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In this study, we investigated lipopolysaccharide (LPS)-induced cognitive impairment and neuroinflammation in C57BL/6J mice by using behavioral tests, immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and Western blot. We found that LPS treatment leads to sickness behavior and cognitive impairment in mice as shown in the Morris water maze and passive avoidance test, and these effects were accompanied by microglia activation (labeled by ionized calcium binding adaptor molecule-1, IBA-1) and neuronal cell loss (labeled by microtubule-associated protein 2, MAP-2) in the hippocampus. The levels of interleukin-4 (IL-4) and interleukin-10 (IL-10) in the serum and brain homogenates were reduced by the LPS treatment, while the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), prostaglandin E2 (PGE 2 ) and nitric oxide (NO) were increased. In addition, LPS promoted the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the brain homogenates. The Western blot analysis showed that the nuclear factor kappa B (NF-κB) signaling pathway was activated in the LPS groups. Furthermore, VIPER, which is a TLR-4-specific inhibitory peptide, prevented the LPS-induced neuroinflammation and cognitive impairment. These data suggest that LPS induced cognitive impairment and neuroinflammation via microglia activation by activating the NF-kB signaling pathway; furthermore, we compared the time points, doses, methods and outcomes of LPS administration between intraperitoneal and intracerebroventricular injections of LPS in LPS-induced neuroinflammation and cognitive impairment, and these data may provide additional insight for researchers performing neuroinflammation research.

Alzheimer’s disease (AD), the most common dementia, is characterized by amyloid plaques (AP) and hyperphosphorylated tau tangles in the brain. Epidemiological evidence suggests that long-term chronic manganese (Mn) exposure increases the risk of AD. Additionally, the levels of Mn are elevated in the blood, cerebrospinal fluid and brain of AD patients, but the mechanisms underlying Mn enhancement of AD development remain unknown. Using the transgenic 3xTg-AD mouse model and mouse-derived microglia and neuroblastoma cell lines, we found that chronic 5-month Mn treatment increased Aβ burden in the cerebral cortex and hippocampus in these 3xTg-AD mice. Furthermore, we found that the β- and γ-secretase cleavage activities were markedly increased while α-secretase cleavage activity was reduced in the brain of Mn-treated AD mice, which might account for the increased Aβ accumulation. Equally important, acute Mn exposure did not alter -secretase 1 (BACE1) gene expression or amyloidosis in amyloidogenic mutant amyloid precursor protein gene hAPPsw-transfected N2a cells (APPsw-N2a); but in APPsw-N2a cells either co-cultured with microglia BV2 or cultured with microglia-conditioned media, Mn exposure increased BACE1 expression and amyloidosis. We further determined that Mn exposure promoted the activation of microglia both in 3xTg-AD mouse brains and in cultured BV2 microglia cells, and increased the secretion of the inflammatory cytokines interleukin-1 (IL-1β) and tumor necrosis factor- (TNF-α). Taken together, these results suggest that Mn may elevate the release of IL-1β and TNF-α from microglia that in turn stimulates the expression of BACE1 gene and protein and hence A production, providing a novel molecular mechanism for chronic Mn exposure to promote amyloidogenesis and AD pathogenesis.

The leader–follower consensus problem in the presence of parameter uncertainty and external disturbances is investigated for multiagent systems (MASs) with actuator faults, which are based on event‐triggered control. First, a new distributed event triggering strategy is proposed which avoids continuous communication between agents and is based on the state estimation of neighbouring agents. Instead, the growing estimation error is reset by communication updates. An adaptive update mechanism is also proposed which does not need any knowledge of the global aspects of the communication topology graph and does not need an upper threshold for parameter uncertainty and external disturbances in the protocol. The results show that the tracking error under the event‐triggered protocol asymptotically converges to zero, while avoiding Zeno behaviour. Finally, a numerical simulation confirms the feasibility of the theoretical results.

Background Cuproptosis, an emerging form of programmed cell death, has recently been identified. However, the association between cuproptosis-related long non-coding RNA (lncRNA) signature and the prognosis in prostate carcinoma remains elusive. This study aims to develop the novel cuproptosis-related lncRNA signature in prostate cancer and explore its latent molecular function. Methods RNA-seq data and clinical information were downloaded from the TCGA datasets. Then, cuproptosis-related gene was identified from the previous literature and further applied to screen the cuproptosis-related differentially expressed lncRNAs. Patients were randomly assigned to the training cohort or the validation cohort with a 1:1 ratio. Subsequently, the machine learning algorithms (Lasso and stepwise Cox (direction = both)) were used to construct a novel prognostic signature in the training cohorts, which was validated by the validation and the entire TCGA cohorts. The nomogram base on the lncRNA signature and several clinicopathological traits were constructed to predict the prognosis. Functional enrichment and immune analysis were performed to evaluate its potential mechanism. Furthermore, differences in the landscape of gene mutation, tumour mutational burden (TMB), microsatellite instability (MSI), drug sensitivity between both risk groups were also assessed to explicit their relationships. Results The cuproptosis-related lncRNA signature was constructed based on the differentially expressed cuproptosis-related lncRNAs, including AC005790.1, AC011472.4, AC099791.2, AC144450.1, LIPE-AS1, and STPG3-AS1. Kaplan–Meier survival and ROC curves demonstrate that the prognosis signature as an independent risk indicator had excellent potential to predict the prognosis in prostate cancer. The signature was closely associated with age, T stage, N stage, and the Gleason score. Immune analysis shows that the high-risk group was in an immunosuppressive microenvironment. Additionally, the significant difference in landscape of gene mutation, tumour mutational burden, microsatellite instability, and drug sensitivity between both risk groups was observed. Conclusions A novel cuproptosis-related lncRNA signature was constructed using machine learning algorithms to predict the prognosis of prostate cancer. It was closely with associated with several common clinical traits, immune cell infiltration, immune-related functions, immune checkpoints, gene mutation, TMB, MSI, and the drug sensitivity, which may be useful to improve the clinical outcome.

The dynamic anisotropy and failure mechanism of shales are greatly affected by bedding surfaces. To reveal the influence of beddings on anisotropic characteristics of shales under dynamic impact, the Brazilian splitting tests were conducted by the split Hopkinson pressure bar system. The fracturing process were monitored by the high-speed camera. Meanwhile, to understand crack initiation and propagation mechanism, the stress buildup, stress shadow and stress transfer were modelled based on the digital image processing and the rock failure process analysis method. The effect of dip angle and bedding spacing on crack initiation, propagation and coalescence was analyzed. Simultaneously, the spatial distribution and energy magnitude of crack-induced acoustic emissions were captured numerically. The results show that the shale discs continue to produce parallel cracks and cambered cracks induced by the high stresses at the tips of initial cracks; the tensile strength under dynamic splitting changes in the U-shaped trend with the bedding dip angle increasing; the cracking percentage of bedding surfaces decreases, and the cracking percentage of rock matrix increases with the bedding dip angle increasing. In addition, the acceleration of crack growth and the rapid growth of AE energy can be regarded as the effective precursors of shale failure.

Ischemic stroke can induce rapid disruption of blood-brain barrier (BBB). It has been suggested that increased BBB permeability can affect the pathological progression of ischemic tissue. However, the impact of increased BBB permeability on microglial activation and synaptic structures following reperfusion after ischemia remains unclear. In this study, we investigated microglial activation, dendritic damage and plasticity of dendritic spines after increasing BBB permeability following transient global cerebral ischemia in the somatosensory cortices in mice. Bilateral common carotid artery ligation (BCAL) was used to induce transient global cerebral ischemia. Mannitol was used to increase the BBB permeability. Intravital two-photon imaging was performed to image the dendritic structures and BBB extravasation. Microglial morphology was quantitated using a skeletonization analysis method. To evaluate inflammation of cerebral cortex, the mRNA expression levels of integrin alpha M , chemokine (C-X-C motif) ligand 10 and tumor necrosis factor alpha were measured by fluorescent quantitative PCR. Intravital two-photon imaging revealed that mannitol caused a drastic increase in BBB extravasation during reperfusion after transient global ischemia. Increased BBB permeability induced by mannitol had no significant effect on inflammation and dendritic spines in healthy mice but triggered a marked de-ramification of microglia; importantly, in ischemic animals, mannitol accelerated de-ramification of microglia and aggravated inflammation at 3 h but not at 3 days following reperfusion after ischemia. Although mannitol did not cause significant change in the percentage of blebbed dendrites and did not affect the reversible recovery of the dendritic structures, excessive extravasation was accompanied with significant decrease in spine formation and increase in spine elimination during reperfusion in ischemic mice. These findings suggest that increased BBB permeability induced by mannitol can lead to acute activation of microglia and cause excessive loss of dendritic spines after transient global cerebral ischemia.

Stroke is a major cause of morbidity and mortality worldwide. There is an urgent need for effective neuroprotective agents to reduce brain injury. SARM1 (sterile alpha and TIR motif-containing 1) has been identified as a key mediator of axonal degeneration. However, its role in stroke and the underlying mechanisms remain insufficiently understood. In the present study, a mouse model of stroke with focal infarction in the cortex was used to investigate the potential relation between SARM1 and post-stroke brain injury. We found that SARM1 expression increased in neurons of the peri-infarct cortex at an early stage after photothrombotic stroke induction (PTI) and was evenly distributed between excitatory and inhibitory neurons. Deficiency of SARM1 improved neurological performance, reduced the infarct volume and the inflammatory response including reactive gliosis and TNF-α level after PTI. Meanwhile, SARM1 deficiency promoted neuronal preservation in the peri-infarct cortex and mitigated axonal degeneration, possibly because of reduced NAD + consumption of neurons in the peri-infarct cortex. Additionally, we found that SARM1 deficiency inhibited glial scar formation and decreased activated microglia. FK866 and DSRM-3716, two recently reported pharmacological inhibitors of SARM1, failed to alleviate brain injury in mice with stroke. Our findings demonstrate that SARM1 deficiency attenuates ischemic neuronal injury and improves neurological performance post PTI, suggesting that the SARM1 signaling pathway could serve as a potential therapeutic target for stroke in the future.

Background Circular RNAs (circRNAs) have been shown to be involved in tumorigenesis and progression. However, the role of circGLIS3 (hsa_circ_0002874) in prostate cancer (PCa) has yet not been reported. Methods Candidate circRNA were determined through comprehensive analysis of public datasets, PCa cell lines, and tissues data. A series of cellular functional assays, including CCK-8, colony formation, wound healing, and transwell assays were performed. Subsequently, RNA sequencing, RNA immunoprecipitation, methylated RNA immunoprecipitation, microRNA pulldown, luciferase reporter assay, and western blot were used to explore the underlying molecular mechanisms. Moreover, the xenograft tumor mouse model was established to elucidate the function of circGLIS3. Results CircGLIS3, derived from exon 2 of the parental GLIS3 gene, was identified as a novel oncogenic circRNA in PCa that was closely associated with the biochemical recurrence. Its expression levels were upregulated in PCa tissues and cell lines as well as enzalutamide high-resistant cells. The cellular functional assays revealed that circGLIS3 promoted PCa cell proliferation, migration, and invasion. METTL3-mediated N 6 -methyladenosine (m 6 A) modification maintained its upregulation by enhancing its stability. Mechanically, CircGLIS3 sponged miR-661 to upregulate MDM2, thus regulating the p53 signaling pathway to promote cell proliferation, migration, and invasion. Furthermore, in vitro and in vivo experiments, the knockdown of circGLIS3 improved the response of PCa cells to ARSI therapies such as enzalutamide. Conclusions METTL3-mediated m 6 A modification of circGLIS3 regulates the p53 signaling pathway via the miR-661/MDM2 axis, thereby facilitating PCa progression. Meanwhile, this study unveils a promising potential target for ARSI therapy for PCa.

Background MAPK8IP2 is one of the JNK-interacting proteins (JIPs) family members, and is involved in the regulation of the JNK and P38 MAPK signaling pathways. MAPK8IP2 has been reported to be closely associated with several cancers. However, the biological function of MAPK8IP2 in prostate cancer (PCa) remains unclear. Methods MAPK8IP2 expression in PCa and subgroups of PCa was analyzed by public databases. The prognostic role of MAPK8IP2 in prostate cancer was analyzed using the Cox regression method. The potential mechanism by which MAPK8IP2 affects PCa progression was investigated by utilizing public data, including genetic alteration, DNA methylation, m6A methylation, and immune infiltration data. We further performed in vitro assays to validate the effect of MAPK8IP2 on PCa cell proliferation, migration and invasion. Results MAPK8IP2 is highly expressed in PCa tissues. Overexpression of MAPK8IP2 is associated with adverse clinicopathological factors and a poor prognosis in PCa. Receiver operating curve analysis showed that MAPK8IP2 can distinguish PCa tissues from non-PCa tissues with a certain accuracy (AUC = 0.814). The MAPK8IP2 genetic alteration rate was 2.6% and MAPK8IP2 alterations correlated with a poor prognosis. We also found that CDK12 and TP53 mutations were associated with MAPK8IP2 expression. The DNA methylation level of MAPK8IP2 was higher in primary tumors than in normal tissues, and the high MAPK8IP2 DNA methylation group of PCa patients had poor survival. Enrichment analysis indicated that MAPK8IP2 was involved in the MAPK signaling pathway. In vitro, knockdown of MAPK8IP2 inhibited PCa cell proliferation, migration and invasion. Conclusion MAPK8IP2 is a potential target for PCa treatment and can serve as a novel biomarker for PCa diagnosis and prognosis evaluation.

Background Viral hepatitis is a major global public health problem that affects millions of people; therefore, accurate and accessible information is essential for both the general public and non-specialist healthcare providers to correctly understand, prevent, and manage the disease. This study evaluated four large language models (LLMs)—Gemini-2.0, Claude-3.5-sonnet, ChatGPT-4.5, and ChatGPT-4—and compared their responses to viral hepatitis–related questions to assess differences in performance across models. Methods This comparative evaluation study, conducted at Nanjing Drum Tower Hospital from March to April 2025, examined 52 questions pertaining to viral hepatitis. Four large language models were assessed based on their responses to these 52 questions which encompassed four domains: concepts, risk factors, diagnosis, and prevention and treatment. Initial evaluation used a three-point scale of good, borderline, and poor. Further evaluation criteria included relevance, comprehensiveness, accuracy, safety, and readability, with each response scored on a scale of 1 to 5. Results ChatGPT-4.5 achieved the highest performance, with 89.1% of its responses rated as good, significantly outperforming Claude-3.5-sonnet (71.15% good), Gemini-2.0 (62.82% good), and ChatGPT-4 (50.64% good). Statistical analysis confirmed superior performance of ChatGPT-4.5 in all evaluated dimensions. Consistently, ChatGPT-4.5 scored the highest across all five criteria: relevance, comprehensiveness, accuracy, safety, and readability. Conclusions ChatGPT-4.5 demonstrates superior performance in addressing viral hepatitis queries compared to other three models. Its high reliability makes it a valuable tool for patients and medical professionals not specializing in viral hepatitis by improving information accessibility.