Understanding Defects in Perovskite Solar Cells through Computation: Current Knowledge and Future Challenge.

Lead halide perovskites with superior optoelectrical properties are emerging as a class of excellent materials for applications in solar cells and light-emitting devices. However, perovskite films often exhibit abundant intrinsic defects, which can limit the efficiency of perovskite-based optoelectronic devices by acting as carrier recombination centers. Thus, an understanding of defect chemistry in lead halide perovskites assumes a prominent role in further advancing the exploitation of perovskites, which, to a large extent, is performed by relying on first-principles calculations. However, the complex defect structure, strong anharmonicity, and soft lattice of lead halide perovskites pose challenges to defect studies. In this perspective, on the basis of briefly reviewing the current knowledge concerning computational studies on defects, this work concentrates on addressing the unsolved problems and proposing possible research directions in future. This perspective particularly emphasizes the indispensability of developing advanced approaches for deeply understanding the nature of defects and conducting data-driven defect research for designing reasonable strategies to further improve the performance of perovskite applications. Finally, this work highlights that theoretical studies should pay more attention to establishing close and clear links with experimental investigations to provide useful insights to the scientific and industrial communities.

Biomimetic Hydrogels Promote Pseudoislet Formation to Improve Glycemic Control in Diabetic Mice.

Islet or ß-cell transplantation is currently considered to be the ideal treatment for diabetes, and three-dimensional (3D) bioprinting of a bionic pancreas with physiological stiffness is considered to be promising for the encapsulation and transplantation of ß-cells. In this study, a 5%GelMA/2%AlgMA hybrid hydrogel with pancreatic physiological stiffness was constructed and used for ß-cell encapsulation, 3D bioprinting, and in vivo transplantation to evaluate glycemic control in diabetic mice. The hybrid hydrogel had good cytocompatibility and could induce insulin-producing cells (IPCs) to form pseudoislet structures and improve insulin secretion. Furthermore, we validated the importance of betacellulin (BTC) in IPCs differentiation and confirmed that IPCs self-regulation was achieved by altering the nuclear and cytoplasmic distributions of BTC expression. In vivo transplantation of diabetic mice quickly restored blood glucose levels. In the future, 3D bioprinting of ß-cells using biomimetic hydrogels will provide a promising platform for clinical islet transplantation for the treatment of diabetes.

Single-Cell Transcriptome Analysis Identified Core Genes and Transcription Factors in Mesenchymal Cell Differentiation during Liver Cirrhosis.

BACKGROUND: Mesenchymal cells, including hepatic stellate cells (HSCs), fibroblasts (FBs), myofibroblasts (MFBs), and vascular smooth muscle cells (VSMCs), are the main cells that affect liver fibrosis and play crucial roles in maintaining tissue homeostasis. The dynamic evolution of mesenchymal cells is very important but remains to be explored for researching the reversible mechanism of hepatic fibrosis and its evolution mechanism of hepatic fibrosis to cirrhosis. METHODS: Here, we analysed the transcriptomes of more than 50,000 human single cells from three cirrhotic and three healthy liver tissue samples and the mouse hepatic mesenchymal cells of two healthy and two fibrotic livers to reconstruct the evolutionary trajectory of hepatic mesenchymal cells from a healthy to a cirrhotic state, and a subsequent integrative analysis of bulk RNA sequencing (RNA-seq) data of HSCs from quiescent to active (using transforming growth factor ß1 (TGF-ß1) to stimulate LX-2) to inactive states. RESULTS: We identified core genes and transcription factors (TFs) involved in mesenchymal cell differentiation. In healthy human and mouse livers, the expression of NR1H4 and members of the ZEB families (ZEB1 and ZEB2) changed significantly with the differentiation of FB into HSC and VSMC. In cirrhotic human livers, VSMCs transformed into HSCs with downregulation of MYH11, ACTA2, and JUNB and upregulation of PDGFRB, RGS5, IGFBP5, CD36, A2M, SOX5, and MEF2C. Following HSCs differentiation into MFBs with the upregulation of COL1A1, TIMP1, and NR1H4, a small number of MFBs reverted to inactivated HSCs (iHSCs). The differentiation trajectory of mouse hepatic mesenchymal cells was similar to that in humans; however, the evolution trajectory and proportion of cell subpopulations that reverted from MFBs to iHSCs suggest that the mouse model may not accurately reflect disease progression and outcome in humans. CONCLUSIONS: Our analysis elucidates primary genes and TFs involved in mesenchymal cell differentiation during liver fibrosis using scRNA-seq data, and demonstrated the core genes and TFs in process of HSC activation to MFB and MFB reversal to iHSC using bulk RNA-seq data of human fibrosis induced by TGF-ß1. Furthermore, our findings suggest promising targets for the treatment of liver fibrosis and provide valuable insights into the molecular mechanisms underlying its onset and progression.

The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity.

Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer's disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system.

Dibutyl phthalate adsorbed on multi-walled carbon nanotubes can aggravate liver injury in mice via the Jak2/STAT3 pathway.

Phthalic acid esters (PAEs) and carbon nanotubes (CNTs) are common environmental pollutants and may degrade differently with different resulting biotoxicity, when present together. This study investigated the toxicological effects of singular or combined exposure to dibutyl phthalate (DBP) and multi-walled carbon nanotubes (MWCNTs) in KM mice. Results indicated that combined exposure led to slower weight gain and an increased leukocyte count in the blood, as well as liver tissue lesions and downregulation of organ coefficients. Additionally, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated in the liver, and glucose, pyruvate, triglyceride (TG), and total cholesterol (T-CHO) were significantly reduced, suggesting compromised liver function. Furthermore, mRNA levels of genes related to hepatic glucose and lipid metabolism were significantly altered. These findings suggest that combined exposure to DBP and MWCNTs can have severe impacts on liver function in mice, highlighting the importance of considering interactions between multiple contaminants in environmental risk assessments.

LINC MIR503HG Controls SC-ß Cell Differentiation and Insulin Production by Targeting CDH1 and HES1.

Stem cell-derived pancreatic progenitors (SC-PPs), as an unlimited source of SC-derived ß (SC-ß) cells, offers a robust tool for diabetes treatment in stem cell-based transplantation, disease modeling, and drug screening. Whereas, PDX1+/NKX6.1+ PPs enhances the subsequent endocrine lineage specification and gives rise to glucose-responsive SC-ß cells in vivo and in vitro. To identify the regulators that promote induction efficiency and cellular function maturation, single-cell RNA-sequencing is performed to decipher the transcriptional landscape during PPs differentiation. The comprehensive evaluation of functionality demonstrated that manipulating LINC MIR503HG using CRISPR in PP cell fate decision can improve insulin synthesis and secretion in mature SC-ß cells, without effects on liver lineage specification. Importantly, transplantation of MIR503HG-/- SC-ß cells in recipients significantly restored blood glucose homeostasis, accompanied by serum C-peptide release and an increase in body weight. Mechanistically, by releasing CtBP1 occupying the CDH1 and HES1 promoters, the decrease in MIR503HG expression levels provided an excellent extracellular niche and appropriate Notch signaling activation for PPs following differentiation. Furthermore, this exhibited higher crucial transcription factors and mature epithelial markers in CDH1High expressed clusters. Altogether, these findings highlighted MIR503HG as an essential and exclusive PP cell fate specification regulator with promising therapeutic potential for patients with diabetes.

Discovery of plant chemical defence mediated by a two-component system involving ß-glucosidase in Panax species.

Plants usually produce defence metabolites in non-active forms to minimize the risk of harm to themselves and spatiotemporally activate these defence metabolites upon pathogen attack. This so-called two-component system plays a decisive role in the chemical defence of various plants. Here, we discovered that Panax notoginseng, a valuable medicinal plant, has evolved a two-component chemical defence system composed of a chloroplast-localized ß-glucosidase, denominated PnGH1, and its substrates 20(S)-protopanaxadiol ginsenosides. The ß-glucosidase and its substrates are spatially separated in cells under physiological conditions, and ginsenoside hydrolysis is therefore activated only upon chloroplast disruption, which is caused by the induced exoenzymes of pathogenic fungi upon exposure to plant leaves. This activation of PnGH1-mediated hydrolysis results in the production of a series of less-polar ginsenosides by selective hydrolysis of an outer glucose at the C-3 site, with a broader spectrum and more potent antifungal activity in vitro and in vivo than the precursor molecules. Furthermore, such ß-glucosidase-mediated hydrolysis upon fungal infection was also found in the congeneric species P. quinquefolium and P. ginseng. Our findings reveal a two-component chemical defence system in Panax species and offer insights for developing botanical pesticides for disease management in Panax species.

HP promotes neutrophil inflammatory activation by regulating PFKFB2 in the glycolytic metabolism of sepsis.

BACKGROUND: Sepsis, described as an inflammatory reaction to an infection, is a very social health problem with high mortality. This study aims to explore the new mechanism in the progression of sepsis. METHODS: We downloaded the GSE69528 dataset to screen differentially expressed genes (DEGs) for WGCNA, in which the key module was identified and analyzed by DMNC algorithm, expression verification and ROC curve analysis to identify the hub gene. Furthermore, the hub gene was analyzed by immunoassay, and the potential mechanism of hub gene in neutrophils was investigated by in vitro experiments. RESULTS: The turquoise module was the key module for sepsis in WGCNA on 94 DEGs. The top 20 genes of DMNC network were verified in GSE69528 and GSE9960, and 10 significant genes were obtained for ROC analysis. Based on the ROC curves, HP was considered the hub gene in sepsis, and its expression difference in sepsis and control groups was substantially significant. Further, it was demonstrated the knockdown of HP and PFKFB3 could suppress glycolysis and inflammatory cytokine levels in dHL-60 cell treated with LPS. CONCLUSION: In conclusion, HP is identified as a potential diagnostic indicator for sepsis patients, and HP promotes neutrophil inflammatory activation by regulating PFKFB2 in the glycolytic metabolism of sepsis confirmed by in vitro experiments. These will help us deepen the molecular mechanism of sepsis.

Septin9 DNA methylation is associated with breast cancer recurrence or metastasis.

OBJECTIVE: We aimed to explore the prognostic value of Septin9 DNA methylation in breast cancer. METHODS: Breast cancer patients with and without recurrence or metastasis and matched non-breast cancer patients were screened retrospectively from 2014 to 2016. Bisulfite conversion and fluorescence quantitative methylation-specific polymerase chain reaction were used to detect the Septin9 methylation status and distribution levels in patient breast tissues. RESULTS: Septin9 DNA methylation was more frequent in breast cancer tissues than in non-breast cancer tissues, but was not significantly correlated with any relevant breast cancer patient clinicopathological characteristic. Septin9 methylation rates were higher in patients with recurrence or metastasis. Septin9 methylation, tumor size, lymph node status, and progesterone receptor (PR) expression could influence prognosis. Septin9 methylation was significantly associated with worse disease-free survival in breast cancer patients, with receiver operating characteristic curve analysis indicating that it had good prognostic ability, with an area under the curve (AUC) value of 0.719. The AUC values increased when Septin9 methylation was combined with tumor size, lymph node status, and PR to predict prognosis. CONCLUSIONS: Septin9 DNA methylation was an independent predictors of breast cancer prognostic risk. This could possibly help improve comprehensive prognosis prediction methods when combined with other risk factors.

Effect of atorvastatin calcium plus clopidogrel in the treatment of patients with transient ischemic attacks and its effect on blood lipids and platelets.

OBJECTIVE: To explore the clinical effect of atorvastatin calcium combined with clopidogrel in the treatment of patients with transient ischemic attacks (TIAs) and its effect on blood lipids and platelets. METHODS: Low-density lipoprotein cholesterol (LDL-C)], platelet-related parameters [prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count (PLT)], incidence of cerebral infarction, and adverse reactions. RESULTS: The clinical outcomes of the experimental group patients were significantly better than those of the control group patients (p < 0.05). The experimental group exhibited notably lower levels of TG, TC, and LDL-C compared to the control group (p < 0.05). Platelet-related indices-PT, APTT, and PLT-showed no significant differences between groups before and after treatment (p > 0.05). The incidence of cerebral infarction was notably lower in the experimental group (p < 0.005), while the occurrence of adverse reactions showed no significant difference between groups (p > 0.05). CONCLUSION: Atorvastatin calcium combined with clopidogrel demonstrates a positive impact on individuals with TIAs by significantly lowering levels of LDL, total cholesterol, and triglycerides. However, it is noteworthy that platelet-related indices did not exhibit significant differences between the experimental and control groups. While the observed improvements in blood lipids are attributed to the effects of atorvastatin, the combination with clopidogrel did not show a substantial influence on platelet-related parameters. Thus, the overall therapeutic impact, particularly on platelet-related indices, may require further investigation and clarification. Despite these nuances, our findings suggest potential benefits in reducing the risk of adverse reactions and cerebral infarction, supporting the consideration of this approach for wider clinical use.

Silencing hsa_circ_0032449 inhibits the pancreatic differentiation of human embryonic stem cells via the hsa_miR-195-5p/CCND1/PI3K/AKT signaling pathway.

Stem cell-derived ß cells (SC-ß cells) differentiated from stem cell-derived pancreatic progenitor (PP) cells are promising tools for enabling normal glucose control of islet transplants and have therapeutic potential for type 1 diabetes treatment. Pancreatic specification is essential for SC-ß cell induction in vitro and low-quality PP cells may convert into derivatives of non-pancreatic lineages both in vivo and in vitro, impeding PP-derived ß cell safety and differentiation efficiency. Circular RNA (circRNA) commonly determines the fate of stem cells by acting as competing endogenous RNA (ceRNA). Currently, the relationships between endogenous circRNA and pancreatic specification remain elusive. Herein, we used whole transcriptome sequencing analysis and functional experiments to reveal that deficiency of hsa_circ_0032449 resulted in posterior foregut-derived PP cells with a weakened the progenitor state with decreased expression of PDX1, NKX6.1 and CCND1. As differentiation processed into maturation, silencing of hsa_circ_0032449 suppressed PP cell development into functionally mature and glucose-responsive SC-ß cells. These SC-ß cells exhibited lower serum C-peptide levels compared with those of control groups in nude mice and had difficulties in reversing hyperglycemia in STZ-induced diabetic nude mice. Mechanistically, loss of hsa_circ_0032449 participated in PI3K-AKT signaling transduction by acting as a ceRNA to sponge miR-195-5p and by influencing the expression of the downstream target CCND1 at transcription and translation levels. Overall, our findings identified hsa_circ_0032449 as an essential PP cell-fate specification regulator, indicating a promising potential in clinical applications and basic research.

Urinary-derived extracellular vesicle microRNAs as non-invasive diagnostic biomarkers for early-stage renal cell carcinoma.

BACKGROUND AND AIMS: The potential of urinary-derived extracellular vesicle (uEV) microRNAs (miRNAs) as noninvasive molecular biomarkers for identifying early-stage renal cell carcinoma (RCC) patients is rarely explored. The present study aims to explore the possibility of uEV miRNAs as novel molecular biomarkers for distinguishing early-stage RCC. MATERIALS AND METHODS: uEVs were extracted by ExoQuick-TC™ kit and miRNA concentrations were measured by RT-qPCR. ROC curves and bioinformatics analysis were employed to predict the diagnostic efficacy and regulatory mechanisms of dysregulated miRNAs. RESULTS: Through a multiphase case-control study on uEV miRNAs screening, training, and validation in RCC cells (ACHN, Caki-1) and control cells (HK-2) and in uEVs of 125 RCC patients and 128 age- and sex-matched controls, we successfully identified four uEVs miRNAs (miR-135b-5p, miR-196b-5p, miR-200c-3p, and miR-203a-3p) were significantly and stably upregulated in RCC in vitro and in vivo. When adjusted with estimated glomerular filtration rate (eGFR), the AUC of the three-uEV miRNA panel (miR-135b-5p, miR-200c-3p, and miR-203a-3p) was 0.785 (95 % CI = 0.729-0.842, P < 0.0001) for discriminating RCC patients from controls. Notably, this panel exhibited similar performance in distinguishing early-stage (stage Ⅰ) RCC patients, with an AUC of 0.786 (95 %CI = 0.727-0.844, P < 0.0001). Bioinformatics analysis predicted that candidate miRNAs were involved in cancer progressing. CONCLUSION: Our study identified a four uEV miRNAs panel (miR-135b-5p, miR-196b-5p, miR-200c-3p, and miR-203a-3p) may serve as an auxiliary noninvasive indication of early-stage RCC.

Geographical heterogeneity in the disease characteristics and management of patients with inflammatory bowel disease, the preliminary results of a Chinese database for IBD (CHASE-IBD).

Background: The incidence of inflammatory bowel disease (IBD) is rapidly increasing in China, a vast country with significant geographical differences. The socioeconomic status of Eastern China is significantly higher than that of Western China. Objectives: This study aimed to describe the geographical heterogeneity in the characteristics and management of patients with IBD in both Eastern and Western China. Design: This was a multicenter, cross-sectional study. Methods: Patients with IBD with ages ⩾18 years up to 18 January 2023 were included in the analysis from the Chinese database for IBD. Logistic regression was used to identify risk factors associated with surgeries among patients with IBD. Results: Among 8305 patients with IBD, the ratio of ulcerative colitis (UC) to Crohn's disease (CD) was 4.13 and 0.33 in Western and Eastern China, respectively. The median age at diagnosis of UC and CD was 40.69 and 28.58 years, respectively. There was a male predominance among patients with UC (54.3%) and CD (68.0%). The two regions exhibited a similar distribution of disease locations in UC. However, Western China had a higher proportion of L2 involvement (30.0% versus 19.1%) and more advanced disease behavior (B2 and B3) (48.8% versus 39.8%) than Eastern China. Patients with IBD in Western China received more 5-aminosalicylic acid and corticosteroids and fewer immunomodulators and biologicals. In terms of surgical risk, Eastern China [versus Western China, odds ratios (OR): 5.36, 95% confidence intervals (CI): 2.96-9.68] was associated with a higher risk of surgery in UC, while Western China (versus Eastern China, OR: 3.39, 95% CI: 2.37-4.86) was associated with a higher risk of surgery in CD. Conclusion: Geographical heterogeneity exists in the disease characteristics and management of IBD in Eastern and Western China. These findings have the potential to guide the formulation of location-specific strategies aimed at enhancing the long-term outcomes of patients with IBD.

Bone Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorated Lipopolysaccharide-Induced Lung Injury Via the miR-21-5p/PCSK6 Pathway.

Acute lung injury (ALI) is a life-threatening disease that currently lacks a cure. Although stem cell-derived small extracellular vesicles (sEVs) have shown promising effects in the treatment of ALI, their underlying mechanisms and responsible components have yet to be identified. Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a gene involved in inflammation and a potential target of miR-21-5p, a microRNA enriched in stem cell-derived sEVs. The current study investigated the role of PCSK6 in lipopolysaccharide (LPS)-induced ALI and its interaction with miR-21-5p. Notably, our results showed that PCSK6 expression was positively correlated with LPS stimulation. Knockdown of PCSK6 ameliorated LPS-induced inhibition of proliferation and upregulation of permeability in human BEAS-2B cells, whereas PCSK6 overexpression displayed the opposite effects. BEAS-2B cells were able to actively internalize the cocultured bone mesenchymal stem cell (MSC)-derived sEVs (BMSC-sEVs), which alleviated the cell damage caused by LPS. Overexpressing PCSK6, however, eliminated the therapeutic effects of BMSC-sEV coculture. Mechanistically, BMSC-sEVs inhibited PCSK6 expression via the delivery of miR-21-5p, which is directly bound to the PCSK6 gene. Our work provides evidence for the role of PCSK6 in LPS-induced ALI and identified miR-21-5p as a component of BMSC-derived sEVs that suppressed PCSK6 expression and ameliorated LPS-induced cell damage. These results reveal a novel molecular mechanism for ALI pathogenesis and highlight the therapeutic potential of using sEVs released by stem cells to deliver miR-21-5p for ALI treatment.

Combined exposure to multiwalled carbon nanotubes and dibutyl phthalates aggravated airway inflammation in rats.

Previous work has shown that mice exposed to dibutyl phthalate (DBP) adsorbed onto multi-walled carbon nanotubes (MWCNTs), via tail vein injection, displayed black lesions in their lungs. To investigate the mechanism causing this toxicity in the lung tissue, we performed an experiment with rats, exposing them to DBP adsorbed onto MWCNTs via a tail vein injection for 14 days. The results revealed pulmonary edema and greyish-black lung tissue in the MWCNTs and the MWCNTs + DBP combined exposure groups. In the combined exposure group there was evident alveolar fragmentation and adhesion, and lung tissue sections showed significant levels of black particles. Sections of the non-cartilaginous region of the trachea had significant folding of the pseudostratified ciliated columnar epithelium and marked thickening of the submucosa. In broncho alveolar lavage fluid, the number of leukocytes (WBC), lymphocytes (Lym), neutrophils (Neu), and eosinophils (Eos), as well as levels of immunoglobulin E (IgE), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin 1ß (IL-1ß) were all significantly higher. TNF-α, IL-6, signal transducer and activator of transcription 3 (STAT3), and α-smooth muscle actin (α-SMA) mRNA expression were all elevated in the lung tissue. The combined exposure group, which had considerable airway remodeling, had a greater degree of tracheal constriction and luminal narrowing, according to the results of the α-SMA immunofluorescence assay. According to these experimental findings, the exposure to both MWCNTs and DBP seemed to have a synergistic effect and exacerbated rats' impaired respiratory function that resulted from exposure to MWCNTs alone.

A-GSTCN: An Augmented Graph Structural-Temporal Convolution Network for Medication Recommendation Based on Electronic Health Records.

Medication recommendation based on electronic health records (EHRs) is a significant research direction in the biomedical field, which aims to provide a reasonable prescription for patients according to their historical and current health conditions. However, the existing recommended methods have many limitations in dealing with the structural and temporal characteristics of EHRs. These methods either only consider the current state while ignoring the historical situation, or fail to adequately assess the structural correlations among various medical events. These factors result in poor recommendation quality. To solve this problem, we propose an augmented graph structural-temporal convolutional network (A-GSTCN). Firstly, an augmented graph attention network is used to model the structural features among medical events of patients' EHRs. Next, the dilated convolution combined with residual connection is applied in the proposed model, which can improve the temporal prediction capability and further reduce the complexity. Moreover, the cache memory module further enhances the model's learning of the history of EHRs. Finally, the A-GSTCN model is compared with the baselines through experiments, and the efficiency of the A-GSTCN model is verified by Jaccard, F1 and PRAUC. Not only that, the proposed model also reduces the training parameters by an order of magnitude.

Discovery of new quaternized norharmane dimers as potential anti-MRSA agents.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA)-caused infections greatly threaten public health. The discovery of natural-product-based anti-MRSA agents for treating infectious diseases has become one of the current research focuses. OBJECTIVES: This study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization. METHODS: A total of 32 norharmane analogues were prepared and characterized. Their antibacterial activities and resistance development propensity were tested by the broth double-dilution method. Cell counting kit-8 and hemolysis experiments were used to assess their biosafety. The plasma stability, bactericidal mode, and biofilm disruption effects were examined by colony counting and crystal violet staining assays. Fluorescence microscopy, metabolomic analysis, docking simulation and spectra titration revealed its anti-MRSA mechanisms. The mouse skin infection model was used to investigate the in vivo efficacy. RESULTS: Compound 5a was selected as a potential anti-MRSA agent, which exhibited potent anti-MRSA activity in vitro and in vivo, low cytotoxicity and hemolysis under an effective dose. Moreover, compound 5a showed good stability in 50% plasma, a low tendency of resistance development and capabilities to disrupt bacterial biofilms. The mechanism studies revealed that compound 5a could inhibit the biosynthesis of bacteria cell walls, damage the membrane, disturb energy metabolism and amino acid metabolism pathways, and interfere with protein synthesis and nucleic acid function. CONCLUSIONS: These results suggested that compound 5a is a promising candidate for combating MRSA infections, providing valuable information for further exploiting a new generation of therapeutic antibiotics.

Click chemistry-based enrichment strategy for tracing cellular fatty acid metabolism by LC-MS/MS.

Fatty acids (FAs), which were initially recognized as energy sources and essential building blocks of biomembranes, serve as the precursors of important signaling molecules. Tracing FA metabolism is essential to understanding the biochemical activity and role of FAs in physiological and pathological events. Inspired by the advances in click chemistry for protein enrichment, we herein established a click chemistry-based enrichment (CCBE) strategy for tracing the cellular metabolism of eicosapentaenoic acid (EPA, 20:5 n-3) in neural cells. Terminal alkyne-labeled EPA (EPAA) used as a surrogate was incubated with N2a, mouse neuroblastoma cells, and alkyne-labeled metabolites (ALMs) were selectively captured by an azide-modified resin via a Cu(I)-catalyzed azide-alkyne cycloaddition reaction for enrichment. After removing unlabeled metabolites, ALMs containing a triazole moiety were cleaved from solid-phase resins and subjected to liquid chromatography mass spectrometry (LC-MS) analysis. The proposed CCBE strategy is highly selective for capturing and enriching alkyne-labeled metabolites from the complicated matrices. In addition, this method can overcome current detection limits by enhancing MS sensitivity of targets, improving the chromatographic separation of sn-position glycerophospholipid regioisomers, facilitating structural characterization of ALMs by a specific MS/MS fragmentation signature, and providing versatile fluorescence detection of ALMs for cellular distribution. This CCBE strategy might be expanded to trace the metabolism of other FAs, small molecules, or drugs.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Incidence and disease-related risk factors for cerebrovascular accidents in patients with inflammatory bowel diseases: A systematic review and meta-analysis.

OBJECTIVES: Risk of cerebrovascular accidents (CVAs) in patients with inflammatory bowel disease (IBD) remains inconclusive. In this systematic review and meta-analysis, we aimed to estimate the incidence of and identify the risk factors for CVA in patients with IBD. METHODS: PubMed, EMBASE and Web of Science were searched for articles published up to January 13, 2023 to identify those reported the incidence of CVA in IBD patients, along with the total person-years or related data to calculate it. The main outcomes were the incidence of and risk factors for CVA in IBD. RESULTS: Based on the analysis of 10 studies, the pooled incidence of CVA in IBD patients was 2.74 per 1000 person-years (95% confidence interval [CI] 1.83-4.10 person-years; I2 = 99.2%), which was higher than that in the general population (incidence rate ratio [IRR] 1.21, 95% CI 1.09-1.34, P = 0.0002; I2 = 84.8%). Risk factors for CVA in IBD patients were age (significance in different definitions), ulcerative colitis (IRR 1.214, 95% CI 1.000-1.474, P = 0.0499; I2 = 81.9%), disease flares (IRR 1.699, 95% CI 1.359-2.122, P < 0.0001; I2 = 28.7%) and chronic activity (IRR 2.202, 95% CI 1.378-3.519, P = 0.0010; I2 = 83.0%). CONCLUSIONS: The risk of CVA modestly increased in IBD patients. Both the traditional and IBD-related risk factors should be managed to prevent CVA in these patients. Since the effects of risk factors were derived from pooled results of only 2-3 studies, further research is needed to confirm our results.