EBioMedicine最新文献

Background: Due to the overlapping clinical features of neurodegenerative dementia (NDD)-including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), accurate diagnosis remains challenging in early stages. Multiple dementias can be caused by short tandem repeat (STR) expansions. However, systematic investigation of known pathogenic STRs in large dementia cohorts remains lacking.

Methods: We used ExpansionHunter (EH) to assess 22 neurodegenerative disease-associated STRs in whole-genome sequencing (WGS) data from 950 patients with AD, 222 patients with FTD, 165 patients with DLB, 231 patients with PSP, and 1522 cognitively normal controls. Repeat primed-polymerase chain reaction (RP-PCR) was performed to validate EH calls that exceeded the intermediate thresholds of STR. We also attempted to use ExpansionHunter Denovo (EHDn) to detect C9orf72 expansions missed by EH.

Findings: EHDn improved the detection rate of C9orf72 expansions. After sample quality control, 33 PCR-validated pathogenic expansions were identified in nine genes (C9orf72, ATXN8OS, NOTCH2NLC, HTT, FMR1, DMPK, AR, CACNA1A, and PPP2R2B) among 1559 patients with NDD, accounting for 2.12% of cases. Burden-based logistic regression analyses demonstrated that the presence of pathogenic STR expansions was significantly associated with NDD status (OR = 3.57, p = 4.70 × 10^-2). Additionally, intermediate-length TBP alleles showed a nominal enrichment in PSP compared with controls (2.61% vs 0.54%; OR = 6.25, p = 2.00 × 10^-2).

Interpretation: Our findings provide evidence for the clinical pleiotropy of STRs in NDD and their involvement in NDD pathogenesis.

Funding: This study was supported by the National Natural Science Foundation of China(U22A20300, 82502244, 823714434, 82071216), the National Key R&D Program of China(2023YFC3603700), STI2030-Major Projects(2021ZD0201803), Outstanding Youth Fund of Hunan Provincial Natural Science Foundation(2024JJ2097), Youth Fund of Hunan Provincial Natural Science Foundation(2025JJ60696), Hunan Health Commission Grant(20232460), Postdoctoral Fellowship Program of CPSF(GZC20233185), China Postdoctoral Science Foundation (2025M772318), and the Scientific Research Program of FuRong Laboratory (2024PT5108).

Background: Hip fracture is a major cause of morbidity and mortality in ageing populations. Although emerging evidence suggests a role of metabolomic profiles in osteoporosis, their association with hip fracture risk has not been well established. We aimed to investigate plasma metabolomic profiles associated with risk of hip fracture.

Methods: We conducted a nested case-control analysis (N = 1234) including 617 hip fracture cases and 617 matched controls (discovery data set) and a prospective cohort analysis including 10,031 participants (replication data set; 475 incident hip fractures) within the Nurses' Health Study and the Health Professionals Follow-Up Study. Conditional logistic regression was applied in the case-control analysis to estimate odds ratios (ORs) per 1 SD increase in metabolite levels, and Cox proportional hazards models were used in the cohort analysis. A total of 653 plasma metabolites were examined, with false discovery rate (FDR) correction applied to control for multiple testing.

Findings: In the nested-case control analysis, six metabolites related to phospholipid metabolism were consistently associated with hip fracture risk (P < 0.05), with five showing inverse associations. After FDR correction, 1-stearoyl-2-dihomo-linolenoyl-GPC, a phosphatidylcholine metabolite, remained significantly associated with lower hip fracture risk (OR 0.76, 95% CI 0.67-0.87, FDR = 0.02), and this association was replicated in the cohort analysis. At the class level, phosphatidylcholine and phosphatidylethanolamine were associated with reduced hip fracture risk (FDR = 0.01 and 0.05, respectively), with similar patterns in the replication cohort.

Interpretation: Plasma metabolomic profiles, particularly phospholipid metabolism pathways and phosphatidylcholine, are associated with hip fracture risk. These findings suggest altered phospholipid metabolism may contribute to the development of hip fracture and highlight potential metabolic targets for prevention.

Funding: This study was supported by NIH grants.

Sepsis is a complex life-threatening condition involving immune dysregulation, endothelial dysfunction, and multi-organ failure. To investigate molecular and systemic processes driving disease progression, in vitro, in vivo, and ex vivo experimental methods have been developed. While these systems have advanced understanding of immune activation, cytokine signalling, and organ injury, differences in complexity, reproducibility, and alignment with human pathophysiology have limited the translation of many promising preclinical findings into clinical success. This review examines current literature on sepsis systems, evaluating them in terms of biological complexity, reproducibility, ethical constraints, and clinical applicability. In parallel, it discusses the potential use of microfluidic technology, particularly organ-on-chip, in replicating human physiology and capturing key features of sepsis. By comparing conventional and advanced systems, this review outlines challenges in sepsis research and identifies key directions for a more integrated approach to sepsis modelling, aiming to improve translational outcomes and therapeutic discovery. We aim to provide a structured basis for comparing models when selecting approaches for a given question or candidate therapy.

Background: Tocilizumab, an interleukin-6 receptor inhibitor, is a promising cytoprotective agent selected by the Stroke Preclinical Assessment Network. It showed a protective effect on infarct volume and functional outcomes in animal stroke models.

Methods: In this investigator-initiated, multicentre, randomised, double-blind, placebo-controlled trial, patients with acute ischaemic stroke undergoing EVT were recruited. Eligible patients were randomly assigned (1:1) to receive tocilizumab or placebo treatment. Both patients and investigators were blinded to the treatment assignments. A single dose of tocilizumab (240 mg) or placebo was administered intravenously as soon as possible within 24 h after stroke onset and within 1 h after randomisation. The primary efficacy outcome was the change in infarct volume from baseline (before EVT and start of study drug) to 72 h. Primary and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT06238024.

Findings: A total of 108 patients were enrolled (n placebo = 57; n tocilizumab = 51). The median change in infarct core volume between baseline and 72 h was 27.0 mL (7.6-62.4) in the placebo group and 8.8 mL (IQR 3.4-20.6) in the tocilizumab group (adjusted mean difference in cubic root volume [ml^1/3] -0.41, 95% CI -0.79 to -0.03, P = 0.04, wald-type test). Symptomatic intracranial haemorrhage occurred in 7 (12%) patients in the placebo group and 3 (6%) patients in the tocilizumab group. The incidence of all-cause death and serious adverse events were similar between the two groups.

Interpretation: Among patients with acute ischaemic stroke undergoing endovascular treatment, tocilizumab tended to reduce infarct volume growth at 72 h post-treatment and is well tolerated. Future trials are necessary to confirm the beneficial effect of tocilizumab on long-term functional outcome following stroke.

Funding: Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Nova Program, National Natural Science Foundation of China, Beijing Natural Science Foundation.

Background: The ways in which Mycobacterium tuberculosis (Mtb) infection affects host metabolism and its implications for disease pathogenesis remain poorly understood. Understanding how Mtb shapes the metabolic state of the host could lead to nutritional and host-directed therapies to improve TB outcomes.

Methods: We performed high-resolution metabolic and lipid profiling on male rhesus macaques infected with Mtb (n = 17). Serial plasma samples were analysed beginning at the time of infection and up to 15-16 weeks post infection. Observed host metabolic changes were examined in a cohort of Mtb-infected (TBI, positive QuantiFERON Gold [QFT]; n = 92) and Mtb-uninfected (TBU, negative QFT; n = 102) participants as well as those with pulmonary TB (PTB; n = 68).

Findings: Using principal component analysis, we found the greatest metabolic changes in NHPs occurred 15-16 weeks after experimental infection. Metabolic changes were characterised by declines in saturated, monounsaturated, and polyunsaturated long chain fatty acids (LCFAs) including linoleic acid, linolenic acid, docosahexaenoic acid, and palmitoleic acid. Humans with TBI also experienced significant declines in plasma concentrations of nearly all species of LCFAs 6 months after Mtb exposure. In participants with PTB, LCFAs were further depleted relative to those with TBI but gradually normalised six months post-TB treatment.

Interpretation: Our study shows the host metabolic response to infection with Mtb is characterised by the systemic depletion of host lipids, which is exacerbated in persons with PTB. Interventions that supplement host lipids should be tested to determine their impact on TB outcomes.

Funding: This work was supported by grants from the U.S. National Institute of Allergy and Infectious Diseases (NIAID) [R01 AI182244, R21 AI178324, K23 AI144040, P30 AI168386, P30 AI050409, K24 AI114444, U19 AI111211]; and the National Center for Advancing Translational Sciences [UL1 TR002378], Bethesda, MD, USA. The study sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

Background: Early-life exposure to exogenous chemicals can disrupt neurodevelopment. Perfluorohexanesulfonic acid (PFHxS), a legacy PFAS widely used and detected globally, remains poorly studied for its neurotoxicity.

Methods: CD-1 mice (n = 90 dams) were exposed to human-relevant dose of PFHxS from gestational day (GD) 0-17. PFHxS levels were measured in maternal plasma and foetal/offspring medial prefrontal cortex (mPFC) (GD 18, postnatal weeks [PNW] 4 and 10) using liquid chromatography tandem mass-spectrometry (LC-MS/MS). Offspring social behaviour was assessed with the Three-Chamber social test. Neurotransmitters in mPFC of PNW 10 offspring were profiled by LC-MS/MS, transcriptomics was performed on GD 18 and PNW 4 mPFC, GABAergic neurons were quantified by immunofluorescence, and glutamate decarboxylase (GAD) expression by western blotting. PFHxS-GAD interactions were examined via molecular docking and microscale thermophoresis (MST).

Findings: Maternal plasma reached 5.1 ± 0.1 ng/mL, equivalent to human biomonitoring data, and PFHxS accumulated in foetal mPFC (68.1 ± 4.1 pg/g). PFHxS exposure induced social deficits at PNW 4 and 10, which were more pronounced in males. The mPFC of PFHxS exposed offspring exhibited an excitatory-tilted neurotransmitter profile, feature with reduced γ-aminobutyric acid (GABA, 90.6 ± 12.2 vs. 70.2 ± 4.3 μg/g, p = 0.008). The differentially expressed genes were enriched in GABAergic and synaptic signalling pathways. Despite unchanged percentage of GABAergic neuron and GAD expression, metabolite GABA/glutamate ratio was attenuated, suggesting impaired GAD function. Both molecular docking and MST suggested moderate-to-strong binding affinity between PFHxS and GAD, affecting GABA synthesis.

Interpretation: Gestational PFHxS exposure at human-relevant levels impairs offspring social behaviour, likely via disruption of GAD-mediated imbalance in excitation/inhibition.

Funding: This work was provided by grants from the National Natural Science Foundation of China (82404221 and 82373586), Anhui Provincial Natural Science Foundation (2308085Y50 and 2408085QH275), Education Department of Anhui Province for Excellent Young Scientist (2022AH030076), and funding from Center for Big Data and Population Health of IHM (JKS2022020).