bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral alcohol metabolism dictates ethanol consumption and drinking microstructure in mice
Authors: Mackowiak Bryan , Haggerty David L. , Lehner Taylor , Lin Yu-Hong , Fu Yaojie , Lu Hongkun , Pawlosky Robert J. , Ren Tianyi , Seo Wonhyo , Feng Dechun , Zhang Li , Lovinger David M. , Gao Bin 
Published: January 2025

AbstractBackgroundEthanol metabolism is intimately linked with the physiological and behavioral aspects of ethanol consumption. Ethanol is mainly oxidized by alcohol dehydrogenase (ADH) to acetaldehyde and further to acetate via aldehyde dehydrogenases (ALDHs). Understanding how ethanol and its metabolites work together to initiate and drive continued ethanol consumption is crucial for identifying interventions for alcohol use disorder (AUD). Therefore, the goal of our study was to determine how ADH1, which is mainly peripherally-expressed and metabolizes >90% of ingested ethanol, modulates ethanol metabolite distribution and downstream behaviors.MethodsEthanol consumption in drinking-in-the-dark (DID) and two-bottle choice (2BC) drinking paradigms, ethanol metabolite concentrations, and lickometry were assessed after ADH1 inhibition and/or inAdh1-knockout (Adh1KO) mice.ResultsWe found thatAdh1KO mice of both sexes exhibited decreased ethanol consumption and preference compared to wild-type (WT) mice in DID and 2BC. ADH1 inhibitor fomepizole (4-MP) also significantly decreased normal and sweetened ethanol consumption in DID studies. Measurement of ethanol and its metabolites revealed that ethanol was increased at 1h but not 15 min, peripheral acetaldehyde was slightly decreased at both time points, and ethanol-induced increases in acetate were abolished after ethanol administration inAdh1KO mice compared to controls. Similarly, ethanol accumulation as a function of consumption was 2-fold higher inAdh1KO or 4-MP treated mice compared to controls. We then used lickometry to determine how this perturbation in ethanol metabolism affects drinking microstructure.Adh1KO mice consume most of their ethanol in the first 30 min like WT mice but display altered temporal shifts in drinking behaviors and do not form normal bout structures, resulting in lower ethanol consumption.ConclusionsOur study demonstrates that ADH1-mediated ethanol metabolism is a key determinant of ethanol consumption, highlighting a fundamental knowledge gap around how ethanol and its metabolites drive ethanol consumption.
Fine-Tuning of Material Properties via Catch Bonds
Authors: Rabbi Md Foysal , Koenderink Gijsje H. , Mulla Yuval , Kim Taeyoon 
Published: January 2025

ABSTRACTSemiflexible polymer networks are ubiquitous in biological systems, including a scaffolding structure within cells called the actin cytoskeleton. The polymers in these networks are often interconnected by transient bonds. For example, actin filaments in the cytoskeleton are physically connected via cross-linkers. The mechanical and kinetic properties of the cross-linkers significantly affect the rheological properties of the actin cytoskeleton. Here, we employed an agent-based model to elucidate how the force-dependent behaviors of the cross-linkers determine the material properties of passive networks without molecular motors and the force generation of active networks with molecular motors. The cross-linkers are assumed to behave as a slip bond whose dissociation rate is proportional to forces or as a catch-slip bond whose dissociation rate is inversely proportional to forces at low force level but proportional to forces at high force level. We found that catch-slip-bond cross-linkers can increase both stress and strain at a yield point by forming force-bearing elements that turn over continuously, which is impossible to achieve without the catch-slip bonds. In addition, we demonstrated that the catch-slip-bond cross-linkers help myosin motors generate greater internal contractile forces by reinforcing the force-bearing parts of the active network.
Assessing Generative Model Coverage of Protein Structures with SHAPES
Authors: Lu Tianyu , Liu Melissa , Chen Yilin , Kim Jinho , Huang Po-Ssu 
Published: January 2025

SUMMARYRecent advances in generative modeling enable efficient sampling of protein structures, but their tendency to optimize for designability imposes a bias toward idealized structures at the expense of loops and other complex structural motifs critical for function. We introduce SHAPES (Structural and Hierarchical Assessment of Proteins with Embedding Similarity) to evaluate five state-of-the-art generative models of protein structures. Using structural embeddings across multiple structural hierarchies, ranging from local geometries to global protein architectures, we reveal substantial undersampling of the observed protein structure space by these models. We use Fréchet Protein Distance (FPD) to quantify distributional coverage. Different models are distinct in their coverage behavior across different sampling noise scales and temperatures; the frequency of TERtiary Motifs (TERMs) further supports the observations. More robust sequence design and structure prediction methods are likely crucial in guiding the development of models with improved coverage of the designable protein space.
RNA sequencing reveals key factors modulating TNFα-stimulated odontoblast-like differentiation of dental pulp stem cells
Authors: Irfan Muhammad , Kim Ji Hyun , Sreekumar Sreelekshmi , Chung Seung 
Published: January 2025

AbstractInflammation is a complex host response to harmful infections or injuries, playing both beneficial and detrimental roles in tissue regeneration. Notably, clinical dentinogenesis associated with caries development occurs within an inflammatory environment. Reparative dentinogenesis is closely linked to intense inflammation, which triggers the recruitment and differentiation of dental pulp stem cells (DPSCs) into the dentin lineage. Understanding how inflammatory responses influence DPSCs is essential for elucidating the mechanisms underlying dentin and pulp regeneration. Given the limited data on this process, a broad approach is employed here to gain a deeper understanding of the complex mechanisms involved and to identify downstream signaling targets. This study aims to investigate the role of inflammation and the complement receptor C5L2 in the odontoblastic differentiation of DPSCs and the associated transcriptomic changes using poly-A RNA sequencing (RNA-seq). RNA-seq techniques provide insight into the transcriptome of a cell, offering higher coverage and greater resolution of its dynamic nature. Following inflammatory stimulation, DPSCs exhibit significantly altered gene profiles, including marked upregulation of key odontogenic genes, highlighting the critical role of inflammation in dentinogenesis. We demonstrate that TNFα-treated odontoblast-like differentiating DPSCs, under C5L2 modulation, exhibit significant differential gene expression and transcriptomic changes. The data presented may provide new avenues for experimental approaches to uncover pathways in dentinogenesis by identifying specific transcription factors and gene profiles.
A genetically based computational drug repurposing framework for rapid identification of candidate compounds: application to COVID-19
Authors: Voloudakis Georgios , Lee Kyung Min , Vicari James M. , Zhang Wen , Hoagland Daisy , Venkatesh Sanan , Bian Jiantao , Anyfantakis Marios , Wu Zhenyi , Rahman Samir , Gao Lina , Cho Kelly , Lee Jennifer S. , Iyengar Sudha K. , Luoh Shiuh-Wen , Assimes Themistocles L. , Hoffman Gabriel E. , tenOever Benjamin R. , Fullard John F. , Lynch Julie A. , Roussos Panos 
Published: January 2025

AbstractBackgroundThe development and approval of novel drugs are typically time-intensive and expensive. Leveraging a computational drug repurposing framework that integrates disease-relevant genetically regulated gene expression (GReX) and large longitudinal electronic medical record (EMR) databases can expedite the repositioning of existing medications. However, validating computational predictions of the drug repurposing framework remains a challenge.MethodsTo benchmark the drug repurposing framework, we first performed a 5-method-rank-based computational drug prioritization pipeline by integrating multi-tissue GReX associated with COVID-19-related hospitalization, with drug transcriptional signature libraries from the Library of Integrated Network-Based Cellular Signatures. We prioritized FDA-approved medications from the 10 top-ranked compounds, and assessed their association with COVID-19 incidence within the Veterans Health Administration (VHA) cohort (~9 million individuals). In parallel, we evaluatedin vitroSARS-CoV-2 replication inhibition in human lung epithelial cells for the selected candidates.ResultsOurin silicopipeline identified seven FDA-approved drugs among the top ten candidates. Six (imiquimod, nelfinavir and saquinavir, everolimus, azathioprine, and retinol) had sufficient prescribing rates or feasibility for further testing. In the VHA cohort, azathioprine (odds ratio [OR]=0.69, 95% CI 0.62–0.77) and retinol (OR=0.81, 95% CI 0.72–0.92) were significantly associated with reduced COVID-19 incidence. Conversely, nelfinavir and saquinavir demonstrated potent SARS-CoV-2 inhibitionin vitro(~95% and ~65% viral load reduction, respectively). No single compound showed robust protection in bothin vivoandin vitrosettings.ConclusionsThese findings underscore the power of GReX-based drug repurposing in rapidly identifying existing therapies with potential clinical relevance; four out of six compounds showed a protective effect in one of the two validation approaches. Crucially, our results highlight how a complementary evaluation—combining epidemiological data andin vitroassays—helps refine the most promising candidates for subsequent mechanistic studies and clinical trials. This integrated validation approach may prove vital for accelerating therapeutic development against current and future health challenges.
Automated characterisation of cerebral microbleeds using their size and spatial distribution on brain MR images
Authors: Sundaresan Vaanathi , Zamboni Giovanna , Dineen Robert A , Auer Dorothee P , Sotiropoulos Stamatios N , Sprigg Nikola , Jenkinson Mark , Griffanti Ludovica 
Published: January 2025

AbstractCerebral microbleeds (CMBs) are small, hypointense hemosiderin deposits in the brain measuring around 2-10 mm in diameter. As one of the important biomarkers of small vessel disease, they have been associated with various neurodegenerative and cerebrovascular diseases. Hence, automated detection, and subsequent extraction of clinically useful metrics (e.g., size and spatial distribution) from CMBs are essential for investigating their clinical impact, especially in large-scale studies. While some work has been done for CMB segmentation, extraction of clinically relevant information is not yet explored. Herein, we propose the first automated method to characterise CMBs using their size and spatial distribution i.e., CMB count in three regions (and their sub-structures) used in microbleed anatomical rating scale (MARS): infratentorial, deep and lobar. Our method uses structural atlases of the brain for determining individual regions. On an intracerebral haemorrhage study dataset, we achieve a mean absolute error of 2mm for size estimation and an overall accuracy>90% for automated rating. The code and the atlas of MARS regions in MNI space are publicly available.Key pointsWe present a method to automatically characterise cerebral microbleeds (size and location).The method achieved a mean absolute error of 2 mm for size estimation.Automated rating for infratentorial, deep and lobar regions achieved overall accuracy >90%We made the code and atlas of MARS regions publicly available.
Long-term patient-derived ovarian cancer organoids closely recapitulate tumor of origin and clinical response
Authors: Thorel L. , Dolivet E. , Morice P-M. , Florent R. , Divoux J. , Perréard M. , Lecouflet L. , Desmartin G. , Marde Alagama C. , Giffard F. , Leconte A. , Lequesne J. , Clarisse B. , Briand M. , Traore A. , Villenet C. , Meneboo JP. , Babin G. , Gaichies L. , Martin-Françoise S. , Le Brun JF. , Rouzier R. , Brotin E. , Denoyelle C. , Vigneron N. , Leman R. , Vaur D. , Castera L. , Blanc-Fournier C. , Elie N. , Plancoulaine B. , Joly F. , Meryet-Figuière M. , Figeac M. , Weiswald L-B. , Poulain L. 
Published: January 2025

AbstractThere is an urgent need of precision medicine for ovarian cancer patients to identify patients who respond to chemotherapy and PARP inhibitors, a therapy targeting homologous recombination deficiency (HRD). Here we established a panel of 37 long-term patient-derived tumor organoids (PDTO) models of various histological subtypes from 224 patients and demonstrated that they mimic the histological and molecular characteristics of original tumors. Screening of chemotherapeutic drugs showed that PDTO exhibit heterogeneous responses, and that response of PDTO from high-grade serous ovarian carcinoma to carboplatin recapitulated patient response to first-line treatment. Additionally, the detection of HRD phenotype of PDTO using functional assay was associated with the results of the HRD test Genomic Instability Scar (GIScar). Although larger-scale investigations are needed to confirm the predictive potential of PDTO, these results provide further evidence of the potential interest of ovarian PDTO for functional precision medicine even if many challenges remain to be addressed.
CD2 expression is co-regulated with stemness- and exhaustion-associated factors in human T cells
Authors: Demetriou Philippos , Iakovou Maria , Gregoriou Gregoria , Vrachnos Dimitris , Chi Jianxiang , Tamamouna Vasilia , Constantinou Stavros , Papanastasiou Vakis , Antoniades Athos , Costeas Paul 
Published: January 2025

ABSTRACTThe CD2-CD58 pathway has been highlighted as a major player in anti-tumour T cell immunity. Our study reveals that CD2 costimulation strength significantly correlates with T cell activation, the average number of cell divisions, fold expansion, and IFN-γ production. Our findings suggest that the correlation of CD2 strength with the level of CD25 expression is a potential regulatory mechanism by which CD2 strength enhances above proliferation parameters. We find that human brain cancer tumour-infiltrating CD8+ and CD4+ T cells exhibit reduced levels of CD2, suggestive of a compromised CD2 strength upon CD2 engagement. Through a genome-wide CRISPR-Cas9 knockout screen, we identified two epigenetic regulators, SUZ12 and BAP1, as positive modulators of CD2 expression. We demonstrate that BAP1 is crucial for the upregulation and sustained high expression of CD2 following T cell activation. We reveal that CD2 is co-regulated with other co-stimulatory/inhibitory receptors, and factors associated with T cell stemness and exhaustion, in a dose-dependent manner. Importantly, we rescue the loss of CD2 due to BAP1 knockout by pharmacological inhibition of histone deacetylases making this a harnessable regulatory pathway. The insight from our study enhance our understanding of CD2-mediated T cell regulation and identify essential regulators of this pathway.
Fine root endophytes forming winter mycorrhiza
Authors: Sentoku Takeshi , Komatsuda Yuki , Shimada Hayato , Arai Michio , Kobae Yoshihiro 
Published: January 2025

SummaryArbuscular mycorrhizal fungi, classified in the subphylum Glomeromycotina, are obligate symbionts that depend on photosynthetic products from plants. There is substantial evidence that AMF support plant and crop growth in natural and agricultural ecosystems. Fine root endophytes (FRE) also co-occur in plant roots with AMF in all but tropical environments. However, their presence remains poorly recognised, and their lifestyle and functionality remain largely unknown. Our analysis demonstrates that, in contrast to AMF, FRE colonise plants during the winter season, when photosynthesis is more challenging. It is also noteworthy that FRE was unable to colonise the roots of spring-sown crops. The results of our laboratory pot experiments demonstrated that low temperatures are not sufficient for FRE colonisation. Furthermore, we observed that FRE, in contrast to AMF, exhibited increased colonisation in soils containing metabolically inactive plants. Our results suggest that FRE does not contribute to the increase of ecosystem biomass through direct photosynthesis in summer, but may play an overlooked role in the formation of mycorrhiza-based soil ecosystems in winter. However, this winter ecosystem can be disrupted by conventional bare fallow management of the field, interrupting the annual cycle.
Age- and estrous-dependent effects of psilocybin in rats
Authors: Zylko AL , Rakoczy RJ , Roberts BF , Wilson M , Powell A , Page A , Heitkamp M , Fiest D , Jones JA , McMurray MS 
Published: January 2025

AbstractPsilocybin, a psychedelic compound in “magic” mushrooms, has promise as a novel treatment for psychiatric disorders, many of which are more prevalent in females and have onsets during adolescence. However, there is a lack of research about how factors such as sex and age affect responses to psilocybin, as well as potential safety concerns with developmental exposure. The primary objectives of this preclinical study were to determine if psilocybin-induced head twitch responses differ between adolescent and adult rats, and if estrous phase contributes to variation in female head twitch responses. Secondarily, this study sought to determine if treatment with psilocybin during adolescence has long-term effects on anxiety-associated behaviors and behavioral flexibility. Results showed that 1 mg/kg intraoral psilocybin failed to elicit head twitch responses in adolescents (P35 and P45) but elicited robust responses in adult rats. Further, adolescent psilocybin exposure did not cause long-term differences in performance on the elevated zero maze or probabilistic reversal learning tasks. Lastly, adult females in diestrus showed increased head twitch responses after 1 mg/kg psilocybin compared to females in proestrus. Head twitch responses are thought to be mediated by 5-HT2Areceptors, but no age-or estrous-related differences in 5-HT2Areceptor expression were observed in the medial prefrontal cortex. Collectively, these results highlight the existence of age-and sex-dependent differences in the effects of psychedelics, while finding no long-term effects on selected behaviors after adolescent exposure. These findings have implications on psychedelic study design, emphasizing the need for inclusive research considering age, sex, and hormonal status.
Real-time diagnostics and personalized wound therapy powered by AI and bioelectronics
Authors: Li Houpu , Yang Hsin-ya , Lu Fan , Hee Wan Shen , Asefifeyzabadi Narges , Baniya Prabhat , Gallegos Anthony , Schorger Kaelan , Zhu Kan , Recendez Cynthia , Tebyani Maryam , Kesapragada Manasa , Keller Gordon , Kim Sujung , Luka George , Zlobina Ksenia , Nguyen Tiffany , Figuerres Sydnie , Franco Celeste , Devarajan Koushik , Barbee Alexie , Lin Kylie , Clayton Shannon M. , Eaton Annabelle , Aslankoohi Elham , Soulika Athena M. , Zhao Min , Teodorescu Mircea , Gomez Marcella , Isseroff Roslyn Rivkah , Rolandi Marco 
Published: January 2025

AbstractImpaired wound healing affects millions worldwide, especially those without timely healthcare access. TheraHeal provides a portable, wireless platform for real-time, continuous, and personalized wound care. The platform integrates a wearable device for wound imaging and delivery of therapy with an AI Physician. The AI Physician analyzes wound images, diagnoses the wound stage, and prescribes therapies to guide optimal healing. Bioelectronic actuators in the wearable device deliver therapies, including electric fields or drugs, dynamically in a closed-loop system. TheraHeal evaluates wound progress, adjusts therapy as needed, and sends updates to human physicians through a graphical user interface, which also supports manual intervention. In a large animal model, TheraHeal enhanced tissue regeneration, reduced inflammation, and accelerated healing, showcasing its potential to transform personalized wound care.
Biological, experimental and analytical determinants influencing bile acids concentrations in human blood: a review and meta-analysis
Authors: Joseph Sebastian , de Buyl Sophie , Leclercq Isabelle A. , Clerbaux Laure-Alix 
Published: January 2025

AbstractBackgroundDespite over three decades of research, the use of peripheral bile acid concentrations or proportions as biomarkers for human liver injury remain inconclusive due to variable and inconsistent findings.ObjectiveThe aim of this systematic review and meta-analysis was to identify factors contributing to the variability in published bile acid research and propose recommendations to enhance the robustness and reproducibility of future studies.MethodsA search of the PubMed database and a systematic manual screening of references until May 2024 for studies reporting peripheral bile acid concentrations in humans was conducted. English-language studies reporting mean or median concentrations of at least one of 15 predetermined circulating bile acids in human cohorts were included. The exclusion criteria were editorials, commentaries, letters to the editor, conference proceedings, abstracts, and monographs. Raw bile acid concentrations, subject demographics (number, average age, sex distribution, health status, fasted/fed status), the blood matrix analysed, the matrix volume analysed, the bile acid extraction process, and analytical technique when available were extracted by a single observer.Results65 studies involving 215 cohorts were selected. Bile acid concentrations in normal cohorts exhibit large intervariability. The analytical technique used to measure bile acid concentrations, the fasted/fed status of patients at the time of sampling, the choice of blood collection matrix, the starting volume of this matrix, and the choice of protein precipitation solvent are found to be determinants of this variability.LimitationsOnly mean or median bile acid concentrations in study cohorts were extracted from studies and compared since bile acid concentrations are rarely reported in individual subjects. Analysing mean or median bile acid concentrations in study cohorts may not give a true sense of bile acid concentrations and therefore their determinants.DiscussionExperimental, analytical and biological sources of mean peripheral bile acid concentration variability were identified. These must be standardised across future studies to clarify the potential of peripheral bile acids as biomarkers.
Geometry effects on protein mobility in a synapse
Authors: Dannenberg Simon , Reshetniak Sofiia , Mohammadinejad Sarah , Rizzoli Silvio O. , Klumpp Stefan 
Published: January 2025

AbstractIt is generally assumed that synaptic function requires a tight regulation of the mobility and localisation of synaptic proteins. Evidence for this hypothesis has been difficult to gather. Protein mobility can be measured via fluorescence recovery after photobleaching (FRAP), but the inter- pretation of the results remains challenging. In this study, we performin silicoFRAP experiments to study the effects of the synaptic geometry and/or protein binding to synaptic vesicles on protein mobility. We matched simulations with published FRAP data for 40 different synaptic proteins, to obtain diffusion coefficients, vesicle binding rates, and binding times. Importantly, we identify two mechanisms that govern the obtained recovery times: redistribution of material inside the synaptic bouton and inflow through the axon. We show that their dissection is crucial for the correct interpretation of FRAP experiments, especially for proteins binding to synaptic vesicles.