bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B
Authors: Touvier Thierry , Veneri Francesca A , Claessens Anke , Ferri Cinzia , Mastrangelo Rosa , Sorgiati Noémie , Bianchi Francesca , Valenzano Serena , Del Carro Ubaldo , Rivellini Cristina , Duong Phu , Shy Michael E , Kelly Jeffery W , Svaren John , Wiseman R Luke , D’Antonio Maurizio
Published: February 2025

Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood.

Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants.

Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.
Proprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy
Authors: Simon Christian M , Delestrée Nicolas , Montes Jacqueline , Sowoidnich Leonie , Gerstner Florian , Carranza Erick , Buettner Jannik M , Pagiazitis John G , Prat-Ortega Genis , Ensel Scott , Donadio Serena , Dreilich Vanessa , Carlini Maria J , Garcia Jose L , Kratimenos Panagiotis , Chung Wendy K , Sumner Charlotte J , Weimer Louis H , Pirondini Elvira , Capogrosso Marco , Pellizzoni Livio , De Vivo Darryl C , Mentis George Z
Published: February 2025

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes.

Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that Type 3 SMA patients exhibit impaired proprioception, and their proprioceptive synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show moderate loss of spinal motor neurons along with reduced excitatory afferent synapses and altered potassium channel expression in motor neurons from Type 1 SMA patients. These are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory Type 3 SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay.

Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.
A non-tender swelling involving the face and chest region of a young child
Authors: Bano Nazneen , Budania Anil , Kumar Shubham , Saha Sukarna , Kaur Navneet , Kumar Deepak , Aggarwal Divya , Jain Vidhi
Published: February 2025

An 18-month-old boy presented with insidious onset gradually progressive erythematous nodulo-plaque over the chin and chest for nine months. He was born to healthy parents with no similar complaints in the family. Gradually developed ulcers and disfigurement over the face.With the help of histopathology and culture diagnosis was made. Despite extensive involvement had good response to oral therapy.
Integrating AI-powered text mining from PubTator into the manual curation workflow at the Comparative Toxicogenomics Database
Authors: Wiegers Thomas C , Davis Allan Peter , Wiegers Jolene , Sciaky Daniela , Barkalow Fern , Wyatt Brent , Strong Melissa , McMorran Roy , Abrar Sakib , Mattingly Carolyn J
Published: February 2025

The Comparative Toxicogenomics Database (CTD) is a manually curated knowledge- and discovery-base that seeks to advance understanding about the relationship between environmental exposures and human health. CTD’s manual curation process extracts from the biomedical literature molecular relationships between chemicals/drugs, genes/proteins, phenotypes, diseases, anatomical terms, and species. These relationships are organized in a highly systematic way in order to make them not only informative but also scientifically computational, enabling inferential hypotheses to be formed to address gaps in understanding. Integral to CTD’s functionality is the use of structured, hierarchical ontologies and controlled vocabularies to describe these molecular relationships. Normalizing text (i.e. translating raw text from the literature into these controlled vocabularies) can be a time-consuming process for biocurators. To facilitate the normalization process and improve the efficiency with which our scientists curate the literature, CTD evaluated and integrated into the curation process PubTator 3.0, a state-of-the-art, AI-powered resource which extracts and normalizes from the literature many of the key biomedical concepts CTD curates. Here, we describe CTD’s long-standing history with Natural Language Processing (NLP), how this history helped form our objectives for NLP integration, the evaluation of PubTator against our objectives, and the integration of PubTator into CTD’s curation workflow.

Database URL: https://ctdbase.org
The Power of The Pill: Evidence from Oral Contraceptive Sales
Authors: Ragan Kelly Suzanne
Published: February 2025

The introduction of oral contraception (’the pill’) was a watershed in fertility control. Yet, the pill’s impact on childbearing has been hard to establish due to limited data. I exploit rich data on pill sales across markets and time to characterize how Swedish teens’ access to pharmacies shaped pill sales and fertility after the pill’s introduction. Pill sales are highly sensitive to pharmacy access, and teen fertility responds strongly to pill sales. The unique data establish an important link in the causal chain from pill access to women’s fertility. Estimated fertility responses to the pill could explain the halving of teen births after the pill’s introduction, a finding which is robust to accounting for trends in female education, abortion provision, and other factors.
Effect of previous cardiac surgery on the outcomes of acute type A aortic dissection repair: a nationwide cohort study
Authors: Lin Chun-Yu , Chen Wei-Min , Chang Shu-Hao , Yu Sheng-Yueh , See Lai-Chu
Published: February 2025

OBJECTIVES

The effect of previous cardiac surgery (PCS) on the outcomes of acute type A aortic dissection (ATAAD) repair remains controversial. This study compared the primary outcome (in-hospital mortality) and secondary outcomes (postoperative complications and post-discharge mortality/aortic reoperation rates up to 5 years) of patients who underwent ATAAD repair with and without PCS through a nationwide cohort analysis.

METHODS

We used Taiwan’s National Health Insurance Research Database to enroll patients who underwent ATAAD repair with and without PCS (94 and 4532, respectively) between 2004–07-01 and 2017–03-31. A 1:4 propensity score matching (PSM) was used to create well-balanced PCS (n = 74) and non-PCS (n = 296) groups. Results before and after PSM were aligned to determine the role of PCS in primary and secondary outcomes.

RESULTS

Before PSM, the PCS group was older and had more comorbidities, including diabetes mellitus, heart failure, atrial fibrillation, and malignancy, but less stroke history than the non-PCS group. More patients in the PCS group received coronary artery bypass grafting during the repair than in the non-PCS group. The PCS group had a higher in-hospital mortality than the non-PCS group. After PSM, the in-hospital mortality was similar between the two groups (27.0% versus 26.7%; P = 0.953). For patients who survived to discharge, the all-cause mortality up to 5 years for PCS and non-PCS groups were 29.7% and 18.4% (P = 0.015) before and 29.6% and 23.1% (P = 0.313) after PSM, respectively. The two groups had similar aortic reoperation rates up to 5 years before (13.5% versus 11.7%; P = 0.727) and after PSM (13.8% versus 11.6%; P = 0.776).

CONCLUSIONS

Patients with PCS who underwent ATAAD repair showed higher in-hospital and long-term mortality rates than those without PCS when not controlled for confounding factors. However, the disparity disappeared after PSM, indicating that worse outcomes might be due to its old age and different perioperative characteristics.
The difficulties of disarmament during the French Wars of Religion: the role of Antoine, comte de Crussol
Authors: Nicoll David
Published: February 2025

Reconciliation following conflict is difficult, and the peace edicts that ended the civil wars in sixteenth-century France took time to be enforced. Disarmament following civil war was a lengthy process. This article provides an original insight into the drawn-out disarmament processes following the First War of Religion (1562–63), through the figure of Antoine, comte de Crussol (later duc d’Uzès). The article outlines Crussol’s important role in disarmament across the regions of Languedoc, Dauphiné and Comtat-Venaissin. It argues that Crussol played a critical yet paradoxical part in disarmament, illustrating the ways in which he both delayed and enforced the peace, while emphasizing his loyalty to the crown throughout. This study also demonstrates the crown’s critical role in bringing peace, the capacity of the provincial nobles for peacemaking and the difficult position nobles who had fought against the crown found themselves in at the end of the war.
Predicting Fitness-Related Traits Using Gene Expression and Machine Learning
Authors: Henry Georgia A , Stinchcombe John R
Published: February 2025

Evolution by natural selection occurs at its most basic through the change in frequencies of alleles; connecting those genomic targets to phenotypic selection is an important goal for evolutionary biology in the genomics era. The relative abundance of gene products expressed in a tissue can be considered a phenotype intermediate to the genes and genomic regulatory elements themselves and more traditionally measured macroscopic phenotypic traits such as flowering time, size, or growth. The high dimensionality, low sample size nature of transcriptomic sequence data is a double-edged sword, however, as it provides abundant information but makes traditional statistics difficult. Machine learning (ML) has many features which handle high-dimensional data well and is thus useful in genetic sequence applications. Here, we examined the association of fitness components with gene expression data in Ipomoea hederacea (Ivyleaf morning glory) grown under field conditions. We combine the results of two different ML approaches and find evidence that expression of photosynthesis-related genes is likely under selection. We also find that genes related to stress and light responses were overall important in predicting fitness. With this study, we demonstrate the utility of ML models for smaller samples and their potential application for understanding natural selection.
Randomized experimental test of a reduced-exposure message for an e-cigarette: comprehension and related misperceptions
Authors: McCaffrey Stacey , Shiffman Saul , Sembower Mark A , Black Ryan A
Published: February 2025

Completely switching from cigarette smoking to electronic nicotine delivery systems (ENDS) reduces exposure to toxic substances. Yet, many smokers believe that ENDS are at least as harmful as smoking, making them less likely to switch from cigarettes to ENDS. Effectively communicating reduced-exposure information is critical, but such messages must be properly understood. This online study evaluated comprehension of a factual message, indicating that smokers who switch completely away from smoking to JUUL-brand ENDS can reduce their exposure to harmful chemicals in cigarette smoke. Participants were 12 557 adults 18+ years (smokers, dual users and former and never users of tobacco) randomized to see the reduced-exposure message or to a Control condition. After exposure to the message, the majority of smokers (89%) understood the need to switch completely from cigarettes to JUUL to achieve reduced exposure. Most smokers and nonusers (>75%) did not misperceive JUUL as completely eliminating exposure to harmful chemicals, and >85% understood that using JUUL has risk. Exposure to the message improved understanding of the intended audience for JUUL. Individuals with limited health literacy showed modestly lower comprehension, regardless of condition. Ensuring adequate comprehension of messages about reduced exposure from ENDS is important to ensuring that such messaging can benefit public health.
Erythrocyte Methotrexate–Polyglutamate Concentrations in Pediatric Inflammatory Bowel Disease
Authors: Vermeer Eva , Struys Eduard A , Lin Marry , van Limbergen Johan E , de Boer Nanne K H , Bulatović-Ćalasan Maja , de Meij Tim G J , de Jonge Robert
Published: February 2025

Background and Aims

Therapeutic drug monitoring (TDM) of methotrexate (MTX) is challenging due to its pharmacokinetics and short plasma half-life. Intracellular MTX–polyglutamates (PG1–5), which accumulate over time, have not been assessed in pediatric inflammatory bowel disease (IBD). This study aimed to evaluate erythrocyte MTX-PG as a potential TDM tool in pediatric IBD.

Methods

In this cross-sectional study, MTX-PG concentrations were measured in erythrocytes of children with IBD on stable low-dose MTX for at least 12 weeks using stable-isotope dilution liquid chromatography–tandem mass spectrometry. The influence of administration route, MTX dosage, and anthropometrics on MTX-PG concentrations was examined.

Results

Seventy-eight patients were included, showing MTX-PG3 as the predominant subspecies (median 27.0 nmol/L) with a median MTX-PGtotal of 74.8 nmol/L. A higher MTX dose correlated significantly with elevated levels of MTX-PG3, MTX-PG4, MTX-PG5, and MTX-PGtotal (P < .01). Adjusted for body surface area, MTX dose remained significantly associated with higher MTX-PG concentrations (P < .01). However, comparison by administration route was limited due to a few patients on subcutaneous MTX (n = 4).

Conclusions

We observed high interindividual variability in the reached erythrocyte MTX-PG concentrations. Body surface adjusted or unadjusted MTX dosage showed a positive linear correlation with erythrocyte MTX-PG concentrations in children with IBD. This is a prerequisite for TDM and provides a strong basis for further research into the relation between TDM of MTX, efficacy, and toxicity.
Research on the generation of localized overheating samples and fault prediction models of transformers and based on brain-inspired spiking neural networks
Authors: Zhang Guoliang , Zhang Peng , Zhou Fei , Du Zexu , Chen Jiangqi , Zhang Zhisong , Kong Qingyu
Published: February 2025

The prediction of transformer failures holds significant importance for maintaining the stability of power systems. This paper investigates the application of a brain-inspired spiking neural network model for fault prediction of transformers. The research is grounded in dissolved gas analysis, employing fuzzy reasoning spiking neural P systems to process fuzzy diagnostic knowledge. It constructs a set of sample data associated with localized overheating and utilizes linguistic variables, membership functions, and an inference rule base to conduct fault analysis. The results indicate that this approach significantly enhances the fault identification and predictive capabilities of transformers.
Xylo-oligosaccharides enhance intestinal and thymic immunity by modulating pyroptosis, gut microbiota and Th17/Treg immune response in LPS-challenged piglets
Authors: Sun Weixiao , Liu Guangmang , Shen Fei , Wu De , Lin Yan , Zhang Ruinan , Che Lianqiang , Feng Bin , Zhuo Yong , Xu Shengyu , Hua Lun , Fang Zhengfeng , Jiang Xuemei , Li Jan , Wang Jing
Published: February 2025

Xylo-oligosaccharides (XOS) have been shown to improve the immune system of weaned piglets, but the molecular mechanism of their action remains unclear. Therefore, this study aimed to investigate the impact of XOS on intestinal and thymic immune function in weaned piglets challenged with lipopolysaccharide (LPS) and elucidate the underlying mechanism. In a 2 × 2 factorial arrangement, consisting of diet treatment (basal diet vs 0.02% XOS diet) and immunological challenge [saline vs LPS], 24 piglets were randomly divided into four groups (n = 6): CON group, basal diet + saline; LPS group, basal diet + LPS; XOS group, 0.02% XOS diet + saline; XOS_LPS group, 0.02% XOS diet + LPS. Piglets were fed either the basal or XOS diet for 21 days, followed by intraperitoneal injections of normal saline or LPS on the 22nd day. Ileum, thymus and colon samples were collected 4 hours after the intraperitoneal saline or LPS injection. The piglets fed XOS diet had higher average daily feed intake and average daily weight gain (P < 0.05). The XOS diet increased ileal villus height and decreased crypt depth. XOS also enhanced ileal and thymic antioxidant enzyme activities, anti-inflammatory cytokine expression, and decreased malondialdehyde levels and mRNA abundance of proinflammatory cytokines in piglets (P < 0.05). The XOS diet also downregulated ileal and thymic NOD-like receptor family pyrin domain containing 3 and gasdermin-D gene and protein expression associated with pyroptosis (P < 0.05). Moreover, The XOS diet increased the mRNA abundance of forkhead box P3, signal transducer and activator of transcription 5, and transforming growth factor beta 1 while decreasing signal transducer and activator of transcription 3 and retinoid-related orphan receptor-gammat mRNA abundance (P < 0.05). The XOS diet enhanced forkhead box P3 protein expression and reduced retinoid-related orphan receptor-gammat protein expression following the LPS challenge (P < 0.05). At the same time, The XOS diet affected the gut microbiota and increased levels of short-chain fatty acids (P < 0.05). In conclusion, XOS may modulate ileal and thymic immune function in weaned piglets following a 4-hour LPS challenge by affecting gut microbiota, pyroptosis and Th17/Treg immune responses.
Perceptions of and Opportunities for AMTA Journals: A Mixed Methods Study
Authors: Beer Laura E , Muralidharan Ananya , Montgomery Jaley A , Quiller Leah , Else Barbara A , LaGasse Blythe
Published: February 2025

The Journal of Music Therapy and Music Therapy Perspectives are journals sponsored by the American Music Therapy Association (AMTA). In recent years, the journal leadership teams have been focused on issues of inclusion, access, equity, and social justice, as they relate to the journals. This focus aligned with AMTA’s reorganization process that began in the early 2020s, where principles of social justice were centered as part of the association’s statements related to organizational change. The purpose of this mixed methods study was to gather data related to readers’ use and perceptions of the journals, including perceptions regarding the integration of diversity and social justice. Board-certified music therapists (N = 409) met inclusion criteria and completed an online survey; these data were used to inform focus group questions. We then conducted five focus groups (N = 16 participants) to gather more personal and in-depth responses. Survey data indicated varying opinions related to the use of the journals and inclusion of social justice principles, whereas the focus groups were more unified in their assessment that more work is needed in this area. Participants in the focus groups brought forward issues related to inclusion and access. The readership indicated that the journals currently incorporate some aspects of these principles; however, many readers would like to see more intentional integration of these principles across the journals. Focus group members also provided a variety of action steps for consideration as the journals move forward.
From Fisher to CARA: the evolution of randomization and randomization-based inference
Authors: Rosenberger William Fisher
Published: February 2025

R. A. Fisher was a devoted Darwinian, and, like Darwin, created science out of nothing. The list is long, but one thinks of likelihood-based estimation, analysis of variance, principles of experimental design, and randomization as standing the tests of time. Such accomplishments ‘from scratch’ (or nearly so) can amaze the fine statisticians who made meaningful incremental contributions to work begun by others, the few ‘greats’ among us who invented something important, and the unusually perceptive introductory statistics student, alike. Fisher thought of randomization in the context of agricultural experiments, but it has impacted most profoundly the science of medicine. Bradford Hill brought randomization to clinical trials. The concept of randomization-based inference, now resurrected in causal inference, was largely forgotten as design and analysis became segregated, perhaps due to analysis software packages. This talk will attempt to give the historical context of randomization and randomization-based inference from Fisher to the present day, including newer concepts such as response-adaptive, covariate-adaptive, and covariate-adjusted response-adaptive randomization. It will be challenging to condense a year of material into one hour, but a devoted Fisherian should be able to be efficient and sufficient.
Signatures of black hole seeding in the local Universe: Predictions from the BRAHMA cosmological simulations
Authors: Bhowmick Aklant K , Blecha Laura , Torrey Paul , Somerville Rachel S , Kelley Luke Zoltan , Weinberger Rainer , Vogelsberger Mark , Hernquist Lars , Natarajan Priyamvada , Kho Jonathan , Matteo Tiziana Di
Published: February 2025

The origin of the “seeds” of supermassive black holes (BHs) continues to be a puzzle, as it is currently unclear if the imprints of early seed formation could survive to today. We examine the signatures of seeding in the local Universe using five [18 Mpc]3  BRAHMA simulation boxes run to z = 0. They initialize 1.5 × 105 M⊙ BHs using different seeding models. The first four boxes initialize BHs as heavy seeds using criteria that depend on dense & metal-poor gas, Lyman-Werner radiation, gas spin, and environmental richness. The fifth box initializes BHs as descendants of lower mass seeds (∼103 M⊙) using a new stochastic seed model built in our previous work. In our simulations, we find that the abundances and properties of ∼105 − 106 M⊙ local BHs hosted in M* ≲ 109 M⊙ dwarf galaxies, are sensitive to the assumed seeding criteria. This is for two reasons: 1) there is a substantial population of local ∼105 M⊙ BHs that are ungrown relics of early seeds from z ∼ 5 − 10; 2) BH growth up to ∼106 M⊙ is dominated by mergers in our simulations all the way down to z ∼ 0. As the contribution from gas accretion increases, the signatures of seeding start to weaken in more massive ≳ 106 M⊙ BHs, and they are erased for ≳ 107 M⊙ BHs. The different seed models explored here predict abundances of local ∼106 M⊙ BHs ranging from ∼0.01 − 0.05 Mpc−3 with occupation fractions of $\sim 20-100~{{\%}}$ for M* ∼ 109 M⊙ galaxies. These results highlight the potential for placing constraints on seeding models using local ∼105 − 106 M⊙ BHs hosted in dwarf galaxies. Since merger dynamics and accretion physics impact the persistence of seeding signatures, and both high and low mass seed models can produce similar local BH populations, disentangling their roles will require combining high and low redshift constraints.
2D watershed void clustering for probing the cosmic large-scale structure
Authors: Song Yingxiao , Gong Yan , Xiong Qi , Chan Kwan Chuen , Chen Xuelei , Guo Qi , Liu Yun , Pei Wenxiang
Published: February 2025

Cosmic void has been proven to be an effective cosmological probe of the large-scale structure (LSS). However, since voids are usually identified in spectroscopic galaxy surveys, they are generally limited to low number density and redshift. We propose to utilize the clustering of two-dimensional (2D) voids identified using Voronoi tessellation and watershed algorithm without any shape assumption to explore the LSS. We generate mock galaxy and void catalogs for the next-generation Stage IV photometric surveys in z = 0.8 − 2.0 from simulations, develop the 2D void identification method, and construct the theoretical model to fit the 2D watershed void and galaxy angular power spectra. We find that our method can accurately extract the cosmological information, and the constraint accuracies of some cosmological parameters from the 2D watershed void clustering are even comparable to the galaxy angular clustering case, which can be further improved by as large as ∼30% in the void and galaxy joint constraints. This indicates that the 2D void clustering is a good complement to galaxy angular clustering measurements, especially for the forthcoming Stage IV surveys that detect high-redshift universe.
Signatures of the Shock Interaction as an Additional Power Source in the Nebular Spectra of SN 2023ixf
Authors: Kumar Amit , Dastidar Raya , Maund Justyn R , Singleton Adam J , Sun Ning-Chen
Published: February 2025

Red supergiants may lose significant mass during the final 100–1000 years before core collapse, shaping their circumstellar environment. The supernova (SN) shockwave propagating through this environment forms a shock-swept dense shell that interacts with the surrounding circumstellar material (CSM), generating secondary shocks that energise the ejecta and may power the SN during the nebular phase. In the present work, we investigate the nebular spectrum of SN 2023ixf, observed one-year post-explosion (at +363 d) with the recently commissioned WEAVE instrument on the 4.2m William Herschel Telescope. This marks the first supernova spectrum captured with WEAVE. In this spectrum, H α exhibits a peculiar evolution, flanked by blueward and redward broad components centred at ∼±5650 km s−1, features that have been observed in only a few SNe as early as one-year post-explosion. These features may indicate energy deposition from shock generated by the interaction of shock-swept dense shell with CSM expelled a few hundred years prior to the explosion. Comparisons of the +363 d spectrum with model spectra from the literature suggest a shock power of at least ∼5 × 1040 erg s−1 at this epoch. Additionally, analysis of the [O i] doublet and other emission lines helped to constrain the oxygen mass (≲ 0.07 − 0.30M⊙), He-core mass (≲ 3M⊙), and zero-age main sequence mass (≲ 12M⊙) for SN 2023ixf. The comparison with other Type II SNe highlights SN 2023ixf’s unique shock interaction signatures and evidence of dust formation, setting it apart in terms of evolution and dynamics.
Genetics of Recurrent Miscarriage and Pregnancy Loss in Women’s Reproductive Health
Authors: Mirakbarova Zebinisa , Pascat Vincent , Akramkhanova Surayyo , Chu Chia-Yi , Yusupov Ulugbek , Scapoli Chiara , Rakhmatullaev Abdushukur , Kapralova Yuliya , Nishanova Sevara , Nazirova Mehribon , Atamurotova Gulsanam , Rudometkin Konstantin , Sodiqova Maftuna , Karimova Lutfiya , Esonova Gulnoza , Meylikov Hurshid , Rejapova Marguba , Nishanova Feruza , Abdurakhimov Abrorjon , Prokopenko Inga , Dalimova Dilbar , Turdikulova Shahlo , Sharhorodska Yevheniya , Abdullaev Alisher
Published: February 2025

Adverse pregnancy outcomes, such as sporadic and recurrent miscarriages and stillbirths, are significant medical concerns, impacting up to 15% of clinically recognised pregnancies. These outcomes are highly complex and multifactorial, with up to 50% of cases classified as idiopathic, highlighting a substantial gap in our understanding of their biological basis. Along with external risk factors, polygenic variability contributes to idiopathic pregnancy loss, suggesting that large-scale genetic studies could offer insights into its mechanisms, reveal novel drug targets, and lead to new treatments. This study assesses current knowledge from genome-wide association studies (GWAS) using genotyping arrays, whole-genome imputation, and sequencing for variant discovery, emphasising genetic predisposition to adverse pregnancy outcomes. We summarise existing efforts identifying 30 genetic loci associated with pregnancy loss and related endophenotypes, integrating them into a polygenic score (PGS) and conducting a phenome-wide PGS association analysis of 280 ICD-10 outcomes in nearly 500,000 UK Biobank participants. We report associations between pregnancy loss PGS and an increased risk for diaphragmatic hernia (OR[95%CI]=1.02[1.01–1.03], P=9.15×10⁻⁷), eosinophilic esophagitis (OR[95%CI]=1.05[1.03–1.06], P=1.44×10⁻⁶), and asthma with exacerbation (OR[95%CI]=1.02[1.01–1.03], P=1.71×10⁻⁵), significant after correction for multiple testing and suggesting new mechanistic pathophysiology in pregnancy loss susceptibility. Additionally, Mendelian Randomisation (MR) studies identified higher BMI and smoking as risk factors for pregnancy loss, while the roles of caffeine and alcohol intake, maternal age, and family history of miscarriage warrant further investigation through adequately powered MR analyses. Well-designed and comprehensive GWAS studies, particularly across diverse ancestry groups, are urgently needed for idiopathic recurrent pregnancy loss. Such studies should overcome issues with identification of women suffering for this condition and related pregnancy losses to support better care and timely interventions, aiming for healthy live birth outcomes.
Synthesis and Biological Evaluation of Nipecotic Acid Derivatives with Terminally Double-Substituted Allenic Spacers as mGAT4 Inhibitors
Authors: Jung Maren , Höfner Georg , Sałat Kinga , Furgała-Wojas Anna , Wanner Klaus T.
Published: February 2025

A series of nipecotic acid derivatives, featuring a four- and five-carbon atom allenic spacer connecting the nitrogen of the polar nipecotic acid head with up to two aromatic residues, has been synthesized. For the synthesis of the respective nipecotic acid derivatives displayingN-substituents consisting of carbon chains with a terminal allenic function with two, mostly aryl residues a CuI-catalyzed cross-coupling of diaryldiazomethanes orN-tosylhydrazones with nipecotic acid derived terminal alkynes served as a key step. Upon characterization of these compounds regarding their inhibitory potency at mGAT1-4 and binding affinity for mGAT1, a highly potent mGAT4 inhibitor has been identified, which is defined as nipecotic acid derivative with a four-carbon atom allenic spacer terminally carrying two 4-chlorophenyl residues. The (S)-enantiomer of this compound, (S)-1-[4,4-bis(4-chlorophenyl)buta-2,3-dien-1-yl]piperidine-3-carboxylic acid [(S)-8d, DDPM-3960], displays potencies in the higher nanomolar range at mGAT4 and its human equivalent hGAT-3 with pIC50values of 6.59 ± 0.01 and 6.49 ± 0.10, respectively, which are significantly higher than that of the well-known mGAT4 inhibitor (S)-SNAP-5114.In vivoevaluation of this compound revealed its significant anticonvulsant activity in several mouse models of chemically- and electrically-induced seizures. In addition to this, anxiolytic-like properties of DDPM-3960 were shown. These beneficial biological effects observed in mice were not accompanied by any serious motor deficits, making DDPM-3960 an interesting lead structure for further development.
Loss of plasma membrane conductance in outside-xylem zone explains non-stomatal control of transpiration
Authors: Jain Piyush , Sen Sabyasachi , Rockwell Fulton E. , Twohey Robert J. , Huber Annika E. , Desai Sahil A. , Wu I-Feng , De Swaef Tom , Ilman Mehmet M. , Studer Anthony J. , Holbrook N. Michele , Stroock Abraham D.
Published: February 2025

The conventional assumption is that stomatal conductance (gs) dominates the regulation of water and carbon dioxide fluxes between leaves and the atmosphere. Here, a nanoreporter of water status at the mesophyll cell surface and local xylem within intact maize leaves documents significant undersaturation of water vapor in the outside-xylem zone (OXZ) and a large loss of conductance of this zone (goxz) at moderate xylem water stress (no turgor loss). The ratio of the resistances (1/goxz)/(1/gs) serves as a predictive phenotype of undersaturation, non-stomatal regulation of transpiration, errors in standard gas exchange analysis, and an increase of intrinsic water use efficiency (iWUE). Cell-scale access to water status reveals symplasmic-apoplasmic disequilibrium and informs a biophysical model that can explain experimental observations quantitatively based on localization of variable conductance to the plasma membrane. This work opens new paths of inquiry into the molecular basis and functional consequences of non-stomatal regulation of transpiration.
Lipid peroxidation and colorectal cancer risk: a time-varying relationship
Authors: Yang Gong , Milne Ginger L. , Nogueira Marina S. , Yi Haoyang , Lan Qing , Gao Yu-Tang , Shu Xiao-Ou , Zheng Wei , Chen Qingxia
Published: February 2025

Importance

We recently observed an inverse and time-dependent association between systemic oxidative stress (OxS), measured by urinary biomarkers of nucleic acid oxidation, and colorectal cancer (CRC) risk. Further investigations into other types of OxS markers are warranted.

Objective

To extend the investigation into systemic lipid peroxidation and CRC risk.

Design, Setting, and Participants

Utilizing a nested case-control design, this study’s primary analysis was performed in two large prospective cohorts in Shanghai, China, and replicated in an independent cohort in the US.

Exposures

Systemic lipid peroxidation was assessed by urinary F2-isoprostanes (F2-IsoPs) using UPLC-MS/MS assays.

Main Outcomes and Measures

During 15.1-year follow-up in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each through incidence-density sampling. In the US cohort, 285 incident CRC cases were included, each matched to two controls. Odds ratios (ORs) for CRC were calculated using multivariable conditional logistic regression models.

Results

Elevated levels of urinary 5-F2t-IsoP (5-iPF2α-VI), a major isomer of F2-IsoPs induced solely by free radicals, were associated with reduced risk of CRC in the Shanghai cohorts. This finding was replicated in the US cohort. Moreover, this inverse association was time-dependent, manifesting only in the later years of cancer development. Multivariable-adjusted ORs (95% CI) for CRC diagnosed within 5 years of enrollment at the 10th and 90th percentiles of 5-F2t-IsoP levels, relative to the median, were 1.57 (1.26-1.96) and 0.61 (0.42-0.89), respectively, indicating a 2.2-fold difference in risk between the two groups. A stronger association was observed when using the composite index of DNA, RNA and lipid OxS markers, showing a 3.9-fold difference in risk between the two groups. No significant association was found for CRC diagnosed beyond 5 years of enrollment.

Conclusions

This study provides new evidence that systemic OxS is inversely and time-dependently associated with CRC risk in humans.

Key Points

Question

Is the time-dependent relationship between oxidative stress and tumorigenesis observed at the cellular level in experimental models also present at the systemic level in a population-based setting?

Findings

Elevated systemic lipid peroxidation, measured by urinary F2-isoprostanes, was associated with a reduced risk of colorectal cancer (CRC) in two large prospective cohort studies in Shanghai, China, which was replicated in an independent cohort in the United States. This association varied over time, showing a stronger effect as cancer advanced.

Meaning

This study provides new evidence that systemic oxidative stress is inversely and time-dependently associated with CRC risk in humans.
Emergent Tissue Shapes from the Regulatory Feedback between Morphogens and Cell Growth
Authors: Kaity Bivash , Lobo Daniel
Published: February 2025

Patterning and morphogenesis in multicellular organisms require precise dynamic coordination between cellular behaviors and mechano-chemical signals. However, the mechanisms underlying the pathways that coordinate and integrate these signals into emergent cellular behaviors and tissue shapes remain poorly understood. Here, we present a cell-centered agent-based mathematical approach to shed light on the feedback mechanisms underlying tissue growth and pattern formation. The model includes cell size dynamics governed by both intercellular diffusible morphogen concentrations and mechanical stress between cells to control their spatial organization, and does not require the use of any superimposed lattice, increasing its applicability and performance. The results show how the precise integration of the feedback loop between cellular behaviors and mechano-chemical signaling is essential for the regulation of shape and spatial patterns across the tissue scale. Furthermore, the regulation of cellular dynamics by patterning processes, such as Turing activator-inhibitor systems, can drive the formation of emergent stable tissue shapes, which, in turn, specify the domain for morphogen patterning— closing the self-regulated loop between tissue shape and morphogenetic signals. Overall, this study highlights the importance of the feedback loop between morphogen patterning and cellular behaviors in regulating tissue growth dynamics and stable shape formation. Moreover, this study establishes a framework for further experiments to understand the regulatory dynamics of whole-body development and regeneration using high spatiotemporal resolution models.

Significance

Tight coordination and interpretation of the multitude of signals at different biological scales are essential during the development of multicellular organisms to control their shape, size, and pattern. In this work, we investigated the leading role of the feedback between mechano-chemical signaling networks and tissue shape through cellular behaviors such as growth, proliferation, and apoptosis. The model explains the interdependence between tissue growth and pattern formation mechanisms in regulating the fundamental properties of morphogenesis. Overall, this study provides mechanistic insights into the regulatory feedback interactions between tissue morphogenesis and patterning dynamics.
Themis and Grb2 form a constitutive structural hub in T cell receptor signalling
Authors: Clancy Danielle M. , Sanz-Sanjuan Alba , Gilis Elisabeth , Tougaard Peter , Velghe Imke , Van Droogenbroeck Yana , Felix Jan , Bloch Yehudi , Cuadrado Álvaro Furones , Merceron Romain , Schenck Stephan , Vandenabeele Peter , Brunner Janine D. , Taghon Tom , Elewaut Dirk , Savvides Savvas N.
Published: February 2025

Positive selection of thymocytes is essential for laying the foundations of the mammalian immune system that include the T cell repertoire, self-tolerance, and prevention of autoimmunity. Themis, the archetypal member of a metazoan protein family featuring distinctive CABIT domains, crucially regulates thymocyte positive selection by linking signalling by the T cell receptor (TCR) to the linker of activation of TCR (LAT). Intriguingly, Themis has been proposed to function via a constitutive complex with the multifunctional adaptor Grb2. Although poised to represent a paradigm shift in our understanding of TCR signalling, the structural and mechanistic basis of such an assembly has remained enigmatic. Here, we present the cryo-EM structure of Themis in complex with Grb2, which reveals how the tandem CABIT domains of Themis engulf the C-terminal SH3 domain of Grb2 (Grb2SH3C) to enable its latching onto the proline rich sequence of Themis. The remaining two domains of Grb2 adopt at least three conformational poses set to interact with other binding partners such as Sos1. Structural insights from unbound Themis unmask the pronounced flexibility of the CABIT domains of Themis, which becomes ordered upon binding to Grb2 to create a binding hotspot for their constitutive complex. Indeed, Themis variants that abrogate interactions with Grb2 also fail to activate the tyrosine phosphatase SHP-1 after TCR stimulation, analogous to the functional phenotype of Themis-deficient cells. Collectively, our study draws the blueprint of the Themis-Grb2 complex as a dynamic structural hub in T cell development.
Does diet contribute to socioeconomic differences in the prevalence of obesity among Indian adolescents?
Authors: Kalita Neelam
Published: February 2025

Background

In India, the risk of obesity in adolescents between 10 and 19 years of age increases with socioeconomic advantage. Diet is a contributing factor to obesity, and obesity is a key risk factor for cardiovascular diseases (CVDs). However, the contribution of diet to socio-economic inequalities in overweight or obesity remains unclear.

Aim

To assess the mediating role of diet in the association between socioeconomic status (SES) and obesity among Indian adolescents.

Data & Methods

Data were obtained from the Comprehensive National Nutrition Dataset survey, a cross-sectional sample of the Indian adolescent population (N=35,830). Maternal educational attainment and household wealth index are used as proxies for SES. Diet quality was estimated using the Dietary Diversity Score (DDS) based on reported weekly intake of different categories of food. BMI for age Z-scores was used as a marker for obesity. Cross-section mediation was applied to estimate the proportions of obesity mediated by diet quality. Robustness checks were conducted by using alternative measures of diet quality.

Results

The log-odds of obesity were estimated to rise by 0.603 (95% CI: 0.334,0.926) and 0.714 (95% CI: 0.573, 0.865) in rural and urban adolescents, respectively, with higher levels of maternal education (post-secondary or above), compared to those from lower maternal education (secondary or below). In wealthier adolescents (from middle-, rich-, richest quintiles), the log-odds of obesity were estimated to rise by 0.710 (95% CI: 0.529, 0.891) and 1.325 (95% CI: 0.924, 0.1.726) in rural and urban adolescents, respectively, compared to poorer adolescents (from poorest and poor quintiles). The proportion of the association mediated by diet varied between <1% and over 4%.

Conclusions

The findings suggested that diet quality mediates socio-economic inequalities in obesity among Indian adolescents, but only a small proportion. Therefore, differences in diet quality might not be the primary route by which SES translates into differences in risk for obesity among Indian adolescents. Focussing on improving diet quality and other risk factors (behavioural, environmental, demographic, socio-cultural) could prevent obesity among Indian adolescents and, therefore, the future burden of CVD in India.
Structural basis of ATP release and ion selectivity in Pannexin1 channels
Authors: Zhang Qingyang , Wang Junjie , Gaullier Guillaume , Kotol David , Blikstad Cecilia , Dahl Gerhard , Barro-Soria Rene , Mim Carsten
Published: February 2025

This study investigated the structural basis of adenosine triphosphate (ATP) release and ion selectivity by Pannexin1 (Panx1). The microinjection of active SRC tyrosine kinase increased Panx1-mediated currents in Panx1-expressing oocytes. Furthermore, a mutation mimicking phosphorylation at Y308 turned Panx1 into a constitutively open ATP-releasing channel with broad ion permeability. Cryogenic electron microscopy showed that for most maps, the channel alternated between wide and narrow conformations. However, in the map of the phosphomimetic Y308E mutation, Panx1 remains in a wide ATP-releasing conformation. The pore-lining residues, W74 and R75, are flexible and create, in concert with the sequestered N-terminal helix, a path for ATP. The data point to phosphorylation as a reversible switch that activates ATP permeability by stabilizing Panx1 in the ATP-releasing conformation, which is crucial for developing modulators for diseases such as cancer and chronic pain.
Cell type transcriptomics reveal shared genetic mechanisms in Alzheimer’s and Parkinson’s disease
Authors: Bhattacharya Anwesha , Fon Edward A. , Dagher Alain , Iturria-Medina Yasser , Stratton Jo Anne , Savignac Chloe , Stanley Jack , Hodgson Liam , Hammou Badr Ait , Bennett David A , Bzdok Danilo
Published: February 2025

Historically, Alzheimer’s disease (AD) and Parkinson’s disease (PD) have been investigated as two distinct disorders of the brain. However, a few similarities in neuropathology and clinical symptoms have been documented over the years. Traditional single gene-centric genetic studies, including GWAS and differential gene expression analyses, have struggled to unravel the molecular links between AD and PD. To address this, we tailor a pattern-learning framework to analyze synchronous gene co-expression at sub-cell-type resolution. Utilizing recently published single-nucleus AD (70,634 nuclei) and PD (340,902 nuclei) datasets from postmortem human brains, we systematically extract and juxtapose disease-critical gene modules. Our findings reveal extensive molecular similarities between AD and PD gene cliques. In neurons, disrupted cytoskeletal dynamics and mitochondrial stress highlight convergence in key processes; glial modules share roles in T-cell activation, myelin synthesis, and synapse pruning. This multi-module sub-cell-type approach offers insights into the molecular basis of shared neuropathology in AD and PD.