Genome-wide characterization of extrachromosomal circular DNA in SLE and functional analysis reveal their association with apoptosis.

Extrachromosomal circular DNA (eccDNA) derived from linear chromosomes, are showed typical nucleosomal ladder pattern in agarose gel which as a known feature of apoptosis and demonstrated to be immunogenicity. In systemic lupus erythematosus (SLE) patients, elevated levels of cell-free DNA (cfDNA) can be found in either linear forms or circular forms, while circular ones are much less common and harder to detect. The molecular characteristics and function of circular forms in plasma SLE patients remains elusive. Herein, we characterized the hallmarks of plasma eccDNA in SLE patients, including the lower normalized number and GC content of eccDNA in SLE plasma than in the healthy, and SLE eccDNA number positively correlated with C3 and negatively with anti-dsDNA antibodies. The differential eccGenes (eccDNAs carrying the protein coding gene sequence) of SLE was significantly enriched in apoptosis-related pathways. The artificially synthesized eccDNA with sequences of the PRF1 exon region could promote transcriptional expression of PRF1, IFNA and IFIT3 and inhibit early-stage apoptosis. Plasma eccDNA can serve as a novel autoantigen in the pathogenesis of SLE.

Proteomic analysis of laser captured tubular tissues reveals complement activation and mitochondrial dysfunction in autoimmune related kidney diseases.

Autoimmune related kidney diseases (ARKDs), including minimal change nephropathy (MCN), membranous nephropathy (MN), IgA nephropathy (IgAN), and lupus nephritis (LN), significantly affect renal function. These diseases are characterized by the formation of local immune complexes and the subsequent activation of the complement system, leading to kidney damage and proteinuria. Despite the known patterns of glomerular injury, the specific molecular mechanisms that contribute to renal tubular damage across ARKDs remain underexplored. Laser capture microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to conduct a comparative proteomic analysis of renal tubular tissues from formalin-fixed paraffin-embedded samples. The cohort comprised of 10 normal controls (NC), 5 MCN, 4 MN, 17 IgAN, and 21 LN patients. Clinical parameters and histopathological assessments were integrated with proteomic findings to comprehensively investigate underlying pathogenic processes. Clinical evaluation indicated significant glomerular damage, as reflected by elevated urinary protein levels and reduced plasma albumin levels in patients with ARKD. Histological analyses confirmed varying degrees of tubular damage and deposition of immune complexes. Proteomic analyses identified significant changes in protein expression, particularly in complement components (C3, C4A, C4B, C8G, CFB, and SERPINA1) and mitochondrial proteins (ATP5F1E and ATP5PD), highlighting the common alterations in the complement system and mitochondrial proteins across ARKDs. These alterations suggest a novel complement-mitochondrial-epithelial-mesenchymal transition (EMT) pathway axis that contributes to tubular damage in ARKDs. Notably, significant alterations in CFB in tubular ARKD patients were revealed, implicating it as a therapeutic target. This study underscores the importance of complement activation and mitochondrial dysfunction in the pathogenesis of ARKDs, and proposes CFB as a potential therapeutic target to inhibit complement activation and mitigate tubular damage. Future research should validate the complement-mitochondrial-EMT pathway axis and explore the effects and mechanisms of CFB inhibitors in alleviating ARKD progression.

AI-Assisted Rational Design and Activity Prediction of Biological Elements for Optimizing Transcription-Factor-Based Biosensors.

The rational design, activity prediction, and adaptive application of biological elements (bio-elements) are crucial research fields in synthetic biology. Currently, a major challenge in the field is efficiently designing desired bio-elements and accurately predicting their activity using vast datasets. The advancement of artificial intelligence (AI) technology has enabled machine learning and deep learning algorithms to excel in uncovering patterns in bio-element data and predicting their performance. This review explores the application of AI algorithms in the rational design of bio-elements, activity prediction, and the regulation of transcription-factor-based biosensor response performance using AI-designed elements. We discuss the advantages, adaptability, and biological challenges addressed by the AI algorithms in various applications, highlighting their powerful potential in analyzing biological data. Furthermore, we propose innovative solutions to the challenges faced by AI algorithms in the field and suggest future research directions. By consolidating current research and demonstrating the practical applications and future potential of AI in synthetic biology, this review provides valuable insights for advancing both academic research and practical applications in biotechnology.

Dynamic and Static Regulation of Nicotinamide Adenine Dinucleotide Phosphate: Strategies, Challenges, and Future Directions in Metabolic Engineering.

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a crucial cofactor in metabolic networks. The efficient regeneration of NADPH is one of the limiting factors for productivity in biotransformation processes. To date, many metabolic engineering tools and static regulation strategies have been developed to regulate NADPH regeneration. However, traditional static regulation methods often lead to the NADPH/NADP+ imbalance, causing disruptions in cell growth and production. These methods also fail to provide real-time monitoring of intracellular NADP(H) or NADPH/NADP+ levels. In recent years, various biosensors have been developed for the detection, monitoring, and dynamic regulate of the intracellular NADP(H) levels or the NADPH/NADP+ balance. These NADPH-related biosensors are mainly used in the cofactor engineering of bacteria, yeast, and mammalian cells. This review analyzes and summarizes the NADPH metabolic regulation strategies from both static and dynamic perspectives, highlighting current challenges and potential solutions, and discusses future directions for the advanced regulation of the NADPH/NADP+ balance.

Circulating B Cell-Derived Small RNA Delivered by Extracellular Vesicles: A Dialogue Mechanism for Long-Range Targeted Renal Mitochondrial Injury in Obesity.

The intricate processes that govern the interactions between peripatetic immune cells and distal renal injury in obesity are not fully understood. Employing transcriptomic analysis of circulating extracellular vesicles (EVs), a marked amplification of small RNA (miR-3960) is discerned within CD3-CD19+ B cells. This RNA is found to be preferentially augmented in kidney tissues, contrasting with its subdued expression in other organs. By synthesizing dual-luciferase reporter assay with co-immunoprecipitation analysis, it is pinpointed that miR-3960 specifically targets the nuclear gene TRMT5, a pivotal actor in the methylation of mitochondrial tRNA. This liaison instigates aberrations in the post-transcriptional modifications of mitochondrial tRNA, engendering deficiencies within the electron respiratory chain, primarily attributable to the diminution of the mitochondrial bioenergetic compound (NDUFA7) complex I. Such perturbations lead to a compromised mitochondrial respiratory capacity in renal tubular cells, thereby exacerbating tubular injury. In contrast, EV blockade or miR-3960 depletion markedly alleviates renal tubular injury in obesity. This investigation unveils a hitherto unexplored pathway by which obesity-induced circulating immune cells remotely manipulate mitochondrial metabolism in target organs. The strategic targeting of obese EVs or infiltrative immune cells and their specifically secreted RNAs emerges as a promising therapeutic avenue to forestall obesity-related renal afflictions.

Recent Advances in Metabolic Engineering for the Biosynthesis of Phosphoenol Pyruvate-Oxaloacetate-Pyruvate-Derived Amino Acids.

The phosphoenol pyruvate-oxaloacetate-pyruvate-derived amino acids (POP-AAs) comprise native intermediates in cellular metabolism, within which the phosphoenol pyruvate-oxaloacetate-pyruvate (POP) node is the switch point among the major metabolic pathways existing in most living organisms. POP-AAs have widespread applications in the nutrition, food, and pharmaceutical industries. These amino acids have been predominantly produced in Escherichia coli and Corynebacterium glutamicum through microbial fermentation. With the rapid increase in market requirements, along with the global food shortage situation, the industrial production capacity of these two bacteria has encountered two bottlenecks: low product conversion efficiency and high cost of raw materials. Aiming to push forward the update and upgrade of engineered strains with higher yield and productivity, this paper presents a comprehensive summarization of the fundamental strategy of metabolic engineering techniques around phosphoenol pyruvate-oxaloacetate-pyruvate node for POP-AA production, including L-tryptophan, L-tyrosine, L-phenylalanine, L-valine, L-lysine, L-threonine, and L-isoleucine. Novel heterologous routes and regulation methods regarding the carbon flux redistribution in the POP node and the formation of amino acids should be taken into consideration to improve POP-AA production to approach maximum theoretical values. Furthermore, an outlook for future strategies of low-cost feedstock and energy utilization for developing amino acid overproducers is proposed.

Enhancing glucaric acid production from myo-inositol in Escherichia coli by eliminating cell-to-cell variation.

Glucaric acid (GA) is a value-added chemical and can be used to manufacture food additives, anticancer drugs, and polymers. The non-genetic cell-to-cell variations in GA biosynthesis are naturally inherent, indicating the presence of both high- and low-performance cells in culture. Low-performance cells can lead to nutrient waste and inefficient production. Furthermore, myo-inositol oxygenase (MIOX) is a key rate-limiting enzyme with the problem of low stability and activity in GA production. Therefore, eliminating cell-to-cell variations and increasing MIOX stability can select high-performance cells and improve GA production. In this study, an in vivo GA bioselector was constructed based on GA biosensor and tetracycline efflux pump protein TetA to continuously select GA-efficient production strains. Additionally, the upper limit of the GA biosensor was improved to 40 g/L based on ribosome-binding site optimization, achieving efficient enrichment of GA high-performance cells. A small ubiquitin-like modifier (SUMO) enhanced MIOX stability and activity. Overall, we used the GA bioselector and SUMO-MIOX fusion in fed-batch GA production and achieved a 5.52-g/L titer in Escherichia coli, which was 17-fold higher than that of the original strain.IMPORTANCEGlucaric acid is a non-toxic valuable product that was mainly synthesized by chemical methods. Due to the problems of non-selectivity, inefficiency, and environmental pollution, GA biosynthesis has attracted significant attention. The non-genetic cell-to-cell variations and MIOX stability were both critical factors for GA production. In addition, the high detection limit of the GA biosensor was a key condition for performing high-throughput screening of GA-efficient production strains. To increase GA titer, this work eliminated the cell-to-cell variations by GA bioselector constructed based on GA biosensor and TetA, and improved the stability and activity of MIOX in the GA biosynthetic pathway through fusing the SUMO to MIOX. Finally, these approaches improved the GA production by 17-fold to 5.52 g/L at 65 h. This study represents a significant step toward the industrial application of GA biosynthetic pathways in E. coli.

Patients, healthcare providers, and general population preferences for hemodialysis vascular access: a discrete choice experiment.

Background: A patient-centered dialysis treatment option requires an understanding of patient preferences for alternative vascular accesses and nephrologists often face difficulties when recommending vascular access to end-stage kidney disease (ESKD) patients. We aimed to quantify the relative importance of various vascular access characteristics to patients, healthcare providers and general population, and how they affect acceptability for patients and healthcare providers. Methods: In a discrete choice experiment, patients with maintenance hemodialysis (MHD), healthcare providers, and individuals from the general population were invited to respond to a series of hypothetical vascular access scenarios that differed in five attributes: cumulative patency, infection rate, thrombosis rate, cost, and time to maturation. We estimated the respondents' preference heterogeneity and relative importance of the attributes with a mixed logit model (MXL) and predicted the willingness to pay (WTP) of respondents via a multinomial logit model (MNL). Results: Healthcare providers (n = 316) and the general population (n = 268) exhibited a favorable inclination toward longer cumulative patency, lower access infection rate and lower access thrombosis rate. In contrast, the patients (n = 253) showed a preference for a 3-year cumulative patency, 8% access infection rate, 35% access thrombosis rate and 1.5 access maturity time, with only the 3-year cumulative patency reaching statistical significance. Among the three respondent groups, the general population found cumulative patency less important than healthcare providers and patients did. Patients demonstrated the highest WTP for cumulative patency, indicating a willingness to pay an extra RMB$24,720(US$3,708) for each additional year of patency time. Conclusion: Patients and healthcare providers had a strong preference for vascular access with superior patency. While the general population preferred vascular access with lower thrombosis rates. These results indicate that most patients prefer autogenous arteriovenous fistula (AVF) as an appropriate choice for vascular access due to its superior patency and lower complications than other vascular access types.

A Reference Profile of N-Glycosylation for Human Kidney and the Identification of Cell-Cell Interactions between Parietal Epithelial Cells and Capillary Endothelial Cells by Single-Cell Glycosylation-Sequencing.

BACKGROUND: N-glycosylation is one of the most common posttranslational modifications in humans, and these alterations are associated with kidney diseases. METHODS: A novel technological approach, single-cell N-acetyllactosamine sequencing (scLacNAc-seq), was applied to simultaneously detect N-glycosylation expression and the transcriptome at single-cell resolution in three human kidney tissues from zero-time biopsy. Cell clusters, glycation abundance in each cell cluster, functional enrichment analysis, cell-cell crosstalk, and pseudotime analysis were applied. RESULTS: Using scLacNAc-seq, 24,247 cells and 22 cell clusters were identified, and N-glycan abundance in each cell was obtained. Transcriptome analysis revealed a close connection between capillary endothelial cells (CapECs) and parietal epithelial cells (PECs). PECs and CapECs communicate with each other through several pairs of ligand receptors (e.g., TGFB1-EGFR, GRN-EGFR, TIMP1-FGFR2, VEGFB-FLT1, ANGPT2-TEK, and GRN-TNFRSF1A). Finally, a regulatory network of cell-cell crosstalk between PECs and CapECs was constructed, which is involved in cell development. CONCLUSIONS: We here, for the first time, constructed the glycosylation profile of 22 cell clusters in the human kidney from zero-time biopsy. Moreover, cell-cell communication between PECs and CapECs through the ligand-receptor system may play a crucial regulatory role in cell proliferation.

Renal and cardiac effects of the PDE9 inhibitor BAY 73-6691 in 5/6 nephrectomized rats.

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3',5'-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73-6691) on the heart and kidney. Two doses of BAY 73-6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73-6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73-6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.

Rewiring Metabolic Flux in Corynebacterium glutamicum Using a CRISPR/dCpf1-Based Bifunctional Regulation System.

Corynebacterium glutamicum, a microorganism classified as generally recognized as safe for use in the industrial production of food raw materials and additives, has encountered challenges in achieving widespread adoption and popularization as microbial cell factories. These obstacles arise from the intricate nature of manipulating metabolic flux through conventional methods, such as gene knockout and enzyme overexpression. To address this challenge, we developed a CRISPR/dCpf1-based bifunctional regulation system to bidirectionally regulate the expression of multiple genes in C. glutamicum. Specifically, through fusing various transcription factors to the C-terminus of dCpf1, the resulting dCpf1-SoxS exhibited both CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) capabilities in C. glutamicum by altering the binding sites of crRNAs. The bifunctional regulation system was used to fine-tune metabolic flux from shikimic acid (SA) and l-serine biosynthesis, resulting in 27-fold and 10-fold increases in SA and l-serine production, respectively, compared to the original strain. These findings highlight the potential of the CRISPR/dCpf1-based bifunctional regulation system in effectively enhancing the yield of target products in C. glutamicum.

Small RNA-big impact: exosomal miRNAs in mitochondrial dysfunction in various diseases.

Mitochondria are multitasking organelles involved in maintaining the cell homoeostasis. Beyond its well-established role in cellular bioenergetics, mitochondria also function as signal organelles to propagate various cellular outcomes. However, mitochondria have a self-destructive arsenal of factors driving the development of diseases caused by mitochondrial dysfunction. Extracellular vesicles (EVs), a heterogeneous group of membranous nano-sized vesicles, are present in a variety of bodily fluids. EVs serve as mediators for intercellular interaction. Exosomes are a class of small EVs (30-100 nm) released by most cells. Exosomes carry various cargo including microRNAs (miRNAs), a class of short noncoding RNAs. Recent studies have closely associated exosomal miRNAs with various human diseases, including diseases caused by mitochondrial dysfunction, which are a group of complex multifactorial diseases and have not been comprehensively described. In this review, we first briefly introduce the characteristics of EVs. Then, we focus on possible mechanisms regarding exosome-mitochondria interaction through integrating signalling networks. Moreover, we summarize recent advances in the knowledge of the role of exosomal miRNAs in various diseases, describing how mitochondria are changed in disease status. Finally, we propose future research directions to provide a novel therapeutic strategy that could slow the disease progress mediated by mitochondrial dysfunction.

Qualitative Proteome-wide Lysine Crotonylation Profiling Reveals Protein Modification Alteration in the Leukocyte Extravasation Pathway in Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease with multiple manifestations. Lysine crotonylation (Kcr) is a newly discovered posttranslational modification epigenetic pattern that may affect gene expression and is linked to diseases causally. METHODS: We collected blood samples from 11 SLE individuals and 36 healthy subjects. Then, we used highly sensitive liquid chromatography-mass spectrometry technology to carry out proteomics and quantitative crotonylome analysis of SLE peripheral blood mononuclear cells in this investigation, which indicated the unique etiology of SLE. Finally, we verified the expression of critical protein in the leukocyte extravasation pathway by online database analysis and Western blot. RESULTS: There were 618 differentially expressed proteins (DEPs), and 612 crotonylated lysine sites for 272 differentially modified proteins (DMPs) found. These DEPs and DMPs are primarily enriched in the leukocyte extravasation signaling pathway, such as MMP8, MMP9, and ITGAM. CONCLUSIONS: This is the first study of crotonylated modification proteomics in SLE. The leukocyte extravasation signaling pathway had a considerable concentration of DEPs and DMPs, indicating that this pathway may be involved in the pathogenic development of SLE.

Dysregulated coagulation system links to inflammation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a significant contributor to end-stage renal disease worldwide. Despite extensive research, the exact mechanisms responsible for its development remain incompletely understood. Notably, patients with diabetes and impaired kidney function exhibit a hypercoagulable state characterized by elevated levels of coagulation molecules in their plasma. Recent studies propose that coagulation molecules such as thrombin, fibrinogen, and platelets are interconnected with the complement system, giving rise to an inflammatory response that potentially accelerates the progression of DKD. Remarkably, investigations have shown that inhibiting the coagulation system may protect the kidneys in various animal models and clinical trials, suggesting that these systems could serve as promising therapeutic targets for DKD. This review aims to shed light on the underlying connections between coagulation and complement systems and their involvement in the advancement of DKD.

Uncovering the mechanism of Qidan Dihuang Granule in the treatment of diabetic kidney disease combined network pharmacology, UHPLC-MS/MS with experimental validation.

Background and aim: Diabetic Kidney Disease (DKD) is a common microvascular complication of diabetes mellitus. Multi-center, randomized controlled trials have shown that Qidan Dihuang Granule (QDDHG) reduces the levels of albuminuria of DKD. However, the specific mechanisms of QDDHG on DKD are not clarified. Thus, this study utilized network pharmacology, UHPLC-MS/MS (Ultra-High Performance Liquid Chromatography - Mass Spectrometry) and animal experiments to reveal the mechanisms of QDDHG on DKD. Experimental procedure: Screening and retrieving active ingredients and corresponding targets of QDDHG on DKD through the TCMSP, ETCM, Disgenet, GeneCards, Omim and DrugBank databases. The PPI were performed with BioGrid, STRING, OmniPath, InWeb-IM. AutoDock Vina molecular docking module to estimate the validation from the compounds and target proteins. Free energy to estimate the binding affinity for identified compounds and target proteins. The ingredients of QDDHG were analyzed utilizing UHPLC-MS/MS. In vivo experiment with db/db mice were used to verify the targets and pathway predicted by network pharmacology. Results and conclusion: The results demonstrated that QDDHG has 18 active compounds and 13 target proteins of QDDHG exerted a crucial role in treatment of DKD. QDDHG affect the multiple biological processes included cellular response to lipid, response to oxidative stress, and various pathways, such as AGE-RAGE, PI3K-Akt, MAPK, TNF, EGFR, STAT3. The results of UHPLC-MS/MS showed that six ingredients predicted by network pharmacology were also verified in experiment. In vivo experiment verified the effects of QDDHG on protecting the renal function mainly through inhibited the expression of EGFR, STAT3 and pERK in the db/db mice.

Corrigendum to "The novel putative methyltransferase METTL7A as one prognostic biomarker potentially associated with immune infiltration in human renal cancer".

[This corrects the article DOI: 10.1016/j.heliyon.2023.e15371.].

CRISPR/Cas9-Mediated Gene Correction in Osteopetrosis Patient-Derived iPSCs.

BACKGROUND: Osteopetrosis represents a rare genetic disease with a wide range of clinical and genetic heterogeneity, which results from osteoclast failure. Although up to 10 genes have been identified to be related with osteopetrosis, the pathogenesis of osteopetrosis remains foggy. Disease-specific induced pluripotent stem cells (iPSCs) and gene-corrected disease specific iPSCs provide a platform to generate attractive in vitro disease cell models and isogenic control cellular models respectively. The purpose of this study is to rescue the disease causative mutation in osteopetrosis specific induced pluripotent stem cells and provide isogenic control cellular models. METHODS: Based on our previously established osteopetrosis-specific iPSCs (ADO2-iPSCs), we repaired the point mutation R286W of the CLCN7 gene in ADO2-iPSCs by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mediated homologous recombination. RESULTS: The obtained gene corrected ADO2-iPSCs (GC-ADO2-iPSCs) were characterized in terms of hESC-like morphology, a normal karyotype, expression of pluripotency markers, homozygous repaired sequence of CLCN7 gene, and the ability to differentiate into cells of three germ layers. CONCLUSIONS: We successfully corrected the point mutation R286W of the CLCN7 gene in ADO2-iPSCs. This isogenic iPSC line is an ideal control cell model for deciphering the pathogenesis of osteopetrosis in future studies.

Machine learning-based intradialytic hypotension prediction of patients undergoing hemodialysis: A multicenter retrospective study.

BACKGROUND AND OBJECTIVE: Intradialytic hypotension (IDH) is closely associated with adverse clinical outcomes in HD-patients. An IDH predictor model is important for IDH risk screening and clinical decision-making. In this study, we used Machine learning (ML) to develop IDH model for risk prediction in HD patients. METHODS: 62,227 dialysis sessions were randomly partitioned into training data (70%), test data (20%), and validation data (10%). IDH-A model based on twenty-seven variables was constructed for risk prediction for the next HD treatment. IDH-B model based on ten variables from 64,870 dialysis sessions was developed for risk assessment before each HD treatment. Light Gradient Boosting Machine (LightGBM), Linear Discriminant Analysis, support vector machines, XGBoost, TabNet, and multilayer perceptron were used to develop the predictor model. RESULTS: In IDH-A model, we identified the LightGBM method as the best-performing and interpretable model with C- statistics of 0.82 in Fall30Nadir90 definitions, which was higher than those obtained using the other models (P<0.01). In other IDH standards of Nadir90, Nadir100, Fall20, Fall30, and Fall20Nadir90, the LightGBM method had a performance with C- statistics ranged 0.77 to 0.89. As a complementary application, the LightGBM model in IDH-B model achieved C- statistics of 0.68 in Fall30Nadir90 definitions and 0.69 to 0.78 in the other five IDH standards, which were also higher than the other methods, respectively. CONCLUSION: Use ML, we identified the LightGBM method as the good-performing and interpretable model. We identified the top variables as the high-risk factors for IDH incident in HD-patient. IDH-A and IDH-B model can usefully complement each other for risk prediction and further facilitate timely intervention through applied into different clinical setting.

Proteomics profiling and lysine malonylation analysis in primary Sjogren's syndrome.

Primary Sjogren's Syndrome (pSS) is a chronic autoimmune disease, with unclear pathogenies. Lysine-malonylation (Kmal) as a novel post-translational modification (PTMs) was found associated with metabolic, immune, and inflammatory processes. For purpose of investigating the proteomic profile and functions of kmal in pSS, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis and bioinformatics analysis are performed based on twenty-eight pSS patients versus twenty-seven healthy controls (HCs). A total of 331 down-regulated proteins and 289 up-regulated proteins are observed in differentially expressed proteins (DEPs) of pSS. We discover the expression of transforming growth factor beta-1 (TGFB1) and CD40 ligand downregulate which enriches in the inflammatory associated pathway. Expression of signal transducer and activator of transcription 1-alpha/beta (STAT1) show upregulation and enrich in type I interferon signaling pathway and IL-27-mediated signaling pathway. In differentially malonylated proteins (DMPs) of pSS, we identify 3 proteins are down-regulated in 7 sites and 18 proteins are up-regulated in 19 sites. Expression of malonylated integrin-linked kinase (ILK) significantly enrich in the focal adhesion pathway. Together, our data provide evidence that downregulation of TGFB1 and CD40LG play a critical role in the inflammatory process of pSS, while upregulation of STAT1 may be associated with IL-27 immunity and pSS immune dysfunction. Moreover, kmal modification at the kinase domain of ILK may destabilize ILK that thus contributing to pSS pathogenies by regulating the focal adhesion pathway. SIGNIFICANCE: Our research offered the first characterization of Kmal, a newly identified form of lysine acylation in pSS, as well as proteomic data on individuals with pSS. In this study, we found that several key DMPs were associated with focal adhesion pathway, which contributes to the development of pSS. The present results provide an informative dataset for the future exploration of Kmal in pSS.

Urinary microbiota and serum metabolite analysis in patients with diabetic kidney disease.

Background: Diabetic kidney disease (DKD) is a common and potentially fatal consequence of diabetes. Chronic renal failure or end-stage renal disease may result over time. Numerous studies have demonstrated the function of the microbiota in health and disease. The use of advanced urine culture techniques revealed the presence of resident microbiota in the urinary tract, undermining the idea of urine sterility. Studies have demonstrated that the urine microbiota is related with urological illnesses; nevertheless, the fundamental mechanisms by which the urinary microbiota influences the incidence and progression of DKD remain unclear. The purpose of this research was to describe key characteristics of the patients with DKD urinary microbiota in order to facilitate the development of diagnostic and therapeutic for DKD. Methods: We evaluated the structure and composition of the microbiota extracted from urine samples taken from DKD patients (n = 19) and matched healthy controls (n = 15) using 16S rRNA gene sequencing. Meanwhile, serum metabolite profiles were compared using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Associations between clinical characteristics, urine microbiota, and serum metabolites were also examined. Finally, the interaction between urine microbiota and serum metabolites was clarified based on differential metabolite abundance analysis. Results: The findings indicated that the DKD had a distinct urinary microbiota from the healthy controls (HC). Taxonomic investigations indicated that the DKD microbiome had less alpha diversity than a control group. Proteobacteria and Acidobacteria phyla increased in the DKD, while Firmicutes and Bacteroidetes decreased significantly (P < 0.05). Acidobacteria was the most prevalent microbiota in the DKD, as determined by the Linear discriminant analysis Effect Size (LEfSe) plot. Changes in the urinary microbiota of DKD also had an effect on the makeup of metabolites. Short-chain fatty acids (SCFAs) and protein-bound uremic toxins (PBUTs) were shown to be specific. Then we discovered that arginine and proline metabolism was the primary mechanism involved in the regulation of diabetic kidney disease. Conclusions: This study placed the urinary microbiota and serum metabolite of DKD patients into a functional framework and identified the most abundant microbiota in DKD (Proteobacteria and Acidobacteria). Arginine metabolites may have a major effect on DKD patients, which correlated with the progression of DKD.