Politicians polarize and experts depolarize public support for COVID-19 management policies across countries

Significance Political polarization impeded public support for policies to address the spread of COVID-19, much as polarization hinders responses to other societal challenges. The present cross-country study demonstrates how the cues from political elites and affective polarization are analogous across countries addressing COVID-19. Far from being an outlier, the United States faces polarization challenges similar to those of other countries. Importantly, the results demonstrate that policies to combat public health crises are more supported when proposed by nonpartisan experts and bipartisan coalitions of political leaders. These results provide clear guidance on depolarizing communication strategies to improve global responses to health crises

In silico assessment of potential druggable pockets on the surface of α1-Antitrypsin conformers

The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α1-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a Kd in the µM–nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

Coextensive space: virtual reality and the developing relationship between the body, the digital and physical space

Virtual Reality (VR) has traditionally required external sensors placed around a designated play space. In contrast, more recent wired and wireless systems, such as the Oculus Rift S (released in March 2019) and the Oculus Quest (released in May 2019) use cameras located on the outside of these devices to monitor their physical position. Users can now mark out a physical space that is then digitally tracked within their display. Once a play space has been established, users are alerted if they come close to breaching this boundary by the visual inclusion of a grid. Should this threshold be breached, the headset display shifts to an image of the surrounding concrete environment. We contend that physical space is increasingly being incorporated into the digital space of VR in a manner that meaningfully differs from older systems. We build our argument in the following way. First, the article explores how theories surrounding VR have implicated only a limited relationship with physical space. Second, the article introduces the concept of coextensive space as a way of understanding the developing relationship between the physical, digital and concrete reality enacted by current VR systems

The influence of a pre-exercise sports drink (PRX) on factors related to maximal aerobic performance

<p>Abstract</p> <p>Background</p> <p>Pre-exercise sports drinks (PRX) are commonly used as ergogenic aids in athletic competitions requiring aerobic power. However, in most cases, claims regarding their effectiveness have not been substantiated. In addition, the ingredients in PRX products must be deemed acceptable by the athletic governing bodies that regulate their use in training and competition. The purpose of this study was to examine the effects of a modified PRX formulation (known as EM·PACT™) from earlier investigations on factors related to maximal aerobic performance during a graded exercise test. The modification consisted of removing creatine to meet the compliance standards set forth by various athletic organizations that regulate the use of nutritional supplements.</p> <p>Methods</p> <p>Twenty-nine male and female college students varying in levels of aerobic fitness participated in a randomized crossover administration of PRX (containing 14 g/serving of fructose, medium-chain triglycerides, and amino acids mixed with 8 oz. of water) and placebo (PL) 30 minutes prior to performing a treadmill test with approximately one week separation between the trials. VO₂max, maximal heart rate (HR), time to exhaustion (Time), and percentage estimated non-protein fat substrate utilization (FA) during two <it>a priori </it>submaximal stages of a graded exercise testing were evaluated.</p> <p>Results</p> <p>The VO₂max mean value of the PRX trial was significantly greater than the PL trial (P < 0.01). The mean value for Time was also observed to be greater for the PRX trial compared to PL (P < 0.05). Additionally, percentage of FA during submaximal stages of the exercise test was greater for PRX trial in comparison to PL (P < 0.01).</p> <p>Conclusions</p> <p>The modified PRX formulation utilized in this investigation supports the findings of the previous investigation and its efficacy for enhancing indices of aerobic performance (specifically VO₂max, Time, & FA) during graded exercise testing.</p

Localization of telomeres and telomere-associated proteins in telomerase-negative Saccharomyces cerevisiae

Cells lacking telomerase cannot maintain their telomeres and undergo a telomere erosion phase leading to senescence and crisis in which most cells become nonviable. On rare occasions survivors emerge from these cultures that maintain their telomeres in alternative ways. The movement of five marked telomeres in Saccharomyces cerevisiae was followed in wild-type cells and through erosion, senescence/crisis and eventual survival in telomerase-negative (est2::HYG) yeast cells. It was found that during erosion, movements of telomeres in est2::HYG cells were indistinguishable from wild-type telomere movements. At senescence/crisis, however, most cells were in G2 arrest and the nucleus and telomeres traversed back and forth across the bud neck, presumably until cell death. Type I survivors, using subtelomeric Y′ amplification for telomere maintenance, continued to show this aberrant telomere movement. However, Type II survivors, maintaining telomeres by a sudden elongation of the telomere repeats, became indistinguishable from wild-type cells, consistent with growth properties of the two types of survivors. When telomere-associated proteins Sir2p, Sir3p and Rap1p were tagged, the same general trend was seen—Type I survivors retained the senescence/crisis state of protein localization, while Type II survivors were restored to wild type

Identifying Critical Non-Catalytic Residues that Modulate Protein Kinase A Activity

Distal interactions between discrete elements of an enzyme are critical for communication and ultimately for regulation. However, identifying the components of such interactions has remained elusive due to the delicate nature of these contacts. Protein kinases are a prime example of an enzyme with multiple regulatory sites that are spatially separate, yet communicate extensively for tight regulation of activity. Kinase misregulation has been directly linked to a variety of cancers, underscoring the necessity for understanding intramolecular kinase regulation.A genetic screen was developed to identify suppressor mutations that restored catalytic activity in vivo from two kinase-dead Protein Kinase A mutants in S. cerevisiae. The residues defined by the suppressors provide new insights into kinase regulation. Many of the acquired mutations were distal to the nucleotide binding pocket, highlighting the relationship of spatially dispersed residues in regulation.The suppressor residues provide new insights into kinase regulation, including allosteric effects on catalytic elements and altered protein-protein interactions. The suppressor mutations identified in this study also share overlap with mutations identified from an identical screen in the yeast PKA homolog Tpk2, demonstrating functional conservation for some residues. Some mutations were independently isolated several times at the same sites. These sites are in agreement with sites previously identified from multiple cancer data sets as areas where acquired somatic mutations led to cancer progression and drug resistance. This method provides a valuable tool for identifying residues involved in kinase activity and for studying kinase misregulation in disease states

Genomic Structure of and Genome-Wide Recombination in the Saccharomyces cerevisiae S288C Progenitor Isolate EM93

The diploid isolate EM93 is the main ancestor to the widely used Saccharomyces cerevisiae haploid laboratory strain, S288C. In this study, we generate a high-resolution overview of the genetic differences between EM93 and S288C. We show that EM93 is heterozygous for >45,000 polymorphisms, including large sequence polymorphisms, such as deletions and a Saccharomyces paradoxus introgression. We also find that many large sequence polymorphisms (LSPs) are associated with Ty-elements and sub-telomeric regions. We identified 2,965 genetic markers, which we then used to genotype 120 EM93 tetrads. In addition to deducing the structures of all EM93 chromosomes, we estimate that the average EM93 meiosis produces 144 detectable recombination events, consisting of 87 crossover and 31 non-crossover gene conversion events. Of the 50 polymorphisms showing the highest levels of non-crossover gene conversions, only three deviated from parity, all of which were near heterozygous LSPs. We find that non-telomeric heterozygous LSPs significantly reduce meiotic recombination in adjacent intervals, while sub-telomeric LSPs have no discernable effect on recombination. We identified 203 recombination hotspots, relatively few of which are hot for both non-crossover gene conversions and crossovers. Strikingly, we find that recombination hotspots show limited conservation. Some novel hotspots are found adjacent to heterozygous LSPs that eliminate other hotspots, suggesting that hotspots may appear and disappear relatively rapidly

Choice of psychological coping in laryngectomized, head and neck squamous cell carcinoma patients versus multiple sclerosis patients

To be treated for cancer must be a frightening experience. Yet quality of life (QoL) of successfully treated cancer patients seems to be relatively similar in comparison with QoL of a general population, with psychological coping partly responsible for this finding. When measuring choice of coping, the nature of coping score levels constituting appropriate scores, and whether score levels rely on the context of the disease has not been settled. We have studied the COPE coping responses as related to disease in successfully treated head and neck squamous cell carcinoma (HNSCC) patient groups (general and laryngectomized), as well as compared to multiple sclerosis (MS) patients. The COPE response patterns have also been compared to the Beck depression inventory (BDI) scores. Age and gender of patients were not directly associated with choice of coping. Within the problem-focused coping indexes, the coping index “active coping” was reported to be most utilized among HNSCC patients, whereas “coping by suppression” and “coping by social support” were most utilized among MS patients. Emotional-focused coping was most prevalent among HNSCC patients and lowest among the MS patients. Level of avoidance coping was similar between the groups. The coping of the general HNSCC patients differed most from the MS patients. An association was shown between increased coping efforts and lowered mood. In particular, avoidance coping was associated with lowered mood. These associations were stronger among the MS patients than HNSCC patients. Drinking to cope was most prevalent among the laryngectomized group, and was correlated with BDI scores in all groups. Furthermore, adequate coping seems to be to limit avoidance coping and promote coping by acceptance. The response pattern of the COPE inventory seems to be valid among HNSCC and MS patients