EBioMedicine最新文献

Background: The non-polio enteroviruses (NPEV) enterovirus D68 (EV-D68) and enterovirus A71 (EV-A71) are highly prevalent and considered pathogens of increasing health concern due to their neurotropic potential. Severe neurological complications of usually mild and self-limiting NPEV infections include meningitis, encephalitis, and acute flaccid paralysis, especially in children and immunocompromised patients. Despite clinical burden, the underlying neuropathogenesis of EV-D68 and EV-A71 remains poorly understood. In particular, the impact of the infection on neural function has not been clearly elucidated.

Methods: We investigate the replication kinetics, cellular tropism, pro-inflammatory cytokine responses, and electrophysiological effects of EV-D68 and EV-A71 infection in a physiologically relevant human pluripotent stem cell-derived neural co-culture model, consisting of excitatory neurons and astrocytes using a micro-electrode array platform.

Findings: All NPEV replicated efficiently in the neural co-cultures and infection was detected in both neurons and astrocytes. Both EV-D68 and EV-A71 infection resulted in decreased neural activity in the co-cultures, with the EV-D68 clade A2/2018 inducing the most rapid and robust negative effect on neural co-cultures, followed by EV-D68 clade B3/2019. Despite the lack of release of infectious virus particles of EV-D68 B3/2019 in the supernatant, the infection could spread in the cultures and reduce neurotransmission. Higher viral load of EV-A71 did not result in enhanced impairment of neural function.

Interpretation: Our results demonstrate that neurotropic NPEVs lead to disruption of spontaneous neural activity in a virus-specific manner, which does not correlate with their replication efficiency.

Funding: The Netherlands Organisation for Health Research, Development and the Dutch Research Council, the Netherlands Organ-on-Chip Initiative.

Infectious diseases (IDs) remain a major threat to global health and societal stability. Because most emerging IDs in humans are zoonotic in origin and shaped by environmental contexts, effective prevention and control call for a One Health approach. Machine learning is widely used for ID modelling and forecasting but often lacks interpretability to explain predictions or guide public health action. Explainable AI (XAI) makes complex models interpretable, enabling attribution of predictions and identification of key outbreak drivers. In this Personal View, we argue that embedding XAI within a One Health framework offers a new organising principle for ID intelligence. We highlight emerging applications in surveillance and forecasting, zoonotic spillover, antimicrobial resistance monitoring and optimisation of resource allocation. We also outline key challenges, including data harmonisation, governance, privacy protection and equitable distribution of risks and benefits. Advancing XAI-enabled One Health systems will require collaboration across sectors and methodological innovation.

The COVID-19 pandemic drove the rapid development of assays to ascertain immune responses, and laboratories were required to adapt to difficult and quickly changing circumstances. While flexibility and innovation were essential, they also introduced heterogeneity in methods, reagents, and reporting practices between labs. This lack of harmonisation made it difficult to compare findings across studies, slowing evidence synthesis, and limiting the usefulness of data for modelling efforts and policy guidance. Drawing on our team's experience synthesising and modelling vaccine immunogenicity data during the pandemic, we discuss the long-term challenges of standardising human immunology research that were highlighted by the COVID-19 pandemic. We argue that vaccine immunogenicity studies require standardised reporting and quality assessment tools. We propose practical solutions to support comparability of laboratory-based practices, while preserving methodological diversity. By implementing changes before the next public health crisis, future research can avoid waste, strengthen certainty, and maximise policy and practice impact.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, solar-powered oxygen concentrator systems were established in rural hospitals of conflict-affected, hard-to-reach regions in Somalia to address acute gaps in oxygen access. We assessed the outcome of treatment of patients and risk factors for death among patients receiving oxygen for hypoxaemia in these settings in Somalia.

Methods: We analysed data on all patients receiving medical oxygen for hypoxaemia in six rural hospitals in Somalia equipped with solar-powered oxygen concentrator systems during the pandemic. The endpoint of the analysis was death. We used the Kaplan-Meier survival analysis and the log-rank test to compare survival curves. We used Cox proportional hazard model to determine the predictors of death.

Findings: We included 1460 patients (age from 1 day to 90 years) with hypoxaemia (peripheral blood saturation level <90%) treated with solar-powered oxygen concentrator systems in six rural hospitals in Somalia between February 2021 and December 2023. There were 103 deaths, 22 of which occurred within 24 h of detection of hypoxaemia in the hospital. The Kaplan-Meier survival analysis showed the cumulative hazard of death at 1.5% (95% CI 1.1-2.3%) during the first 24 h of admission, 11.9% (95% CI 8.1-17.3%) on day 7 post-admission conditional on surviving the first 24 h. Patients aged 1-11 months had a significantly increased hazard of death (aHR 7.71 [95% CI 2.54-23.41]) while those admitted with birth asphyxia were 4 times more likely to die compared to patients with pneumonia (aHR 3.83 [95% CI 1.12-13.06]). Improved patient outcomes were associated with higher oxygen saturation levels on admission. One unit increase in SpO₂ level was associated with nearly 10% decrease in the hazard ratio of death (aHR 0.9 [95% CI 0.88-0.92]).

Interpretation: The availability of solar-powered oxygen concentrator systems can be a reliable solution to address oxygen insecurity in fragile, vulnerable health systems and conflict-affected countries, and can be associated with improved patient outcomes. Early detection and rapid initiation of oxygen therapy for hypoxaemic illness can support improved survival in patients of all ages, and with different conditions, if health care facilities without reliable electricity are fitted with solar-powered oxygen concentrator systems.

Funding: The authors have received no funding for this study.

Background: Heart failure (HF) is a currently incurable disorder that increases the risk for stroke and sudden cardiac death. Shortened telomeres have been linked to the development of cardiomyocyte abnormalities and dysfunction, and telomere reprotection has become a favourable strategy for designing novel heart failure therapies. This study aims to design a pan-HF gene therapy where modified human telomerase expression is driven by cardiac troponin promoter and to evaluate cardiac protection.

Methods: Telomere shortening was determined in cardiomyocytes from Macaca fascicularis (cynomolgus monkey) and patients with HF by quantitative fluorescence in situ hybridisation (Q-FISH) assays. We bioengineered a catalytic inactivation and nuclear retaining modified human TERT (telomerase reverse transcriptase) gene therapy (AAV9-modhTERT^{Y707F, D868A}). In transverse aortic constriction (TAC)-induced WT and myocardial p53 deficient (p53^CKO) mice HF model, as well as Ang II-induced human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we evaluate cardiac protection of modhTERT via echocardiography, RNA-sequence, Western blotting, Proteome Profiler Mouse XL Cytokine Array panel, RT-qPCR, transmission electron microscopy, and immunofluorescence.

Findings: AAV9-modhTERT^{Y707F, D868A} reversed cardiac function decline and prevented onset of cardiac fibrosis in TAC-induced HF murine. At cellular level, modhTERT alleviated contractile dysfunction and aberrant calcium handling in cardiomyocytes isolated from TAC hearts and prevented Ang II-stimulated hiPSC-CMs hypertrophy. Overexpression of modhTERT blocked telomeric DNA damage response (DDR) and p53 ser15-phosphorylation. Myocardial chronic inflammation and reactive oxygen species (ROS) levels were reverted by modhTERT overexpression. Additionally, modhTERT rescued mitochondrial ultrastructure, increased mitochondrial DNA (mtDNA) copy, and restored ATP production through restoration of PGC-1 α and TFAM expression.

Interpretation: We provide evidence that telomere re-protection confers cardiac protection and may serve as a potential gene therapeutic option for treating heart failure.

Funding: This research was supported by the National Natural Science Foundation of China (82070248, 82300282, 82300476), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (0900000024), 2023 Shanghai Action Plan for Promoting Scientific and Technological Innovation and Industrial Development of Gene Therapy (23J11900600).

The pathoanatomy of local cancer spread is approached by the ontogenetic cancer field model, deduced from aspects of evolution, development, immunity, and wound healing/regeneration in multicellular animals, postulating: (1) Cancer cells canonically respond to the disruption of tissue homeostasis caused by their uncontrolled proliferation with progressive de-differentiation, which paradoxically enlarges the cancer wound instead of healing it. (2) The de-differentiating cancer cells adhere in reverse sequence to a principle of topological order laid down during embryonic development by the metazoan cell type differentiation trajectory. The model predicts with high anatomical accuracy ontogenetic stage-dependent permissive tissue territories for local cancer propagation, i.e., cancer fields, as demonstrated for cancers of the alimentary and genital tracts. Assuming the 'export' of the local cancer field into the draining lymph nodes by tissue macrophages and regulatory T cells, the model is also applicable for regional carcinoma spread. The clinical translation into cancer field surgery has led to a marked reduction of locoregional recurrences and to increased cure rates.

Background: Circadian rhythms play a crucial role in human health, including reproductive health. Disruption of circadian rhythm is associated with female infertility. However, how circadian disruption affects ovarian function remains unclear. The main purpose of this study is to verify the impact of long-photoperiod exposure on follicular development and ovarian function.

Methods: In this study, we employed long-photoperiod (LP) conditions (18 h lightness/6 h darkness) in rats to mimic increased light exposure in human lifestyles. Hormone indicators, oestrus cycle, ovary morphology, follicular development and ovulation were used to validate the ovarian function. To investigate the underlying mechanisms, a series of experiments, including RNA sequencing, metabolomics, ChIP/qPCR, transmission electron microscopy, immunofluorescence, and western blotting, were conducted. Additionally, the impact of nicotinamide mononucleotide (NMN) on ovarian function was evaluated using the mentioned methods above.

Findings: LP exposure reduced the number of growing ovarian follicles and retrieved oocytes. Mechanistically, LP exposure led to granulosa cell oxidative stress and mitochondria dysfunction via inhibiting SIRT3 activity and SOD2 deacetylation. Metabolomic analysis showed that LP exposure lowered NAD⁺ levels, a cofactor that determines SIRT3 deacetylase activity. Further study showed that NAMPT, the rate-limiting enzyme in NAD⁺ synthesis, exhibited a circadian rhythmic expression pattern in the ovary, and LP exposure disrupted the ovarian circadian expression of NAMPT through the core clock protein BMAL1. Treatment with the NAD⁺ metabolic precursor nicotinamide mononucleotide could ameliorate mitochondria function and increase the numbers of antral follicles (49.56 ± 0.55 vs. 21.83 ± 1.35, p = 0.001) and retrieved oocytes (18.40 ± 1.91 vs. 3.80 ± 1.16, p < 0.001) in LP-exposed rats.

Interpretation: Our study demonstrates that circadian rhythm disruption by LP exposure affect follicular development and ovulation through impaired NAD⁺ metabolism, and suggests targeting NAD⁺ pathways as a potential therapeutic strategy for ovarian diseases.

Funding: This work was supported by the National Natural Science Foundation of China - Joint Fund for Regional Innovation and Development, the National Natural Science Foundation of China, the National Key Research and Development Program of China.

Background: Pathogenic germline variants in certain genes are associated with somatic tumour mutation signatures. The use of somatic tumour mutation data has the potential to improve the identification of true pathogenic variants but remains underexplored. We investigated the integration of tumour homologous recombination (HR) deficiency status as a predictor of pathogenicity for germline BRCA1 and BRCA2 variants, building on the established link between HR deficiency and germline pathogenic variants in these genes.

Methods: We analysed breast tumour whole-genome sequence and matching germline data from 350 patients across four datasets: Familial Breast Cancer (N = 77), The Cancer Genome Atlas (TCGA-BRCA, N = 96), the MAGIC study (N = 136), and Q-IMPROvE (N = 41). A total of 15,156 germline variants (including structural variations) in BRCA1, BRCA2, and other cancer genes (ATM, BARD1, BRIP1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53) underwent variant curation. Patients were categorised based on germline classification as BRCA1 positive (N = 27), BRCA2 positive (N = 21), and BRCA1/2 negative (N = 232), excluding those with BRCA1/2 variants of uncertain significance (N = 8) and pathogenic or only uncertain variants in other cancer genes (N = 62). Somatic HR status (deficient or proficient) was predicted using three algorithms: HRDetect, CHORD, and HRDsum. HR-deficient and HR-proficient status were significant predictors of germline BRCA1/2 pathogenic variant status (positive and negative directions).

Findings: The CHORD algorithm, which estimates BRCA1 and BRCA2 subtype specifically, added precision contributing evidence towards pathogenicity for the corresponding gene, reaching pathogenic moderate strength for the relevant gene-subtype. Finally, we assessed CHORD HR predictions for variants of uncertain significance in BRCA1 and BRCA2, and reported their tumour HR status for potential use as additional evidence in variant curation.

Interpretation: Analysis across multiple tumour whole-genome sequencing datasets has shown that HR status prediction algorithms can separate profiles for BRCA1 and BRCA2 pathogenic variants and provide further evidence at increased weight to aid in the classification of germline BRCA1 and BRCA2 variants. Tumour sequencing offers a promising strategy for reducing the uncertainty in germline variant interpretation.

Funding: This work was funded by the National Breast Cancer Foundation.