61 Matching Annotations
  1. Jan 2024
  2. Nov 2023
    1. The fact that most free software is privacy-respecting is due to cultural circumstances and the personal views of its developers
  3. Oct 2023
    1. Die EU hat offiziell mit der Einführung des sog. Klimazolls“ begonnen, also einer Abgabe für Produkte aus Ländern, in denen mit mehr Emissionen produziert wird als in der EU. Dabei geht es um Zement, Eisen und Stahl, Aluminium, Dünger, Strom und Wasserstoff. In einer zweijährigen Übergangsphase werden zunächst nur die nötigen Informationen gesammelt. https://taz.de/Einfuhr-von-Stahl-Duenger-und-Co/!5963230/

    1. we findsomething like a common mechanism.

      In every literary theorist structure there is a common conflict in the identification of a subject

      "common mechanism"



    1. 04:00 shame as feedback and driving growth (most powerful emotion)

      • also see how anxiety can be used and leveraged for growth (as a whisper that aids, rather than destroying)
  4. Apr 2023
    1. Review coordinated by Life Science Editors Foundation

      Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation

      Potential Conflicts of Interest: None

      Punch line: Rare risk variants associated with schizophrenia converge on the cAMP/PKA pathway.

      Why is this interesting? The cAMP/PKA pathway could be a mechanism & therapeutic target for neuropsychiatric disorders arising from different mutations.

      Background: * About 1-4% of people will develop psychosis or schizophrenia. * Schizophrenia is a highly heritable disease. * Genetic loci associated with schizophrenia can be common variants, which typically have small effects on risk, or rare variants, which can have large effects. * Rare, protein-truncating variants substantially increase the risk for mental illnesses like schizophrenia. * Disease-associated genes have diverse functions (e.g.): 1. RNA binding (RBM12) 2. transcriptional regulation (SP4, RB1CC1, SETD1A) 3. splicing (SRRM2) 4. signaling (AKAP11) 5. ion transport (CACNA1G, GRIN2A, GRIA3) 6. neuronal migration and growth (TRIO) 7. nuclear transport (XPO7) 8. ubiquitin ligation (CUL1, HERC1) ** What are the pathological mechanisms?* * A genetic screen identified the risk gene RBM12 as a novel repressor of GPCR/cAMP signaling (Semesta et al., PLOS Genetics, 2020). * Dysregulation of GPCR activity in the brain contributes to the pathophysiology of several neurological and neuropsychiatric disorders. * cAMP is a critical second messenger that mediates all important aspects of neuronal function, including development, excitability, and plasticity.

      Results: * Use knockout HEK293 cells to verify that RBM12 is novel repressor of the GPCR/cAMP pathway that extends to multiple GPCRs coupled to the stimulatory G protein (e.g. dopamine 1 receptor, beta-2 adrenergic receptor). * Show RBM12 also represses this pathway in iPSC-derived neurons. RBM12 knockdown yielded hyperactive upregulation of NR4A1 and FOS mRNAs, two known CREB-dependent immediate early genes induced by neuronal activity. * RBM12 loss leads to increased PKA activity and supraphysiological CREB-dependent transcriptional responses. * RBM12 loss increased expression of the endogenous β2-AR transcriptional target mRNAs, PCK1 and FOS. * RBM12 loss increased CREB transcriptional reporter expression in response to a panel of endogenous or synthetic β2-AR agonists.<br /> * Transcriptional responses are orchestrated from endosomal β2-ARs in wild-type cells but from both plasma membrane and endosomal β2-ARs in RBM12 knockout cells. * Their results suggest that cAMP production and transcriptional signaling are independently subject to RBM12 regulation. * The neuropsychiatric disease-linked mutations fail to rescue GPCR-dependent hyperactivation in cells depleted of RBM12. * Defined β2-AR-dependent transcriptional targets in “wild-type” and RBM12 knockdown neurons by differential expression analysis between each respective basal and isoproterenol conditions. 669 unique β2-AR-dependent transcriptional targets across the two cell lines. * Discerned β2-AR-dependent targets that were exclusive to wild-type or RBM12 knockdown only (qualitatively distinct targets) versus targets that are in wt and RBM12 kd but upregulated to different extents (quantitatively distinct targets). * 21 wild-type- and 115 RBM12 knockdown-specific target genes. Factors involved in synaptic plasticity and schizophrenia such as JUN, ARC (encoding the activity-regulated cytoskeleton-associated protein), BDNF, and NRXN3 (encoding the cell adhesion molecule neurexin-3-alpha) were induced by GPCR signaling only in RBM12 knockdown neurons, while GRIA2 (encoding the AMPA receptor) and CBLN2 (encoding cerebellin 2 precursor) were upregulated upon GPCR signaling only in wt neurons. * the remaining 533 genes were induced in both wt & RBM12-depeleted, with a trend toward RBM12-dependent hyperactivation. * loss of RBM12 leads to aberrant expression of ADCY, PDE, and PRKACA, suggesting this mechanism underlies the hyperactive GPCR/cAMP/PKA signaling phenotypes.

      Discussion: * Dysregulation of GPCR signaling could contribute to the neuronal pathologies stemming from loss of RBM12. * RBM12 function is required for normal cAMP production downstream of many Gαs-coupled receptors with established roles in the nervous system consistent with dysregulation of cAMP/PKA pathway. Specifically, the entire repertoire of targets, many of which orchestrate processes essential for neuronal differentiation, gene reprogramming, and memory and learning, shows a trend towards hyperactivation in RBM12 depleted neurons. * Over 100 genes are induced in response to receptor stimulation only in the knockdown (e.g. ARC and BDNF, with crucial roles in synaptic function, plasticity, and learning. * RBM12 could act through other mechanisms, given that RBM12 knockdown neurons also affects the expression of genes involved in neuron differentiation, synapse organization, and neurogenesis. * A study on post-mortem brains of patients with bipolar affective disorder demonstrated elevated levels of the PKAcat subunit Cα in temporal and frontal cortices compared to matched normal brains. * A different report on patient-derived platelet cells found that the catalytic subunit of cAMP-dependent protein kinase was significantly upregulated in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects. * Mutations in the schizophrenia risk gene histone methyltransferase SET domain-containing protein 1 A (SETD1A) also led to transcriptional and signaling signatures supporting hyperactivation of the cAMP pathway through upregulation of adenylyl cyclases and downregulation of PDEs. This in turn resulted in increased dendritic branching and length and altered network activity in human iPSC-derived glutamatergic neurons.

      Beautiful follow up to their PLOS Genetics paper, and compelling pathological mechanism in combination with the recent SETD1A Cell Reports paper.

      Future work: * Does loss of RBM12 increase dendritic branching and length and alter network activity in human iPSC-derived glutamatergic neurons (e.g. does it phenocopy loss of SETD1A). * Does pharmacologically targeting the cAMP pathway rescue the phenotypes caused by loss of RBM12? * If RBM12 is ubiquitously expressed, why is the disease neuronal? What is the relevant GPCR/neuronal mechanism? * How does RBM12 affect the abundance of the transcripts encoding the GPCR/cAMP effectors? * Do mutations in any of these other rare risk genes converge on GPCR? (transcriptional regulation (SP4, RB1CC1), splicing (SRRM2). signaling (AKAP11). ion transport (CACNA1G, GRIN2A, GRIA3), neuronal migration and growth (TRIO), nuclear transport (XPO7). ubiquitin ligation (CUL1, HERC1))

  5. Feb 2023
    1. Review coordinated by Life Science Editors.

      Reviewed by: Dr. Angela Andersen, Life Science Editors

      Potential Conflicts of Interest: Dr. Mill has worked with Life Science Editors on other manuscripts.

      Background: Retinitis pigmentosa (RP) is a group of rare eye diseases that cause vision loss. Symptoms usually start in childhood, and most people eventually lose most of their sight. There is no cure for RP. Mutations in retinitis pigmentosa GTPase regulator (RPGR) cause RP and compromise the renewal of light-sensitive “disc” membranes (specialized cilia) at the outer segment of photoreceptors, resulting in the loss of these cells over time. Evidence suggests that disc formation is similar to the release of ectosomes (small extracellular vesicles) and that both rely on the actin cytoskeleton. Knockdown of RPGR in retinal pigmented epithelium cells showed stronger actin filaments and reduced cilia suggesting that it may regulate nascent photoreceptor disc formation by regulating actin-mediated membrane extension in the retina (Gakovic et al., Human Molecular Genetics, 2011). In addition, RPGR patient iPSC-retinal models displayed phenotypes consistent with abnormal actin regulation (Megaw et al., Nature Communications, 2017; Karam et al., J Personalized Medicine, 2022).

      Question: What function of RPGR is compromised in photoreceptors to cause RP?

      Advance: The authors generated novel Rpgr mutant mice harboring human disease-causing mutations that recapitulate human disease phenotypes: aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. RPGR is located at the site of disc formation – to test if it plays a role in disc genesis, they engineered a novel reporter mouse to track outer segment turnover. Rhodopsin was tagged with the self-labelling peptide SNAP- Rhodopsin is the major protein component of outer segment discs, and so incubating RhodSNAP retinal slice cultures with SNAP fluorophores results in outer segment labelling. Perturbation of RPGR resulted in a slowed rate of disc formation, leading to shortened outer segments and increased vesicle shedding. To me, the breakthrough is in the last figure: the actin depolymerizing drug Cytochalasin D in PBS was injected intravitreally, and fixed retinas were analyzed 6 hours later by electron microscopy. Cytochalasin D treatment significantly reduced the number of shed vesicles from the base of the outer segment in Rpgr-mutant mice (they now look like wild-type).

      Significance: Nails down the disease-relevant function of RPGR and a molecular mechanism of RP in photoreceptor cells, in vivo, in mice. Pharmacological rescue not only demonstrates the importance of the mechanism to disease but also sheds light on a potential therapeutic avenue for RP.

  6. Dec 2022
  7. Nov 2022
    1. we propose the Transformer, a model architecture eschewing recurrence and insteadrelying entirely on an attention mechanism to draw global dependencies between input and output.The Transformer allows for significantly more parallelization a

      Using the attention mechanism to determine global dependencies between input and output instead of using recurrent links to past states. This is the essence of their new idea.

  8. Aug 2022
    1. Assuming honest MKR governance, oracle manipulation may be reasonably controlled.

      Controlling the manipulation with hourly price delays, median price feed implies majority collusion, maximum oracle price limits, price delays give ample time for global settlement.

  9. Mar 2022
  10. Feb 2022
    1. https://www.scientificamerican.com/article/an-ancient-greek-astronomical-calculation-machine-reveals-new-secrets/

      Overview and history of the Antikythera mechanism and the current state of research surrounding it.

      Antikythera mechanism found in diving expedition in 1900 by Elias Stadiatis. It was later dated between 60 and 70 BCE, but evidence suggests it may have been made around 205 BCE.


      One of the primary purposes of the device was to predict the positions of the planets along the ecliptic, the plane of the solar system.

      The device was also used to track the positions of the sun and moon. This included the moon's phase, position and age (the number of days from a new moon). It also included the predictions of eclipses.

      Used to track the motions of the 5 known planets including 289 synodic cycles in 462 years for Venus and 427 synodic cycles in 442 years for Saturn.

      Risings and settings of stars indexed to a zodiac dial


      metonic cycle, a 19-year period over which 235 moon phases recur; named after Greek astronomer Meton, but discovered much earlier by the Babylonians. The Greeks refined it to a 76 year period.

      saros cycle, the 223 month lunar cycle which was used by the Babylonians to predict eclipses. A dial on the Antikythera mechanism was used to predict the dates of the solar and lunar eclipses using this cycle.

      synodic events: conjunctions with the sun and its stationary points


      Archimedes - potentially the designer of an early version of the Antikythera mechanism

      Elias Stadiatis - diver who discovered the Antikythera mechanism

      Albert Rehm - German philologist who the numbers 19, 76 and 223 inscribed on fragments of the device in the early 1900s

      Derek J. de Solla Price, published Gears from the Greeks in 1974. Identified the gear train and developed a complete model of the gearing.

      Michael Wright - 3D x-ray study in 1990 using linear tomography; identified tooth counts of the gears and understood the upper dial on the back of the device

      Tony Freeth - author of article and researcher whose made recent discoveries.

    2. the moon has variable motion because it has an elliptical orbit: when it is farther from Earth, it moves more slowly against the stars; when it is closer, it moves more quickly. The moon’s orbit, however, is not fixed in space: the whole orbit rotates in a period of just under nine years.
  11. Nov 2021
  12. Oct 2021
  13. Sep 2021
    1. The Uncomfortable Truth is the Difficult and Unpopular Decisions are Now Unavoidable.

      Topic is relevant across a span of global issues. Natural resources are Finite.....period! Timely decisions are critical to insure intelligent use of resources. DENIAL is the enemy and 800lb gorilla in the room. Neoliberisim and social dysfunction feed on any cognitive dissonance and poop it out as "crap". True believers of American Capitalism (yes there is a difference) have become "cult-like" and drink the fluid of the cult to the very end, human consequence is of no concern.

      Point being: Reality is always elusive within a cult controlled (authoritative) mindset. Cult members are weak sheep, incapable of individual logic/reason. Authority can not be challenged. -- Denial, a human defense mechanism has been and is the common denominator in all personal and global conflict. Denial can be traced throughout modern history and rears its ugly head whenever the stakes are high.

  14. Aug 2021
  15. Jun 2021
    1. As the speed of unperturbed electrophoretic polynucleotide passage precludes the resolution of individual nucleotides, a DNA- or RNA-binding motor enzyme is added to the system to gain a processive and slowed down passage (millisecond scale per nucleotide) of the polynucleotide through the nanopore
    2. single-stranded polynucleotide is electrophoretically threaded through a protein or solid-state nanopore.
  16. May 2021
  17. Mar 2021
  18. Feb 2021
  19. Jan 2021
  20. Nov 2020
    1. intracellular signaling

      This is an important mechanism that cells can respond to their environment and extracellular cues. Cells sense their environment and modify genes, mRNA splicing, protein expression and protein modifying to respond to these cues.

  21. Sep 2020
  22. Aug 2020
    1. Martino, C., Kellman, B. P., Sandoval, D. R., Clausen, T. M., Marotz, C. A., Song, S. J., Wandro, S., Zaramela, L. S., Benítez, R. A. S., Zhu, Q., Armingol, E., Vázquez-Baeza, Y., McDonald, D., Sorrentino, J. T., Taylor, B., Belda-Ferre, P., Liang, C., Zhang, Y., Schifanella, L., … Knight, R. (2020). Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity. BioRxiv, 2020.08.17.238444. https://doi.org/10.1101/2020.08.17.238444

  23. Jul 2020
  24. Jun 2020
  25. May 2020
  26. Apr 2020
  27. Nov 2019
  28. Sep 2019
    1. move away from identifying correlative relationships between characteristics of the microbiome and system-level processes, and towards identifying more causative and mechanistic relationships
  29. Aug 2019
    1. relationships between characteristics of microbiomes and the system-level processes that they influence are often evaluated in the absence of a robust conceptual framework and reported without elucidating the underlying causal mechanisms. The reliance on correlative approaches limits the potential to expand the inference of a single relationship to additional systems and advance the field
  30. Jan 2019
    1. 计算机领域在分布式处理过程中追求高效、一致。对错误数据记录的修复和更正,通常会另行设计一套机制来保证。相对传统数据库,区块链由于需要保证事后数据的不可篡改,引入了共识机制,为错误的出现和修复提供更多的容忍度。这一重要思想通常被许多区块链设计者所忽略,众多项目纷纷追求提高短交易及确认速度,这会导致弱化甚至牺牲其他节点对数据的验证过程。同时,更早更快的确认也会带来问题。参与生成数据的节点需要满足生成数据不能出错等更严苛要求,导致现在很多区块链项目的在落地过程中出现困难。因为系统使用方会背上了数据必须一次性正确输入的包袱,需要非常保守和谨慎地选择上链数据。最终,区块链落地应用范围的狭窄,许多存在出错可能性的数据难以结合区块链的优点参与业务升级改造。

      <big>评:</big><br/><br/> 传统数据库与区块链式处理,哪个才是更佳的业务模式?这个问题的回答早已在我们的日常工作中得以体现,但却迫于某种难以逾越的权力边界而成了难言之隐。「事中容错,事后一致」是一种颇为崇高的境界,甚至可以从中一窥理想社会的光耀图景,但人们目前尚未能大规模应用这套 workflow,究其原因,并非目标遥远,而是由于决策权被少部分人掌控着,和数据打交道的主体只是把数据当作本职工作,并未主动贡献、积极参与。系统使用方背上的不是「数据必须一次性正确输入」的包袱,他们直面的,是将权利拱手让人后的自责,是与民主开放的理想世界背道而驰的困惑。

  31. Oct 2018
  32. Jun 2018
    1. Mechanism design studies solution concepts for a class of private-information games. Leonid Hurwicz explains that 'in a design problem, the goal function is the main "given", while the mechanism is the unknown. Therefore, the design problem is the "inverse" of traditional economic theory, which is typically devoted to the analysis of the performance of a given mechanism.'[1] So, two distinguishing features of these games are: that a game "designer" chooses the game structure rather than inheriting one that the designer is interested in the game's outcome

      Advantages over traditional game theory for token econimics:

      • a game "designer" chooses the game structure rather than inheriting one
      • that the designer is interested in the game's outcome
  33. Jun 2017
    1. incidents are an unavoidable reality of working with distributed systems, no matter how reliable. A prompt alerting solution should be an integral part of the design,

      see how it can hook into the current logging mechanism