bluuebunny/crossref_metadata_2025_split huggingface dataset:
AI-Enhanced Reconstruction of the 12-Lead Electrocardiogram via 3-Leads with Accurate Clinical Assessment
Authors: Mason Federico , Pandey Amitabh C. , Gadaleta Matteo , Topol Eric J. , Muse Evan D. , Quer Giorgio 
Published: January 2024

ABSTRACTThe 12-lead electrocardiogram (ECG) is an integral component to the diagnosis of a multitude of cardiovascular conditions. It is performed using a complex set of skin surface electrodes, limiting its use outside traditional clinical settings. We developed an artificial intelligence algorithm, trained over 600,000 clinically acquired ECGs, to explore whether fewer leads as input are sufficient to reconstruct a full 12-lead ECG. Two limb leads (I and II) and one precordial lead (V3) were required to generate a reconstructed synthetic 12-lead ECG highly correlated with the original ECG. An automatic algorithm for detection of acute myocardial infarction (MI) performed similarly for original and reconstructed ECGs (AUC=0.94). When interpreted by cardiologists, reconstructed ECGs achieved an accuracy of 81.4±5.0% in identifying ST elevation MI, comparable with the original 12-lead ECGs (accuracy 84.6±4.6%). These results will impact development efforts to innovate ECG acquisition methods with simplified tools in non-specialized settings.
SAR324 and related lineages are associated with the evolutionary history and origins of dsr-mediated sulfur oxidation
Authors: Klier Katherine M. , Martin Cody , Langwig Marguerite V. , Anantharaman Karthik 
Published: January 2024

ABSTRACTMicroorganisms play vital roles in sulfur cycling through the oxidation of elemental sulfur and reduction of sulfite. These metabolisms are catalyzed by dissimilatory sulfite reductases (dsr) which function in the reductive (dsr) or reverse, oxidative direction (rdsr). Dsr-based sulfite reduction is an ancient metabolism and has been proposed to fuel energy metabolism in some of Earth’s earliest microorganisms. Conversely, sulfur oxidation is believed to have evolved later in association with the widespread availability of oxygen on Earth. Organisms are generally believed to carry out either the reductiveoroxidative pathway, yet a subset of bacterial phyla have recently been discovered with gene combinations that implicate them in both pathways. A comprehensive global investigation into the metabolisms of these phyla regarding dsr can shed light on the evolutionary underpinnings of sulfur metabolism but is currently lacking. In this study, we selected one of these phyla, the abundant and metabolically versatile candidate phylum SAR324, to study the ecology and evolution of dsr and rdsr. We confirmed that phylogenetically, environmentally, and geographically diverse SAR324 contained dsr, rdsr, or both. Comprehensive phylogenetic analyses with other dsr-encoding bacterial and archaeal phyla revealed that organisms encoding both dsr and rdsr genes are constrained to a few phyla, which we term “transitionary clades for sulfur oxidation”, and these phyla are phylogenetically positioned at the interface between well-defined oxidative and reductive bacterial clades. Together, this research suggests that SAR324 and other transitionary clades are associated with the evolutionary history and origins of the reverse dsr pathway in bacteria.
The Fanconi anemia pathway repairs colibactin-induced DNA interstrand cross-links
Authors: Altshuller Maria , He Xu , MacKrell Elliot J. , Wernke Kevin M. , Wong Joel W. H. , Sellés-Baiget Selene , Wang Ting-Yu , Chou Tsui-Fen , Duxin Julien P. , Balskus Emily P. , Herzon Seth B. , Semlow Daniel R. 
Published: January 2024

AbstractColibactin is a secondary metabolite produced by bacteria present in the human gut and is implicated in the progression of colorectal cancer and inflammatory bowel disease. This genotoxin alkylates deoxyadenosines on opposite strands of host cell DNA to produce DNA interstrand cross-links (ICLs) that block DNA replication. While cells have evolved multiple mechanisms to resolve (“unhook”) ICLs encountered by the replication machinery, little is known about which of these pathways promote resistance to colibactin-induced ICLs. Here, we useXenopusegg extracts to investigate replication-coupled repair of plasmids engineered to contain site-specific colibactin-ICLs. We show that replication fork stalling at a colibactin-ICL leads to replisome disassembly and activation of the Fanconi anemia ICL repair pathway, which unhooks the colibactin-ICL through nucleolytic incisions. These incisions generate a DNA double-strand break intermediate in one sister chromatid, which can be repaired by homologous recombination, and a monoadduct (“ICL remnant”) in the other. Our data indicate that translesion synthesis past the colibactin-ICL remnant depends on Polη and a Polκ-REV1-Polζ polymerase complex. Although translesion synthesis past colibactin-induced DNA damage is frequently error-free, it can introduce T>N point mutations that partially recapitulate the mutation signature associated with colibactin exposurein vivo. Taken together, our work provides a biochemical framework for understanding how cells tolerate a naturally-occurring and clinically-relevant ICL.
Detailing organelle division and segregation inPlasmodium falciparum
Authors: Verhoef Julie M.J. , Boshoven Cas , Evers Felix , Akkerman Laura J. , Gijsbrechts Barend C.A. , van de Vegte-Bolmer Marga , van Gemert Geert-Jan , Vaidya Akhil B. , Kooij Taco W.A. 
Published: January 2024

AbstractThe malaria causing parasite,Plasmodium falciparum, replicates through a tightly orchestrated process termed schizogony, where approximately 32 daughter parasites are formed in a single infected red blood cell and thousands of daughter cells in mosquito or liver stages. One-per-cell organelles, such as the mitochondrion and apicoplast, need to be properly divided and segregated to ensure a complete set of organelles per daughter parasites. Although this is highly essential, details about the processes and mechanisms involved remain unknown. We developed a new reporter parasite line that allows visualization of the mitochondrion in blood and mosquito stages. Using high-resolution 3D-imaging, we found that the mitochondrion orients in a cartwheel structure, prior to stepwise, non-geometric division during the last stage of schizogony. Analysis of focused ion beam scanning electron microscopy (FIB-SEM) data confirmed these mitochondrial division stages. Furthermore, these data allowed us to elucidate apicoplast division steps, highlighted its close association with the mitochondrion, and showed putative roles of the centriolar plaques (CPs) in apicoplast segregation. These observations form the foundation for a new detailed mechanistic model of mitochondrial and apicoplast division and segregation duringP. falciparumschizogony and pave the way for future studies into the proteins and protein complexes involved in organelle division and segregation.
Metabolic fingerprinting reveals roles ofArabidopsis thalianaBGLU1, BGLU3 and BGLU4 in glycosylation of various flavonoids
Authors: Frommann Jana-Freja , Pucker Boas , Sielmann Lennart Malte , Müller Caroline , Weisshaar Bernd , Stracke Ralf , Schweiger Rabea 
Published: January 2024

AbstractFlavonoids are specialized metabolites that play important roles in plants, including interactions with the environment. The high structural diversity of this metabolite group is largely due to enzyme-mediated modifications of flavonoid core skeletons. In particular, glycosylation with different sugars is very common. In this study, the functions of theArabidopsis thalianaglycoside hydrolase family 1-type glycosyltransferase proteins BGLU1, BGLU3 and BGLU4 were investigated, using a reverse genetics approach and untargeted metabolic fingerprinting. We screened for metabolic differences betweenA. thalianawild type, loss-of-function mutants and overexpression lines and partially identified differentially accumulating metabolites, which are putative products and/or substrates of the BGLU enzymes. Our study revealed that the investigated BGLU proteins are glycosyltransferases involved in the glycosylation of already glycosylated flavonoids using different substrates. While BGLU1 appears to be involved in the rhamnosylation of a kaempferol diglycoside in leaves, BGLU3 and BGLU4 are likely involved in the glycosylation of quercetin glycosides inA. thalianaseeds. In addition, we present evidence that BGLU3 is a multifunctional enzyme that catalyzes other metabolic reactions with more complex substrates. This study deepens our understanding of the metabolic pathways and enzymes that contribute to the high structural diversity of flavonoids.HighlightThe proteins BGLU1, BGLU3 and BGLU4 are involved in glycosylations of different, already glycosylated flavonoids inArabidopsis thaliana. BGLU3 appears to be multifunctional, acting on several complex substrates.
Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion
Authors: Badaut J. , Hippauf L. , Malinconi M. , Noarbe B.P. , Obenaus A. , Dubois C. J. 
Published: January 2024

AbstractDue to the assumed plasticity of immature brain, early in life brain alterations are thought to lead to better recoveries in comparison to the mature brain. Despite clinical needs, how neuronal networks and associated behaviors are affected by early in life brain stresses, such as pediatric concussions, have been overlooked. Here we provide first evidence in mice that a single early in life concussion durably increases neuronal activity in the somatosensory cortex into adulthood, disrupting neuronal integration while the animal is performing sensory-related tasks. This represents a previously unappreciated clinically relevant mechanism for the impairment of sensory-related behavior performance. Furthermore, we demonstrate that pharmacological modulation of the endocannabinoid system a year post-concussion is well-suited to rescue neuronal activity and plasticity, and to normalize sensory-related behavioral performance, addressing the fundamental question of whether a treatment is still possible once post-concussive symptoms have developed, a time-window compatible with clinical treatment.
RNA N6-adenine methylation dynamics impactHyaloperonospora arabidopsidisresistance inArabidopsis
Authors: Furci Leonardo , Berthelier Jérémy , Saze Hidetoshi 
Published: January 2024

AbstractIn plants, epitranscriptomic mark N6-adenine methylation (m6A) is dynamically regulated by (a)biotic stressors. However, there is limited knowledge on m6A dynamics at single nucleotide resolution on specific RNA molecule under stresses, and their role in environmental adaptation. By using Oxford Nanopore Technology direct RNA sequencing (ONT-DRS) and a neural network model, here we show transcript-specific dynamics of m6A modification at single nucleotide resolution by biotic stress duringHyaloperonospera arabidopsidis(Hpa) infection inArabidopsis. In wild-type seedlings, pathogen infection causes significant reduction of global m6A ratios, which correlates with activation of m6A-modified transcripts. Defect of m6A deposition in the m6A mutanthakai-1mimics m6A reduction fromHpainfection at ∼70% of sites, resulting in constitutive overexpression of basal defence genes and enhanced resistance against the pathogen. Our results demonstrate that m6A dynamics impact defence response against pathogen, providing a promising target for future crop improvement strategies.
Eicosatetraynoic Acid Regulates Pro-Fibrotic Pathways in an Induced Pluripotent Stem Cell Derived Macrophage:Human Intestinal Organoid Model of Crohn’s Disease
Authors: Jurickova Ingrid , Dreskin Benjamin W. , Angerman Elizabeth , Bonkowski Erin , Tominaga Kentaro , Iwasawa Kentaro , Braun Tzipi , Takebe Takanori , Helmrath Michael A. , Haberman Yael , Wells James M. , Denson Lee A. 
Published: January 2024

AbstractBackground and AimsWe previously identified small molecules predicted to reverse an ileal gene signature for future Crohn’s Disease (CD) strictures. Here we used a new human intestinal organoid (HIO) model system containing macrophages to test a lead candidate, eicosatetraynoic acid (ETYA).MethodsInduced pluripotent stem cell lines (iPSC) were derived from CD patients and differentiated into macrophages and HIOs. Macrophages and macrophage:HIO co-cultures were exposed to lipopolysaccharide (LPS) with and without ETYA pre-treatment. Cytospin and flow cytometry characterized macrophage morphology and activation markers, and RNA sequencing defined the global pattern of macrophage gene expression. TaqMan Low Density Array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to measure macrophage cytokine production and HIO pro-fibrotic gene expression and collagen content.ResultsiPSC-derived macrophages exhibited morphology similar to primary macrophages and expressed inflammatory macrophage cell surface markers including CD64 and CD68. LPS-stimulated macrophages expressed a global pattern of gene expression enriched in CD ileal inflammatory macrophages and matrisome secreted products, and produced cytokines and chemokines including CCL2, IL1B, and OSM implicated in refractory disease. ETYA suppressed CD64 abundance and pro-fibrotic gene expression pathways in LPS stimulated macrophages. Co-culture of LPS-primed macrophages with HIO led to up-regulation of fibroblast activation genes includingACTA2andCOL1A1, and an increase in HIO collagen content. ETYA pre-treatment prevented pro-fibrotic effects of LPS-primed macrophages.ConclusionsETYA inhibits pro-fibrotic effects of LPS-primed macrophages upon co-cultured HIO. This model may be used in future untargeted screens for small molecules to treat refractory CD.
Spatiotemporal structure of multimodal cues influences color and odor integration in a model insect, the bumblebeeBombus impatiens
Authors: Graver Katelyn , Sommer Jessica , Rao Vijay , Tafuri Giovanni , Sprayberry Jordanna D. H. 
Published: January 2024

AbstractBumblebees rely on diverse sensory information to locate flowers while foraging. The majority of research exploring the relationship between visual and olfactory floral cues is performed at local spatial scales and applicable to understanding floral selection. Floral-cue use during search remains underexplored. This study investigates how the bumblebeeBombus impatiensuses visual versus olfactory information from flowers across behavioral states and spatial scales. At local spatial scales, non-flying animals in an associative learning paradigm will generalize to either unimodal attribute of a learned color + odor cue with equal likelihood. However, bumblebees flying in a wind tunnel shift cue-use strategy depending on the spatiotemporal scale of cue encounter. When both color and odor cues mimic local/ within patch spatial scale, bumblebees weigh color information of a learned floral-cue more heavily. When cues mimic an intermediate/ between patch spatial scale, bumblebees weigh color and odor information equally, and show the highest response to fully intact multimodal cues. Thus the spatiotemporal scale of sensory information influences how bumblebees utilize multimodal floral cues.Statements and DeclarationsThis work was internally funded by Muhlenberg College. The authors have no competing interests
Modeling platinum resistance in a stem-like patient-derived ovarian cancer sample
Authors: Suzuki Tise , Conant Ashlyn , Jung Yeonkyu , Bax Ryan , Antonissen Ashley , Chen Wanqiu , Yu Gary , Ioffe Yevgeniya J. , Wang Charles , Unternaehrer Juli J. 
Published: January 2024

AbstractBackgroundChemoresistance and tumor recurrence remain a significant challenge in ovarian cancer. Particularly in the context of platinum resistance, many mechanisms have been identified, including the activation of cellular processes like epithelial-mesenchymal transition (EMT), which generates cells with stemness characteristics. Current models of platinum resistance are limited or not adequate representations of the heterogeneity of the disease. Thus, to advance our understanding of chemoresistance in the context of cancer stem cells (CSC) in ovarian cancer, this study aims to develop an effective model for cisplatin resistance using a patient-derived cancer stem-like sample.MethodsPDX4, a patient-derived cancer cell line with stem-like properties, was exposed to increasing concentrations of cisplatinin vitroin parallel with vehicle treated cells. Once chemoresistance was established and confirmed, the resistance model was validated through comprehensive molecular profiling through RNA- and miRNA-sequencing, followed by the assessment of alterations in cell morphology, protein expression, and functional properties in the context of EMT and cancer stemness. Moreover, we explored potential signaling pathways involved in cisplatin resistance in these stem-like cancer cells.ResultsOur findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin resistant PDX4 compared to their sensitive counterparts. Furthermore, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic. JAK-STAT, hypoxia, and PI3K signaling pathways were enriched in these cells, indicating the activation of pathways that assist in DNA damage tolerance and cellular stress management.ConclusionThis novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapeutic strategies tailored to combat resistance in stem-like ovarian cancer.
Hepatoblast iterative apicobasal polarization is regulated by extracellular matrix remodeling
Authors: Delpierre Julien , Valenzuela José Ignacio , Bovyn Matthew , Martins Nuno Pimpao , Belicova Lenka , Repnik Urska , Bebelman Maarten , Seifert Sarah , Haas Pierre A , Kalaidzidis Yannis L , Zerial Marino 
Published: January 2024

SummaryHepatocytes have a unique multiaxial polarity with several apical and basal surfaces. The prevailing model for the emergence of this multipolarity and the coordination of lumen formation between adjacent hepatocytes is based on asymmetric cell division. Here, investigating polarity generation in liver cell progenitors, the hepatoblasts, during liver developmentin vivoandin vitro, we found that this model cannot explain the observed dynamics of apical lumen formation in the embryonic liver. Instead, we identified a new mechanism of multi-axial polarization: We found that polarization can be initiated in a cell-autonomous manner by re-positioning apical recycling endosomes (AREs) to the cell cortex via fibronectin sensing through Integrin αV. Using live cell imaging we showed that this process repeats, leading to multiaxial polarity independently of cell division. We found that establishment of oriented trafficking leads to secretion of the metalloprotease MMP13, allowing neighboring hepatoblasts to synchronize their polarization by sensing extracellular matrix (ECM) distribution and enabling lumen opening. Finally, active remodeling of ECM in proximity of nascent apical surfaces closes a positive feedback loop of polarization, whereas disruption of this loop by either blocking MMP13 or downregulating Integrin αV prevents formation of the bile canaliculi network. Integration of this feedback loop into a simple mathematical model reproduces the observed dynamics of bile canaliculi network formation during liver development quantitatively. Our combined findings thus suggest a new mechanism of polarization coupling to self-organization at the tissue scale.
Incorporation of a cost of deliberation time in perceptual decision making
Authors: Kira Shinichiro , Zylberberg Ariel , Shadlen Michael N. 
Published: January 2024

AbstractMany decisions benefit from the accumulation of evidence obtained sequentially over time. In such circumstances, the decision maker must balance speed against accuracy, and the nature of this tradeoff mediates competing desiderata and costs, especially those associated with the passage of time. A neural mechanism to achieve this balance is to accumulate evidence in suitable units and to terminate the deliberation when enough evidence has accrued. To accommodate time costs, it has been hypothesized that the criterion to terminate a decision may become lax as a function of time. Here we tested this hypothesis by manipulating the cost of time in a perceptual choice-reaction time task. Participants discriminated the direction of motion in a dynamic random-dot display, which varied in difficulty across trials. After each trial, they received feedback in the form of points based on whether they made a correct or erroneous choice. They were instructed to maximize their points per unit of time. Unbeknownst to the participants, halfway through the experiment, we increased the time pressure by canceling a small fraction of trials if they had not made a decision by a provisional deadline. Although the manipulation canceled less than 5% of trials, it induced the participants to make faster decisions while lowering their decision accuracy. The pattern of choices and reaction times were explained by bounded drift-diffusion. In all phases of the experiment, stopping bounds were found to decline as a function of time, consistent with the optimal solution, and this decline was exaggerated in response to the time-cost manipulation.
Hydrodynamical approach to chirality production during axion inflation
Authors: Gorbar E. V. , Momot A. I. , Prikhodko O. O. , Teslyk O. M. 
Published: January 2024

We study chirality production in the pseudoscalar inflation model of magnetogenesis, taking into account the Schwinger effect and particle collisions in plasma in the relaxation time approximation. We consider the Schwinger production of one Dirac fermion species by an Abelian gauge field in two cases: (i) fermions carry only the weak charge with respect to the U(1) group and (ii) they are also charged with respect to another strongly coupled gauge group. While the gradient-expansion formalism is employed for the description of the evolution of the gauge field, plasma is described by a hydrodynamical approach, which allows us to determine the number, energy density, and chirality of produced fermions. It is found that, while chirality production is very efficient for both weakly and strongly interacting fermions, the resulting gauge field is typically stronger in the case of strongly interacting fermions, due to suppression of the Schwinger conductivity by particle collisions.

Published by the American Physical Society
2024