bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Thompson Sampling by Roulette Wheel Selection for Screening Ultra-Large Combinatorial Libraries
Authors: Zhao Hongtao , Nittinger Eva , Tyrchan Christian 
Published: May 2024

ABSTRACTChemical space exploration has gained significant interest with the increase in available building blocks, which enables the creation of ultra-large virtual libraries containing billions or even trillions of compounds. However, the challenge of selecting most suitable compounds for synthesis arises, and one such challenge is hit expansion. Recently, Thompson sampling, a probabilistic search approach, has been proposed by Walterset al. to achieve efficiency gains by operating in the reagent space rather than the product space. Here, we aim to address some of its shortcomings and propose optimizations. We introduce a warmup routine to ensure that initial probabilities are set for all reagents with a minimum number of molecules evaluated. Additionally, a roulette wheel selection is proposed with adapted stop criteria to improve sampling efficiency, and belief distributions of reagents are only updated when they appear in new molecules. We demonstrate that a 100% recovery rate can be achieved by sampling 0.1% of the fully enumerated library, showcasing the effectiveness of our proposed optimizations.
Gastrointestinal germinal center B cell depletion and reduction in IgA+plasma cells in HIV-1 infection
Authors: Cossarini Francesca , Shang Joan , Krek Azra , Al-Taie Zainab , Hou Ruixue , Canales-Herrerias Pablo , Tokuyama Minami , Tankelevich Michael , Tillowiz Adam , Jha Divya , Livanos Alexandra E. , Leyre Louise , Uzzan Mathieu , Martinez-Delgado Gustavo , Taylor Matthew D. , Sharma Keshav , Bourgonje Arno R , Cruz Michael , Ioannou Giorgio , Dawson Travis , D’Souza Darwin , Kim-Schulze Seunghee , Akm Ahmed , Aberg Judith A. , Chen Benjamin K. , Kwon Douglas S. , Gnjatic Sacha , Polydorides Alexandros D. , Cerutti Andrea , Argmann Carmen , Vujkovic-Cvijin Ivan , Suarez-Fariñas Mayte , Petralia Francesca , Faith Jeremiah J. , Mehandru Saurabh 
Published: May 2024

AbstractGastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. IgA+PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)-treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia.One Sentence SummaryIntestinal germinal center B cell reduction in HIV-1 infection linked to reduced IgA+plasma cells and systemic inflammation.
Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease
Authors: Handsaker Robert E. , Kashin Seva , Reed Nora M. , Tan Steven , Lee Won-Seok , McDonald Tara M. , Morris Kiely , Kamitaki Nolan , Mullally Christopher D. , Morakabati Neda , Goldman Melissa , Lind Gabriel , Kohli Rhea , Lawton Elisabeth , Hogan Marina , Ichihara Kiku , Berretta Sabina , McCarroll Steven A. 
Published: May 2024

AbstractHuntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAGn) in thehuntingtin(HTT) gene leads to neurodegeneration after decades of apparent latency. InheritedHTTalleles with a longer CAG repeat hasten disease onset; the length of this repeat also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence HD age-at-onset. To understand the relationship between a cell’s CAG-repeat length and its biological state, we developed a single-cell method for measuring CAG-repeat length together with genome-wide RNA expression. We found that theHTTCAG repeat expands from 40-45 CAGs to 100-500+ CAGs in HD-vulnerable SPNs but not in other striatal cell types, with these long DNA-repeat expansions acquired at different times by individual SPNs. Surprisingly, somatic expansion from 40 to 150 CAGs had no apparent effect upon gene expression – but neurons with 150-500+ CAGs shared profound gene-expression changes. These expression changes involved hundreds of genes, escalated alongside further CAG-repeat expansion, eroded positive and then negative features of neuronal identity, and culminated in expression of senescence/apoptosis genes. Rates of striatal neuron loss across HD stages reflected the rates at which neurons entered this biologically distorted state. Our results suggest thatHTTCAG repeats in striatal neurons undergo decades of biologically quiet expansion, then, as they asynchronously cross a high threshold, cause SPNs to degenerate quickly and asynchronously. We conclude that, at any moment in the course of HD, most neurons have an innocuous (but unstable)huntingtingene, and that HD pathogenesis is a DNA process for almost all of a neuron’s life.
Accelerating Genome- and Phenome-Wide Association Studies using GPUs – A case study using data from the Million Veteran Program
Authors: Rodriguez Alex , Kim Youngdae , Nandi Tarak Nath , Keat Karl , Kumar Rachit , Bhukar Rohan , Conery Mitchell , Liu Molei , Hessington John , Maheshwari Ketan , Schmidt Drew ,   VA Million Veteran Program, Begoli Edmon , Tourassi Georgia , Muralidhar Sumitra , Natarajan Pradeep , Voight Benjamin F , Cho Kelly , Gaziano J Michael , Damrauer Scott M , Liao Katherine P , Zhou Wei , Huffman Jennifer E , Verma Anurag , Madduri Ravi K 
Published: May 2024

AbstractThe expansion of biobanks has significantly propelled genomic discoveries yet the sheer scale of data within these repositories poses formidable computational hurdles, particularly in handling extensive matrix operations required by prevailing statistical frameworks. In this work, we introduce computational optimizations to the SAIGE (Scalable and Accurate Implementation of Generalized Mixed Model) algorithm, notably employing a GPU-based distributed computing approach to tackle these challenges. We applied these optimizations to conduct a large-scale genome-wide association study (GWAS) across 2,068 phenotypes derived from electronic health records of 635,969 diverse participants from the Veterans Affairs (VA) Million Veteran Program (MVP). Our strategies enabled scaling up the analysis to over 6,000 nodes on the Department of Energy (DOE) Oak Ridge Leadership Computing Facility (OLCF) Summit High-Performance Computer (HPC), resulting in a 20-fold acceleration compared to the baseline model. We also provide a Docker container with our optimizations that was successfully used on multiple cloud infrastructures on UK Biobank and All of Us datasets where we showed significant time and cost benefits over the baseline SAIGE model.
Spatial cell graph analysis reveals skin tissue organization characteristic for cutaneous T cell lymphoma
Authors: Sarkar Suryadipto , Möller Anna , Hartebrodt Anne , Erdmann Michael , Ostalecki Christian , Baur Andreas , Blumenthal David B. 
Published: May 2024

ABSTRACTCutaneous T cell lymphomas (CTCLs) are non-Hodgkin lymphomas caused by malignant T cells which migrate to the skin. The cancerous T cells lead to rash-like lesions which can be difficult to distinguish from inflammatory skin conditions like atopic dermatitis (AD) and psoriasis (PSO). To characterize CTCL in comparison to these differential diagnoses, we carried out multi-antigen imaging on 69 skin tissue samples (21 CTCL, 23 AD, 25 PSO). The resulting spatially resolved protein abundance maps were then analyzed via scoring functions to quantify heterogeneity of the individual cells’ neighborhoods within spatial graphs inferred from the cells’ positions in the tissue samples (available as a Python package athttps://github.com/bionetslab/SHouT). Our analyses reveal several characteristic patterns of skin tissue organization in CTCL, including a combination of increased local entropy and egophily as characteristic properties of spatial T cell neighborhoods in CTCL as compared to AD and PSO. These results could not only pave the way for high-precision diagnosis of CTCL, but may also facilitate further insights into cellular disease mechanisms.
Evaluating genomic offset predictions in a forest tree with high population genetic structure
Authors: Archambeau Juliette , Benito-Garzón Marta , de-Miguel Marina , Changenet Alexandre , Bagnoli Francesca , Barraquand Frédéric , Marchi Maurizio , Vendramin Giovanni G. , Cavers Stephen , Perry Annika , González-Martínez Santiago C. 
Published: May 2024

AbstractPredicting how tree populations will respond to climate change is an urgent societal concern. An increasingly popular way to make such predictions is the genomic offset (GO) approach, which aims to use genomic and climate data to identify populations that may experience climate maladaptation in the near future. More precisely, GO tries to represent the change in allele frequencies required to maintain the current gene-climate relationships under climate change. However, the GO approach has major limitations and, despite promising validation of its predictions using height data from common gardens, it still lacks broad empirical testing. In the present study, we evaluated the consistency and empirical validity of GO predictions in maritime pine (Pinus pinasterAit.), a tree species from southwestern Europe and North Africa with a marked population genetic structure. First, gene-climate relationships were estimated using 9,817 SNPs genotyped in 454 trees from 34 populations; and candidate SNPs potentially involved in climate adaptation were identified. Second, GO was predicted using four methods, namely Gradient Forest (GF), Redundancy Analysis (RDA), latent factor mixed model (LFMM) and Generalised Dissimilarity Modeling (GDM), two sets of SNPs (candidate and control SNPs) and five climate general circulation models (GCMs) to account for uncertainty in future climate predictions. Last, the empirical validity of GO predictions was evaluated within a Bayesian framework by estimating the associations between GO predictions and two independent data sources: mortality data from National Forest Inventories (NFI), and mortality and height data from five common gardens in contrasting environments. We found high variability in GO predictions across methods, SNP sets and GCMs. Regarding validation, GO predictions with GDM and GF (and to a lesser extent RDA) based on the candidate SNPs showed the strongest and most consistent associations with mortality rates in common gardens and NFI plots. We found almost no association between GO predictions and tree height in common gardens, most likely due to the overwhelming effect of population genetic structure on tree height in this species. Our study demonstrates the imperative to validate GO predictions with a range of independent data sources before they can be used as informative and reliable metrics in conservation or management strategies.
No effect of additional education on long-term brain structure – a preregistered natural experiment in thousands of individuals
Authors: Judd Nicholas , Kievit Rogier 
Published: May 2024

AbstractEducation is related to a wide variety of beneficial health, behavioral, and societal outcomes. However, whether education causes long-term structural changes in the brain remains unclear. A pressing challenge is that individuals self-select into continued education, thereby introducing a wide variety of environmental and genetic confounders. Fortunately, natural experiments allow us to isolate the causal impact of increased education from individual (and societal) characteristics. Here, we exploit a policy change in the UK (the 1972 ROSLA act) that increased the amount of mandatory schooling from 15 to 16 years of age to study the impact of education on long-term structural brain outcomes in the UK Biobank. Using regression discontinuity – a causal inference method – we find no evidence of an effect from an additional year of education on any structural neuroimaging outcomes. This null result is robust across modalities, regions, and analysis strategies. An additional year of education is a substantial cognitive intervention, yet we find no evidence for sustained experience-dependent plasticity. Our results provide a challenge for prominent accounts of cognitive or ‘brain reserve’ theories which identify education as a major protective factor to lessen adverse aging effects. Our preregistered findings are one of the first implementations of regression discontinuity on neural data – opening the door for causal inference in population-based neuroimaging.
Novel phylogenomic inference and ‘Out of Asia’ biogeography of cobras, coral snakes, and their allies
Authors: Weinell Jeffrey L. , Burbrink Frank T. , Das Sunandan , Brown Rafe M. 
Published: May 2024

AbstractEstimation of evolutionary relationships among lineages that rapidly diversified can be challenging, and, in such instances, inaccurate or unresolved phylogenetic estimates can lead to erroneous conclusions regarding historical geographical ranges of lineages. One example underscoring this issue has been the historical challenge posed by untangling the biogeographic origin of elapoid snakes, which includes numerous dangerously venomous species as well as species not known to be dangerous to humans. The worldwide distribution of this lineage makes it an ideal group for testing hypotheses related to historical faunal exchanges among the many continents and other landmasses occupied by contemporary elapoid species. We developed a novel suite of genomic resources, included worldwide sampling, and inferred a robust estimate of evolutionary relationships, which we leveraged to quantitatively estimate geographical range evolution through the deep-time history of this remarkable radiation. Our phylogenetic and biogeographical estimates of historical ranges definitively reject a lingering former ‘Out of Africa’ hypothesis and support an ‘Out of Asia’ scenario involving multiple faunal exchanges between Asia, Africa, Australasia, the Americas, and Europe.
Carbonyl Reductase 1: a novel regulator of blood pressure in Down Syndrome
Authors: Malbon Alexandra J , Czopek Alicja , Beekman Andrew M , Goddard Zoë R , Boyle Aileen , Ivy Jessica R , Stewart Kevin , Denham Scott , Simpson Joanna P , Homer Natalie Z , Walker Brian R , Dhaun Neeraj , Bailey Matthew A , Morgan Ruth A 
Published: May 2024

AbstractBackgroundApproximately one in every 800 children is born with the severe aneuploid condition of Down Syndrome (DS), a trisomy of chromosome 21. Low blood pressure (hypotension) is a common condition associated with DS and can have a significant impact on exercise tolerance and quality of life. Little is known about the factors driving this hypotensive phenotype and therefore therapeutic interventions are limited. Carbonyl reductase 1 (CBR1) is an enzyme contributing to the metabolism of prostaglandins, glucocorticoids, reactive oxygen species and neurotransmitters, encoded by a gene (CBR1) positioned on chromosome 21 with potential to impact blood pressure.MethodsUtilising genetically modified mice and telemetric blood pressure measurement, we tested the hypothesis that CBR1 influences blood pressure and that its overexpression contributes to hypotension in DS.ResultsIn a mouse model of DS (Ts65Dn), which exhibit hypotension, CBR1 activity was increased and pharmacological inhibition of CBR1 increased blood pressure. Mice heterozygous null forCbr1had reduced CBR1 enzyme activity and elevated blood pressure. Further experiments indicate that the underlying mechanisms include alterations in sympathetic tone and prostaglandin metabolism.ConclusionsWe conclude that CBR1 activity contributes to blood pressure homeostasis and inhibition of CBR1 may present a novel therapeutic opportunity to correct symptomatic hypotension in DS.
The Ca2+-activated Cl-channel TMEM16B shapes the response time course of olfactory sensory neurons
Authors: Reisert Johannes , Pifferi Simone , Guarneri Giorgia , Ricci Chiara , Menini Anna , Dibattista Michele 
Published: May 2024

SummaryMammalian olfactory sensory neurons (OSNs) generate an odorant-induced response by sequentially activating two ion channels, which are in their ciliary membranes. First, a cationic, Ca2+-permeable cyclic nucleotide-gated channel is opened following odorant stimulation via a G protein-coupled transduction cascade and an ensuing raise in cAMP. Second, the increase in ciliary Ca2+opens the excitatory Ca2+-activated Cl-channel TMEM16B that carries most of the odorant-induced receptor current. While the role of TMEM16B in amplifying the response has been well established, it is less understood how this secondary ion channel contributes to response kinetics and action potential generation during single as well as repeated stimulation and, on the other hand, which response properties the CNG channel determines. We first demonstrate that basic membrane properties such as input resistance, resting potential and voltage-gated currents remained unchanged in OSNs that lack TMEM16B. The CNG channel predominantly determines the response delay and adaptation during odorant exposure, while the absence of the Cl-channels shortens both the time the response requires to reach its maximum as well as to terminate after odorant stimulation. This faster response termination inTmem16bknockout OSNs allows them, somewhat counterintuitively, to fire action potentials more reliably when stimulated repeatedly in rapid succession, a phenomenon that occurs both in isolated OSNs as well as in OSNs within epithelial slices. Thus, while the two olfactory ion channels act in concert to generate the overall response, each one controls specific aspects of the odorant-induced response.
Newton’s Cradle: Cell Cycle Regulation by Two Mutually Inhibitory Oscillators
Authors: Dragoi Calin-Mihai , Tyson John J. , Novák Béla 
Published: May 2024

AbstractThe cell division cycle is a fundamental physiological process displaying a great degree of plasticity during the course of multicellular development. This plasticity is evident in the transition from rapid and stringently-timed divisions of the early embryo to subsequent size-controlled mitotic cycles. Later in development, cells may pause and restart cell proliferation in response to myriads of internal or external signals, or permanently exit the cell cycle following terminal differentiation or senescence. Beyond this, cells can undergo modified cell division variants, such as endoreplication, which increases their ploidy, or meiosis, which reduces their ploidy. This wealth of behaviours has led to numerous conceptual analogies intended as frameworks for understanding the proliferative program. Here, we aim to unify these mechanisms under one dynamical paradigm. To this end, we take a control theoretical approach to frame the cell cycle as a pair of arrestable and mutually-inhibiting, doubly amplified, negative feedback oscillators controlling chromosome replication and segregation events, respectively. Under appropriate conditions, this framework can reproduce fixed-period oscillations, checkpoint arrests of variable duration, and endocycles. Subsequently, we use phase plane and bifurcation analysis to explain the dynamical basis of these properties. Then, using a physiologically realistic, biochemical model, we show that the very same regulatory structure underpins the diverse functions of the cell cycle control network. We conclude that Newton’s cradle may be a suitable mechanical analogy of how the cell cycle is regulated.Declaration of interestThe authors declare no competing or financial interests.
SARS-CoV-2 variants from long-term, persistently infected immunocompromised patients have altered syncytia formation, temperature-dependent replication, and serum neutralizing antibody escape
Authors: Wouters Camille , Sachithanandham Jaiprasath , Akin Elgin , Pieterse Lisa , Fall Amary , Truong Thao T. , Bard Jennifer Dien , Yee Rebecca , Sullivan David J. , Mostafa Heba H. , Pekosz Andrew 
Published: May 2024

AbstractSARS-CoV-2 infection of immunocompromised individuals often leads to prolonged detection of viral RNA and infectious virus in nasal specimens, presumably due to the lack of induction of an appropriate adaptive immune response. Mutations identified in virus sequences obtained from persistently infected patients bear signatures of immune evasion and have some overlap with sequences present in variants of concern. We characterized virus isolates from two COVID-19 patients undergoing immunosuppressive cancer therapy, with all isolates obtained greater than 100 days after the initial COVID-19 diagnoses and compared to an isolate from the start of the infection. Isolates from an individual who never mounted an antibody response specific to SARS-CoV-2 despite the administration of convalescent plasma showed slight reductions in plaque size and some showed temperature-dependent replication attenuation on human nasal epithelial cell culture compared to the virus that initiated infection. An isolate from another patient - who did mount a SARS-CoV-2 IgM response – showed temperature dependent changes in plaque size as well as increased syncytia formation and escape from serum neutralizing antibody. Our results indicate that not all virus isolates from immunocompromised COVID-19 patients display clear signs of phenotypic change, but increased attention should be paid to monitoring virus evolution in this patient population.
SLUR(M)-py: A SLURM Powered Pythonic Pipeline for Parallel Processing of 3D (Epi)genomic Profiles
Authors: Roth Cullen , Venu Vrinda , Bacot Sasha , Steadman Christina R. , Starkenburg Shawn R. 
Published: May 2024

AbstractThere is increasing demand to quickly process multiple types of sequencing-based data to completely capture epigenetic alterations and associated changes in chromatin structure underlying cellular responses. Furthermore, the need for a set of bioinformatic tools that leverage high performance computing and parallelization for processing omics data from many experiments has become apparent. Here we present SLUR(M)-py: a flexible command line tool (written in Python) that leverages the Simple Linux Utility for Resource Management system (SLURM) to process, align, and analyze sequencing data from three-dimensional and epigenomic assays in a high-performance computing environment. SLUR(M)-py is designed with host-pathogen infection experiments in mind, and contains unique scripts and functions that automate calls to SLURM for processing paired-end sequenced reads from chromatin characterization experiments, including whole-genome, ChIP-seq, ATAC-seq and Hi-C. ATAC-seq and Hi-C data from viral infection experiments as well as data from the ENCODE project are utilized to demonstrate processing speed, which outpace current high-performance computing pipelines. We explore the effect of dropping duplicate sequenced reads in ATAC-seq data and demonstrate how SLUR(M)-py can be used for quality control and to detect artifacts in Hi-C experiments from viral infection experiments. Finally, we utilize SLUR(M)-py to explore the dynamics of inter-chromosomal contacts in mammalian cells exposed to vaccinia virus, the vaccine for smallpox.