Computing Highly Correlated Positions Using Mutual Information and Graph Theory for G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) are a superfamily of seven transmembrane-spanning proteins involved in a wide array of physiological functions and are the most common targets of pharmaceuticals. This study aims to identify a cohort or clique of positions that share high mutual information. Using a multiple sequence alignment of the transmembrane (TM) domains, we calculated the mutual information between all inter-TM pairs of aligned positions and ranked the pairs by mutual information. A mutual information graph was constructed with vertices that corresponded to TM positions and edges between vertices were drawn if the mutual information exceeded a threshold of statistical significance. Positions with high degree (i.e. had significant mutual information with a large number of other positions) were found to line a well defined inter-TM ligand binding cavity for class A as well as class C GPCRs. Although the natural ligands of class C receptors bind to their extracellular N-terminal domains, the possibility of modulating their activity through ligands that bind to their helical bundle has been reported. Such positions were not found for class B GPCRs, in agreement with the observation that there are not known ligands that bind within their TM helical bundle. All identified key positions formed a clique within the MI graph of interest. For a subset of class A receptors we also considered the alignment of a portion of the second extracellular loop, and found that the two positions adjacent to the conserved Cys that bridges the loop with the TM3 qualified as key positions. Our algorithm may be useful for localizing topologically conserved regions in other protein families

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Adverse Childhood Experiences (ACE) among American Indians in South Dakota and Associations with Mental Health Conditions, Alcohol Use, and Smoking.

OBJECTIVES: To assess the prevalence of Adverse Childhood Experiences (ACEs) and their association with behavioral health in American Indian (AI) and non-AI populations in South Dakota. METHODS: We included the validated ACE questionnaire in a statewide health survey of 16,001 households. We examined the prevalence of ACEs and behavioral health conditions in AI and non-AI populations and associations between ACEs and behavioral health. RESULTS: Compared with non-AIs, AIs displayed higher prevalence of ACEs including abuse, neglect, and household dysfunction and had a higher total number of ACEs. For AIs and non-AIs, having six or more ACEs significantly increased the odds for depression, anxiety, PTSD, severe alcohol misuse, and smoking compared with individuals with no ACEs. CONCLUSIONS: American Indians in South Dakota experience more ACEs, which may contribute to poor behavioral health. Preventing and mitigating the effects of ACEs may have a significant impact on health disparities in AI populations

Understanding Treatment Gaps for Mental Health, Alcohol, and Drug Use in South Dakota: A Qualitative Study of Rural Perspectives.

PURPOSE: More than 25% of US adults experience mental health or substance use conditions annually, yet less than half receive treatment. This study explored how rural participants with behavioral health conditions pursue and receive care, and it examined how these factors differed across American Indian (AI) and geographic subpopulations. METHODS: We undertook a qualitative follow-up study from a statewide survey of unmet mental health and substance use needs in South Dakota. We conducted semistructured phone interviews with a purposive sample of key informants with varying perceptions of need for mental health and substance use treatment. RESULTS: We interviewed 33 participants with mental health (n = 18), substance use (n = 9), and co-occurring disorders (n = 6). Twenty participants (61.0%) lived in rural communities that did not overlap with AI tribal land. Twelve participants (34.3%) were AI, 8 of whom lived on a reservation (24.2%). The discrepancy between actual and perceived treatment need was related to how participants defined mental health, alcohol, and drug use problems. Mental health disorders and excessive alcohol consumption were seen as a normal part of life in rural and reservation communities; seeking mental health care or maintaining sobriety was viewed as the result of an individual\u27s willpower and frequently related to a substantial life event (eg, childbirth). Participants recommended treatment gaps be addressed through multicomponent community-level interventions. DISCUSSION: This study describes how rural populations view mental health, alcohol, and drug use. Enhancing access to care, addressing discordant perceptions, and improving community-based interventions may increase treatment uptake