bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Retinal Imaging for Shock Resuscitation in Critical Ill Adults II (D-RISC II)
Authors: Cooper George , Burke Jamie , Hamid Charlene , Godden Emily , Dhaun Neeraj , King Stuart , MacGillivray Thomas J. , Baillie J. Kenneth , Griffith David M. , MacCormick Ian J.C.
Published: February 2025

Background

Shock involves microcirculatory dysfunction that is not suitably captured well by measurements of large vessels, such as systemic blood pressure. The outer retinal microcirculation (the choroid) can be measured non-invasively and may reflect dysfunction in other organs. We tested the feasibility of measuring the retinal choroid in an intensive care setting and explored associations between choroidal measurements and severity of disease.

Methods

We performed optical coherence tomography on patients admitted to the intensive treatment unit, and repeated imaging once 12-72 hours later. We measured choroidal anatomy using automated image segmentation, compared this to routine clinical data, and described change over time.

Results

Of fifteen patients recruited, 80% (12) had successful baseline imaging and 40% (6) of these had follow-up imaging within intensive care. At baseline, patients with thicker choroids and larger vascularity had larger cumulative fluid balance, and lower disease severity (Acute Physiology and Chronic Health Evaluation II) score, haematocrit, and albumin. A measurable suprachoroidal space was seen in 75% (9) patients and the size of this space tended to be larger in patients with lower heart rates. There was substantial intraindividual variation in choroidal measurements over time.

Comment

Measuring the retinal choroid is feasible in patients with critical illness. Exploratory associations with systemic variables suggest that the choroid may provide information about the microvascular function of other major organs. Size and change of choroidal measurements may reflect perfusion pressure or vascular leak in response to inflammation.
Auditory steady-state response deficits in Fragile X Syndrome implicate deficits in stimulus representation maintenance and GABAergic modulation
Authors: Norris Jordan E. , De Stefano Lisa A. , McKinney Walker S. , Schmitt Lauren M. , Miyakoshi Makoto , Gross Christina , Piloto Sebastian , Heald Braeden , Pedapati Ernest V. , Erickson Craig A. , Sweeney John A. , Ethridge Lauren E.
Published: February 2025

Background

Fragile X Syndrome (FXS) is a rare, neurodevelopmental disorder caused by a mutation to the Fragile X messenger ribonucleoprotein 1 (Fmr1) gene and characterized by sensory processing abnormalities and sensitivities, including neural auditory oscillatory disruptions and reduced neural entrainment to chirp stimuli. The present study aims to evaluate the 40 Hz auditory steady state response (ASSR) in FXS to evaluate stimulus representation maintenance in FXS.

Methods

Adolescents and adults (N = 67; 34 FXS and 33 age, sex-matched typically developed controls (TDC)) completed a 40 Hz auditory steady state task during electroencephalography (EEG). Time-frequency analyses using Morlet wavelets were completed to evaluate intertrial phase coherence (ITC) and event-related spectral perturbation (ERSP), including characterization of the transient and sustained components of the 40 Hz ASSR.

Results

Both ITC (p= .003) and ERSP (p= .004) at 40 Hz were reduced for FXS compared to TDC. Interestingly, TDC exhibited a significantly elevated early, transient component (100 – 400 ms) which reduced in both ITC and ERSP during transition to the sustained component (650 – 3000 ms) whereas FXS were consistently reduced across the ASSR suggesting a reduced ability for FXS to mount a transient response.

Conclusions

Individuals with FXS exhibit robust reductions in magnitude and temporal precision of neural entrainment to the steady state stimulus. The reduced ability to mount a transient response may represent reduced GABAergic modulation where the overall reduction in ITC and ERSP may reflect reduced excitatory/inhibitory balance between NMDA and GABAergic input.
Modern approaches to predicting vaccine hesitancy: A scoping review
Authors: Gandhi Keshav , Alahmadi Sami , Hanneke Rosie , Gutfraind Alexander
Published: February 2025

Introduction

Motivated by the disproportionate burden of infectious diseases on vulnerable populations and the risk of future pandemics, we conducted a scoping review to analyze the state of the literature about “vaccine uptake indices,” defined as models that predict vaccination rates by geospatial area. We analyzed novel vaccine uptake indices created in response to the recent COVID-19 pandemic. The aim of this scoping review is to survey the state of the literature regarding vaccine uptake indices relating to COVID-19 and other infectious diseases.

Methods

We conducted a scoping review with a systematic search strategy to identify relevant articles from the databases Embase, PubMed, and Web of Science with title and abstract screening, full-text review, and data extraction.

Results

Database searches resulted in 3,615 potential articles, of which 229 reports were included. Fifteen studies (7%) were determined to be methodologically advanced vaccine uptake indices that had at least three of the following characteristics: the use of individual- and population-level predictor variables (100 [44%]), geo-spatiotemporal analysis (58 [25%]), data usage agnostic to vaccine specificity (50 [22%]), or sociobehavioral frameworks of health (such as the Health Belief Model and Theory of Planned Behavior) (30 [13%]).

Conclusion

This scoping review offers suggestions for future research of next-generation vaccine uptake indices before use in vaccination campaigns of recurring or novel infectious diseases. Areas to pursue include utilizing individual-level data about vaccination behaviors in conjunction with administrative data, solving the challenge of implementing small-area spatiotemporal analysis, using vaccine-agnostic methods that consider data from more than one infectious disease, and assisting causal inference with theoretical frameworks.
Incorporating exon-exon junction reads enhances differential splicing detection
Authors: Pham Mai T. , Milevskiy Michael J.G. , Visvader Jane E. , Chen Yunshun
Published: February 2025

Motivation

RNA sequencing (RNA-seq) is a gold standard technology for studying gene and transcript expression. Different transcripts from the same gene are usually determined by varying combinations of exons within the gene, formed by splicing events. One method of studying differential alternative splicing between groups in short-read RNA-seq experiments is through differential exon usage (DEU) analyses, which use exon-level read counts along with downstream statistical testing strategies. Popular pipelines for these analyses includeRsubreadfor read alignment and exon-level count quantification, andedgeRandlimmafor statistical testing of differential splicing. However, the standardRsubread::featureCountscount summarization method does not consider exon-junction information, which may reduce the statistical power in differential splicing analyses.

Results

A new feature quantification approach is proposed to incorporate both exon and exon-junction reads into the popularRsubread-edgeRandRsubread-limmaframeworks for detecting differential splicing events. This new Differential Exon-Junction Usage (DEJU) analysis pipeline demonstrates increased statistical power compared to existing popular methods while effectively controlling the false discovery rate.

Availability and implementation

Data and code to reproduce the results shown in this article are available fromhttps://github.com/TamPham271299/DEJU.
Anxiety-like behavior during protracted morphine withdrawal is driven by gut microbial dysbiosis and attenuated with probiotic treatment
Authors: Oppenheimer Mark , Tao Junyi , Moidunny Shamsudheen , Roy Sabita
Published: February 2025

The development of anxiety during protracted opioid withdrawal heightens the risk of relapse into the cycle of addiction. Understanding the mechanisms driving anxiety during opioid withdrawal could facilitate the development of therapeutics to prevent negative affect and promote continued abstinence. Our lab has previously established the gut microbiome as a driver of various side effects of opioid use, including analgesic tolerance and somatic withdrawal symptoms. We therefore hypothesized that the gut microbiome contributes to the development of anxiety-like behavior during protracted opioid withdrawal.

In this study, we first established a mouse model of protracted morphine withdrawal, characterized by anxiety-like behavior and gut microbial dysbiosis. Next, we used fecal microbiota transplantation (FMT) to show that gut dysbiosis alone is sufficient to induce anxiety-like behavior. We further demonstrate that probiotic therapy during morphine withdrawal attenuates the onset of anxiety-like behavior, highlighting its therapeutic potential. Lastly, we examined transcriptional changes in the amygdala of morphine-withdrawn mice treated with probiotics to explore mechanisms by which the gut-brain axis mediates anxiety-like behavior.

Our results support the use of probiotics as a promising therapeutic strategy to prevent gut dysbiosis and associated anxiety during opioid withdrawal, with potential implications for improving treatment outcomes in opioid recovery programs.
Salicylic acid represses primary root growth through the Glucose-Target of Rapamycin-E2Fa pathway in Arabidopsis
Authors: Rawat Sanjay Singh , Laxmi Ashverya
Published: February 2025

In addition to their role as energy sources, sugars function as signaling molecules, modulating gene expression. Plants perceive nutrient availability and translate this information into cellular signals, to trigger various developmental responses, including primary root growth. In particular, glucose stimulates root development by activating the root meristem. Recent studies have documented the role of the defense hormone, salicylic acid (SA) as a negative regulator of root growth and developmental processes. Here, we characterized the modulation of primary root growth by the cross-talk of glucose and SA. Our results indicate that auxin is a critical mediator of SA-induced root growth inhibition. Attenuation of auxin signaling or transport pathways alters the inhibitory effect of SA on root growth. Moreover, we provide evidence for the involvement of the role of Target of Rapamycin (TOR) signaling in SA-induced root growth repression. Furthermore, SA negatively regulates the expression of E2Fa, a key transcription factor required for cell cycle progression and root growth and development. Our findings elucidate mechanism(s) whereby SA, through the interconnected glucose, auxin and TOR signaling pathways, inhibits primary root growth.
VIVIDHA: Variant Prediction and Visualization Interface for Dynamic High-throughput Analysis
Authors: Barasiya Tarang , Bharti Neeraj , Gadhari Renu , Bayaskar Avinash , Jain Sankalp , Saxena Amit , Kasibhatla Sunitha Manjari , Joshi Rajendra
Published: February 2025

Large scale genome sequencing projects have produced huge datasets that pose challenges of high processing times especially for variant calling, a significant downstream analysis step. Efficient utilization of computational resources for accurate variant prediction in a timely manner is possible using Hadoop MapReduce framework. We have developed VIVIDHA (Variant Prediction and Visualization Interface for Dynamic High-throughput Analysis), a high throughput methodology for prediction of variants based on splitting the alignment file using overlapping regions using Hadoop MapReduce framework. The size of overlap region is user-defined. Three variant callers viz. GATK, VarScan2 and BCFTools have been included to predict variants using a consensus approach. Speed-up observed provides the rationale of better performance as number of compute cores and file size are increased. VIVIDHA is available in both GUI as well as command-line modes and can be downloaded from URL: https://github.com/bioinformatics-cdac/VividhaInstaller
c-Rel drives pancreatic cancer metastasis through Fibronectin-Integrin signaling-induced isolation stress resistance and EMT activation
Authors: Bakırdöğen D. , Görgülü K. , Xin J. , Alcalá S. , Ruiz-Cañas L. , Frank K. , Wu N. , Diakopoulos K. N. , Dai C. , Öztürk H. , Demircioğlu D. , Peschke K. , Ranjan R. , Fusco F. , Martinez-Useros J. , Fernandez-Aceñero M. J. , Chhabra N. F. , López-Gil J.C. , Ai J. , Ruess D. A. , Kaya-Aksoy E. , Steiger K. , Schmidt F. , Kohlmann L. , Berninger A. , Schmid R. M. , Reichert M. , Adli M. , Lesina M. , Sainz B. , Algül H.
Published: February 2025

Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, with limited treatment options and a high recurrence rate. Recurrence happens often with metastasis, for which cancer cells must adapt to isolation stress to successfully colonize distant organs. While the fibronectin-integrin axis has been implicated in this adaptation, its regulatory mechanisms require further elaboration. Here, we identify c-Rel as an oncogenic driver in PDAC, promoting epithelial-to-mesenchymal transition (EMT) plasticity, extracellular matrix (ECM) remodeling, and resistance to isolation stress. Mechanistically, c-Rel directly regulates fibronectin (Fn1) and CD61 (itgb3) transcription, enhancing cellular plasticity and survival under anchorage-independent conditions. Fibronectin is not essential for EMT, but its absence significantly impairs metastatic colonization, highlighting a tumor-autonomous role for FN1 in isolation stress adaptation. These findings establish c-Rel as a key regulator of PDAC metastasis by controlling circulating tumor cell (CTC) niche and survival, suggesting that targeting the c-Rel–fibronectin–integrin axis could provide new therapeutic strategies to mitigate disease progression and recurrence.
Arctic plant species display contrasting levels of chloroplast DNA copy numbers
Authors: Kamenova Stefaniya , Moinard Sylvain , Dwinnell Samantha Paige Huset , Laporte Frédéric , Coissac Éric
Published: February 2025

DNA metabarcoding has revolutionised our ability to characterise biodiversity at unprecedented spatial and temporal scales, outperforming most traditional methods for biodiversity monitoring. However, DNA metabarcoding is not without limitations, in particular regarding the quantitative relationship between sequence read abundances and species numerical abundances or biomass (i.e., quantitative performance). Variation in DNA copy numbers has been often pinpointed as a potentially important factor biasing DNA metabarcoding quantitative performance but empirical comparisons of DNA copy number variation across species remain rare. Here, we identify chloroplast DNA copy number variation (cpDNA CNV) in plants as a potentially important factor that could impact quantitative performance in DNA metabarcoding studies. Using digital droplet PCR, we quantified chloroplast copy number variation in four common high Arctic plant species and between two plant tissue types (green tissues and roots). The amount of cpDNA per unit of dry mass varied by a factor of 3 (for roots) to 7.6 (for green tissues) among species, and up to 67 when comparing cpDNA copy numbers between green and root tissues from the same species. Despite significant differences in cpDNA copy numbers among species for both green tissues and roots, the most pronounced differences in cpDNA copy numbers were clearly between the two tissue types tested. These findings suggest that variation in cpDNA copy numbers among plant species and particularly plant tissue types can be an important but underestimated factor impacting plant sequence reads abundance in DNA metabarcoding datasets. We call for more extensive cpDNA CNV referencing efforts from wild-ranging plants to improve the use of DNA metabarcoding for research and biodiversity monitoring.
Preventing large deletions and chromosome loss in engineered human primary T cells by CasPlus with optimized guide RNAs
Authors: Yang Qiaoyan , Abebe Jonathan S. , Mai Michelle , Konishi Colin , Devinsky Orrin , Long Chengzu
Published: February 2025

Genetically engineered T-cell therapies rely heavily on genome editing tools, such as the CRISPR/Cas9 system. However, unintended on-target chromosomal alterations, including large deletions and chromosome loss can occur and pose significant risks including tumorigenesis. Here we combined CasPlus and optimized guide RNAs to reduce these issues in CRISPR/Cas9 engineering human primary T cells. CasPlus, which integrates an engineered T4 DNA polymerase with Cas9 nuclease and guide RNA, promotes favorable small insertions (1-2 bp) while reducing large deletions and chromosome loss in T cells. Our optimized guide RNAs favoring small insertions reduced large deletions and chromosome loss by two- to five-fold versus those favoring small deletions. Moreover, combining optimized guide RNA with T4 DNA polymerase further synergistically reduced large deletions and chromosome loss by additional two-fold. Notably, replacing currently used guide RNA pairs in clinically applications with optimized pairs biased towards small insertions, along with CasPlus instead of Cas9, for editing greatly reduced large deletions and chromosome loss in gene-edited human primary T cells. These findings demonstrated that pre-selecting target sites favoring small insertions via guide RNA optimization coupled with CasPlus editing is a safer and more effective strategy to improve genome stability in T-cell engineering and other gene-editing applications.
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

Background

Brugada 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.

Methods

Plasmids 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.

Conclusion

In 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

Histone 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

Background

Breath 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.

Methods

In 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.

Results

Twenty 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.

Conclusions

In 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

Task-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

Objective

To 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).

Methods

Fifteen 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.

Results

Post-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.

Conclusion

While 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

Background

Chronic 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.

Methods

Patients 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 Results

42 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).

Conclusions

Gastric 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

Prostate 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

Early 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

Genecis-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

The 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.

Significance

Peptidoglycan 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

Motivation

Taxonomic 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.

Results

We 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

At 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

Cardiomyopathy 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

MraY, 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
Antiviral Activity of Rosemary Extract Against Zika Virus in Human Dermal Fibroblasts
Authors: Masi Jordan T. , Crozier Robert W.E. , Coish Jeremia M. , Hicks Natalie J. , Tsiani Evangelia , Patterson Edward I. , MacNeil Adam J.
Published: February 2025

Flaviviruses have increasingly emerged and re-emerged in recent decades, infecting millions of people annually. Zika virus is particularly concerning due to its associated pathological complications, including microcephaly in newborns and Guillain-Barré syndrome in adults, posing a significant threat to public health. Despite efforts made by the scientific community, no licensed drugs against flaviviruses have been developed. Medicinal plants show promise as a novel source of antiviral agents, as they possess a diverse array of biologically active secondary metabolites, making them potential candidates for therapeutic use. We sought to investigate the antiviral potential of rosemary extract (RE) against ZIKV in human dermal fibroblasts (HFF-1 cells), one of the earliest targets of infection. ZIKV was treated with various concentrations of RE or its individual major polyphenols, including rosmarinic acid (RA), carnosic acid (CA), and carnosol (CO), and the remaining infectivity of each sample was measured by plaque reduction assay. To evaluate the impact of RE on different stages of the ZIKV replication cycle, HFF-1 cells were treated before, during, and after infection, or the virus was treated before infection. RE exerted potent antiviral activity against ZIKV in both Vero and HFF-1 cells by directly acting on virus particles before infection. Importantly, RE significantly inhibited the later stages of the virus replication cycle by interfering with post-entry mechanisms within the host cell. Moreover, major RE-derived polyphenols CA and CO, but not RA, were shown to significantly reduce ZIKV infectivity. Overall, RE significantly impairs ZIKV infectionin vitroby directly interacting with virus particles prior to adsorption and interfering with post-entry processes of the ZIKV replication cycle. This study provides rigorous evidence indicating the potential development of RE as an antiviral agent, warranting further investigation into the mechanisms underlying its inhibitory activity against ZIKV and its effects on other medically important flaviviruses.
Geometric influences on the regional organization of the mammalian brain
Authors: Pang James C. , Robinson Peter A. , Aquino Kevin M. , Levi Priscila T. , Holmes Alexander , Markicevic Marija , Shen Xilin , Funck Thomas , Palomero-Gallagher Nicola , Kong Ru , Yeo B.T. Thomas , Tiego Jeggan , Bellgrove Mark A. , Constable R. Todd , Lake Evelyn MR , Breakspear Michael , Fornito Alex
Published: February 2025

The mammalian brain is comprised of anatomically and functionally distinct regions. Substantial work over the past century has pursued the generation of ever-more accurate maps of regional boundaries, using either expert judgement or data-driven clustering of functional, connectional, and/or architectonic properties. However, these approaches are often purely descriptive, have limited generalizability, and do not elucidate the underlying generative mechanisms that shape the regional organization of the brain. Here, we develop a novel approach that leverages a simple, hierarchical principle for generating a multiscale parcellation of any brain structure in any mammalian species using only its geometry. We show that this approach yields regions at any resolution scale that are more homogeneous than those defined in nearly all existing benchmark brain parcellations in use today across hundreds of anatomical, functional, cellular, and molecular brain properties measured in humans, macaques, marmosets, and mice. We additionally show how our method can be generalized to previously unstudied mammalian species for which no parcellations exist. Finally, we demonstrate how our approach captures the essence of a simple, hierarchical reaction-diffusion mechanism, in which the geometry of a brain structure shapes the spatial expression of putative patterning molecules linked to the formation of distinct regions through development. Our findings point to a highly conserved and universal influence of geometry on the regional organization of the mammalian brain.
Altered kinship vocal dynamics in marmosets with valproic acid–induced model of autism
Authors: Mimura Koki , Nakagaki Keiko , Morishita Hirofumi , Ichinohe Noritaka
Published: February 2025

Autism spectrum disorder (ASD) is characterised by social communication impairments and repetitive behaviours. Language deficits, including echolalia and restricted vocabulary, heighten caregiver stress and negatively affect the family’s quality of life. Although animal models have advanced the understanding of individual ASD traits, their influence on kinship dynamics remains underexplored. To address this issue, we developed a clinically relevant ASD model in common marmosets by prenatal exposure to valproic acid (VPA) to produce ASD-like pups alongside their typically developing parents. We analysed 28,418 kinship calls from nine VPA-exposed and seven unexposed (UE) pups, along with their parents. Kinship vocalisations in VPA families exhibited significant alterations, including increased isolation calls, decreased affiliative calls, disruption of structured repetition patterns, and reduced developmental maturations. These deviations intensified after weaning, suggesting a link between social communicative stressors and altered family dynamics. Parental weight loss was correlated with kinship vocal deviations, potentially reflecting increased caregiver stress. This observation aligns with clinical reports of heightened stress in families raising children with ASD. VPA pups also displayed premature locomotion independence, indicating broader social and communication disruptions. These findings suggest that VPA marmosets are valuable models for investigating ASD-like traits in individuals and kinship-level dynamics. Kinship vocalisations provide critical insights into the interplay between communication impairments and caregiver stress, offering a promising avenue for developing non-invasive biomarkers for ASD-related challenges.