Crit Care. 2025 Dec 22. doi: 10.1186/s13054-025-05758-0. Online ahead of print. ABSTRACT PURPOSE: Humoral immunity proteins-immunoglobulins, complement proteins, and antimicrobial peptides-have key antimicrobial and immunomodulatory functions in sepsis. We hypothesised that their circulating levels are lower in non-survivors, potentially resulting in impaired bacterial clearance and persistent or recurrent infections. METHODS: We performed a systematic review and meta-analysis evaluating differences in humoral immunity proteins between survivors and non-survivors in adult patients with sepsis. PubMed and Embase were searched without date restrictions. Random-effects meta-analyses were used to estimate pooled standardised mean differences (SMD) with 95% confidence intervals (CI). Sensitivity analyses included data from the MIMIC-IV ICU database, and further supplemented by three proteomic studies. RESULTS: Thirty-six studies including 6,330 patients were analysed. Thirteen reported on immunoglobulins, 17 on complement proteins, and 7 on the antimicrobial peptide heparin-binding protein (HBP). Survivors had significantly higher levels of complement proteins C3 (SMD 0.53 [0.07-0.99]) and C4 (SMD 0.51 [0.09-0.94]) compared to non-survivors. Conversely, C4a (SMD – 1.17 [-1.77 to – 0.56]) and IgA (SMD – 0.21 [-0.39 to – 0.03]) were significantly lower in survivors. No differences were found for IgG (SMD 0.00 [-0.18 to 0.18]), IgM (SMD – 0.02 [-0.13 to 0.08]), C5, C5a, or HBP. Sensitivity analyses using MIMIC-IV (n = 2,452) and proteomic datasets supported these findings. Proteomic data revealed early depletion of classical complement components (C3, C4B) and regulatory proteins in non-survivors. CONCLUSION: Sepsis non-survivors exhibit lower C3 and C4 levels and higher C4a, consistent with complement activation and/or depletion. Complement proteins may serve as potential biomarkers and therapeutic targets in sepsis. PMID:41430733 | DOI:10.1186/s13054-025-05758-0

Nat Commun. 2025 Dec 20. doi: 10.1038/s41467-025-67614-7. Online ahead of print. ABSTRACT Extrachromosomal DNAs (ecDNAs) are circular DNA molecules prevalent in human cancers that drive tumor evolution and drug resistance. Their circular topology, which disrupts topological domains and rewires regulatory circuits, has typically been studied via pairwise interactions. Here we develop ec3D, a computational method for reconstructing three-dimensional ecDNA structures from Hi-C data. Given a candidate ecDNA sequence and whole-genome Hi-C data, ec3D reconstructs spatial structures by maximizing the Poisson likelihood of observed interactions. We validate ec3D using simulated structures, previously characterized cancer cell lines, and microscopy imaging. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range regulatory interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex structures with duplicated segments, identify multi-way interactions, and identify potential intermolecular (trans) interactions. Our findings provide insights into how ecDNA’s spatial organization bypasses normal chromosomal constraints and contributes to increased oncogene expression. PMID:41422275 | DOI:10.1038/s41467-025-67614-7

Nat Commun. 2025 Dec 10. doi: 10.1038/s41467-025-67257-8. Online ahead of print. ABSTRACT Estrogen receptor-positive breast cancer remains a leading cause of cancer-related death in women, with mortality largely driven by late recurrence of treatment-resistant disease. Loss of MLH1 promotes resistance to estrogen-targeting therapies by uncoupling cell cycle progression from estrogen regulation. Here, we show that even when MLH1 is abundantly expressed, aberrant cytoplasmic localization in a subset of tumor cells drives endocrine therapy resistance by enabling estrogen-independent growth. This resistance arises from failure to undergo robust cell cycle arrest in response to endocrine therapy, creating acute dependency on CDK4/6 activity. Consequently, CDK4/6 inhibitors induce strong regression in cells with cytoplasmic MLH1 compared to cells with nuclear MLH1. As cytoplasmic localization occurs in ~11% of ER+ patients, it represents a contributor to MLH1 dysregulation. Incorporating cytoplasmic MLH1 localization into diagnostics could guide the use of CDK4/6 inhibitors in this hard-to-treat subset. PMID:41372237 | DOI:10.1038/s41467-025-67257-8

Cell. 2025 Dec 4:S0092-8674(25)01310-8. doi: 10.1016/j.cell.2025.11.014. Online ahead of print. ABSTRACT Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4^R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease. PMID:41349546 | DOI:10.1016/j.cell.2025.11.014

medRxiv [Preprint]. 2025 Nov 28:2025.11.26.25341098. doi: 10.1101/2025.11.26.25341098. ABSTRACT Sudden Unexpected Infant Death (SUID), the third leading cause of infant death, has increasing incidence and multifactorial etiology. Identification of preventative interventions has hitherto been hindered by etiologic studies limited to genetic or environmental effects in isolation. Here we report a multifactorial genome x environment analysis of SUID risk. Births in San Diego County California from 2005-2018 were linked to hospital discharge summaries and death files, yielding 212 SUID cases and 620,392 infants alive at age 1 year. Whole genome sequencing (WGS) identified probable and possible genetic etiologies in 16% and 48% of SUID cases, respectively. Genetic risks were extremely heterogeneous with 144 loci contributing 173 risks in 57% of SUID cases. Genetic risk was very strong (Prevalence Risk Ratio, PRR >99) or strong (PRR 3.7 – 99) in 12% and 34% of SUID cases, respectively. Six of sixteen significant environmental risks lost significance when SUID cases without strong or very strong genetic risk were compared with infants alive at age 1 year, while SUID risk associated with prenatal cannabis increased from adjusted hazard ratio (aHR) 3.7 to 6.0, other substance abuse from aHR 2.6 to 3.5, and black race from aHR 1.9 to 2.5. Thus, genome x environment analysis of a large cohort unveiled etiologic heterogeneity and hidden SUID risks, highlighting cannabis and genetic diseases as strong risk factors. Since preventative or therapeutic interventions were available for 83% of genetic risks, newborn screening by WGS has potential for substantial SUID reduction. Educational campaigns for SUID should emphasize perinatal cannabis avoidance. ONE SENTENCE SUMMARY: Multifactorial genome x environment analysis of a large cohort identified heterogeneous etiology in Sudden Unexpected Infant Death and unveiled strong risks from prenatal cannabis and genetic diseases. PMID:41358299 | PMC:PMC12676543 | DOI:10.1101/2025.11.26.25341098

Am J Med Genet A. 2025 Nov 26:e70007. doi: 10.1002/ajmga.70007. Online ahead of print. ABSTRACT SLC30A9 mutations are linked to Birk-Landau-Perez syndrome, which is characterized by neurodevelopmental and renal disease, thought to result from impaired zinc homeostasis. In this report, we describe a patient with a homozygous likely pathogenic SLC30A9 variant with atypical chorio-retinal degeneration, suggesting retinal involvement in SLC30A9-associated diseases. The patient has bilateral sensorineural hearing loss, developmental delay, intellectual disability, abnormal balance, and Tourette syndrome. Ophthalmic manifestations include vascular attenuation, optic disc pallor, and pigmentation. In addition, the patient is noted to have high myopia. Our case highlights the importance of broad genetic testing in diagnosing rare multi-systemic disorders. Further research into the molecular mechanisms by which SLC30A9 results in photoreceptor disease is essential to understand its role in retinal degeneration and to develop potential therapeutic strategies. PMID:41293997 | DOI:10.1002/ajmga.70007

BMJ Open. 2025 Nov 13;15(11):e098609. doi: 10.1136/bmjopen-2024-098609. ABSTRACT INTRODUCTION: In the last 60 years, newborn bloodspot screening (NBS) has expanded as a public health intervention from a single severe childhood genetic disease (SCGD) to up to as many as 80 SCGD and testing of ~40 million newborns/year worldwide. However, the gap between current NBS and its potential to increase the efficiency, effectiveness and global equity of healthcare delivery for SCGD is large and rapidly growing. There are now effective therapeutic interventions-drugs, diets, devices and surgeries-for up to 2000 SCGD. Since almost all SCGD can be identified by bloodspot genome sequencing, it has been a longstanding goal to supplement current NBS with genome sequencing-based NBS (gNBS) for all eligible SCGD. We recently described a novel gNBS platform (named Begin Newborn Genome Sequencing (BeginNGS)) with the potential to overcome several major challenges to gNBS (cost, scalability, false positives and an unprepared healthcare workforce). A pilot clinical trial of BeginNGS for 412 SCGD in a level IV neonatal intensive care unit (NICU) had a true positive rate of 4.2%, sensitivity of 83%, positive predictive value of 100% and clinical utility rate of 4.2%, indicating readiness of the platform for use in a powered, multicentre study. METHODS AND ANALYSIS: The BeginNGS study is a single group, international, multicentre, adaptive clinical trial to compare utility, acceptability, feasibility and cost-effectiveness of BeginNGS gNBS (experimental intervention) with standard NBS (control). A minimum of 10 000 neonates (aged <28 days, maximum of 100 000) will be enrolled across 25 racial, ethnic and ancestry populations and five enrolment site types (high-risk obstetrician offices, labour induction office visits, newborn nurseries, NICUs and well-baby visits). BeginNGS is gNBS for circa 2000 SCGD (currently 508 SCGD). The primary objective of the trial is to generate equitable evidence to support broad implementation of gNBS. Enrolled newborns receive both interventions (BeginNGS and standard of care NBS). Newborns who screen positive receive confirmatory testing and medical follow-up for at least 1 year to obtain outcomes data. The primary outcome measure is clinical utility, defined as the proportion of diagnoses identified by BeginNGS and state NBS during infancy that are likely to benefit (likely to have an improved outcome) from treatment. We hypothesise that BeginNGS has a greater rate of clinical utility than standard NBS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, equitable and ethical by addition or removal of SCGD and genetic variants, population enrichment (for under-represented racial, ethnic and ancestral groups) and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of gNBS, providing greater power to test utility in ultra-rare SCGD. Parents will be approached (in person, via phone or via electronic communication) to provide informed consent to enrol their newborns prenatally, postnatally in newborn nurseries or NICUs or at well baby outpatient visits. This study is part of phase III of the BeginNGS programme. Patient and public voices have been engaged in the design and execution of each BeginNGS phase through individuals and groups joining the BeginNGS consortium and participating in the family and community engagement work group. gNBS has the potential to transform the way we diagnose and treat childhood genetic diseases. Preliminary data suggest that national adoption of BeginNGS for all births has the potential to improve outcomes of >50 000 US children per year. ETHICS AND DISSEMINATION: This study was approved by the WCG Clinical institutional review board on 14 February 2024, and the most recent amendment approved on 7 October 2025 (approval number 20235517). Study findings will be shared through research consortium workshops, national and international conferences, community presentations and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT06306521. PMID:41238356 | DOI:10.1136/bmjopen-2024-098609

Cell Stem Cell. 2025 Nov 3:S1934-5909(25)00374-1. doi: 10.1016/j.stem.2025.10.006. Online ahead of print. ABSTRACT Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches. PMID:41187745 | DOI:10.1016/j.stem.2025.10.006

J Pediatr. 2025 Oct 31:114889. doi: 10.1016/j.jpeds.2025.114889. Online ahead of print. ABSTRACT OBJECTIVE: To compare 1-year healthcare costs and quality-adjusted life years (QALYs) for two diagnostic strategies in critically ill infants with suspected genetic disorders: 1) early rapid genome sequencing (within 7 days of admission) for all infants, and 2) early targeted neonatal gene sequencing (NewbornDx) for all infants, followed by later rGS (after 7 days) for undiagnosed infants. STUDY DESIGN: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a multicenter, prospective study that enrolled 400 hospitalized infants under one year of age with suspected genetic disorders. All participants underwent both rGS and NewbornDx. Using patient-level GEMINI data and 2023 Medicare rates, we developed a decision tree to compare total costs and QALYs over a 1-year period for these two hypothetical testing strategies. RESULTS: The diagnostic yield and upfront testing costs were higher for rGS (49%; $12,297) than NewbornDx (27%; $2,449; p<0.05). As neither early testing nor diagnosis significantly affected QALYs, we conducted a cost-minimization analysis, focusing solely on cost differences between strategies. Over one year, early rGS was estimated to save $158,592 per patient (95% CI: $63,701-$253,292) compared with early NewbornDx with later rGS if necessary. CONCLUSIONS: Early rGS results in substantial healthcare cost savings, highlighting the need to expand reimbursement to improve access early in a hospitalization for critically ill infants. PMID:41177396 | DOI:10.1016/j.jpeds.2025.114889

HGG Adv. 2025 Oct 25:100539. doi: 10.1016/j.xhgg.2025.100539. Online ahead of print. ABSTRACT Human development is a complex process that requires precise control of gene expression through regulatory proteins. Recently, heterozygous variants in PRR12, encoding a proline-rich regulatory protein, were found to cause a variable phenotype involving developmental delay/cognitive impairment, neuropsychiatric diagnoses, structural eye anomalies, congenital heart and kidney defects, and poor growth. QSER1, encoding glutamine- and serine-rich protein 1, represents a paralog of PRR12 that shares 28% overall identity at the protein level and stronger conservation (43%) in the C-terminal region. QSER1 deficiency in human embryonic stem cells causes hypermethylation of many key transcription factor genes, implicating it in the development of multiple organs. Here we present three unrelated individuals with neurodevelopmental phenotypes, variable other multisystem anomalies, and heterozygous variants in QSER1. This includes two novel de novo frameshift alleles (p.(Lys1565Argfs*36) and p.(Phe896fs*28)), and one ultra-rare canonical splice site variant resulting in a combination of abnormal transcripts, frameshift (p.(Glu1393Glyfs*26)) and in-frame deletion of a conserved amino acid (p.(Glu1393del)), supported by in silico predictions and minigene assays. In situ hybridization revealed dynamic and broad expression of qser1 in zebrafish embryos, including a strong presence in the developing brain. These data suggest a possible role for QSER1/qser1 in vertebrate development and human disease. PMID:41139957 | DOI:10.1016/j.xhgg.2025.100539