In CASP, blind testing of model accuracy estimation methods has been conducted on models submitted by tertiary structure prediction servers. In CASP14, model accuracy estimation results were ...evaluated in terms of both global and local structure accuracy, as in the previous CASPs. Unlike the previous CASPs that did not show pronounced improvements in performance, the best single‐model method (from the Baker group) showed an improved performance in CASP14, particularly in evaluating global structure accuracy when compared to both the best single‐model methods in previous CASPs and the best multi‐model methods in the current CASP. Although the CASP14 experiment on model accuracy estimation did not deal with the structures generated by AlphaFold2, new challenges that have arisen due to the success of AlphaFold2 are discussed.
Worldwide, racial and ethnic minorities have been disproportionately impacted by COVID-19 with increased risk of infection, its related complications, and death. In the initial phase of ...population-based vaccination in the United States (U.S.) and United Kingdom (U.K.), vaccine hesitancy may result in differences in uptake. We performed a cohort study among U.S. and U.K. participants who volunteered to take part in the smartphone-based COVID Symptom Study (March 2020-February 2021) and used logistic regression to estimate odds ratios of vaccine hesitancy and uptake. In the U.S. (n = 87,388), compared to white participants, vaccine hesitancy was greater for Black and Hispanic participants and those reporting more than one or other race. In the U.K. (n = 1,254,294), racial and ethnic minority participants showed similar levels of vaccine hesitancy to the U.S. However, associations between participant race and ethnicity and levels of vaccine uptake were observed to be different in the U.S. and the U.K. studies. Among U.S. participants, vaccine uptake was significantly lower among Black participants, which persisted among participants that self-reported being vaccine-willing. In contrast, statistically significant racial and ethnic disparities in vaccine uptake were not observed in the U.K sample. In this study of self-reported vaccine hesitancy and uptake, lower levels of vaccine uptake in Black participants in the U.S. during the initial vaccine rollout may be attributable to both hesitancy and disparities in access.
Given the continued burden of COVID-19 worldwide, there is a high unmet need for data on the effect of social distancing and face mask use to mitigate the risk of COVID-19. We examined the ...association of community-level social distancing measures and individual face mask use with risk of predicted COVID-19 in a large prospective U.S. cohort study of 198,077 participants. Individuals living in communities with the greatest social distancing had a 31% lower risk of predicted COVID-19 compared with those living in communities with poor social distancing. Self-reported 'always' use of face mask was associated with a 62% reduced risk of predicted COVID-19 even among individuals living in a community with poor social distancing. These findings provide support for the efficacy of mask-wearing even in settings of poor social distancing in reducing COVID-19 transmission. Despite mass vaccination campaigns in many parts of the world, continued efforts at social distancing and face mask use remain critically important in reducing the spread of COVID-19.
An essential part of the cellular response to environmental stress is a reversible translational suppression, taking place in dynamic cytoplasmic structures called stress granules (SGs). We ...discovered that HDAC6, a cytoplasmic deacetylase that acts on tubulin and HSP90 and also binds ubiquitinated proteins with high affinity, is a novel critical SG component. We found that HDAC6 interacts with another SG protein, G3BP (Ras-GTPase-activating protein SH3 domain-binding protein 1), and localizes to SGs under all stress conditions tested. We show that pharmacological inhibition or genetic ablation of HDAC6 abolishes SG formation. Intriguingly, we found that the ubiquitin-binding domain of HDAC6 is essential and that SGs are strongly positive for ubiquitin. Moreover, disruption of microtubule arrays or impairment of motor proteins also prevents formation of SGs. These findings identify HDAC6 as a central component of the stress response, and suggest that it coordinates the formation of SGs by mediating the motor-protein-driven movement of individual SG components along microtubules.
Genome editing is crucial for genetic engineering of organisms for improved traits, particularly in microalgae due to the urgent necessity for the next generation biofuel production. The most ...advanced CRISPR/Cas9 system is simple, efficient and accurate in some organisms; however, it has proven extremely difficult in microalgae including the model alga Chlamydomonas. We solved this problem by delivering Cas9 ribonucleoproteins (RNPs) comprising the Cas9 protein and sgRNAs to avoid cytotoxicity and off-targeting associated with vector-driven expression of Cas9. We obtained CRISPR/Cas9-induced mutations at three loci including MAA7, CpSRP43 and ChlM, and targeted mutagenic efficiency was improved up to 100 fold compared to the first report of transgenic Cas9-induced mutagenesis. Interestingly, we found that unrelated vectors used for the selection purpose were predominantly integrated at the Cas9 cut site, indicative of NHEJ-mediated knock-in events. As expected with Cas9 RNPs, no off-targeting was found in one of the mutagenic screens. In conclusion, we improved the knockout efficiency by using Cas9 RNPs, which opens great opportunities not only for biological research but also industrial applications in Chlamydomonas and other microalgae. Findings of the NHEJ-mediated knock-in events will allow applications of the CRISPR/Cas9 system in microalgae, including "safe harboring" techniques shown in other organisms.
Structure prediction of protein-ligand complexes, called protein-ligand docking, is a critical computational technique that can be used to understand the underlying principle behind the protein ...functions at the atomic level and to design new molecules regulating the functions. Protein-ligand docking methods have been employed in structure-based drug discovery for hit discovery and lead optimization. One of the important technical challenges in protein-ligand docking is to account for protein conformational changes induced by ligand binding. A small change such as a single side-chain rotation upon ligand binding can hinder accurate docking. Here we report an increase in docking performance achieved by structure alignment to known complex structures. First, a fully flexible compound-to-compound alignment method CSAlign is developed by global optimization of a shape score. Next, the alignment method is combined with a docking algorithm to dock a new ligand to a target protein when a reference protein-ligand complex structure is available. This alignment-based docking method, called CSAlign-Dock, showed superior performance to
docking methods in cross-docking benchmark tests. Both CSAlign and CSAlign-Dock are freely available as a web server at https://galaxy.seoklab.org/csalign.
Proteins perform their functions by interacting with other biomolecules. For these interactions, proteins often form homo‐ or hetero‐oligomers as well. Thus, oligomer protein structures provide ...important clues regarding the biological roles of proteins. To this end, computational prediction of oligomer structures may be a useful tool in the absence of experimentally resolved structures. Here, we describe our server and human‐expert methods used to predict oligomer structures in the CASP14 experiment. Examples are provided for cases in which manual domain‐splitting led to improved oligomeric domain structures by ab initio docking, automated oligomer structure refinement led to improved subunit orientation and terminal structure, and manual oligomer modeling utilizing literature information generated a reasonable oligomer model. We also discussed the results of post‐prediction docking calculations with AlphaFold2 monomers as input in comparison to our blind prediction results. Overall, ab initio docking of AlphaFold2 models did not lead to better oligomer structure prediction, which may be attributed to the interfacial structural difference between the AlphaFold2 monomer structures and the crystal oligomer structures. This result poses a next‐stage challenge in oligomer structure prediction after the success of AlphaFold2. For successful protein assembly structure prediction, a different approach that exploits further evolutionary information on the interface and/or flexible docking taking the interfacial conformational flexibilities of subunit structures into account is needed.
Young women who have had contact with the criminal justice system (justice-involved young women) have an increased risk of being a victim of violence. However, no reviews have synthesized the ...evidence on interventions to prevent or respond to violence against justice-involved young women. We conducted a scoping review to identify interventions designed to prevent or respond to violence against justice-involved young women. We searched Medline, Criminal Justice Abstracts, Web of Science, and Google Scholar for peer-reviewed and gray literature published in English from January 1, 2000 until March 23, 2021. Consistent with the public health approach to violence, we included primary, secondary, and tertiary interventions. Excluding duplicates, our search returned 5,603 records, 14 of which met our inclusion criteria. We narratively synthesized the included studies, all of which were conducted in the United States. Most included studies examined a tertiary intervention (n = 10), and few examined a primary (n = 2) or secondary (n = 2) intervention. Across the Joanna Briggs Institute Critical Appraisal Tools, the percentage of items met ranged from 0% to 78%. There was some limited evidence that tertiary interventions that included cognitive behavioral therapy reduced the mental health impacts of violence victimization among justice-involved young women. There was little evidence on primary and secondary interventions. Effective and evidence-based interventions to prevent violence victimization and revictimization against justice-involved young women remains a critical gap in knowledge.
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