Dynamic Profiling of β-Coronavirus 3CL M^proProtease Ligand-Binding Sites

Data availability statement: The trajectories of Mpro simulations and models of the metastable states can be downloaded from 10.5281/zenodo.4782284.β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand–protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.There was no funding for this wor

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

A Guide to Posting and Managing Preprints

Posting preprints online allows psychological scientists to get feedback, speed dissemination, and ensure public access to their work. This guide is designed to help psychological scientists post preprints and manage them across the publication pipeline. We review terminology, provide a historical and legal overview of preprints, and give guidance on posting and managing preprints before, during, or after the peer-review process to achieve different aims (e.g., get feedback, speed dissemination, achieve open access). We offer concrete recommendations to authors, including: post preprints that are complete and carefully proof-read; post preprints in a dedicated preprint server that assigns DOIs, provides editable metadata, is indexed by GoogleScholar, supports review and endorsements, and supports version control; include a draft date and information about the paper’s status on the cover page; license preprints with CC BY licenses that permit public use with attribution; and keep preprints up to date after major revisions. Although our focus is on preprints (unpublished versions of a work), we also offer information relevant to postprints (author-formatted, post-peer-review versions of a work) and work that will not otherwise be published (e.g., theses and dissertations)

Pathways to Ethnic-Racial Identity Development and Psychological Adjustment: The Differential Associations of Cultural Socialization by Parents and Peers

Ethnic-racial identity (ERI) development is a central developmental process for youth of color. Although a great deal of research establishes the importance of cultural socialization by parents to the development of ERI, limited empirical work has examined peers’ role in these processes. This study uses four cross-sectional data sets (N = 127, 312, 257, and 238, mean age = 17.96 -18.24) followed by a meta-analytic summary to test a path model of ERI development and parent and peer cultural socialization and their associations with psychological adjustment in a diverse sample of emerging adults. The final sample size adjusted meta-analytic model indicated that parent ethnic socialization predicted both ERI exploration and commitment while only peer preparation for bias predicted ERI commitment. In turn, ERI commitment and exploration predicted more positive mental health. The findings of this study highlight the importance of both parents and peers to cultural socialization processes during emerging adulthood. In particular, this study suggests that the messages peers impart about prejudice play a unique role in the development of ERI. The findings have important implications about the unique role peers play in communicating messages about prejudice as well as for ERI and the psychological adjustment of youth of color at this developmental stage. Additionally, these cross-sectional findings provide a preliminary but robust model from which researchers can frame future longitudinal work in this area

Microbial transformations of artemisinin – anti-malaria drug

In recent years, artemisinin (1) has remained an effective drug to treat malaria. Numerous approaches have been adapted to increase the efficacy of (1) against antibiotic resistant malarial parasite. Microbial biotransformation of (1) has been used recently to produce promising derivatives of (1) on a large scale with low costs. During the last decade several biotransformation studies on (1), by using microorganisms, have been reported. This literature review focuses on the most recent microbial transformation studies on artemisinin and its derivatives

Biotechnological transformation of artemisinin: toward an effective antim-malaria drug

In recent years, artemisinin (1) has remained an effective drug to treat malaria. Numerous approaches have been adapted to increase the efficacy of (1) against antibiotic resistant malarial parasite. Microbial biotransformation of (1) has been used recently to produce promising derivatives of (1) on a large scale with low costs. During the last decade several biotransformation studies on (1), by using microorganisms, have been reported. This literature review focuses on the most recent microbial transformation studies on artemisinin and its derivatives

An Update on Emergent Nano-Therapeutic Strategies against Pediatric Brain Tumors

Pediatric brain tumors are the major cause of pediatric cancer mortality. They comprise a diverse group of tumors with different developmental origins, genetic profiles, therapeutic options, and outcomes. Despite many technological advancements, the treatment of pediatric brain cancers has remained a challenge. Treatment options for pediatric brain cancers have been ineffective due to non-specificity, inability to cross the blood–brain barrier, and causing off-target side effects. In recent years, nanotechnological advancements in the medical field have proven to be effective in curing challenging cancers like brain tumors. Moreover, nanoparticles have emerged successfully, particularly in carrying larger payloads, as well as their stability, safety, and efficacy monitoring. In the present review, we will emphasize pediatric brain cancers, barriers to treating these cancers, and novel treatment options