bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank
Authors: Fawcett Katherine A. , Demidov German , Shrine Nick , Paynton Megan L , Ossowski Stephan , Sayers Ian , Wain Louise V. , Hollox Edward J. 
Published: December 2021

AbstractBackgroundThe role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availability of whole-exome sequencing (WES) in large biobank studies provides an unprecedented opportunity to study the role of CNVs in asthma.MethodsWe called common CNVs in 49,953 individuals in the first release of UK Biobank WES using ClinCNV software. CNVs were tested for association with asthma in a stage 1 analysis comprising 7,098 asthma cases and 36,578 controls from the first release of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 with an additional 17,280 asthma cases and 115,562 controls from the second release of UK Biobank exome sequencing, followed by validation and fine-mapping.ResultsFive of 189 CNVs were associated with asthma in stage 2, including a deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising from under-mapping of reads from non-reference HLA haplotypes, and that the CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes within the HLA region. Bayesian fine-mapping of the HLA region suggested that there are two independent asthma association signals. The variants with the largest posterior inclusion probability in the two credible sets were an amino acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine or leucine at residue 11).ConclusionsAt least two independent loci characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are likely to account for association of SNPs and CNVs in this region with asthma. The high divergence of haplotypes in the HLA can give rise to spurious CNVs, providing an important, cautionary tale for future large-scale analyses of sequencing data.
A prospective validation of nomograms based on BC-116 and BC-106 urine peptide biomarker panels for bladder cancer diagnostics and monitoring
Authors: Mengual Lourdes , Frantzi Maria , Mokou Marika , Ingelmo-Torres Mercedes , Vlaming Michiel , Merseburger Axel S. , Roesch Marie C. , Culig Zoran , Alcaraz Antonio , Vlahou Antonia , Mischak Harald , Van der Heijden Antoine G. 
Published: December 2021

AbstractPurposeNon-invasive urine-based biomarkers for bladder cancer (BC) diagnosis and surveillance can potentially improve current diagnostic and monitoring protocols by guiding cystoscopy. Here, we aim to access the diagnostic performance of nomograms based on published biomarker panels for BC detection (BC-116) and monitoring of recurrence (BC-106) in combination with cytology, in two prospectively collected patient cohorts.Experimental Design602 recruited patients were screened for presence of BC, out of which 551 were found eligible for further analysis. For the primary setting, urine samples from 73 eligible patients were analyzed from those diagnosed with primary BC (n=27) and benign urological disorders (n=46). For the surveillance setting, 478 eligible patients were considered (83 BC recurrences; 395 negative for recurrence). Urine samples were analyzed with capillary electrophoresis coupled to mass spectrometry and the biomarker score was estimated via a support vector machine-based software.ResultsValidation of the BC-116 biomarker panel resulted in 89% sensitivity and 67% specificity (AUCBC-116=0.82), similar to the published estimates. The nomogram based on cytology and BC-116 resulted in good (AUCNom116=0.85) but not significantly better performance than the BC-116 alone (P=0.5672). BC-106 biomarker panel showed 89% sensitivity and 32% specificity for surveillance, while improved performance was achieved when a nomogram including BC-106 and cytology was evaluated (AUCNom106=0.82), significantly outperforming both cytology (AUCcyt=0.72;P=0.0022) and BC-106 alone (AUCBC-106=0.67;P=0.0012).ConclusionsBC-116 biomarker panel is a useful test for detecting primary BC. BC-106 classifier integrated with cytology and showing >95% negative predictive value, might be useful for decreasing the number of cystoscopies during surveillance.
Racial disparity in distant recurrence-free survival in localized breast cancer patients: A pooled analysis of NSABP trials
Authors: Kim Gina , Pastoriza Jessica M. , Qin Jiyue , Lin Juan , Karagiannis George S. , Condeelis John S. , Yothers Greg , Anderson Stewart , Julian Thomas , Entenberg David , Rohan Thomas E. , Xue Xiaonan , Sparano Joseph A. , Oktay Maja H. 
Published: December 2021

AbstractBackgroundBlack race is associated with worse outcome in patients with breast cancer. We evaluated distant relapse-free survival (DRFS) between Black and White women with localized breast cancer who participated in NCI-sponsored clinical trials.MethodsWe analyzed pooled data from eight National Surgical Adjuvant Breast and Bowel Project (NSABP) trials including 9,702 women with localized breast cancer treated with adjuvant chemotherapy (AC, n=7,485) or neoadjuvant chemotherapy (NAC, n=2,217), who self-reported as Black (n=1,070) or White (n=8,632). The association between race and DRFS was analyzed using log-rank tests and multivariate Cox regression.ResultsAfter adjustment for covariates including age, tumor size, nodal status, body mass index and taxane use, and treatment (AC vs. NAC), Black race was associated with an inferior DRFS in ER-positive (HR 1.24 [95% CI 1.05-1.46], p=0.01), but not in ER-negative disease (HR 0.97 [95% CI 0.83-1.14], p=0.73), and significant interaction between race and ER status was observed (p=0.03). There was no racial disparity in DRFS among patients with pathologic complete response (pCR) (Log-rank p =0.8). For patients without pCR, black race was associated with worse DRFS in ER-positive (HR 1.67 [95% CI 1.14-2.45], p=0.01), but not in ER-negative disease (HR 0.91 [95% CI 0.65-1.28], p=0.59).ConclusionBlack race was associated with significantly inferior DRFS in ER-positive localized breast cancer treated with AC or NAC, but not in ER-negative disease. In the NAC group, racial disparity was also observed in patients with residual ER-positive breast cancer at surgery, but not in those who had a pathologic complete response.Lay SummaryBlack women with breast cancer have worse outcome compared to White women. We investigated if this held true in the context of clinical trials which provide controlled treatment setting. Black women with cancer containing estrogen receptors (ER) had worse outcome than White women. If breast cancers did not contain ER there was no racial disparity in outcome. Moreover, we observed racial disparity in women who received chemotherapy before their cancer was removed, but only if they had cancer with ER and residual disease upon completion of treatment. If cancer disappeared upon pre-surgical chemotherapy, there was no racial disparity.
Antigenic and virological properties of an H3N2 variant that will likely dominate the 2021-2022 Northern Hemisphere influenza season
Authors: Bolton Marcus J. , Ort Jordan T. , McBride Ryan , Swanson Nicholas J. , Wilson Jo , Awofolaju Moses , Greenplate Allison R. , Drapeau Elizabeth M. , Pekosz Andrew , Paulson James C. , Hensley Scott E. 
Published: December 2021

AbstractInfluenza viruses have circulated at very low levels during the COVID-19 pandemic, and population immunity against these viruses is low. Influenza virus cases have been increasing in the Northern Hemisphere involving an H3N2 strain (3C.2a1b.2a2) with a hemagglutinin (HA) that has several substitutions relative to the 2021-2022 H3N2 vaccine strain. Here, we show that one of these substitutions eliminates a key glycosylation site on HA and alters sialic acid binding. Using glycan array profiling, we show that the 3C.2a1b.2a2 H3 maintains binding to an extended bi-antennary sialoside and replicates to high titers in human airway cells. We found that antibodies elicited by the 2021-2022 Northern Hemisphere influenza vaccine poorly neutralize the new H3N2 strain. Together, these data indicate that 3C.2a1b.2a2 H3N2 viruses efficiently replicate in human cells and could potentially cause an antigenic mismatch if they continue to circulate at high levels during the 2021-2022 influenza season.
Development and Validation of Suspicious Liver Lesion Deep Learning Algorithm for Computed Tomography
Authors: Johnson Jacob , Senevirathne Kaneel , Ngo Lawrence 
Published: December 2021

AbstractIn this work, we report the results of a deep-learning based liver lesion detection algorithm. While several liver lesion segmentation and classification algorithms have been developed, none of the previous work has focused on detecting suspicious liver lesions. Furthermore, their generalizability remains a pitfall due to their small sample size and sample homogeneity. Here, we developed and validated a highly generalizable deep-learning algorithm for detection of suspicious liver lesions. The algorithm was trained and tested on a diverse dataset containing CT exams from over 2,000 hospital sites in the United States. Our final model achieved an AUROC of 0.84 with a specificity of 0.99 while maintaining a sensitivity of 0.33.
Spindle pole body-associated Atg11, an autophagy-related protein, regulates microtubule dynamics essential for high-fidelity chromosome segregation
Authors: Reza Md. Hashim , Aggarwal Rashi , Verma Jigyasa , Podh Nitesh Kumar , Chowdhury Ratul , Mehta Gunjan , Manjithaya Ravi , Sanyal Kaustuv 
Published: December 2021

AbstractEmerging studies hint at the roles of autophagy-related proteins in various cellular processes in a eukaryotic cell. To understand if autophagy-related proteins influence genome stability, we examined a cohort of 35 autophagy mutants inSaccharomyces cerevisiae.We observed cells lacking Atg11 show poor mitotic stability of minichromosomes. Atg11 molecules dynamically localize to the spindle pole bodies (SPBs). Loss of Atg11 leads to a delayed cell cycle progression. Such cells accumulate at metaphase at an elevated temperature that is relieved when the spindle assembly checkpoint is inactivated. Indeed,atg11Δ cells have stabilized securin levels, that prevent anaphase onset, confirming chromosome biorientation defects associated with the mutant. Atg11 functions in the Kar9-dependent spindle positioning pathway and maintains Kar9 asymmetry by facilitating proper dynamic instability of astral microtubules (aMTs). Taken together, this study uncovers a non-canonical role of Atg11 in facilitating MT dynamics crucial for chromosome segregation.
Discovery of lipid-mediated protein-protein interactions in living cells using metabolic labeling with photoactivatable clickable probes
Authors: Fedoryshchak Roman O. , Gorelik Andrii , Shen Mengjie , Shchepinova Maria M. , Pérez-Dorado Inmaculada , Tate Edward W. 
Published: December 2021

AbstractProtein-protein interactions (PPIs) are essential and pervasive regulatory elements in cell biology. Despite development of a range of techniques to probe PPIs in living systems, there is a dearth of approaches to capture interactions driven by specific post-translational modifications (PTMs). Myristoylation is a lipid PTM added to more than 200 human proteins, where it may regulate membrane localization, stability or activity. Here we report design and synthesis of a panel of novel photocrosslinkable and clickable myristic acid analog probes, and their characterization as efficient substrates for human N-myristoyltransferases NMT1 and NMT2, both biochemically and through X-ray co-crystallography. We demonstrate metabolic incorporation of probes to label NMT substrates in cell culture and in situ intracellular photoactivation to form a covalent crosslink between modified proteins and their interactors, capturing a snapshot of interactions driven by the presence of the lipid PTM. Proteomic analyses revealed both known and multiple novel interactors of a series of myristoylated proteins, including ferroptosis suppressor protein FSP1 and spliceosome-associated RNA helicase DDX46. The concept exemplified by these probes offers an efficient approach for exploring the PTM-specific interactome, which may prove broadly applicable to other PTMs.
The MyLo CRISPR-Cas9 Toolkit: A Markerless Yeast Localization and Overexpression CRISPR-Cas9 Toolkit
Authors: Bean Björn D.M. , Whiteway Malcolm , Martin Vincent J.J. 
Published: December 2021

ABSTRACTThe genetic tractability of the yeast Saccharomyces cerevisiae has made it a key model organism for basic research and a target for metabolic engineering. To streamline the introduction of tagged genes and compartmental markers with powerful CRISPR-Cas9-based genome editing tools we constructed a Markerless Yeast Localization and Overexpression (MyLO) CRISPR-Cas9 toolkit with three components: (i) a set of optimized S. pyogenes Cas9-guide RNA (gRNA) expression vectors with five selectable markers and the option to either pre-clone or co-transform the gRNAs; (ii) vectors for the one-step construction of integration cassettes expressing an untagged or GFP/RFP/HA-tagged gene of interest at one of three levels, supporting localization and overexpression studies; and (iii) integration cassettes containing moderately expressed GFP- or RFP-tagged compartmental markers for colocalization experiments. These components allow rapid, high efficiency genomic integrations and modifications with only transient selection for the Cas9 vector, resulting in markerless transformations. To demonstrate the ease of use, we applied our complete set of compartmental markers to co-label all target subcellular compartments with GFP and RFP. Thus, the MyLO toolkit packages CRISPR-Cas9 technology into a flexible, optimized bundle to simplify yeast research.
Seed sourcing for climate-resilient grasslands: the role of seed source diversity during early restoration establishment
Authors: Lindstrom Jessica , Ahlering Marissa , Hamilton Jill 
Published: December 2021

ABSTRACTRestoration often advocates for the use of local seed in restoration, however increasingly new strategies have been proposed to incorporate diverse sources to maintain evolutionary potential within seed mixes. Increasing seed sources per species within a seed mix should increase genetic variation, however, few empirical studies have evaluated how seed source diversity impacts plant community composition following restoration. Thus, the goal of this research was to compare the use of single or multi-source seed mix treatments to plant community diversity following restoration. Using 14 species commonly applied in grassland restoration, we examined plant community diversity following restoration comparing seed mixes with either one or five sources per species across two restoration sites in Minnesota and South Dakota, United States. Following seeding, species establishment and abundance were recorded to calculate plant diversity for each seed mix treatment. There were no major effects of seed mix treatment on community emergence and diversity observed, with the majority of plant establishment reflecting non-seeded species. However, site-specific differences were observed. Heterogeneous land-use history associated with the Minnesota site likely contributed to differences across the restoration treatments. In contrast, community diversity at the South Dakota site was homogeneous across seed mix treatments with changes in plant community influenced solely by early season species establishment. This suggests land-use history irrespective of seed mix treatment influences establishment and persistence, particularly in the first year following restoration. Future monitoring across seasons will be needed to evaluate if community diversity changes in response to seed mix treatment.
Genome size distributions in bacteria and archaea are strongly linked to phylogeny
Authors: Martinez-Gutierrez Carolina A. , Aylward Frank O. 
Published: December 2021

AbstractThe evolutionary forces that determine genome size in bacteria and archaea have been the subject of intense debate over the last few decades. Although the preferential loss of genes observed in prokaryotes is explained through the deletional bias, factors promoting and preventing the fixation of such gene losses remain unclear. Moreover, statistical analyses on this topic have typically been limited to a narrow diversity of bacteria and archaea without considering the potential bias introduced by the shared recent ancestry of many lineages. In this study, we used a phylogenetic generalized least-squares (PGLS) analysis to evaluate the effect of different factors on the genome size of a broad diversity of bacteria and archaea. We used dN/dS to estimate the strength of purifying selection, and 16S copy number as a proxy for ecological strategy, which have both been postulated to play a role in shaping genome size. After model fit, Pagel’s lambda indicated a strong phylogenetic signal in genome size, suggesting that the diversification of this trait is strongly influenced by shared evolutionary histories. As a predictor variable, dN/dS showed a poor predictability and non-significance when phylogeny was considered, consistent with the view that genome reduction can occur under either weak or strong purifying selection depending on the ecological context. Copies of 16S rRNA showed poor predictability but maintained significance when accounting for non-independence in residuals, suggesting that ecological strategy as approximated from 16S rRNA copies might play a minor role in genome size variation. Altogether, our results indicate that genome size is a complex trait that is not driven by any singular underlying evolutionary force, but rather depends on lineage- and niche-specific factors that will vary widely across bacteria and archaea.Author SummaryThe evolutionary forces driving genome size in bacteria and archaea have been subject to debate during the last decades. Independent comparative analyses have suggested that unique variables, such as the strength of selection, environmental complexity, and mutation rate, are the main drivers of this trait, which complicates generalizations across the Tree of Life. Here, we applied a phylogeny-based statistical approach to assess how tightly genome size is linked to evolutionary history in bacteria and archaea. Moreover, we also evaluated the predictability of genome size from the strength of purifying selection and ecological strategy on a broad diversity of bacteria and archaea genomes. Our approach indicates that genome size in prokaryotes is strongly dependent on phylogenetic history, and that genome size is the result of the interaction of variables like past events, current selection regimes, and environmental complexity that are clade dependent.
Loss of Cohesin regulator PDS5A reveals repressive role of Polycomb loops
Authors: Bsteh Daniel , Moussa Hagar F. , Michlits Georg , Yelagandula Ramesh , Wang Jingkui , Elling Ulrich , Bell Oliver 
Published: December 2021

ABSTRACTPolycomb Repressive Complexes 1 and 2 (PRC1, PRC2) are conserved epigenetic regulators that promote transcriptional silencing. PRC1 and PRC2 converge on shared targets, catalyzing repressive histone modifications. In addition, a subset of PRC1/PRC2 targets engage in long-range interactions whose functions in gene silencing are poorly understood. Using a CRISPR screen in mouse embryonic stem cells, we identified that the cohesin regulator PDS5A links transcriptional silencing by Polycomb and 3D genome organization. PDS5A deletion impairs cohesin unloading and results in derepression of subset of endogenous PRC1/PRC2 target genes. Importantly, derepression is not associated with loss of repressive Polycomb chromatin modifications. Instead, loss of PDS5A leads to aberrant cohesin activity, ectopic insulation sites and specific reduction of ultra-long Polycomb loops. We infer that these loops are important for robust silencing at a subset of Polycomb target genes and that maintenance of cohesin-dependent genome architecture is critical for Polycomb regulation.
Decreased retinal vascular complexity is an early biomarker of MI supported by a shared genetic control
Authors: Villaplana-Velasco Ana , Engelmann Justin , Rawlik Konrad , Canela-Xandri Oriol , Tochel Claire , Lona-Durazo Frida , Krishnan Mookiah Muthu Rama , Doney Alex , Parra Esteban J. , Trucco Emanuele , MacGillivray Tom , Rannikmae Kristiina , Tenesa Albert , Pairo-Castineira Erola , Bernabeu Miguel O. 
Published: December 2021

AbstractThere is increasing evidence that the complexity of the retinal vasculature (measured as fractal dimension, Df) might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present here a genome-wide association study (GWAS) aimed to elucidate the genetic component of Df and to analyse its relationship with CAD. To this end, we obtained Df from retinal fundus images and genotyping information from ∼38,000 white-British participants in the UK Biobank. We discovered 9 loci associated with Df, previously reported in pigmentation, retinal width and tortuosity, hypertension, and CAD studies. Significant negative genetic correlation estimates endorse the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD fatal outcomes. This strong association motivated us to developing a MI predictive model combining clinical information, Df, a CAD polygenic risk score and using a random forest algorithm. Internal cross validation evidenced a considerable improvement in the area under the curve (AUC) of our predictive model (AUC=0.770) when comparing with an established risk model, SCORE, (AUC=0.719). Our findings shed new light on the genetic basis of Df, unveiling a common control with CAD, and highlights the benefits of its application in individualised MI risk prediction.
Exploring the attitude towards the adoption of a sustainable diet: a cross-country comparison
Authors: Pucci Tommaso , Casprini Elena , Sogari Giovanni , Zanni Lorenzo 
Published: December 2021

PurposeUnderstanding the determinants that influence consumers' attitude to adopt sustainable diets represents an important area of research to promote sustainable food consumption. The aim of this study is to investigate how (1) the individual openness to new foods (ONFs), (2) the involvement in food trends (IFTs) and (3) the social media use (SMU) can potentially impact the attitude towards the adoption of a sustainable diet (ATSD).Design/methodology/approachThe authors conducted a structured survey in eight countries: Italy, Germany, Poland, USA, Brazil, Japan, Korea and China. The final sample of 5,501 individuals was analysed applying a structural equation model.FindingsThe main results show that attitude towards the ATSD is influenced differently by the antecedents investigated in each country. In particular, the ONF positively influences the ATSD only in Italy, USA and Germany. IFT positively influences the ATSD only in Italy, Poland and USA, while negatively in Germany. SMU has a positive influence on the ATSD only in Japan, USA and Germany, while a negative one in Brazil and Korea.Originality/valueThis study presents a cross-country comparison about the antecedents of attitude towards the ATSD, thus providing evidence for the need of ad hoc marketing strategies by companies and policies by institutions at single country level.