Background: Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer’s disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. Methods: To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory. Results: In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner. Conclusions: Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions. Graphical

TAF participated in the progression of various cancers, including PA via the release of soluble factors. Exosomes belonged to extracellular vesicles, which were revealed as a crucial participator in intercellular communication. However, the expression pattern and effect of TAF-derived exosomes remained largely unknown in PA. In the present study, we performed in silico analysis based on public RNA-seq datasets to generate the circRNA/miRNA regulatory network. The qRT-PCR, Western blotting, RNA pull-down, and luciferase assay were performed to investigate the effect of TAF-derived exosomes. TAF-derived exosomal circDennd1b was significantly upregulated in PA and promoted the proliferation, migration, and invasion of PA cells via sponging miR-145-5p in PA cells. In addition, miR-145-5p directly regulated One Cut homeobox 2 (ONECUT2/OC2) expression and inhibited the promoting effect of ONECUT2 on PA. We further demonstrated that ONECUT2 transcriptionally increased fibroblast growth factor receptor 3 (FGFR3) expression, which further activates the mitogen-activated protein kinases (MAPK) pathway, thus promoting PA progression. Moreover, the suppression of TAFs by ABT-263 and ONECUT2 by CSRM617 inhibited the growth of PA. In conclusion, our study illustrated that TAF-derived exosomal circDennd1b affected PA progression via regulating ONECUT2 expression, which provides a potential therapeutic strategy against aggressive PA.

Spinal tuberculosis (TB), the most common form of musculoskeletal tuberculosis, is an infection-related disease globally, with paraplegia occurring in severe cases. Therefore, identification of spinal TB at an early stage is important for early intervention and eventual therapy. In this study, we conducted a prospective cohort study in routine clinical practice to investigate the diagnosis of different TB tests. A total of 519 patients were recruited based on the radiology of spinal TB. The diagnostic model was computed by regression analysis and was determined by receiver operating characteristic (ROC) curve analysis. Specificity, sensitivity, predictive value, likelihood ratio, and accuracy were also computed and compared. GeneXpert MTB/RIF showed a higher positive rate compared to that in the acid-fast bacilli smear andMycobacteriumculture. The results also showed that theMycobacterium tuberculosis-specific antigen/phytohemagglutinin ratio in the T-SPOT assay had a good performance in the preoperative diagnosis and prediction of spinal TB. The diagnostic model based on the ratio of tuberculosis-specific antigen/phytohemagglutinin combined with GeneXpert MTB/RIF showed better efficiency for spinal TB diagnosis. In summary, the tuberculosis-specific antigen/phytohemagglutinin ratio combined with GeneXpert MTB/RIF could provide an early diagnosis of spinal TB.

Background: Pituitary adenoma (PA) bone invasion results in adverse outcomes, such as reduced rates of complete surgical resection and biochemical remission as well as increased recurrence rates, though few studies have been conducted. Methods: We collected clinical specimens of PAs for staining and statistical analysis. Evaluation of the ability of PA cells to induce monocyte–osteoclast differentiation by coculturing PA cells with RAW264.7 in vitro. An in vivo model of bone invasion was used to simulate the process of bone erosion and evaluate the effect of different interventions in alleviating bone invasion. Results: We found an overactivation of osteoclasts in bone-invasive PAs and concomitant aggregation of inflammatory factors. Furthermore, activation of PKCθ in PAs was established as a central signaling promoting PA bone invasion through the PKCθ/NF-κB/IL-1β pathway. By inhibiting PKCθ and blocking IL1β, we were able to significantly reverse bone invasion in an in vivo study. Meanwhile, we also found that celastrol, as a natural product, can obviously reduce the secretion of IL-1β as well as alleviate the progression of bone invasion. Conclusions: By activating the PKCθ/NF-κB/IL-1β pathway, pituitary tumors are able to induce monocyte–osteoclast differentiation in a paracrine manner and promote bone invasion, which can be alleviated by celastrol.

Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer’s disease (AD), and thus identifying who among the increasing T2DM populations may develop into AD is important for early intervention. By using TMT-labeling coupled high-throughput mass spectrometry, we conducted a comprehensive plasma proteomic analysis in none-T2DM people (Ctrl, n = 30), and the age-/sex-matched T2DM patients with mild cognitive impairment (T2DM-MCI, n = 30) or T2DM without MCI (T2DM-nMCI, n = 25). The candidate biomarkers identified by proteomics and bioinformatics analyses were verified by ELISA, and their diagnostic capabilities were evaluated with machine learning. A total of 53 differentially expressed proteins (DEPs) were identified in T2DM-MCI compared with T2DM-nMCI patients. These DEPs were significantly enriched in multiple biological processes, such as amyloid neuropathies, CNS disorders, and metabolic acidosis. Among the DEPs, alpha-1-antitrypsin (SERPINA1), major viral protein (PRNP), and valosin-containing protein (VCP) showed strong correlation with AD high-risk genes APP, MAPT, APOE, PSEN1, and PSEN2. Also, the levels of PP2A cancer inhibitor (CIP2A), PRNP, corticotropin-releasing factor-binding protein (CRHBP) were significantly increased, while the level of VCP was decreased in T2DM-MCI patients compared with that of the T2DM-nMCI, and these changes were correlated with the Mini-Mental State Examination (MMSE) score. Further machine learning data showed that increases in PRNP, CRHBP, VCP, and rGSK-3β(T/S9) (ratio of total to serine-9-phosphorylated glycogen synthase kinase-3β) had the greatest power to identify mild cognitive decline in T2DM patients.

The hypothalamus orchestrates systemic homeostasis by integrating neuroendocrine, autonomic, and immune–metabolic functions. In this review, we synthesize evidence that hypothalamic microglia act as dual hubs along a periphery–central–periphery axis across three domains: Peripheral effects: Microglia decode circulating cues and relay them to hypothalamic circuits, thereby modulating autonomic tone and endocrine pathways that impact immune–metabolic balance. Central mechanisms: Microglia sense and shape hypothalamic neural circuits via cytokine–neurotransmitter crosstalk, synaptic remodeling, and glial–neuronal signaling that tune neuroendocrine output. Translational links: Microglial states associate with biomarkers and clinical phenotypes in metabolic and inflammatory disorders, suggesting therapeutic entry points. Drawing on the literature from the last 20 years, we highlight convergent mechanisms, unresolved heterogeneity across models, and priorities for causal dissection and target validation. This framework clarifies how hypothalamic microglia coordinate local CNS processes with systemic physiology in health and disease.