confirmed for their selectivity? 

      We did not independently verify the selectivity of the antagonist concentrations used in our study. However, the persistence of depolarizations despite the use of high concentrations of mecamylamine (10 μM) and amiloride (2 mM) provides strong evidence that neither nAChRs nor ASICs are primarily responsible for mediating these responses. The high concentrations used, while potentially raising concerns about specificity, actually strengthen our conclusion that these receptor types are not involved in the observed effect.

      Glutamate receptor antagonists, used in combination, were 10uM CNQX, 50uM DAP5, and 2mM kynurenic acid. These concentrations are twice what most use. Please discuss. 

      We intentionally used higher-than-typical concentrations of glutamate receptor antagonists in our experimental design. Our rationale for this approach was to ensure maximal blockade of glutamate receptors, thereby minimizing the possibility of residual receptor activity confounding our results.

      Also, it would be very interesting to know if the glutamate receptor is AMPA, Kainic acid, or NMDA. Were metabotropic antagonists ever tested? That would be logical because CNQX/DAPR/Kynurenic acid did not block all of the depolarization.

      We appreciate the reviewer's interest in the specific glutamate receptor subtypes involved in our study. Our research primarily focused on ionotropic glutamate receptors as a group, without differentiating the individual contributions of AMPA, Kainate, and NMDA receptors. This approach, while broad, allowed us to establish the involvement of glutamatergic signalling in the observed effects. We acknowledge that we did not investigate metabotropic glutamate receptors in this study. Importantly, we demonstrate later in our manuscript that the larval products contain both glutamate and aspartate. Therefore the precise nature of the glutamate-dependent depolarization observed using a particular experimental preparation would depend on the specific types of neurons exposed to the homogenate and the expression profile of different glutamate receptor subtypes on these neurons.

      They also showed the elevated K+ in the homogenate (~11 mM) could not account for the depolarization. However, the experiment with K+ was not done in a low Mg2+o buffer (Or was it -please clarify). 

      The experiment where 11.39 mM K+ as well as the experiment with T. crass. Homogenate with a cesium internal and added TTX were all done in standard 2 mM Mg2+ containing aCSF.

      They also confirmed that only small molecules led to the depolarization after filtering out very large molecules. That supports the conclusion that glutamate - which is quite small - could be responsible. It is logical to test substance P because the Intro points out prior work links the larvae and seizures by inflammation and implicates substance P. However, why focus on nAChRs and ASIC?

      These were chosen as they are ionotropic receptors which mediate depolarization and hence could conceivably be responsible for the homogenate-induced depolarization we observed.

      The depolarizations caused seizure-like events in slices. The slices were exposed to a proconvulant buffer though- low Mg2+o. This buffer can cause spontaneous seizure-like events so it is important to know what the buffer did alone.

      We agree that a low M2+ buffer solution can elicit seizure-like events in organotypic slices alone. However, the timing of the onset of the seizure-like event in the example presented in Figure 1 strongly suggests that it was triggered by the T. crass homogenate puff. Nonetheless, on the suggestion of the other reviewers we have reduced emphasis on our experimental evidence for the ability of T. crass. homogenate to illicit seizure-like events.  

      They suggest the effects could underlie seizure generation in NCC. However, there is only one event that is seizure-like in the paper and it is just an inset. Were others similar? How frequency were they? How long?

      Please see the response above as well as our response to Reviewer 1 who raised a similar concern.

      Using Glutamate-sensing fluorescent reporters they found the larvae contain glutamate and can release it, a strength of the paper.

      Fig. 4. Could an inset be added to show the effects are very fast? That would support an effect of glutamate.

      We have not added an inset. However, given the scale bar (500 ms) for the trace provided, the response is very fast.  

      Why is aspartate relatively weak and glutamate relatively effective as an agonist?

      Glutamate generally has a higher affinity for glutamate receptors compared to aspartate. This is particularly true for AMPA and kainate receptors, where glutamate is the primary endogenous agonist. Similarly iGluSnFR has a higher sensitivity for glutamate over aspartate (Marvin et al., 2013).

      Could some of the variability in Fig 4G be due to choice of different cell types? That would be consistent with Fig 5B where only a fraction of cells in the culture showed a response to the larvae nearby. 

      Whilst differences in cell types could contribute to the variability in Fig 4G, all the responses were recorded from hippocampal pyramidal neurons and hence it is more likely that the variability is a function of other sources of variation including differences in iGluSnFR expression, depth of the cell imaged, the proximity of the puffer pipette etc. In Fig. 5B we think the lack of response may be due to the fact that any released glutamate by the live larvae was not able reach the iGluSnFR neurons at sufficient concentrations due to the nature of our submerged recording setup. We have added the following sentence to the results. ‘Our submerged recording setup might have led to swift diffusion or washout of released glutamate, possibly explaining the lack of observable changes.’

      On what basis was the ROI drawn in Fig. 5B.

      The ROI drawn in Fig. 5B was selected to include all iGluSnFR expressing neurons in the brain slice. which were captured in the field of view.

      Also in 5B, I don't see anything in the transmitted image. What should be seen exactly?

      We agree that it is difficult to resolve much in the transmitted image. However, both the brain slice on the left as well as a T. crass. larva on the right is visible and outlined with a green or orange dashed line respectively.

      Human brain slices were from temporal cortex of patients with refractory epilepsy. Was the temporal cortex devoid of pathology and EEG abnormalities? This area may be quite involved in the epilepsy because refractory epilepsy that goes to surgery is often temporal lobe epilepsy. Please discuss the limitations of studying the temporal cortex of humans with epilepsy since it may be more susceptible to depolarizations of many kinds, not just larvae.

      We acknowledge the important limitations of using temporal cortex tissue from patients with refractory epilepsy. While we aimed to use visually normal tissue, we recognize that the tissue may have underlying pathology or functional abnormalities not visible to the naked eye. It may also be more susceptible to induced depolarizations due to epilepsy-related changes in neuronal excitability. Despite these limitations, we believe our human tissue data still provides valuable data that the larval homogenates can induce depolarization in human as well as rodent neurons.  

      Please discuss the limitations of the cultures - they are from very young animals and cultured for 6-14 days.

      We acknowledge the potential limitations of our experimental model using organotypic hippocampal slice cultures from young animals. The use of relatively immature tissue may not fully represent the adult nervous system due to developmental differences in receptor expression, synaptic connections, and network properties. The 6-14 day culture period, while allowing some maturation, may induce changes that differ from the in vivo environment, including alterations in cellular physiology and network reorganization. Despite these limitations, this model provides a valuable balance between preserved local circuitry and experimental accessibility. Future studies comparing results with acute adult slices and in vivo models would be beneficial to validate and extend our findings.

      References:

      Gähwiler, B.H. et al. (1997) ‘Organotypic slice cultures: a technique has come of age.’, Trends in neurosciences, 20(10), pp. 471–7.

      Marvin, J.S. et al. (2013) ‘An optimized fluorescent probe for visualizing glutamate neurotransmission.’, Nature methods, 10(2), pp. 162–70. Available at: https://doi.org/10.1038/nmeth.2333.

      Raimondo, J.V. et al. (2012) ‘Optogenetic silencing strategies differ in their effects on inhibitory synaptic transmission.’, Nat. Neurosci., 15(8), pp. 1102–4. Available at: https://doi.org/10.1038/nn.3143.

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  26. www.biorxiv.org www.biorxiv.org
    DNA O-MAP uncovers the molecular neighborhoods associated with specific genomic loci
    3
    1. Public_Reviews 28 Oct 2024

      Reviewer #2 (Public review):

      Summary

      Liu and MacGann et al. introduce the method DNA O-MAP that uses oligo-based ISH probes to recruit horseradish peroxidase for targeted proximity biotinylation at specific DNA loci. The method's specificity was tested by profiling the proteomic composition at repetitive DNA loci such as telomeres and pericentromeric alpha satellite repeats. In addition, the authors provide proof-of-principle for the capture and mapping of contact frequencies between individual DNA loop anchors.

      Strengths

      Identifying locus-specific proteomes still represents a major technical challenge and remains an outstanding issue (1). Theoretically, this method could benefit from the specificity of ISH probes and be applied to identify proteomes at non-repetitive DNA loci. This method also requires significantly fewer cells than other ISH- or dCas9-based locus-enrichment methods. Another potential advantage to be tested is the lack of cell line engineering that allows its application to primary cell lines or tissue.

      Weaknesses

      The authors indicate that DNA O-MAP is superior to other methods for identifying locus-specific proteomes. Still, no proof exists that this method could uncover proteomes at non-repetitive DNA loci. Also, there is very little validation of novel factors to confirm the superiority of the technique regarding specificity.<br /> The authors first tested their method's specificity at repetitive telomeric regions, and like other approaches, expected low-abundant telomere-specific proteins were absent (for example, all subunits of the telomerase holoenzyme complex). Detecting known proteins while identifying noncanonical and unexpected protein factors with high confidence could indicate that DNA O-MAP does not fully capture biologically crucial proteins due to insufficient enrichment of locus-specific factors. The newly identified proteins in Figure 1E might still be relevant, but independent validation is missing entirely. In my opinion, the current data cannot be interpreted as successfully describing local protein composition.

      Finally, the authors could have discussed the limitations of DNA O-MAP and made a fair comparison to other existing methods (2-5). Unlike targeted proximity biotinylation methods, DNA O-MAP requires paraformaldehyde crosslinking, which has several disadvantages. For instance, transient protein-protein interactions may not be efficiently retained on crosslinked chromatin. Similarly, some proteins may not be crosslinked by formaldehyde and thus will be lost during preparation (6).

      (1) Gauchier M, van Mierlo G, Vermeulen M, Dejardin J. Purification and enrichment of specific chromatin loci. Nat Methods. 2020;17(4):380-9.<br /> (2) Dejardin J, Kingston RE. Purification of proteins associated with specific genomic Loci. Cell. 2009;136(1):175-86.<br /> (3) Liu X, Zhang Y, Chen Y, Li M, Zhou F, Li K, et al. In Situ Capture of Chromatin Interactions by Biotinylated dCas9. Cell. 2017;170(5):1028-43 e19.<br /> (4) Villasenor R, Pfaendler R, Ambrosi C, Butz S, Giuliani S, Bryan E, et al. ChromID identifies the protein interactome at chromatin marks. Nat Biotechnol. 2020;38(6):728-36.<br /> (5) Santos-Barriopedro I, van Mierlo G, Vermeulen M. Off-the-shelf proximity biotinylation for interaction proteomics. Nat Commun. 2021;12(1):5015.<br /> (6) Schmiedeberg L, Skene P, Deaton A, Bird A. A temporal threshold for formaldehyde crosslinking and fixation. PLoS One. 2009;4(2):e4636.

      Review 2
    2. Public_Reviews 28 Oct 2024

      Reviewer #3 (Public review):

      Significance of the Findings:

      The study by Liu et al. presents a novel method, DNA-O-MAP, which combines locus-specific hybridisation with proximity biotinylation to isolate specific genomic regions and their associated proteins. The potential significance of this approach lies in its purported ability to target genomic loci with heightened specificity by enabling extensive washing prior to the biotinylation reaction, theoretically improving the signal-to-noise ratio when compared with other methods such as dCas9-based techniques. Should the method prove successful, it could represent a notable advancement in the field of chromatin biology, particularly in establishing the proteomes of individual chromatin regions - an extremely challenging objective that has not yet been comprehensively addressed by existing methodologies.

      Strength of the Evidence:

      The evidence presented by the authors is somewhat mixed, and the robustness of the findings appears to be preliminary at this stage. While certain data indicate that DNA-O-MAP may function effectively for repetitive DNA regions, a number of the claims made in the manuscript are either unsupported or require further substantiation. There are significant concerns about the resolution of the method, with substantial biotinylation signals extending well beyond the intended target regions (megabases around the target), suggesting a lack of specificity and poor resolution, particularly for smaller loci. Furthermore, comparisons with previous techniques are unfounded since the authors have not provided direct comparisons with the same mass spectrometry (MS) equipment and protocols. Additionally, although the authors assert an advantage in multiplexing, this claim appears overstated, as previous methods could achieve similar outcomes through TMT multiplexing. Therefore, while the method has potential, the evidence requires more rigorous support, comprehensive benchmarking, and further experimental validation to demonstrate the claimed improvements in specificity and practical applicability.

      Review 3
    3. Public_Reviews 28 Oct 2024

      Author response:

      Public Reviews:

      Reviewer #1 (Public review):

      Summary:

      The authors describe a method to probe both the proteins associated with genomic elements in cells, as well as 3D contacts between sites in chromatin. The approach is interesting and promising, and it is great to see a proximity labeling method like this that can make both proteins and 3D contacts. It utilizes DNA oligomers, which will likely make it a widely adopted method. However, the manuscript over-interprets its successes, which are likely due to the limited appropriate controls, and of any validation experiments. I think the study requires better proteomic controls, and some validation experiments of the "new" proteins and 3D contacts described. In addition, toning down the claims made in the paper would assist those looking to implement one of the various available proximity labeling methods and would make this manuscript more reliable to non-experts.

      Strengths:

      (1) The mapping of 3D contacts for 20 kb regions using proximity labeling is beautiful.

      (2) The use of in situ hybridization will probably improve background and specificity.

      (3) The use of fixed cells should prove enabling and is a strong alternative to similar, living cell methods.

      Weaknesses:

      (1) A major drawback to the experimental approach of this study is the "multiplexed comparisons". Using the mtDNA as a comparator is not a great comparison - there is no reason to think the telomeres/centrosomes would look like mtDNA as a whole. The mito proteome is much less complex. It is going to provide a large number of false positives. The centromere/telomere comparison is ok, if one is interested in what's different between those two repetitive elements. But the more realistic use case of this method would be "what is at a specific genomic element"? A purely nuclear-localized control would be needed for that. Or a genomic element that has nothing interesting at it (I do not know of one). You can see this in the label-free work: non-specific, nuclear GO terms are enriched likely due to the random plus non-random labeling in the nucleus. What would a Telo vs general nucleus GSEA look like? (GSEA should be used for quantitative data, no GO). That would provide some specificity. Figures 2G and S4A are encouraging, but a) these proteins are largely sequestered in their respective locations, and b) no validation by an orthogonal method like ChIP or Cut and Run/Tag is used.

      You can also see this in the enormous number of "enriched" proteins in the supplemental volcano plots. The hypothesis-supporting ones are labeled, but do the authors really believe all of those proteins are specific to the loci being looked at? Maybe compared to mitochondria, but it's hard to believe there are not a lot of false positives in those blue clouds. I believe the authors are more seeing mito vs nucleus + Telo than the stated comparison. For example, if you have no labeling in the nucleus in the control (Figures 1C and 2C) you cannot separate background labeling from specific labeling. Same with mito vs. nuc+Telo. It is not the proper control to say what is specifically at the Telo.

      I would like to see a Telo vs nuclear control and a Centromere vs nuc control. One could then subtract the background from both experiments, then contrast Telo vs Cent for a proper, rigorous comparison. However, I realize that is a lot of work, so rewriting the manuscript to better and more accurately reflect what was accomplished here, and its limitations, would suffice.

      (2) A second major drawback is the lack of validation experiments. References to literature are helpful but do not make up for the lack of validation of a new method claiming new protein-DNA or DNA-DNA interactions. At least a handful of newly described proximal proteins need to be validated by an orthogonal method, like ChIP qPCR, other genomic methods, or gel shifts if they are likely to directly bind DNA. It is ok to have false positives in a challenging assay like this. But it needs to be well and clearly estimated and communicated.

      (3) The mapping of 3D contacts for 20 kb regions is beautiful. Some added discussion on this method's benefits over HiC-variants would be welcomed.

      (4) The study claims this method circumvents the need for transfectable cells. However, the authors go on to describe how they needed tons of cells, now in solution, to get it to work. The intro should be more in line with what was actually accomplished.

      (5) Comments like "Compared to other repetitive elements in the human genome...." appear to circumvent the fact that this method is still (apparently) largely limited to repetitive elements. Other than Glopro, which did analyze non-repetitive promoter elements, most comparable methods looked at telomeres. So, this isn't quite the advancement you are implying. Plus, the overlap with telomeric proteins and other studies should be addressed. However, that will be challenging due to the controls used here, discussed above.

      We thank the Reviewer for their careful reading of manuscript and constructive suggestions. We plan to substantially revise the framing and presentation of manuscript to address the concerns raised by all three reviewers.

      Reviewer #2 (Public review):

      Summary

      Liu and MacGann et al. introduce the method DNA O-MAP that uses oligo-based ISH probes to recruit horseradish peroxidase for targeted proximity biotinylation at specific DNA loci. The method's specificity was tested by profiling the proteomic composition at repetitive DNA loci such as telomeres and pericentromeric alpha satellite repeats. In addition, the authors provide proof-of-principle for the capture and mapping of contact frequencies between individual DNA loop anchors.

      Strengths

      Identifying locus-specific proteomes still represents a major technical challenge and remains an outstanding issue (1). Theoretically, this method could benefit from the specificity of ISH probes and be applied to identify proteomes at non-repetitive DNA loci. This method also requires significantly fewer cells than other ISH- or dCas9-based locus-enrichment methods. Another potential advantage to be tested is the lack of cell line engineering that allows its application to primary cell lines or tissue.

      Weaknesses

      The authors indicate that DNA O-MAP is superior to other methods for identifying locus-specific proteomes. Still, no proof exists that this method could uncover proteomes at non-repetitive DNA loci. Also, there is very little validation of novel factors to confirm the superiority of the technique regarding specificity.

      The authors first tested their method's specificity at repetitive telomeric regions, and like other approaches, expected low-abundant telomere-specific proteins were absent (for example, all subunits of the telomerase holoenzyme complex). Detecting known proteins while identifying noncanonical and unexpected protein factors with high confidence could indicate that DNA O-MAP does not fully capture biologically crucial proteins due to insufficient enrichment of locus-specific factors. The newly identified proteins in Figure 1E might still be relevant, but independent validation is missing entirely. In my opinion, the current data cannot be interpreted as successfully describing local protein composition.

      Finally, the authors could have discussed the limitations of DNA O-MAP and made a fair comparison to other existing methods (2-5). Unlike targeted proximity biotinylation methods, DNA O-MAP requires paraformaldehyde crosslinking, which has several disadvantages. For instance, transient protein-protein interactions may not be efficiently retained on crosslinked chromatin. Similarly, some proteins may not be crosslinked by formaldehyde and thus will be lost during preparation (6).

      (1) Gauchier M, van Mierlo G, Vermeulen M, Dejardin J. Purification and enrichment of specific chromatin loci. Nat Methods. 2020;17(4):380-9.

      (2) Dejardin J, Kingston RE. Purification of proteins associated with specific genomic Loci. Cell. 2009;136(1):175-86.

      (3) Liu X, Zhang Y, Chen Y, Li M, Zhou F, Li K, et al. In Situ Capture of Chromatin Interactions by Biotinylated dCas9. Cell. 2017;170(5):1028-43 e19.

      (4) Villasenor R, Pfaendler R, Ambrosi C, Butz S, Giuliani S, Bryan E, et al. ChromID identifies the protein interactome at chromatin marks. Nat Biotechnol. 2020;38(6):728-36.

      (5) Santos-Barriopedro I, van Mierlo G, Vermeulen M. Off-the-shelf proximity biotinylation for interaction proteomics. Nat Commun. 2021;12(1):5015.

      (6) Schmiedeberg L, Skene P, Deaton A, Bird A. A temporal threshold for formaldehyde crosslinking and fixation. PLoS One. 2009;4(2):e4636.

      We thank the Reviewer for their constructive feedback on our work. As noted above, we plan to substantially revise the framing and presentation of manuscript to address the concerns raised by all three reviewers.

      Reviewer #3 (Public review):

      Significance of the Findings:

      The study by Liu et al. presents a novel method, DNA-O-MAP, which combines locus-specific hybridisation with proximity biotinylation to isolate specific genomic regions and their associated proteins. The potential significance of this approach lies in its purported ability to target genomic loci with heightened specificity by enabling extensive washing prior to the biotinylation reaction, theoretically improving the signal-to-noise ratio when compared with other methods such as dCas9-based techniques. Should the method prove successful, it could represent a notable advancement in the field of chromatin biology, particularly in establishing the proteomes of individual chromatin regions - an extremely challenging objective that has not yet been comprehensively addressed by existing methodologies.

      Strength of the Evidence:

      The evidence presented by the authors is somewhat mixed, and the robustness of the findings appears to be preliminary at this stage. While certain data indicate that DNA-O-MAP may function effectively for repetitive DNA regions, a number of the claims made in the manuscript are either unsupported or require further substantiation. There are significant concerns about the resolution of the method, with substantial biotinylation signals extending well beyond the intended target regions (megabases around the target), suggesting a lack of specificity and poor resolution, particularly for smaller loci. Furthermore, comparisons with previous techniques are unfounded since the authors have not provided direct comparisons with the same mass spectrometry (MS) equipment and protocols. Additionally, although the authors assert an advantage in multiplexing, this claim appears overstated, as previous methods could achieve similar outcomes through TMT multiplexing. Therefore, while the method has potential, the evidence requires more rigorous support, comprehensive benchmarking, and further experimental validation to demonstrate the claimed improvements in specificity and practical applicability.

      We thank the Reviewer for providing detailed critiques of our manuscript. As noted above, we plan to substantially revise the framing and presentation of manuscript to address the concerns raised by all three reviewers.

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  27. parser.glc.ru parser.glc.ru
    JWT-токены от и до. Разбираемся с JSON Web Tokens и атаками на них
    1
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  28. readingpoetryatmit.wordpress.com readingpoetryatmit.wordpress.com
    “Ode on a Grecian Urn” by Keats
    1
    1. paigedzenutis 28 Oct 2024
      O Attic shape! Fair attitude! with brede         Of marble men and maidens overwrought,With forest branches and the trodden weed;

      Attic - Athenian Marble men - statues of gods and important people in ancient times Forest branches and the trodden weed - vases and urns played a large part of story telling in ancient times. This could suggest that the story of ones life was entirely lived in the forest.

      Notes on Nymphs in Greek mythology: The Meliai (Meliae) were nymphs of the ash-trees. They were born when Gaia (Gaea, the Earth) was impregnated by the blood of the castrated Ouranos (Uranus, the Sky). They were wed by the men of the Silver Age--in the time before the first woman was created--and from them mankind was descended.

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  29. www.planalto.gov.br www.planalto.gov.br
    L8987compilada
    1
    1. hvs 25 Oct 2024
      Art. 11
      • Informativo nº 827
      • SEGUNDA TURMA
      • Compartilhe:
      • Processo:REsp 1.990.245-SP, Rel. Ministro Afrânio Vilela, Segunda Turma, por unanimidade, julgado em 17/9/2024, DJe 19/9/2024.

      Ramo do Direito DIREITO ADMINISTRATIVO, DIREITO CIVIL

      TemaIndústria, inovação e infraestrutura Paz, Justiça e Instituições Eficazes Parcerias e meios de implementação <br /> Concessão de serviço público. Subsolo. Túneis do metrô. Bens de uso especial. Instalação de infraestrutura de telecomunicações. Contraprestação ao direito de passagem. Possibilidade. Art. 11 da Lei n. 8.987/1995. Exceção prevista no art. 12 da Lei n. 13.116/2015. Não aplicável.

      Destaque - É legítima a retribuição financeira exigida por concessionária responsável pelos túneis do metrô em face de empresa privada prestadora de serviço de interesse público para a instalação de infraestrutura de telecomunicações, na forma do art. 11 da Lei 8.987/1995.

      Informações do Inteiro Teor - Cinge-se a controvérsia acerca da possibilidade de cobrança pelo uso do subsolo do Metrô para instalação de infraestrutura de telecomunicações.

      • O Supremo Tribunal Federal, ao julgar a ADI 6.482/DF, por meio da qual restou definida a constitucionalidade do art.12, da Lei n. 13.116/2015, afirmou a competência legislativa privativa da União sobre normas gerais que instituam a gratuidade do direito de passagem e reconheceu que a referida norma instituiu verdadeiro ônus real sobre os bens de que trata, relativizando o direito à propriedade pública sobre esses bens, a fim de preservar a prestação de serviços públicos essenciais à coletividade, nos quais se amolda o serviço de telefonia.

      • O mencionado dispositivo é uma exceção à política estabelecida no art. 11 da Lei n. 8.987/1995, reclamando interpretação restritiva às situações elencadas na lei especial. Dessa forma, não alcança o exercício do direito de passagem aos túneis do Metrô, em virtude da não adequação do bem a qualquer uma das situações dispostas na Lei Geral das Antenas, quais sejam, vias públicas, faixas de domínio e outros bens públicos de uso comum do povo.

      • Trata-se, em verdade, de bem de uso especial, na forma do art. 99, II, do Código Civil de 2002, que, aliás, define os bens públicos a partir da sua destinação à execução dos serviços públicos e, por isso mesmo, são considerados instrumentos desses serviços, e têm uma finalidade pública permanente.

      • Falta aos túneis do Metrô de São Paulo característica essencial para que sejam classificados como bem de uso comum: a submissão aos mandamentos da isonomia, da generalidade, da ausência de restrições. Os subsolos do metrô estão afetados ao serviço público de transporte metroviário de passageiros, amoldando-se mais adequadamente à definição de bem de uso especial de uso administrativo externo do que à definição de bem de uso comum do povo, porquanto o seu uso é restrito aos usuários do serviço de transporte subterrâneo.

      • Também é acertada a conclusão sobre o excesso na função regulamentadora do Decreto n. 10.480/2020, especialmente em seu art. 9º. Isso porque, nas obras indicadas no dispositivo, incluem-se aquelas de "implantação ou ampliação de sistemas de transporte público sobre trilhos ou subterrâneos", quando o bem não se adequa à definição de nenhum daqueles estabelecidos na lei que regulamenta (vias públicas, faixas de domínio e bens públicos de uso comum do povo).

      • O mencionado Decreto, por sua própria natureza, deve ser analisado conforme os contornos determinados na Lei n. 13.116/2015, não podendo ampliar o que está disposto na lei, sob pena de ofensa ao princípio da reserva legal, conforme já decidido pelo Superior Tribunal de Justiça (AgRg no AREsp: 231.652 PR 2012/0196057-6, relator Ministro Napoleão Nunes Maia Filho, Data de Julgamento: 7/3/2017, T1 - Primeira Turma, Data de Publicação: DJe de 21/3/2017).

      • Por fim, é legítima a retribuição financeira exigida por concessionária em face de outra empresa privada prestadora de serviço de interesse público, a fim de obter rendimentos alternativos, complementares, acessórios ou de projetos associados, na forma do art. 11 da Lei n. 8.987/1995, desde que haja previsão contratual, diante dos impactos para a promoção de modicidade tarifária e do favorecimento à melhor satisfação do interesse público.

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  30. drive.google.com drive.google.com
    The Protestant Ethic and the Spirit of Capitalism
    2
    1. AnGordon24301 25 Oct 2024
      o speak here of a reflection ofmaterial conditions in the ideal superstructure would be patentnonsense

      not just material conditions or consumption bc same values of capitalism excited in the back woods

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  31. www.americanyawp.com www.americanyawp.com
    Journal of Christopher Columbus, 1492 | The American Yawp Reader
    1
    1. laurenschneider1 25 Oct 2024
      He also understood that, far away, there were men with one eye, and others with dogs’ noses who were cannibals, and that when they captured an enemy they beheaded him and drank his blood…

      Here, I wonder if Christopher was scared of this happening to the Europeans. Did he think that this would happen when he first landed on the island? They had to have done intensive research and maybe were spying on them before they actually landed. I can't imagine them coming all that way just o be eaten alive.

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  32. drive.google.com drive.google.com
    Desenho de e-atividades para ambientes digitais
    49
    1. silviacunha 25 Oct 2024
      3.2. SIGNIFICADO DAS E-ATIVIDADES NO PROCESSO DE ENSINO--APRENDIZAGEMDe acordo com Salmon (2013) e o seu modelo de cinco estágios, ase-atividades são um elemento-chave para uma aprendizagem ativa online.Este modelo enfatiza a importância da construção de comunidades virtuaisde aprendizagem para o sucesso das e-atividades de ensino e aprendizagemonline. Temos, pois, que essas e-atividades podem ser desenhadas paraatender a cada um dos cinco estágios do modelo e com isso ajudar osalunos a construir comunidades virtuais de aprendizagem e a alcançar osseus objetivos de aprendizagem online.CAPÍTULO 3

      O modelo de cinco estágios de Salmon oferece uma estrutura robusta para o ensinio online, e reconheço um valor significativo em sua natureza progressiva. Cada estágio desempenha um papel crucial no incentivo dos formandos, inicialmente com o apoio técnico e a motivação, até atingir um resultado de colaboração profunda e relevante. Entendo que as e-atividades são planeadas para aumentar a complexidade, incentivam a uma aprendizagem mais colaborativa e reflexiva. Contudo, para o bom funcionamento deste modelo, é essencial que o facilitador mantenha uma comunicação eficiente e proporcione um acompanhamento apropriado em cada etapa, assegura que os estudantes não permaneçam estagnados em etapas iniciais.

    2. silvinosantos 19 Oct 2024
      E-atividade é a designação que normalmente se aplica à estrutura de umaformação ativa e interativa online. As e-atividades podem ser utilizadas devárias formas, mas têm algumas características comuns.As e-atividades permitem uma aprendizagem online ativa, participativa,individual ou em grupo. São importantes porque empregam princípios úteispara a aprendizagem bem como uma escolha de tecnologias adequadas.

      Após a leitura dos materiais partilhados, deixo aqui um contributo do que me parece essencial: A seleção das atividades eletrónicas é crucial para um ensino e uma aprendizagem eficazes em ambientes virtuais. Almenara, Osuna & Cejudo (2014) sugerem critérios para a seleção da melhor atividade eletrónica, incluindo a consideração das caraterísticas dos alunos, a mobilização de diferentes aptidões, a promoção de diversas competências e a maior motivação. As actividades electrónicas são cruciais para a aprendizagem dos alunos, apoiando os objectivos e integrando-se no currículo. A motivação é essencial para reforçar as necessidades de aprendizagem. O feedback imediato é crucial para compreender os progressos e identificar as áreas a melhorar. As actividades electrónicas permitem uma aprendizagem online ativa e participativa, utilizando princípios e tecnologias apropriados. A escolha de uma estrutura de atividade eletrónica depende das opções pedagógicas, didácticas e metodológicas.

    4. Joao_Brito 17 Oct 2024
      3.6. CONCLUSÃO

      Deixo só um último comentário onde acho que esta maneira de analisar um documento em conjunto, assim como o software da semana passada onde analisámos um vídeo em conjunto são plataformas que eu desconhecia mas que acredito terem um grande potencial pois fazem com que trabalhos mundanos fiquem mais divertidos com o conjunto de ideias que são partilhados por todos!

    5. Joao_Brito 17 Oct 2024
      Para que tal aconteça é importante quese verifique uma correta adequação entre os conteúdos e a atividadeproposta; é igualmente pertinente que os alunos percebam a utilidade daatividade para a sua aprendizagem e que a mesma seja clara; é tambémrelevante que as atividades propostas ao longo da ação formativa sejamdiversificadas e estejam de acordo com o nível educativo dos alunos;

      Este ponto é um que eu considero que muitos formadores deixam de fora, é muito importante que alunos percebam porque estão a ser avaliados! Muitas pessoas, incluindo eu, não funcionam com base no porque sim. E conseguirmos explicar os motivos da avaliação e mostrar-lhes que se feita de uma forma adequada e correta é benéfica para todos, especialmente para eles, será uma grande ajuda para que o processo de avaliação corra de maneira positiva, promovendo a evolução dos alunos.

    6. Joao_Brito 17 Oct 2024
      Alémdisso, as estratégias de ensino devem ser avaliadas regularmente paragarantir que elas estejam atingindo os seus objetivos de aprendizagem eajudando os alunos a desenvolver habilidades e conhecimentos relevantes.

      Este é um ponto que parece esquecido no ensino português. Quase sempre, se um aluno não tem boas notas, a culpa é dada ao aluno e por vezes até com razão, mas quase nunca se questiona se o método de avaliação é o mais adequado. Penso que esta questão é muito importante para todos os formadores/professores!

    7. AllanL 15 Oct 2024

      Para criar atividades de aprendizagem em ambientes digitais temos de combinar objetivos pedagógicos com as oportunidades oferecidas pela tecnologia, promovendo interação e colaboração entre os estudantes. Acho essencial definir metas claras e propor atividades relevantes que incentivem uma participação ativa,Os momentos síncronos e assíncronos, permite um maior envolvimento dos estudantes, Uma aprendizagem ativa, baseada na resolução problemas, também deve ser incentivada, com desafios práticos que permitam aplicar o conhecimento de forma crítica. Devemos contar com um feedback contínuo, tanto por parte do professor como dos colegas, que ajuda os estudantes a atingir uma aprendizagem mais rica e reflexiva. Para garantir a inclusão e acessibilidade, devemos criar atividades flexíveis, que se adaptem às necessidades de todos os estudantes. Ao usarmos ferramentas tecnológicas adequadas facilitamos a criação de um ambiente interativo e estimulante.

    8. rosagaspar 15 Oct 2024

      O texto sublinha a importância das e-atividades no contexto do planeamento de estratégias pedagógicas, destacando a sua capacidade para diversificar as formas de ensino e promover uma aprendizagem mais dinâmica e interativa. A utilização de e-atividades possibilita um envolvimento mais profundo dos alunos, ao integrar processos digitais alinhados com as práticas tecnológicas contemporâneas.

      Um ponto relevante é a necessidade de adequar o conteúdo ao formato digital, assegurando que as ferramentas tecnológicas selecionadas sejam adequadas aos objetivos de cada atividade. Simultaneamente, o planeamento deve fomentar a colaboração e a interação entre os estudantes, promovendo um ambiente de aprendizagem partilhada.

      Outro aspeto essencial abordado é a inclusão e acessibilidade das e-atividades. Tendo em conta a diversidade de competências e o acesso desigual a recursos tecnológicos por parte dos alunos, é fundamental garantir que estas atividades sejam concebidas de forma a não excluir ninguém. Isto evita a exclusão digital e assegura uma experiência educativa equitativa.

      Destaca-se igualmente a importância da coerência entre os resultados esperados, as metodologias selecionadas, o tipo de feedback e o sistema de avaliação. Esta coerência é essencial para o sucesso do processo de ensino-aprendizagem, garantindo que as e-atividades não sejam apenas uma adição tecnológica, mas sim um elemento integrado e eficaz da estratégia pedagógica.

      Em suma, o texto realça a importância de uma abordagem consciente e inclusiva ao incorporar e-atividades nas práticas educativas, promovendo uma aprendizagem mais rica, acessível e conectada às realidades tecnológicas dos alunos. (pp32.33)

    9. Paula_Antunes 14 Oct 2024
      O nosso principal objetivo foi enquadrar as e-atividades no contexto doensino e aprendizagem em ambientes virtuais.

      A ideia das e-atividades centradas nos estudantes promove uma aprendizagem mais significativa, uma vez que eles deixa de ser somente recetores de informação, para passarem a ser parte ativa do processo de criação e partilha de conhecimento.

      O futuro do ensino, sobretudo a distância, são estas redes de conhecimento, em que todos seremos consumidores e produtores de recursos.

    10. Margarida_Cunha_Nunes 14 Oct 2024
      motivação

      A motivação é um elemento muito importante na construção das e-atividades, é certo que muitos estudantes conseguem automotivar-se, mas não se deve esperar que isso aconteça com todos os estudantes. Tendo em conta que atualmente, devido à utilização das redes sociais, em que somos constantemente bombardeados com conteúdo curto e estimulante e aos jogos que "alimentam" o cérebro com "recompensas" constantes, torna-se menos fácil ao estudante sentir satisfação e motivação com os métodos de aprendizagem tradicionais. É, assim, essencial garantir variedade das e-atividades, que estas promovam o envolvimento do estudante e que haja feedback relevante e construtivo para que o estudante consiga compreender a sua evolução e saber em que áreas necessita de se dedicar mais.

    11. Margarida_Cunha_Nunes 14 Oct 2024
      Taxonomia Digital de Bloom

      A Taxonomia Digital de Bloom fornece uma estrutura orientadora para a criação de e-atividades. A sua utilização é simples e estruturada. Requer do educador a definição de objetivos de aprendizagem claros, o que lhe permite selecionar a categoria adequada e os verbos de ação correspondentes. E desta forma há uma transmissão de orientações claras aos estudantes. Isso assegura que as atividades sejam alinhadas com as competências a serem desenvolvidas, promovendo uma aprendizagem mais estruturada e eficaz. A TDB pode ser usada conjuntamente com Modelos de desenho de e-atividades.

    12. vanessaruivo 14 Oct 2024
      Cabe aoprofessor, aquando da planificação e implementação das e-atividades,utilizar as estratégias mais adequadas para aumentar o envolvimento e amotivação dos alunos.

      Concordo que o formador tem um papel importantíssimo em toda a dinâmica da formação. Desde a planificação até ao desenvolvimento das e-atividades, é essencial que o formador se coloque também no papel de aluno, de modo a criar e-atividades que irão motivar os alunos. Além disso, e tal como foi referido na sessão síncrona do passado dia 10 de outubro, o formador tem um importante papel de mediador, pois para além de e-atividades motivadoras, é essencial que hajam orientações pertinentes e feedback de modo a que os alunos se sintam apoiados em todo o seu processo formativo.

    13. Paula_Antunes 14 Oct 2024
      Refere a necessidade de identificar os momentos críticos paraa intervenção docente, bem como o papel dos estudantes e facilitadores

      Enquanto docente saber reconhecer os momentos criticos da nossa intervenção é fulcral. São pontos chave no processo de aprendizagem em que é essencial orientar ou motivar, garantindo que os estudantes alcancem os objetivos de aprendizagem propostos.

      Podem ocorrem no início da e-atividade (esclarecendo os objetivos por exemplo), durante a sua realização (esclarecendo dúvidas, fornecendo feedback); e na conclusão (feedback destacando os pontos fortes e as áreas a melhorar futuramente).

    14. Paula_Antunes 14 Oct 2024
      Churches (2009) realizou uma revisão da taxonomia de Bloom (TaxonomiaDigital de Bloom) para o apoiar no sentido de realizar e-atividades variáveis

      A Taxonomia Digital de Bloom (adaptação da Taxonomia de Bloom, atualizada para o mundo digital), pretende organizar o processo cognitivo em níveis, como na versão "original", mas incorpora verbos / ações associados às ferramentas digitais.

      Com base nesses verbos (de ação), podemos construir atividades que levem os estudantes a aplicar essa capacidade. Exemplos: atividades "lembrar" podem incluir pesquisas online, atividades "criar" podem envolver a produção de conteúdos multimédia, blogs, etc...

      Ao estruturar as e-atividades de acordo com os níveis da TDB, os docentes conseguem estimular o pensamento crítico e fomentar uma aprendizagem mais inclusa e envolvente

    15. Paula_Antunes 14 Oct 2024
      Um outro elemento importante em todo este processo é o feedback.

      Não há ensino sem feedback. O feedback [de e para o professor] é absolutamente fundamental na aprendizagem dos estudantes, permitindo-lhes compreender os objetivos e o seu progresso, identificando áreas de melhoria.

      O professor deve assim ser claro, específico, dando feedback construtivo e orientado para a ação (ajudando a promover autonomia).

    16. Paula_Antunes 14 Oct 2024
      nossos

      As e-atividades são estratégias essenciais não só para o desenvolvimento de competências como para o cimentar de conhecimento. De forma a serem eficazes precisam de fomentar a motivação extrínseca, ser pedagogicamente eficazes e favorecer a inovação e participação dinâmica dos estudantes.

    17. Paula_Antunes 14 Oct 2024
      Ao desenhar estratégias de aprendizagem que incluam e-atividades,é importante considerar alguns aspetos

      As e-atividades são estratégias essenciais não só para o desenvolvimento de competências como para o cimentar de conhecimento. De forma a serem eficazes precisam fomentar a motivação extrínseca, ser pedagógicamente eficazes e favorecer a inovação e participação dinâmica dos estudantes.

    18. csilva2304684 13 Oct 2024
      objetivo de aprendizagem

      O que preciso ensinar para que os alunos adquiram o conhecimento / competências necessários para atingir os objetivos propostos? Esta será sempre a pergunta mais importante a fazer. Carla Silva

    19. csilva2304684 13 Oct 2024
      Devem produzir conhecimento e promovero desenvolvimento de competências

      Uma e-atividade bem estruturada deve motivar, envolver para uma aprendizagem ativa, autonôma, em que o estudante seja ajudado a elaborar o seu conhecimento, com a formulação de questões, para depois as resumir, entender, relacionar e concluir; deve estimular a comunicação com todos os participantes. Saudações académicas. Carla Silva

    20. luzgomes 13 Oct 2024
      planificação e implementação das e-atividades

      Características das e-atividades de qualidade:

      • Promovem o papel ativo do estudante: o aluno é o protagonista da sua aprendizagem, buscando e construindo conhecimento de forma autónoma.
      • Estimulam a interação: a colaboração entre os alunos e com o professor é fundamental para o processo de aprendizagem.
      • Promovem a investigação e a resolução de problemas: os alunos são desafiados a procurar soluções para problemas reais ou simulados, utilizando os seus conhecimentos e habilidades.
      • Desenvolvem o pensamento crítico: as e-atividades incentivam os alunos a analisar, refletir e questionar as informações que recebem.
      • Promovem a comunicação e o trabalho em equipe: os alunos aprendem a comunicar-se de forma eficaz, a negociar ideias e a trabalhar juntos para alcançar objetivos comuns.
      • Utilizam recursos digitais de forma criativa: as e-atividades exploram o potencial das ferramentas digitais para promover a aprendizagem.
    21. Cesar_Costa 13 Oct 2024
      o feedback deve ser construtivo, específicoe orientado para a ação, com vista a encorajar o aluno e a ajudá-lo aprogredir em relação aos objetivos de aprendizagem. Por isso, este deveser cuidadosamente integrado nas e-atividades para, além do que acaboude ser dito, ajudar a desenvolver alunos mais independentes e autónomos.CAPÍTULO 3

      Da minha experiência é igualmente importante que o feedback seja integrado cuidadosamente nas e-atividades, garantindo sempre que o aluno o recebe de forma clara e atempada. Isso contribui para o desenvolvimento de competências essenciais, como a autonomia e a capacidade crítica, promovendo aprendizes mais independentes e capazes de autorregulação. Quando aplicado adequadamente, o feedback transforma-se numa ferramenta poderosa para melhorar o desempenho e consolidar o conhecimento. Não dispenso nas minhas atividades sejam elas presenciais ou em ambientes virtuais.

    22. Cesar_Costa 13 Oct 2024
      s e-atividades, ou seja, as atividades realizadas por meio de dispositivoseletrónicos, têm um papel importante no desenho das estratégias deaprendizagem. Isso porque essas atividades podem ser utilizadas paradiversificar as formas de aprendizagem e envolver os alunos em processosmais dinâmicos e interativos

      Concordo plenamente! O conhecimento das tecnologias é um ponto de partida essencial, mas a experiência prática na utilização e construção de e-atividades é o que realmente faz a diferença. A prática permite ao docente ou formador não só dominar as ferramentas, mas também compreender melhor como integrá-las de forma eficaz nas suas estratégias pedagógicas. A experiência permite ajustar o uso das tecnologias às necessidades dos alunos, explorar diferentes abordagens e solucionar problemas que possam surgir durante a implementação.

    23. Margarida_Carvalho 13 Oct 2024
      o feedback deve ser construtivo, específicoe orientado para a ação, com vista a encorajar o aluno e a ajudá-lo aprogredir em relação aos objetivos de aprendizagem. Por isso, este deveser cuidadosamente integrado nas e-atividades para, além do que acaboude ser dito, ajudar a desenvolver alunos mais independentes e autónomos

      O feedback construtivo como é referido no texto é uma mais valia, apesar de concordar com a colega Mileidy, pois nem todos os formandos aceitam o parecer dado, por vezes temos que justificar minuciosamente o porquÊ daquele feedback. Contudo quando dado ao longo da e-atividade os formandos tendem a aceitar melhor e a procurar formas de resolver as suas dúvidas com as sugestões dadas pelo formado, pelos colegas ou através de si próprios, ganhando alguma autonomia no desenvolvimento das mesma. Na minha área uma das fases da realização das e-atividades passa pela exposição em grande grupo das respostas dadas individualmente ou da apresentação do trabalho desenvolvido em grupo, havendo espaço para debate onde todos são chamados a participar, incluindo o formador. Nalgumas situações é o ponto de partida para as fases seguintes, onde já serão inseridas melhorias e sugestões dadas.

    24. VaniaMota 13 Oct 2024
      opções pedagógicas, didáticas e metodológicas queestão na base da escolha da estrutura de uma e-atividade tendo emconta, por um lado, os conteúdos a explorar e as opções tecnológicas.Por outro, a forma como o fazem e as razões que nos levaram a adotardeterminado modelo

      Muito importante é o cálculo do tempo para cada e-atividade. É necessário ter em conta os conteúdos, as opções tecnológicas, o trabalho autónomo, o trabalho na sala de aula virtual síncrona, e o trabalho na sala de aula virtual assíncrona. É imprescindível ganhar competências pedagógico-digitais para decidir os recursos mais adequadas a cada objetivo.

    25. VaniaMota 13 Oct 2024
      Ao fornecer feedback sobre as e-atividades que estão aser desenvolvidas ou já foram finalizadas, os professores podem ajudar osalunos, por um lado, a compreender a sua evolução face aos objetivosde aprendizagem; por outro, fornecer orientações sobre como melhoraro seu desempenho.

      A estrutura e os objetivos da avaliação devem ser alinhados com o objetivo pedagógico. Os métodos de avaliação devem ser sempre bem definidos e informados aos alunos/formandos.

    26. VaniaMota 13 Oct 2024
      e-atividades, são importantes para ajudar os alunosa desenvolver competências relevantes para o mundo digital, onde seinclui o pensamento crítico, a resolução de problemas, a colaboração ea comunicação.

      Pensar, estruturar e planificar e-atividades é de extrema importância. O principal objetivo, além da construção de conhecimento, é o desenvolvimento do pensamento crítico, da resolução de problemas, do trabalho em equipa e da comunicação.

    27. IStaats 13 Oct 2024
      As e-atividades, ou seja, as atividades realizadas por meio de dispositivoseletrónicos, têm um papel importante no desenho das estratégias deaprendizagem.

      Por esta razão é essencial o conhecimento das tecnologias existentes ao dispor do docente/formador antes da estruturação das e-actividades.

    28. MartaLepage 13 Oct 2024
      Identificar o objetivo da aprendizagem: O que se quer que osalunos aprendam com a atividade. O objetivo de aprendizagemdeve ser claro e específico e deve estar em linha de conta comos objetivos gerais da unidade curricular/ curso.2. Definir as etapas da atividade: Determinar as etapas que os alunosirão precisar para concluir a atividade. Estas devem ser clarase sequenciadas para ajudar os alunos a compreender e seguiro processo. Também se deve fazer uma previsão do tempo deelaboração da e-atividade.3. Fornecer orientações claras: Indicar o que os alunos precisam fazer,como devem fazê-lo e quais os critérios de avaliação. Devemtambém definir-se os recursos, o formato e o tipo de participação(individual, grupal, trabalho colaborativo...).4. Fornecer feedback: Após a conclusão da atividade deve serfornecido feedback construtivo aos alunos, destacando o queeles fizeram bem e onde podem melhorar.

      As etapas da construção de uma e-atividade devem ser tidas em conta como uma guia, ou também como uma lista de verificação. Começando com a importância de definir objetivos SMART (específicos, mensuráveis, atingíveis, relevantes e limitados no tempo). Passando pela definição clara de como as e-atividades se irão desenvolver, para que o aluno possa organizar o seu tempo e método de trabalho e pela definição clara de critérios do que e como será avaliado. Por último e não menos importante feedback. Acrescentaria a importância deste feedback ser atempado e até mesmo a impostância de incentivar o feedback de pares, pois o próprio fornecimento de feedback implica a mobilização de pensamento crítico e de reflexão sobre o nosso próprio desempenho, quer enquanto alunos, que enquanto professores.

    29. francisco_meneses 12 Oct 2024

      È de fundamental importância identificar claramente o objetivo de aprendizagem numa atividade educacional/formativa. Ao definir o que os alunos /formandos precisam aprender, o formador/professor pode alinhar melhor a escolha de atividades com os objetivos educacionais/formativos . Este processo de identificação também facilita a escolha da categoria da Taxonomia de Bloom (TDB) mais adequada para a atividade, o que ajuda a orientar o nível de complexidade cognitiva a ser trabalhada.

    30. francisco_meneses 12 Oct 2024
      Analisar as e-atividades como estratégias pedagógicas dentro deum curso online

      Analisar as e-atividades como estratégias pedagógicas dentro de um curso online" obriganos" examinar o papel destas atividades no processo de ensino-aprendizagem digital( estas deverão ser pertinentes , objetivas e assertivas). Neste contexto, estas tarefas realizadas por meio de plataformas digitais, deverão estimular a interação entre alunos/formandos,o conteúdo e os professores/formadores. Estas desempenham um papel crucial em cursos online porque facilitam ointeesse/motivação e a construção ativa do conhecimento.

    31. Mariabarreto 12 Oct 2024
      Funções das e-atividades

      Tal como a autora nos diz, as funções de uma e-atividade são variadas, num breve resumo penso que as poderemos sistematizar ao seguinte: a) Facilitam o envolvimento ativo dos alunos; b) Promovem a autonomia; c) A possibilidade de Feedback imediato com em algumas LMS; d) Incentivam a colaboração dos estudantes; e) têm como características a adaptabilidade e flexibilidade; f) vão ao encontro dos diferentes estilos de aprendizagem;

      Saudações Maria Barreto

    32. Mariabarreto 12 Oct 2024
      a coerência que deve existir entre osresultados esperados, a metodologia de aprendizagem que selecionámos,o tipo de feedback e a avaliação proposta

      Nesta passagem do texto, destaco a importância da "coerência" , de facto a coerência é essencial para garantir que todos os elementos de um processo de ensino e de aprendizagem sejam alinhados, de modo a promover uma aprendizagem integrada e significativa, que possa ser mobilizada ao longo da vida.

      Saudações académicas Maria Barreto

    33. holy0122 12 Oct 2024
      Como vimos anteriormente existe uma panóplia de tipologias de e-atividades.A pergunta que se impõe é saber como selecionar a e-atividade maisadequada ao nosso propósito.

      A seleção da e-atividade mais adequada depende de vários fatores, incluindo os objetivos de aprendizagem. Definir objetivos de aprendizagem, a ter clareza sobre o que se pretende que os alunos aprendam ou desenvolvam; conhecer o perfil dos alunos. as características, como a idade, o nível de conhecimento, as preferências de aprendizagem e as habilidades tecnológicas; analisar os recursos disponíveis, sejam tecnológicos ou humanos disponíveis; escolher a tipologia da E-Atividade, através Quizzes e Testes Interativos, Fóruns de Discussão, Vídeos e Webinars, Projetos Colaborativos Online, Simulações e Jogos Educativos e por fim avaliar a eficácia, através de feedback dos alunos, análise de desempenho e reflexões sobre o processo de aprendizagem.

      Fernando Santos

    34. holy0122 12 Oct 2024
      As e-atividades, ou seja, as atividades realizadas por meio de dispositivoseletrónicos, têm um papel importante no desenho das estratégias deaprendizagem. Isso porque essas atividades podem ser utilizadas paradiversificar as formas de aprendizagem e envolver os alunos em processosmais dinâmicos e interativos.

      As e-atividades, ao serem integradas nas estratégias de aprendizagem, oferecem várias vantagens, como diversificar as formas de aprendizagem, ao utilizar dispositivos eletrónicos que permitam a criação de atividades variadas, como quizzes interativos, vídeos educacionais ou fóruns de discussão; a motivação, dinamismo e interatividade, com as e-atividades podemos tornar o processo de aprendizagem mais ativo, ao em vez de serem apenas recetores passivos de informação, os alunos participam ativamente e a flexibilidade e a acessibilidade pois com o uso de dispositivos eletrónicos, os alunos podem aceder ao material de aprendizagem a qualquer hora e em qualquer lugar. Fernando Santos

    35. Mariabarreto 12 Oct 2024
      formato digital

      No que respeita ao "formato digital" penso ser oportuno, remeter para o paradigma de educação digital, sabemos que tem vindo a transformar significativamente a forma como o ensino e a aprendizagem acontecem, que o covid-19, acelerou estes processos que já estavam a ser desenvolvidos, permitindo a flexibilidade e personalização do ensino. Ultimamente temos assistido ao avanço das tecnologias colaborativas, como plataformas de e-learning, cada vez mais especializadas para a educação. A integração de ambientes virtuais e híbridos possibilita não apenas a superação das barreiras geográficas, mas também a criação de novos cenários pedagógicos, indo ao encontro do desenvolvimento de competências digitais, colaborativas e pensamento crítico. No entanto, este novo paradigma também traz desafios, como a necessidade de garantir o acesso equitativo às tecnologias e de formar tanto os professores quantos os alunos para uma utilização eficaz e ética. A este respeito da educação digital, do hibridismo, multimodalidade, poderemos ler um artigo muito interessante sobre a importância da educação digital ao longo da vida, dos autores Schlemmer e Moreira (2020), cuja referência partilho.

      Schlemmer, E. e Moreira, A. (2020). Ampliando conceitos para o paradigma de educação digital onlife. Interações , 55, 103-122.

      Saudações académicas maria barreto

    36. SRuivinho 11 Oct 2024
      om as atividades referimo-nos a diferentes ações que os alunos realizamem completa relação com os conteúdos e as informações que lhe foramdadas. Se estas atividades, são apresentadas, realizadas ou transferidasatravés da rede, então podemos considerá-las como e-atividades” (p.11).

      Estas estratégias podem ser ensinadas e devem ser adaptadas às necessidades e estilos dos alunos, sendo fundamentais para a aprendizagem autônoma. Por sua vez, as estratégias de ensino referem-se às técnicas e métodos que os professores utilizam para transmitir conceitos e habilidades, variando conforme o conteúdo e os objetivos educacionais.

    37. Mariabarreto 11 Oct 2024
      As e-atividades estão centradas nos estudantes, para que possam construir,trabalhar e partilhar conhecimento. Estas estão suportadas pela ideia deque o conhecimento é construído pelos estudantes de forma colaborativa,ativa e participativa. Elas são um caminho de construção do conhecimento.Pensar desta forma facilita muito o fazer pedagógico do docente

      Não obstante esta ideia, sobre a importância de uma e-atividade para a construção do conhecimento, do meu ponto de vista um outro aspeto a realçar, relaciona-se a avaliação, Considero que a avaliação desempenha um papel central numa e-atividade, pois é através dela que se mede o progresso dos estudantes, se ajusta o processo de ensino-aprendizagem e se promove a reflexão sobre o conhecimento adquirido. Em ambientes digitais, tais como nos outros, a avaliação formativa é muito relevante devido às características dos modelos de autonomia e flexibilidade que marcam a educação online. A avaliação é, portanto, uma "ferramenta" essencial para garantir a eficácia das e-atividades e deve ser projetada com base em princípios pedagógicos sólidos. Saudações académicas

    38. Antonio_Costa 11 Oct 2024
      orientação para a construçãode uma e-atividade

      Há premissas importantes que servem para estruturar o pensamento na fase de conceção das e-atividades. Gostaria de sublinhar a importância de que elementos como a correta adequação dos conteúdos e os consequentes objetivos de aprendizagem estejam logicamente alinhados. A clareza das instruções/orientações deve ser condição fundamental, para assim existir uma progressão lógica nas diferentes etapas/fases da e-atividade, garantindo, desta forma, uma aprendizagem efetiva por parte dos alunos. Também será importante que o professor divulgue os resultados e faça um balanço de uma dada e-atividade, garantindo assim que os alunos tomam consciência da medida de concretização dos objetivos propostos, validando dessa forma eventuais oportunidades de melhoria. António Costa

    39. EJesus 11 Oct 2024

      Num contexto de ensino a distância digital, a planificação de E-atividades proporciona ao formando uma maior noção da sua assimilação de conceitos, conteúdos e consiste num método de avaliação de aprendizagens. São sem dúvida uma forma dinâmica e interativa de promover uma aprendizagem ativa, autónoma e onde se privilegia o pensamento crítico. De acordo com Almenara, Osuna & Cejudo (2014) e transportando-nos para um ambiente virtual, as e-atividades são o elemento que facilita a inter-relação entre o Ensino e a Aprendizagem. Na perspetiva do formador os desafios que se colocam ao desenhar uma e-atividade são vários, nomeadamente, ser objetivo, claro, adequar os conteúdos, conhecer os públicos, definir o tempo, apresentar recursos, selecionar o formato mais adequado, diversificar e avaliar.

      Em forma de conclusão as e-atividades permitem uma aprendizagem online ativa, participativa, colaborativa, seja desenvolvida de forma individual ou em grupo e cujo principal objetivo centra-se nas aprendizagens.

    40. AnaMonteiro 11 Oct 2024
      Como vimos anteriormente existe uma panóplia de tipologias de e-atividades.A pergunta que se impõe é saber como selecionar a e-atividade maisadequada ao nosso propósito.

      Esta tarefa que nos cabe a nós não é fácil, porque temos de ter vários fatores em consideração, tais como, o objetivo e finalidade do curso, a faixa etária, a aplicabilidade prática, etc...

    41. AnaMonteiro 11 Oct 2024
      Fornecer feedback: Após a conclusão da atividade deve serfornecido feedback construtivo aos alunos, destacando o queeles fizeram bem e onde podem melhorar

      o feedback é muito importante, ajuda os alunos a compreenderem melhor seus erros e acertos, proporcionando uma direção clara sobre como melhorar suas habilidades e conhecimentos.

    42. AnaMonteiro 11 Oct 2024
      observar que essas e-atividades podem ser concebidas para darresposta a cada um dos cinco estágios do modelo e, com isso, ajudar osalunos a construir comunidades virtuais de aprendizagem e a alcançar osseus objetivos de aprendizagem online

      Tendo por base na minha opinião a minha experiência como formadora de informática/programação a adolescentes, eu incentivava bastante trabalhos de grupo, primeiro porque é uma condição essencial para se estar em sociedade e eles demonstravam bastante interesse e empenhavam-se mais do que quando eram trabalhos individuais. Sentia que entre eles havia entreajuda e esforçavam-se para que o resultado final e a apresentação do trabalho fosse o melhor.

    43. AnaMonteiro 11 Oct 2024
      Isso porque essas atividades podem ser utilizadas paradiversificar as formas de aprendizagem e envolver os alunos em processosmais dinâmicos e interativos.

      Não conhecia esta ferramenta hypothes.is software que tem como objetivo recolher comentários sobre declarações feitas em qualquer conteúdo acessível pela web. Esta passagem apela à diversificação para cativar a atenção e interesse dos alunos/formandos. Eu dei formação de programação a adolescentes e tive algum sucesso quando usei ferramentas como: kahoot para elaborar quizz , Scratch: que é uma plataforma de programação visual que permite aos alunos criar projetos interativos utilizando blocos de código de forma lúdica, e o **CoSpaces ** que é uma aplicação que permite criar conteúdos de realidade virtual.

    44. Rui_Ventura 11 Oct 2024
      é importante garantir que as e-atividades sejam inclusivas eacessíveis a todos os alunos, independentemente das suas habilidades erecursos tecnológicos disponíveis.

      A inclusão representa um ato de igualdade entre os diferentes indivíduos na sociedade que permite que todos tenham o direito de integrar e participar das várias dimensões do seu ambiente, sem sofrer qualquer tipo de discriminação e preconceito. Assim, na minha opinião a importância das e-atividades inclusivas está diretamente ligada à necessidade de garantir que todos os alunos, independentemente das suas condições físicas, cognitivas, culturais ou socio-económicas, tenham igualdade de oportunidades no processo de aprendizagem. A inclusão é um princípio fundamental em ambientes de educação, presencial ou digital, e torna-se ainda mais relevante em plataformas online, onde as barreiras tecnológicas podem aumentar as desigualdades se não forem devidamente consideradas. Saudações Rui Ventura

    45. Mariabarreto 11 Oct 2024
      as atividades realizadas por meio de dispositivoseletrónicos, têm um papel importante no desenho das estratégias deaprendizagem. Isso porque essas atividades podem ser utilizadas paradiversificar as formas de aprendizagem e envolver os alunos em processosmais dinâmicos e interativos.

      Nesta passagem anotada na pg. 32, a autora relembra quanto importantes são os dispositivos eletrónicos no desenvolvimento de estratégias de ensino e de aprendizagem. Quando integramos as tecnologias, nos processos de ensino e de aprendizagem, vamos no caminho da diversificação dos métodos de ensino, tornando a aprendizagem mais dinâmica e interativa. Esta situação vai estimular o envolvimento dos alunos e possibilita abordagens mais personalizadas, adaptando-se às diferentes formas de aprender de cada discente. Por outro lado, o uso de atividades mediadas por tecnologias digitais no âmbito da educação vai facilitar o acesso a recursos variados, consequentemente o professor vai promover a autonomia dos alunos, ampliando suas oportunidades de aprendizagem dentro e fora da sala de aula e ao longo da vida. Maria Barreto

    46. liserra 11 Oct 2024
      o desenhar uma e-atividade é importante seguir alguns passos e ter algunselementos em atenção. Isto para que os alunos tenham a perceção da suautilidade para a formação que estão a ter e, assim, se consigam motivare envolver na sua realização. Para que tal aconteça é importante quese verifique uma correta adequação entre os conteúdos e a atividadeproposta; é igualmente pertinente que os alunos percebam a utilidade daatividade para a sua aprendizagem e que a mesma seja clara; é tambémrelevante que as atividades propostas ao longo da ação formativa sejamdiversificadas e estejam de acordo com o nível educativo dos alunos; os doisúltimos itens a ter em conta são o conhecimento dos critérios de avaliaçãoe a adequação do tempo para a realização da tarefa. É importante queo professor faça uma adequada planificação da tarefa para proporcionaraos alunos o tempo necessário para dar oportunidades a que todos possamrefletir e responder ao desafio proposto

      Na minha perspetiva, considero que a criatividade e o fator surpresa são elementos muito importantes na criação de atividades e e-atividades. Criar experiências de aprendizagem "fora da caixa", devidamente enquadradas, conduzidas e avaliadas, despertam uma maior curiosidade, maior envolvimento, bem como são mais facilmente recordadas ao longo do tempo.

      Todos os elementos aqui retratados são cruciais, mas gostava de salientar a importância da diversificação, uma vez que podem ser criadas e-atividades muito adequdas, mas se são uma repetição de formato, facilmente perdem o seu impacto na aprendizagem do formando, o qual terá menos interesse, motivação e envolvimento na sua realização.

    48. mileidymarquesmartins 10 Oct 2024
      feedback

      A importância do feedback no processo de aprendizagem: os formandos tomarem conhecimento da sua evolução, de acordo com os objetivos de aprendizagem;, serem orientados pelos formadores ou professores no sentido de melhorarem o seu desempenho, mas não é algo fácil de fazer na minha opinião. Porque do outro lado nem sempre é bem aceite.

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  33. 52.2.80.92:1336 52.2.80.92:1336
    Edm8ker
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    1. Himangiv 25 Oct 2024
      Get in touch with our team,

      This sshould be configured as a mailt o link that opens the user's default email client when clicked, directing them to send an email to hello@edm8ker.com.

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  34. www.csfd.cz www.csfd.cz
    Zmizení (2013) | ČSFD.cz
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    1. blueronin 25 Oct 2024
      Silné téma, vynikající scénář plný zvratů a životní herecké výkony poskládaly dohromady thriller o pátrání po dvou zmizelých děvčatech, který je napínavý až k nesnesení. Keller Dover (Hugh Jackman) čelí asi nejhorší noční můře každého rodiče, jeho šestiletá dcera Anna a její kamarádka Joy jednoho večera na Díkuvzdání zmizí. Jejich hledání nebere konce, hodiny se vlečnou a dívky jsou stále pohřešovány. Do objektu zájmu se při pátrání dostane zchátralý karavan, který parkoval před jejich domem a u kterého si dívky naposledy hrály. K případu je povolán detektiv Loki (Jake Gyllenhaal), který zatýká řidiče karavanu, retardovaného Alexe Jonese (Paul Dano), ale pro nedostatek důkazů je Jones po nějaké době propuštěn. Oficiální pátrání sice stále pokračuje, ale Dover se cítí bezradný, jeho strach se mísí se vztekem a zlobou. Bere spravedlnost do svých rukou a bez ohledu na následky se rozhodne vyslechnout jediné pojítko k případu sám, po svém a bez rukaviček.
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  35. www.csfd.cz www.csfd.cz
    Duna (2021)
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    1. blueronin 25 Oct 2024
      Kultovní sci-fi dílo vypráví o mocenských bojích uvnitř galaktického Impéria, v nichž jde o ovládnutí planety Arrakis: zdroje vzácného koření - melanže, jež poskytuje zvláštní psychické schopnosti, které umožňují cestování vesmírem. Padišáh imperátor svěří správu nad Arrakisem a s ní i komplikovanou těžbu neobyčejné látky vévodovi rodu Atreidů. Celá anabáze je ale součástí spiknutí, z něhož se podaří vyváznout jen vévodovu synovi Paulovi a jeho matce, kteří uprchnou do pouště. Jejich jedinou nadějí jsou nedůvěřiví domorodí obyvatelé fremeni, schopní trvale přežít ve vyprahlé pustině. Mohl by Paul Atreides být spasitelem, na kterého tak dlouho čekají?
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  36. www.biorxiv.org www.biorxiv.org
    On the discovered Cancer Driving Nucleotides (CDNs) –Distributions across genes, cancer types and patients
    1
    1. Public_Reviews 25 Oct 2024

      Author response:

      The following is the authors’ response to the original reviews.

      eLife Assessment <br /> This valuable study is a companion to a paper introducing a theoretical framework and methodology for identifying Cancer Driving Nucleotides (CDNs). While the evidence that recurrent SNVs or CDNs are common in true cancer driver genes is solid, the evidence that many more undiscovered cancer driver mutations will have CDNs, and that this approach could identify these undiscovered driver genes with about 100,000 samples, is limited. 

      Same criticism as in the eLife assessment of eLife-RP-RA-2024-99340 (https://elifesciences.org/reviewed-preprints/99340). Hence, please refer to the responses to the companion paper.

      Public Reviews:

      Reviewer #1 (Public Review):

      The study investigates Cancer Driving Nucleotides (CDNs) using the TCGA database, finding that these recurring point mutations could greatly enhance our understanding of cancer genomics and improve personalized treatment strategies. Despite identifying 50-150 CDNs per cancer type, the research reveals that a significant number remain undiscovered, limiting current therapeutic applications, and underscoring the need for further larger-scale research.

      Strengths:

      The study provides a detailed examination of cancer-driving mutations at the nucleotide level, offering a more precise understanding than traditional gene-level analyses. The authors found a significant number of CDNs remain undiscovered, with only 0-2 identified per patient out of an expected 5-8, indicating that many important mutations are still missing. The study indicated that identifying more CDNs could potentially significantly impact the development of personalized cancer therapies, improving patient outcomes.

      Weaknesses:

      The study is constrained by relatively small sample sizes for each cancer type, which reduces the statistical power and robustness of the findings. ICGC and other large-scale WGS datasets are publicly available but were not included in this study.

      Thanks. We indeed have used all public data, including GENIE (figure 7 of the companion paper), ICGC and other integrated resources such as COSMIC. The main study is based on TCGA because it is unbiased for estimating the probability of CDN occurrences. In many datasets, the numerators are given but the denominators are not (the number of patients with the mutation / the total number of patients surveyed). In GENIE, we observed that E(u) estimated upon given sequencing panels are much smaller than in TCGA, this might be due to the selective report of nonsynonymous mutations for synonymous mutations are generally considered irrelevant in tumorigenesis.

      To be able to identify rare driver mutations, more samples are needed to improve the statistical power, which is well-known in cancer research. The challenges in direct functional testing of CDNs due to the complexity of tumor evolution and unknown mutation combinations limit the practical applicability of the findings.

      We fully agree. We now add a few sentences, making clear that the theory allows us to see how much more can be gained by each stepwise increase in sample size. For example, when the sample size reaches 106, further increases will yield almost no gain in confidence of CDNs identified (see figures of eLife-RP-RA-2024-99340. As pointed out in our provisional responses, an important strength of this pair of studies is that the results are testable. The complexity is the combination of mutations required for tumorigenesis and the identification of such combinations is the main goal and strength of this pair of studies. We add a few sentences to this effect.

      While the importance of large sample sizes in identifying cancer drivers is well-recognized, the analytical framework presented in the companion paper (https://elifesciences.org/reviewed-preprints/99340) goes a step further by quantitatively elucidating the relationship between sample size and the resolution of CDN detection.

      The question is very general as it is about multigene interactions, or epistasis. The challenges are true in all aspects of evolutionary biology, for example, the genetics of reproductive isolation(Wu and Ting 2004). The issue of epistasis is difficult because most, if not all, of the underlying mutations have to be identified in order to carry out functional tests. While the full identification is rarely feasible, it is precisely the objective of the CDN project. When the sample size increases to 100,000 for a cancer type, all point mutations for that cancer type should be identifiable.

      The QC of the TCGA data was not very strict, i.e, "patients with more than 3000 coding region point mutations were filtered out as potential hypermutator phenotypes", it would be better to remove patients beyond +/- 3*S.D from the mean number of mutations for each cancer type. Given some point mutations with >3 hits in the TCGA dataset, they were just false positive mutation callings, particularly in the large repeat regions in the human genome.

      Thanks. The GDC data portal offers data calls from multiple pipelines, enabling us to select mutations detected by at least two pipelines. While including patients with hypermutator phenotypes could introduce potential noise, as shown in Eq. 10 of the main text, our method for defining the upper limit of i* is relative robust to the fluctuations in the E(u) of the corresponding cancer population. Since readers may often ask about this, we expand the Methods section somewhat to emphasize this point.

      The codes for the statistical calculation (i.e., calculation of Ai_e, et al) are not publicly available, which makes the findings hard to be replicated.

      We have now updated the section of “Data Availability” in both papers. The key scripts for generating the major results are available at: https://gitlab.com/ultramicroevo/cdn_v1.

      Reviewer #2 (Public Review):

      Summary:

      The study proposes that many cancer driver mutations are not yet identified but could be identified if they harbor recurrent SNVs. The paper leverages the analysis from Paper #1 that used quantitative analysis to demonstrate that SNVs or CDNs seen 3 or more times are more likely to occur due to selection (ie a driver mutation) than they are to occur by chance or random mutation.

      Strengths:

      Empirically, mutation frequency is an excellent marker of a driver gene because canonical driver mutations typically have recurrent SNVs. Using the TCGA database, the paper illustrates that CDNs can identify canonical driver mutations (Figure 3) and that most CDNs are likely to disrupt protein function (Figure 2). In addition, CDNs can be shared between cancer types (Figure 4).

      Weaknesses:

      Driver alteration validation is difficult, with disagreements on what defines a driver mutation, and how many driver mutations are present in a cancer. The value proposed by the authors is that the identification of all driver genes can facilitate the design of patient-specific targeting therapies, but most targeted therapies are already directed towards known driver genes. There is an incomplete discussion of oncogenes (where activating mutations tend to target a single amino acid or repeat) and tumor suppressor genes (where inactivating mutations may be more spread across the gene). Other alterations (epigenetic, indels, translocations, CNVs) would be missed by this type of analysis.

      The above paragraph has three distinct points. We shall respond one by one.

      First, …  can facilitate the design of patient-specific targeting therapies, but most targeted therapies are already directed towards known driver genes…

      We state in the text of Discussion the following that shows only a few best-known driving mutations have been targeted. It is accurate to say that < 5% of CDNs we have identified are on the current targeting list. Furthermore, this list we have compiled is < 10% of what we expect to find.

      Direct functional test of CDNs would be to introduce putative cancer-driving mutations and observe the evolution of tumors. Such a task of introducing multiple mutations that are collectively needed to drive tumorigenesis has been done only recently, and only for the best-known cancer driving mutations (Ortmann et al. 2015; Takeda et al. 2015; Hodis et al. 2022). In most tumors, the correct combination of mutations needed is not known. Clearly, CDNs, with their strong tumorigenic strength, are suitable candidates.

      Second, “There is an incomplete discussion of oncogenes (where activating mutations tend to target a single amino acid or repeat) and tumor suppressor genes (where inactivating mutations may be more spread across the gene).”

      We sincerely thank the reviewer for this insightful comment. Below are two new paragraphs in the Discussion pertaining to the point:

      In this context, we should comment on the feasibility of targeting CDNs that may occur in either oncogenes (ONCs) or tumor suppressor genes (TSGs). It is generally accepted that ONCs drive tumorigenesis thanks to the gain-of-function (GOF) mutations whereas TSGs derive their tumorigenic powers by loss-of-function (LOF) mutations. It is worthwhile to point out that, since LOF mutations are likely to be more widespread on a gene, CDNs are biased toward GOF mutations. The often even distribution of non-sense mutations along the length of TSGs provide such evidence. As gene targeting aims to diminish gene functions, GOF mutations are perceived to be targetable whereas LOF mutations are not. By extension, ONCs should be targetable but TSGs are not. This last assertion is not true because mutations on TSGs may often be of the GOF kind as well.

      The data often suggest that mis-sense mutations on TSGs are of the GOF kind. If mis-sense mutations are far more prevalent than nonsense mutations in tumors, the mis-sense mutations cannot possibly be LOF mutations. (After all, it is not possible to lose more functions than nonsense mutations.) For example, AAA to AAC (K to Q) is a mis-sense mutation while AAA to AAT (K to stop) is a non-sense mutation. In a separate study (referred to as the escape-route analysis), we found many cases where the mis-sense mutations on TSGs are more prevalent (> 10X) than nonsense mutations. Another well-known example is the distribution of non-sense mutations TSGs. For example, on APC, a prominent TSG, non-sense mutations are far more common in the middle 20% of the gene than the rest (Zhang and Shay 2017; Erazo-Oliveras et al. 2023). The pattern suggests that even these non-sense mutations could have GOF properties. 

      The following response is about the clinical implications of our CDN analysis. Canonical targeted therapy often relies on the Tyrosine Kinase Inhibitors (TKIs) (Dang et al. 2017; Danesi et al. 2021; Waarts et al. 2022). Theoretically, any intervention that suppresses the expression of gain-of-function (GOF) CDNs could potentially have therapeutic value in cancer treatment. This leads us to a discussion of oncogenes versus TSGs in the context of GOF / LOF (loss of function) mutations. Not all mutations on oncogenes have oncogenic effect, besides, truncated mutations in oncogenes are often subject to negative selection (Bányai et al. 2021), the identification of CDNs within oncogenes is therefore crucial for developing effective cancer treatment guidelines. Secondly, while TSGs are generally believed to promote cancer development via loss of function mutations, research suggests that certain mutations within TSGs can have GOF-like effect, such as the dominant negative effect of truncated TP53 mutations (Marutani et al. 1999; de Vries et al. 2002; Gerasimavicius et al. 2022). Characterizing driver mutations as GOF or LOF mutations could potentially expand the scope of targeted cancer therapy. We’ll address this issue in a third study in preparation.

      The method could be more valuable when applied to the noncoding genome, where driver mutations in promoters or enhancers are relatively rare, or as yet to be discovered. Increasingly more cancers have had whole genome sequencing. Compared to WES, criteria for driver mutations in noncoding regions are less clear, and this method could potentially provide new noncoding driver CDNs. Observing the same mutation in more than one cancer specimen is empirically unusual, and the authors provide a solid quantitative analysis that indicates many recurrent mutations are likely to be cancer-driver mutations.

      Again, we are grateful for the comments which prompt us to expand a paragraph in Discussion, reproduced below.

      The CDN approach has two additional applications. First, it can be used to find CDNs in non-coding regions. Although the number of whole genome sequences at present is still insufficient for systematic CDN detection, the preliminary analysis suggests that the density of CDNs in non-coding regions is orders of magnitude lower than in coding regions. Second, CDNs can also be used in cancer screening with the advantage of efficiency as the targeted mutations are fewer. For the same reason, the false negative rate should be much lower too. Indeed, the false positive rate should be far lower than the gene-based screen which often shows a false positive rate of >50% (supplement File S1).

      Again, we are grateful that Reviewer #2 have addressed the potential value of our study in finding cancer drivers in non-coding regions. A major challenge in this area lies in defining the appropriate L value as presented in Eq. 10. In the main text, we used a gamma distribution to account for the variability of mutation rates across sites in coding region. For the non-coding region, we will categorize these regions based on biological annotations. The goal is to set different i* cutoffs for different genomic regions (such as heterochromatin / euchromatin, GC-rich regions or centromeric regions), and avoid false positive calls for CDN in repeated regions (Elliott and Larsson 2021; Peña et al. 2023).

      References

      Bányai L, Trexler M, Kerekes K, Csuka O, Patthy L. 2021. Use of signals of positive and negative selection to distinguish cancer genes and passenger genes. Elife 10:e59629.

      Danesi R, Fogli S, Indraccolo S, Del Re M, Dei Tos AP, Leoncini L, Antonuzzo L, Bonanno L, Guarneri V, Pierini A, et al. 2021. Druggable targets meet oncogenic drivers: opportunities and limitations of target-based classification of tumors and the role of Molecular Tumor Boards. ESMO Open 6:100040.

      Dang CV, Reddy EP, Shokat KM, Soucek L. 2017. Drugging the “undruggable” cancer targets. Nat Rev Cancer 17:502–508.

      Elliott K, Larsson E. 2021. Non-coding driver mutations in human cancer. Nat Rev Cancer 21:500–509.

      Erazo-Oliveras A, Muñoz-Vega M, Mlih M, Thiriveedi V, Salinas ML, Rivera-Rodríguez JM, Kim E, Wright RC, Wang X, Landrock KK, et al. 2023. Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin. Nat Commun 14:4342.

      Gerasimavicius L, Livesey BJ, Marsh JA. 2022. Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure. Nat Commun 13:3895.

      Hodis E, Triglia ET, Kwon JYH, Biancalani T, Zakka LR, Parkar S, Hütter J-C, Buffoni L, Delorey TM, Phillips D, et al. 2022. Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment. Science 376:eabi8175.

      Marutani M, Tonoki H, Tada M, Takahashi M, Kashiwazaki H, Hida Y, Hamada J, Asaka M, Moriuchi T. 1999. Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastoma multiforme. Cancer Res 59:4765–4769.

      Ortmann CA, Kent DG, Nangalia J, Silber Y, Wedge DC, Grinfeld J, Baxter EJ, Massie CE, Papaemmanuil E, Menon S, et al. 2015. Effect of Mutation Order on Myeloproliferative Neoplasms. N Engl J Med 372:601–612.

      Peña MV de la, Summanen PAM, Liukkonen M, Kronholm I. 2023. Chromatin structure influences rate and spectrum of spontaneous mutations in Neurospora crassa. Genome Res. 33:599–611.

      Takeda H, Wei Z, Koso H, Rust AG, Yew CCK, Mann MB, Ward JM, Adams DJ, Copeland NG, Jenkins NA. 2015. Transposon mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression. Nat Genet 47:142–150.

      de Vries A, Flores ER, Miranda B, Hsieh H-M, van Oostrom CThM, Sage J, Jacks T. 2002. Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proceedings of the National Academy of Sciences 99:2948–2953.

      Waarts MR, Stonestrom AJ, Park YC, Levine RL. 2022. Targeting mutations in cancer. J Clin Invest 132:e154943.

      Wu C-I, Ting C-T. 2004. Genes and speciation. Nat Rev Genet 5:114–122.

      Zhang L, Shay JW. 2017. Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer. JNCI: Journal of the National Cancer Institute 109:djw332.

      AuthorResponse
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  37. www.americanyawp.com www.americanyawp.com
    Thomas Paine calls for American independence, 1776 | The American Yawp Reader
    1
    1. MEEHANM2 24 Oct 2024
      Every spot of the old world is overrun with oppression. Freedom hath been hunted round the globe. Asia, and Africa, have long expelled her. — Europe regards her like a stranger, and England hath given her warning to depart. O! receive the fugitive, and prepare in time an asylum for mankind.

      This highlights the time Paine lived, where most continents were ruled by monarchies, or if not that something similar. This shows how much of a step the colonies are taking, which in effect was fighting a system of government that was in charge of almost every nation on Earth.

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  38. www.planalto.gov.br www.planalto.gov.br
    L8112compilado
    1
    1. hvs 24 Oct 2024
      Art. 125
      • Informativo nº 828
      • 8 de outubro de 2024.
      • PRIMEIRA TURMA
      • Compartilhe:
      • Processo: Processo em segredo de justiça, Rel. Ministra Regina Helena Costa, Primeira Turma, por unanimidade, julgado em 1/10/2024, DJe 4/10/2024.

      Ramo do Direito DIREITO ADMINISTRATIVO

      TemaSaúde e Bem-Estar Paz, Justiça e Instituições Eficazes<br /> Processo administrativo disciplinar. Controle de legalidade. Independência mitigada entre as instâncias. Sentença penal absolutória imprópria. Inimputabilidade fundada no art. 26 do Código Penal. Repercussão sobre a esfera administrativa. Exclusão da culpabilidade. Sanção administrativa. Impossibilidade. Dever de avaliar licença para tratamento de saúde ou de aposentadoria por invalidez.

      Destaque - Quando o juízo criminal reconhece a inimputabilidade do agente fundada no art. 26 do Código Penal e profere sentença absolutória imprópria, com imposição de medida de segurança, descabe a fixação de sanção administrativa, impondo-se à Administração Pública, ao revés, o dever de avaliar a eventual concessão de licença para tratamento de saúde ou de aposentadoria por invalidez.

      Informações do Inteiro Teor - Cinge-se a controvérsia acerca do controle de legalidade de Processo Administrativo Disciplinar, notadamente para aferir se, diante da incontroversa inimputabilidade da Impetrante reconhecida em âmbito criminal, viável a subsistência de penalidade disciplinar pelos mesmos fatos.

      • A jurisprudência do Superior Tribunal de Justiça firmou-se no sentido de que o controle jurisdicional de processos administrativos disciplinares se restringe ao exame da regularidade do procedimento e da legalidade do ato, à luz dos princípios do contraditório, da ampla defesa e do devido processo legal, sendo vedada qualquer incursão no mérito administrativo.

      • Os artigos 66 do Código de Processo Penal, 935 do Código Civil, e 125 e 126 da Lei n. 8.112/1990, consagram o princípio da relativa independência entre as instâncias civil, administrativa e penal, possibilitando apurações distintas no âmbito de cada esfera de responsabilidade, ressalvada, como regra, a prevalência da jurisdição criminal quanto à afirmação categórica acerca da inocorrência da conduta ou quando peremptoriamente afastada a contribuição do agente para sua prática.

      • Além das hipóteses expressamente previstas em lei, à luz do princípio constitucional da culpabilidade, impõe-se observar a comunicação entre as órbitas penal e administrativa quando o juízo criminal reconhece, de maneira contundente, a inimputabilidade do agente fundada no art. 26 do Código Penal e profere sentença absolutória imprópria, com imposição de medida de segurança, especificamente em situações nas quais, constatada enfermidade psíquica, o acusado era, ao tempo da ação ou omissão, inteiramente incapaz de entender o caráter ilícito do fato ou de determinar-se de acordo com esse entendimento, porquanto causa excludente da culpa em sentido lato.

      • A certificação da inimputabilidade exige acentuada incursão fática, prévia instauração de incidente de insanidade mental (art. 149 do CPP) e detida análise de laudos médicos para avaliar a higidez psíquica do acusado, de modo que a conclusão positiva acerca da carência de discernimento cognitivo encerra juízo de certeza impassível de ulterior revisão ou desconsideração na via administrativa. Nessas circunstâncias, a despeito da ausência de disposição legal expressa determinando a repercussão da sentença penal absolutória imprópria sobre a decisão administrativa, admitir a subsistência da responsabilidade disciplinar quando rechaçada a punição criminal em razão de causa biopsicológica excludente de culpabilidade traduziria evidente incoerência.

      • Constatada a prática de falta disciplinar quando o agente estava em surto psicótico e absolutamente incapaz de entender o caráter ilícito do fato cometido, descabe a fixação de sanção administrativa, impondo-se à Administração Pública, ao revés, o dever de avaliar a eventual concessão de licença para tratamento de saúde ou de aposentadoria por invalidez, sendo inviável o apenamento de pessoa mentalmente enferma à época da conduta imputada.

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  39. accessmedicina.mhmedical.com accessmedicina.mhmedical.com
    Corazón | Anatomía macroscópica. Un panorama general, 2e | AccessMedicina | McGraw Hill Medical
    1
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  40. www.facebook.com www.facebook.com
    (7) Saigon Dining Guide 🍽️ | Facebook
    1
    1. A.Tun 24 Oct 2024
      Trả nợ ân tình tàu ngầm ăn chơi cho group bằng một chiếc quán Huế xinh ơi là xinh trong một con hẻm nhỏ giữa Q3. Nghe thông tin hành lang chưa xác minh thì đây là nhà của em gái nhạc sĩ Trịnh Công Sơn. OMA nằm cuối con hẻm với khoảnh sân rợp bóng cây, không gian bên trong nhỏ xinh dễ chịu lắm, rất phù hợp để đi 2 người hoặc nhóm nhỏ 5-7 người trở xuống thôi vì ít bàn. Mình với người bạn gọi bún hến, bún bò, dấm nuốc và gỏi mít. Tất cả đều nêm nếm rất vừa vặn theo khẩu vị của mình - người hàng xóm đến từ Đà Nẽng. Phần gỏi mít hơi bé, nhưng 3 món còn lại đầy đặn nha. Dấm nuốc mình ăn thử cho biết, cg ngon nhưng ko phải gu mình vì mình thấy vị nước lèo bún ko giống bún mà mì quảng cg ko ra mì quảng. Nhưng ngon. Bún hến siêu ngon, nước hến ko bị tanh, thoang thoảng vị gừng. Bạn mình cg khen bún bò, vị “rất Huế”. Gỏi mít rất ngon, gỏi nhưng mít âm ấm rất đúng gu mình hay ăn ở Huế (gỏi vả ăn ở Huế cg ấm chứ ko lạnh tanh). Chia nhau ăn nhiêu đó xong uống ấm trà xanh nóng là no căng, bill tầm hơn 500k. Ăn xong đi bộ qua hẻm kế bên có cafe Okkio, hoặc đối diện có Thái Yên mới mở, dù thở ko nổi nữa nhưng SG mấy nay mùa thu mát trời vẫn phải tạt vào ngồi ở sân làm ly cafe ngắm trời mây.Oma Eatery - 47F Phạm Ngọc Thạch, Q3#saigondiningguide#saigondining_monViet#saigondining_quan3

      .

      #saigondiningguide #saigondining_monViet #saigondining_quan3
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  41. docs.google.com docs.google.com
    Formato CFE XML
    1
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  42. eur-lex.europa.eu eur-lex.europa.eu
    Getin Noble Bank
    4
    1. Carla_BLANCO 23 Oct 2024
      ¿Deben interpretarse el artículo 2 TUE, el artículo 6 TUE, apartados 1 y 3, y elartículo 19 TUE, apartado 1, párrafo segundo, en relación con el artículo 47, [párrafosprimero y segundo], de la Carta y con el artículo 267 TFUE, párrafo tercero el artículo 38 dela Carta y el artículo 7, apartados 1 y 2, de la Directiva 93/13 en el sentido de que lasdisposiciones constitucionales de un Estado miembro de la Unión [...] relativas al sistemajudicial o al nombramiento de los jueces que impiden examinar la eficacia del nombramientode un juez pueden, con arreglo al Derecho de la Unión [...], impedir la declaración de la faltade independencia de un órgano jurisdiccional o de la independencia de un juez que lo integredebido a las circunstancias mencionadas en las cuestiones primera a quinta?

      Si estas disposiciones deben interpretarse de manera que las normas constitucionales de un Estado miembro, que impiden examinar la validez del nombramiento de un juez, puedan impedir la declaración de falta de independencia de un tribunal o juez.

      Considera si, según el Derecho de la Unión, es posible que las circunstancias mencionadas en cuestiones anteriores puedan afectar la independencia judicial.

      Esencialmente, la pregunta es si la interpretación de estas disposiciones puede permitir que las normas constitucionales de un Estado miembro que obstaculizan la revisión de nombramientos judiciales impidan determinar la falta de independencia e imparcialidad de un juez o tribunal.

    2. Carla_BLANCO 23 Oct 2024
      ¿Deben interpretarse el artículo 2 TUE, el artículo 4 TUE, apartado 3, el artículo 6 TUE,apartados 1 y 3, y el artículo 19 TUE, apartado 1, párrafo segundo, en relación con elartículo 47, [párrafos primero y segundo], de la Carta y con el artículo 267 TFUE, párrafotercero, el artículo 38 de la Carta y el artículo 7, apartados 1 y 2, de la Directiva 93/13 en elsentido de que es un órgano jurisdiccional independiente e imparcial y con la calificaciónadecuada, a efectos del Derecho de la Unión, un órgano en el que ejerce una personanombrada por primera vez o sucesivamente (para un órgano jurisdiccional de instanciasuperior) para desempeñar el cargo de juez, cuya candidatura para el nombramiento a esecargo fue propuesta en un procedimiento tramitado ante el órgano que examinaba a loscandidatos [Krajowa Rada Sądownictwa (Consejo Nacional del Poder Judicial)], si dichoprocedimiento no cumplía los requisitos de publicidad y transparencia de las normas deselección de los candidatos, lo que podría socavar la confianza que debe inspirar la judicaturaen una sociedad democrática

      pregunta 5 = La pregunta plantea si deben interpretarse ciertos artículos del Tratado de la Unión Europea (TUE), la Carta de Derechos Fundamentales de la Unión Europea (Carta), el Tratado de Funcionamiento de la Unión Europea (TFUE) y la Directiva 93/13/CEE para considerar si un órgano jurisdiccional es independiente e imparcial.

      La pregunta se enfoca en un juez cuya candidatura fue propuesta en un procedimiento ante el Consejo Nacional del Poder Judicial (Krajowa Rada Sądownictwa). Se cuestiona si este procedimiento, al no cumplir con los requisitos de publicidad y transparencia, puede socavar la confianza en la judicatura en una sociedad democrática.

      En resumen, la cuestión es si, dadas las faltas de transparencia y publicidad en el nombramiento, se puede considerar que el juez forma parte de un órgano independiente e imparcial bajo el derecho de la Unión Europea.

    3. Carla_BLANCO 23 Oct 2024
      en elsentido de que es un órgano jurisdiccional independiente e imparcial y con la calificaciónadecuada, a los efectos del Derecho de la Unión, un órgano en el que ejerce una persona quefue nombrada por primera vez o sucesivamente (para un órgano jurisdiccional de instanciasuperior) para desempeñar el cargo de juez por una autoridad política del poder ejecutivo deun Estado con un sistema de gobierno totalitario, no democrático y comunista

      pregunta 1 = según esos artículos;;; es adminisible considerar al juez democrático

    4. Carla_BLANCO 23 Oct 2024
      egún el órgano jurisdiccional remitente, los elementos fácticos y jurídicos relativos alnombramiento de un juez deben examinarse en cada etapa del procedimiento judicial, con el finde comprobar la independencia de la formación de enjuiciamiento a la que pertenece dicho juez.Así, el respeto de las exigencias de independencia e imparcialidad debe apreciarse, en su opinión,en cada caso concreto, teniendo en cuenta la eventual incidencia de las modalidades denombramiento de los jueces en el asunto examinado.43 El órgano jurisdiccional remitente considera que apreciar la independencia de un tribunal o laregularidad del nombramiento de un juez in abstracto, es decir, sin analizar la existencia de unaeventual incidencia sobre el asunto examinado del proceso de nombramiento del juez de que setrate, permitiría eludir las normas relativas a la inamovilidad de los jueces que, en principio, estánprevistas en disposiciones constitucionales. A este respecto, el órgano jurisdiccional remitentesubraya que, a la luz de la Constitución y de la jurisprudencia constitucional polacas, en teoría, esimposible cuestionar el nombramiento de un juez.44 Así, según el órgano jurisdiccional remitente, únicamente un examen en cada caso concreto de las«características individuales» de un juez, como su postura ética, en el contexto de la apreciaciónde su independencia, permitiría mantener la confianza de los justiciables en las institucionesjudiciales

      ARGUMENTO PARTE 1

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  43. Local file Local file
    Untitled document
    2
    1. brunosouza 22 Oct 2024
      solipsista

      Um solipsista é uma pessoa que adere à doutrina filosófica do solipsismo. Essa teoria sugere que a única realidade que podemos ter certeza de existir é a nossa própria mente e consciência. Em outras palavras, o solipsista acredita que o mundo exterior, incluindo outras pessoas, objetos e eventos, pode não ser mais do que uma construção da nossa própria mente.

      Em resumo, um solipssista acredita que:

      • A realidade é subjetiva: O mundo que percebemos é uma criação da nossa mente.
      • Não há garantia da existência de outros: Não podemos ter certeza de que outras pessoas ou coisas existem fora da nossa própria percepção.
      • O "eu" é o centro de tudo: A própria consciência é o único ponto de referência confiável.

      É importante notar:

      • Solipsismo é uma teoria filosófica: É uma forma de pensar sobre a natureza da realidade, e não um fato comprovado.
      • É uma posição extrema: A maioria das pessoas não acredita no solipsismo, pois a experiência cotidiana nos leva a acreditar na existência de um mundo exterior.
      • Tem implicações profundas: Se o solipsismo fosse verdade, teria implicações profundas para a ética, a ciência e a nossa compreensão da realidade.

      Por que as pessoas se interessam pelo solipsismo?

      • Dúvidas sobre a natureza da realidade: O solipsismo pode surgir como uma resposta a questões profundas sobre a natureza da consciência e da percepção.
      • Experiências pessoais: Algumas pessoas podem se sentir isoladas ou desconectadas do mundo, o que pode levar a questionamentos sobre a realidade daquilo que as cerca.
      • Interesse em filosofia: O solipsismo é um tema comum em debates filosóficos sobre a epistemologia (teoria do conhecimento) e a metafísica (estudo da natureza da realidade).

      Em suma, o solipsismo é uma ideia fascinante, mas controversa, que nos convida a refletir sobre a natureza da nossa própria consciência e a relação entre a mente e o mundo.

      Gostaria de saber mais sobre algum aspecto específico do solipsismo?

      Por exemplo, posso te explicar como o solipsismo se relaciona com outras correntes filosóficas, ou te dar exemplos de filósofos que defenderam essa ideia.

    2. brunosouza 22 Oct 2024
      cataplasmas

      Cataplasma, no dicionário: "papa medicamentosa feita de farinhas, polpas ou pó de raízes e folhas que se aplica sobre alguma parte do corpo dolorida ou inflamada." Também é traduzida como o mesmo que emplastro, ou seja: "é uma compressa umedecida (e às vezes aquecida) aplicada na pele para aliviar sintomas de infecções, inflamações, dores e abscessos superficiais."

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  44. www.medrxiv.org www.medrxiv.org
    Serum metabolome indicators of early childhood development in the Brazilian National Survey on Child Nutrition (ENANI-2019)
    1
    1. Public_Reviews 22 Oct 2024

      Author response:

      Reviewer #1 (Public Review):

      Padilha et al. aimed to find prospective metabolite biomarkers in serum of children aged 6-59 months that were indicative of neurodevelopmental outcomes. The authors leveraged data and samples from the cross-sectional Brazilian National Survey on Child Nutrition (ENANI-2019), and an untargeted multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS) approach was used to measure metabolites in serum samples (n=5004) which were identified via a large library of standards. After correlating the metabolite levels against the developmental quotient (DQ), or the degree of which age-appropriate developmental milestones were achieved as evaluated by the Survey of Well-being of Young Children, serum concentrations of phenylacetylglutamine (PAG), cresol sulfate (CS), hippuric acid (HA) and trimethylamine-N-oxide (TMAO) were significantly negatively associated with DQ. Examination of the covariates revealed that the negative associations of PAG, HA, TMAO and valine (Val) with DQ were specific to younger children (-1 SD or 19 months old), whereas creatinine (Crtn) and methylhistidine (MeHis) had significant associations with DQ that changed direction with age (negative at -1 SD or 19 months old, and positive at +1 SD or 49 months old). Further, mediation analysis demonstrated that PAG was a significant mediator for the relationship of delivery mode, child's diet quality and child fiber intake with DQ. HA and TMAO were additional significant mediators of the relationship of child fiber intake with DQ.

      Strengths of this study include the large cohort size and study design allowing for sampling at multiple time points along with neurodevelopmental assessment and a relatively detailed collection of potential confounding factors including diet. The untargeted metabolomics approach was also robust and comprehensive allowing for level 1 identification of a wide breadth of potential biomarkers. Given their methodology, the authors should be able to achieve their aim of identifying candidate serum biomarkers of neurodevelopment for early childhood. The results of this work would be of broad interest to researchers who are interested in understanding the biological underpinnings of development and also for tracking development in pediatric populations, as it provides insight for putative mechanisms and targets from a relevant human cohort that can be probed in future studies. Such putative mechanisms and targets are currently lacking in the field due to challenges in conducting these kind of studies, so this work is important.

      However, in the manuscript's current state, the presentation and analysis of data impede the reader from fully understanding and interpreting the study's findings.

      Particularly, the handling of confounding variables is incomplete. There is a different set of confounders listed in Table 1 versus Supplementary Table 1 versus Methods section Covariates versus Figure 4. For example, Region is listed in Supplementary Table 1 but not in Table 1, and Mode of Delivery is listed in Table 1 but not in Supplementary Table 1. Many factors are listed in Figure 4 that aren't mentioned anywhere else in the paper, such as gestational age at birth or maternal pre-pregnancy obesity.

      We thank the reviewer for their comment. We would like to clarify that initially, the tables had different variables because they have different purposes. Table 1 aims to characterize the sample on variables directly related to the children’s and mother’s features and their nutritional status. Supplementary File 1(previously named supplementary table 1) summarizes the sociodemographic distribution of the development quotient. Neither of the tables concerned the metabolite-DQ relationships and their potential covariates, they only provide context for subsequent analyses by characterizing the sample and the outcome. Instead, the covariates included in the regression models were selected using the Direct Acyclic Graph presented in Figure 1.

      To avoid this potential confusion however, we included the same variables in Table 1 and Supplementary File 1(page 38) and we discussed the selection of model covariates in Figure 4 in more detail here in the letter and in the manuscript.

      The authors utilize the directed acrylic graph (DAG) in Figure 4 to justify the further investigation of certain covariates over others. However, the lack of inclusion of the microbiome in the DAG, especially considering that most of the study findings were microbial-derived metabolite biomarkers, appears to be a fundamental flaw. Sanitation and micronutrients are proposed by the authors to have no effect on the host metabolome, yet sanitation and micronutrients have both been demonstrated in the literature to affect microbiome composition which can in turn affect the host metabolome.

      Thank you for your comment. We appreciate that the use of DAG and lack of the microbiome in the DAG are concerns. This has been already discussed in reply #1 to the editor that has been pasted below for convenience:

      Thank you for the comment and suggestions. It is important to highlight that there is no data on microbiome composition. We apologize if there was an impression such data is available. The main goal of conducting this national survey was to provide qualified and updated evidence on child nutrition to revise and propose new policies and nutritional guidelines for this demographic. Therefore, collection of stool derived microbiome (metagenomic) data was not one of the objectives of ENANI-2019. This is more explicitly stated as a study limitation in the revised manuscript on page 17, lines 463-467:

      “Lastly, stool microbiome data was not collected from children in ENANI-2019 as it was not a study objective in this large population-based nutritional survey. However, the lack of microbiome data does not reduce the importance/relevance, since there is no evidence that microbiome and factors affecting microbiome composition are confounders in the association between serum metabolome and child development.”

      Besides, one must consider the difficulties and costs in collecting and analyzing microbiome composition in a large population-based survey. In contrast, the metabolome data has been considered a priority as there was already blood specimens collected to inform policy on micronutrient deficiencies in Brazil. However, due to funding limitations we had to perform the analysis in a subset of our sample, still representative and large enough to test our hypothesis with adequate study power (more details below).

      We would like to argue that there is no evidence that microbiome and factors affecting microbiome composition are confounders on the association between serum metabolome and child development. First, one should revisit the properties of a confounder according to the epidemiology literature that in short states that confounding refers to an alternative explanation for a given conclusion, thus constituting one of the main problems for causal inference (Kleinbaum, Kupper, and Morgenstern, 1991; Greenland & Robins, 1986; VanderWeele, 2019). In our study, we highlight that certain serum metabolites associated with the developmental quotient (DQ) in children were circulating metabolites (e.g., cresol sulfate, hippuric acid, phenylacetylglutamine, TMAO) previously reported to depend on dietary exposures, host metabolism and gut microbiota activity. Our discussion cites other published work, including animal models and observational studies, which have reported how these bioactive metabolites in circulation are co-metabolized by commensal gut microbiota, and may play a role in neurodevelopment and cognition as mediated by environmental exposures early in life.

      In fact, the literature on the association between microbiome and infant development is very limited. We performed a search using terms ‘microbiome’ OR ‘microbiota’ AND ‘child development’ AND ‘systematic’ OR ‘meta-analysis’ and found only one study: ‘Associations between the human immune system and gut microbiome with neurodevelopment in the first 5 years of life: A systematic scoping review’ (DOI 10.1002/dev.22360). The authors conclude: ‘while the immune system and gut microbiome are thought to have interactive impacts on the developing brain, there remains a paucity of published studies that report biomarkers from both systems and associations with child development outcomes.’ It is important to highlight that our criteria to include confounders on the directed acyclic graph (DAG) was based on the literature of systematic reviews or meta-analysis and not on single isolated studies.

      In summary, we would like to highlight that there is no microbiome data in ENANI-2019 and in the event such data was present, we are confident that based on the current stage of the literature, there is no evidence to consider such construct in the DAG, as this procedure recommends that only variables associated with the exposure and the outcome should be included. Please find more details on DAG below.

      Moreover, we would like to clarify that we have not stated that sanitation and micronutrients have no effect on the serum metabolome, instead, these constructs were not considered on the DAG.

      To make it clearer, we have modified the passage about DAG in the methods section. New text, page 9, lines 234-241:

      “The subsequent step was to disentangle the selected metabolites from confounding variables. A Directed Acyclic Graph (DAG; Breitling et al., 2021) was used to more objectively determine the minimally sufficient adjustments for the regression models to account for potentially confounding variables while avoiding collider variables and variables in the metabolite-DQ causal pathways, which if controlled for would unnecessarily remove explained variance from the metabolites and hamper our ability to detect biomarkers. To minimize bias from subjective judgments of which variables should and should not be included as covariates, the DAG only included variables for which there was evidence from systematic reviews or meta-analysis of relationships with both the serum metabolome and DQ (Figure 1). Birth weight, breastfeeding, child's diet quality, the child's nutritional status, and the child's age were the minimal adjustments suggested by the DAG. Birth weight was a variable with high missing data, and indicators of breastfeeding practice data (referring to exclusive breastfeeding until 6 months and/or complemented until 2 years) were collected only for children aged 0–23 months. Therefore, those confounders were not included as adjustments. Child's diet quality was evaluated as MDD, the child's nutritional status as w/h z-score, and the child's age in months.”

      Additionally, the authors emphasized as part of the study selection criteria the following, "Due to the costs involved in the metabolome analysis, it was necessary to further reduce the sample size. Then, samples were stratified by age groups (6 to 11, 12 to 23, and 24 to 59 months) and health conditions related to iron metabolism, such as anemia and nutrient deficiencies. The selection process aimed to represent diverse health statuses, including those with no conditions, with specific deficiencies, or with combinations of conditions. Ultimately, through a randomized process that ensured a balanced representation across these groups, a total of 5,004 children were selected for the final sample (Figure 1)."

      Therefore, anemia and nutrient deficiencies are assumed by the reader to be important covariates, yet, the data on the final distribution of these covariates in the study cohort is not presented, nor are these covariates examined further.

      Thank you for the comments. We apologize for the misunderstanding and will amend the text to make our rationale clearer in the revised version of the manuscript.

      We believed the original text was clear enough in stating that the sampling process was performed aiming to maintain the representativeness of the original sample. This sampling process considered anemia and nutritional deficiencies, among other variables. However, we did not aim to include all relevant covariates of the DQ-metabolome relationship; these were decided using the DAG, as described in the manuscript and other sessions of this letter. Therefore, we would like to emphasize that our description of the sampling process does not assumes anemia and nutritional deficiencies are important covariates for the DQ-metabolome relationship.

      We rewrote this text part, page 11, lines 279-285:

      “Due to the costs involved in the metabolome analysis, it was necessary to reduce the sample size that is equivalent to 57% of total participants from ENANI-2019 with stored blood specimens. Therefore, the infants were stratified by age groups (6 to 11, 12 to 23, and 24 to 59 months) and health conditions such as anemia and micronutrient deficiencies. The selection process aimed to represent diverse health statuses to the original sample. Ultimately, 5,004 children were selected for the final sample through a random sampling process that ensured a balanced representation across these groups (Figure 2).”

      The inclusion of specific covariates in Table 1, Supplementary Table 1, the statistical models, and the mediation analysis is thus currently biased as it is not well justified.

      We appreciate the reviewer comment. However, it would have been ideal to receive a comment/critic with a clearer and more straightforward argumentation, so we could try to address it based on our interpretation.

      Please refer to our response to item #1 above regarding the variables in the tables and figures. The covariates in the statistical models were selected using the DAG, which is a cutting-edge procedure that aims to avoid bias and overfitting, a common situation when confounders are adjusted for without a clear rationale. We elaborate on the advantages of using the DAG in response to item #6 and in page 9 of the manuscript. The statistical models we use follow the best practices in the field when dealing with a large number of collinear predictors and a continuous outcome (see our response to the editor’s 4th comment). Finally, the mediation analyses were done to explore a few potential explanations for our results from the PLSR and multiple regression analyses. We only ran mediation analyses for plausible mechanisms for which the variables of interest were available in our data. Please see our response to reviewer 3’s item #1 for a more detailed explanation on the mediation analysis.

      Finally, it is unclear what the partial-least squares regression adds to the paper, other than to discard potentially interesting metabolites found by the initial correlation analysis.

      Thank you for the question. As explained in response to the editor’s item #4, PLS-based analyses are among the most commonly used analyses for parsing metabolomic data (Blekherman et al., 2011; Wold et al., 2001; Gromski et al. 2015). This procedure is especially appropriate for cases in which there are multiple collinear predictor variables as it allows us to compare the predictive value of all the variables without relying on corrections for multiple testing. Testing each metabolite in separate correlations corrected for multiple comparisons is less appropriate because the correlated nature of the metabolites means the comparisons are not truly independent and would cause the corrections (which usually assume independence) to be overly strict. As such, we only rely on the correlations as an initial, general assessment that gives context to subsequent, more specific analyses. Given that our goal is to select the most predictive metabolites, discarding the less predictive metabolites is precisely what we aim to achieve. As explained above and in response to the editor’s item #4, the PLSR allows us to reach that goal without introducing bias in our estimates or losing statistical power.  

      Reviewer #2 (Public Review):

      A strength of the work lies in the number of children Padilha et al. were able to assess (5,004 children aged 6-59 months) and in the extensive screening that the Authors performed for each participant. This type of large-scale study is uncommon in low-to-middle-income countries such as Brazil.

      The Authors employ several approaches to narrow down the number of potentially causally associated metabolites.

      Could the Authors justify on what basis the minimum dietary diversity score was dichotomized? Were sensitivity analyses undertaken to assess the effect of this dichotomization on associations reported by the article? Consumption of each food group may have a differential effect that is obscured by this dichotomization.

      Thank you for the observation. We would like to emphasize that the child's diet quality was assessed using the minimum dietary diversity (MDD) indicator proposed by the WHO (World Health Organization & United Nations Children’s Fund (UNICEF), 2021). This guideline proposes the cutoff used in the present study. We understand the reviewer’s suggestion to use the consumption of healthy food groups as an evaluation of diet quality, but we chose to follow the WHO proposal to assess dietary diversity. This indicator is widely accepted and used as a marker and provides comparability and consistency with other published studies.

      Could the Authors specify the statistical power associated with each analysis?

      To the best of our knowledge, we are not aware of power calculation procedures for PLS-based analyses. However, given our large sample size, we do not believe power was an issue with the analyses. For our regression analyses, which typically have 4 predictors, we had 95% power to detect an f-squared of 0.003 and an r of 0.05 in a two-sided correlation test considering an alpha level of 0.05.

      New text, page 11, lines 296-298:

      “Given the size of our sample, statistical power is not an issue in our analyses. Considering an alpha of 0.05 for a two-sided test, a sample size of 5000 has 95% power to detect a correlation of r = 0.05 and an effect of f2 = 0.003 in a multiple regression model with 4 predictors.”

      Could the Authors describe in detail which metric they used to measure how predictive PLSR models are, and how they determined what the "optimal" number of components were?

      We chose the model with the fewest number of components that maximized R2 and minimized root mean squared error of prediction (RMSEP). In the training data, the model with 4 components had a lower R2 but a lower RMSEP, therefore we chose the model with 3 components which had a higher R2 than the 4-component model and lower RMSEP than the model with 2 components. However, the number of components in the model did not meaningfully change the rank order of the metabolites on the VIP index.

      New text, page 8, lines 220-224:

      “To better assess the predictiveness of each metabolite in a single model, a PLSR was conducted. PLS-based analyses are the most commonly used analyses when determining the predictiveness of a large number of variables as they avoid issues with collinearity, sample size, and corrections for multiple-testing (Blekherman et al., 2011; Wold et al., 2001; Gromski et al. 2015).”

      New text, page 12, lines 312-314:

      “In PLSR analysis, the training data suggested that three components best predicted the data (the model with three components had the highest R2, and the root mean square error of prediction (RMSEP) was only slightly lower with four components). In comparison, the test data showed a slightly more predictive model with four components (Figure 3—figure supplement 2).”

      The Authors use directed acyclic graphs (DAG) to identify confounding variables of the association between metabolites and DQ. Could the dataset generated by the Authors have been used instead? Not all confounding variables identified in the literature may be relevant to the dataset generated by the Authors.

      Thank you for the question. The response is most likely no, the current dataset should not be used to define confounders as these must be identified based on the literature. The use of DAGs has been widely explored as a valid tool for justifying the choice of confounding factors in regression models in epidemiology. This is because DAGs allow for a clear visualization of causal relationships, clarify the complex relationships between exposure and outcome. Besides, DAGs demonstrate the authors' transparency by acknowledging factors reported as important but not included/collected in the study. This has been already discussed in reply #1 to the editor that has been pasted below for convenience.

      Thank you for the comment and suggestions. It is important to highlight that there is no data on microbiome composition. We apologize if there was an impression such data is available. The main goal of conducting this national survey was to provide qualified and updated evidence on child nutrition to revise and propose new policies and nutritional guidelines for this demographic. Therefore, collection of stool derived microbiome (metagenomic) data was not one of the objectives of ENANI-2019. This is more explicitly stated as a study limitation in the revised manuscript on page 17, lines 463-467:

      “Lastly, stool microbiome data was not collected from children in ENANI-2019 as it was not a study objective in this large population-based nutritional survey. However, the lack of microbiome data does not reduce the importance/relevance, since there is no evidence that microbiome and factors affecting microbiome composition are confounders in the association between serum metabolome and child development.”

      Besides, one must consider the difficulties and costs in collecting and analyzing microbiome composition in a large population-based survey. In contrast, the metabolome data has been considered a priority as there was already blood specimens collected to inform policy on micronutrient deficiencies in Brazil. However, due to funding limitations we had to perform the analysis in a subset of our sample, still representative and large enough to test our hypothesis with adequate study power (more details below).

      We would like to argue that there is no evidence that microbiome and factors affecting microbiome composition are confounders on the association between serum metabolome and child development. First, one should revisit the properties of a confounder according to the epidemiology literature that in short states that confounding refers to an alternative explanation for a given conclusion, thus constituting one of the main problems for causal inference (Kleinbaum, Kupper, and Morgenstern, 1991; Greenland & Robins, 1986; VanderWeele, 2019). In our study, we highlight that certain serum metabolites associated with the developmental quotient (DQ) in children were circulating metabolites (e.g., cresol sulfate, hippuric acid, phenylacetylglutamine, TMAO) previously reported to depend on dietary exposures, host metabolism and gut microbiota activity. Our discussion cites other published work, including animal models and observational studies, which have reported how these bioactive metabolites in circulation are co-metabolized by commensal gut microbiota, and may play a role in neurodevelopment and cognition as mediated by environmental exposures early in life.

      In fact, the literature on the association between microbiome and infant development is very limited. We performed a search using terms ‘microbiome’ OR ‘microbiota’ AND ‘child development’ AND ‘systematic’ OR ‘meta-analysis’ and found only one study: ‘Associations between the human immune system and gut microbiome with neurodevelopment in the first 5 years of life: A systematic scoping review’ (DOI 10.1002/dev.22360). The authors conclude: ‘while the immune system and gut microbiome are thought to have interactive impacts on the developing brain, there remains a paucity of published studies that report biomarkers from both systems and associations with child development outcomes.’ It is important to highlight that our criteria to include confounders on the directed acyclic graph (DAG) was based on the literature of systematic reviews or meta-analysis and not on single isolated studies.

      In summary, we would like to highlight that there is no microbiome data in ENANI-2019 and in the event such data was present, we are confident that based on the current stage of the literature, there is no evidence to consider such construct in the DAG, as this procedure recommends that only variables associated with the exposure and the outcome should be included. Please find more details on DAG below.

      Moreover, we would like to clarify that we have not stated that sanitation and micronutrients have no effect on the serum metabolome, instead, these constructs were not considered on the DAG.

      To make it clearer, we have modified the passage about DAG in the methods section. New text, page 9, lines 234-241:

      “The subsequent step was to disentangle the selected metabolites from confounding variables. A Directed Acyclic Graph (DAG; Breitling et al., 2021) was used to more objectively determine the minimally sufficient adjustments for the regression models to account for potentially confounding variables while avoiding collider variables and variables in the metabolite-DQ causal pathways, which if controlled for would unnecessarily remove explained variance from the metabolites and hamper our ability to detect biomarkers. To minimize bias from subjective judgments of which variables should and should not be included as covariates, the DAG only included variables for which there was evidence from systematic reviews or meta-analysis of relationships with both the serum metabolome and DQ (Figure 1). Birth weight, breastfeeding, child's diet quality, the child's nutritional status, and the child's age were the minimal adjustments suggested by the DAG. Birth weight was a variable with high missing data, and indicators of breastfeeding practice data (referring to exclusive breastfeeding until 6 months and/or complemented until 2 years) were collected only for children aged 0–23 months. Therefore, those confounders were not included as adjustments. Child's diet quality was evaluated as MDD, the child's nutritional status as w/h z-score, and the child's age in months.”

      Were the systematic reviews or meta-analyses used in the DAG performed by the Authors, or were they based on previous studies? If so, more information about the methodology employed and the studies included should be provided by the Authors.

      Thank you for the question. The reviews or meta-analyses used in the DAG have been conducted by other authors in the field. This has been laid out more clearly in our methods section.

      New text, page 9, lines 234-241:

      “The subsequent step was to disentangle the selected metabolites from confounding variables. A Directed Acyclic Graph (DAG; Breitling et al., 2021) was used to more objectively determine the minimally sufficient adjustments for the regression models to account for potentially confounding variables while avoiding collider variables and variables in the metabolite-DQ causal pathways, which if controlled for would unnecessarily remove explained variance from the metabolites and hamper our ability to detect biomarkers. To minimize bias from subjective judgments of which variables should and should not be included as covariates, the DAG only included variables for which there was evidence from systematic reviews or meta-analysis of relationships with both the metabolome and DQ (Figure 1). Birth weight, breastfeeding, child's diet quality, the child's nutritional status, and the child's age were the minimal adjustments suggested by the DAG. Birth weight was a variable with high missing data, and indicators of breastfeeding practice data (referring to exclusive breastfeeding until 6 months and/or complemented until 2 years) were collected only for children aged 0–23 months. Therefore, those confounders were not included as adjustments. Child's diet quality was evaluated as MDD, the child's nutritional status as w/h z-score, and the child's age in months.”

      Approximately 72% of children included in the analyses lived in households with a monthly income superior to the Brazilian minimum wage. The cohort is also biased towards households with a higher level of education. Both of these measures correlate with developmental quotient. Could the Authors discuss how this may have affected their results and how generalizable they are?

      Thank you for your comment. This has been already discussed in reply #6 to the editor and that has been pasted below for convenience.

      Thank you for highlighting this point. The ENANI-2019 is a population-based household survey with national coverage and representativeness for macroregions, sex, and one-year age groups (< 1; 1-1.99; 2-2.99; 3-3.99; 4-5). Furthermore, income quartiles of the census sector were used in the sampling. The study included 12,524 households 14,588 children, and 8,829 infants with blood drawn.

      Due to the costs involved in metabolome analysis, it was necessary to further reduce the sample size to around 5,000 children that is equivalent to 57% of total participants from ENANI-2019 with stored blood specimens. To avoid a biased sample and keep the representativeness and generability, the 5,004 selected children were drawn from the total samples of 8,829 to keep the original distribution according age groups (6 to 11 months, 12 to 23 months, and 24 to 59 months), and some health conditions related to iron metabolism, e.g., anemia and nutrient deficiencies. Then, they were randomly selected to constitute the final sample that aimed to represent the total number of children with blood drawn. Hence, our efforts were to preserve the original characteristics of the sample and the representativeness of the original sample.

      The ENANI-2019 study does not appear to present a bias towards higher socioeconomic status. Evidence from two major Brazilian population-based household surveys supports this claim. The 2017-18 Household Budget Survey (POF) reported an average monthly household income of 5,426.70 reais, while the Continuous National Household Sample Survey (PNAD) reported that in 2019, the nominal monthly per capita household income was 1,438.67 reais. In comparison, ENANI-2019 recorded a household income of 2,144.16 reais and a per capita income of 609.07 reais in infants with blood drawn, and 2,099.14 reais and 594.74 reais, respectively, in the serum metabolome analysis sample.

      In terms of maternal education, the 2019 PNAD-Education survey indicated that 48.8% of individuals aged 25 or older had at least 11 years of schooling. When analyzing ENANI-2019 under the same metric, we found that 56.26% of ≥25 years-old mothers of infants with blood drawn had 11 years of education or more, and 51.66% in the metabolome analysis sample. Although these figures are slightly higher, they remain within a reasonable range for population studies.

      It is well known that higher income and maternal education levels can influence child health outcomes, and acknowledging this, ENANI-2019 employed rigorous sampling methods to minimize selection biases. This included stratified and complex sampling designs to ensure that underrepresented groups were adequately included, reducing the risk of skewed conclusions. Therefore, the evidence strongly suggests that the ENANI-2019 sample is broadly representative of the Brazilian population in terms of both socioeconomic status and educational attainment.

      Further to this, could the Authors describe how inequalities in access to care in the Brazilian population may have affected their results? Could they have included a measure of this possible discrepancy in their analyses?

      Thank you for the concern.

      The truth is that we are not in a position to answer this question because our study focused on gathering data on infant nutritional status and there is very limited information on access to care to allow us to hypothesize. Another important piece of information is that this national survey used sampling procedures that aimed to make the sample representative of the 15 million Brazilian infants under 5 years. Therefore, the sample is balanced according to socio-economic strata, so there is no evidence to make us believe inequalities in access to health care would have played a role.

      The Authors state that the results of their study may be used to track children at risk for developmental delays. Could they discuss the potential for influencing policies and guidelines to address delayed development due to malnutrition and/or limited access to certain essential foods?

      The point raised by the reviewer is very relevant. Recognizing that dietary and microbial derived metabolites involved in the gut-brain axis could be related to children's risk of developmental delays is the first step to bringing this topic to the public policy agenda. We believe the results can contribute to the literature, which should be used to accumulate evidence to overcome knowledge gaps and support the formulation and redirection of public policies aimed at full child growth and development; the promotion of adequate and healthy nutrition and food security; the encouragement, support, and protection of breastfeeding; and the prevention and control of micronutrient deficiencies.  

      Reviewer #3 (Public Review):

      The ENANI-2019 study provides valuable insights into child nutrition, development, and metabolomics in Brazil, highlighting both challenges and opportunities for improving child health outcomes through targeted interventions and further research.

      Readers might consider the following questions:

      (1) Should investigators study the families through direct observation of diet and other factors to look for a connection between food taken in and gut microbiome and child development?

      As mentioned before, the ENANI-2019 did not collect data on stool derived microbiome. However, there is data on child dietary intake with 24-hour recall that can be further explored in other studies.

      (2) Can an examination of the mother's gut microbiome influence the child's microbiome? Can the mother or caregiver's microbiome influence early childhood development?

      The questions raised by the reviewer are interesting and has been explored by other authors. However, we do not have microbiota data from the child nor from the mother/caregiver.

      (3) Is developmental quotient enough to study early childhood development? Is it comprehensive enough?

      Yes, we are confident it is comprehensive enough.

      According to the World Health Organization, the term Early Childhood Development (ECD) refers to the cognitive, physical, language, motor, social and emotional development between 0 - 8 years of age. The SWCY milestones assess the domains of cognition, language/communication and motor. Therefore, it has enough content validity to represent ECD.

      The SWYC is recommended for screening ECD by the American Society of Pediatrics. Furthermore, we assessed the internal consistency of the SWYC milestones questionnaire using ENANI-2019 data and Cronbach's alpha. The findings indicated satisfactory reliability (0.965; 95% CI: 0.963–0.968).

      The SWCY is a screening instrument and indicates if the ECD is not within the expected range. If one of the above-mentioned domains are not achieved as expected the child may be at risk of ECD delay. Therefore, DQ<1 indicates that a child has not reached the expected ECD for the age group. We cannot say that children with DQ≥1 have full ECD, since we do not assess the socio-emotional domains. However, DQ can track the risk of ECD delay.

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      Sheldrick RC, Schlichting LE, Berger B, et al. Establishing New Norms for Developmental Milestones. Pediatrics 2019;144(6) doi: 10.1542/peds.2019-0374 [published Online First: 2019/11/16]

      Drachler Mde L, Marshall T, de Carvalho Leite JC. A continuous-scale measure of child development for population-based epidemiological surveys: a preliminary study using Item Response Theory for the Denver Test. Paediatric and perinatal epidemiology 2007;21(2):138-53. doi: 10.1111/j.1365-3016.2007.00787.x [published Online First: 2007/02/17]

      VanderWeele, TJ Princípios de seleção de fatores de confusão. Eur J Epidemiol 34, 211–219 (2019). https://doi.org/10.1007/s10654-019-00494-6

      David G. Kleinbaum, Lawrence L. Kupper; Hal Morgenstern. Epidemiologic Research: Principles and Quantitative Methods. 1991

      Yan R, Liu X, Xue R, Duan X, Li L, He X, Cui F, Zhao J. Association between internet exclusion and depressive symptoms among older adults: panel data analysis of five longitudinal cohort studies. EClinicalMedicine 2024;75. doi: 10.1016/j.eclinm.2024.102767.

      Zhong Y, Lu H, Jiang Y, Rong M, Zhang X, Liabsuetrakul T. Effect of homemade peanut oil consumption during pregnancy on low birth weight and preterm birth outcomes: a cohort study in Southwestern China. Glob Health Action. 2024 Dec 31;17(1):2336312.

      Aristizábal LYG, Rocha PRH, Confortin SC, et al. Association between neonatal near miss and infant development: the Ribeirão Preto and São Luís birth cohorts (BRISA). BMC Pediatr. 2023;23(1):125. Published 2023 Mar 18. doi:10.1186/s12887-023-03897-3

      Al-Haddad BJS, Jacobsson B, Chabra S, et al. Long-term risk of neuropsychiatric disease after exposure to infection in utero. JAMA Psychiatry. 2019;76(6):594-602. doi:10.1001/jamapsychiatry.2019.0029

      Chan, A.Y.L., Gao, L., Hsieh, M.HC. et al. Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother–child pairs. Nat Med 30, 1416–1423 (2024).

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      Emergencia es una situación en la que la vida de una persona está en peligro o existe un riesgo significativo de daño permanente . Urgencia medica es una situación en la que una persona requiere atención médica inmediata para prevenir daños graves o la perdida de vida Importancia de emergencia y urgencia medica. estar preparado para responder y conocer los protocolos y procedimientos establecidos y trabajar en equipo con otros profesionales para salvar vidas y prevenir daños problemas cardíacos. Ejemplos de urgencia medica 1. Prevenir daños 2. Accidentes y traumas Ejemplos de emergencia 1. Emergencia médica 2.emergencia quirúrgica

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      The algorithmic complexity of jointly sampling and com-puting the log-det-Jacobian terms of the inference modelscales as O(LN 2) + O(KD), where L is the number ofdeterministic layers used to map the data to the parame-ters of the flow, N is the average hidden layer size, K isthe flow-length and D is the dimension of the latent vari-ables. Thus the overall algorithm is at most quadratic mak-ing the overall approach competitive with other large-scalesystems used in practice.

      Normalizing Flows가 많은 수의 레이어를 가질 경우에는 추론하는데 걸리는 시간이 어떻게 되나요? 특히 실시간 추론이나 아주 큰 데이터셋에서는 성능 저하 문제가 생길 것 같은데 이는 어떻게 해결할 수 있을까요?

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      servo_jp()o Which takes a 1x4 array of joint values in degrees to be sent directly to the actuators andbypasses interpolation● interpolate_jp()o Which takes a 1x4 array of joint values and an interpolation time in ms to get there● measured_js()o Which takes two boolean values, named GETPOS and GETVEL. Only return the results forthe requested data, and set the rest to zero. This will be important because if we want tocollect position data very fast, we will not want to slow the system down by also acquiringunnecessary velocity data.o Which returns a 2x4 array that contains current joint positions in degrees (1st row) and/orcurrent joint velocities (2nd row).● setpoint_js()o Which returns a 1x4 array that contains current joint set point positions in degrees. Ifinterpolation is being used and you request this during motion, it will return the currentintermediate set point.● goal_js()o Which returns a 1x4 array that contains the end-of-motion joint setpoint positions indegrees. Note that this should be stored directly in your robot object (be sure to set it abovewhen making new setpoints), it does not need to be requested from the controller.

      These would all be separated into their own code blocks with function requirements and demo instructions in text blocks above

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      Durante mucho tiempo, la odontología se enfocó en procedimientos mecánicos como extraer o reparar dientes. En los últimos años, ha evolucionado hacia una ciencia enfocada en la prevención y conservación de los tejidos bucales.

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      Let us go • ewin m • . ,, h II . tnto thth lodge. The world is gomg bad. Sot ey a went m. And theysa·d " eear h h I d h l • I ' Let11the people together enter t e eart o ge; t e wor d 1sgoing bad ,,a So at noon they all entered the earth lodge. Then it blew. It blew te.rriblyEvery kind of tree fell down westward.

      This probably means a house or a place to keep safe and when they said the world is going bad i think they ment a storm because they said it blew terably and every tree fell down. I see that they knew that bad things were going ot happen and they have plans on what to do so they won't get hurt by it.

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    1. AnGordon24301 20 Oct 2024
      which the doctrine of the prophetsenters into everyday life, as the function of a permanent institution. Thedisciples or apostles of the prophets thereupon become mystagogues,·teachers, priests or pastors (o~ a combination of them all), serving anassociation dedicated to exclusively religious purposes, namely the con-gregation of laymen

      Spiritual designations make move towards organizational designations, as doctrine is institutionalized and incorporated into everyday life.

    2. AnGordon24301 15 Oct 2024
      It was Moses' great achieve-ment to find a compromise solution of, or prophylactic for, these conflicts(e.g., the seisachtheia of the Year of Release)4 and to o!':"ganize the Israeliteconfederacy with an integral national god

      Moses transitioned from a prophet to lawgiver, finding solutions to economic conflict and oriented Israelites as a nation towards a god.

    4. AnGordon24301 13 Oct 2024
      Thisis most conspicuous under gerontoeratic and purely patriarchal domina-tion, which cannot use an administrative machinery against the members

      necessary to keep traditional orientation in trad domination which has no admin to keeps things running w/o members compliance

    6. AnGordon24301 12 Oct 2024
      Experience shows that in no instance does domination vOluntarilylimit itself to the appeal to material or affectual or ideal motives as a basisfor its continuance. In addition every such system attempts to establishand to cultivate the belief in its legitimacy

      legitimacy promotes dominance w/o making a convincing case that they help participants achieve material, affective, or idyllic motives.

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  54. doc.cat-v.org doc.cat-v.org
    new_c_compiler.pdf
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  55. learn.cantrill.io learn.cantrill.io
    [ASSOCIATESHARED] [DEMO] Creating an Animals4life AMI - PART1
    1
    1. minhthanh 19 Oct 2024

      Welcome back and in this demo lesson you'll be creating an AMI from a pre-configured EC2 instance.

      So you'll be provisioning an EC2 instance, configuring it with a popular web application stack and then creating an AMI of that pre-configured web application.

      Now you know in the previous demo where I said that you would be implementing the WordPress manual install once?

      Well I might have misled you slightly but this will be the last manual install of WordPress in the course, I promise.

      What we're going to do together in this demo lesson is create an Amazon Linux AMI for the animals for life business but one which includes some custom configuration and an install of WordPress ready and waiting to be initially configured.

      So this is a fairly common use case so let's jump in and get started.

      Now in order to perform this demo you're going to need some infrastructure, make sure you're logged into the general AWS account, so the management account of the organization and as always make sure that you have the Northern Virginia region selected.

      Now attached to this lesson is a one-click deployment link, go ahead and click that link.

      This will open the quick create stack screen, it should automatically be populated with the AMI demo as the stack name, just scroll down to the bottom, check this capabilities acknowledgement box and then click on create stack.

      We're going to need this stack to be in a create complete state so go ahead and pause the video and we can resume once the stack moves into create complete.

      Okay so that stacks now moved into a create complete state, we're good to continue with the demo.

      Now you're going to be using some command line commands within an EC2 instance as part of creating an Amazon machine image so also attached to this lesson is the lessons command document which contains all of those commands so go ahead and open that document.

      Now you might recognize these as the same commands that you used when you were performing a manual WordPress installation and that's the case we're running the same manual installation process as part of setting up our animals for life AMI so you're going to need all of these commands but as you've already experienced them in the previous demo lesson I'm going to run through them a lot quicker in this demo lesson so go back to the AWS console and we need to move to the EC2 area of the console so click on the services drop down, type EC2 into this search box and then open that in a new tab.

      Once you there go ahead and click on running instances, close down any dialogues about any console changes we want to maximize the amount of screen space that we have, we're going to connect to this A4L public EC2 instance this is the instance that we're going to use to create our AMI so we're going to set the instance up manually how we want it to be and then we're going to use it to generate an AMI so we need to connect to this instance so right click select connect we're going to use EC2 instance connect to do the work within our browser so make sure the username is EC2-user and then connect to this instance then once connected we're going to run through the commands to install WordPress really quickly we're going to start again by setting the variables that will use throughout the installation so you can just go ahead and copy and paste those straight in and press enter now we're going to run through all of the next set of commands really quickly because you use them in the previous demo lesson so first we're going to go ahead and install the MariaDB server Apache and the Wget utility while that's installing copy all of the commands from step 3 so these are commands which enable and start Apache and MariaDB go ahead and paste all of those four in and press enter so now Apache and MariaDB are both set to start when the instance boots as well as being set to currently started I'll just clear the screen to make this easier to see next we're going to set the DB root password again that's this command using the contents of the variable that you set at the start next we download WordPress once it's downloaded we move into the web root folder we extract the download we copy the files from within the WordPress folder that we've just extracted into the current folder which is the web root once we've done that we remove the WordPress folder itself and then we tidy up by deleting the download I'm going to clear the screen we copy the template configuration file into its final file name so wp-config.php then we're going to replace the placeholders in that file we're going to start with the database name using the variable that you set at the start next we're going to use the database user which you also set at the start and finally the database password and then we're going to set the ownership on all of these files to be the Apache user and the Apache group clear the screen next we need to create the DB setup script that are demonstrated in the previous demo so we need to run a collection of commands the first to enter the create database command the next one to enter the create user command and set that password the next one to grant permissions on the database to that user then flush the permissions then we need to run that script using the MySQL command line interface that runs all of those commands and performs all of those operations and then we tidy up by deleting that file now at this point we've done the exact same process that we did in the previous demo we've installed and set up WordPress and if everything's working okay we can go back to the AWS console click on instances select the running a4l-public ec2 instance copy down its IP address again make sure you copy that down don't click this link and then open that in a new tab if everything's working as expected you should see the WordPress installation dialogue now this time because we're creating an AMI we don't want to perform the installation we want to make sure that when anyone uses this AMI they're also greeted with this installation so we're going to leave this at this point we're not going to perform the installation instead we're going to go back to the ec2 instance now because this ec2 instance is for the animals for life business we want to customize it and make sure that everybody knows that this is an animals for life ec2 instance now to do that we're going to install an animal themed utility called cow say I'm going to clear the screen to make it easier to see and then just to demonstrate exactly what cow say does I'm going to run a cow say oh hi and if all goes well we see a cow using ASCII art saying the oh hi message that we just typed so we're going to use this to create a message of the day welcome when anyone connects to this ec2 instance to do that we're going to create a file inside the configuration folder of this ec2 instance so we're going to use shudu nano and we're going to create this file so forward slash etc forward slash update hyphen motd dot d forward slash 40 hyphen cow so we're going to create that file this is the file that's going to be used to generate the output when anyone logs in to this ec2 instance so we're going to copy in these two lines and then press enter so this means when anyone logs into the ec2 instance they're going to get an animal themed welcome so use control o to save that file and control x to exit clear the screen to make it easier to see we're going to make sure that file that we've just edited has the correct permissions then we're going to force an update of the message of the day so this is going to be what's displayed when anyone logs into this instance and then finally now that we've completed this configuration we're going to reboot this ec2 instance so we're going to use this command to reboot it and just to illustrate how this works I'm going to close down that tab and return to the ec2 console give this a few moments to restart that should have rebooted by now so we're going to select it right click go to connect again use ec2 instance connect assuming everything's working now when we connect to the instance we'll see an animal themed login banner so this is just a nice way that we can ensure that anyone logging into this instance understands that a he uses the Amazon Linux 2 AMI and be that it belongs to animals for life so we've created this instance using the Amazon Linux 2 AMI we've performed the WordPress installation and initial configuration we've customized the banner and now we're going to use this as our template instance to create our AMI that can then be used to launch other instances okay so this is the end of part one of this lesson it was getting a little bit on the long side and so I wanted to add a break it's an opportunity just to take a rest or grab a coffee part 2 will be continuing immediately from the end of part one so go ahead complete the video and when you're ready join me in part two

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  56. learn.cantrill.io learn.cantrill.io
    [ASSOCIATESHARED] [DEMO] EBS Volumes - PART1
    1
    1. minhthanh 19 Oct 2024

      Welcome back and we're going to use this demo lesson to get some experience of working with EBS and Instant Store volumes.

      Now before we get started, this series of demo videos will be split into two main components.

      The first component will be based around EBS and EBS snapshots and all of this will come under the free tier.

      The second component will be based on Instant Store volumes and will be using larger instances which are not included within the free tier.

      So I'm going to make you aware of when we move on to a part which could incur some costs and you can either do that within your own environment or watch me do it in the video.

      If you do decide to do it in your own environment, just be aware that there will be a 13 cents per hour cost for the second component of this demo series and I'll make it very clear when we move into that component.

      The second component is entirely optional but I just wanted to warn you of the potential cost in advance.

      Now to get started with this demo, you're going to need to deploy some infrastructure.

      To do that, make sure that you're logged in to the general account, so the management account of the organization and you've got the Northern Virginia region selected.

      Now attached to this demo is a one click deployment link to deploy the infrastructure.

      So go ahead and click on that link.

      That's going to open this quick create stack screen and all you need to do is scroll down to the bottom, check this capabilities box and click on create stack.

      Now you're going to need this to be in a create complete state before you continue with this demo.

      So go ahead and pause the video, wait for that stack to move into the create complete status and then you can continue.

      Okay, now that's finished and the stack is in a create complete state.

      You're also going to be running some commands within EC2 instances as part of this demo.

      Also attached to this lesson is a lesson commands document which contains all of those commands and you can use this to copy and paste which will avoid errors.

      So go ahead and open that link in a separate browser window or separate browser tab.

      It should look something like this and we're going to be using this throughout the lesson.

      Now this cloud formation template has created a number of resources, but the three that we're concerned about are the three EC2 instances.

      So instance one, instance two and instance three.

      So the next thing to do is to move across to the EC2 console.

      So click on the services drop down and then either locate EC2 under all services, find it in recently visited services or you can use the search box at the top type EC2 and then open that in a new tab.

      Now the EC2 console is going through a number of changes so don't be alarmed if it looks slightly different or if you see any banners welcoming you to this new version.

      Now if you click on instances running, you'll see a list of the three instances that we're going to be using within this demo lesson.

      We have instance one - az a.

      We have instance two - az a and then instance one - az b.

      So these are three instances, two of which are in availability zone A and one which is in availability zone B.

      Next I want you to scroll down and locate volumes under elastic block store and just click on volumes.

      And what you'll see is three EBS volumes, each of which is eight GIB in size.

      Now these are all currently in use.

      You can see that in the state column and that's because all of these volumes are in use as the boot volumes for those three EC2 instances.

      So on each of these volumes is the operating system running on those EC2 instances.

      Now to give you some experience of working with EBS volumes, we're going to go ahead and create a volume.

      So click on the create volume button.

      The first thing you'll need to do when creating a volume is pick the type and there are a number of different types available.

      We've got GP2 and GP3 which are the general purpose storage types.

      We're going to use GP3 for this demo lesson.

      You could also select one of the provisioned IOPS volumes.

      So this is currently IO1 or IO2.

      And with both of these volume types, you're able to define IOPS separately from the size of the volume.

      So these are volume types that you can use for demanding storage scenarios where you need high-end performance or when you need especially high performance for smaller volume sizes.

      Now IO1 was the first type of provisioned IOPS SSD introduced by AWS and more recently they've introduced IO2 and enhanced it which provides even higher levels of performance.

      In addition to that we do have the non-SSD volume types.

      So SC1 which is cold HDD, ST1 which is throughput optimized HDD and then of course the original magnetic type which is now legacy and AWS don't recommend this for any production usage.

      For this demo lesson we're going to go ahead and select GP3.

      So select that.

      Next you're able to pick a size in GIB for the volume.

      We're going to select a volume size of 10 GIB.

      Now EBS volumes are created within a specific availability zone so you have to select the availability zone when you're creating the volume.

      At this point I want you to go ahead and select US-EAST-1A.

      When creating volume you're also able to specify a snapshot as the basis for that volume.

      So if you want to restore a snapshot into this volume you can select that here.

      At this stage in the demo we're going to be creating a blank EBS volume so we're not going to select anything in this box.

      We're going to be talking about encryption later in this section of the course.

      You are able to specify encryption settings for the volume when you create it but at this point we're not going to encrypt this volume.

      We do want to add a tag so that we can easily identify the volume from all of the others so click on add tag.

      For the key we're going to use name.

      For the value we're going to put EBS test volume.

      So once you've entered both of those go ahead and click on create volume and that will begin the process of creating the volume.

      Just close down any dialogues and then just pay attention to the different states that this volume goes through.

      It begins in a creating state.

      This is where the storage is being provisioned and then made available by the EBS product.

      If we click on refresh you'll see that it changes from creating to available and once it's in an available state this means that we can attach it to EC2 instances.

      And that's what we're going to do so we're going to right click and select attach volume.

      Now you're able to attach this volume to EC2 instances but crucially only those in the same availability zone.

      EBS is an availability zone scoped service and so you can only attach EBS volumes to EC2 instances within that same availability zone.

      So if we select the instance box you'll only see instances in that same availability zone.

      Now at this point go ahead and select instance 1 in availability zone A.

      Once you've selected it you'll see that the device field is populated and this is the device ID that the instance will see for this volume.

      So this is how the volume is going to be exposed to the EC2 instance.

      So if we want to interact with this instance inside the operating system this is the device that we'll use.

      Now different operating systems might see this in slightly different ways.

      So as this warning suggests certain Linux kernels might rename SDF to XVDF.

      So we've got to be aware that when you do attach a volume to an EC2 instance you need to get used to how that's seen inside the operating system.

      How we can identify it and how we can configure it within the operating system for use.

      And I'm going to demonstrate that in the next part of this demo lesson.

      So at this point just go ahead and click on attach and this will attach this volume to the EC2 instance.

      Once that's attached to the instance and you see the state change to in use then just scroll up on the left hand side and select instances.

      We're going to go ahead and connect to instance 1 in availability zone A.

      This is the instance that we just attached that EBS volume to so we want to interact with this instance and see how we can see the EBS volume.

      So right click on this instance and select connect and then you could either connect with an SSH client or use instance connect and to keep things simple we're going to connect from our browser so select the EC2 instance connect option make sure the user's name is set to EC2-user and then click on connect.

      So now we connected to this EC2 instance and it's at this point that we'll start needing the commands that are listed inside the lesson commands document and again this is attached to this lesson.

      So first we need to list all the block devices which are connected to this instance and we're going to use the LSBLK command.

      Now if you're not comfortable with Linux don't worry just take this nice and slowly and understand at a high level all the commands that we're going to run.

      So the first one is LSBLK and this is list block devices.

      So if we run this we'll be able to see a list of all of the block devices connected to this EC2 instance.

      You'll see the root device this is the device that's used to boot the instance it contains the instance operating system you'll see that it's 8 gig in size and then this is the EBS volume that we just attached to this instance.

      You'll see that device ID so XVDF and you'll see that it's 10 gig in size.

      Now what we need to do next is check whether there is a file system on this block device.

      So this block device we've created it with EBS and then we've attached it to this instance.

      Now we know that it's blank but it's always safe to check if there's any file system on a block device.

      So to do that we run this command.

      So we're going to check are there any file systems on this block device.

      So press enter and if you see just data that indicates that there isn't any file system on this device and so we need to create one.

      You can only mount file systems under Linux and so we need to create a file system on this raw block device this EBS volume.

      So to do that we run this command.

      So shoo-doo again is just giving us admin permissions on this instance.

      MKFS is going to make a file system.

      We specify the file system type with hyphen t and then XFS which is a type of file system and then we're telling it to create this file system on this raw block device which is the EBS volume that we just attached.

      So press enter and that will create the file system on this EBS volume.

      We can confirm that by rerunning this previous command and this time instead of data it will tell us that there is now an XFS file system on this block device.

      So now we can see the difference.

      Initially it just told us that there was data, so raw data on this volume and now it's indicating that there is a file system, the file system that we just created.

      Now the way that Linux works is we mount a file system to a mount point which is a directory.

      So we're going to create a directory using this command.

      MKDIR makes a directory and we're going to call the directory forward slash EBS test.

      So this creates it at the top level of the file system.

      This signifies root which is the top level of the file system tree and we're going to make a folder inside here called EBS test.

      So go ahead and enter that command and press enter and that creates that folder and then what we can do is to mount the file system that we just created on this EBS volume into that folder.

      And to do that we use this command, mount.

      So mount takes a device ID, so forward slash dev forward slash xvdf.

      So this is the raw block device containing the file system we just created and it's going to mount it into this folder.

      So type that command and press enter and now we have our EBS volume with our file system mounted into this folder.

      And we can verify that by running a df space hyphen k.

      And this will show us all of the file systems on this instance and the bottom line here is the one that we've just created and mounted.

      At this point I'm just going to clear the screen to make it easier to see and what we're going to do is to move into this folder.

      So cd which is change directory space forward slash EBS test and then press enter and that will move you into that folder.

      Once we're in that folder we're going to create a test file.

      So we're going to use this command so shudu nano which is a text editor and we're going to call the file amazing test file dot txt.

      So type that command in and press enter and then go ahead and type a message.

      It can be anything you just need to recognize it as your own message.

      So I'm going to use cats are amazing and then some exclamation marks.

      Then I'm going to press control o and enter to save that file and then control x to exit again clear the screen to make it easier to see.

      And then I'm going to do an LS space hyphen LA and press enter just to list the contents of this folder.

      So as you can see we've now got this amazing test file dot txt.

      And if we cat the contents of this so cat amazing test file dot txt you'll see the unique message that you just typed in.

      So at this point we've created this file within the folder and remember the folder is now the mount point for the file system that we created on this EBS volume.

      So the next step that I want you to do is to reboot this EC2 instance.

      To do that type sudo space and then reboot and press enter.

      Now this will disconnect you from this session.

      So you can go ahead and close down this tab and go back to the EC2 console.

      Just go ahead and click on instances.

      Okay, so this is the end of part one of this lesson.

      It was getting a little bit on the long side and so I wanted to add a break.

      It's an opportunity just to take a rest or grab a coffee.

      Part two will be continuing immediately from the end of part one.

      So go ahead complete the video and when you're ready join me in part two.

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  57. arxiv.org arxiv.org
    2406.17305v1.pdf
    7
    1. quannnn 19 Oct 2024
      ference with out-domain examples. Duringinference, since examples from the automaticallyconstructed data is not aligned with the domainsand schemas of the human-annotated benchmarks,we refer to them as out-domain examples. Fig. 4shows the results of inference with out-domain ex-amples using diverse retrieval strategies. We usethe model trained with NN strategy here. After ap-plying example filtering such as BM25 scoring, in-ference with out-domain examples shows improve-ments compared to the baseline, suggesting theneed of example filtering when implementing RAGwith out-domain examples

      Qúa trình infer với các mẫu out-domain: Trong quá trình infer, bởi vì các mẫu từ tập dữ liệu xây dựng tự động có domain và format không giống với dữ liệu được gán nhãn bởi con người, các mẫu này sẽ được gọi là out-domain.

      Trong thực nghiệm ở hình 4, mô hình RA-IT được huấn luyện với chiến lược truy xuất NN. Sau khi áp dụng bộ lọc BM25, việc infer với các mẫu out-domain cho thấy cải thiện so với baseline, từ đó cho thấy tầm quan trọng trong việc thêm bộ lọc khi áp dụng RAG với các mẫu out-domain.

    2. quannnn 19 Oct 2024
      Training with diverse retrieval strategies. Fig.3 visualize the results of training with various re-trieval strategies. We conduct inference with andwithout examples for each strategy, and set the re-trieval strategy of inference the same as of training.The most straight forward method NN shows bestperformances, suggesting the benefits of semanti-cally similar examples. Random strategy, though in-Figure 4: Impacts of inferece with out-domain examplesusing various retrieval strategies. The average F1 valueof the evaluated benchmarks are reported. w/o exmp.means inference without example. Applying examplefiltering strategy such as BM25 filtering benefits RAGwith out-domain examples.Figure 5: Impacts of inference with in-domain examples.The average F1 value of the evaluated benchmarks arereported. N -exmp. means the example pool of size N .Sufficient in-domain examples are helpful for RAG.ferior to NN, also shows improvements, indicatingthat random examples might introduce some gen-eral information of NER taks to the model. Mean-while, inference with examples does not guaranteeimprovements and often hurt performances. Thismay due to the differences of the annotation schemabetween the automatically constructed data and thehuman-annotated benchmarks

      Huấn luyện với các chiến lược truy xuất khác nhau: Được thể hiện ở hình 3. Qúa trình infer được tiến hành có hoặc không có các mẫu tham khảo với mỗi chiến lược trích xuất, và chiến lược trích xuất trong cả quá trình huấn luyện và quá trình infer là giống nhau.

      Kết quả cho thấy NN là chiến lược truy xuất tốt nhất, từ đó cho thấy tầm quan trọng của các mẫu tham khảo có sự tương đồng về mặt ngữ nghĩa. Trong khi đó, việc infer với các ví dụ thì không đảm bảo sự tăng tiến và thường ảnh hưởng tiêu cực đến kết quả.

    3. quannnn 19 Oct 2024
      The main results are summarized in Table 1 and2 respectively. We report the results of inferencewithout examples for RA-IT here, since we foundthis setting exhibits more consistent improvements.The impacts of inference with examples are studiedin Section 3.5. As shown in the tables, RA-ITshows consistent improvements on English andChinese across various data sizes. This presumablybecause the retrieved context enhance the model

      Kết quả chính: Được thể hiện ở bảng 1 và bảng 2. Chú ý rằng, thực nghiệm trong 2 bảng này đã thực hiện quá trình infer mà không có few-shot, lý do bởi việc infer này đem lại sự tăng tiến bền vững trong kết quả.

      Kết quả cho thấy RA-IT đạt kết quả tốt nhất. Lý do cho sự tăng tiến này được cho là nhờ ngữ cảnh được truy xuất đã làm tăng cường khả năng hiểu đầu vào của mô hình, từ đó thể hiện sự cần thiết của các mẫu instruction có tăng cường ngữ cảnh.

    4. quannnn 19 Oct 2024
      We conduct a preliminary study on IT data effi-ciency in targeted distillation for open NER byexploring the impact of varous datas sizes: [0.5K,1K, 5K, 10K, 20K, 30K, 40K, 50K]. We use vanillaIT for preliminary study. Results are visualized inFig. 2. The following observations are consistentin English and Chinese: (1) a small data size al-ready surpass ChatGPT’s performances. (2) Perfor-mances are improving as the data sizes increased to10K or 20K, but begin to decline and then remainat a certain level as data sizes further increased to50K. Recent work for IT data selection, Xia et al.Figure 2: Preliminary study of IT data efficiency foropen NER in English (left) and Chinese (right) scenar-ios, where the training data are Pile-NER and Sky-NERrespectively. Average zero-shot results of evaluatedbenchmarks are illustrated. The performance does notnecessarily improve as the data increases.(2024); Ge et al. (2024); Du et al. (2023) also findthe superior performances of only limited data size.We leave selecting more beneficial IT data for IEas future work. Accordingly, we conduct mainexperiments on 5K, 10K and 50K data sizes

      Nghiên cứu chuẩn bị cho đánh giá hiệu quả của dữ liệu: Nghiên cứu chuẩn bị được tiến hành cho việc đánh giá hiệu quả của bộ dữ liệu IT trong việc chiết xuất có mục tiêu của bài toán open NER bằng cách khám phá mức độ ảnh hưởng của dữ liệu ở nhiều kích thước khác nhau: [0.5K, 1K, 5K,...]. Mẫu IT đơn thuần được sử dụng để thực hiện nghiên cứu này.

      Các kết luận rút ra: - Một lượng nhỏ dữ liệu đã có thể vượt qua được khả năng của chatGPT. - Kết quả có sự tăng tiến thuận theo độ tăng của kích thước mô hình (từ 10K lên 20K), nhưng bắt đầu giảm và ổn định ở một mức cụ thể khi dữ liệu tiếp tục tăng đến mức 50k. Các nghiên cứu gần đây về việc chọn dữ liệu IT cũng cho ra kết quả việc trội của bộ dữ liệu nhỏ có kích thước hạn chế.

    5. quannnn 18 Oct 2024
      RA-IT. We explore an alternative way to conductIT in targeted distillation: we introduce RA-IT, acontext-enhanced tuning approach, of which theoverview is in Fig. 1. In our RA-IT approach,each data is augmented with a retrieved context,which consists of k semantically similar exam-ples retrieved from the training dataset. The re-trieved context is prepended to the original conver-sation, forming the retrieval augmented instruction.By fine tuning LMs in this recipe, we equip theLMs with the ability to generate NER answer withon-demand RAG. This means we could flexiblyadapting LMs to different scenarios by determin-ing whether to use RAG during inference based onthe specific characteristics of the scenario.

      RA-IT: Một cách khác để thực hiện instruction-tuning trong việc chiết xuất có mục tiêu, được thể hiện khái quát ở hình 1. Trong cách tiếp cận này, mỗi mẫu sẽ được tăng cường với một đoạn ngữ cảnh được truy xuất. Đoạn ngữ cảnh này bao gồm k mẫu dữ liệu tương đồng về mặt ngữ cảnh được trích xuất từ bộ dữ liệu huấn luyện. Đoạn ngữ cảnh này được thêm vào đoạn hội thoại gốc. từ đó tạo ra mẫu instruction được tăng cường truy xuất. Bằng cách tinh chỉnh các mô hình ngôn ngữ (LMs) theo hướng này, LMs sẽ được trang bị khả năng tạo sinh câu trả lời NER cùng với RAG. Điều này có nghĩa là LMs có thể được cài đặt dễ dàng để thích ứng với nhiều kịch bản khác nhau bằng cách xác định xem có cần sử udngj RAG trong quá trình infer ko dựa trên các đặc tính cụ thể của kịch bản

    6. quannnn 18 Oct 2024
      Vanilla IT. The original instruction tuning tem-plate used in targeted distillation is shown in thebottom part of Fig. 1, which we refer to as VanillaIT, where each passage and its associated entityoutput are converted into a multi-turn conversation.

      IT đơn thuần: Mẫu instruction tuning ban đầu được sử dụng trong quá trình chiết xuất có mục tiêu được thể hiện ở bên dưới của hình 1, còn được gọi là mẫu IT đơn thuần. Trong mẫu này, mỗi câu đầu vào thô và các thực thể liên quan sẽ được hoán đổi thành một đoạn hội thoại có nhiều lượt.

    7. quannnn 18 Oct 2024
      (1) RA-ITachieves consistent improvements on various datasizes, suggesting the need for context-enhancedfine-tuning. (2) Retrieving semantically similar ex-amples benefits the most for training among variousretrieval strategies. Random retrieval also exhibitsimprovement but shows inferior performance tosimilar examples. (3) Retrieving out-domain ex-amples for inference requires applying examplefiltering strategies to achieve improvements. Pro-viding in-domain examples benefits inference.

      Các kết luận thu được: - RA-IT đạt được độ cải thiện bền vững với dữ liệu ở nhiều phạm vi khác nhau, từ đó thể hiện sự cần thiết của việc fine-tuning với ngữ cảnh được mở rộng. - Việc truy xuất các mẫu tương đồng về mặt ngữ cảnh làm cải thiện đáng kể chất lượng huấn luyện, tùy thuộc vào chiến lược chọn mẫu trích xuất. - Việc truy xuất các mẫu out-domain trong quá trình infer yêu cầu các chiến lược lọc mẫu để đạt được hiệu quả mong muốn. Ngược lại, việc cung cấp các mẫu in-domain sẽ làm gia tăng hiệu quả của quá trình infer.

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  58. thewasteland.info thewasteland.info
    New - T. S. ELIOT
    3
    1. Maeve_MacLeish 19 Oct 2024
      Quando fiam uti chelidon—O swallow swallow

      The 6th line of Eliot’s final stanza in “The Waste Land” reads, “Quando fiam uti chelidon”, or “when shall I be as the swallow”. This line was taken from Pervigilium Veneris, translated by Allen Tate, which recalls the story of Philomena, an Athenian princess who was raped by a king, and later turned into a bird. In order to gain a better sense of Eliot’s reference, we can look at it in the context of the stanza in the Pervigilium Veneris, which reads “She sings, we are silent. When will my spring come? Shall I find my voice when I shall be as the swallow? … Silent, I lost the muse. Return, Apollo!”. The mention of spring harkens back to the beginning of “The Waste Land”, where spring plays a major theme. In the Pervigilium Veneris, Philomena attributes spring to herself, calling it “my spring”, suggesting that spring represents her own rebirth and restoration. Thus, we might be able to interpret Eliot’s “spring” in a similar manner. Philomena’s seeking out of her voice is also interesting in terms of “The Waste Land”, which is built on fragmented dialogue and ever changing voices. Interestingly, Philomena seems to have lost “the muse”, or the divine inspiration, and in frustration, she calls out to Apollo to inspire her once again. Eliot, through his biblical references and prayers seems to be calling out to the divine, perhaps for his own inspiration as well. Another significant part of the Pervigilium Veneris are the repeating lines, “Tomorrow may loveless, may lover tomorrow make love.” Through these repeating and ambiguous lines, the reader can get a sense of the future, and the contrast between lovelessness and making love in that future. The word “may” expresses possibility, but can also be interpreted as expressing a wish, or hope. At the final stanza, this phrase shifts into, “Tomorrow let loveless, let lover tomorrow make love.” The newly introduced word, “let”, seems to acknowledge how fate is in the hands of the gods, as it is more of a direct expression of desire. Ultimately this repetition and prayer falls in line with similar repetitions such as “HURRY UP IT IS TIME” in “The Waste Land”, suggesting Eliot’s intensifying attempts at communication with the divine.

    2. yhuang25 17 Oct 2024
      Quando fiam uti chelidon—O swallow swallow

      This line comes from The Vigil of Venus, roughly translating to “when shall I become like the swallow?” The Latin, along with the em-dash and the “Oh swallow swallow” that follow are interesting especially when viewed in conjunction with the story of Philomela. The line suggests Philomela’s longing for transformation or escape, but the swallow itself is a problematic symbol. While her metamorphosis allows her to transcend her human form and escape her oppressor, it also represents the irretrievable loss of voice and agency. In this context, I think that Eliot evokes this myth again to express the breakdown of communication in the modern world. The inability to articulate trauma or sorrow pervades TWL. In Philomela’s case, the act of weaving her story into a tapestry suggests that language, when it fails to convey meaning, can be transformed into a form of visual representation or symbolic action. The swallow thus becomes a double-edged metaphor: on one hand, it allows Philomela to escape her human condition, but on the other, it forever silences her voice. The form of this final part of TWL can also be read with reference to Philomela’s story. Eliot alludes that in this world, ordinary modes of speech and storytelling no longer suffice, just as Philomela is unable to speak. The poet, like Philomela, is left to weave fragments of culture and myth into a tapestry of purpose, even if that meaning is incomplete or incomprehensible. This explains the calling-back of a lot of mythical sources mentioned earlier in the poem.

    3. addiecirulis 16 Oct 2024
      Fishing, with the arid plain behind me

      It does not take more than one read to identify the starkly obvious allusion to the Fisher King here. In fact, it appears that the narrator has taked on the role of the Fisher King himself. He sits on a shore, a place of indistinct borders, an in-between space. This feels apt if we assume that the general omnipotent narrator is Tiresius, as Eliot intended. Tiresius, embodies the state of in-between, at once assuming both and neither gender. If Tiresius is the Fisher King here, we are confronted with simultaneous ideas of infertility, disability and prophecy, suggesting a bleak future for the landscape on which the Fisher King is set in this stanza.

      I would like to call attention to the positionality in this moment. The narrator is described to have their back to this “arid plain.” In Dante’s Purgatorio, thirst is an essential element of the environment he creates: “‘O you who go along behind the others, // not from sloth but, it may be, with reverence, // answer me, since I burn with thirst and fire. // ‘It is not I alone who crave your answer. // All these others thirst for it more than the Indian // or Ethiopian who craves cold water” (Dante, 26.16-21). Not only are the shades literally thirsty in their fiery prison, but their desire that Dante speaks to them is likened to thirst as well. With this in mind, elements of the others sources certainly suggest that the “arid plane” behind the narrator is in fact Dante’s puragtorio, or some kind of hellscape.

      We can justify this with the Book of Isiah, wherein salvation is explicitly described as when God “hast cast all my sins behind thy back” (Isiah 38.17). (Maybe Eliot even drew from “cast” here, as in casting a fishing line). Then, in Weston’s chapter about the Fisher King, this idea of the back turned toward hell is further reinforced with, “the writer of the article in The Open Court asserts that ‘the Fish was sacred to those deities who were supposed to lead men back from the shadows of death to life.’ If this be really the case we can understand the connection of the symbol first with Orpheus, later with Christ, as Eisler remarks: ‘Orpheus is connected with nearly all the mystery, and a great many of the ordinary chthonic, cults in Greece and Italy. Christianity took its first tentative steps into the reluctant world of Graeco-Roman Paganism under the benevolent patronage of Orpheus’” (Weston, 7). Both Orpheus and Dante make similar journeys out of hell, which further corroborates the theory that the “arid plain” behind the narrator in “The Waste Land” is Dante’s creation in Purgatorio. Clearly, the correlations here between fish/The Fisher King and the positioning of hell behind the back in the context of the “The Waste Land” are impossible to deny. The Fisher King looks away from hell, perhaps spinning the end of “The Waste Land” in a hopeful tone, although he continues to sit, fishing fruitlessly, awaiting the arrival of the Grail. In many ways, we have ended the poem exactly where we started it.

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  59. www.biorxiv.org www.biorxiv.org
    Direct and Indirect Salt Effects on Homotypic Phase Separation
    1
    1. Public_Reviews 18 Oct 2024

      Author response:

      The following is the authors’ response to the original reviews.

      Reviewer #1 (Public Review): 

      Summary: 

      The authors examined the salt-dependent phase separation of the low-complexity domain of hnRN-PA1 (A1-LCD). Using all-atom molecular dynamics simulations, they identified four distinct classes of salt dependence in the phase separation of intrinsically disordered proteins (IDPs), which can be predicted based on their amino acid composition. However, the simulations and analysis, in their current form, are inadequate and incomplete. 

      Strengths: 

      The authors attempt to unravel the mechanistic insights into the interplay between salt and protein phase separation, which is important given the complex behavior of salt effects on this process. Their effort to correlate the influence of salt on the low-complexity domain of hnRNPA1 (A1-LCD) with a range of other proteins known to undergo salt-dependent phase separation is an interesting and valuable topic. 

      Weaknesses: 

      (1) The simulations performed are not sufficiently long (Figure 2A) to accurately comment on phase separation behavior. The simulations do not appear to have converged well, indicating that the system has not reached a steady state, rendering the analysis of the trajectories unreliable.

      We have extended the simulations for an additional 500 ns, to 1500 ns. The last 500 ns show reasonably good convergence (see Figure 2A).

      (2) The majority of the data presented shows no significant alteration with changes in salt concentration. However, the authors have based conclusions and made significant comments regarding salt activities. The absence of error bars in the data representation raises questions about its reliability. Additionally, the manuscript lacks sufficient scientific details of the calculations.  

      We have now included error bars. With the error bars, the salt dependences of all the calculated properties (exception for Rg) show a clear trend. Additionally, we have expanded the descriptions of our calculations (p. 15-16).

      (3) In Figures 2B and 2C, the changes in the radius of gyration and the number of contacts do not display significant variations with changes in salt concentration. The change in the radius of gyration with salt concentration is less than 1 Å, and the number of contacts does not change by at least 1. The authors' conclusions based on these minor changes seem unfounded. 

      The variation of ~ 1 Å for the calculated Rg is similar to the counterpart for the experimental Rg. As for the number of contacts, note that this property is presented on a per-residue basis, so a value of 1 means that each residue picks up one additional contact, or each protein chain gains a total of 131 contacts, when the salt concentration is increased from 50 to 1000 mM.

      Reviewer #2 (Public Review): 

      This is an interesting computational study addressing how salt affects the assembly of biomolecular condensates. The simulation data are valuable as they provide a degree of atomistic details regarding how small salt ions modulate interactions among intrinsically disordered proteins with charged residues, namely via Debye-like screening that weakens the effective electrostatic interactions among the polymers, or through bridging interactions that allow interactions between like charges from different polymer chains to become effectively attractive (as illustrated, e.g., by the radial distribution functions in Supplementary Information). However, this manuscript has several shortcomings: 

      (i) Connotations of the manuscript notwithstanding, many of the authors' concepts about salt effects on biomolecular condensates have been put forth by theoretical models, at least back in 2020 and even earlier. Those earlier works afford extensive information such as considerations of salt concentrations inside and outside the condensate (tie-lines). But the authors do not appear to be aware of this body of prior works and therefore missed the opportunity to build on these previous advances and put the present work with its complementary advantages in structural details in the proper context.

      (ii) There are significant experimental findings regarding salt effects on condensate formation [which have been modeled more recently] that predate the A1-LCD system (ref.19) addressed by the present manuscript. This information should be included, e.g., in Table 1, for sound scholarship and completeness. 

      (iii) The strengths and limitations of the authors' approach vis-à-vis other theoretical approaches should be discussed with some degree of thoroughness (e.g., how the smallness of the authors' simulation system may affect the nature of the "phase transition" and the information that can be gathered regarding salt concentration inside vs. outside the "condensate" etc.). Accordingly, this manuscript should be revised to address the following. In particular, the discussion in the manuscript should be significantly expanded by including references mentioned below as well as other references pertinent to the issues raised. 

      (1) The ability to use atomistic models to address the questions at hand is a strength of the present work. However, presumably because of the computational cost of such models, the "phase-separated" "condensates" in this manuscript are extremely small (only 8 chains). An inspection of Fig.1 indicates that while the high-salt configuration (snapshot, bottom right) is more compact and droplet-like than the low-salt configuration (top right), it is not clear that the 50 mM NaCl configuration can reasonably correspond to a dilute or homogeneous phase (without phase separation) or just a condensate with a lower protein concentration because the chains are still highly associated. One may argue that they become two droplets touching each other (the chains are not fully dispersed throughout the simulation box, unlike in typical coarse-grained simulations of biomolecular phase separation). While it may not be unfair to argue from this observation that the condensed phase is less stable at low salt, this raises critical questions about the adequacy of the approach as a stand-alone source of theoretical information. Accordingly, an informative discussion of the limitation of the authors' approach and comparisons with results from complementary approaches such as analytical theories and coarsegrained molecular dynamics will be instructive-even imperative, especially since such results exist in the literature (please see below). 

      We now discuss the limitations of our all-atom simulations and also other approaches (p. 13; see below).

      (2) The aforementioned limitation is reflected by the authors' choice of using Dmax as a sort of phase separation order parameter. However, no evidence was shown to indicate that Dmax exhibits a twostate-like distribution expected of phase separation. It is also not clear whether a Dmax value corresponding to the linear dimension of the simulation box was ever encountered in the authors' simulated trajectories such that the chains can be reliably considered to be essentially fully dispersed as would be expected for the dilute phase. Moreover, as the authors have noted in the second paragraph of the Results, the variation of Dmax with simulation time does not show a monotonic rank order with salt concentration. The authors' explanation is equivalent to stipulating that the simulation system has not fully equilibrated, inevitably casting doubt on at least some of the conclusions drawn from the simulation data. 

      First off, with the extended simulations, the Dmax values converge to a tiered order rank, with successively decreasing values from low salt (50 mM) to intermediate salt (150 and 300 mM) to high salt (500 and 1000 mM). Secondly, as we now state (p. 13), our low-salt simulations mimic a homogenous solution whereas our high-salt simulations mimic the dense phase of a phase-separated system. The intermediate-salt simulations also mimic the dense phase but at a somewhat lower concentration (hence the intermediate Dmax value).

      (3) With these limitations, is it realistic to estimate possible differences in salt concentration between the dilute and condensed phases in the present work? These features, including tie-lines, were shown to be amenable to analytical theory and coarse-grained molecular dynamics simulation (please see below).  

      The differences in salt effects that we report do not represent those between two phases. Rather, as explained in the preceding reply, they represent differences between a homogenous solution at low salt and the dense phase at higher salt. We also acknowledge salt effects calculated by analytical theory and coarse-grained simulations (p. 13).

      (4) In the comparison in Fig.2B between experimental and simulated radius of gyration as a function of [NaCl], there is an outlier among the simulated radii of gyration at [NaCl] ~ 250 mM. An explanation should be offered.  

      After extending the simulations and analyzing the last 500 ns, the Rg data no longer show an outlier though still have some fluctuations from one salt concentration to another.

      (5) The phenomenon of no phase separation at zero and low salt and phase separation at higher salt has been observed for the IDP Caprin1 and several of its mutants [Wong et al., J Am Chem Soc 142, 24712489 (2020) [https://pubs.acs.org/doi/full/10.1021/jacs.9b12208], see especially Fig.9 of this reference]. This work should be included in the discussion and added to Table 1. 

      We now have added Caprin1 to Table 1 (new ref 26) and discuss this paper (p. 13).

      (6) The authors stated in the Introduction that "A unifying understanding of how salt affects the phase separation of IDPs is still lacking". While it is definitely true that much remains to be learned about salt effects on IDP phase separation, the advances that have already been made regarding salt effects on IDP phase separation is more abundant than that conveyed by this narrative. For instance, an analytical theory termed rG-RPA was put forth in 2020 to provide a uniform (unified) treatment of salt, pH, and sequence-charge-pattern effects on polyampholytes and polyelectrolytes (corresponding to the authors' low net charge and high net charge cases). This theory offers a means to predict salt-IDP tie-lines and a comprehensive account of salt effect on polyelectrolytes resulting in a lack of phase separation at extremely low salt and subsequent salt-enhanced phase separation (similar to the case the authors studied here) and in some cases re-entrant phase separation or dissolution [Lin et al., J Chem Phys 152. 045102 (2020) [https://doi.org/10.1063/1.5139661]]. This work is highly relevant and it already provided a conceptual framework for the authors' atomistic results and subsequent discussion. As such, it should definitely be a part of the authors' discussion. 

      We now cite this paper (new ref 34) in Introduction (p. 4). We also discuss its results for Caprin1 (new ref 18; p. 13).

      (7) Bridging interactions by small ions resulting in effective attractive interactions among polyelectrolytes leading to their phase separation have been demonstrated computationally by Orkoulas et al., Phys Rev Lett 90, 048303 (2003) [https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.90.048303]. This result should also be included in the discussion. 

      We now cite this paper (new ref 41; p. 11).

      (8) More recently, the salt-dependent phase separations of Caprin1, its RtoK variants and phosphorylated variant (see item #5 above) were modeled (and rationalized) quite comprehensively using rG-RPA, field-theoretic simulation, and coarse-grained molecular dynamics [Lin et al., arXiv:2401.04873 [https://arxiv.org/abs/2401.04873]], providing additional data supporting a conceptual perspective put forth in Lin et al. J Chem Phys 2020 (e.g., salt-IDP tie-lines, bridging interactions, reentrance behaviors etc.) as well as in the authors' current manuscript. It will be very helpful to the readers of eLife to include this preprint in the authors' discussion, perhaps as per the authors' discretion along the manner in which other preprints are referenced and discussed in the current version of the manuscript. 

      We now cite this paper (new ref 18) and discuss it along with new ref 26 in Discussion (p. 13).

      Reviewer #3 (Public Review): 

      Summary: 

      This study investigates the salt-dependent phase separation of A1-LCD, an intrinsically disordered region of hnRNPA1 implicated in neurodegenerative diseases. The authors employ all-atom molecular dynamics (MD) simulations to elucidate the molecular mechanisms by which salt influences A1-LCD phase separation. Contrary to typical intrinsically disordered protein (IDP) behavior, A1-LCD phase separation is enhanced by NaCl concentrations above 100 mM. The authors identify two direct effects of salt: neutralization of the protein's net charge and bridging between protein chains, both promoting condensation. They also uncover an indirect effect, where high salt concentrations strengthen pi-type interactions by reducing water availability. These findings provide a detailed molecular picture of the complex interplay between electrostatic interactions, ion binding, and hydration in IDP phase separation. 

      Strengths: 

      Novel Insight: The study challenges the prevailing view that salt generally suppresses IDP phase separation, highlighting A1-LCD's unique behavior. 

      Rigorous Methodology: The authors utilize all-atom MD simulations, a powerful computational tool, to investigate the molecular details of salt-protein interactions. 

      Comprehensive Analysis: The study systematically explores a wide range of salt concentrations, revealing a nuanced picture of salt effects on phase separation. 

      Clear Presentation: The manuscript is well-written and logically structured, making the findings accessible to a broad audience. 

      Weaknesses: 

      Limited Scope: The study focuses solely on the truncated A1-LCD, omitting simulations of the full-length protein. This limitation reduces the study's comparative value, as the authors note that the full-length protein exhibits typical salt-dependent behavior. A comparative analysis would strengthen the manuscript's conclusions and broaden its impact.

      Perhaps we did not impress on the reviewer how expensive the all-atom MD simulations on A1-LCD were: the systems each contained half a million atoms and the simulations took many months to complete. That said, we agree with the reviewer that, ideally, a comparative study on a protein showing the typical screening class of salt dependence would have made our work more complete. However, we are confident of the conclusions for several reasons. First, the three salt effects – charge neutralization, bridging, and strengthening of pi-types of interactions – revealed by the all-atom simulations are physically sound and well-supported by other studies. Second, these effects led us to develop a unified picture for the salt dependence of homotypic phase separation, in the form of a predictor for the classes of salt dependence based on amino-acid composition. This predictor works well for nearly 30 proteins. Third, recent studies using analytical theory and coarse-grained simulations (new ref 18) also strongly support our conclusions.

      Reviewer #1 (Recommendations For The Authors): 

      (1) In Figure 1, the color scheme should be updated and the figure remade, as the current set of color choices makes it very difficult to distinguish the magenta spheres.  

      We have increased the sizes of ions in Figure 1 to make them distinguishable.

      (2) Within the framework of atomistic simulations, the influence of salt concentration alteration on protein conformational plasticity is worth investigating. This could be correlated (with proper details) with the effect of salt-concentration-modulated protein aggregation behavior. 

      We now use RMSF to measure conformational plasticity, which shows a clear salt-dependent trend with a 27% reduction in fluctuations from 50 mM to 1000 mM NaCl (new Fig. S1).

      (3) The authors should mention the protein concentrations employed in the simulations and whether these are consistent with experimentally used concentrations.  

      We have mentioned the initial concentration (3.5 mM). We now further state that this concentration is maintained in the low-salt simulations, indicating absence of phase separation, but is increased to 23 mM in the high-salt simulations, indicating phase separation. The latter value is consistent with the measured concentrations in the dense phase (last two paragraphs of p. 5).

      (4) It would be useful to test the salt effect for at least two extreme salt concentrations at various protein concentrations, consistent with experimental protein concentration ranges.  

      In simulation studies of short peptides (ref 37), we have shown that the initial concentration does not affect the final concentration in the dense phase, as expected for phase-separation systems. We expect that the same will be true for the A1-LCD system at intermediate and high salt where phase separation occurs. Though this expectation could be tested by simulations at a different initial protein concentration, such simulations would be expensive but unlikely to yield new physical insight.

      (5) Importantly, the simulations do not appear to have converged well enough (Figure 2A). The authors should extend the simulation trajectories to ensure the system has reached a steady state.  

      We extended the simulations for an additional 500 ns, which now appear to show convergence. In Figure 2A we now see Dmax values converge to a tiered order rank, with successively decreasing values from low salt (50 mM) to intermediate salt (150 and 300 mM) to high salt (500 and 1000 mM). 

      (6) The authors mention "phase separation" in the title, but with only a 1 μs simulation trajectory, it is not possible to simulate a phenomenon like phase separation accurately. Since atomistic simulations cannot realistically capture phase separation on this timescale, a coarse-grained approach is more suitable. To properly explore salt effects in the context of phase separation, long timescale simulation trajectories should be considered. Otherwise, the data remain unreliable. 

      Our all-atom simulations revealed rich salt effects that might have been missed in coarse-grained simulations. It is true that coarse-grained models allow the simulations of the phase separation process, but as we have recently demonstrated (refs 36 and 37), all-atom simulations on the μs timescale are also able to capture the spontaneous phase separation of peptides and small IDPs. A1-LCD is much larger than those systems, so we had to use a relatively small chain number (8 chains here vs 64 used in ref 37 and 16 used in ref 37). S2ll, we observe the condensation into a dense phase at high salt. We discuss the pros and cons of all-atom vs. coarse-grained simulations in p. 13.

      (7) In Figure 5E, the plot does not show that g(r) has reached 1. If it does, the authors should show the full curve. The same issue remains with supplementary figures 1, 2, 3, etc.  

      We now show the approach to 1 in the insets of Figs. S2, S3, S4, and 5E.

      (8) None of the data is represented with error bars. The authors should include error bars in their data representations. 

      We have now included error bars in all graphs that report average values.

      (9) The authors state that "the net charge of the system reduces to only +8 at 1000 mM NaCl (Figure 3C)" but do not explain how this was calculated. 

      We now add this explanation in methods (p. 16).

      (10). The authors mention "similar to the role played by ATP molecules in driving phase separation of positively charged IDPs." However, ATP can inhibit aggregation, and its induction of phase separation is concentration-dependent. Given ATP's large aromatic moiety, its comparison to ions is not straightforward and is more complex. This comparison can be at best avoided. 

      In this context we are comparing the bridging capability of ATP molecules in driving phase separation of positively charged IDPs in ref 36 to the bridging capability of the ions here. In ref 36 the authors show ATP bridging interactions between protein chains similar to what we show here with ions.

      (11) Many calculations are vaguely represented. The process for calculating the number of bridging ions, for example, is not well documented. The authors should provide sufficient details to allow for the reproducibility of the data. 

      We have now expanded the methods section to include more detailed information on calculations done.

      Reviewer #3 (Recommendations For The Authors): 

      Include error bars or standard deviations for all results averaged over four replicates, particularly for the number of ions and contacts per residue. This would provide a clearer picture of the data's reliability and variability. 

      We have now included error bars in all graphs that report averaged values.

      Strengthen the support for the conclusion that "each Arg sidechain often coordinates two Cl- ions, multiple backbone carbonyls often coordinate a single Na+ ion." While Fig. 3A clearly demonstrates ArgCl- coordination, the Na+ coordination claim for a 131-residue protein requires further clarification. Consider including the integration profile of radial distribution functions for Na+ ions to bolster this assertion. 

      We now report the number of Na+ ions that coordinate with multiple backbone carbonyls (p. 7) as well as the number of Na+ ions that bridge between A1-LCD chains via coordination with multiple backbone carbonyls (p. 9). Please note that Figure 4A right panel displays an example of Na+ coordinating with multiple backbone carbonyls.

      Address the following typographical errors in the main text: o Page 11, line 25: "distinct classes of sat dependence" should be "distinct classes of salt dependence" o Page 14, line 9: "for Cl- and 3.0 and 5.4 A" should be "for Cl- and 3.0 and 5.4 √Ö" o Page 14, line 18: "As a control, PRDFs for water were also calculated" should be "As a control, RDFs for water were also calculated" (assuming PRDF was meant to be RDF) 

      We have now corrected these typos.

      Consider expanding the study to include simulations of the full-length protein to provide a more comprehensive comparison between the truncated A1-LCD and the complete protein's behavior in various salt concentrations. 

      As we explained above, even with eight chains of A1-LCD, which has 131 residues, the systems already contain half a million atoms each and the all-atom simulations took many months to complete. Full-length A1 has 314 residues so a multi-chain system would be too large to be feasible for all-atom simulations.

      AuthorResponse
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  60. inst-fs-iad-prod.inscloudgate.net inst-fs-iad-prod.inscloudgate.net
    someTitle
    1
    1. ChengchengYan 18 Oct 2024
      Paul Pham related a similar patt ern of expectations among students: if “a person with a completely diff erent background” joined a class or activity that was “mostly Asian,” “that person would actually receive a lot of att ention— positive att ention,” simply for showing up at something conceived to be out of the ordinary for a Latina/o.56 Although Paul inter-preted this to have a positive meaning, a more troubling interpretation, in accordance with Claude Steele’s concept of disidentifi cation, would be the following: if someone who was “diff erent” (i.e., non- Asian) joined an AP class or a challenging extracurricular activity, she would be greeted with surprise and praise for exceeding expectations of low achievement. Devalued with the stigma of low expectations from the outset, the student would grow increasingly likely to disengage with academics, unless this patt ern was interrupted by mentors or other factors that recognized and nurtured her abilities and potential.

      Paul Pham shares an interesting take on how expectations play out in schools. He points out that if a student from a different background, like a Latina/o, joins a mostly Asian class or activity, they often get a lot of positive attention just for being there. While Paul sees this as a good thing, there’s a deeper issue tied to Claude Steele’s idea of disidentification. In this view, if a non-Asian student joins an AP class or a tough extracurricular, they might be greeted with surprise and praise for doing something unexpected. This reinforces the stereotype that they’re exceeding low expectations. This stigma can make them feel disengaged from academics unless they have mentors or support that recognize and encourage their abilities. It really shows how crucial it is to challenge these stereotypes and create a more welcoming environment for everyone.

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    inst-fs-iad-prod.inscloudgate.net/files/22aee84f-480d-41f5-a8f2-bf5d725f7aea/Chang, Ch. 2, The Asian and the Latino Thing in Schools, in Changs Next Door to the Diazes.pdf
  61. inscripcion-diplomado.condusef.gob.mx inscripcion-diplomado.condusef.gob.mx
    Diplomado
    1
    1. Franck_hr 17 Oct 2024
      Solamente 57 millones de personas de 18 a 70 años (68%) tienen al menos un producto financiero, lo que representa sólo 3 millones más de personas con respecto a 2018. En el mismo sentido, solo el 49 por ciento de la población adulta en México tiene una cuenta en un banco o institución financiera. (CNBV-INEGI, 2021, Encuesta Nacional de Inclusión Financiera 2021).
      • Hay un aumento en personas jóvenes con al menos un producto financiero
      • Menos del 50% de las personas adultas tienen una cuenta bancaria
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  62. www.pbs.org www.pbs.org
    Africans in America/Part 1/Equiano's autobiography
    1
    1. tknight1952 17 Oct 2024
      I remember, in the vessel in which I was brought over, in the men's apartment, there were several brothers, who, in the sale, were sold in different lots; and it was very moving on this occasion, to see and hear their cries at parting. O, ye nominal Christians! might not an African ask you -- Learned you this from your God, who says unto you, Do unto all men as you would men should do unto you? Is it not enough that we are torn from our country and friends, to toil for your luxury and lust of gain? Must every tender feeling be likewise sacrificed to your avarice?

      Like Equiano wrote about earlier he writes about how slaves that came together on the ships were still torn from their families and sold. Unlike Equiano, Cinqué was taken from his family that remained in Africa while he was taken to North America.

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  63. wol.jw.org wol.jw.org
    “Ven a Macedonia y ayúdanos” — BIBLIOTECA EN LÍNEA Watchtower
    1
    1. ClaudioM 17 Oct 2024
      b) ¿Qué tácticas siguen usando contra nosotros Satanás y la gente que actúa bajo su influencia?

      Las mismas que en aquel momento, usan mentiras para fomentar el odio y la Opcion, debido al nacionalismo. O tradiciones. Por lo que muchos hermanos terminan golpeados o en prisión. Lo bueno es que Jehová está al tanto de todo éso 1 Pedro 3:12 dice que nada está escondido a Jehová y que además el escucha el ruego de los justos.

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  64. transreads.org transreads.org
    Girl, Woman, Other
    1
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  65. kumu.brocku.ca kumu.brocku.ca
    Baron.pdf
    1
    1. dfoster_14 17 Oct 2024
      o regulate their own thoughts and actions, and that in turn can have det-rimental effects on their capacity to meet important goals or standards.

      too much positive affect (happiness pride, energy, joy, enthusiasm), can lead to lack of focus...

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  66. new.express.adobe.com new.express.adobe.com
    My Museum - August 22, 2024 at 09.44.54
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  67. Local file Local file
    A System for Writing: How an Unconventional Approach to Note-Making Can Help you Capture Ideas, Think Wildly, and Write Constantly
    2
    1. chrisaldrich 16 Oct 2024
      “Personal knowledge management,” or “PKM” as it’s oen called,provides an umbrella under which people of disparate vocations engage indiscourse surrounding not only notes and note-taking, but every niche andnuance of managing information.

      Is he poking fun at the PKM space here? This non-definition definition would seem to be a subtle jab certainly.

      definitions personal knowledge management

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  68. www.csfd.cz www.csfd.cz
    Dealer (1996) | Galerie - Z filmu | ČSFD.cz
    1
    1. blueronin 16 Oct 2024
      Po komplikovaném a neúspěšném obchodu s heroinem přijde drobný drogový dealer Frank o peníze i o zboží a ocitne se v obrovském dluhu u balkánského narkobarona Mila. Frank se tváří v tvář Milově rostoucí frustraci pokouší splatit peníze, ale čas plyne a tlak narůstá. Dealer, dánský kriminální thriller z roku 1996 a debut Nicolase Windinga Refna, je adrenalinová jízda po kodaňském drogovém podsvětí. Zároveň se jedná o herecký debut známého dánského herce Madse Mikkelsena. (Film Europe)
      🥑seed/film
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  69. www.biorxiv.org www.biorxiv.org
    Single-nucleus transcriptomics reveal the cytological mechanism of conjugated linoleic acids in regulating intramuscular fat deposition
    2
    1. Public_Reviews 16 Oct 2024

      Author response:

      The following is the authors’ response to the original reviews.

      Reviewer #1 (Public Review):

      Summary:

      The authors aimed to elucidate the cytological mechanisms by which conjugated linoleic acids (CLAs) influence intramuscular fat deposition and muscle fiber transformation in pig models. Utilizing single-nucleus RNA sequencing (snRNA-seq), the study explores how CLA supplementation alters cell populations, muscle fiber types, and adipocyte differentiation pathways in pig skeletal muscles.

      Thanks!

      Strengths:

      Innovative approach: The use of snRNA-seq provides a high-resolution insight into the cellular heterogeneity of pig skeletal muscle, enhancing our understanding of the intricate cellular dynamics influenced by nutritional regulation strategy.

      Robust validation: The study utilizes multiple pig models, including Heigai and Laiwu pigs, to validate the differentiation trajectories of adipocytes and the effects of CLA on muscle fiber type transformation. The reproducibility of these findings across different (nutritional vs genetic) models enhances the reliability of the results.

      Advanced data analysis: The integration of pseudotemporal trajectory analysis and cell-cell communication analysis allows for a comprehensive understanding of the functional implications of the cellular changes observed.

      Practical relevance: The findings have significant implications for improving meat quality, which is valuable for both the agricultural and food industry.

      Thanks!

      Weaknesses:

      Model generalizability: While pigs are excellent models for human physiology, the translation of these findings to human health, especially in diverse populations, needs careful consideration.

      Thanks!

      Reviewer #2 (Public Review):

      Summary:

      This study comprehensively presents data from single nuclei sequencing of Heigai pig skeletal muscle in response to conjugated linoleic acid supplementation. The authors identify changes in myofiber type and adipocyte subpopulations induced by linoleic acid at depth previously unobserved. The authors show that linoleic acid supplementation decreased the total myofiber count, specifically reducing type II muscle fiber types (IIB), myotendinous junctions, and neuromuscular junctions, whereas type I muscle fibers are increased. Moreover, the authors identify changes in adipocyte pools, specifically in a population marked by SCD1/DGAT2. To validate the skeletal muscle remodeling in response to linoleic acid supplementation, the authors compare transcriptomics data from Laiwu pigs, a model of high intramuscular fat, to Heigai pigs. The results verify changes in adipocyte subpopulations when pigs have higher intramuscular fat, either genetically or diet-induced. Targeted examination using cell-cell communication network analysis revealed associations with high intramuscular fat with fibro-adipogenic progenitors (FAPs).  The authors then conclude that conjugated linoleic acid induces FAPs towards adipogenic commitment. Specifically, they show that linoleic acid stimulates FAPs to become SCD1/DGAT2+ adipocytes via JNK signaling. The authors conclude that their findings demonstrate the effects of conjugated linoleic acid on skeletal muscle fat formation in pigs, which could serve as a model for studying human skeletal muscle diseases.

      Thanks!

      Strengths:

      The comprehensive data analysis provides information on conjugated linoleic acid effects on pig skeletal muscle and organ function. The notion that linoleic acid induces skeletal muscle composition and fat accumulation is considered a strength and demonstrates the effect of dietary interactions on organ remodeling. This could have implications for the pig farming industry to promote muscle marbling. Additionally, these data may inform the remodeling of human skeletal muscle under dietary behaviors, such as elimination and supplementation diets and chronic overnutrition of nutrient-poor diets. However, the biggest strength resides in thorough data collection at the single nuclei level, which was extrapolated to other types of Chinese pigs.

      Thanks!

      Weaknesses:

      While the authors generated a sizeable comprehensive dataset, cellular and molecular validation needed to be improved. For example, the single nuclei data suggest changes in myofiber type after linoleic acid supplementation, yet these data are not validated by other methodologies. Similarly, the authors suggest that linoleic acid alters adipocyte populations, FAPs, and preadipocytes; however, no cellular and molecular analysis was performed to reveal if these trajectories indeed apply. Attempts to identify JNK signaling pathways appear superficial and do not delve deeper into mechanistic action or transcriptional regulation. Notably, a variety of single cell studies have been performed on mouse/human skeletal muscle and adipose tissues. Yet, the authors need to discuss how the populations they have identified support the existing literature on cell-type populations in skeletal muscle.Moreover, the authors nicely incorporate the two pig models into their results, but the authors only examine one muscle group. It would be interesting if other muscle groups respond similarly or differently in response to linoleic acid supplementation.Further, it was unclear whether Heigai and Laiwu pigs were both fed conjugated linoleic acid or whether the comparison between Heigai-fed linoleic acid and Laiwu pigs (as a model of high intramuscular fat). With this in mind, the authors do not discuss how their results could be implicated in human and pig nutrition, such as desirability and cost-effectiveness for pig farmers and human diets high in linoleic acid. Notably, while single nuclei data is comprehensive, there needs to be a statement on data deposition and code availability, allowing others access to these datasets. Moreover, the experimental designs do not denote the conjugated linoleic acid supplementation duration. Several immunostainings performed could be quantified to validate statements. This reviewer also found the Nile Red staining hard to interpret visually and did not appear to support the conclusions convincingly. Within Figure 7, several letters (assuming they represent statistical significance) are present on the graphs but are not denoted within the figure legend.

      Thanks for your suggestions! We accepted your suggestion to revised our manuscript.

      For changes in myofiber type, we performed qPCR to verify the changes of muscle fiber type related gene expression after CLA treatment (Figure 2E); for changes of adipocyte and preadipocyte populations, we also performed immunofluorescence staining, qPCR, and western blotting in LDM tissues and FAPs to verify the alterations of cell types after feeding with CLA (Figure 3D, 3E, 6G, 7C, and 7D). Hence, we think these cellular and molecular results could support our conclusions.

      For JNK signaling pathway, we selected this signaling pathway based on snRNA-seq dataset and verified by activator in vitro experiment. However, we did not explore the mechanistic action and the downstream transcriptional regulators need to be further discussed. We have added these in the discussion part (line 443-448).

      We have added the comparation between different cell-type populations in skeletal muscles (line 362-368 and 385-390).

      For changes in myofiber type of Laiwu pigs, we have discussed in our previous study(Wang et al., 2023). Interestingly, we also found in high IMF content Laiwu pigs, the percentage of type IIa myofibers had an increased tendency (29.37% vs. 23.95%) while the percentage of type IIb myofibers had a decreased tendency (38.56% vs. 43.75%) in this study. We also added this discussion in the discussion part (line 392-395).

      We have supplied the information of treatment in the materials and methods part (line 469-478). We also added the discussion about significance of our study for human and pig nutrition in the discussion part (line 375-376 and 446-447).

      Our data will be made available on reasonable request (line 574-576).

      We have supplied the information of the CLA supplementation duration in the materials and methods part (line 465).

      Porcine FAPs have little lipid droplets and we improved the image quality (Figure 7A). In Figure 7, the Nile Red staining could be quantified and we have the quantification of Oil Red O staining (Figure 7B and 7J). We also added the statistical significance in figure legend.

      Recommendations for the authors:

      Reviewer #1 (Recommendations For The Authors):

      Suggestions for Improved or Additional Experiments, Data, or Analyses

      Cross-species analysis: To strengthen the generalizability of the results, it would be beneficial to include a comparative analysis with other species, such as human, bovine, or rodent models, using publicly available snRNA-seq datasets.

      Thanks! Our previous study has compared the conserved and unique signatures in fatty skeletal muscles between different species(Wang, Zhou, Wang, & Shan, 2024). We mainly focused on the regulatory mechanism of CLAs in regulating intramuscular fat deposition. However, there is still a blank in the snRNA-seq or scRNA-seq datasets about the effects of CLAs on regulating fat deposition in muscles across other species, including human, bovine or rodent models. Hence, we only analyze the regulatory mechanisms of CLAs influencing intramuscular fat deposition in pigs.

      Functional link: the authors should discuss in the manuscript how the muscles differ in terms of texture, flavor, aroma, etc. before and after CLA administration or between Heigai and Laiwu to provide context and help readers better understand how the observed high-resolution cellular changes relate to these functional properties of meat.

      Thanks! We have added these in the introduction part (line 90-98).

      Improve figures: some figures, particularly those involving Oil Red O and Nail Red, could be improved by including higher magnification images to assess the organization of lipid droplets of individual adipocytes (Figure 7A, I, and K).

      Thanks! Porcine FAPs have little lipid droplets and we improved the image quality (Figure 7A).

      Reviewer #2 (Recommendations For The Authors):

      All of my comments are above. However, I would recommend improving the writing as several areas throughout the results needed clarity.

      Thanks! We have revised our manuscript carefully after accepting your revisions.

      Wang, L., Zhao, X., Liu, S., You, W., Huang, Y., Zhou, Y., . . . Shan, T. (2023) Single-nucleus and bulk RNA sequencing reveal cellular and transcriptional mechanisms underlying lipid dynamics in high marbled pork NPJ Sci Food 7: 23. https://doi.org/10.1038/s41538-023-00203-4

      Wang, L., Zhou, Y., Wang, Y., & Shan, T. (2024) Integrative cross-species analysis reveals conserved and unique signatures in fatty skeletal muscles Sci Data 11: 290. https://doi.org/10.1038/s41597-024-03114-5

      AuthorResponse
    2. Public_Reviews 15 Oct 2024

      Reviewer #1 (Public review):

      In this revised manuscript, the authors aim to elucidate the cytological mechanisms by which conjugated linoleic acids (CLAs) influence intramuscular fat deposition and muscle fiber transformation in pig models. They have utilized single-nucleus RNA sequencing (snRNA-seq) to explore the effects of CLA supplementation on cell populations, muscle fiber types, and adipocyte differentiation pathways in pig skeletal muscles. Notably, the authors have made significant efforts in addressing the previous concerns raised by the reviewers, clarifying key aspects of their methodology and data analysis.

      Strengths:

      (1) Thorough validation of key findings: The authors have addressed the need for further validation by including qPCR, immunofluorescence staining, and western blotting to verify changes in muscle fiber types and adipocyte populations, which strengthens their conclusions.

      (2) Improved figure presentation: The authors have enhanced figure quality, particularly for the Oil Red O and Nile Red staining images, which now better depict the organization of lipid droplets (Figure 7A). Statistical significance markers have also been clarified (Figure 7I and 7K).

      Weaknesses:

      (1) Cross-species analysis and generalizability of the results: Although the authors could not perform a comparative analysis across species due to data limitations, they acknowledged this gap and focused on analyzing regulatory mechanisms specific to pigs. Their explanation is reasonable given the current availability of snRNA-seq datasets on muscle fat deposition in other human and mouse.

      (2) Mechanistic depth in JNK signaling pathway: While the inclusion of additional experiments is a positive step, the exploration of the JNK signaling pathway could still benefit from deeper analysis of downstream transcriptional regulators. The current discussion acknowledges this limitation, but future studies should aim to address this gap fully.

      (3) Limited exploration of other muscle groups: The authors did not expand their analysis to additional muscle groups, leaving some uncertainty regarding whether other muscle groups might respond differently to CLA supplementation. Further studies in this direction could enhance the understanding of muscle fiber dynamics across the organism.

      Review 1
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    biorxiv.org/content/10.1101/2024.05.30.596608v2
  70. pressbooks.library.torontomu.ca pressbooks.library.torontomu.ca
    Emily Dickinson
    1
    1. bgjyzeli 16 Oct 2024
      I’m nobody! Who are you? Are you nobody, too?

      the repetition of the "o" and "oo" sound is interesting, it is like Dickinson is playing with language to create different sounds

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  71. www.pulshr.pl www.pulshr.pl
    Coś się ruszyło na rynku pracy. Takiego odbicia nie mieliśmy już od dawna | pulshr.pl
    1
    1. pyxelr 15 Oct 2024
      Niewielkie wzrosty odnotował też marketing i sprzedaż - o 1 proc. czy sektor IT - o 5 proc.

      In September, employers in Poland published 12% more job offers y/y (288 thousand).

      The increase has been going on for 4 months, and now it has reached the highest level since March 2022. The largest increase in the number of job offers is in medical professions (24%) and manual workers (13%). Decrease among financiers (-15%), HR specialists (-10%) and lawyers (-7%). In IT, the number of offers increased by 5%, and in marketing and sales by 1%.

      work data polish
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  72. www.planalto.gov.br www.planalto.gov.br
    L13105compilada
    1
    1. paulaslemos 15 Oct 2024
      Defensoria Pública

      Entendimento do STF: é devido o pagamento de honorários sucumbenciais à Defensoria Pública, quando representa parte vencedora em demanda ajuizada contra qualquer ente público, inclusive aquele que integra → ⚠ cancelamento da Súmula 421 do STF

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    planalto.gov.br/ccivil_03/_ato2015-2018/2015/lei/L13105compilada.htm
  73. Local file Local file
    Untitled document
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    1. aaclancy 15 Oct 2024
      o claim that AI models like ChatGPT and DALL-E will replace art created bypeople is to ignore both the ineffable qualities of the human touch and the critical flaws of thesemodels—or so say the artists and writers.

      Testing ideas

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  74. www.youtube.com www.youtube.com
    U.S. NAVY ADVANCED TYPING DUPLICATING AND MANUSCRIPT TYPEWRITER INSTRUCTIONAL FILM 58184
    1
    1. chrisaldrich 15 Oct 2024

      Advanced Typing: Duplicating and Manuscript. Vol. MN-1512d, 1943. https://www.youtube.com/watch?v=7ve5JnTUzvo.

      Stencils

      Before writing stencils, be sure to clean your type. (Don't use liquid solvent.)

      Be sure to place the cushion sheet properly behind the stencil.

      Place the paper bail rollers at the extreme left and right of the stencil to prevent them from marking the master.

      For errors, rub individual characters separately with a burnisher using a circular motion.

      Hectograph masters, Hectograph ribbon (ditto ribbon)

      Wax pencils

      Typefaces

      20% more type on a page with elite than 10 inch pica.

      Pica allows approximately 26-40 lines on standard letterhead giving 300-450 words to a page.

      Special characters: - o for degrees ' and " for feet and inches or minutes and seconds along with superscript - division: - backspace colon - pound sterling: L backspace f - exclamation point: period backspace ' - equal sign: hyphen backspace variable hyphen - paragraph mark: P backspace I

      proofreaders' marks<br /> # followed by a number is used to mean insert that number of spaces

      Centering timestamp 19:37

      typewriters typewriter stencils Lenor Fenton Hectograph masters burnisher wax pencils ditto machines Hectograph pencils direct offset process offset masters Underwood justifying typewriter Electromatic proportional spacing machine (typewriter) Varityper type styles pica elite proofreading centering watch dublicating
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  75. viewer.athenadocs.nl viewer.athenadocs.nl
    Untitled document
    2
    1. NaomiDeRijk 15 Oct 2024
      Methods are often not rigorous enough o It must be considered whether the new instrument actually adds something to relative to already existing instruments, this is called incremental validity

      Twijfelpunten emic approach: - Methoden zijn vaak niet rigoureus (=streng) genoeg. - Nieuwe instrument heroverwegen; incrementele validiteit.

    2. NaomiDeRijk 15 Oct 2024
      Many instruments are adopted from the English language, which is a risk for ethnocentrism. o With many comparing and looking for similarities between cultures, important details are quickly skipped, creating a blind spot

      Twijfelpunten etic approach: - Oorspronkelijke Engelse instrumenten leiden tot etnocentrisme (=minder kijken naar andere culturen). - Vergelijken en overeenkomsten zoeken leidt tot belangrijke details overslaan (=blinde vlek).

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    viewer.athenadocs.nl/api/course/tiu-psy-1007/TIU-PSY-1007-3/
  76. inst-fs-iad-prod.inscloudgate.net inst-fs-iad-prod.inscloudgate.net
    view
    1
    1. Gloria.martinez 15 Oct 2024
      Billings, 1994). Conclusion Schools such as Seguin High School are faced with a special challenge. To significantly alter the stubborn pattern of underachievement, they need to become authentically caring institutions. To become authentically caring institutions, the'y need to at once stop sub-tracting resources from youth and deal with th~ effects of subtraction. Although it is up to each school to determine what a more additive perspective might entail, my study suggests that an important point of departure is a critical examination of the existing curriculum. The operant model of schooling structurally deprives acculturated, U.S.-born youth o

      Combatting the problem of poor achievement in institutions such as Seguin High School requires real attention to the students. In creating true, loving schools, schools can meet the needs of diverse students and counteract the consequences of subtraction of resources. The suggestion that we must evaluate the curriculum as we know it is important. This ensures that schools offer a broader and more fulfilling educational experience that is more responsive to the cultural and personal desires of US-born children.

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    inst-fs-iad-prod.inscloudgate.net/files/a3b4a0e5-23d3-4412-b25b-62c4f95f1624/Valenzuela, Subtractive Schooling and MexicanAmerican Youth.pdf
  77. www.researchgate.net www.researchgate.net
    (5) (PDF) Comunicación estratégica / F.J. Garrido M.
    6
    1. aguevaraa6 15 Oct 2024
      3. La estrategia de comunicación es un inductor de la naturaleza de largo plazo en la que se desarrolla la imagen de la empresa, la que como hemos visto se construye a partir de la relación que la organización desarrolla en la sociedad (esa mirada de largo plazo que la visión estratégica requiere, es perfectamente simbiótica con la naturaleza misma del proceso de comunicación en las organizaciones con vista a su imagen). Quizás el pensamiento estratégico no traiga novedades aparejadas en la inducción de tiempos y plazos que los expertos reconocen en la comunicación empresarial, pero sin duda es un aporte para traer al consciente de muchos la explicitación de dicho elemento y su necesidad de sistematización. Algunos directivos orientados hacia la consolidación de metas de corto plazo o de retorno acelerado de la inversión podrían preguntarse ¿por qué la estrategia de comunicación debe ser edificada para un mediano o largo plazo? ya que se trata de la estrategia de un sujeto social que busca permanecer en el tiempo, el análisis conceptual y el diseño de un concepto integral de desarrollo13 se construirá sobre la base de las posibilidades reales de acción y mensajes de la empresa que le aseguren consistencia; es decir, buscando valorizar lo que resulte de su realidad inmediata y que a la vez de diferenciarla pueda servir para generar un mensaje sostenible y creíble a través del tiempo (en tal sentido los diferenciadores no se inventan, sino surgen del rescate de elementos existentes en la empresa, para luego potenciarlos de la mejor manera posible).

      El texto subraya la importancia de la estrategia de comunicación como un proceso de largo plazo para construir una imagen empresarial sostenible y creíble. Este enfoque estratégico requiere coherencia entre los mensajes emitidos y la realidad de la organización, rescatando elementos diferenciadores ya existentes y potenciándolos. A pesar de que algunos directivos puedan cuestionar la necesidad de una visión a largo plazo, el autor argumenta que las empresas buscan permanencia en el tiempo, y por tanto, la consistencia de los mensajes es clave para generar confianza. De esta manera, la estrategia de comunicación se convierte en un pilar fundamental para el desarrollo organizacional sostenido.

      Comunicación Estrategia Empresa Imagen Mensajes
    2. VALEPEREZ 15 Oct 2024
      En algún momento del tiempo los ejecutivos y las empresas despiertan a la necesidad de planificar hacia el largo plazo la inversión en su recurso comunicacional, especialmente cuando su item de promoción o de comunicación no le resultan rentables y dicha inversión parece más bien un pesado costo: aparece entonces una variable económica que resulta gatilladora del proceso de minimización del gasto o bien de su incorporación como una variable transversal de la planificación estratégica

      La comunicación estratégica es una herramienta clave para el éxito organizacional y no debería ser vista como un área en la que se puede reducir costos sin consecuencias. La planificación a largo plazo permite que las empresas mantengan coherencia en sus mensajes y relaciones con los stakeholders, lo que a su vez refuerza su reputación y capacidad de respuesta ante crisis. Si bien es comprensible que los ejecutivos busquen eficiencias financieras, reducir el presupuesto de comunicación puede debilitar la imagen pública y generar costos mayores a largo plazo. Invertir de manera adecuada en estrategias de comunicación robustas es esencial para garantizar sostenibilidad y confianza.

    3. AlexTS593 15 Oct 2024
      a.- La estrategia será un patrón de decisiones: los autores señalan que estemodelo o patrón debe ser coherente en todos los niveles de la firma, debiendoademás tender a reunir y aunar los esfuerzos de modo integrado

      Si no existen patrones coherentes, la estrategia se pierde y a su vez se genera un vacio el cual puede llegar a ser una problemática, por ello la delimitación y definición clara de objetivos es primordial para que existan patrones adecuados y útiles.

    4. periodiconaranjito 13 Oct 2024

      La estrategia se convierte además en un selector de negocios de la organización, una especie de paradigma que imprime un avanzar a la empresa en el que ella escoge y opta por ciertos espacios y nichos de mercados actuales y mercados (en comunicación preferimos hablar de sociedad) a futuro. Cuando la estrategia actúa generando una manera selectiva de comportamiento en la organización, está generando una distinción o diferenciación de la compañía y en su modo de operar que impregnará las visiones de sus miembros y que trascenderá a su sólo ser social. Con la presencia de este componente la estrategia clarificará el “donde está operando o donde estará haciéndolo en el futuro” la empresa, tal como se evidencia en el discurso que construimos de la organización para decir “algo” respecto a nosotros (donde estamos, quienes somos y hacia donde vamos), donde el selector de negocios o visión paradigmática de la que hablamos es un componente conceptual que generará modos de ver que pueden y deben ser integrados en la cultura e identidad de la compañía.

      Una empresa se sostiene mediante las estrategias y cuando estas crean un precedente se benefician cada integrante de la misma. El trabajo en equipo por parte de quienes forman parte de la institución deben manejar un mismo lenguaje en cuanto a la definición de metas, acuerdos y el cumplimiento de los mismos, prácticamente un acuerdo que se ejecuta a rajatabla.

    5. Joancheis04 13 Oct 2024
      Según Quinn9 “estrategia se define como un plan o pauta que integra losobjetivos, las políticas y la secuencia de acciones principales de una organizaciónen un todo coherente”; para el autor la estrategia será una guía teórica que incideen la puesta en práctica de acciones, en torno a un objetivo determinado por lacompañía. Mintzberg10 por su parte definió estrategia sustantivamente al señalarlacomo una “pauta o patrón en el flujo de decisiones”, es decir, un modelo que surgedel análisis y comprensión de las conductas pasadas de la empresa (programadaso no) para a partir de ellas implementar la toma de decisiones futuras; desde talperspectiva una nueva empresa (que no puede hacer una lectura de su pasado oque no lo tiene) sería incapaz de definir un actuar estratégico nacido en suspropias fronteras. En investigaciones posteriores el autor agrega la idea de que sibien es cierto él opta por la construcción estratégica “algunas estrategias exitosaspueden surgir sin planeación previa, como respuestas frecuentes a circunstanciasno previstas”, se puede considerar entonces a la estrategia como un procesoplanificado que es “intentado” y a la vez como un proceso naciente que se definecomo “emergente”, es decir y procedimientoeso de permanente reconstrucción yadaptación (concepto de Seguimiento de negocios) que considerará las nuevas variables queincidan en la conducción de la empresa.

      El texto presenta dos definiciones complementarias de estrategia organizacional, aportadas por Quinn y Mintzberg. Según Quinn, la estrategia es un plan que integra objetivos, políticas y acciones, sirviendo como una guía para la ejecución. Por su parte, Mintzberg propone que la estrategia es un patrón de decisiones basado en el análisis del comportamiento pasado de la empresa, aunque reconoce que algunas estrategias pueden surgir sin planificación previa, adaptándose a circunstancias imprevistas. En conjunto, se considera que la estrategia puede ser tanto planificada como emergente, en un proceso continuo de adaptación y reconstrucción.

      Estrategia Planificación Decisiones Adaptación
    6. carodrouet 12 Oct 2024
      La estrategia se convierte además en un selector de negocios de la organización, una especie de paradigma que imprime un avanzar a la empresa en el que ella escoge y opta por ciertos espacios y nichos de mercados actuales y mercados (en comunicación preferimos hablar de sociedad) a futuro. Cuando la estrategia actúa generando una manera selectiva de comportamiento en la organización, está generando una distinción o diferenciación de la compañía y en su modo de operar que impregnará las visiones de sus miembros y que trascenderá a su sólo ser social. Con la presencia de este componente la estrategia clarificará el “donde está operando o donde estará haciéndolo en el futuro” la empresa, tal como se evidencia en el discurso que construimos de la organización para decir “algo” respecto a nosotros (donde estamos, quienes somos y hacia donde vamos), donde el selector de negocios o visión paradigmática de la que hablamos es un componente conceptual que generará modos de ver que pueden y deben ser integrados en la cultura e identidad de la compañía.

      Pienso que la estrategia debe convertirse en un precedente que evidencie, antes que nada un trabajo en equipo, donde los integrantes de la compañía, empresa, institución manejen un mismo lenguaje y estén convencidos de que las etapas de cada proceso que lleven a cabo los va a llevar al cumplimiento de metas que beneficiarán a cada miembro de la empresa.

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    researchgate.net/publication/31735796_Comunicacion_estrategica_FJ_Garrido_M
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    Astrocyte aquaporin mediates a tonic water efflux maintaining brain homeostasis
    1
    1. Public_Reviews 14 Oct 2024

      Author response:

      The following is the authors’ response to the current reviews.

      Many thanks to the editors for the reviewing of the revised manuscript.

      We are very grateful to the Reviewers for their time and for the appreciation of the revision.

      We thank the Reviewer 3 for acknowledging the use of sulforhodamine B (SRB) fluorescence as a real-time readout of astrocyte volume dynamics. Experimental data in brain slices were provided to validate this approach.<br /> The incomplete matching of our observation with early reported data in cultured astrocytes (e.g., Solenov et al., AJP-Cell, 2004), might reflect certain of their properties differing from the slice/in vivo counterparts as discussed in the manuscript.<br /> The study (T.R. Murphy et al., Front Cell Neurosci., 2017) showed that AQP4 knockout increased astrocyte swelling extent in response to hypoosmotic solution in brain slices (Fig 9), and discussed '... AQP4 can provide an efficient efflux pathway for water to leave astrocytes.’ Correspondingly, our data suggest that AQP4 mediate astrocyte water efflux in basal conditions.<br /> We have discussed the study (Igarashi et al., NeuroReport 2013); our current data would help to understand the cellular mechanisms underlying the finding of Igarashi et al.

      The following is the authors’ response to the original reviews.

      Public Reviews:

      Reviewer #1 (Public Review):

      Summary:

      Pham and colleagues provide an illuminating investigation of aquaporin-4 water flux in the brain utilizing ex vivo and in vivo techniques. The authors first show in acute brain slices, and in vivo with fiber photometry, SRB-loaded astrocytes swell after inhibition of AQP4 with TGN-020, indicative of tonic water efflux from astrocytes in physiological conditions. Excitingly, they find that TGN-020 increases the ADC in DW-MRI in a region-specific manner, potentially due to AQP4 density. The resolution of the DW-MRI cannot distinguish between intracellular or extracellular compartments, but the data point to an overall accumulation of water in the brain with AQP4 inhibition. These results provide further clarity on water movement through AQP4 in health and disease.

      Overall, the data support the main conclusions of the article, with some room for more detailed treatment of the data to extend the findings.

      Strengths:

      The authors have a thorough investigation of AQP4 inhibition in acute brain slices. The demonstration of tonic water efflux through AQP4 at baseline is novel and important in and of itself. Their further testing of TGN-020 in hyper- and hypo-osmotic solutions shows the expected reduction of swelling/shrinking with AQP4 blockade.

      Their experiment with cortical spreading depression further highlights the importance of water efflux from astrocytes via AQP4 and transient water fluxes as a result of osmotic gradients. Inhibition of AQP4 increases the speed of tissue swelling, pointing to a role in the efflux of water from the brain.

      The use of DW-MRI provides a non-invasive measure of water flux after TGN-020 treatment.

      We thank the reviewer for the insightful comments.

      Weaknesses:

      The authors specifically use GCaMP6 and light sheet microscopy to image their brain sections in order to identify astrocytic microdomains. However, their presentation of the data neglects a more detailed treatment of the calcium signaling. It would be quite interesting to see whether these calcium events are differentially affected by AQP4 inhibition based on their cellular localization (ie. processes vs. soma vs. vascular end feet which all have different AQP4 expressions).

      Following the suggestion, we provide new data on the effect of AQP4 inhibition on spontaneous calcium signals in perivascular astrocyte end-feet. As shown now in Fig.S2, acute application of TGN020 induced Ca2+ oscillations in astrocyte end-feet regions where the GCaMP6 labeling lines the profile of the blood vessel. It is noted that on average, the strength of basal Ca2+ signals in the end-feet is higher than that observed across global astrocyte territories (4.65 ± 0.55 vs. 1.45 ± 0.79, p < 0.01), as does the effect of TGN (8.4 ± 0.62 vs. 6.35 ± 0.97, p < 0.05; Fig S2 vs. Fig 2B). This likely reflects the enrichment of AQP4 in astrocyte end-feet. We describe the data in Fig.S2, and on page 8, line 20 – 23.  

      We now use the transgenic line GLAST-GCaMP6 for cytosolic GCaMP6 expression in astrocytes. Spontaneous calcium signals, reflected by transient fluorescence rises, occur in discrete micro-domains whereas the basal GCaMP6 fluorescence in the soma is weak. In the present condition, it is difficult to unambiguously discriminate astrocyte soma from the highly intermingled processes. 

      The authors show the inhibition of AQP4 with TGN-020 shortens the onset time of the swelling associated with cortical spreading depression in brain slices. However, they do not show quantification for many of the other features of CSD swelling, (ie. the duration of swelling, speed of swelling, recovery from swelling).

      Regarding the features of the CSD swelling, we have performed new analysis to quantify the duration of swelling, speed of swelling and the recovery time from swelling in control condition and in the presence of TGN-020. The new analysis is now summarized in Fig. S5. Blocking AQP4 with TGN-020 increases the swelling speed, prolongs the duration of swelling and slows down the recovery from swelling, confirming our observation that acute inhibition of AQP4 water efflux facilitates astrocyte swelling while restrains shrinking. We describe the result on page 11, line 19-21. 

      Significance:

      AQP4 is a bidirectional water channel that is constitutively open, thus water flux through it is always regulated by local osmotic gradients. Still, characterizing this water flux has been challenging, as the AQP4 channel is incredibly water-selective. The authors here present important data showing that the application of TGN-020 alone causes astrocytic swelling, indicating that there is constant efflux of water from astrocytes via AQP4 in basal conditions. This has been suggested before, as the authors rightfully highlight in their discussion, but the evidence had previously come from electron microscopy data from genetic knockout mice.

      AQP4 expression has been linked with the glymphatic circulation of cerebrospinal fluid through perivascular spaces since its rediscovery in 2012 [1]. Further studies of aging[2], genetic models[3], and physiological circadian variation[4] have revealed it is not simply AQP4 expression but AQP4 polarization to astrocytic vascular endfeet that is imperative for facilitating glymphatic flow. Still, a lingering question in the field is how AQP4 facilitates fluid circulation. This study represents an important step in our understanding of AQP4's function, as the basal efflux of water via AQP4 might promote clearance of interstitial fluid to allow an influx of cerebrospinal fluid into the brain. Beyond glymphatic fluid circulation, clearly, AQP4-dependent volume changes will differentially alter astrocytic calcium signaling and, in turn, neuronal activity.

      (1) Iliff, J.J., et al., A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Sci Transl Med, 2012. 4(147): p. 147ra111.

      (2) Kress, B.T., et al., Impairment of paravascular clearance pathways in the aging brain. Ann Neurol, 2014. 76(6): p. 845-61.

      (3) Mestre, H., et al., Aquaporin-4-dependent Glymphatic Solute Transport in the Rodent Brain. eLife, 2018. 7.

      (4) Hablitz, L., et al., Circadian control of brain glymphatic and lymphatic fluid flow. Nature Communications, 2020. 11(1).

      We thank the reviewer in acknowledging the significance of our study and the functional implication in brain glymphatic system. We have now highlighted the mentioned studies as well as the potential implication glymphatic fluid circulation (page 4, line 9-10; page 5, line 1-3; and page 19, line 3-10). 

      Reviewer #2 (Public Review):

      Summary:

      The paper investigates the role of astrocyte-specific aquaporin-4 (AQP4) water channel in mediating water transport within the mouse brain and the impact of the channel on astrocyte and neuron signaling. Throughout various experiments including epifluorescence and light sheet microscopy in mouse brain slices, and fiber photometry or diffusion-weighted MRI in vivo, the researchers observe that acute inhibition of AQP4 leads to intracellular water accumulation and swelling in astrocytes. This swelling alters astrocyte calcium signaling and affects neighboring neuron populations. Furthermore, the study demonstrates that AQP4 regulates astrocyte volume, influencing mainly the dynamics of water efflux in response to osmotic challenges or associated with cortical spreading depolarization. The findings suggest that AQP4-mediated water efflux plays a crucial role in maintaining brain homeostasis, and indicates the main role of AQP4 in this mechanism. However authors highlight that the report sheds light on the mechanisms by which astrocyte aquaporin contributes to the water environment in the brain parenchyma, the mechanism underlying these effects remains unclear and not investigated. The manuscript requires revision.

      Strengths:

      The paper elucidates the role of the astrocytic aquaporin-4 (AQP4) channel in brain water transport, its impact on water homeostasis, and signaling in the brain parenchyma. In its idea, the paper follows a set of complimentary experiments combining various ex vivo and in vivo techniques from microscopy to magnetic resonance imaging. The research is valuable, confirms previous findings, and provides novel insights into the effect of acute blockage of the AQP4 channel using TGN-020.

      We thank the reviewer for the constructive comments.

      Weaknesses:

      Despite the employed interdisciplinary approach, the quality of the manuscript provides doubts regarding the significance of the findings and hinders the novelty claimed by the authors. The paper lacks a comprehensive exploration or mention of the underlying molecular mechanisms driving the observed effects of astrocytic aquaporin-4 (AQP4) channel inhibition on brain water transport and brain signaling dynamics. The scientific background is not very well prepared in the introduction and discussion sections. The important or latest reports from the field are missing or incompletely cited and missconcluded. There are several citations to original works missing, which would clarify certain conclusions. This especially refers to the basis of the glymphatic system concept and recently published reports of similar content. The usage of TGN-020, instead of i.e. available AER-270(271) AQP4 blocker, is not explained. While employing various experimental techniques adds depth to the findings, some reasoning behind the employed techniques - especially regarding MRI - is not clear or seemingly inaccurate. Most of the time the number of subjects examined is lacking or mentioned only roughly within the figure captions, and there are lacking or wrongly applied statistical tests, that limit assessment and reproducibility of the results. In some cases, it seems that two different statistical tests were used for the same or linked type of data, so the results are contradictory even though appear as not likely - based on the figures. Addressing these limitations could strengthen the paper's impact and utility within the field of neuroscience, however, it also seems that supplementary experiments are required to improve the report.

      The current data hint at a tonic water efflux from astrocyte AQP4 in physiological condition, which helps to understand brain water homeostasis and the functional implication for the glymphatic system. The underlying molecular and cellular mechanisms appear multifaceted and functionally interconnected, as discussed (page 14 line 8 –page 15, line 3). We agree that a comprehensive exploration will further advance our understanding.

      The introduction and discussion are now strengthened by incorporating the important advances in glymphatic system while highlighting the relevant studies. 

      The use of TGN-020 was based on its validation by wide range of ex vivo and in vivo studies including the use of heterologous expression system and the AQP4 KO mice. The validation of AER-270(271, the water soluble prodrug) using AQP4 KO mice is reported recently (Giannetto et al., 2024). AER-271 was noted to impact brain water ADC (apparent diffusion coefficient evaluated by diffusion-weighted MRI) in AQP4 KO mice ~75 min after the drug application (Giannetto et al., 2024). This likely reflects that AER270(271) is also an inhibitor for κΒ nuclear factor (NF-κΒ) whose inhibition could reduce CNS water content independent of AQP4 targeting (Salman et al., 2022). In addition, the inhibition efficiency of AER-270(271) seems lower than TGN-020 (Farr et al., 2019; Giannetto et al., 2024; Huber et al., 2009; Salman et al., 2022). We have now supplemented this information in the manuscript (page 7, line 1-6 and page15, line 7-17).

      The description on the DW-MRI is now updated (page 4, line 10-14). 

      We also performed new experiments and data analysis as described in a point-to-point manner below in the section ‘Recommendations For The Authors’.

      Reviewer #3 (Public Review):

      Summary:

      In this manuscript, the authors propose that astrocytic water channel AQP4 represents the dominant pathway for tonic water efflux without which astrocytes undergo cell swelling. The authors measure changes in astrocytic sulforhodamine fluorescence as the proxy for cell volume dynamics. Using this approach, they perform a technically elegant series of ex vivo and in vivo experiments exploring changes in astrocytic volume in response to AQP4 inhibitor TGN-020 and/or neuronal stimulation. The key finding is that TGN-020 produces an apparent swelling of astrocytes and modifies astrocytic cell volume regulation after spreading depolarizations. Additionally, systemic application of TGN-020 produced changes in diffusion-weighted MRI signal, which the authors interpret as cellular swelling. This study is perceived as potentially significant. However, several technical caveats should be strongly considered and perhaps addressed through additional experiments.

      Strengths:

      (1) This is a technically elegant study, in which the authors employed a number of complementary ex vivo and in vivo techniques to explore functional outcomes of aquaporin inhibition. The presented data are potentially highly significant (but see below for caveats and questions related to data interpretation).

      (2) The authors go beyond measuring cell volume homeostasis and probe for the functional significance of AQP4 inhibition by monitoring Ca2+ signaling in neurons and astrocytes (GCaMP6 assay).

      (3) Spreading depolarizations represent a physiologically relevant model of cellular swelling. The authors use ChR2 optogenetics to trigger spreading depolarizations. This is a highly appropriate and much-appreciated approach.

      We thank the reviewer for the effort in evaluating our work.

      Weaknesses:

      (1) The main weakness of this study is that all major conclusions are based on the use of one pharmacological compound. In the opinion of this reviewer, the effects of TGN-020 are not consistent with the current knowledge on water permeability in astrocytes and the relative contribution of AQP4 to this process.

      Specifically: Genetic deletion of AQP4 in astrocytes reduces plasmalemmal water permeability by ~two-three-fold (when measured a 37oC, Solenov et al., AJP-Cell, 2004). This is a significant difference, but it is thought to have limited/no impact on water distribution. Astrocytic volume and the degree of anisosmotic swelling/shrinkage are unchanged because the water permeability of the AQP4null astrocytes remains high. This has been discussed at length in many publications (e.g., MacAulay et al., Neuroscience, 2004; MacAulay, Nat Rev Neurosci, 2021) and is acknowledged by Solenov and Verkman (2004).

      Keeping this limitation in mind, it is important to validate astrocytic cell volume changes using an independent method of cell volume reconstruction (diameter of sulforhodamine-labeled cell bodies? 3D reconstruction of EGFP-tagged cells? Else?)

      Solenov and coll. used the calcein quenching assay and KO mice demonstrating AQP4 as a functional water channel in cultured astrocytes (Solenov et al., 2004). AQP4 deletion reduced both astrocyte water permeability and the absolute amplitude of swelling over comparable time, and also slowed down cell shrinking, which overall parallels our results from acute AQP4 blocking. Yet in Solenovr’s study, the time to swelling plateau was prolonged in AQP4 KO astrocytes, differing from our data from the pharmacological acute blocking. This discrepancy may be due to compensatory mechanisms in chronic AQP4 KO, or reflect the different volume responses in cultured astrocytes from brain slices or in vivo results as suggested previously (Risher et al., 2009). 

      Soma diameter might be an indicator of cell volume change, yet it is challenging with our current fluorescence imaging method that is diffraction-limited and insufficient to clearly resolve the border of the soma in situ. In addition, the lateral diameter of cell bodies may not faithfully reflect the volume changes that can occur in all three dimensions. Rapid 3D imaging of astrocyte volume dynamics with sufficient high Z-axis resolution appears difficult with our present tools. 

      We have now accordingly updated the discussion with relevant literatures being cited (page 17 line 14 – page 18, line 3).

      (2) TGN-020 produces many effects on the brain, with some but not all of the observed phenomena sensitive to the genetic deletion of AQP4. In the context of this work, it is important to note that TGN020 does not completely inhibit AQP4 (70% maximal inhibition in the original oocyte study by Huber et al., Bioorg Med Chem, 2009). Thus, besides not knowing TGN-020 levels inside the brain, even

      "maximal" AQP4 inhibition would not be expected to dramatically affect water permeability in astrocytes.

      This caveat may be addressed through experiments using local delivery of structurally unrelated AQP4 blockers, or, preferably, AQP4 KO mice.

      It is an important point that TGN-020 partially blocks AQP4, implying the actual functional impact of AQP4 per se might be stronger than what we observed. TGN provides a means to acutely probe AQP4 function in situ, still we agree, its limitation needs be acknowledged. We mention this now on page 15, line 7-9 and 14-17.

      We agree that local delivery of an alternative blocker will provide additional information. Meanwhile, local delivery requires the stereotaxic implantation of cannula, which would cause inflammations to surrounding astrocytes (and neurons). The recently introduced AQP4 blocker AER-270(271) has received attention that it influences brain water dynamics (ADC in DW-MRI) in AQP4 KO mice (Giannetto et al., 2024), recalling that AER-270(271) is also an inhibitor for κΒ nuclear factor (NF-κΒ). This pathway can potentially perturb CNS water content and influence brain fluid circulation, in an AQP4independent manner (Salman et al., 2022). The inhibition efficiency on mouse AQP4 of AER-270 (~20%, Farr et al., 2019; Salman et al., 2022) appears lower than TGN-020 (~70%, Huber et al., 2009).

      We chose to use the pharmacological compound to achieve acute blocking of AQP4 thereby avoiding the chronic genetics-caused alterations in brain structural, functional and water homeostasis. Multiple lines of evidence including the recent study (Gomolka et al., 2023), have shown that AQP4 KO mice alters brain water content, extracellular space and cellular structures, which raises concerns to use the transgenic mouse to pinpoint the physiological functions of the AQP4 water channel. 

      We have now mentioned the concerns on AQP4 pharmacology by supplementing additional literatures in the field (page 15, line 8-18). 

      (3) This reviewer thinks that the ADC signal changes in Figure 5 may be unrelated to cellular swelling. Instead, they may be a result of the previously reported TGN-020-induced hyphemia (e.g., H. Igarashi et al., NeuroReport, 2013) and/or changes in water fluxes across pia matter which is highly enriched in AQP4. To amplify this concern, AQP4 KO brains have increased water mobility due to enlarged interstitial spaces, rather than swollen astrocytes (RS Gomolka, eLife, 2023). Overall, the caveats of interpreting DW-MRI signal deserve strong consideration.

      The previous observation show that TGN-020 increases regional cerebral blood flow in wild-type mice but not in AQP4 KO mice (Igarashi et al., 2013). Our current data provide a possible mechanism explanation that TGN-020 blocking of astrocyte AQP4 causes calcium rises that may lead to vasodilation as suggested previously (Cauli and Hamel, 2018). We now add updates to the discussion on page 15, line 3-7.

      We are in line with the reviewer regarding the structural deviations observed with the AQP4 KO mice

      (Gomolka et al., 2023), now mentioned on page 19, line 3-5. Following the Reviewer’s suggestion, we have also updated the interpretation of the DW-MRI signal and point that in addition to being related to the astrocyte swelling, the ADC signal changes may also be caused by indirect mechanisms, such as the transient upregulation of other water-permeable pathways in compensating AQP4 blocking. We now describe this alternative interpretation and the caveats of the DW-MRI signals (page 20, line 1-8). 

      Recommendations for the authors:

      Reviewer #1 (Recommendations For The Authors):

      Private recommendations

      My more broad experimental suggestions are in the "weaknesses" section. Some minor points that would improve the manuscript are included below:

      (1) A more detailed explanation for why SRB fluorescence reflects the astrocyte volume changes, whereas typical intracellular GFP does not.

      As an engineered fluorescence protein, the GFP has been used to tag specific type of cells. Meanwhile, as a relatively big protein (MW, 26.9 kDa), the diffusion rate of EGFP is expected to be much less than SRB, a small chemical dye (MW, 558.7 Da). Also, the IP injection of SRB enables geneticsless labeling of brain astrocytes, so to avoid the influence of protein overexpression on astrocyte volume and water transport responses. We have now stated this point in the manuscript (page 13, line 21 – page 14, line 4).

      (2) Figure 1 panel B should have clear labels on the figure and a description in the legend to delineate which part of the panel refers to hyper- or hypo-osmotic treatment.

      We have now updated the figure and the legend.  

      (3) For Figure 2, what is the rationale for analyzing the calcium signaling data between the cell types differently?

      We analyzed calcium micro-domains for astrocytes as their spontaneous signals occur mainly in discrete micro-domains (Shigetomi et al., 2013). While for neurons, we performed global analysis by calculating the mean fluorescence of imaging field of view, because calcium signal changes were only observed at global level rather than in micro-domains. This information is now included (page 24, line1820).

      (4) For Figure 3, the authors mention that TGN-020 likely caused swelling prior to the hypotonic solution administration. Do they have any measurements from these experiments prior to the TGN-020 application to use as a "true baseline" volume?

      The current method detects the relative changes in astrocyte volume (i.e., transmembrane water transport), which nevertheless is blind to the absolute volume value. We have no readout on baseline volumes.  

      (5) For Figures 3 and 4, did the authors see any evidence for regulatory volume decrease? And is this impaired by TGN-020? It is a well-characterized phenomenon that astrocytes will open mechanosensitive channels to extrude ions during hypo-osmotic induced swelling. This process is dependent on AQP4 and calcium signaling [5]

      Mola and coll. provided important results demonstrating the role of AQP4 in astrocyte volume regulation (Mola et al., 2016). In the present study in acute brain slices, when we applied hypotonic solution to induce astrocyte swelling, our protocol did not reveal rapid regulatory volume decrease (e.g., Fig. 3D). When we followed the volume changes of SRB-labeled astrocytes during optogenetically induced CSD, we observed the phase of volume decrease following the transient swelling (Fig. 4F), where the peak amplitude and the degree of recovery were both reduced by inhibiting AQP4 with TGN020. These data imply that regulatory astrocyte volume decrease may occur in specific conditions, which intriguingly has been suggested to be absent in brain slices and in vivo (e.g., Risher et al., 2009). We have not specifically investigated this phenomenon, and now briefly discuss this point on page18 line 6-14.

      (6) Figure 5 box plots do not show all data points, could the authors modify to make these plots show all the animals, or edit the legend to clarify what is plotted?

      We have now updated the plot and the legend. This plot is from all animals (n = 7 per condition).

      (7) pg. 9 line 6, there is a sentence that seems incomplete or otherwise unfinished. "We first followed the evoked water efflux and shrinking induced by hypertonic solution while."

      Fixed (now, page 9 line 17-18). 

      (8)  During the discussion on pg 13 line 11, it may be more clear to describe this as the cotransport of water into the cells with ions/metabolites as reviewed by Macaulay 2021 [6].

      We agree; the text is modified following this suggestion (now page14, line 12-13).  

      (1) Iliff, J.J., et al., A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Sci Transl Med, 2012. 4(147): p. 147ra111.

      (2) Kress, B.T., et al., Impairment of paravascular clearance pathways in the aging brain. Ann Neurol, 2014. 76(6): p. 845-61.

      (3) Mestre, H., et al., Aquaporin-4-dependent Glymphatic Solute Transport in the Rodent Brain. eLife, 2018. 7.

      (4) Hablitz, L., et al., Circadian control of brain glymphatic and lymphatic fluid flow. Nature Communications, 2020. 11(1).

      (5) Mola, M., et al., The speed of swelling kinetics modulates cell volume regulation and calcium signaling in astrocytes: A different point of view on the role of aquaporins. Glia, 2016. 64(1).

      (6) MacAulay, N., Molecular mechanisms of brain water transport. Nat Rev Neurosci, 2021. 22(6): p. 326-344.

      We thank the reviewer. These important literatures are now supplemented to the manuscript together with the corresponding revisions.

      Reviewer #2 (Recommendations For The Authors):

      In its concept, the paper is interesting and provides additional value - however, it requires revision.

      Below, I provide the following remarks for the following sections/ pages/lines:

      ABSTRACT/page 2 (remarks here refer to the rest of the manuscript, where these sentences are repeated):

      - It seems that the 'homeostasis' provides not only physical protection, but also determines the diffusion of chemical molecules...' Please correct the sentence as it is grammatically incorrect.

      It is now corrected (page 2, line 1).

      - The term 'tonic water' is not clear. I understand, after reading the paper, that it is about tonicity of the solutes injected into the mouse.

      We use the term ‘tonic’ to indicate that in basal conditions, a constant water efflux occurs through the APQ4 channel.

      - 'tonic aquaporin water efflux maintains volume equilibrium' - I believe it is about maintaining volume and osmotic equilibrium?

      This description is now refined (now page 2, line 10).

      - It is not clear whether the tonic water outflow refers to the cellular level or outflow from the brain parenchyma (i.e., glymphatic efflux)

      It refers to the cellular level. 

      INTRODUCTION/page 3:

      - 'clearance of waste molecules from the brain as described in the glymphatic system' - The original papers describing the phenomena are not cited: Iliff et al. 2012, 2013, Mestre et al. 2018, as well as reviews by Nedergaard et al.

      Indeed. We have now cited these key literatures (now page 4, line 10).

      - 'brain water diffusion is the basis for diffusion-weighted magnetic resonance imaging (DW-MRI)' - The statement is wrong. it is the mobility of the water protons that DWI is based on, but not the diffusion of molecules in the brain. This should be clarified and based on the DW-MRI principle and the original works by Le Bihan from 1986, 1988, or 2015.

      This sentence is now updated (page 4, line10-14).

      - Similarly, I suggest correcting or removing the citations and the sentence part regarding the clinical use of DWI, as it has no value here. Instead, it would be worth mentioning what actually ADC reflects as a computational score, and what were the results from previous studies assessing glymphatic systems using DWI. This is especially important when considering the mislocalization of the AQP4 channel.

      We now states recent studies using DW-MRI to evaluate glymphatic systems (page 4, line16-17).  

      - 'In the brain, AQP4 is predominantly expressed in astrocytes'-please review the citations. I suggest reading the work by Nielsen 1997, Nagelhus 2013, Wolburg 2011, and Li and Wang from 2017. To my best knowledge, in the brain AQP4 is exclusively expressed in astrocytes.

      Thanks for the reviewer. It is described that while enriched in astrocytes, AQP4 is also expressed in ependymal cells lining the ventricles (e.g., (Mayo et al., 2023; Verkman et al., 2006)). ‘predominantly’ is now removed (page 4, line 21).

      - The conclusion: ' Our finding suggests that aquaporin acts as a water export route in astrocytes in physiological conditions, so as to counterbalance the constitutive intracellular water accumulation caused by constant transmitter and ion uptake, as well as the cytoplasmic metabolism processes. This mechanism hence plays a necessary role in maintaining water equilibrium in astrocytes, thereby brain water homeostasis' seems to be slightly beyond the actual findings in the paper. I suggest clarifying according to the described phenomena.

      We have now refined the conclusion sticking to the experimental observations (page 5, line16-18).

      - The introduction lacks important information on existing AQP4 blockers and their effects, pros and cons on why to use TGN-020. Among others, I would refer to recent work by Giannetto et al 2024, as well as previous work of Mestre et al. 2018 and Gomolka et al. 2023.

      We initiated the study by using TGN-020 as an AQP4 blocker because it has been validated by wide range of ex vivo and in vivo studies as documented in the text (page 7, line 1-6). We also update discussions on the recent advances in validating the AQP4 blocker AER-270(271) while citing the relevant studies (page 15, line 7-17).  

      RESULTS:

      - Page 5, lines 19-20: '...transport, we performed fluorescence intensity translated (FIT) imaging.' - this term was never introduced in the methods so it is difficult for the reader to understand it at first sight. -'To this end,' - it is not clear which action refers to 'this'. (is it about previous works or the moment that the brain samples were ready for imaging? Please clarify, as it is only starting to be clear after fully reading the methods.

      We now refine the description give the principle of our imaging method first, then explain the technical steps. To avoid ambiguity, the term ‘To this end’ is removed. The updated text is now on page 6, line 1-3.  

      - From page 6 onwards - all references to Figures lack information to which part of the figure subpanel the information refers (top/middle bottom or left/middle/right).

      We apologize. The complementary indication is now added for figure citations when applicable.  

      - 'whereas water export and astrocyte shrinking upon hyperosmotic manipulation increased astrocyte fluorescence (Figure 1B). Hence, FIT imaging enables real-time recording of astrocyte transmembrane water transport and volume dynamics.' - this part seems to be undescribed or not clear in the methods.

      We have now refined this description (page 6, line 19-20).

      - Page 6, lines 17-22: TGN-020. In addition to the above, I suggest familiarizing also with the following works by Igarashi 2011. doi: 10.1007/s10072-010-0431-1, and by Sun 2022. doi: 10.3389/fimmu.2022.870029.

      These studies are now cited (page 7, line 3-4).

      - Page 7: ' AQP4 is a bidirectional channel facilitating... ' - AQP4 water channel is known as the path of least resistance for water transfer, please see Manley, Nature Medicine, 2000 and Papadopoulos, Faseb J, 2004.

      This sentence is now updated (page 7, line 12-13).

      - ' astrocyte AQP4 by TGN-020 caused a gradual decrease in SRB fluorescence intensity, indicating an intracellular water accumulation' - tissue slice experiment is a very valuable method. However it seems right, the experiment does not comment on the cell swelling that may occur just due to or as a superposition of tissue deterioration and the effect of TGN-020. The AQP4 channel is blocked, and the influx of water into astrocytes should be also blocked. Thus, can swelling be also a part of another mechanism, as it was also observed in the control group? I suggest this should be addressed thoroughly.

      We performed this experiment in acute brain slices to well control the pharmacological environment and gain spatial-temporal information. Post slicing, the brain slices recovered > 1hr prior to recording, so that the slices were in a stable state before TGN-020 application as evidenced by the stable baseline. The constant decrease in the control trace is due to photobleaching which did not change its curve tendency in response to vehicle. TGN-020, in contrast, caused a down-ward change suggesting intracellular water accumulation and swelling. 

      The experiment was performed at basal condition without active water influx; a decrease in SRB fluorescence hints astrocyteintracellular water buildup. This result shows that in basal condition, astrocyte aquaporin mediates a constant (i.e., tonic) water efflux; its blocking causes intracellular water accumulation and swelling. 

      We have accordingly updated the description of this part (page 7, line 15-20).

      - From the Figure 1 legend: Only 4 mice were subjected to the experiment, and only 1 mouse as a control. I suggest expanding the experiment and performing statistics including two-way ANOVA for data in panels B, C, and D, as no results of statistical tests confirm the significance of the findings provided.

      The panel B confirms that cytosolic SRB fluorescence displays increasing tendency upon water efflux and volume shrinking, and vice versa. As for the panel C, the number of mice is now indicated. Also, the downward change in the SRB fluorescence was now respectively calculated for the phases prior and post to TGN (and vehicle) application, and this panel is accordingly updated. TGN-020 induced a declining in astrocyte SRB fluorescence, which is validated by t-test performed in MATLAB. To clarify, we now add cross-link lines to indicate statistical significance between the corresponding groups (Fig 1C, middle). As for panel D, we calculated the SRB fluorescence change (decrease) relative to the photobleaching tendency illustrated by the dotted line. The significance was also validated by t-test performed in MATLAB.  

      - Figure 1: Please correct the figure - pictures in panel A are low quality and do not support the specificity of SRB for astrocytes. Panels B-D are easier to understand if plotted as normal X/Y charts with associated statistical findings. Some drawings are cut or not aligned.

      In GFAP-EGFP transgenic, astrocytes are labeled by EGFP. SRB labeling (red fluorescence) shows colocalization with EGFP-positive astrocytes, meanwhile not all EGFP-positive astrocytes are labeled by SRB. The PDF conversion procedure during the submission may also somehow have compromised image quality. We have tried to update and align the figure panels.  

      - Page 12: ' TGN-020 increased basal water diffusion within multiple regions including the cortex,

      hippocampus and the striatum in a heterogeneous manner (Figure 5C).'

      This sentence is updated now (page 12, line 12 – page13, line 2). It reads ‘The representative images reveal the enough image quality to calculate the ADC, which allow us to examine the effect of TGN-020 on water diffusion rate in multiple regions (Fig. 5C).’

      - The expression of AQP4 within the brain parenchyma is known to be heterogenous. Please familiarize yourself with works by Hubbard 2015, Mestre 2018, and Gomolka 2023. A correlation between ADC score and AQP4 expression ROI-wise would be useful, but it is not substantial to conduct this experiment.

      We thank the reviewer. This point is stressed on page 19, line 12-14.

      DISCUSSION:

      - Most of the issues are commented on above, so I suggest following the changes applied earlier. -Page 16: 'We show by DW-MRI that water transport by astrocyte aquaporin is critical for brain water homeostasis.' This statement is not clear and does not refer to the actual impact of the findings. DWI is allowed only to verify the changes of ADC fter the application of TGN-020. I suggest commenting on the recent report by Giannetto 2024 here.

      This sentence is now refined (page 19, line 1-2), followed by the updates commenting on the recent studies employing DW-MRI to evaluate brain fluid transport, including the work of (Giannetto et al., 2024) (page 19, line 3-10). 

      METHODS:

      - Page 18: no total number of mice included in all experiments is provided, as well as no clearly stated number of mice used in each experiment. Please correct.

      We have now double checked the number of the mice for the data presented and updated the figure legends accordingly (e.g., updates in legends fig1, fig5, etc).

      -  Page 18, line 7: 'Axscience' is not a producer of Isoflurane, but a company offering help with scientific manuscript writing. If this company's help was used, it should be stated in the acknowledgments section. Reference to ISOVET should be moved from line 15 to line 7.

      We apologize. We did not use external writing help, and now have removed the ‘Axcience’. The Isoflurane was under the mark ‘ISOVET’ from ‘Piramal’. This info is now moved up (page 21, line 11). 

      - Page 18, line 9: ' modified artificial cerebrospinal fluid (aCSF)'. Additional information on the reason for the modified aCSF would be useful for the reader.

      In this modified solution, the concentration of depolarizing ions (Na+, Ca2+) was reduced to lower the potential excitotoxicity during the tissue dissection (i.e., injury to the brain) for preparing the brain slices. Extra sucrose was added to balance the solution osmolarity. This solution has been used previously for the dissection and the slicing steps in adult mice (Jiang et al., 2016). We now add this justification in the text and quote the relevant reference (page 21, line14-16). 

      - Page 19, line 6: a reasoning for using Tamoxifen would be helpful for the reader.

      The Glast-CreERT2 is an inducible conditional mouse line that expresses Cre recombinase selectively in astrocytes upon tamoxifen injection. We now add this information in the text (page 22, line 10-11). 

      - Line 8 - 'Sigma'

      Fixed.

      - Line 7/8: It is not clear if ethanol is of 10% solution or if proportions of ethanol+tamoxifen to oil were of 1:9. The reasoning for each performed step is missing.

      We have now clarified the procedure (page 22, line 11-15).

      - Line 10: '/' means 'or'?

      Here, we mean the bigenic mice resulting from the crossing of the heterozygous Cre-dependent GCaMP6f and Glast-CreERT2 mouse lines. We now modify it to ‘Glast-CreERT2::Ai95GCaMP6f//WT’, in consistence with the presentation of other mouse lines in our manuscript (page 22, line 16).

      - Lines 22-23: being in-line with legislation was already stated at the beginning of the Methods so I suggest combining for clearance.

      Done. 

      - Page 21, line 4: it is good to mention which printer was used, but it would be worth mentioning the material the chamber was printed from - was it ABS?

      Yes. We add this info in the text now (page 24, line 5).

      - Line 9 -'PI' requires spelling out.

      It is ‘Physik Instrumente’, now added (page 24, line 10).

      - Line 11-12: What is the reason for background subtraction - clearer delineation of astrocytes/ increasing SNR in post-processing, or because SRB signal was also visible and changing in the background over time? Was the background removed in each frame independently (how many frames)? How long was the time-lapse and was the F0 frame considered as the first frame acquired? The background signal should be also measured and plotted alongside the astrocytic signal, as a reference (Figure 1). This should be clarified so that steps are to be followed easily.

      We sought to follow the temporal changes in SRB fluorescence signal. The acquired fluorescent images contain not only the SRB signals, but also the background signals consisting of for instance the biological tissue autofluorescence, digital camera background noise and the leak light sources from the environments. The value of the background signal was estimated by the mean fluorescence of peripheral cell-free subregions (15 × 15 µm²) and removed from all frames of time-lapse image stack. The traces shown in the figures reflect the full lengths of the time-lapse recordings. F0 was identified as the mean value of the 10 data points immediately preceding the detected fluorescence changes. The text is now updated (page 24 line 21 - page 25 line 5).

      - Line 15: Was astrocyte image delineation performed manually or automatically? Where was the center of the region considered in the reference to the astrocyte image? It would be good to see the regions delineated for reference.

      Astrocytes labeled by SRB were delineated manually with the soma taken as the center of the region of interest. We now exemplify the delineated region in Fig 1A, bottom.

      - Page 22, line 2: 'x4 objective'.

      Added (now, page 25, line 16). 

      - Line 3: 'barrels' - reference to publication or the explanation missing.

      The relevant reference is now added on barrel cortex (Erzurumlu and Gaspar, 2020) (page 25, line 19-20). 

      - Line 19: were the coordinates referred to = bregma?

      Yes. This info is now added (page 26, line 12). 

      - Line 20: was the habituation performed directly at the acquisition date? It is rather difficult to say that it was a habituation, but rather acute imaging. I suggest correcting, that mice were allowed to familiarize themselves with the setup for 30 minutes prior to the imaging start.

      In this context, although it is a very nice idea and experiment, the influence of acute stress in animals familiar with the setup only from the day of acquisition is difficult to avoid. It is a major concern, especially when considering norepinephrine as a master driver of neuronal and vascular activity through the brain, and strong activation of the hypothalamic-adrenal axis in response to acute stress. It is well known, that the response of monoamines is reduced in animals subjected to chronic v.s acute stress, but still larger than that if the stressor is absent.

      Major remark: The animals should, preferably, be imaged at least after 3 days of habituation based on existing knowledge. I suggest exploring the topic of the importance of habituation. It is difficult though, to objectively review these findings without considering stress and associated changes in vascular dynamics.

      Many thanks for the reviewer to help to precise this information. The text is accordingly updated to describe the experiment (now page 26, line 14). 

      - Page 23, line 17: number of animals included in experiments missing.

      The number of animals is added in Methods (page 27, line 12) and indicated in the legend of Figure 5. 

      - Line 18/19: were the respiratory effects observed after injection of saline or TGN-020? Since DWI was performed, the exclusion of perfusive flow on ADC is impossible.

      I suggest an additional experiment in n=3 animals per group, verifying the HR (and if possible BP) response after injection of TGN-020 and saline in mice.

      The respiratory rate has been recorded. We added the averaged respiratory rate before and after injection of TGN-020 or saline (now, Fig. S6; page 13, line 5-6).

      - Line 22: Please, provide the model of the scanner, the model of the cryoprobe, as well as the model of the gradient coil used, otherwise it is difficult to assess or repeat these experiments.

      We have now added the information of MRI system in Methods section (page 27, line17-21).

      - Page 24: line 3/4: although the achieved spatial resolution of DWI was good and slightly lower than desired and achievable due to limitations of the method itself as well as cryoprobe, it is acceptable for EPI in mice.

      Still, there is no direct explanation provided on the reasoning for using surface instead of volumetric coil, as well as on assuming an anisotropic environment (6 diffusion directions) for DWI measurements. This is especially doubtful if such a long echo-time was used alongside lower-thanpossible spatial resolution. Longer echo time would lower the SNR of the depicted signal but also would favor the depiction of signal from slow-moving protons and larger water pools. On the other hand, only 3 b-values were used, which is the minimum for ADC measurements, while a good research protocol could encompass at least 5 to increase the accuracy of ADC estimation and avoid undersampling between 250 and 1800 b-values. What was the reason for choosing this particular set of b-values and not 50, 600, and 2000? Besides, gradient duration time was optimally chosen, however, I have concerns about the decision for such a long gradient separation times.

      If the protocol could have been better optimized, the assessment could have been also performed in respiratory-gated mode, allowing minimization of the effects of one of the glymphatic system driving forces.

      Thus, I suggest commenting on these issues.

      We chose the cryoprobe to increase the signal-to-noise ratio (SNR) in DW-MRI with long echo-time and high b-value. The volume coil has a more homogeneous SNR in the whole brain rather than the cryoprobe, but SNR should be reduced compared with cryoprobe. We confirmed that, even at the ventral part of the brain, the image quality of DW-MRI images was enough to investigate the ADC with cryoprobe (Fig. 5B-C). This is mentioned now in Methods (page 27, line 17-21).

      We performed DW-MRI scanning for 5 min at each time-point using the condition of anisotropic resolution and 3 b-values, to investigate the time-course of ADC change following the injection of TGN020. Because the effect of TGN-020 appears about dozen of minutes post the injection (Igarashi et al., 2011), fast DW-MRI scanning is required. If isotropic DW-MRI with lower echo-time and more direction is used, longer scan time at each time point is required, maybe more than 1h. We agree that three bvalues is minimum to calculate the ADC and more b-values help to increase the accuracy. However, to achieve the temporal resolution so as to better catch the change of water diffusion, we have decided to use the minimum b-values. The previous study also validates the enough accuracy of DW-MRI with three b-values (Ashoor et al., 2019). Furthermore, previous study that used long diffusion time (> 20 ms) and long echo time (40 ms) shows the good mean diffusivity (Aggarwal et al., 2020), supporting that our protocol is enough to investigate the ADC. We have now updated the description (page 28 line 5-9).  The reason why we choose the b = 250 and 1800 s/mm² is that 2000 s/mm² seems too high to get the good quality of image. In the previous study, we have optimized that ADC is measurable with b = 0, 250, and 1800 s/mm² (Debacker et al., 2020). 

      - Page 24, line 7: What was the post-processing applied for images acquired over 70 minutes? Did it consider motion-correction, co-registration, or drift-correction crucial to avoid pitfalls and mismatches in concluding data?

      The motion correction and co-registration were explained in Methods (page 28, line 12-14).

      Also, were these trace-weighted images or magnitude images acquired since DTI software was used for processing - while ADC fitting could be reliably done in Matlab, Python, or other software. Thus, was DSI software considering all 3 b-values or just used 0 and 1800 for the calculation of mean diffusivity for tractography (as ADC). The details should be explained.

      DSIstudio was used with all three b values (b = 0, 250, and 1800 s/mm²) to calculate the ADC. We added the description in Methods (page 28, line 16-18).

      To make sure that the results are not affected by the MR hardware, I suggest performing 3 control measurements in a standard water phantom, and presenting the results alongside the main findings.

      Thanks for this suggestion. We have performed new experiments and now added the control measurement with three phantoms, that is water, undecane, and dodecane. These new data are summarized now in Fig. S7, showing the stability of ADC throughout the 70 min scanning. We have updated the description on Method part (page 28, line 9-11) and on the Results (page 13, line 6-8).  

      - Line 13: were the ROI defined manually or just depicted from previously co-registered Allen Brain atlas?

      The ROIs of the cortex, the hippocampus, and the striatum were depicted with reference to Allen mouse brain atlas (https://scalablebrainatlas.incf.org/mouse/ABA12). This is explained in Methods (page 28, line 14-16).

      - Line 10: why the average from 1st and 2nd ADC was not considered, since it would reduce the influence of noise on the estimation of baseline ADC?

      We are sorry that it was a typo. The baseline was the average between 1st and 2nd ADC. We corrected the description (page 28, line 20).

      STATISTIC:

      Which type of t-test - paired/unpaired/two samples was used and why? Mann-Whitney U-tets are used as a substitution for parametric t-tests when the data are either non-parametric or assuming normal distribution is not possible. In which case Bonferroni's-Holm correction was used? - I couldn't find any mention of any multiple-group analysis followed by multiple comparisons. Each section of the manuscript should have a description of how the quantitative data were treated and in which aim. I suggest carefully correcting all figures accordingly, and following the remarks given to the Figure 1.

      We used unpaired t-test for data obtained from samples of different conditions. Indeed, MannWhitney U-test is used when the data are non-parametric deviating from normal distributions.  Bonferroni-Holm correction was used for multiple comparisons (e.g., Fig. 4D-E).

      Reviewer #3 (Recommendations For The Authors):

      I think that the following statement is insufficient: "The authors commit to share data, documentation, and code used in analysis". My understanding is eLife expects that all key data to be provided in a supplement.

      We thank the reviewer; we follow the publication guidelines of eLife. 

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    1. JoyBoy93 14 Oct 2024
      nnym ważnym aspektem jest to, że obecny DSM-5 uważa ADHD za zaburzenie neurorozwojowe (1), ponieważ objawy wykazują normatywne zmiany w czasie (57). Badania Shaw i in. pokazują, że ADHD podąża za podobnym sekwencyjnym wzorcem typowego rozwoju korowego, jednak opóźnionym o nawet 2–3 lata, w zależności od konkretnego regionu korowego, dochodząc do wniosku, że zgodne opóźnienie zarówno w grubości kory, jak i powierzchni w ADHD reprezentuje globalne zakłócenie w mechanizmach kierujących dojrzewaniem kory (58, 59). Dlatego wyższe sieci mogą nie być bezpośrednio upośledzone w ADHD, ale wpływane przez inne obwody, które mogą zmieniać optymalny rozwój i wydajność wyższych funkcji poznawczych, takich jak EF.

      Opóźnione dojrzewanie korowe w ADHD

      Połączenia funkcjonalne EF Etiologia ADHD
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    chatgpt.com/c/670cfdbc-c574-800e-b554-115df42a4895
  80. drive.google.com drive.google.com
    Overview.pdf
    3
    1. roi44096 14 Oct 2024

      Annotation 3: Connection "Demographic changes have sparked an intensifying global competition for workers and talent. Consider three countries. Italy, with a population of 59 million, is projected to shrink by almost half, to 32 million, by 2100, with those above age 65 increasing from 24 to 38 percent of the population. Mexico, traditionally an emigration country, has seen its fertility rate drop to barely replacement level. Nigeria,

      by contrast, is expected to expand its population from 213 million to 791 million, becoming the second- most populous country in the world, after India, by the end of the century (figure O.1)."

      This quote highlights how demographic shifts, such as aging populations in wealthier countries and declining fertility rates in traditional emigration nations like Mexico, are creating a global competition for workers. As populations shrink or age in certain regions, these countries will increasingly rely on migrants to sustain their economies and meet social obligations. At the same time, middle-income countries that once sent large numbers of migrants abroad are facing their own demographic challenges, leading them to compete for the same foreign labor they once provided. This demographic shift connects migration to broader global economic trends, where both origin and destination countries must adjust their policies to attract and retain talent in an evolving labor market.

    2. Jeph 14 Oct 2024

      "When migrants do not bring skills and attributes in demand at their destination, the costs to destination countries exceed the benefits. If there are gains for migrants and origin countries, these gains are not sustainable unless destination countries take action to reduce and manage their own costs (figure O.5)."

      Workers/refugees from these developing countries are essentially forced to have a certain skillset needed to find better opportunities in other wealthier countries.

    3. fran.kersman 14 Oct 2024

      "Labor economics focuses on the “match” between migrants’ skills and related attributes and desti- nation countries’ needs (figure O.2, panel a). The starting point for migration policies in many destina- tion countries is a simple question: Does migration yield benefits that exceed the costs? Migrants bring skills for which there are different levels of demand. The more migrants’ skills match the needs of the destination labor market, the larger are the gains for the destination economies and the migrants them- selves—and often for the origin countries as well (through remittances and knowledge transfers).17 This applies regardless of skills level and legal status. But migrants also use public services, and they must be integrated into a society that can be unfamiliar. Both involve costs, at least in the short term. The net gains can thus be either positive or negative."

      The author is emphasizing that migration can bring economic benefits when migrants' skills align with the labor needs of the destination country, benefiting both parties and sometimes the origin country through remittances. However, migration also incurs short-term costs, such as public service usage and societal integration challenges. This passage directly relates to the inquiry question by addressing how the balance of these benefits and costs determines whether migration is economically advantageous.

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    drive.google.com/file/d/1eIa5g-EjbWHGMsY7ug88OV9NeNYr3nmb/view
  81. wol.jw.org wol.jw.org
    Lo que Jehová ha hecho para rescatar a los seres humanos del pecado y la muerte — BIBLIOTECA EN LÍNEA Watchtower
    1
    1. ClaudioM 13 Oct 2024
      ¿Cómo demostró Jesús que vino a llamar a pecadores?

      Jesús prestaba especial atención a quienes se sentían muy mal porque eran pecadores, y los invitaba a seguirlo.

      Por eso tomaba la iniciativa de acercarse a hombres y mujeres que tenían la reputación de ser pecadores. De hecho, él mismo puso este ejemplo: “Los que están sanos no necesitan un médico, pero los enfermos sí”. Y añadió: “No vine a llamar a justos, sino a pecadores” (Mat. 9:12, 13).

      Lo demostró con hechos, perdonado los pecados de la mujer pecadora que le lavó sus pues con sus lágrimas, o cuando le enseño importantes verdades a la samaritana. Y cuando resucitó muertos con el poder que Dios le dió (Luc. 7:37-50). (Juan 4:7, 17-19, 26). (Mat. 11:5).

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    wol.jw.org/es/wol/d/r4/lp-s/2024530
  82. discuss.ipfs.tech discuss.ipfs.tech
    Social Media Architecture with IPFS - Ecosystem - IPFS Forums
    2
    2. gyuri 13 Oct 2024
      Social Media Architecture with IPFS

      not just distributed but personal first, local first, interpersonal interest based autonomous social networks

      for - hyperpost

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    discuss.ipfs.tech/t/social-media-architecture-with-ipfs/4625
  83. pressbooks.pub pressbooks.pub
    Song of Myself – The Open Anthology of Earlier American Literature: A PSU-Based Project
    2
    1. looseleafpaper 12 Oct 2024
      Perhaps I might tell more. Outlines! I plead for my brothers and sisters. Do you see O my brothers and sisters? It is not chaos or death — it is form, union, plan — it is eternal life — it is Happiness.

      This sounds like a cult leaderrr

    2. dylantulk 10 Oct 2024
      Shoulder your duds dear son, and I will mine, and let us hasten forth, Wonderful cities and free nations we shall fetch as we go.

      reminds me of his O Pioneers O Pioneers poem

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    pressbooks.pub/openeal/chapter/song-of-myself/
  84. Local file Local file
    A Feast for Crows
    2
    1. Aphemera 11 Oct 2024
      He seemed surprised when Cerseigathered him up in her arms and kissed him on his brow. “What’sthat for, Mother? Why are you crying?”Because you’re safe, she wanted to tell him. Because no harm willever come to you. “You are mistaken. A lion never cries.” Therewould be time later to tell him about Margaery and her cousins.“There are some warrants that I need you to sign.”For the king’s sake, the queen had left the names o the arrestwarrants. Tommen signed them blank, and pressed his seal into thewarm wax happily, as he always did.

      ughh she does care for him to an extent

    2. Aphemera 11 Oct 2024
      Guest right don’t mean so much as it used to,” said the girl. “Notsince m’lady come back from the wedding. Some o’ them swingingdown by the river gured they was guests too.

      nooo

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  85. outraspalavras.net outraspalavras.net
    Webserie expõe vida dos haitianos no Brasil - Outras Palavras
    1
    1. bssgeo 11 Oct 2024
      Nesse ponto, não está mais claro quem treina quem, quem é o mestre e quem é o servo

      Fico pensando na influência desse comportamento na Psicanálise, em especial nos Discurso de Lacan, principalmente no Discurso do Mestre e o Discurso do Capitalista (o quinto discurso)

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    outraspalavras.net/tecnologiaemdisputa/anova-santa-alianca-e-seus-objetivos-opacos/
  86. practicos_martin--correlacional.netlify.app practicos_martin--correlacional.netlify.app
    Estadística Correlacional - Práctico 5: Asociación entre categóricas
    1
    1. juancarloscastillo 11 Oct 2024
      Por otro lado, el sentido de injusticia distribuva se mide con un indicador denominado evaluación de injusticia (Jasso, 1980). Este representa cuanta justicia evalúan las personas en la distribución de recompensas de una situación. En este caso, representa la evalaución de qué tan justa es la distribución de ingresos de un gerente hipótetico, en tanto este representa el extremo mayor del espectro ocupacional. El indicador (en una versión simplificada) se lee de la siguiente manera:

      no se entiende, al resumir e intentar simplificar se pierde el sentido. Dar detalles de cómo se construye esto, o elegir otro item para el práctico que no requiera tanta necesidad de explicaciones, me iría por algo más simple. Ya lo de justificación de la violencia requiere explicación, y con eso basta. Ahora, se puede intentar explicar igual ...

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    practicos_martin--correlacional.netlify.app/assignment/05-practico
  87. www.estgv.ipv.pt www.estgv.ipv.pt
    Microsoft Word - Cap1_erros.doc
    1
    1. fmiranda 10 Oct 2024
      Exemplo: Determinar um limite superior do erro absoluto do volume de uma esfera,

      Será que o cálculo do limite superior do erro absoluto do valor aproximado do volume da esfera está correto? Para vos ajudar, calculem o erro absoluto verdadeiro do valor aproximado dado por 26.508, considerando que os valores exatos de pi e de d são 3.14159 e 3.75, respetivamente.

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    estgv.ipv.pt/paginaspessoais/nconceicao/20042005_2/Cap1_erros.pdf
  88. www.poetryfoundation.org www.poetryfoundation.org
    When Lilacs Last in the Dooryard Bloom’d by Walt Whitman
    1
    1. Isamar.ws1 10 Oct 2024
      Come lovely and soothing death, Undulate round the world, serenely arriving, arriving, In the day, in the night, to all, to each, Sooner or later delicate death. Prais’d be the fathomless universe, For life and joy, and for objects and knowledge curious, And for love, sweet love—but praise! praise! praise! For the sure-enwinding arms of cool-enfolding death. Dark mother always gliding near with soft feet, Have none chanted for thee a chant of fullest welcome? Then I chant it for thee, I glorify thee above all, I bring thee a song that when thou must indeed come, come unfalteringly. Approach strong deliveress, When it is so, when thou hast taken them I joyously sing the dead, Lost in the loving floating ocean of thee, Laved in the flood of thy bliss O death. From me to thee glad serenades, Dances for thee I propose saluting thee, adornments and feastings for thee, And the sights of the open landscape and the high-spread sky are fitting, And life and the fields, and the huge and thoughtful night. The night in silence under many a star, The ocean shore and the husky whispering wave whose voice I know, And the soul turning to thee O vast and well-veil’d death, And the body gratefully nestling close to thee. Over the tree-tops I float thee a song, Over the rising and sinking waves, over the myriad fields and the prairies wide, Over the dense-pack’d cities all and the teeming wharves and ways, I float this carol with joy, with joy to thee O death.

      In the seven consecutive unrhymed four-line stanzas, Whitman provides the song's lyrics. An apostrophe directly addresses the celebration of death in these stanzas. Whitman wishes for death to arrive since he believes it will eventually come to everyone, day or night, and he sees it as a peaceful incident. He praises the universe and love in the second of these stanzas, but he also hails death, as if it were an equal partner in love. He addresses death as a mother and welcomes her in the song's third verse. The fifth verse claims that Whitman will sing with the dead when their time comes since death is an ocean of love and happiness, using the bird's song as a metaphor. This subject is carried over into the last three stanzas of the bird's song. Death, for body and soul alike, is welcome wherever it occurs. The song in favor of death is spread throughout the nation, over cities, fields, and prairies, as the final verse makes clear. It is a song of joy even if it is a song of death.

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    poetryfoundation.org/poems/45480/when-lilacs-last-in-the-dooryard-bloomd