bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUMMIT-FA: A new resource for improved transcriptome imputation using functional annotations
Authors: Melton Hunter J. , Zhang Zichen , Wu Chong 
Published: February 2023

AbstractTranscriptome-wide association studies (TWAS) integrate gene expression prediction models and genome-wide association studies (GWAS) to identify gene–trait associations. The power of TWAS is determined by the sample size of GWAS and the accuracy of the expression prediction model. Here, we present a new method, the Summary-level Unified Method for Modeling Integrated Transcriptome using Functional Annotations (SUMMIT-FA), that improves the accuracy of gene expression prediction by leveraging functional annotation resources and a large expression quantitative trait loci (eQTL) summary-level dataset. We build gene expression prediction models using SUMMIT-FA with a comprehensive functional database MACIE and the eQTL summary-level data from the eQTLGen consortium. By applying the resulting models to GWASs for 24 complex traits and exploring it through a simulation study, we show that SUMMIT-FA improves the accuracy of gene expression prediction models in whole blood, identifies significantly more gene-trait associations, and improves predictive power for identifying “silver standard” genes compared to several benchmark methods.
BrainstemDbh+Neurons Control Chronic Allergen-Induced Airway Hyperreactivity
Authors: Su Yujuan , Xu Jinhao , Zhu Ziai , Chin Ji , Xu Le , Yu Haoze , Nudell Victoria , Dash Barsha , Moya Esteban A. , Ye Li , Nimmerjahn Axel , Sun Xin 
Published: February 2023

AbstractChronic exposure of the lung to irritants such as allergen is a primary cause of asthma characterized by exaggerated airway constriction, also called hyperreactivity, which can be life-threatening. Aside from immune cells, vagal sensory neurons are important for airway hyperreactivity1–4. However, the identity and signature of the downstream nodes of this adaptive circuit remains poorly understood. Here we show that a single population ofDbh+neurons in the nucleus of the solitary tract (nTS) of the brainstem, and downstream neurons in the nucleus ambiguous (NA), are both necessary and sufficient for chronic allergen-induced airway hyperreactivity. We found that repeated exposures of mice to inhaled allergen activates nTS neurons in a mast cell-, interleukin 4 (IL-4)-and vagal nerve-dependent manner. Single-nucleus RNA-seq of the nTS at baseline and following allergen challenges reveals that aDbh+population is preferentially activated. Ablation or chemogenetic inactivation ofDbh+nTS neurons blunted, while chemogenetic activation promoted hyperreactivity. Viral tracing indicates thatDbh+nTS neurons, capable of producing norepinephrine, project to the NA, and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that then directly drive airway constriction. Focusing on transmitters, delivery of norepinephrine antagonists to the NA blunted allergen-induced hyperreactivity. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. The knowledge opens the possibility of targeted neural modulation as an approach to control refractory allergen-induced airway constriction.
The Suppression ofPlasmodium bergheiinAnopheles coluzziiinfected later withVavraia culicis
Authors: Vyas-Patel Nayna 
Published: February 2023

AbstractThe suppression of malaria parasites in the presence of an existing microsporidian infection ofVavraia culicis, was examined using fluorescentPlasmodium berghei. Younger hosts infected withV. culicishad a greater suppressive effect on the subsequent development ofP. bergheithan older infected hosts. This effect was density dependant on the numbers of microsporidian spores present, consequently it was also dependant on the age at which mosquitoes were infected with microsporidia, as larvae infected later harboured comparatively fewerV. culicisspores. The timing of primary and secondary infections of larval and adult mosquitoes (host age) with different parasites affects parasite development and hence disease outcomes. The use of green fluorescentP. bergheienabled easier and rapid visualisation and separation of malaria oocysts fromV. culicisspores. Different degrees of melanisation ofV. culicisspores was seen in a number of hosts and merits further investigation.
Taxonomical and ontological analysis of verified natural and laboratory human coronavirus hosts
Authors: Wang Yang , Ye Muhui , Zhang Fengwei , Freeman Zachary Thomas , Yu Hong , Ye Xianwei , He Yongqun 
Published: February 2023

AbstractTo fully understand COVID-19, it is critical to identify and analyze all the possible hosts of SARS-CoV-2 (the pathogen of COVID-19) and compare them with the hosts of other human coronaviruses. In this study, we collected, annotated, and performed taxonomical and ontological analysis of all the reported and verified hosts for all human coronaviruses including SARS-CoV, MERS-CoV, SARS-CoV-2, and four others that cause the common cold. A total of 37 natural hosts and 19 laboratory animal hosts of host human coronaviruses were identified based on experimental or clinical evidence. Our taxonomical ontology-based analysis found that all the verified susceptible natural and laboratory animals belong to therian mammals. Specifically, these 37 natural therian hosts include one wildlife marsupial mammal (i.e., Didelphis virginiana) and 36 Eutheria mammals (a.k.a. placental mammals). The 19 laboratory animal hosts are also classified as placental mammals. While several non-therian animals (including snake, housefly, zebrafish) were reported to be likely SARS-CoV-2 hosts, our analysis excluded them due to the lack of convincing evidence. Genetically modified mouse models with human Angiotensin-converting enzyme 2 (ACE2) or dipeptidyl peptidase-4 (DPP4) protein were more susceptible to virulent human coronaviruses with clear symptoms. Coronaviruses often became more virulent and adaptive in the mouse hosts after a series of viral passages in the mice. To support knowledge standardization and analysis, we have also represented the annotated host knowledge in the Coronavirus Infectious Disease Ontology (CIDO) and provided ways to automatically query the knowledge.
Functional characteristics and computational model of abundant hyperactive loci in the human genome
Authors: Hudaiberdiev Sanjarbek , Ovcharenko Ivan 
Published: February 2023

AbstractEnhancers and promoters are classically considered to be bound by a small set of TFs in a sequence-specific manner. This assumption has come under increasing skepticism as the datasets of ChIP-seq assays of TFs have expanded. In particular, high-occupancy target (HOT) loci attract hundreds of TFs with often no detectable correlation between ChIP-seq peaks and DNA-binding motif presence. Here, we used a set of 1,003 TF ChIP-seq datasets (HepG2, K562, H1) to analyze the patterns of ChIP-seq peak co-occurrence in combination with functional genomics datasets. We identified 43,891 HOT loci forming at the promoter (53%) and enhancer (47%) regions. HOT promoters regulate housekeeping genes, whereas HOT enhancers are involved in tissue-specific process regulation. HOT loci form the foundation of human super-enhancers and evolve under strong negative selection, with some of these loci being located in ultraconserved regions. Sequence-based classification analysis of HOT loci suggested that their formation is driven by the sequence features, and the density of mapped ChIP-seq peaks across TF-bound loci correlates with sequence features and the expression level of flanking genes. Based on the affinities to bind to promoters and enhancers we detected 5 distinct clusters of TFs that form the core of the HOT loci. We report an abundance of HOT loci in the human genome and a commitment of 51% of all TF ChIP-seq binding events to HOT locus formation thus challenging the classical model of enhancer activity and propose a model of HOT locus formation based on the existence of large transcriptional condensates.
Homodecameric Rad52 promotes single-position Rad51 nucleation in homologous recombination
Authors: Deveryshetty Jaigeeth , Chadda Rahul , Mattice Jenna , Karunakaran Simrithaa , Rau Michael J. , Basore Katherine , Pokhrel Nilisha , Englander Noah , Fitzpatrick James A.J. , Bothner Brian , Antony Edwin 
Published: February 2023

AbstractHomologous recombination (HR) is a pathway for the accurate repair of double-stranded DNA breaks. These breaks are resected to yield single-stranded DNA (ssDNA) that are coated by Replication Protein A (RPA).Saccharomyces cerevisiaeRad52 is a mediator protein that promotes HR by facilitating formation of Rad51 nucleoprotein filaments on RPA-coated ssDNA. Canonically, Rad52 has been described to function by displacing RPA to promote Rad51 binding. However,in vitro, Rad51 readily forms a filament by displacing RPA in the absence of Rad52. Yet,in vivo, Rad52 is essential for HR. Here, we resolve how Rad52 functions as a mediator using single-particle cryo-electron microscopy and biophysical approaches. We show that Rad52 functions as a homodecamer and catalyzes single-position nucleation of Rad51. The N-terminal half of Rad52 is a well-ordered ring, while the C-terminal half is disordered. An intrinsic asymmetry within Rad52 is observed, where one or a few of the C-terminal halves interact with the ordered N-terminal ring. Within the C-terminal half, we identify two conserved charged patches that harbor the Rad51 and RPA interacting motifs. Interactions between these two charged patches regulate a ssDNA binding. These features drive Rad51 binding to a single position on the Rad52 decameric ring. We propose a Rad52 catalyzed single-position nucleation model for the formation of pre-synaptic Rad51 filaments in HR.
Signatures of antibiotic tolerance and persistence in response to divergent stresses
Authors: Wang Huijing , McElfresh GW , Wijesuriya Nishantha , Podgorny Adam , Hecht Andrew D. , Ray J. Christian J. 
Published: February 2023

AbstractIn an environment with overly abundant lactose, a strain of the Gram-negative bacteriumE. coliinduces a persister-enriched phenotype and a heterogeneous pattern of growth rates. In high lactose conditions, the majority of cells are fast-growing, while a minority stochastically switch to a slow-growing, persister-prone phenotype that has higher ampicillin tolerance. Previously, bulk bacterial RNA-seq demonstrated broad changes in gene expression profiles for cells cultured in different lactose conditions, revealing multiple pathway regulatory regime switches enhancing its survivability for counteracting osmotic pressure in high lactose conditions with overflow metabolism.We hypothesized that a set of unique gene regulatory signatures underlies antibiotic tolerance in the high lactose condition. To further understand the gene regulatory regime in slow-growing cells, the subpopulation of persister-prone cells was enriched with ampicillin treatment. The resulting culture was collected for transcriptomic analysis. The transcriptomic data were then analyzed for differentially expressed genes, signature genes, GO term enrichment, pathway enrichment, and flux balance analysis.Our results show that under opposing stresses, the cells have similar and divergent responses. Cells exhibit upregulated assimilation pathways and downregulated biosynthesis pathways when encountering stresses. Post ampicillin treatment, cells in both high and low lactose conditions exhibit downregulated central metabolism to reduce growth. In the high-lactose concentration medium after ampicillin treatment, persisters may arise due to ferric imbalance-induced cell growth arrest and gene regulation due tossrA-mediated downregulation-induced error-prone transcription.
From autopoiesis to self-optimization: Toward an enactive model of biological regulation
Authors: Froese Tom , Weber Natalya , Shpurov Ivan , Ikegami Takashi 
Published: February 2023

AbstractThe theory of autopoiesis has been influential in many areas of theoretical biology, especially in the fields of artificial life and origins of life. However, it has not managed to productively connect with mainstream biology, partly for theoretical reasons, but arguably mainly because deriving specific working hypotheses has been challenging. The theory has recently undergone significant conceptual development in the enactive approach to life and mind. Hidden complexity in the original conception of autopoiesis has been explicated in the service of other operationalizable concepts related to self-individuation: precariousness, adaptivity, and agency. Here we advance these developments by highlighting the interplay of these concepts with considerations from thermodynamics: reversibility, irreversibility, and path-dependence. We interpret this interplay in terms of the self-optimization model, and present modeling results that illustrate how these minimal conditions enable a system to re-organize itself such that it tends toward coordinated constraint satisfaction at the system level. Although the model is still very abstract, these results point in a direction where the enactive approach could productively connect with cell biology.
Long term association between frailty and survival in patients with pleural disease: a cohort study protocol
Authors: Barton E , Carter B , Verduri A , Hughes J , Hewitt J , Maskell NA 
Published: February 2023

AbstractIntroductionAs the population ages, frailty is becoming more common and understanding how frailty impacts on patient outcomes has become an integral part of clinical care. To date, there is no evidence available on the relationship between frailty and patient outcomes in pleural disease. In this study we explore the relationship between frailty and both malignant and non-malignant pleural disease using the modified frailty index (mFI).Methods and AnalysisOutpatients with pleural disease will be identified from a prospectively collected single-centre UK database and their data and notes retrospectively analysed. An mFI will be calculated for each patient and the correlation between their frailty index, final diagnosis and mortality analysed.DisseminationStudy findings will be disseminated by publication in an appropriate journal and presentations at Respiratory and/or Geriatric medicine meetings.
The kinesin Kif21b regulates radial migration of cortical projection neurons through a non-canonical function on actin cytoskeleton
Authors: Alvarez José Rivera , Asselin Laure , Tilly Peggy , Benoit Roxane , Batisse Claire , Richert Ludovic , Batisse Julien , Morlet Bastien , Levet Florian , Schwaller Noémie , Mély Yves , Ruff Marc , Reymann Anne-Cécile , Godin Juliette D. 
Published: February 2023

AbstractCompletion of neuronal migration is critical for brain development. Kif21b is a plus-end directed kinesin motor protein that promotes intracellular transport and controls microtubule dynamics in neurons. Here we report a physiological function of Kif21b during radial migration of projection neurons in the mouse developing cortex.In vivoanalysis in mouse and live imaging on cultured slices demonstrate that Kif21b regulates the radial glia-guided locomotion of new-born neurons independently of its motility on microtubules. Unexpectedly we show that Kif21b directly binds and regulates the actin cytoskeleton bothin vitroandin vivoin migratory neurons. We establish that Kif21b-mediated regulation of actin cytoskeleton dynamics influences branching and nucleokinesis during neuronal locomotion. Altogether, our results reveal atypical roles of Kif21b on the actin cytoskeleton during migration of cortical projection neurons.
Physiological adaptation in flagellar architecture improvesVibrio alginolyticuschemotaxis in complex environments
Authors: Grognot Marianne , Nam Jong Woo , Elson Lauren E. , Taute Katja M. 
Published: February 2023

AbstractBacteria navigate natural habitats with a wide range of mechanical properties, from the ocean to the digestive tract and soil, by rotating helical flagella like propellers. Species differ in the number, position, and shape of their flagella, but the adaptive value of these flagellar architectures is unclear. Many species traverse multiple types of environments, such as pathogens inside and outside a host.We investigate the hypothesis that flagellar architectures mediate environment-specific benefits in the marine pathogenVibrio alginolyticuswhich exhibits physiological adaptation to the mechanical environment. In addition to its single polar flagellum, the bacterium produces lateral flagella in environments that differ mechanically from water. These are known to facilitate surface motility and attachment. We use high-throughput 3D bacterial tracking to quantify chemotactic performance of both flagellar architectures in three archetypes of mechanical environments relevant to the bacterium’s native habitats: water, polymer solutions, and hydrogels. We reveal that lateral flagella impede chemotaxis in water by lowering the swimming speed but improve chemotaxis in both types of complex environments. Statistical trajectory analysis reveals two distinct underlying behavioral mechanisms: In viscous solutions of the polymer PVP K90, lateral flagella increase the swimming speed. In agar hydrogels, despite lowering the swimming speed, lateral flagella improve overall chemotactic performance by preventing trapping in pores.Our findings show that lateral flagella are multi-purpose tools with a wide range of applications beyond surfaces. They implicate flagellar architecture as a mediator of environment-specific benefits and point to a rich space of bacterial navigation behaviors in complex environments.
Hormonal Interventions for optimizing reproductive efficiency in pigs at Farmers’ field
Authors: Kumar Sunil , Islam Rafiqul , Banik Santanu , Barman Keshab , Das P.J. , Mohan N.H. , Kumar Satish , Gupta Vivek Kumar 
Published: February 2023

AbstractObjectiveOptimizing reproductive efficiency in terms of estrus induction and production performance using simplified hormonal intervention using GnRH, gonadotropins and progesterone at farmers’ field conditions to bred animals with superior quality semen and also to reduce the maintenance cost.MethodThe present study was planned for optimizing reproductive efficiency using four different easily available hormonal agents with simplified protocols at farmers’ field. A total of 126 females were used in the study. Hormonal protocols I, II, III and IV using GnRH + (PMSG+ hCG), (PMSG+ hCG), PMSG alone and prepared progesterone gel respectively were used for estrus induction in gilts and sows.ResultsThe estrus induction/rate was (77.77%, 81.36%, 78.57% and 50% respectively. The corresponding figures for interval (hrs) of heat exhibition from hormonal administration (121.33±4.93, 121.54±3.60, 78.52±4.52 and 192±24), conception rate (%) (72.22%, 81.25%, 68.18% and 33.33%) farrowing rate (55.55%, 68.29%, 68.18% and 33.33 %), total litter size at birth (7.2±0.64, 7.90±0.47, 8.90±0.47 and 7.00±0) and hormonal cost (Rs.) per animal (570, 335, 280 and 250 Rs.) were respectively. The easier to use protocol was III followed by II, I and IV.ConclusionIt was found that protocol II and III are effective and easier so can be used for optimizing reproductive efficiency in pigs at farmers’ field.
xTrimoDock: Rigid Protein Docking via Cross-Modal Representation Learning and Spectral Algorithm
Authors: Luo Yujie , Li Shaochuan , Sun Yiwu , Wang Ruijia , Tang Tingting , Hongdu Beiqi , Cheng Xingyi , Shi Chuan , Li Hui , Song Le 
Published: February 2023

AbstractProtein-protein interactions are the basis for the formation of protein complexes which are essential for almost all cellular processes. Knowledge of the structures of protein complexes is of major importance for understanding the biological function of these protein-protein interactions and designing protein drugs. Here we address the problem of rigid protein docking which assumes no deformation of the involved proteins during interactions. We develop a method called, xTrimoDock, which leverages a cross-modal representation learning to predict the protein distance map, and then uses a spectral initialization and gradient descent to obtain the roto-translation transformation for docking. We show that, on antibody heavy-chain and light-chain docking, and antibody-antigen docking, xTrimoDock consistently outperforms the state-of-the-art such as AlphaFold-Multimer and HDock, and can lead to as much as a 10% improvement in DockQ metric. xTrimoDock has been applied as a useful tool in protein drug design at BioMap.
Phenotypical mapping of TP53 unique missense mutations spectrum in human cancers
Authors: Malhotra Lakshay , Singh Alankrita , Kaur Punit , Ethayathulla Abdul S. 
Published: February 2023

AbstractThe p53 tumor suppressor is one of the most mutated genes responsible for tumorigenesis in most human cancers. Out of 29,891 genomic mutations reported in the TP53 Database (https://tp53.isb-cgc.org/), 1297 are identified as unique missense somatic mutants excluding frameshift, intronic, deletion, nonsense, silent, splice and other unknown mutations. we have comprehensively analyzed all these 1297 unique missense mutations and created a phenotypical map based on the distribution of mutants in each domain, the functional state of the protein, and their occurrence in different types of tissues and organs. Our mutation map shows that almost 118 unique missense mutants are reported in the transactivation domain (TADs) and proline-rich domain (PRR), 1,065 in the central DNA-binding domain (DBD), and 113 in the oligomerization (OD) and regulatory domain (RD). Based on the phenotype these 1297 mutations are subdivided into 46 super trans, 491 functional, 315 partially functional, and 415 non-functional mutants. The prevalence of all these mutations was checked in 71 different types of tissues and found the mutant R248Q is reported in 51 types of tissues followed by R175H and R273H in 46 types. The propensity calculation of mutation for each amino acid in p53, showed Proline, Arginine, and Leucine/Glutamic acid are the most frequently mutated residues in the TAD domain, DBD, and TD respectively. We have correlated the impact of these mutations in the structure and function of p53 and highlighted the TP53 unique missense mutants that can be a potential therapeutic drug target with tremendous clinical applications.