Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.

Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.

Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.

Prevalence, Predictors, and Outcomes of Pulmonary Hypertension in Patients with Lupus Nephritis.

Background and Objectives: This study aimed to assess the prevalence, predictors, and outcomes of pulmonary hypertension (PH) in patients with lupus nephritis (LN). Materials and Methods: Baseline characteristics and clinical outcomes of 387 patients with LN were retrospectively collected from 2007 to 2017. PH was defined as pulmonary artery systolic pressure ≥40 mmHg assessed by resting transthoracic echocardiography. The primary endpoint was all-cause mortality. The secondary endpoint was renal events, defined as the doubling of baseline serum creatinine or end-stage renal disease. Associations between PH and outcomes were analyzed by Cox regression models. Results: A total of 15.3% (59/387) of patients with LN were diagnosed with PH, and the prevalence of PH was higher for patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 compared to those with an eGFR ≥ 30 mL/min/1.73 m2 (31.5% vs. 12.6%). Higher mean arterial pressure, lower hemoglobin, and lower triglyceride levels were associated with greater odds of having PH. After adjusting for relevant confounding variables, PH was independently associated with a higher risk for death (HR: 2.01; 95% CI: 1.01-4.00; p = 0.047) and renal events (HR: 2.07; 95% CI: 1.04-4.12; p = 0.039). Conclusions: PH is an independent risk factor for all-cause mortality and adverse renal outcomes in patients with LN.

The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-ß1-induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.

Trends in parkinson's disease mortality in China from 2004 to 2021: a joinpoint analysis.

BACKGROUND: This study aimed to analyze the trends of Parkinson's disease (PD) mortality rates among Chinese residents from 2004 to 2021, provide evidence for the formulation of PD prevention and control strategies to improve the quality of life among PD residents. METHODS: Demographic and sociological data such as gender, urban or rural residency and age were obtained from the National Cause of Death Surveillance Dataset from 2004 to 2021. We then analyzed the trends of PD mortality rates by Joinpoint regression. RESULTS: The PD mortality and standardized mortality rates in China showed an overall increasing trend during 2004-2021 (average annual percentage change [AAPC] = 7.14%, AAPCASMR=3.21%, P < 0.001). The mortality and standardized mortality rate in male (AAPC = 7.65%, AAPCASMR=3.18%, P < 0.001) were higher than that of female (AAPC = 7.03%, AAPCASMR=3.09%, P < 0.001). The PD standardized mortality rates of urban (AAPC = 5.13%, AAPCASMR=1.76%, P < 0.001) and rural (AAPC = 8.40%, AAPCASMR=4.29%, P < 0.001) residents both increased gradually. In the age analysis, the mortality rate increased with age. And the mortality rates of those aged > 85 years was the highest. Considering gender, female aged > 85 years had the fastest mortality trend (annual percentage change [APC] = 5.69%, P < 0.001). Considering urban/rural, rural aged 80-84 years had the fastest mortality trend (APC = 6.68%, P < 0.001). CONCLUSIONS: The mortality rate of PD among Chinese residents increased from 2004 to 2021. Male sex, urban residence and age > 85 years were risk factors for PD-related death and should be the primary focus for PD prevention.

Quantum spin driven Yu-Shiba-Rusinov multiplets and fermion-parity-preserving phase transition in K3C60.

Magnetic impurities in superconductors are of increasing interest due to emergent Yu-Shiba-Rusinov (YSR) states and Majorana zero modes for fault-tolerant quantum computation. However, a direct relationship between the YSR multiple states and magnetic anisotropy splitting of quantum impurity spins remains poorly characterized. By using scanning tunneling microscopy, we systematically resolve individual transition-metal (Fe, Cr, and Ni) impurities induced YSR multiplets as well as their Zeeman effects in the K3C60 superconductor. The YSR multiplets show identical d orbital-like wave functions that are symmetry-mismatched to the threefold K3C60(1 1 1) host surface, breaking point-group symmetries of the spatial distribution of YSR bound states in real space. Remarkably, we identify an unprecedented fermion-parity-preserving quantum phase transition between ground states with opposite signs of the uniaxial magnetic anisotropy that can be manipulated by an external magnetic field. These findings can be readily understood in terms of anisotropy splitting of quantum impurity spins, and thus elucidate the intricate interplay between the magnetic anisotropy and YSR multiplets.

Proteomics-Based Identification of Potential Therapeutic Targets of Artesunate in a Lupus Nephritis MRL/lpr Mouse Model.

This study aimed to identify potential therapeutic targets of artesunate in an MRL/lpr lupus nephritis mouse model by quantitative proteomics. We detected serum autoimmune markers and proteinuria in 40 female mice that were divided into 4 groups (n = 10): normal C57BL/6 control group; untreated MRL/lpr lupus; 9 mg/kg/day prednisone positive control MRL/lpr lupus; and 15 mg/kg/day artesunate-treated MRL/lpr lupus groups. Renal pathology in the untreated MRL/lpr lupus and artesunate groups was examined by Periodic acid-Schiff (PAS) staining. Artesunate treatment in lupus mice decreased serum autoantibody levels and proteinuria while alleviating lupus nephritis pathology. Through tandem mass tag-tandem mass spectrometry (TMT-MS/MS) analyses, differentially expressed proteins were identified in the artesunate group, and subsequent functional prediction suggested associations with antigen presentation, apoptosis, and immune regulation. Data are available via ProteomeXchange with the identifier PXD046815. Parallel reaction monitoring (PRM) analysis of the top 19 selected proteins confirmed the TMT-MS/MS results. Immunohistochemistry, immunofluorescence, and Western blotting of an enriched protein from PRM analysis, cathepsin S, linked to antigen presentation, highlighted its upregulation in the untreated MRL/lpr lupus group and downregulation following artesunate treatment. This study suggests that artesunate holds potential as a therapeutic agent for lupus nephritis, with cathepsin S identified as a potential target.

The multilevel extensive diversity across the cynomolgus macaque captured by ultra-deep adaptive immune receptor repertoire sequencing.

The extent to which AIRRs differ among and within individuals remains elusive. Via ultra-deep repertoire sequencing of 22 and 25 tissues in three cynomolgus macaques, respectively, we identified 84 and 114 novel IGHV and TRBV alleles, confirming 72 (85.71%) and 100 (87.72%) of them. The heterogeneous V gene usage patterns were influenced, in turn, by genetics, isotype (for BCRs only), tissue group, and tissue. A higher proportion of intragroup shared clones in the intestinal tissues than those in other tissues suggests a close intra-intestinal adaptive immunity network. Significantly higher mutation burdens in the public clones and the inter-tissue shared IgM and IgD clones indicate that they might target the shared antigens. This study reveals the extensive heterogeneity of the AIRRs at various levels and has broad fundamental and clinical implications. The data generated here will serve as an invaluable resource for future studies on adaptive immunity in health and diseases.

Characterizing 226Ra and its daughters in coastal zone groundwater of a typical human-activity affected bay: occurrence, safety, and source evaluation.

Due to their extremely toxic properties, 226Ra and it daughters (222Rn, 210Pb, and 210Po) in drinking groundwater require monitoring. Recent studies have reported exceptionally high levels of natural 210Po (up to 10,000 Bq/m3), 226Ra, and 222Rn isotopes in groundwater. This study aims to provide background data on 226Ra and its daughter radionuclides in the typical agricultural-industrial Dongshan Bay (DSB) before the construction of Zhangzhou Nuclear Power Plant (Zhangzhou NPP). The measurement results indicate that no abnormally high activities of 210Po and 210Pb were detected in the investigated wells. Strong positive correlations between 210Pb and 210Po, as well as between 222Rn and 210Pb activities, suggest that the origins of 210Pb and 210Po in groundwater are strongly influenced by the decay of the parent radionuclides 222Rn and 210Pb, respectively. In the DSB coastal zone groundwater, significant deficiencies of 210Po relative to 210Pb and 210Pb relative to 222Rn were observed, providing further evidence that 210Po and 210Pb are also effectively scavenged due to their geochemical properties (specifically particle affinity) within the groundwater-aquifer system. A systematic comparison among all relevant water bodies in the DSB revealed that the activity concentrations of 210Pb and 210Po in groundwater were the highest, except for rainwater. Based on the evaluation of 210Pb sources, the results imply that submarine groundwater discharge (SGD) is an important pathway for transferring radionuclides (such as 210Pb) from land to the nearshore marine environment, even though the study area has a lower 210Pb background groundwater. By considering all the 210Pb's sources in the DSB, we found low 210Pb background groundwater discharge still needs to be taken into account for small-scale bays. This is because SGD was calculated to be one of the most important 210Pb sources in the bay during observation season. Regardless of whether the system is in a normal state or a nuclear accident emergency state, greater attention should be paid to the groundwater discharge of radionuclides into the ocean.

Fresh and saline groundwater nutrient inputs and their impacts on the nutrient budgets in a human-effected bay.

Submarine groundwater discharge (SGD) can be highly enriched in nutrients, especially in bays with strong human activity, but has often been overlooked in coastal nutrient budgets. This study investigated the impact of both fresh and saline SGD on nutrient budgets in Sanmen Bay, China, a region heavily influenced by human activities. Based on the 224Ra mass balance model, the total SGD flux was estimated to be (1.1 ± 0.1) × 108 m3 d-1 (13.9 ± 0.5 cm d-1). Additionally, a water-salt mass balance model revealed that fresh SGD flux accounted for ~9.0 % of the total SGD flux. The results highlight the significance of fresh SGD as a freshwater source, contributing to 35.9 % of the total dissolved inorganic phosphorus (DIP) flux via SGD. Considering all nutrient sources and sinks in the Sanmen Bay, SGD was identified as the primary source of nutrients in Sanmen Bay, contributing 53.9 % and 11.9 % of the total dissolved inorganic nitrogen (DIN) and DIP input, respectively. Furthermore, the discharge of industrial/domestic sewage and mariculture wastewater also posed a potential threat to nutrient levels in the bay. Thus, initiatives such as reasonable control of culture species and scale, strengthening wastewater discharge and SGD management are crucial for maintaining the ecological environment of the Sanmen Bay.

Rapid dissolution microneedle based on polyvinyl alcohol/chitosan for local oral anesthesia.

At present, the main clinical methods of oral local anesthesia are direct injection of anesthetic and surface ointment. However, the pain and fear caused by the injection, the discomfort of topical anesthetic creams, and the scour and moist oral environment during the procedure pose great challenges to oral anesthesia. Herein, we designed a Lido-PVP/PVA DMNP microneedle (MN) for oral local anesthesia. The microneedle tip was consisted of Polyvinylpyrrolidone/Polyvinyl alcohol (PVP/PVA), which can quickly dissolve and release the lidocaine hydrochloride (Lido) drug within 5 min to achieve rapid anesthesia. The backing was composed of polyvinyl alcohol/chitosan (PVA/CS), and its excellent adhesion can overcome saliva erosion and anchor firmly to the oral mucosa, significantly improving the utilization rate of drugs, as well as the patient compliance. MNs have good mechanical properties for tissue insertion while possessing high drug loading (3 mg/MNs). Von Frey tests proved that MNs showed a faster and more effective local anesthetic effect (anesthesia takes effect at 5 min) compared to cream (anesthesia takes effect at 30 min). In addition, the excellent biocompatibility and no skin irritation endowed Lido-PVP/PVA DMNP MNs a great potential for oral local anesthesia in the oral cavity.

Guidelines of integrated Chinese and western medicine for diagnosis and treatment of chronic obstructive pulmonary disease (2022).

Chronic obstructive pulmonary disease (COPD), with high prevalence rate, mortality, disability rate, and heavy disease burden, has become a critical chronic disease seriously threatening public health worldwide. Traditional Chinese medicine and Western medicine both have shown advantages in diagnosing and treating COPD, which has been widely applied in the clinics. In order to improve the diagnostic and treatment level for COPD with integrated traditional Chinese and Western medicine, the Guidelines of Integrated Chinese and Western Medicine for Diagnosis and Treatment of COPD were developed by the Internal Medicine Committee of the World Federation of Chinese Medicine Societies. First, a multidisciplinary working group was established. Development methods and processes of international clinical practice guidelines were adopted in the whole research. In final, a total of 13 recommendations for the diagnosis and treatment of COPD were established based on available evidence with the best quality. Meanwhile, characteristics of integrated traditional Chinese and Western medicine in treating COPD were taken into account with pros and cons of each intervention. The guidelines could be used as a reference for physicians in respiratory medicine departments (traditional Chinese medicine, integrated traditional Chinese and Western medicine, and Western medicine) at various levels of medical institutions in their diagnosis and treatment.

A pedigree with retinitis pigmentosa and its concomitant ophthalmic diseases.

AIM: To characterize the ophthalmic clinical phenotype of a family with retinitis pigmentosa (RP) and closed-angle glaucoma and to detect pathogenic genes and mutation sites causing RP in this family. METHODS: Ophthalmic clinic performance was examined in detail in 8 enrolled family members. Genomic DNA was extracted from the peripheral blood of 4 family members for whole-exome sequencing (WES) to select potential genetic mutations whose structures were identified by bioinformatics analysis. Then, Sanger sequencing was used in 12 family members and control group members to validate and confirm the disease-causing mutation loci, and we analyzed the genotype-phenotype relationships. RESULTS: The known c.512C>T (p.P171L) mutation in the rhodopsin (RHO) gene was only found in afflicted family members and was confirmed by WES and Sanger sequencing as the pathogenic mutation in this family. In addition to being diagnosed with RP, family member III:4 was found to have bilateral closed-angle glaucoma, high myopia, and concurrent cataracts, and family members II:2 and II:4 had pathological changes of anterior chamber angle narrowing. Family members IV:3 and IV:4 were found to have retinoschisis. CONCLUSION: Glaucoma and related pathological changes, such as retinoschisis, in family members are preliminarily considered RP complications caused by RHO mutation.

Bu-Fei Yi-Shen Granules Reduce Acute Exacerbations in Patients with GOLD 3-4 COPD: A Randomized Controlled Trial.

Purpose: Chronic obstructive pulmonary disease (COPD) is a disease characterized by frequent acute exacerbations (AEs), especially in severe and very severe cases. We aimed to evaluate the efficacy and safety of Bu-fei Yi-shen granules (BYGs) for COPD. Patients and Methods: We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of 348 COPD patients with GOLD 3-4 COPD. The patients were randomly assigned into experimental or control groups in a 1:1 ratio. Patients in the experimental group were prescribed BYG, while those in the control group were administered a placebo, orally, twice daily, with 5 days on and 2 days off per week for 52 weeks. The outcomes included AEs, pulmonary function, clinical signs and symptoms, dyspnea scores (mMRC), quality of life scores, and a 6-minute walk test (6MWT). Results: A total of 280 patients completed the trial, including 135 patients in the experimental group and 145 in the control group. Compared to the control group, significant differences were observed in frequencies of AEs (mean difference: -0.35; 95% CI: -0.61, -0.10; P = 0.006) and AE-related hospitalizations (-0.18; 95% CI: -0.36, -0.01; P = 0.04), 6MWD (40.93 m; 95% CI: 32.03, 49.83; P < 0.001), mMRC (-0.57; 95% CI: -0.76, -0.37; P < 0.001), total symptoms (-2.18; 95% CI: -2.84, -1.53; P < 0.001), SF-36 (11.60; 95% CI: 8.23, 14.97; P < 0.001), and mCOPD-PRO (-0.45; 95% CI: -0.57, -0.33; P < 0.001) after treatment. However, there were no significant differences in mortality, pulmonary function, and mESQ-PRO scores (P > 0.05). No obvious adverse events were observed. Conclusion: BYG, as compared to a placebo, could significantly reduce the frequencies of AEs and AE-related hospitalizations for GOLD 3-4 COPD patients. Clinical symptoms, treatment satisfaction, quality of life, and exercise capacity improved. There was no significant improvement in mortality and pulmonary function.

SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation.

"Cytokine storm" is common in critically ill COVID-19 patients, however, mechanisms remain largely unknown. Here, we reported that overexpression of SARS-CoV-2 N protein in diabetic db/db mice significantly increased tubular death and the release of HMGB1, one of the damage-associated molecular patterns (DAMPs), to trigger M1 proinflammatory macrophage activation and production of IL-6, TNF-α, and MCP-1 via a Mincle-Syk/NF-κB-dependent mechanism. This was further confirmed in vitro that overexpression of SARS-CoV-2 N protein caused the release of HMGB1 from injured tubular cells under high AGE conditions, which resulted in M1 macrophage activation and production of proinflammatory cytokines via a Mincle-Syk/NF-κB-dependent mechanism. This was further evidenced by specifically silencing macrophage Mincle to block HMGB1-induced M1 macrophage activation and production of IL-6, TNF-α, and MCP-1 in vitro. Importantly, we also uncovered that treatment with quercetin largely improved SARS-CoV-2 N protein-induced AKI in db/db mice. Mechanistically, we found that quercetin treatment significantly inhibited the release of a DAMP molecule HMGB1 and inactivated M1 pro-inflammatory macrophage while promoting reparative M2 macrophage responses by suppressing Mincle-Syk/NF-κB signaling in vivo and in vitro. In conclusion, SARS-CoV-2 N protein-induced AKI in db/db mice is associated with Mincle-dependent M1 macrophage activation. Inhibition of this pathway may be a mechanism through which quercetin inhibits COVID-19-associated AKI.

Comparison of the Oral Calcimimetics Evocalcet and Cinacalcet in East Asian Patients on Hemodialysis with Secondary Hyperparathyroidism.

Introduction: Evocalcet is an oral calcimimetic agent with proven efficacy and safety in treating secondary hyperparathyroidism (SHPT) in Japanese patients on dialysis. Methods: This randomized, double-blind, intrapatient dose-adjustment, parallel-group, international multicenter study compared the efficacy and safety of evocalcet versus cinacalcet for 52 weeks in East Asian hemodialysis patients with SHPT. Results: In total, 203 and 200 patients were randomized to receive evocalcet or cinacalcet, respectively (overall, 70.1% had baseline intact parathyroid hormone (PTH) levels ≥500 pg/ml, with no between-group difference). Mean percentage changes in intact PTH levels from baseline were -34.7% and -30.2% in the evocalcet and cinacalcet groups at 52 weeks (between-group difference -4.4%, 95% confidence interval [CI] -13.1%, 4.3%, below the predefined 15% noninferiority margin). Overall, 67.3% and 58.7% of patients in the evocalcet and cinacalcet groups, respectively, achieved ≥30% decrease in intact PTH levels from baseline (between-group difference 8.6%; 95% CI -1.8%, 19.1%). No major safety concerns were observed. Gastrointestinal adverse events (AEs) were significantly less frequent with evocalcet compared with cinacalcet (33.5% vs. 50.5%, P = 0.001), whereas the incidence of hypocalcemia did not differ. Conclusion: Evocalcet might be a better alternative to cinacalcet for East Asian patients on hemodialysis with SHPT.

The fragmentomic property of plasma cell-free DNA enables the non-invasive detection of diabetic nephropathy in patients with diabetes mellitus.

Background: Diabetic nephropathy (DN) is one of the most prevalent complications of diabetes mellitus (DM). However, there is still a lack of effective methods for non-invasive diagnosis of DN in clinical practice. We aimed to explore biomarkers from plasma cell-free DNA as a surrogate of renal biopsy for the differentiation of DN patients from patients with DM. Materials and methods: The plasma cell-free DNA (cfDNA) was sequenced from 53 healthy individuals, 53 patients with DM but without DN, and 71 patients with both DM and DN. Multidimensional features of plasma DNA were analyzed to dissect the cfDNA profile in the DM and DN patients and identify DN-specific cfDNA features. Finally, a classification model was constructed by integrating all informative cfDNA features to demonstrate the clinical utility in DN detection. Results: In comparison with the DM patients, the DN individuals exhibited significantly increased cfDNA concentration in plasma. The cfDNA from the DN patients showed a distinct fragmentation pattern with an altered size profile and preferred motifs that start with "CC" in the cfDNA ending sites, which were associated with deoxyribonuclease 1 like 3 (DNASE1L3) expression in the kidney. Moreover, patients with DM or DN were found to carry more alterations in whole-genome cfDNA coverage when compared with healthy individuals. We integrated DN-specific cfDNA features (cfDNA concentration, size, and motif) into a classification model, which achieved an area under the receiver operating characteristic curve (AUC) of 0.928 for the differentiation of DN patients from DM patients. Conclusion: Our findings showed plasma cfDNA as a reliable non-invasive biomarker for differentiating DN patients from DM patients. The utility of cfDNA in clinical practice in large prospective cohorts is warranted.

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.

The Progress in the Application of Dissolving Microneedles in Biomedicine.

In recent years, microneedle technology has been widely used for the transdermal delivery of substances, showing improvements in drug delivery effects with the advantages of minimally invasive, painless, and convenient operation. With the development of nano- and electrochemical technology, different types of microneedles are increasingly being used in other biomedical fields. Recent research progress shows that dissolving microneedles have achieved remarkable results in the fields of dermatological treatment, disease diagnosis and monitoring, and vaccine delivery, and they have a wide range of application prospects in various biomedical fields, showing their great potential as a form of clinical treatment. This review mainly focuses on dissolving microneedles, summarizing the latest research progress in various biomedical fields, providing inspiration for the subsequent intelligent and commercial development of dissolving microneedles, and providing better solutions for clinical treatment.