Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin\u27s binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (

Multiple syndemic psychosocial factors are associated with reduced engagement in HIV care among a multinational, online sample of HIV-infected MSM in Latin America

ABSTRACT Latin America has some of the highest levels of antiretroviral therapy (ART) coverage of any developing region in the world. Early initiation and optimal adherence to ART are necessary for improved health outcomes and reduction in onward transmission. Previous work has demonstrated the role of psychosocial problems as barriers to uptake and adherence to ART, and recently, a syndemic framework has been applied to the role of multiple psychosocial syndemic factors and adherence to ART, in the USA. However, to our knowledge, these associations have not been investigated outside of the USA, nor in a multi-country context. To address these gaps, we assessed the association between multiple co-occurring psychosocial factors and engagement in HIV-related medical care and adherence to ART among a large, multinational sample of sexually-active HIV-infected men who have sex with men in Latin America. Among the 2020 respondents, 80.7% reported currently receiving HIV-related medical care, 72.3% reported currently receiving ART; among those, 62.5% reported 100% adherence. Compared with experiencing no psychosocial health problems, experiencing five or more psychosocial health problems is associated with 42% lower odds of currently receiving HIV-related medical care (adjusted odds ratio, aOR = 0.58, 95% CI 0.36, 0.95) and of currently receiving ART (aOR = 0.58, 95% CI 0.38, 0.91). The number of psychosocial health problems experienced was associated with self-reported ART adherence in a dose–response relationship; compared to those with none of the factors, individuals with one syndemic factor had 23% lower odds (aOR = 0.77, 95% CI 0.60, 0.97) and individuals with five or more syndemic factors had 72% lower odds (aOR = 0.28, 95% CI 0.14, 0.55) of reporting being 100% adherent to ART. Addressing co-occurring psychosocial problems as potential barriers to uptake and adherence of ART in Latin America may improve the effectiveness of secondary prevention interventions

The magnetic field in the Milky Way filamentary bone G47

Funding: R.J.S. acknowledges funding from an STFC ERF (grant ST/N00485X/1).Star formation primarily occurs in filaments where magnetic fields are expected to be dynamically important. The largest and densest filaments trace the spiral structure within galaxies. Over a dozen of these dense (∼104 cm−3) and long (>10 pc) filaments have been found within the Milky Way, and they are often referred to as "bones." Until now, none of these bones has had its magnetic field resolved and mapped in its entirety. We introduce the SOFIA legacy project FIELDMAPS which has begun mapping ∼10 of these Milky Way bones using the HAWC+ instrument at 214 μm and 18′′.2 resolution. Here we present a first result from this survey on the ∼60 pc long bone G47. Contrary to some studies of dense filaments in the Galactic plane, we find that the magnetic field is often not perpendicular to the spine (i.e., the center line of the bone). Fields tend to be perpendicular in the densest areas of active star formation and more parallel or random in other areas. The average field is neither parallel nor perpendicular to the Galactic plane or the bone. The magnetic field strengths along the spine typically vary from ∼20 to ∼100 μG. Magnetic fields tend to be strong enough to suppress collapse along much of the bone, but for areas that are most active in star formation, the fields are notably less able to resist gravitational collapse.Peer reviewe

Protocol of the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy

The Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy (CPSS), sponsored by Janssen Pharmaceutical Research & Development LLC, is an Alzheimer's disease (AD) biomarker enriched observational study that began 3 July 2015 CPSS aims to identify and validate determinants of AD, alongside cognitive, functional and biological changes in older adults with or without detectable evidence of AD pathology at baseline. CPSS is a dual-site longitudinal cohort (3.5 years) assessed quarterly. Cognitively normal participants (60-85 years) were recruited across Greater London and Edinburgh. Participants are classified as high, medium (amnestic or non-amnestic) or low risk for developing mild cognitive impairment-Alzheimer's disease based on their Repeatable Battery for the Assessment of Neuropsychological Status performance at screening. Additional AD-related assessments include: a novel cognitive composite, the Global Preclinical Alzheimer's Cognitive Composite, brain MRI and positron emission tomography and cerebrospinal fluid analysis. Lifestyle, other cognitive and functional data, as well as biosamples (blood, urine, and saliva) are collected. Primarily, study analyses will evaluate longitudinal change in cognitive and functional outcomes. Annual interim analyses for descriptive data occur throughout the course of the study, although inferential statistics are conducted as required. CPSS received ethical approvals from the London-Central Research Ethics Committee (15/LO/0711) and the Administration of Radioactive Substances Advisory Committee (RPC 630/3764/33110) The study is at the forefront of global AD prevention efforts, with frequent and robust sampling of the well-characterised cohort, allowing for detection of incipient pathophysiological, cognitive and functional changes that could inform therapeutic strategies to prevent and/or delay cognitive impairment and dementia. Dissemination of results will target the scientific community, research participants, volunteer community, public, industry, regulatory authorities and policymakers. On study completion, and following a predetermined embargo period, CPSS data are planned to be made accessible for analysis to facilitate further research into the determinants of AD pathology, onset of symptomatology and progression. The CHARIOT:PRO SubStudy is registered with clinicaltrials.gov (NCT02114372). Notices of protocol modifications will be made available through this trial registry. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial

IMPORTANCE Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. OBJECTIVE To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. INTERVENTIONS Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200mg (n = 588), or placebo (n = 587). MAIN OUTCOMES AND MEASURES The primary outcomewas incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase–polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. RESULTS The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5%vs 15.2%; odds ratio, 0.43 [95%CI, 0.28-0.68]; P < .001; absolute risk difference, −6.6 [95%CI, −10.7 to −2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). CONCLUSIONS AND RELEVANCE Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy

Can, Want and Try: Parents' Viewpoints Regarding the Participation of Their Child with an Acquired Brain Injury

BACKGROUND: Acquired brain injury (ABI) is a leading cause of permanent disability, currently affecting 20,000 Australian children. Community participation is essential for childhood development and enjoyment, yet children with ABI can often experience barriers to participation. The factors which act as barriers and facilitators to community participation for children with an ABI are not well understood. AIM: To identify the viewpoints of parents of children with an ABI, regarding the barriers and facilitators most pertinent to community participation for their child. METHODS: Using Q-method, 41 parents of children with moderate/severe ABI sorted 37 statements regarding barriers and facilitators to community participation. Factor analysis identified three viewpoints. RESULTS: This study identified three distinct viewpoints, with the perceived ability to participate decreasing with a stepwise trend from parents who felt their child and family "can" participate in viewpoint one, to "want" in viewpoint two and "try" in viewpoint three. CONCLUSIONS: Findings indicated good participation outcomes for most children and families, however some families who were motivated to participate experienced significant barriers. The most significant facilitators included child motivation, supportive relationships from immediate family and friends, and supportive community attitudes. The lack of supportive relationships and attitudes was perceived as a fundamental barrier to community participation. SIGNIFICANCE: This research begins to address the paucity of information regarding those factors that impact upon the participation of children with an ABI in Australia. Findings have implications for therapists, service providers and community organisations

Th17 Cells Are Involved in the Local Control of Tumor Progression in Primary Intraocular Lymphoma

BACKGROUND: Th17 cells play an important role in the pathogenesis of many autoimmune diseases, but despite some reports of their antitumor properties, too little is known about their presence and role in cancers. Specifically, knowledge is sparse about the relation of Th17 to lymphoma microenvironments and, more particularly, to the microenvironment of primary intraocular B-cell lymphoma (PIOL), an aggressive lymphoma with a poor prognosis. METHODS AND PRINCIPAL FINDINGS: In this work, we investigated the presence of Th17 cells and their related cytokines in a syngeneic model of PIOL, a subtype of non-Hodgkin lymphoma. The very small number of lymphocytes trafficking in normal eyes, which represent a low background as compared to tumor-bearing eyes, allows us to develop the present model to characterize the different lymphocyte subsets present when a tumor is developing. IL-21 mRNA was expressed concomitantly with IL-17 mRNA in tumor-bearing eyes and intracellular expression of IL-17A and IL-21 in infiltrating CD4(+) T lymphocytes. Interestingly, IL-17A production by T cells was negatively correlated with tumor burden. We also showed that IL-21 but not IL-17 inhibits tumor cell proliferation in vitro. CONCLUSIONS: These data demonstrate that IL-17A and IL-21-producing CD4(+) T cells, referred as Th17 cells, infiltrate this tumor locally and suggest that Th17-related cytokines may counteract tumor progression via IL-21 production. Thus, Th17 cells or their related cytokines could be considered to be a new therapeutic approach for non-Hodgkin B-cell lymphomas, particularly those with an ocular localization

Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes

<p>Abstract</p> <p>Background</p> <p>Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts.</p> <p>Methods</p> <p>rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population-based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity.</p> <p>Results</p> <p>Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV₁and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant.</p> <p>Conclusion</p> <p>Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus.</p

Social mindfulness predicts concern for nature and immigrants across 36 nations

People cooperate every day in ways that range from largescale contributions that mitigate climate change to simple actions such as leaving another individual with choice – known as social mindfulness. It is not yet clear whether and how these complex and more simple forms of cooperation relate. Prior work has found that countries with individuals who made more socially mindful choices were linked to a higher country environmental performance – a proxy for complex cooperation. Here we replicated this initial finding in 41 samples around the world, demonstrating the robustness of the association between social mindfulness and environmental performance, and substantially built on it to show this relationship extended to a wide range of complex cooperative indices, tied closely to many current societal issues. We found that greater social mindfulness expressed by an individual was related to living in countries with more social capital, more community participation and reduced prejudice towards immigrants. Our findings speak to the symbiotic relationship between simple and more complex forms of cooperation in societies

Moral expansiveness around the world:The role of societal factors across 36 countries

International audienceWhat are the things that we think matter morally, and how do societal factors influence this? To date, research has explored several individual-level and historical factors that influence the size of our ‘moral circles.' There has, however, been less attention focused on which societal factors play a role. We present the first multi-national exploration of moral expansiveness—that is, the size of people’s moral circles across countries. We found low generalized trust, greater perceptions of a breakdown in the social fabric of society, and greater perceived economic inequality were associated with smaller moral circles. Generalized trust also helped explain the effects of perceived inequality on lower levels of moral inclusiveness. Other inequality indicators (i.e., Gini coefficients) were, however, unrelated to moral expansiveness. These findings suggest that societal factors, especially those associated with generalized trust, may influence the size of our moral circles