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Autism spectrum disorders (ASDs) are a group of highly inheritable neurodevelopmental disorders. Functional mutations in TRIO, especially in the GEF1 domain, are strongly implicated in ASDs, whereas the underlying neurobiological pathogenesis and molecular mechanisms remain to be clarified. Here we characterize the abnormal morphology and behavior of embryonic migratory interneurons (INs) upon Trio deficiency or GEF1 mutation in mice, which are mediated by the Trio GEF1-Rac1 activation and involved in SDF1α/CXCR4 signaling. In addition, the migration deficits are specifically associated with altered neural microcircuit, decreased inhibitory neurotransmission, and autism-like behaviors, which are reminiscent of some features observed in patients with ASDs. Furthermore, restoring the excitatory/inhibitory (E/I) imbalance via activation of GABA signaling rescues autism-like deficits. Our findings demonstrate a critical role of Trio GEF1 mediated signaling in IN migration and E/I balance, which are related to autism-related behavioral phenotypes.

Background: Hypertension remains a leading cause of cardiovascular morbidity and mortality globally, and insulin resistance (IR) and systemic inflammation are implicated in the pathogenesis of hypertension. Limited evidence exists on the predictive role of the triglyceride-glucose (TyG) index and its related indices (TyG-WHtR and TyG-WC) for hypertension. This study aimed to investigate these associations across multiple Chinese cohorts. Methods: Data from 31,224 participants (Fuqing, CHNS, CHARLS) were analyzed. TyG indices were calculated using fasting triglycerides, glucose, and anthropometrics. Hypertension was defined as SBP/DBP ≥ 140/90 mmHg, or physician diagnosis, or antihypertensive treatment. Logistic/Cox regression models were used to examine associations, adjusting for demographics, lifestyle, and metabolic factors. Mediation analysis quantified the role of neutrophil-to-lymphocyte ratio (NLR) in mediating the TyG–hypertension relationship. Results: Elevated TyG index and its obesity-adjusted variants consistently predicted incident hypertension across cohorts (all p < 0.001). Each 1-unit TyG increase was associated with 9–36% higher odds of hypertension in Fuqing (OR = 1.09–1.36). NLR mediated 20.4–29.4% of these associations (p < 0.001). Subgroup analyses revealed effect modifications by age, sex, and residence. Sensitivity analyses confirmed robustness when redefining hypertension thresholds (ACC/AHA criteria). Conclusions: TyG index and its related indices are robust predictors of (new-onset) hypertension, with NLR statistically accounting for approximately 25% of these associations in the mediation model. These findings underscore the interplay between metabolic dysregulation, inflammation, and hypertension and advocate for integrated biomarker strategies in risk stratification and prevention, while external validation in multi-ethnic populations is warranted.

Background: Multifunctional magnetic nanoparticles (MNP) have been newly developed for tumor-targeted drug carriers. To address challenges including biocompatibility, stability, nontoxicity, and targeting efficiency, here we report the novel drug deliverer poly(ethylene glycol) carboxyl–poly(ɛ-caprolactone) modified MNP (PEG–PCCL-MNP) suitable for magnetic targeting based on our previous studies.Methods: Their in vitro characterization and cytotoxicity assessments, in vivo cytotoxicity assessments, and antitumor efficacy study were elaborately investigated.Results: The size of PEG–PCCL-MNP was 79.6 ± 0.945 nm. PEG–PCCL-MNP showed little in vitro or in vivo cytotoxicity and good biocompatibility, as well as effective tumor-specific cell targeting for drug delivery with the presence of external magnetic field.Discussion: PEG–PCCL-MNP is a potential candidate of biocompatible and tumor-specific targeting drug vehicle for hydrophobic drugs.

In this study, porous scaffold materials based on polyvinyl alcohol (PVA) and gelatin (Gel) were successfully fabricated and characterized. The mechanism of the reaction, morphology, and crystallinity were investigated by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). In addition, thermogravimetric analysis (TGA) was performed together with differential scanning calorimetry (DSC) for examining the thermostability and phase transformation of the scaffolds. Degradation and swelling studies of PVA/Gel composite scaffold materials were performed in phosphate-buffered saline. Finally, the mechanical performances had been determined. According to the results, the polymer matrix that was formed by the combination of PVA and gelatin had better thermal stability. The synthesized composite scaffold was amorphous in nature. The addition of gelatin did not affect the fishbone-like microstructure of PVA, which ensures the excellent mechanical properties of the PVA scaffold. The denaturation temperature and elastic modulus of the PVA scaffold were improved by the gelatin addition, but the physical and chemical properties of the PVA scaffold were weakened when the gelatin content exceeded 10%. In addition, the PVA-10G sample has suitable degradability. Therefore, the PVA/Gel composite scaffold might potentially be applied in the field of tissue engineering that demands high strength.

Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio , a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio -deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.

Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio , a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio -deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.

Wolbachia species are bacteria that live within the cells of many insects. Like mitochondria, they are only inherited from females. Wolbachia often increases the number of infected females to promote spread of infection using a type of male sterility called cytoplasmic incompatibility (CI): when uninfected females mate with infected males, most embryos die; if both are similarly infected, embryos develop normally, giving infected females an advantage in producing offspring. Wolbachia is an obligate intracellular bacterium that can alter reproduction of its arthropod hosts, often through a mechanism called cytoplasmic incompatibility (CI). In CI, uninfected females fertilized by infected males yield few offspring, but if both are similarly infected, normal embryo viability results (called “rescue”). CI factors (Cifs) responsible for CI are pairs of proteins encoded by linked genes. The downstream gene in each pair encodes either a deubiquitylase (Ci d B) or a nuclease (Ci n B). The upstream gene products, CidA and CinA, bind their cognate enzymes with high specificity. Expression of CidB or CinB in yeast inhibits growth, but growth is rescued by expression of the cognate CifA protein. By contrast, transgenic Drosophila male germ line expression of both cifA and cifB was reported to be necessary to induce CI-like embryonic arrest; cifA expression alone in females is sufficient for rescue. This pattern, seen with genes from several Wolbachia strains, has been called the “2-by-1” model. Here, we show that male germ line expression of the cinB gene alone, from a distinct clade of cif genes from w No Wolbachia , is sufficient to induce nearly complete loss of embryo viability. This male sterility is fully rescued by cognate cinA w No expression in the female germ line. The proteins behave similarly in yeast. CinB w No toxicity depends on its nuclease active site. These results demonstrate that highly divergent CinB nucleases can induce CI, that rescue by cognate CifA factors is a general feature of Wolbachia CI systems, and that CifA is not strictly required in males for CI induction. IMPORTANCE Wolbachia bacteria live within the cells of many insects. Like mitochondria, they are only inherited from females. Wolbachia often increases the number of infected females to promote spread of infection using a type of male sterility called cytoplasmic incompatibility (CI): when uninfected females mate with infected males, most embryos die; if both are similarly infected, embryos develop normally, giving infected females an advantage in producing offspring. CI is being used against disease-carrying mosquitoes and agricultural pests. Wolbachia proteins called CifA and CifB, which bind one another, cause CI, but how they work has been unclear. Here, we show that a CifB protein singly produced in fruit fly males causes sterility in crosses to normal females, but this is rescued if the females produce the CifA partner. These findings clarify a broad range of observations on CI and will allow more rational approaches to using it for insect control.

HER2-positive breast cancer (BC) invasiveness and drug-resistance issue is the critical treatment obstacle recently. We investigated the total and phosphorylated status EZH2 expression in database and BC tissue microarray. We demonstrated for the first time that EZH2 is distributed both in cytoplasm and nucleus of breast cancer cells in a phosphorylation site-specific manner. High expressed-EZH2 cases more frequently had an advanced clinical stage (lymph node metastasis) and aggressive features than EZH2-low cases, potentially indicating the high risk of HER2-positive BC (p < 0.05). Notably, highly expressed phosphorylated EZH2 is differently located in cytoplasm or nucleus in a site-specific manner in breast cancer cells. Nucleus-located pEZH2-S21 is expressed in invasive and lymph node metastatic HER2-positive BC cases (p = 0.144, p = 0.001). Cytoplasmic pEZH2-T487 is correlated with HER2 positive status (p = 0.014). In conclusion, high expression of nucleus-located EZH2 might be a predictor of invasive BC. Activation of phosphorylated EZH2-S21 site in nucleus would be a potential predictor of HER2-positve BC and poor efficacy of HER2-target therapy. These results point to a PRC2-independent non-epigenetic mechanism and therapeutic strategy of EZH2 in HER2-positive BC.