bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilizing Electronic Health Records (EHR) and Tumor Panel Sequencing to Demystify Prognosis of Cancer of Unknown Primary (CUP) patients
Authors: Moon Intae , LoPiccolo Jaclyn , Baca Sylvan C. , Sholl Lynette M. , Kehl Kenneth L. , Hassett Michael J. , Liu David , Schrag Deborah , Gusev Alexander 
Published: December 2022

AbstractWhen a standardized diagnostic test fails to locate the primary site of a metastatic cancer, it is diagnosed as a cancer of unknown primary (CUP). CUPs account for 3-5% of all cancers but do not have established targeted therapies, leading to typically dismal outcomes. Here, we develop OncoNPC, a machine learning classifier of CUP, trained on targeted next generation sequencing data from 34,567 tumors across 22 primary cancer types collected as part of routine clinical care at three institutions under AACR Project GENIE initiative [1]. OncoNPC achieved a weighted F1 score of 0.94 for high confidence predictions on known cancer types (65% of held-out samples). To evaluate its clinical utility, we applied OncoNPC to 971 CUP tumor samples from patients treated at the Dana-Farber Cancer Institute (DFCI). OncoNPC CUP subtypes exhibited significantly different survival outcomes, and identified potentially actionable molecular alterations in 23% of tumors. Importantly, patients with CUP, who received first palliative intent treatments concordant with their OncoNPC predicted sites, showed significantly better outcomes (Hazard Ratio 0.348, 95% C.I. 0.210 - 0.570, p-value 2.32×10−5) after accounting for potential measured confounders. As validation, we showed that OncoNPC CUP subtypes exhibited significantly higher polygenic germline risk for the predicted cancer type. OncoNPC thus provides evidence of distinct CUP subtypes and offers the potential for clinical decision support for managing patients with CUP.
Seroprevalence of anti-SARS-CoV-2 antibodies before and after implementation of anti-COVID-19 vaccination among hospital staff in Bangui, Central African Republic
Authors: Manirakiza Alexandre , Malaka Christian , Mossoro-Kpinde Hermione Dahlia , Yambiyo Brice Martial , Mossoro-Kpinde Christian Diamant , Fandema Emmanuel , Yakola Christelle Niamathe , Doyama-Woza Rodrigue , Kangale-Wando Ida Maxime , Komba Elliot Kosh , Nzapali Guiagassomon Sandra Manuella Bénedicte , de la Grace Namsenei-Dankpea Lydie Joella-Venus , Gomelle Coti-Reckoundji Cathy Sandra , Bouhouda Modeste , Gody Jean-Chrisostome , Grésenguet Gérard , Vernet Guy , Vernet Marie-Astrid , Nakoune Emmanuel 
Published: December 2022

AbstractIntroductionHealthcare workers (HCWs) are at high to very high risk for SARS-CoV-2 infection. The persistence of this pandemic worldwide has instigated the need for an investigation of the level of prevention through immunization and vaccination against SARS-CoV-2 among HCWs. The objective of our study was to evaluate any changes in anti-COVID-19 serological status before and after the vaccination campaign of health personnel in the Central African Republic.MethodWe carried out a repeated cross-sectional serological study on HCWs at the university hospital centers of Bangui. Blood samples were collected and tested for anti-SARS-CoV-2 IgM and IgG using the ELISA technique on blood samples.ResultsA total of 179 and 141 HCWs were included in the first and second surveys, respectively. Of these staff, 31.8% of HCWs were positive for anti-SARS-CoV-2 IgG in the first survey, whereas 95.7% were positive for anti-SARS-CoV-2 IgG in the second survey. However, the proportion of HCWs positive for SARS-CoV-2 IgM antibodies was low (9.7% in the first survey and 3.6% in the second survey).ConclusionThese findings showed a sharp increase in seroprevalence over a one-year period. This increase is primarily due to the synergistic effect of the infection and the implementation of vaccines against COVID-19. Further studies to assess the persistence of anti-SARS-CoV-2 antibodies are needed.
Sex-specific DNA methylation in saliva from the multi-ethnic Fragile Families and Child Wellbeing Study
Authors: Reiner Allison , Bakulski Kelly M. , Fisher Jonah D. , Dou John F. , Schneper Lisa , Mitchell Colter , Notterman Daniel A. , Zawistowski Matthew , Ware Erin B. 
Published: December 2022

AbstractThe prevalence of many diseases differs by sex, potentially due to sex-specific patterns in DNA methylation. Autosomal sex-specific differences in DNA methylation have been observed in cord blood and placental tissue, but are not well studied in saliva or in diverse populations. We sought to characterize sex-specific DNA methylation on autosomal chromosomes in saliva samples from children in the Fragile Families and Child Wellbeing Study, a multi-ethnic prospective birth cohort containing an oversampling of Black, Hispanic and low-income families. DNA methylation from saliva samples were analyzed on 796 children at both ages 9 and 15 with DNA methylation measured using the Illumina HumanMethylation 450k array. An epigenome-wide association analysis of the age 9 samples identified 8,430 sex-differentiated autosomal DNA methylation sites at age 9 (P < 2.4×10−7), of which 76.2% had higher DNA methylation in female children. The strongest sex-difference was in the cg26921482 probe, in theAMDHD2gene, with 30.6% higher DNA methylation in female compared to male children (P < 1×10−300). Treating the age 15 samples as an internal replication set, we observed highly consistent results between the age 9 and age 15 measurements, indicating stable and replicable sex-differentiation. Further, we directly compared our results to previously published DNA methylation sex differences in both cord blood and saliva and again found strong consistency. Our findings support widespread and robust sex-differential DNA methylation across age, human tissues, and populations. These findings help inform our understanding of potential biological processes contributing to sex differences in human physiology and disease.
Paf1 complex subunit Rtf1 stimulates H2B ubiquitylation by interacting with the highly conserved N-terminal helix of Rad6
Authors: Fetian Tasniem , McShane Brendan M. , Horan Nicole L. , Shodja Donya N. , True Jason D. , Mosley Amber L. , Arndt Karen M. 
Published: December 2022

AbstractHistone modifications coupled to transcription elongation play important roles in regulating the accuracy and efficiency of gene expression. The mono-ubiquitylation of a conserved lysine in H2B (K123 inSaccharomyces cerevisiae; K120 in humans) occurs co-transcriptionally and is required for initiating a histone modification cascade on active genes. H2BK123 ubiquitylation (H2BK123ub) requires the RNA polymerase II (RNAPII)-associated Paf1 transcription elongation complex (Paf1C). Through its Histone Modification Domain (HMD), the Rtf1 subunit of Paf1C directly interacts with the ubiquitin conjugase Rad6, leading to the stimulation of H2BK123ubin vivoandin vitro. To understand the molecular mechanisms that target Rad6 to its histone substrate, we identified the site of interaction for the HMD on Rad6. Usingin vitrocrosslinking followed by mass spectrometry, we localized the primary contact surface for the HMD to the highly conserved N-terminal helix of Rad6. Using a combination of genetic and biochemical experiments, we identified separation-of-function mutations inS. cerevisiae RAD6that greatly impair H2BK123 ubiquitylation but not other Rad6 functions. Finally, by employing RNA-sequencing as a sensitive approach for comparing mutant phenotypes, we show that mutating either side of the proposed Rad6-HMD interface yields strikingly similar transcriptome profiles that extensively overlap with those of a mutant that lacks the site of ubiquitylation in H2B. Our results fit a model in which a specific interface between a transcription elongation factor and a ubiquitin conjugase guides substrate selection toward a highly conserved chromatin target during active gene expression.Significance StatementTranscription by RNAPII is tightly coordinated with mechanisms that control chromatin structure. Disruption of this interplay leads to deleterious effects on gene expression and genome architecture. Proteins that associate with RNAPII during transcription elongation play an important role in coupling histone modifications to active transcription. Paf1C, a conserved member of the RNAPII active elongation complex, is required for the ubiquitylation of histone H2B, a modification with effects on nucleosome stability and the methylation and acetylation state of chromatin. Here, we provide new insights into how a conserved domain in Paf1C, which we previously showed to be necessary and sufficient for Paf1C-mediated stimulation of H2B ubiquitylation, interacts with the ubiquitin conjugase for H2B thereby guiding its specificity.
Identifying efficient linkage strategies for HIV self-testing (IDEaL): a study protocol for an individually randomized control trial
Authors: Dovel Kathryn , Balakasi Kelvin , Hubbard Julie , Phiri Khumbo , Nichols Brooke E. , Coates Thomas J. , Kulich Michal , Chikuse Elijah , Phiri Sam , Long Lawrence , Hoffman Risa , Choko Augustine 
Published: December 2022

ABSTRACTIntroductionMen in sub-Saharan Africa are less likely than women to initiate antiretroviral therapy (ART) and are more likely to have longer cycles of disengagement from ART programs. Treatment interventions that meet the unique needs of men are needed, but they must be scalable. We will conduct a study to test the impact of various interventions on six-month retention in ART programs among men living with HIV who are not currently engaged in care.Methods and AnalysisWe will conduct a programmatic, individually randomized, non-blinded, non-inferiority controlled trial. “Non-engaged” men will be randomized 1:1:1 to either a Stepped, Low-Intensity, or High-Intensity arm. In the Stepped arm, intervention activities build in intensity over time for those who do not reengage in care with the following steps: 1) one-time male-specific counseling + facility navigation ⟶ 2) ongoing male mentorship + facility navigation ⟶ outside-facility ART initiation + male-specific counseling + facility navigation for follow-up ART visits. The Low-Intensity Intervention includes one-time male-specific counseling + facility navigation only and the High-Intensity Intervention offers immediate outside-facility ART initiation + male-specific counseling + facility navigation for follow-up ART visits. Our primary outcome is 6-month retention in care. Secondary outcomes include cost-effectiveness and rates of adverse events.Ethics and DisseminationThe Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi have approved the trial protocol. Findings will be disseminated rapidly in national and international forums, as well as in peer-reviewed journals and are expected to provide urgently needed information to other countries and donors.ARTICLE SUMMARYStrengths and limitationsIDEAL provides male-specific differentiated models of care aimed to improve men’s ART outcomes. We specifically focus on building trusting relationships with health care workers and developing client-led, individualized strategies to overcome barriers to care.IDEAL will test the impact of a stepped intervention for men. This approach promises to improve the efficiency and reach of HIV programs for men as the highest-resource interventions will only be received by the minority of men who are most in need.IDEAL develops and tests male-specific counseling curriculum that, if effective, could easily be taken to scale. Findings from the study will identify critical components for male-specific counseling, especially among men who struggle to be retained in HIV care.
chiLife: An open-source Python package forin silicospin labeling and integrative protein modeling
Authors: Tessmer Maxx H. , Stoll Stefan 
Published: December 2022

AbstractHere we introduce chiLife, a Python package for site-directed spin label (SDSL) modeling for electron paramagnetic resonance (EPR) spectroscopy, in particular double electron–electron resonance (DEER). It is based on in silico attachment of rotamer ensemble representations of spin labels to protein structures. chiLife enables the development of custom protein analysis and modeling pipelines using SDSL EPR experimental data. It allows the user to add custom spin labels, scoring functions and spin label modeling methods. chiLife is designed with integration into third-party software in mind, to take advantage of the diverse and rapidly expanding set of molecular modeling tools available with a Python interface. This article describes the main design principles of chiLife and presents a series of examples.Author summaryThanks to modern modeling methods like AlphaFold2, RosettaFold, and ESMFold, high-resolution structural models of proteins are widely available. While these models offer insight into the structure and function of biomedically and technologically significant proteins, most of them are not experimentally validated. Furthermore, many proteins exhibit functionally important conformational flexibility that is not captured by these models. Site-directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy is a powerful tool for probing protein structure and conformational heterogeneity, making it ideal for validating, refining, and expanding protein models. To extract quantitative protein backbone information from experimental SDSL EPR data, accurate modeling methods are needed. For this purpose, we introduce chiLife, an open-source Python package for SDSL modeling designed to be extensible and integrable with other Python-based protein modeling packages. With chiLife, appropriate SDSL EPR experiments for protein model validation can be designed, and protein models can be refined using experimental SDSL EPR data as constraints.
Formal cooperation in macaque monkeys obtained via single-payoff change from formal coordination games
Authors: van Coeverden Charlotte , Schultz Wolfram 
Published: December 2022

AbstractCoordination and cooperation are hallmarks of the behavior of social animals. Coordination requires common choices to obtain maximum benefit, whereas cooperation requires to forgo immediate selfish outcome for later common maximum benefit. A well validated economic game for investigating cooperation is Prisoner Dilemma (PD). Recent studies show that monkeys cooperate to a limited extent when playing an iterated PD. In our experiment, macaque monkeys made choices on a touchscreen to obtain juice reward whose amount depended on the choices of both animals. We designed four coordination games and two cooperation games (iterated PD) that differed only in a single payoff (the so-called temptation) while all other payoffs remained constant. The increasing temptation payoff resulted in performance that varied somewhat in the coordination game (probability of common choice between p = 0.55 and p = 0.70) but dropped in both cooperation games while nevertheless remaining significant (p = 0.28 to p = 0.68). The response time of the second player increased significantly when the first player chose the cooperative option across all games, suggesting reciprocation; further, the animals seemed to benefit from seeing the action of the other player, indicating that the choices incorporated a social component. Taken together, our results demonstrate good cooperation in the iterated PD by macaque monkeys after being primed with coordination games.
Evolution of mate harm resistance in females fromDrosophila melanogasterpopulations selected for faster development and early reproduction
Authors: Verma Tanya , Das Susnato , Lobo Saunri Dhodi , Mishra Ashish Kumar , Bhattacharyya Soumi , Nandy Bodhisatta 
Published: December 2022

AbstractInterlocus sexual conflict is predicted to result in sexually antagonistic coevolution between male competitive traits, which are also female-detrimental, and mate harm resistance (MHR) in females. Little is known about connection life-history evolution and sexually antagonistic coevolution. Here, we investigated the evolution of MHR in a set of experimentally evolved populations, where mate-harming ability has been shown to have evolved in males as a correlated response to the selection for faster development and early reproduction. We measured mortality and fecundity of females of these populations and those of their matched controls, under different male exposure conditions. We observed that the evolved females were more susceptible to mate harm - suffering from significantly higher mortality under continuous exposure to control males within the twenty-day assay period. Though these evolved females are known to have shorter lifespan, such higher mortality was not observed under virgin and single-mating conditions. We used fecundity data to show that this higher mortality in evolved females is unlikely due to cost of egg production. Further analysis indicated that this decreased MHR is unlikely to be due purely to the smaller size of these females. Instead, it is more likely to be an indirect experimentally evolved response attributable to the changed breeding ecology, and/or male trait evolution. Our results underline the implications of changes in life history traits, including lifespan, to the evolution of MHR in females.
Cataloguing and profiling of the gut virome in Chinese populations uncover extensive viral signatures across common diseases
Authors: Li Shenghui , Yan Qiulong , Zhang Yue , Guo Ruochun , Zhang Pan , Lv Qingbo , Chen Fang , Li Zhiming , Meng Jinxin , Li Jing , Wang Guangyang , Chen Changming , Ullah Hayan , Cheng Lin , Fan Shao , Li Rui , You Wei , Zhang Yan , Ma Jie , Sun Wen , Ma Xiaochi 
Published: December 2022

AbstractThe gut viral community has been linked to human physiology and health, but our knowledge of its genetic and functional contents and disease dependence is far from complete. Here, we collected 11,327 bulk or viral metagenomes from fecal samples from large-scale Chinese populations to establish a Chinese gut virus catalogue (cnGVC) comprising 67,096 nonredundant viral genomes. This catalogue included ∼70% of novel viruses that are not represented in existing gut viral databases, and allowed us to characterize the functional diversity and specificity of the gut virome. Using cnGVC, we 1) profiled the gut virome in large-scale populations and evaluated their sex- and age-related variations, 2) investigated the diversity and compositional patterns of the gut virome across common diseases by analyzing 6,314 bulk metagenomes spanning 28 disease or unhealthy statuses, and 3) identified a large number of universal viral signatures of diseases and validated their predictive ability for health status. Overall, our resources and results would contribute to the grand effort of expanding the knowledge of the human gut virome and addressing a full picture of the associations between viruses and common diseases.
Backstage researching resilience researchers – dilemmas and principles for data collection in the resilience in healthcare research program
Authors: Wiig Siri , Haraldseid-Driftland Cecilie , Dombestein Heidi , Lyng Hilda Bø , Ree Eline , Fagerdal Birte , Schibevaag Lene , Guise Veslemøy 
Published: December 2022

PurposeResilience in healthcare is fundamental for what constitutes quality in healthcare. To understand healthcare resilience, resilience research needs a multilevel perspective, diverse research designs, and taking advantage of different data sources. However, approaching resilience researchers as a data source is a new approach within this field and needs careful consideration to ensure that research is trustworthy and ethically sound. The aim of this short “backstage” general review paper is to give a snapshot of how the Resilience in Healthcare (RiH) research program identified and dealt with potential methodological and ethical challenges in researching researcher colleagues.Design/methodology/approachThe authors first provide an overview of the main challenges and benefits from the literature on researching researcher colleagues. Second, the authors demonstrate how this literature was used to guide strategies and principles adopted in the RiH research process.FindingsThe paper describes established principles and a checklist for data collection and analysis to overcome potential dilemmas and challenges to ensure trustworthiness and transparency in the process.Originality/valueMining the knowledge and experience of resilience researchers is fundamental for taking the research field to the next step, and furthermore an approach that is relevant across different research fields. This paper provides guidance on how other research projects can approach researcher colleagues in similar ways to gain new insight, build theory and advance their research field based on insider competence.
The influence of socio-cognitive mindfulness and resilience on middle managers' stress and thriving during COVID-19: results from two studies
Authors: Slaymaker Rachel R. , O'Byrne Kristin Koetting , Williams Peter E. 
Published: December 2022

PurposeThe purpose of this study was to examine the influence of socio-cognitive mindfulness on resilience, stress and thriving among middle managers in higher education at two separate periods during the COVID-19 pandemic. In Study 1, the authors examined how socio-cognitive mindfulness predicted perceived stress and whether the relationship between mindfulness and perceived stress was mediated by resilience. In Study 2, the authors replicated the first study and further hypothesized that the link between mindfulness and thriving was also mediated by resilience.Design/methodology/approachThe authors conducted cross-sectional correlational studies to test the hypotheses using data from 163 middle managers in higher education early in the pandemic in Study 1 and 204 middle managers a year later in Study 2.FindingsStudy 1 findings showed socio-cognitive mindfulness predicted perceived stress, and that resilience fully mediated this relationship. In Study 2, socio-cognitive mindfulness did not predict perceived stress, but it did predict thriving, and that relationship was fully mediated by resilience.Originality/valueThis research is the first to address how socio-cognitive mindfulness directly impacts perceived stress and thriving and its impact through building resilience. To date, few studies have focused on stress in higher education middle managers or addressed the importance of building socio-cognitive mindfulness and resilience to thrive amid ongoing challenges. Implications of the pandemic's influence on the results are also addressed.