1,370 Matching Annotations
  1. Last 7 days
    1. As to the mechanics of research, I take notes on four-by-six indexcards, reminding myself about once an hour of a rule I read long agoin a research manual, “Never write on the back of anything.”

      Barbara Tuchman took her notes on four-by-six inch index cards.

      She repeated the oft-advised mantra to only write on one side of a sheet.

      What manual did she read this in? She specifically puts quotes on "Never write on the back of anything." so perhaps it might be something that could be tracked down?

      Who was the earliest version of this quote? And was it always towards the idea of cutting up slips or pages and not wanting to lose material on the back? or did it also (later? when?) include ease-of-use and user interface features even when not cutting things up?

      At what point did double sided become a thing for personal printed materials? Certainly out of a duty to minimize materials, but it also needed the ability to duplex print pages or photocopy them that way.

  2. Nov 2023
    1. we've got to leave the bottom left-hand corner and that only gives you three other spaces to go to and I've already noted that one of those spaces may be a place that has a certain utility short-run 00:50:27 but don't try to build your culture there because you can't do it it's a place that you want to be in for a while but then you wanna leave so it really only gives you two places
      • for: major cultural paradigms, modernity - leaving, cultural transition, cultural evolution, MET, Major Evolutionary Transition, kiey insight - 4 major cultural paradigms

      • comment

      • key insight: 4 major cultural paradigms

        • This matrix doesn't quite capture what Ruben is proposing because he later talks about neo-indigenous, which means taking elements of modernity but within an overall indigenous framework, so a hybrid
        • It would be worth exploring implications for an evolutionary framework of Major Evolutionary Transitions (MET)
    1. Reviewer #4 (Public Review):

      The study compares the number of sporozoites expelled by mosquitoes with different Plasmodium infection burden. To my knowledge this is the first report comparing the number of expelled P. falciparum sporozoites and their relation to oocyst burden (intact and ruptured) and residual sporozoites in salivary glands. The study provides important evidence on malaria transmission biology although conclusions cannot be drawn on direct impact on transmission.

      Although there is some evidence from malaria challenge studies that the burden of sporozoites injected into a host is directly correlated with the likelihood of infection, this has been done using experimental infection models which administer sporozoites intravenously. It is unclear whether the same correlation occurs with natural infections and what the actual threshold for infection may be. Host immunity and other host related factors also play a critical role in transmission and need to be taken into consideration; these have not been mentioned by the authors. This is of particular importance as host immunity is decreasing with reduction in transmission intensity.

      The natural infections reported in the study were not natural as the authors described. Gametocyte enrichment was done to attain high oocyst infection numbers. Studying natural infections would have been better without the enrichment step. The infected mosquitoes have much larger infection burden than what occurs in the wild.<br /> Nevertheless, the findings support the same results as in the experiments conducted in the Netherlands and therefore are of interest. I suggest the authors change the wording. Rather than calling these "natural" infections, they could be called, for example, "experimental infections with wild parasite strains".

      I do not believe the study results generate sufficient evidence to conclude that lower infection burden in mosquitoes is likely to result in changes to transmission potential in the field. In study limitations section, the authors say "In addition, our quantification of sporozoite inoculum size is informative for comparisons between groups of high and low-infected mosquitoes but does not provide conclusive evidence on the likelihood of achieving secondary infections. Given striking differences in sporozoite burden between different Plasmodium species - low sporozoite densities appear considerably more common in mosquitoes infected with P. yoelli and P. Berghei the association between sporozoite inoculum and the likelihood of achieving secondary infections may be best examined in controlled human infection studies. However, in the abstract conclusion the authors state "Whilst sporozoite expelling was regularly observed from mosquitoes with low infection burdens, our findings indicate that mosquito infection burden is associated with the number of expelled sporozoites and may need to be considered in estimations of transmission potential." Kindly consider ending the sentence at "expelled sporozoites." Future studies on CHMI can be recommended as a conclusion if authors feel fit.

    1. Reviewer #4 (Public Review):

      This work by Fleck et al. and colleagues documented the auxin feeding-induced effects in adult flies, since auxin could be used in temporally controlled gene expression using a modified Gal4/Gal80 system. Overall, the experiments were well-designed and carefully executed. The results were quantified with appropriate statistical analyses. The paper was also well-written and the results were presented logically. The findings demonstrate that auxin-fed flies have significantly lower triglyceride levels than the control flies using Ultra High-pressure Liquid Chromatography-Mass Spectrometry (UHPLC-MS)-based metabolomics assays. Further transcriptome analyses using the whole flies show changes in genes involved in fatty acid metabolism. However, female oogenesis and fecundity do not seem to be affected, at least using the current assays. These results indicate that auxin may not be used in experiments involving lipid-related metabolism, but could be appropriate to be applied for other biological processes.

  3. Oct 2023
    1. There are several occasions where the massebah is not associated with pagan worship. When the massebah is associated with the worship of Yahweh, the massebah is accepted as a valid expression of commitment to Yahweh.

      Massebah for pagan worship: - Exodus 23:24 (https://hypothes.is/a/r3m5QmyDEe6SC8eLYcJE1Q) - Hosea 10:1 (https://hypothes.is/a/4PK2GGyDEe6wZg_r2YpVCA ) - 2 Kings 18:4 - 2 Kings 23:14

      Massebah for worship of Yahweh: - Genesis 28:18 Jacob's pillow (https://hypothes.is/a/NF5p8Gx6Ee65Rg_J4tfaMQ)<br /> - Genesis 31:44-45 Jacob and Laban's covenant - Exodus 24:4 - Joshua 24:25-27

    2. in violation of the demands of the covenant, the people of Israel erected sacred stones dedicated to other gods (Hosea 10:1). In their religious reforms, both Hezekiah (2 Kings 18:4) and Josiah (2 Kings 23:14) destroyed the sacred pillars which the people of Israel had dedicated to the worship of Baal.
    3. During the establishment of the covenant between Yahweh and Israel, the people were commanded to destroy the sacred stones of the Canaanites, “You must demolish them and break their sacred stones (masseboth) to pieces” (Exodus 23:24).

      In neighboring cultures in which both have oral practices relating to massebah, one is not just destroying "sacred stones" to stamp out their religion, but it's also destroying their culture and cultural memory as well as likely their laws and other valuable memories for the function of their society.

      View this in light also of the people of Israel keeping their own sacred stones (Hosea 10:1) as well as the destruction of pillars dedicated to Baal in 2 Kings 18:4 and 2 Kings 23:14.

      (Link and) Compare this to the British fencing off the land in Australia and thereby destroying Songlines and access to them and the impact this had on Indigenous Australians.

      It's also somewhat similar to the colonialization activity of stamping out of Indigenous Americans and First Nations' language in North America, though the decimation of their language wasn't viewed in as reciprocal way as it might be viewed now. (Did colonizers of the time know about the tremendous damage of language destruction, or was it just a power over function?)

    4. (Joshua 4:20).

      connect this to:

      The helps whereof by this art memorative, they would prove to be as effectual, by these conceived fictions in the eye of the mind,12 as those we remember by the visible eye of the body, for example whereof say they, concerning the latter we read in the holy Scriptures of 12 stones, that were erected in the river Jordan in memory of the wonderful transpassage of the Israelites, Josh. 24.27.—The Memory Arts in Renaissance England by William E. Engel, Rory Loughnane, and Grant Williams

    5. When the people of Israel crossed the Jordan, Joshua commanded the people to set up twelve stones which were taken from the Jordan River as a memorial celebrating that defining moment in the life of Israel, the entrance of the people into the land God had promised to their ancestors (Joshua 4:20). The purpose of those memorial stones was to remind future generations of how the people “crossed the Jordan River on dry ground” (Joshua 4:22).

      Description of the arrangement? Circle? Further or suggested usage?

      Link to Genesis 28:18: https://hypothes.is/a/NF5p8Gx6Ee65Rg_J4tfaMQ

    1. Reviewer #4 (Public Review):

      This is an admirable piece of work. The authors build on a previous dataset they assembled, but expand it to include all stages of early development in the nematode Caenorhabditis elegans. Cell collection was done manually, which is very impressive, and is clearly far better than pooled unidentified cells. I will not comment on the specific sequencing and analysis, since this is not my expertise, but will comment on the general conclusions and comparative framework in which the authors place their results.

      While the Introduction and Discussion sections are actually fairly short, much of the presentation of the results is based on a certain comparative framework, which is explicitly a comparison between C. elegans and Drosophila melanogaster. This is an important perspective, but I feel the authors' interpretation is in some places exaggerated and in other places almost trivial.

      Drosophila and C. elegans are two of the main models for developmental biology. However, it has been clear for over two decades that both species are highly derived and specialized and therefore, treating them as representative for their taxa is problematic. Much of the authors' discussion hinges on the question of comparing syncytial and lineage-dependent development. The syncytial early development of Drosophila is very specific and is clearly a recent innovation within a restricted group of flies. The canonical Drosophila segmentation cascade is mostly a novelty and most elements within the cascade are recent. Specifically, the expression of gap genes in regional stripes is not found very broadly. Conversely, the polarizing role of Caudal is very ancient and is probably found in all Bilateria. When making comparisons with a distantly related species, it is important to keep this in mind. Not as much is known about development of other nematodes, but the little that is known indicates that C. elegans is also unusual, and specifically the eutelic development (conserved cell lineages in development) is not found in all nematodes.

      The authors suggest that regional expression of transcription factors in stripes is a conserved characteristic of development. This is true for Hox genes and has been known for decades. The regional expression they show for other genes is not convincing as "stripes". It is no surprise that developmental transcription factors are regionalized, but linking this to the stripes of Drosophila gap genes and even more so to Drosophila pair-rule and segment-polarity genes is a bit far-fetched. Yes, many genes are expressed in restricted domains along the A-P axis, but that is all that can be said based on the data. Calling them "Drosophila-like" is unfounded.

  4. Sep 2023
    1. Der französische Konzern TotalEnergies fördert in den USA mit 17 00 Förderanlagen via Fracking Erdgas, das dann verflüssigt wird. Allein in der Region von Arlington in Texas sind dadurch 420.000 Menschen toxischen Emissionen ausgesetzt. Die Libération publiziert die Ergebnisse einer gemeinsamen mit Disclose durchgeführten Recherche. Das produzierte LNG wird auch nach Frankreich und Europa verschifft.


      Disclose-Veröffentlichung: https://disclose.ngo/fr/article/gaz-de-schiste-totalenergies-au-coeur-dun-scandale-sanitaire-et-environnemental-au-texas

    1. Reviewer #4 (Public Review):

      Summary:<br /> The work by Dasgupta et al identifies Sema7a as a novel guidance molecule in hair cell sensory systems. The authors use the both genetic and imaging power of the zebrafish lateral-line system for their research. Based on expression data and immunohistochemistry experiments, the authors demonstrate that Sema7a is present in lateral line hair cells. The authors then examine a sema7a mutant. In this mutant, Sema7a proteins levels are nearly eliminated. Importantly, the authors show that when Sema7a is absent, afferent terminals show aberrant projections and fewer contacts with hair cells. Lastly the authors show that ectopic expression of the secreted form of Sema7a is sufficient to recruit aberrant terminals to non-hair cell targets. The sema7a innervation defects are well quantified. Overall, the paper is extremely well written and easy to follow.

      Strengths:<br /> 1. The axon guidance phenotypes in sema7a mutants are novel, striking and thoroughly quantified.<br /> 2. By combining both loss of function sema7a mutants and ectopic expression of the secreted form of Sema7a the authors demonstrate the Sema7a is both necessary and sufficient to guide sensory axons

      Weaknesses:<br /> 1. Control. There should be an uninjected heatshock control to ensure that heatshock itself does not cause sensory afferents to form aberrant arbors. This control would help support the hypothesis that exogenously expressed Sema7a (via a heatshock driven promoter) is sufficient to attract afferent arbors.<br /> 2. Synapse labeling. The numbers obtained for postsynaptic labeling in controls do not match up with the published literature - they are quite low. Although there are clear differences in postsynaptic counts between sema7a mutants and controls, it is worrying that the numbers are so low in controls. In addition, the authors do not stain for complete synapses (pre- and post-synapses together). This staining is critical to understand how Sema7a impacts synapse formation.<br /> 3. Hair cell counts. The authors need to provide quantification of hair cell counts per neuromast in mutant and control animals. If the counts are different, certain quantification may need to be normalized.<br /> 4. Developmental delay. It is possible that loss of Sema7a simply delays development. The latest stage examined was 4 dpf, an age that is not quite mature in control animals. The authors could look at a later age, such as 6 dpf to see if the phenotypes persist or recover.

    1. Reviewer #4 (Public Review):

      This manuscript describes a complex, highly ambitious set of modeling and experimental studies that appear designed to compare the structural and functional properties of beta cell subpopulations within the islet network in terms of their influence on network synchronization. The authors conclude that the most functionally coupled cell subpopulations in the islet network are not those that are most structurally coupled via gap junctions but those that are most metabolically active.

      Strengths of the paper include (1) its use of an interdisciplinary collection of methods including computer simulations, FRAP to monitor functional coupling by gap junctions, the monitoring of Ca2+ oscillations in single beta cells embedded in the network, and the use of sophisticated approaches from probability theory. Most of these methods have been used and validated previously. Unfortunately, however, it was not clear what the underlying premise of the paper actually is, despite many stated intentions, nor what about it is new compared to previous studies, an additional weakness.

      Although the authors state that they are trying to answer 3 critical questions, it was not clear how important these questions are in terms of significance for the field. For example, they state that a major controversy in the field is whether network structure or network function mediates functional synchronization of beta cells within the islet. However, this question is not much debated. As an example, while it is known that there can be long-range functional coupling in islets, no workers in the field believe there is a physical structure within islets that mediates this, unlike the case for CNS neurons that are known to have long projections onto other neurons. Beta cells within the islets are locally coupled via gap junctions, as stated repeatedly by the authors but these mediate short-range coupling. Thus, there are clearly functional correlations over long ranges but no structures, only correlated activity. This weakness raises questions about the overall significance of the work, especially as it seems to reiterate ideas presented previously.

      Specific Comments

      1. The authors state it is well accepted that the disruption of gap junctional coupling is a pathophysiological characteristic of diabetes, but this is not an opinion widely accepted by the field, although it has been proposed. The authors should scale back on such generalizations, or provide more compelling evidence to support such a claim.<br /> 2. The paper relies heavily on simulations performed using a version of the model of Cha et al (2011). While this is a reasonable model of fast bursting (e.g. oscillations having periods <1 min.), the Ca2+ oscillations that were recorded by the authors and shown in Fig. 2b of the manuscript are slow oscillations with periods of 5 min and not <1 min, which is a weakness of the model in the current context. Furthermore, the model outputs that are shown lack the well-known characteristics seen in real islets, such as fast-spiking occurring on prolonged plateaus, again as can be seen by comparing the simulated oscillations shown in Fig. 1d with those in Fig. 2b. It is recommended that the simulations be repeated using a more appropriate model of slow oscillations or at least using the model of Cha et al but employed to simulate in slower bursting.<br /> 3. Much of the data analyzed whether obtained via simulation or through experiment seems to produce very small differences in the actual numbers obtained, as can be seen in the bar graphs shown in Figs. 1e,g for example (obtained from simulations), or Fig. 2j (obtained from experimental measurements). The authors should comment as to why such small differences are often seen as a result of their analyses throughout the manuscript and why also in many cases the observed variance is high. Related to the data shown, very few dots are shown in Figs. 1e-g or Fig 4e and 4h even though these points were derived from simulations where 100s of runs could be carried out and many more points obtained for plotting. These are weaknesses unless specific and convincing explanations are provided.<br /> 4. The data shown in Fig. 4i,j are intended to compare long-range synchronization at different distances along a string of coupled cells but the difference between the synchronized and unsynchronized cells for gcoup and gKglyc was subtle, very much so.<br /> 5. The data shown in Fig. 5 for Cx36 knockout islets are used to assess the influence of gap junctional coupling, which is reasonable, but it would be reassuring to know that loss of this gene has no effects on the expression of other genes in the beta cell, especially genes involved with glucose metabolism.<br /> 6. In many places throughout the paper, it is difficult to ascertain whether what is being shown is new vs. what has been shown previously in other studies. The paper would thus benefit strongly from added text highlighting the novelty here and not just restating what is known, for instance, that islets can exhibit small-world network properties. This detracts from the strengths of the paper and further makes it difficult to wade through. Even the finding here that metabolic characteristics of the beta cells can infer profound and influential functional coupling is not new, as the authors proposed as much many years ago. Again, this makes it difficult to distill what is new compared to what is mainly just being confirmed here, albeit using different methods.

    1. In 1807, he started writing a dictionary, which he called, boldly, An American Dictionary of the English Language. He wanted it to be comprehensive, authoritative. Think of that: a man sits down, aiming to capture his language whole.

      Johnson's dictionary is much like this article describes too.

      Perhaps we need more dictionaries with singular voices rather than dictionaries made by committee?

    2. John McPhee — one the great American writers of nonfiction, almost peerless as a prose stylist — once wrote an essay for the New Yorker about his process called “Draft #4.” He explains that for him, draft #4 is the draft after the painstaking labor of creation is done, when all that’s left is to punch up the language, to replace shopworn words and phrases with stuff that sings.

      I quite like the idea of this Draft #4 concept.

    1. Reviewer #4 (Public Review):

      This manuscript covers an important topic of gender biases in the authorship of scientific publications. Specifically, it investigates potential mechanisms behind these biases, using a solid approach, based on a survey of researchers.

      Main strengths

      The topic of the MS is very relevant given that across sciences/academia representation of genders is uneven, and identified as concerning. To change this, we need to have evidence on what mechanisms cause this pattern. Given that promotion and merit in academia are still largely based on the number of publications and impact factor, one part of the gap likely originates from differences in publication rates of women compared to men.

      Women are underrepresented compared to men in journals with high impact factor. While previous work has detected this gap, as well as some potential mechanisms, the current MS provides strong evidence, based on a survey of close to 5000 authors, that this gap might be due to lower submission rates of women compared to men, rather than the rejection rates. The data analysis is appropriate to address the main research aims. The results interestingly show that there is no gender bias in rejection rates (desk rejection or overall) in three high-impact journals (Science, Nature, PNAS). However, submission rates are lower for women compared to men, indicating that gender biases might act through this pathway. The survey also showed that women are more likely to rate their work as not groundbreaking, and be advised not to submit to prestigious journals

      With these results, the MS has the potential to inform actions to reduce gender bias in publishing, and actions to include other forms of measuring scientific impact and merit.

      Main weakness and suggestions for improvement

      1) The main message/further actions: I feel that the MS fails to sufficiently emphasise the need for a different evaluation system for researchers (and their research). While we might act to support women to submit more to high-impact journals, we could also (and several initiatives do this) consider a broader spectrum of merits (e.g. see https://coara.eu/ ). Thus, I suggest more space to discuss this route in the Discussion. Also, I would suggest changing the terms that imply that prestigious journals have a better quality of research or the highest scientific impact (line 40: journals of the highest scientific impact) with terms that actually state what we definitely know (i.e. that they have the highest impact factor). And think this could broaden the impact of the MS

      2) Methods: while methods are all sound, in places it is difficult to understand what has been done or measured. For example, only quite late (as far as I can find, it's in the supplement) we learn the type of authorship considered in the MS is the corresponding authorship. This information should be clear from the very start (including the Abstract).

      Second, I am unclear about the question on the perceived quality of research work. Was this quality defined for researchers, as quality can mean different things (e.g. how robust their set-up was, how important their research question was)? If researchers have different definitions of what quality means, this can cause additional heterogeneity in responses. Given that the survey cannot be repeated now, maybe this can be discussed as a limitation.

      I was surprised to see that discipline was considered as a moderator for some of the analyses but not for the main analysis on the acceptance and rejection rates.

      I was also suppressed not to see publication charges as one of the reasons asked for not submitting to selected journals. Low and middle-income countries often have more women in science but are also less likely to support high publication charges.

      Finally, academic rank was asked of respondents but was not taken as a moderator.

  5. Aug 2023
    1. https://www.lochby.com/collections/frontpage/products/venture-pouch<br /> Lochby Venture Pouch<br /> $44.00

      Acquired one of these in early 2023 on sale?

      several internal sections including for pens. <br /> will easily fit a handful or so of 4 x 6" index cards for quick travel

    1. Reviewer #3 (Public Review):

      In this manuscript, the authors challenge the fundamental concept that all neurons are derived from ectoderm. Specifically, they aim to show that while the early ENS arises embryologically from neural crest (NENs), with age it is slowly replaced by mesoderm-derived neurons (MENs). This claim is based on an array of transgenic reporter mice, immunofluorescence, and transcriptomics. They further propose that the transition from NENs to MENs is regulated by a changing balance in GDNF-RET versus HGF-MET signaling, respectively.

      This is a provocative and potentially paradigm-changing proposal, but the data presented and the interpretation of that data fall short of establishing it.

      1) MENs share more common characteristics with fibroblasts. The authors interpret this as representing neurons with fibroblast characteristics. Why not fibroblasts with neuronal characteristics? The ability to express neurotransmitter receptors and calcium channels is common in fibroblasts, but that isn't sufficient to characterize a neuron. For example, many cell types express neurotransmitters (CGRP in ILCs, Penk in fibroblasts). Expressing one of the Hu proteins (Elavl2) probably isn't enough to call these "neurons," especially when neurons usually express Elavl3-4 (HuC/D). Including calcium imaging and showing presence of action potentials would strengthen the argument that these are in fact neurons.

      2) The scRNA-seq is unconvincing. There are several technical issues and the analysis omits important information required to make an unbiased assessment.

      a. One issue in the interpretation is that MENs are shown by IHC to constitute half the neuronal population, with NENs making up the other half. The authors state that they performed an unbiased approach, sequencing all cells in the muscularis. If it were truly unbiased, then why do they detect a 28-fold increase in MENs in the single cell data? This does not reflect the IHC findings and points to an issue in technique that needs to be addressed.

      b. Cell populations annotated by the author are confusing. The "unknown" population expresses many genes that are epithelial markers. This is puzzling because the authors state that they only sequenced the muscularis. This leads to questions regarding the initial samples and whether they were dissected appropriately or contaminated by another population.

      c. The authors report a population of ICCs at P21 which is not identified at 6-months. Closer inspection of their data shows bona fide ICC markers, Ano1 and Kit, in their SMC cluster at 6-months, with failure to identify ICC clusters, raising questions about whether they have identified a new cell type.

      d. While the authors critically examine other scRNA-seq datasets and claim that those groups mislabeled their populations, the above does not instill confidence in their ability to counter the unified literature.

      3) MENs are identified based on genes that could be related to neurons, including calcium channels, neurotransmitter receptors, etc. It is worth noting that mesenchymal cells, ICCs, and smooth muscle also possess these characteristics. Therefore, it hard to justify why these MENs are considered "neurons." The authors should perform an analysis to examine homology between clusters in order to show which clusters the MENs are more similar to, neurons or otherwise.

      4) Several issues raise questions about the quality of the scRNA-seq data, making interpretations very difficult:

      a. MENs are identified to have higher UMI counts than other cells, which the authors interpret as the cells being bigger than others. If this is the case, why is this only observed in the P21 dataset and not at 6 months. Notably, high UMIs are also a sign of doublet contamination.

      b. Authors include data from RBCs. As they do not have a nucleus, RNA abundance is low as expected. However, markers for RBCs include smooth muscle specific markers, MYH11 (an MEN marker) and Acta2. The presence of these markers can indicate high levels of "ambient RNA" which enters droplets from other cells lysed during digestion. Interestingly, MENs appear to cluster close to RBCs.

      c. In light of the above possible evidence of doublet contamination and high levels of ambient RNA, the markers of MENs need to be reconsidered. MENs are stated to express markers that were previously (up until this manuscript) accepted markers of intestinal mesothelium (Ukp3b Krt19, WT1), smooth muscle cells (Myh11), and fibroblasts (Dcn, C3, Col6a1), raising the possibility that MENs are an erroneous cluster containing RNA from all these cell types.

      5) The MEN population appears to be the largest cell population in the gut, which is unprecedented. The authors compare their scRNA-seq data to several other studies that have not made similar observations. Such analysis of other datasets is used to inform on the new data being generated. In the current manuscript, however, this takes the reverse approach and the authors analyze other data based on the assumption that they all mislabeled the MEN population.

      a. In their assessment of Drokhlyansky et al., the authors claim that their mesothelium annotation is wrong despite expressing known mesothelial markers. This includes the gene Upk3b which is a bona fide mesothelial marker in the gut but is also expressed by "MENs." They proceed to analyze the Elmentaite et al. dataset and state that their "transitional fibroblast" population are actually MENs. That paper also has a population of Upk3b+ mesothelial cells and it is unclear why those are not actually MENs like in the Drokhlyansky et al. study.

      b. The authors often refer to the study of May-Zhang et al. and their cluster annotated as "mesenchymal neurons" in the gut. It should be known that the original authors never made this claim. Rather, they acknowledge that the clusters in their study with poor correlation to neuronal profiles exhibit strong predictions for mesenchymal and vascular/immune cell types. They state: "We considered the possibility that these clusters might be non-neuronal." If these are "mesenchymal neurons" then the same logic would indicate that there are vascular neurons and immune cell neurons, and therefore this does not make a very compelling case.

      6) A weakness of this study is that a lot of the data relies on reporter gene expression. The authors need to acknowledge several weaknesses of this approach. First, Wnt1-tdT recombination may be incomplete or one can have "Cre mosaicism" and therefore the lack of tdT is not sufficient evidence to say that those neurons are not neural crest-derived. Second, one can have off-target or leaky Cre expression, leading to low-level tdT expression, as seen in many of the images in this study. Third, Cre can exhibit toxicity and this may be more problematic in older mice given the long-term continuous expression of Cre (He et al, Am J Pathology, 2014;184:1660; Loonstra et al, PNAS, 2001;98:9209; Forni et al, J Neurosci, 2006;26:9593; Rehmani et al, Molecules, 2019;24:1189; Gillet et al, Sci Rep, 2019;9:19422; Stifter and Greter, Eur J Immunol, 2020;50:338).

  6. Jul 2023
    1. four mitigating factors that make power appear to corrupt when something else is actually going on.
      • four mitigating factors that make power appear to corrupt when something else is actually going on.
        • dirty hands
          • people in power often are faced with no good alternatives and your hands will appear dirty, even when you choose the lesser of the evils
        • the idea of learning
          • authoritarian leaders are new to the job in the beginning and they have to learn to be good at being bad. Their leadership may appear to get worse but they are just learning how to be more effectively ruthless - on-the-job training
        • the problem of opportunity
          • a scaling effect. A leader of a country has far more people they can harm with his/her decision than a janitor.
        • the problem of scrutiny
          • people in power get more scrutiny
          • if you are not in power, you could be committing a crime but never get caught because you are not scrutinized to the same degree - think Donald Trump
    2. What are your four main arguments about power?
      • four main arguments about power
          1. worse people get power, corruptible people seek power
          1. power makes people worse, power corrupts
        • 3 we are drawn to the wrong kinds of leaders for all the wrong reasons
        • 4 we can design systems to make better people end up in power
    1. Reviewer #4 (Public Review):

      This is potentially a landmark study with far-reaching consequences for archaeology, palaeoanthropology, and more widely. The antiquity of intentional human mark marking is a hot topic but this study – understood as initial – has as yet incomplete sources of evidence and methods; and it will be interesting to follow how the study develops in subsequent studies.

      Strengths and points to build on:

      * Heuristic potential: As knowledge advances it poses a risk to accepted knowledge – and we should accept that one such risk is moving on from long-held disciplinary tenets. In this case, there has been a growing quantum of evidence – all hotly debated – for the deep antiquity of mark-making and even symbolism by species other than ourselves. Most researchers now accept Neanderthal symbolic capacity actualised in burials, intentional mark-making and the like. The evidence here presented is not unequivocal but is very suggestive and an ideal test case for applying multi-disciplinary techniques of analysis and interpretation beyond the expertise of the listed authors *see comments in 'weaknesses'). This work by itself may be equivocal but when taken together with other such work, points to a 'human' sensu lato past that is as complex as it is long. This work then helps all researchers to at least be alive to the possibility of things like anthropic marks and residues in a context not normally thought to have it.

      * Decentering speciesism: As per the above comment, I appreciate empirical studies that erode speciesism – in particular studies that open up our minds to the possibility that multiple members of the Genus Homo were capable of intentional mark-making and even 'symbolic' behaviour, though this latter term is not well understood or uniformly used. This is probably because of continuous unconscious bias on our part as currently the only exemplar of our genus living - in contrast to most of the past in which different species and genera co-existed - if not on the same landscape and/or at exactly the same time, then with enough overlap that people would have realised 'others' were about either by sight and/or by encountering their physical remains and artefacts.

      * Problematising 'firsts' and deep time: A strength – but which needs to be developed in this manuscript – is our understanding of time and change. We have a plethora of dating techniques but relatively few substantive monographs, articles, and think tanks on time – and especially on how change comes about and what causes it. This leads us to privilege 'firsts' and the 'oldest' finds in 'deep' time above those that are more recent and in 'shallow' time. I would suggest in addition to the claims for the oldest of the reported marks, the authors develop nascent remarks on the possibility the suite of marks may have been made over time. This will help counter criticism that these marks – if established to be anthropic – were not just a singularity, but part of patterned behaviour, which would move it towards the realm of 'symbolic' cognitive behaviour. And indeed, it would be good to hear more about why in this place, these marks were made to establish a replicable model for identifying early anthropic marks.

      Ultimately, this manuscript presents evidence that those who are pro the deep antiquity of intentional mark-making by Homo (and possibly even other genera) will find enough evidence to support; while those sceptical of such claims will find enough methodological flaws and evidential limits to refute those claims. The next decade of work will likely be definitive and this article makes a key contribution to the debate.

      Weaknesses and points to attend to:

      * Definitions: The term 'rock engraving' is used rather uncritically and also the term 'etching' – and it would be useful to have a short definition of how the authors understand the term. Rock art scholars regularly debate these terms and whether they are or are not 'rock art' with its overwhelmingly visual bias; which this discovery may usefully help overthrow and advance.

      * Dating: There is no evidence provided for dating the marks found in the cave system. They could, for example, have been made more recently than the dates claimed – and by another species (if we accept their anthropogenic authorship). This is a perennial problem of much rock art research – especially when it comes to understanding the wider archaeological/palaeoanthropological context. More crucially, accurate dating allows a more reliable understanding of authorship and who/what was responsible for a particular artefact or feature. This has not been demonstrated in this case, though we do have fossil evidence of Homo naledi in the cave system. The article title is this incorrect / and unsupported claim as the marks, if they are anthropic, have not been dated and are of unknown age. The authors allow that there may have been multiple episodes, but not that the marks can belong to a time other than they posit – either earlier, later, or distributed over a long period as the authors allow for in their concluding remarks.

      * Authorship: The study does not utilise either a geoscientist as one of the authorial team, or a rock art specialist. These are key oversights as the former would help better contextualise the dating of the marks reported on, as well as explore alternative non-anthropogenic agents that may have created the marks reported on. For example, the marks and 'pitting' etc may be the result of water bringing abrasive agents during times of flooding, hitting prominent rock features in the cave system. Some explanation is given from lines 114-124, but are uncited. The overlying 'sediment' may be similar to the mondmilch found in cave systems and which is of natural origin. It may be that these non-anthropogenic causes are easy to discount; but the arguments do need to be made. Or, that the polishing was made by Homo naledi brushing against the surfaces as they moved in the cave system, independent of any mark-making. A Table showing the pros and cons of intentional anthropic versus natural authorship would be very effective - as well as showing some of the natural linear marks in the cave system to avoid any confirmation or similar bias. FTIR analysis of the panel A-C would be more than useful to determine whether an additional layer of material has been added. This is mentioned for future work, but this seems a rather post-hoc research programme.

      * Use-wear analysis: If the marks are anthropic in origin; they are likely to have been made by a stone tool, which would leave characteristic marks, directionality and sequencing, distinct from natural causes. It is vital this work – such as was done on the Blombos engraved ochre – is done here – for example, linking to the chert and other tools described on lines 152-158. Note Figure 19, of such a tool, is very hard to make out. The Blombos – and Klasies River Mouth engraved ochres (curiously not referenced) – have very similar geometric markings and there is a real opportunity to compare these in securely dated contexts of 70-120 kya –which could support the argument made here for Homo naledi's cognitive capacity. On figure 16 it would be good to know on what basis some marks were selected as anthropic – and why others were not; this would help demonstrate the methodology and ability to distinguish between the two kinds of marks.

      * Viewshed: The rock art specialist would have added essential expertise on how to study anthropic marks. For example, the images of the marks shown are all of individual or small collections of motifs rather than showing each panel as well as all panels together, to help understand the iconographic context as an ensemble – a 'feature' rather than isolated 'artefacts' or 'motifs'. Line 60 mentions being able to see these as a 'triptych' but the reader is not able to have this view in this manuscript. From the cave map, it is not clear whether all three 'panels' (an unfortunate art historical term that suggests a framed entity - better to use a term like 'cluster') can be viewed simultaneously or in sequence. The view shed in relation to the area where the bodies were recovered is vaguely stated as 'only a few metres away' and is worth developing. I understand 3D scans have been made so it would be useful to have a version showing the marks in relation to where the bodies were recovered and as a 3-cluster ensemble.

      * Image enhancements: Also, in addition to polarised images, have colour enhancement tools like DStretch been tried to see if, for example, attempts at colouring with different coloured sands were made? Similarly, a 3D scan of the motif and panel – (Metashape is mentioned but not shown) – might assist in understanding how the marks and the rock they are on might relate to each other- as research in European upper Palaeolithic contexts has shown. Here, experimenting with different kinds of lighting - or in the absence of lighting, of tactility and how these marks and their rock support may have been experienced by those who may have made and interacted with them? As a note, it would be useful to have a scale in each image of the 'engravings' and it is a pity the one in situ photograph with the scale is not a standard rock art colour-corrected scale as is commonly used in rock art research.

    1. Reviewer #4 (Public Review):

      Berger et al. 2023a argues that Homo naledi intentionally buried their dead within the Rising Star cave system by digging pits and covering the bodies with infilled sediment. The authors identified two burials: Dinaledi Feature 1 from the Dinaledi Chamber, and the Hill Antechamber Feature from the Hill Antechamber. The evolutionary and behavioral implications for such behavior are highly significant and would be the first instance of a relatively small-brained hominin engaging is complex behavior that is often found in association with Homo sapiens and Homo neanderthalensis. Thus, the scientific rigor to validate these findings should be of the highest quality, and thus, provide clear documentation of intentional burial. In an attempt to meet these standards, the authors stated a series of tests that would support their hypothesis of intentional burials in the Rising Star Cave system:

      "The key observations are (1) the difference in sediment composition within the feature compared to surrounding sediment; (2) the disruption of stratigraphy; (3) the anatomical coherence of the skeletal remains; (4) the matrix-supported position of some skeletal elements; and (5) the compatibility of non-articulated material with decomposition and subsequent collapse." (page 5)

      To find support for the first (1) test, the authors collected sediment samples from various locations within the Rising Star Cave system, including sediment from within and outside Dinaledi Feature 1. However:

      • The authors did not select sediment samples from within the Hill Antechamber Feature, so this test was only used to assess Dinaledi Feature 1.

      • The sediment samples were analyzed using x-ray diffraction (XRD) and x-ray fluorescence (XRF) to test the mineralogy and chemistry of the samples from within and outside the feature. The XRF results were presented as weighted percentages (not intensities) with no control source reported. The weighted percentages were analyzed using a principal components analysis (PCA) while the particle-size distribution was analyzed using GRADISTAT statistics package and the Folk and Ward Method to summarize "mean grain size, sorting, skewness and kurtosis in addition to the percentages of clay, silt and sand in each sample." (page 28).

      • The PCA results were reported solely as a biplot without showing the PC scores projected into the loading space, which is unusual and does not present the data accurately. Instead, the authors present the scores of a single component (PC2, figure 3) because the authors interpreted this component as "distinctly delineates fossil-bearing sediments from sterile sediments based on the positive loadings of P and S" (Page 6). However, the supplementary table that reports XRF bulk chemistry results as a weighted percentage of minerals within each sample (SI Table 1) shows mostly an absence of data for both Na and S. Since Na is at the lower end of detection limits for the method, and S seems to just be absent from the list, the intentions of the authors for showing the inclusion of these elements in their PCA results is unclear. Given that this is the author's primary method for demonstrating a burial, this issue is particularly concerning and requires additional attention.

      • Regardless of the missing data, this reviewer attempted to replicate the XRF PCA results using the data provided in SI Table 1 and was unsuccessful. The samples that were collected from within the feature (SB) cluster with samples collected from sterile sediments and other locations around the cave system. Thus, these results are not replicable as currently reported.

      • Visual comparisons of sediment grain size, shape, and composition were qualitatively summarized. Grain size was plotted as a line graph and is buried as supplemental Figure S13 showing sample by color and area, but these results do not distinguish samples from WITHIN the burial compared to OUTSIDE the burial as the authors state in the methods as a primary goal.

      To test the second (2) aim, the "stratigraphy" was primarily described in text.

      • For Dinaledi Feature 1, the authors state that the layer around Feature 1 "is continuous in the profile immediately to the east of the feature; it is disrupted in the sediment profile at the southern extent of the feature (fig. 3b)." Upon examination of figure 3b, the image shows an incredibly small depiction of the south (?) profile view with an extremely large black box overlaying a large portion of the photograph containing a small 5 cm scale. Visually, there is no difference in the profile that would suggest a disruption in the form of a pit. The LORM (orange-red mud layer) does seem to become fragmentary, but no micromorphological analysis was conducted on this section to provide an evaluation of stratigraphic composition. Also, by only excavating a portion of the feature, the authors were unable to adequately demonstrate the full extent of this feature.

      • The authors attempt to describe "a bowl-shaped concave layer of clasts and sediment-free voids make up the bottom of the feature" (page 13) and refer to figures and supplementary information that do not depict any stratigraphic profile. Moreover, the authors state that "the leg, foot, and adjacent [skeletal?] material cut across stratigraphy" indicating that the skeleton is orientated on a flat plane against the surrounding stratigraphy that is "30{degree sign} slope of floor and underlying strata" (page 51, fig. 10c captions). There is no mention of infilled sediment from a pit and how this relates to the skeleton or the slope of the floor. It is therefore extremely unclear what the authors are meaning to describe without any visual or micromorphological supplementation to demonstrate a "bowl-shaped concave layer".

      The third (3) test was to evaluate the anatomical coherence of the skeletal remains using macro- and micro-CT (computed tomography) of the Hill Antechamber Feature that was removed during excavation. To visually assess the anatomy of the Dinaledi Feature 1 burial, the authors describe the spatial relationship of skeletal elements as they were being excavated but halted partway through the excavation.

      • The authors do not provide any documentation (piece-plotting, 3D rendering of stages of excavation, etc.) of the elements that were removed from the Dinaledi Feature. Figure 4 and SI Fig. S22 show the spatial relationship between identifiable skeletal elements that remain in the Feature. However, in Fig. 4, it is unclear why the authors chose to plot 2023-2014 excavated material along with material reported here, and it's even more difficult to understand the anatomical positioning of the elements given their color and point size choices. Although, the authors do provide a 3D rendering of the unexcavated remains showing some skeletal cohesion, apart from the mandible and teeth being re-located near the pelvis (Fig. 9). That said, it is very difficult to visually confirm the elements from this model or understand the original placement of the skeleton.

      • 3D renderings of the Hill Antechamber feature skeletal material is clearly shown in SI Fig. S26. Contrary to what the authors state in text, there is a rather wide dispersal and rearrangement of elements for a "burial" that is theoretically protected from scavengers and other agents that would aid in dispersing bone from the surface. The authors do not offer any alternatives to explain disturbance, such as human activity, which clearly took place.

      • Moreover, there does not appear to be any intentional arrangement of limbs that may suggest symbolic orientation of the dead (another line of evidence often used to support intentional burial but omitted by the authors). Thus, skeletal cohesion is not enough evidence to support the hypothesis of an intentional burial.

      The fourth (4) test was attempted by evaluating whether some elements were vertically aligned from 3D reconstructed models of Hill Antechamber Feature and a photogrammetric model of the Dinaledi Feature 1. The authors state that "the spatial arrangement of the skeletal remains is consistent with primary burial of the fleshed body" (page 8 in reference to Dinaledi Feature 1) without providing any evidence, qualitative or quantitative, that this is the case for either burial.

      Since this reviewer was unable to understand the fifth (5) test as it was written by the authors, I am unable to comment on the evidence to support this test and will default to the other reviewers for evaluation of this claim.

      In addition to a lack of evidence to support the claims of intentional burial, this paper was also written extremely poorly. For example, the authors often overused 'persuasive communication devices' (see eLife article, https://elifesciences.org/articles/88654) to mislead readers:

      "During this excavation, we recognized that the developing evidence was suggestive of a burial, due to the spatial configuration of the feature and the evidence that the excavated material seemed to come from a single body." (page 5)

      As an opening statement to introduce Dinaledi Feature 1, the authors state the interpretation and working hypothesis as fact before the authors present any evidence. This is known as "HARKing" and "gives the impression that a hypothesis was formulated before data were collected" (Corneille et al. 2023). This type of writing is pervasive throughout the manuscript and requires extensive editing. I recommend that the authors review the article provided by eLife (https://elifesciences.org/articles/88654) and carefully review the manuscript. Moreover, as this text demonstrates, the authors’ word choice is indicative of storytelling for a popular news article instead of a scientific paper. I highly suggest that the authors review the manuscript carefully and present the data prior to giving conclusions in a clear and concise manner.

      Moreover, the writing structure is inconsistent. Information that should be included in results is included in the methods, text in the results should be in discussions, and so forth. This inconsistency is pervasive throughout the entire manuscript, making it incredibly difficult to adequately understand what the authors had done and how the results were interpreted.

      Finally, the "artifact" that was described and visualized using CT models is just that - a digitally colored model. The object in question has not been analyzed. Until this object is removed from the dirt and physically analyzed, this information needs to be removed from the manuscript as there is nothing to report before the object is physically examined.

      Overall, there is not enough evidence to support the claim that Homo naledi intentionally buried their dead inside the Rising Star Cave system. Unfortunately, the manuscript in its current condition is deemed incomplete and inadequate, and should not be viewed as finalized scholarship.

    1. "I keep a dated diary of sorts on index cards, though they rarely go past one card a day."This is something I haven't heard of before. So, you journal/diary on index cards, one per day?

      reply to u/taurusnoises (Bob Doto) at tk

      Yep, for almost a full year now on 4x6" index cards. (Receipts for the kids: https://boffosocko.com/wp-content/uploads/2023/07/wp-1688411021709-scaled.jpg)

      Previously I'd used a Hobonichi Cousin (page per day) journal for this. (Perhaps I should have stayed with the A6 size instead of the larger A5 for consistency?) Decades ago (around 1988ish?) I had started using a 2 page per day DayTimer pocket planners (essentially pre-printed/timed index cards spiral bound into monthly booklets which they actually shipped in index card-like plastic boxes for storage/archival purposes). Technically I've been doing a version of this for a really long time in one form or another.

      It generally includes a schedule, to do lists (bullet journal style), and various fleeting notes/journaling similar to the older Memindex format, just done on larger cards for extra space. I generally either fold them in half for pocket storage for the day or carry about in groups for the coming week(s) when I'm away from my desk for extended periods (also with custom blank index card notebooks/pads).

      I won't go into the fact that in the 90's I had a 5,000+ person rolodex... or an index card (in the entertainment they called them buck slips) with the phone numbers and names of \~100 people I dealt with regularly when early brick cell phones didn't have great (or any) storage/functionality.

    1. Reviewer #4 (Public Review):

      This work aims at analyzing the impact of histone variants and histone modifications on chromatin states of the Arabidopsis genome. Authors claim that histone variants are as significant as histone modifications in determining chromatin states. They also study the effect of mutations in the DDM1 gene on the exchange of H2A.Z to H2A.W, which convert the silent state of transposons into a chromatin state normally found on protein coding genes.

      This is an interesting and well done study on the organization of the Arabidopsis genome in different chromatin states, adding to the previous reports on this issue.

  7. Jun 2023
    1. stern

      severe, or showing disapproval 嚴厲的,苛刻的

    2. moult

      (of a bird or animal) to lose feathers, skin, or hair as a natural process at a particular time of year so that new feathers, skin, or hair can grow (鳥或動物)脫毛;褪皮;換羽

    3. plumes

      a large feather 羽毛,翎

    4. vapors

      gas or extremely small drops of liquid that result from the heating of a liquid or solid 蒸氣;霧氣

    5. zenith

      the best or most successful point or time 頂峰;鼎盛時期

    6. countenance

      the appearance or expression of someone's face 面容;臉色;面部表情

    7. gaily

      happily or brightly 歡樂地,喜氣洋洋地;閃亮地,明亮地

    8. mottled

      covered with areas of different colours that do not form a regular pattern 雜色的;斑駁的

    9. elapsed

      If time elapses, it goes past.(時間)流逝,過去

    10. pierced

      to go into or through something, making a hole in it using a sharp point 刺穿,刺透,刺破

    11. slumbe


    1. Reviewer #4 (Public Review):

      A combination of optogenetic behavioral experiments and functional imaging are employed to identify the role of mechanosensory neurons in food swallowing in adult Drosophila. While some of the findings are intriguing and the overall goal of mapping a sensory to motor circuit for this rhythmic movement are admirable, the data presented could be improved.

      The circuit proposed (and supported by GRASP contact data) shows these multi-dendritic neurons connecting to pharyngeal motor neurons. This is pretty direct - there is no evidence that they affect the hypothetical central pattern generator - just the execution of its rhythm. The optogenetic activation and inhibition experiments are constitutive, not patterned light, and they seem to disrupt the timing of pumping, not impose a new one. A slight slowing of the rhythm is not consistent with the proposed function.

      The mechanosensory channel mutants nompC, piezo, and TMC have a range of defects. The role of these channels in swallowing may not be sufficiently specific to support the interpretation presented. Their other defects are not described here and their overall locomotor function is not measured. If the flies have trouble consuming sufficient food throughout their development, how healthy are they at the time of assay? The level of starvation or water deprivation can affect different properties of feeding - meal size and frequency. There is no description of how starvation state was standardized or measured in these experiments.

      The brain is likely to move considerably during swallow, so the GCaMP signal change may be a motion artifact. Sometimes this can be calculated by comparing GCaMP signal to that of a co-expressed fluorescent protein, but there is no mention that this is done here. Therefore, the GAaMP data cannot be interpreted.

    1. At 9¢/card these are very expensive in comparison to bulk cards which usually can be found for 1-2¢/card. The difference however is in the luxuriousness of the silky smooth texture. Whether you're writing with your favorite fountain pen or a carefully chosen pencil. I don't know if these are the same brand of Bristol cards that Vladimir Nabokov used for his writing, but one could easily image him using such lovely material.

      These provide a very smooth writing experience for fountain pens, gel pens and pencils. I particularly love the way my Tennessee Reds and Blackwing 602s glide over their surface. In comparison to some Japanese stationery, I'd put these cards somewhere between tsuru tsuru (slippery) and sara sara (smooth). If you're looking for a toothier paper, you'll definitely want to look elsewhere. They take fountain pens pretty well with no feathering or ghosting. My juiciest fountain pen dries in about 15 seconds, while a drier extra fine is dry in about 7 seconds, so it may take some care not to smear ink if you're on the messier end of the spectrum.

      Pencil erases reasonably well, though there may be some minimal residual ghosting here. At 205 gsm, they've got a satisfying thickness unseen in most index cards and one is unlikely to rip or crinkle them when erasing. They're also thick enough that the wettest Sharpie won't bleed much less ghost through. You have to hold a card up to a backlight to see the appearance of any ghosting through it and even then, not well.

      For the sticklers used to using standard 4 x 6" index cards, one should take note that the dimensions of these are slightly shorter in both dimensions—they're closer to 3.94" x 5.91". This means that you might have to take some care that while flipping through mixed company of cards your Exacompta can potentially hide between larger imperial sized cards. They're also close to, but not quite A6 in size either (105 x 148.5 mm or 4.1 x 5.8 inches).

    1. Reviewer #4 (Public Review):

      The authors have collected an impressive array of physiological data and provided some beautiful 3D images of SBCs with dendrites. These are clearly strengths. The computational models for mechanisms of SBC responses, however, are made to fit what may be inadequate anatomical data. Instead of conclusions, perhaps they need to reword their discussions to refer to the anatomy as hypothetical substrates.

  8. May 2023
    1. Reviewer #4 (Public Review):

      In this manuscript, Clary and colleagues use two-photon imaging to visualize the dynamics of Merkel cells and their innervating sensory axons using a combination of transgenic lines, where these parts of the mechanosensory organs of the skin are labelled with distinct fluorescent proteins. It is noteworthy that this study does not stand alone, but should be compared to prior published work cited by the authors, such as Wright et al., Developmental Biology 422 (2017) 4-13.

      The study demonstrates a comparably high degree of remodelling, with a large fraction of Merkel cells (50% in three weeks) and a similar fraction of elaborated (cup-like) axons endings disappearing. It appears by timing and correlation that changes in Merkel cells can clearly drive axonal remodelling, while axons can still remodel even if the Merkel cells remain stable by the parameters measured here. Moreover, changes in Merkel cells partially relate to the hair growth cycle.

      The imaging approach chosen is straightforward and clearly suited in principle to reveal the dynamism of the studied cellular structures. To co-visualize two synaptic partners in a vertebrate sensory organ in vivo - while not unprecedented - certainly remains quite challenging, and represents a strength of the paper. Similarly, understanding how stable structures in the nervous system are under homeostatic (rather than developmental) conditions, remains an understudied topic. I also found some of the correlative analysis in the later parts of the study quite interesting, albeit not always straightforward to interpret.

      My central concern is the very high disappearance rate of Merkel cells. This, in my view is not compatible with a steady state situation in an adult animal - and not with the prior literature (especially the similar study by Wright et al. cited above). Obviously, if this rate were to continue, Merkel cells would all be lost in early adulthood in mice. Whether this is the case in the specific anatomical location was not examined in the study - but it would also imply that the study really addresses a dynamic developmental remodelling situation and should be written up accordingly. I am more suspicious of the depilation agent (plus the shaving). As Wright et al. already show that shaving causes some changes in Merkel cell dynamics (but, as far as I can tell, did not chemically depilate), I would not be surprised that we see an artificially high remodelling rate. Such skin treatment-related biology is probably less relevant in the context of neurobiology (albeit probably quite interesting to other audiences). So, my recommendation to the authors would be to invest some energy to find out, what causes the swift Merkel cell loss.

      Another technical point that warrants discussion is the axonal labelling - first, I do not find the innervation patterns always easy to discern in the images provided, so I am not always sure how reliable this part is. Any artefact here creates the impression of dynamics, as during in vivo imaging stability is more reassuring than change. There are many ways not to see or recognize something, while there are few options to explain by an artefact why something did not change. Additionally, it might be good to explicitly mention that the TrkC mice are knock-in/knock-out (this is how I understood the JAX entry) - so the observations were made under reduced TrkC expression. It would help to explain, why this cannot affect axonal dynamics or Merkel cell-axon interactions.

      Overall, while I feel that the authors performed an interesting in vivo imaging study, I think technical aspects make it difficult to conclude with confidence, whether we are watching a normal and physiological process here or dynamics that are induced by specific interventions. While these interventions might represent conditions that can occur also outside the laboratory, it would be important to clarify how the reader should contextualize this study.

    1. l y a une forme de plaisir masochiste  à surfer sur les sites de rencontres.

      Il s'agit à nouveau d'une opinion de l'auteur et d'un jugement. Premièrement, il suppose que les gens ont de mauvaises expériences et, deuxièmement, qu'ils disposent d'options pour rencontrer de nouvelles personnes.

    2. Mais si on ne séduit pas dans la vraie vie, on ne séduit pas sur les sites de rencontre.

      C'est l'avis de l'auteur sur la base de son expérience des personnes qu'il a rencontrées. Il s'agit d'une extrapolation d'un comportement qu'il ne peut pas prédire.

    1. Reviewer #4 (Public Review):

      This work aims at analyzing the impact of histone variants and histone modifications on chromatin states of the Arabidopsis genome. Authors claim that histone variants are as significant as histone modifications in determining chromatin states. They also study the effect of mutations in the DDM1 gene on the exchange of H2A.Z to H2A.W, which convert the silent state of transposons into a chromatin state normally found on protein coding genes.

      This is an interesting and well done study on the organization of the Arabidopsis genome in different chromatin states, adding to the previous reports on this issue.

    1. Reviewer #4 (Public Review):

      This is an admirable piece of work. The authors build on a previous dataset they assembled, but expand it to include all stages of early development in the nematode Caenorhabditis elegans. Cell collection was done manually, which is very impressive, and is clearly far better than pooled unidentified cells. I will not comment on the specific sequencing and analysis, since this is not my expertise, but will comment on the general conclusions and comparative framework in which the authors place their results.

      While the Introduction and Discussion sections are actually fairly short, much of the presentation of the results is based on a certain comparative framework, which is explicitly a comparison between C. elegans and Drosophila melanogaster. This is an important perspective, but I feel the authors' interpretation is in some places exaggerated and in other places almost trivial.

      Drosophila and C. elegans are two of the main models for developmental biology. However, it has been clear for over two decades that both species are highly derived and specialized and therefore, treating them as representative for their taxa is problematic. Much of the authors' discussion hinges on the question of comparing syncytial and lineage-dependent development. The syncytial early development of Drosophila is very specific and is clearly a recent innovation within a restricted group of flies. The canonical Drosophila segmentation cascade is mostly a novelty and most elements within the cascade are recent (the authors are invited to browse my 2020 review in Curr. Top. Dev. Biol.) Specifically, the expression of gap genes in regional stripes is not found very broadly. Conversely, the polarizing role of Caudal is very ancient and is probably found in all Bilateria. When making comparisons with a distantly related species, it is important to keep this in mind. Not as much is known about development of other nematodes, but the little that is known indicates that C. elegans is also unusual, and specifically, the eutelic development (conserved cell lineages in development) is not found in all nematodes.

      The authors suggest that regional expression of transcription factors in stripes is a conserved characteristic of development. This is true for Hox genes and has been known for decades. The regional expression they show for other genes is not convincing as "stripes". It is no surprise that developmental transcription factors are regionalized, but linking this to the stripes of Drosophila gap genes and even more so to Drosophila pair-rule and segment-polarity genes is a bit far-fetched. Yes, many genes are expressed in restricted domains along the A-P axis, but that is all that can be said based on the data. Calling them "Drosophila-like" is unfounded.

      Beyond these broad homology statements, the rest of the presentation is fine and I have no major comments.

  9. Apr 2023
    1. strife

      "an act of contention" 爭吵

    2. bewail

      "to express deep sorrow for usually by wailing and lamentation" 悲嘆

    3. repented

      "to feel regret or contrition" 懺悔

    4. indignant

      "feeling or showing anger because of something unjust or unworthy" 憤慨

    5. temperance

      "moderation in action, thought, or feeling" 節制

    6. zeal

      "eagerness and ardent interest in pursuit of something" 熱誠

    7. avarice

      "excessive or insatiable desire for wealth or gain : GREEDINESS, CUPIDITY" 貪心、貪婪

    8. stoop

      "to bend the body or a part of the body forward and downward sometimes simultaneously bending the knees" 彎腰

    9. conjure

      "to charge or entreat earnestly or solemnly" 懇求

    10. toil

      "long strenuous fatiguing labor" 勞苦

    11. jurisdiction

      "the authority of a sovereign power to govern or legislate"; 管轄範圍

    12. drachm’

      "a unit of weight formerly used by apothecaries, equivalent to 60 grains or one eighth of an ounce." 德拉克馬

    13. vengeance

      "punishment inflicted in retaliation for an injury or offense" 報仇

    14. rejoice

      "to feel joy or great delight" 開心

    15. woe

      "a condition of deep suffering from misfortune, affliction, or grief" 悲痛

    16. endorse

      "to approve openly" 認可

    17. vicar

      "an ecclesiastical agent: such as: a Church of England incumbent receiving a stipend but not the tithes of a parish" 牧師

    18. hail

      "precipitation in the form of small balls or lumps usually consisting of concentric layers of clear ice and compact snow" 冰雹

    19. flax

      "any of a genus (Linum of the family Linaceae, the flax family) of herbs especially : a slender erect annual (L. usitatissimum) with blue flowers commonly cultivated for its bast fiber and seed" 亞麻

    20. ample

      "generous or more than adequate in size, scope, or capacity" 寬闊

    21. brethren

      "plural of BROTHER" 弟兄們

    22. boon

      "a timely benefit" 福利

    23. quenched

      "to put out the light or fire of" 熄滅

    24. motionless

      "not moving; stationary" 不動

    25. assailed

      "to attack violently" 攻擊

    26. dew

      "moisture condensed upon the surfaces of cool bodies especially at night" 露水

    27. perforates

      "to make a hole through"; 穿過

    28. tares

      "the seed of a vetch" 稗子

    29. slough

      "a place of deep mud or mire" 泥沼

    30. negligence

      "the quality or state of being negligent" 忽略、忽視

    31. laggard

      "lagging or tending to lag : slow especially compared to others of the same kind" 遲緩的、落後的

    32. courtesy

      "behavior marked by polished manners or respect for others"; 禮節、禮儀

    33. benignity

      "showing kindness and gentleness" 良性

    34. outrage

      "an act of violence or brutality" 暴行

    35. treachery

      "violation of allegiance or of faith and confidence"; 叛變

    36. desist

      "to cease to proceed or act" 斷念

    37. headlong

      "without pause or delay"; 猛然地

    38. astonishment

      "a feeling of great surprise and wonder" 驚愕

    39. pilgrim

      "one who travels to a shrine or holy place as a devotee" 朝聖

    40. brows

      "eyebrow" 眉毛

    41. unwonted

      "being out of the ordinary : RARE, UNUSUAL" 非習常的

    42. agile

      "marked by ready ability to move with quick easy grace" 俐落

    43. scorn

      "open dislike and disrespect or mockery often mixed with indignation" 鄙視、蔑視

    44. bend

      "to constrain or strain to tension by curving" 彎曲

    45. enswathes

      "to enfold or enclose with or as if with a covering"; 包裹住

    46. lingering

      "to move slowly" 逗、留

    47. reproach

      "an expression of rebuke or disapproval"; 批評的話語

    48. vermilion

      "a vivid reddish orange" 珠

    49. slopes

      "to lie or fall in a slant : INCLINE" 傾斜

    50. meridian circle

      "an astronomical transit instrument having its vertical circle very accurately graduated for precise measurements of declination" 經絡圈

    51. forebode

      "to have an inward conviction of (something, such as a coming ill or misfortune)"; 預示、預感

    52. fangs.

      “a long sharp tooth”; 獠牙

    53. hinders

      "to make slow or difficult the progress of";妨礙

    54. stain

      "to suffuse with color" 弄髒

    55. vanquish

      "to overcome in battle : subdue completely" 擊敗、征服

    56. ooze

      "a soft deposit (as of mud, slime, or shells) on the bottom of a body of water" 爛泥

    57. infamy

      “evil reputation brought about by something grossly criminal, shocking, or brutal”; 醜惡的、聲名狼藉的

    58. nape

      "the back of the neck";頸背

  10. Mar 2023
    1. repose

      to rest or lie 休息;憩息;臥眠

    2. Because of that great longing to excel, 80whereon my heart was set, I certainlywould not have been so courteous while I lived.Here is the forfeit paid for pride like this;nor should I be here yet, had it not beenthat, while I still could sin, I turned to God.

      Doing nothing is also a sin. Dante thinks you should stand up for your ideal.

    3. therefrom

      from that or from there; from a thing or place that has been previously mentioned 由此;從那裡;從那一點

    4. I’ve shown him all the people who are guilty;and now I mean those spirits to reveal, 65who ’neath thy jurisdiction cleanse themselves

      Dante gives sinners a second chance, kind of humanism.

    5. thereupon

      on the thing that has been mentioned 關於那,就該事

    6. Great sorrow filled my heart on hearing this,because I knew of people of great worth,who in that Borderland suspended were.

      He still not understand that God is justice itself.

    7. against me this one seemed to be advancingwith head erect and with such raging hunger,that even the air seemed terrified thereby—and of a she-Wolf, which with every lustseemed in her leanness laden, and had caused 50many ere now to lead unhappy lives.

      This imply that lust is the most difficult one for humans to overcome.

    8. Art thou that Virgil, then, that fountain-headwhich poureth forth so broad a stream of speech?”

      Why does Dante choose Virgil?

    9. When half way through the journey of our lifeI found that I was in a gloomy wood,because the path which led aright was lost.

      This is also Dante reminding himself.

    10. I had his hair wrapped round my hand already,and more than one shock had I plucked from him,while he was barking, with his eyes turned down

      Now Dante fully accepted the fact that God is justice. Those people deserve to be punished like this.

    1. Reviewer #4 (Public Review):

      In this manuscript, Tornini and colleagues identify two previously un-characterized micropeptides encoded by linc-mipep and linc-wrb as important modulators of day-time activity in zebrafish larvae. The authors demonstrate that each single mutant shows an increase in day-time activity and that double mutants show a more pronounced effect. Of interest, ubiquitous overexpression of the ORF encoding the linc-mipep-derived peptide can rescue the day-time over-activity phenotype of linc-mipep mutant larvae, establishing that linc-mipep acts indeed as a protein and not at the level of RNA. Using a series of experimental approaches, including ATAC-Seq from double mutant brains and scRNA-Seq and scATAC-seq analyses from linc-mipep mutants as well as linc-mipep and linc-wrb CHIP analyses, the authors furthermore identify differences in chromatin accessibility and gene expression in specific cell types of the larval brain in the absence of linc-mipep (and in case of globale ATAC-Seq, in the absence of both peptides). They conclude that the micropeptides regulate behavior and neuronal states by modulating chromatin accessibility, revealing functional similarities to their known vertebrate homolog HMGN1.

      Overall, the key finding of this paper, namely the identification of two functional microproteins that had previously been misannotated as lincRNAs but have homology to HMGN1 both based on their sequence and function is an exciting discovery since relatively few newly predicted micropeptides have been functionally characterized to date, and because it advances our understanding of the molecular mechanisms underlying vertebrate-specific neuronal function and diversity. The F0 screen leading to the identification of 2 functional micropeptides provides a major advance to the field since so far screens in the F0 generation have not been typically done (rather germline-transmission). Thus, this work provides a major step forward in this regard. In addition, it includes a series of scRNA- and scATAC analyses that are technologically at the forefront and not easy to conduct and analyse.

      The weakest part of the paper in its current form is on the one hand missing the link between the behavioral phenotype in mutants and the molecular phenotypes in the larval brain. It remains unclear how one can reconcile the broad neuronal expression (in the case of linc-mipep preferentially in Purkinje cells) and linc-wrb with the cell-specific effects. Moreover, it is not clear whether both peptides act redundantly or in parallel but distinct pathways since the rescue is only shown for the single linc-mipep mutant by linc-mipep overexpression (and no rescue is shown for linc-wrb or the double mutant). While the authors suggest throughout the manuscript that both peptides have similar functions (act redundantly), no clear data is provided for this, and the use of either single linc-mipep mutants (all single-cell analyses in the last Figure) or double linc-mipep/linc-wrb mutants (global brain ATAC-Seq analyses) for different brain analyses makes the molecular analyses inconsistent and not easy to interpret. While the overall finding(s) of the paper is really interesting, to make this paper really solid, additional controls and analyses will be needed.

    1. 1930s Wilson Memindex Co Index Card Organizer Pre Rolodex Ad Price List Brochure

      archived page: https://web.archive.org/web/20230310010450/https://www.ebay.com/itm/165910049390

      Includes price lists

      List of cards includes: - Dated tab cards for a year from any desired. - Blank tab cards for jottings arranged by subject. - These were sold in 1/2 or 1/3 cut formats - Pocket Alphabets for jottings arranged by letter. - Cash Account Cards [without tabs]. - Extra Record Cards for permanent memoranda. - Monthly Guides for quick reference to future dates. - Blank Guides for filing records by subject.. - Alphabet Guides for filing alphabetically.

      Memindex sales brochures recommended the 3 x 5" cards (which had apparently been standardized by 1930 compared to the 5 1/2" width from earlier versions around 1906) because they could be used with other 3 x 5" index card systems.

      In the 1930s Wilson Memindex Company sold more of their vest pocket sized 2 1/4 x 4 1/2" systems than 3 x 5" systems.

      Some of the difference between the vest sized and regular sized systems choice was based on the size of the particular user's handwriting. It was recommended that those with larger handwriting use the larger cards.

      By the 1930's at least the Memindex tag line "An Automatic Memory" was being used, which also gave an indication of the ubiquity of automatization of industrialized life.

      The Memindex has proved its success in more than one hundred kinds of business. Highly recommended by men in executive positions, merchants, manufacturers, managers, .... etc.

      Notice the gendering of users specifically as men here.

      Features: - Sunday cards were sold separately and by my reading were full length tabs rather than 1/6 tabs like the other six days of the week - Lids were custom fit to the bases and needed to be ordered together - The Memindex Jr. held 400 cards versus the larger 9 inch standard trays which had space for 800 cards and block (presumably a block to hold them up or at an angle when partially empty).

      The Memindex Jr., according to a price sheet in the 1930s, was used "extensively as an advertising gift".

      The Memindex system had cards available in bundles of 100 that were labeled with the heading "Things to Keep in Sight".

    1. 312 Oak Midget Tray WWeesCoverEquipped same as]No.324,price.55CTohold cards14x3.No.423.Equippedasabove,tohold65Ccards 24x4, priceNo. 533. Standard size.to hold card 3x5, equip-ped as above,price..........No. 7- Nickel ....PrepaidinU. S.onreceiptofpriceNo. 324OakMidgetTraytheCoverWeis75cNo. 644. To hold cards4x6,equipped$1.10(StyleNos.312,423.533and644)asabove......(Style No. 324,213.335and446.)Send for catalog showing many other time-saving office devices. Our goods are soldyour dealer does not carry our line we can supply you direct from the factory.To hold cards 24x4. lengthof tray2%in..equippedwithAtoZindexand100record cards 45cNo. 213. To hold cards 14x3in,, lenght of tray 24in..equipped asabove40cNo.335.Standardsize,tohold3x5 cards.equipped asabove50c80cNo. 446. To hold 4x6 cards,equipped asabove.Any of these trays sent pre-paid in U. S. on receipt ofpriceby stationers everywhere. IfNo. 6 Union St.The WeisManufacturing Co.,Monroe,Mich.,U. S.A.Please mention SYSTEM when writing to advertisers

      Notice the 1 1/4" x 3" cards, 2 1/4 x 4" cards in addition to the 3 x 5" and 4 x 6".

    1. The width of the drawers of both McDowell & Craig and Steelcase desks is just wide enough to accommodate two rows of 4 x 6" index cards side by side with enough space that one might insert a sizeable, but thin divider between them

      I suspect that this is a specific design choice in a world in which card indexes often featured in the office environment of the mid-twenty first century.

      Were other manufacturers so inclined to do this? Is there any evidence that this was by design? Did people use it for this? Was there a standard drawer width?

      The metal inserts to section off the desk drawer area could have also been used for this sort of purpose and had cut outs to allow for expanding and contracting the interior space.

      Keep in mind that some of these tanker desks were also manufactured with specific spaces or areas intended for typewriters or for storing them.

    1. The black line in Fig. 5 shows that redistribution is not enough; if everyone’s emissions are equalized at escape from poverty levels, then we would still overshoot the climate boundaries
      • First stage of characterizing the Safe and Just Corridor
      • The black line in Fig. 5 shows that
      • redistribution is not enough
        • if everyone’s emissions are equalized at escape from poverty levels, then
        • we would STILL overshoot the climate boundaries (annotator's emphasis)
        • hypothetical pressure from 62% of humanity that is lacking humane access to resources is equal to the pressure exerted by 4% of the elits of humanity
    1. Analog Supplies

      I should mention that the Stockroom Plus 4 x 6" cards I got a while back are great with even my juiciest fountain pens. They're some of the least expensive gridded cards I've been able to find and are a fraction of the cost of the Exacompta.

  11. Feb 2023
    1. Every visual creative work is a manifestation of the character of thedesigner.

      This emphasizes the importance of the designer understanding how their work ties into how people determine their level as designers.

    2. The resulting International Style leapt from Europe to the United States, spreading valuesof neutrality, objectivity, and rationality expressed through tightly gridded layouts andrestricted typography.

      The values that this style presented were impactful enough to reach the U.S thus foreshadowing it's importance.

    3. turned revolutIonary avant-garde Ideals Into forMal Method–ologIes, detachIng desIgn froM a dIsruptIve aesthetIc agenda.

      This can relate to their approaches to design and how they may relate to our approaches.

    4. A movementcalled the New Typography emergedfrom the Bauhaus

      This will be important to keep in mind for later in the reading.

    1. ZFIN: ZDB-ALT-150417-4

      DOI: 10.1016/j.cub.2023.01.039

      Resource: RRID:ZFIN_ZDB-ALT-150417-4

      Curator: @evieth

      SciCrunch record: RRID:ZFIN_ZDB-ALT-150417-4

      What is this?

    2. ZFIN: ZDB-ALT-160119-4

      DOI: 10.1016/j.cub.2023.01.039

      Resource: (ZFIN Cat# ZDB-ALT-160119-4,RRID:ZFIN_ZDB-ALT-160119-4)

      Curator: @evieth

      SciCrunch record: RRID:ZFIN_ZDB-ALT-160119-4

      What is this?

    1. People have some control over the timing of their death and can hold on until after important occasions or die quickly after having lost someone important to them

      I thought this was the most interesting fact because it is crazy that as humans we can get to a point in our lives where we literally decide what time is the best to die. It makes sense but also leaves me with so many questions. How is this possible? Can everyone do this? Do you have to be at the point of hospice for the to be possible? I just feel this is crazy that we can control when our time is whether or not we have a will to live. I added a link that goes deeper and adds examples of this subject from the Washington Post.


    1. Signature par le président du conseil régional et le préfet de régiond’une convention régionale pluriannuelle de coordination del’emploi, de l’orientation et de la formation (L6123-4 du code dutravail)
  12. Jan 2023
    1. Lo digital se carateriza por su fragilidad: copias y versiones que se pierden, cambios sin control, ausencia de historia

      cambios controlados y presentes si se hacen necesarios

    1. Reviewer #4 (Public Review):

      In the manuscript the author tried to find the cellular level mechanism that causes sudden cardiac death in elite athletes. They found that there are more ventricular fibrosis, ventricular extrasystole burden, longer action potential duration, higher ventricular fibrillation (VF) inducibility, higher HCN4 expression and decreased Ito in sustained trained dog model.

      The author successfully conducted large animal training model, showed bradycardia and ventricular fibrosis as a finding similar in athletes and demonstrated the increased ventricular arrhythmia susceptibility to electrical stimulation. The finding of increased action potential duration can be postulated to be a factor of sudden cardiac death in these athletes. However, the interpretation of these findings should be cautious just like all the animal studies. Human has a more complex interaction with the environment and individual variabilities. Will the higher susceptibility of VF to electrical stimulation be the same in athletes is still hard to answer.

      Still, it is the first study to provide a large animal model of sustained training mimicking trained athletes and to give insights into the cellular level of change in an athlete's heart. The young death of this special group is a tragedy and the importance of these studies cannot be overemphasized.

    1. Reviewer #4 (Public Review):

      Hu et al introduced the MS2-Suntag system into C. elegans to tag and image the dynamics of individual mRNAs in a live animal. The system involves CRISPR-based integration of 8x MS2 motifs into the target gene, and two transgene constructs (MCP-Suntag; scFv-sfGFP) that can potentially recruit up to 384 GFP molecule to an mRNA to amplify the fluorescent signal. The images show very high signal to background ratio, indicating a large range of optimization to control phototoxicity for live imaging and/or artifacts caused by excessive labeling. The use of epidermal wound repair as a case study provides a simplified temporal context to interpret the results, such as the initiation of transcription upon wounding. The preliminary results also reveal potentially novel biology such as localization of mRNAs and dynamic RNP complexes in wound response and repair. On the other hand, the system recruits a large protein complex to an mRNA molecule, an immediate question is to what extent it may interfere with in vivo regulation. Phenotypic assays, e.g., in development and wound repair, would have been a powerful argument but are not explored. In all, C. elegans is powerful system for live imaging, and the genome is rich in RNA binding proteins as well as miRNAs and other small RNAs for rich posttranscriptional regulation. The manuscript provides an important technical progress and valuable resource for the field to study posttranscriptional regulation in vivo.

    1. May 19, 2004 #1 Hello everyone here at the forum. I want to thank everyone here for all of the helpful and informative advice on GTD. I am a beginner in the field of GTD and wish to give back some of what I have received. What is posted below is not much of tips-and-tricks I found it very helpful in understanding GTD. The paragraphs posted below are from the book Lila, by Robert Pirsig. Some of you may have read the book and some may have not. It’s an outstanding read on philosophy. Robert Pirsig wrote his philosophy using what David Allen does, basically getting everything out of his head. I found Robert Pirsigs writing on it fascinating and it gave me a wider perspective in using GTD. I hope you all enjoy it, and by all means check out the book, Lila: An Inquiry Into Morals. Thanks everyone. arthur

      Arthur introduces the topic of Robert Pirsig and slips into the GTD conversation on 2004-05-19.

      Was this a precursor link to the Pile of Index Cards in 2006?

      Note that there doesn't seem to be any discussion of any of the methods with respect to direct knowledge management until the very end in which arthur returns almost four months later to describe a 4 x 6" card index with various topics he's using for filing away his knowledge on cards. He's essentially recreated the index card based commonplace book suggested by Robert Pirsig in Lila.

    1. Reviewer #4 (Public Review):

      This is an extraordinary study that will serve as key resource for all researchers in the field of Drosophila testis development. The lineages that derive from the germline stem cells and somatic stem cells are described in a detail that has not been previously achieved. The RNAseq approaches have permitted the description of cell states that have not been inferred from morphological analyses, although it is the combination of RNAseq and morphological studies that makes this study exceptional. The field will now have a good understanding of interactions between specific cell states in the somatic lineage with specific states in the germ cell lineage. This resource will permit future studies on precise mechanisms of communication between these lineages during the differentiation process, and will serve as a model for studies of co-differentiation in other stem cell systems. The combination of snRNAseq and scRNAseq has conclusively shown differences in transcriptional activation and RNA storage at specific stages of germ cell differentiation and is a unique study that will inform other studies of cell differentiation.

      Could the authors please describe whether genes on the Y chromosome are expressed outside of the male germline. For example, what is represented by the spots of expression within the seminal vesicle observed in Figure 3D?

      I would appreciate some discussion of the "somatic factors" that are observed to be upregulated in spermatocytes (e.g. Mhc, Hml, grh, Syt1). Is there any indication of functional significance of any of these factors in spermatocytes?

      In the discussion of cyst cell lineage differentiation following cluster 74 the authors state that neither the HCC or TCC lineages were enriched for eya (Figure 6V). It seems in this panel that cluster 57 shows some enrichment for eya - is this regarded as too low expression to be considered enriched?

    1. Ai Ebihara is the kind of character that you expect to hate from the get-go, but her struggle surprisingly becomes one of the better links in the game. Ai is pretty and rich, and she knows it – something that makes her insufferable at the start. She is always stroking her own ego, keeping up appearances, and spends her time being generally self-centered. But it takes a form of rejection to show Ai is dealing with some heavy feelings, even suicidal thoughts. What I loved so much about Ai’s social link is that it’s unpredictable – a rollercoaster of uncertainty. Every time you think you know where you stand with the girl and make progress, you get slapped in the face with an unsettling event or revelation. The question the link poses: Is there a redeeming quality about her? Can a kind soul be all it takes to save someone? Watching it all unfold is beautiful.  

      "The question the link poses: Is there a redeeming quality about [Ai Ebihara]? Can a kind soul be all it takes to save someone?"

      This is a beautiful write-up of the Ai Ebihara social link in Persona 4. I would be curious what the author thinks the answers are to the two questions presented. In my view, Ai's redeeming quality -- that is the quality she uses to redeem her character in the end -- is the same quality that drove her unpleasant personality early in the arc -- introspection. The player "saves" Ai by giving Ai the courage to save herself. Part of the beauty of the link is that the rest is for Ai to figure out as she goes forward.

  13. Dec 2022
    1. The drawers are jammed with jokes typed on 4-by-6-inch cards — 52 drawers, stacked waist-high, like a card catalog of a certain comedian’s life’s work, a library of laughs.

      Joan Rivers had an index card catalog with 52 drawers of 4-by-6-inch index cards containing jokes she'd accumulated over her lifetime of work. She had 18 2 drawer stackable steel files that were common during the mid-1900s. Rather than using paper inserts with the label frames on the card catalogs, she used a tape-based label maker to designate her drawers.

      Scott Currie, who worked with Melissa Rivers on a book about her mother, Joan Rivers, at the comedian’s former Manhattan office. Many of her papers are stored there.Credit...Hiroko Masuike/The New York Times

      Note carefully that the article says 52 drawers, but the image in the article shows a portion of what can be surmised to be 18 2-drawer cabinets for a total of 36 drawers. (14 2-drawer cabinets are pictured, but based on size and perspective, there's one row of 4 2-drawer boxes not shown.)

    1. Reviewer #4 (Public Review):

      The study employs a number of methods, including TEM morphometric analysis, immunochemistry, western blotting, genomics, genetically modified models, whole heart measurements.

      However, the manuscript seems to be a collection of two unfinished works: one on the transition p20-p60 in post-natal development of the heart, second about the role of ephrinB1 in the maturation of the crests of the sarcolemma. Otherwise, it is not clear why in the first figure there is no staining for ephB1, and why there is staining for claudin 5 instead.<br /> The authors are trying to defend the idea that development of the heart in rats doesn't finish on postnatal day 20 and goes on for up to day 60. However, it is not convincing.<br /> It is no surprise transcription profile is different between day 20 and day 60, I am sure as life goes on development continues into aging and any comparison of samples collected with sufficient time lapse will give transcriptional differences. Whether these differences represent a truly separate development stage is not a clear-cut story.<br /> Most of the argument is based on morphometric study of TEM images. However, the method is not described at all. There is reference to another paper by the authors, but this paper doesn't provide a concise description of the morphometry either. It is unclear how randomisation of images and fields of view has been achieved and what statistical methods has been implemented. In TEM it is often possible to find all sorts of oddities depending on how you choose the images.<br /> Why didn't the authors use microscopy of live isolated cells, which may be more relevant to study crest hight?<br /> Both claudin5 and EphrinB1 seem to be expressed highly after p5, which doesn't correlate with the proposed maturation of crests at days 20 to 60.<br /> There is no causative relationship between the lack of ephrinb1 and crest maturing, at least to my mind.

    1. Reviewer #4 (Public Review):

      This retrospective study addresses an important aspect of breast cancer treatment for prolonging survival and minimizing adverse events. Moreover, the findings could improve the treatment response of HR+ DCIS patients, which is very promising for the treatment. The article is mostly well-written and supported by encouraging data. The major strength of the study is the finding that ET after mastectomy should not be used for the treatment of HR+ DCIS patients. Nevertheless, only the Chinese population was analyzed, and that is the only limitation. This study would greatly help in the management of HR+ DCIS patients and in clinical decision-making.