Prenatal maternal psychological distress, particularly depression, has been increasingly recognized as a factor that influences fetal growth; however, its impact on early childhood development remains less well understood. The present study investigated the association between prenatal depression and children's growth trajectories, as well as the odds of overweight and obesity from 1 to 36 months, while also accounting for maternal anxiety and stress. We analyzed data from 4710 mother-child dyads in the Jiangsu Birth Cohort, assessing maternal psychological distress across trimesters and categorizing participants into groups with mild, moderate, and severe depressive symptomatology. Children's weight-for-length z-scores (WLZ) were used to assess overweight/obesity prevalence, and growth patterns were identified through trajectory models. The results from the generalized estimating equations analysis showed that greater depressive symptomatology during pregnancy was associated with a 28% to 41% increase in the odds of childhood overweight/obesity across all three trimesters, compared with mild depressive symptomatology. We identified five distinct WLZ growth trajectory patterns, and found that mothers with greater depressive symptomatology were 39%-47% more likely to have children who followed a very-high-stable growth trajectory, compared with mothers with mild depressive symptomatology. These findings highlight the significant impact of prenatal depression on adverse growth patterns and childhood overweight/obesity, underscoring the need for early intervention.

Interferon-related genes are involved in antiviral responses, inflammation, and immunity, which are closely related to sepsis-associated acute respiratory distress syndrome (ARDS). We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS (MEARDS), the Molecular Epidemiology of Sepsis in the ICU (MESSI), and the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls. First, we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression (GReX). Second, we examined the association of the confirmed gene (interferon regulatory factor 1, IRF1) with ARDS risk and survival and conducted a mediation analysis. Through discovery and validation, we found that the GReX of IRF1 was associated with ARDS risk (odds ratio [OR_MEARDS] = 0.84, P = 0.008; OR_MESSI = 0.83, P = 0.034). Furthermore, individual-level measured IRF1 expression was associated with reduced ARDS risk (OR = 0.58, P = 8.67 × 10⁻⁴), and improved overall survival in ARDS patients (hazard ratio [HR_28-day] = 0.49, P = 0.009) and sepsis patients (HR_28-day = 0.76, P = 0.008). Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex, including HLA-F, which mediated more than 70% of protective effects of IRF1 on ARDS. The findings were validated by in vitro biological experiments including time-series infection dynamics, overexpression, knockout, and chromatin immunoprecipitation sequencing. Early prophylactic interventions to activate IRF1 in sepsis patients, thereby regulating HLA-F, may reduce the risk of ARDS and mortality, especially in severely ill patients.

While a healthy lifestyle is known to reduce the risk of stroke, the extent to which blood pressure (BP) mediates this association remains unclear. The present study aimed to quantify the mediating role of BP in the association between combined lifestyle factors and stroke incidence. Using data from 51929 participants free of major cardiovascular diseases or cancer at baseline, we employed structural equation modeling to assess the mediating effects of systolic (SBP) and diastolic (DBP) blood pressure. During the follow-up, 2811 incident stroke cases were identified. A healthy lifestyle was significantly associated with a reduced risk of stroke, with SBP mediating 44.70% (β = −0.0014, 95% confidence interval [CI]: −0.0016 to −0.0012) and DBP mediating 37.81% (β = −0.0012, 95% CI: −0.0015 to −0.0009) of this association. The mediating effects were attenuated but remained significant for ischemic stroke (SBP: 33.21%; DBP: 27.24%). In conclusion, approximately two-fifths of the protective association between a healthy lifestyle and stroke may be mediated by BP. These findings suggest that BP control may serve as an important early indicator for evaluating the effectiveness of lifestyle interventions in reducing stroke risk.

As the prevalence of obesity increases dramatically, obesity-associated cardiac dysfunction constitutes a considerable challenge to human health. This study aimed to identify more useful lipid/inflammatory markers to predict the risk of obesity-associated cardiac dysfunction. By retrospectively analyzing the clinical characteristics of 5648 cardiac disease patients, we found that both the plasma level of high-density lipoprotein cholesterol (HDL-C) and the blood monocyte count were significantly associated with impairment of the left ventricular ejection fraction (LVEF). Univariate and multivariate regression analyses revealed that the monocyte to HDL-C ratio (MHR) was a more powerful predictor of the risk of LVEF decline than either HDL-C or monocyte alone. Mediation analysis further revealed a mediating effect of a high MHR on the decline in obesity-associated cardiac systolic function. Collectively, our results demonstrate a superior role of MHR in predicting the risk of an obesity-associated decline in cardiac systolic function among routine metabolic/inflammatory markers.

V-raf-leukemia viral oncogene 1 (RAF1), a serine/threonine protein kinase, is well established to play a crucial role in tumorigenesis and cell development. However, the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown. In this study, we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity (DIO) mice. Under normal chow diet feeding, overexpression ofRaf1in AgRP neurons led to obesity in mice characterized by increased body weight, fat mass, and impaired glucose tolerance. Conversely,Raf1knockout in AgRP neurons protected against diet-induced obesity, reducing fat mass and improving glucose tolerance. Mechanistically,Raf1activated the MAPK signaling pathway, culminating in the phosphorylation of cAMP response element-binding protein (CREB), which enhanced transcription ofAgrpandNpy. Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis, highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance. Collectively, these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis, positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.

Diabetic retinopathy (DR), a common complication of diabetes, is characterized by retinal angiogenesis and inflammation. The role of hepatoma-derived growth factor (HDGF) in mediating inflammation during DR remains unclear. We measured HDGF levels in the aqueous humor and found that HDGF was increased in DR but decreased after anti-angiogenesis treatment. Using public single-cell RNA sequencing datasets, we found that elevated HDGF in DR was mainly produced by Müller cells and targeted microglia. Additionally, integrin beta 2 (Itgb2), a target gene of HDGF that induces microglial activation, was significantly upregulated in DR. To verify these results, we performed enzyme-linked immunosorbent assays, quantitative reverse transcription-PCR, Western blotting, and fluorescence immunostaining in cultured Müller and microglial cells treated with HDGF or anti-HDGF, as well as in DR mice receiving intravitreal injections of HDGF or its antibody. Exogenous HDGF further promoted microglial activation, migration, and secretion of pro-inflammatory cytokines, while neutralization of HDGF suppressed these effects caused by high glucose. Furthermore, the HDGF receptor nucleolin was overexpressed in microglia under high glucose stimulation. Therefore, blocking HDGF from Müller cells in DR reduced the excessive inflammatory response in microglia, highlighting HDGF as a potential therapeutic target.

Acute kidney injury (AKI) is a critical condition with limited effective therapies. Akkermansia muciniphila (A. muciniphila) is a probiotic with multiple beneficial effects, including the regulation of epithelial cell tight junctions. Since renal pathophysiology is associated with gut barrier integrity, we hypothesized that A. muciniphila may have preventive effects on AKI. We established a lipopolysaccharide (LPS)-induced AKI mouse model to evaluate the effects of A. muciniphila. Our findings showed that pretreatment with A. muciniphila significantly attenuated kidney injury, as evidenced by reduced serum creatinine and urea nitrogen levels, alongside decreased tubular necrosis and apoptosis. A. muciniphila preserved intestinal barrier integrity and induced marked shifts in gut microbial ecology and the metabolome. A. muciniphila notably induced an increase in the relative abundance of the phylum Proteobacteria while decreasing in that of the phylum Bacteroidetes. At the genus level, Prevotella, Faecalibaculum, Moraxella, and Lactobacillus were more abundant in A. muciniphila-pretreated mice. Metabolomic analysis revealed that A. muciniphila altered the gut metabolome, with changes involving pathways such as tyrosine metabolism, alanine/aspartate/glutamate homeostasis, cancer-related carbon flux, and GABAergic synaptic signaling. In conclusion, our findings indicate that A. muciniphila exerts renoprotective effects by modulating the gut-kidney axis, thereby establishing a foundation for future studies to explore the connection between gut microbiota and AKI.

Clostridioides difficile (C. difficile) is one of the major causes of nosocomial infections. Pregnant women, who are generally considered at low risk for C. difficile infection (CDI), have attracted attention because of an increasing number of reports. Oral vancomycin, the only first-line treatment for pregnant women infected with C. difficile, has been associated with increasing strain resistance, leading to decreased efficacy. Fecal microbiota transplantation (FMT) is recommended for severe, fulminant, and recurrent CDI; however, it is generally avoided in pregnant women because of safety concerns. We report a case of a pregnant woman with a primary ribotype 027 CDI who experienced a successful outcome with washed microbiota transplantation (WMT), an improved form of FMT, via enema. The specific strain of ribotype 027 is related to severe outcomes but has not previously been reported in pregnant women. The follow-up lasted for two years, during which the patient's diarrhea was fully alleviated without recurrence. The baby showed normal growth and development, and no adverse events were recorded for either. This case provides evidence for the efficacy and safety of WMT in pregnant women infected with C. difficile, indicating that WMT via enema may be a viable therapeutic strategy for this population for treating CDI.