Structural basis of nucleosome-dependent cGAS inhibition Boyer, Joshua A; Spangler, Cathy J; Strauss, Joshua D ...
Science (American Association for the Advancement of Science),
10/2020, Letnik:
370, Številka:
6515
Journal Article
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Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory ...diseases, and cancer. By contrast, cGAS reactivity against self-DNA in the nucleus is suppressed by chromatin tethering. We report a 3.3-angstrom-resolution cryo-electron microscopy structure of cGAS in complex with the nucleosome core particle. The structure reveals that cGAS uses two conserved arginines to anchor to the nucleosome acidic patch. The nucleosome-binding interface exclusively occupies the strong double-stranded DNA (dsDNA)-binding surface on cGAS and sterically prevents cGAS from oligomerizing into the functionally active 2:2 cGAS-dsDNA state. These findings provide a structural basis for how cGAS maintains an inhibited state in the nucleus and further exemplify the role of the nucleosome in regulating diverse nuclear protein functions.
Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug‐induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other ...channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J–Tpeak) and late repolarization (global Tpeak–Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug‐related cardiac electrophysiology.
Clinical Pharmacology & Therapeutics (2014); 96 5, 549–558. doi:10.1038/clpt.2014.155
Immunoglobulin A is the dominant antibody isotype found in mucosal secretions and enforces host-microbiota symbiosis in mice, yet selective IgA-deficiency (sIgAd) in humans is often described as ...asymptomatic. Here, we determined the effects of IgA deficiency on human gut microbiota composition and evaluated the possibility that mucosal secretion of IgM can compensate for a lack of secretory IgA. We used 16S rRNA gene sequencing and bacterial cell sorting to evaluate gut microbiota composition and taxa-specific antibody coating of the gut microbiota in 15 sIgAd subjects and matched controls. Despite the secretion of compensatory IgM into the gut lumen, sIgAd subjects displayed an altered gut microbiota composition as compared to healthy controls. These alterations were characterized by a trend towards decreased overall microbial diversity as well as significant shifts in the relative abundances of specific microbial taxa. While secretory IgA in healthy controls targeted a defined subset of the microbiota via high-level coating, compensatory IgM in sIgAd subjects showed less specificity than IgA and bound a broader subset of the microbiota. We conclude that IgA plays a critical and non-redundant role in controlling gut microbiota composition in humans and that secretory IgA has evolved to maintain a diverse and stable gut microbial community.
Drug‐induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is ...preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first‐of‐a‐kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart‐rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart‐rate corrected J‐Tpeak (J‐Tpeakc) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J‐Tpeakc may add value beyond only assessing QTc.
Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à ...gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo “thorough QT” studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J−Tpeak), and late repolarization (Tpeak−Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.
Clinical Pharmacology & Therapeutics (2014); 95 5, 501–508. doi:10.1038/clpt.2013.238
Social inequality is a consistent feature of animal societies, often manifesting as dominance hierarchies, in which each individual is characterized by a dominance rank denoting its place in the ...network of competitive relationships among group members. Most studies treat dominance hierarchies as static entities despite their true longitudinal, and sometimes highly dynamic, nature.
To guide study of the dynamics of dominance, we propose the concept of a longitudinal hierarchy: the characterization of a single, latent hierarchy and its dynamics over time. Longitudinal hierarchies describe the hierarchy position (r) and dynamics (∆) associated with each individual as a property of its interaction data, the periods into which these data are divided based on a period delineation rule (p) and the method chosen to infer the hierarchy. Hierarchy dynamics result from both active (∆a) and passive (∆p) processes. Methods that infer longitudinal hierarchies should optimize accuracy of rank dynamics as well as of the rank orders themselves, but no studies have yet evaluated the accuracy with which different methods infer hierarchy dynamics.
We modify three popular ranking approaches to make them better suited for inferring longitudinal hierarchies. Our three “informed” methods assign ranks that are informed by data from the prior period rather than calculating ranks de novo in each observation period and use prior knowledge of dominance correlates to inform placement of new individuals in the hierarchy. These methods are provided in an R package.
Using both a simulated dataset and a long‐term empirical dataset from a species with two distinct sex‐based dominance structures, we compare the performance of these methods and their unmodified counterparts. We show that choice of method has dramatic impacts on inference of hierarchy dynamics via differences in estimates of ∆a. Methods that calculate ranks de novo in each period overestimate hierarchy dynamics, but incorporation of prior information leads to more accurately inferred ∆a. Of the modified methods, Informed MatReorder infers the most conservative estimates of hierarchy dynamics and Informed Elo infers the most dynamic hierarchies.
This work provides crucially needed conceptual framing and methodological validation for studying social dominance and its dynamics.
Dominance is an important aspect of the biology of social organisms. Despite its shifting nature, dominance is most often considered a static phenomenon because of constraints on estimating the dynamics of dominance hierarchies. The authors propose the “longitudinal dominance hierarchy” framework and accompanying methods for investigating the dynamics of dominance.
Abstract The polytropic index is a fundamental physical parameter related to the thermodynamic processes present in space and astrophysical plasmas. This paper investigates the theoretical ...relationship between the polytropic index and the temperature anisotropy for flow parameters relevant to space plasmas. The derivation is based on the Chew–Goldberger–Low double-adiabatic equations of state and the finite Larmor radius correction. On the basis of this, we present the polytropic index relation, taking into account the temperature anisotropy, flow speed, and magnetic field of the plasma. This relation was further analyzed for the limit of the quasi-parallel and quasi-transversal cases. The quasi-transversal limit gives a polytropic index as a function of the anisotropic temperature γ = 1 + 22 T ⊥ − T ∥ /2 T ⊥ + T ∥ . Using this result, we analyze the polytropic index for the bulk proton parameters derived from Ulysses spacecraft data spanning the interval from 1992 January 1 to 2009 June 30, and we find an average polytropic index of γ ∼ 1.43. This value is close to that of recently published results. However, unlike previous statistical studies, this research computes the polytropic index without relying on power-law fitting, and its variation is now associated with the anisotropic temperature.
Abstract Although retroperitoneal sarcomas are rare tumors, they can be encountered by a wide variety of clinicians as they can be incidental findings on imaging or present with non specific symptoms ...and signs. Surgical resection can offer hope of cure and patient outcomes are improved when patients are managed in high volume specialist centers. Failure to recognize retroperitoneal sarcomas on imaging can lead to inappropriate management in inexperienced centers. Therefore it is critical that a diagnosis of retroperitoneal sarcoma should be considered in the differential diagnosis of a retroperitoneal mass with prompt referral to a soft tissue sarcoma unit. In particular, the most common retroperitoneal sarcoma subtypes, liposarcoma and leiomyosarcoma, have characteristic imaging appearances which are discussed. This review therefore aims to set the context and guide clinicians through a diagnostic pathway for retroperitoneal masses in adults which arise extrinsic to the solid abdominal viscera.
Abstract
Both the recent 2009 and 2020 solar minima were classified as unusually quiet and characterized with unusually high galactic cosmic-ray (GCR) levels. However, unlike the trends from previous ...decades, in which anomalous cosmic-ray (ACR) and GCR levels strongly agreed, the ACR intensities did not reach such high, record-setting levels. This discrepancy between the behavior of GCRs and ACRs is investigated in this work by simulating the acceleration and transport of GCR and ACR oxygen under different transport conditions. After using recent observations to constrain any remaining free parameters present in the model, we show that less turbulent conditions are characterized by higher GCR fluxes and lower ACR fluxes, due to less efficient ACR acceleration at the solar wind termination shock. We offer this as an explanation for the ACR/GCR discrepancy observed during 2009 and 2020, when compared to previous solar cycles.
Teen die einde van die 18de eeu is virusse ontdek en getipeer as skynbare oorgangsentiteite tussen nielewende en lewende dinge. Dit het aanleiding tot verskeie (wysgerige) grensprobleme gegee. Aan ...die een kant word aandag geskenk aan die vermeende gelyktydige ontstaan van proteïene en kernsuur en aan die ander kant word besin oor die vraag wat 'n plant is. Simpson en Von Bertalanffy word betrek om te beklemtoon dat molekules nie lééf nie. Dit open die weg na enkele gedagtes oor die aard van stoflike entiteite. Vervolgens word aandag geskenk aan die grensvraag na die oomblik van die dood en afgesluit met enkele juridiese oorwegings.
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