Annexin A1 may contribute to the morphological changes in podocytes by mediating endocytic vesicle fusion and transport via promotion of SNARE assembly in idiopathic membranous nephropathy.

BACKGROUND: Annexin A1 is a membrane-associated calcium-binding protein that participates in the progression of many diseases by facilitating vesicle aggregation. It has been documented that reducing vesicle formation alleviates podocyte injury and albuminuria in idiopathic membranous nephropathy (IMN). However, the role of Annexin A1 (ANXA1) in IMN is unknown. METHODS: Electron microscopy was used to observe the numbers of vesicles in podocytes. The expression of ANXA1 in IMN was investigated by bioinformatics analysis. We validated the hub genes with the Nephroseq V5 online tool and microarray data from the GEO. Immunohistochemical staining and qPCR were performed to measure gene and protein expression. RESULTS: The numbers of vesicles in IMN podocytes were significantly increased. Bioinformatics analysis showed that ANXA1, one of the differentially expressed genes, was upregulated in glomeruli from IMN patients. In the validation database and dataset, we confirmed that ANXA1 expression was upregulated in the glomeruli of IMN patients. We revealed that the increased expression of ANXA1 was negatively correlated with the glomerular filtration rate (GFR) and proteinuria. Moreover, ANXA1 was enriched in the biological process of vesicle fusion, in which the expression of SNAREs and the SNARE complex was increased. Finally, the expression of ANXA1 and genes related to SNAREs and the SNARE complex was upregulated in glomeruli from IMN patients according to immunohistochemical staining and qPCR. CONCLUSION: We conclude that ANXA1 may mediate endocytic vesicle fusion and transport by promoting SNARE assembly, contributing to the morphological changes in podocytes and massive proteinuria in IMN.

Normal-weight visceral obesity promotes a higher 10-year atherosclerotic cardiovascular disease risk in patients with type 2 diabetes mellitus-a multicenter study in China.

BACKGROUND: Visceral obesity is associated with high cardiovascular events risk in type 2 diabetes mellitus (T2DM). Whether normal-weight visceral obesity will pose a higher atherosclerotic cardiovascular disease (ASCVD) risk than body mass index (BMI)-defined overweight or obese counterparts with or without visceral obesity remains unclear. We aimed to explore the relationship between general obesity and visceral obesity and 10-year ASCVD risk in patients with T2DM. METHODS: Patients with T2DM (6997) who satisfied the requirements for inclusion were enrolled. Patients were considered to have normal weight when 18.5 kg/m2 ≤ BMI < 24 kg/m2; overweight when 24 kg/m2 ≤ BMI < 28 kg/m2; and obesity when BMI ≥ 28 kg/m2. Visceral obesity was defined as a visceral fat area (VFA) ≥ 100 cm2. Patients were separated into six groups based on BMI and VFA. The odd ratios (OR) for a high 10-year ASCVD risk for different combinations of BMI and VFA were analysed using stepwise logistic regression. Receiver operating characteristic (ROC) curves for diagnosing the high 10-year ASCVD risk were constructed, and areas under the ROC curves were estimated. Potential non-linear relationships between VFA levels and high 10-year ASCVD risk were examined using restricted cubic splines (knot = 4). Multilinear regression was used to identify factors affecting VFA in patients with T2DM. RESULTS: In patients with T2DM, subjects with normal-weight visceral obesity had the highest 10-year ASCVD risk among the six groups, which had more than a 2-fold or 3-fold higher OR than those who were overweight or obese according to BMI but did not have visceral obesity (all P < 0.05). The VFA threshold for high 10-year ASCVD risk was 90 cm2. Multilinear regression showed significant differences in the effect of age, hypertension, drinking, fasting serum insulin, fasting plasma glucose, 2 h postprandial C-peptide, triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol on VFA in patients with T2DM (all P < 0.05). CONCLUSIONS: T2DM patients with normal-weight visceral obesity had a higher 10-year ASCVD risk than BMI-defined overweight or obese counterparts with or without visceral obesity, which should initiate standardised management for ASCVD primary prevention.

APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis.

Idiopathic membranous nephropathy (IMN) belongs to an important pathogenic category of adult nephrotic syndrome. PLA2R1 exposure is critical for triggering the pathogenesis of PLA2R1-related IMN. However, the pathogenesis of IMN and the molecular mechanism of treatment remain to be further clarified. The expression changes of activated protein C (APC) and PLA2R1 in IMN patients were quantified by qPCR. A zymosan activated serum (ZAS)-induced IMN podocyte model was established in vitro. Podocyte apoptosis was detected via flow cytometry and caspase­3 assay. The expression levels of APC, p-ERK1/2, ERK1/2, YB-1 and PLA2R1 were detected by western blotting. The regulation relationship between YB-1 and PLA2R1 was detected by dual fluorescent reporter system. In IMN patients, the expression level of PLA2R1 was increased, whereas the expression level of APC was decreased. When APC was added to podocytes in vitro, the phosphorylation of ERK1/2 was increased, which could promote the translocation of YB-1 to the nucleus that reduces the expression of PLA2R1 at the cellular transcriptional level, thereby inhibiting podocyte apoptosis. Our study is the first to report that APC can improve membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis. This study will provide a new targeted therapy for IMN patients with high PLA2R1 expression.

Roles of interferon regulatory factor 4 in the AKI-CKD transition, glomerular diseases and kidney allograft rejection.

Interferon regulatory factor 4 (IRF4) is expressed in immune cells and is a member of the interferon regulatory factor family. Recently, it has been found that IRF4 plays important roles in the acute kidney injury (AKI)-chronic kidney disease (CKD) transition, glomerular diseases and kidney allograft rejection. In particular, the relationship between IRF4 and the AKI-CKD transition has attracted widespread attention. Furthermore, it was also found that the deficiency of IRF4 hindered the transition from AKI to CKD through the suppression of macrophage-to-fibroblast conversion, inhibition of M1-M2 macrophage polarization, and reduction in neutrophil inward flow. Additionally, an examination of the crucial role of IRF4 in glomerular disease was conducted. It was reported that inhibiting IRF4 could alleviate the progression of glomerular disease, and potential physiopathology mechanisms associated with IRF4 were postulated. Lastly, IRF4 was found to have detrimental effects on the development of antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR).

Kruppel Like Factor 5 Enhances High Glucose-Induced Renal Tubular Epithelial Cell Transdifferentiation in Diabetic Nephropathy.

Background - Diabetic nephropathy (DN) is a principal reason for kidney disease worldwide. High glucose (HG) is a major factor for DN. Kruppel like factor 5 (KLF5) participates in DN development. In the present study, we aim to elaborate the role of KLF5 in HG-induced renal tubular epithelial cell (RTEC) transdifferentiation in DN. Methods - RTECs (HK-2 cells) were treated with HG and were transfected with si-KLF5 or oe-HMGB1. Afterwards, expression of KLF5 and HMGB1 was detected, HK cell viability was determined, and levels of alpha-smooth muscle actin (α-SMA), E-cadherin, vimentin, and transforming growth factor beta 1 (TGF-ß1) were assessed. Additionally, the binding relation between KLF5 and HMGB1 was analyzed. Results - In HK-2 cells with HG treatment, expression of KLF5 and HMGB1 was upregulated; levels of α-SMA, vimentin, and TGF-ß1 were increased; and E-cadherin level was decreased. Moreover, KLF5 silencing resulted in down-regulated levels of α-SMA, vimentin, and TGF-ß1 but upregulated level of E-cadherin. On the other hand, KLF5 could bind to the HMGB1 promoter and activate HMGB1 transcription. HMGB1 overexpression partially counteracted the inhibitive effect of KLF5 silencing on HG-induced HK-2 transdifferentiation. Conclusion - HG induced overexpressed KLF5 in RTECs, and as a transcription factor, KLF5 could bind to the HMGB1 promoter, thereby promoting HMGB1 transcription and RTEC transdifferentiation.

LncRNA Dlx6os1 Accelerates Diabetic Nephropathy Progression by Epigenetically Repressing SOX6 via Recruiting EZH2.

INTRODUCTION: Diabetic nephropathy (DN) is the leading cause of kidney failure worldwide. To explore the pathogenesis and effective biological target of DN is beneficial to seeking novel treatment strategies. OBJECTIVE: This study aimed to investigate the role of the lncRNA Dlx6os1/SOX6/EZH2 axis in DN progression. METHODS: PAS staining was performed to evaluate extracellular matrix accumulation; ELISA was carried out to assess the levels of urine microalbumin and blood glucose concentration; RT-qPCR was carried out to detect the levels of lncRNA Dlx6os1, TNF-α, IL-1ß, IL-6, SOX6, and EZH2. Western blot was performed to assess the levels of Col-IV, FN, TGF-ß1, and SOX6 proteins. RIP assay was carried out to verify the interaction between lncRNA Dlx6os1 and EZH2. ChIP-qPCR was conducted to verify the interaction between EZH2 and SOX6 promoter. RESULTS: Our results illustrated that lncRNA Dlx6os1 was highly expressed in DN mice and HG-induced SV40 MES13 cells. LncRNA Dlx6os1 knockdown inhibited HG-induced SV40 MES13 cell proliferation, fibrosis, and inflammatory cytokine release. LncRNA Dlx6os1 inhibited SOX6 expression by recruiting EZH2 in HG-SV40 MES13 cells, and SOX6 mediated the effects of lncRNA Dlx6os1 on proliferation, fibrosis, and inflammatory factor release of HG-induced SV40 MES13 cells. CONCLUSION: LncRNA Dlx6os1 accelerates the progression of DN by epigenetically repressing SOX6 via recruiting EZH2.

VEGFA promotes the occurrence of PLA2R-associated idiopathic membranous nephropathy by angiogenesis via the PI3K/AKT signalling pathway.

BACKGROUND: The M-type phospholipase A2 receptor (PLA2R)-associated idiopathic membranous nephropathy (IMN) is a common immune-related disease in adults. Vascular endothelial growth factor A (VEGFA) is the key mediator of angiogenesis, which leads to numerous kidney diseases. However, the role of VEGFA in IMN is poorly understood. METHODS: In the present study, we downloaded the microarray data GSE115857 from Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) were identified with R software. The cytoHubba plug-in were used to identify hub genes from the protein-protein interaction network. Gene set enrichment analysis (GSEA) was used to identify signalling pathway in IMN. CCK8 was performed to assess the cell viability in human vascular endothelial cells (HVECs). Then, passive Heymann nephritis (PHN) was induced in rats by a single tail vein injection of anti-Fx1A antiserum. Animals treated with VEGFA inhibitor bevacizumab (BV), with saline as a positive control. Proteinuria was evaluated by biochemical measurements. Immunohistochemistry and immunofluorescence was used to evaluate relative proteins expression. Electron microscopy was performed to observe the thickness of the glomerular basement membrane (GBM). RESULTS: We revealed 3 hub genes, including one up-regulated gene VEGFA and two down-regulated genes JUN and FOS, which are closely related to the development of PLA2R-associated IMN. Pathway enrichment analysis found that the biological process induced by VEGFA is associated with PI3K/Akt signalling. GSEA showed that the signalling pathway of DEGs in GSE115857 was focused on angiogenesis, in which VEGFA acts as a core gene. We confirmed the high expression of VEGFA, PI3K, and AKT in IMN renal biopsy samples with immunohistochemistry. In HVECs, we found that BV suppresses cell viability in a time and dose dependent manner. In vivo, we found low dose of BV attenuates proteinuria via inhibiting VEGFA/PI3K/AKT signalling. Meanwhile, low dose of BV alleviates the thickening of the GBM. CONCLUSION: VEGFA/PI3K/AKT signalling may play significant roles in the pathogenesis of IMN, which may provide new targets for the treatment of IMN.

Long Non-Coding RNA (LncRNA) CASC15 Is Upregulated in Diabetes-Induced Chronic Renal Failure and Regulates Podocyte Apoptosis.

BACKGROUND CASC15 has been recently characterized as an oncogenic lncRNA. This study aimed to investigate the role of CASC15 in diabetic patients complicated with chronic renal failure (DCRF). MATERIAL AND METHODS Levels of CASC15 in plasma derived from 3 groups of participants were measured by qPCR and compared by ANOVA and Tukey test. The interaction between CASC15 and miR-34c was analyzed by performing cell transfections. Cell apoptosis assay was performed to analyze the effects of transfections on the apoptosis of CIHP-1 cells (podocytes). RESULTS We found that CASC15 in plasma was upregulated in DCRF compared with diabetic patients (no obvious complications) and healthy controls. Upregulation of CASC15 distinguished DCRF patients from healthy controls and diabetic patients. High D-glucose environment induced the upregulation of CASC15 in cells of the human podocyte cell line CIHP-1. Overexpression of CASC15 did not affect miR-34c in CIHP-1 cells, but bioinformatics analysis showed that CASC15 can sponge miR-34c. Overexpression of CASC15 led to an increased apoptotic rate of CIHP-1 cells, and miR-34c overexpression led to a decreased apoptotic rate of CIHP-1 cells. In addition, CASC15 overexpression attenuated the effects of miR-34c overexpression on cell apoptosis. CONCLUSIONS Therefore, CASC15 is upregulated in DCRF patients and promotes the apoptosis of podocytes by sponging miR-34c. Our study adds to our understanding of the pathogenesis of DCRF and suggests that CASC15 could serve as a potential therapeutic target of DCRF.

Factors Associated with a Large Decline in Renal Function or Progression to Renal Insufficiency in Hospitalized Atrial Fibrillation Patients with Early-Stage CKD.

Clinicians must consider renal function when administering anticoagulants for atrial fibrillation (AF). Determination of risk factors for renal function decline may enable identification of patients who require closer monitoring. We investigated the characteristics associated with renal function decline in patients with AF. The study cohort consisted of 631 AF patients who had at least one readmission during the follow-up period and stages 1-3 chronic kidney disease (CKD). The primary outcome measure was large renal function decline (≥30% decrease from baseline estimated glomerular filtration rate [eGFR]). The secondary outcome measure was a final eGFR < 60 mL/minute/1.73 m2 for those with a baseline eGFR above this level. The mean eGFR was 74.4 ± 18.5 mL/minute/1.73 m2, and the mean follow-up time was 30.2 ± 13.2 months. The primary outcome occurred in 155 patients (24.6%) and was associated with congestive heart failure (CHF), proteinuria, type of AF, and left atrial diameter (LAD) ≥ 45 mm. Among 478 patients with a baseline eGFR ≥ 60 mL/minute/1.73 m2, 137 (28.7%) progressed to renal failure (eGFR < 60 mL/minute/1.73 m2). A decreasing eGFR was associated with age ≥ 75 years, CHF, lower baseline eGFR, and LAD ≥ 45 mm. CHF, proteinuria, type of AF, and LAD ≥ 45 mm were associated with eGFR decline ≥ 30% in AF patients with CKD stages 1-3. Advanced age, CHF, lower baseline eGFR, and LAD ≥ 45 mm were associated with progression to renal insufficiency. These results should be considered when identifying patients who require more frequent monitoring of eGFR.

The Role of Y-Box Binding Protein 1 in Kidney Injury: Friend or Foe?

Y-box-binding protein 1 (YB-1) is a multifunctional protein involved in various cellular processes via the transcriptional and translational regulation of target gene expression. YB-1 promotes acute or chronic kidney injury through multiple molecular pathways; however, accumulating evidence suggests that significantly increased YB-1 levels are of great importance in renoprotection. In addition, YB-1 may contribute to obesity-related kidney disease by promoting adipogenesis. Thus, the role of YB-1 in kidney injury is complicated, and no comprehensive review is currently available. In this review, we summarise recent progress in our understanding of the function of YB-1 in kidney injury and provide an overview of the dual role of YB-1 in kidney disease. Moreover, we propose that YB-1 is a potential therapeutic target to restrict kidney disease.

Hypothalamic-Pituitary-Gonadal Axis in Aging Men and Women: Increasing Total Testosterone in Aging Men.

BACKGROUND: Aging is associated with variations in hypothalamic-pituitary-gonadal (HPG) axis hormones. However, it is not clear how aging changes these hormones. This study examined the natural alterations in the HPG axis in aging men and women in China. METHODS: Data were obtained from our cross-sectional study (SPECT-China) in 16 areas of three provinces in East China between February and June 2014. There were 6,825 subjects selected, including 2,908 men and 3,917 women aged 25-93 years who had no diseases affecting HPG hormones and did not take exogenous supplements. Total testosterone (TT), estradiol (E2), free testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured. RESULTS: In men, the ranges of the 10-90th percentiles for each hormone were as follows: TT, 9.9-23.4 nmol/l; SHBG, 20.6-79.54 nmol/l; E2, 34.84-187 pmol/l. TT values were higher in men aged 25-30 years than in those aged 31-35 years and began to increase progressively at the age of 41-50 years until men reached their eighties. The unadjusted annual age trend (ß) was 0.079 nmol/l/year (p < 0.001). A linear regression analysis, after full adjustment for demographic variables, metabolic factors, other hormones, lifestyle and co-morbidities, showed that higher TT levels were still associated with aging (p < 0.05). However, the ratio of TT to LH decreased with age (ß = -0.272/year, p < 0.001). E2 and SHBG increased with age (ß = 1.774 pmol/l/year and 1.118 nmol/l/year, respectively, p < 0.001). In women, the 10-90th percentile range of E2 was 32.79-565.8 pmol/l. E2 began to decrease at the age of 46-50 years, declined sharply at the age of 51-55 years (ß = -5.73 pmol/l/year, p < 0.001) and then stabilized at a low concentration after the age of 55 years. The 10-90th percentile ranges of LH and FSH in men were 2.4-9.2 and 3.4-15.5 IU/l, and in women they were 3-36.6 and 4-89.28 IU/l, respectively. FSH increased by 7.11% per annum in men and by 12.76% per annum in women, but LH increased by only approximately 4.00% per annum in both sexes. CONCLUSIONS: The influence of aging on the HPG axis is sex dependent. The pattern of age-related TT was different in Chinese Han men when compared with previous studies in Western populations. TT values increased in aging men, so it is not suitable to estimate the life quality of older Chinese men just based on TT.

Investigation of vitamin D status and its correlation with insulin resistance in a Chinese population.

OBJECTIVE: Although many studies worldwide have focused on the relationship between vitamin D and insulin resistance, results remain controversial. Furthermore, concentrations of serum 25-hydroxyvitamin D (25(OH)D) in the Chinese population are unclear. We aimed to investigate vitamin D status and its correlation with insulin resistance among a Chinese adult population. DESIGN: Serum 25(OH)D, fasting blood glucose, fasting insulin, glycated Hb (HbA1c) and other metabolic parameters were assessed. Neck circumference, waist circumference, hip circumference, weight and height were also measured. Lifestyle factors including smoking and drinking status were obtained. Diabetes mellitus was diagnosed by HbA1c according to the 2010 American Diabetes Association criteria. SETTING: Eastern China. SUBJECTS: Of 7200 residents included, 6597 individuals were ultimately analysed. RESULTS: We enrolled 2813 males (mean age 52·7 (sd 13·5) years) and 3784 females (52·3 (sd 13·5) years); mean serum 25(OH)D concentration was 43·1 (sd 11·6) and 39·6 (sd 9·8) nmol/l, respectively. Additionally, 83·3 % of participants were 25(OH)D deficient. A significant difference in 25(OH)D was observed between males and females in winter and spring (P<0·001). Furthermore, 25(OH)D concentrations were inversely associated with the homeostasis model assessment of insulin resistance (HOMA-IR) in the overweight and pre-diabetic populations. After adjusting for several variables, 25(OH)D was significantly associated with HOMA-IR in winter. When 25(OH)D values were categorized into quartiles, HOMA-IR was significantly associated with decreasing 25(OH)D. CONCLUSIONS: The majority of the Chinese population was vitamin D deficient and this deficiency was negatively associated with insulin resistance, particularly in the overweight and pre-diabetic populations. Moreover, these associations might be more evident in the winter.

The progress of inflammation and oxidative stress in patients with chronic kidney disease.

BACKGROUND: The variations and their correlation of inflammation and oxidative stress in chronic kidney disease (CKD) have not been thoroughly understood. MATERIALS AND METHODS: Biomarkers of inflammation and oxidative stress were measured in a cohort of 176 patients with CKD ranging from stage 1 to 5 and 67 healthy controls. Correlation analysis in levels between inflammation and oxidative stress was also performed with estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula. Concentrations of serum creatinine (Scr), hs-CRP (hypersensitive C reactive protein) and MDA (malondialdehyde) of these participants were measured again after 12 month follow-up. RESULTS: In the present study, with the development of CKD, serum levels of hs-CRP, interleukin-6 (IL-6) and MDA were significantly increased, and the serum levels of SOD (superoxide dismutase) and GSH-PX (glutathione peroxidase) were significantly decreased in these participants. eGFR was inversely associated with MDA and positively with SOD and GSH-PX when adjusting for age and hypertension therapy. IL-6 and hs-CRP were positively correlated with MDA, and negatively associated with SOD and GSH-PX. Notably, after 12-month follow-up, the increase in Scr was positively associated with the increase in hs-CRP (p < 0.01) and MDA (p < 0.05), respectively. CONCLUSIONS: Inflammation and oxidative stress interacted with each other and played pivotal roles in the development of CKD. Variation in eGFR was parallel with the changes of oxidative stress and inflammation when CKD developing.

The relationship between deiodinase activity and inflammatory responses under the stimulation of uremic toxins.

BACKGROUND: It is unclear to what extent uremic toxins participate in inflammatory responses and the activities of deiodinases, as well as the effects of deiodinases on inflammatory cytokines. MATERIALS AND METHODS: Hepatocellular carcinoma cell lines (HepG2) were transfected with small interfering ribonucleic acid (siRNA) specific for deiodinase type 1 (DIO1) and cultured with or without uremic toxins. The mRNA expression of DIO1, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α was detected by quantitative real-time PCR. The presence of selenoprotein M (SelM) and DIO1 was assessed by western blotting. Sonicate deiodinase activities in HepG2 cells were measured by a dithiothreitol-stimulated assay. The NF-κB, AP-1 and CREB-1 inflammatory signal pathways were confirmed by EMSA. RESULTS: After culturing for 24 h, the mRNA expression of DIO1 was significantly decreased by the specific siRNA (reduced by 76%, P = 0.0002). Uremic toxins significantly increased the mRNA expression (P < 0.01) of IL-1ß, IL-6 and TNF-α and inhibited DIO1 mRNA expression (P < 0.01) compared with controls. Suppression of DIO1 by siRNA significantly decreased the mRNA expression of IL-1ß and IL-6 (P < 0.05) but not TNF-α (P = 0.093). Uremic toxins and specific siRNA synchronously reduced the protein expression of SelM and DIO1. CONCLUSIONS: Uremic toxins activate the expression of inflammatory cytokines. The major findings of this study indicate that the uremic toxins, more than inflammatory cytokines, play direct inhibitory roles in DIO1 enzyme activity, which then provides a negative feedback to the growing accumulation of inflammatory cytokines.

Hot bath for the treatment of chronic renal failure.

BACKGROUND: Dialysis and its complications were debated recently. There was lack of an adjuvant renal replacement method to reduce the complications of patients with chronic renal failure and dialysis itself. MATERIALS AND METHODS: In this article, we reviewed the role of thermal sweating in treating of the patients with chronic renal failure, and the role of traditional Chinese medicine in the therapy of chronic kidney diseases. RESULTS: Thermal sweating can reduce interdialytic weight gain and improve the patients' blood pressure; Chinese herbal medicine can promote the excretion of uremic toxicities and relieve the skin disorders of these patients. CONCLUSIONS: Traditional Chinese medicine-mediated hot bath could be one of the adjuvant renal replacement methods.

Adaptive selection of local and non-local attention mechanisms for speech enhancement.

In speech enhancement tasks, local and non-local attention mechanisms have been significantly improved and well studied. However, a natural speech signal contains many dynamic and fast-changing acoustic features, and focusing on one type of attention mechanism (local or non-local) cannot precisely capture the most discriminative information for estimating target speech from background interference. To address this issue, we introduce an adaptive selection network to dynamically select an appropriate route that determines whether to use the attention mechanisms and which to use for the task. We train the adaptive selection network using reinforcement learning with a developed difficulty-adjusted reward that is related to the performance, complexity, and difficulty of target speech estimation from the noisy mixtures. Consequently, we propose an Attention Selection Speech Enhancement Network (ASSENet) with the innovative dynamic block that consists of an adaptive selection network and a local and non-local attention based speech enhancement network. In particular, the ASSENet incorporates both local and non-local attention and develops the attention mechanism selection technique to explore the appropriate route of local and non-local attention mechanisms for speech enhancement tasks. The results show that our method achieves comparable and superior performance to existing approaches with attractive computational costs.

A novel link between melatonin and circ_0005753/PTBP1/TXNIP regulatory network in the modulation of osteogenic potential in mesenchymal stem cells.

Labeled with pluripotent potential, the transplantation of bone marrow mesenchymal stem cells (BMSCs) is considered as a promising strategy for treating osteoporosis (OP). Melatonin (MEL) has been investigated to be an essential regulator involved in bone metabolism, as well as BMSCs differentiation. Circular RNAs (circRNAs) are a unique kind of non-coding RNA and play an important regulatory role in OP. However, whether circRNAs are implicated in the effects of MEL on BMSCs osteogenic differentiation remains largely indeterminate. Expression of circ_0005753 in human BMSCs with MEL treatment, clinical specimens diagnosed with OP, either with ovariectomy (OVX)-induced mice, was measured by RT-qPCR. Western blot was conducted to analyze protein levels of osteogenesis-related molecules (Opg, RUNX2, ALP, BMP4) and TXNIP. RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to validate the binding relationship among circ_0005753, PTBP1, and TXNIP. Alkaline phosphatase (ALP) and alizarin red staining (ARS) were performed to evaluate osteogenic capacity of BMSCs. OP mouse model was established by ovariectomy, as evaluated pathologic changes via hematoxylin-eosin (HE), Masson, and Immunohistochemistry (IHC) staining. Expression of circ_0005753 was remarkably decreased during MEL-induced osteogenic differentiation of BMSCs. Interestingly, not only circ_0005753 knockdown significantly promoted osteogenic differentiation of BMSCs, but circ_0005753 overexpression also weakened osteogenic differentiation induced by MEL treatment. Mechanistically, circ_0005753 maintained the stabilization of TXNIP mRNA via recruiting PTBP1. Additionally, reinforced circ_0005753 abrogated MEL-mediated protective effects on OP pathogenesis in a mouse model. This work shows that MEL facilitates osteogenic differentiation of BMSCs via the circ_0005753/PTBP1/TXNIP axis, which may shed light on the development of a novel therapeutic strategy to prevent OP.

V2IED: Dual-view learning framework for detecting events of interictal epileptiform discharges.

Interictal epileptiform discharges (IED) as large intermittent electrophysiological events are associated with various severe brain disorders. Automated IED detection has long been a challenging task, and mainstream methods largely focus on singling out IEDs from backgrounds from the perspective of waveform, leaving normal sharp transients/artifacts with similar waveforms almost unattended. An open issue still remains to accurately detect IED events that directly reflect the abnormalities in brain electrophysiological activities, minimizing the interference from irrelevant sharp transients with similar waveforms only. This study then proposes a dual-view learning framework (namely V2IED) to detect IED events from multi-channel EEG via aggregating features from the two phases: (1) Morphological Feature Learning: directly treating the EEG as a sequence with multiple channels, a 1D-CNN (Convolutional Neural Network) is applied to explicitly learning the deep morphological features; and (2) Spatial Feature Learning: viewing the EEG as a 3D tensor embedding channel topology, a CNN captures the spatial features at each sampling point followed by an LSTM (Long Short-Term Memories) to learn the evolution of these features. Experimental results from a public EEG dataset against the state-of-the-art counterparts indicate that: (1) compared with the existing optimal models, V2IED achieves a larger area under the receiver operating characteristic (ROC) curve in detecting IEDs from normal sharp transients with a 5.25% improvement in accuracy; (2) the introduction of spatial features improves performance by 2.4% in accuracy; and (3) V2IED also performs excellently in distinguishing IEDs from background signals especially benign variants.

Vitamin K supplementation and vascular calcification: a systematic review and meta-analysis of randomized controlled trials.

Background: Vascular calcification (VC) is a complex process that has been linked to conditions including cardiovascular diseases and chronic kidney disease. There is an ongoing debate about whether vitamin K (VK) can effectively prevent VC. To assess the efficiency and safety of VK supplementation in the therapies of VC, we performed a systematic review and meta-analysis of recent studies. Methods: We searched major databases, including PubMed, the Cochrane Library, Embase databases, and Web of Science up until August 2022. 14 randomized controlled trials (RCTs) describing the outcomes of treatment for VK supplementation with VC have been included out of 332 studies. The results were reported in the change of coronary artery calcification (CAC) scores, other artery and valve calcification, vascular stiffness, and dephospho-uncarboxylated matrix Gla protein (dp-ucMGP). The reports of severe adverse events were recorded and analyzed. Results: We reviewed 14 RCTs, comprising a total of 1,533 patients. Our analysis revealed that VK supplementation has a significant effect on CAC scores, slowing down the progression of CAC [I2 = 34%, MD= -17.37, 95% CI (-34.18, -0.56), p = 0.04]. The study found that VK supplementation had a significant impact on dp-ucMGP levels, as compared to the control group, where those receiving VK supplementation had lower values [I2 = 71%, MD = -243.31, 95% CI (-366.08, -120.53), p = 0.0001]. Additionally, there was no significant difference in the adverse events between the groups [I2 = 31%, RR = 0.92, 95% CI (-0.79,1.07), p = 0.29]. Conclusion: VK may have therapeutic potential for alleviating VC, especially CAC. However, more rigorously designed RCTs are required to verify the benefits and efficacy of VK therapy in VC.

LncRNA SNHG1 knockdown inhibits hyperglycemia induced ferroptosis via miR-16-5p/ACSL4 axis to alleviate diabetic nephropathy.

BACKGROUND: Hyperglycemia accelerates the development of diabetic nephropathy (DN) by inducing renal tubular injury. Nevertheless, the mechanism has not been elaborated fully. Here, the pathogenesis of DN was investigated to seek novel treatment strategies. METHODS: A model of diabetic nephropathy was established in vivo, the levels of blood glucose, urine albumin creatinine ratio (ACR), creatinine, blood urea nitrogen (BUN), malondialdehyde (MDA), glutathione (GSH), and iron were measured. The expression levels were detected by qRT-PCR and Western blotting. H&E, Masson, and PAS staining were used to assess kidney tissue injury. The mitochondria morphology was observed by transmission electron microscopy (TEM). The molecular interaction was analyzed using a dual luciferase reporter assay. RESULTS: SNHG1 and ACSL4 were increased in kidney tissues of DN mice, but miR-16-5p was decreased. Ferrostatin-1 treatment or SNHG1 knockdown inhibited ferroptosis in high glucose (HG)-treated HK-2 cells and in db/db mice. Subsequently, miR-16-5p was confirmed to be a target for SNHG1, and directly targeted to ACSL4. Overexpression of ACSL4 greatly reversed the protective roles of SNHG1 knockdown in HG-induced ferroptosis of HK-2 cells. CONCLUSIONS: SNHG1 knockdown inhibited ferroptosis via the miR-16-5p/ACSL4 axis to alleviate diabetic nephropathy, which provided some new insights for the novel treatment of diabetic nephropathy.