bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomic analysis of the effect of endocannabinoid metabolism inhibition in ovalbumin-induced allergic airway inflammation in Guinea pigs
Authors: Abohalaka Reshed , Karaman Yasemin , Recber Tuba , Onder Sevgen Celik , Nemutlu Emirhan , Bozkurt Turgut Emrah 
Published: March 2024

AbstractBackground and aimsAsthma manifests as a multifaceted airway inflammation. The therapeutic potential of targeting endocannabinoids in mitigating asthma remains incompletely elucidated. Therefore, we aim to scrutinize metabolic alterations, deepen our comprehension of the endocannabinoids’ therapeutic role, and discern novel biomarkers for monitoring allergic airway inflammation.MethodsGuinea pigs were sensitized with ovalbumin (150μg) or PBS on days 1, 4, and 7. On day 14, they were exposed to aerosols containing 0.3% ovalbumin or PBS. Treatment groups were administered inhibitors of fatty acid amide hydrolase (FAAH) and/or monoacylglycerol lipase (MAGL) one hour prior to aerosol exposure. Subsequently, bronchoalveolar lavage (BAL), blood, and lung samples were collected on the following day for analysis using GC-MS. Metabolites were meticulously categorized into 10 distinct classifications based on their chemical and biological functions. Subsequently, they were further organized into 5 principal metabolic pathways for a comprehensive metabolomic analysis.ResultsOvalbumin exposure exclusively altered the metabolic profile in the lung. Conversely, inhibition of endocannabinoids metabolism induced a systemic shift in energy metabolites such as carbohydrates, amino and fatty acids.ConclusionsAllergen exposure induced an elevation in metabolites associated with glycolytic metabolism particularly in the lungs, indicating enhanced activation and increased numbers of immune cells. Notably, inhibition of endocannabinoids mitigated these shifts, underscoring its anti-inflammatory efficacy.
Enhanced Place Specificity of the Parallel Auditory Brainstem Response: An Electrophysiological Study
Authors: Stoll Thomas J , Maddox Ross K 
Published: March 2024

AbstractPurposeThis study investigates the effect of parallel stimulus presentation on the place specificity of the auditory brainstem response (ABR) in human listeners. Frequency-specific stimuli do not guarantee a response from the place on the cochlea corresponding only to that characteristic frequency – especially for brief and high-level stimuli. Adding masking noise yields responses that are more place specific, and a prior modeling study has suggested similar effects when multiple frequency-specific stimuli are presented in parallel. We tested this hypothesis experimentally here, comparing the place specificity of responses to serial and parallel stimuli at two stimulus frequencies and three stimulus rates.MethodsParallel ABR (pABR) stimuli were presented alongside high-pass filtered noise with a varied cutoff frequency. Serial presentation was also tested by isolating and presenting single-frequency stimulus trains from the pABR ensemble. Latencies of the ABRs were examined to assess place specificity of responses. Response bands were derived by subtracting responses from different high pass noise conditions. The response amplitude from each derived response band was then used to determine how much individual frequency regions of the auditory system were contributing to the overall response.ResultsWe found that parallel presentation improves place specificity of ABRs for the lower stimulus frequency and at higher stimulus rates. At a higher stimulus frequency, serial and parallel presentation were equally place specific.ConclusionParallel presentation can provide more place specific responses than serial for lower stimulus frequencies. The improvement increases with higher stimulus rates and is in addition to the pABR’s primary benefit of faster test times.
Lower limb joint Loading during high-impact activities: implication for bone health
Authors: Altai Zainab , Hayford Claude Fiifi , Phillips Andrew , Moran Jason , Zhai Xiaojun , Liew Bernard X.W. 
Published: March 2024

AbstractOsteoporosis, a significant concern among the elderly, results in low-trauma fractures affecting millions globally. Despite the inclusion of physical activities in strategies to mitigate osteoporosis-related fractures, the optimal exercises for bone health remain uncertain. Determining exercises that enhance bone mass requires an understanding of loading on lower limb joints. This study investigates hip, knee, and ankle joint loading during walking, running, jumping, and hopping exercises, assessing impacts at various intensities (maximal, medium, and minimum efforts).A total of 37 healthy, active participants were recruited, with a mean (SD) age of 40.3 (13.1) years, height of 1.7 (0.08) m, and mass of 68.4 (11.7) kg. Motion capture data were collected for each participant while performing six different exercises: a self-selected level of walking, running, counter-movement jump, squat jump, unilateral hopping, and bilateral hopping. A lower body musculoskeletal model was developed for each participant in OpenSim. The static optimization method was used to calculate muscle forces and hip joint contact forces.The study reveals that running and hopping induce increased joint contact forces compared to walking, with increments of 83% and 21%, respectively, at the hip; 134% and 94%, respectively, at the knee; and 94% and 77%, respectively, at the ankle. Jump exercises exhibit less hip and ankle loading compared to walking, with reductions of 36% and 19%, respectively. Joint loading varies across exercises and intensities, running faster increases forces on all joints, especially the hip. Sprinting raises hip forces but lowers forces on the knee and ankle. Higher jumps intensify forces on the hip, knee, and ankle, whereas hopping faster reduces forces on all joints.The study emphasizes the site-specific impact of exercises on lower limb joint loadings, highlighting the potential of running and hopping for bone formation compared to jumping alone. These findings offer insights for optimizing exercise routines to improve bone health, with potential implications for risk prevention, rehabilitation, and prosthetic development.
MuViSS : Muscle, Visceral and Subcutaneous Segmentation by an automatic evaluation method using Deep Learning
Authors: Wasielewski Edouard , Boudjema Karim , Sulpice Laurent , Pecot Thierry 
Published: March 2024

AbstractPurposePatient body composition is a major factor in patient management. Indeed, assessment of SMI as well as VFA and, to a lesser extent, SFA is a major factor in patient survival, particularly in surgery. However, to date, there is no simple, rapid, open-access assessment method. The aim of this work is to provide a simple, rapid and accurate tool for assessing patients’ body composition.Material and methodsA total of 343 patients underwent liver transplantation at the University Hospital of Rennes between January 1st, 2012 and December 31s, 2018. Image analysis was performed using the open source software ImageJ. Tissue distinction was based on Hounsfield density. The training dataset used 332 images (320 for training and 12 for validation). The model was evaluated on 11 patients. The complete software and video package is available athttps://github.com/tpecot/MuViSS.ResultsIn total, the model was trained with 332 images and evaluated on 11 images. Model accuracy is 0.974 (SD 0.003), Jaccard’s index is 0.98 for visceral fat, 0.895 for muscle and 0.94 for subcutaneous fat. The Dice index is 0.958 (SD 0.003) for visceral fat, 0.944 (SD: 0.012) for muscle and 0.970 (SD: 0.013) for subcutaneous fat. Finally, the Normalized root mean square error is 0.007 for visceral fat, 0.0518 for muscle and 0.0124 for subcutaneous fat.ConclusionTo our knowledge, this is the first freely available model for assessing body composition. The model is fast, simple and accurate, based on Deep Learning.Statements and declarationsAll authors declare no conflict of interest
What do we have here? A Systematic Review of Mental Health Policy in Colombia
Authors: Juan Norha Vera San , Garavito German Alarcón , Gort Monica Gonzalez , Sanguinetti Maria Cecilia Dedios , Burgess Rochelle , Lucumí Diego 
Published: March 2024

AbstractBackgroundColombia’s mental health policy is currently under the spotlight due to the global call of prioritising mental health services quality and innovation and the Colombian vision of having an articulated mental health system based on inclusion and community participation. Despite the interest in this topic and proliferation of policy documents, there is no clarity around mental health concepts underlying the compendium of mental health policies, plans and legislation, which are crucial for successful development and implementation of public mental health.MethodThis study is a novel Systematic Collaborative Policy Review which includes a structured approach to identifying and synthesising relevant institutional documents, alongside a realist approach including consultations with experts throughout the review process to increase the applicability of results.Results295 records were screened at title and main content stage, 66 were assessed in full text and 46 were included in this review. Most documents identified were created by the Ministry of Health, the Unit for the Attention and Integral Reparation to the Victims, and regional governments.We found Colombian institutional documents had a holistic understanding of mental health, including considerations around the importance of prevention through the creation of healthy protective environments, as well as protecting right to receive a diagnosis, treatment and rehabilitation for people who require mental health care. There was a strong focus on childhood wellbeing and addressing issues related to illegal drug use. Numerous preventive programmes were listed such as specific programmes for LGTB+ and indigenous communities.ConclusionColombia has a strong mental health legal and programmatic baseline, with ample coverage of aspects ranging from prevention and promotion to quality treatment. However, the extent to which these plans are implemented is unclear. There is a need for clear implementation paths to be included in policy plans, and identification of measurable outputs to monitor success.
Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting
Authors: Steinbrecht David , Minia Igor , Milek Miha , Meisig Johannes , Blüthgen Nils , Landthaler Markus 
Published: March 2024

AbstractEukaryotic mRNAs are transcribed, processed, translated, and degraded in different subcellular compartments. Here, we measured mRNA flow rates between subcellular compartments in mouse embryonic stem cells. By combining metabolic RNA labeling, biochemical fractionation, mRNA sequencing, and mathematical modeling, we determined the half-lives of nuclear pre-, nuclear mature, cytosolic, and membrane-associated mRNAs from over 9000 genes. In addition, we estimated transcript elongation rates. Many matured mRNAs have long nuclear half-lives, indicating nuclear retention as the rate-limiting step in the flow of mRNAs. In contrast, mRNA transcripts coding for transcription factors show fast kinetic rates, and in particular short nuclear half-lives. Differentially localized mRNAs have distinct rate constant combinations, implying modular regulation. Membrane stability is high for membrane-localized mRNA and cytosolic stability is high for cytosol-localized mRNA. mRNAs encoding target signals for membranes have low cytosolic and high membrane half-lives with minor differences between signals. Transcripts of nuclear-encoded mitochondrial proteins have long nuclear retention and cytoplasmic kinetics that do not reflect co-translational targeting. Our data and analyses provide a useful resource to study spatiotemporal gene expression regulation.
Multiomics Analysis Reveals Extensive Remodeling of the Extracellular Matrix and Cellular Metabolism Due to Plakophilin-2 Knockdown in Guinea Pigs
Authors: Song Rui , Wu Haiyan , Yu Lihui , Yu Jingning , Yang WenHui , Wu WenJun , Sun Fei , Wang Haizhen 
Published: March 2024

AbstractArrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death (SCD) in young individuals, yet the mechanisms underlying its pathogenesis, particularly the role of plakophilin-2 (PKP2), remain incompletely understood. This study aimed to elucidate the profile of molecular and metabolic consequences of PKP2 knockdown in a guinea pig model of ARVC. We employed adeno-associated virus serotype 9 (AAV9) to deliver PKP2 shRNA, establishing a model that recapitulates key features of human ARVC, including right ventricular (RV) enlargement, sudden death, and cardiac lipid accumulation. Proteomic analysis revealed significant dysregulation of extracellular matrix (ECM) proteins, PI3K-Akt signaling, and energy metabolism in PKP2-deficient RVs. Metabolomic profiling further highlighted alterations in lipid metabolism and inter-metabolites of TCA cycle, with a notable shift towards fatty acid oxidation. These findings suggest that PKP2 deficiency triggers a cascade of molecular events leading to ECM remodeling, metabolic reconfiguration, and potential mitochondrial dysfunction, which may contribute to the development of ARVC. Our study provides novel insights into the early molecular mechanisms of ARVC and identifies potential therapeutic targets for this underexplored disease.
Chemoproteomic profiling of serine hydrolases reveals the dynamic role of lipases inPhaeodactylum tricornutum
Authors: Dolui Achintya Kumar , Yaakov Beery , Jasinska Weronika , Barak Simon , Brotman Yariv , Khozin-Goldberg Inna 
Published: March 2024

AbstractPhaeodactylum tricornutumis a model oleaginous pennate diatom, widely investigated for the accumulation of triacylglycerols (TAG) in lipid droplets during nitrogen (N) starvation. However, lipid droplet breakdown, TAG catabolism, and remobilization upon N replenishment during growth restoration are less studied. Serine hydrolases (SH) constitute a diverse family encompassing proteases, amidases, esterases, and lipases. In this report, we adopted a chemoproteomic approach called Activity-Based Protein Profiling (ABPP) to explore the repertoire of active serine hydrolases to elucidate the mechanisms of lipid metabolism inP. tricornutum(strain Pt4). A superfamily-wide profile of serine hydrolases revealed a differentially active proteome (activome) during N starvation and after nutrient replenishment. We report 30 active serine hydrolases, which were broadly categorized into metabolic serine hydrolases and serine proteases. Lipases appeared to be the major metabolic linchpins prevalent during lipid remobilization. Global transcriptomics analysis provided a complementary insight into the gene expression level of the detected serine hydrolases. It revealed putative phospholipases as central players in membrane lipid turnover and remodeling involved in cellular lipid homeostasis and TAG accumulation. TAG remobilization and lipid droplet breakdown were impaired in the presence of phenyl mercuric acetate (PMA), whose activity as an SH inhibitor was validated by competitive ABPP. Lipid species profiling corroborated the impairment in TAG degradation and the buildup of structural lipids in the presence of PMA after nutrient replenishment. Collectively, our functional proteome approach, coupled with the transcriptome and lipidome data, provides a comprehensive landscape ofbona fideactive serine hydrolases, including lipases in this model diatom.
NEMO: Improved and accurate models for identification of 6mA using Nanopore sequencing
Authors: Kulkarni Onkar , Zaveri Lamuk , Mathew Reuben Jacob , Singh Nitesh Kumar , Ara Sreenivas , Garde Shambhavi , Reddy Manjula , Tallapaka Karthik Bharadwaj , Sowpati Divya Tej 
Published: March 2024

AbstractDNA methylation plays a key role in epigenetic regulation across lifeforms. Nanopore sequencing enables direct detection of base modifications. While multiple tools are currently available for studying 5-methylcytosine (5mC), there is a paucity of models that can detect 6-methyladenine (6mA) from raw nanopore data. Leveraging the motif-driven nature of bacterial methylation systems, we generated 6mA identification models that vastly surpass the accuracy of the current best model. Our work enables the study of 6mA at a single-base resolution in new as well as existing nanopore datasets.
Border-zone cardiomyocytes and macrophages contribute to remodeling of the extracellular matrix to promote cardiomyocyte invasion during zebrafish cardiac regeneration
Authors: Constanty Florian , Wu Bailin , Wei Ke-Hsuan , Lin I-Ting , Dallmann Julia , Guenther Stefan , Lautenschlaeger Till , Priya Rashmi , Lai Shih-Lei , Stainier Didier Y.R. , Beisaw Arica 
Published: March 2024

AbstractDespite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion using live-imaging and histological approaches. We observed close interactions between protruding cardiomyocytes and macrophages at the wound border zone, and macrophage-deficientirf8mutant zebrafish exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression ofmmp14b, which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone, including cardiomyocytes, macrophages, fibroblasts, and endocardial/endothelial cells. Genetic deletion ofmmp14bled to a decrease in 1) macrophage recruitment to the border zone, 2) collagen degradation at the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression ofmmp14bwas sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.
Mesenchymal stromal cell chondrogenesis under ALK1/2/3-specific BMP inhibition: A revision of the prohypertrophic signalling network concept
Authors: Diederichs Solvig , Dreher Simon I. , Nüesch Sarah-Anna , Schmidt Sven , Merle Christian , Richter Wiltrud 
Published: March 2024

ABSTRACTBackgroundIn vitro chondrogenesis of mesenchymal stromal cells (MSCs) driven by the essential chondro-inducer transforming growth factor (TGF)-β is instable and yields undesired hypertrophic cartilage predisposed to bone formation in vivo. TGF-β can non-canonically activate bone morphogenetic protein-associated ALK1/2/3 receptors. These have been accused of driving hypertrophic MSC misdifferentiation, but data remained conflicting. We here tested the antihypertrophic capacity of two highly specific ALK1/2/3 inhibitors – compound A (CompA) and LDN 212854 (LDN21) – in order to reveal potential prohypertrophic contributions of these BMP/non-canonical TGF-β receptors during MSC in vitro chondrogenesis.MethodsStandard chondrogenic pellet cultures of human bone marrow-derived MSCs were treated with TGF-β and CompA (500 nM) or LDN21 (500 nM). Daily 6-hour pulses of parathyroid hormone-related peptide (PTHrP[1–34], 2.5 nM, from day 7) served as potent antihypertrophic control treatment. Day 28 samples were subcutaneously implanted into immunodeficient mice.ResultsAll groups underwent strong chondrogenesis, but GAG/DNA deposition andACANexpression were slightly but significantly reduced by ALK inhibition compared to solvent controls along with a mild decrease of the hypertrophy markersIHH-, SPP1-mRNA, and Alkaline phosphatase (ALP) activity. When corrected for the degree of chondrogenesis (COL2A1expression), only pulsed PTHrP but not ALK1/2/3 inhibition qualified as antihypertrophic treatment. In vivo, all subcutaneous cartilaginous implants mineralized within 8 weeks, but PTHrP pretreated samples formed less bone and attracted significantly less haematopoietic marrow than ALK1/2/3 inhibitor groups.ConclusionsOverall, our data show that BMP-ALK1/2/3 inhibition cannot program mesenchymal stromal cells toward stable chondrogenesis. BMP-ALK1/2/3 signalling is no driver of hypertrophic MSC misdifferentiation and BMP receptor induction is not an adverse prohypertrophic side effect of TGF-β that leads to endochondral MSC misdifferentiation. Instead, the prohypertrophic network comprises misregulated PTHrP/hedgehog signalling and WNT activity, and a potential contribution of TGF-β-ALK4/5-mediated SMAD1/5/9 signalling should be further investigated to decide about its postulated prohypertrophic activity. This will help to successfully engineer cartilage replacement tissues from MSCs in vitro and translate these into clinical cartilage regenerative therapies.
Dissection of core promoter syntax through single nucleotide resolution modeling of transcription initiation
Authors: He Adam Y. , Danko Charles G. 
Published: March 2024

AbstractHow the DNA sequence ofcis-regulatory elements encode transcription initiation patterns remains poorly understood. Here we introduce CLIPNET, a deep learning model trained on population-scale PRO-cap data that predicts the position and quantity of transcription initiation with single nucleotide resolution from DNA sequence more accurately than existing approaches. Interpretation of CLIPNET revealed a complex regulatory syntax consisting of DNA-protein interactions in five major positions between−200 and+50 bp relative to the transcription start site, as well as more subtle positional preferences among transcriptional activators. Transcriptional activator and core promoter motifs work non-additively to encode distinct aspects of initiation, with the former driving initiation quantity and the latter initiation position. We identified core promoter motifs that explain initiation patterns in the majority of promoters and enhancers, including DPR motifs and AT-rich TBP binding sequences in TATA-less promoters. Our results provide insights into the sequence architecture governing transcription initiation.