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Active LXR signaling, coupled with elevated mitochondrial and glycolytic metabolism contributes to GM-CSF–induced trained immunity
No full textGranulocyte-macrophage colony-stimulating factor (GM-CSF) contributes to the host defense and the pathogenesis of inflammatory diseases at least in part through inducing trained immunity (TI), however, the mechanism remains poorly characterized. In this paper, we systematically investigated the associated metabolic and epigenetic reprogramming, with a particular focus on the role of liver X receptors (LXRs) in this process. We employed a comprehensive experimental approach, including in vitro isolation and purification of human monocytes from healthy donors, cytokine assays, quantitative PCR, Seahorse metabolic analysis, flow cytometry, and chromatin immunoprecipitation (ChIP), shotgun lipidomics, as well as transcriptomic data analysis to investigate GM-CSF–induced trained immunity. Our results demonstrate that GM-CSF induces TI by enhancing cellular metabolism, as evidenced by increased glycolysis, mitochondrial activity, fatty acid oxidation, and pyruvate metabolism. Lipidomics and RNA sequencing analyses revealed upregulation of lipid synthesis, high triglyceride storage, and acetyl-CoA–producing pathways, leading to increased histone acetylation in GM-CSF–trained cells. Furthermore, glycolysis and mitochondrial metabolism are essential for establishing TI in these cells. Notably, pharmacological inhibition of GM-CSF activated LXR signaling, which potentially mediated via PPARγ, attenuated GM-CSF–induced TI via reducing glycolytic flux and histone acetylation while activation of LXR amplified these effects. Together, these results highlight the role of LXR in linking cellular metabolism with epigenetic reprogramming and demonstrate that elevated metabolic activity and active LXR signaling both are essential for GM-CSF–induced trained immunity. Importantly, these pathways may represent therapeutic targets for modulating GM-CSF–driven maladaptive inflammation in chronic inflammatory diseases
Perioperative anesthesia management of high-molecular-weight kininogen deficiency: a case report and literature review
No full textA prolonged activated partial thromboplastin time (APTT) is a common abnormal finding in preoperative coagulation screening. Failure to accurately identify its underlying etiology can lead to a misjudgment of bleeding risk, potentially resulting in surgical delays, unnecessary transfusion of blood products, or even invasive further investigations. These consequences, in turn, increase both healthcare costs and patient risk. The prolongation of APTT is attributable to a variety of pathophysiological states, including coagulation factor deficiencies and the presence of pathological inhibitors. Among these, High Molecular Weight Kininogen (HMWK) deficiency is an extremely rare autosomal recessive disorder, characteristically marked by a significantly prolonged APTT in vitro, yet without a corresponding clinical bleeding tendency. This study report provides a detailed account of the anesthesia management during the perioperative period in a patient with HMWK deficiency. The patient is a 27-year-old female who, due to a markedly prolonged APTT, underwent genetic testing that revealed a defect in the kininogen-1 gene (KNG1) and was diagnosed with HMWK deficiency. She was scheduled to undergo laparoscopic salpingostomy, ovarian lesion resection, and hysteroscopic endometrial lesion resection due to abnormal uterine bleeding, bilateral hydrosalpinx, and a left ovarian cyst. The patient did not receive prophylactic transfusion of blood products, such as fresh frozen plasma or coagulation factors, nor any pharmacological intervention during the perioperative period. No abnormal bleeding or thrombotic events were observed. This case report, incorporating a systematic literature review and based on the pathophysiological principle of intact hemostatic function in patients with HMWK deficiency, culminates in the formulation of a set of perioperative anesthetic management strategies for this patient population
Physics-informed neural network–transformer for dual-objective prediction and mix optimization of backfill materials
No full textTo address the issues of traditional backfill material mix design relying on experience and low efficiency, this study proposes a physics-informed neural network (PINN)–transformer method that integrates physical constraints. A dual-task prediction framework is constructed considering material strength and slump, embedding strength development monotonicity, convexity constraints, and slump rheological principles into model training to improve the accuracy and physical reasonableness of the prediction results. Experimental results show that this method improves the mean absolute error (MAE) metric by 6.0% compared to the transformer in strength prediction and improves the slump prediction MAE metric by 6.5%. A multi-objective mix optimization system is established based on prediction results and economic analysis, proposing three optimization strategies adapted to different engineering requirements. This method breaks through the limitations of traditional empirical design and provides efficient and reliable technical support for scientific mix design and engineering decision-making regarding mine backfill materials
The predictive effects of individual difference factors on L2 writing complexity, accuracy, and fluency
No full textDrawing on the control-value theory and the individual-environmental model of writing, this study investigated the predictive effects of various individual difference factors (i.e., L2 writing grit, enjoyment, anxiety, motivation, and working memory) on L2 writing syntactic complexity, accuracy, lexical complexity, and fluency (CALF) performance. Questionnaires were distributed to 390 high school students to measure their L2 writing grit, enjoyment, anxiety, and motivation. A reading span test and an operation span test were conducted to assess the students' working memory. All participants completed a writing task within 30 minutes. The structural equation modeling results revealed that L2 writing anxiety directly predicted syntactic complexity and accuracy, and L2 writing motivation directly predicted lexical complexity and fluency. Although L2 writing grit did not directly predict CALF performance, it predicted syntactic complexity and accuracy through anxiety. In addition, L2 writing grit predicted lexical complexity and fluency through the serial mediating roles of emotions and motivation. Specifically, the mediating effect of enjoyment and motivation was larger than that of anxiety and motivation in the relationship between grit and lexical complexity as well as between grit and fluency
A novel variant in SIAH1 associated with autosomal dominant Buratti-Harel syndrome
No full textIntroductionBuratti-Harel syndrome (BURHAS) is a rare autosomal dominant neurodevelopmental disorder caused by SIAH1 (Siah1 E3 ubiquitin ligase) variants, characterized by infantile hypotonia, global developmental delay, and variable multisystem involvement. To date, 13 pathogenic SIAH1 variants have been reported in 13 patients, but the functional and phenotypic implications of mutations in the SIAH1 zinc finger domain remain poorly characterized. This study included a Chinese pediatric patient with unexplained neurodevelopmental and multisystem abnormalities.MethodsTrio whole-exome sequencing (WES) was performed to identify potential causative variants. Structural modeling was used to analyze the impact of the identified variant on SIAH1 protein structure. Additionally, a comparative genotype-phenotype analysis was conducted on 14 genetically confirmed BURHAS cases (including the present patient).ResultsA de novo missense variant [c.288C > G (p.Phe96Leu)] in the zinc finger domain of SIAH1 was identified in the patient. Structural modeling revealed that this variant destabilized the zinc finger domain (DDG = –2.09 kcal/mol), which may disrupt the ZnF-1 domain function by impairing zinc ion-mediated structural stability. Comparative analysis of 14 genetically confirmed cases (including this study) demonstrated a genotype-phenotype correlation: zinc finger domain variants (n = 4) exhibited broader phenotypic heterogeneity compared to RING domain variants (n = 7), which were enriched for severe developmental delay and reproductive anomalies.DiscussionThis study expands the mutational spectrum of SIAH1-associated disorders. We advocate for the inclusion of SIAH1 in diagnostic panels for patients with unexplained neurodevelopmental disorders and multisystem dysmorphisms
Oophorectomy followed by postoperative chemotherapy for ovarian metastasis of colorectal cancer: a retrospective analysis
No full textBackgroundThe incidence of ovarian metastasis from colorectal cancer is low but the prognosis is extremely poor; however, the prognostic factors remain unclear and there are currently no guidelines for the treatment of ovarian metastasis from colorectal cancer. This study evaluated the impact of resection of ovarian metastasis from colorectal cancer and postoperative chemotherapy on patient prognosis.MethodsThis retrospective study analyzed patients with ovarian metastasis from colorectal cancer between January 2009 and December 2019. Factors with P < 0.1 in univariable analysis were considered as potentially prognostic factors and were incorporated into multivariable analysis with Cox proportional hazards regression models. Hazard ratios (HRs) with 95% confidence intervals (CIs) were analyzed. A two-sided P value < 0.05 was considered significant.ResultA total of 213 patients with ovarian metastasis from colorectal cancer were included in the study. Univariable analysis identified that the resection of primary tumor, extraovarian metastasis, oophorectomy, postoperative chemotherapy and mismatch repair (MMR) status as potentially prognostic factors. The median survival times in patients with and without oophorectomy were 25 and 11 months, respectively. Chemotherapy after surgery was associated with a longer median overall survival compared with patients without chemotherapy (25 versus 20 months). The median survival time for patients with dMMR status was 36 months, compared to 25 months for those with pMMR status. Multivariable analysis confirmed that oophorectomy (HR = 10.476, 95% CI, 5.536–19.825; P < 0.001), postoperative chemotherapy (HR = 2.232, 95% CI, 1.538–3.238; P < 0.001) and MMR status (HR = 1.967, 95% CI, 1.026-3.772; P = 0.042) were independent prognostic factors for overall survival in patients with ovarian metastasis from colorectal cancer.ConclusionOophorectomy, postoperative chemotherapy, and dMMR status may offer survival benefits for colorectal cancer patients with ovarian metastasis; however, the main findings from current study warrant further validations
Post-translational modification of NK cell receptors offers clues to antigenic specificity riddle
No full textNatural killer (NK) cells protect against infections through a distinctive combination of innate and adaptive immune capabilities. They exhibit characteristics of immunological memory by enhanced secondary response to pathogen exposure. We discuss current progress in identifying long-lived NK cell clones with enhanced memory functionality and the capacity for intensive cytokine and cytotoxic granule production upon re-encountering external antigens. We examine data related to how various NK cell receptors facilitate the recognition of specific foreign peptides in particular human leukocyte antigen (HLA) contexts and may promote the formation of memory clones. Finally, we propose and substantiate a model that resolves the accumulated fundamental contradictions and explains the semi-antigen-specific nature of the NK cell response through the clonally imprinted expression patterns of enzymes involved in the post-translational modification of HLA-binding receptors
Chrononutrition interventions for mental health: addressing atypical depression, ultra-processed food use disorder, and circadian dysregulation
No full textBackgroundAtypical depression frequently presents with metabolic and immuno-inflammatory comorbidities, often exacerbated by chronic intake of ultra-processed foods (UPFs), which can exhibit addictive-like properties. However, these dietary underpinnings are rarely a focus in standard psychiatric care. Emerging research in chronobiology reveals that meal timing—commonly referred to as a zeitgeber—can help realign disrupted circadian rhythms that underlie various psychiatric symptoms, from atypical depression and anxiety to insomnia and impulsivity.AimThis perspectives paper proposes a Time-Restricted Eating (TRE) approach within the framework of chrononutrition to simultaneously target the metabolic, circadian, and behavioral roots of mental health disorders. By reducing reliance on ultra-processed foods and restructuring daily food intake windows, clinicians may observe improvements in both mood-related and neurovegetative symptoms across a range of psychiatric conditions.Methods/ApproachWe synthesize emerging evidence on how circadian misalignment, metabolic dysfunction, and inflammatory processes intersect in mental health. We then discuss how a structured chrononutrition intervention, particularly TRE, can serve as both a screening and therapeutic tool for patient populations exhibiting symptoms such as hypersomnia, anxiety, agitation, compulsivity, and impaired focus.ConclusionChrononutrition, alongside established psychiatric treatments, may offer a low-risk, high-yield strategy for improving mental health outcomes. Further research is needed to solidify consensus on definitions, assessment tools, and best practices for addressing ultra-processed food addiction and circadian disruption in clinical settings
Muscle quality correlates with hearing thresholds: a cross-sectional analysis
No full textIntroductionMuscle health, including muscle volume, is an independent risk factor for physical disability and metabolic disorders. Although low muscle mass has been associated with hearing loss, the association between computed tomography (CT)-derived muscle quality and hearing has not been explored.MethodsThis cross-sectional study examined associations between abdominal body composition and hearing thresholds in 7,774 adults (4,537 men and 3,237 women) aged ≥40 years undergoing routine health check-ups. Abdominopelvic CT and pure-tone audiometry were performed, and total abdominal muscle area (TAMA), normal-attenuation muscle area (NAMA), low-attenuation muscle area (LAMA), intermuscular adipose tissue (IMAT), visceral fat area (VFA), and subcutaneous fat area (SFA) were quantified from CT-based muscle quality maps. The best-ear pure-tone average (PTA, 1–4 kHz) was analyzed as the loge-transformed PTA. Multivariable linear regression models were fitted separately for men and women, adjusting for age, cardiovascular risk factors, and lifestyle variables.ResultsThe loge-transformed LAMA index was independently associated with hearing in both sexes. Each 10% increase in the loge-transformed LAMA index corresponded to an estimated 0.11 dB worsening of PTA in men and 0.14 dB worsening in women. In women, TAMA, NAMA, and VFA indices were associated with PTA; these associations were confined to women in their 50s and 60s in decade-stratified analyses. No abdominal body composition indices were significantly associated with hearing thresholds in any age group among men.ConclusionsThese findings suggest that abdominal body composition is associated with age-related hearing loss (ARHL), particularly in midlife women, and highlight skeletal muscle health as a potential target for hearing preservation
Diabetes and tumor risk: a 23-year Danish national cohort study
No full textIntroductionDiabetes mellitus is a recognized risk factor for cancer, yet the relationship between diabetes type and tumor risk remains unclear. This study aimed to estimate the overall tumor burden, including benign, premalignant, and malignant tumors, in individuals with type 1 and type 2 diabetes.MethodsIn this nationwide cohort study spanning 23 years (1999–2022), data on diabetes diagnosis, tumor development, and potential confounding variables were retrieved from multiple Danish national health registries. The cohort included more than 6.5 million individuals and 128,647 tumor events among individuals with diabetes. Crude and adjusted hazard ratios (HRs) were estimated using Cox regression. ResultsFor individuals with type 1 diabetes, adjusted HRs indicated no association for overall tumor development compared to individuals without diabetes. For individuals with type 2 diabetes, adjusted HRs suggested a slightly decreased hazard for overall tumor development compared to individuals without diabetes. When excluding tumors in the skin, the association between type 1 and type 2 diabetes and overall tumor development, suggested an increased hazard compared with individuals without diabetes. Our exploratory sub-analyses were stratified by tumor topography based on Systematized Nomenclature of Medicine (SNOMED) codes. Among individuals with type 1 diabetes, eight of 28 tumor groups showed reduced hazard, including the pancreas, bile ducts, and kidney. For type 2 diabetes, one group showed reduced hazard, while 22 groups, including the heart, blood vessels, and liver, showed increased hazard. Estimates from exploratory analyses should be interpreted with caution. DiscussionOur findings provide population-level evidence that advances our understanding of the possible complex metabolic links between diabetes and tumor development. Further exploration of SNOMED-based tumor classifications in future studies may provide valuable knowledge on pathological differences and refine future tumor and cancer surveillance strategies in individuals with diabetes
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