bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripherin: a novel early diagnostic and prognostic plasmatic biomarker in Amyotrophic Lateral Sclerosis
Authors: Bombaci Alessandro , Marco Giovanni De , Casale Federico , Salamone Paolina , Marchese Giulia , Fuda Giuseppe , Calvo Andrea , Chiò Adriano 
Published: January 2025

AbstractBackground and aimMotor neuron diseases (MND) are heterogeneous and complex neurodegenerative disorders. Biomarkers could facilitate early diagnosis, prognosis determination, and patient stratification. Among the most studied biomarkers are neurofilaments, with peripherin (PRPH), a specific type predominantly expressed in peripheral nervous system neurons, gaining attention. To date, no studies have evaluated PRPH levels in human plasma.Methodssandwich-ELISA was used to quantify plasma peripherin from 120 MND (100 ALS, 4 PMA, 15 PLS), 73 MND-mimics (including myelopathy, radiculopathy, axonal neuropathies, Hirayama disease, IBM, benign fasciculation syndrome, functional syndrome, myasthenia, post-polio syndrome) and 38 healthy-controls (HCs). Plasma was collected at the time of diagnosis or some months earlier. 41 ALS were evaluated longitudinally. ALSFRSr, MRC, spirometry, genetic tests, disease progression rate (PR), blood examinations, and neuropsychological tests were performed. Statistical analyses included Kruskal-Wallis, Mann-Whitney, Cox-regression, and Kaplan-Meier curves.ResultsPRPH plasma levels is different between groups (p<0.0001); Bonferroni’s correction shows higher PRPH in MND compared to MND-mimics and HCs. Comparing PLS with HSP PRPH resulted to be higher (p=0.0001). Differences are confirmed co-variating for age and sex. ROC curve shows a good capability of PRPH to discriminate ALS from MND mimics (AUC= 0.85).PRPH levels correlated directly with ALSFRSr, and with lower body involvement while inversely with PR. Higher PRPH levels were associated with survival advantages.DiscussionPlasma PRPH levels are elevated in MND, particularly ALS, from the early disease stages, distinguishing MND from mimics and correlating with clinical parameters and survival. Further multicentre studies incorporating additional biomarkers are required to refine the diagnostic and prognostic utility of PRPH in MND.
Sotrovimab versus usual care in patients admitted to hospital with COVID-19: a randomised, controlled, open-label, platform trial (RECOVERY)
Authors: Horby Peter W , Emberson Jonathan R , Peto Leon , Staplin Natalie , Campbell Mark , Pessoa-Amorim Guilherme , Stewart Richard , Ghosh Dipansu , Cooke Graham , Blencowe Natalie , Moreno-Cuesta Jeronimo , Desai Purav , Hine Paul , Underwood Jonathan , Easom Nicholas , Majumdar Jaydip , Bhagani Sanjay , Baillie J Kenneth , Buch Maya H , Faust Saul N , Jaki Thomas , Jeffery Katie , Juszczak Edmund , Knight Marian , Lim Wei Shen , Montgomery Alan , Mukherjee Aparna , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Mafham Marion , Haynes Richard , Landray Martin J ,   Group RECOVERY Collaborative
Published: January 2025

SUMMARYBackgroundSotrovimab is a neutralising monoclonal antibody that has been proposed as a treatment for patients admitted to hospital with COVID-19.MethodsIn this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 pneumonia. In the sotrovimab comparison, eligible and consenting patients were randomly allocated to either usual care alone or usual care plus a single 1g dose of sotrovimab, using web-based unstratified randomisation. Participants were retrospectively categorised according to their baseline serum SARS-CoV-2 nucleocapsid antigen concentration as ‘high-antigen’ or ‘low-antigen’, using the median concentration as a cut-off. The primary outcome was 28-day mortality assessed by intention to treat. Secondary outcomes were time to discharge alive from hospital, and, among those not on invasive ventilation at baseline, progression to invasive ventilation or death. Recruitment closed on 31 March 2024 when funding ended. ISRCTN (50189673) andclinicaltrials.gov(NCT04381936).FindingsFrom 4 January 2022 to 19 March 2024, 1723 patients were recruited to the sotrovimab comparison. 720 (42%) were classified as high-antigen, 717 (42%) as low-antigen, and 286 (17%) had unknown antigen status. Over 80% of patients were vaccinated, over 80% had anti-spike antibodies at randomisation, and almost all were infected with Omicron variants. In the prespecified primary efficacy population of high-antigen patients, 82/355 (23%) allocated sotrovimab versus 106/365 (29%) allocated usual care died within 28 days (rate ratio 0.75; 95% CI 0.56-0.99; p=0.046). In an analysis of all randomised patients (regardless of antigen status), 177/828 (21%) allocated sotrovimab versus 201/895 (22%) allocated usual care died within 28 days (rate ratio 0.95; 95% CI 0.77-1.16; p=0.60).InterpretationIn patients hospitalised with COVID-19, sotrovimab was associated with reduced mortality in the primary analysis population of patients with a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).
Registered Clinical Trial Trends Evolved Differently in East Asia versus the United States during 2014 to 2023
Authors: Lee Eun Hye , Lee San , Shin Jae Il , Ioannidis John P.A. 
Published: January 2025

ABSTRACTIntroductionEast Asia, including China, Japan, South Korea, and Taiwan, has become a major hub for clinical trials. However, comprehensive comparisons betweenClinicalTrials.govand local registries remain limited. This study analyzes registered clinical trial trends in East Asia over the past decade (2014–2023) and compares them to trends in the United States.MethodsWe extracted clinical trial data through the International Clinical Trials Registry Platform (ICTRP), including data from local registries andClinicalTrials.govfor China, Japan, South Korea, Taiwan, and the United States. We analyzed overall clinical trial trends and filtered randomized controlled trials (RCTs), categorizing them by location, target size, and disease category.ResultsChina experienced rapid growth in clinical trials, surpassing both Japan and the United States in total trials and RCTs. By 2023, China led with 16,612 total trials (7,798 RCTs), while the United States registered 9,100 (4,619 RCTs). Except for China, all other countries showed some decline in recent years. Neoplastic diseases and cardiovascular and metabolic diseases were prominent in both regions, but the U.S. showed growing focus on mental health. China’s RCTs were predominantly domestic, while the U.S. maintained a higher proportion of international trials. Japan, South Korea, and Taiwan showed moderate growth, with fewer international trials than the United States. We recorded some inconsistencies and missing information across existing registries.ConclusionThe study highlights the increasing prominence of East Asia, particularly China, in registered clinical trials, though with a primarily domestic focus. Improvements in existing trial registries covering East Asia are desirable.
JNK2 pathway in colonocytes enhances gut barrier integrity in response to microbial acetate
Authors: Chongtham Chen , Biswas Trisha , Kumari Namaste , Kar Raunak ,   Jyotsna, Jayalakshmi S , Pant Archana , Patil Veena S. , Arimbasseri Gopalakrishnan Aneeshkumar 
Published: January 2025

SUMMARYThe weaning process accompanies changes in the nutritional profile, metabolism, and gut immune tolerance of offspring. However, the molecular changes associated with this transition and their implications for gut health are not well understood. Here, we show that post-weaning milk-based diets modulate the gut microbiome of pups by enrichingDubosiella newyorkensis.This, in turn, enhances gut barrier function by activating the JNK2 pathway in the epithelium through acetate. However, an inflammation-inducing lard-based high-fat diet, a brief pharmacological inhibition of JNK2, or a two-week delay in the initiation of milk-based diets post-weaning leads to the activation of P38 in the epithelial cells, which leads to inflammation. These observations reveal a microbiome-dependent, short-chain fatty acid-driven dichotomy between JNK2 and P38 pathways in the gut epithelium that modulate gut inflammation. These results provide a framework connecting diets, microbiome, and molecular changes in the epithelium, which may aid the design of microbiome-directed dietary interventions.
Fasting-induced hepatic gluconeogenesis is compromised inAnxa6−/−mice
Authors: Alvarez-Guaita A , Bernaus-Esqué M , Blanco-Muñoz P , Liu Y , Sebastian D , Meneses-Salas E , Nguyen MKL , Zorzano A , Tebar F , Enrich C , Grewal T , Rentero C 
Published: January 2025

ABSTRACTMaintaining constant blood glucose levels is essential for energizing glucose-dependent tissues. During the fed state, insulin lowers elevated blood glucose, while in the fasted state, glucagon maintains blood glucose levels through hepatic stimulation of fatty acid oxidation, glycogenolysis, and gluconeogenesis (GNG). The liver plays a crucial role in these metabolic adaptations. Deregulation of GNG is a hallmark of type 2 diabetes mellitus (T2DM), driven by hepatic insulin resistance, elevated glucagon levels, and excess circulating free fatty acids. Despite normal insulin-sensitive control of glucose levels and effective glycogen mobilization,Anxa6knockout (Anxa6−/−) mice display rapid hypoglycaemia during fasting. This metabolic disarrangement, in particular during the early stages of fasting is characterized by a low respiratory exchange ratio (RER) and increased lipid oxidation during the diurnal period, indicating a reliance on lipid oxidation due to hypoglycaemia. Elevated glucagon levels during fasting suggest deficiencies in GNG. Further analysis reveals thatAnxa6−/−mice are unable to utilize alanine for hepatic GNG, highlighting a specific impairment in the glucose-alanine cycle in fastedAnxa6−/−mice, underscoring the critical role of ANXA6 in maintaining glucose homeostasis under metabolic stress. During fasting, slightly reduced expression levels of alanine aminotransferase 2 (Gpt2) and lactate dehydrogenase (Ldha2), enzymes converting alanine to pyruvate, and the hepatic alanine transporter SNAT4 might contribute to these observations in theAnxa6−/−mice. These findings identify that ANXA6 deficiency causes an inability to maintain glycolytic metabolism under fasting conditions due to impaired alanine-dependent GNG.
Identification of a novel false-positive mechanism in RapidFire mass spectrometry and application in drug discovery
Authors: Lin De , Pearson Lesley-Anne , Ahmad Shamshad , O’Neill Sandra , Post John , Robinson Colin , Scott Duncan E. , Gilbert Ian H. 
Published: January 2025

AbstractFalse-positives plague High Throughput Screening in general and are costly as they consume resource and time to resolve. Methods that can rapidly identify such compounds at the initial screen are therefore of great value. Advances in mass spectrometry have led to the ability to screen inhibitors in drug discovery applications by direct detection of an enzyme reaction product. The technique is free from some of the artefacts that trouble classical assays such as fluorescence interference. Its direct nature negates the need for coupling enzymes and hence is simpler with fewer opportunities for artefacts. Despite its myriad advantages, we report here a mechanism for false-positive hits which has not been reported in the literature. Further we have developed a pipeline for detecting these false-positive hits and suggest a method to mitigate against them.Graphical Abstract
Transcription driven repurposing of cardiotonic steroids for Lithium treatment of severe depression
Authors: Killick Richard , Hooper Claudie , Fernandes Cathy , Elliott Christina , Aarsland Dag , Kjosavik Svein R. , Østerhus Ragnhild Djønne , Williams Gareth 
Published: January 2025

AbstractLithium is prescribed as a mood stabiliser in bipolar disorder and severe depression. However, the mechanism of action of Lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates.Given that the drug mechanism may be encoded in transcriptional changes we have generated the gene expression profile for acute Lithium treatment of cortical neuronal cultures. We found that the Lithium associated transcription response harbours a significant component that is the reverse of that seen in human brain samples from patients with Major Depression, Bipolar Disorder and a mouse model of depression. Interrogating publicly available drug driven expression data we found that cardiotonic steroids drive gene expression in a correlated manner to our acute Lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription.Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for Lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.
3D Reconstruction of Dinoflagellate Chromosomes from Hi-C Data Refutes the Cholesteric Liquid Crystal Hypothesis
Authors: Philipp Lucas , Marinov Georgi K. , Todd Stephen , Weber Stephanie C. 
Published: January 2025

Dinoflagellates contain permanently condensed chromosomes that are often described as liquid crystalline. Specifically, a Cholesteric Liquid Crystal (CLC) model was proposed in which DNA is organized into parallel fibers within stacked discs, such that the fiber orientation rotates by a constant angle between adjacent discs. Extrachromosomal loops extending from the discs were hypothesized to be more accessible and thus to contain transcriptionally active genes. Although the CLC model captures some features of dinoflagellate chromosome structure, its validity has not been rigorously tested against modern genomic data. Here, we use chromatin conformation capture (Hi-C) data to simulate 3D conformations of chromosome scaffolds for two dinoflagellate species,Symbiodinium kawagutiiandSymbiodinium microadriaticum. These polymer conformations are compact helices with significant orientational and nematic order. However, we find no evidence of cholesteric discs. Moreover, simulated Hi-C contact maps of CLC structures lack topologically associating domains (TADs), which are observed in experimental Hi-C contact maps for these species. Finally, by mapping RNA-seq data onto our simulated conformations, we show that actively transcribed genes are present throughout the entire chromosome, and not exclusively on extrachromosomal loops or at the surface. Our results refute the long-standing CLC model and suggest that dinoflagellate chromosomes are organized into condensed but non-crystalline structures that do not impede transcription.Significance StatementDinoflagellates have permanently condensed chromosomes that are structurally unique among eukaryotes. These chromosomes are often described as cholesteric liquid crystals (CLCs). In this article, we generate three-dimensional polymer conformations from chromatin conformation capture (Hi-C) data. Our results indicate that, while dinoflagellate chromosomes are organized into compact helical structures, they do not contain parallel stacks of flat discs and are therefore not CLCs. Mapping RNA-seq data onto our simulated conformations reveals actively transcribed genes throughout the entire chromosome, contradicting CLC model predictions and raising questions as to the role of condensation and extrachromosomal loops in regulating gene expression.
SVCROWS: A User-Defined Tool for Delineating Biologically Significant Structural Variants in Heterogeneous Datasets
Authors: Brown Noah , Danis Charles , Ahmedjonova Vazira , Guler Jennifer L. 
Published: January 2025

AbstractSummarySVCROWS is an option-rich R package that generates summarized and quantified structural variant (SV) regions from large and heterogeneous datasets. By using a size-weighted reciprocal overlap framework for comparisons, SVCROWS ensures that regions are delineated without size bias. User input directs stringency of comparisons, exhibiting different levels of resolution in complex regions of the genome.AvailabilitySVCROWS can be downloaded as a Package or R-Markdown file athttps://github.com/A-Crow-Nowhere/SVCROWS.gitContactjlg5fw@virginia.edu;njb8sg@virginia.edu
Multi-modal analysis of satellite cells reveals early impairments at pre-contractile stages of myogenesis in Duchenne muscular dystrophy
Authors: Franzmeier Sophie , Chakraborty Shounak , Mortazavi Armina , Stöckl Jan B. , Jiang Jianfei , Pfarr Nicole , Sabass Benedikt , Fröhlich Thomas , Kaufhold Clara , Stirm Michael , Wolf Eckhard , Schlegel Jürgen , Matiasek Kaspar 
Published: January 2025

AbstractRecent studies on the role of myogenic satellite cells (SC) in Duchenne muscular dystrophy (DMD) documented altered division capacities and impaired regeneration potential of SC in DMD patients and animal models. It remains unknown, however, if SC-intrinsic effects trigger these deficiencies at pre-contractile stages of myogenesis rather than resulting from the pathologic environment. Addressing this, we isolated SC from muscle biopsies of a porcine DMD model for characterization. Traction force microscopy (TFM) revealed that DMD SC produce a significantly higher strain energy than wild-type cells (WT; 0.136 ± 0.016 µJ vs. 0.057 ± 0.008 µJ). By RNA-seq, we identified 1,390 differentially expressed genes and proteomics measurements detected 1,261 proteins with altered abundance in DMD vs. WT. Dysregulated pathways uncovered by Gene Ontology (GO) enrichment analysis included sarcomere organization, focal adhesion, and response to hypoxia. We integrated the data using multi-omics factor analysis (MOFA) and identified five factors accounting for the variance with an overall higher contribution of the transcriptomic (61.95 %) than the proteomic data (54.02 %). Our findings suggest SC impairments result from their inherent genetic abnormality rather than environmental influences. The observed biological changes are independent and not reactive to the pathological surrounding of DMD muscle.
Atomic scale description of the allosteric coupling between a lipid bilayer and a membrane protein
Authors: Fourel Clarisse , Gautier Yanna , Pozza Alexandre , Giraud François , Point Elodie , Le Bon Christel , Moncoq Karine , Stirnemann Guillaume , Hénin Jérôme , Lescop Ewen , Catoire Laurent J. 
Published: January 2025

AbstractBiological membranes are complex environments whose functions are closely tied to the dynamic interactions between lipids and proteins. Here, we utilize high-pressure NMR of lipid nanodiscs paired with molecular dynamics simulations to elucidate at the atomic scale the allosteric dialog between the lipid bilayer and a bacterial model membrane protein, OmpX. We discover that OmpX delays the gelation process by liquefying the annular shell of lipids through hydrophobic and roughness matching processes at the protein surface. Furthermore, the alteration of the mechanical properties of the lipid bilayer directly impacts the energy landscape of amino acid side chains at the lipid/protein interface, but also, unexpectedly, at the protein core. Our work highlights a potential thermodynamically coupled but kinetically uncoupled allosteric pathway linking lipid dynamics with the interior of membrane proteins, directly impacting our understanding of membrane function.Graphical Abstract
Deciphering Multiway Multiscale Brain Network Connectivity: Insights from Birth to 6 Months
Authors: Li Qiang , Fu Zening , Walum Hasse , Seraji Masoud , Bajracharya Prerana , Calhoun Vince , Shultz Sarah , Iraji Armin 
Published: January 2025

AbstractConverging evidence suggests that understanding the human brain requires more than just examining pairwise functional brain interactions. The human brain is a complex, nonlinear system, and focusing solely on linear pairwise functional connectivity often overlooks important nonlinear and higher-order relationships. Infancy is a critical period marked by significant brain development that could contribute to future learning, health, and life success. Exploring higher-order functional relationships in the brain can provide insight into brain function and development. To the best of our knowledge, there is no existing research on multiway, multiscale brain network interactions in infants. In this study, we comprehensively investigate the interactions among brain intrinsic connectivity networks (ICNs), including both pairwise (pair-FNC) and triple relationships (tri-FNC). We focused on an infant dataset collected between birth and six months, a critical period for brain maturation. Our results revealed significant hierarchical, multiway, multiscale brain functional network interactions in the infant brain. These findings suggest that tri-FNC provide additional insights beyond what pairwise interactions reveal during early brain development. The tri-FNC predominantly involve the default mode, sensorimotor, visual, limbic, language, salience, and central executive domains. Notably, these triplet networks align with the classical triple network model of the human brain, which includes the default mode network, the salience network, and the central executive network. This suggests that the brain network system might already be initially established during the first six months of infancy. Interestingly, tri-FNC in the default mode and salience domains showed significantly stronger nonlinear interactions with age compared to pair-FNC. We also found that pair-FNC were less effective at detecting these networks. The present study suggests that exploring tri-FNC can offer additional insights beyond pair-FNC by capturing higher-order nonlinear interactions, potentially yielding more reliable biomarkers to characterize developmental trajectories.
Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy
Authors: Louie Ke’ale W. , Hasegawa Eva H. , Farr Gist H. , Ignacz Amanda , Paguio Alison , Maenza Alyssa , Paquette Alison G. , Henry Clarissa , Maves Lisa 
Published: January 2025

AbstractDuchenne muscular dystrophy (DMD) is the most common inherited muscle disease. There are currently few effective therapies to treat the disease, although many approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models, and the HDACi givinostat has recently gained FDA approval for DMD. Our goal was to identify additional HDACi, or other classes of epigenetic small molecules, that are beneficial for DMD. Using an established animal model for DMD, the zebrafishdmdmutant strainsapje, we screened a library of over 800 epigenetic small molecules of various classes. We used a quantitative muscle birefringence assay to assess and compare the effects of these small molecule treatments ondmdmutant zebrafish skeletal muscle. Our screening identified a new HDACi, SR-4370, that ameliorateddmdmutant zebrafish skeletal muscle degeneration, in addition to HDACi previously shown to improvedmdzebrafish. We find that a single early treatment of HDACi can amelioratedmdzebrafish. Furthermore, we find that HDACi that improvedmdmuscle also cause increased histone acetylation in zebrafish larvae, whereas givinostat does not appear to increase histone acetylation or improve zebrafishdmdmuscle. Our results add to the growing evidence that HDACi are promising candidates for treating DMD. Our study also provides further support for the effectiveness of small-molecule screening indmdzebrafish.Graphical abstract