A Scaled Proteomic Discovery Study for Prostate Cancer Diagnostic Markers Using ProteographTM and Trapped Ion Mobility Mass Spectrometry.

There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate cancer progression. Additionally, optimized machine learning classifier analysis reveals proteomic signatures capable of detecting the disease prior to biopsy, performing on par with an accepted clinical risk calculator benchmark.

Realizing ampere-level CO2 electrolysis at low voltage over a woven network of few-atom-layer ultralong silverene nanobelts with ultrahigh aspect ratio by pairing with formaldehyde oxidation.

The development of advanced multi-functional electrocatalysts and their industrial operation on paired electrocatalysis systems presents a promising avenue for the gradual penetration of renewable energy into practical production. Herein, a self-supported conductive network of silverene nanobelts (Ag-ene NBs) was delicately assembled (Ag-NB-NWs), in which ultralong and few-atom-layer Ag-ene NBs with a high edge-to-facet ratio were interconnected, serving as "superreactors" for electron transfer and mass transport during the reaction. Such superstructures as electrocatalysts delivered an unparalleled performance toward the CO2-to-CO conversion with exclusively high faradaic efficiency (FE) and partial current densities of up to 1 A cm-2. Remarkably, the membrane electrode assembly (MEA) cell with Ag-NB-NWs as the cathode was capable of ultrastable and continuous operation for over 240 h at 0.4 A with ∼100% selectivity. More importantly, by further using Ag-NB-NWs as a bifunctional electrocatalyst, a record-low voltage overall CO2 electrolysis system coupling cathodic CO2 reduction with anodic formaldehyde oxidation in MEA cell was performed to achieve concurrent feed gas generation and formate production, substantially improving electrochemical techno-economic feasibility.

An Aryl-ether-linked Covalent Organic Framework Modified with Thioamide Groups for Selective Extraction of Palladium from Strong Acid Solutions.

Efficient adsorption of palladium ions from acid nuclear waste solution is crucial for ensuring the safety of vitrification process for radioactive waste. However, the limited stability and selectivity of most current adsorbents hinder their practical applications under strong acid and intense radiation conditions. Herein, to address these limitations, we designed and synthesized an aryl-ether-linked covalent organic framework (COF-316-DM) grafted dimethylthiocarbamoyl groups on the pore walls. This unique structure endows COF-316-DM with high stability and exceptional palladium capture capacity. The robust polyarylether linkage enables COF-316-DM to withstand irradiation doses of 200 or 400 kGy of ß/γ ray. Furthermore, COF-316-DM demonstrates fast adsorption kinetics, high adsorption capacity (147 mg g-1 ), and excellent reusability in 4 M nitric acid. Moreover, COF-316-DM exhibits remarkable selectivity for palladium ions in the presence of 17 interference ions, simulating high level liquid waste scenario. The superior adsorption performance can be attributed to the strong binding affinity between the thioamide groups and Pd2+ ions, as confirmed by the comprehensive analysis of FT-IR and XPS spectra. Our findings highlight the potential of COFs with robust linkers and tailored functional groups for efficient and selective capture of metal ions, even in harsh environmental conditions.

Roles of mesangial C3 and C1q deposition in the clinical manifestations and prognosis of IgAN.

BACKGROUND AND AIM: Immunoglobulin A nephropathy (IgAN) is regarded as the most common type of glomerulonephritis around the world and has the potential to result in renal failure. Complement activation has been addressed by a great body of evidence in the pathogenesis of IgAN. We aimed to evaluate the predictive value of C3 and C1q deposition for disease progression in IgAN patients in this retrospective study. METHODS: We recruited 1191 biopsy-diagnosed IgAN patients, and they were divided into different groups according to their glomerular immunofluorescence examination of renal biopsy tissues: 1) C3 deposits ≥ 2 + group (N = 518) and C3 deposits < 2 + group (N = 673). 2) C1q deposit-positive group (N = 109) and C1q deposit-negative group (N = 1082). The renal outcomes were end-stage renal disease (ESRD) and/or an estimated glomerular filtration rate (eGFR) decrease greater than 50% from the baseline value. Kaplan-Meier analyses were performed to evaluate renal survival. Univariate and multivariate Cox proportional hazard regression models were used to evaluate the effect of C3 and C1q deposition on renal outcome in IgAN patients. In addition, we compared the predictive value of mesangial C3 and C1q deposition in IgAN patients. RESULTS: The median follow-up period was 53 months (interquartile range 36-75 months). During follow-up, 7% (84) of patients progressed to ESRD, and 9% (111) of patients had an eGFR decline ≥ 50%. IgAN patients complicated with C3 deposits ≥ 2 + were associated with more severe renal dysfunction and pathologic lesions at the time of renal biopsy. The crude incidence rates for the endpoint were 12.5% (84 out of 673) and 17.2% (89 out of 518) in the C3 < 2 + and C3 ≥ 2 + groups, respectively (P = 0.022). Of C1q deposit-positive and C1q deposit-negative patients, 22.9% (25 out of 109) and 13.7% (148 out of 1082) reached the composite endpoint, respectively (P = 0.009). Adding C3 deposition to clinical and pathologic models had better predictability of renal disease progression than C1q. CONCLUSION: Glomerular C3 and C1q deposits affected the clinicopathologic features of IgAN patients and emerged as independent predictors and risk factors for renal outcomes. In particular, the predictive ability of C3 was slightly better than that of C1q.

Association of obesity with the development of end stage renal disease in IgA nephropathy patients.

Background and aim: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We aimed to evaluate whether obesity is a risk factor for IgAN patients. Methods: A total of 1054 biopsy-proven IgAN patients were analyzed in this retrospective study. Patients were divided into four groups according to their body weight index (BMI) at the period of renal biopsy: underweight group (BMI< 18.5, N=75), normal weight group (18.5≤BMI<24, N=587), overweight group (24≤BMI<28, N=291) and obesity group (28≤BMI, N=101). The endpoint of our study was end stage renal disease (ESRD: eGFR <15 mL/min/1.73 m2 or having renal replacement treatment). Kaplan-Meier analyses and Cox proportional hazard models were performed to evaluate renal survival. Propensity-score matching (PSM) was performed to get the matched cohort to evaluate the role of obesity in IgAN patients. Besides, the effect modification of obesity and hypertension in IgAN patients was clarified by the synergy index. Results: IgAN patients complicated with obesity had more severe renal dysfunction at the time of renal biopsy than those with optimal body weight. In addition, patients with obesity tended to have higher risk of metabolic disorders, such as hyperuricemia (64.4% vs 37%, p<0.001), hypertriglyceridemia (71.3% vs 32.5%, p<0.001) and hypercholesterolemia (46.5% vs 35.6%, p=0.036). It was observed that obesity patients had higher rate of unhealthy behaviors, such as smoking (27.7% vs 16.4%, p=0.006) and alcohol drinking (29.7% vs 19.9%, p=0.027). Although obesity was not confirmed as an independent risk factor for IgAN patients, we found that IgAN patients with obesity presented with higher incidence of hypertension, as well as lower event-free renal survival rate (log-rank p < 0.001), especially in patients with 24-h urine protein ≥ 1g (log-rank p =0.002). In addition, the synergy index showed that there was positive interaction between obesity and hypertension in IgAN. Conclusion: Obesity is an important risk factor for IgAN patients when combined with hypertension. Hypertension appears to be common in obese IgAN patients.

Effectiveness of Microecological Preparations for Improving Renal Function and Metabolic Profiles in Patients With Chronic Kidney Disease.

Background: Determining whether microecological preparations, including probiotics, prebiotics, and synbiotics, are beneficial for patients with chronic kidney disease (CKD) has been debated. Moreover, determining which preparation has the best effect remains unclear. In this study, we performed a network meta-analysis of randomized clinical trials (RCTs) to address these questions. Methods: MEDLINE, EMBASE, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials were searched. Eligible RCTs with patients with CKD who received intervention measures involving probiotics, prebiotics, and/or synbiotics were included. The outcome indicators included changes in renal function, lipid profiles, inflammatory factors, and oxidative stress factors. Results: Twenty-eight RCTs with 1,373 patients were ultimately included. Probiotics showed greater effect in lowering serum creatinine [mean difference (MD) -0.21, 95% confidence interval (CI) -0.34, -0.09] and triglycerides (MD -9.98, 95% CI -19.47, -0.49) than the placebo, with the largest surface area under the cumulative ranking curve, while prebiotics and synbiotics showed no advantages. Probiotics were also able to reduce malondialdehyde (MDA) (MD -0.54, 95% CI -0.96, -0.13) and increase glutathione (MD 72.86, 95% CI 25.44, 120.29). Prebiotics showed greater efficacy in decreasing high-sensitivity C-reactive protein (MD -2.06, 95% CI -3.79, -0.32) and tumor necrosis factor-α (MD -2.65, 95% CI -3.91, -1.39). Synbiotics showed a partially synergistic function in reducing MDA (MD -0.66, 95% CI -1.23, -0.09) and high-sensitivity C-reactive protein (MD -2.01, 95% CI -3.87, -0.16) and increasing total antioxidant capacity (MD 145.20, 95% CI 9.32, 281.08). Conclusion: The results indicated that microbial supplements improved renal function and lipid profiles and favorably affected measures of oxidative stress and inflammation in patients with CKD. After thorough consideration, probiotics provide the most comprehensive and beneficial effects for patients with CKD and might be used as the best choice for microecological preparations. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022295497, PROSPERO 2022, identifier: CRD42022295497.

Triglyceride-Glucose Index May Predict Renal Survival in Patients with IgA Nephropathy.

Background: The triglyceride−glucose (TyG) index is a simple, novel and reliable surrogate marker of insulin resistance. However, evidence for the prognostic impact of an elevated TyG index on IgA nephropathy (IgAN) is limited. Therefore, we evaluated the relationship between the TyG index and the risk of renal progression in IgAN. Method: This cohort study involved biopsy-proven IgAN between January 2009 and December 2018 in West China Hospital, in which patients were assigned to two groups based on the cut-off value of TyG using receiver operating characteristic (ROC) curves. A 1:1 matched-pair analysis was established to optimize the bias in IgAN by propensity score matching (PSM). The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The composite endpoint was defined by eGFR decreased ≥50% of the baseline level, end-stage kidney disease (ESKD), renal transplantation and/or death. Univariable and multivariable Cox proportional hazard models were applied to confirm the predictive value of the optimal marker. Results: Before PSM, a total of 1210 participants were ultimately included. During a median follow-up period of 55.8 months (range 37.20−79.09 months), 129 participants progressed to the composite endpoint (10.7%). After PSM, 366 patients were enrolled in the matched cohort, of whom 34 (9.3%) patients reached the endpoints. Based on the cut-off value of the TyG index, patients were divided into the low TyG index group (TyG ≤ 8.72, n = 690) and the high TyG index group (TyG > 8.72, n = 520). Further analysis demonstrated that a higher TyG index was significantly associated with a higher risk of reaching composite endpoints in IgAN patients in both the unmatched and matched cohorts (before PSM: HR 2.509, 95% CI 1.396−4.511, p = 0.002; after PSM: HR 2.654, 95% CI 1.299−5.423, p = 0.007). Conclusion: A high TyG index is associated with a higher risk of renal progression.

Prognostic Value of Triglyceride to High-Density Lipoprotein Cholesterol Ratio (TG/HDL-C) in IgA Nephropathy Patients.

Background: The triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio is an easy-to-use atherogenic and prognostic marker which has attracted increasing attention these days. However, whether TG/HDL-C correlate with outcomes in IgA nephropathy (IgAN) patients remains unknown. To clarify these issues, we conducted this study. Methods: A total of 1146 patients from West China Hospital of Sichuan University were retrospectively analysed between 2008 and 2018.The demographic, clinical and pathological data of all patients at the time of biopsy were collected. Then, patients were divided into the high TG/HDL group (TG/HDL ≥ 1.495, N=382) and the low TG/HDL group (TG/HDL-C < 1.495, N=764) based on the optimal cut-off value of the TG/HDL-C using receive operating curve. Cox proportional hazard models and Kaplan-Meier curves were used to evaluate the renal outcomes of IgAN. Results: The median age of the patients was 33 (26-42) years, and 44.5% were men. By correlation analysis, we found that the TG/HDL-C ratio was negatively correlated with the eGFR (r = 0.250, P < 0.001) but positively correlated with proteinuria (r = 0.230, P< 0.001), BMI (r=0.380, P<0.001) and serum uric (r =0.308, P< 0.001). Patients with a higher TG/HDL-C ratio tended to have hypertension [odds ratio (OR), 1.987; 95% CI, 1.527-2.587; P<0.001] and more severe pathologic lesions with tubular atrophy/interstitial fibrosis (OR, 1.610; 95% CI, 1.203-2.154; P=0.001). During a median follow-up period of 54.1 (35.6-73.2) months, a high TG/HDL ratio was strongly associated with worse renal survival in IgAN patients (log-rank: P <0.001). Multivariate Cox analysis demonstrated that a high TG/HDL-C ratio (HR 1.775, 95% CI 1.056-2.798; P=0.029) was an independent predictive marker to ESRD. Conclusion: In this study, we addressed the importance of TG/HDL-C ratio as a predictive marker for IgAN progression.

Arterial-Arteriolar Sclerosis Is Independently Associated With Poor Renal Outcome in IgA Nephropathy Patients.

Aim: This study aimed to investigate the clinicopathological features and prognosis of immunoglobulin A nephropathy (IgAN) with arterial-arteriolar sclerosis (AS). Methods: Patients with biopsy-proven IgAN from the West China Hospital of Sichuan University were retrospectively enrolled. Clinicopathological features were collected. Patients were categorized based on the presence and the severity of the AS. All the patients were regularly followed-up until a composite end point. The correlation between AS and prognosis of IgAN was assessed. Results: A total of 1,424 patients were recruited and followed for 60.0 ± 28.7 months. Patients with AS tended to have older age, higher blood pressure, heavier proteinuria, higher serum creatinine, uric acid, and total triglyceride (TG). Meanwhile, they were more likely to have a lower estimated glomerular filtration rate (eGFR), hemoglobin, and albumin. At the end of follow-up, 126 patients in the AS group and 47 patients in the non-AS group had reached the composite end point (p < 0.001). AS was associated with the renal outcome (log-rank p < 0.001) and was an independent risk factor for the progression of IgAN (p = 0.049). The severity of AS was associated with renal outcomes (log-rank p < 0.001) and there was a trend that it might serve as an independent risk marker for progression of IgAN. In the subgroup analysis, patients presenting with AS and lower eGFR, albumin, and hemoglobin or higher proteinuria, uric acid, and TG had a significant trend for a shorter time to reach the end point (log-rank p < 0.001). Conclusion: AS was commonly seen in patients with IgAN and was independently associated with the poor prognosis.

Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis.

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.

Renewable electrochemical sensor for PARP-1 activity detection based on host-guest recognition.

Poly (ADP-ribose) polymerase-1 (PARP-1) was defined as a new biomarker, which has achieved wide attention in recent years. In this work, we designed a renewable electrochemical sensor based on host-guest recognition for the detection of PARP-1 activity. Mono-(6-Mercapto-6-deoxy)-beta-Cyclodextrin (SH-ß-CD) was modified on the electrode surface to recognize the trans-azobenzene labeled dsDNA (Abz-dsDNA). In the presence of PARP-1, PAR with abundant PO43- was generated and reacted with MoO42- to form PMo12O403-, producing strong current. The proposed method avoided the unspecific adsorption effectively and improved the detection accuracy. Under UV irradiation, Abz-dsDNA was removed from the electrode surface because of the configuration change of azobenzene from trans to cis structure, allowing the electrode to be recycled. The sensor realized the linear detection of PARP-1, ranging from 0.01 U to 1.0 U with a detection limit of 0.008 U, which is comparable to results from reported methods. It is expected to be a potential tool for clinical detection because of its high sensitivity and selectivity.

Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.

The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8,823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria, we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally, we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt-signaling pathways in the aging of human liver.

The chromatin remodeling subunit Baf200 promotes normal hematopoiesis and inhibits leukemogenesis.

BACKGROUND: Adenosine triphosphate (ATP)-dependent chromatin remodeling SWI/SNF-like BAF and PBAF complexes have been implicated in the regulation of stem cell function and cancers. Several subunits of BAF or PBAF, including BRG1, BAF53a, BAF45a, BAF180, and BAF250a, are known to be involved in hematopoiesis. Baf200, a subunit of PBAF complex, plays a pivotal role in heart morphogenesis and coronary artery angiogenesis. However, little is known on the importance of Baf200 in normal and malignant hematopoiesis. METHODS: Utilizing Tie2-Cre-, Vav-iCre-, and Mx1-Cre-mediated Baf200 gene deletion combined with fetal liver/bone marrow transplantation, we investigated the function of Baf200 in fetal and adult hematopoiesis. In addition, a mouse model of MLL-AF9-driven leukemogenesis was used to study the role of Baf200 in malignant hematopoiesis. We also explored the potential mechanism by using RNA-seq, RT-qPCR, cell cycle, and apoptosis assays. RESULTS: Tie2-Cre-mediated loss of Baf200 causes perinatal death due to defective erythropoiesis and impaired hematopoietic stem cell expansion in the fetal liver. Vav-iCre-mediated loss of Baf200 causes only mild anemia and enhanced extramedullary hematopoiesis. Fetal liver hematopoietic stem cells from Tie2-Cre + , Baf200 f/f or Vav-iCre + , Baf200 f/f embryos and bone marrow hematopoietic stem cells from Vav-iCre + , Baf200 f/f mice exhibited impaired long-term reconstitution potential in vivo. A cell-autonomous requirement of Baf200 for hematopoietic stem cell function was confirmed utilizing the interferon-inducible Mx1-Cre mouse strain. Transcriptomes analysis revealed that expression of several erythropoiesis- and hematopoiesis-associated genes were regulated by Baf200. In addition, loss of Baf200 in a mouse model of MLL-AF9-driven leukemogenesis accelerates the tumor burden and shortens the host survival. CONCLUSION: Our current studies uncover critical roles of Baf200 in both normal and malignant hematopoiesis and provide a potential therapeutic target for suppressing the progression of leukemia without interfering with normal hematopoiesis.

Structural basis of dual Ca2+/pH regulation of the endolysosomal TRPML1 channel.

The activities of organellar ion channels are often regulated by Ca2+ and H+, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca2+/pH regulation of TRPML1, a Ca2+-release channel crucial for endolysosomal function. TRPML1 mutations cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by neurodegeneration, mental retardation and blindness. We obtained crystal structures of the 213-residue luminal domain of human TRPML1 containing three missense MLIV-causing mutations. This domain forms a tetramer with a highly electronegative central pore formed by a novel luminal pore loop. Cysteine cross-linking and cryo-EM analyses confirmed that this architecture occurs in the full-length channel. Structure-function studies demonstrated that Ca2+ and H+ interact with the luminal pore and exert physiologically important regulation. The MLIV-causing mutations disrupt the luminal-domain structure and cause TRPML1 mislocalization. Our study reveals the structural underpinnings of TRPML1's regulation, assembly and pathogenesis.

Treatment of interstitial peumopathy by fei tong oral liquid in the malignant tumor patients after radio- and/or chemotherapy.

Fei Tong Kou Fu Ye ([symbol: see text]) Fei Tong Oral Liquid) was used to treat 30 cases of interstitial pneumopathy after radio- and/or chemotherapy. In comparison with the control group (15 cases) treated with hormones, the therapeutic effects in improving dyspnea, cough, respiratory rate, cyanosis, findings in X-films and CT examination, partial pressure of oxygen in artery, FVC and VC were found significantly better (P < 0.05). The total effective rate obtained was 83.33%.