eLife: latest articles by subject

Concerted changes in the pediatric single-cell intestinal ecosystem before and after anti-TNF blockade

jose.ordovas-montanes@childrens.harvard.edu (Alexandre Albanese) — Tue, 01 Sep 2026 00:00:00 +0000

Crohn’s disease is an inflammatory bowel disease (IBD) commonly treated through anti-TNF blockade. However, most patients still relapse and inevitably progress. Comprehensive single-cell RNA-sequencing (scRNA-seq) atlases have largely sampled patients with established treatment-refractory IBD, limiting our understanding of which cell types, subsets, and states at diagnosis anticipate disease severity and response to treatment. Here, through combining clinical, flow cytometry, histology, and scRNA-seq methods, we profile diagnostic human biopsies from the terminal ileum of treatment-naive pediatric patients with Crohn’s disease (pediCD; n = 14), matched repeat biopsies (pediCD-treated; n = 8) and from non-inflamed pediatric controls with functional gastrointestinal disorders (FGIDs; n = 13). To resolve and annotate epithelial, stromal, and immune cell states among the 201,883 baseline single-cell transcriptomes, we develop a principled and unbiased tiered clustering approach, ARBOL. Through flow cytometry and scRNA-seq, we observe that treatment-naive pediCD and FGID have similar broad cell type composition. However, through high-resolution scRNA-seq analysis and microscopy, we identify significant differences in cell subsets and states that arise during pediCD relative to FGID. By closely linking our scRNA-seq analysis with clinical meta-data, we resolve a vector of T cell, innate lymphocyte, myeloid, and epithelial cell states in treatment-naive pediCD (pediCD-TIME) samples, which can distinguish patients along the trajectory of disease severity and anti-TNF response. By using ARBOL with integration, we position repeat on-treatment biopsies from our patients between treatment-naive pediCD and on-treatment adult CD. We identify that anti-TNF treatment pushes the pediatric cellular ecosystem toward an adult, more treatment-refractory state. Our study jointly leverages a treatment-naive cohort, high-resolution principled scRNA-seq data analysis, and clinical outcomes to understand which baseline cell states may predict Crohn’s disease trajectory.

Correction: p16 deficiency attenuates intervertebral disc degeneration by adjusting oxidative stress and nucleus pulposus cell cycle

Fri, 21 Aug 2026 00:00:00 +0000

A novel prognostic score based on carbohydrate antigen 125, alpha-fetoprotein and carcinoembryonic antigen for Predicting postoperative prognosis in endometrial cancer: Results from a retrospective cohort study

yangh9@sj-hospital.org (Bo Wang) — Mon, 10 Aug 2026 00:00:00 +0000

Background: Endometrial cancer (EC) is a common gynecological malignancy with increasing incidence. While several serum biomarkers have been studied for EC, their combined prognostic value remains unclear. This study aimed to evaluate the prognostic significance of preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP levels in EC patients and develop a risk score for predicting survival outcomes.

Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2

J.Guy@ed.ac.uk (Adrian Bird) — Mon, 10 Aug 2026 00:00:00 +0000

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline stop motif (-PPX) generated by a shift to the +2 reading frame. CTDs that shift to the +1 frame avoid this motif and are benign. Replacing the stop codon of the PPX motif with tryptophan restores MeCP2 expression and rescues RTT-like phenotypes in a CTD mouse model. An adenine base editor efficiently introduces this substitution in cultured cells. These findings define a reliable prognostic distinction between benign and pathogenic CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations.

Evaluating the applicability of replication success metrics in animal-to-human translation: A simulation study

rachel.heyard@uzh.ch (Benjamin Victor Ineichen) — Fri, 07 Aug 2026 00:00:00 +0000

Translation failure, in which promising animal study results cannot be reproduced in human trials, is a challenge in biomedical research. Metrics for replication success are widely used to evaluate reproducibility, that is the extent to which the results of a study agree with those of replication studies. The relevance of these metrics in assessing animal-to-human translation success (or failure) is unclear. We conducted a simulation study to examine whether these metrics can quantify translation success, and how their performance varies under different conditions. Using parameters from a meta-analysis on prenatal amino acid supplementation and maternal blood pressure, we simulated animal and human studies under 648 scenarios, varying effect sizes, heterogeneity, animal sample sizes, and number of pooled animal studies. Nine metrics were assessed, namely the two-trials rule, meta-analysis, replication Bayes factor, unweighted and weighted Edgington’s methods, golden skeptical p-value, and three versions of controlled skeptical p-value. Most metrics, except meta-analysis and replication Bayes factor, controlled false positive rates under no heterogeneity, but became liberal as heterogeneity increased, particularly between human studies. Translation power (i.e. the probability of true positive translation success) was constrained by the weaker evidence of the two findings; for example, small sample size in the animal studies resulted in lower translation power. The metric based on meta-analysis frequently indicated success when either of the species found strong evidence, while skeptical p-values were more conservative. The skeptical p-value that controls overall type-one error and the weighted version of Edgington’s method performed relatively consistently across scenarios. However, no metric was uniformly optimal. Metrics developed for replication studies can inform assessments of translation, but their utility depends on the underlying evidence and assumptions. Using multiple metrics in combination, with attention to their strengths and limitations, is recommended for evaluating the translation of animal findings to human outcomes.

Magnesium isoglycyrrhizinate alleviates alcohol-associated liver disease through targeting HSD11B1

liyan181@smu.edu.cn (Hao Wang) — Tue, 28 Jul 2026 00:00:00 +0000

While magnesium isoglycyrrhizinate (MgIG) is a clinically approved therapy for alcohol-associated liver disease (ALD), its precise molecular targets and mechanisms remain uncharacterized. This study aimed to define MgIG’s hepatoprotective actions in chronic-binge ALD mouse models and ethanol/palmitic acid-exposed AML-12 hepatocytes. Through an integrated strategy encompassing RNA sequencing, molecular docking, and microscale thermophoresis, we discovered that MgIG directly binds to hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) at residue 187, a finding corroborated by molecular dynamics simulations. In vivo, MgIG markedly attenuated alcohol-induced liver injury, evidenced by ameliorated histological damage, reduced hepatic steatosis, and normalized liver-to-body weight ratios. In vitro, it effectively reduced lipid accumulation, inflammation, and apoptosis. Mechanistically, RNA sequencing identified isopentenyl diphosphate delta isomerase 1 (IDI1) as a key downstream effector. Hepatocyte-specific genetic manipulations confirmed that MgIG modulates the SREBP2–IDI1 axis, thereby suppressing lipogenesis, inflammatory responses, and apoptotic pathways. We reveal HSD11B1 as a novel direct molecular target of MgIG and elucidate its therapeutic mechanism through the HSD11B1–SREBP2–IDI1 signaling axis, which profoundly impacts ALD pathogenesis. These findings not only validate MgIG’s clinical utility but also highlight a promising new therapeutic target for ALD.

Correction: Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue

Thu, 09 Jul 2026 00:00:00 +0000

Navigating the path: Advice to physician-scientists on choosing a clinical specialty

christopher.williams@vanderbilt.edu (Ali Zarrinpar) — Fri, 03 Jul 2026 00:00:00 +0000

Choosing a clinical specialty is a critical decision for physician-scientist trainees, influencing both clinical practice and research trajectory. This article provides a structured approach to specialty selection, emphasizing the importance of aligning clinical interests with long-term research goals, evaluating training pathways, and considering lifestyle implications. Physician-scientists, including MD-PhD and other dual-degree graduates, as well as MD graduates with research-intensive training, often pursue specialties with established research pathways. We outline key decision-making factors, including mentorship, clinical exposure, research commitment, and financial sustainability. Additionally, we compare research track and categorical residency pathways, detailing differences in training structure, funding opportunities, and career outcomes. The article explores the evolving role of physician-scientists across career stages, from residency through senior faculty leadership, highlighting strategies to maintain research engagement while balancing clinical responsibilities. By critically evaluating these factors and leveraging mentorship and institutional support, physician-scientists can make informed decisions that align with their aspirations, ensuring a fulfilling and impactful career in both medicine and research.

Differential regulation of hepatic macrophage fate by Chi3l1 in metabolic dysfunction-associated steatotic liver disease

shanzhaolab@163.com (Bo Chen) — Fri, 26 Jun 2026 00:00:00 +0000

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression involves the replacement of protective embryo-derived Kupffer cells (KCs) by inflammatory monocyte-derived macrophages (MoMFs), yet the regulatory mechanisms remain unclear. Here, we identify chitinase 3-like 1 (Chi3l1/YKL-40) as a critical metabolic regulator of hepatic macrophage fate. We observed high expression of Chi3l1 in both KCs and MoMFs during MASLD development. Genetic deletion of Chi3l1 specifically in KCs significantly exacerbated MASLD severity and metabolic dysfunction, whereas MoMF-specific Chi3l1 deletion showed minimal metabolic effects. Mechanistic studies revealed that this cell type-specific regulation arises from differential metabolic requirements: KCs display elevated glucose metabolism compared to MoMFs. Chi3l1 directly interacts with glucose to inhibit its cellular uptake, thereby selectively protecting glucose-dependent KCs from metabolic stress-induced cell death while having negligible effects on less glucose-dependent MoMFs. These findings uncover a novel Chi3l1-mediated metabolic checkpoint that preferentially maintains KCs populations through glucose metabolism modulation, providing important new insights into the pathogenesis of MASLD and potential therapeutic strategies targeting macrophage-specific metabolic pathways.

Direct MRI of collagen

weiger@biomed.ee.ethz.ch (Emily Louise Baadsvik) — Thu, 04 Jun 2026 00:00:00 +0000

Collagen is the most abundant protein in the human body and has an important role in healthy tissue as well as in a range of prevalent diseases. Medical research and diagnostics, hence, call for means of mapping collagen in vivo. Magnetic resonance imaging (MRI) is a natural candidate for this task, offering full 3D capability and versatile contrast non-invasively. However, collagen has so far been invisible to MRI due to extremely short lifetime of its resonances. Here, we report the direct imaging of collagen in vivo by magnetic resonance on the microsecond scale. The dynamics of resonance signals from collagen were first assessed in samples of bovine tendon and cortical bone. On this basis, imaging was performed at echo times down to 10 microseconds, yielding collagen-specific depiction by echo subtraction. The same approach was then extended for use in vivo, enabling direct collagen imaging of a human forearm. This capability suggests significant promise for biomedical science and clinical use.

Hyperactivated glycolysis drives spatially patterned Kupffer cell depletion in MASLD

shanzhao@ynu.edu.cn (Cheng Xie) — Tue, 26 May 2026 00:00:00 +0000

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is characterized by hepatic inflammation and cell death, yet the mechanisms underlying Kupffer cell (KC) loss remain poorly understood. Here, we sought to elucidate the metabolic basis of KC death during MASLD. Using metabolomics, immunostaining, and flow cytometry, we evaluated metabolic alterations and KC death throughout early MASLD progression. We found that KC death is an early hallmark of MASLD, exhibiting greater susceptibility and a spatial distribution consistent with KC zonation. Moreoever, KCs undergo progressive metabolic reprogramming toward enhanced glucose utilization during MASLD development, which is correlated with KC death. In combination with biochemical agonist, isotope tracing, and primary KC culture, we further demonstrated that augmented glycolytic metabolism directly drives KC death in vitro. Consistently, using Chi3l1-deficient mice, we further demonstrated that increased glucose utilization accelerates KC death in vivo. Together, these findings establish a causal link between glycolytic activation and KC loss during MASLD progression, highlighting glucose metabolic pathways as potential therapeutic targets to preserve KC homeostasis and mitigate MASLD.

Teaching early-career researchers how to respond to peer reviewers

e.kalkhoven@umcutrecht.nl (Eric Kalkhoven) — Thu, 23 Apr 2026 00:00:00 +0000

The process of publishing a research article in a scientific journal inevitably involves revising the original version of the article to respond to the concerns raised by peer reviewers. In this article we describe a course module that introduces MSc students at Utrecht University in the Netherlands to this part of the publication process. During the module the students and an invited speaker actively discuss the revision process for a recent article by the speaker. Feedback from students and speakers on the module – which could be readily transferred to other courses in the life and biomedical sciences – has been largely positive.

Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle

jayanthag@imcb.a-star.edu.sg (Christopher G Sobey) — Fri, 17 Apr 2026 00:00:00 +0000

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

Global molecular landscape of early MASLD progression in human obesity

hyung_won_choi@nus.edu.sg (Gabriele Sakalauskaite) — Mon, 23 Mar 2026 00:00:00 +0000

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic early on but can progress to irreversible conditions like cirrhosis. Due to limited access to human liver biopsies, systematic and integrative molecular resources remain scarce. In this study, we performed transcriptomic analyses on liver and metabolomic analyses on liver and plasma samples from morbidly obese individuals without liver pathology or at early-stage MASLD. While the plasma metabolomic profile did not fully mirror liver histological features, dual-omics integration of liver samples revealed significantly remodeled lipid and amino acid metabolism pathways. Integrative network analysis uncoupled metabolic remodeling and gene expression as independent features of hepatic steatosis and fibrosis progression, respectively. Notably, GTPases and their regulators emerged as a novel class of genes linked to early liver fibrosis. This study offers a detailed molecular landscape of early MASLD in obesity and highlights potential targets of obesity-linked liver fibrosis.

Sperm motility in mice with oligo-astheno-teratozoospermia restored by in vivo injection and electroporation of naked mRNA

jessica.escoffier@univ-grenoble-alpes.fr (Altan Yavuz) — Tue, 03 Mar 2026 00:00:00 +0000

Oligo-astheno-teratozoospermia (OAT), a recurrent cause of male infertility, is the most frequent disorder of spermatogenesis with a predominantly genetic origin. Patients and mice bearing mutations in the ARMC2 gene exhibit reduced sperm concentration, multiple morphological defects, and impaired motility, defining a canonical OAT phenotype. Intracytoplasmic sperm injection (ICSI) is required to treat this condition; however, it is associated with a slightly increased risk of birth defects compared with natural conception, highlighting the need for novel targeted therapies. Here, in vivo testicular injection followed by electroporation of capped, polyadenylated naked messenger RNA (mRNA) was evaluated as a strategy to treat ARMC2-related infertility in mice. mRNAs encoding reporter proteins were used to assess expression efficiency and kinetics using in vivo and in vitro 2D and 3D imaging. Reporter proteins were detected in germ cells for up to three weeks, demonstrating the feasibility of mRNA-based approaches. These results were compared with a non-integrative plasmid Enhanced Episomal Vector, which induced weak and transient expression in spermatogenic cells. Delivery of Armc2 mRNA restored morphologically normal and motile sperm in deficient males, capable of producing embryos via in vitro fertilization and ICSI. These findings provide proof-of-concept that mRNA electroporation can restore sperm motility and fertilizing potential, offering a novel strategy to correct monogenic male infertility.

Single transcript level atlas of oxytocin and the oxytocin receptor in the mouse brain

vitaly.ryu@mssm.edu (Anisa Azatovna Gumerova) — Mon, 23 Feb 2026 00:00:00 +0000

Oxytocin (OXT), a primitive nonapeptide known to regulate reproduction and social behaviors, is synthesized primarily in the hypothalamus and is secreted via the hypophyseal-portal system of the posterior pituitary gland. In line with the premise that pituitary hormones, traditionally thought of as regulators of single targets, display an array of central and peripheral actions, we found that OXT directly affects bone and body composition. The effect of OXT on bone remodeling is physiologically relevant, as elevated OXT levels during pregnancy and lactation cause calcium mobilization from the maternal skeleton for intergenerational calcium transfer towards fetal bone mineralization. There is an equally large body of evidence that has established the presence of OXT receptors (OXTRs) in the brain through which central functions, such as social bonding, and peripheral functions, such as the regulation of body composition, are exerted. To purposefully address effects of OXT on the brain, we used RNAscope to map OXT and OXTR expression, at the single transcript level, in the whole female and male mouse brains. Identification of brain nuclei with the highest OXT and OXTR transcript density sheds further light on functional OXT nodes that could be further interrogated experimentally to define new physiologic circuitry.

Gender differences in submission behavior exacerbate publication disparities in elite journals

vincent.lariviere@umontreal.ca (Cassidy R Sugimoto) — Fri, 20 Feb 2026 00:00:00 +0000

Women are particularly underrepresented as leading authors of papers in journals of the highest impact factor, with substantial consequences for their careers. While a large body of research has focused on the outcome and the process of peer review, fewer articles have explicitly focused on gendered submission behavior and the explanations for these differences. In our study of nearly 5000 active authors, we find that women are less likely to report having submitted papers to journals of the highest impact (e.g., Science, Nature, or PNAS) and to submit fewer manuscripts, on average, than men when they do submit. Women were more likely to indicate that they did not submit their papers (in general and their subsequently most cited papers) to high-impact journals because they were advised not to. In the aggregate, no statistically significant difference was observed between men and women in how they rated the quality of their work. Nevertheless, regardless of discipline, women were more likely than men to indicate that their ‘work was not ground-breaking or sufficiently novel’ as a rationale for not submitting to one of the listed prestigious journals. Men were more likely than women to indicate that the ‘work would fit better in a more specialized journal’. We discuss the implications of these findings and interventions that can serve to mitigate the disparities caused by gendered differences in submission behavior.

MRI sets its sights on collagen

fritz.schick@med.uni-tuebingen.de (Fritz Schick) — Mon, 02 Feb 2026 00:00:00 +0000

Reducing the echo time of a whole-body MRI scanner makes it possible to image collagen, an important structural protein found in bones and tendons.

A titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation

gmmahmud@uic.edu (Abhinaya Baskaran) — Thu, 22 Jan 2026 00:00:00 +0000

Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes, such as TTN, have also been implicated in AF pathogenesis, partly through the development of atrial myopathy; however, the underlying mechanisms are poorly understood. While TTN truncating variants (TTNtvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear. We show that rare TTNmvs are associated with worse clinical outcomes in a single-center ethnic minority clinical cohort and uncover a pathogenic mechanism by which the T32756I variant drives AF. Modeling the TTN-T32756I variant using human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) revealed that the mutant cells display aberrant contractility, increased activity of a cardiac potassium channel (KCNQ1, Kv7.1), and dysregulated calcium homeostasis without compromising the sarcomeric integrity of the atrial cardiomyocytes. We also show that a titin-binding protein, the Four-and-a-Half Lim domains 2 (FHL2), has increased binding with KCNQ1 and its modulatory subunit KCNE1 in the TTN-T32756I-iPSC-aCMs, enhancing the slow delayed rectifier potassium current (I_ks). Suppression of FHL2 in mutant iPSC-aCMs normalized the I_ks, supporting FHL2 as an I_ks modulator. Our findings demonstrate that a single amino acid substitution in titin not only impairs its function but also remodels ion channels, contributing to AF. These findings underscore the importance of high-throughput screening to assess the pathogenicity of TTNmvs and establish a mechanistic connection between titin, potassium ion channels, and sarcomeric proteins, which may represent a novel therapeutic target.

Association between continuous glucose monitoring-derived metrics and coronary plaque vulnerability: A retrospective exploratory analysis

ogawa@med.kobe-u.ac.jp (Hikaru Sugimoto) — Thu, 15 Jan 2026 00:00:00 +0000

Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia

ck6cb@virginia.edu (Chia-Yi Kuan) — Mon, 29 Dec 2025 00:00:00 +0000

Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in the brain by impairing blood oxygen supply and the cerebral metabolic rate of oxygen (CMRO₂), is a leading cause of neonatal brain injury. However, it is unclear how post-HI hypothermia helps to restore the balance, as cooling reduces CMRO₂. Also, how transient HI leads to secondary energy failure (SEF) in neonatal brains remains elusive. Using photoacoustic microscopy, we examined the effects of HI on CMRO₂ in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO₂, it sparks a prolonged CMRO₂-surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis—indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO₂-surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hr post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO₂-surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO₂ measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.

GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain

xuzz@zju.edu.cn (Ange Dai) — Tue, 23 Dec 2025 00:00:00 +0000

Neuropathic pain, a major health problem affecting 7–10% of the global population, lacks effective treatment due to its elusive mechanisms. Cholecystokinin-positive (CCK⁺) neurons in the spinal dorsal horn (SDH) are critical for neuropathic pain, yet the underlying molecular mechanisms remain unclear. Here, we show that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER/GPR30) in spinal neurons was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK⁺ neurons reversed CCI-induced neuropathic pain. Furthermore, GPR30 in spinal CCK⁺ neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Moreover, GPR30 was expressed in spinal CCK⁺ neurons that received direct projection from the primary sensory cortex (S1-SDH). Chemogenetic inhibition of S1-SDH post-synaptic neurons alleviated CCI-induced neuropathic pain. Conversely, chemogenetic activation of these neurons mimicked neuropathic pain symptoms, which were attenuated by spinal inhibition of GPR30. Finally, we confirmed that GPR30 in S1-SDH post-synaptic neurons was required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK⁺ neurons and S1-SDH post-synaptic neurons is pivotal for neuropathic pain, thereby representing a promising therapeutic target for neuropathic pain.

Are peer reviewers influenced by their work being cited?

a.barnett@qut.edu.au (Adrian Barnett) — Tue, 23 Dec 2025 00:00:00 +0000

Peer reviewers sometimes comment that their own journal articles should be cited by the journal article under review. Comments concerning relevant articles can be justified, but comments can also be unrelated coercive citations. Here, we used a matched observational study design to explore how citations influence the peer review process. We used a sample of more than 37,000 peer reviews from four journals that use open peer review and make all article versions available. We find that reviewers who were cited in versions after version 1 were more likely to make a favourable recommendation (odds ratio = 1.61; adjusted 99.4% CI: 1.16–2.23), whereas being cited in the first version did not improve their recommendation (odds ratio = 0.84; adjusted 99.4% CI: 0.69–1.03). For all versions of the articles, the reviewers who commented that their own articles should be cited were less likely to recommend approval compared to the reviewers who did not, with the strongest association after the first version (odds ratio = 0.15; adjusted 99.4% CI: 0.08–0.30). Reviewers who included a citation to their own articles were much more likely to approve a revised article that cited their articles compared to a revised article that did not (odds ratio = 3.5; 95% CI: 2.0–6.1). Some reviewers’ recommendations depend on whether they are cited or want to be cited. Reviewer citation requests can turn peer review into a transaction rather than an objective critique of the article.

Addressing cultural and knowledge barriers to enable preclinical sex inclusive research

Natasha.Karp@astrazeneca.com (Amrita Ahluwalia) — Wed, 10 Dec 2025 00:00:00 +0000

For over 30 years, research has highlighted a sex bias in early research, risking the validity of biological knowledge. The first step towards change is effectively challenging misconceptions, allowing researchers to perceive sex inclusive research as doable. Utilising the theory of planned behaviour, we quantified researchers’ intention as a proxy measure for conducting sex inclusive research and explored attitude (value of the behaviour), subjective norm (perceived social pressure), and behavioural control (ability to conduct the behaviour). Additionally, we quantified the knowledge gap, prevalence of misconceptions, and assessed perceived benefits and barriers. We tested a workshop intervention that directly challenges the cultural embedded barriers. The data shows researchers’ intentions were high, but they had weak statistical knowledge and misunderstandings leading to a perception that inclusive research is prohibitive due to cost and animal use. We demonstrate that participation in the training intervention improved knowledge, altered the perceived barriers, and cultural expectations.

The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming

jss156@case.edu (Dawson Miller) — Mon, 17 Nov 2025 00:00:00 +0000

Acute myocardial infarction (MI) is a leading cause of morbidity and mortality, and therapeutic options remain limited. Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by S-nitrosylation, entailing specific enzymes that form and degrade S-nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here, we show that mice lacking SCoR2/AKR1A1 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels, and polyol homeostasis via S-nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an S-nitrosylation signature of metabolic reprogramming, mirroring SCoR2^−/− mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways—ketone body utilization, glycolysis, pentose phosphate shunt, and polyol metabolism—to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target.

Cell-autonomous and non-cell-autonomous effects of Arginase 2 on cardiac aging

duilio.potenza@unifr.ch (Andrea Brenna) — Tue, 04 Nov 2025 00:00:00 +0000

Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for cardiac aging and its susceptibility to injury are not fully understood. Although literature reports a role for mitochondrial Arginase 2 (ARG2) in heart failure, contradictory results are reported. How ARG2 participates in cardiac aging is still unknown. In this study, we demonstrate that Arg2 is not expressed in cardiomyocytes from aged mice and humans but is upregulated in non-myocyte cells, including macrophages, fibroblasts, and endothelial cells. Mice with genetic deficiency of Arg2 (Arg2^-/-) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that ARG2 mediates IL-1β release from macrophages of old mice, contributing to the cardiac aging phenotype. In addition, ARG2 enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of ARG2 on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1β from aging macrophages as well as a cell-autonomous effect of ARG2 through mtROS in fibroblasts contributing to cardiac aging phenotype.

Critique of impure reason: Unveiling the reasoning behaviour of medical large language models

shamus@qmed.asia (Shamus Zi Yang Sim) — Tue, 28 Oct 2025 00:00:00 +0000

Despite the current ubiquity of large language models (LLMs) across the medical domain, there is a surprising lack of studies which address their reasoning behaviour. We emphasise the importance of understanding reasoning behaviour as opposed to high-level prediction accuracies, since it is equivalent to explainable AI (XAI) in this context. In particular, achieving XAI in medical LLMs used in the clinical domain will have a significant impact across the healthcare sector. Therefore, in this work, we adapt the existing concept of reasoning behaviour and articulate its interpretation within the specific context of medical LLMs. We survey and categorise current state-of-the-art approaches for modelling and evaluating reasoning in medical LLMs. Additionally, we propose theoretical frameworks which can empower medical professionals or machine learning engineers to gain insight into the low-level reasoning operations of these previously obscure models. We also outline key open challenges facing the development of large reasoning models. The subsequent increased transparency and trust in medical machine learning models by clinicians as well as patients will accelerate the integration, application as well as further development of medical AI for the healthcare system as a whole.

Monitoring circulating cell-free HPV DNA in metastatic or recurrent cervical cancer: clinical significance and treatment implications

juejue3149@163.com (Hanmei Lou) — Wed, 17 Sep 2025 00:00:00 +0000