AB043. BRD4 promotes immune escape of glioma cells by upregulating PD-L1 expression.

BACKGROUND: Glioblastoma multiforme (GBM) poses significant challenges in treatment due to its aggressive nature and immune escape mechanisms. Despite recent advances in immune checkpoint blockade therapies, GBM prognosis remains poor. The role of bromodomain and extraterminal domain protein 4 (BRD4) in GBM, especially its interaction with immune checkpoints, is not well understood. METHODS: Bioinformatic gene expression and survival analysis for BRD4 was utilized in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Clone formation assay, Transwell, Cell Counting Kit-8 (CCK8), and wound healing assay were utilized to validate BRD4's promotion of glioma cell proliferation, invasion, and migration. Chromatin immunoprecipitation (ChIP) assay was conducted to confirm BRD4 binding to the programmed death ligand 1 (PD-L1) promoter. A co-culture model was utilized with activated cluster of differentiation 8 (CD8)+ T cells and glioma cells. GL261 cells with BRD4 short hairpin RNA (shRNA) and/or PD-L1 cDNA were intracranially injected into mice to investigate tumor growth and survival time. Tumor tissue characteristics were analyzed using hematoxylin-eosin (H&E) and immunohistochemistry (IHC) staining and immune cell infiltration were assessed by flow cytometry. RESULTS: Bioinformatics analyses reveal elevated BRD4 expression in high-grade gliomas, correlating with poor patient survival. In vitro studies confirm that BRD4 promotes proliferation, invasion, and migration in GBM cells. BRD4 is a regulator of PD-L1 at the transcriptional level, implying its involvement in GBM's immune escape mechanisms. Co-culture experiments with CD8+ T cells demonstrate that BRD4 inhibition enhances tumor cell apoptosis. In vivo studies indicate that BRD4 knockout reduces immunosuppression, improves prognosis. Simultaneous manipulation of BRD4 and PD-L1 levels provides insights into their intertwined roles in shaping the immune landscape of GBM. CONCLUSIONS: BRD4 has the capability to regulate the growth of glioblastoma and enhance immune suppression by promoting PD-L1 expression. Targeting BRD4 represents a promising direction for future research and treatment.

The MYC2 and MYB43 transcription factors cooperate to repress HMA2 and HMA4 expression, altering cadmium tolerance in Arabidopsis thaliana.

Cadmium (Cd) represents a hazardous heavy metal, prevalent in agricultural soil due to industrial and agricultural expansion. Its propensity for being absorbed by edible plants, even at minimal concentrations, and subsequently transferred along the food chain poses significant risks to human health. Accordingly, it is imperative to investigate novel genes and mechanisms that govern Cd tolerance and detoxification in plants. Here, we discovered that the transcription factor MYC2 directly binds to the promoters of HMA2 and HMA4 to repress their expression, thereby altering the distribution of Cd in plant tissues and negatively regulating Cd stress tolerance. Additionally, molecular, biochemical, and genetic analyses revealed that MYC2 interacts and cooperates with MYB43 to negatively regulate the expression of HMA2 and HMA4 and Cd stress tolerance. Notably, under Cd stress conditions, MYC2 undergoes degradation, thereby alleviating its inhibitory effect on HMA2 and HMA4 expression and plant tolerance to Cd stress. Thus, our study highlights the dynamic regulatory role of MYC2, in concert with MYB43, in regulating the expression of HMA2 and HMA4 under both normal and Cd stress conditions. These findings present MYC2 as a promising target for directed breeding efforts aimed at mitigating Cd accumulation in edible plant roots.

Chromosome doubling increases PECTIN METHYLESTERASE 2 expression, biomass, and osmotic stress tolerance in kiwifruit.

Chromosome doubling-induced polyploidization is a popular tool for crop breeding. Polyploidy crops commonly have multiple advantages, including increased biomass and stress tolerance. However, little is known about the genes responsible for these advantages. We found kiwifruit (Actinidia chinensis cv. Hongyang) PECTIN METHYLESTERASE 2 (AcPME2)is substantially upregulated in artificially created tetraploid plants that show increased biomass and enhanced tolerance to osmotic stress. Overexpression (OE) of AcPME2 led to increased biomass and enhanced stress tolerance in Arabidopsis (Arabidopsis thaliana), tomato (Solanum lycopersicum), and kiwifruit. Upon short-term osmotic stress treatment, AcPME2-OE plants showed higher levels of demethylesterified pectins and more Ca2+ accumulation in the cell wall than Col-0 plants, which led to increased cell wall stiffness. The stress-induced plasmolysis assays indicated that AcPME2 dynamically mediated the cell wall stiffness in response to osmotic stress, which is dependent on Ca2+ accumulation. Transcriptomic analysis discovered that dozens of stress-responsive genes were significantly upregulated in the AcPME2-OE plants under osmotic stress. Besides, AcPME2-mediated cell wall reinforcement prevented cell wall collapse and deformation under osmotic stress. Our results revealed a single gene contributes to two advantages of polyploidization (increased biomass and osmotic stress tolerance) and that AcPME2 dynamically regulates cell wall stiffness in response to osmotic stress.

An n-doping cross-linkable quinoidal compound as a new type of electron transport material for fully stretchable inverted organic solar cells.

The photocatalytic activity and inherent brittleness of ZnO, which is commonly used as an electron transport layer (ETL) in inverted organic solar cells (OSCs), have impeded advancements in device stability and the development of fully stretchable OSCs. In this study, we have developed an intrinsically stretchable ETL for inverted OSCs through a side-chain cross-linking strategy. Specifically, cross-linking between bromine atoms on the side chains of a quinoidal compound and the amino groups in polyethylenimine resulted in a film, designated QBr-PEI-50, with high electrical conductivity (0.049 S/m) and excellent stretchability (crack-onset strain >45%). When used as the ETL in inverted OSCs, QBr-PEI-50 was markedly superior to ZnO in terms of device performance and stability, yielding a power conversion efficiency (PCE) of 18.27% and a T80 lifetime exceeding 10000 h. Moreover, incorporation of QBr-PEI-50 in fully stretchable inverted OSCs yielded a PCE of 14.01%, and 80% of the initial PCE was maintained after 21% strain, showcasing its potential for wearable electronics.

Ruscogenin Exerts Anxiolytic-Like Effect via Microglial NF-κB/MAPKs/NLRP3 Signaling Pathways in Mouse Model of Chronic Inflammatory Pain.

Long-term inflammation can cause chronic pain and trigger patients' anxiety by sensitizing the central nervous system. However, effective drugs with few side effects for treating chronic pain-induced anxiety are still lacking. The anxiolytic and anti-inflammatory effects of ruscogenin (RUS), an important active compound in Ophiopogon japonicus, were evaluated in a mouse model of chronic inflammatory pain and N9 cells. RUS (5, 10, or 20 mg/kg/day, i.g.) was administered once daily for 7 days after CFA injection; pain- and anxiety-like behaviors were assessed in mice. Anti-inflammatory effect of RUS (0.1, 1, 10 µM) on N9 microglia after LPS treatment was evaluated. Inflammatory markers (TNF-α, IL-1ß, IL-6, CD86, IL-4, ARG-1, and CD206) were measured using qPCR. The levels of IBA1, ROS, NF-κB, TLR4, P-IKK, P-IκBα, and P65, MAPKs (ERK, JNK, and P38), NLRP3 (caspase-1, ASC, and NLRP3) were detected by Western blotting or immunofluorescence staining. The potential target of RUS was validated by molecular docking and adeno-associated virus injection. Mice in CFA group exhibited allodynia and anxiety-like behaviors. LPS induced neuroinflammation in N9 cells. Both CFA and LPS increased the levels of IBA1, ROS, and inflammatory markers. RUS (10 mg/kg in vivo and 1 µM in vitro) alleviated these alterations through NF-κB/MAPKs/NLRP3 signaling pathways but had no effect on pain hypersensitivity. TLR4 strongly interacted with RUS, and TLR4 overexpression abolished the effects of RUS on anxiety and neuroinflammation. RUS exerts anti-inflammatory and anxiolytic effects via TLR4-mediated NF-κB/MAPKs/NLRP3 signaling pathways, which provides a basis for the treatment of chronic pain-induced anxiety.

The dual role of POSTN in maintaining glioblastoma stem cells and the immunosuppressive phenotype of microglia in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by glioblastoma stem cells (GSCs). The interplay between GSCs and immunosuppressive microglia plays crucial roles in promoting the malignant growth of GBM; however, the molecular mechanisms underlying this crosstalk are unclear. This study aimed to investigate the role of POSTN in maintaining GSCs and the immunosuppressive phenotype of microglia. METHODS: The expression of POSTN in GBM was identified via immunohistochemistry, quantitative real-time PCR, and immunoblotting. Tumorsphere formation assay, Cell Counting Kit-8 assay and immunofluorescence were used to determine the key role of POSTN in GSC maintenance. ChIP-seq and ChIP-PCR were conducted to confirm the binding sequences of ß-catenin in the promoter region of FOSL1. Transwell migration assays, developmental and functional analyses of CD4+ T cells, CFSE staining and analysis, enzyme-linked immunosorbent assays and apoptosis detection tests were used to determine the key role of POSTN in maintaining the immunosuppressive phenotype of microglia and thereby promoting the immunosuppressive tumor microenvironment. Furthermore, the effects of POSTN on GSC maintenance and the immunosuppressive phenotype of microglia were investigated in a patient-derived xenograft model and orthotopic glioma mouse model, respectively. RESULTS: Our findings revealed that POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVß3/PI3K/AKT/ß-catenin/FOSL1 pathway. In addition to its intrinsic effects on GSCs, POSTN can recruit microglia and upregulate CD70 expression in microglia through the αVß3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment. In both in vitro models and orthotopic mouse models of GBM, POSTN depletion disrupted GSC maintenance, decreased the recruitment of immunosuppressive microglia and suppressed GBM growth. CONCLUSION: Our findings reveal that POSTN plays critical roles in maintaining GSCs and the immunosuppressive phenotype of microglia and provide a new therapeutic target for treating GBM.

Associations of multiple blood metals with cardiac structure and function: A cross-sectional study in a CAD population.

Coronary artery disease (CAD) is often accompanied by abnormal cardiac structure and function, leading to an increased prognostic risk. However, less is known about the associations of mixed metals with abnormal cardiac structure and function in CAD patients. Here, we aimed to investigate the associations of exposure to metal mixtures with cardiac structure and function and potential interactions in a CAD population. We conducted a cross-sectional study from Southwest China that included 1555 CAD patients. The blood concentrations of 14 metals were measured via inductively coupled plasma spectrometry. CAD was defined as at least one vessel having stenosis ≥50% the vessel diameter. Echocardiography was used for cardiac structural and functional measurements. Bayesian kernel machine regression was applied to explore the overall effect, metal weight, and dose effect. Linear regression analysis was used to analyze the effects of single metals, metal‒metal interactions and metal‒traditional interactions. Finally, we found that the negative associations of mixed metals with cardiac structure was significant when the levels of all metals were below the 60th percentile. For cardiac function, changes in metals from 50th to 75th were associated with 0.954% and 0.683% decrease in left ventricular ejection fraction and left ventricular fractional shortening, respectively. Negative associations of copper and manganese with cardiac structure and function, whereas positive associations of titanium, selenium and molybdenum with several parameters were found. Antagonistic interactions between copper and tin and between selenium and several metals (manganese, copper and aluminum) (all Pinteraction terms < 0.05) were found. In conclusion, mixed metal exposure was negatively associated with cardiac structure and function in CAD patients. The main metals contributing to this negative associations were copper and manganese. Selenium or tin supplementation may reduce the adverse associations of copper and manganese with cardiac structure and function.

The SINA1-BSD1 Module Regulates Vegetative Growth Involving Gibberellin Biosynthesis in Tomato.

In plants, vegetative growth is controlled by synergistic and/or antagonistic effects of many regulatory factors. Here, the authors demonstrate that the ubiquitin ligase seven in absentia1 (SINA1) mammalian BTF2-like transcription factors, Drosophila synapse-associated proteins, and yeast DOS2-like proteins (BSD1) function as a regulatory module to control vegetative growth in tomato via regulation of the production of plant growth hormone gibberellin (GA). SINA1 negatively regulates the protein level of BSD1 through ubiquitin-proteasome-mediated degradation, and the transgenic tomato over-expressing SINA1 (SINA1-OX) resembles the dwarfism phenotype of the BSD1-knockout (BSD1-KO) tomato plant. BSD1 directly activates expression of the BSD1-regulated gene 1 (BRG1) via binding to a novel core BBS (standing for BSD1 binding site) binding motif in the BRG1 promoter. Knockout of BRG1 (BRG1-KO) in tomato also results in a dwarfism phenotype, suggesting BRG1 plays a positive role in vegetative growth as BSD1 does. Significantly, GA contents are attenuated in transgenic SINA1-OX, BSD1-KO, and BRG1-KO plants exhibiting dwarfism phenotype and exogenous application of bioactive GA3 restores their vegetative growth. Moreover, BRG1 is required for the expression of multiple GA biosynthesis genes and BSD1 activates three GA biosynthesis genes promoting GA production. Thus, this study suggests that the SINA1-BSD1 module controls vegetative growth via direct and indirect regulation of GA biosynthesis in tomato.

Curcumin Alleviates Microglia-Mediated Neuroinflammation and Neuronal Ferroptosis Following Experimental Subarachnoid Hemorrhage by Modulating the Nrf2/HO-1 Signaling Pathway.

Early brain injury caused by subarachnoid hemorrhage (SAH) is associated with inflammatory response and ferroptosis. Curcumin alleviates neuroinflammation and oxidative stress by as yet unknown neuroprotective mechanisms. The objective of this study was to investigate the impact of curcumin on neuronal ferroptosis and microglia-induced neuroinflammation following SAH. By examining Nrf2/HO-1 expression levels and ferroptosis biomarkers expression both in vitro and in vivo, it was demonstrated that curcumin effectively suppressed ferroptosis in neurons after SAH through modulation of the Nrf2/HO-1 signaling pathway. Furthermore, by analyzing the expression levels of Nrf2, HO-1, p-p65, and inflammation-related genes, it was confirmed that curcumin could prevent the upregulation of pro-inflammatory factors following SAH by regulating the Nrf2/HO-1/NF-κB signaling pathway in microglia. The ability of curcumin to reduce neuronal damage and cerebral edemas after SAH in mice was validated using TUNEL staining, Nissl staining, and measurement of brain tissue water content. Additionally, through implementation of the modified Garcia test, open field test, and Y-maze test, it was established that curcumin ameliorated neurobehavioral impairments in mice post-SAH. Taken together, these data suggest that curcumin may offer a promising therapeutic approach for improving outcomes following SAH by concurrently attenuating neuronal ferroptosis and reducing neuroinflammation.

Novel mitochondrial-related gene signature predicts prognosis and immunological status in glioma.

Background: Mitochondria are the center of cellular metabolism. The relationship between mitochondria and diseases has also been studied for a long time. However, the prognostic role of mitochondrial-related genes (MRGs) in patients with glioma and their biological effects are still unclear. The aim of the study was to construct a mitochondria-related model to assess prognosis and potential biological effects like immune infiltration, gene pathway and mutation, and give some predictive chemotherapeutic agents. Methods: The data of 675 patients from The Cancer Genome Atlas (TCGA) database were used to identify MRG signature and construct a prognostic model. After validating its robustness in Chinese Glioma Genome Atlas (CGGA), two risk groups derived from the prognostic model were then conducted with Gene Set Enrichment Analysis (GSEA), immune status, mutation status and chemotherapeutic agents prediction. Results: The prognostic model built from six gene signatures can successfully predict the prognosis and reflect clinicopathological characteristics. Patients in high-risk group displayed significantly worse overall survival (OS), immunosuppression effects, and mutation markers with worse prognosis. Twelve chemotherapeutic agents with strongly correlated sensitivity and risk scores were selected as potential agents. Conclusions: The novel MRG signatures (TYMP, TSFM, MGME1, BOLA3, TRMT5, NDUFA9) can predict prognosis and immunological status in glioma.

CDR1, a DUF946 domain containing protein, positively regulates cadmium tolerance in Arabidopsis thaliana by maintaining the stability of OPT3 protein.

Industrial and agricultural production processes lead to the accumulation of cadmium (Cd) in soil, resulting in crops absorb Cd from contaminated soil and then transfer it to human body through the food chain, posing a serious threat to human health. Thus, it is necessary to explore novel genes and mechanisms involved in regulating Cd tolerance and detoxification in plants. Here, we found that CDR1, a DUF946 domain containing protein, localizes to the plasma membrane and positively regulates Cd stress tolerance. The cdr1 mutants exhibited Cd sensitivity, accumulated excessive Cd in the seeds and roots, but decreased in leaves. However, CDR1-OE transgenic plants not only showed Cd tolerance but also significantly reduced Cd in seeds and roots. Additionally, both in vitro and in vivo assays demonstrated an interaction between CDR1 and OPT3. Cell free protein degradation and OPT3 protein level determination assays indicated that CDR1 could maintain the stability of OPT3 protein. Moreover, genetic phenotype analysis and Cd content determination showed that CDR1 regulates Cd stress tolerance and affect the distribution of Cd in plants by maintaining the stability of OPT3 protein. Our discoveries provide a key candidate gene for directional breeding to reduce Cd accumulation in edible seeds of crops.

Evaluation of a novel 177Lu-labelled therapeutic Affibody molecule with a deimmunized ABD domain and improved biodistribution profile.

PURPOSE: Fusion of Affibody molecules with an albumin-binding domain (ABD) provides targeting agents, which are suitable for radionuclide therapy. To facilitate clinical translation, the low immunogenic potential of such constructs with targeting properties conserved is required. METHODS: The HER2-targeting Affibody molecule ZHER2:2891 was fused with a deimmunized ABD variant and DOTA was conjugated to a unique C-terminal cysteine. The novel construct, PEP49989, was labelled with 177Lu. Affinity, specificity, and in vivo targeting properties of [177Lu]Lu-PEP49989 were characterised. Experimental therapy in mice with human HER2-expressing xenografts was evaluated. RESULTS: The maximum molar activity of 52 GBq/µmol [177Lu]Lu-PEP49989 was obtained. [177Lu]Lu-PEP49989 bound specifically to HER2-expressing cells in vitro and in vivo. The HER2 binding affinity of [177Lu]Lu-PEP49989 was similar to the affinity of [177Lu]Lu-ABY-027 containing the parental ABD035 variant. The renal uptake of [177Lu]Lu-PEP49989 was 1.4-fold higher, but hepatic and splenic uptake was 1.7-2-fold lower than the uptake of [177Lu]Lu-ABY-027. The median survival of xenograft-bearing mice treated with 21 MBq [177Lu]Lu-PEP49989 (> 90 days) was significantly longer than the survival of mice treated with vehicle (38 days) or trastuzumab (45 days). Treatment using a combination of [177Lu]Lu-PEP49989 and trastuzumab increased the number of complete tumour remissions. The renal and hepatic toxicity was minimal to mild. CONCLUSION: In preclinical studies, [177Lu]Lu-PEP49989 demonstrated favourable biodistribution and a strong antitumour effect, which was further enhanced by co-treatment with trastuzumab.

TRIM37 interacts with EZH2 to epigenetically suppress PTCH1 and regulate stemness in glioma stem cells through sonic hedgehog pathway.

BACKGROUND: Glioma stem cells (GSCs), which are known for their therapy resistance, play a substantial role in treatment inefficacy for glioblastoma multiforme (GBM). TRIM37, a member of the tripartite motif (TRIM) protein family initially linked to a rare growth disorder, has been recognized for its oncogenic role. However, the mechanism by which TRIM37 regulates tumor growth in glioma and GSCs is unclear. METHODS: For the in vitro experiments, gene expression was measured by western blotting, RT-qPCR, and immunofluorescence. Cell viability was detected by CCK-8, and cell apoptosis was detected by flow cytometry. The interaction between Enhancer of Zeste Homolog 2 (EZH2) and TRIM37 was verified by co-immunoprecipitation (Co-IP). The interaction between EZH2 and the PTCH1 promoter was verified using dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP). For the in vivo experiments, an orthotopically implanted glioma mouse model was used to validate tumor growth. RESULTS: The expression of TRIM37 is higher in GSCs compared with matched non-GSCs. TRIM37 knockdown promotes apoptosis, decreased stemness in GSCs, and reduces tumor growth in GSCs xenografts of nude mice. TRIM37 and EZH2 co-localize in the nucleus and interact with each other. TRIM37 knockdown or EZH2 inhibition downregulates the protein expressions associated with the Sonic Hedgehog (SHH) pathway. EZH2 epigenetically downregulates PTCH1 to activate SHH pathway in GSCs. CONCLUSIONS: TRIM37 maintains the cell growth and stemness in GSCs through the interaction with EZH2. EZH2 activates SHH stem cell signaling pathway by downregulating the expression of SHH pathway suppressor PTCH1. Our findings suggest that TRIM37 may be a potential therapeutic target for GBM.

Controlled Nucleation and Oriented Crystallization of Methylammonium-Free Perovskites via In Situ Generated 2D Perovskite Phases.

Enhancing stability while maintaining high efficiency is among the primary challenges in the commercialization of perovskite solar cells (PSCs). Here, a crystal growth technique assisted by in situ generated 2D perovskite phases has been developed to construct high-quality 2D/3D perovskite films. The in situ generated 2D perovskite serve as templates for regulating the nucleation and oriented crystal growth in the α-FAPbI3-rich film. This led to a high film quality with much reduced trap density and an ultralong carrier lifetime. The obtained perovskite film shows excellent stability under extreme environment conditions (T = 200 °C, RH = 75 ± 5%). The corresponding PSC achieved an efficiency of 26.16% (certified 25.84%), along with excellent operational stability (T93 > 1300 h, T ≅ 50 °C) as well as outstanding high and low temperature cycle stability.

Foot and mouth disease vaccine efficacy in Africa: a systematic review and meta-analysis.

Background: Several factors, such as diverse serotypes, vaccination methods, weak biosecurity, and animal movements, contribute to recurrent Foot-and-Mouth Disease Virus (FMDV) outbreaks in Africa, establishing endemicity. These outbreaks cost over $2 billion annually, prompting a high-priority focus on FMDV vaccination. Despite extensive efforts, vaccine efficacy varies. This study aims to evaluate routine foot and mouth disease (FMD) vaccines in Africa via systematic review and meta-analysis. Methods: A systematic review and meta-analysis were carried out following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was conducted to assess the efficacy of FMDV vaccination using the meta for package of R. Results: Vaccinated animals have roughly a 69.3% lower chance of FMDV infection compared to unvaccinated animals, as indicated by the pooled results from the random-effects model, which showed a risk ratio (RR) of 0.3073. There was a statistically significant heterogeneity (p < 0.05) across all of the included articles. Conclusion: Overall findings suggest that if properly planned and implemented, FMDV vaccination programs and strategies in Africa could help control the spread of the disease throughout the continent and beyond.

CBD2: A functional biomarker database for colorectal cancer.

The rapidly evolving landscape of biomarkers for colorectal cancer (CRC) necessitates an integrative, updated repository. In response, we constructed the Colorectal Cancer Biomarker Database (CBD), which collected and displayed the curated biomedicine information for 870 CRC biomarkers in the previous study. Building on CBD, we have now developed CBD2, which includes information on 1569 newly reported biomarkers derived from different biological sources (DNA, RNA, protein, and others) and clinical applications (diagnosis, treatment, and prognosis). CBD2 also incorporates information on nonbiomarkers that have been identified as unsuitable for use as biomarkers in CRC. A key new feature of CBD2 is its network analysis function, by which users can investigate the visible and topological network between biomarkers and identify their relevant pathways. CBD2 also allows users to query a series of chemicals, drug combinations, or multiple targets, to enable multidrug, multitarget, multipathway analyses, toward facilitating the design of polypharmacological treatments for CRC. CBD2 is freely available at http://www.eyeseeworld.com/cbd.

TRIM35 Monoubiquitinates H2B in Cardiac Cells, Implications for Heart Failure.

BACKGROUND: The tumor suppressor and proapoptotic transcription factor P53 is induced (and activated) in several forms of heart failure, including cardiotoxicity and dilated cardiomyopathy; however, the precise mechanism that coordinates its induction with accessibility to its transcriptional promoter sites remains unresolved, especially in the setting of mature terminally differentiated (nonreplicative) cardiomyocytes. METHODS: Male and female control or TRIM35 (tripartite motif containing 35) overexpression adolescent (aged 1-3 months) and adult (aged 4-6 months) transgenic mice were used for all in vivo experiments. Primary adolescent or adult mouse cardiomyocytes were isolated from control or TRIM35 overexpression transgenic mice for all in vitro experiments. Adenovirus or small-interfering RNA was used for all molecular experiments to overexpress or knockdown, respectively, target genes in primary mouse cardiomyocytes. Patient dilated cardiomyopathy or nonfailing left ventricle samples were used for translational and mechanistic insight. Chromatin immunoprecipitation and DNA sequencing or quantitative real-time polymerase chain reaction (qPCR) was used to assess P53 binding to its transcriptional promoter targets, and RNA sequencing was used to identify disease-specific signaling pathways. RESULTS: Here, we show that E3-ubiquitin ligase TRIM35 can directly monoubiquitinate lysine-120 (K120) on histone 2B in postnatal mature cardiomyocytes. This epigenetic modification was sufficient to promote chromatin remodeling, accessibility of P53 to its transcriptional promoter targets, and elongation of its transcribed mRNA. We found that increased P53 transcriptional activity (in cardiomyocyte-specific Trim35 overexpression transgenic mice) was sufficient to initiate heart failure and these molecular findings were recapitulated in nonischemic human LV dilated cardiomyopathy samples. CONCLUSIONS: These findings suggest that TRIM35 and the K120Ub-histone 2B epigenetic modification are molecular features of cardiomyocytes that can collectively predict dilated cardiomyopathy pathogenesis.

LncRNA Gm15834 Aggravates Cardiac Hypertrophy by Interacting with Sam68 and Activating NF-κB Mediated Inflammation.

BACKGROUND: Cardiac hypertrophy is the common pathological process of multiple cardiovascular diseases. However, the molecular mechanisms of cardiac hypertrophy are unclear. Long non-coding RNA (lncRNA), a newly discovered type of transcript that has been demonstrated to function as crucial regulators in the development of cardiovascular diseases. This study revealed a novel regulatory pathway of lncRNA in cardiac hypertrophy. METHODS: The cardiac hypertrophy models were established by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) in HL-1 cardiomyocytes. Adeno-associated virus 9 (AAV9) in vivo and lncRNA Gm15834 and shRNA plasmids in vitro were used to overexpress and knock down lncRNA Gm15834. The myocardial tissue structure, cardiomyocyte area, cardiac function, protein expressions, and binding of lncRNA Gm15834 and Src-associated substrate during mitosis of 68 KDa (Sam68) were detected by hematoxylin and eosin (HE) staining, immunofluorescence staining, echocardiography, western blot and RNA immunoprecipitation (RIP), respectively. RESULTS: In cardiac hypertrophy models, inhibiting lncRNA Gm15834 could decrease Sam68 expression and nuclear factor kappa-B (NF-κB) mediated inflammatory activities in vivo and in vitro, but overexpressing lncRNA Gm15834 showed the opposite results. RIP experiments validated the binding activities between lncRNA Gm15834 and Sam68. Overexpression of Sam68 could counteract the anti-hypertrophy effects of lncRNA Gm15834 knockdown. Meanwhile, in vivo inhibition of lncRNA Gm15834 could inhibit Sam68 expression, reduce NF-κB mediated inflammatory activity and attenuate cardiac hypertrophy. CONCLUSION: Our study revealed a novel regulatory axis of cardiac hypertrophy, which comprised lncRNA Gm15834/Sam68/NF-κB/inflammation, shedding a new light for identifying therapy target of cardiac hypertrophy in clinic.

Reduced graphene oxide-wrapped ZnS-SnS2 heterojunction bimetallic hollow cubic boxes as high-magnification and long lifespan supercapacitor anode materials.

Metal sulfides have attracted extensive attention due to their excellent electrochemical performance. However, issues such as poor conductivity and severe volume expansion during charge and discharge processes affect the applications of sulfides as electrode materials. Here, a combination of coprecipitation and high-temperature sulfidation methods are employed to synthesize a ZnS-SnS2 composite with a hollow cubic structure, which is further composited with reduced graphene oxide (RGO) to form ZnS-SnS2 hollow cubic boxes encapsulated in a conductive framework of reduced graphene oxide (RGO) (denoted as ZnS-SnS2@RGO) for electrode materials. The hollow structure effectively alleviates the pulverization of ZnS-SnS2@RGO caused by volume expansion during charge and discharge processes. The heterogeneous structure formed by ZnS and SnS2 effectively reduces the electron transfer resistance of the material. The use of RGO wrapping enhances the conductivity of the ZnS-SnS2 hollow cubic boxes, and RGO's dispersion effect on the ZnS-SnS2 cubes improves particle agglomeration, further mitigating volume expansion of the material. These results indicate the outstanding electrochemical performance of heterostructural ZnS-SnS2 hollow cubic electrodes encapsulated with reduced graphene oxide as a conductive framework. The fabrication process provides a novel approach for addressing volume expansion and poor conductivity issues in other pseudocapacitive materials.