bluuebunny/crossref_metadata_2025_split huggingface dataset:
p.D372H: A novel SCN5A mutation associated with Brugada syndrome
Authors: Xie Xianghuan , Chen Yanghui , Li Zhiqiang , Jiang Xian-Cheng , Sun Yang , Chen Guangzhi 
Published: February 2025

AbstractBackgroundBrugada syndrome (BrS) is a genetic cardiac arrhythmia disorder inherited in an autosomal dominant manner, characterized by ST-segment elevation in the right precordial leads (V1-V3) on electrocardiograms (ECGs). This syndrome predominantly affects young individuals with structurally normal hearts and significantly increases the risk of ventricular arrhythmias and sudden cardiac death (SCD). The most common genotype found among BrS patients is caused by mutations in the SCN5A gene, which lead to a loss of function of the cardiac sodium (Na+) channel (Nav1.5) by different mechanisms.MethodsPlasmids containing SCN5A were constructed using PCR and site-directed mutagenesis to create the D372H mutation. HEK293 cells were cultured and transfected with the wild-type and mutant constructs. Patch-clamp recordings assessed sodium current characteristics. Confocal microscopy visualized channel localization. Quantitative RT-PCR analyzed mRNA expression levels, while Western blot evaluated protein expression using specific antibodies. We identified a novel missense mutation, D372H, in the SCN5A gene associated with Brugada syndrome. Functional assays in HEK293 cells expressing the D372H mutant revealed a near-complete loss of sodium currents. Subsequent experiments with co-transfection of WT and D372H plasmids demonstrated that co-expression led to a significant reduction in current density in WT-expressing cells (P < 0.05). The D372H mutation also resulted in a hyperpolarizing shift of approximately 20 mV in the voltage dependence of inactivation, while activation and recovery kinetics remained unaffected. Additionally, confocal microscopy showed reduced membrane localization of the D372H mutant, with a significant decrease in protein expression levels confirmed by Western blot and RT-qPCR analyses.ConclusionIn summary, our findings indicate that the D372H mutation in the Nav1.5 sodium channel leads to significant reductions in sodium current density, altered channel expression, and impaired membrane localization. These changes contribute to the pathophysiology of Brugada syndrome by disrupting cardiac action potential dynamics.
Histone Deacetylase Inhibitor Largazole Deactivates A Subset of Superenchancers and Causes Mitotic Chromosome Mis-alignment by Suppressing SP1 and BRD4
Authors: Sanchez Gilson J. , Liu Zeyu , Hunter Samuel , Xu Quanbin , Westfall Jessica T. V. , Wheeler Graycen E. , Toomey Cathryn , Taatjes Dylan , Allen Mary , Dowell Robin D. , Liu Xuedong 
Published: February 2025

SUMMARYHistone deacetylase inhibitors have been investigated as potential therapeutic agents for cancer and other diseases. HDIs are known to promote histone acetylation, resulting in an open chromatin conformation and generally increased gene expression. In previous work, we reported that a subset of genes, particularly those regulated by superenhancers, can be suppressed by the HDAC inhibitor largazole. To elucidate the molecular mechanisms underlying gene repression by largazole, we conducted transposase-accessible chromatin sequencing, ChIP-seq, and RNA-seq studies. Our findings revealed that while largazole treatment generally enhances chromatin accessibility, it selectively decreases the accessibility of a subset of superenhancer regions. These genomic regions, showing the most significant changes in the presence of largazole, were enriched with transcription factor binding motifs for SP1, BRD4, CTCF, and YY1. ChIP-seq analysis confirmed reduced binding of BRD4 and SP1 at their respective sites on chromatin, particularly at superenhancers regulating genes such as ID1, c-Myc and MCMs. Largazole exerts its effects by inhibiting DNA replication, RNA processing, and cell cycle progression, partially through the suppression of SP1 expression. Depletion of SP1 by shRNA mimics several key biological effects of largazole and increases cellular sensitivity to the drug. Specific to cell cycle regulation, we demonstrated that largazole disrupts G/M transition by interfering with chromosome alignment during metaphase, a phenotype also observed with SP1 depletion. Our results suggest that largazole exerts its growth-inhibitory effect by suppressing BRD4 and SP1 at super-enhancers, leading to cytostatic responses and mitotic dysfunction.
Breath Acetone Correlates with Capillary β-hydroxybutyrate in Type 1 Diabetes
Authors: Jones Kai E. , Petersen Max C. , Markov Alexander M. , Salam Maamoun , Krutilova Petra , McKee Alexis M. , Bohnert Kathryn L. , Adamson Samantha E. , McGill Janet B. 
Published: February 2025

AbstractBackgroundBreath acetone (BrACE) is an end product of ketone metabolism that is measurable by noninvasive breath ketone analyzers. We assessed the correlation between capillary blood β-hydroxybutyrate (BOHB) and BrACE in people with type 1 diabetes (T1D) during 14 days of outpatient care with and without dapagliflozin treatment and during supervised insulin withdrawal studies with and without dapagliflozin.MethodsIn this randomized crossover study, participants completed 14-day two outpatient periods with or without dapagliflozin 10 mg daily. Each 14-day unsupervised outpatient period was followed by a one-day supervised insulin withdrawal study. Paired BOHB and BrACE measurements were obtained three times daily during outpatient periods, then hourly during supervised insulin withdrawal. The correlation between BrACE and BOHB was assessed by Spearman’s ρ.ResultsTwenty people with T1D completed the study. During outpatient periods, BrACE and BOHB were moderately correlated (n=1425 paired readings; ρ = 0.41; 95% CI: 0.36 to 0.45;P< 0.0001). However, BrACE and BOHB were strongly correlated during insulin withdrawal (n=246 paired values, ρ = 0.81; 95% CI: 0.77 to 0.85). In ROC analysis, BrACE > 5 ppm demonstrated optimal sensitivity (93%) and specificity (87%) for detecting capillary BOHB ≥ 1.5 mmol/L. No serious adverse events occurred.ConclusionsIn adults with T1D, measurement of breath acetone provides a noninvasive estimate of blood BOHB concentration. The correlation between BrACE and BOHB was suboptimal during unsupervised outpatient care, but was strong during supervised insulin withdrawal.Trial registration:clinicaltrials.gov(NCT05541484)
Enhancing task fMRI individual difference research with neural signatures
Authors: Baranger David AA , Gorelik Aaron J , Paul Sarah E , Hatoum Alexander S , Dosenbach Nico , Bogdan Ryan 
Published: February 2025

AbstractTask-based functional magnetic resonance imaging (tb-fMRI) has advanced our understanding of brain-behavior relationships. Standard tb-fMRI analyses suffer from limited reliability and low effect sizes, and machine learning (ML) approaches often require thousands of subjects, restricting their ability to inform how brain function may arise from and contribute to individual differences. Using data from 9,024 early adolescents, we derived a classifier (‘neural signature’) distinguishing between high and low working memory loads in an emotional n-back fMRI task, which captures individual differences in the separability of activation to the two task conditions. Signature predictions were more reliable and had stronger associations with task performance, cognition, and psychopathology than standard estimates of regional brain activation. Further, the signature was more sensitive to psychopathology associations and required a smaller training sample (N=320) than standard ML approaches. Neural signatures hold tremendous promise for enhancing the informativeness of tb-fMRI individual differences research and revitalizing its use.
Effects of multimodal and unimodal physical training interventions on visual function in glaucoma and elderly controls – a pilot study
Authors: Moffack DC , Al-Nosairy KO , Beyer R , Freitag C , Stolle FH , Behrens M , Behrendt T , Prabhakaran GT , Thieme H , Schega L , Hoffmann MB 
Published: February 2025

AbstractObjectiveTo investigate the effect of a 12-week multimodal motor-cognitive and resistance training (MMI) compared to a unimodal resistance training intervention (UMI) on static and dynamic visual function in glaucoma patients (GLA) and healthy controls (HC).MethodsFifteen GLA and 24 age-matched HC participated in this randomized, controlled longitudinal pilot study. Visual function was assessed using clinical parameters and, on a treadmill, (TM) while standing (static, S0) as well as during walking at 3.5 km/h (S3.5) and a self-preferred speed (SSelf). The following outcomes were measured pre and post 12-weeks of intervention (MMI or UMI): (a) standard clinical measures and (b) TM-related measures, i.e. (i) best-corrected visual acuity without (VAS) and with crowding (VAC), (ii) visual field sensitivity (VF), and (iii) contrast sensitivity (CS). A 4-factorial repeated-measures ANOVA (SPEED [S0; S3.5; SSelf] x TIME [pre; post] x INTERVENTION [UMI; MMI] x GROUP [GLA; HC]) was applied to determine significant interaction effects (p ≤ 0.05) and the effect size partial-eta-squared was calculated.ResultsPost-interventional improvement of visual function was absent or minor. Only for standard clinical measures a main effect of TIME (visual acuity; p=0.024) and a TIME x INTERVENTION interaction (foveal sensitivity; p=0.039) were found. For S0vs S3.5small effects appeared in post-hoc comparisons, but TIME and TIME x SPEED just failed to reach significance for CS (p=0.059) and VAs(p=0.052), respectively.ConclusionWhile trends were evident, the effect of the 12-week interventions on visual function were small and, especially for TM-walking, largely independent of group and intervention type. In future studies a greater sample of more advanced glaucoma cases should be included to probe for significant visual function differences between groups and intervention types.
Predicting symptomatic response to prokinetic treatment using Gastric Alimetry
Authors: Varghese Chris , Van Hove Sibylle , Schamberg Gabriel , Wu Billy , Poonawala Nooriyah , Law Mikaela , Dachs Nicky , Johnston Gen , Fitt India , Foong Daphne , Parkman Henry P. , Abell Thomas , Ho Vincent , Calder Stefan , Gharibans Armen A , Andrews Christopher N , O’Grady Gregory 
Published: February 2025

AbstractBackgroundChronic neurogastroduodenal disorders are challenging to manage, with therapy often initiated on a trial and error basis. Prokinetics play a significant role in management, but responses are variable and have been associated with adverse events, impacting widespread use. We investigated whether body surface gastric mapping (BSGM) biomarkers (using Gastric Alimetry®) could inform patient selection for prokinetic therapy.MethodsPatients with chronic gastroduodenal symptoms taking oral prokinetic, regardless of gastric emptying status, were prospectively recruited and underwent BSGM (30 m baseline, 482 kcal standardised meal, 4 h postprandial recording) whilst off prokinetic. Patients were followed up with daily symptom diaries. A subset was compared to matched patients not taking prokinetics. Prokinetic responders were defined based on symptom improvement greater than a minimum clinically important difference methodology.Key Results42 patients (88% female; median age 36; median BMI 26) taking prokinetics were analysed. Prokinetic prescribing, compared to matched patients, was independent of BSGM metrics (p>0.15). In patients on existing prokinetics (withheld for BSGM), lower amplitudes predicted reduced symptom burden, whereas low rhythm stability predicted a worse symptom burden (p<0.05). In prokinetic-naive patients (i.e. started on a prokinetic during the study), a lower postprandial amplitude predicted responders (mean 37.5±10.6 uV in responders [n=5] vs mean 54.8±6.6 uV among non-responders [n=3], p=0.047).ConclusionsGastric Alimetry biomarkers may help in the prediction of prokinetic response in patients with chronic gastroduodenal symptoms. Lower post-prandial amplitudes, indicating a reduced meal response, appear to predict benefit, whilst impaired rhythm stability predicted poorer therapeutic response.
CRISPR screening reveals SYCP3 as a key driver of metastasis in prostate cancer
Authors: Rodrigo-Faus Maria , del Monte-Garcia Ines , Hermosilla-Trespaderne Marina , Gordo-Vega Alicia , Vidal Natalia , Puente Javier , Saiz-Pardo Melchor , Cuesta Ángel M , Qu Hui-Qi , Hakonarson Hakon , Porras Almudena , Sanchez-Parcerisa Daniel , Bragado Paloma , Gutierrez-Uzquiza Álvaro 
Published: February 2025

SUMMARYProstate cancer (PCa) is a prevalent male cancer with high survival rates, except in advanced or metastatic stages, for which effective treatments are lacking. Metastatic PCa involves complex mechanisms including loss of tumor suppressor genes and DNA repair molecules, which impacts therapy responses. We have reanalyzed data from a CRISPR/Cas9 genome wide screening previously performed to identify essential regulators of invasive abilities of the metastatic cell line DU145 identifyingSYCP3as a regulator of metastatic invasion. Subsequent analyses of tumor samples demonstrated thatSYCP3expression is frequently upregulated in PCa tumors from patients in advanced stages. Furthermore,SYCP3genetic depletion significantly reduced the invasive and migratory abilities of DU145 cells and increased their adhesion capacity. Additionally, and due to the implication ofSYCP3on DNA repair processes, we have analyzed the role ofSYCP3on the cellular response to radiotherapy (RT) and found that its depletion induced RT resistance, suggesting a role forSYCP3in DNA damage response and genomic instability. All these data support a role forSYCP3in PCa metastasis and provides opportunities for personalized medicine.
Biological Drivers of Early Childhood Caries in Preschool Children of Northern Arizona and Hawaii
Authors: Whealy Ryann N. , Furstenau Tara N. , Roberts Alexander , Cocking Jill Hager , Erickson Daryn , Brock Breezy , McCormick Rowan , Timm Skylar , Pacheco Misty , Mochida-Meek Summer , Fofanov Viacheslav Y. 
Published: February 2025

ABSTRACTEarly childhood caries (ECC) is the most prevalent chronic childhood disease, disproportionately affecting children from specific racial/ethnic groups. While ECC is a multifactorial disease influenced by demographic, behavioral, and environmental factors, it is also widely associated with the presence ofStreptococcus mutansin the oral microbiome. To better understand the interplay between demographic and microbial factors and ECC risk, we collected saliva samples from 408 preschool children aged 1-6 years, including 266 from northern Arizona and 142 from Hawaii, representing racially and geographically diverse populations. Logistic regression showed that the odds of developing ECC increased 80.09% with each year of age, and that compared to White children, the odds were significantly higher for Native Hawaiian/Pacific Islander (330.94%), Native American (282.35%), and Hispanic (245.22%) children. OralS. mutanscolonization increased odds by 360.49%. TheS. mutans-positive samples were genotyped using a multiplexed targeted amplicon sequencing assay. Phylogenetic analysis showed high genetic diversity inS. mutansbetween and within populations, with no geographic clustering. SomeS. mutansclades were associated with up to a 33-fold increase in ECC odds. Only Native Hawaiian/Pacific Islander children were more likely to carryS. mutansstrains from higher-risk clades. Markers associated with high riskS. mutansstrains were identified in genes involved in carbohydrate metabolism, pH regulation, and biofilm formation. This study underscores the multifaceted nature of ECC, linking demographic disparities with strain-specific features ofS. mutansand identifies new genetic markers that may play a role inS. mutansvirulence.
The KRAB-Zinc Finger protein ZKSCAN3 represses enhancers via embedded retrotransposons
Authors: Moore Daniel , Wong Eugenia , Arnal Charles , Schoenfelder Stefan , Spivakov Mikhail , Andrews Simon , Christophorou Maria A. 
Published: February 2025

SummaryGenecis-regulatory sequences are increasingly recognised as containing “domesticated” transposable elements that impact their function. The KRAB Zinc Finger Protein (KZFP) family of transcription factors is typically associated with transposable element silencing through establishment of heterochromatin. Here, using acute protein depletion in embryonic stem cells, we reveal that the KZFP ZKSCAN3 represses enhancer activity through targeting enhancer-embedded retrotransposons and that ZKSCAN3-mediated repression does not rely on the induction of heterochromatin. ZKSCAN3, which exhibits strong genetic association with the neurodevelopmental disorder schizophrenia, operates during neural differentiation and is necessary for proper cell specification and expression of genes that regulate axon guidance, neuronal motility and pathfinding. These findings define ZKSCAN3 as an enhancer regulator and uncover a heterochromatin-independent KZFP. Additionally, they exemplify how a KZFP epigenetically regulates enhancers in a native setting and highlight how transposable elements and their KZFP binders have shaped gene expression networks.
Visualization of peptidoglycan layer isolated from gliding diderm bacteria,Flavobacterium johnsoniaeandMyxococcus xanthus, by quick-freeze deep-etch replica electron microscopy
Authors: tahara Yuhei O , Mignot Tâm , Miyata Makoto 
Published: February 2025

AbstractThe bacterial peptidoglycan layer plays an important role in protecting the bacteria from turgor pressure, viruses, and predators. However, it also acts as a barrier in transmitting forces generated on the cell membrane to adhesion proteins on the surface during gliding locomotion. In this study, peptidoglycan layers were isolated from two species of gliding diderm, i.e., Gram-negative bacteria, and their structures were visualized by quick-freeze deep-etch replica electron microscopy. The diameter of pores in the peptidoglycan layer ofM. xanthusand the area of surface pores were 51 nm and 14.6%, respectively, which were significantly larger than those ofE. coli(32 nm and 5.8%) andF. johnsoniae(29 nm and 7.0%). Based on this, we discussed the mechanism by which diderm bacteria transmit forces across the PG layer to the bacterial surface.SignificancePeptidoglycan is a rigid meshwork that protects bacterial cells from turgor stress, virus, and predators. Bacteria move to get nutrients and escape from predators. The force for motility is generated in the cell membrane and transmitted to the surface across the peptidoglycan layer. In this study, the peptidoglycan structures of two representative gliding Gram-negative bacteria were visualized to understand the transmission mechanism.
Predicting coarse-grained representations of biogeochemical cycles from metabarcoding data
Authors: Belcour Arnaud , Megy Loris , Stephant Sylvain , Michel Caroline , Rad Sétareh , Bombach Petra , Dopffel Nicole , de Jong Hidde , Ropers Delphine 
Published: February 2025

AbstractMotivationTaxonomic analysis of environmental microbial communities is now routinely performed thanks to advances in DNA sequencing. Determining the role of these communities in global biogeochemical cycles requires the identification of their metabolic functions, such as hydrogen oxidation, sulfur reduction, and carbon fixation. These functions can be directly inferred from metagenomics data, but in many environmental applications metabarcoding is still the method of choice. The reconstruction of metabolic functions from metabarcoding data and their integration into coarse-grained representations of geobiochemical cycles remains a difficult bioinformatics problem today.ResultsWe developed a pipeline, called Tabigecy, which exploits taxonomic affiliations to predict metabolic functions constituting biogeochemical cycles. In a first step, Tabigecy uses the tool EsMeCaTa to predict consensus proteomes from input affiliations. To optimise this process, we generated a precomputed database containing information about 2,404 taxa from UniProt. The consensus proteomes are searched using bigecyhmm, a newly developed Python package relying on Hidden Markov Models to identify key enzymes involved in metabolic function of biogeochemical cycles. The metabolic functions are then projected on coarse-grained representation of the cycles. We applied Tabigecy to two salt cavern datasets and validated its predictions with microbial activity and hydrochemistry measurements performed on the samples. The results highlight the utility of the approach to investigate the impact of microbial communities on geobiochemical processes.
The NIH BRAIN Initiative’s Impacts in Systems and Computational Neuroscience, 2014-2023
Authors: Bader Farah , Bingham Clayton , David Karen K. , Gebrehiwet Hermon , Lantz Crystal , Peng Grace C.Y. , Rangel-Gomez Mauricio , Gnadt James 
Published: February 2025

ABSTRACTAt the 10-year anniversary of the NIH BRAIN Initiative, this report analyzes the impact of the initiative’s functional neuroscience ecosystem as funding experiments in the domains of systems and integrative neuroscience, and computational neuroscience, with an eye on comparison with other funding models and best practices.
Statins do not reduce the parasite burden during experimentalTrypanosoma cruziinfection
Authors: Razzaq Sarah , Olmo Francisco , Lakshminarayana Suresh B. , Chen Ying-Bo , Jayawardhana Shiromani , Rao Srinivasa P.S. , Kelly John M. , Fortes Francisco Amanda 
Published: February 2025

ABSTRACTCardiomyopathy is the most common pathology associated withTrypanosoma cruziinfection. Reports that statins have both cardioprotective and trypanocidal activity have generated interest in their potential as a therapeutic treatment. Using a highly-sensitive bioluminescent mouse model, we show that 5 days treatment with statins has no significant impact on parasite load. The free systemic concentrations fail to reach the level required for potency. Hence, clinical trials to investigate trypanocidal activity of statins lack experimental justification.
1,2,4-Triazole-based first-in-class non-nucleoside inhibitors of bacterial enzyme MraY
Authors: Berida Tomayo , Huang Tzu-Yu , Weck Stefanie C. , Lutz Marcel , McKee Samuel R. , Kagerah Nathalie , Manning Destinee , Jahan Mohamed E. , Mishra Sushil K. , Doerksen Robert J. , Stallings Christina L. , Ducho Christian , Roy Sudeshna 
Published: February 2025

ABSTRACTMraY, a bacterial enzyme crucial for the synthesis of peptidoglycans, represents a promising yet underexplored target for the development of effective antibacterial agents. Nature has provided several classes of nucleoside inhibitors of MraY and scientists have modified these structures further to obtain natural product-like inhibitors of MraY. The natural products and their synthetic analogs suffer from non-optimalin vivoefficacy, and the synthetic complexity of the structures renders the synthesis and structure-activity relationship (SAR) studies of these molecules particularly challenging. In this study, we present our findings on the discovery of first-in-class 1,2,4-triazole-based MraY inhibitors that are not nucleoside-derived. A series of 1,2,4-triazole analogous were identified by a structure–activity-relationship (SAR) study using a structure-based drug design strategy. Compound1, with an IC50of 171 µM against MraY fromStaphylococcus aureus(MraYSA), was optimized to compound12a, exhibiting an IC50of 25 µM. Molecular docking studies against MraYSAprovided insights into these compounds’ binding interactions and activity. Furthermore, screening against the ESKAPE bacterial panel was also conducted, through which we discovered compounds demonstrating broad-spectrum antibacterial activity againstE. faecium, methicillin-resistantS. aureus(MRSA), vancomycin-resistant Enterococci (VRE) strains andMycobacterium tuberculosis. The novel, first-in-class non-nucleoside inhibitors of MraY highlighted in this work provide a strong proof-of-concept of how to leverage structural information of the protein to develop future antibacterial agents targeting MraY.Abstract Figure