Genomic architecture of autism from comprehensive whole-genome sequence annotation.

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

PC71BM as Morphology Regulator for Highly Efficient Ternary Organic Solar Cells with Bulk Heterojunction or Layer-by-Layer Configuration.

The ternary strategy is one of the effective methods to regulate the morphology of the active layer in organic solar cells (OSCs). In this work, the ternary OSCs with bulk heterojunction (BHJ) or layer-by-layer (LbL) active layers are prepared by using the polymer donor PM6 and the non-fullerene acceptor L8-BO as the main system and the fullerene acceptor PC71BM as the third component. The power conversion efficiencies (PCEs) of BHJ OSCs and LbL OSCs are increased from 17.10% to 18.02% and from 17.20% to 18.20% by introducing PC71BM into the binary active layer, respectively. The in situ UV-vis absorption spectra indicate that the molecular aggregation and crystallization process can be prolonged by introducing PC71BM into the PM6:L8-BO or PM6/L8-BO active layer. The molecular orientation and molecular crystallinity in the active layer are optimized by introducing the PC71BM into the binary BHJ or LbL active layers, which can be confirmed by the experimental results of grazing incidence wide-angle X-ray scattering. This study demonstrates that the third component PC71BM can be used as a morphology regulator to regulate the morphology of BHJ or LbL active layers, thus effectively improving the performance of BHJ and LbL OSCs.

Highly Efficient Organic Solar Cells with the Highly Crystalline Third Component as a Morphology Regulator.

The morphology of the active layer is crucial for highly efficient organic solar cells (OSCs), which can be regulated by selecting a rational third component. In this work, the highly crystalline nonfullerene acceptor BTP-eC9 is selected as the morphology regulator in OSCs with PM6:BTP-BO-4Cl as the main system. The addition of BTP-eC9 can prolong the nucleation and crystallization progress of acceptor and donor molecules, thereby enhancing the order of molecular arrangement. Meanwhile, the nucleation and crystallization time of the donor is earlier than that of the acceptors after introducing BTP-eC9, which is beneficial for obtaining a better vertical structural phase separation. The exciton dissociation, charge transport, and charge collection are promoted effectively by the optimized morphology of the active layer, which improves the short-circuit current density and filling factor. After introducing BTP-eC9, the power conversion efficiencies (PCEs) of the ternary OSCs are improved from 17.31% to 18.15%. The PCE is further improved to 18.39% by introducing gold nanopyramid (Au NBPs) into the hole transport layer to improve photon utilization efficiency. This work indicates that the morphology can be optimized by selecting a highly crystalline third component to regulate the nucleation and crystallization progress of the acceptor and donor molecules.

Borna disease virus 1 induces ferroptosis, contributing to lethal encephalitis.

Borna disease virus 1 (BoDV-1) is a neurotropic RNA virus that has been linked to fatal BoDV-1 encephalitis (BVE) in humans. Ferroptosis represents a newly recognized kind of programmed cell death that marked by iron overload and lipid peroxidation. Various viral infections are closely related to ferroptosis. However, the link between BoDV-1 infection and ferroptosis, as well as its role in BVE pathogenesis, remains inadequately understood. Herein, we used primary rat cortical neurons, human microglial HMC3 cells, and Sprague‒Dawley rats as models. BoDV-1 infection induced ferroptosis, as ferroptosis characteristics were detected (iron overload, reactive oxygen species buildup, decreased antioxidant capacity, lipid peroxidation, and mitochondrial damage). Analysis via qRT-PCR and Western blot demonstrated that BoDV-1-induced ferroptosis was mediated through Nrf2/HO-1/SLC7a11/GPX4 antioxidant pathway suppression. Nrf2 downregulation was due to BoDV-1 infection promoting Nrf2 ubiquitination and degradation. Following BoDV-1-induced ferroptosis, the PTGS2/PGE2 signaling pathway was activated, and various intracellular lipid peroxidation products and damage-associated molecular patterns were released, contributing to BVE occurrence and progression. More importantly, inhibiting ferroptosis or the ubiquitin‒proteasome system effectively alleviated BVE. Collectively, these findings demonstrate the interaction between BoDV-1 infection and ferroptosis and reveal BoDV-1-induced ferroptosis as an underlying pathogenic mechanism of BVE.

ELAVL4 promotes the tumorigenesis of small cell lung cancer by stabilizing LncRNA LYPLAL1-DT and enhancing profilin 2 activation.

Small cell lung cancer (SCLC) is one of the most malignant tumors that has an extremely poor prognosis. RNA-binding protein (RBP) and long noncoding RNA (lncRNA) have been shown to be key regulators during tumorigenesis as well as lung tumor progression. However, the role of RBP ELAVL4 and lncRNA LYPLAL1-DT in SCLC remains unclear. In this study, we verified that lncRNA LYPLAL1-DT acts as an SCLC oncogenic lncRNA and was confirmed in vitro and in vivo. Mechanistically, LYPLAL1-DT negatively regulates the expression of miR-204-5p, leading to the upregulation of PFN2, thus, promoting SCLC cell proliferation, migration, and invasion. ELAVL4 has been shown to enhance the stability of LYPLAL1-DT and PFN2 mRNA. Our study reveals a regulatory pathway, where ELAVL4 stabilizes PFN2 and LYPLAL1-DT with the latter further increasing PFN2 expression by blocking the action of miR-204-5p. Upregulated PFN2 ultimately promotes tumorigenesis and invasion in SCLC. These findings provide novel prognostic indicators as well as promising new therapeutic targets for SCLC.

Sustained exposure to Helicobacter pylori induces immune tolerance by desensitizing TLR6.

Helicobacter pylori (H. pylori, Hp) has been designated a class I carcinogen and is closely associated with severe gastric diseases. During colonization in the gastric mucosa, H. pylori develops immune escape by inducing host immune tolerance. The gastric epithelium acts as the first line of defense against H. pylori, with Toll-like receptors (TLRs) in gastric epithelial cells being sensitive to H. pylori components and subsequently activating the innate immune system. However, the mechanism of immune tolerance induced by H. pylori through the TLR signalling pathway has not been fully elucidated. In this research, we detected the expression of TLRs and inflammatory cytokines in GES-1 cells upon sustained exposure to H. pylori or H. pylori lysate from 1 to 30 generations and in Mongolian gerbils infected with H. pylori for 5 to 90 weeks. We found that the levels of TLR6 and inflammatory cytokines first increased and then dropped during the course of H. pylori treatment in vitro and in vivo. The restoration of TLR6 potentiated the expression of IL-1ß and IL-8 in GES-1 cells, which recruited neutrophils and reduced the colonization of H. pylori in the gastric mucosa of gerbils. Mechanistically, we found that persistent infection with H. pylori reduces the sensitivity of TLR6 to bacterial components and regulates the expression of inflammatory cytokines in GES-1 cells through TLR6/JNK signaling. The TLR6 agonist obviously alleviated inflammation in vitro and in vivo. Promising results suggest that TLR6 may be a potential candidate immunotherapy drug for H. pylori infection.

Lotusine ameliorates propionic acid-induced autism spectrum disorder-like behavior in mice by activating D1 dopamine receptor in medial prefrontal cortex.

Autism spectrum disorder (ASD) is a multifaceted neuropsychiatric condition for which effective drug therapy for core clinical symptoms remains elusive. Lotusine, known for its neuroprotective properties in the treatment of neurological disorders, holds potential in addressing ASD. Nevertheless, its specific efficacy in ASD remains uncertain. This study aims to investigate the therapeutic potential of lotusine in ASD and elucidate the underlying molecular mechanisms. We induced an ASD mouse model through intracerebroventricular-propionic acid (ICV-PPA) injection for 7 days, followed by lotusine administration for 5 days. The efficacy of lotusine was evaluated through a battery of behavioral tests, including the three-chamber social test. The underlying mechanisms of lotusine action in ameliorating ASD-like behavior were investigated in the medial prefrontal cortex (mPFC) using whole-cell patch-clamp recordings, western blotting, immunofluorescence staining, molecular docking, and cellular thermal shift assay. The efficacy and mechanisms of lotusine were further validated in vitro. Lotusine effectively alleviated social deficits induced by ICV-PPA injection in mice by counteracting the reduction in miniature excitatory postsynaptic current frequency within the mPFC. Moreover, lotusine enhanced neuronal activity and ameliorated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor dysfunction in ICV-PPA infusion mice by upregulating c-fos, p-GluA1 Ser 845, and p-GluA1 Ser 831 protein levels within the mPFC. Our findings also suggest that lotusine may exert its effects through modulation of the D1 dopamine receptor (DRD1). Furthermore, the rescuing effects of lotusine were nullified by a DRD1 antagonist in PC12 cells. In summary, our results revealed that lotusine ameliorates ASD-like behavior through targeted modulation of DRD1, ultimately enhancing excitatory synaptic transmission. These findings highlight the potential of lotusine as a nutritional supplement in the treatment of ASD.

Metformin and survival of women with breast cancer: A meta-analysis of randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Metformin has been suggested to confer anticancer efficacy. However, it remains uncertain whether additional use of metformin could improve survival of women with breast cancer. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the influence of metformin on survival outcome in women with breast cancer. METHODS: Relevant RCTs were obtained by search of PubMed, Embase and Cochrane's Library databases from inception to 15 May 2021. A random-effects model incorporating the potential publication bias was used to pool the results. RESULTS AND DISCUSSION: Five phase II RCTs including 396 non-diabetic women with breast cancer were included in the meta-analysis. Pooled results showed that additional use of metformin was not associated with improved progression-free survival (PFS, hazard ratio [HR]: 1.00, 95% confidence interval [CI]: 0.70 to 1.43, p = 0.98; I2  = 32%) or overall survival (OS, HR: 1.00, 95% CI: 0.71 to 1.39, p = 0.98; I2  = 0%). Sensitivity analysis by excluding one study at a time showed consistent results (HR for PFS: 0.91 to 1.14, p all >0.05; HR for OS: 0.88 to 1.21, P all >0.05). WHAT IS NEW AND CONCLUSION: Current evidence from phase II clinical trials does not support that additional use of metformin could improve the survival outcome in women with breast cancer.

Large Relative Surface Area of Hematomas Predict a Poor Outcome in Patients with Spontaneous Intracerebral Hemorrhage.

OBJECTIVE: The aim of this study is to investigate the predictive value of relative surface area of hematoma on poor prognosis of spontaneous intracerebral hemorrhage (sICH). MATERIALS AND METHODS: We retrospectively analyzed 102 patients with sICH who met the inclusion criteria, attending to Yongchuan Hospital of Chongqing Medical University from January 2019 to September 2020. Cranial CT within 6 h of onset was completed and repeated in 24 h. The volume and surface area of the hematoma are measured by software, and the relative surface area is calculated from the above data. The primary outcome was 90-day modified Rankin Scale(mRS) score, which was classified as good prognosis (≤2 points) and poor prognosis (>2 points) according to the results. Univariate analysis and binary logistic regression analysis were used to calculate the effect of each variable on poor prognosis. RESULTS: The study is comprised of 52 patients with favorable functional prognosis and 50 patients with unfavorable one. The findings showed that admission National Institutes of Health Stroke Scale(NIHSS), hematoma volume, relative surface area, hematoma expansion(HE) and serum calcium concentration were independent influencing factors for poor prognosis(P=0.004,0.007,0.023,0.001,0.035, respectively). ROC curve analysis revealed that the area under the curve of the relative surface area of the hematoma predicted poor prognosis was 0.894(95% CI 0.830-0.985, P<0.001), which was better than the rest of the variables. CONCLUSIONS: The relative surface area of hematoma in sICH is an independent risk factor for poor prognosis with a high predictive value, and large relative surface area suggests poor prognosis.

Evaluation of Reduced-Dose Decitabine and Azacitidine for Treating Myelodysplastic Syndromes: A Retrospective Study.

BACKGROUND Hypomethylating agents (HMA) are considered the first-line therapy for high-risk myelodysplastic syndromes (MDS). However, as the efficacy and safety of rational dosing regimens are lacking, we evaluated the effectiveness and safety of reduced-dose azacitidine (AZA) vs. decitabine (DAC) in adult MDS patients. MATERIAL AND METHODS This retrospective study was conducted at the Institute of Hematology & Blood Diseases Hospital, for hospitalized MDS patients diagnosed (WHO 2008 classification criteria) from May 2006 to February 2020. These AZA- and DCA-naive patients treated with AZA 100 mg/(m²·day) for 5 days to 7 days or DAC 20 mg/(m²·day) for 3 days to 4 days, or 20 mg/(m²·day) 1 day/week for 3 weeks/month were assessed for treatment responses and adverse events. RESULTS Of the 158 enrolled MDS patients, 120 and 38 patients were administered reduced-dose DAC and AZA, respectively. All the patients received a median of 2 treatment cycles. The overall response rates (ORR) were 50.0% and 73.3% in the AZA and DAC groups, respectively (P=0.007). The percentage of platelet transfusion dependence in the AZA group was lower than the DAC group (P=0.026). The multivariate analysis demonstrated that the DAC treatment was a significant factor for improved responses (OR 2.928; 95% CI 1.267-6.896; P=0.012), and the absolute neutrophil count (ANC) was a predictor of the ORR (OR 0.725; 95% CI 0.558-0.898; P=0.008). Neutropenia (P=0.016) and infection (P=0.032) incidences were higher in the DAC group. CONCLUSIONS The reduced-dose DAC group demonstrated a better response than the AZA group in MDS patients with different prognostic risks. The patients' pre-treatment ANC was a significant factor associated with the ORR.

OGR1 negatively regulates ß-casein and triglyceride synthesis and cell proliferation via the PI3K/AKT/mTOR signaling pathway in goat mammary epithelial cells.

Goat milk in some cases is less allergenic than cow milk, therefore, more people drink goat milk in the world, so it is necessary for us to improve the yield and quality of goat milk. Previous studies have shown that some genes are closely related to lactation. Ovarian cancer G protein-coupled 1 (OGR1) is a G protein-coupled receptor discovered recently. OGR1 is widely found in various tissues of organisms and is involved in cell skeleton reorganization, carcinogenesis, cell proliferation, and apoptosis by regulating multiple signaling pathways in cells. However, the modulating effect of OGR1 in lactation is still unknown. Therefore, the objective of this study is to investigate the function of OGR1 in goat mammary epithelial cells (GMECs). Flow cytometry, CCK8, EDU, enzyme-linked immunosorbent assay, and triglyceride test kit assays were performed and we found that OGR1 regulated Bcl-2/Bax ratio, Fas protein expression as well as the phosphorylation of AKT and mammalian target of rapamycin (mTOR). si-OGR1 could enhance the proliferation of GMECs by promoting G1/S phase progression and the synthesis of ß-casein and triglyceride. By contrast, OGR1 repressed GMECs proliferation and down-regulated the synthesis of ß-casein and triglyceride by blocking the PI3K/AKT/mTOR signaling pathway in GMECs.

Machine Learning-Driven Models to Predict Prognostic Outcomes in Patients Hospitalized With Heart Failure Using Electronic Health Records: Retrospective Study.

BACKGROUND: With the prevalence of cardiovascular diseases increasing worldwide, early prediction and accurate assessment of heart failure (HF) risk are crucial to meet the clinical demand. OBJECTIVE: Our study objective was to develop machine learning (ML) models based on real-world electronic health records to predict 1-year in-hospital mortality, use of positive inotropic agents, and 1-year all-cause readmission rate. METHODS: For this single-center study, we recruited patients with newly diagnosed HF hospitalized between December 2010 and August 2018 at the First Affiliated Hospital of Dalian Medical University (Liaoning Province, China). The models were constructed for a population set (90:10 split of data set into training and test sets) using 79 variables during the first hospitalization. Logistic regression, support vector machine, artificial neural network, random forest, and extreme gradient boosting models were investigated for outcome predictions. RESULTS: Of the 13,602 patients with HF enrolled in the study, 537 (3.95%) died within 1 year and 2779 patients (20.43%) had a history of use of positive inotropic agents. ML algorithms improved the performance of predictive models for 1-year in-hospital mortality (areas under the curve [AUCs] 0.92-1.00), use of positive inotropic medication (AUCs 0.85-0.96), and 1-year readmission rates (AUCs 0.63-0.96). A decision tree of mortality risk was created and stratified by single variables at levels of high-sensitivity cardiac troponin I (<0.068 µg/L), followed by percentage of lymphocytes (<14.688%) and neutrophil count (4.870×109/L). CONCLUSIONS: ML techniques based on a large scale of clinical variables can improve outcome predictions for patients with HF. The mortality decision tree may contribute to guiding better clinical risk assessment and decision making.

Exploring the mechanism of cisplatin resistance by transcriptome sequencing and reversing the chemoresistance by autophagy inhibition in small cell lung cancer.

Cisplatin plays a key role in treating small cell lung cancer (SCLC); however, the rapid development of cisplatin resistance limits its treatment effect. The detailed mechanisms of cisplatin-resistance, particularly in SCLC, remain unclear. We analyzed the differentially expressed genes (DEGs) between cisplatin-resistant small cell lung cancer cell line H446/CDDP and its parental cell line H446, using the transcriptome sequencing technique. Gene ontology (GO) analysis and the subsequent tests demonstrated that the functions of protein ubiquitination and autophagy are more active in the H446/CDDP cells. Autophagy plays a protective role in the H446/CDDP cells by using the autophagy inhibitors, 3-methyladenine and bafilomycin A1. Moreover, antimalarial drugs that inhibit autophagy by increasing the pH of lysosomes can also enhance cisplatin-induced cell death.

Effects of single or conjoint administration of lactic acid bacteria as potential probiotics on growth, immune response and disease resistance of snakehead fish (Channa argus).

Lactic acid bacteria (LAB) has been documented to promoting growth, enhancing immunity and disease resistance. In this study, we aimed to evaluate the single or conjoint effects of Lactococcus lactis L19 (Genbank: MT102745.1) and Enterococcus faecalis W24 (Genbank: MT102746.1) isolated from the intestine of Channa argus (C. argus) on growth performance, immune response and disease resistance of C. argus. A total of 720 apparently healthy C. argus (9.50 ± 0.03 g) were randomly divided into four equal groups. Fish were fed with a basal diet (CK) supplemented with L. lactis (L19), E. faecalis (W24), and L. lactis L19 + E. faecalis W24 (L + W) at 1.0 × 108 cfu/g basal diet for 56 days. After feeding, the final body weight (FBW), weight gain (WG), feed efficiency ratio (FER), specific growth rate (SGR) and protein efficiency ratio (PER) had significantly increased (p < 0.05), especially with L19. The results indicated that single or conjoint administration of LAB as potential probiotics can induce high levels of IgM, ACP, AKP, LZM, C3 and C4 activity in serum, which may effectively induce humoral immunity, and L19 induce even higher levels. Meanwhile, when compared to CK group, the results of qPCR showed that LAB administration significantly up-regulated (p < 0.05) the expression of IL-1ß, IL-6, IL-10, TNF-α, IFN-γ, HSP70, HSP90, TGF-ß in the spleen, head kidney, gill, liver and intestine of C. argus. After challenge with Aeromonas veronii, the survival rates in all LAB-fed groups were significantly higher (p < 0.05) than that of the CK group, and the L19 group showed the highest (63.3%) disease resistance. Our data indicated that L. lactis L19 and E. faecalis W24, as a feed additive at 1.0 × 108 cfu/g feed, could promote growth performance, enhance immune response and disease resistance of C. argus, with greatest effects in fish fed L. lactis L19 for 56 days. Hence, these LAB additives could be used as promising probiotics for C. argus. L19 was more effective than W24 or the mixture of the two for promoting growth performance, enhancing immune response and disease resistance of C. argus.

Pharmacological and genetic inhibition of fatty acid-binding protein 4 alleviated cisplatin-induced acute kidney injury.

Fatty acid-binding protein 4 (FABP4) has been confirmed to be involved in the pathogenesis of ischaemia/reperfusion- and rhabdomyolysis-induced acute kidney injury (AKI), and targeting inhibition of FABP4 might be a potential strategy for AKI. Cisplatin as a commonly used cancer chemotherapeutic drug possessed a dose-limited side effect of nephrotoxicity. However, whether FABP4 inhibition exerted a favourable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by renal dysfunction and pathological changes, companied by the high expression of FABP4 in tubular epithelial cells. Selective inhibition of FABP4 by BMS309403 at 40 mg/kg/d for 3 days and genetic knockout of FABP4 significantly attenuated the serum creatinine, blood urea nitrogen level and renal tubular damage. Mechanistically, cisplatin injection induced the increased apoptosis and regulated the corresponding protein expression of BCL-2, BCL-XL, BAX, cleaved caspase 3 and caspase 12 in the injured kidney tissues. Cisplatin also triggered multiple signal mediators of endoplasmic reticulum (ER) stress including double-stranded RNA-activated protein kinase-like ER kinase, activating transcription factor-6 and inositol-requiring enzyme-1 pathway, as well as CHOP, GRP78 and p-JNK proteins in the kidneys. Oral administration of BMS309403 significantly reduced the number of renal TUNEL-positive apoptotic cells. Knockout of FABP4 and BMS309403 notably improved ER stress-related apoptotic responses. In summary, pharmacological and genetic inhibition of FABP4 modulated apoptosis via the inactivation of ER stress in the tubular epithelial cells of cisplatin-induced AKI.

Computational identification and analysis of early diagnostic biomarkers for kidney cancer.

Renal cell carcinoma is one of the most common urinary system tumors in adults, it is usually asymptomatic in its early stage and the patients are often diagnosed late. MicroRNA has a higher diagnostic accuracy than traditional markers and may become a new type of early diagnostic biomarker for kidney cancer. Three computational methods and several bioinformatic methods including PPI network, overall survival analysis and enrichment analysis were used to identify the significant differentially expressed miRNAs. Thirteen miRNAs that were significantly differentially expressed in RCC patients were identified, 10 of them have been proved to be associated with kidney cancer in other studies, miR-576, miR-616 and miR-133a-2 are three newly discovered biomarkers of RCC in this study. We found that the target genes of miR-576 (CUL3 and RAC1) are involved in the regulation of multiple cancer-related biological pathways, and the target gene of miR-616 (ASB13 and FBXW2) has been reported to be associated with the development of other cancers. Our findings may have guiding significance for the early diagnosis of renal cell carcinoma.

Label- and modification-free-based in situ selection of bovine serum albumin specific aptamer.

Systematic evolution of ligands by exponential enrichment is a traditional approach to select aptamer, which has a great potential in biosensing field. However, chemical modifications of DNA library or targets before selection might block the real recognition and binding sites between aptamers and their targets. In this study, a label- and modification-free-based in situ selection strategy was developed to overcome this limitation. The strategy is an attempt to screen bovine serum albumin aptamers according to the principle of electrophoretic mobility shift assay, and allowed single-stranded DNA sequence to be fully exposed to interact with bovine serum albumin which was mixed with the agarose gel beforehand. After eight rounds of selection, specific aptamer with low dissociation constant (Kd ) value of 69.44 ± 7.60 nM was selected and used for subsequent establishment of fluorescence biosensor. After optimization, the optimal aptasensor exhibited a high sensitivity toward bovine serum albumin with a limit of detection of 0.24 ng/mL (linear range from 1 to 120 ng/mL). These results indicated that the label- and modification-free-based in situ selection strategy proposed in this work could effectively select specific aptamer to develop aptasensor for sensitive detection of bovine serum albumin or other targets in actual complicated samples.

Enhanced histone H3K9 tri-methylation suppresses steroidogenesis in rat testis chronically exposed to arsenic.

Arsenic poses a profound health risk including male reproductive dysfunction upon prolonged exposure. Histone methylation is an important epigenetic driver; however, its role in arsenic- induced steroidogenic pathogenesis remains obscure. In current study, we investigated the effect of histone H3K9 tri-methylation (H3K9me3) on expression pattern of steroidogenic genes in rat testis after long-term arsenic exposure. Our results revealed that arsenic exposure down-regulated the mRNA expressions of all studied steroidogenic genes (Lhr, Star, P450scc, Hsd3b, Cyp17a1, Hsd17b and Arom). Moreover, arsenic significantly increased the H3K9me3 level in rat testis. The plausible explanation of increased H3K9me3 was attributable to the up-regulation of histone H3K9me3 methyltransferase, Suv39h1 and down-regulation of demethylase, Jmjd2a. Since H3K9me3 activation leads to gene repression, we further investigated whether the down-regulation of steroidogenic genes was ascribed to the increased H3K9me3 level. To elucidate this, we determined the H3K9me3 levels in steroidogenic gene promoters, which also showed significant increase of H3K9me3 in the investigated regions after arsenic exposure. In conclusion, arsenic exposure suppressed the steroidogenic gene expression by activating H3K9me3 status, which contributed to steroidogenic inhibition in rat testis.

Effect of sub-chronic exposure to lead (Pb) and Bacillus subtilis on Carassius auratus gibelio: Bioaccumulation, antioxidant responses and immune responses.

Lead (Pb) poisoning in humans and fish represents a significant global problem. Bacillus subtilis (B. subtilis) is a widely used probiotic in aquaculture. Carassius auratus gibelio (C. gibelio) is one of the most important aquaculture species with great commercial value. The objective of this study was to evaluate the potential of B. subtilis in ameliorating lead-induced toxicity in C. gibelio. The fish were exposed for 60 days to waterborne Pb at 0, 0.05, 0.5 and 1 mg/L and/or dietary B. subtilis at 109 cfu/g. After 30 and 60 days, the fish were sampled and bioaccumulation, antioxidant activity and immune responses were assessed. The results revealed that B. subtilis confers significant protective effects against lead toxicity by preventing alterations in the levels of bioaccumulation, superoxide dismutase, catalase and glutathione. B. subtilis also assists in the recovery of blood δ-aminolevulinic acid dehydratase, lysozyme, and IgM levels while regulating the expression of immune-related genes including IL-10, lysozyme, TNF-α, IgM and Hsp70 after 60 days of lead exposure. Our results suggest that administration of B. subtilis (109 cfu/g) has the potential to combat lead toxicity in C. gibelio.

Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort.

Two common missense variants in APOL1 (G1 and G2) have been definitively linked to CKD in black Americans. However, not all individuals with the renal-risk genotype develop CKD, and little is known about how APOL1 variants drive disease. Given the association of APOL1 with HDL particles, which are cleared by the kidney, differences in the level or quality of mutant APOL1­HDL particles could be causal for disease and might serve as a useful risk stratification marker. We measured plasma levels of G0 (low risk), G1, and G2 APOL1 in 3450 individuals in the Dallas Heart Study using a liquid chromatography-MS method that enabled quantitation of the different variants. Additionally, we characterized native APOL1­HDL from donors with no or two APOL1 risk alleles by size-exclusion chromatography and analysis of immunopurified APOL1­HDL particles. Finally, we identified genetic loci associated with plasma APOL1 levels and tested for APOL1-dependent association with renal function. Although we replicated the previous association between APOL1 variant status and renal function in nondiabetic individuals, levels of circulating APOL1 did not associate with microalbuminuria or GFR. Furthermore, the size or known components of APOL1­HDL did not consistently differ in subjects with the renal-risk genotype. Genetic association studies implicated variants in loci harboring haptoglobin-related protein (HPR), APOL1, and ubiquitin D (UBD) in the regulation of plasma APOL1 levels, but these variants did not associate with renal function. Collectively, these data demonstrate that the risk of renal disease associated with APOL1 is probably not related to circulating levels of the mutant protein.