bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beta-Hydroxybutyrate Attenuates Bronchial Smooth Muscle Pro-Inflammatory Cytokine Production
Authors: Fastiggi V. Amanda , Mank Madeleine M. , Poynter Matthew E. 
Published: February 2025

AbstractAsthma is a common airway condition causing breathing difficulties due to reversible airflow obstruction. It often affects obese individuals, with symptoms triggered by environmental factors that induce immune responses, leading to inflammation and bronchoconstriction. Bronchial smooth muscle (BSM) plays a central role in airway narrowing, driven by type 2 immune responses involving cytokines like IL-4, IL-5, and IL-13, along with leukocytes including eosinophils and type 2 T-helper cells. These responses cause structural changes such as fibrosis and airway thickening, while BSM cells worsen asthma by releasing pro-inflammatory cytokines in response to allergens, microbial signals, or inflammatory cytokines from other cells. While current treatments manage asthma in most patients, alternative therapies are needed for difficult-to-treat cases, particularly prevalent in obese, allergic individuals. Emerging research suggests that therapeutic ketosis, induced by dietary changes or ketone supplementation, may reduce airway hyperresponsiveness and inflammation. The primary ketone body, β-hydroxybutyrate (BHB), produced during carbohydrate scarcity, acts via cell-surface receptors and transporters, potentially mitigating asthma symptoms. Weight loss and caloric restriction increase ketone levels, correlating with reduced inflammation and improved asthma outcomes. We hypothesized that β-hydroxybutyrate (BHB) reduces bronchoconstriction and inflammation in asthma by targeting bronchial smooth muscle. Using human bronchial smooth muscle cells (HBSMC)in vitro,we demonstrate herein that BHB suppresses IL-1β-induced pro-inflammatory cytokine production through Free Fatty Acid Receptor 3 (FFAR3) activation. These findings suggest that bronchial smooth muscle is a key target of therapeutic ketosis, supporting BHB’s potential benefits in preclinical asthma models.
Alternate dyes for image-based profiling assays
Authors: Sivagurunathan Suganya , Byrne Patrick , Muñoz Alán F. , Arevalo John , Carpenter Anne E. , Singh Shantanu , Kost-Alimova Maria , Cimini Beth A. 
Published: February 2025

AbstractBackgroundCell Painting, the leading image-based profiling assay, involves staining plated cells with six dyes that mark the different compartments in a cell. Such profiles can then be used to discover connections between samples (whether different cell lines, different genetic treatments, or different compound treatments) as well as to assess particular features impacted by each treatment. Researchers may wish to vary the standard dye panel to assess particular phenotypes, or image cells live while maintaining the ability to cluster profiles overall.MethodsIn this study, we evaluate the performance of dyes that can either replace or augment the traditional Cell Painting dyes or enable tracking live cell dynamics. We perturbed U2OS cells with 90 different compounds and subsequently stained them with either standard Cell Painting dyes (Revvity), or with MitoBrilliant (Tocris) replacing MitoTracker or Phenovue phalloidin 400LS (Revvity) replacing phalloidin. We also tested the live-cell compatible ChromaLive dye (Saguaro).ResultsAll dye sets effectively separated biological replicates of the same sample vs. negative controls (phenotypic activity), although separating from replicates of all other compounds (phenotypic distinctiveness) proved challenging for all dye sets. While individual dye substitutions within the standard Cell Painting panel had minimal impact on assay performance, the live cell dye exhibited distinct performance profiles across different compound classes compared to the standard panel, with later time points more distinct than earlier ones.DiscussionSubstituting MitoBrilliant or Phenovue phalloidin 400LS for standard mitochondrial or actin dyes minimally impacted Cell Painting assay performance. Phenovue phalloidin 400LS offers the advantage of isolating actin features from Golgi or plasma membrane while accommodating an additional 568nm dye. Live cell imaging, enabled by ChromaLive dye, provides real-time assessment of compound-induced morphological changes. Combining this with the standard Cell Painting assay significantly expands the feature space for enhanced cellular profiling. Our findings provide data-driven options for researchers selecting dye sets for image-based profiling.
Fatty acid synthesis supports tumor progression through keeping TORC1 receptive for Insulin/PI3K signaling
Authors: Károlyi Dorottya , Bótor Sólyom Bálint , Neuhauser Natali , Péter Mária , Balogh Gábor , O’Farrell Fergal , Takáts Szabolcs 
Published: February 2025

AbstractBiosynthesis of lipids and fatty acids (FAs) is a tightly regulated and complex process essential for the normal functioning of various cellular processes as is sufficient lipid availability for the progression of several malignant tumor types. Despite its importance, the roles of the individual steps in lipid biosynthesis during tumor growth and their subsequent interaction with intracellular signaling pathways are still not well understood. In our study, we used the RasV12, Scribble deficient carcinoma model inDrosophilato demonstrate that upregulation of de novo FA and lipid synthesis is a conserved characteristic of malignant tumors. Performing a small-scale genetic screen by tumor cell specific silencing of components of neutral lipid biosynthetic apparatus revealed that the loss of several enzymes involved in FA and diacylglycerol synthesis significantly inhibited tumor growth. Further characterization of the role of acetyl-CoA carboxylase (ACC), the enzyme responsible for the first step of FA synthesis, revealed that loss of ACC significantly reduced late-stage tumor growth due to increased apoptotic activity. However, early tumor development was unaffected. This correlated with our observation that perturbation of FA synthesis led to inactivation of TORC1 (Target of Rapamycin Complex 1) – the master regulator of cell growth and survival – accompanied by activation of the catabolic process autophagy. Moreover, we also demonstrated that TORC1 activity cannot be restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC deficient tumor cells but supplementation of ACC deficient tumors with ectopically added oleic acid alone could improve TORC1 activity and thereby tumor progression. Hence, our findings highlight a new role of FAs in regulating TORC1, rendering it receptive to upstream activatory signals, explaining why cancer cells are extremely dependent on de novo FA synthesis.
Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer’s disease
Authors: Dan Xiuli , Croteau Deborah L. , Liu Wenlong , Chu Xixia , Robbins Paul D , Bohr Vilhelm A. 
Published: February 2025

AbstractDysfunctional mitophagy is a key component of Alzheimer’s disease (AD) pathology, yet directin vivoevidence and mechanistic insights remain limited. Using a mitophagy reporter in an AD mouse model (APP/PSEN1/mt-Keima), we identified mitochondrial plaques (MPs) composed of accumulated mitochondria within or outside lysosomes in AD, but not normal mouse brains. Similar structures were also found in AD human brains, but not in healthy controls. Abnormal mitochondrial accumulation in dystrophic neurites, defective mitophagy, and impaired lysosomal function disrupted proper mitochondrial degradation, resulting in excessive mitochondria accumulation both within and outside autophagic vesicles. The resulting intensive mitochondria-containing neurites coalesce into MPs, which co-develop with amyloid plaques to form mixed plaques. These findings establish MPs as novel pathological entity and a promising therapeutic target in AD.
Evolution of Eukaryotic Specific DNA Binding Sites in Asgard Archaeal RecA Recombinases
Authors: Ferlez Bryan , Huang Peter Towei , Hu Jingyi , Brooks Crickard J. 
Published: February 2025

AbstractRecA-type recombinases are essential for genome maintenance in all domains of life, promoting homologous recombination (HR). While the general reaction catalyzed by recombinases is the same in all domains, key differences at the amino acid level can lead to the specialization of this family of proteins. A key example of this is in the domain of Eukarya, which can utilize two different RecA homologs depending on the life cycle stage of the organism, with the activity of Rad51 utilized during mitotic growth and the activity of Dmc1 used during meiosis. Why most eukaryotes utilize two RecA homologs is an open question. A missing piece of information in this story is the identity of RecA homologs before the divergence of Rad51 and Dmc1, which occurred in early eukaryotes. We analyzed sequence data from the Archaeal homolog, RadA, in the Asgard Archaea superphyla. Our findings include evidence for the evolution of a eukaryotic-specific DNA binding site II within the Asgard lineage. We also identify sequence variants within DNA binding loops L1 and L2, part of binding site I, that imply higher mismatch tolerance within the Asgard and DPANN superphylum. These loops are also observed in the meiosis-specific recombinase Dmc1 within Eukarya. Our phylogenetic analysis suggests the last Archaeal ancestor of Rad51 and Dmc1 was more Dmc1-like in character and likely of lower fidelity.
Examination of germline and somatic intercellular bridges inHydra vulgarisreveals insights into the evolutionarily conserved mechanism of intercellular bridge formation
Authors: Price Kari L. , Tharakan Dyuthi M. , Salvenmoser Willi , Ayers Kathleen , Mah Jasmine , Dunn Casey , Hobmayer Bert , Cooley Lynn 
Published: February 2025

AbstractIncomplete cytokinesis results in the formation of stable intercellular bridges that have been extensively studied in bilaterians, where they play essential roles in cell-cell communication and coordination of differentiation. However, little is known about their structure and molecular composition in non-bilaterian animals. This study characterizes germline and somatic intercellular bridges in the cnidarianHydra vulgaris, providing insights into their evolutionary origins and functional significance. We identified key conserved components, including KIF23, F-actin, and phosphotyrosine. Notably, we observed microtubule localization withinHydraring canals, suggesting previously unrecognized functions for this cytoskeletal component in intercellular bridge formation. Bioinformatic analyses confirmed the conserved expression ofKif23and suggested its role as a molecular marker for identifying ring canal-associated components. EdU incorporation during DNA replication demonstrated that cells connected by ring canals exhibit synchronized cell cycles, which may be critical for the coordination of division and differentiation. Our findings reveal that the molecular and structural features of intercellular bridges inHydraare conserved across evolutionary lineages, highlighting their ancient origins and functional significance in cellular connectivity. The presence of synchronized cell cycles in ring canal-connected cells underscores their role in promoting coordinated cellular behaviors, processes fundamental to multicellular organization. This study provides new perspectives on the evolution of incomplete cytokinesis and establishes a framework for comparative investigations into the diversity and conservation of intercellular bridge mechanisms across metazoans.
Inborn errors of immunity: manifestation, treatment, and outcome – an ESID registry 1994-2024 report on 30,628 patients
Authors: Kindle Gerhard , Alligon Mickaël , Albert Michael H. , Buckland Matthew , Edgar J. David , Gathmann Benjamin , Ghosh Sujal , Gkantaras Antonios , Nieters Alexandra , Pignata Claudio , Robinson Peter , Rusch Stephan , Schuetz Catharina , Sharapova Svetlana , Shillitoe Benjamin , Candotti Fabio , Cant Andrew J. , Casanova Jean-Laurent , Etzioni Amos , Fischer Alain , Meyts Isabelle , Notarangelo Luigi D. , Pergent Martine , Smith C. I. Edvard ,   ESID Registry Working Party, Hammarström Lennart , Grimbacher Bodo , Seppänen Mikko , Mahlaoui Nizar , Ehl Stephan , Seidel Markus G. 
Published: February 2025

AbstractTheEuropean Society for Immunodeficienciespatient registry (ESID-R), established in 1994, is one of the world’s largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy. Data from 194 centers in 33 countries capture clinical manifestations and treatments from birth onward, with annually expected updates. This report reviews the ESID-R’s structure, data content, and impact.The registry includes 30,628 patient datasets (aged 0–97.9 years; median follow-up: 7.2 years; total 825,568.2 patient-years), with 13,550 cases in 15 sub-studies. It has produced 84 peer-reviewed publications (mean citation rate: 95). Findings highlight real-world observations of IEI diagnoses, genetic causes, treatments, and survival trends. The ESID-R fosters global collaboration, advancing IEI research and patient care. Early declining survival probabilities for many IEI subcategories suggest expanding newborn screening beyond severe combined immune deficiencies. This report highlights the key role of the multi-national ESID-R, led by an independent medical society, in evidence-based discovery.SummaryWorldwide, most patient registries for inborn errors of immunity are national, with limited geographical and temporal scope. This 30-year ESID registry analysis of 30,628 patients’ longitudinal datasets enables robust epidemiological studies on natural disease courses including diagnosis, treatment, and survival, supporting expanded newborn screening and future AI applications in IEI research.
Exploration of Key Markers Driving Ferroptosis in the Progression of Non-Alcoholic Fatty Liver Disease
Authors: Zhang Jiyong , Li Weiyan , Qiu Xiaoying , Wang Yuanyuan , Zeng Yongmei 
Published: February 2025

AbstractNon-alcoholic fatty liver disease (NAFLD) is a prevalent condition strongly linked to obesity, diabetes, and metabolic syndrome. Its global incidence is steadily increasing, placing a significant health burden on both patients and society. Despite existing treatments, such as lifestyle changes and medications, the lack of effective biomarkers and therapeutic strategies leaves many patients at risk for disease progression. This study aims to identify ferroptosis-related differentially expressed genes (DEGs) through bioinformatics analysis and to explore their roles in NAFLD. By comparing samples from NAFLD patients and healthy controls, we identified 1,770 significant DEGs, with 1,073 being upregulated and 697 downregulated. Pathway analysis revealed a marked decrease in expression within certain key metabolic pathways (such as the one-carbon pool by folate) in the NAFLD group, while expression in DNA repair-related pathways (such as non-homologous end joining) was significantly increased. Additionally, immune cell infiltration analysis showed significant differences in 19 immune cell types between the NAFLD and control groups, with 12 types exhibiting increased infiltration in the NAFLD group. Through protein-protein interaction (PPI) network analysis, we identified 41 critical intersecting genes, and ROC curve validation demonstrated that 25 of these genes had an AUC value exceeding 0.85, highlighting their potential as biomarkers for NAFLD. In conclusion, this study sheds light on the underlying molecular mechanisms of NAFLD and identifies promising genes as potential biomarkers, providing a crucial foundation for future early diagnosis and personalized treatment.
Mendelian randomization analyses uncover causal relationships between brain structural connectome and risk of psychiatric disorders
Authors: Xiao Kanwei , Chang Xinle , Ye Chenfei , Zhang Zhiguo , Ma Ting , Su Jingyong 
Published: February 2025

AbstractGrowing evidence suggests abnormalities of brain structural connectome in psychiatric disorders, but the causal relationships remain underexplored. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causal links between 206 white-matter connectivity phenotypes (n = 26,333, UK Biobank) and 13 major psychiatric disorders (n = 14,307 to 1,222,882). Forward MR analyses identified causal effects of genetically predicted five white-matter structural connectivity phenotypes on six psychiatric disorders, with associations being significant or suggestive. For instance, structural connectivity between the left-hemisphere frontoparietal control network and right-hemisphere default mode network was significantly negatively associated with autism spectrum disorder risk, while increased structural connectivity between the right-hemisphere frontoparietal control network and hippocampus was significantly linked to decreased anorexia nervosa and cannabis use disorder risk. Reverse MR analyses revealed significantly or suggestively causal relationships between the risk of two psychiatric disorders and four different white-matter structural connectivity phenotypes. For example, the susceptibility of anorexia nervosa was found to be significantly negatively associated with structural connectivity between the left-hemisphere visual network and pallidum. These findings offer new insights into the etiology of psychiatric disorders and highlight potential biomarkers for early detection and prevention at the brain structural connectome level.
Characterization of perceptual and electrophysiological responses to high-speed robot-controlled pinprick stimulation
Authors: Poux Sofía , Youssif Abed , Van Den Broeke Emanuel N. , Baumgärtner Ulf , Biurrun Manresa José A. , Mista Christian A. 
Published: February 2025

ABSTRACTObjectiveMechanical pinprick stimuli delivered via robotic systems have been applied using parameters derived from studies using handheld stimulators. This work evaluates the effects of stimulus force and duration on neurophysiological responses and subjective perception.MethodsTwenty-seven healthy volunteers received pinprick stimuli on the right volar forearm using different combinations of force and duration that configured three stimulus intensities: low, medium and high impulse. The robotic system recorded stimulus force and duration in real-time, and participants rated the perceived intensity after each stimulus on a numerical rating scale (NRS). The peak amplitudes and latencies of the pinprick evoked potentials (PEPs) were compared for the stimulation impulse intensities. The NRS ratings were analysed using linear mixed models, and the PEP features were evaluated through spatio-temporal cluster permutation tests.ResultsThe NRS ratings were 2.5 [7.0] for low, 16.4 [18.0] for medium, and 28.5 [31.1] for high impulse stimuli. Differences in brain activity were found when comparing all impulse intensities. Peak N2 latency was longer for high compared to low and for medium compared to low. P2 latency showed no differences across impulse intensities. N2 was more negative for high vs. low and for medium vs. low, with no significant difference between high and medium impulses.ConclusionsBoth cortical and subjective responses depend on the applied impulse intensity. Stimulation parameters should be selected based on the specific effect under investigation, as a range of peripheral afferents may be activated by mechanical stimuli.
Open-Source Retrieval Augmented Generation Framework for Retrieving Accurate Medication Insights from Formularies for African Healthcare Workers
Authors: Owoyemi Joshua , Abubakar Shamsudeen , Owoyemi Ayomide , Togunwa Taofeeq Oluwatosin , Madubuko Favour Chiemerie , Oyatoye Samuel , Oyetolu Zeenat , Akyea Kelvin , Mohammed Afeez Olamilekan , Adebakin Abimbola 
Published: February 2025

AbstractAccessing accurate medication insights is vital for enhancing patient safety, minimizing errors, and supporting clinical decision-making. However, healthcare professionals in Africa often rely on manual and time-consuming processes to retrieve drug information, exacerbated by limited access to pharmacists due to brain drain and healthcare disparities. This paper presents “Drug Insights,” an open-source Retrieval-Augmented Generation (RAG) chatbot designed to streamline medication lookup for healthcare workers in Africa. By leveraging a corpus of Nigerian pharmaceutical data and advanced AI technologies, including Pinecone databases and GPT models, the system delivers accurate, context-specific responses with minimal hallucination. The chatbot integrates prompt engineering and S-BERT evaluation to optimize retrieval and response generation. Preliminary tests, including pharmacist feedback, affirm the tool’s potential to improve drug information access while highlighting areas for enhancement, such as UI/UX refinement and extended corpus integration.
VDAC isoforms play distinct roles in modulating metabolism and maintaining mitochondrial function
Authors: Rajendran Megha , Rosencrans William M. , Fitzgerald Wendy , Huynh Diana , Beyene Bethel G. , Quan Baiyi , Hwang Julie , Bautista Nina , Chou Tsui-Fen , Bezrukov Sergey M. , Rostovtseva Tatiana K. 
Published: February 2025

AbstractThe Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC 1, 2, and 3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms can conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome in distinctly different manners, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.