Adolescent Isolation Interacts With DISC1 Point Mutation to Impair Adult Social Memory and Synaptic Functions in the Hippocampus

Disrupted-in-schizophrenia 1 (DISC1) is a strong candidate susceptibility gene for a spectrum of neuropsychiatric diseases including schizophrenia, bipolar disorder and major depression, all of which are thought to result from interactions between gene mutations and environmental risk factors such as influenza, trauma and stress. Adolescence is a key period susceptible to stress and stress-related mental illnesses. In a previous study, we found that although DISC1 L100P point mutation mice shows object recognition deficits, their sociability and social memory are relatively normal. Therefore, in this article, we investigated whether the interaction between adolescent stress and DISC1 L100P point mutation affects adult social memory, and we explored the underlying mechanisms. We found that adolescent stress (isolation from 5 weeks to 8 weeks of age) specifically impaired social memory of adult DISC1 L100P mice but not that of WT littermates, which could be rescued by administration of atypical antipsychotic drug clozapine. On the other hand, it did not induce anxiety or depression in adult mice. Adolescent isolation exacerbated adult neurogenesis deficits in the hippocampus of DISC1 L100P mice, while it had no effect on WT mice. In addition, we found that adolescent isolation led to long lasting changes in synaptic transmission and plasticity in the hippocampal circuits, some of which are specific for DISC1 L100P mice. In summary, we identified here the specific interaction between genetic mutation (DISC1 L100P) and adolescence social stress that damages synaptic function and social memory in adult hippocampal circuits.Highlights–Adolescent isolation (from 5 weeks to 8 weeks of age) impairs adult social memory when combined with DISC1 L100P point mutation.–Adolescent isolation exacerbates adult neurogenesis deficit in the hippocampus of L100P mice but has no similar effect on WT mice.–Adolescent isolation causes long lasting changes in synaptic transmission and plasticity of the hippocampal network in DISC1 L100P mice

Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet

BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2, which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating. Whole-cell patch-clamp recordings of CA1 pyramidal neurons revealed a decrease in intrinsic excitability and reduced frequency of inhibitory post-synaptic currents in MD F1 mice compared to the CD F1 controls. AAV-based overexpression of Kcnmb2 in dorsal CA1 ameliorated changes in neuronal excitability, synaptic transmission, and plasticity in MD F1 mice. Our findings thus indicate that a transient paternal exposure to a methyl donor-rich diet prior to mating alters Kcnmb2-sensitive hippocampal functions in offspring animals

Nf-κb Inhibition Rescues Cardiac Function By Remodeling Calcium Genes In A Duchenne Muscular Dystrophy Model

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-κB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-κB rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-κB acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function

Exposure of benzo[a]pyrene induces HCC exosome‐circular RNA to activate lung fibroblasts and trigger organotropic metastasis

Abstract Background Benzo[a]pyrene (B[a]P), a carcinogen pollutant produced by combustion processes, is present in the western diet with grilled meats. Chronic exposure of B[a]P in hepatocellular carcinoma (HCC) cells promotes metastasis rather than primary proliferation, implying an unknown mechanism of B[a]P‐induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer‐stroma communications for a toxicologically associated microenvironment. Method Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404‐100Bap Exo) at an environmental relevant dose (100 nmol/L). Lung pre‐education animal model was prepared via injection of exosomes and cytokines. The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array. HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis. Profile of B[a]P‐exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull‐down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the “on‐off” interaction of circRNA‐miRNA pairs. We further developed an adeno‐associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA‐miRNA cascade. Results Lung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404‐100Bap Exo. In the exosome‐educated in vivo model, fibrosis factors and pro‐inflammatory molecules of are up‐regulated when injected with exosomes. Compared to non‐exposed 7404 cells, circ_0011496 was up‐regulated following B[a]P treatment and was mainly packaged into 7404‐100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR‐486‐5p in recipient fibroblasts. The down‐regulation of miR‐486‐5p converted fibroblast to cancer‐associated fibroblast via regulating the downstream of Twinfilin‐1 (TWF1) and matrix metalloproteinase‐9 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer‐stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre‐metastatic niche formation. Conclusion We demonstrated that B[a]P‐induced tumor exosomes can deliver circ_0011496 to activate miR‐486‐5p/TWF1/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis

A Novel Approach to Making the Gas-Filled Liposome Real: Based on the Interaction of Lipid with Free Nanobubble within the Solution

Nanobubbles with a size less than 1 μm could make a promising application in ultrasound molecular imaging and drug delivery. However, the fabrication of stable gas encapsulation nanobubbles is still challenging. In this study, a novel method for preparation of lipid- encapsulated nanobubbles was reported. The dispersed phospholipid molecules in the prefabricated free nanobubbles solution can be assembled to form controllable stable lipid encapsulation gas-filled ultrasound-sensitive liposome (GU-Liposome). The optimized preparation parameters and formation mechanism of GU-Liposome were investigated in detail. Results showed that this type of GU-Liposome had mean diameter of 194.4 ± 6.6 nm and zeta potential of −25.2 ± 1.9 mV with layer by layer self-assembled lipid structure. The acoustic imaging analysis in vitro indicated that ultrasound imaging enhancement could be acquired by both perfusion imaging and accumulation imaging. The imaging enhancement level and duration time was related with the ratios of lipid to gas in the GU-Liposome structure. All in all, by this novel and controllable nanobubble construction technique, it will broaden the future theranostic applications of nanobubbles

Copper-Catalyzed Domino Cyclization/Trifluoromethylthiolation of Unactivated Alkenes: Access to SCF₃‑Containing Pyrrolines

A novel and efficient copper-catalyzed cascade cyclization/trifluoromethylthiolation of unactivated olefins has been achieved with the stable and readily available AgSCF₃ as the SCF₃ source. A range of SCF₃-substituted pyrrolines have been easily obtained under mild conditions in good yields via the present process. This method represents a facile and rapid access to valuable pyrrolines with fluorine-containing groups, and it is amenable to gram-scale synthesis

Controlled Drug Release and Hydrolysis Mechanism of Polymer–Magnetic Nanoparticle Composite

Uniform and multifunctional poly­(lactic acid) (PLA)–nanoparticle composite has enormous potential for applications in biomedical and materials science. A detailed understanding of the surface and interface chemistry of these composites is essential to design such materials with optimized function. Herein, we designed and investigated a simple PLA–magnetic nanoparticle composite system to elucidate the impact of nanoparticles on the degradation of polymer–nanoparticle composites. In order to have an in-depth understanding of the mechanisms of hydrolysis in PLA–nanoparticle composites, degradation processes were monitored by several surface sensitive techniques, including scanning electron microscopy, contact angle goniometry, atomic force microscopy, and sum frequency generation spectroscopy. As a second-order nonlinear optical technique, SFG spectroscopy was introduced to directly probe in situ chemical nature at the PLA–magnetic nanoparticle composite/aqueous interface, which allowed for the delineation of molecular mechanisms of various hydrolysis processes for degradation at the molecular level. The best PLA–NP material, with a concentration of 20% MNP in the composite, was found to enhance the drug release rate greater than 200 times while maintaining excellent controlled drug release characteristics. It was also found that during hydrolysis, various crystalline-like PLA domains on the surfaces of PLA–nanoparticle composites influenced various hydrolysis behaviors of PLA. Results from this study provide new insight into the design of nanomaterials with controlled degradation and drug release properties, and the underlined molecular mechanisms. The methodology developed in this study to characterize the polymer–nanoparticle composites is general and widely applicable

Additional file 1 of Individualized detection of TMPRSS2-ERG fusion status in prostate cancer: a rank-based qualitative transcriptome signature

Additional file 1: Table S1. List of maker genes in cell annotation. Table S2. Annotation results of cells from scRNA-seq samples in single-cell analysis. Fig. S1. Five stability indexes (F-stastic, outlier, entropy, CV and MAD) distribution of normal, stable and unstable genes in training dataset. Fig. S2. Performance of ERG in the training and validation datasets Fig. S3. Venn map of diagnosis results between 5-cs-ERG-mRPs and fusion prediction tools for 495 TCGA samples. Fig. S4. UMAP of tumor-infiltrating (A-B) T or (C-D) B lymphocytes annotated from samples GSM4089155 or GSM4089156