32 Matching Annotations
  1. Aug 2020
    1. In a pure cloud world, this atomic unit of documents seems increasingly archaic. Documents are more a constraint of a pre-cloud world. And once you assume storing them online is table stakes, the question becomes where is actual collaboration happening that then leads people to wherever they need to do work.

      The document model, stored in the cloud, as pioneered by Dropbox and Box, hinges on the archaic metaphor of "a document". Kwok points out that: "documents are a constraint of a pre-cloud world". When storing documents online becomes trivial, people still need to coordinate on where (i.e. in which document) the collaboration is happening.

    1. Amylin interacts cooperatively with leptin. The anorexigenic effects of lepin when paired with amylin are greater than the sum of leptin and amylin’s independent anorexigenic effects. In other words, there is a greater-than-additive effect on satiety when leptin and amylin signaling pathways are simultaneously activated. The ventromedial nucleus of the hypothalamus (VMH) is one site of amylin-leptin interactions. The administration of amylin enhances leptin binding in the VMH, and both leptin and amylin receptor activation initiate some of the same signaling cascades (e.g., STAT3, Akt, and ERK). The STAT3 pathway seems to be particularly important in the interaction between leptin and amylin. Amylin-enhanced leptin signaling in the VMH requires amylin’s induction of interleukin 6 (IL-6). Notably, even following the development of leptin insensitivity (e.g., in obese individuals), amylin administration can restore leptin sensitivity.

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    2. Pramlintide is an amylin agonist approved for the treatment of T1DM and T2DM. Pramlintide is co-administered with insulin analogs and contributes to suppression of postprandial blood glucose by delaying gastric emptying, inhibiting glucagon secretion, and reducing food consumption. Like amylin, pramlintide is primarily deactivated by renal clearance, which also likely involves degradation by insulin-degrading enzyme. In obesity, satiety signals often have a diminished capacity to elicit their anorexigenic effects due to decreased receptor sensitivity. This is particularly true in the case of the adipose tissue-derived satiety signal leptin. In obesity, leptin insensitivity (also called leptin resistance) is profound. However, amylin receptor agonists remain potent appetite-suppressing agents in obese individuals but require continuous administration to effectively treat obesity. Furthermore, in some cases, amylin enhances the anorexigenic effects of other satiety signals (e.g., CCK, PYY, insulin, leptin) when co-administered.

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    3. The delay in gastric emptying induced by amylin is most likely achieved through central effects on the dorsal vagal complex of the hindbrain. The dorsal vagal complex contains multiple nuclei and plays a critical role in regulating gastric motility. The dorsal vagal complex includes the area postrema, the nucleus of the solitary tract (NTS), and the dorsal motor nucleus of the vagus nerve (DMV). The area postrema mediates some of the physiological and behavioral effects of amylin, and projects to the NTS. The NTS integrates both neural and endocrine signals (including amylin) and relays the integrated signals to the DMV. The DMB projects preganglionic axons toward the stomach, providing autonomic control over gastric motility. One proposed (though not yet validated) mechanism by which amylin delays gastric emptying is through excitation of the NTS. Amylin may accomplish this excitation of the NTS by interacting with the area postrema to promote the area postrema’s excitation of the NTS (possibly complimenting excitatory glutamatergic vagal input to the NTS) or by directly exciting the NTS. When the NTS is excited by amylin (whether directly or indirectly), the NTS could then modulate the activity of the DMV, resulting in DMV-mediated reductions in gastric motility and delayed gastric emptying. In support of this proposed pathway, gastric emptying is accelerated during hypoglycemia to increase the rate of glucose absorption to raise blood glucose to normal levels. Amylin-activated neurons in the area postrema have been shown to exhibit significant reductions in activity when exposed to low plasma glucose, which, through the same proposed pathway, would yield the increased rate in gastric emptying evident in hypoglycemia. Hypoglycemia may also diminish these neurons’ responsiveness to amylin.

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    4. Due to its reliable (albeit reduced) incretin effect, GLP-1 signaling has received more attention than GIP as a viable target for the treatment of T2DM and certain related disorders. By potentiating glucose-dependent insulin secretion, impairing glucose-dependent glucagon secretion, and delaying gastric emptying, exogenous administration of GLP-1 can completely normalize blood glucose in T2DM patients. However, GLP-1 itself is not a practical treatment for T2DM and related disorders because of its short half-life.

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    5. In addition to the roles of GLP-1 in regulating energy homeostasis at the level of the hypothalamus, another interesting hypothalamic effect of GLP-1R activation is to promote the secretion of gonadotropin releasing hormone (GnRH) into the hypophyseal portal system, at which point GnRH can stimulate gonadotropin release from the anterior pituitary. This promotion of GnRH secretion is accomplished through an interesting signaling pathway. In GnRH neurons, there is continuous production of 2-arachidonoylglycerol (2-AG, an endocannabinoid) by the enzyme diacylglycerol lipase (DGL) and a tonic retrograde release of 2-AG. The tonic retrograde release of 2-AG inhibits excitatory GABAergic inputs (GABA is usually inhibitory, but GABA is excitatory to GnRH neurons). GLP-1R activation on GnRH neurons increases the production of anandamide (another endocannabinoid). Anandamide in GnRH neurons activates TRPV1 receptors, leading to the inhibition of DGL. This prevents the production and tonic retrograde release of 2-AG. Furthermore, GLP-1R activation also increases the activity of adenylyl cyclase, leading to increased cAMP production, and the consequent activation of protein kinase A (PKA). PKA activates nitric oxide synthase (nNOS), which produces nitric oxide (NO). Nitric oxide is released as a retrograde signal to the excitatory GABAergic inputs, where it promotes GABA release. Thus, GLP-1R activation suppresses 2-AG-mediated inhibition of GABAergic excitation, while also promoting GABAergic excitation through retrograde NO signaling. Both of these effects of GLP-1R activation increase the excitatory GABAergic input to GnRH neurons, resulting in increased excitation of GnRH neurons.

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    6. The role of histamine in the stomach explains how antihistamines alter digestive processes: by blocking histamine-mediated excretion of hydrochloric acid.

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  2. Jul 2020
    1. BOX,G.E.P.andCOX, D. R. (1964). An analysis of transformations (with discussion).J. Roy.Statist. Soc. Ser. B26211–252.
  3. Dec 2019
    1. Paradise Lost

      PLACEHOLDER -- box-highlight

      couldn't find any extra-textual marks on this page pertaining to Paradise Lost.

    2. Coleridge's Antient Mariner.

      In the Thomas Copy, the allusion to Coleridge, "but I shall kill no albatross" is not attributed in text, but rather added by hand as a citation at the bottom of the page: "x Coleridge's Ancient Mariner x"

    3. This letter ought to be re-written

      In the Thomas copy, a note at the bottom of the page stipulates: "This letter ought to be re-written". The first three paragraphs and the final paragraph were to be substantively rewritten in the 1831 edition.

    4. If there were ever to be another edition of this book, I should re-write these two first chapters. The incidents are tame and ill-arranged—the language sometimes childish.—They are unworthy of the rest of the w booknarration.

      In the Thomas Copy, Mary's marginal note outlines her dissatisfaction with the opening chapters of the 1818 edition. Indeed, these chapters would be heavily augmented and revised for the 1831, presumably in accordance with Shelley's observations here.

    5. impossible:

      In the Thomas copy beneath the line "This manuscript will doubtless afford you the greatest <u>pleasure</u>," is written a the single word: "impossible." We cannot tell if this was Mary's comment or was put in by another reader.

    6. you said your family was not sientific.

      In the Thomas Copy, at the bottom of this page, an unknown hand states: "You said your family was not scientific." If this notation is in Mary's hand, she may be speaking to her character Victor, noting a discrepancy in his account of their familiarity with the sciences.

    7. bad

      In the Thomas copy this passage, deleted in 1831, is tagged by Shelley in the margins as "bad".

    1. Second, there are some fantastic projects out there like Create React App, preact-cli, nwb, and much more that avoid the boilerplate problem but at the expense of some other tradeoffs. Your configuration could be black-boxed and not able to be modified. They could force you to eject your configuration, making maintenance of the entire build dependency tree and configuration your responsibility again, and also preclude future configuration updates.
  4. Nov 2019
  5. Feb 2019
  6. Apr 2018
  7. Mar 2017
    1. Any communication between people about the same thing isa common revelatory experience about informational models of that thing.Each model is a conceptual structure of abstractions formulated initially inthe mind of one of the persons who would communicate, and if the conceptsin the mind of one would-be communicator are very different from those inthe mind of another, there is no common model and no communication

      cf. Wittgenstein Beetle in a Box

    1. What I do know is that I get the very distinct feeling that certain systems I use are not convivial. Google+, Facebook, WordPress, Twitter while full of humans, feel closed, feel like templates to be filled in not spaces to be lived in. Hence, the need for outsiders more than ever to raise the question especially in this week of connected courses where we are talking about the why of why.

      Absolutely.

      Very much depends from which perspective we are looking.

      This is absolutely key.

    2. System B is oppressive, closed, degenerative, and exhausting.
    1. Mia talked about translating meaning through boxes, inside boxes.

      Key. translation of meaning through boxes, inside boxes

  8. Jan 2017
    1. An anomaly is thus a mere difference in degree for which the norm will serve as metric.

      Normal is a powerful, potent, and potentially pernicious black box. And it is frequently a black box deployed against rhetoric.

  9. Jun 2016
    1. reate a note by selecting some text and clicking the button

      This is not a test

  10. Apr 2016
    1. According to Stemler, consistency estimates of interrater reliability assume that it is not necessary for judges to share a common meaning of the rating scale, so long as each judge is consistent in their classifications.

      Wittgenstein's beetle in a box

  11. Feb 2016
  12. Jan 2016
    1. the internet has become essential to our everyday life

      What if we had pockets of non-Internet connectivity, though? A mesh network doesn’t necessarily need to have nodes on the Internet. For instance, a classroom could have a “course in a box”, with all sorts of resources provided on local network, but without a connection to the whole Internet… So many teachers keep complaining about their students’ use of the Internet that they end up banning devices. But what if we allowed devices and even encouraged them, as long as they’re not on the Internet? WiFi connections tend to be spotty, to this day, and some classes are cellular deadzones. A bit like Dogme 95, getting used to sans-Internet connectivity could help us “get creative”. What would we do if we were to do a tech-savvy course on the proverbial “desert island”, without Internet?