bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Surveillance Identifies SARS-CoV-2 Transmission Patterns in Local University Populations, Wisconsin, USA, 2020–2022
Authors: Ramaiah Arunachalam , Khubbar Manjeet , Bauer Amy , Akinyemi Katherine , Weiner Joshua , Bhattacharyya Sanjib 
Published: July 2022

AbstractNovel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge as the current coronavirus disease 2019 (COVID-19) pandemic extends into its third year. Understanding SARS-CoV-2 circulation in university populations is vital for effective interventions in a higher education setting that will inform pubic health policy during pandemics. In this study, we performed whole-genome sequencing of 537 of 1,717 SARS-CoV-2 positive nasopharyngeal/nasal swab samples collected for nearly 20 months from the two university populations in Wisconsin, United States. We observed that the viral sequences were distributed into 57 lineages/sub-lineages belonging to 15 clades of which the majority were from 21K (Omicron, 36.13%) and 21J (Delta, 30.91%). Nearly 40% (213) of the sequences were Omicron of which BA.1 and its eight descendent lineages account for 91%, while the remaining belong to BA.2 and its six descendent lineages. The independent analysis of these two universities sequences revealed significant differences in circulating the SARS-CoV-2 variants. The genome-based analysis of closely-related strains along with phylogenetic clusters had identified that potential virus transmission occurred within as well as between universities, and between the university and local community. Although this study improves our understanding of distinct transmission patterns of circulating variants in local universities, expanding the genomic surveillance capacity will aid local jurisdictions in identifying emerging SARS-CoV-2 variants like BA.4 and BA.5, and improve data-driven public health mitigation and policy efforts.
Multimorbidity and risk of incident dementia: role of disease clusters and genetic risk for dementia in a cohort of 206,960 participants
Authors: Calvin Catherine M. , Conroy Megan C. , Moore Sarah F. , Kuźma Elżbieta , Littlejohns Thomas J. 
Published: July 2022

AbstractImportanceIndividual conditions have been identified as risk factors for dementia, however, it is important to consider the role of multimorbidity as conditions often co-occur.ObjectiveTo investigate whether multimorbidity is associated with incident dementia, and whether associations vary by different clusters of disease, and genetic risk for dementia.DesignA population-based prospective study.SettingThe UK Biobank cohort.Participants206,960 dementia-free women and men aged ≥60 years old at baseline Exposures: Medical conditions were captured as part of a nurse-led verbal interview conducted at assessment centres. The presence of ≥2 long-term conditions from a preselected list of 42 conditions was used to define multimorbidity. High genetic risk for dementia was based on presence of one or two Apolipoprotein (APOE) ε4 alleles.Main outcomeIncident dementia was derived from hospital inpatient and death registry records.Results89,201 (43%) participants had multimorbidity. Over a mean of 11.8 years (standard deviation=2.2), 6,182 participants developed dementia. The incidence rate per 1,000 person years was 1.87 (95% Confidence Interval [CI] 1.80-1.94) and 3.41 (95% CI 3.30-3.53) for those without and with multimorbidity, respectively. In Cox-proportional-hazards models adjusted for age, sex, ethnicity, education, socioeconomic status and APOE-ε4 carrier status, multimorbidity was associated with a 63% increased risk of incident dementia (Hazard Ratio [HR]=1.63, 95% CI 1.55-1.71). The highest dementia risk was observed for the hypertension/diabetes/coronary heart disease (HR=2.20, 95% CI 1.98-2.46) and pain/osteoporosis/dyspepsia (HR=2.00, 95% CI 1.68-2.37) clusters in females and diabetes/hypertension (HR=2.24, 95% CI 1.97-2.55) and coronary heart disease/hypertension/stroke clusters (HR=1.94, 95% CI 1.71-2.20) in males, compared to no multimorbidity. The relative associations were stronger in those with a lower genetic risk of dementia, but the absolute difference in risk between absence and presence of multimorbidity was greater in those with a higher genetic risk for dementia.Conclusions and RelevanceMultimorbidity was strongly associated with an increased risk of dementia. The strength of associations varied by clusters of disease and genetic risk for dementia. These findings could help with the identification of individuals at high risk of dementia as well as the development of targeted interventions to reduce or delay dementia incidence.
Increased mutation rate and interlocus gene conversion within human segmental duplications
Authors: Vollger Mitchell R. , DeWitt William S. , Dishuck Philip C. , Harvey William T. , Guitart Xavi , Goldberg Michael E. , Rozanski Allison N. , Lucas Julian , Asri Mobin ,   The Human Pangenome Reference Consortium, Munson Katherine M. , Lewis Alexandra P. , Hoekzema Kendra , Logsdon Glennis A. , Porubsky David , Paten Benedict , Harris Kelley , Hsieh PingHsun , Eichler Evan E. 
Published: July 2022

ABSTRACTSingle-nucleotide variants (SNVs) within segmental duplications (SDs) have not been systematically assessed because of the difficulty in mapping short-read sequence data to virtually identical repetitive sequences. Using 102 phased human haplotypes, we constructed 1:1 unambiguous alignments spanning high-identity SDs and compared the pattern of SNVs between unique and SD regions. We find that human SNVs are elevated 60% in SDs compared to unique regions. We estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with >7 Mbp of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of ~800 protein-coding genes. The latter includes 171 genes that have “relocated” on average 1.61 Mbp in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are evolutionarily older when compared to unique sequences with most of this signal originating from putative IGC loci. SNVs within SDs, however, also exhibit a distinct mutational spectrum where there is a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts. In addition, we observe a 7.6% reduction in the frequency of CpG associated mutations when compared to unique DNA. We hypothesize that these distinct mutational properties help to maintain an overall higher GC content of SD DNA when compared to unique DNA, and we show that these GC-favoring mutational events are likely driven by GC-biased conversion between paralogous sequences.
Origin and segregation of the human germline
Authors: Castillo-Venzor Aracely , Penfold Christopher A. , Morgan Michael D. , Tang Walfred W. C. , Kobayashi Toshihiro , Wong Frederick C. K. , Bergmann Sophie , Slatery Erin , Boroviak Thorsten E. , Marioni John C. , Surani M. Azim 
Published: July 2022

AbstractHuman germline-soma segregation occurs during weeks 2-3 in gastrulating embryos. While direct studies are hindered, here we investigate the dynamics of human primordial germ cell (PGCs) specification using in vitro models with temporally resolved single-cell transcriptomics and in-depth characterisation to in vivo datasets from human and non-human primates, including a 3D marmoset reference atlas. We elucidate the molecular signature for the transient gain of competence for germ cell fate during peri-implantation epiblast development. Further, we show that both the PGCs and amnion arise from transcriptionally similar TFAP2A positive progenitors at the posterior end of the embryo. Notably, genetic loss of function experiments show that TFAP2A is crucial for initiating the PGC fate without detectably affecting the amnion, and its subsequently replaced by TFAP2C as an essential component of the genetic network for PGC fate. Accordingly, amniotic cells continue to emerge from the progenitors in the posterior epiblast, but importantly, this is also a source of nascent PGCs.
A toolkit to handle T-less alignment for U insertion/deletion RNA editing
Authors: Zhang Fan , Aphasizhev Ruslan , Afasizheva Inna , Zhang Liye 
Published: July 2022

AbstractSummaryIn the mitochondrial genome of kinetoplastids, the targeted insertion and deletion of uridine in cryptic mRNA is essential to generate functional protein-coding mRNAs, but such process leads to a highly hetergenous and complex RNA population. Few tools were developped to perform alignment based on a T depleted strategy for such mRNA population, however to our knowledge no downstream analysis tool is available so far to allow easy data processing and interpretation. Here, we fill this gap with the T-less-Alignment-Toolkit, which provides useful functions such as duplication removal with UMI, alignment strandness analysis, statistical summary and visualization.Availability and ImplementationScripts and toolkits can be downloaded at https://gitee.com/Zhanglab/tless-alignment-toolkit
A deep learning approach for improved detection of homologous recombination deficiency from shallow genomic profiles
Authors: Andre Gregoire , Coletta Tommaso , Pozzorini Christian , Marques Ana C. , Bieler Jonathan , Kempfer Rieke , Chong Chloe , Saitta Alexandra , Smith Ewan , Macheret Morgane , Janiszewski Adrian , Bonilla Ximena , Bonet Jaume , Santos-Silva Hugo , Postl Magdalena , Wozelka-Oltjan Lisa , Arrigo Nils , Willig Adrian , Grimm Christoph , Müllauer Leonhard , Xu Zhenyu 
Published: July 2022

AbstractHomologous Recombination Deficiency (HRD) is a predictive biomarker of poly-ADP ribose polymerase 1 inhibitors (PARPi) response. Most HRD detection methods are based on genome wide enumeration of scarring events and require deep genome sequence profiles (> 30x). The cost and workflow-specific biases introduced by these genome profiling methods currently limits clinical adoption of HRD testing.We introduce the Genomic Integrity Index (GII), a Convolutional Neuronal Network, that leverages features from low pass (1x) Whole Genome Sequencing data to distinguish HRD positive and negative samples. In a cohort of 230 ovarian and breast cancer, we found GII supports accurate stratification of samples yielding results that are highly concordant with state-of-the-art HRD detection methods (0.865<AUC<0.996) which require 50x deeper coverage.We conclude that the deep learning framework supporting GII allows accurate detection of HRD from shallow genome profiles, reducing biases and data generation costs making it uniquely suited for clinical applications.
Accessibility and Reproducible Research Practices in Cardiovascular Literature
Authors: Heckerman Gabriel , Tzng Eileen , Campos-Melendez Arely , Ekwueme Chisomaga , Mueller Adrienne L. 
Published: July 2022

AbstractBackgroundSeveral fields have described low reproducibility of scientific research and poor accessibility in research reporting practices. Although previous reports have investigated accessible reporting practices that lead to reproducible research in other fields, to date no study has explored the extent of accessible and reproducible research practices in cardiovascular science literature.MethodsTo study accessibility and reproducibility in cardiovascular research reporting, we screened 400 randomly selected articles published in 2019 in three top cardiovascular science publications: Circulation, the European Heart Journal, and the Journal of the American College of Cardiology (JACC). We screened each paper for accessible and reproducible research practices using a set of accessibility criteria including protocol, materials, data, and analysis script availability, as well as accessibility of the publication itself. We also quantified the consistency of open research practices within and across cardiovascular study types and journal formats.ResultsWe identified that fewer than 2% of cardiovascular research publications provide sufficient resources (materials, methods, data, and analysis scripts) to fully reproduce their studies. After calculating an accessibility score as a measure of the extent to which an articles makes its resources available, we also showed that the level of accessibility varies across study types (p = 2e-16) and across journals (p = 5.9e-13). We further show that there are significant differences in which study types share which resources. We also describe the relationship between accessibility scores and corresponding author nationality.ConclusionAlthough the degree to which reproducible reporting practices are present in publications varies significantly across journals and study types; current cardiovascular science reports frequently do not provide sufficient materials, protocols, data, or analysis information to reproduce a study. In the future, having higher standards of accessibility mandated by either journals or funding bodies will help increase the reproducibility of cardiovascular research.FundingAuthors Gabriel Heckerman, Arely Campos-Melendez, and Chisomaga Ekwueme were supported by an NIH R25 grant from the National Heart Lung and Blood Institute (R25HL147666). Eileen Tzng was supported by an AHA Institutional Training Award fellowship (18UFEL33960207).
Distinct positions of genetic and oral histories: Perspectives from India
Authors: Biddanda Arjun , Bandyopadhyay Esha , de la Fuente Castro Constanza , Witonsky David , Urban Aragon Jose A. , Pasupuleti Nagarjuna , Moots Hannah M. , Fonseca Renée , Freilich Suzanne , Stanisavic Jovan , Willis Tabitha , Menon Anoushka , Mustak Mohammed S. , Kodira Chinnappa Dilip , Naren Anjaparavanda P. , Sikdar Mithun , Rai Niraj , Raghavan Maanasa 
Published: July 2022

AbstractOver the past decade, genomic data has contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 158 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Great’s army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Andaman Islanders. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.
Sequence analysis and structural predictions of lipid transfer bridges in the repeating beta groove (RBG) superfamily reveals past and present domain variations affecting form, function and interactions of VPS13, ATG2, SHIP164, Hobbit and Tweek
Authors: Levine Tim P 
Published: July 2022

AbstractLipid transfer between organelles requires proteins that shield the hydrophobic portions of lipids as they cross the cytoplasm. In the last decade a new structural form of lipid transfer protein (LTP) has been found: long hydrophobic grooves made of beta-sheet that bridge between organelles at membrane contact sites. Eukaryotes have five families of bridge-like LTPs: VPS13, ATG2, SHIP164, Hobbit and Tweek. These are unified into a single superfamily through their bridges being composed of just one domain, called the repeating beta groove (RBG) domain, which builds into rod shaped multimers with a hydrophobic-lined groove and hydrophilic exterior. Here, sequences and predicted structures of the RBG superfamily were analyzed in depth. Phylogenetics showed that the last eukaryotic common ancestor contained all five RBG proteins, with duplicate VPS13s. These appear to have arisen in even earlier ancestors from shorter forms with 4 RBG domains. The extreme ends of most RBG proteins have amphipathic helices that might be an adaptation for direct or indirect bilayer interaction, although this has yet to be tested. The one exception to this is the C-terminus of SHIP164, which instead has a coiled-coil. Finally, almost the entire length of the exterior surfaces of the RBG bridges are shown to have conserved residues, indicating sites for partner interactions almost all of which are unknown. These findings can inform future cell biological and biochemical experiments.
Host-specific plasmid evolution explains the variable spread of clinical antibiotic-resistance plasmids
Authors: Benz F. , Hall A. R. 
Published: July 2022

AbstractAntibiotic resistance encoded on plasmids is a pressing global health problem. Predicting which plasmids spread/decline in the long term remains a huge challenge, even though some key parameters influencing plasmid stability have been identified, such as plasmid growth costs and horizontal transfer rates. Here, we show these parameters evolve in a strain-specific way among clinical plasmids/bacteria, and this occurs rapidly enough to alter the relative likelihoods of different bacterium-plasmid combinations spreading/declining. We used experiments with Escherichia coli and antibiotic-resistance plasmids isolated from patients, paired with a mathematical model, to show long-term plasmid stability (beyond antibiotic exposure) was better explained by evolutionary changes in plasmid-stability traits than by initial variation among bacterium-plasmid combinations. Evolutionary trajectories were specific to particular bacterium-plasmid combinations. Genome sequencing and genetic manipulation helped explain this, revealing epistatic (here, strain-dependent) effects of key genetic changes affecting horizontal plasmid transfer. Several genetic changes involved mobile elements and pathogenicity islands. Rapid strain-specific evolution can thus outweigh ancestral phenotypes as a predictor of plasmid stability. Accounting for strain-specific plasmid evolution in natural populations could improve our ability to anticipate and manage successful bacterium-plasmid combinations.
Conjunctive and complementary CA1 hippocampal cell populations relate sensory events to immobility and locomotion
Authors: Inayat Samsoon , McAllister Brendan B. , Whishaw Ian Q. , Mohajerani Majid H. 
Published: July 2022

AbstractThis study investigated the dynamics of recruitment of cells in the CA1 region of the hippocampus in response to sensory stimuli presented during immobility, movement, and their transitions. Two-photon calcium imaging of somal activity in CA1 neuron populations was done in head fixed mice. Sensory stimuli, either a light flash or an air stream, were delivered to the mice when at rest, when moving spontaneously, and while they were induced to run a fixed distance on the conveyor belt. Overall, 99% of 2083 identified cells (from 5 mice) were active across one or more of 20 sensorimotor events. A larger proportion of cells were active during locomotion. Nevertheless, for any given sensorimotor event, only about 17% of cells were active. When considering pairs of sensorimotor event types, the active cell population consisted of conjunctive (C ∈ A and B) cells, active across both events, and complementary (C ∈ A not B or C ∈ B not A) cells that were active only during individual events. Whereas conjunctive cells characterised stable representations of repeated sensorimotor events, complementary cells characterised recruitment of new cells for encoding novel sensorimotor events. The moment-to-moment recruitment of conjunctive and complementary cells across changing sensorimotor events signifies the involvement of the hippocampus in functional networks integrating sensory information with ongoing movement. This role of the hippocampus is well suited for movement guidance that secondarily might include spatial behavior, episodic learning and memory, context representation, and scene construction.
A New CUT&RUN Low Volume-Urea (LoV-U) protocol uncovers Wnt/β-catenin tissue-specific genomic targets
Authors: Zambanini Gianluca , Nordin Anna , Jonasson Mattias , Pagella Pierfrancesco , Cantù Claudio 
Published: July 2022

AbstractUpon WNT/β-catenin pathway activation, stabilized β-catenin travels to the nucleus where it associates with the TCF/LEF family of transcription factors, which constitutively bind to genomic Wnt Responsive Elements (WREs), to activate transcription of target genes. Discovering the binding profile of β-catenin is therefore required to unambiguously assign direct targets of WNT signaling. Cleavage Under Target and Release Using Nuclease (CUT&RUN) has recently emerged as a prime technique for mapping the binding profile of chromatin interacting proteins. In our attempts to profile different regulators of the WNT/β-catenin transcriptional complex, CUT&RUN performed reliably when targeting transcription factors such as TCF/LEF, but it failed to produce consistent binding patterns of the non-DNA-binding β-catenin. Here, we present a biochemical modification of the CUT&RUN protocol, which we refer to as LoV-U (Low Volume and Urea), that enables the generation of robust and reproducible β-catenin binding profiles. CUT&RUN-LoV-U uncovers direct WNT/β-catenin target genes in human cells, as well as in ex vivo cells isolated from developing mouse tissue. CUT&RUN-LoV-U can profile all classes of chromatin regulators tested and is well suited for simultaneous processing of several samples. We submit that the application of our protocol will allow the detection of the complex system of tissue-specific WNT/β-catenin target genes, together with other non-DNA-binding transcriptional regulators that act downstream of ontogenetically fundamental signaling cascades.
Active shrinkage protects neurons following axonal transection
Authors: Aydın Mehmet Şerif , Bay Sadık , Yiğit Esra Nur , Özgül Cemil , Oğuz Elif Kaval , Konuk Elçin Yenidünya , Ayşit Neşe , Cengiz Nureddin , Erdoğan Ender , Him Aydın , Koçak Mehmet , Eroglu Emrah , Öztürk Gürkan 
Published: July 2022

AbstractTrauma, vascular events, or neurodegenerative processes can lead to axonal injury and eventual transection (axotomy). Neurons can survive axotomy, yet the underlying mechanisms are not fully understood. Excessive water entry into injured neurons poses a particular risk due to swelling and subsequent death. Using in vitro and in vivo neurotrauma model systems based on laser transection, we demonstrated that axotomy triggers actomyosin contraction coupled with calpain activity. As a consequence, neurons shrink acutely to force water out through aquaporin channels preventing swelling and bursting. Inhibiting shrinkage increased the probability of neuronal cell death by about three-fold. These studies reveal a previously unrecognized cytoprotective response mechanism to neurotrauma and offer a fresh perspective on pathophysiological processes in the nervous system.One-Sentence SummaryWhen the axon of a neuron is cut, its soma shrinks to pump out water to avoid deadly swelling.