bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Extended Admixture Pulse Model Reveals the Limitations to Human–Neandertal Introgression Dating
Authors: Iasi Leonardo N M , Ringbauer Harald , Peter Benjamin M 
Published: July 2021

AbstractNeandertal DNA makes up 2–3% of the genomes of all non-African individuals. The patterns of Neandertal ancestry in modern humans have been used to estimate that this is the result of gene flow that occurred during the expansion of modern humans into Eurasia, but the precise dates of this event remain largely unknown. Here, we introduce an extended admixture pulse model that allows joint estimation of the timing and duration of gene flow. This model leads to simple expressions for both the admixture segment distribution and the decay curve of ancestry linkage disequilibrium, and we show that these two statistics are closely related. In simulations, we find that estimates of the mean time of admixture are largely robust to details in gene flow models, but that the duration of the gene flow can only be recovered if gene flow is very recent and the exact recombination map is known. These results imply that gene flow from Neandertals into modern humans could have happened over hundreds of generations. Ancient genomes from the time around the admixture event are thus likely required to resolve the question when, where, and for how long humans and Neandertals interacted.
RoboCOP: jointly computing chromatin occupancy profiles for numerous factors from chromatin accessibility data
Authors: Mitra Sneha , Zhong Jianling , Tran Trung Q , MacAlpine David M , Hartemink Alexander J 
Published: July 2021

Abstract
Chromatin is a tightly packaged structure of DNA and protein within the nucleus of a cell. The arrangement of different protein complexes along the DNA modulates and is modulated by gene expression. Measuring the binding locations and occupancy levels of different transcription factors (TFs) and nucleosomes is therefore crucial to understanding gene regulation. Antibody-based methods for assaying chromatin occupancy are capable of identifying the binding sites of specific DNA binding factors, but only one factor at a time. In contrast, epigenomic accessibility data like MNase-seq, DNase-seq, and ATAC-seq provide insight into the chromatin landscape of all factors bound along the genome, but with little insight into the identities of those factors. Here, we present RoboCOP, a multivariate state space model that integrates chromatin accessibility data with nucleotide sequence to jointly compute genome-wide probabilistic scores of nucleosome and TF occupancy, for hundreds of different factors. We apply RoboCOP to MNase-seq and ATAC-seq data to elucidate the protein-binding landscape of nucleosomes and 150 TFs across the yeast genome, and show that our model makes better predictions than existing methods. We also compute a chromatin occupancy profile of the yeast genome under cadmium stress, revealing chromatin dynamics associated with transcriptional regulation.
The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation
Authors: Sharma Tapan , Robinson Daniel C L , Witwicka Hanna , Dilworth F Jeffrey , Imbalzano Anthony N 
Published: July 2021

Abstract
Skeletal muscle regeneration is mediated by myoblasts that undergo epigenomic changes to establish the gene expression program of differentiated myofibers. mSWI/SNF chromatin remodeling enzymes coordinate with lineage-determining transcription factors to establish the epigenome of differentiated myofibers. Bromodomains bind to acetylated lysines on histone N-terminal tails and other proteins. The mutually exclusive ATPases of mSWI/SNF complexes, BRG1 and BRM, contain bromodomains with undefined functional importance in skeletal muscle differentiation. Pharmacological inhibition of mSWI/SNF bromodomain function using the small molecule PFI-3 reduced differentiation in cell culture and in vivo through decreased myogenic gene expression, while increasing cell cycle-related gene expression and the number of cells remaining in the cell cycle. Comparative gene expression analysis with data from myoblasts depleted of BRG1 or BRM showed that bromodomain function was required for a subset of BRG1- and BRM-dependent gene expression. Reduced binding of BRG1 and BRM after PFI-3 treatment showed that the bromodomain is required for stable chromatin binding at target gene promoters to alter gene expression. Our findings demonstrate that mSWI/SNF ATPase bromodomains permit stable binding of the mSWI/SNF ATPases to promoters required for cell cycle exit and establishment of muscle-specific gene expression.
Narrative, Second-Person Experience, and Self-Perception: A Reason it is Good to Conceive of One’s Life Narratively
Authors: Hibshman Grace 
Published: July 2021

Abstract
It is widely held that it is good to conceive of one's life narratively, but why this is the case has not been well established. I argue that conceiving of one's life narratively can contribute to one's flourishing by mediating to oneself a second-person experience of oneself, furnishing one with valuable second-personal productive distance from oneself and as a result self-understanding. Drawing on Eleonore Stump's theory that narratives re-present to their audiences the second-person experiences they depict, I argue that conceiving of one's life narratively facilitates taking on the second-person experience that an audience would have in hearing one's life narrative, mediating how someone from a second-person perspective might perceive oneself and as a result yielding valuable self-understanding. I conclude with some practical implications.
Disagreement in the Equity Options Market and Stock Returns
Authors: Golez Benjamin , Goyenko Ruslan 
Published: July 2021

Abstract
We estimate investor disagreement from synthetic long and short stock trades in the equity options market. We show that high disagreement predicts low stock returns after positive earnings surprises and high stock returns after negative earnings surprises. The negative effect is stronger for high-beta stocks and stocks that are more difficult to sell short. In the cross-section of all stocks and the subset of the 500 largest companies, high disagreement robustly predicts low monthly and weekly stock returns.
The Economics of Sick Calves: The Use of Calves for Smallpox Vaccine Lymph Production in Britain and its Empire, 1870s–1900s
Authors: Brig-Ortiz Kristin 
Published: July 2021

Summary
In this essay, I explore how the production and distribution of animal lymph benefited public and private producers by allowing them to use the calf’s body to profit from compulsory vaccination legislation. Through this process, a market was created in which the state competed with and was beholden to commercial entities for public health administration. By establishing its own vaccine-producing sites, the state participated in this public health market, where it competed with private producers. Building on scholarly work on the history of public health and animal histories, the essay understands how late nineteenth-century British vaccine administration hinged on a view of lymph production that encompassed the calf’s importance to vaccine administration and the commodification of the resulting vaccine lymph. These perspectives shaped how the state and medical practitioners approached and administered vaccination, refashioning lymph from a free tool to a market commodity.
Disparities in Access to High-Volume Surgeons Within High-Volume Hospitals for Hysterectomy
Authors: Knisely Anne , Huang Yongmei , Melamed Alexander , Gockley Allison , Tergas Ana I. , St. Clair Caryn M. , Hou June Y. , Khoury-Collado Fady , Accordino Melissa , Hershman Dawn L. , Wright Jason D. 
Published: July 2021

OBJECTIVE:
To examine access to high-volume surgeons in comparison with low-volume surgeons who perform hysterectomies within high-volume hospitals and to compare perioperative morbidity and mortality between high-volume and low-volume surgeons within these centers.

METHODS:
Women who underwent hysterectomy in New York State between 2000 and 2014 at a high-volume (top quartile by volume) hospital were included. Surgeons were classified into quartiles based on average annual hysterectomy volume. Multivariable models were used to determine characteristics associated with treatment by a low-volume surgeon in comparison with a high-volume surgeon and to estimate the association between physician volume, and morbidity and mortality.

RESULTS:
A total of 300,586 patients cared for by 5,505 surgeons at 59 hospitals were identified. Women treated by low-volume surgeons, in comparison with high-volume surgeons, were more often Black (19.4% vs 14.3%; adjusted odds ratio [aOR] 1.26; 95% CI 1.09–1.46) and had Medicare insurance (20.6% vs 14.5%; aOR 1.22; 95% CI 1.04–1.42). Low-volume surgeons were more likely to perform both emergent–urgent procedures (26.1% vs 6.4%; aOR 3.91; 95% CI 3.26–4.69) and abdominal hysterectomy, compared with minimally invasive hysterectomy (77.8% vs 54.7%; aOR 1.91; 95% CI 1.62–2.24). Compared with patients cared for by high-volume surgeons, those operated on by low-volume surgeons had increased risk of a complication (31.0% vs 10.3%; adjusted risk ratios [aRR] 1.84; 95% CI 1.71–1.98) and mortality (2.2% vs 0.2%; aRR 3.04; 95% CI 2.20–4.21). In sensitivity analyses, differences in morbidity and mortality remained for emergent–urgent procedures, elective operations, cancer surgery, and noncancer procedures.

CONCLUSION:
Socioeconomic disparities remain in access to high-volume surgeons within high-volume hospitals for hysterectomy. Patients who undergo hysterectomy at a high-volume hospital by a low-volume surgeon are at substantially greater risk for perioperative morbidity and mortality.
Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes
Authors: Urbanellis Peter , McEvoy Caitriona M. , Škrtić Marko , Kaths J. Moritz , Kollmann Dagmar , Linares Ivan , Ganesh Sujani , Oquendo Fabiola , Sharma Manraj , Mazilescu Laura , Goto Toru , Noguchi Yuki , John Rohan , Mucsi Istvan , Ghanekar Anand , Bagli Darius , Konvalinka Ana , Selzner Markus , Robinson Lisa A. 
Published: July 2021

Background.
Normothermic ex vivo kidney perfusion (NEVKP) has demonstrated superior outcomes for donation-after-cardiovascular death grafts compared with static cold storage (SCS). To determine the mechanisms responsible for this, we performed an unbiased genome-wide microarray analysis.

Methods.
Kidneys from 30-kg Yorkshire pigs were subjected to 30 min of warm ischemia followed by 8 h of NEVKP or SCS, or no storage, before autotransplantation. mRNA expression was analyzed on renal biopsies on postoperative day 3. Gene set enrichment analysis was performed using hallmark gene sets, Gene Ontology, and pathway analysis.

Results.
The gene expression profile of NEVKP-stored grafts closely resembled no storage kidneys. Gene set enrichment analysis demonstrated enrichment of fatty acid metabolism and oxidative phosphorylation following NEVKP, whereas SCS-enriched gene sets were related to mitosis, cell cycle checkpoint, and reactive oxygen species (q < 0.05). Pathway analysis demonstrated enrichment of lipid oxidation/metabolism, the Krebs cycle, and pyruvate metabolism in NEVKP compared with SCS (q < 0.05). Comparison of our findings with external data sets of renal ischemia-reperfusion injury revealed that SCS-stored grafts demonstrated similar gene expression profiles to ischemia-reperfusion injury, whereas the profile of NEVKP-stored grafts resembled recovered kidneys.

Conclusions.
Increased transcripts of key mitochondrial metabolic pathways following NEVKP storage may account for improved donation-after-cardiovascular death graft function, compared with SCS, which promoted expression of genes typically perturbed during IRI.
Global Monitoring of the Impact of COVID-19 Pandemic through Online Surveys Sampled from the Facebook User Base
Authors: Astley Christina M. , Tuli Gaurav , Cord - De Iaco Kimberly A. Mc , Cohn Emily L. , Rader Benjamin , Chiu Samantha , Deng Xiaoyi , Stewart Kathleen , Farag Tamer H. , Barkume Kris M. , LaRocca Sarah , Morris Katherine A. , Kreuter Frauke , Brownstein John S. 
Published: July 2021

AbstractSimultaneously tracking the global COVID-19 impact across multiple populations is challenging due to regional variation in resources and reporting. Leveraging self-reported survey outcomes via an existing international social media network has the potential to provide reliable and standardized data streams to support monitoring and decision-making world-wide, in real time, and with limited local resources. The University of Maryland Global COVID Trends and Impact Survey (UMD-CTIS), in partnership with Facebook, invites daily cross-sectional samples from the social media platform’s active users to participate in the survey since launch April 23, 2020. COVID-19 indicators through December 20, 2020, from N=31,142,582 responses representing N=114 countries, weighted for nonresponse and adjusted to basic demographics, were benchmarked with government data. COVID-19-related signals showed similar concordance with reported benchmark case and test positivity. Bonferroni significance and minimal Spearman correlation strength thresholds were met in the majority. Light Gradient Boost machine learning trained on national and pooled global data verified known symptom indicators, and predicted COVID-19 trends similar to other signals. Risk mitigation behavior trends are correlated with, but sometimes lag, risk perception trends. In regions with strained health infrastructure, but active social media users, we show it is possible to define suitable COVID-19 impact trajectories. This syndromic surveillance public health tool is the largest global health survey to date, and, with brief participant engagement, can provide meaningful, timely insights into the COVID-19 pandemic and response in regions under-represented in epidemiological analyses.Significance StatementThe University of Maryland Global COVID Trends and Impact Survey (UMD-CTIS), launched April 23, 2020, is the largest remote global health monitoring system. This study includes about 30 million UMD-CTIS responses over 34 weeks (through December 2020) from N=114 countries with survey-weights to adjust for nonresponse and demographics. Using limited self-reported data, sampled daily from an international cohort of Facebook users, we demonstrate validity and utility for COVID-19 impacts trends, even in regions with scant or delayed government data. We predict COVID-19 cases in the absence of testing, and characterize perceived COVID-19 risk versus risk-lowering measures. The UMD-CTIS has the potential to support existing monitoring systems for the COVID-19 pandemic, as well as other new, as-yet-undefined global health threats.
Mitigating outbreaks in congregate settings by decreasing the size of the susceptible population
Authors: Blumberg Seth , Lu Phoebe , Hoover Christopher M. , Lloyd-Smith James O. , Kwan Ada T. , Sears David , Bertozzi Stefano M. , Worden Lee 
Published: July 2021

ABSTRACTWhile many transmission models have been developed for community spread of respiratory pathogens, less attention has been given to modeling the interdependence of disease introduction and spread seen in congregate settings, such as prisons or nursing homes. As demonstrated by the explosive outbreaks of COVID-19 seen in congregate settings, the need for effective outbreak prevention and mitigation strategies for these settings is critical. Here we consider how interventions that decrease the size of the susceptible populations, such as vaccination or depopulation, impact the expected number of infections due to outbreaks. Introduction of disease into the resident population from the community is modeled as a branching process, while spread between residents is modeled via a compartmental model. Control is modeled as a proportional decrease in both the number of susceptible residents and the reproduction number. We find that vaccination or depopulation can have a greater than linear effect on anticipated infections. For example, assuming a reproduction number of 3.0 for density-dependent COVID-19 transmission, we find that reducing the size of the susceptible population by 20% reduced overall disease burden by 47%. We highlight the California state prison system as an example for how these findings provide a quantitative framework for implementing infection control in congregate settings. Additional applications of our modeling framework include optimizing the distribution of residents into independent residential units, and comparison of preemptive versus reactive vaccination strategies.
Progressive Increase in Virulence of Novel SARS-CoV-2 Variants in Ontario, Canada
Authors: Fisman David N. , Tuite Ashleigh R. 
Published: July 2021

AbstractBackgroundThe period from February to June 2021 was one during which initial wild-type SARS-CoV-2 strains were supplanted in Ontario, Canada, first by variants of concern (VOC) with the N501Y mutation (Alpha/B1.1.17, Beta/B.1.351 and Gamma/P.1 variants), and then by the Delta/B.1.617 variant. The increased transmissibility of these VOCs has been documented but data for increased virulence is limited. We used Ontario’s COVID-19 case data to evaluate the virulence of these VOCs compared to non-VOC SARS-CoV-2 infections, as measured by risk of hospitalization, intensive care unit (ICU) admission, and death.MethodsWe created a retrospective cohort of people in Ontario testing positive for SARS-CoV-2 and screened for VOCs, with dates of test report between February 7 and June 27, 2021 (n=212,332). We constructed mixed effects logistic regression models with hospitalization, ICU admission, and death as outcome variables. Models were adjusted for age, sex, time, vaccination status, comorbidities, and pregnancy status. Health units were included as random intercepts.ResultsCompared to non-VOC SARS-CoV-2 strains, the adjusted elevation in risk associated with N501Y-positive variants was 52% (43-62%) for hospitalization; 89% (67-116%) for ICU admission; and 51% (30-74%) for death. Increases with Delta variant were more pronounced: 108% (80-138%) for hospitalization; 234% (164-331%) for ICU admission; and 132% (47-230%) for death.InterpretationThe progressive increase in transmissibility and virulence of SARS-CoV-2 VOCs will result in a significantly larger, and more deadly, pandemic than would have occurred in the absence of VOC emergence.
Clonotype pattern in T-cell lymphomas map the cell of origin to immature lymphoid precursors
Authors: Iyer Aishwarya , Hennessey Dylan , Gniadecki Robert 
Published: July 2021

AbstractBackgroundMature T-cell lymphomas (TCLs) are rare, clinically heterogeneous hematologic cancers of high medical need. TCLs have inferior prognosis compared with their B-cell counterparts, which is attributed to poor understanding of their pathogenesis. Based on phenotypic similarities between normal and neoplastic lymphocytes it has been assumed that TCLs develop in the periphery, directly from various subtypes of normal T-cells.Methods and findingsTo address the debated question of the cell of origin in TCLs we analyzed to identify the highly variable complementarity determining regions (CDR3) regions of T-cell receptor (TCR) to trace the clonal history of the T-cells. We have collected previously published whole genome-exome, and -transcriptome sequencing data from 574 TCL patients comprising five nodal lymphomas [anaplastic large cell lymphoma (n=67), peripheral T-cell lymphoma (PTCL, n=55), adult T-cell lymphoma/leukemia (n=135), natural killer T-cell lymphoma (NKCL, n=25), not specified/other (n=30)] and three extranodal, cutaneous T-cell lymphomas [mycosis fungoides (n=122), Sezary syndrome (n=130), and subcutaneous panniculitis-like T-cell lymphoma (n=10)]. TCR clonotypes contained in the tumor cell fraction, representing the clonotypes of malignant cells, were identified by de novo assembly of CDR3 regions of TCR γ, β and α. We have found that the vast majority of TCLs are clonotypically oligoclonal, although the pattern oligoclonality varied. Anaplastic large cell lymphoma was most diverse comprising multiple clonotypes of TCRγ, β and α whereas adult T-cell lymphoma/leukemia and peripheral T-cell lymphomas often showed monoclonality for TCRγ and β but had diverse TCRα clonotypes. These patterns of rearrangements were not compatible with the current mature T-cell precursor model and indicated that TCLs are initiated at the level of the lymphoid precursor. In keeping with this hypothesis, TCR rearrangements in TCLs resembled the pattern seen in the human thymus showing biased usage of V and J segments of high combinatorial probability resulting in recurrent, “public” CDR3 sequences shared between unrelated patients and across different clinical TCL entities. Frequencies of malignant clonotypes followed Zipf-Mandelbrot scaling law suggesting that TCLs comprise an interconnected system of expanding tumor clones.The major limitation of this study is that it is based on the analysis of the TCR clonotypes and does not directly inform about developmental trajectories of cellular clones.ConclusionsLymphoid precursors are the likely cells of origin for mature T-cell lymphomas. Anaplastic large cell lymphoma seems to be derived from the most immature precursors with germline TCR whereas peripheral T-cell lymphoma and adult T-cell lymphoma/leukemia map to the later stages after TCRβ rearrangement stage. Clonotypically diverse initiating cells may seed target tissues being responsible for disease relapses after therapy.
RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer
Authors: Engebraaten Olav , Yau Christina , Berg Kristian , Borgen Elin , Garred Øystein , Berstad Maria E.B. , Fremstedal Ane S.V. , De Michele Angela , van’t Veer Laura , Esserman Laura , Weyergang Anette 
Published: July 2021

ABSTRACTPURPOSETargeted therapeutics strongly depends on validated biomarkers in order to select patients most likely to benefit from the treatment. HER2 serves as a predictive biomarker for HER2-targeted tyrosine kinase inhibitors and monoclonal antibodies. HER2 may, however, also be utilized as a transport gate for delivery of cytotoxic agents into the cell, such as for HER2-targeted antibody drug conjugates (ADCs; e.g. trastuzumab emtansine (T-DM1)). The predictive biomarkers for such ADCs may be more complex, also reflecting the intracellular transport.METHODSFive HER2-positive breast and ovarian cancer cell lines were evaluated with respect to T-DM1 sensitivity and correlated to the expression levels of proteins involved in endocytic trafficking including RAB4A, RAB5A and RAB11A, with possible impact on ADC pharmacology. The results were confirmed in a clinical cohort consisting of patients from the adaptive breast cancer clinical trial I-SPY2 where pathological complete response (pCR) was correlated to the RNA expression level of RAB4A, RAB5A and RAB11A. A subset of the clinical KAMILLA trial including 19 patients was used as a verification cohort where semi-quantitative IHC of RAB5A was correlated to progression free survival (PFS).RESULTSThe early endosome marker RAB5A, was found to correlate positively to T-DM1 sensitivity in the cell line panel. Correlation between RAB5A expression and T-DM1 sensitivity (pCR) was confirmed in patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial, but not in the trastuzumab/paclitaxel control arm. The clinical correlation was verified in the patients from the KAMILLA trial where semi-quantitative RAB5A IHC staining correlated significantly positive to PFS.CONCLUSIONThe present results indicate that RAB5A is a predictive biomarker for T-DM1 and outline, for the first time, proteins involved in endocytic trafficking as predictive biomarkers for ADCs.