bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlations Between Community-Level HIV Preexposure Prophylaxis Coverage and Individual-Level Sexual Behaviors among US Men Who Have Sex with Men
Authors: Mann Laura M. , Guillou Adrien Le , Goodreau Steven M. , Marcus Julia L. , Sanchez Travis , Weiss Kevin M. , Jenness Samuel M. 
Published: July 2021

ABSTRACTBackgroundHIV preexposure prophylaxis (PrEP) has been associated with changes in sexual behavior after PrEP initiation. However, behavioral differences may also emerge among PrEP non-users in communities with high PrEP coverage.MethodsWe used demographic, behavioral, and sexual network data from ARTnet, a cross-sectional study of US men who have sex with men conducted during 2017–2019. Multivariable regression models with a Bayesian modeling framework in which individuals were nested within their residential geographic areas were used to estimate associations between area-level PrEP coverage and five sexual behavior outcomes (number of total, main, and casual male partners [network degree]; count of one-time partnerships; and consistent condom use in one-time partnerships), controlling for individual PrEP use.ResultsPrEP coverage ranged from 10.3% (Philadelphia) to 38.9% (San Francisco). Total degree was highest in Miami (1.35) and lowest in Denver (0.78), while the count of one-time partners was highest in San Francisco (11.7/year) and lowest in Detroit (1.5/year). Adjusting for individual PrEP use and demographics, community PrEP coverage was associated with higher total degree (adjusted incidence rate ratio [aIRR]=1.73; 95% CrI, 0.92–3.44), casual degree (aIRR=2.05; 95% CrI, 0.90–5.07), and count of one-time partnerships (aIRR=1.90; 95% CrI, 0.46–8.54). Without adjustment for individual PrEP use, these associations were amplified. There were weaker associations with main degree (aIRR=1.21; 95% CrI, 0.48–3.20) and consistent condom use in one-time partnerships (aIRR=1.68; 95% CrI, 0.86–3.35).ConclusionsMost of the associations between community PrEP coverage and sexual behavior were explained by individual PrEP use. However, there were residual associations after controlling for individual PrEP use, suggesting that PrEP coverage may partially drive community-level changes in sexual behavior.
Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma
Authors: Lu Xiuxiu , Sabbasani Venkata R. , Osei-Amponsa Vasty , Evans Christine N. , King Julianna C. , Tarasov Sergey G. , Dyba Marzena , Chan King C. , Schwieters Charles D. , Choudhari Sulbha , Fromont Caroline , Zhao Yongmei , Tran Bao , Chen Xiang , Matsuo Hiroshi , Andresson Thorkell , Chari Raj , Swenson Rolf E. , Tarasova Nadya I. , Walters Kylie J. 
Published: July 2021

AbstractProteasome substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru β-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13Pru) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13Pru, causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis and increased p62 levels. These data establish hRpn13 as an anti-cancer target for multiple myeloma and introduce an hRpn13-targeting scaffold that can be optimized for preclinical trials against hRpn13Pru-producing cancer types.
Novel Hendra virus variant detected by sentinel surveillance of Australian horses
Authors: Annand Edward J. , Horsburgh Bethany A. , Xu Kai , Reid Peter A. , Poole Ben , de Kantzow Maximillian C. , Brown Nicole , Tweedie Alison , Michie Michelle , Grewar John D. , Jackson Anne E. , Singanallur Nagendrakumar B. , Plain Karren M. , Kim Karan , Tachedjian Mary , van der Heide Brenda , Crameri Sandra , Williams David T. , Secombe Cristy , Laing Eric D. , Sterling Spencer , Yan Lianying , Jackson Louise , Jones Cheryl , Plowright Raina K. , Peel Alison J. , Breed Andrew C. , Diallo Ibrahim , Dhand Navneet K. , Britton Philip N. , Broder Christopher C. , Smith Ina , Eden John-Sebastian 
Published: July 2021

AbstractA novel Hendra virus (HeV) variant, not detected by routine testing, was identified and isolated from a Queensland horse that suffered acute, fatal disease consistent with HeV infection. Whole genome sequencing and phylogenetic analysis demonstrated the variant to have ~83% nucleotide identity to the prototype HeV strain. An updated RT-qPCR assay was designed for routine HeV surveillance. In silico and in vitro comparison of the receptor-binding protein with prototypic HeV showed that the human monoclonal antibody m102.4 used for post-exposure prophylaxis, as well as the current equine vaccine, should be effective against this variant. Genetic similarity of this virus to sequences detected from grey-headed flying-foxes suggests the variant circulates at-least in this species. Studies determining infection kinetics, pathogenicity, reservoir-species associations, viral–host co-evolution and spillover dynamics for this virus are urgently needed. Surveillance and biosecurity practices should be updated to appreciate HeV spillover risk across all regions frequented by flying foxes.
Interpreting Polygenic Score Effects in Sibling Analysis
Authors: Fletcher Jason , Wu Yuchang , Li Tianchang , Lu Qiongshi 
Published: July 2021

AbstractResearchers often claim that sibling analysis can be used to separate causal genetic effects from the assortment of biases that contaminate most downstream genetic studies. Indeed, typical results from sibling models show large (>50%) attenuations in the associations between polygenic scores and phenotypes compared to non-sibling models, consistent with researchers’ expectations about bias reduction. This paper explores these expectations by using family (quad) data and simulations that include indirect genetic effect processes and evaluates the ability of sibling models to uncover direct genetic effects. We find that sibling models, in general, fail to uncover direct genetic effects; indeed, these models have both upward and downward biases that are difficult to sign in typical data. When genetic nurture effects exist, sibling models create “measurement error” that attenuate associations between polygenic scores and phenotypes. As the correlation between direct and indirect effect changes, this bias can increase or decrease. Our findings suggest that interpreting results from sibling analysis aimed at uncovering direct genetic effects should be treated with caution.
A quantitative approach to easily characterize and predict cell death and escape to β-lactam treatments
Authors: Andreani Virgile , Gross Viktoriia , You Lingchong , Glaser Philippe , El Meouche Imane , Batt Gregory 
Published: July 2021

AbstractCommensal and pathogenicE. colistrains are increasingly found to be resistant to β-lactams, one of the most widely prescribed classes of antibiotics. Understanding escape to such treatments is complex since β-lactams have several cellular targets and since several mechanisms might be involved in treatment escape in a combined manner. Surprisingly, the accumulated knowledge has not yet proven effective enough to predict the bacterial response to antibiotic treatments at both cellular and population levels with quantitative accuracy for -producing bacteria. Here, we propose a mathematical model that captures in a comprehensive way key phenomena happening at the molecular, cellular, and population levels, as well as their interactions. Our growth-fragmentation model gives a central role to cellular heterogeneity and filamentation as a way for cells to gain time until the degradation of the antibiotic by the β-lactamases released by the dead cell population. Importantly, the model can account for the observed temporal evolution of the total (live and dead) biomass and of the live cell numbers for various antibiotic concentrations. To our knowledge, this is the first model able to quantitatively reconciliate these two classical views on cell death (OD and CFUs) for clinical isolates expressing extended-spectrum beta-lactamases (ESBL). Moreover, our model has a strong predictive power. When calibrated using a slight extension of OD-based data that we propose here, it can predict the CFU profiles in initial and delayed treatments despite inoculum effects, and suggest non-trivial optimal treatments. Generating quality data in quantity has been essential for model development and validation on non-model E. coli strains. We developed protocols to increase the reproducibility of growth kinetics assays and to increase the throughput of CFU assays.
Pathogenic potential in catheter-associated Escherichia coli is associated with separable biofilm and virulence gene determinants
Authors: Zou Zongsen , Potter Robert F. , McCoy William H. , Katumba George L. , Mucha Peter J. , Dantas Gautam , Henderson Jeffrey P. 
Published: July 2021

AbstractUrinary catheterization facilitates Escherichia coli colonization of the urinary tract and increases infection risk. While specific pathotypes are well-recognized for some E. coli infections, it is unclear whether strain-specific characteristics among E. coli are associated with infection risk in catheterized patients. Here we used comparative genomics and a simulated catheter biofilm model to compare strains associated with catheter-associated urinary tract infection (CAUTI) and catheter-associated asymptomatic bacteriuria (CAASB). CAUTI was associated with a phylotype B2 sub-clade dominated by the multidrug resistant ST131 lineage, while CAASB isolates were genetically more diverse. Catheter-associated biofilm formation was widespread but quantitatively variable among isolates. Network community analysis resolved distinct groups of genes associated with infection or biofilm formation, with iron acquisition-associated genes prominent throughout. Using a reporter construct and targeted mutagenesis, we detected a biofilm phenotype for the ferric citrate transport (Fec) system, the most prominent correlate of high catheter biofilm formation in these patients. In mixed cultures, catheter biofilms formed by some CAASB strains suppressed catheter colonization by ST131 CAUTI isolates. These results are consistent with a paradigm in which catheter biofilm-associated genes increase infection risk in strains with a high pathogenic potential and decrease infection risk through niche exclusion in strains with low pathogenic potential.
The M2 Gene Is a Determinant of Reovirus-Induced Myocarditis
Authors: Zita Marcelle Dina , Phillips Matthew B. , Stuart Johnasha D. , Kumarapeli Asangi R. , Snyder Anthony J. , Paredes Amairani , Sridharan Vijayalakshmi , Boerma Marjan , Danthi Pranav , Boehme Karl W. 
Published: July 2021

ABSTRACTAlthough a broad range of viruses cause myocarditis, the mechanisms that underlie viral myocarditis are poorly understood. Here, we report that the M2 gene is a determinant of reovirus myocarditis. The M2 gene encodes outer capsid protein μ1, which mediates host membrane penetration during reovirus entry. We infected newborn C57BL/6 mice with reovirus strain type 1 Lang (T1L) or a reassortant reovirus in which the M2 gene from strain type 3 Dearing (T3D) was substituted into the T1L genetic background (T1L/T3DM2). T1L was non-lethal in wild-type mice, whereas greater than 90% of mice succumbed to T1L/T3DM2 infection. T1L/T3DM2 produced higher viral loads than T1L at the site of inoculation. In secondary organs, T1L/T3DM2 was detected with more rapid kinetics and reached higher peak titers than T1L. We found that hearts from T1L/T3DM2-infected mice were grossly abnormal, with large lesions indicative of substantial inflammatory infiltrate. Lesions in T1L/T3DM2-infected mice contained necrotic cardiomyocytes with pyknotic debris, and extensive lymphocyte and histiocyte infiltration. In contrast, T1L induced the formation of small purulent lesions in a small subset of animals, consistent with T1L being mildly myocarditic. Finally, more activated caspase-3-positive cells were observed in hearts from animals infected with T1L/T3DM2 compared to T1L. Together, our findings indicate that substitution of the T3D M2 allele into an otherwise T1L genetic background is sufficient to change a non-lethal infection into a lethal infection. Our results further indicate that T3D M2 enhances T1L replication and dissemination in vivo, which potentiates the capacity of reovirus to cause myocarditis.IMPORTANCEReovirus is a non-enveloped virus with a segmented double-stranded RNA genome that serves as a model for studying viral myocarditis. The mechanisms by which reovirus drives myocarditis development are not fully elucidated. We found that substituting the M2 gene from strain type 3 Dearing (T3D) into an otherwise type 1 Lang (T1L) genetic background (T1L/T3DM2) was sufficient to convert the non-lethal T1L strain into a lethal infection in neonatal C57BL/6 mice. T1L/T3DM2 disseminated more efficiently and reached higher maximum titers than T1L in all organs tested, including the heart. T1L is mildly myocarditic and induced small areas of cardiac inflammation in a subset of mice. In contrast, hearts from mice infected with T1L/T3DM2 contained extensive cardiac inflammatory infiltration and more activated caspase-3-positive cells, which is indicative of apoptosis. Together, our findings identify the reovirus M2 gene as a new determinant of reovirus-induced myocarditis.
Increased microbial diversity and decreased prevalence of common pathogens in the gut microbiomes of wild turkeys compared to domestic turkeys
Authors: Craft Julia , Edington Hyrum , Christman Nicholas D. , Chaston John , Erickson David , Wilson Eric 
Published: July 2021

AbstractTurkeys (Meleagris gallopavo) provide a globally important source of protein and constitute the second most important source of poultry meat in the world. Bacterial diseases are common in commercial poultry production causing significant production losses for farmers. Due to the increasingly recognized problems associated with large-scale/indiscriminant antibiotic use in agricultural settings, poultry producers need alternative methods to control common bacterial pathogens. In this study we compared the cecal microbiota of wild and domestic turkeys, hypothesizing that environmental pressures faced by wild birds may select for a disease-resistant microbial community. Sequence analysis of 16S rRNA genes amplified from cecal samples indicate that free-roaming wild turkeys carry a rich and variable microbiota compared to domestic turkeys raised on large-scale poultry farms. Wild turkeys also had very low levels of Staphylococcus, Salmonella and E. coli when compared to domestic turkeys. E. coli strains isolated from wild or domestic turkey cecal samples also belong to distinct phylogenetic backgrounds and differ in their propensity to carry virulence genes. E. coli strains isolated from factory-raised turkeys were far more likely to carry genes for capsule (kpsII, kpsIII) or siderophore (iroN, fyuA) synthesis than those isolated from wild turkeys. These results suggest that the microbiota of wild turkeys may provide colonization resistance against common poultry pathogens.ImportanceDue to the increasingly recognized problems associated with antibiotic use in agricultural settings, poultry producers need alternative methods to control common bacterial pathogens. In this study we compare the microbiota of wild and domestic turkeys. Results suggest that free ranging wild turkeys carry a distinct microbiome when compared to farm raised turkeys. The microbiome of wild birds contains very low levels of poultry pathogens compared to farm raised birds. The microbiomes of wild turkeys may be used to guide development of new ways to control disease in large scale poultry production.
A vast evolutionarily transient translatome contributes to phenotype and fitness
Authors: Wacholder Aaron , Parikh Saurin Bipin , Coelho Nelson Castilho , Acar Omer , Houghton Carly , Chou Lin , Carvunis Anne-Ruxandra 
Published: July 2021

SummaryTranslation is the process by which ribosomes synthesize proteins. Ribosome profiling recently revealed that many short sequences previously thought to be noncoding are pervasively translated. To identify protein-coding genes in this noncanonical translatome, we combine an integrative framework for extremely sensitive ribosome profiling analysis, iRibo, with high-powered selection inferences tailored for short sequences. We construct a reference translatome forSaccharomyces cerevisiaecomprising 5,400 canonical and almost 19,000 noncanonical translated elements. Only 14 noncanonical elements were evolving under detectable purifying selection. Surprisingly, a representative subset of translated elements lacking signatures of selection demonstrated involvement in processes including DNA repair, stress response and post-transcriptional regulation. Our results suggest that most translated elements are not conserved protein-coding genes and contribute to genotype-phenotype relationships through fast-evolving molecular mechanisms.
DNA sliding and loop formation by E. coli SMC complex: MukBEF
Authors: Zhou Man 
Published: July 2021

AbstractSMC (structural maintenance of chromosomes) complexes share conserved architectures and function in chromosome maintenance via an unknown mechanism. Here we have used single-molecule techniques to study MukBEF, the SMC complex in Escherichia coli. Real-time movies show MukB alone can compact DNA and ATP inhibits DNA compaction by MukB. We observed that DNA unidirectionally slides through MukB, potentially by a ratchet mechanism, and the sliding speed depends on the elastic energy stored in the DNA. MukE, MukF and ATP binding stabilize MukB and DNA interaction, and ATP hydrolysis regulates the loading/unloading of MukBEF from DNA. Our data suggests a new model for how MukBEF organizes the bacterial chromosome in vivo; and this model will be relevant for other SMC proteins.
Understanding transfer of learning from an online self-directed learning and clinical decision support resource (BMJ Best Practice) for health professions education: a capability approach perspective
Authors: Zhang Da , Xiao Li , Duan Jingqi , Chang Xinxin , Walsh Kieran , Sandars John , Brown Jeremy , Dang Xiaorong , Shen Wei , Du Junjie , Cao Yanjie 
Published: July 2021

ABSTRACTObjectiveTo understand transfer of learning of an online self-directed learning and clinical decision support resource for health professionals (BMJ Best Practice) informed by Sen’s capability approach.DesignA semi-structured questionnaire was used to identify the extent to which BMJ Best Practice enabled participants to achieve their valued outcomes and the factors that enabled and constrained their achievement.SettingThis study was carried out in a single centre, which is a tertiary care medical institution containing around 1500 inpatient beds.Participants200 physicians at Air Force Medical Center were invited to take part in this study. 184 physicians completed the online questionnaire.Results78 percent of physicians felt that BMJ Best Practice enabled them to achieve their valued outcomes and to apply their new knowledge to inform their practice. The main factors that constrained their achievement were technological.ConclusionSen’s capability approach offers an innovative and useful model to further understand health professions education since it highlights the importance of the learner perspective of valued outcomes, including the difficulties associated with the effective transfer of learning in CPD.Strengths and limitations of this studyThis is a real-life study based on the experiences of physicians who are directly providing care to patients.The study has strong theoretical foundations – being based as it is on Sen’s capability approach.The study covers the vital subject of the application of medical knowledge in actual practice.The research design is a cross-sectional survey; the study did not investigate whether physicians’ reflections on their valued outcomes and achievements might have changed over time.This study was carried out in a single centre.
Defining the Sensitivity Landscape of 74,389 EGFR Variants to Tyrosine Kinase Inhibitors
Authors: An Lei , Chen Shuqing , Wu Guangyao , Liu Chang , Wang Zhenxing , Wang Chunli , Shi Zeyuan , Niu Chenguang , Li Xiaodong , Tang Wenxue , Xu Hongen , Wang Yueqiang 
Published: July 2021

AbstractBackgroundTyrosine kinase inhibitors (TKIs) therapy is a standard treatment for patients with advanced non-small-cell lung carcinoma (NSCLC) when activating epidermal growth factor receptor (EGFR) mutations are detected. However, except for the well-studiedEGFRmutations, mostEGFRmutations lack treatment regimens.MethodsWe constructed twoEGFRvariant libraries containing substitutions, deletions, or insertions using the saturation mutagenesis method. All the variants were located in theEGFRmutation hotspot (exons 18–21). The sensitivity of these variants to afatinib, erlotinib, gefitinib, icotinib, and osimertinib was systematically studied by determining their enrichment in massively parallel cytotoxicity assays using an endogenous EGFR-depleted cell line, PC9.ResultsA total of 3,914 and 70,475 variants were detected in the constructedEGFRSubstitution-Deletion (Sub-Del) and exon 20 Insertion (Ins) libraries, accounting for 99.3% and 55.8% of the designed variants, respectively. Of the 3,914 Sub-Del variants, 813 were highly enriched in the reversible TKI (erlotinib, gefitinib, icotinib) cytotoxicity assays and 51 were enriched in the irreversible TKI (afatinib, osimertinib) cytotoxicity assays. For the 70,475 Ins variants, insertions at amino acid positions 770–774 were highly enriched in all the five TKI cytotoxicity assays. Moreover, the top 5% of the enriched insertion variants included a glycine or serine insertion at high frequency.ConclusionsWe present a comprehensive reference for the sensitivity ofEGFRvariants to five commonly used TKIs. The approach used here should be applicable to other genes and targeted drugs.
From the Modern Synthesis to the Molecular Synthesis: updating how we teach and assess evolution by natural selection
Authors: Sievers Matt , Reemts Connor , Dickinson Katherine J. , Mukerji Joya , Beltran Ismael Barreras , Theobald Elli J. , Velasco Vicente , Freeman Scott 
Published: July 2021

AbstractEvolution by natural selection is recognized as both the most important concept in undergraduate biology and the most difficult to teach. Unfortunately, teaching and assessment of evolution have been impaired by legacy approaches that focus on Darwin’s original insights and the Modern Synthesis’ integration of Mendelian genetics, but ignore or downplay advances from what we term the Molecular Synthesis. To create better alignment between instructional approaches and contemporary research in the biosciences, we propose that the primary learning goal in teaching evolution should be for students to connect genotypes, phenotypes, and fitness. To support this approach, we developed and tested assessment questions and scoring rubrics called the Extended Assessing Conceptual Reasoning of Natural Selection (E-ACORNS) instrument. Initial E-ACORNS data suggest that after traditional instruction, few students recognize the molecular synthesis—prompting us to propose that introductory course sequences be re-organized with the molecular synthesis as their central theme.