Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble

The influenza virus subtype H5N1 has raised concerns of a possible human pandemic threat because of its high virulence and mutation rate. Although several approved anti-influenza drugs effectively target the neuraminidase, some strains have already acquired resistance to the currently available anti-influenza drugs. In this study, we present the synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS-Map) to identify putative ‘hot spots’ within flexible binding regions of N1 neuraminidase. Using representative conformations of the N1 binding region extracted from a clustering analysis of four concatenated 40-ns MD simulations, CS-Map was utilized to assess the ability of small, solvent-sized molecules to bind within close proximity to the sialic acid binding region. Mapping analyses of the dominant MD conformations reveal the presence of additional hot spot regions in the 150- and 430-loop regions. Our hot spot analysis provides further support for the feasibility of developing high-affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

Substance abuse and addiction are the most costly of all the neuropsychiatric disorders. In the last decades, much progress has been achieved in understanding the effects of the drugs of abuse in the brain. However, efficient treatments that prevent relapse have not been developed. Drug addiction is now considered a brain disease, because the abuse of drugs affects several brain functions. Neurological impairments observed in drug addicts may reflect drug-induced neuronal dysfunction and neurotoxicity. The drugs of abuse directly or indirectly affect neurotransmitter systems, particularly dopaminergic and glutamatergic neurons. This review explores the literature reporting cellular and molecular alterations reflecting the cytotoxicity induced by amphetamines, cocaine and opiates in neuronal systems. The neurotoxic effects of drugs of abuse are often associated with oxidative stress, mitochondrial dysfunction, apoptosis and inhibition of neurogenesis, among other mechanisms. Understanding the mechanisms that underlie brain dysfunction observed in drug-addicted individuals may contribute to improve the treatment of drug addiction, which may have social and economic consequences.http://www.sciencedirect.com/science/article/B6SYS-4S50K2J-1/1/7d11c902193bfa3f1f57030572f7034

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A method for identifying Prime Biodiversity Areas in a Natural Area in West Sussex

SIGLEAvailable from British Library Document Supply Centre-DSC:3775.10607(EN-RR--180) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Survey of selected sites and habitats for spined loach Cobitis taenia

SIGLEAvailable from British Library Document Supply Centre-DSC:3775.10607(303) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The habitat and management requirements of spined loach Cobitis taenia

SIGLEAvailable from British Library Document Supply Centre-DSC:3775.10607(244) / BLDSC - British Library Document Supply CentreGBUnited Kingdo