bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel naphthyridones targeting Pannexin 1 for colitis management
Authors: Hsueh Wen-Yun , Wu Yi-Ling , Weng Meng-Tzu , Liu Shin-Yun , Santavanond Jascinta P , Liu Yi-Chung , Lin Ching-I , Lai Cheng-Nong , Lu Yi-Ru , Hsu Jing Yin , Gao Hong-Yu , Lee Jinq-Chyi , Wei Shu-Chen , Lyu Ping-Chiang , Poon Ivan K H , Hsieh Hsing-Pang , Chiu Yu-Hsin 
Published: September 2024

AbstractPannexin 1 (PANX1) forms cell-surface channels capable of releasing signaling metabolites for diverse patho-physiological processes. While inhibiting dysregulated PANX1 is proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, we performed hit-to-lead optimization and identified a naphthyridone, compound12, as a new PANX1 inhibitor with an IC50of 0.73 μM that does not affect pannexin-homologous LRRC8/SWELL1 channels. Using structure-activity relationship analysis, mutagenesis, cell thermal shift assays, and molecular docking, we revealed that compound12directly engages PANX1 Trp74 residue. Using a dextran sodium sulfate mouse model of IBD, we found that compound12markedly reduced colitis severity, highlighting new PANX1 inhibitors as a proof-of-concept treatment for IBD. These data describe the mechanism of action for a new PANX1 inhibitor, identify the binding site for future drug design, and present a targeted strategy for treating IBD.TeaserA specific PANX1 inhibitor presents a proof-of-concept treatment for inflammatory bowel disease.
An accessible platform to quantify oxygen diffusion in cell-laden hydrogels and its application to alginate-immobilized pancreatic beta cells
Authors: Champion Kurtis S. , Ebrahimi Orimi Hamid , Gauvin Laurier , Brassard Jonathan A. , Strand Berit L. , Leask Richard L. , Hoesli Corinne A. 
Published: September 2024

AbstractHydrogels are commonly used to immobilize mammalian cells, serving various purposes such as providing mechanical cues in three-dimensional cultures and acting as barriers for immunoprotection in transplantation. For instance, islet encapsulation holds promise in delivering insulin-producing cells for diabetes cellular therapy. Cell immobilization, by creating a barrier to bulk fluid motion, leads to diffusion-limited molecular transport and concentration gradients of nutrients such as oxygen being consumed by the immobilized cells. Oxygen mass transport models aid in designing immobilization strategies but rely on input parameters like oxygen diffusivity, often assumed rather than experimentally measured due to limited resources or expertise. We propose an accessible, cost-effective, and easy to operate system to experimentally determine the diffusion coefficient of cell-laden hydrogels, with application tested to alginate-immobilized pancreatic beta cell (MIN6). As compared to water, the oxygen diffusion coefficient was significantly reduced in alginate gels. The oxygen diffusion coefficient was inversely correlated with the dynamic loss modulus for gels with similar chemical composition, and significantly reduced when the alginate concentration was increased from 2% to 5%. The viability of immobilized MIN6 cells was highly dependent both on gel concentration and cell density, as predicted by Thiele modulus and effectiveness factor values calculated from measured oxygen diffusion coefficients. The proposed platform, combining a simple experimental setup and the use of dimensionless numbers, offers a straightforward means to predict maximal diffusion distances in cell immobilization strategies. This platform can be implemented in the rational design of cell encapsulation, immobilized cell culture, and tissue engineering strategies.
Extensive intrachromosomal duplications in a virulence-associated fungal accessory chromosome
Authors: Dijkstra Jelmer , van Westerhoven Anouk C. , Gómez-Gil Lucía , Aguilera-Galvez Carolina , Nakasato-Tagami Giuliana , Garnier Sebastien D. , Yamazaki Masaya , Arie Tsutomu , Kamakura Takashi , Arazoe Takayuki , Pietro Antonio Di , Seidl Michael F. , Kema Gert H.J. 
Published: September 2024

AbstractFilamentous fungi have evolved compartmentalized genomes consisting of conserved core regions and dynamic accessory regions, which aid the adaptation to changing environments including the interaction with host organisms. In theFusarium oxysporumspecies complex, accessory regions play an important role during infection and it has been reported that these regions undergo extensive duplications, however, it is currently unknown how such duplications shape accessory regions. Moreover, the function of accessory regions apart from encoding virulence effectors is not completely understood. Here we determined the karyotype ofF. oxysporumTropical Race 4 (TR4), which causes the ongoing pandemic of Fusarium wilt of banana (FWB). We show that the single accessory chromosome of TR4 isolate II5 has undergone extensive intrachromosomal duplications, resulting in triplication of the chromosome size compared to other closely related TR4 strains. By obtaining mutant strains that have lost the accessory chromosome, we demonstrate that this chromosome is dispensable for vegetative growth but is required for full virulence on banana. Lastly, we found that the loss of chromosome 12 co-occurs with structural rearrangements of core chromosomes, which are generally co-linear between members of theF. oxysporumspecies complex. Together, our results provide new insights into the chromosome dynamics of the banana infecting TR4 lineage of theF. oxysporumspecies complex.SignificanceFusarium oxysporumis a major fungal plant pathogen that causes vascular wilt disease on a wide variety of agronomically important crops. A current epidemic of Fusarium wilt of banana (FWB), caused by tropical race 4 (TR4), poses a major threat to global banana production and threatens food security in tropical and subtropical regions where banana is an important staple crop. Controlling TR4 requires a better understanding of the molecular mechanisms underlying pathogenicity, including the evolution of pathogenicity-related accessory regions. Here we demonstrate that intrachromosomal duplications are a key mechanism of accessory chromosome evolution in theF. oxysporumspecies complex. We identified a single accessory chromosome and show that TR4 mutants that lost this accessory chromosome display significantly reduced virulence on banana plants. Our results provide insight into the evolution of accessory chromosomes in theF. oxysporumspecies complex, underscore their importance in pathogenicity, and provide new clues for the development of resistant banana plants.
Ipsilateral stimulation shows somatotopy of thumb and shoulder auricular points on the left primary somatosensory cortex using high-density fNIRS
Authors: Okorie Ernest C. , Santosa Hendrik , Alter Benedict J. , Chelly Jacques E. , Vogt Keith M. , Huppert Theodore J. 
Published: September 2024

AbstractSignificanceAuriculotherapy is a technique based on stimulation applied to specific ear points. Its mechanism of active and clinical efficacy remain to be established. This study aims to assess the role that primary somatosensory cortex may play to validate auriculotherapy mechanisms.AimThis study examined whether tactile stimulation at specific auricular points is correlated with distinct cortical activation in the primary somatosensory cortex.ApproachSeventeen healthy adults participated in the study. Tactile stimuli were delivered to the thumb, shoulder, and skin master points on the ear using von Frey filaments. Functional near-infrared spectroscopy was used to measure and spatially map cortical responses.ResultsThis study revealed distinct hemodynamic activity patterns in response to ear point stimulation, consistent with the classic homunculus model of somatotopic organization. Ipsilateral stimulation showed specific cortical activations for the thumb and shoulder points, while contralateral stimulation showed less significant activity. Functional near-infrared spectroscopy effectively captured localized cortical responses to ear tactile stimuli, supporting the somatotopic mapping hypothesis.ConclusionThese findings enhance the understanding of sensory processing with auricular stimulation and supports the concepts of auricular cartography that underpins some schools of auriculotherapy practice. Future research should explore bilateral cortical mapping and the integration of other neuroimaging techniques.
High-throughput amino acid-level characterization of the interactions of plasminogen activator inhibitor-1 with variably divergent proteases
Authors: Haynes Laura M , Holding Matthew L , DiGiovanni Hannah , Siemieniak David , Ginsburg David 
Published: September 2024

AbstractWhile members of large paralogous protein families share structural features, their functional niches often diverge significantly. Serine protease inhibitors (SERPINs), whose members typically function as covalent inhibitors of serine proteases, are one such family. Plasminogen activator inhibitor-1 (PAI-1) is a prototypic SERPIN, which canonically inhibits tissue-and urokinase-type plasminogen activators (tPA and uPA) to regulate fibrinolysis. PAI-1 has been shown to also inhibit other serine proteases, including coagulation factor XIIa (FXIIa) and transmembrane serine protease 2 (TMPRSS2). The structural determinants of PAI-1 inhibitory function toward these non-canonical protease targets, and the biological significance of these functions, are unknown. We applied deep mutational scanning (DMS) to assess the effects of ∼80% of all possible single amino acid substitutions in PAI-1 on its ability to inhibit three putative serine protease targets (uPA, FXIIa, and TMPRSS2). Selection with each target protease generated a unique PAI-1 mutational landscape, with the determinants of protease specificity distributed throughout PAI-1’s primary sequence. Next, we conducted a comparative analysis of extant orthologous sequences, demonstrating that key residues modulating PAI-1 inhibition of uPA and FXIIa, but not TMPRSS2, are maintained by purifying selection. PAI-1’s activity toward FXIIa may reflect how protease evolutionary relationships predict SERPIN functional divergence, which we support via a cophylogenetic analysis of all secreted SERPINs and their cognate serine proteases. This work provides insight into the functional diversification of SERPINs and lays the framework for extending these studies to other proteases and their regulators.
Muscle fiber proteomics reveals sex- and fiber type-specific adaptations to resistance training
Authors: Moesgaard Lukas , Moreno-Justicia Roger , Schmalbruch Johann , Jessen Søren , Stocks Ben , Bangsbo Jens , Deshmukh Atul S. , Hostrup Morten 
Published: September 2024

AbstractSkeletal muscle hypertrophy is a hallmark of resistance training that positively impacts health and longevity. However, despite physiological differences between sexes and fiber types, the underlying proteome changes with resistance training have not been studied in a sex- and fiber type-specific manner. Herein, we show sex differences in the fiber type-specific proteome, predominantly in type II fibers. Following 8 weeks of resistance training, substantial remodeling of the human skeletal muscle proteome occurred in a sex- and fiber type-specific manner. Notably, type II fibers exhibited much greater adaptations across both sexes, whereas the main sex-difference was a greater remodeling of intermediate filaments in females. In addition, baseline abundance of proteins involved in translation was highly correlated with fiber hypertrophy, and differed between sexes and fiber types. Thus, translational capacity may partially explain differences in resistance training-induced hypertrophy. Our findings demonstrate key aspects of sex- and fiber type differences in muscle physiology and their contributions to resistance training-induced adaptions.
Commitment to cytokinetic furrowing requires the coordinate activity of microtubules and Plk1
Authors: Day Charles A. , Langfald Alyssa , Lukes Tana , Middlebrook Hanna , Vaughan Kevin T. , Daniels David , Hinchcliffe Edward H. 
Published: September 2024

SummaryAt anaphase, spindle microtubules (MTs) position the cleavage furrow and trigger actomyosin assembly by localizing the small GTPase RhoA and the scaffolding protein anillin to a narrow band along the equatorial cortex [1–6]. Using vertebrate somatic cells we examined the temporal control of furrow assembly. Although its positioning commences at anaphase onset, furrow maturation is not complete until ∼10-11 min later. The maintenance of the RhoA/anillin scaffold initially requires continuous signaling from the spindle; loss of either MTs or polo-like kinase 1 (Plk1) activity prevents proper RhoA/anillin localization to the equator, thereby disrupting furrowing. However, we find that at ∼6 min post-anaphase, the cortex becomes “committed to furrowing”; loss of either MTs or Plk1 after this stage does not prevent eventual furrowing, even though at this point the contractile apparatus has not fully matured. Also at this stage, the RhoA/anillin scaffold at the equator becomes permanent. Surprisingly, concurrent loss of both MTs and Plk1 activity following the “commitment to furrowing” stage results in persistent, asymmetric “half-furrows”, with only one cortical hemisphere retaining RhoA/anillin, and undergoing ingression. This phenotype is reminiscent of asymmetric furrows caused by a physical block between spindle and cortex [7–9], or by acentric spindle positioning [10–12]. The formation of these persistent “half-furrows” suggests a potential feedback mechanism between the spindle and the cortex that maintains cortical competency along the presumptive equatorial region prior to the “commitment to furrowing” stage of cytokinesis, thereby ensuring the eventual ingression of a symmetric cleavage furrow.
Noisy hemoglobin consumption by erythrocyticPlasmodium falciparumparasites: origins and possible implications
Authors: Perko Joseph R. , Singh Abhyudai , Lopez Secilia I. , Luckhart Shirley , Vasdekis Andreas E. 
Published: September 2024

AbstractNon-genetic cell-to-cell phenotypic differences can significantly impact pathogen physiol-ogy and virulence, leading to unexpected phenomena such as antibiotic persistence. Here, we introduce the role of such non-genetic phenotypic differences in the host, with a focus on hemoglobin consumption byPlasmodium falciparumduring the erythrocytic stage of parasite development. Through imaging, we quantified the substantial variability in hemoglobin (Hb) concentration among uninfected red blood cells (RBCs), and subse-quently measured the rate of Hb consumption by parasites at different stages of their life cycle. This revealed a similarly significant variability among different infected RBCs. By employing a mathematical model, we demonstrated that this variability in Hb consumption can be attributed to non-genetic differences in host RBCs, marking the first evidence of this phenomenon in malaria parasite physiology. These findings underscore the im-portance of incorporating non-genetic host variability into models of disease progression and treatment strategies for malaria and potentially other pathogen-related diseases.
Untargeted and Semi-Targeted Metabolomics Approach for Profiling Small Intestinal and Fecal Metabolome Using High-Resolution Mass Spectrometry
Authors: Tronel Alexandre , Roger-Margueritat Morgane , Plazy Caroline , Cunin Valérie , Mohanty Ipsita , Dorrestein Pieter C. , Soranzo Thomas , Le Gouellec Audrey 
Published: September 2024

AbstractThe gut microbiome is a complex ecosystem varying along different gut sections, consisting of metabolites from food, host, and microbes. Microbially-derived metabolites like bile acids and short-chain fatty acids interact with host physiology. Current studies often use fecal samples, which don’t fully represent the upper gut due to stratification. To sample the proximal gut microbiome, endoscopic methods or new non-invasive devices are used. We developed an approach combining untargeted and semi-targeted metabolomics using a Q-Exactive Plus Orbitrap mass spectrometer to profile gut metabolites. We initially selected 49 key metabolites based on specific criteria, validated them through repeatability tests, and created a compound database with TraceFinder software. Our workflow enables molecule annotation in untargeted studies while validating 37 metabolites in semitargeted analyses. This method, applied to clinical trial samples (NCT05477069), shows promise in discovering new gut metabolites.HighlightsInnovative Combined Metabolomics Workflow:The study introduces a combined approach that integrates semi-targeted and untargeted metabolomics analyses to characterized small intestinal and fecal metabolomes. This method allows for the relative quantification of carefully selected metabolites and the reanalysis of these metabolites using evolving curated databases, enhancing the understanding of the gut microbiome-health axis.Untargeted Metabolomics Strategy:The untargeted approach aims to determine the global metabolic profile of samples and discover new metabolites. This involves processing data through a detailed pipeline, statistical analysis, and feature annotation using tools like MZmine, MetaboAnalyst, and the GNPS platform.Proof of Concept on Clinical Samples:The combined approach was tested on clinical samples from a participant in a clinical trial, revealing distinct metabolomes between small intestinal content and fecal samples. This proof of concept demonstrated the method’s ability to identify and quantify metabolites, showing significant differences in metabolite abundance between the two sample types and highlighting the potential for discovering new bile acids through molecular networking.
Optic nerve crush does not induce retinal ganglion cell loss in the contralateral eye
Authors: Schoot Uiterkamp Florianne E. , Maes Margaret E. , Alamalhoda MohammadAmin , Firoozi Arsalan , Colombo Gloria , Siegert Sandra 
Published: September 2024

AbstractPurposeOptic nerve crush (ONC) is a model for studying optic nerve trauma. Unilateral ONC induces massive retinal ganglion cell (RGC) degeneration in the affected eye, leading to vision loss within a month. A common assumption has been that the non-injured contralateral eye is unaffected due to the minimal anatomical decussation of the RGC projections at the chiasm. Yet, recently, microglia, the brain-resident macrophages, have shown a responsive phenotype in the contralateral eye after ONC. Whether RGC loss accompanies this phenotype is still controversial.MethodsUsing the available RGCode algorithm and developing our own RGC-Quant deep-learning-based tool, we quantify RGC’s total number and density across the entire retina after ONC.ResultsWe confirm a short-term microglia response in the contralateral eye after ONC, but this did not affect microglia number. Furthermore, we cannot confirm the previously reported RGC loss between naïve and contralateral retinas five weeks after ONC induction across the commonly used Cx3cr1creERT2and C57BL6/J mouse models. Neither sex nor the direct comparison of the RGC markers Brn3a and RBPMS, with Brn3a co-labeling, on average, 89% of the RBPMS+-cells, explained this discrepancy, suggesting that the early microglia-responsive phenotype does not have immediate consequences on the RGC number.ConclusionsOur results corroborate that unilateral optic nerve injury elicits a microglial response in the uninjured contralateral eye but without RGC loss. Therefore, the contralateral eye should be treated separately and not as an ONC control.
Suppression of optokinesis in the reafferent direction during pursuit eye movements
Authors: Bachtoula Omar , Miraval Melanie Ellul , Serrano-Pedraza Ignacio , Souto David 
Published: September 2024

AbstractWhen tracking with the eyes an object moving against a textured background, the background retinal image moves in the opposite direction to the smooth pursuit eye movement. Optokinetic responses, such as optokinetic nystagmus (OKN) or ocular tracking, to this reafferent signal must be suppressed to sustain pursuit of the object-of-interest. We varied the contrast of a brief background motion to tell apart two plausible accounts of the suppression of optokinesis during pursuit; a visuomotor gain modulation account, which predicts that ocular tracking of background motion is suppressed in the same proportion at irrespective of contrast, and a sensory attenuation account, which predicts that larger contrasts are needed to elicit the same response. Unexpectedly, neither account fits ocular tracking in the reafferent signal direction. The combination of contrast-dependent gating, with maximal suppression observed with higher contrasts, and visuomotor gain modulation, provides a good fit for most observers’ data. Contrast-dependent gating promotes visuomotor stability in response to most salient signals, as a likely adaptation to the statistics of the environment.Significance statementFor humans to be able to track small moving objects, there is a need for a mechanism to cancel optokinesis, that is reflexive eye movements towards prevalent visual motion. We show that this cancellation is not a simple “volume-control” reduction of responses to motion signals, as expected. This suppression also involves contrast-dependent gating, meaning that most salient signals are not allowed to modify the ongoing movement. This additional component could have arisen from an adaptation to image statistics of motion signals prevalent in natural environments.
Integrated View of Baseline Protein Expression in Human Tissues using public Data Independent Acquisition datasets
Authors: Prakash Ananth , Collins Andrew , Vilmovsky Liora , Fexova Silvie , Jones Andrew R. , Vizcaino Juan Antonio 
Published: September 2024

AbstractThe PRIDE database is the largest public data repository of mass spectrometry-based proteomics data and currently stores more than 40,000 datasets covering a wide range of organisms, experimental techniques and biological conditions. During the past few years, PRIDE has seen a significant increase in the amount of submitted Data-Independent Acquisition (DIA) proteomics datasets. This provides an excellent opportunity for large scale data reanalysis and reuse.We have reanalysed 15 public label-free DIA datasets across various healthy human tissues, to provide a state-of-the-art view of the human proteome in baseline conditions (without any perturbations). We computed baseline protein abundances and compared them across various tissues, samples and datasets. Our second aim was to compare protein abundances obtained here from the results of previous analyses using human baseline Data-Dependent Acquisition (DDA) datasets. We observed a good correlation across some tissues, especially in liver and colon but weak correlations were found in others, such as lung and pancreas. The reanalysed results including protein abundance values and curated metadata are made available to view and download from the resource Expression Atlas.For TOC Only