The treatment landscape for Chronic Hand Eczema (CHE) is evolving; however, evidence on patients' preferences regarding CHE treatment attributes is sparse. This discrete choice experiment (DCE) assessed how treatment attributes influence preferences among patients with moderate to severe CHE in the USA. Adults with moderate to severe CHE recruited from an online panel completed a web-based DCE survey (August-September 2025). Seven treatment attributes, identified via literature review, qualitative patient interviews, and clinical expert input, reflected efficacy (improvements in itch, skin appearance, and pain), safety (risks of infections, cancer, and major heart problems), and administration mode/frequency. Patient preferences were analyzed using conditional logistic regression. Attributes' relative importance and willingness to trade off were calculated. Sensitivity analysis excluding participants who failed ≥ 1 validity test was conducted. Of the 300 participants with CHE included (mean age: 44.9 years; 50% female; 84.7% employed), most reported multiple CHE subtypes (70.3%). The vast majority of participants reported life impairment due to CHE, including for activities of daily living (96.3%) and work productivity (92.9%). In the DCE, all treatment attributes had a significant impact on treatment preferences (p < 0.001). Attributes with the highest relative importance were related to efficacy: itch improvement (22%) and skin appearance improvement (21%); followed by those related to safety: avoiding risk of cancer (16%) and risk of infections (14%). Other important attributes for patients included pain improvement (13%) and administration mode/frequency (7%). Participants would forgo 28.1, 11.4, and 1.3 percentage points of itch improvement probability to avoid a 1-percentage-point risk of cancer, major heart problems, and infections, respectively. Improvement in efficacy outcomes (itch and skin appearance) and lower risks of certain adverse events (cancer, infections) were the most important treatment attributes for patients with CHE. This study provides insights that may help support shared decision-making to ultimately improve treatment satisfaction and adherence.
Limited data exist on long-term trajectories of functional scores before and after stroke diagnosis. We analyzed 1325, 754, 3907, and 2902 incident strokes from China Health and Retirement Longitudinal Study (CHARLS), English Longitudinal Study of Ageing (ELSA), Health and Retirement Study (HRS), and Survey of Health, Ageing and Retirement in Europe (SHARE), respectively. Two non-stroke participants were matched to each stroke case by age and gender. Linear mixed models estimated trajectories of functional scores over time in individuals with and without stroke. Here we show that individuals with stroke have fewer memory but more depressive symptoms than those without stroke in most years from stroke onset with the largest difference several years after stroke onset. A steeper decline in memory is found among stroke patients for several years before and after stroke onset (adjusted β (95% CI) for annual change in CHARLS: -0.062 (-0.074, -0.049), ELSA: -0.024 (-0.03, -0.018), HRS: -0.026 (-0.03, -0.023)). Stroke participants have greater limitations in activities of daily living (ADL) than non-stroke participants, starting several years before stroke onset, with the difference increasing for five years after stroke onset. After that, the difference remains stable or decreases. Similar results are seen in instrumental ADL and the frailty index. Women have greater increases in CESD, mobility limitations, and frailty index compared with men. Our analysis of data from multiple countries identifies the period when related functional scores show the greatest change, highlighting a critical window for stroke prevention and management. Stroke is a leading cause of disability, often affecting a person’s memory, daily independence, mood, and overall health. Using long-term health data from over 8000 stroke survivors and matched controls in China, the UK, Europe, and the US, we tracked changes in memory, daily activities, depression, and frailty. We found that people who had a stroke experienced faster declines in memory and more rapid increases in depression and difficulties with daily tasks, both before and after their diagnosis, compared to those without stroke. The most significant changes occurred in the few years immediately surrounding the stroke event. These results identify a critical window—spanning the years just before and after a stroke—when function declines most rapidly. This highlights the opportunity for targeted prevention and rehabilitation strategies to improve long-term outcomes for stroke survivors.
To investigate the distribution characteristics of myopia among primary and secondary school students in Inner Mongolia Autonomous Region in 2020, and to comprehensively analyze its influencing factors at both school and individual levels, thereby providing scientific evidence for developing targeted myopia prevention and control strategies. A multistage stratified random cluster sampling method was employed to conduct vision examinations and questionnaire surveys among students from fourth grade to senior high school in Inner Mongolia Autonomous Region, collecting information on students' visual habits, school and family environmental factors. A multilevel regression model was used to analyze the factors influencing myopia detection rates at both school and individual levels. A total of 130 601 students were included, with a myopia prevalence rate of 68.42%. The prevalence was higher among females (72.75%) than males (64.13%), in urban areas (73.63%) than in suburban counties (66.38%), and overall rates increased with educational level (trend test χ2=4 545.53, P < 0.001). Multilevel analysis revealed that at the individual level, female gender (OR=1.553), higher grade level (junior high OR=2.049, senior high OR=3.061), homework duration ≥1 h after school (≥1 h OR=1.050, ≥2 h OR=1.079), poor close-up vision habits (OR=1.059), prolonged close-up vision activities (0.5 h OR=1.070, ≥1 h OR=1.061), infrequent desk/chair height adjustments based on height (OR=1.006), and parental myopia (one parent OR=1.822, both parents OR=2.412) were risk factors for myopia; while ethnic minority status (Mongolian OR=0.956, other ethnicities OR=0.929), daily outdoor activity exceeding 2 hours (OR=0.986), performing eye exercises (1 session OR=0.891, ≥2 sessions OR=0.920), and adequate sleep (OR=0.925) served as protective factors. At the school level, qualified blackboard reflectance ratio (OR=0.874) and qualified blackboard surface illuminance uniformity (OR=0.973) were associated with reduced myopia risk among students. The model indicated that the included variables collectively explained approximately 31.04% of the variance at the school level. The prevalence of myopia among primary and secondary school students in Inner Mongolia Autonomous Region remains high, with influencing factors distributed across multiple levels including individual and school contexts. Comprehensive prevention strategies are recommended, focusing on female students, older grades, and those with genetic predispositions while intensifying interventions on modifiable factors like outdoor activities and visual habits. Improving classroom lighting environments is also crucial to reduce students' myopia risk.
Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematological malignancy. Here, to better define this clinically taxing and translationally challenging malignancy, we applied a multiomics approach, consisting of 13 modalities to analyze 173 treatment-naive individuals with AML. By integrating these 'omes', we identified distinct AML subtypes, genotype-phenotype associations, biomarkers and pathobiological mechanisms. Across the spectrum of primitive and committed AML, we found extensive metabolomic and lipidomic reprogramming driven by divergent MYC and mTOR activity. We linked metabolic changes to striking hyperacetylation of mitochondrial proteins in CEBPA-mutant AML. Protein-centric subtyping revealed a distinct NPM1-mutant subset characterized by outlier expression of FOXC1 and HOXB8/9. To nominate therapeutic targets across subtypes, we developed a multiomic machine-learning approach and validated MTA1 as a contributor to panobinostat resistance. Altogether our findings underscore the complex nature of AML and provide a clinically and translationally informed unified view that reveals coalescent phenotypes across multiomic layers.
Colorectal cancer (CRC) ranks second in cancer-related mortality worldwide. Its clinical intractability and chemoresistance pose significant challenges, often driven by cancer stem cells (CSCs). Wnt/β-catenin signaling is a lynchpin of CSC self-renewal, but targetable upstream drivers remain elusive. Using bioinformatics, we identified the proteoglycan SPOCK1 (encoding the protein Testican-1) as a Wnt-associated marker. High SPOCK1 gene expression predicted poor patient prognosis and reduced progression-free survival following first-line chemotherapy. In vitro assays demonstrated that Testican-1 levels modulated Wnt/β-catenin activity. Testican-1 downregulation inhibited β-catenin nuclear translocation and TCF/LEF-mediated transcription, leading to concurrent suppression of CRC proliferation and spheroid-forming potential. Conversely, Testican-1 overexpression promoted β-catenin nuclear translocation and TCF/LEF-mediated transcription, which enhanced CRC malignant properties. This Testican-1-driven pro-tumorigenic effect was reversed by the β-catenin/TCF/LEF inhibitor iCRT3, demonstrating Testican-1's dependence on Wnt transcriptional activation. We validated this functional role in vivo using a Testican-1-overexpressing xenograft model and ex vivo using patient-derived organoids (PDOs), both confirming increased growth and β-catenin nuclear localization. Furthermore, data-independent acquisition (DIA) mass spectrometry of Testican-1-overexpressing tumors showed enrichment in Wnt/β-catenin and pro-tumorigenic pathways, including c-Myc and oxidative phosphorylation. Notably, Testican-1 expression was associated with remodeling of the tumor microenvironment, characterized by desmoplastic features. In summary, our findings establish a novel Testican-1/Wnt/β-catenin axis driving CRC tumorigenesis and progression, positioning it as a promising therapeutic target to overcome Wnt-mediated progression and resistance.
ObjectivesIntracerebral hemorrhage is a cerebrovascular disease associated with high mortality and disability rates. Electrolyte disorders are common in intensive care unit patients; however, most current studies have focused on the association between a single electrolyte abnormality and intracerebral hemorrhage prognosis, lacking a comprehensive quantitative assessment of multiple electrolyte disturbances. This study aimed to explore the prognostic value of a multielectrolyte disturbance scoring system for adverse outcomes in intensive care unit patients with intracerebral hemorrhage.MethodsThis retrospective observational cohort study analyzed data from the Medical Information Mart for Intensive Care IV database. A scoring system covering six electrolytes was constructed, with scores assigned according to the abnormal range, number of concurrent abnormalities, and duration. Multivariate logistic and Cox regression analyses were used to evaluate the association between the score and 30-day severe disturbance of consciousness or in-hospital mortality. Subgroup analyses and restricted cubic spline analyses were further performed.ResultsAmong 1540 patients, 321 (20.84%) developed 30-day severe disturbance of consciousness. The electrolyte disturbance score was significantly higher in patients with disturbance of consciousness than in those without disturbance of consciousness. Multivariate regression analysis (Model 3, adjusted for all covariates) showed that, compared with T1, both T2 and T3 were associated with an increased risk of 30-day severe disturbance of consciousness and in-hospital mortality. Subgroup analyses confirmed a stable association across most subgroups. Restricted cubic spline analysis revealed a nonlinear positive correlation between the score and both outcomes, with accelerated risk elevation when the score exceeded 2.ConclusionThe constructed electrolyte disturbance scoring system is a reliable prognostic tool for predicting 30-day severe disturbance of consciousness and in-hospital mortality in intensive care unit patients with intracerebral hemorrhage. A score >2 was associated with a significantly accelerated risk of adverse outcomes, providing a practical threshold for clinical intervention and individualized management.
Cervical cancer (CC) remains a major threat to women's health globally. Although miR-557 is a tumor suppressor in multiple cancers, its role in CC remains unclear. This study investigated whether miR-557 regulates CC progression by targeting TAOK1. This study collected 113 pairs of cervical cancer tissues and adjacent tissues. The expression of miR-557 was detected by qRT-PCR, and its relationship with clinicopathological features and prognosis was analyzed. In HeLa and SiHa cell lines, we performed functional assays (CCK-8, Transwell) and measured ferroptosis-related indicators (Fe²⁺, GSH, GSH-Px) after transfecting miR-557 mimic or TAOK1 overexpression vectors. The miR-557/TAOK1 targeting relationship was validated by dual-luciferase reporter assay and rescue experiments. miR-557 was significantly downregulated in CC tissues and cell lines. Low miR-557 expression correlated with advanced FIGO stage, LNM, and poor prognosis. Functionally, miR-557 overexpression inhibited CC cell proliferation, migration, and invasion, accompanied by increased Fe²⁺ levels and decreased GSH and GSH-Px activity. TAOK1 was identified as a direct target of miR-557, and its overexpression reversed the tumor-suppressive effects and ferroptosis-related changes induced by miR-557. miR-557 is significantly downregulated in CC and exerts tumor-suppressive functions. By targeting TAOK1, it inhibits the malignant progression of CC cells and may act as a promising biomarker for CC.
Shugoshin proteins SGO1 and SGO2 regulate chromosome cohesion and segregation during mitosis and meiosis, and their aberrant expression is implicated in several cancers. However, the mechanistic involvement of these two proteins in papillary renal cell carcinoma (KIRP) and their contribution to immune evasion remains unclear. Therefore, in the present study, we aimed to determine SGO1 and SGO2 expression patterns and prognostic significance, clarify their functional involvement in driving tumor progression, and evaluate their impact on the tumor immune microenvironment. We performed an integrative analysis using multi-omics datasets retrieved from TCGA, GTEx, and GEO, complemented by single-cell transcriptomics, immunohistochemistry of patient samples, and functional assays in renal cancer cell lines. We also investigated the expression, clinical relevance, and mechanistic roles of SGO1 and SGO2 in KIRP progression and tumor immune regulation. SGO1 and SGO2 were significantly upregulated in KIRP, correlating with advanced tumor stage and poor overall survival. Receiver operating characteristic analyses demonstrated strong diagnostic performance, particularly when SGO1 and SGO2 were evaluated jointly. Functional knockdown experiments revealed that both SGO1 and SGO2 promote the proliferation, migration, and invasion of renal cancer cells. Gene enrichment analyses further linked these proteins to E2F signaling, genomic stability, and immune-related pathways. Importantly, high SGO1 and SGO2 expression was strongly associated with increased infiltration of immunosuppressive cells, including regulatory T cells, M2 macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells, suggesting their potential contribution to an immune-evasive tumor microenvironment. SGO1 and SGO2 are associated with aggressive tumor biology in papillary renal cell carcinoma and correlate with remodeling of the tumor immune microenvironment toward an immunosuppressive state. Importantly, while these findings highlight a strong association with the tumor immune microenvironment, they remain correlative, and further mechanistic studies are warranted to establish a direct causal relationship. Nevertheless, their associations with both tumor progression and immunosuppressive features suggest potential as prognostic biomarkers and targets for future mechanistic studies.
Stroke induces profound neuroinflammation in which macrophages play a complex dual role, contributing to both injury and repair. The traditional M1/M2 classification is increasingly recognized as oversimplified. Advances in single-cell RNA sequencing (scRNA-seq) have revealed a spectrum of dynamic macrophage subpopulations with distinct functional and metabolic states, fundamentally reshaping our understanding of post-stroke immunity. This review synthesizes recent insights into macrophage heterogeneity from a single-cell perspective, highlighting novel subsets such as an LCP1⁺ population defined by coupled glycolipid metabolism. We discuss how metabolic reprogramming, including glycolysis, oxidative phosphorylation, cholesterol metabolism, hypoxia‑driven gradients, and mitochondrial dynamics, critically underpins macrophage polarization. Glycolysis fuels pro-inflammatory (M1-like) responses, whereas oxidative phosphorylation and fatty acid oxidation support anti-inflammatory and reparative (M2-like) functions. We further explore innovative nano‑therapeutic strategies, including engineered liposomes, exosomes, and responsive polymeric nanoparticles, that enable spatiotemporally precise modulation of macrophage activity. Based on these advances, we propose an integrative framework that directly links scRNA‑seq‑defined macrophage subsets to their metabolic pathways, druggable targets, and tailored nano‑interventions. We also critically examine clinical translation barriers and prioritize actionable targets (e.g., CCR2, PPARγ, Nrf2) for future stroke therapy. The convergence of single‑cell genomics, immunometabolism, and nanotechnology offers a transformative path toward precision immunomodulation in stroke. Moving beyond the static M1/M2 dichotomy to target macrophage subpopulations and their metabolic drivers guided by an integrated framework holds significant promise for developing more effective therapies.
The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.
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Drug delivery to the oesophagus poses unique challenges, including rapid transit time due to gravity and the presence of a stratified squamous non-keratinized epithelium. Here, to rapidly identify formulations of excipients for enhanced drug delivery to the oesophagus, we developed an oesophageal tissue screening system consisting of specialized custom plates, to incorporate gravity effects, and excised oesophageal mucosa tissues. Using the screening system, we built an excipient library identifying the most effective non-toxic permeation enhancers and selected the formulation that could prolong the retention on the oesophageal mucosa. We identified an absorption enhancer that resulted in a 876-fold increase in the oesophageal transport of a model drug (4 kDa) in pig tissue. We validated this formulation in human oesophageal tissue and in vivo in pigs with the model drug and infliximab (149 kDa), demonstrating enhanced permeability. We characterized the mechanism of the approach, noting its capacity for enhanced delivery without causing cellular disruption of the oesophageal tissue. The oesophageal tissue screening system shows promise for high-throughput screening of effective oesophageal drug delivery systems.
Cisplatin chemotherapy is widely used for cancer treatment but frequently induces skeletal muscle atrophy, which compromises physical function and patient outcomes. The molecular mechanisms underlying this process remain incompletely understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, classically involved in innate immune responses, has recently been implicated in cellular stress and tissue dysfunction. Whether cGAS-STING signaling contributes to cisplatin-induced skeletal muscle atrophy remains unclear. We employed both pharmacological and genetic approaches. Wild-type (WT) mice received a single intraperitoneal injection of the STING agonist DMXAA prior to cisplatin administration. Genetic models included global cGAS and STING knockout mice, as well as skeletal muscle-specific cGAS knockout mice. Cisplatin was administered intraperitoneally (3 mg/kg/day) for four consecutive days. Body weight, skeletal muscle mass, myofiber cross-sectional area (CSA), and fiber diameter were assessed. Molecular and transcriptional analyses were performed using Western blotting, quantitative polymerase chain reaction, and RNA sequencing. Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass. Skeletal muscle-specific cGAS deficiency preserved muscle weight and myofiber diameter following cisplatin exposure. Although CSA was also assessed, no significant difference was observed between groups. Transcriptomic analysis identified 696 differentially expressed genes upon cGAS deletion, with enrichment in pathways related to inflammatory signaling, proteasome function, and autophagy. Further analyses in skeletal muscle-specific cGAS-deficient mice showed reduced expression of muscle atrophy-associated genes (FBXO32 and Murf1), together with preservation of key myogenic regulators after cisplatin treatment. Consistently, NF-κB signaling and interferon-stimulated gene expression were diminished, accompanied by altered Beclin1 responses and partial attenuation of selected autophagy-related genes. These findings support a role for cGAS-STING signaling in cisplatin-induced skeletal muscle atrophy, associated with enhanced innate immune and inflammatory signaling, proteolytic and autophagy-related alterations, and impaired myogenic regulation. Targeting the cGAS-STING pathway may represent a potential therapeutic strategy to mitigate chemotherapy-associated skeletal muscle atrophy.
In order to guarantee the safety of food and quality control of drugs, it is crucial to develop a rapid, accurate and sensitive method for myricetin detection. In this study, vanadium-doped carbon dots (V-CDs) with peroxidase-like activity (POD) were synthesized through a one-step hydrothermal method. Based on the redox reaction between myricetin and the reactive oxygen species generated by V-CDs catalyzed H2O2, a colorimetric sensor was developed. This sensor featured high sensitivity, excellent selectivity and rapid detection capability, showing a good linear relationship within the range 1.0-50 µM, with a detection limit as low as 0.47 µM. Furthermore, using a smartphone a visual sensing platform was established and successfully realized monitoring of myricetin in samples. The proposed method avoids complex instrumentation and tedious sample pretreatment, making it highly suitable for on-site screening. This work not only presented a new type of carbon dots-nanozyme, but also provided an economical, user-friendly and detection method for myricetin.
Although immunotherapy is approved for patients with high PD-L1 expression, optimal therapeutic strategies for PD-L1-negative populations remain undefined. This study (ChiCTR2300071681) assessed the efficacy and safety of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus chemotherapy in patients with PD-L1-negative advanced non-small-cell lung cancer (NSCLC). The primary endpoint, 12-month progression-free survival (PFS) rate, is 42.1% (95% CI, 29.6%-60.0%), which has reached the prespecified threshold. Secondary endpoints include a median overall survival of not reached, a median PFS of 9.7 months, an objective response rate of 66.0%, a disease control rate of 100.0%, and a median duration of response of 9.5 months. Grade ≥3 treatment-related adverse events occur in 26 (52.0%) patients. cfDNA methylation-based molecular response predicts the actual clinical response approximately 5 cycles earlier than conventional radiographic evaluation. Baseline differentially methylated fragments scores show a significant correlation with PFS, with low-risk patients demonstrating a longer median PFS compared to high-risk patients (11.4 months versus 6.9 months). Overall, first-line cadonilimab plus chemotherapy shows an encouraging efficacy with a manageable safety profile for challenging-to-treat PD-L1-negative advanced NSCLC, warranting further evaluation in controlled studies.
Cryo-electron microscopy (cryo-EM) data acquisition is time-intensive given that a large amount of data is required to obtain a high-resolution reconstruction. Here, we eliminate camera-induced delay time by continuously recording during beam-image shift acquisition using a method called Continuous Recording Beam-Image Shift (CR-BIS). The utilization of CR-BIS with K3 and Falcon 4 direct electron detectors and conventional data acquisition conditions enables the acquisition of ~34,000 micrographs and ~1,000 tilt series per 24 h in single-particle analysis mode and cryo-electron tomography mode, respectively. Three-dimensional reconstructions of single-particle and tomographic datasets show that CR-BIS accelerates data collection and maintains data quality. CR-BIS is broadly applicable for efficient high-resolution cryo-EM since it can be implemented into existing acquisition software through scripting and it does not require hardware modification.
Second-generation antipsychotics, a cornerstone of psychiatric disorder management, render treated patients highly prone to metabolic abnormalities. To address this unmet clinical need, this post-hoc analysis drew on data from a previous trial to examine the correlations between plasma short-chain fatty acid (SCFA) level alterations and metabolic changes in the context of probiotic-fiber intervention. In this trial, individuals diagnosed with schizophrenia or bipolar disorder, who were undergoing stable atypical antipsychotic therapy, were recruited for this study. They were subsequently randomized in a 1:1:1:1 ratio to four treatment groups: combined probiotics (1680 mg/d) and dietary fiber (60 g/d); probiotics (1680 mg/d) with dietary fiber placebo; dietary fiber (60 g/d) with probiotics placebo; and double placebo (probiotics placebo plus dietary fiber placebo). Assessments were conducted at screening/baseline, week 4, and week 12, and the measurement of circulating SCFAs was performed via liquid chromatography-mass spectrometry. The analysis, employing the last-observation-carried-forward method, encompassed 79 participants who provided at least one follow-up plasma sample for the quantification of SCFAs. The 12-week combined administration of probiotics and dietary fiber was associated with changes in circulating levels of SCFAs and improvements in metabolic indices. More importantly, the higher levels of propionate were associated with decreased weight (adjusted odds ratio [OR]: 0.61 per quartile increase, 95% confidence interval [CI]: 0.38-0.96) and homeostatic model assessment of insulin resistance (HOMA-IR) (adjusted OR:0.58, 95% CI: 0.36-0.94). Also, the higher levels of butyrate were associated with a 42% lower odds (adjusted OR: 0.58, 95%CI:0.36-0.93) of elevated body mass index (BMI) and a 49% lower odds (adjusted OR: 0.51, 95%CI:0.31-0.86) of elevated insulin levels. The findings of this study suggested that elevated circulating levels of butyrate and propionate might be associated with reduced weight gain and improved insulin resistance in individuals receiving antipsychotic medications. ClinicalTrials.gov NCT03379597, trial registration date: 11/29/2017. Overall Recruitment Status: completed.
While the central dogma outlines DNA-to-protein information flow, existing gene regulators mainly target transcription. Here, we developed the λN-Guided RNA Targeting System (λGRTS), a CRISPR-independent platform enhancing mammalian mRNA translation via specific translation-guiding RNAs (tgRNAs). λGRTS integrates λN (high-affinity BoxB binder), mutated eIF4E1 (ablated non-specific 5' cap binding, retains TIC recruitment), and auxiliary factors (HuR for dsRNA stabilization, PABP and RRM2-RRM3 for mRNA closed loops). Optimized 22-nt tgRNAs (targeting 58 bp upstream of mRNA ATG in 5' UTR) and NES-tagged proteins maximized efficacy. λGRTS outperformed dCasRX (smaller ~ 50 kDa vs. ~ 150 kDa, single tgRNA vs. crRNA-tracrRNA), boosting functional proteins (e.g., GFP). It activated P53/PTEN, suppressing GBM cell proliferation, inducing G1 arrest, and reducing invasion in vitro. In vivo, lentiviral λGRTS inhibited orthotopic GBM in nude mice, extended survival by approximately 35-40 days, with IHC confirming P53/PTEN upregulation. Mass spectrometry showed no off-target effects. Cross-species tests (human, mouse, bovine cells) validated broad applicability via conserved eIF4E1. λGRTS offers a specific, safe translation-centric tool for gene regulation and oncology research.
Medical knowledge accumulation and clinical practice form a closed loop, yet enabling effective cooperation between the two elements, namely autonomously distilling updated knowledge from dynamic data to guide practice, remains challenging, especially in the emergency department (ED). To overcome this, we developed an autonomous AI agent that integrates established medical knowledge graphs with dynamic clinical data into a hybrid graph of over 800,000 nodes. Using large language models (LLMs) for knowledge extraction and semantic mapping, the system dynamically selects the most relevant graph to power specialized tools for ED recognition, prediction, and decision-making. The agent achieves average improvements over state-of-the-art baselines of 23.13% in ED triage, 13.05% in drug-drug interaction detection, 1.58% in readmission prediction, and 5.47% in medication recommendation, demonstrating superior performance across all task categories. This demonstrates an effective framework for synergizing established medical knowledge and dynamic clinical data in emergency care.
Alumina-based eutectic ceramics exhibited high high-temperature strength but their intrinsic brittleness constrained broad structural applications. Here, we broke this limitation by introducing high-entropy rare-earth aluminate (REAlO3, RE = Gd0.25Eu0.25Nd0.25Sm0.25) into the Al2O3 matrix via directional solidification. The resulting dual-phase eutectics exhibited a unique architecture where single-crystalline Al2O3 was interlocked with bicrystalline high-entropy REAlO3, forming nanoscale coherent grain boundaries (~57.5 nm) and semi-coherent phase boundaries (lattice misfit <5.1%). The tailored microstructure and orientation relationship enabled a synergistic enhancement of Vickers hardness (19.4 GPa) and fracture toughness (5.5 MPa·m1/2), outperforming all reported binary alumina-based counterparts. The property synergy originated from a cascaded strengthening mechanism that spanned atomic-scale lattice distortion to nanoscale coherent interfaces, coupled with multi-mode toughening via crack deflection, bifurcation, and bridging. Our work establishes a high-entropy eutectic design strategy for engineering ceramics with exceptional mechanical performance under extreme conditions.