搜索结果：Reversed

Depression involves dysregulation across distributed cortico-limbic circuits, and ketamine is notable for its rapid antidepressant effects. Although depression and ketamine treatment have been linked to altered brain network topology, how within-frequency and cross-frequency coupling are jointly reorganized at the brain-wide level remains unclear. Here, we developed a frequency-varying multilayer brain functional network (FMBFN) framework to analyze local field potential recordings from eight brain regions in male C57BL/6 mice. This framework integrates within- and cross-frequency coupling and extracts multi-scale network features to characterize brain network structure. Applying this approach in the chronic social defeat stress (CSDS) model, we found that CSDS was associated with frequency-specific hyperconnectivity and selective alterations in network integration during social interaction. Ketamine reversed social avoidance and induced the distinct reorganization of multilayer network topology, including region-specific nodal changes. Notably, the lateral habenula showed the response pattern opposite to that of the other recorded regions. As an exploratory cross-modal extension, we further examined gut microbial features and found that specific ketamine-associated microbial changes were linked to global network topology, suggesting candidate gut-brain association patterns. Together, these findings establish the FMBFN framework as a systems-level tool for characterizing brain-wide neural dynamics in psychiatric disorders and for linking network-level alterations to biological contexts.

Radiotherapy is a cornerstone treatment for unresectable lung cancer. However, radiation-induced bystander effects (RIBE) remain a major obstacle to its therapeutic efficacy. LINC01234, showing high expression in lung cancer RIBE, its role and mechanism remain unclear. Beas-2B cells were cultured in conditioned medium derived from A549 lung cancer cells exposed to 4.0 Gy X-ray irradiation to establish an in vitro RIBE model. Models with LINC01234 knockdown and MECOM overexpression were constructed. Mitochondrial alterations were examined by transmission electron microscopy. The expression of ferroptosis-related and MAPK pathway-associated factors was assessed to elucidate the relationship between LINC01234 and MECOM. Co-immunoprecipitation (Co-IP) was used to investigate interactions between MECOM and JNK, p38, and Erk1/2. RIBE reduced cell viability and promoted apoptosis in bystander cells. Knockdown of LINC01234 significantly alleviated RIBE-induced injury. Mechanistically, LINC01234 silencing suppressed Fe²⁺ accumulation, ROS generation, MDA levels, GSSG, and ACSL4 expression, while enhancing GSH, GPX4, and SLC7A11 expression. In parallel, phosphorylation of JNK, p38, and Erk1/2 was inhibited. The ferroptosis inhibitor ferrostatin-1 produced effects comparable to LINC01234 knockdown. Moreover, LINC01234 silencing downregulated MECOM expression. Overexpression of MECOM reversed the protective effects of LINC01234 knockdown, whereas co-silencing LINC01234 or treatment with the MAPK pathway inhibitor osmundacetone abrogated MECOM-induced effects. Co-IP confirmed that MECOM interacts with JNK, p38, and Erk1/2. Downregulation of LINC01234 suppresses ferroptosis in RIBE cells by inhibiting MECOM-mediated phosphorylation of p38/JNK/Erk1/2, thereby mitigating radiotherapy-associated side effects.

Immune rejection after liver transplantation remains a major challenge impacting the long-term survival of liver transplant recipients. Inhibiting macrophage M1 polarization exerts a positive effect on alleviating post-transplant immune rejection. Arctiin, an active component derived from traditional Chinese medicine, may suppress macrophage M1 polarization by inhibiting the release of pro-inflammatory cytokines. This study employed experimental techniques including ELISA, double-label flow cytometry, Western blot analysis, and cellular immunofluorescence to investigate the potential mechanism underlying the effect of arctiin on macrophage M1/M2 phenotypic switching in vitro. Results demonstrated that arctiin promoted the conversion of M0 macrophages to the M2 phenotype, significantly downregulated the levels of pro-inflammatory cytokines IL-6 and TNF-α, inhibited the expression of the M1 macrophage marker inducible nitric oxide synthase (iNOS), and reduced the proportion of M1-type macrophages. Furthermore, arctiin notably enhanced STAT6 phosphorylation and TRAF6 protein expression in M1 macrophages while suppressing STAT1 phosphorylation. However, these beneficial effects of arctiin were significantly reversed by a CB2R antagonist. Additional experiments showed that a CB2R agonist exerted similar effects to arctiin. Treatment with a TRAF6 inhibitor abrogated the inhibitory effect of arctiin or the CB2R agonist on macrophage M1 polarization, increased STAT1 phosphorylation, and decreased STAT6 phosphorylation. In conclusion, this study indicates that arctiin can activate CB2R and exert anti-inflammatory effects through the TRAF6-STAT1/6 pathway, thereby promoting the phenotypic switch of macrophages from M1 to M2.

Cystic echinococcosis (CE) is a global zoonotic parasitic disease caused by the larval stage of Echinococcus granulosus (Eg). The hydatid cysts of CE mainly develop in the liver, causing serious liver damage and even endangering the life of the host. Ras-related protein Rab18, which is involved in liver injury, represents a crucial protein in these disease and a potential therapeutic target. However, the regulation mechanism by which Rab18 from hydatid cyst on host hepatocytes has not been fully elucidated. Therefore, we expressed Rab18 recombinant protein (rRab18) in prokaryotic expression system and analysed its secretion characteristics and localisation. Then, the effects of rRab18 on the proliferation, apoptosis, and autophagy of AML12 cells were detected. In addition, the involvement of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/ AKT/mTOR) pathway was identified by western blot. The results showed that rRab18 was mainly expressed in the protoscoleces and could be secreted into the host liver tissue. rRab18 inhibited proliferation of AML12 cells. Moreover, rRab18 induced AML12 cells apoptosis, as evidenced by the increase in the number of cells with damaged cell membranes, and increased apoptosis rate, Bax/Bcl-2 ratio, and activated cleaved caspase-3 levels. Furthermore, rRab18 induced autophagy in AML12 cells by enhancing the expression of LC3-II and decreasing the p62. rRab18 inhibited the PI3K/AKT/mTOR pathway in AML12 cells, as shown by decreased p-PI3K, p-AKT and p-mTOR expression, and the PI3K inhibitor LY294002 promoted these changes and enhanced rRab18 induced apoptosis and autophagy, whereas the PI3K agonist 740Y-P reversed these effects. These results indicated that rRab18 may induce apoptosis and autophagy through PI3K/Akt/mTOR pathway, which provided a preliminary basis for further studying the interaction between hydatid cyst and the liver of host.

Some subtypes of head and neck squamous cell carcinoma (HNSCC) exhibit aggressive progression and poor prognosis, underscoring the need for novel therapeutic targets. While procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is implicated in tumour collagen remodelling, its functional role and regulatory mechanisms in HNSCC remain elusive. PLOD1 expression and clinical relevance were analysed using TCGA-HNSC data, patient tissues and cell lines. Functional impacts were assessed via in vitro assays (CCK-8, flow cytometry, Transwell) and in vivo xenograft models. Mechanistic insights were explored through co-immunoprecipitation, Western blotting, bioinformatics and pharmacological inhibition. PLOD1 was significantly upregulated in HNSCC tissues and correlated with adverse clinical outcomes. In vitro, PLOD1 overexpression potentiated proliferation, invasion and cell cycle progression while suppressing apoptosis; PLOD1 knockdown elicited opposing effects. PLOD1 activated the FAK/PI3K/AKT/mTOR pathway and directly interacted with prolyl 4-hydroxylase subunit alpha 2 (P4HA2). P4HA2 rescue reversed PLOD1 knockdown-mediated suppression of oncogenicity and pathway activation. The FAK inhibitor Y15 abrogated PLOD1-driven malignant phenotypes. In vivo, PLOD1 silencing inhibited tumour growth and reduced FAK/PI3K/AKT/mTOR phosphorylation. PLOD1 drives HNSCC progression by modulating P4HA2 and activating the FAK/PI3K/AKT/mTOR signalling cascade, positioning the PLOD1-P4HA2 axis as a promising prognostic biomarker and therapeutic target.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by athletes and those who exercise, yet their influence on the molecular responses to exercise remains unclear. Prior studies have often focused on a limited set of molecular pathways, potentially overlooking broader regulator effects of NSAIDs on skeletal muscle signaling. Therefore, we conducted a systems biology study of skeletal muscle biopsies taken before and after exercise, in combination with NSAID consumption, using transcriptomics and metabolomics, to identify differentially enriched pathways and biofunctions. We conducted a randomized, counterbalanced, double-masked, crossover trial (NCT05512013) in which 12 healthy adults ingested ibuprofen (IBU, 800 mg), celecoxib (CEL, 200 mg), flurbiprofen (FLU, 100 mg), or placebo (PLA) before a 10 × 10 bout of plyometric exercise. Skeletal muscle biopsies were collected before NSAID consumption and three hours post-exercise. Whole transcriptome profiling was performed using RNA-seq, and the metabolomics profile was assessed via untargeted mass spectrometry. Differential expression analysis and pathway enrichment were used to evaluate NSAID-specific effects across biological domains. FLU regulated the largest number of differentially expressed transcripts, followed by IBU and CEL. All NSAIDs activated immune-related gene networks and reversed exercise-induced lipid catabolism, with IBU enhancing adaptive immune signaling and CEL modulating both innate and adaptive pathways. Muscle remodeling pathways, including angiogenesis and cell migration, were activated across all NSAIDs, though cachexia-related genes were also upregulated. Interestingly, FLU uniquely upregulated transcripts involved in neuritogenesis. NSAIDs trigger drug-specific molecular responses in skeletal muscle post-exercise, affecting early recovery through changes in immune, metabolic, and neuronal signaling.

Sepsis is a life-threatening syndrome of organ dysfunction driven by a dysregulated immune response. Effective therapeutic strategies to restore immune homeostasis remain limited. Hypoacylated lipooligosaccharides (ALOS) from Akkermansia muciniphila have emerged as potential immunomodulatory postbiotics, yet their therapeutic potential in sepsis and the underlying mechanisms remain unexplored. This study aims to investigate whether ALOS confers protection in experimental models of sepsis induced by toxic lipopolysaccharides (LPS) or cecal ligation and puncture (CLP), and the mechanism by which ALOS exerts its anti-inflammatory and regulatory effects. In LPS or CLP-induced mouse sepsis models and a porcine sepsis model, ALOS (0.2 mg/kg, i.p.) was administered once every two days before challenge or half an hour post-surgery. Survival rates, physiological and biochemical parameters were assessed. Based on 16S rRNA gene amplicon sequencing and barrier function assessment, the changes of the colonic microbiota and metabolites and anti-inflammatory capacity were analyzed. The anti-inflammatory and immunomodulatory mechanisms of ALOS were investigated through dendritic cell phenotyping, transcriptomic analysis, inhibitor assays, and conditioned medium experiments. Finally, the safety of ALOS was evaluated in C57BL/6J mice following one-week administration (0.2 mg/kg, i.p.). ALOS pretreatment significantly suppresses sepsis, reduces the proportion of pro-inflammatory Th17 cells, and increases regulatory T cells (Treg). Mechanistically, ALOS induced semi‑mature dendritic cells with upregulated IDO1 expression, leading to enhanced production of kynurenine (Kyn). Kyn activated the aryl hydrocarbon receptor (AhR) to drive Treg differentiation. The protective effect of ALOS was completely reversed by NLG919, whereas Kyn administration mimicked the therapeutic benefit. ALOS also produced therapeutic protection on sepsis. In a porcine sepsis model, pretreatment of ALOS exerted systemic anti‑inflammatory effects and protected multiple organs. This study highlights the protective role of ALOS in sepsis and identifies the IDO1-Kyn-AhR immune axis as the major underlying mechanism.

Osteosarcoma (OSA) is the most common primary malignant bone tumor in children and adolescents, while no further improvement in survival has been achieved in the past few decades. Microwave ablation (MWA) is an emerging thermal therapy to ablate malignant bone tumors that induces antitumor immunity, while intrinsic mechanisms remain elusive. This study uncovered that MWA treatment promoted interleukin (IL)-18 expression and enhanced the dendritic cell (DC) functions, as well as CD8+ T cells infiltration. Combining IL-18 and anti-programmed cell death protein 1 (PD-1) displayed the additive tumor suppression effects. MWA treated OSA was co-cultured with bone marrow dendritic cells (BMDC) in vitro. RNA-sequencing was performed to analyze the intrinsic mechanism of BMDC after stimulated with MWA treated OSA. Mouse model of primary osteosarcoma of the femur was established for in vivo immune response evaluation, and this model was used to measure the additive tumor eradication of IL-18 and anti-PD-1 combination therapy. MWA promoted the activation, antigen uptake and antigen cross-presentation of BMDCs. Mouse models demonstrated that MWA treatment could elevate the proportion of CD8+ T cells and CD11c+DCs both in tumors and draining lymph nodes. The tumor suppression was mediated through the release of IL-18 by MWA-treated OSA and interaction with the IL-18 receptor on DCs, which was reversed after anti-IL-18 antibodies application. Besides, IL-18 cytokine exerted the tumor eradication effect and showed the additive role against OSA when combining anti-PD-1 therapy. Our study demonstrated a critical role of IL-18-mediated signaling in the induction of protective immune responses against OSA, which provided a novel mechanism to the explanation of MWA-induced immune activation, and IL-18 cytokine treatment could be considered a feasible, effective therapeutic approach for OSA in the clinic.

Heavy alcohol consumption has multiple negative cognitive, psychological, and neurobiological consequences for people with epilepsy. However, the psychopharmacological interactions remain unclear with limited therapeutic interventions. In this study, we investigated the diverse impact of alcohol on experimental simulated pentylenetetrazol-induced seizures and alcohol-use disorder, and the effects of silymarin, a polyphenolic compound with neuroprotective properties. Following seven days of ethanol binge exposure (2 g/kg, oral gavage) in mice, maximal and sub-convulsive pentylenetetrazol-induced seizures were administered from days 8 to 14, alongside silymarin (50 and 100 mg/kg) or diazepam (3 mg/kg) oral administration. This study evaluated the interplay between ethanol and pentylenetetrazol-induced seizures, assessing behavioural comorbidities, dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis, neurochemical and neurotrophic alterations, oxidative stress, and neuroinflammation in the hippocampus, prefrontal-cortex, and striatum, which are involved in the disease. Ethanol increased seizure severity and frequency caused by pentylenetetrazol, and worsened anxiety-like and depressive behaviours, along with spatial working memory deficits linked to higher alcohol preference. These effects were reduced by silymarin. Ethanol also increased corticosterone release and reduced GABA-dependent glutamic acid decarboxylase activity, raising glutamate levels, while decreasing serotonin and brain-derived neurotrophic factor across the studied brain regions. Silymarin significantly reduced neuroinflammatory markers such as myeloperoxidase, TNF-α, IL-6, nitrite, and malondialdehyde, while enhancing IL-10 levels and antioxidant defenses, including catalase, superoxide dismutase and glutathione in the brain regions. These findings suggest alcoholism with alcohol-use disorders worsens epilepsy, notably involving neurochemical imbalance, neurotropic, HPA-axis upregulation, oxidative stress, and neuroinflammation, which were reversed by silymarin.

Type 2 Diabetes Mellitus (T2DM) is a metabolic disease, which is associated with low-grade chronic inflammation in various tissues, such as white adipose tissue, and this plays a vital role in the development of insulin resistance. Ginsenoside Rk1 is a minor ginsenoside that is found in steamed or puffed ginseng. It has various pharmacological effects, including protection against endothelial dysfunction and β-cell apoptosis. However, its anti-diabetic effects have not been studied. This study investigated the anti-inflammatory and anti-diabetic effects of Ginsenoside Rk1 in bone marrow-derived macrophages (BMDMs) and high-fat diet (HFD)-induced diabetic mice, with a focus on adipose tissue inflammation. In diabetic BMDMs and mice, we investigated whether Ginsenoside Rk1 possessed anti-diabetic and anti-inflammatory effects. We used different molecular biology techniques to study the underlying mechanisms of Ginsenoside Rk1 in mediating these effects. We also investigated the role of signal transducer and activator of transcription 3 (STAT3) in mediating the anti-inflammatory and anti-diabetic effects by using a Stat3 inhibitor, Stattic. We demonstrated that Ginsenoside Rk1 exerted anti-diabetic effects in diabetic mice, including reducing fasting blood glucose levels, and improving glucose tolerance and insulin resistance. These protective effects were through suppressing adipose tissue inflammation. The alleviation of adipose tissue inflammation was via enhancing interleukin-10 (IL-10) levels, reducing pro-inflammatory cytokine levels, and inducing M2 polarization. These effects were also confirmed in diabetic BMDMs. The IL-10/STAT3 pathway was shown to be crucial for the alleviation of adipose tissue inflammation by Ginsenoside Rk1, and STAT3 was also found to be a potential direct target of Ginsenoside Rk1. STAT3 inhibition reversed the protective effects of Ginsenoside Rk1 in diabetic mice. Our findings unveiled the remarkable anti-diabetic effects of Ginsenoside Rk1 in diabetic mice, emphasizing the pivotal role of STAT3 in alleviating adipocyte hypertrophy, adipose tissue inflammation and T2DM.

Circular_RNAs (circ_RNAs) are involved in the development and progression of human malignancies, including breast cancer. Novel circ_RNAs for breast cancer remain to be further determined. This study investigates the role and mechanism of a novel circ_RNA circ_0048766 in triple-negative breast cancer (TNBC) progression. Bioinformatics analysis was performed using the GSE165884 database to identify differentially expressed circ_RNAs. The expression of circ_0048766 was validated in various breast cancer cell lines through quantitative real-time PCR. Functional assays, including CCK-8, flow cytometry, colony formation, and Transwell assays, were conducted in BT-549 and MDA-MB-231 cells. The mechanisms involving methyltransferase-like 3 (METTL3), miR-329-3p, and C-X-C Motif Chemokine Receptor 4 (CXCR4) were examined through bioinformatics, dual-luciferase reporter assays, RNA immunoprecipitation, and RNA pull-down. In vivo studies were conducted using a nude mouse xenograft model to evaluate tumor growth and CXCR4 expression. Circ_0048766 was significantly upregulated in TNBC cell lines compared to normal breast epithelial cells. Knockdown of circ_0048766 resulted in reduced cell viability, colony formation, migration, and invasion while increasing apoptosis in BT-549 and MDA-MB-231 cells. Mechanistically, circ_0048766 was confirmed to function as a sponge for miR-329-3p. Moreover, miR-329-3p directly suppressed CXCR4 expression, and circ_0048766 regulated CXCR4 in a miR-329-3p-dependent manner. Additionally, circ_0048766 promoted epithelial-mesenchymal transition, as evidenced by its regulation of E-cadherin, N-cadherin, and Vimentin expression via miR-329-3p. MiR-329-3p inhibition or CXCR4 overexpression reversed the effects of circ_0048766 knockdown. In vivo, circ_0048766 knockdown significantly diminished tumor growth and weight, along with decreased CXCR4 levels. METTL3 was identified as an upstream regulator mediating m6A modification of circ_0048766. Functionally, METTL3 knockdown suppressed CXCR4 expression and cell proliferation, effects that were rescued by CXCR4 overexpression. Circ_0048766 is a novel oncogenic circ_RNA that promotes TNBC progression through the miR-329-3p/CXCR4 signaling axis, regulated by METTL3. This study highlights the potential of targeting the METTL3/circ_0048766/miR-329-3p/CXCR4 axis as a novel therapeutic strategy for TNBC treatment. Not applicable.

Heat stress (HS) markedly impairs broiler growth, muscle function, and meat quality. In this study, broilers were subjected to a 2&#x2009;&#xd7;&#x2009;2 factorial design with sodium selenite or yeast &#x3b2;-glucan selenium nanoparticles (yeast &#x3b2;-Glu-SeNPs) as the selenium source (0.3 mg/kg total selenium) under thermoneutral or HS conditions. We aimed to investigate the protective effects and underlying mechanisms of yeast &#x3b2;-Glu-SeNPs against HS-induced muscle damage. HS markedly impaired growth performance and induced systemic oxidative stress and inflammation, while also compromising meat quality and disrupting postmortem glycolysis, as evidenced by reduced glycogen availability and excessive lactate accumulation. Yeast &#x3b2;-Glu-SeNPs significantly improved growth performance, mitigated oxidative stress and inflammation, and restored meat quality in both breast and thigh muscles. Postmortem energy metabolism was preserved, as reflected by increased muscle glycogen and glycolytic potential, reduced lactate accumulation and glycolytic enzyme activities, and a stabilized pH decline. Meanwhile, skeletal muscle Se deposition, glutathione peroxidase activity, and key selenoprotein expression were markedly enhanced. Notably, HS promoted a phenotypic shift toward fast glycolytic muscle fibers, as evidenced by increased expression of MYHC2b and Fast-MyHC (P&#x2009;<&#x2009;0.05), accompanied by reduced levels of MYHC1, MYHC2a, and Slow-MyHC (P&#x2009;<&#x2009;0.05). This maladaptive transition was effectively reversed by yeast &#x3b2;-Glu-SeNPs, which favored oxidative fiber formation, characterized by the upregulation of MYHC1 and MYHC2a, along with the suppression of MYHC2b (P&#x2009;<&#x2009;0.05). At the mitochondrial level, yeast &#x3b2;-Glu-SeNPs preserved ultrastructural integrity and enhanced mitochondrial function, as reflected by increased ATP content, elevated mtDNA copy number, and the upregulation of mitochondrial biogenesis-related genes, including AMPK, PGC-1&#x3b1;, NRF1, and TFAM (P&#x2009;<&#x2009;0.05). Correlation analysis, molecular docking, and co-immunoprecipitation demonstrated that SelO interacts with AMPK, supporting a SelO-dependent AMPK/PGC-1&#x3b1; axis that drives mitochondrial biogenesis and oxidative fiber remodeling. Overall, yeast &#x3b2;-Glu-SeNPs mitigated HS-induced muscle metabolic dysfunction and meat quality deterioration via SelO-mediated mitochondrial and myofiber reprogramming.

Working memory (WM) deficits and maladaptive rumination are hallmark features of major depressive disorder (MDD), yet the stage-specific electrophysiological mechanisms remain poorly understood. This study investigated neural dynamics during WM encoding and maintenance in individuals with depressive episode (DE) and their associations with rumination subfactors. A total of 59 DEs and 49 healthy controls (HCs) performed an n-back task (0-back and 2-back) while 64-channel electroencephalography (EEG) was recorded. Behavioral results demonstrated that the DEs exhibited impaired WM updating, characterized by significantly lower accuracy and slower reaction time (RT) under high cognitive load. Electrophysiological analyses revealed that during encoding, the DEs showed attenuated load-related modulation of the frontal N2 amplitude. During maintenance, the DEs demonstrated pathologically elevated occipital alpha power. Crucially, a significant group &#xd7; alpha interaction (Wald &#x3c7;&#xb2; (1)&#x2009;=&#x2009;9.258, p&#x2009;=&#x2009;0.002) in predicting RT was observed. Higher alpha power was associated with slower RT in HCs (&#x3b2;&#x2009;=&#x2009;0.006, p&#x2009;=&#x2009;0.021), whereas this neurobehavioral coupling was disrupted and paradoxically reversed in the DEs (&#x3b2;&#x2009;=&#x2009;-0.003, p&#x2009;=&#x2009;0.063). Within the DE group, alpha power was significantly negatively associated with brooding (&#x3b2;&#x2009;=&#x2009;-0.962, p&#x2009;=&#x2009;0.006) and reflective pondering (&#x3b2;&#x2009;=&#x2009;-0.692, p&#x2009;=&#x2009;0.035) independent of task load. Our findings reveal that impaired resource mobilization during encoding and disorganized functional inhibition during maintenance converge to drive WM deficits in depressive patients, with the latter uniquely tied to maladaptive rumination.

Depression is a common psychiatric disorder during pregnancy and the postnatal period. Consequently, antidepressant treatment is primordial for the safety of the mother and the neonate. Clomipramine (CMI) is a tricyclic antidepressant that has been prescribed even when the evidence suggests potential adverse effects on the neurodevelopment of the offspring, considering that antidepressant drugs can be transferred through breast milk. Nevertheless, in some cases, when the benefits outweigh the risks, it is used to treat severe depression in pregnant women. In rodents, postnatal administration of CMI causes persistent behavioral and neurophysiological alterations in adulthood. By contrast, a rewarding experience, such as mating, improves motivational and copulatory behavior in rodents through neuroplasticity in brain structures involved in reproduction. In a previous work, we reported that postnatal exposure to CMI disrupts the motivational and copulatory components of female sexual behavior during a single copulatory test. Therefore, the purpose of this study was to examine the effects of postnatal CMI treatment on female sexual behavior and reproductive tissues, and to determine whether sexual experience serves as a modulatory factor that ameliorates its potential impact on sexual performance. Female pups were divided in two groups, CMI group (30&#xa0;mg/Kg) and the control group (NaCl 0.9%). Each group received a daily subcutaneous injection with CMI or saline solution from the 8th to 21st postnatal days. Behavioral test and histological analysis were performed at 3 months of age. The results indicated that postnatal CMI administration disrupts receptive but not proceptive behaviors. Repeated sexual encounters with males partially reversed the receptivity impairment in CMI-treated females, as it occurs in control rats. Histological data showed that CMI reduces the population of primordial and primary follicles; however, no morphological modifications were detected in the uterine layers. In conclusion, the data show that even when sexual experience partially improved copulatory behavior in female rats exposed to CMI during the postnatal period, ovarian development was affected, which could compromise fertility.

Community-based chest X-ray (CXR) screening has been widely performed to improve tuberculosis identification in elderly populations, but comparative evidence against mode of symptom-driven case finding remains scarce. We conducted three annual rounds of mass CXR screening among individuals aged over 60 years in Lanxi City, China, from 2021 to 2023. Tuberculosis cases identified through CXR screening were compared with concurrent, symptom-driven case presentations via routine surveillance. Restricted cubic spline and multivariable logistic regression analyses were used to examine factors associated with distinct detection pathways. At the individual level, a total of 831 tuberculosis cases were identified through two modes. CXR mass screening detected more patients with less typical symptoms, while symptom-driven detection was more effective in females (aOR&#x2009;=&#x2009;0.59, 95% CI 0.39-0.88), bacteriologically confirmed cases (aOR&#x2009;=&#x2009;0.42, 95% CI 0.27-0.63), and those aged greater than 80 (aOR&#x2009;=&#x2009;0.50, 95% CI 0.30-0.82). Age showed a nonlinear association with mass screening yield, with peak effectiveness between 60 and 66 years while no significance was found for BMI. In population-level analysis, CXR mass screening outperformed symptom-driven detection for case identification in the first round but declined and reversed by the third round. Subgroup analyses revealed potential benefits among individuals with diabetes or prior tuberculosis history, particularly within two years post-diagnosis or treatment. Community-based CXR screening could effectively detect incremental tuberculosis cases with atypical or mild symptoms. The young-old would benefit from mass CXR screening, while more accessible services were needed for the very elderly. Elderly individuals with diabetes or prior tuberculosis history should be prioritized, with intensified monitoring within two years after diagnosis or treatment completion.

Accumulating evidence indicates that adult hippocampal neurogenesis (AHN) undergoes heterogeneous alterations in depression, yet the underlying mechanisms remain incompletely understood. In this study, we established a corticosterone (CORT)-induced mouse model of depression and combined pharmacological, molecular biological, and genetic approaches to investigate the mechanisms through which CORT suppresses AHN and induces depressive-like behaviors. Our results demonstrated that chronic CORT treatment led to depressive-like phenotypes in mice, including decreased sucrose preference and behavioral despair, accompanied by impaired AHN, manifested by a reduction in immature neurons (DCX&#x207a;BrdU&#x207a;) but an increase in proliferating cells (Ki67&#x207a;). Further mechanistic studies revealed that CORT upregulates dynorphin A in the dentate gyrus (DG), leading to overactivation of the &#x3ba;-opioid receptor (KOR). This subsequently inhibits the expression of Pax6 and its downstream targets Neurog2 and NeuroD1, thereby obstructing neuronal differentiation. The KOR antagonist nor-BNI effectively reversed both the depressive-like behaviors and AHN abnormalities induced by CORT. Moreover, overexpression of Pax6 alleviated depressive behaviors and restored neurogenesis, whereas knockdown of Pax6 was sufficient to induce depressive phenotypes and impair AHN. Our study unveils a central role of the KOR/Pax6 signaling axis in AHN suppression and depression pathogenesis, providing a theoretical foundation for antidepressant strategies targeting KOR or Pax6.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered as classic targeted drugs for EGFR-mutated non-small cell lung cancer (NSCLC), but induce EGFR-TKI-resistance and immunosuppression at advanced stage. The targeted inhibition of YES-associated proteins (YAP) combined with immunomodulation is expected to be a distinctive supplementary approach for EGFR-TKI-resistant NSCLC therapy. Herein an endoplasmic reticulum (ER)-targeting Zn/Cu-bi-single-atom nanoplatform (Zn/Cu-BSRGT) was prepared for EGFR-TKI resistance reversion, cascaded ER stress and immunoactivation. Specifically, after precisely targeting to the ER, Zn/Cu-BSRGT NPs provided simultaneous release of &#xb7;OH and 1O2 through the efficient chemodynamic therapy (CDT) and sonodynamic therapy (SDT), triggering intense ER stress. Meanwhile, the released YAP-siRNA interfered with the expression of YAP and the EGFR bypass signaling pathway, reversing the AXL-mediated resistance to EGFR-TKI. Furthermore, significant glucose consumption and ER stress triggered the immunogenic cell death (ICD) and systemic immune activation, and down-regulated the PERK-Nrf2 signaling pathway and multidrug resistance protein (MRP1). In summary, the combined application of single-atom-nanozyme catalytic technology and gene-targeted silencing technology successfully reversed EGFR-TKI resistance and promoted immunoactivation in NSCLC under ER-targeting assistance, providing support for the new strategic development of drug-resistant NSCLC.

The pervasive integration of digital technologies into adolescent daily life raises critical questions about the interplay between core neurocognitive capacities and emotional development. Although both executive function (EF) and emotion regulation (ER) have been independently linked to digital media exposure, few studies have examined how these two constructs are associated within digitally mediated contexts, and fewer still have modeled digital engagement as a contextual moderator rather than a simple predictor. A sample of 368 adolescents aged 12-17 completed behavioral assessments of inhibitory control, working memory, and cognitive flexibility alongside self-report and task-based measures of emotion regulation strategies. Objective screen time data, including application-category breakdowns, were collected over a 14-day monitoring period using device-level tracking applications. Structural equation modeling was employed to test cross-sectional associations between EF and ER, and to examine whether objectively measured digital use intensity moderated these associations in both directions. Exploratory analyses additionally examined whether moderation patterns differed across digital activity categories. The structural model revealed significant cross-sectional associations in both directions: stronger EF was associated with greater use of cognitive reappraisal, while effective regulation was positively linked to executive performance; conversely, habitual expressive suppression was associated with diminished EF. Among EF components, inhibitory control showed the strongest association with adaptive regulation. Digital use intensity moderated both directional associations, though the attenuating effect was somewhat more pronounced for the EF-reappraisal link than for the reverse pathway. A threshold pattern emerged, with high-intensity users showing marked declines relative to moderate and low users. Exploratory, unadjusted analyses tentatively suggested that the moderation was concentrated in social media and short-form video use, whereas gaming and educational activities showed weaker or non-significant patterns; these category-specific results are hypothesis-generating rather than confirmatory. These cross-sectional findings are consistent with a context-sensitive view in which EF and ER show reciprocal concurrent associations-what we describe here as cross-sectional bidirectional associations rather than temporal feedback-and digital engagement functions as an environmental moderator shaping that coupling. The results suggest that integrated intervention approaches combining executive function training, social-emotional learning, and constructive digital literacy may hold promise. However, given the cross-sectional design, the present findings should be regarded as preliminary evidence for future longitudinal research that can directly evaluate temporal ordering.

The perioperative regimen of chemotherapy plus PD-1 inhibitors in gastric cancer has significantly improved event-free survival (EFS), yet its translation into overall survival (OS) benefits remains frequently inadequate, constituting a core clinical dilemma. This review systematically elucidates the potential reasons for the significant improvement in event-free survival (EFS) but insufficient improvement in overall survival (OS) from the perspective of the immune microenvironment, particularly emphasizing the incomplete remodeling of the immunosuppressive microenvironment, which specifically includes the failure to induce stem cell-like memory T cells capable of conferring long-term protection. In this field, current research is increasingly focused on interleukin-2 (IL-2) variants, with PD-1/IL-2 bispecific antibodies, in particular, representing a significant research hotspot that holds considerable promise for achieving breakthroughs. Through precise synergy with existing regimens, they achieve profound immune reprogramming across three dimensions: expanding tumor-specific T cell clones, reversing T cell exhaustion and driving memory differentiation, and inverting the balance between effector cells and suppressor cells in the. Overall, the emergence of PD-1/IL-2 bispecific antibodies, represents a promising approach in cancer therapy with the potential to enhance long-term survival outcomes for patients.