bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examination of the coverage of functional assessments in the OMOP common data model
Authors: French Margaret A. , Hartman Paul , Hayes Heather A. , Ling Leah , Magel John , Thackeray Anne 
Published: May 2024

ABSTRACTBackgroundHigh-value care aims to enhance meaningful patient outcomes while reducing costs. Curating data across healthcare systems with common data models (CDMs) would help these systems move towards high-value healthcare. However, meaningful patient outcomes, such as function, must be represented in commonly used CDMs, such as Observational Medical Outcomes Partnership Model (OMOP). Yet the extent that functional assessments are included in the OMOP CDM is unclear.ObjectiveExamine the extent that functional assessments used in neurologic and orthopaedic conditions are included in the OMOP CDM.MethodsAfter identifying functional assessments from clinical practice guideline, two reviewer teams independently mapped the neurologic and orthopaedic assessments into the OMOP CDM. After this mapping, we measured agreement with the reviewer team with the number of assessments mapped by both reviewers, one reviewer but not the other, or neither reviewer. The reviewer teams then reconciled disagreements, after which we again examined agreement and the average number of concept ID numbers per assessment.ResultsOf the 81 neurologic assessments, 48.1% were initially mapped by both reviewers, 9.9% were mapped by one reviewer but not the other, and 42% were unmapped. After reconciliation, 46.9% of neurologic assessments were mapped by both reviewers and 53.1% were unmapped. Of the 79 orthopaedic assessments, 46.8% were initially mapped by both reviewers, 12.7% were mapped by one reviewer but not the other, and 48.1% were unmapped. After reconciliation, 48.1% of orthopaedic assessments were mapped by both reviewers and 51.9% were unmapped. Most assessments that were mapped had more than one concept ID number (neurologic assessments: 2.2±1.3; orthopaedic assessments: 4.3±4.4).ConclusionsThe OMOP CDM includes a portion of functional assessments recommended for use in neurologic and orthopaedic conditions. Many assessments did not have any term in the OMOP CDM. Thus, expanding the OMOP CDM to include recommended functional assessments and creating guidelines for mapping functional assessments would improve our ability to harmonize these data across healthcare systems.
Generation of spermatogonia from pluripotent stem cells in humans and non-human primates
Authors: Whelan Eoin C. , Hwang Young Sun , Seita Yasunari , Yokomizo Ryo , Leu N. Adrian , Cheng Keren , Sasaki Kotaro 
Published: May 2024

AbstractFailures in germline development drive male infertility, but the lack of model systems that recapitulate human spermatogenesis hampers therapeutic development. Here, we have developed a system to differentiate human induced pluripotent stem cells (iPSCs) into primordial germ cell-like cells that self-organize within xenogeneic reconstituted testes (xrTestes) generated from mouse fetal testicular cells. Subsequent transplant of xrTestes into immunodeficient mice resulted in efficient generation of undifferentiated and differentiated spermatogonia as well as preleptotene spermatocytes with striking similarities to theirin vivocounterparts. As future clinical application will require testing in non-human primates, we utilized a similar strategy to differentiate rhesus iPSCs through all fetal germ cell stages into spermatogonia-like cells. Together, these models will serve as steppingstone to completion of human male in vitro gametogenesis.
The impact of insecticide decay on the rate of insecticide resistance evolution for monotherapies and mixtures
Authors: Hobbs Neil Philip , Hastings Ian Michael 
Published: May 2024

AbstractThe issue of insecticide decay in the public health deployments of insecticides is frequently highlighted as an issue for disease control. There are additional concerns insecticide decay also impacts the selection for insecticide resistance. Despite these concerns insecticide decay is lacking from models evaluating insecticide resistance management strategies. The impact of insecticide decay is modelled using a model which assumes a polygenic basis of insecticide resistance. Single generation selection events covering the insecticide efficacy and insecticide resistance space for both monotherapies and mixtures are conducted. With the outcome being the between generation change in the bioassay survival to the insecticides. The monotherapy sequence strategy and mixture strategy were compared against each other when including insecticide decay, with the outcome being the difference in strategy lifespan. The results demonstrate that as insecticides decay, they can apply a greater selection pressure than newly deployed insecticides, a process which can occur for both monotherapies and mixtures. For mixtures, it is seen that the rate of selection is highest when both insecticides are at reduced efficacies which would occur if reduced dose mixtures were used. Inclusion of insecticide decay in simulations was found to reduce the benefit of mixtures against monotherapy sequences, and this is especially so when reduced-dose mixtures are used. Insecticide decay is often highlighted as an important consideration for mixtures. The inclusion of insecticide decay in models is often lacking, and these results indicate this is absence may be over-inflating the performance of full-dose mixtures. As insecticides decay, they still provide selection pressures with reduced ability to control transmission, replenishing worn-out insecticides more frequently should be considered.
Reproducible single cell annotation of programs underlying T-cell subsets, activation states, and functions
Authors: Kotliar Dylan , Curtis Michelle , Agnew Ryan , Weinand Kathryn , Nathan Aparna , Baglaenko Yuriy , Zhao Yu , Sabeti Pardis C. , Rao Deepak A. , Raychaudhuri Soumya 
Published: May 2024

AbstractT-cells recognize antigens and induce specialized gene expression programs (GEPs) enabling functions including proliferation, cytotoxicity, and cytokine production. Traditionally, different classes of helper T-cells express mutually exclusive responses – for example, Th1, Th2, and Th17 programs. However, new single-cell RNA sequencing (scRNA-Seq) experiments have revealed a continuum of T-cell states without discrete clusters corresponding to these subsets, implying the need for new analytical frameworks. Here, we advance the characterization of T-cells with T-CellAnnoTator (TCAT), a pipeline that simultaneously quantifies pre-defined GEPs capturing activation states and cellular subsets. From 1,700,000 T-cells from 700 individuals across 38 tissues and five diverse disease contexts, we discover 46 reproducible GEPs reflecting the known core functions of T-cells including proliferation, cytotoxicity, exhaustion, and T helper effector states. We experimentally characterize several novel activation programs and apply TCAT to describe T-cell activation and exhaustion in Covid-19 and cancer, providing insight into T-cell function in these diseases.
Proliferation-driven mechanical feedback regulates cell dynamics in growing tissues
Authors: Sinha Sumit , Li Xin , Malmi-Kakkada Abdul N , Thirumalai D. 
Published: May 2024

AbstractLocal stresses in a tissue, a collective property, regulate cell division and apoptosis. In turn, cell growth and division induce active stresses in the tissue. As a consequence, there is a feed-back between cell growth and local stresses. However, how the cell dynamics depend on local stress-dependent cell division and the feedback strength is not fully understood. Here, we probe the consequences of stress-mediated growth and cell division on cell dynamics using agent-based simulations of a two-dimensional growing tissue. We discover a rich dynamical behavior of individual cells, ranging from jamming (mean square displacement, Δ(t) ∼tαwithαless than unity), to hyperdiffusion (α >2) depending on cell division rate and the strength of the mechanical feedback. Strikingly, Δ(t) is determined by the tissue growth law, which quantifies cell proliferation (number of cellsN(t) as a function of time). The growth law (N(t) ∼tλat long times) is regulated by the critical pressure that controls the strength of the mechanical feedback and the ratio between cell division-apoptosis rates. We show thatλ∼α, which implies that higher growth rate leads to a greater degree of cell migration. The variations in cell motility are linked to the emergence of highly persistent forces extending over several cell cycle times. Our predictions are testable using cell-tracking imaging techniques.
SEQSIM – A novel bioinformatics tool for comparisons of upstream gene regions – a case study of calcium binding protein spermatid associated 1 (CABS1)
Authors: Santos Joy Ramielle L. , Sun Weijie , Befus A. Dean , Marcet-Palacios Marcelo 
Published: May 2024

AbstractThe regulation of gene expression is carefully overseen by upstream gene regions (UGRs) which include promoters, enhancers, and other regulatory elements. Understanding these regions is difficult using standard bioinformatic approaches due to the scale of the human genome. Here we present SEQSIM, a novel bioinformatics tool based on a modified Needleman-Wunsch algorithm that allows for fast, comprehensive, and accurate comparison of UGRs across the human genome.In this study, we detailed the applicability and validity of SEQSIM through an extensive case study of the calcium binding protein spermatid-associated 1 (CABS1). By analyzing 2000 base pairs upstream of every human gene, SEQSIM identified distinct clusters of UGRs, revealing conserved motifs and suggesting potential regulatory interactions. Our analysis identified 41 clusters, the second largest of which contains the CABS1 UGR. Studying the other members of the CABS1 cluster could offer new insights into its regulatory mechanisms and suggest broader implications for genes involved in similar pathways or functions.The development and implementation of SEQSIM represents a significant step forward for the genomics field, providing a powerful new tool to dissect the complexity of the human genome and gain a better understanding of how gene expression is regulated. The study not only shows that SEQSIM is an effective means to identify potential regulatory elements and gene clusters, but also opens up new lines of inquiry to understand overall genomic architecture.
Arkypallidal neurons in the external globus pallidus can mediate inhibitory control by altering competition in the striatum
Authors: Giossi Cristina , Bahuguna Jyotika , Rubin Jonathan E. , Verstynen Timothy , Vich Catalina 
Published: May 2024

AbstractReactive inhibitory control is crucial for survival. Traditionally, this control in mammals was attributed solely to the hyperdirect pathway, with cortical control signals flowing unidirectionally from the subthalamic nucleus (STN) to basal ganglia output regions. Yet recent findings have put this model into question, suggesting that the STN is assisted in stopping actions through ascending control signals to the striatum mediated by the external globus pallidus (GPe). Here we investigate this suggestion by harnessing a biologically-constrained spiking model of the corticobasal ganglia-thalamic (CBGT) circuit that includes pallidostriatal pathways originating from arkypallidal neurons. Through a series of experiments probing the interaction between three critical inhibitory nodes (the STN, arkypallidal cells, and indirect path-way spiny projection neurons), we find that the GPe acts as a critical mediator of both ascending and descending inhibitory signals in the CBGT circuit. In particular, pallidostriatal pathways regulate this process by weakening the direct pathway dominance of the evidence accumulation process driving decisions, which increases the relative suppressive influence of the indirect pathway on basal ganglia output. These findings delineate how pallidostriatal pathways can facilitate action cancellation by managing the bidirectional flow of information within CBGT circuits.
Oxygen partitioning into biomolecular condensates is governed by protein density
Authors: Garg Ankush , Brasnett Christopher , Marrink Siewert J. , Koren Klaus , Kjaergaard Magnus 
Published: May 2024

AbstractBiomolecular condensates form through the self-assembly of proteins and nucleic acids to create dynamic compartments in cells. By concentrating specific molecules, condensates establish distinct microenvironments that regulate biochemical reactions in time and space. Macromolecules and metabolites partition into condensates depending on their interactions with the macromolecular constituents, however, the partitioning of gases has not been explored. We investigated oxygen partitioning into condensates formed by intrinsically disordered repeat proteins with systematic sequence variations using microelectrodes and phosphorescence lifetime imaging microscopy (PLIM). Unlike other hydrophobic metabolites, oxygen is partially excluded from the condensate with partitioning constants more strongly modulated by changes in protein length than hydrophobicity. For repeat proteins, the dense phase protein concentration drops with chain length resulting in a looser condensate. We found that oxygen partitioning is anti-correlated with dense phase protein concentration. Several mechanisms could explain such an anti-correlation including excluded volume or salting out effects. Molecular dynamics simulations suggest that oxygen does not form strong and specific interactions with the scaffold and is dynamic on the nanosecond timescale. Biomolecular condensates thus result in variation of oxygen concentrations on nanometer length-scales, which may tune the oxygen concentration available for biochemical reactions within the cell.
Acoustic target strengths and swimbladder morphology of Chub mackerelScomber japonicusin the Northwest Pacific Ocean
Authors: Yoon Euna , Lee Hyungbeen , Lee Yong-Deuk , Choo Yong Jin , Lee Jeong-Hoon , Kim Jung Nyun 
Published: May 2024

AbstractThe Northwest Pacific chub mackerel (Scomber japonicus) is one of the most productive, economically important fishery resources worldwide. Due to fluctuations in their abundance and distribution, there is a pressing need to accurately assess this species and to ensure total allowable catch limits are followed. Acoustic target strength (TS; dB) measurements ofScomber japonicuswere conducted at 38, 70, and 120 kHz using a split-beam echosounder of individuals from nine size groups (mean fork length, 10.8∼28.3 cm) swimming freely in a net cage within a seawater tank. An underwater camera was utilized to simultaneously measure the swimming angle. A least-squares regression analysis revealed that when the slope was constrained to 20, as per the generally applicable morphometric equation, the resulting values for the constant term (b20) were ‒67.7, ‒66.6, and – 67.3 dB at 38, 70, and 120 kHz, respectively. The mean swimming angle ofS. japonicusacross the groups was –10.5∼9.6° (standard deviation (SD), 16.3∼33.3°). In addition, the ratio of swimbladder height to swimbladder length, swimbladder length to fork length, and tilt angle of the swimbladder (mean ± SD) were 0.191 ± 0.060, 0.245 ± 0.055, and 9.6 ± 3.0°, respectively. These results can be used for the acoustic stock assessment ofS. japonicusin the Northwest Pacific Ocean.
A molecular representation to identify isofunctional molecules
Authors: Pinel Philippe , Guichaoua Gwenn , Devaux Nicolas , Gaston-Mathé Yann , Hoffmann Brice , Stoven Véronique 
Published: May 2024

AbstractThe challenges of drug discovery from hit identification to clinical development sometimes involve addressing scaffold hopping issues, in order to optimize biological activity or ADME properties, improve selectivity or mitigate toxicology concerns of a drug candidate, not to mention intellectual property reasons. Docking is usually viewed as the method of choice for identification of isofunctional molecules, i.e. highly dissimilar molecules that share common binding modes with a protein target. However, in cases where the protein structure has low resolution or is unknown, docking may not be suitable. In such cases, ligand-based approaches offer promise but are often inadequate to handle large-step scaffold hopping, because they usually rely on the molecular structure. Therefore, we propose the Interaction Fingerprints Profile (IFPP), a molecular representation that captures molecules binding modes based on docking experiments against a panel of diverse high-quality protein structures. Evaluation on the Large-Hops (LH) benchmark demonstrates the utility of IFPP for identification of isofunctional molecules. Nevertheless, computation of IFPPs is expensive, which limits the scalability for screening very large molecular libraries. We propose to overcome this limitation by leveraging Metric Learning approaches, allowing fast estimation of molecules’ IFPP similarities, thus providing an efficient pre-screening strategy applicable to very large molecular libraries. Overall, our results suggest that IFPP provides an interesting and complementary tool alongside existing methods, in order to address challenging scaffold hopping problems effectively in drug discovery.
The evolutionary history and functional specialization of microRNA genes inArabidopsis halleriandA. lyrata
Authors: Pavan Flavia , Azevedo Favory Jacinthe , Lacoste Eléanore , Beaumont Chloé , Louis Firas , Blassiau Christelle , Cruaud Corinne , Labadie Karine , Gallina Sophie , Genete Mathieu , Kumar Vinod , Kramer Ute , Batista Rita A. , Patiou Claire , Debacker Laurence , Ponitzki Chloé , Houzé Esther , Durand Eléonore , Aury Jean-Marc , Castric Vincent , Legrand Sylvain 
Published: May 2024

AbstractMicroRNAs (miRNAs) are a class of small non-coding RNAs that play important regulatory roles in plant genomes. While some miRNA genes are deeply conserved, the majority appear to be species-specific, raising the question of how they emerge and integrate into cellular regulatory networks. To better understand this, we first performed a detailed annotation of miRNA genes in the closely related plantsArabidopsis halleriandA. lyrataand evaluated their phylogenetic conservation across 87 plant species. We then characterized the process by which newly emerged miRNA genes progressively acquire the properties of “canonical” miRNA genes, in terms of size and stability of the hairpin precursor, loading of their cleavage products into Argonaute proteins, and potential to regulate downstream target genes. Nucleotide polymorphism was lower in the mature miRNA sequence than in the other parts of the hairpin (stem, terminal loop), and the regions of coding sequences targeted by miRNAs also had reduced diversity as compared to their neighboring regions along the genes. These patterns were less pronounced for recently emerged than for evolutionarily conserved miRNA genes, suggesting a weaker selective constraint on the most recent miRNA genes. Our results illustrate the rapid birth-and-death of miRNA genes in plant genomes, and provide a detailed picture of the evolutionary processes by which a small fraction of them eventually integrate into “core” biological processes.
In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency
Authors: Kubota Casie S. , Myers Stephanie L. , Seppälä Toni T. , Burkhart Richard A. , Espenshade Peter J. 
Published: May 2024

AbstractCancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. Using parallel in vitro and in vivo CRISPR knockout screens, we identified terpenoid backbone biosynthesis genes as essential for pancreatic ductal adenocarcinoma (PDAC) tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated thatgeranylgeranyl diphosphate synthase 1(GGPS1) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model. These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells.
IFNγ activates an immune-like regulatory network in the cardiac vascular endothelium
Authors: Arthur Timothy D. , Joshua Isaac N. , Nguyen Jennifer P. , D’Antonio-Chronowska Agnieszka , D’Antonio Matteo , Frazer Kelly A. 
Published: May 2024

AbstractThe regulatory mechanisms underlying the response to pro-inflammatory cytokines in cardiac diseases are poorly understood. Here, we use iPSC-derived cardiovascular progenitor cells (CVPCs) to model the response to interferon gamma (IFNγ) in human cardiac tissue. We generate RNA-seq and ATAC-seq for four CVPCs that were treated with IFNγ and compare them with paired untreated controls. Transcriptional differences after treatment show that IFNγ initiates an innate immune cell-like response, shifts the CVPC transcriptome towards coronary artery and aorta profiles, and stimulates expression of endothelial cell-specific genes. Analysis of the accessible chromatin shows that IFNγ is a potent chromatin remodeler and establishes an IRF-STAT immune-cell like regulatory network. Finally, we show that 11 GWAS risk variants for 8 common cardiac diseases overlap IFNγ-upregulated ATAC-seq peaks. Our findings reveal insights into IFNγ-induced activation of an immune-like regulatory network in the cardiac vascular endothelium and the potential role that regulatory elements in this pathway play in common cardiac diseases.Graphical AbstractPaired RNA-seq and ATAC-seq was generated for induced pluripotent stem cell derived cardiovascular progenitor cells (CVPCs) treated with interferon-gamma (IFNγ) and matched controls to model the effect of the pro-inflammatory cytokine on human cardiac tissue. Using the RNA-seq, transcriptomic changes were characterized by performing differential gene expression analysis, integrating gene expression data from hundreds of samples of adult cardiac tissues, and using single cell RNA-seq to evaluate cell type-specificity. Using the ATAC-seq, epigenomic changes were characterized by performing differential chromatin accessibility and transcription factor binding analyses, and annotating ATAC-seq peaks with chromatin states from over 800 tissues. Genetic variants in risk loci associated with cardiac diseases were intersected with ATAC-seq peaks to evaluate whether they were in chromatin that is only accessible after IFNγ treatment. The findings demonstrate the utility of using CVPCs to model the effects of cytokines on cardiac tissues and provide the framework for conducting large scale studies to further evaluate GWAS loci that are explained by context-specific regulatory variation.