eLife: latest articles by subject

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 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 are 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

Correction: Association of human breast cancer CD44^-/CD24^- cells with delayed distant metastasis

Wed, 10 Sep 2025 00:00:00 +0000

Heterozygous variants in PLCG1 affect hearing, vision, cardiac, and immune function

hbellen@bcm.edu (Aimee Allworth) — Wed, 27 Aug 2025 00:00:00 +0000

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca²⁺ release from the endoplasmic reticulum (ER). PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these variants in vivo, we generated the analogous variants in the Drosophila ortholog, small wing (sl). We created a null allele sl^T2A and assessed its expression pattern. sl is broadly expressed, including wing discs, eye discs, and a subset of neurons and glia. sl^T2A mutant flies exhibit wing size reductions, ectopic wing veins, and supernumerary photoreceptors. We document that mutant flies also exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-type sl in sl^T2A mutant flies rescues the loss-of-function phenotypes, whereas the variants increase lethality. Ectopic expression of an established hyperactive PLCG1 variant, p.(Asp1165His) in the wing pouch causes elevated Ca²⁺ activity and severe wing phenotypes. These phenotypes are also observed when the p.(Asp1019Gly) or p.(Asp1165Gly) variants are overexpressed in the wing pouch, arguing that these are gain-of-function variants. However, the wing phenotypes associated with p.(His380Arg) or p.(Leu597Phe) overexpression are either mild or only partially penetrant. Our data suggest that the heterozygous missense variants reported here affect protein function differentially and contribute to the clinical features observed in the affected individuals.

A pair of congenic mice for imaging of transplants by positron emission tomography using anti-transferrin receptor nanobodies

thomas.balligand@unamur.be (Bart De Strooper) — Mon, 18 Aug 2025 00:00:00 +0000

Two anti-transferrin receptor (TfR) nanobodies, V_HH123 specific for mouse TfR and V_HH188 specific for human TfR, were used to track transplants non-invasively by PET/CT in mouse models, without the need for genetic modification of the transferred cells. We provide a comparison of the specificity and kinetics of the PET signals acquired when using nanobodies radiolabeled with ⁸⁹Zr, ⁶⁴Cu, and ¹⁸F, and find that the chelation of the ⁸⁹Zr and ⁶⁴Cu radioisotopes to anti-TfR nanobodies results in radioisotope release upon endocytosis of the radiolabeled nanobodies. We used a knock-in mouse that expresses a TfR with a human ectodomain (Tfrc^hu/hu) as a source of bone marrow for transplants into C57BL/6 recipients and show that V_HH188 detects such transplants by PET/CT. Conversely, C57BL/6 bone marrow and B16.F10 melanoma cell line transplanted into Tfrc^hu/hu recipients can be imaged with V_HH123. In C57BL/6 mice impregnated by Tfrc^hu/hu males, we saw an intense V_HH188 signal in the placenta, showing that TfR-specific V_HHs accumulate at the placental barrier but do not enter the fetal tissue. We were unable to observe accumulation of the anti-TfR radiotracers in the central nervous system (CNS) by PET/CT but showed evidence of CNS accumulation by radiospectrometry. The model presented here can be used to track many transplanted cell types by PET/CT, provided cells express TfR, as is typically the case for proliferating cells such as tumor lines.

Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans

pkapahi@buckinstitute.org (Lizellen La Follette) — Tue, 12 Aug 2025 00:00:00 +0000

Acute aerobic exercise intensity does not modulate pain potentially due to differences in fitness levels and sex effects: results from a pharmacological fMRI study

j.nold@uke.de (Christian Büchel) — Wed, 06 Aug 2025 00:00:00 +0000

Exercise might lead to a release of endogenous opioids, potentially resulting in pain relief. However, the neurobiological underpinnings of this effect remain unclear. Using a pharmacological within-subject functional magnetic resonance imaging (fMRI) study with the opioid antagonist naloxone and different levels of aerobic exercise and pain, we investigated exercise-induced hypoalgesia (N = 39, 21 female). Overall, high-intensity (HI) aerobic exercise did not reduce pain as compared to low-intensity aerobic exercise. Accordingly, we observed no significant changes in the descending pain modulatory system. The µ-opioid antagonist naloxone significantly increased overall pain ratings but showed no interaction with exercise intensity. An exploratory analysis suggested an influence of fitness level (as indicated by the functional threshold power) and sex, where males showed greater hypoalgesia after HI exercise with increasing fitness levels. This effect was attenuated by naloxone and mirrored by fMRI signal changes in the medial frontal cortex, where activation also varied with fitness level and sex, and was reversed by naloxone. These results indicate that different aerobic exercise intensities have no differential effect on pain in a mixed population sample, but individual factors such as fitness level and sex might play a role. The current study underscores the need for personalised exercise interventions to enhance pain relief in healthy as well as chronic pain populations, taking into account the sex and fitness status as well as the necessity to further investigate the opioidergic involvement in exercise-induced pain modulation.

Correction: Increase of cell surface vimentin is associated with vimentin network disruption and subsequent stress-induced premature senescence in human chondrocytes

Thu, 31 Jul 2025 00:00:00 +0000

Efficacy and safety of neoadjuvant stereotactic body radiation therapy plus dalpiciclib and exemestane for hormone receptor-positive, HER2-negative breast cancer: A prospective pilot study

everbright99@163.com (Ailin Li) — Mon, 28 Jul 2025 00:00:00 +0000

Therapeutic effects of PDGF-AB/BB against cellular senescence in human intervertebral disc

hicham.drissi@emory.edu (Changli Zhang) — Wed, 16 Jul 2025 00:00:00 +0000

Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. While previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptotic and pro-anabolic effects, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 d. Transcriptome profiling by mRNA sequencing revealed that NP and AF cells responded to the treatment in similar yet distinct ways. The effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, rhPDGF-AB/BB treatment downregulated genes related to neurogenesis and mechanical stimulus response in AF cells, while in NP cells, metabolic pathways were predominantly suppressed. In both NP and AF cells, rhPDGF-AB/BB treatment upregulated genes involved in cell cycle regulation and response to reduced oxygen levels, while downregulating genes related to senescence-associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence-related regulators. Our findings reveal a novel anti-senescence role of PDGF in the IVD, making it a promising potential candidate to delay aging-induced IVD degeneration.

EPHA4 signaling dysregulation links abnormal locomotion and the development of idiopathic scoliosis

jgzhang_pumch@yahoo.com (Anas M Khanshour) — Tue, 15 Jul 2025 00:00:00 +0000

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited pronounced scoliosis during later stages of development, effectively recapitulating the IS phenotype. We observed that the epha4a mutants displayed defects in left-right coordination during locomotion, which arose from disorganized neural activation in these mutants. Our subsequent experiments indicated that the disruption of the central pattern generator (CPG) network, characterized by abnormal axon guidance of spinal cord interneurons, contributed to the disorganization observed in the mutants. Moreover, when knocked down efnb3b, the ligand for Epha4a, we observed similar CPG defects and disrupted left-right locomotion. These findings suggested that ephrin B3-Epha4 signaling is vital for the proper functioning of CPGs, and defects in this pathway could lead to scoliosis in zebrafish. Furthermore, we identified two cases of IS in NGEF, a downstream molecule in the EPHA4 pathway. Collectively, our data provide compelling evidence that neural patterning impairments and disruptions in CPGs may underlie the pathogenesis of IS.

Magnetically steered cell therapy for reduction of intraocular pressure as a treatment strategy for open-angle glaucoma

ross.ethier@bme.gatech.edu (Anamik Jhunjhunwala) — Mon, 07 Jul 2025 00:00:00 +0000

Trabecular meshwork (TM) cell therapy has been proposed as a next-generation treatment for elevated intraocular pressure (IOP) in glaucoma, the most common cause of irreversible blindness. Using a magnetic cell steering technique with excellent efficiency and tissue-specific targeting, we delivered two types of cells into a mouse model of glaucoma: either human adipose-derived mesenchymal stem cells (hAMSCs) or induced pluripotent cell derivatives (iPSC-TM cells). We observed a 4.5 [3.1, 6.0] mmHg or 27% reduction in intraocular pressure (IOP) for 9 months after a single dose of only 1500 magnetically steered hAMSCs, explained by increased outflow through the conventional pathway and associated with a higher TM cellularity. iPSC-TM cells were also effective, but less so, showing only a 1.9 [0.4, 3.3] mmHg or 13% IOP reduction and increased risk of tumorigenicity. In both cases, injected cells remained detectable in the iridocorneal angle 3 weeks post-transplantation. Based on the locations of the delivered cells, the mechanism of IOP lowering is most likely paracrine signaling. We conclude that magnetically steered hAMSC cell therapy has potential for long-term treatment of ocular hypertension in glaucoma.

The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence

jaehyuck.shim@umassmed.edu (Chunjie Wang) — Mon, 07 Jul 2025 00:00:00 +0000

The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, the elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway, such as in lysosomal storage diseases. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice

n-sasaki@kobepharma-u.ac.jp (Aga Krisnanda) — Thu, 03 Jul 2025 00:00:00 +0000

Chronic inflammation via dysregulation of T cell immune responses is critically involved in the pathogenesis of atherosclerotic cardiovascular disease. Improving the balance between proinflammatory T cells and anti-inflammatory regulatory T cells (Tregs) may be an attractive approach for treating atherosclerosis. Although C-C chemokine receptor 4 (CCR4) has been shown to mediate the recruitment of T cells to inflamed tissues, its role in atherosclerosis is unclear. Here, we show that genetic deletion of CCR4 in hypercholesterolemic mice accelerates the development of early atherosclerotic lesions characterized by an inflammatory plaque phenotype. This was associated with the augmentation of proinflammatory T helper type 1 (Th1) cell responses in peripheral lymphoid tissues, para-aortic lymph nodes, and atherosclerotic aorta. Mechanistically, CCR4 deficiency in Tregs impaired their suppressive function and tended to inhibit their migration to the atherosclerotic aorta, and subsequently augmented Th1 cell-mediated immune responses through defective regulation of dendritic cell function, which accelerated aortic inflammation and atherosclerotic lesion development. Thus, we revealed a previously unrecognized role for CCR4 in controlling the early stage of atherosclerosis via Treg-dependent regulation of proinflammatory T cell responses. Our data suggest that CCR4 is an important negative regulator of atherosclerosis.

Gamma Knife stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: a phase II trial analysis

wangliang@jnu.edu.cn (Hanyang Guan) — Thu, 26 Jun 2025 00:00:00 +0000

Multiple roles for a mitochondrial enzyme

hqiu@arizona.edu (Hongyu Qiu) — Mon, 16 Jun 2025 00:00:00 +0000

The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.