Intrinsically disordered proteins access a range of hysteretic phase separation behaviors.

The phase separation behavior of intrinsically disordered proteins (IDPs) is thought of as analogous to that of polymers that undergo equilibrium lower or upper critical solution temperature (LCST and UCST, respectively) phase transition. This view, however, ignores possible nonequilibrium properties of protein assemblies. Here, by studying IDP polymers (IDPPs) composed of repeat motifs that encode LCST or UCST phase behavior, we discovered that IDPs can access a wide spectrum of nonequilibrium, hysteretic phase behaviors. Experimentally and through simulations, we show that hysteresis in IDPPs is tunable and that it emerges through increasingly stable interchain interactions in the insoluble phase. To explore the utility of hysteretic IDPPs, we engineer self-assembling nanostructures with tunable stability. These findings shine light on the rich phase separation behavior of IDPs and illustrate hysteresis as a design parameter to program nonequilibrium phase behavior in self-assembling materials

Cellulose synthase ‘class specific regions’ are intrinsically disordered and functionally undifferentiated

Cellulose synthases (CESAs) are glycosyltransferases that catalyze formation of cellulose microfibrils in plant cell walls. Seed plant CESA isoforms cluster in six phylogenetic clades, whose non‐interchangeable members play distinct roles within cellulose synthesis complexes (CSCs). A ‘class specific region’ (CSR), with higher sequence similarity within versus between functional CESA classes, has been suggested to contribute to specific activities or interactions of different isoforms. We investigated CESA isoform specificity in the moss, Physcomitrella patens (Hedw.) B. S. G. to gain evolutionary insights into CESA structure/function relationships. Like seed plants, P. patens has oligomeric rosette‐type CSCs, but the PpCESAs diverged independently and form a separate CESA clade. We showed that P. patens has two functionally distinct CESAs classes, based on the ability to complement the gametophore‐negative phenotype of a ppcesa5 knockout line. Thus, non‐interchangeable CESA classes evolved separately in mosses and seed plants. However, testing of chimeric moss CESA genes for complementation demonstrated that functional class‐specificity is not determined by the CSR. Sequence analysis and computational modeling showed that the CSR is intrinsically disordered and contains predicted molecular recognition features, consistent with a possible role in CESA oligomerization and explaining the evolution of class‐specific sequences without selection for class‐specific function

2020-05-16/17 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: Only 1 case in NM state prisons. NM case count. NM travel warning. NM web-based recovery reporting system. NM Mask Madness Tournament. Face covering in ABQ. NM graduate medical program funding. ABQ Memorial Day cancellation. NM affordable housing funding. Taos farmers market drive through opening. US correctional facility cases. Social distancing works. Dogs sniffing out COVID-19. Germany\u27s soccer league to restart. Mask effectiveness. Mask comfort w/cardboard cutout. Ammonium cleaning ineffective. CDC contact tracing guidance. Spanish immunity. CDC epidemic intelligence fellowship. Speaking transmits virus. Decontaminating workers. CDC advisory for children. Addressing ER fears. Indoor presymptomatic virus transfer. Virus transmission of currency. Safety advice for reopening. Lessons learned from universities. Dutch safe sex guidelines for singles. Recommendations are given on invasive management of acute coronary syndrome, onco-gynecologic surgery, endoscopy, hemodialysis, on resuming orthopedic surgery, clozapine monitoring, starting ADHD medications, orthodontics, and scaling up virtual services. At-home sample collection kit. Hydroxychloroquine no benefit. Tocilizumab reduces mortality rate. Calcium channel blockers beneficial. COVID-19 opinion/review vs. primary research. Disease severity and biomarkers. Concomitant liver injury. Gastrointestinal and liver involvement. Diabetes mortality. High incidence venous thrombosis. Monitoring global emotions with twitter

2020-05-29/30/31 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: NM Highlights: NM case count. Navajo Nation case update. Largest COVID-19 surge in Taos. ABQ BioPark to reopen. NM public schools reopening plan. NM unemployment claims. Rise in domestic and sexual abuse. US Highlights: Protests inspire fear of surge. Trump withdraws from WHO. Last aid bill. No new NY patients. ICE detainees sick. International Highlights: South Korea schools close. Undercounting in Russia. South African overburdened health care system. Economics, Workforce, Supply Chain, PPE: Reusable protection system. Protective household products. Longterm economic challenges. Epidemiology Highlights: Estimate virus reproduction numbers. Hypertension & cardiovascular disease impact on mortality. Gastrointestinal manifestations. Healthcare Policy Recommendations: Immunity passports are bad idea. Evaluation of hand WHO-recommended products. Opioid use-related challenges of COVID-19 management. Practice Guidelines: NICE guidelines on COVID-19 and acute kidney injury. Example of rapid conversion of an outpatient psychiatric hospital to a virtual telepsychiatry clinic. JAMA recommendations on conducting and reporting COVID-19 clinical research. Testing: Comparison of 4 antigen tests. Validation of antibody assays. Drugs, Vaccines, Therapies, Clinical Trials: Encouraging results of Ruxolitinib phase II RCT. Benefits of adjunctive herbal medicine. Potential inhibitors of viral protease screened. Anticoagulation alone is unlikely to protect from COVID-19 related morbidity and mortality. Open access database Covid19db for COVID-19 drugs. 49 new trials registered. Other Science: COVID-19 collateral damage. Telomere length and COVID-19 outcomes. Wastewater RNA early warning. Neurologic manifestation review. MRI reveals predominant anosmia cases. Self-quarantine weight gain. Immunosuppression vs. cytokine storm. Combatting misinformation

New Mechanics of Spinal Injury

The prediction and prevention of spinal injury is an important aspect of preventive health science. The spine, or vertebral column, represents a chain of 26 movable vertebral bodies, joint together by transversal viscoelastic intervertebral discs and longitudinal elastic tendons. This paper proposes a new locally-coupled loading-rate hypothesis}, which states that the main cause of both soft- and hard-tissue spinal injury is a localized Euclidean jolt, or SE(3)-jolt, an impulsive loading that strikes a localized spine in several coupled degrees-of-freedom simultaneously. To show this, based on the previously defined covariant force law, we formulate the coupled Newton-Euler dynamics of the local spinal motions and derive from it the corresponding coupled SE(3)-jolt dynamics. The SE(3)-jolt is the main cause of two basic forms of spinal injury: (i) hard-tissue injury of local translational dislocations; and (ii) soft-tissue injury of local rotational disclinations. Both the spinal dislocations and disclinations, as caused by the SE(3)-jolt, are described using the Cosserat multipolar viscoelastic continuum model. Keywords: localized spinal injury, coupled loading-rate hypothesis, coupled Newton-Euler dynamics, Euclidean jolt dynamics, spinal dislocations and disclinationsComment: 14 pages, 1 figure, Late

Deconstructing the lesbian, gay, bisexual, transgender victim of sex trafficking: Harm, exceptionality and religion–sexuality tensions

Contrary to widespread belief, sex trafficking also targets lesbian, gay, bisexual, transgender (LGBT) communities. Contemporary social and political constructions of victimhood lie at the heart of regulatory policies on sex trafficking. Led by the US Department of State, knowledge about LGBT victims of trafficking constitutes the newest frontier in the expansion of criminalization measures. These measures represent a crucial shift. From a burgeoning range of preemptive measures enacted to protect an amorphous class of ‘all potential victims’, now policies are heavily premised on the risk posed by traffickers to ‘victims of special interest’. These constructed identities, however, are at odds with established structures. Drawing on a range of literatures, the core task of this article is to confront some of the complexities and tensions surrounding constructions of LGBT trafficking victims. Specifically, the article argues that discourses of ‘exceptional vulnerability’ and the polarized notions of ‘innocence’ and ‘guilt’ inform hierarchies of victimhood. Based on these insights, the article argues for the need to move beyond monolithic understandings of victims, by reframing the politics of harm accordingly

2020-06-29/30 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: NM Highlights: NM cases update. ABQ nursing home hit hard. UNM student family housing closure. White Sands National Park reopening. 52% of federal COVID-19 relief money for tribal communities. Bill signed to help NM taxpayers. US Highlights: Polarization of political elite response on Twitter. International Highlights: China’s military to use Ad5-nCoV vaccine in trials. Economics, Workforce, Supply Chain, PPE: Decontaminate N95 respirators using a microwave. Epidemiology Highlights: Mask-wearing prevents transmission. Face-masks associated with Italy’s declining epidemic. Healthcare Policy Recommendations: Social distancing reassessed? Lessons learned from previous pandemics. Digital tools against COVID-19. Investigating cultural and psychological factors to reduce spread. Practice Guidelines: Preserving couple relationships during COVID-19. Testing: No difference in viral load between symptomatic and asymptomatic individuals. A new fast point-of-care virus detection test. Few patient serum samples have virus RNA (at low viral load) and these are not associated with infectious disease. Symptoms and temperature reports are informative to screen health care workers. Drugs, Vaccines, Therapies, Clinical Trials: 37 new trials registered June 29-30. Other Science: Multisystem pediatric inflammatory syndrome. Hazardous postoperative outcomes. Childhood immunization in Africa. Citizen science and protein folding

Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor β Superfamily Type 1 Receptors.

The transforming growth factor β (TGFβ) superfamily includes TGFβ, activins, inhibins, and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by coordinately regulating cell proliferation, differentiation, and migration. Aberrant signaling of superfamily members, however, is associated with fibrosis as well as tumorigenesis, cancer progression, metastasis, and drug-resistance mechanisms in a variety of cancer subtypes. Given their involvement in human disease, the identification of novel selective inhibitors of TGFβ superfamily receptors is an attractive therapeutic approach. Seven mammalian type 1 receptors have been identified that have context-specific roles depending on the ligand and the complex formation with the type 2 receptor. Here, we characterize the biologic effects of two transforming growth factor β receptor 1 (TGFBR1) kinase inhibitors designed to target TGFβ signaling. AZ12601011 [2-(2-pyridinyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine]; structure previously undisclosed] and AZ12799734 [4-({4-[(2,6-dimethyl-3-pyridinyl)oxy]-2-pyridinyl}amino)benzenesulfonamide] (IC50 = 18 and 47 nM, respectively) were more effective inhibitors of TGFβ-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC50 = 84 nM) and LY2157299 [4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide monohydrate]] (galunisertib) (IC50 = 380 nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors activin A receptor type 1B (ALK4), TGFBR1, and activin A receptor type 1C (ALK7). AZ12799734, however, is a pan TGF/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by activin A receptor type 1L, bone morphogenetic protein receptor type 1A, and bone morphogenetic protein receptor type 1B and phosphorylation of SMAD2 by ALK4, TGFBR1, and ALK7. AZ12601011 was highly effective at inhibiting basal and TGFβ-induced migration of HaCaT keratinocytes and, furthermore, inhibited tumor growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumor model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFβ- and BMP-regulated signaling pathways to disease states

The STOP COVID 2 study: Fluvoxamine vs placebo for outpatients with symptomatic COVID-19, a fully remote randomized controlled trial

BACKGROUND: Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50 mg on day 1, 100 mg twice daily thereafter) or placebo for 15 days. The primary modified intent-to-treat (mITT) population included participants who started the intervention within 7 days of symptom onset with a baseline oxygen saturation ≥92%. The primary outcome was clinical deterioration within 15 days of randomization, defined as having both (1) shortness of breath (severity ≥4 on a 0-10 scale or requiring hospitalization) RESULTS: A total of 547 participants were randomized and met mITT criteria (n = 272 fluvoxamine, n = 275 placebo). The Data Safety Monitoring Board recommended stopping early for futility related to lower-than-predicted event rates and declining accrual concurrent with vaccine availability in the United States and Canada. Clinical deterioration occurred in 13 (4.8%) participants in the fluvoxamine group and 15 (5.5%) participants in the placebo group (absolute difference at day 15, 0.68%; 95% CI, -3.0% to 4.4%; log-rank CONCLUSIONS: This trial did not find fluvoxamine efficacious in preventing clinical deterioration in unvaccinated outpatients with symptomatic COVID-19. It was stopped early and underpowered due to low primary outcome rates. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT04668950