Publications by Year: 2026

All genomes have mobile genetic segments called transposable elements (TEs)1. Here we describe a system, which we term SOS splicing, that protects Caenorhabditis elegans and human genes against DNA-transposon-mediated disruption by excising these TEs from host mRNAs. SOS splicing, which seems to operate independently of the spliceosome, is a pattern-recognition system triggered by the base-pairing of inverted terminal repeat elements, which are a defining feature of DNA transposons. We identify three factors required for SOS splicing in both C. elegans and human cells: AKAP17A, which binds TE-containing mRNAs; the RNA ligase RTCB; and CAAP1, which bridges RTCB and AKAP17A to allow RTCB to ligate mRNA fragments generated by TE excision. We propose that SOS splicing is a previously undescribed conserved and RNA-structure-directed mode of mRNA splicing, and that an identified function of SOS splicing is to genetically buffer animals from the deleterious effects of DNA-transposon-mediated gene perturbation.

Frataxin is a key component of an ancient, mitochondrial iron-sulfur cluster biosynthetic machinery, serving as an allosteric activator of the cysteine desulfurase NFS1 (refs. 1-5). Loss of frataxin levels underlies Friedreich's ataxia6, the most common inherited ataxia. Yeast, Caenorhabditis elegans and human cells can tolerate loss of frataxin when grown in 'permissive' low oxygen tensions7. Here we conducted an unbiased, genome-scale forward genetic screen in C. elegans leveraging permissive and non-permissive oxygen tensions to discover suppressor mutations that bypass the need for frataxin. All mutations act dominantly and are in the ferredoxin FDX2/fdx-2 or in the cysteine desulfurase NFS1/nfs-1 genes, resulting in amino-acid substitutions at the FDX2-NFS1 binding interface. Our genetic and biochemical analyses show that the suppressor mutations boost iron-sulfur cluster levels in the absence of frataxin. We also demonstrate that an excess of FDX2 inhibits frataxin-stimulated NFS1 activity in vitro and blocks the synthesis of iron-sulfur clusters in mammalian cell culture. These findings are consistent with structural and biochemical evidence that frataxin and FDX2 compete for occupancy at the same site on NFS1 (refs. 8,9). We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich's ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich's ataxia.

BACKGROUND: Dysregulation of mitochondrial dynamics, including fusion/fission, transport, mitophagy and biogenesis, plays a crucial role in neurodegenerative diseases. However, a systematic quantitative mapping of the knowledge structure (i.e., key research themes, foundational references, and citation/collaboration clusters) and evolving research trends (i.e., research hotspots over time) in this research field is lacking.

METHODS: Empirical and review article on mitochondrial dynamics in neurodegenerative diseases, which published in English from 2005 to 2025, were retrieved from the Web of Science Core Collection and Scopus. BibliometriX, VOSviewer, and CiteSpace were applied to perform the bibliometric analysis and science mapping. Scientific performance analyses, collaborative networks of authors/institutions/countries, reference co-citation networks, keyword bursts analysis were conducted.

RESULTS: A total of 834 documents were included, revealing a rapid growth in scientific productivity from 2005 to 2025. The United States, China, and Germany were the most productive countries, with institutions such as Case Western Reserve University and Texas Tech University serving as major hubs. Co-citation and keyword burst analyses reveal a distinct temporal shift: from foundational studies of fusion/fission machinery and oxidative stress toward an integrated Mitochondrial Quality Control paradigm encompassing mitophagy, dynamics, and biogenesis. Key emerging hotspots include mitochondrial biogenesis, mitochondrial transport, and quality control mechanisms. Translational frontiers prioritize enhancing PINK1/Parkin-mediated mitophagy, inhibiting Drp1-driven excessive fission, and activating PGC-1α-dependent biogenesis.

CONCLUSION: This bibliometric study maps the intellectual structure and evolutionary trajectory of mitochondrial dynamics research in neurodegenerative diseases. It documents a field-wide paradigm shift toward a translational agenda centered on the MQC framework. Furthermore, the findings highlight the necessity of integrating pharmacological interventions with lifestyle modifications and precision medicine approaches to overcome translational barriers and develop effective disease-modifying strategies.

OBJECTIVE: We examined psychopathological conditions accounting for the highest risk of role impairment among university students.

METHOD: Cross-sectional online survey of first-year students (60 universities, 10 countries) assessing role impairment due to emotional problems in previous 30 days with the 3-item emotional subscale of the VR-36. Cross-tabulations and Poisson regression examined associations between 12 psychopathological conditions (8 probable mental disorders and 4 SITB) and socio-demographics with "significant role impairment" ("most"/"all of the time" in 2+ VR-36 items). We used machine learning methods to predict probabilities (risk) of significant role impairment based on the 12 psychopathological conditions. Observed prevalence of significant role impairment was examined within and across the 20 population ventiles to assess risk concentration using sensitivity (SN) and positive predictive value (PPV).

RESULTS: 43,990 students responded to the survey (median age = 19, IQR = 18-23). 27.1 % had significant role impairment due to emotional problems and 65.8 % had at least one psychopathological condition. Students with one or more of these conditions were more likely to have significant impairment than those without (RR = 3.9; 95 %CI: 3.6-4.2). In multivariable analyses, probable Depression and Bipolar disorders were the strongest correlates of significant impairment. Most (69.6 %) of the observed significant role impairment occurred among the roughly 35 % of respondents with highest predicted risk (PPV = 53.2 %).

CONCLUSION: Significant role impairment due to emotional problems is highly prevalent among university students. High risk of significant role impairment concentrates in one third of the students, those with several psychopathological conditions. Assessing these conditions should help identifying highest role impairment risk university students.

AIMS OF THE STUDY: Anoxic brain injury following cardiac arrest is a leading cause of death in the United States. Withdrawal of life-sustaining therapy (WLST) is a common end-of-life decision in these patients, but its contributing factors and outcomes remain poorly understood. We developed machine learning models to enable large-scale, automated phenotyping to identify patients who died following WLST.

METHODS: We used structured and unstructured EHR (Electronic Health Record) data from two major hospitals to train models that identify (1) patients with cardiac arrest and coma, and (2) patients who died after WLST. Performance was evaluated using the area under the receiver operating characteristic (AUROC) and precision-recall (AUPRC) curves, as well as other precision metrics.

RESULTS: On holdout (internal) testing the models achieved AUROC/AUPRC values of 0.984/0.968 (cardiac arrest) and 0.992/0.991 (WLST). Cross-hospital evaluation showed strong performance for the cardiac arrest phenotype but variable generalizability for the WLST phenotype, with sensitivity depending on the training site. Population-level error rates were low (<0.5 %) for the cardiac arrest phenotype; estimates for WLST varied by hospital.

CONCLUSION: These models establish a reproducible framework for automated cohort identification. Nearly half of comatose post-arrest patients died following WLST, with 42 % of these deaths occurring within 72 h, highlighting the impact of early prognostication decisions. The models enable rapid cohort identification for research on neuroprognostication, including how WLST decisions may perpetuate self-fulfilling prophecies. Broader validation across health systems and larger cohorts will improve generalizability and inform evidence-based end-of-life decision-making. Institutional review board approval: Mass General Brigham IRB BIDMC: 2022P000481; MGB: 2013P001024. All procedures complied with institutional and national ethical standards; informed consent was waived for use of de-identified data.

BACKGROUND: The involvement and sponsorship of pharmaceutical and medical technology (MedTech) companies in deprescribing and medication optimization activities raise questions about conflicts of interest. We surveyed registrants and attendees of previous International Conferences on Deprescribing to explore views on the acceptability and impact of such involvement and sponsorship.

METHODS: We conducted two unlinked, anonymous cross-sectional surveys among all participants of the 2022 and 2024 International Conferences on Deprescribing (376 unique email addresses). The first survey addressed pharmaceutical companies; the second focused on MedTech. Quantitative data were analysed descriptively. Free-text responses were analysed thematically.

FINDINGS: The response rate was 33% (n = 116/355) for the pharmaceutical survey and 20% (n = 68/335) for the MedTech survey. Trust in deprescribing information was low for pharmaceutical companies, with 52% reporting distrust (n = 47/91). Trust was somewhat higher for MedTech companies, with 27% expressing distrust (n = 14/52). Forty-eight percent (n = 42/87) said they would be less likely to attend an international deprescribing conference with pharmaceutical sponsorship versus 26% (n = 13/49) for MedTech. Among clinicians and clinician-scientists who completed the survey, 27% (n = 18/67) said pharmaceutical companies, and 27% (n = 10/37) said MedTech companies, somewhat or very much influence their deprescribing decisions.

CONCLUSIONS: Despite broad scepticism about private-sector involvement and sponsorship of deprescribing activities, views varied.

BACKGROUND AND OBJECTIVE: Accurate prediction of recurrence and progression risk in non-muscle invasive bladder cancer (NMIBC) is essential for patient counseling and risk-adapted management. However, conventional models fail to account for the decrease in baseline risk over time. We therefore examined the conditional survival free of recurrence and progression in older adults with NMIBC to develop a dynamic risk prediction model.

METHODS: We identified patients 66 to 89 years with Ta/Tis/T1 cN0 cM0 urothelial bladder cancer treated with transurethral resection of bladder tumor (TURBT) between 2000 and 2017 in SEER-Medicare. Conditional recurrence-free (RFS) and progression-free (PFS) survival were estimated using the Kaplan-Meier method. The associations of baseline characteristics with RFS and PFS at prespecified landmark times were evaluated using Cox-proportional hazards models.

KEY FINDINGS AND LIMITATIONS: A total of 39,862 patients were included. Of these, 26,339 (66%) had Ta, 11,758 (29%) had T1, and 1,765 (4%) had Tis-disease. Median follow-up was 65 months. The 60-month RFS and PFS increased from 0.39 and 0.85 at baseline to 0.73 and 0.89 at 24-months event-free survival. Conditional RFS rapidly improved within the first 24 months before plateauing. Patients with T1-disease demonstrated the greatest improvement in conditional RFS. On multivariable analyses, T stage and tumor grade were less predictive of RFS with longer landmark times. Limitations include measurement error and risk heterogeneity within grade and stage subgroups.

CONCLUSIONS AND CLINICAL IMPLICATIONS: Among patients with NMIBC, recurrence and progression risks decrease with longer event-free intervals, particularly among patients at highest risk of each event as reflected by tumor stage and grade. A dynamic risk prediction model can improve patient counseling and support risk-adapted management during follow-up.

Copper-dependent proteins (such as lysyl oxidase, LOX) require copper acquisition within the Golgi apparatus to achieve enzymatic activation, and insufficient activation of these proteins is a key factor limiting fascia regeneration. To address this issue, this study, for the first time, proposes and validates a Golgi-targeted copper delivery system (LNP-ATOX1/GHK-Cu@PCL-GelMA). In this system, GHK-Cu serves as a stable copper source to provide a sustained release of Cu ions for cellular uptake, while lipid nanoparticles (LNPs) are used to deliver mRNA encoding the copper chaperone ATOX1. Upregulation of ATOX1 facilitates the transport of copper into the Golgi apparatus via ATP7A/B, thereby enhancing the activity of copper-dependent proteins. In addition, ATOX1 promotes the copper-dependent translocation of ATP7A and Rac1 to the plasma membrane, synergistically accelerating neovascularization. In vitro studies demonstrated that this material system significantly increased copper accumulation within the Golgi apparatus, elevated LOX activity to 1.78 times that of the control group, and enhanced angiogenic capacity. In a rabbit fascia defect model, this strategy effectively promoted collagen alignment and neovascularization, improving extracellular matrix reconstruction and facilitating fascia regeneration. In conclusion, this work establishes a novel Golgi-targeted copper delivery strategy, providing a practical therapeutic approach for regenerative disorders caused by insufficient activation of copper-dependent proteins, such as fascia defects.

Members of NASPAG provide reproductive health care to adolescent patients. This document aims to provide a comprehensive overview of the recommended counseling for any clinician caring for an adolescent patient with a positive pregnancy test, while addressing legal, ethical, and clinical considerations. The document will discuss strategies for guiding patients through the pregnancy testing process, as well as various issues to consider when ordering tests, disclosing results, and managing the situation if the test is positive. Due to variability between institutions and clinical scenarios, this review will not explicitly advise for or against universal pregnancy testing in medical settings.

Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations.