bluuebunny/crossref_metadata_2025_split huggingface dataset:
VENO-VENOUS EXTRACORPOREAL MEMBRANE OXYGENATION IMPROVES OUTCOMES IN TRAUMA PATIENTS SUFFERING RESPIRATORY FAILURE
Authors: Powell Elizabeth K. , Betzold Richard , Lammers Daniel T. , Podell Jamie , Wan Ryan , Teeter William , Hardin Ronald D. , Scalea Thomas M. , Galvagno Samuel M 
Published: October 2024

ABSTRACT

Introduction: Veno-venous extracorporeal membrane oxygenation (VV ECMO) improves hypoxemia and carbon dioxide clearance in patients with severe respiratory derangements. A greater understanding of the potential benefits of VV ECMO in trauma patients could lead to broader adoption. We hypothesize that trauma patients who receive VV ECMO have improved mortality outcomes when compared to those receiving conventional ventilator management given the rapid stabilization VV ECMO promotes. Methods: We performed a single-center, propensity score-matched cohort study. All trauma patients from January 1, 2014, to October 30, 2023, who were placed on VV ECMO or who would have met institutional guidelines for VV ECMO but were managed with conventional ventilator strategies were matched 1:1. The primary outcome analysis was survival at hospital discharge. Significance was defined as P < 0.05. Results: Eighty-one trauma VV ECMO patients and 128 patients who received conventional management met criteria for inclusion. After matching, VV ECMO and conventional treatment cohort characteristics were similar in age and mechanism of injury. Matched ISS, SI, lactate levels, and frequency of traumatically brain injured were also similar. Finally, respiratory parameters including preintervention, pH, partial pressure of carbon dioxide, lactate levels, and oxygen saturation were similar between matched groups. VV ECMO patients had higher survival rates at discharge when compared to the matched conventional treatment group (70% vs. 41%, P < 0.001). Corresponding hazard ratio for VV ECMO use was 0.31 (95% CI 0.18–0.52; P < 0.001). The odds ratio of mortality in matched trauma patients who receive VV ECMO versus conventional treatment was 0.29 (95% CI 0.14–0.58; P < 0.001). Conclusion: VV ECMO may represent a safe, alternative treatment approach for appropriately screened trauma patients with acute respiratory failure; however, further studies are warranted.
SLB-msSIM: a spectral library-based multiplex segmented SIM platform for single-cell proteomic analysis
Authors: Senavirathna Lakmini , Ma Cheng , Duong Van-An , Tsai Hong-Yuan , Chen Ru , Pan Sheng 
Published: October 2024

ABSTRACTMass spectrometry (MS)-based single-cell proteomics, while highly challenging, offers unique potential for a wide range of applications to interrogate cellular heterogeneity, trajectories, and phenotypes at a functional level. We report here the development of the spectral library-based multiplex segmented selected ion monitoring (SLB-msSIM) method, a conceptually unique approach with significantly enhanced sensitivity and robustness for single-cell analysis. The single-cell MS data is acquired by msSIM technique, which sequentially applies multiple isolation cycles with the quadrupole using a wide isolation window in each cycle to accumulate and store precursor ions in the C-trap for a single scan in the Orbitrap. Proteomic identification is achieved through spectral matching using a well-defined spectral library. We applied the SLB-msSIM method to interrogate cellular heterogeneity among multiple cell lines and to analyze cellular trajectories during epithelial-mesenchymal transition. Our results demonstrate that SLB-msSIM is a highly sensitive and robust platform applicable to a wide range of single-cell proteomic studies.
Acquisition and reversal of glioblastoma chemoresistance are mediated by the Rho GTPase pathway
Authors: Magalhaes Yuli Thamires , Boell Viktor Kalbermatter , Forti Fabio Luis 
Published: October 2024

ABSTRACTGlioblastoma (GBM) are highly aggressive tumors treated mainly with surgery, radiotherapy, and chemotherapy. Innovative multimodal therapies are needed, targeting the immune system, tumor metabolism, and cell signaling. Our research focuses on the role of the actin cytoskeleton and Rho GTPases in modulating DNA damage repair and therapeutic sensitivity in GBM cells. We developed GBM sublines resistant to temozolomide (TMZ) and cisplatin (CP), and assessed actin stress fiber organization, Rho pathway activity, and resistance phenotype. TMZ-resistant clones exhibited increased Rho pathway activity, elevated p53 and DNA double-strand break (DSB) repair pathways, but reduced MMR protein levels. Importantly, Rho GTPase inhibition restored TMZ-resistant clones’ sensitivity to TMZ and CP, counteracting chemoresistance. While both drugs reduced DNA repair capacity in normal GBM cells—exacerbated by Rho inhibition—TMZ-resistant clones with overactivated Rho pathways did not show this effect. This response was p53-wild-type dependent, as p53-mutant GBM cells were unresponsive to Rho inhibition. However, p53-mutant cells treated with PRIMA-1 showed restored sensitivity to chemotherapeutics with Rho inhibition. Furthermore, modulation of the actin cytoskeleton and Rho GTPases affected sensitivity and viability in GBM spheroid models exposed to chemotherapy. In summary, Rho pathway activity and actin cytoskeleton dynamics are critical for both the development and reversal of chemoresistance in GBM tumors.STATEMENT OF SIGNIFICANCEChemoresistance in glioblastomas modulates the Rho GTPases pathway and actin cytoskeleton, while negatively affecting DNA repair. Downmodulating the actin circuitry in resistant GBMs sensitizes them to TMZ and CP drugs.
Probing DNA damage sites reveals context-dependent and novel DNA damage response factors
Authors: da Silva Richard Cardoso , Recchia Davide C. , Portegijs Vincent , Sanchez Maria Cristina Trueba , Stecker Kelly E. , van den Heuvel Sander , Baubec Tuncay 
Published: October 2024

AbstractDNA damage is a constant threat to genome integrity and function. Diminished capacity for DNA repair is linked to many human diseases, therefore understanding the molecular pathways responding to DNA damage is key for developing novel therapies. Lack of unbiased probes to report DNA damage dynamics and the associated proteins in living cells and animals limit our current efforts to completely understand DNA repair processes. In this study we overcome these limitations by engineering protein probes containing the tandem-BRCT domain of MCPH1, which we show to have a specific affinity for the DNA-damage-associated histone mark γH2AX. We employ these probes to track DNA damage dynamics in living cells exposed to a panel of different genotoxic insults and to visualize programmed double strand breaks during gametogenesis in living animals. We further utilize the binding selectivity of our probe to tether TurboID biotin ligases to chromatin and identify the DNA damage-associated proteome via proximity ligation. By comparing five different DNA damaging agents, we reveal the proteome associated with specific lesions, and identify multiple novel proteins with potential implications in damage response and repair. Among these novel proteins, we characterize the ubiquitin ligase UBE3A, the methyl-binding and proteasome-recruiting protein L3MBTL3, and the spliceosomal factor U2SURP, as previously uncharacterized effectors of DNA damage response. These functional datasets reveal the DNA damage-dependent proteomes and reveal novel insights into DNA damage response.
Utilizing data imbalance to enhance compound-protein interaction prediction models
Authors: Lin Wei , Fung Chi Chung Alan 
Published: October 2024

AbstractIdentifying potential compounds for target proteins is crucial in drug discovery. Current compound-protein interaction prediction models concentrate on utilizing more complex features to enhance capabilities, but this often incurs substantial computational burdens. Indeed, this issue arises from the limited understanding of data imbalance between proteins and compounds, leading to insufficient optimization of protein encoders. Therefore, we introduce a sequence-based predictor named FilmCPI, designed to utilize data imbalance to learn proteins with their numerous corresponding compounds. FilmCPI consistently outperforms baseline models across diverse datasets and split strategies, and its generalization to unseen proteins becomes more pronounced as the datasets expand. Notably, FilmCPI can be transferred to unseen protein families with sequence-based data from other families, exhibiting its practicability. The effectiveness of FilmCPI is attributed to different optimization speeds for diverse encoders, elucidating optimization imbalance in compound-protein prediction models. Additionally, these advantages of FilmCPI do not depend on increasing parameters, aiming to lighten model design with data imbalance.
How the Structure of Signaling Regulation Evolves: Insights from an Evolutionary Model
Authors: Asgari Danial , Tate Ann T. 
Published: October 2024

AbstractTo remain responsive to environmental changes, signaling pathways attenuate their activity with negative feedback loops (NFLs), where proteins produced upon stimulation downregulate the response. NFLs function both upstream of signaling to reduce input and downstream to reduce output. Unlike upstream NFLs, downstream NFLs directly regulate gene expression without the involvement of intermediate proteins. Thus, we hypothesized that downstream NFLs evolve under more stringent selection than upstream NFLs. Indeed, genes encoding downstream NFLs exhibit a slower evolutionary rate than upstream genes. Such differences in selective pressures could result in the robust evolution of downstream NFLs while making the evolution of upstream NFLs more sensitive to changes in signaling proteins and stimuli. Here, we test these assumptions within the context of immune signaling. Our minimal model of immune signaling predicts robust evolution of downstream NFLs to changes in model parameters. This is consistent with their critical role in regulating signaling and the conservative rate of evolution. Furthermore, we show that the number of signaling steps needed to activate a downstream NFL is influenced by the cost of signaling. Our model predicts that upstream NFLs are more likely to evolve under a shorter half-life of signaling proteins, absence of host-pathogen co-evolution, and a high infection rate. Although it has been proposed that NFLs evolve to reduce the cost of signaling, we show that a high cost does not necessarily predict the evolution of upstream NFLs. The insights from our model have broad implications for understanding the evolution of regulatory mechanisms across signaling pathways.
Evolutionary-Scale Enzymology Enables Biochemical Constant Prediction Across a Multi-Peaked Catalytic Landscape
Authors: Muir Duncan F. , Asper Garrison P. R. , Notin Pascal , Posner Jacob A. , Marks Debora S. , Keiser Michael J. , Pinney Margaux M. 
Published: October 2024

AbstractQuantitatively mapping enzyme sequence-catalysis landscapes remains a critical challenge in understanding enzyme function, evolution, and design. Here, we expand an emerging microfluidic platform to measure catalytic constants—kcatandKM—for hundreds of diverse naturally occurring sequences and mutants of the model enzyme Adenylate Kinase (ADK). This enables us to dissect the sequence-catalysis landscape’s topology, navigability, and mechanistic underpinnings, revealing distinct catalytic peaks organized by structural motifs. These results challenge long-standing hypotheses in enzyme adaptation, demonstrating that thermophilic enzymes are not slower than their mesophilic counterparts. Combining the rich representations of protein sequences provided by deep-learning models with our custom high-throughput kinetic data yields semi-supervised models that significantly outperform existing models at predicting catalytic parameters of naturally occurring ADK sequences. Our work demonstrates a promising strategy for dissecting sequence-catalysis landscapes across enzymatic evolution and building family-specific models capable of accurately predicting catalytic constants, opening new avenues for enzyme engineering and functional prediction.
IntelliProfiler: a novel analytic tool for behavior dynamics of multiple animals in a home cage
Authors: Ochi Shohei , Inada Hitoshi , Osumi Noriko 
Published: October 2024

AbstractThere is a growing demand for sophisticated behavioral analysis systems that minimize bias in multi-animal and semi-natural environments. We present “IntelliProfiler,” an advanced system using radio frequency identification (RFID) technology to enable fully automated behavior analyses of multiple mice within a home cage. IntelliProfiler continuously monitors up to 16 mice, capturing both locomotor activity and social dynamics over extended periods. Our findings revealed that male mice maintain broader social distances than females, with group size playing a key role in shaping male social network dynamics. Furthermore, aging in males significantly impacts both locomotor activity and social interaction in a group size-dependent manner. With its ability to provide in-depth analysis of individual and group behaviors, IntelliProfiler offers a novel approach for exploring complex social interactions and group dynamics, advancing the field of behavioral science.
Single-nucleus transcriptional and chromatin accessibility analyses of maturing mouse Achilles tendon uncover the molecular landscape of tendon stem/progenitor cells
Authors: Tsutsumi Hiroki , Chiba Tomoki , Fujii Yuta , Matsushima Takahide , Kimura Tsuyoshi , Kanai Akinori , Kishida Akio , Suzuki Yutaka , Asahara Hiroshi 
Published: October 2024

AbstractTendons and ligaments are crucial connective tissues linking bones and muscles, yet achieving full functional recovery after injury remains challenging. We investigated the characteristics of tendon stem/progenitor cells (TSPCs) by focusing on the declining tendon repair capacity with growth. Using single-cell RNA sequencing on Achilles tendon cells from 2- and 6-week-old mice, we identifiedCd55andCd248as novel surface antigen markers for TSPCs. Combining single-nucleus ATAC and RNA sequencing analyses revealed thatCd55andCd248positive fractions in tendon tissue are TSPCs, with this population decreasing at 1 weeks. We also identified candidate upstream transcription factors regulating these fractions. Functional analyses of isolated CD55/CD248 positive cells demonstrated high clonogenic potential and tendon differentiation capacity, forming functional tendon-like tissuein vitro. This study establishes CD55 and CD248 as novel TSPC surface antigens, potentially advancing tendon regenerative medicine and contributing to the development of new treatment strategies for tendon and ligament injuries.
Algorithms to reconstruct past indels: the deletion-only parsimony problem
Authors: Moutet Jordan , Rivals Eric , Pardi Fabio 
Published: October 2024

AbstractAncestral sequence reconstruction is an important task in bioinformatics, with applications ranging from protein engineering to the study of genome evolution. When sequences can only undergo substitutions, optimal reconstructions can be efficiently computed using well-known algorithms. However, accounting for indels in ancestral reconstructions is much harder. First, for biologically-relevant problem formulations, no polynomial-time exact algorithms are available. Second, multiple reconstructions are often equally parsimonious or likely, making it crucial to correctly display uncertainty in the results.Here, we consider a parsimony approach where any indel event has the same cost, irrespective of its size or the branch where it occurs. We thoroughly examine the case where only deletions are allowed, while addressing the aforementioned limitations. First, we describe an exact algorithm to obtain all the optimal solutions. The algorithm runs in polynomial time if only one solution is sought. Second, we show that all possible optimal reconstructions for a fixed node can be represented using a graph computable in polynomial time. While previous studies have proposed graph-based representations of ancestral reconstructions, this result is the first to offer a solid mathematical justification for this approach. Finally we discuss the relevance of the deletion-only case for the general case.Author summaryAn exciting frontier in evolutionary biology is the ability to reconstruct DNA or protein sequences from species that lived in the distant past. By analyzing sequences from present-day species, we aim to infer the sequences of their common ancestors —a process known as ancestral sequence reconstruction. This task has far-reaching applications, such as resurrecting ancient proteins and studying the biology of extinct organisms. However, a significant challenge remains: the lack of well-established methods for inferring past deletions and insertions —–mutations that remove or add segments of genetic code. In this paper, we present algorithms that lay the groundwork for addressing this gap. We show that finding the reconstructions involving only deletion events, while minimizing their number, can be done efficiently. Additionally, we show that all optimal solutions can be represented using specialized graphs. While previous studies have proposed graph-based representations of ancestral reconstructions, we are the first to provide a rigorous mathematical foundation for the use of these graphs.
Composition of saliva metabolome is significantly associated with SARS-CoV2 infection and with severity of COVID-19 disease
Authors: Larios-Serrato Violeta , Vázquez-Manjarrez Natalia , Resendis-Antonio Osbaldo , Rios-Sarabia Nora , Meza-Marquez Beatriz , Fiehn Oliver , Torres Javier 
Published: October 2024

AbstractBackgroundThe metabolome of COVID-19 patients has been studied sparsely, with most research focusing on a limited number of plasma metabolites or small cohorts. This is the first study to test saliva metabolites in COVID-19 patients in a comprehensive way, revealing significant changes linked to disease severity and highlighting saliva is potential as a non-invasive diagnostic tool.MethodsWe included 30 asymptomatic subjects with no prior COVID-19 infection or vaccination, 102 patients with mild SARS-CoV-2 infection, and 61 hospitalized patients with confirmed SARS-CoV-2 status. Saliva samples were analyzed using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS/MS) in positive and negative ionization modes.ResultsSignificant changes in metabolites were identified in COVID-19 patients, with distinct patterns based on disease severity. Healthy individuals exhibited a well-regulated bacterial network, while severe cases showed disordered microbial networks. Elevated dipeptides such as Val-Glu and Met-Gln in moderate cases suggest specific protease activity related to SARS-CoV-2. Increased acetylated amino acids like N-Acetylserine and N-Acetylhistidine indicate potential biomarkers for stress and disease severity. Bacterial metabolites, including muramic acid and indole-3-carboxaldehyde, were higher in mild-moderate cases, indicating oral microbiota changes. In severe cases, polyamines and organ damage-related metabolites, such as N-acetylspermine and 3-methylcytidine, were significantly increased. Interestingly, metabolites reduced in moderate cases were elevated in severe cases.ConclusionsSaliva metabolomics offers insight into disease progression and potential biomarkers for COVID-19.
Monocytes-derived cxcl12 guides a directional migration of blood vessels in zebrafish
Authors: Lu Xiaofeng , Wang Xiaoning , Li Bowen , Wang Xin , Duan Xuchu , Liu Dong 
Published: October 2024

AbstractBackgroundSprouting blood vessels, reaching the aimed location, and establishing the proper connections are vital for building vascular networks. Such biological processes are subject to precise molecular regulation. So far, the mechanistic insights into understanding how blood vessels grow to the correct position are limited. In particular, the guiding cues and the signaling-originating cells remain elusive.MethodsLive imaging analysis was used to observe the vascular developmental process of zebrafish. Whole-mount in situ hybridization and fluorescent in situ hybridization were used to detect the expression profiles of the genes. Single-cell sequencing analysis was conducted to identify the guiding protein and its originating cells.ResultsTaking advantage of live imaging analysis, we described a directional blood vessel migration in the vascularization process of zebrafish pectoral fins. We demonstrated that pectoral fin vessel c (PFVc) migrated over long distances and was anastomosed with the second pair of intersegmental vessels (ISVs). Furthermore, we found the cxcl12a-cxcr4a axis specifically guided this long-distance extension of PFVc-ISV, and either inhibition or over-expression of cxcl12a-cxcr4a signaling both mislead the growth of PFVc to ectopic areas. Finally, based on an analysis of single-cell sequencing data, we revealed that a population of monocytes expresses the Cxcl12a, which guides the migration of the vascular sprout.ConclusionsOur study identified Cxcl12a as the signaling molecule for orchestrating organotypic-specific long-distance migration and anastomosis of the pectoral fin vessel and ISVs in zebrafish. We discovered a specific cluster of gata1-positive monocytes that are responsible for expressing Cxcl12a. The findings offer novel insights into the mechanisms underlying organotypic vascularization in vertebrates.
Syntaxin11 Deficiency Inhibits CRAC Channel Priming To Suppress Cytotoxicity And Gene Expression In FHLH4 Patient T Lymphocytes
Authors: Datta Sritama , Gupta Abhikarsh , Jagetiya Kunal Mukesh , Tiwari Vikas , Yamashita Megumi , Ammann Sandra , Shahrooei Mohammad , Yande Atharva Rahul , Sowdhamini Ramanathan , Dani Adish , Prakriya Murali , Vig Monika 
Published: October 2024

AbstractCRAC channels enable calcium entry from the extracellular space in response to a variety of stimuli and are crucial for gene expression and granule exocytosis in lymphocytes. Here we find that Syntaxin11, a Q-SNARE, associated with FHLH4 disease in human patients, directly binds Orai1, the pore forming subunit of CRAC channels. Syntaxin11 depletion strongly inhibited SOCE, CRAC currents, IL-2 expression and cytotoxicity in cell lines and FHLH4 patient T lymphocytes. Constitutively active H134 Orai1 mutant completely reconstituted calcium entry in Syntaxin11 depleted cells and the defects of granule exocytosis as well as gene expression could be bypassed by ionomycin induced calcium influx in FHLH4 T lymphocytes. Our data reveal a Syntaxin11 induced pre-activation state of Orai which is necessary for its subsequent coupling and gating by the endoplasmic reticulum resident Stim protein. We propose that ion channel regulation by specific SNAREs is a primary and conserved function which may have preceded their role in vesicle fusion.