bluuebunny/crossref_metadata_2025 huggingface dataset:
Silica-mediated exacerbation of inflammatory arthritis: A novel murine model
Authors: Janssen Lisa M.F. , de Ocampo Caroline , Kono Dwight H. , Ronsmans Steven , Ghosh Manosij , Hoet Peter H.M. , Pollard K. Michael , Mayeux Jessica M.
Published: January 2025

Objective

The mucosal origin hypothesis in rheumatoid arthritis (RA) posits that inhalant exposures, such as cigarette smoke and crystalline silica (c-silica), trigger immune responses contributing to disease onset. Despite the established risk posed by these exposures, the mechanistic link between inhalants, lung inflammation, and inflammatory arthritis remains poorly understood, partly from the lack of a suitable experimental model. As c-silica accelerates autoimmune phenotypes in lupus models and is a recognized risk factor for several autoimmune diseases, we investigated whether c-silica exposure could induce RA-like inflammatory arthritis in mice.

Methods

Two arthritis-prone mouse strains, BXD2/TyJ and HLA-DR4 transgenic (DR4-Tg), were exposed to c-silica or PBS via oropharyngeal instillation. Arthritis was evaluated by clinical signs and histopathology. Autoimmunity was further evaluated by serological analysis, including autoantibodies and cytokines and chemokines. Lung pathology was evaluated by histopathology and immunofluorescent staining for lymphocyte and macrophages.

Results

C-silica exposure induced chronic pulmonary silicosis in all mice. In BXD2 mice, this was associated with rapid arthritis development, marked by synovitis, bone erosion, and elevated serum autoantibody levels targeting various antigens, including snRNP and citrullinated protein. Additionally, BXD2 mice exhibited inducible bronchus-associated lymphoid tissue (iBALT) formation and elevated autoantibodies in bronchoalveolar lavage fluid (BALF). Conversely, DR4-Tg mice had no significant arthritis, negligible autoantibody responses, and milder lung inflammation lacking iBALT.

Conclusion

We introduce a novel model of c-silica-mediated inflammatory arthritis, creating a novel platform to unravel the molecular and cellular underpinnings of RA and advance understanding of the mucosal origin hypothesis.

Graphical abstract
Predicting Personalised Therapeutic Combinations in Non-Small Cell Lung Cancer UsingIn SilicoModelling
Authors: Clarke Matthew A. , Barker Charlie George , Nicholls Ashley , Handler Matt P. , Pickard Lisa , Shah Amna , Walter David , Braekeleer Etienne De , Banerji Udai , Choudhary Jyoti , Ahmed Saif , McDermott Ultan , Hannon Gregory J. , Fisher Jasmin
Published: January 2025

The disease burden from non-small cell lung cancer (NSCLC) adenocarcinoma is substantial, with around a million new cases diagnosed globally each year, and a 5-year survival rate of less than 20%. A lack of therapeutic options personalized to individual patient genetics, and the targeted therapies that exist quickly succumbing to resistance, leads to high variation in survival. Patient stratification combined with greater personalisation of therapies have the potential to improve outcomes, however, the wide variation in mutations found in NSCLC adenocarcinoma patients mean that experimentally determining suitable treatment combinations is time-consuming and expensive. Here we present anin silicomodel encompassing tumour intrinsic key oncogenic signalling pathways, including EGFR, AKT, JAK/STAT and WNT for efficiently predicting rational drug-drug and drug-radiotherapy combination therapies in NSCLC. Using this model, we simulate diverse genetic profiles and test over 10,000 therapeutic strategies to identify optimal strategies to overcome resistance mechanisms specific to genetic profiles and p53 status. Ourin silicomodel reproduces drug additivity experiments, predicts radio-sensitising genes validated in a CRISPR screen and identifies 53BP1 as a potential drug target that improves the therapeutic window during radiotherapy, as well as potential to use ATM inhibitors to overcome p53 loss-of-function driven radiotherapy resistance. We further use thein silicomodel to identify a 19-gene signature to stratify patients most likely to benefit from radiotherapy and validated this using TCGA data. These results further demonstrate the utility ofin silicomechanistic modelling and present a bespoke computational resource for large-scale screening of personalised therapies applied to NSCLC.
From larval stage to adulthood? Habitat type-specific chemical fingerprints of fire salamander larvae might give first indication for adult mate preference
Authors: Schulte Laura , Friedrichs Jeanne , Müller Caroline , Caspers Barbara A.
Published: January 2025

Assortative mating can play a major role in the divergence of a population with gene flow. In a fire salamander population near Bonn, Germany, the larvae differ genetically according to the habitat type they are found in, i.e. ponds or streams. Neither sound nor vision are a source for assortative mating in fire salamanders, but it is known that females can discriminate between sexes and habitat types of the males based on chemical cues. The adults share the same terrestrial habitat which leads to the question whether there is a habitat type-specific chemical fingerprint already existing in the larvae that may be used in the adult stage as the base for assortative mating. We took water samples and captured larvae at two ponds and two streams and used polydimethylsiloxane and TD-GC-MS to collect and analyze samples of the environmental background as well as from the surface of the larvae. We found a significantly different composition of chemical features in the environmental back-ground samples. Additionally, we found the larvae to carry habitat type-specific chemical features. These finding allow to speculate that the features on the larval surface may be used
Severe Fe deficiency promotes hypoxia inducible responses inArabidopsis thaliana
Authors: Telara Yuri , Maghrebi Moez , Lavilla Mikel , La Monaca Noemi , Ambrogini Giulia , Sbrana Alessio , Delucchi Sara , Perata Pierdomenico , Vigani Gianpiero , Giuntoli Beatrice
Published: January 2025

In plants, Fe homeostasis and O2metabolism are strictly related, indeed several Fe-requiring enzymes catalyze reactions that also involve oxygen, as a reagent, product, entry or end point of the metabolic pathway in which the enzyme takes part. Oxygen sensing itself relies on Fe-dependent enzymes, the Plant cysteine oxidase (PCO) family of 2-OG independent thiol dioxygenases. PCOs are responsible for the degradation of ERFVII ethylene-responsive factors through a proteasomal N-degron pathway that connects hypoxia-inducible responses to the stabilization of the ERFVII transcription factors. Here, we investigated the interplay between low oxygen and Fe-deficiency stresses inA. thaliana. We used plants expressing a genetically encoded reporter of ERFVII protein stability and measured the expression of anaerobic genes to infer PCO activityin vivo. Our results highlight that Fe deprivation can elicit hypoxia-like responses depending on its severity. To test the involvement the ERFVII factors further, we examined the response of a pentupleerfVIImutant to Fe-deficiency stress, individually or combined with low oxygen. Our data indicate that the ERFVIIs might take part to the acclimation to chronic Fe deficiency by acting as positive regulators of starvation-responsive genes. Moreover, our results suggest that the ERFVIIs fine-tune nutrient mobilization to the shoots of submerged plants growing on moderately Fe-deficient substrates. This work expands the known functions of the ERFVII factors and provides new information to understand plant responses to combined environmental stresses.
Diversity, connectivity and negative interactions define robust microbiome networks across land, stream, and sea
Authors: Kajihara Kacie T. , Yuan Mengting , Amend Anthony S. , Cetraro Nicolas , Darcy John L. , Fraiola Kauaoa M.S. , Frank Kiana , McFall-Ngai Margaret , Medeiros Matthew C.I. , Nakayama Kirsten K. , Nelson Craig E. , Rollins Randi L. , Sparagon Wesley J. , Swift Sean O. I. , Téfit Mélisandre A. , Yew Joanne Y. , Yogi Danyel , Hynson Nicole A.
Published: January 2025

In this era of rapid global change, factors influencing the stability of ecosystems and their functions have come into the spotlight. For decades the relationship between stability and complexity has been investigated in modeled and empirical systems, yet results remain largely context dependent. To overcome this we leverage a multiscale inventory of fungi and bacteria ranging from single sites along an environmental gradient, to habitats inclusive of land, sea and stream, to an entire watershed. We use networks to assess the relationship between microbiome complexity and robustness and identify fundamental principles of stability. We demonstrate that while some facets of complexity are positively associated with robustness, others are not. Beyond positive biodiversityxrobustness relationships we find that the number of “gatekeeper” species or those that are highly connected and central within their networks, and the proportion of predicted negative interactions are universal indicators of robust microbiomes. With the potential promise of microbiome engineering to address global challenges ranging from human to ecosystem health we identify properties of microbiomes for future experimental studies that may enhance their stability. We emphasize that features beyond biodiversity and additional characteristics beyond stability such as adaptability should be considered in these efforts.
Biased sampling confounds machine learning prediction of antimicrobial resistance
Authors: Yu Yanying , Wheeler Nicole E , Barquist Lars
Published: January 2025

Antimicrobial resistance (AMR) poses a growing threat to human health. Increasingly, genome sequencing is being applied for the surveillance of bacterial pathogens, producing a wealth of data to train machine learning (ML) applications to predict AMR and identify resistance determinants. However, bacterial populations are highly structured and sampling is biased towards human disease isolates, meaning samples and derived features are not independent. This is rarely considered in applications of ML to AMR. Here, we demonstrate the confounding effects of sample structure by analyzing over 24,000 whole genome sequences and AMR phenotypes from five diverse pathogens, using pathological training data where resistance is confounded with phylogeny. We show resulting ML models perform poorly, and increasing the training sample size fails to rescue performance. A comprehensive analysis of 6,740 models identifies species- and drug-specific effects on model accuracy. We provide concrete recommendations for evaluating future ML approaches to AMR.
Nonlinear effects of temperature on mosquito parasite infection across a large geographic climate gradient
Authors: Farner Johannah E. , Lyberger Kelsey P. , Couper Lisa I. , Cruz-Loya Mauricio , Mordecai Erin A.
Published: January 2025

Temperature drives ectothermic host – parasite interactions, making them particularly sensitive to climatic variation and change. To isolate the role of temperature, lab-based studies are increasingly used to assess and forecast disease risk under current and future climate conditions. However, in the field, the effects of temperature on parasitism may be mediated by other sources of variation, including local adaptation. To address the key knowledge gaps of how temperature influences host – parasite interactions and whether thermal responses measured in controlled experiments capture infection across temperature gradients in nature, we paired an extensive field survey of parasitism—by the ciliateLambornella clarkion its tree hole mosquito host,Aedes sierrensis—with laboratory experiments describing parasitism thermal performance curves (TPCs) for six host populations from varying climates. We also investigated the mechanisms underlying the thermal biology of the host – parasite interaction by separately measuring TPCs for infection, host immunity, and parasite growth rates. Along the west coast of North America, across an 1100 km climate gradient spanning 12°C mean rainy season temperature variation, we found that parasitism peaked at intermediately cold temperatures, and was consistent both between field seasons and with the lab experiment results. The experiments produced no evidence of host intraspecific variation in temperature sensitivity to parasitism. Importantly, parasitism peaked at temperatures below the thermal optimum for free-livingL. clarkidue to the balance of temperature effects on parasite growth and reproduction against the strength of the host melanization immune response. The results suggest that nonlinear responses to temperature drive parasitism in nature, and that simple lab and field studies can accurately capture the thermal biology of multilayered host – parasite interactions.

Data and code for this submission are provided on Dryad:http://datadryad.org/stash/share/CfZkk4LsJzljetJJnFZMDMrjuciTXMxrkrc95I2J3tA.
sCCIgen: A high-fidelity spatially resolved transcriptomics data simulator for cell-cell interaction studies
Authors: Song Xiaoyu , Chavez-Fuentes Joselyn C. , Ma Weiping , Fu Weijia , Wang Pei , Yuan Guo-Cheng
Published: January 2025

Spatially resolved transcriptomics (SRT) provides an invaluable avenue for examining cell-cell interactions within native tissue environments. The development and evaluation of analytical tools for SRT data necessitate tools for generating synthetic datasets with known ground truth of cell-cell interaction induced features. To address this gap, we introduce sCCIgen, a novel real-data-based simulator tailored to generate high-fidelity SRT data with a focus on cell-cell interactions. sCCIgen preserves transcriptomic and spatial characteristics in SRT data, while comprehensively models various cell-cell interaction features, including cell colocalization, spatial dependence among gene expressions, and gene-gene interactions between nearby cells. We implemented sCCIgen as an interactive, easy-to-use, realistic, reproducible, and well-documented tool for studying cellular interactions and spatial biology.
Compensation of Hyperexcitability with Simulation-Based Inference
Authors: Müller-Komorowska Daniel , Fukai Tomoki
Published: January 2025

The activity of healthy neuronal networks is tightly regulated, and a shift towards hyperexcitability can cause various problems, such as epilepsies, memory deficits, and motor disorders. Numerous cellular, synaptic, and intrinsic mechanisms of hyperexcitability and compensatory mechanisms to restore healthy activity have been proposed. However, quantifying multiple compensatory mechanisms and their dependence on specific pathophysiological mechanisms has proven challenging, even in computational models. We use simulation-based inference to quantify the interactions of compensatory mechanisms in a spiking neuronal network model. Various parameters of the model can compensate for changes in other parameters to maintain baseline activity, and we rank them by their compensatory potential. Furthermore, specific causes of hyperexcitability - interneuron loss, excitatory recurrent synapses, and principal cell depolarization - have distinct compensatory mechanisms that can restore normal excitability. Our results show that spiking neuronal network simulators could provide the quantitative foundation for targeting pathophysiological network mechanisms with precise interventions.
Variants inNR6A1as a cause for congenital renal, vertebral and uterine anomalies
Authors: Jacquinet Adeline , Flasse Lydie , Dohet Manon , Vanhaeren Romane , Pendeville Hélène , Saunders Carol , Lehman Anna , Pienkowski Catherine , Morcel Karine , Guerrier Daniel , Bours Vincent , Peers Bernard
Published: January 2025

The underlying cause for renal and uterine agenesis remains unknown in many cases, whereas recurrence in some families strongly suggests the involvement of genetic factors. Here, we identify 5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies and costovertebral defects associated with heterozygous deleterious variants inNR6A1. The variant spectrum includes both inherited missense as well asde novoloss of function, with the latter associated with a perinatal lethal phenotype characterized by bilateral renal agenesis.In vitrostudies demonstrated partial loss-of-function for both missense variants. To investigate the role ofNR6A1in development, CRISPR-Cas9 knockout zebrafish models targeting the orthologuesnr6a1aandnr6a1bwere generated. Mutants recapitulate the human phenotype, exhibiting impaired kidney development, including pronephros segmentation defects and adult kidney hypoplasia, along with axial skeletal abnormalities, cloacal anomalies, and disrupted anteroposterior expression of posterior hox genes. This study provides strong evidence linkingNR6A1heterozygous loss-of-function variants to renal, uterine and costovertebral defects in humans.
Non communicable diseases and resistant tuberculosis, a growing burden among people living with HIV in Eastern Kenya
Authors: Muriuki Patrick Kiogora , Ngayo Musa Otieno , Njire Moses , Mungiria Juster , Nyanya Winnie , Owuor Daniel , Ndung’u Perpetual
Published: January 2025

Human Immunodeficiency Virus (HIV) and tuberculosis (TB) still poses a significant health burden in Kenya. Countries with the highest burden of people living with HIV (PLWH) have a substantial burden of non-communicable diseases (NCDs) including type 2 diabetes (T2D) and hypertension (HPT). This study evaluated the burden and predictors of T2D, HPT and TB including resistant strains among PLWH receiving antiretroviral therapy (ART) in Eastern Kenya. Blood and sputum samples were obtained from 280 consenting PLWH and a detailed sociodemographic questionnaire was administered. TB and rifampicin resistance was determined by Cepheid’s GeneXpert system while Glycated hemoglobin (HbA1c) was determined using SD A1cCare™ analyzer. Blood pressure (BP) measurements with systolic BP readings of≥140 mmHg and/or diastolic BP≥90 mmHg was considered hypertensive. The participants CD4 cell counts, plasma HIV-1 RNA, full blood cells and blood chemistry were also measured. The patients mean (SD) age was 35.6 (±9.8) years, with 169 (82.4%) being on the first line ART regimen and a median (IQR) duration living with of 7 (4 to 8) years. The majority of the patients 179 (63.9%) were HIV mono-infected. The dual coinfections reported included; 58 (20.7%) HIV/TB, 42 (15%) HIV/ T2D, 33 (11.8%) HIV/HPT. Triple coinfections included; 18 (6.4%) HIV/T2D/HPT, 9(3.2%) HIV/TB/T2D, 9 (3.2%) HIV/TB/HPT with quadruple coinfection of HIV/TB /T2 /HPT among 4 (1.4%) patients. Six 6 (2.1%) HIV patients were coinfected with multidrug resistant TB. In the multivariable model, being on ARV only (aOR 0.5; 95% CI 0.4 – 0.6, p = 0.0001) and virological suppression (aOR 0.8; 95% CI 0.6 – 0.9, p = 0.017) were protective to HIV/TB coinfection. Previously hospital admission (aOR 1.2; 95% CI 1.1 – 1.4, p = 0.049) and previous TB infection (aOR 1.6; 95%CI 1.0 – 3.0, p = 0.034) were associated with HIV/TB coinfection. This study shows that Eastern Kenya is experiencing a syndemic of NCDs and TB including resistant strains among PLWH denoting the need to integrate the management of NCDs among HIV and TB treatment programs in Kenya.
DNA Methylation Differences Stratified by Normalized Fetal/Placental Weight Ratios Suggest Neurodevelopmental Deficits in Neonates with Congenital Heart Disease
Authors: Jacobwitz Marin , Xie Michael , Catalano Jamie , Helbig Ingo , Gaynor J. William , Burnham Nancy , Linn Rebecca L. , Gebb Juliana , Russell Mark W. , Chaiyachati Barbara H. , Cristancho Ana G.
Published: January 2025

Background

We lack early biomarkers for predicting neurodevelopment (ND) outcomes in children with congenital heart disease (CHD). Placentas of fetuses with CHD have abnormalities, including unbalanced fetal/placental weight ratios (F/P). Although DNA methylation profiles have revealed insights into the maternal-fetal environment (MFE), it is unknown if DNA methylation correlates to normalized F/P weight ratio groups and how these differences relate to ND outcomes.

Methods

We prospectively recruited a cohort of pregnant women carrying a fetus with CHD. A subset of the cohort had DNA methylation performed on either umbilical cord blood or postnatal blood (45 full-term neonates). We calculated normalized F/P weight ratios, focusing on three normalized F/P ratio groups for analysis. We calculated differential methylation signals in eight ND disabilities-associated gene sets. Normalized F/P ratios were compared to 18-month Bayley Scales of Infant Development-III scores (BSID-III).

Results

Unbiased gene ontology enrichment analysis of differentially methylated regions revealed enrichment for brain development-related pathways. Although there were no significant differences between normalized F/P weight ratio groups and BSID-III, disease-associated gene set pathway analysis revealed significant methylation differences between the most severely unbalanced F/P weight ratio and normal F/P weight ratio groups.

Conclusion

Gene ontology enrichment analysis of differential methylation regions revealed significant differences between normalized F/P weight ratio groups in neurogenesis genes. Furthermore, our data identified methylation differences between unbalanced and balanced normalized F/P weight ratio groups in gene pathways associated with ND dysfunction common in the aging CHD population suggesting converging pathways for ND disorders that should be investigated further.
Unique transcriptional profiles of adult human immature neurons in healthy aging, Alzheimer’s disease, and cognitive resilience
Authors: Tosoni G , Ayyildiz D , Penning A , Snoeck S , Santiago-Mujika E , Ruiz Ormaechea O , Lee H , Poovathingal SM , Davie K , Bryois J , Macnair W , Anink J , De Vries LE , Verhaagen J , Aronica E , Thuret S , Basak O , Roybon L , Fitzsimons CP , Lucassen PJ , Salta E
Published: January 2025

The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain controversial. While rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus under both healthy conditions and in Alzheimer’s disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD and dementia-resilient human hippocampus to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. Employing a novel experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles distinct from both fetal counterparts and adult mature hippocampal neurons. These profiles were associated with ‘juvenile’ cellular functions, suggesting that the presence of these immature neuronal populationsper semay actively contribute to maintaining homeostasis within the aged human hippocampus, a role that may be disrupted in AD. In the resilient brain, immature neurons were involved in transcriptional programs and intercellular interactions associated with anti-inflammatory, neurotrophic, neuroprotective, myelinating, anti-apoptotic and anti-amyloidogenic signaling pathways, suggesting active roles for the immature cells in enhancing cognitive resilience in the presence of AD pathology. Our findings reveal novel, putative physiological roles for immature neurons in the healthy and resilient adult human brain, and offer a resource for probing new strategies with potential functional relevance in AD.
Deficiency ofShank3in the Nucleus Accumbens Reveals a Loss of Social-Specific Motivation
Authors: Folkes Oakleigh M. , Donahue Meaghan , Wang Sung Eun , Oo Nicole Xinyen , Qiao Sheng-nan , Wang Xiaoming , Negrón-Moreno Paola N. , Jiang Yong-hui
Published: January 2025

Deficits in social interaction are a hallmark symptom of autism and other neuropsychiatric disorders.SHANK3encodes a postsynaptic density scaffold protein and is one of the most common causal genes for autism. SHANK3 protein is highly expressed in the nucleus accumbens (NAc), a critical brain region underlying motivated behavior, including social motivation. We previously reported that globalShank3Δe4–22deletion mice have decreased motivation for palatable food, increased unilateral social investigation, and show a hypoactive NAc and NAc-connected circuits. We thus developed a newShank3flox/floxmouse tool to conditionally knockdown SHANK3 in a region-specific manner. We found that knockdown ofShank3in the NAc decreased social preference in the 3-chamber assay and decreased social motivation in the social conditioned place preference (sCPP) assay.Shank3-NAc deletion did not alter food reward seeking, reciprocal social investigation, or anxiety-like behaviors, that we report in globalShank3Δe4–22deletion mice. These data establish a novel and specific role ofShank3in the NAc on social motivation.
Mechanical impact on neural stem cell lineage decisions in human brain organoids
Authors: Lampersperger Hanna , Tranchina Michael , Meth Bastian , Han Dandan , Nayebzadeh Negar , Reiter Nina , Kuth Sonja , Lorke Markus , Boccaccini Aldo R , Budday Silvia , Karow Marisa , Falk Sven
Published: January 2025

During neurodevelopment neural stem cells give rise to a spatially patterned tissue in which a regionally differentially regulated balance between proliferation and differentiation produces the fine-tuned number of neurons and macroglia necessary for a functional central nervous system. The cells driving these highly intricated developmental processes of patterning, growth and differentiation are constantly exposed to a mechanical environment that is however variable between different brain regions and along differentiation trajectories. Here we demonstrate that both, acute mechanical manipulations as well as a persistent change in the mechanical environment provided to human brain organoids, instruct neural stem cell lineage decisions. Furthermore, we dissect the underlying changes in the molecular program of organoid-resident cells by bulk- and single cell RNA-sequencing and reveal that mechanical manipulations impact on molecular programs governing early patterning events as well as cell-type specifically alter cellular metabolism. Thus, our results unravel a regulatory network linking mechanics and neural stem cell lineage decisions.
Intestinal RICT-1 regulates the larval germline progenitor pool via the vitellogenin VIT-3 inC. elegans
Authors: Kloock Anke , Hubbard E. Jane Albert
Published: January 2025

Populations of proliferating cells such as stem cells and tumors are often nutrient responsive. Highly conserved signaling pathways communicate information about the surrounding environmental, organismal, and cellular nutrient conditions. One such pathway is the Target of Rapamycin (TOR) pathway. The TOR kinase exists in two complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). TORC1 has been researched extensively and its regulation, particularly by amino acids, is well characterized. TORC1 activity promotes both stem cell fate and proliferation in theCaenorhabditis eleganshermaphrodite germline stem cell system to facilitate expansion of the larval germline Progenitor Zone (PZ) pool in response to nutrients. By contrast, a role for TORC2 in germline development has not been investigated. Here, we show that RICT-1, the sole ortholog of the TORC2-specific component RICTOR, also promotes expansion of the larval PZ, acting largely through SGK-1. Further, unlike the germline-autonomous role for TORC1 components, intestinalrict-1is both necessary and sufficient for full germline PZ pool establishment. Furthermore, neither DAF-2/IIS nor DAF-7/TGF-ß pathways mediate the effects of RICT-1. Rather, intestinal RICT-1 likely acts via vitellogenins, intestinally produced yolk proteins previously characterized for provisioning the adult germ line, but not previously characterized for a role in larval germ line development. By comparative RNA-seq on staged L4 larvae, we found vitellogenin genes among highly differentially abundant mRNAs. Genetic analysis supports a role forvit-3in germline development in a linear pathway withrict-1. Our results establish theC. elegansgerm line as a fruitful model for investigating TORC2 and its connection to stem cells and lipid biology.
A Heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy
Authors: Van de Vondel Liedewei , De Winter Jonathan , Monticelli Alice , Camacho Natacha , Deconinck Tine , Janssens Katrien , Malfroid Goedele , Alonso-Jiménez Alicia , Demidov German , Laurie Steven , De Ridder Willem , Ermanoska Biljana , Timmerman Vincent , Baets Jonathan
Published: January 2025

We report a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing theSPTAN1gene. The deletion was detected through exome-sequencing based copy number variant detection, segregates in four patients and is non-penetrant in two other relatives. Electromyography, muscle MRI and muscle biopsy revealed a myopathic disease phenotype. Cellular consequences of the deletion were investigated using qPCR and western blotting on patient-derived fibroblasts, which revealed a reduction of RNA but not protein levels. Immunocytochemistry was performed on muscle tissue which did not reveal reduction of α-II-spectrin.SPTAN1loss-of-function variants have previously been reported to cause distal hereditary motor neuropathy and recently distal myopathy. Here, we confirm the role ofSPTAN1haploinsufficiency as a cause of distal myopathy. We propose an age-dependent lack of α-II-spectrin and suggest CNV detection in repurposed exome sequencing as an important diagnostic tool.
Anatomic and Functional Outcomes of Lamellar Macular Hole Surgery: Predictive Factors and Associated Complications
Authors: Er-reguyeg Yosra , Doukkali Sihame , Hébert Mélanie , You Eunice Linh , Bourgault Serge , Caissie Mathieu , Tourville Éric , Dirani Ali
Published: January 2025

Purpose

To analyze the anatomic and functional outcomes of lamellar macular hole (LMH) surgery.

Patients and methods

This is a retrospective interventional cohort study of ninety patients with unilateral idiopathic LMH who underwent pars plana vitrectomy (PPV) with membrane peeling for LMH between 2014 and 2021. We evaluated the anatomic and functional success of PPV with membrane peeling for treating LMH, compared surgical outcomes between the two LMH subtypes (“true” LMH and epiretinal foveoschisis (ERMF)), and identified predictive factors for anatomical and functional success. Primary outcomes included final postoperative best-corrected visual acuity (BCVA) and LMH closure. Variables associated with final BCVA were assessed using a multiple linear regression model.

Results

51 subjects presented with ERMF, while 39 presented with “true” LMH. LMH closure occurred in 80 cases. “True” LMH cases had a lower rate of closure (“true” LMH closure rate: 76.9%, vs. ERMF closure rate: 94.2%, p=0.005) and were more at risk of developing a postoperative macular hole (p=0.008). A significant difference was observed between median [Q1, Q3] preoperative BCVA (0.42 [0.26, 0.61]) and final BCVA (0.31 [0.14, 0.48], p=0.024). “True” LMH without epiretinal proliferation (β=0.194, p=0.040) was associated with worse final BCVA in multivariate analysis.

Conclusion

Results support the effectiveness of PPV as a treatment for LMH. “True” LMHs had worse anatomic outcomes than ERMFs.
Significant Reduction in Manual Annotation Costs in Ultrasound Medical Image Database Construction Through Step by Step Artificial Intelligence Pre-annotation
Authors: Zheng Fu , XingMing Liu , JuYing Xu , MengYing Tao , BaoJian Yang , Yan Shan , KeWei Ye , ZhiKai Lu , Cheng Huang , KeLan Qi , XiHao Chen , WenFei Du , Ping He , RunYu Wang , Ying Ying , XiaoHui Bu
Published: January 2025

This study investigates the feasibility of reducing manual image annotation costs in medical image database construction by utilizing a step by step approach where the Artificial Intelligence model(AI model) trained on a previous batch of data automatically pre-annotates the next batch of image data, taking ultrasound image of thyroid nodule annotation as an example. The study used yolov8 as the AI model. During the AI model training, in addition to conventional image augmentation techniques, augmentation methods specifically tailored for ultrasound images were employed to balance the quantity differences between thyroid nodule classes and enhance model training effectiveness. The study found that training the model with augmented data significantly outperformed training with raw images data. When the number of original images number was only 1,360, with 7 thyroid nodule classifications, pre-annotation using the AI model trained on augmented data could save at least 30% of the manual annotation workload for junior physicians. When the scale of original images number reached 6,800, the classification accuracy of the AI model trained on augmented data was consistent with that of junior physicians, eliminating the need for manual preliminary annotation.
Characteristics of individuals who received a complete, 2-dose mpox vaccine regimen as part of the public health response to the mpox epidemic in Ontario, Canada: A CIRN study
Authors: Grewal Ramandip , Lau Cindy , Kwong Jeffrey C , Burchell Ann N , Friedman Lindsay , Navarro Christine , Okpokoro Evaezi , Tan Darrell H S , Zygmunt Austin , Mishra Sharmistha , Buchan Sarah A
Published: January 2025

Background

In May 2022, an outbreak of mpox emerged in Canada. In June 2022, the province of Ontario began offering first doses of a 2-dose regimen of Modified Vaccinia Ankara–Bavaria Nordic (MVA-BN) to those at high risk of exposure. Second doses became available in September 2022. To help increase dose 2 access and uptake, we sought to understand how individuals who received 2 doses differed from those who received only 1 dose.

Methods

We linked provincial health administrative data of individuals who received ≥1 dose of MVA-BN between June 6, 2022 and October 31, 2023 in Ontario. We used age-adjusted Poisson regression to examine the association between demographic, social, and economic characteristics; co-morbidities; and proxies for sexual exposure (e.g., bacterial sexually transmitted infection [STI] diagnoses) and proxies for healthcare engagement (e.g., syphilis testing, past receipt of other vaccines) with MVA-BN dose 2 receipt.

Results

Among 33,012 individuals with ≥1 MVA-BN dose, 38.2% (12,620) received 2 doses. Receipt of dose 2 versus only dose 1 was associated with region (e.g., Ottawa versus Toronto [prevalence ratio, PR=1.08, 95% confidence interval, CI 1.06-1.09]); syphilis testing (≥4 tests PR=1.12, 95%CI 1.11-1.14) or receiving a COVID-19, influenza, or other vaccine (PR=1.12, 95%CI 1.11-1.14) in the year before dose 1; and syphilis testing (≥4 tests PR=1.19, 95%CI 1.18- 1.20) or bacterial STI diagnoses >3 months after dose 1 (≥4 diagnoses PR=1.07, 95% CI 1.05- 1.08). Refugees were less likely to get dose 2 versus Canadian-born individuals or long-term immigrants (PR=0.93, 95%CI 0.91-0.95).

Conclusions

Our findings suggest lower healthcare access and/or engagement may play a role in limiting dose 2 receipt in Ontario. Public messaging around availability and eligibility of second doses, tailored strategies for eligible refugees, increased access outside healthcare venues, and adopting promotion strategies from regions with high uptake, may help increase dose 2 coverage.
A Randomised Controlled Trial of the effects of Galacto-Oligosaccharides on the gut brain-axis of young females
Authors: Johnstone Nicola , Kadosh Kathrin Cohen
Published: January 2025

Background

Galacto-oligosaccharides (GOS) are prebiotics linked to gut microbiota modulation and potential gut-brain axis effects on neurochemistry, mental health and cognition. This study evaluated the influence of GOS along the gut-brain axis, integrating assessments of mental health, neurochemistry, gut microbiome composition, cognition, and nutrition in healthy females.

Methods

In a randomised, double-blind, placebo-controlled trial, 83 females (17–25 years) received GOS or placebo for 28 days. Assessments occurred at baseline, endline, and 28 days post-supplementation. The primary outcome was trait anxiety, with secondary outcomes including neurochemical measures of GABA and glutamate via 1H-MRS in the dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC), and inferior occipital gyrus (IOG) of the brain, and gut microbiome composition. Tertiary outcomes included social anxiety, depression, emotion behaviour, reaction times, and nutritional intake. Analyses included intention-to-treat, per-protocol, and sensitivity approaches.

Results

Trait anxiety did not differ significantly between groups at endline (p = .443), though trends favoured lower anxiety in the GOS group at follow-up (p = .069). GOS reduced GABA at trend significance in the inferior occipital gyrus (p = .053) and dorsolateral prefrontal cortex (p = .088) in high-anxious participants, with effects persisting at follow-up. GOS increased Bifidobacterium abundance (p = .001) but did not affect overall microbiome diversity. Tertiary outcomes showed no significant changes in social anxiety or depression but faster reaction rates in high-anxious participants for simple (p = .036) and choice tasks (p < .001). Nutritional intake was unaffected.

Conclusion

While GOS supplementation did not significantly reduce trait anxiety, it produced neurochemical changes and transient modulations of the gut microbiome in Bifidobacterium abundance. These findings suggest GOS-induced changes can be traced along the gut-brain axis, with implications for mental health and cognitive function that warrant further investigation.
White matter tracts associated with iTBS-induced heart rate deceleration and treatment response in major depressive disorder
Authors: Wilkening Jonas , Goya-Maldonado Roberto
Published: January 2025

Intermittent theta burst stimulation (iTBS) is a well-established treatment for major depressive disorder (MDD), but predicting clinical outcomes remains challenging. Heart rate modulation induced by iTBS has emerged as a potential biomarker for treatment response, yet the role of white matter (WM) properties in mediating these effects is largely unexplored. In this quadruple-blind, crossover study, we investigated the relationship between WM microstructure, iTBS-driven heart rate deceleration, and antidepressant effects. Using correlational tractography, we analyzed four major WM tracts—the cingulum, fornix, superior longitudinal fasciculus, and uncinate fasciculus—and examined short-term WM microstructural changes to assess their predictive value for therapeutic outcomes. Baseline WM findings revealed that in the fornix and right dorsal cingulum fractional anisotropy (FA) negatively correlated with heart rate deceleration. Radial and mean diffusivity (MD, RD) in the fornix positively correlated with heart rate deceleration. FA in the right ventral cingulum positively correlated while MD and RD negatively correlated with symptom improvement. Longitudinally, FA increases in the left cingulum were significantly associated with greater symptom alleviation after treatment. Notably, iTBS-induced heart rate modulations correlated with clinical improvement after six weeks, while WM microstructural properties in the fornix and cingulum demonstrated predictive value for both heart rate modulation and treatment response. WM changes in the cingulum, evident as early as four weeks, highlight its unique neuroplasticity potential along iTBS intervention. Together, these findings provide novel insights into the structural connectivity patterns influencing iTBS outcomes, offering a novel foundation for more personalized therapeutic strategies in MDD.
Inequalities in access to health care: an exploration of the cascade of care for in-transit migrants and asylum seekers, and the general population in Mexico
Authors: Banerjee Arjun , Rodríguez-Chavez César , Sepúlveda Jaime , Strathdee Steffanie , Bojorquez Ietza
Published: January 2025

BACKGROUND

All over the world, migrants experience inequalities in access to health care. While this issue has been amply explored among immigrants and refugees in high-income countries, there is a dart of information on the situation of in-transit migrants and asylum seekers (IMAS) in low- or middle-income countries. Since these are the main recipient countries for this population, it is important to document inequalities in access to care in this context, especially for countries such as Mexico, in which IMAS are entitled to health care in par with the general population.

OBJECTIVE

to assess the inequalities in access to health care experienced by in-transit migrants in Mexico, as compared to the general population of Mexico, employing a cascade of care approach.

METHODS

We analyzed data from a cross-sectional survey of IMAS in shelters in Tijuana (November 2020-April 2021, n=481), and from ENSANUT-COVID 2020, a representative survey of the general population in Mexico conducted at about the same time (unweighted n=25,959). We compared the cascade of care – the self-reported presence of health needs, whether participants sought care given the need, and whether they received care – of the two samples.

RESULTS

A higher percentage of IMAS had experienced a health need in the past three months, as compared to the general population of Mexico (43.0% vs 21.9%). IMAS were less likely to seek care given the need (58.9% vs 81.8%), to receive care when they sought it (86.9% vs 97.7%), and to receive care in the public health system (19.7% vs 43.3%).

CONCLUSIONS

Inequalities in access to care were apparent, even in a health system that normatively should provide care regardless of migration status. Understanding why this occurs is important, and our results represent a baseline from which to evaluate future improvements in universal health coverage in Mexico.
Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish
Authors: Eski Sema Elif , Mi Jiarui , Pozo-Morales Macarena , Hovhannisyan Gabriel Garnik , Perazzolo Camille , Manco Rita , Ez-Zammoury Imane , Barbhaya Dev , Lefort Anne , Libert Frederick , Marini Federico , Gurzov Esteban N. , Andersson Olov , Singh Sumeet Pal
Published: January 2025

The liver's regenerative ability depends on injury extent. Minor injuries are repaired by hepatocyte self-duplication, while severe damage triggers cholangiocyte involvement in hepatocyte recovery. This paradigm is well-documented for adult animals but is less explored during rapid growth. We design two new partial liver injury models in zebrafish, which were investigated during growth spurts: 1) partial ablation, killing half the hepatocytes; and 2) partial hepatectomy, removing half a liver lobe. In both injuries, de novo hepatocytes emerged alongside existing ones. Single-cell transcriptomics and lineage tracing with Cre-driver lines generated by genome editing identified cholangiocytes as the source of de novo hepatocytes. We further identify active mTORC1 signalling in the uninjured liver of growing animal to be a regulator of the enhanced plasticity of cholangiocytes. Our study suggests cholangiocyte-to-hepatocyte transdifferentiation as the primary mechanism of liver regeneration during periods of rapid growth.
A Rational Information Gathering Account of Infant Habituation
Authors: Karni Gili , Mattar Marcelo G. , Emberson Lauren , Daw Nathaniel D.
Published: January 2025

Gaze is one of the primary experimental measures for studying cognitive development, especially in preverbal infants. However, the field is only beginning to develop a principled explanatory framework for making sense of the various factors affecting gaze. We approach this issue by addressing infant gaze from first principles, using rational information gathering. In particular, we revisit the influential descriptive account of Hunter and Ames (1988) (H&A), which posits a set of regularities argued to govern how gaze preference for a stimulus changes with experience and other factors. When H&A’s model is reconsidered from the perspective of rational information gathering (as recently also proposed by other authors), one feature of the model emerges as surprising: that preference for a stimulus is not monotonic with exposure. This claim, which has at least some empirical support, is in contrast to most statistical measures of informativeness, which strictly decline with experience. We present a normative, computational theory of visual exploration that rationalizes this and other features of the classic account. Our account suggests that H&A’s signature nonmonotonic pattern is a direct manifestation of a ubiquitous principle of the value of information in sequential tasks, other consequences of which have recently been observed in a range of settings including deliberation, exploration, curiosity, and boredom. This is that the value of information gathering, putatively driving gaze, depends on the interplay of a stimulus’ informativeness (calledGain, the focus of other rationally motivated accounts) with a second factor (calledNeed) reflecting the estimated chance that information will be used in the future. This computational decomposition draws new connections between infant gaze and other cases of exploration, and offers novel, quantitative interpretations and predictions about the factors that may impact infant exploratory attention.
Alpha and beta desynchronization during consolidation of newly learned words
Authors: Zappa A. , León-Cabrera P. , Ramos-Escobar N. , Laine M. , Rodriguez-Fornells A. , François C.
Published: January 2025

While a growing body of literature exists on initial word-to-meaning mapping and retrieval of fully lexicalized words, our understanding on the learning of semantic knowledge that occurs between these two stages remains limited. The current study investigated the neural correlates of retrieving newly learned word meanings using oscillatory brain dynamics. Participants learned to associate new words with unknown objects and performed overt and covert naming tasks during the first and last days of a five-day training period. Behavioral results showed improved overt naming on Day 5 compared to Day 1. Selecting only words that were successfully produced in the overt naming task, we examined alpha (8-12 Hz) and beta (13-25 Hz) band oscillatory activity associated with lexical-semantic retrieval while participants produced new words covertly, both pre-(Day 1) and post (Day 5) lexicalization. The results showed a robust alpha and lower beta power decrease during covert naming after learning. We hypothesize that this alpha-beta power decrease indexes successful word retrieval following lexical-semantic integration and consolidation.