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Abstract：Background:Early recognition of sepsis remains difficult in clinical practice because conventional humoral biomarkers such as C-reactive protein, procalcitonin, and interleukin-6 (IL-6) exhibit unfavorable, slow-release kinetics and rise hours after the onset of infection. Flow cytometry enables upstream, cell-based immunomonitoring, but its clinical use is restricted by poor standardization of fluorescence measurements. In this study, the neutrophil cellular response capacity (CRC) was developed and evaluated as a standardized approach for rapid assessment of systemic inflammation in bacteremia and sepsis.Methods:The CRC is based on a flow cytometry-based framework that defines a stable maximal stimulation reference point for neutrophil granulocytes. The CRC was evaluated in a human ex vivo whole blood bacteremia model with graded exposure to Escherichia coli and compared with humoral inflammatory markers. Next, the CRC was assessed in a prospective intensive care unit sepsis cohort. Moreover, preliminary validation was performed in an independent sepsis cohort and in patients undergoing cardiac surgery.Results:In the bacteremia model, the CRC of neutrophil markers CD10, CD11b, and CD66b increased in a dose-dependent manner with increasing bacterial burden and detected inflammation at lower pathogen burdens than IL-6 and other humoral mediators, with a superior area under the receiver operating characteristic curve. In clinical sepsis, the CRC discriminated patients from age- and sex-matched healthy volunteers, with the CRC of CD11b showing the highest diagnostic performance. CRC values increased over time in patients with sepsis, consistent with immunological recovery. The maximal stimulation reference point for CD11b remained stable across inflammatory states, cohorts, and instruments. In addition, the CRC more precisely captured the onset and resolution of surgery-induced inflammation than conventional biomarkers.Conclusions:The CRC provides a rapid, standardized, and robust cell-based immunomonitoring tool that outperforms traditional humoral markers in experimental bacteremia and reliably identifies sepsis in clinical cohorts, strongly supporting its use as a novel biomarker for earlier, more precise sepsis diagnosis and monitoring.Keywords：sepsis;Bacteremia;Immunomonitoring;Neutrophil granulocytes;flow cytometry;Escherichia coli (E. coli)3|0|0
Updated：2026-05-11 -
Abstract：Nanobodies (Nbs), the antigen-binding single-domain fragments derived from camelid heavy-chain antibodies (Abs), have rapidly become a focus of biomedical research due to their compact size, high stability, strong antigen affinity, and ease of molecular engineering. This review systematically outlines their structural and functional features, current strategies for acquisition, screening, optimization, and large-scale production, and comprehensively discusses their wide-ranging applications in therapeutics, diagnostics, and basic research. Specifically, Nbs have shown outstanding efficacy in tumor, toxin, infectious, and cardiovascular disease treatments, while serving as versatile tools for molecular imaging, biosensing, protein purification, structural analysis, and intracellular regulation. The challenges of immunogenicity, off-target effects, and industrial-scale manufacturing are also critically examined. Furthermore, the integration of artificial intelligence in structure prediction, de novo design, and immunogenicity assessment has opened powerful new avenues for rational Nb engineering. Combined with emerging technologies such as gene therapy, nanomaterial delivery, and multispecific architectures, these advances promise to accelerate clinical translation. Overall, Nb technology is poised to become a cornerstone of next-generation precision medicine and biotechnology, offering innovative solutions for disease diagnosis, targeted therapy, and molecular discovery.Keywords：Nanobody (Nb);Molecular structure;Functional characteristics;Preparation methods;Diagnostic and therapeutic applications0|0|0Updated：2026-05-11 -
Abstract：Background:Spiral ganglion neurons (SGNs) relay auditory sensory information from the cochlea to the brain. Their loss results in permanent hearing impairment in humans due to their limited regenerative capacity. Progress in hearing restoration has been constrained by the inaccessibility of human inner ear tissue and challenges in generating functionally mature human SGN-like neurons from stem cells in vitro.Methods:To generate human SGN-like neurons from human induced pluripotent stem cells (hiPSCs), we recapitulated key signaling pathways involved in human inner ear development. On day (D) 11 of differentiation, nerve growth factor receptor-positive cells (precursors of pre-placodal ectoderm and neural crest) were isolated using magnetic sorting. From D18 to D25, cultures were treated with sonic hedgehogs to induce otic neural progenitors. Neuronal maturation was subsequently promoted by a cocktail of brain-derived neurotrophic factor, neurotrophin-3, and insulin-like growth factor-1, which supports SGN development. Cellular identity and functionality were assessed using single-cell RNA sequencing, immunocytochemistry, whole-cell patch-clamp electrophysiology, co-culture assays, and calcium ion (Ca2+) imaging.Results:hiPSC-derived SGN-like neurons exhibited morphological, molecular, electrophysiological, and functional characteristics of SGNs in vivo. Neurons acquired bipolar morphology and were wrapped by glial cells. Transcriptomic analysis revealed that SGN-like neurons were distinct from other neuronal lineages and showed similarity to type I and type Ⅱ SGNs based on expression of synaptic and intrinsic excitability-related genes. Electrophysiological recordings revealed progressive hyperpolarization of resting membrane potential and emergence of overshooting action potentials, consistent with neuronal maturation. In co-culture systems, human SGN-like neurons formed functional synaptic connections with mouse cochlear hair cells and cochlear nucleus neurons, evidenced by Ca2+ transients and induction of the immediate early gene c-Fos.Conclusions:This study reports a robust and reproducible protocol for generating human SGN-like neurons from hiPSCs, providing a versatile platform for studying human auditory development, disease modeling, drug screening, and cell-based therapies for hearing restoration.Keywords：Spiral ganglion neurons (SGNs);Human induced pluripotent stem cells (hiPSCs);Auditory neurons;cochlea;Inner ear1|1|0Updated：2026-05-11 -
Abstract：Three-dimensional (3D) bioprinting integrates engineering, materials science, and biology to fabricate living tissues with precise spatial control. By enabling the layer-by-layer deposition of cells and biomaterials, it overcomes many limitations of traditional scaffold-based tissue engineering and offers new opportunities for regenerative and personalized medicine. This review presents a comprehensive overview of recent advances in 3D bioprinting. It introduces a systematic, ASTM-aligned classification of key bioprinting modalities, extrusion, jetting, and vat photopolymerization, along with their respective material and biological design requirements. It also summarizes recent progress in bio-ink development and crosslinking strategies that improve print fidelity and functional tissue maturation. In addition, the review highlights applications in both systemic disease modelling and treatment (such as cardiovascular, endocrine/metabolic, and neurodegenerative disorders) and localized tissue repair (including skin, musculoskeletal, cartilage, and bone), emphasizing their relevance to civilian healthcare and military medicine. By combining technological innovation, biological insights, and regulatory considerations, this review outlines how advances in multi-modal bioprinting and intelligent process control can accelerate the translation of laboratory research into clinically viable, patient-specific therapies, driving the next generation of regenerative medicine.Keywords：Biofabrication;Three-dimensional (3D) bioprinting;Bio-inks;Disease modelling;Tissue regeneration;Clinical translation;Multi-modal bioprinting;Machine learning (ML);Regulatory challenges0|0|0Updated：2026-05-11 -
Abstract：From cold-weather training to deployments in high altitude and arctic conditions, frostbite injury and its sequelae remain a serious concern in military operations. Frostbite harms tissue in two distinct ways. The first involves ice crystal formation within tissue, resulting in mechanical damage and ischemia. The second occurs secondary to the inflammatory and prothrombotic state caused by reperfusion from rewarming frozen tissue. Frostbite injuries can be classified in a number of ways, but no perfect system exists. Initial work-up and diagnosis are primarily clinical. However, in equipped treatment facilities, advanced imaging modalities such as technetium-99m (99mTc) bone scintigraphy, magnetic resonance angiography, single-photon emission computed tomography/computed tomography (SPECT/CT), and more can play a role in diagnosis and treatment. In resource-constrained environments, such as the deployed setting, management should involve an algorithmic approach. After concurrent hypothermia and/or trauma have been evaluated for and treated, active rewarming should take place so long as there is no risk of refreezing. During re-warming, surgical consultation and evacuation considerations should be considered. Once evacuated to a definitive treatment facility, thrombolytic as well as other therapies may be indicated. Unless there is evidence of severe damage or infection, surgical management is typically delayed until injury margins are fully demarcated. Longer-term prognosis is dependent on severity, with deeper injuries often resulting in longer hospital stays, more amputations, and chronic disability. Looking forward, future frostbite research should aim to bridge field and hospital care with the goal of minimizing tissue loss and accelerating functional recovery.Keywords：Cold weather injury;Frostbite;Field care of frostbite;Military medicine1|0|0Updated：2026-05-11 -
Abstract：Background:Mitochondrial quality control is essential for limiting myocardial injury induced by ischemia/reperfusion(I/R), a major contributor to adverse outcomes after reperfusion therapy. This study aimed to determine whether the deubiquitinase ubiquitin-specific protease 18 (USP18) regulates mitophagy during cardiac I/R injury and thereby represents a potential therapeutic target to attenuate myocardial I/R injury.Methods:Cardiac-specific USP18 knockout mice were subjected to cardiac I/R injury. To elucidate the role of USP18 in mitophagy regulation and cardiac I/R injury, we performed RNA sequencing, proteomic mass spectrometry, transmission electron microscopy, and mitophagy assays. In parallel, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of USP18, knockdown of Parkin and phosphatase and tensin homolog-long (PTEN-L), and administration of an anti-PTEN-L neutralizing antibody were used to elucidate the underlying mechanisms. Additionally, serum samples from patients with ST-segment elevation myocardial infarction (STEMI) were collected to assess clinical relevance.Results:USP18 expression was upregulated in mouse hearts following I/R injury and in ischemic human heart tissue. Cardiac-specific USP18 deficiency mitigated I/R-induced acute myocardial injury, mitochondrial dysfunction, and adverse cardiac remodeling, whereas USP18 overexpression exacerbated these pathological changes. Mechanistically, USP18 interacted with PTEN-L, which in turn bound to and inhibited the phosphorylation and translocation of Parkin to mitochondria, thereby suppressing mitophagy. Parkin knockdown abolished the cardioprotective effects conferred by USP18 deficiency, whereas PTEN-L knockdown reversed the detrimental effect of USP18 overexpression. Moreover, PTEN-L also exerted pathogenic effects via a paracrine mechanism, as neutralizing PTEN-L with an antibody attenuated cardiac I/R injury. Serum PTEN-L levels were elevated in STEMI patients, particularly postintervention.Conclusions:USP18 impairs mitophagy and exacerbates cardiac I/R injury through a PTEN-L-Parkin axis, involving both intracellular and paracrine mechanisms. Targeting the USP18-PTEN-L pathway may represent a novel therapeutic strategy to alleviate myocardial I/R injury.Keywords：Myocardial ischemia/reperfusion (I/R) injury;Ubiquitin-specific protease 18 (USP18);Mitophagy;Phosphatase and tensin homolog-long (PTEN-L);Parkin0|0|0Updated：2026-05-11 -
Abstract：Background:Working memory deficits, one of the earliest hallmarks of Alzheimer’s disease (AD), are closely linked to abnormal neural activity in the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation(tDCS), a non-invasive neuromodulation therapy, has been shown to ameliorate early AD working memory deficits by modulating excitatory activity in the DLPFC, yet the underlying mechanisms remain incompletely understood.Methods:This investigation was structured around three experimental phases. We initially applied tDCS to stimulate the left prefrontal cortex (PFC) of transgenic mice with 5 familial AD (5×FAD) 5 d per week for 4 weeks. Subsequently, we employed optogenetic (Opt) techniques to modulate left PFC glutamatergic neurons. Finally, we inhibited soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) expression in the left PFC to elucidate the essential function of SNARE complex assembly with chaperone molecules in orchestrating synaptic vesicle release.Results:tDCS treatment improved working memory deficits in early-stage AD mice. This was accompanied by increased cerebral blood flow, enhanced neuronal excitability, amelioration of neurochemical metabolic disorders, and reduced amyloid β-protein (Aβ) deposition in the left PFC. Opt stimulation of PFC glutamatergic neurons similarly improved working memory, indicating the association between tDCS’s therapeutic effects and synaptic plasticity of excitatory neurons. Crucially, tDCS facilitated synaptic vesicle fusion and release, evidenced by increased vesicle numbers, enhanced release probability, improved synaptic transmission efficacy, and upregulation of the SNARE complex, Snap25, and Syt1. Inhibiting SNARE expression in the left PFC attenuated the tDCS-induced improvements in synaptic vesicle release and working memory.Conclusion:These findings collectively demonstrate that left PFC-targeted tDCS modulates interactions between the SNARE complex and chaperone molecules, thereby promoting synaptic vesicle fusion and release. This mechanism underlies the amelioration of early AD-like working memory impairment by tDCS.Keywords：Transcranial direct current stimulation (tDCS);Dorsolateral prefrontal cortex (DLPFC);Glutamatergic neurons;Synaptic vesicle transport;Working memory0|0|0Updated：2026-05-11 -
Abstract：Post-traumatic stress disorder (PTSD) is a complex neurobehavioral disorder that disproportionately affects military service members. The clinical presentation of PTSD is heterogeneous and may overlap with other psychiatric conditions. According to the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), common symptoms include memory loss, mood and personality changes, impulsiveness, aggression, anxiety, and depression. The pathophysiological mechanisms underlying PTSD remain incompletely understood, although research implicates pathways involving the hypothalamic-pituitary-adrenal (HPA) axis, dysfunctional neural circuitry, neurochemical imbalances, neuroinflammatory processes, and genetic and epigenetic factors. Approximately 7% of the U.S. adult population has met the diagnostic criteria for PTSD in their lifetime, with a substantially higher prevalence of 12%–30% among military personnel. Multiple animal models, including single-stressor, intermediate complexity, social interaction, predator stress, and blast exposure paradigms, have been employed to investigate PTSD mechanisms. Current treatment strategies typically integrate pharmacotherapy and psychotherapy. Military service members are at increased risk for blast injuries, which frequently result in traumatic brain injury (TBI). Although some symptoms of TBI may resolve, approximately 20% of affected individuals develop new symptoms, including PTSD. Evidence suggests that exposure to blast shock waves (BSWs) serves as a critical trigger for the clinical manifestations of both TBI and PTSD. Recent studies have identified several mechanisms contributing to BSW-induced brain dysfunction, including intraneuronal accumulation of phosphorylated Tau (p-Tau), activation of the dynorphin/kappa opioid receptor, and activation of metabotropic glutamate receptor 2/3 signaling pathways. This review provides an overview of the clinical features, treatments, pathophysiology, and epidemiology of PTSD, as well as animal models and their limitations in replicating PTSD-like symptoms. It further examines the relationship between BSW exposure, brain injury, and PTSD, discusses animal models that simulate blast trauma and PTSD-like symptoms, and evaluates potential therapies to mitigate BSW-induced PTSD. Finally, the review addresses the limitations of current models and proposes future directions for elucidating the mechanisms linking brain trauma to PTSD.Keywords：Post-traumatic stress disorder (PTSD);Traumatic brain injuries (TBIs);Axonal injury;Blast shock waves;Cognitive impairment;Hypothalamic-pituitary-adrenal axis;Mood dysfunction;Neuroinflammation0|0|0Updated：2026-05-11 -
Abstract：Background:Antimicrobial resistance (AMR) constitutes a critical global health challenge with major implications for public health and economic stability, increasing infection- and sepsis-related mortality. Despite growing evidence on its contribution to disease burden, comprehensive assessments of long-term trends at the regional level remain limited in the World Health Organization (WHO) Southeast Asia Region (SEAR) and Western Pacific Region (WPR).Methods:We used data from the Global Research on Antimicrobial Resistance (GRAM) Project to evaluate sepsis-and AMR-related deaths and disability-adjusted life-years (DALYs) for 11 infectious syndromes, 22 pathogens, and 84 pathogen-drug combinations across 42 countries and territories in the WHO SEAR and WPR from 1990 to 2021. AMR burden was estimated under two counterfactual scenarios: deaths and DALYs attributable to AMR (representing the burden if drug-resistant infections were replaced by drug-susceptible infections), and deaths and DALYs associated with AMR (representing the burden if infections did not occur at all). We reported numbers, crude rates, and age-standardized rates, and generated forecasts of AMR burden to 2050 using an autoregressive integrated moving average model.Results:In SEAR and WPR, there were 8.36×106 [95% uncertainty interval (UI) 7.93–8.79] sepsis-related deaths in 1990, which decreased to 6.03×106 (95% UI 5.68–6.39) in 2019 before increasing to 8.31×106 (95% UI 7.86–8.76) in 2021. The number of deaths associated with AMR ranged from 2,445,875 (95% UI 2,221,769–2,670,192) in 1990 to 2,358,190 (95% UI 2,173,521–2,545,190) in 2021, while deaths attributable to AMR ranged from 546,479 (95% UI 487,669–605,277) to 587,103 (95% UI 534,165–639,903) over the same period. From 1990 to 2021, deaths attributable to AMR decreased among people <25 years, with a 76.1% [95% confidence interval (CI) 70.6–81.6] reduction occurring among children <5 years, while those among adults aged ≥70 years more than doubled, increasing from 133,013 (95% UI 124,066–141,922) to 298,366 (95% UI 284,023–312,475). The largest increase in the number of deaths attributable to AMR was caused by methicillin-resistant Staphylococcus aureus [from 30,168 (95% UI 24,956–35,351) in 1990 to 66,946 (95% UI 57,544–76,479) in 2021]. In 2021, Kiribati had the highest age-standardized mortality rate (per 100,000 person-years) attributable to AMR [30.9 (95% UI 24.1–37.8)], whereas New Zealand had the lowest [3.2 (95% UI 2.6–3.8)] among the two regions. By 2050, the number of deaths associated with AMR is predicted to reach 3,875,753 (95% UI 1,502,402–9,998,297) in these two regions, of which 952,592 (95% UI 766,353–1,184,090) deaths are attributable to AMR.Conclusions:This study highlights the escalating burden of AMR in SEAR and WPR, emphasizing the urgent need for attention to this persistent and growing crisis. Our analyses underscore the dual challenge of sustaining gains among people <25 years while addressing the alarming increase of AMR in elderly populations. Given the high variability of AMR burden by pathogen, age group, and country, strengthened surveillance and improved laboratory capacity are essential to accurately characterize resistance patterns and guide clinical decision-making.Keywords：Antimicrobial resistance;Burden;Southeast Asia Region (SEAR);Western Pacific Region (WPR)0|0|0Updated：2026-05-11 -
Abstract：Background:Bladder cancer (BLCA) is a prevalent malignancy characterized by high recurrence and poor prognosis, particularly muscle-invasive bladder cancer (MIBC). Histopathology, the gold standard for assessing muscle invasion, often suffers from sampling errors and operator dependency, underscoring the need for non-invasive, accurate preoperative assessment methods. This study aimed to develop and validate a hybrid artificial intelligence (AI) model based on computed tomography (CT) radiomics and deep learning (DL) to predict MIBC and overall survival (OS) preoperatively in BLCA patients.Methods:A total of 1370 patients from 6 academic medical centers were retrospectively included. Preoperative contrast-enhanced CT scans were analyzed to extract handcrafted radiomic features using PyRadiomics and DL features using ResNet101, followed by machine learning (ML)-based modeling for prediction. A hybrid model combining radiomic and DL features was constructed and validated in internal and external cohorts. Model performance was evaluated using metrics such as the area under the curve (AUC) and Cox proportional hazards analysis for OS prediction.Results:The DL radiomics nomogram (DLRN) model demonstrated superior diagnostic performance, achieving an AUC of 0.807 in the internal validation cohort and 0.783 in the external multi-center validation cohort for predicting muscle invasion. The DLRN generated an imaging-derived risk score (DLRN score), which was subsequently incorporated as one covariate into a multivariable Cox proportional hazards model together with clinicopathological variables to evaluate OS. Using this approach, patients were effectively stratified into high- and low-risk groups for OS, showing robust generalizability across diverse clinical settings. AI-assisted diagnostics significantly improved the sensitivity and accuracy of urologists, particularly among less experienced clinicians.Conclusion:The DLRN model provides a reliable, non-invasive tool for preoperative assessment of muscle invasion and prognosis in BLCA. Addressing histopathology limitations, it offers valuable insights for personalized treatment strategies, paving the way for precision oncology in real-world clinical applications.Keywords：Bladder cancer (BLCA);Deep learning (DL);Multi-center study;Artificial intelligence (AI);Radiomics0|0|0Updated：2026-05-11 -
Abstract：Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, transactive response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.Keywords：Amyotrophic lateral sclerosis;Alzheimer’s disease;Huntington’s disease;Multiple system atrophy;Neurodegenerative diseases (NDs);Parkinson’s disease;Ubiquitin-proteasome system (UPS);E3 ubiquitin ligase10|0|0Updated：2026-05-11 -
Abstract：Background:Metabolic syndrome (MetS) is characterized by chronic low-grade inflammation and immune dysregulation, which may increase susceptibility to sepsis. However, epidemiologic evidence remains limited. This study aimed to evaluate the association of MetS with the risk of sepsis and sepsis-related mortality.Methods:This study included 359,633 participants from the UK Biobank and 152,317 participants from the Kailuan Study. MetS was defined as the presence of ≥3 metabolic abnormalities. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of MetS with risk of sepsis and 28-day mortality following sepsis. Stratified analyses were conducted to assess potential effect modification. In the UK Biobank, we further evaluated the dose-response relationship between the number of MetS components and sepsis outcomes, explored potential mediation by inflammatory and immune biomarkers, and investigated the joint effect of MetS and lifestyle; in the Kailuan Study, we further investigated the impact of MetS evolution on sepsis risk. Sensitivity analyses were performed to evaluate the robustness of the results.Results:During a median follow-up of 13.7 years, 11,040 sepsis cases were identified in the UK Biobank, whereas 5672 cases were documented in the Kailuan Study during a median follow-up of 16.4 years. After multivariable adjustment, MetS was associated with higher risks of sepsis (HR=1.55, 95% CI 1.49–1.61) and 28-day mortality following sepsis (HR=1.51, 95% CI 1.37–1.65) in the UK Biobank; corresponding HRs were 1.32 (95% CI 1.25–1.40) and 1.49 (95% CI 1.32–1.69) in the Kailuan Study, respectively (all P<0.001). These associations were generally consistent across stratified analyses. Moreover, the risk of sepsis outcomes increased with the number of MetS components and was partly mediated by inflammation. Compared with individuals free of MetS, individuals with MetS and an unfavorable lifestyle had substantially higher risks of sepsis (HR=1.91, 95% CI 1.81–2.00) and 28-day mortality following sepsis (HR=1.84, 95% CI 1.64–2.07), whereas those with MetS but a favorable lifestyle showed only a modestly increased risk of sepsis and no excess risk of 28-day mortality (HR=1.18, 95% CI 1.09–1.28 and HR=1.05, 95% CI 0.88–1.27, respectively). In analyses of MetS evolution, using individuals with persistently normal metabolic status as the reference, those with a persistent MetS demonstrated the highest risks of sepsis (HR=1.46, 95% CI 1.32–1.61) and 28-day mortality following sepsis (HR=1.88, 95% CI 1.50–2.35), followed by individuals with progressive MetS (HR=1.17, 95% CI 1.05–1.31 and HR=1.36, 95% CI 1.04–1.77, respectively), whereas those who recovered from MetS did not show a significantly increased risk (HR=1.09, 95% CI 0.96–1.25 and HR=1.19, 95% CI 0.87–1.61, respectively). Sensitivity analyses confirmed the robustness of the findings.Conclusions:This study demonstrated that MetS was associated with an increased risk of sepsis and sepsis-related mortality. These associations were partially mediated through inflammatory responses. The findings highlight the importance of maintaining metabolic health as well as promoting healthy lifestyles as strategies to reduce its burden.Keywords：Metabolic syndrome (MetS);sepsis;Inflammation;Mortality;UK Biobank;Kailuan Study7|0|0Updated：2026-05-11 -
Abstract：Background:Bacteria-mediated cancer therapy leverages bacteria to modulate the tumor immune microenvironment and deliver therapeutics. However, its clinical application is limited by toxicity, off-target effects, and uncontrolled drug release. Improving tumor targeting and precise payload delivery through rational bacterial engineering is essential for increasing efficacy and safety.Methods:An attenuated Salmonella ΔhtrA::luxI-VNP20009 strain expressing OmpA-SpyTag (AISI-ST) was constructed for the modular surface conjugation of SpyCatcherΔ (SC)-fused quadruple arginine-glycine-aspartic acid (RGD) peptides (named AISI-ST/SC-RGD×4) and for building biointerfaces for enhanced tumor adhesion via RGD-mediated integrin αvβ3 interactions. The tumor-bearing mice received intravenous injections of AISI-ST/SC-RGD×4, and their biodistribution was analyzed using bioluminescence imaging and colony-forming unit (CFU) counts. Quorum-sensing (QS)-regulated high-temperature requirement A (HtrA) and anti-programmed cell death protein 1 (anti-PD1) nanobody expression based on the LuxI promoter in strains was validated by Western blotting. Immune responses were assessed using flow cytometry.Results:The incubation of the fused proteins with the AISI-ST strain for 1 h was sufficient to form a stable biological interface. The quadruple RGD-modified bacteria (AISI-ST/SC-RGD×4) exhibited greater enrichment in various solid tumors and lung metastases with reduced off-target accumulation. QS induced the expression of the HtrA protein within tumors, resulting in enhanced extracellular polysaccharide-mediated immunogenicity to activate immune cells. Further expression of anti-PD1 nanobodies synergistically enhanced antitumor immunity, increasing the percentage of M1 macrophages (MACS) and CD8+ T cell proliferation while suppressing M2 MACS and regulatory T cells (Tregs). This approach achieves potent tumor suppression via targeted immune remodeling.Conclusions:This study presents octopus-inspired engineered bacteria with a “plug-and-display” system and tumor-specific drug delivery that achieves enhanced tumor targeting and potent antitumor effects. This study describes a promising strategy for the precise and safe clinical translation of bacteria-mediated cancer immunotherapy.Keywords：Microbial therapeutics;Chemical biological modification;Quorum-sensing (QS);Tumor-targeted delivery;Immune activation7|0|0Updated：2026-05-11 - Keywords：Diabetes care;Mortality;Life expectancy;Lifestyle factors6|0|0Updated：2026-05-11
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Abstract：Background:Different glycemic indicators and diagnostic criteria for prediabetes and diabetes identify overlapping but distinct populations. However, the extent to which these definitions lead to differences in estimated prevalence and associated health outcomes remains unclear. This study aimed to compare the prevalence of prediabetes and newly diagnosed diabetes across different glycemic indicators and diagnostic criteria, and to examine their associations with mortality and life expectancy.Methods:We analyzed data from 141,945 adults from a nationally representative cohort study (the 2013 cycle of China Chronic Disease and Risk Factors Surveillance) in China, with follow-up through December 2021. Using fasting plasma glucose (FPG), 2-hour postload glucose (2hPG), and hemoglobin A1c (HbA1c) levels, prediabetes was defined according to the American Diabetes Association (ADA), World Health Organization (WHO), or International Expert Committee (IEC) criteria, and newly diagnosed diabetes was defined according to the ADA criteria. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of all-cause and cause-specific mortality associated with different definitions, with adjustment for demographic characteristics, socioeconomic status, lifestyle factors, dietary factors, and baseline comorbidities. Life expectancy was estimated using sex- and age-specific abridged life tables by integrating population mortality rates with exposure-specific HRs and prevalence.Results:Prediabetes prevalence varied widely across glycemic indicators, with the highest estimate of 26.2% (95% CI 24.0–28.4) based on ADA FPG criteria and the lowest estimate of 3.0% (95% CI 2.8–3.2) based on IEC HbA1c criteria, while the prevalence of newly diagnosed diabetes was 4.4% (95% CI 4.1–4.8) based on ADA FPG, 2.6% (95% CI 2.4–2.8) based on ADA HbA1c, and 3.6% (95% CI 3.3–3.8) based on ADA 2hPG. Over a median follow-up of 9.0 years, a total of 6924 deaths were documented. Compared with people with normoglycemia, prediabetes defined by FPG (either ADA or WHO criteria) was not significantly associated with increased risks of all-cause or cardiovascular disease (CVD) mortality (all P-values >0.05). In contrast, prediabetes defined by 2hPG or HbA1c (either ADA or IEC criteria), was associated with higher risks of all-cause mortality (HRs ranged from 1.13 to 1.23; all P-values <0.001) and CVD mortality (HRs ranged from 1.12 to 1.25; all P-values <0.001). Prediabetes defined by 2hPG or HbA1c, but not FPG, was associated with 1.1–2.3 years reduction in life expectancy, with the largest loss observed for IEC HbA1c. In addition, diabetes defined by FPG, 2hPG or HbA1c was each significantly associated with a higher risk of all-cause and CVD mortality (HRs ranged from 1.25 to 1.51; all P-values <0.001), and a reduction in life expectancy (2.0–3.7 years). Furthermore, the 2hPG-based definition of prediabetes and diabetes was associated with mortality risk, independent of FPG and HbA1c levels.Conclusions:These findings suggest that reliance on FPG alone may fail to identify certain individuals at elevated mortality risk. In contrast, 2hPG and HbA1c provide additional prognostic information beyond FPG.Keywords：Diabetes;Prediabetes;Mortality;Life expectancy;Prospective study7|0|0Updated：2026-05-11 -
Abstract：With the advancement of manned spaceflight technology, significant progress has been made in the fields of aerospace medicine and space biology to address the needs of astronauts in terms of health, safety, and mission performance. The physiological and pathological changes during microgravity exposure, including perception, response, and adaptation mechanisms, are gradually being unraveled. This study aimed to systematically summarize the common features of various molecules and structures within the cell membrane, cytoplasm, and nucleus responsible for sensing microgravity. It further examined the heterogeneous responses across different tissues, organs, and cells, as well as systemic-level interactions and synergies, and proposed a novel multilevel gravity-sensing theory. Additionally, the study highlighted cutting-edge in-orbit health monitoring technologies, including rapid fluid analysis using sensitive biomarkers and non-invasive evaluation using two-photon fluorescence microscopy. Furthermore, it explored the promising applications of emerging therapeutic approaches for microgravity adaptation, including small nucleic acid drugs targeting gene regulation, exosome-based drug delivery systems, and natural small-molecule drugs aimed at combating microgravity effects.Keywords：Spaceflight;Microgravity;Hierarchical stratum response system;Mechanical sensing11|0|0Updated：2026-05-11 -
Abstract：Background:Cancer in women represents a significant disease burden, posing challenges for prevention, treatment, and caregiving. This study aimed to analyze the epidemiological trends of the women’s cancer burden and the main influencing factors in the group of twenty (G20) from 1990 to 2023.Methods:Incidence, prevalence, mortality, and disability-adjusted life years (DALYs) for breast, cervical, uterine, and ovarian cancers, as well as fertility rates for G20 and its 98 locations, were sourced from the Global Burden of Disease Study 2023. Age-standardized rates (ASRs), quality of care index (QCI), and 5-year relative survival of integrated women’s cancers were calculated. Average annual percent changes (AAPCs) were used to determine the temporal trends by age and region. Decomposition analysis identified drivers of changes in case numbers, linear regression assessed the associations with DALY rate changes, and dominance analysis identified dominant predictors.Results:In 2023, the incidence, prevalence, mortality, and DALYs from women’s cancers in G20 were 3.29 [95% uncertainty interval (UI) 2.60–4.14], 26.71 (95% UI 21.99–32.40), 1.16 (95% UI 0.91–1.45), and 36.58 million (95% UI 28.40–46.32), respectively, with ASRs of 87.63/100,000 (95% UI 65.12–115.85), 706.16/100,000 (95% UI 555.75–890.02), 30.03/100,000 (95% UI 22.10–39.58), and 994.79/100,000 (95% UI 728.43–1328.81). The QCI was 75.13 [95% confidence interval (CI) 73.67–76.59], and the 5-year relative survival rate was 65.74% (95% CI 65.53–65.95). From 1990 to 2023, there was a significant increase in incidence, prevalence, mortality, and DALYs in G20, primarily driven by population growth. Age-standardized incidence rate, QCI, and 5-year relative survival increased, while age-standardized mortality and DALY rates decreased. Changes in prevalence rates of breast cancer and cervical cancer for women aged 15–49 years were positively associated with changes in DALY rates of women’s cancers, whereas changes in the total fertility rate were negatively associated. Dominance analysis confirmed these three factors consistently as dominant predictors between 1990 and 2023. Reducing the prevalence of breast and cervical cancers and increasing fertility among women aged 15–49 years could lower the overall DALY burden attributable to women’s cancer.Conclusions:The incidence, prevalence, mortality, and DALYs of women’s cancers in G20 have increased substantially from 1990 to 2023. Tailored prevention strategies should consider age and cancer type, emphasizing reproductive health for women of reproductive age.Keywords：Women’s cancers;Global Burden of Diseases;Survival;Dominance analysis;Fertility6|0|0Updated：2026-05-11 -
Abstract：Histone deacetylase 6 (HDAC6) is a unique, predominantly cytoplasmic enzyme that regulates a broad spectrum of cellular and physiological processes, including cell proliferation, migration, intracellular transport, and differentiation. Its distinct structural configuration, comprising two catalytic deacetylase domains and a zinc finger ubiquitin-binding domain (ZnF-BUZ), enables HDAC6 to deacetylate a variety of non-histone substrates, such as α-tubulin, heat shock protein 90 (Hsp90), cortactin, and peroxiredoxin (Prdx). Furthermore, HDAC6 plays a key role in cellular stress responses and cell survival by facilitating the clearance of misfolded proteins, inducing autophagy, and modulating the unfolded protein response. Despite its cytoprotective roles, HDAC6 has emerged as a therapeutic target due to its involvement in multiple pathological pathways and age-related disorders. Tubastatin A (Tub A), a novel and highly selective HDAC6 inhibitor, demonstrates strong therapeutic potential against neurodegenerative, cardiovascular, autoimmune, metabolic, cancer, and other diseases. Tub A enhances the acetylation of both histone and non-histone proteins, thereby modulating gene expression and diverse cellular processes. It shows pharmacological effects, including anti-inflammatory, neuroprotective, anti-diabetic, anti-obesity, anti-oxidant, and other activities. Moreover, preclinical evidence suggests that Tub A effectively regulates multiple pathological pathways by inhibiting HDAC6, which contributes to ameliorating age-related disorders. Therefore, Tub A represents a promising epigenetic modulator with broad therapeutic relevance. Hence, further comprehensive and large-scale investigations are warranted to elucidate its clinical potential and its roles in disease management, as no clinical data related to Tub A activity are available. This review highlights the therapeutic potential of the selective HDAC6 inhibitor Tub A across various pathological conditions, discusses current preclinical findings, and outlines key challenges and future directions for clinical translation.Keywords：Tubastatin A (Tub A);Histone deacetylase 6 (HDAC6);Age-related diseases;Neurodegenerative diseases;Diabetes;Cancer7|0|0Updated：2026-05-11 -
Abstract：Hypoxia is a central pathophysiological driver of inflammatory airway diseases, shaping disease progression largely through hypoxia-inducible factor 1α (HIF-1α) signaling. Across these disorders, hypoxia exacerbates airway inflammation through shared mechanisms. As a key signaling hub, HIF-1α disrupts epithelial barrier integrity and initiates inflammatory cascades; reprograms immune responses, promoting the activation and trafficking of eosinophils, T cells, and macrophages while reshaping cytokine profiles, to drive tissue injury; and accelerates airway remodeling, thereby worsening airflow limitation and perpetuating inflammatory cycles. Realizing effective targeted therapies will require rigorous validation of HIF-1α as a therapeutic node and the development of disease-tailored interventions aligned with distinct pathological features. In parallel, strengthened translational and clinical research on hypoxia is essential to build a robust evidence base for practice. This review synthesizes hypoxia-driven mechanisms shared across airway diseases, articulates a unifying framework for HIF-1α signaling across pathological contexts, and highlights the therapeutic implications of fundamental discoveries. By addressing the paucity of cross-disease analyses of hypoxia pathways, it provides both a conceptual foundation and a practical roadmap for developing precise and efficient targeted therapies for inflammatory respiratory diseases.Keywords：Respiratory inflammatory diseases;hypoxia;Hypoxia-inducible factor;Epithelial barrier;Immune imbalance;Inflammation12|0|0Updated：2026-05-11 -
Abstract：Background:Abnormal glucose metabolism often contributes to myofibroblast activation and the pathogenesis of skin fibrotic diseases. All-trans retinoic acid (ATRA), the active component of tretinoin cream, can regulate glucose metabolism and activate myofibroblasts. Importantly, investigating the potential of ATRA to inhibit myofibroblast activation by modulating glucose metabolism could reveal the translational significance of ATRA in attenuating hypertrophic scar (HS) formation.Methods:We first conducted a multicenter, double-blind, randomized controlled trial (RCT) to compare the effects of tretinoin cream with those of the first-line medication, silicone gel. In the mechanistic study, the characteristics of glucose metabolic reprogramming and the activation of hypertrophic scar fibroblasts (HSFs) after ATRA treatment were identified through multi-omics profiling, complemented by glucose metabolism assays and functional validations. Besides, genetic overexpression targeting the potential downstream molecules of ATRA, including hypermethylated in cancer 1 (HIC1), phosphoenolpyruvate carboxykinase (PCK)1, and PCK2, was conducted in vitro in HSFs and in vivo in skin fibroblasts of Col1a2-CreER mice.Results:Our RCT demonstrated that tretinoin cream is non-inferior to silicone gel in preventing HS formation, with the absdute risk difference of incidence rates [–8.65% 90% two-sided (confidence interval) CI –23.03 to 5.74] and in decreasing scar thickness [(2856.20±211.83) μm vs. (1664.57±273.50) μm], attributing to the reduction in HSF proliferation and the proportion of myofibroblasts. Moreover, tretinoin cream effectively mitigated HS formation in both mice and rabbits without impeding normal wound healing. Mechanistically, HSFs underwent glucose reprogramming, characterized by increased aerobic glycolysis, which facilitated the transition of HSFs to myofibroblasts and their proliferation. However, ATRA upregulated HIC1, PCK1, and PCK2 expression through retinoic acid receptor alpha (RARα) activation, thereby inhibiting the fibrotic phenotypes of HSFs by suppressing aerobic glycolysis and facilitating gluconeogenesis. The fibroblast-specific overexpression of HIC1, PCK1, or PCK2 in Col1a2-CreER mice significantly reduced myofibroblast activation and hypertrophic scarring.Conclusions:Our study not only substantiated that topical tretinoin cream could serve as an effective strategy to prevent HSs in clinical settings, but also established ATRA as a regulator of glucose metabolism. Importantly, ATRA/RARα-mediated glucose reprogramming was identified as a potential therapeutic target for attenuating HS formation.Keywords：All-trans retinoic acid (ATRA);Randomized controlled trial (RCT);Glucose metabolic reprogramming;Myofibroblast activation;hypertrophic scar6|0|0Updated：2026-05-11
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