iEnhance: a multi-scale spatial projection encoding network for enhancing chromatin interaction data resolution.

Although sequencing-based high-throughput chromatin interaction data are widely used to uncover genome-wide three-dimensional chromatin architecture, their sparseness and high signal-noise-ratio greatly restrict the precision of the obtained structural elements. To improve data quality, we here present iEnhance (chromatin interaction data resolution enhancement), a multi-scale spatial projection and encoding network, to predict high-resolution chromatin interaction matrices from low-resolution and noisy input data. Specifically, iEnhance projects the input data into matrix spaces to extract multi-scale global and local feature sets, then hierarchically fused these features by attention mechanism. After that, dense channel encoding and residual channel decoding are used to effectively infer robust chromatin interaction maps. iEnhance outperforms state-of-the-art Hi-C resolution enhancement tools in both visual and quantitative evaluation. Comprehensive analysis shows that unlike other tools, iEnhance can recover both short-range structural elements and long-range interaction patterns precisely. More importantly, iEnhance can be transferred to data enhancement of other tissues or cell lines of unknown resolution. Furthermore, iEnhance performs robustly in enhancement of diverse chromatin interaction data including those from single-cell Hi-C and Micro-C experiments.

Identification of gene biomarkers for brain diseases via multi-network topological semantics extraction and graph convolutional network.

BACKGROUND: Brain diseases pose a significant threat to human health, and various network-based methods have been proposed for identifying gene biomarkers associated with these diseases. However, the brain is a complex system, and extracting topological semantics from different brain networks is necessary yet challenging to identify pathogenic genes for brain diseases. RESULTS: In this study, we present a multi-network representation learning framework called M-GBBD for the identification of gene biomarker in brain diseases. Specifically, we collected multi-omics data to construct eleven networks from different perspectives. M-GBBD extracts the spatial distributions of features from these networks and iteratively optimizes them using Kullback-Leibler divergence to fuse the networks into a common semantic space that represents the gene network for the brain. Subsequently, a graph consisting of both gene and large-scale disease proximity networks learns representations through graph convolution techniques and predicts whether a gene is associated which brain diseases while providing associated scores. Experimental results demonstrate that M-GBBD outperforms several baseline methods. Furthermore, our analysis supported by bioinformatics revealed CAMP as a significantly associated gene with Alzheimer's disease identified by M-GBBD. CONCLUSION: Collectively, M-GBBD provides valuable insights into identifying gene biomarkers for brain diseases and serves as a promising framework for brain networks representation learning.

Comparative efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet for the treatment of vascular calcification in patients with haemodialysis: a systematic review and network meta-analysis.

BACKGROUND: Up to now, there is no unequivocal intervention to mitigate vascular calcification (VC) in patients with hemodialysis. This network meta-analysis aimed to systematically evaluate the clinical efficacy of sodium thiosulfate, bisphosphonates, and cinacalcet in treating vascular calcification. METHODS: A comprehensive study search was performed using PubMed, Web of Science, the Cochrane Library, EMBASE and China National Knowledge Internet (CNKI) to collect randomized controlled trials (RCTs) of sodium thiosulfate, bisphosphonates, and cinacalcet for vascular calcification among hemodialysis patients. Then, network meta-analysis was conducted using Stata 17.0 software. RESULTS: In total, eleven RCTs including 1083 patients were qualified for this meta-analysis. We found that cinacalcet (SMD - 0.59; 95% CI [-0.95, -0.24]) had significant benefit on vascular calcification compared with conventional therapy, while sodium thiosulfate or bisphosphonates did not show such efficiency. Furthermore, as for ranking the efficacy assessment, cinacalcet possessed the highest surface under the cumulative ranking curve (SUCRA) value (88.5%) of lessening vascular calcification and was superior to sodium thiosulfate (50.4%) and bisphosphonates (55.4%). Thus, above results suggested that cinacalcet might be the most promising drug for vascular calcification treatment in hemodialysis patients. Mechanistically, our findings illustrated that cinacalcet reduced serum calcium (SMD - 1.20; 95% CI [-2.08, - 0.33]) and showed the tendency in maintaining the balance of intact Parathyroid Hormone (iPTH) level. CONCLUSIONS: This network meta-analysis indicated that cinacalcet appear to be more effective than sodium thiosulfate and bisphosphonates in mitigating vascular calcification through decreasing serum calcium and iPTH. And cinacalcet might be a reasonable option for hemodialysis patients with VC in clinical practice. SYSTEMATIC REVIEW REGISTRATION: [ http://www.crd.york.ac.uk/PROSPERO ], identifier [CRD42022379965].

Association of Vascular Calcification with Serum lncRNA H19 and Runx2 mRNA Expression in Patients with Uremia.

Background: The objective of this study was to investigate the relationship between vascular calcification, serum lncRNA H19, and Runt-Related Transcription Factor 2 mRNA expression in patients with uremia. Methods: This study is a retrospective study which recruited 146 patients with uremia on dialysis from December 2021 to November 2022. Participants were divided into the VC and non-VC groups based on their chest X-ray calcification ratings. General and clinical data were collected from all patients. Serum H19, Runx2 mRNA, mineral bone disease effectors, and other blood markers were tested. Univariate analysis was performed to compare the changes in each clinical index between these two groups of patients. A multi-factor logistic regression analysis of risk factors for VC was performed. Receiver operating characteristics analyzed the H19 and Runx2 for their diagnostic values for VC. Pearson's test was used to analyze the correlation between the H19 and Runx2 expression and the factors influencing VC. Results: Patients in the VC group had significantly higher creatinine, serum phosphorus, calcium, BMP-2, FGF-23, OPG, and iPTH levels than those in the non-VC group (P < .05), while their albumin levels were significantly lower than those in the non-VC group (P < .05). The expression of H19 and Runx2 mRNA was significantly upregulated in the serum of VC patients (P < .05). H19 was significantly positively correlated with creatinine, serum phosphorus, calcium, BMP-2, OPG, and iPTH (P < .05). Runx2 mRNA was significantly positively correlated with creatinine, FGF-23, and iPTH (P < .05 ), while there was no significant correlation with other factors(P > .05). Albumin, BMP-2, iPTH, H19, and Runx2 were independent correlative-factors of uremic VC. In addition, the combined H19 and Runx2 test (AUC=0.850; 95% CI: 0.781-0.903) had good diagnostic values for the development of VC. Conclusion: Serum H19 and Runx2 levels are significantly associated with VC-related factors and are independent risk factors for uremic VC, and their levels contribute to the diagnosis of uremic VC.

The role of sacubitril/valsartan in abnormal renal function patients combined with heart failure: a meta-analysis and systematic analysis.

AIMS: This study aimed to investigate the efficacy and safety of sacubitril/valsartan in abnormal renal function (eGFR < 60 ml/min/1.73m2) patients combined with heart failure based on randomized controlled trials (RCTs) and observational studies. METHODS: The Embase, PubMed and the Cochrane Library were searched for relevant studies from inception to December 2023. Dichotomous variables were described as event counts with the odds ratio (OR) and 95% confidence interval (CI) values. Continuous variables were expressed as mean standard deviation (SD) with 95% CIs. RESULTS: A total of 6 RCTs and 8 observational studies were included, involving 17335 eGFR below 60 ml/min/1.73m2 patients combined with heart failure. In terms of efficacy, we analyzed the incidence of cardiovascular events and found that sacubitril/valsartan significantly reduced the risk of cardiovascular death or heart failure hospitalization in chronic kidney disease (CKD) stages 3-5 patients with heart failure (OR: 0.65, 95%CI: 0.54-0.78). Moreover, sacubitril/valsartan prevented the serum creatinine elevation (OR: 0.81, 95%CI: 0.68-0.95), the eGFR decline (OR: 0.83, 95% CI: 0.73-0.95) and the development of end-stage renal disease in this population (OR:0.73, 95%CI:0.60-0.89). As for safety outcomes, we did not find that the rate of hyperkalemia (OR:1.31, 95%CI:0.79-2.17) and hypotension (OR:1.57, 95%CI:0.94-2.62) were increased in sacubitril/valsartan group among CKD stages 3-5 patients with heart failure. CONCLUSIONS: Our meta-analysis proves that sacubitril/valsartan has a favorable effect on cardiac function without obvious risk of adverse events in abnormal renal function patients combined with heart failure, indicating that sacubitril/valsartan has the potential to become perspective treatment for these patients.

Relationship between effective blood flow rate and clinical outcomes in maintenance hemodialysis patients: a single-center study.

The association between blood flow rate (BFR) and clinical outcomes in patients undergoing maintenance hemodialysis (MHD) is inconclusive. This retrospective study included 175 patients undergoing MHD treatment between July 2015 and March 2022, divided into two groups based on time-averaged effective blood flow rate (eBFR) median value. We investigated arteriovenous fistula (AVF) outcomes and the association of eBFR with all-cause mortality and new major adverse cardiovascular events (MACE). Mean ± SD and median time-averaged eBFR values were 276 ± 24 and 275 mL/min, respectively. After adjusting for relevant factors including age, sex, vintage, diabetes, CVD, receiving hemodiafiltration (HDF) treatment and spKt/V, Cox models indicated a low time-averaged eBFR (≤ 275 ml/min) was associated with increased risks of all-cause mortality (hazard ratio [HR] 14.18; 95% confidence interval [CI], 3.14-64.1) and new MACE (HR 3.76; 95% CI, 1.91-7.40) in MHD patients. Continuous Cox models demonstrated each 20 ml/min increase in eBFR linked to a 63% decrease in the risk of all-cause mortality (HR: 0.37, 95% CI: 0.23-0.59) and a 38% decrease in the occurrence of new MACE (HR: 0.62, 95% CI: 0.46-0.84). There was no significant difference in AVF outcomes between the two groups. Our study noted higher eBFR (>275 mL/min) is associated with lower risks of both all-cause mortality and new MACE compared with low eBFR (≤275 mL/min). Increased eBFR is not associated with a higher risk of AVF failure.

How does ultrasound-assisted ionic liquid treatment affect protein? A comprehensive review of their potential mechanisms, safety evaluation, and physicochemical and functional properties.

Proteins are essential to human health with enormous food applications. Despite their advantages, plant and animal proteins often exhibit limited molecular flexibility and poor solubility due to hydrogen bonds, hydrophobic interactions, and ionic interactions within their molecular structures. Thus, there is an urgent need to modify the rigid structure of proteins to enhance their stability and functional properties. Ultrasound-assisted ionic liquid (UA-IL) treatment for developing compound modification and producing proteins with excellent functional properties has received interest. However, no review specifically addresses the interactions between UA-ILs and proteins. Hence, this review focused on recent research advancements concerning the effects and potential reaction mechanisms of UA-ILs on the physicochemical properties (including particle size; primary, secondary, and tertiary structure; and surface morphology) as well as the functionality (such as solubility, emulsifying properties, and foaming ability) of proteins. Moreover, the safety evaluation of modified proteins was also discussed from various perspectives, such as acute and chronic toxicity, genotoxicity, cytotoxicity, and environmental and microbial toxicity. This review demonstrated that UA-IL treatment-induced protein structural changes significantly impact the functional characteristics of proteins. This treatment approach efficiently promotes protein structure stretching and spatial rearrangement through cavitation, thermal effects, and ionic interactions. As a result, the functional properties of modified proteins exhibited an obvious enhancement, thereby bringing more opportunities to utilize modified protein products in the food industry. Potential future directions for protein modification using UA-ILs were also proposed.

PDA-PRGCN: identification of Piwi-interacting RNA-disease associations through subgraph projection and residual scaling-based feature augmentation.

BACKGROUND: Emerging evidences show that Piwi-interacting RNAs (piRNAs) play a pivotal role in numerous complex human diseases. Identifying potential piRNA-disease associations (PDAs) is crucial for understanding disease pathogenesis at molecular level. Compared to the biological wet experiments, the computational methods provide a cost-effective strategy. However, few computational methods have been developed so far. RESULTS: Here, we proposed an end-to-end model, referred to as PDA-PRGCN (PDA prediction using subgraph Projection and Residual scaling-based feature augmentation through Graph Convolutional Network). Specifically, starting with the known piRNA-disease associations represented as a graph, we applied subgraph projection to construct piRNA-piRNA and disease-disease subgraphs for the first time, followed by a residual scaling-based feature augmentation algorithm for node initial representation. Then, we adopted graph convolutional network (GCN) to learn and identify potential PDAs as a link prediction task on the constructed heterogeneous graph. Comprehensive experiments, including the performance comparison of individual components in PDA-PRGCN, indicated the significant improvement of integrating subgraph projection, node feature augmentation and dual-loss mechanism into GCN for PDA prediction. Compared with state-of-the-art approaches, PDA-PRGCN gave more accurate and robust predictions. Finally, the case studies further corroborated that PDA-PRGCN can reliably detect PDAs. CONCLUSION: PDA-PRGCN provides a powerful method for PDA prediction, which can also serve as a screening tool for studies of complex diseases.

A comprehensive analysis of copy number variations in diverse apple populations.

BACKGROUND: As an important source of genetic variation, copy number variation (CNV) can alter the dosage of DNA segments, which in turn may affect gene expression level and phenotype. However, our knowledge of CNV in apple is still limited. Here, we obtained high-confidence CNVs and investigated their functional impact based on genome resequencing data of two apple populations, cultivars and wild relatives. RESULTS: In this study, we identified 914,610 CNVs comprising 14,839 CNV regions (CNVRs) from 346 apple accessions, including 289 cultivars and 57 wild relatives. CNVRs summed to 71.19 Mb, accounting for 10.03% of the apple genome. Under the low linkage disequilibrium (LD) with nearby SNPs, they could also accurately reflect the population structure of apple independent of SNPs. Furthermore, A total of 3,621 genes were covered by CNVRs and functionally involved in biological processes such as defense response, reproduction and metabolic processes. In addition, the population differentiation index ([Formula: see text]) analysis between cultivars and wild relatives revealed 127 CN-differentiated genes, which may contribute to trait differences in these two populations. CONCLUSIONS: This study was based on identification of CNVs from 346 diverse apple accessions, which to our knowledge was the largest dataset for CNV analysis in apple. Our work presented the first comprehensive CNV map and provided valuable resources for understanding genomic variations in apple.

KAP1 modulates osteogenic differentiation via the ERK/Runx2 cascade in vascular smooth muscle cells.

BACKGROUND: Osteoblast phenotypic transition in vascular smooth muscle cells (VSMCs) has been unveiled as a common cause of vascular calcification (VC). Krüppel-Associated Box (KRAB)-Associated Protein 1(KAP1) is a transcriptional corepressor that modulates various intracellular pathological processes from gene expression to DNA repair to signal transduction. However, the function and mechanism of KAP1 on the osteoblastic differentiation of VSMCs have not been evaluated yet. METHODS AND RESULTS: We demonstrate that the expression of KAP1 in VSMCs is significantly enhanced in vivo and in vitro calcification models. Downregulating the expression of KAP1 suppresses the osteoblast phenotypic transition of VSMCs, which is indicated by a decrease in the expression of osteoblast marker collagenase type I (COL I) and an increase in the expression of VSMC marker α-smooth muscle actin (α-SMA). Conversely, exogenous overexpression of KAP1 could promote osteoblast phenotypic transition of VSMCs. Moreover, KAP1 upregulated the expression of RUNX family transcription factor 2 (Runx2), an inducer of osteoblast that positively regulates many osteoblast-related genes, such as COL I. Evaluation of the potential mechanism demonstrated that KAP1 promoted osteoblast phenotypic transition of VSMCs by activating the extracellular regulated protein kinases (ERK) signaling pathway, which could activate Runx2. In support of this finding, KAP1-induced cell osteoblast phenotypic transition is abolished by treatment with PD0325901, a specific ERK inhibitor. CONCLUSIONS: The present study suggested that KAP1 participated in the osteoblast differentiation of VSMCs via the ERK/Runx2 cascade and served as a potential diagnostics and therapeutics target for vascular calcification.

The susceptibility of Hyphantria cunea larvae to microbial pesticides Bacillus thuringiensis and Mamestra brassicae nuclear polyhedrosis virus under Cd stress.

Heavy metal pollution is an abiotic factor that can affect the efficiency of pest control. In this study, two microbial pesticides, Bacillus thuringiensis and Mamestra brassicae nuclear polyhedrosis virus (MbNPV), were used to treat Hyphantria cunea larvae with Cd pre-exposure, and the humoral and cellular immunity of H. cunea larvae with Cd exposure were evaluated. The results showed that Cd exposure increased the susceptibility of H. cunea larvae to microbial pesticides B. thuringiensis and MbNPV, and the lethal effect of Cd exposure and microbial pesticides on H. cunea larvae was synergistic. Cd exposure significantly decreased the expression of pathogen recognition genes (GNBP1 and GNBP3), signal transduction genes (Relish, Myd88, Tube, and Imd), and antimicrobial peptide gene (Lebocin) in the humoral immunity of H. cunea larvae compared with the untreated larvae. Parameters of cellular immunity, including the number of hemocytes, phagocytic activity, melanization activity, encapsulation activity, and the expression of three phagocytic regulatory genes (HEM1, GALE1, GALE2), were also found to decrease significantly in Cd-treated larvae. TOPSIS analysis showed that humoral immunity, cellular immunity, and total immunity levels of H. cunea larvae with Cd exposure were weaker than those in untreated larvae. Correlation analysis showed that the mortality of two microbial pesticides investigated in H. cunea larvae was negatively correlated with the humoral and cellular immunity of larvae. Taken togther, Cd exposure results in immunotoxic effects on H. cunea larvae and the use of microbial pesticides are an effective strategy for pest control in heavy metal-polluted areas.

SET8, a novel regulator to ameliorate vascular calcification via activating PI3K/Akt mediated anti-apoptotic effects.

Previous studies have shown that the apoptosis of vascular smooth muscle cells (VSMCs) underlies the mechanism of pathological calcification in patients with chronic kidney disease (CKD). SET domain-containing protein 8 (SET8) is an efficient protein that modulates apoptosis in hepatocellular carcinoma cells, esophageal squamous cells, and neuronal cells by regulating pathological processes, such as cell cycle progression and transcription regulation. However, whether SET8 is involved in high phosphorus-induced vascular calcification by mediating apoptosis remains unclear. Here, we report that SET8 is located both in the nucleus and cytoplasm and is significantly downregulated in calcification models. SET8 deficiency promoted apoptosis of VSMCs, as indicated by the increased Bax/Bcl-2 and cleaved caspase-3/total caspase-3 ratios. Mechanistically, the PI3K/Akt pathway was mediated by SET8, and inhibition of the PI3K/Akt signaling pathway by administering LY294002 or transfecting the Akt phosphorylation-inactivated mutation plasmid increased apoptosis and calcification. Akt phosphorylation constitutively activated mutations can reduce the apoptosis and calcification of VSMCs. Furthermore, exogenous overexpression of SET8 reversed the effect of PI3K/Akt inhibition on VSMC apoptosis and calcification. In summary, our research suggests that SET8 overexpression ameliorates high phosphorus-induced calcification of VSMCs by activating PI3K/Akt mediated anti-apoptotic effects.

Development and validation of a nomogram for prediction of cervical lymph node metastasis in middle and lower thoracic esophageal squamous cell carcinoma.

BACKGROUND: Estimates of cervical lymph node (LN) metastasis in patients with middle and lower thoracic esophageal squamous cell carcinoma (ESCC) are important. A nomogram is a useful tool for individualized prediction. METHODS: A total of 235 patients were enrolled in this study. Univariate and multivariate analyses were performed to screen for independent risk factors and construct a nomogram to predict the risk of cervical LN metastasis. The nomogram performance was assessed by discrimination, calibration, and clinical use. RESULTS: Totally, four independent predictors, including the maximum diameter of tumor, paraesophageal lymph node status, recurrent laryngeal nerve lymph node status, and the CT-reported cervical LN status, were enrolled in the nomogram. The AUC of the nomogram model in the training and validation dataset were 0.833 (95% CI 0.762-0.905), 0.808 (95% CI 0.696-0.920), respectively. The calibration curve demonstrated a strong consistency between nomogram and clinical findings in predicting cervical LN metastasis. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: We developed a nomogram that could be conveniently used to predict the individualized risk of cervical LN metastasis in patients with middle and lower thoracic ESCC.

Benefit of an Internet-Based Management System among Hemodialysis Patients at the Risk of Intradialytic Hypotension and Muscle Cramps: A Controlled before and after Study.

BACKGROUND: The purpose of this study was to observe the impact of an internet-based management system on the incidence of intradialytic hypotension (IDH) and muscle cramps in hemodialysis patients. METHODS: The patients, who underwent maintenance hemodialysis in the center from January 2018 to June 2020, were recruited and divided into the pre-intervention group (before operation of the internet-based hemodialysis management system, from January 2018 to December 2018) and intervention group (after operation of the system, from June 2019 to June 2020). The clinical outcomes were compared between groups. RESULTS: The compound endpoint of >1 IDH or muscle cramps happened in 182 patients (61.7%) in the pre-intervention group and 99 participants (30.8%) in the intervention group (relative risk [RR] = 0.50 [95% confidence interval [CI], 0.42; 0.60]). IDH occurred in 122 patients (1-5 episodes in 47 patients, 6-10 episodes in 25 patients, and >10 episodes in 50 patients) and 33 patients (30 patients had 1-5 episodes and 3 patients had 6-10 episodes) before and after execution of the internet-based management system, respectively (RR = 0.25 [95% CI, 0.18; 0.35]). The incidence of muscle cramps was significantly decreased (RR = 0.57 [95% CI, 0.45; 0.73]) after the implementation of the system, and the number of patients with 6-10 episodes dropped from 10 to 1. Multivariate analyses also showed significantly lower RRs in the intervention group: 0.29 ([95% CI, 0.20; 0.41]) for IDH and 0.58 ([95% CI, 0.45; 0.74]) for muscle cramps. Compared with the pre-intervention, participants in the intervention group had a large improvement in self-management (p < 0.001) and self-efficacy (p < 0.001). CONCLUSION: The study found that the internet-based hemodialysis management system was effective in reducing the IDH and muscle cramp events and improving self-management. It provided a significant implication for the development and application of internet-based programs in hemodialysis management.

The immunotoxicity of Cd exposure to gypsy moth larvae: An integrated analysis of cellular immunity and humoral immunity.

Heavy metal exposure-triggered growth retardation and physiology disorder in phytophagous insects have been widely understood, but only a few studies have investigated its immunomodulatory effects on herbivorous insects. Here, the innate immunity of gypsy moth (Lymantria dispar) larvae under Cd stress was evaluated by integrating cellular and humoral immunity, and the immunomodulation mechanism of Cd stress was further understood by the proteomics analysis of larval hemolymph. Our results showed that the total hemocyte count, as well as phagocytic, encapsulation and bacteriostatic activity, of hemolymph in gypsy moth larvae exposed to Cd stress was significantly lower than that in un-treated larvae. Further proteomic analysis revealed that Cd exposure may reduce the total hemocyte count in larval hemolymph by inducing endoplasmic reticulum pathway-mediated hemocyte apoptosis, thereby causing the collapse of cellular immunity in gypsy moth larvae. In addition, the transcriptional level of signal transduction genes (IMD, Toll, Relish, JAK and STAT) and antimicrobial peptide genes (cecropin and lebocin), as well as the protein abundance of pattern recognition receptors (PGRP and GNBP3) in the Toll, IMD and JAK/STAT signaling pathways was significantly decreased in Cd-treated larvae, clearly implying an immunosuppresive effect of Cd stress on pathogen recognition, signal transduction and effector synthesis of humoral immunity in gypsy moth larvae. Taken together, these results suggest that Cd exposure decreases both cellular immunity and humoral immunity of gypsy moth larvae, and provides a new entry point for systematically and comprehensively unraveling the heavy metal pollutants-caused immunotoxicity.

Cd exposure-triggered susceptibility to Bacillus thuringiensis in Lymantria dispar involves in gut microbiota dysbiosis and hemolymph metabolic disorder.

The immunotoxicity induced by heavy metals on herbivorous insects reflect the alterations of the susceptibility to entomopathogenic agents in herbivorous insects exposed to heavy metal. In the present study, the susceptibility of gypsy moth larvae to Bacillus thuringiensis under Cd treatment at low and high dosages was investigated, and the gut microbiome-hemolymph metabolome responses that affected larval disease susceptibility caused by Cd exposure were examined. Our results showed that mortality of gypsy moth larvae caused by B. thuringiensis was significantly higher in larvae pre-exposed to Cd stress, and there was a synergistic effect between Cd pre-exposure and bacterial infection. Exposure to Cd significantly decreased the abundance of several probiotics (e.g., Serratia for the low Cd dosage and Weissella, Aeroonas, and Serratia for the high Cd dosage) and increased the abundances of several pathogenic bacteria (e.g., Stenotrophomonas, Gardnerella, and Cutibacterium for the low Cd dosage and Pluralibacter and Tsukamurella for the high Cd dosage) compared to the controls. Moreover, metabolomics analysis indicated that amino acid biosynthesis and metabolism were significantly perturbed in larval hemolymph under Cd exposure at both the low and high dosages. Correlation analysis demonstrated that several altered metabolites in larval hemolymph were significantly correlated with changes in the gut microbial community. The results demonstrate that prior exposure to Cd increases the susceptibility of gypsy moth larvae to B. thuringiensis in a synergistic fashion due to gut microbiota dysbiosis and hemolymph metabolic disorder, and thus microbial-based biological control may be the best pest control strategy in heavy metal-polluted areas.

Genome-wide identification, characterization and expression analysis of MATE family genes in apple (Malus × domestica Borkh).

BACKGROUND: As an important group of the multidrug efflux transporter family, the multidrug and toxic compound extrusion (MATE) family has a wide range of functions and is distributed in all kingdoms of living organisms. However, only two MATE genes in apple have been analyzed and genome-wide comprehensive analysis of MATE family is needed. RESULTS: In this study, a total of 66 MATE (MdMATE) candidates encoding putative MATE transporters were identified in the apple genome. These MdMATE genes were classified into four groups by phylogenetic analysis with MATE genes in Arabidopsis. Synteny analysis reveals that whole genome duplication (WGD) and segmental duplication events played a major role in the expansion of MATE gene family in apple. MdMATE genes show diverse expression patterns in different tissues/organs and developmental stages. Analysis of cis-regulatory elements in MdMATE promoter regions indicates that the function of MdMATE genes is mainly related to stress response. Besides, the changes of gene expression levels upon different pathogen infections reveal that MdMATE genes are involved in biotic stress response. CONCLUSIONS: In this work, we systematically identified MdMATE genes in apple genome using a set of bioinformatics approaches. Our comprehensive analysis provided valuable resources for improving disease resistance in apple and further functional characterization of MATE genes in other species.

Nephrotoxicity in patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies: a systematic review and meta-analysis.

Background Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) have dramatically improved cancer therapy for many patients. Adverse kidney effects have been found to be an important complication but have unclear mechanisms. Methods We searched Embase, PubMed, and the Cochrane Library to identify potential eligible studies. All included studies were randomized controlled trials (RCTs) examining patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies (mAbs) and/or chemotherapy. The relative risk (RR) was used to assess the risk of nephrotoxic events. Results We included 27 clinical trials (15,063 patients). Compared with chemotherapy, the RR of all-grade nephritis was significantly increased with anti-PD-1/PD-L1 mAbs (RR = 2.77, 95% CI: 1.09-6.99, P = 0.03). Furthermore, anti-PD-1/PD-L1 mAbs plus chemotherapy can significantly increase the RR of all-grade nephritis (RR = 2.99, 95% CI: 1.07-8.35, P = 0.04). There was also a significant increase in the RRs of all-grade increased blood creatinine (RR = 1.88, 95% CI: 1.24-2.86, P = 0.003) and acute kidney injury (AKI) (RR =3.35, 95% CI: 1.48-7.60, P = 0.004). Conclusions Anti-PD-1/PD-L1 mAbs can significantly increase nephrotoxicity in patients with solid tumors, especially when combined with chemotherapy. During the application of these drugs, we should remain aware of nephrotoxicity for better efficacy. Trial registration number and date of registration Not applicable.

The safety outcomes of sodium-glucose cotransporter 2 inhibitors in patients with different renal function: A systematic review and meta-analysis.

AIMS: We aimed to assess whether the safety outcomes exerted by sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with different renal function at baseline. DATA SYNTHESIS: We searched randomized controlled trials comparing SGLT2 inhibitors with placebo in participants simultaneously involving the entire range of estimated glomerular filtration rate (eGFR) levels at baseline in one study. According to eGFR, we divided the population into two subgroups with eGFR <60 ml/min/1.73 m2 and eGFR≥60 ml/min/1.73 m2. Data from the CANVAS program, CREDENCE, EMPA-REG OUTCOME, DECLARE-TIMI 58, DAPA-HF, and EMPA-REG RENAL were included. SGLT2 inhibitors significantly reduced the risk of all serious adverse events (HR 0.91 [95% CI 0.87 to 0.95], p < 0.001) and acute kidney injury (HR 0.74 [95% CI 0.64 to 0.85], p < 0.001). Except for high risk of genital infection, SGLT2 inhibitors did not increase the risk of amputation, fracture, hyperkalemia, hypoglycemia, volume depletion, or urinary tract infection. Further analyses showed that these safety outcomes were similar between subgroups (p-interaction > 0.05). For osmotic diuresis, SGLT2 inhibitors significantly increased the risk by 75% (p = 0.036), and subgroup analyses showed that this effect was completely attributed to the increase in patients with eGFR ≥60 ml/min/1.73 m2 (p-interaction<0.001). CONCLUSION: The indication of no risk of osmotic diuresis in patients with eGFR<60 ml/min/1.73 m2 and the consistency of other safety outcomes across different baseline renal function may allow additional individuals to safely use SGLT2 inhibitors.

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to alkalinization-induced vascular calcification in vitro.

OBJECTIVE: In order to find new strategies for the prevention of vascular calcification in uremic individuals especially treated by dialysis and develop novel therapeutic targets in vascular calcification, we explore the role of KCa3.1 in alkalinization-induced VSMCs calcification in vitro. METHOD: Rat VSMCs calcification model was established by beta-glycerophosphate (ß-GP, 10 mM) induction. The pH of Dulbecco's modified Eagle's medium (DMEM) was adjusted every 24 h with 10 mM HCl or 10 mM NaHCO3 . The mineralization was measured by Alizarin Red staining and O-cresolphthalein complex one method. mRNA and protein expression were detected by RT-PCR and Western blot or immunofluorescence. Ca2+ influx was measured by Elisa. RESULT: The results indicated that alkalization induced an increase in Ca2+ influx to enhance VSMCs calcification. Furthermore, the increase of calcification was associated with the expression of KCa3.1 via advanced expression of osteoblastic differentiation markers alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2). Blocking KCa3.1 with TRAM-34 or shRNA vector can significantly lowered the effects of calcification in the activity of ALP and Runx2 expression. CONCLUSION: Together all, our studies suggested that alkalinization can promote vascular calcification by upregulating KCa3.1 channel and enhancing osteogenic/chondrogenic differentiation by upregulating Runx2. The specific inhibitor TRAM-34 and KCa3.1-shRNA ameliorated VSMCs calcification by downregulating KCa3.1.