bluuebunny/crossref_metadata_2025 huggingface dataset:
UBIQUITIN-CONJUGATING ENZYME34 mediates pyrophosphatase AVP1 turnover and regulates abiotic stress responses in Arabidopsis
Authors: Xu Qiyu , Zhang Xingjian , Zhao Ruifeng , Li Shengjun , Liesche Johannes
Published: January 2025

Understanding the molecular mechanisms of abiotic stress responses in plants is instrumental for the development of climate-resilient crops. Key factors in abiotic stress responses, such as the proton-pumping pyrophosphatase (AVP1), have been identified, but their function and regulation remain elusive. Here, we explored the post-translational regulation of AVP1 by the ubiquitin-conjugating enzyme UBC34 and its relevance in the salt stress and phosphate starvation responses of Arabidopsis (Arabidopsis thaliana). Through in vitro and in vivo assays, we established that UBC34 interacts with and ubiquitylates AVP1. Mutant lines in which UBC34 was downregulated showed higher tolerance to salt and low inorganic phosphate (Pi) stresses, while we observed the opposite for plants overexpressing UBC34. Our results showed that UBC34 co-localizes with AVP1, and AVP1 activity is enhanced in the plasma membrane fractions of ubc34 mutants, indicating that UBC34 mediates the turnover of plasma membrane-localized AVP1. We also observed that UBC34 affects the apoplastic pH but not the vacuolar pH of root cells. Based on our results, we propose a mechanistic model in which UBC34 mediates AVP1 turnover at the plasma membrane of root epidermal cells. Downregulation of UBC34 under salt and phosphate starvation conditions enhances AVP1 activity, leading to a higher proton gradient available for sodium sequestration and phosphate uptake.
The clinical characteristics and treatment outcomes of patients with systemic polyarteritis nodosa: a single-centre study from India
Authors: Jha Avanish , R Chitra , Yadav Bijesh , Simon Betty , Mathew Ashish J , Mathew John , Thomas Meera , Goel Ruchika
Published: January 2025

Objective

To describe the clinical profile and compare the long-term outcomes of patients with systemic polyarteritis nodosa (S-PAN) treated with various treatment regimens at our centre in the last two decades.

Methods

Data regarding clinical presentation, treatment allocation, relapses and outcomes of patients fulfilling American College of Rheumatology (ACR) 1990 criteria for PAN in the last two decades were recorded from electronic medical records. Relapse-free survival and predictors were analysed using Kaplan–Meier survival statistics and regression analysis.

Results

Altogether, 53 patients, including two with hepatitis B infection, were included. Cutaneous lesions and peripheral neuropathy were the commonest manifestations. Most patients (64.2%) presented with a five-factor score (FFS) of 0. Disease-attributable hypertension and peripheral gangrene were the most common manifestations of severe disease. During a median follow-up period of 53.5 months in 49 patients who had a follow up, 43 (87.8%) attained complete response while 3 (6.1%) had a partial response. Among 46 patients who had follow up of more than 3 months, 19 (41.3%) patients relapsed at a median duration of 82 (interquartile range 36.3–127.7) months. The relapse-free survival in patients who received induction with mycophenolate (n = 26) was comparable to that with cyclophosphamide (n = 21) [adjusted hazard ratio (HR): 0.68]. Smoking history was an independent predictor of relapse (HR = 6.28, P = 0.013) while age was protective (HR = 0.94, P = 0.015). Overall, fatality was observed in 5 (10%) patients. FFS and BVAS at 3 months were among the predictors of mortality.

Conclusion

In our cohort of S-PAN, relapses were observed in 41.3% of patients. Mycophenolate was similar to cyclophosphamide in maintaining relapse-free survival. Only 10% fatality was recorded. FFS and BVAS at 3 months were predictors of mortality.
Association of total testosterone levels with cardiometabolic diseases in men with erectile dysfunction
Authors: Chen Bing-Tau , Tsai Ping-Ju , Jiann Bang-Ping
Published: January 2025

Background

Both serum testosterone (T) levels and erectile dysfunction (ED) are associated with systemic diseases in men and ED is the most common presenting symptom of hypogonadism.

Aim

To evaluate the association of serum total testosterone (TT) levels with cardiometabolic diseases in men with ED.

Methods

Serum endogenous TT levels were determined to evaluate their associations with cardiometabolic diseases in men with ED in outpatient clinics. Participants were divided into hypogonadal with TT < 350 ng/dL (12.1 nmol/L) and eugonadal groups, as well as into four equal quartiles based on TT levels. The Framingham risk score was used to estimate individual 10-year coronary heart disease (CHD) risk.

Main Outcome Measures

Cardiometabolic factors included obesity, diabetes mellitus (DM), hypertension (HT), dyslipidemia, and the Framingham risk score.

Results

From 2010 to 2021, a total of 4467 subjects with ED were consecutively recruited for this study, and 3909 subjects’ (87.5%) data with a mean age of 53.0 ± 12.9 (20.0–88.0) years had data eligible for analysis. Testosterone levels declined with age and a higher body mass index (BMI) was associated with lower T levels across all age groups (P < .001). Compared to the eugonadal group, the hypogonadal group was older and had a higher BMI and more cardiometabolic diseases (all P < .01). In multivariate analysis, odds ratio (OR) for hypogonadism was highest in men with obesity (2.51), followed by age group of ≥70 years (2.32), DM (1.59), HT (1.41), and dyslipidemia (1.26). Compared with the lowest TT quartile, higher quartiles of TT had significantly lower risk for cardiometabolic diseases (all P < .001). Among men over 50 yrs, hypogonadal men had a higher 10-year CHD risk than eugonadal men as predicted by the Framingham risk score (P < .001).

Clinical implications

Our results highlight the value of determining TT levels in men with ED because of their association with cardiometabolic diseases and the potential benefits of T therapy for improving men’s health.

Strengths and Limitations

Strengths of this study include a relatively large sample and detailed medical history collection. Limitations included a small portion of subjects with repeat TT tests, and the lack of data on free T and bioavailable T levels, and single-site recruitment.

Conclusions

TT levels are independently associated with cardiometabolic diseases including obesity, DM, HT, and dyslipidemia, and indicate a higher risk for CHD in men with ED. Measuring TT levels in men with ED presents an opportunity to improve overall health and reduce CV risk.
Shining disco: shedding light into the systematics of the family Discodorididae (Gastropoda: Nudibranchia)
Authors: Fernández-Vilert Robert , Arnedo Miquel A , Salvador Xavi , Valdés Ángel , Schrödl Michael , Moles Juan
Published: January 2025

The evolutionary relationships among genera within the nudibranch family Discodorididae remain poorly understood, with comprehensive molecular studies still largely absent. Discodoris, the most species-rich genus within this family, has historically represented a wastebasket taxon where species with ‘discodoridid’ morphology were placed. In this study, we present molecular data to evaluate the taxonomic classification of the family and to investigate potential (pseudo)cryptic diversity. Our molecular analyses comprised a multilocus phylogenetic analysis of 199 specimens, including 20 type species. The dataset included 142 specimens belonging to Discodorididae, 24 from Dorididae, and 33 outgroup taxa. A total of 52 specimens from 30 different species of Discodorididae, including six type taxa, were sequenced from the Mediterranean Sea, Eastern Atlantic Ocean, and Central and South America. Phylogenetic analyses recovered the monophyly of the family Discodorididae but including the doridid Aphelodoris, revealing evidence of hidden diversity in several genera such as Taringa, Tayuva, Paradoris, and Geitodoris. Our study unveiled the paraphyly of the genera Discodoris and Diaulula, which warrant a critical appraisal of their morphology. Overall, we provide relevant molecular information to infer the most complete phylogeny of Discodorididae to date and identify new questions for future studies.
Amplitude and Phase Changes in Electrocochleographic Real-Time Recordings During Cochlear Implantation and Its Relation to Pre- and Postoperative Hearing
Authors: Dalbert Adrian , Bester Christofer , Collins Aaron , Razmovski Tayla , Gerard Jean-Marc , O’Leary Stephen
Published: January 2025

Background

The aim of this study was to relate response patterns of electrocochleography (ECochG) recordings during cochlear implantation to pre- and postoperative hearing.

Methods

Thirty subjects with either flat (FA, n = 9) or sloping (SA, n = 21) audiograms before cochlear implantation were prospectively included. Real-time ECochG recordings were conducted via the cochlear implant. The difference curve (DIF) signal of the ECochG recordings was analyzed regarding alteration of the waveform, amplitude changes, and relative phase shifts during insertion.

Results

Five subjects (56%) with FA and 13 (62%) with SA exhibited DIF signal drops in the early phase of the insertion. In subjects with FA, alterations of the DIF signal waveform in the early phase of the insertion occurred in 8 subjects (90%), whereas such changes were detectable in only 2 out of 21 subjects (10%) with SA (p < 0.001). DIF signal drops with relative phase shifts of >0.7 radians but without alterations of the waveform occurred in 5 subjects (56%) with FA and 11 (52%) with SA. Such drops were associated with larger postoperative hearing losses than DIF signal drops without phase changes in both groups (FA: 43 versus 20 dB, p = 0.045; SA: 30 versus 14 dB, p = 0.001).

Conclusion

Residual cochlear function in basal regions leads to alteration of the DIF signal waveform during insertion, probably not associated with cochlear injury. A decrease of the DIF signal amplitude with a simultaneous relative phase shift but no alteration of the waveform is associated with greater loss of residual hearing independent from the preoperative hearing.
Utility of Multiparametric Breast MRI Radiomics to Predict Cyclin D1 and TGF-β1 Expression
Authors: Zheng Mengying , Xu Jiaqi , Yu Shujie , Zhao Zhenhua , Zhang Yu , Wei Mingzhu
Published: January 2025

Objective:

To develop a machine learning model that integrates clinical features and multisequence MRI radiomics for noninvasively predicting the expression status of prognostic-related factors cyclin D1 and TGF-β1 in breast cancer, providing additional information for the clinical development of personalized treatment plans.

Methods:

A total of 123 breast cancer patients confirmed by surgical pathology were retrospectively enrolled in our Hospital from January 2016 to July 2022. The patients were randomly divided into a training group (87 cases) and a validation group (36 cases). Preoperative routine and dynamic contrast-enhanced magnetic resonance imaging scans of the breast were performed for treatment subjects. The region of interest was manually outlined, and texture features were extracted using AK software. Subsequently, the LASSO algorithm was employed for dimensionality reduction and feature selection to establish the MRI radiomics labels. The diagnostic efficacy and clinical value were assessed through receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA).

Results:

In the cyclin D1 cohort, the area under the receiver operating characteristic (ROC) curve in the clinical prediction model training and validation groups was 0.738 and 0.656, respectively. The multisequence MRI radiomics prediction model achieved an AUC of 0.874 and 0.753 in these respective groups, while the combined prediction model yielded an AUC of 0.892 and 0.785. In the TGF-β1 cohort, the ROC AUC for the clinical prediction model was found to be 0.693 and 0.645 in the training and validation groups, respectively. For the multiseries MRI radiomics prediction model, it achieved an AUC of 0.875 and 0.760 in these respective groups; whereas for the combined prediction model, it reached an AUC of 0.904 and 0.833. Decision curve analysis (DCA) demonstrated that both cohorts indicated a higher clinical application value for the combined prediction model compared with both individual models—clinical prediction model alone or radiomics model.

Conclusion:

The integration of clinical features and multisequence MRI radiomics in a combined modeling approach holds significant predictive value for the expression status of cyclin D1 and TGF-β1. The model provides a noninvasive, dynamic evaluation method that provides effective guidance for clinical treatment.
Morphology of male genitalia and legs reveals the classification of Mesozoic Zoraptera (Insecta)
Authors: Kočárek Petr , Kočárková Ivona , Kundrata Robin
Published: January 2025

Zoraptera is a small insect order with less than 50 described species from mostly tropical and subtropical regions of the World. The current system of extant Zoraptera is based on the results of molecular phylogeny combined with the morphology of male genitalia, and supplemented by the characters on the male abdomen and a number of metatibial spurs. However, fossil representatives of Zoraptera have not yet been classified into the modern system and most of them remained in the collecting genusZorotypusSilvestri, 1913, because the genitalia were not observable or examined in detail. In this study, for the first time, we describe and critically evaluate the male genitalia and other principal diagnostic characters of all available Mesozoic Zoraptera. Our results lead to the first proposal of the generic classification of Mesozoic Zoraptera. We describe two new genera,Cretozorosgen. nov. andBurmazorosgen. nov., reinstatePaleospinosusKaddumi, 2005, stat. restit. from synonymy with the subgenusOctozorosEngel, 2003 (inZorotypus), and elevateOctozorosEngel, 2003 to a genus level.Cretozorosgen. nov.,Paleospinosusstat. restit. andOctozorosstat. nov. are classified in Spiralizoridae: Latinozorinae, whileBurmazorosgen. nov. andXenoburmiticusEngel & Grimaldi, 2002 are classified in Zorotypidae: Zorotypinae. Altogether, it was possible to classify nine out of the 11 currently recognized species of Mesozoic Zoraptera.Zorotypus hukawngiChen & Su 2019 is synonymized withCretozoros acanthothorax(Engel & Grimaldi, 2002), comb. nov. andZorotypus hirsutusMashimo, 2018 is synonymized withOctozoros robustus(Liu, Zhang, Cai & Li, 2018), stat. restit., comb. nov., which is simultaneously restituted from the synonymy withOctozoros cenomanianus(Yin, Cai & Huang, 2018), comb. nov. The classification of Mesozoic Zoraptera into the modern system enables us to better understand the diversity of their internal lineages during the early evolution of this enigmatic insect order.
Freshwater fish community assessment using eDNA metabarcoding vs. capture-based methods: differences in efficiency and resolution coupled to habitat and ecology
Authors: Curto Manuel , Batista Sofia , Santos Carlos D. , Ribeiro Filipe , Nogueira Sofia , Ribeiro Diogo , Prindle Benjamin , Licari Daniel , Riccioni Giulia , Dias Diogo , Pina-Martins Francisco , Jentoft Sissel , Veríssimo Ana , Alves Maria Judite , Gante Hugo F.
Published: January 2025

Environmental DNA (eDNA) metabarcoding has revolutionized ecological and environmental research by describing communities without relying on direct observations, making it a powerful, non-invasive, and cost-effective tool in biodiversity monitoring. However, implementation of eDNA as a standard protocol in long-term monitoring programs, that have traditionally relied on capture-based methods, poses challenges in terms of data comparability. Here, we compared freshwater fish communities assessed through eDNA metabarcoding and electrofishing, across 35 sampling sites in the lower Tagus River basin, Portugal. For most species or species-groups analyzed individually (13 out of 17), there was a significant correspondence between electrofishing and eDNA metabarcoding detections. The correspondence was weaker when comparing the number of specimens captured by electrofishing with the number of eDNA metabarcoding reads, with seven out of 13 taxa showing significant relationships. Species richness estimates based on the two methods were very similar at the basin level. The methods yielded significantly different species compositions, although these differences were driven by samples collected in the Tagus main channel, which is wider and has higher flow rates than tributaries. Benthic and shoreline fish communities showed similar species composition in the two methods, but this was not the case for pelagic communities, probably due to the higher water turnover of the pelagic zone and electrofishing inefficiency. Our results highlight the high potential of eDNA metabarcoding as a complementary method to electrofishing for freshwater fish monitoring, though further validation is needed to assess biases related to site-specific hydrological conditions and the ecology of the target species.
Evolution of SARS-CoV-2 T cell responses as a function of multiple COVID-19 boosters
Authors: da Silva Antunes Ricardo , Fajardo-Rosas Vicente , Yu Esther Dawen , Gálvez Rosa Isela , Abawi Adam , Alexandar Escarrega E. , Martínez-Pérez Amparo , Johansson Emil , Goodwin Benjamin , Frazier April , Dan Jennifer M. , Crotty Shane , Seumois Grégory , Weiskopf Daniela , Vijayanand Pandurangan , Sette Alessandro
Published: January 2025

The long-term effects of repeated COVID-19 vaccinations on adaptive immunity remain incompletely understood. Here, we conducted a comprehensive three-year longitudinal study examining T cell and antibody responses in 78 vaccinated individuals without reported symptomatic infections. We observed distinct dynamics in Spike-specific humoral and cellular immune responses across multiple vaccine doses. While antibody titers incrementally increased and stabilized with each booster, T cell responses rapidly plateaued, maintaining remarkable stability across CD4+ and CD8+ subsets. Notably, approximately 30% of participants showed CD4+ T cell reactivity to non-Spike antigens, consistent with asymptomatic infections. Single-cell RNA sequencing revealed a diverse landscape of Spike-specific T cell phenotypes, with no evidence of increased exhaustion or significant functional impairment. However, qualitative changes were observed in individuals with evidence of asymptomatic infection, exhibiting unique immunological characteristics, including increased frequencies of Th17-like CD4+ T cells and GZMKhi/IFNR CD8+ T cell subsets. Remarkably, repeated vaccinations in this group were associated with a progressive increase in regulatory T cells, potentially indicating a balanced immune response that may mitigate immunopathology. By regularly stimulating T cell memory, boosters contribute to a stable and enhanced immune response, which may provide better protection against symptomatic infections.
A dietary intervention following incretin analog treatment restores adipose tissue functions in diet-induced obese mice
Authors: Seuntjens Joke , De Gols Jente , Davies Bethan K , Van Looy Fien , Stockmans Ingrid , Moermans Karen , Carmeliet Geert , Matthys Christophe , Vangoitsenhoven Roman , Van der Schueren Bart , Stegen Steve , Shimobayashi Mitsugu
Published: January 2025

Obesity affects more than 15% of the world population and is associated with the development of glucose intolerance and type 2 diabetes. In recent years, incretin analogs are prescribed at a high rate for treatment of obesity and diabetes due to their potent effects on lowering bodyweight and improving glucose homeostasis. However, recent studies suggest that many patients do not stay on incretin analog therapy and thereby rapidly regain bodyweight. The non-compliance of patients to incretin analog therapy is not only due to drug shortage but also insufficient knowledge on the long-term effects of the therapy. To address this knowledge gap and provide a long-term therapy strategy for obesity, we examined the effects of incretin analog treatment and withdrawal on adipose tissue functions in diet-induced obese mice. Our transcriptome data suggest that incretin analog treatment restored most of obesity-mediated deregulated gene expression in adipose tissue. However, genes encoding lipogenic enzymes, downregulated by diet-induced obesity, were not restored by incretin analog treatment. Upon therapy withdrawal, mice displayed rapid bodyweight regain, impaired adipose tissue function, and glucose intolerance. In contrast, a dietary intervention following incretin analog therapy withdrawal restored lipogenic gene expression in adipose tissue, maintained glucose homeostasis, increased lean mass and minimized body weight regain. Our findings revealed the effects of incretin analog therapy and therapy withdrawal on adipose tissue and highlight the importance of a dietary intervention following incretin analog therapy, which may contribute to the development of long-term therapy guidelines of incretin analog therapy for patients with obesity.
Molecular mechanisms of sexual dimorphism in cancer through improved miRNA regulation-level network-based approach: MIRROR2
Authors: Alfano Caterina , Filetti Marco , Farina Lorenzo , Petti Manuela
Published: January 2025

A current open challenge in precision medicine is sex-specific medicine: the study of how sex-based biological differences influence people’s health. With recent advancements in high-throughput technologies, large-scale molecular data are being generated for individual cancer patients, however, extracting meaningful insights from these complex datasets remains a challenge. Network-based approaches, being inherently holistic, can lead to a better understanding of the molecular mechanisms underlying a disease. For this reason, this study focuses on the development of a network-based method to investigate sexual dimorphism in cancer using transcriptomic data. Previous studies have already shown how miRNAs are involved in differentiating patients by sex in different types of cancer; however, they focused only on evaluating changes in the expression level, without conducting a more comprehensive analysis of miRNA expression or investigating miRNAs’ targets. The aim of this study is therefore to carry out a multi-layer study involving both miRNAs and their target genes’ expression data. In particular, we developed a generalizable algorithm (MIRROR2), which can be used on cancer patients to help identify key regulatory mechanisms and molecules that act as differentiators between males and females. Here we implemented and tested MIRROR2 on three different cancers (colon adenocarcinoma, hepatocellular carcinoma, and low-grade gliomas) and assessed its performance by comparing it to state-of-the-art approaches. This revealed MIRROR2’s efficacy in identifying sex-specific key genes (and how to integrate them with clinical features), presenting it as a viable alternative to state-of-the-art methods which fail to capture these differences.
High-precision cell-type mapping and annotation of single-cell spatial transcriptomics with STAMapper
Authors: Shen Qunlun , Dong Kangning , Zhang Shuqin , Zhang Shihua
Published: January 2025

Recent advances in single-cell spatial transcriptomics (scST) have enabled the analysis of gene transcription levels in individual cells while preserving their spatial positions. Cell-type mapping and annotation are crucial in understanding the complex interactions between cells and their microenvironments within a spatial context. To this end, we develop a heterogeneous graph neural network, STAMapper, to transfer the cell-type labels from single-cell RNA-seq data to scST data. STAMapper captures both the expression similarity among cells and the expression relationships between cells and genes and adopts a graph attention classifier to conduct semi-supervised learning for more accurate cell-type prediction. We collected 81 scST datasets consisting of 344 slices and 16 paired scRNA-seq datasets from eight technologies and five tissues to validate the efficiency of STAMapper. STAMapper achieved the best performance on 75 out of 81 datasets compared to competing methods in accuracy. STAMapper demonstrated enhanced performance over manual annotations, particularly at the boundaries of cell clusters, enabled the unknown cell-type detection in scST data, and exhibited precise cell subtype annotations. Additionally, STAMapper provided biologically meaningful gene embeddings, facilitating the identification of shared or unique gene modules across datasets.
Phylogenomic synteny analysis tracks conserved ancient polyploid-derived triplicated genomic blocks across Asteraceae genomes
Authors: Feng Tao , McKibben Michael , Lovell John , Michelmore Richard , Rieseberg Loren H. , Barker Michael , Schranz Eric M.
Published: January 2025

The Asteraceae (Compositae) is the largest flowering plant family, ubiquitous in most terrestrial communities, and morphologically hyper-diverse. An ancient whole genome triplication (paleo-hexaploidization) occurred at approximately the same time as the evolutionary innovation and adaptive radiation of the family during the middle Eocene. Despite its importance, the genomic contents arising from this triplication have yet to be tracked in context of the Asteraceae genome evolution. We applied a synteny oriented phylogenomic analysis of 21 Asterales genomes and to study the paleo-hexaploidization and its consequences to gene, trait, and genome evolution. We identified 15 ancestral linkage groups (ALGs) that date back to the common diploid ancestor of all Asteraceae. Each of these groups was triplicated, resulting in 45 genomic blocks (3×15), which serve as the foundation for cross-family analyses. We demonstrate the complex evolutionary dynamics of the 45 genomic blocks across the Asteraceae phylogeny. We found that modern genomes are genetic mosaics of three progenitor genomes by extensive genomic exchange, chromosomal shuffling and gene fractionation. 157 genes retained three paleo-hexaploid derived syntenic paralogs across most Asteraceae species. Transcription factors (TFs) and auxin-related genes are significantly overrepresented in the conserved triplets, and expression of the paleo-hexaploidy paralogs is spatiotemporally differentiated. These genes are involved in the development of floral capitulum, a remarkable morphological innovation of the family. The discovery of conserved triplicated genes can direct further study to understand the evolutionary innovation, and the synteny-phylogenomic framework and ALGs provide a comparative framework to characterize newly sequenced Asteraceae genomes.
Impaired Myelination in Multiple Sclerosis Organoids: p21 Links Oligodendrocyte Dysfunction to Disease Subtype
Authors: Daviaud Nicolas , Mehta Tanmay , Holzman William , McDermott Annie , Sadiq Saud A
Published: January 2025

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are strongly implicated in its pathogenesis. We derived cerebral and spinal cord organoids from induced pluripotent stem cells (iPSC) from healthy controls as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients to investigate and compare oligodendrocyte differentiation and myelination capacity in healthy subjects and MS subtypes. In MS organoids, particularly in PPMS, we observed a decrease in p21 expression associated with a dysregulation of PAK1 and E2F1 expression. In parallel, a decrease in oligodendrocyte maturation was detected in long-term cultured cerebral and spinal cord organoids, especially in PPMS, leading to a reduced myelination capacity. Disruption of astrocyte and neuronal populations was also observed. Our findings demonstrate that in MS, inherent deficits in the p21 pathway may alter glial and neuronal cell populations and may contribute to the disease pathogenesis by reducing the capacity for myelin repair.

Summary Statement

Using cerebral and spinal cord organoids derived from multiple sclerosis patients, we found an innate disruption of oligodendrocyte differentiation and myelination capacity as well as excitotoxicity, associated with PAK1 and E2F1-induced p21 dysregulation.
Deep topic modeling of spatial transcriptomics in the rheumatoid arthritis synovium identifies distinct classes of ectopic lymphoid structures
Authors: Periyakoil Preethi K. , Smith Melanie H. , Kshirsagar Meghana , Ramirez Daniel , DiCarlo Edward F. , Goodman Susan M. , Rudensky Alexander Y. , Donlin Laura T. , Leslie Christina S.
Published: January 2025

Single-cell RNA sequencing studies have revealed the heterogeneity of cell states present in the rheumatoid arthritis (RA) synovium. However, it remains unclear how these cell types interact with one anotherin situand how synovial microenvironments shape observed cell states. Here, we use spatial transcriptomics (ST) to define stable microenvironments across eight synovial tissue samples from six RA patients and characterize the cellular composition of ectopic lymphoid structures (ELS). To identify disease-relevant cellular communities, we developed DeepTopics, a scalable reference-free deconvolution method based on a Dirichlet variational autoencoder architecture. DeepTopics identified 22 topics across tissue samples that were defined by specific cell types, activation states, and/or biological processes. Some topics were defined by multiple colocalizing cell types, such as CD34+fibroblasts and LYVE1+macrophages, suggesting functional interactions. Within ELS, we discovered two divergent cellular patterns that were stable across ELS in each patient and typified by the presence or absence of a “germinal-center-like” topic. DeepTopics is a versatile and computationally efficient method for identifying disease-relevant microenvironments from ST data, and our results highlight divergent cellular architectures in histologically similar RA synovial samples that have implications for disease pathogenesis.
Protenix - Advancing Structure Prediction Through a Comprehensive AlphaFold3 Reproduction
Authors:   ByteDance AML AI4Science Team, Chen Xinshi , Zhang Yuxuan , Lu Chan , Ma Wenzhi , Guan Jiaqi , Gong Chengyue , Yang Jincai , Zhang Hanyu , Zhang Ke , Wu Shenghao , Zhou Kuangqi , Yang Yanping , Liu Zhenyu , Wang Lan , Shi Bo , Shi Shaochen , Xiao Wenzhi
Published: January 2025

In this technical report, we present Protenix, a comprehensive reproduction of AlphaFold3 (AF3), aimed at advancing the field of biomolecular structure prediction. Protenix tackles the challenges of predicting complex interactions involving proteins, ligands, and nucleic acids, while enhancing accessibility and reproducibility. Across diverse benchmarks, including PoseBusters V2, low-homology PDB sets, and CASP15 RNA, Protenix achieves state-of-the-art performance in protein-ligand, protein-protein, and protein-nucleic acid predictions. We also address limitations, such as potential memorization effects, and outline future directions for improvement. By open-sourcing Protenix, we aim to democratize advanced structure prediction tools and accelerate interdisciplinary research in computational biology and drug discovery.
Escherichia coliouter membrane vesicles encapsulating small molecule antibiotics improve drug function by facilitating transport
Authors: Wu Meishan , Harrower Rachael M. , Li Ziang , Brown Angela C.
Published: January 2025

The development of novel antimicrobial agents that are effective against Gram-negative bacteria is hindered by the dual membrane cell wall structure of these bacteria. To reach their intracellular targets, most antibiotics must therefore pass through protein channels called porins; however, a common mechanism of acquired resistance is decreased expression of these proteins. Inspired by the ability of outer membrane vesicles (OMVs) to deliver cargo to the bacterial cytosol, we hypothesized that encapsulation of small molecule antibiotics within OMVs would improve the activity of the drugs by facilitating uptake. To test this, we investigated the ability of antibiotic- encapsulated OMVs to inhibit the growth of both Gram-negative and Gram-positive bacteria, including multidrug-resistant clinical isolates. We also demonstrated that this mechanism of delivery does not require porin expression. Together, our results demonstrate the potential of OMVs as novel antibiotic delivery vehicles to treat antibiotic-resistant bacterial infections.
C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis
Authors: Jiang Ruiji , Chouchane Malek , Moey Ching , Bunt Jens , Li Jiang , Alkuraya Fowzan , Alobeid Eman , Richards Linda , Ullian Erik , Sherr Elliott
Published: January 2025

Biallelic recurrent loss of function mutations inC12ORF57, a novel open reading frame, underlie Temtamy syndrome (TS)—a neurodevelopmental disorder characterized by dysgenesis of the corpus callosum, epilepsy, and severe intellectual disability. Investigate the function of this gene, we used a knockout (KO) mouse model of its murine ortholog,Grcc10.Grcc10KO mice exhibit the characteristic phenotypic features seen in human TS patients, including increased epileptiform activity. Corresponding with this seizure susceptibility, hippocampal neurons in these mice exhibited significantly increased AMPA receptor expression levels and higher amplitude of miniature excitatory postsynaptic currents (mEPSCs). We also find that GRCC10/C12ORF57 modulates the activity of calcium/calmodulin dependent kinase 4 (CAMK4) and regulates the expression of CREB and ARC, which are involved in the synaptic scaling of AMPA receptors. Through multiple lines of inquiry, we establish that C12ORF57/GRCC10 plays a central modulatory role in synaptic homeostasis and uncover a novel mechanism for neuronal excitatory tuning.
Replay builds an efficient cognitive map offline to avoid computation online
Authors: Ou Jianxin , Qu Yukun , Xu Yue , Xiao Zhibing , Behrens Tim , Liu Yunzhe
Published: January 2025

How do humans integrate fragmented experiences into a coherent structure for novel inferences? Although offline replay is proposed to reorganize memories, whether it constructs an integrated cognitive map remains unclear. Using magnetoencephalography, we tracked neural activity as participants learned one-dimensional, pairwise rank relationships that together formed a two-dimensional (2D) conceptual map, and then inferred unobserved relationships. Offline replay during rest integrated piecemeal memories into a 2D representation, predicting future inference accuracy. This offline replay and fast on-task replay during inference correlated with grid-cell-like code, representing a generalizable schema that minimized effortful online computations. In contrast, slow on-task replay focusing on trial-specific details, negatively correlated with grid-like codes and inference performance. Together, replay builds an efficient cognitive map offline, reducing reliance on deliberate computations online.
Social dysfunction relates to altered default mode network functional integrity across neuropsychiatric disorders: A replication and generalization study
Authors: Braak Simon , Mennes Maarten , Su Tanja , Pijnenburg Yolande , Bakker Geor , Arango Celso , van der Wee Nic , Bauduin Stéphanie , Moya Ana Ortiz-Tallo , Lopez-Morinigo Javier-David , Dawson Gerard R. , Abrahams Abigail B. , Beckenstrom Amy Christine , Beckmann Christian F. , Marston Hugh M. , Penninx Brenda W.J.H. , Kas Martien J. H.
Published: January 2025

Background

Social dysfunction is an early manifestation of neuropsychiatric disorders that may relate to altered Default Mode Network (DMN) integrity. This study aimed to replicate previous findings linking social dysfunction with diminished resting-state DMN functional connectivity and altered task-based DMN functional activation in response to emotional faces across schizophrenia (SZ), Alzheimer’s disease (AD), and healthy controls (HC), and to extend these findings to major depressive disorder (MDD).

Methods

Resting-state fMRI and task-based fMRI data on implicit facial emotional processing were acquired in an overlapping cohort (resting-state fMRI: N=167; SZ=32, MDD=44, AD=29, HC=62. Task-based fMRI: N=152; SZ=30, MDD=42, AD=26, HC=54). Additionally, mega-analyses (N=317 for resting-state fMRI; N=291 for task-based fMRI) of the current and a prior independent sample were conducted. Social dysfunction was indexed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness (LON) scale.

Results

The association between higher mean SFS+LON social dysfunction scores and diminished DMN connectivity within the dorsomedial prefrontal cortex across SZ/AD/HC participants was replicated, and extended to MDD patients. Similar observations within the dorsomedial and rostromedial prefrontal cortex were found in the mega-analysis. Associations between social dysfunction and DMN activation in response to sad and happy faces were not replicated or found in the mega-analysis.

Conclusions

Diminished dorsomedial prefrontal cortex DMN connectivity emerged as a transdiagnostic neurobiological marker for social dysfunction, suggesting a potential treatment target for precision medicine approaches. DMN functional responses to emotional faces may not be a sensitive biomarker for social dysfunction.
Generation and Characterization of a Knockout Mouse of an Enhancer ofEBF3
Authors: Hurtado Emily Cordova , Wotton Janine M. , Gulka Alexander , Burke Crystal , Ng Jeffrey K. , Bah Ibrahim , Manuel Juana , Heins Hillary , Murray Stephen A. , Gorkin David U. , White Jacqueline K. , Peterson Kevin A. , Turner Tychele N.
Published: January 2025

Genomic studies of autism and other neurodevelopmental disorders have identified several relevant protein-coding and noncoding variants. One gene with an excess of protein-codingde novovariants isEBF3that also is the gene underlying the Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS). In previous work, we have identified noncodingde novovariants in an enhancer ofEBF3called hs737 and further showed that there was an enrichment of deletions of this enhancer in individuals with neurodevelopmental disorders. In this present study, we generated a novel mouse line that deletes the highly conserved, orthologous mouse region of hs737 within the Rr169617 regulatory region, and characterized the molecular and phenotypic aspects of this mouse model. This line contains a 1,160 bp deletion within Rr169617 and through heterozygous crosses we found a deviation from Mendelian expectation (p = 0.02) with a significant depletion of the deletion allele (p = 5.8 × 10-4).Rr169617+/-mice had a reduction ofEbf3expression by 10% andRr169617-/-mice had a reduction ofEbf3expression by 20%. Differential expression analyses in E12.5 forebrain, midbrain, and hindbrain inRr169617+/+versusRr169617-/-mice identified dysregulated genes including histone genes(i.e.,Hist1h1e,Hist1h2bk,Hist1h3i,Hist1h2ao)and other brain development related genes (e.g.,Chd5,Ntng1).A prioriphenotyping analysis (open field, hole board and light/dark transition) identified sex-specific differences in behavioral traits when comparingRr169617-/-males versus females; whereby, males were observed to be less mobile, move slower, and spend more time in the dark. Furthermore, both sexes when homozygous for the enhancer deletion displayed body composition differences when compared to wild-type mice. Overall, we show that deletion within Rr169617 reduces the expression ofEbf3and results in phenotypic outcomes consistent with potential sex specific behavioral differences. This enhancer deletion line provides a valuable resource for others interested in noncoding regions in neurodevelopmental disorders and/or those interested in the gene regulatory network downstream ofEbf3.
Genomic and metagenomic survey of microbial carbonic anhydrase genes reveals novel clades, high diversity, and biome-specificity
Authors: Franco Mario E.E. , Singer Esther , Roux Simon , Meredith Laura K. , U’Ren Jana M.
Published: January 2025

Carbonic anhydrase (CA) enzymes catalyze the interconversion of carbon dioxide and bicarbonate with an efficiency exceeded only by superoxide dismutase. CA enzymes have convergently evolved multiple times from phylogenetically distant organisms into structurally unrelated classes (α, β, γ,δ,ζ,η, θ, ι) with conserved physiological functions involved in photosynthesis, respiration, pH homeostasis, CO2transport, and carbonyl sulfide hydrolysis that play central roles in medicine and the environment. Here, we leverage the recent surge in publicly available genomes and metagenomes to re-examine our understanding of the abundance, diversity, and phylogenetic relationships of the three major CA classes in Bacteria/Archaea and microbial Eukaryotes (Fungi, algae). We recovered a total of 57,218 α-, β-, and γ-CA sequences from 24,184 metagenomes and genomes, including the first detection of α-CA from an Archaeal species. CA sequences formed 3,859 protein clusters (1,188 with ≥ 3 sequences) that were taxonomically conserved at higher levels (i.e., Superkingdom, Phylum, Class). When viewed within a phylogenetic framework, the majority of subclades contained CAs representing multiple Superkingdoms, although numerous novel β-CA clades appear unique to Fungi. Queries of CA Hidden Markov models (HMMs) against all public meta-genome and -transcriptome datasets revealed that CA is a ubiquitous enzyme present in virtually all sampled environments. However, CA clusters that were taxonomically conserved also appeared environment-specific, generating high CA diversity. This work represents an important contribution to the evolution, diversity, and environmental distribution of an enzyme that is key for life and has broad environmental and industrial applications.
Plasma-driven biocatalysis using the cytochrome P450 enzyme CYP152BSβ
Authors: Dirks Tim , Klopsch Sabrina , Stoesser Davina , Trenkle Sophie Desdemona , Yayci Abdulkadir , Schüttler Steffen , Golda Judith , Bandow Julia Elisabeth
Published: January 2025

Plasma-driven biocatalysis utilizesin situH2O2production by atmospheric pressure plasmas to drive H2O2-dependent enzymatic reactions. Having previously established plasma-driven biocatalysis using recombinant unspecific peroxygenase fromAgrocybe aegerita(rAaeUPO) to produce (R)-1-phenylethanol from ethylbenzene (ETBE), we here employed CYP152 fromBacillus subtilis(CYP152BSβ). CYP152BSβnaturally hydroxylates medium and long-chain carboxylic acids, and, with short-chain carboxylic acids as decoy molecules, also converts non-natural substrates such as ETBE. To produce active CYP152BSβoverexpression and heme loading were optimized. The conversion of the non-natural substrates guaiacol and ABTS with heptanoic acid as decoy molecule and H2O2from stock solution yielded 18.28 and 21.13 nmol product min-1, respectively. These reactions also served to assess compatibility of CYP152BSβwith plasma-driven biocatalysis regarding temperature and H2O2operating windows. To establish CYP152BSβ-based plasma-driven biocatalysis, immobilized enzyme in a rotating bed reactor (5 ml reaction volume) was then supplied with H2O2from a capillary plasma jet operated with 1280 ppm H2O in helium. After a 120 min run time a turnover number (TON) of 18.82 mol(R)-1-PhOlwas reached. We conclude that plasma-driven biocatalysis can be extended to other H2O2-dependent enzymes. Future efforts will be directed at increasing the TON and product range.
Temporal Dynamics of Transcriptional Responses to Repeated mRNA Vaccination: Insights from Third Dose Profiling
Authors: Rinchai Darawan , Deola Sara , Ahamed Kabeer Basirudeen Syed , Gentilcore Giusy , Toufiq Mohammed , Mathew Lisa , Liu Li , Vempalli Fazulur Rehaman , Mubarak Ghada , Lorenz Stephan , Augustine Tracy , Panhuys Nicholas Van , Bedognetti Davide , Grivel Jean-Charles , Chaussabel Damien
Published: January 2025

mRNA vaccines have played a crucial role in combating the COVID-19 pandemic, but the long-term dynamics of immune responses to repeated vaccination remain poorly understood. In this study, we extend our previous work on first and second dose responses by characterizing the immune signatures elicited by a third dose of COVID-19 mRNA vaccines using high-resolution temporal profiling of blood transcriptomes collected daily for 9 days post-vaccination. We observed distinct patterns of gene expression related to interferon responses, inflammation, erythroid cell signatures, and plasmablast activity across the three doses. While the first dose elicited a modest response primarily characterized by interferon signaling, the second dose induced a robust, polyfunctional response. The third dose, administered approximately nine months later, maintained this polyfunctional character and matched the second dose in magnitude, though with distinct temporal dynamics. The interferon component peaked on day 2 (similar to the first dose) rather than day 1 (as seen in the second dose), while the erythroid signature showed a markedly different trajectory, with sustained elevation rather than decrease over the following week. Notably, we observed a progressive amplification of the plasmablast response across the three doses, with an earlier peak (day 4) compared to other vaccines, potentially a unique feature of mRNA vaccines. These findings demonstrate that the heightened, polyfunctional responsiveness induced by the second dose is robustly maintained even after a prolonged interval, suggesting effective immune memory. Our results contribute to understanding mRNA vaccine-induced immunity, with implications for optimizing booster strategies and developing next-generation vaccines.
The N-terminal order-disorder transition is a critical determinant for a metamorphosis of IscU
Authors: Na Jongbum , Heo Joongyu , Jeong Minchan , Ji Sangho , Ko Young Ho , Shafiei Alaleh , Baldir Nilufer , DeMirci Hasan , Yu Wookyung , Kim Jin Hae
Published: January 2025

IscU, a key scaffold protein mediating the biogenesis of iron-sulfur (Fe-S) clusters, exhibits metamorphic characteristics crucial for its versatile and efficient function. Previous studies have demonstrated that IscU has two interconverting conformations: the structured state (S-state) and the disordered state (D-state), each contributing to its distinct functionality and interaction network. Despite its physiological importance, the precise mechanism underpinning the maintenance of IscU’s unique structural heterogeneity has remained elusive. In this study, we used computational and experimental approaches to reveal that the N-terminal order-disorder plays a critical role in the metamorphic modulation of IscU. We found that the N-terminal region displays greater structural plasticity, which is linked to other regions of IscU through coevolutionary relationships. Moreover, we demonstrated that the degree of orderliness in the N-terminal region correlates positively with the stabilization of IscU’s S-state and negatively with its affinity for HscA. This indicates that the flexibility in the N-terminal region is finely tuned to optimize IscU’s physiological efficiency and efficacy. Finally, our data suggest that a peptide mimicking the N-terminal motif can modulate IscU’s metamorphic properties, suggesting a novel therapeutic potential for related pathogenic processes.