bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mice with Reduced PAR4 Reactivity show Decreased Venous Thrombosis and Platelet Procoagulant Activity
Authors: Knauss Elizabeth A. , Guci Johana , Luc Norman , Disharoon Dante , Huang Grace H. , Gupta Anirban Sen , Nieman Marvin T. 
Published: October 2024

AbstractBackgroundHypercoagulation and thrombin generation are major risk factors for venous thrombosis. Sustained thrombin signaling through PAR4 promotes platelet activation, phosphatidylserine exposure, and subsequent thrombin generation. A single-nucleotide polymorphism in PAR4 (rs2227376) changes proline to leucine extracellular loop 3 (P310L), which decreases PAR4 reactivity and is associated with a lower risk for venous thromboembolism (VTE) in a GWAS meta-analysis.ObjectiveThe goal of this study is to determine the mechanism for the association of rs2227376 with reduced risk for VTE in using mice with a homologous mutation (PAR4-P322L).MethodsVenous thrombosis was examined using our recently generated PAR4-P322L mice in the inferior vena cava stasis and stenosis models. Coagulation and clot stability was measured using rotational thromboelastometry (ROTEM). Thrombin generating potential was measured in platelet-rich plasma. Phosphatidylserine surface expression and platelet-neutrophil aggregates were analyzed using flow cytometry.ResultsPAR4P/Land PAR4L/Lhad reduced incidence and size of venous clots at 48 hours. PAR4P/Land PAR4L/Lplatelets had progressively decreased phosphatidylserine in response to thrombin and convulxin, which led to decreased thrombin generation and decreased PAR4-mediated platelet-neutrophil aggregation.ConclusionsThe leucine allele in extracellular loop 3, PAR4-322L leads to fewer procoagulant platelets and decreased endogenous thrombin potential. This decreased ability to generate thrombin offers a mechanism for PAR4’s role in VTE highlighting a key role for PAR4 signaling.
Detecting ecosystem trends in response to climate and disturbance across continental plot networks: a power analysis
Authors: Guerin Greg R. , Martín-Forés Irene , Gallagher Rachael V. , Munroe Samantha E.M. , Sparrow Ben 
Published: October 2024

AbstractPlant communities are dynamic: cyclical, directional and stochastic changes in species composition make interpretation of responses complex. The multi-dimensionality of ecological change is reduced by ecosystem indicators that quantify functional responses to environmental drivers. However, thresholds of detectable change in indicators may vary by ecosystem or the spatial configuration of monitoring sites within regions.We quantified the power of a continental terrestrial ecosystem plot network (TERN Ausplots, Australia) to detect change in ecological indicators linked to disturbance and climate: community temperature index (CTI), proportional abundance of photosynthetic pathways (C4%), and species abundance distribution (SAD). We simulated trend and noise scenarios and calculated power and effect size across spatial clusters of plots using linear mixed effects models. We then assessed factors that influenced change detection capacity.Power varied substantially across the network. Trends with a minimum magnitude of 0.5–3.0°C in CTI, 0.01–0.3 in C4% and 0.1–0.5 in the SAD sigma were detectable, depending on cluster identity and noise. Increased plot replication within a spatial cluster increased power and lower variance among baseline replicates increased effect size for CTI and C4% but not SAD. Latitudinal patterns in change detection capacity emerged for CTI and C4%. The effect size of increasing CTI was greater in the tropics due to lower among-plot variance, while power to detect increasing C4% was higher in the temperate south, where C4is rare.Indicators reveal trends in complex ecological data that can inform decision-making. Increasing spatial replication and minimising spatial variation by stratifying plots to the same ecological community enhance change detection, albeit with different effectiveness by indicator. The results suggest change detection differs by location, irrespective of sampling factors such as number of plots. Strategies and thresholds for change detection may therefore apply unequally across environments and should be considered by region and response parameter.
Intestinal microbiota changes due toGiardia intestinalisinfections in a longitudinal Ecuadorian birth cohort and impact on cobalamin biosynthesis
Authors: Damania Ashish , Arévalo-Cortés Andrea , Lopez Andrea , Seco-Hidalgo Victor , Garcia-Ramon Diana , Lefoulon Emilie , Long Courtney , Drake Evan , Slatko Barton , Cooper Philip J , Mejia Rojelio 
Published: October 2024

AbstractBackgroundGiardia intestinalisis a protozoal parasite infecting the gastrointestinal tract worldwide. Chronic infections/reinfections are common, with adverse nutritional consequences for critical growth during the first five years of life. Vitamin B12 (cobalamin) is absorbed primarily in the ileum of the small intestine, whereGiardiatrophozoites attach and replicate. Bacteria activate bioavailable vitamin B12, which is essential for human DNA synthesis and development. A disturbance in cobalamin biosynthesis caused by giardiasis may contribute to impairment of childhood development and growth.Methodology/Principal FindingsWe performed a longitudinal analysis on 61 Ecuadorian children using multi-parallel real-time quantitative PCR and whole genome sequencing. Children had increasedGiardiaDNA burden from ages 3 to 5 (p = 0.0012) and 7.58 times more frequentGiardiainfections (1.31 to 34.33, P = 0.0176). There was an increased alpha diversity/Giardiafg/µl in three-year-olds compared to age-matched non-infected (30.20 vs 4.37, p = 0.050), but decreased alpha diversity/Giardiafg/µl in five-year-olds compared to age-matched non-infected children (0.21 vs 4.31, p = 0.021). Alpha diversity/Giardiafg/µl was also decreased in samples collected longitudinally from the same children at five compared to 3 years (p = 0.031). Cobalt transport protein (CbiN) (FDR < 0.003) and IPR011822 (Cobalamin-dependent methionine synthase) sequences were decreased in infected children (p < 0.002) and among those with greatestGiardiaburdens (p < 0.001).Conclusion/SignificanceGiardia intestinalisinfection may affect bacterial diversity in the ileum where vitamin B12 is activated, as suggested by a reduced proportion of Cobalt transport protein component (CbiN) gene sequences in the gut microbiome of infected children. These findings are potentially important to our understanding of howGiardiainfections may affect childhood growth.
Heart Block Identification from 12-Lead ECG: Exploring the Generalizability of Self-Supervised AI
Authors: Bergamaschi Teya S. , Stultz Collin M. , Alam Ridwan 
Published: October 2024

AbstractTimely diagnosis and treatment of heart blocks are critical for preventing fatal outcomes in patients with cardiac conduction disorders. Expert analysis of clinical 12-lead electro-cardiograms (ECG) remains the standard diagnosis apparatus. In this study, we propose a self-supervised deep learning model that can detect evidence of heart blocks in ECG signals. We build a multichannel residual neural network (KRes) and train this model in a self-supervised contrastive fashion leveraging 3.6 million ECG from patients at the Massachusetts General Hospital (MGH) to learn robust ECG representations. We evaluate the utility of such representations on a large public dataset, PTB-XL, through fine-tuning and linear probing for identifying heart blocks. To compare, we also build a baseline supervised model by adapting KRes. The training data contains a subset of 10.6 thousand PTB-XL ECG from patients with and without heart block patterns, and a holdout set of 1319 ECG is used for evaluation. We compare the performances of the finetuning and the linear probing of the self-supervised representations with that of the supervised model using the area under the receiver-operating curve (AUC), sensitivity, specificity, and predictive values, and found those performing equally well. Moreover, we repeat the training cycles of the three pipelines while reducing the number of training samples and demonstrate that the performance of the self-supervised representations remain steady even when labeled data is limited. This research underscores the potential of self-supervised learning in cardiac diagnostics, emphasizing generalizability and performance across diverse datasets and clinical settings, especially in data-scarce paradigms.
Serum total cholesterol and fatal subarachnoid hemorrhage in 120,000 Japanese: a pooled analysis of data from 12 cohorts
Authors: Satoh Atsushi , Arima Hisatomi , Tanaka-Mizuno Sachiko , Fujiyoshi Akira , Kadota Aya , Miura Katsuyuki , Ueshima Hirotsugu , Okamura Tomonori , Murakami Yoshitaka ,   EPOCH JAPAN Research Group
Published: October 2024

AbstractBackgroundThe aim of this study was to clarify the association between serum total cholesterol and fatal subarachnoid hemorrhage in Japanese men and women.MethodsThe study involved a pooled analysis of data from 12 well-qualified cohort studies conducted in Japan. A total of 120,973 participants (70,947 women and 50,026 men) aged 18– 96 years at baseline underwent follow-up for a median of 12.7 years. The participants were classified according to their serum total cholesterol levels: <4.14 mmol/L (<160 mg/dL), 4.14–4.64 mmol/L (160–180 mg/dL), 4.65–5.16 mmol/L (180–199 mg/dL), 5.17–5.68 mmol/L (200–219 mg/dL), 5.69–6.20 mmol/L (220–239 mg/dL), and ≥6.21 mmol/L (≥240 mg/dL). The outcome of the analysis was death from subarachnoid hemorrhage.ResultsDuring the median follow-up of 12.7 years, 261 participants died from subarachnoid hemorrhage. In women, both low (<5.69 mmol/L [<220 mg/dL]) and high (≥6.21 mmol/L [≥240 mg/dL]) serum total cholesterol levels were significantly associated with a higher risk of fatal subarachnoid hemorrhage compared with the reference group (5.69–6.20 mmol/L [220–239 mg/dL]). These associations remained significant after adjustment for confounding factors. In contrast, no associations were observed in men.ConclusionsBoth low and high serum total cholesterol levels were associated with a higher risk of fatal subarachnoid hemorrhage in 70,947 female participants from 12 cohort studies throughout Japan.
Oxygen deprivation implicated in rapid coral mortality – an emerging perilous threat to coral reefs
Authors: Dhillon Max S. , Klein Shannon G. , Parry Anieka J. , Moret Alessandro , Duarte Carlos M. , Aranda Manuel 
Published: October 2024

AbstractTropical coral reefs are undergoing unprecedented degradation1, primarily due to the increasing intensity and frequency of marine heatwaves with climate change2-4. Coral bleaching is a well-known ramification of marine heatwaves, but rapid coral mortality is an emerging paradigm that visually manifests as the ‘sloughing’ of tissue from the coral skeleton. Unlike coral bleaching, coral tissue sloughing precludes any prospect of holobiont recovery beyond the initial onset1,5,6, indicating a life-or-death tipping point. Here, we experimentally confirm this phenomenon occurs when temperatures increase within temporal windows of hours to days, consistent with field observations7,8. Through microscale measurements of dissolved oxygen in the diffusive boundary layers of two abundant, keystone reef-building corals, we demonstrate that rapid temperature increases coincide with intrinsic oxygen deprivation, occurring before gross tissue disintegration or coral tissue sloughing. We propose that this distinct phenomenon arises from rapid heating, rendering the coral holobiont incapable of engaging in reactive processes to counteract the combined effects of heightened aerobic demands and impaired photosynthetic function. The passive diffusion of O2from the surrounding bulk water is likely insufficient to meet the holobiont’s requirements, as explained by the Einstein–Smoluchowski kinetic theory of gases and Brownian motion9,10. These insights into coral tissue sloughing underscore the complexity of holobiont responses to stress and biophysical consequences of heatwaves. A granular understanding of these mechanisms is urgently needed, particularly regarding how heating rates may change under future climate scenarios, to re-evaluate the potentially under-recognised threats facing coral reefs.
Stabilization of HSA32, an aggregation-prone protein, by the protein disaggregase HSP101 plays a critical role in maintaining acquired thermotolerance in Arabidopsis
Authors: Mitra Suma , Yu Shih-Jiun , Liu Nai-Yu , Hsu Chuan-Chih , Li Hong-Yi , Borah Akankshita , Shen Yu-Yen , Wu Shang-hao , Hsu Yang-Hsin , Fu Hongyong , Charng Yee-yung 
Published: October 2024

ABSTRACTHeat acclimation confers acquired thermotolerance (AT), and heat-acclimation memory (HAM) is the maintenance of AT for some time. In Arabidopsis and rice, the heat-stress-associated 32-kDa protein (HSA32) and the protein disaggregase heat shock protein101 (HSP101) form a positive feedback loop at the protein level to maintain AT; HSA32 mitigates HSP101 degradation, and HSP101 positively regulates the accumulation of HSA32. Here, we report the underpinning mechanism regarding how HSP101 affects the HSA32 level in Arabidopsis. We found that, without HSP101, nascent HSA32 was rapidly degraded, and the proteasome inhibitor, bortezomib, inhibited the degradation. In response to heat stress, the nascent HSA32-GFP fusion protein was present in liquid condensates and diffused in the cytosol after returning to non-stress temperature. Proximity labeling with HSA32-TurboID identified HSP101 and five other protein chaperones and co-chaperones as the primary interactors. Disturbing the interaction between HSA32 and HSP101 destabilized HSA32 and compromised HAM. HSA32 is predicted as a TIM-barrel protein with three intrinsically disordered regions of high aggregation propensity. Recombinant HSA32 expressed inE. coliwas partitioned into insoluble fractions, suggesting that HSA32 is aggregation-prone. Our findings highlight how the interplay between an aggregation-prone protein and a protein disaggregase can maintain plant stress memory.
Copy number variation analysis of 9,482Mycobacterium tuberculosisisolates identifies lineage-specific molecular determinants
Authors: Bhalla Nikhil , Behera Anil , Gupta Ashish , Kumar Nanda Ranjan 
Published: October 2024

AbstractBackgroundClinical manifestations of tuberculosis (TB) caused byMycobacterium tuberculosis(Mtb) show lineage-specific differences contributed by genetic polymorphism such as phylo-single nucleotide variations (PhyloSNPs) and insertion or deletions (INDELs). Intragenomic rearrangement events, such as gene duplications and deletions, may cause gene copy number differences in Mtb, contributing to lineage-specific phenotypic variations, if any, which need better understanding.ResultsThe relative gene copy number differences in high-quality publicly available whole genome sequencing datasets of 9,482 clinical Mtb isolates were determined by repurposing and modifying an RNA-seq data analysis pipeline. The pipeline included various steps, viz., alignment of reads, sorting by coordinate, GC bias correction, and variant stabilising transformation. The strategy showed maximum separation of lineage-specific clusters in two principal components, capturing ∼54% variability. Unsupervised hierarchical clustering of the top 100 genes and pairwise comparisons between Mtb lineages revealed an overlapping subset of genes (n=42) having significantly perturbed copy numbers (Benjamin Hochberg adjusted P-value < 0.05 and log2(drug-resistant/sensitive) > ± 1). These 42 genes formed multiple tandem gene clusters and are known to be involved in virulence, pathogenicity and defence response to invading phages. A separate comparison showed a significantly high copy number of phage genes and a recently reported druggable target Rv1525 in pre- and extensively drug-resistant (Pre-XDR, XDR) compared to drug-sensitive clinical Mtb isolates.ConclusionThe identified gene sets in Mtb clinical isolates may be useful targets for lineage-specific therapeutics and diagnostics development.
A Model-Driven Meta-Analysis Supports the Emerging Consensus View that Inhibitory Neurons Dominate BOLD-fMRI Responses
Authors: Sundqvist Nicolas , Podéus Henrik , Sten Sebastian , Engström Maria , Dura-Bernal Salvador , Cedersund Gunnar 
Published: October 2024

AbstractFunctional magnetic resonance imaging (fMRI) is a pivotal tool for mapping neuronal activity in the brain. Traditionally, the observed hemodynamic changes are assumed to reflect the activity of the most common neuronal type: excitatory neurons. In contrast, recent experiments, using optogenetic techniques, suggest that the fMRI-signal instead reflects the activity of inhibitory interneurons. However, these data paint a complex picture, with numerous regulatory interactions, and where the different experiments display many qualitative differences. It is therefore not trivial how to quantify the relative contributions of the different cell types and to combine all observations into a unified theory. To address this, we present a new model-driven meta-analysis, which provides a unified and quantitative explanation for all data. This model-driven analysis allows for quantification of the relative contribution of different cell types: the contribution to the BOLD-signal from the excitatory cells is <20 % and 50-80 % comes from the interneurons. Our analysis also provides a mechanistic explanation for the observed experiment-to-experiment differences, e.g. a biphasic vascular response dependent on different stimulation intensities and an emerging secondary post-stimulation peak during longer stimulations. In summary, our study provides a new, emerging consensus-view supporting the larger role of interneurons in fMRI.
Unveiling the Functional Connectivity of Astrocytic Networks with AstroNet, a Graph Reconstruction Algorithm Coupled to Image Processing
Authors: Zonca L. , Bellier F.C. , Milior G. , Aymard P. , Visser J. , Rancillac A. , Rouach N. , Holcman D. 
Published: October 2024

AbstractAstrocytes form extended intercellular networks, displaying complex calcium activity. However, the specific organization of these astrocytic networks and the precise extent of their functional connectivity in different brain areas remain unexplored. To unveil the functional architecture of astrocytic networks, we developed, using a data-driven methodology, a novel algorithm called AstroNet that uses two-photon calcium imaging to map temporal correlations in activation events among neighboring astro-cytes. Our approach involves reconstructing functional astrocytic networks by organizing individual astrocyte activation events chronologically. This chronological order creates activity paths that enable the extraction of local astrocyte functional correlations. Ultimately, by tallying the occurrences of direct co-activations between pairs of cells along these pathways, we construct a graph that mirrors the underlying astrocyte functional network. By applying this method to two distinct brain regions (CA1 hippocampus and motor cortex), we identified notable differences in local network organizations in sub-regions of around 20-40 astrocytes. Specifically, the cortex exhibited a lower connectivity, while astrocytes in the hippocampus displayed stronger connections. Moreover, we found that in both regions, astrocytic networks consist of smaller, tightly connected sub-networks embedded within a larger, more loosely connected one. Altogether, our innovative method enables the identification of activation paths among astrocytes, facilitates the characterization of local network functional connectivity, and quantifies distinct connectivity patterns among astrocytes from different brain regions. This approach sheds light on the heterogeneous functional organization of astrocytic networks within the brain, pointing to region-specific astrocyte connectivity.
The role of auxin-mediated gene activation in the bryophyte,Physcomitrium patens
Authors: Bascom Carlisle , Tu Danielle , Estelle Mark 
Published: October 2024

AbstractPerception and response to the hormone auxin is critical to plant growth and development. Expression of auxin-response genes is tightly regulated via known mechanisms of both activation and repression. Across the plant lineage, auxin-response gene induction is performed by AUXIN-REPSONSE FACTOR (ARF) activating transcription factors. Conversely, AUXIN/INDOLE ACETIC ACID proteins repress expression. Studies of gain-of-function constitutive-repression lines andARFloss-of-function mutants have advanced the field. Yet, there is a need for a comparative study of aberrant auxin-signaling mutants to understand the developmental consequences of constitutive repression versus the absence of auxin-mediated gene induction. Using CRISPR/Cas9 gene-editing tools, we mutated each activatingARFgene in the model bryophyte,Physcomitrium patens.The resulting septuple loss-of-function mutant line (arfasept) has severe developmental phenotypes and a diminished ability to respond to exogenous auxin. However, phenotypic analysis revealed that thearfaseptline is not as severely affected as the constitutive-repression lines. Expression analysis of several auxin-response genes demonstrate that auxin-mediated gene induction is abolished in botharfaseptand constitutive-repression lines but that basal expression levels are higher in thearfaseptlines. Our results suggest that the expression of auxin-regulated genes important for developmental progression is maintained, albeit at reduced levels, in the absence of ARFs.HighlightResearchers used CRIPSR/Cas9 to produce a septuple Auxin Response Factor mutant in the model bryophytePhyscomitrium patensrevealing the consequences of the complete loss of auxin-mediated gene activation on development.
Biomass allocation of trees in response to mono- and heterospecific neighbourhoods
Authors: Perles-Garcia Maria D. , Fichtner Andreas , Haider Sylvia , Gu Hanjiao , Bu Wensheng , Kunz Matthias , Härdtle Werner , von Oheimb Goddert 
Published: October 2024

AbstractCarbon sequestration by trees is crucial to mitigate the effects of the current climate crisis. The extent to trees sequester and allocate carbon to above- or belowground structures in turn is mediated by neighbouring species. Although many studies have demonstrated positive effects of diverse neighbourhoods on a tree’s productivity, little is known about biomass allocation responses to mono-vs. heterospecific neighbourhoods. In the present study we quantified above- and belowground biomass production and root-to-shoot ratios (RSR) of trees grown in mono- and heterospecific neighbourhoods. To this end we analysed growth of mono- and heterospecific tree species pairs (TSPs) established in a greenhouse and a field experiment. In the greenhouse experiment response variables were measured after one year of growth after sapling harvest. In the field experiment, conducted in the context of a forest biodiversity experiment in subtropical China, we analysed biomass density and RSR over three years using terrestrial laser scanner and minirhizotrons. RSR of trees in heterospecific TSPs were significantly higher than in monospecific TSPs. In the greenhouse experiment, this was related to a stronger below-than aboveground overyielding in heterospecific TSPs. In the field experiment, trees in heterospecific TSPs showed a stronger increase in aboveground investments over time than in monospecific TSPs, indicating that positive diversity effects became stronger for aboveground structures with progressing tree development. Our findings are consistent with the optimal biomass partitioning theory and highlight the importance of tree-tree interactions on biomass allocation. Higher RSR in mixtures further suggest a higher resistance or resilience of tree saplings against environmental stressors related to climate change (drought, heat waves).