A Defective Disc-Like Cu1.96 S Anode Material with the Efficient Cu Vacancies for High-Performance Sodium-Ion Storage.

Due to their significant capacity and reliable reversibility, transition metal sulphides (TMSs) have received attention as potential anode materials for sodium-ion batteries (SIBs). Nonetheless, a prevalent challenge with TMSs lies in their significant volume expansion and sluggish kinetics, impeding their capacity for rapid and enduring Na+ storage. Herein, a Cu1.96 S@NC nanodisc material enriched with copper vacancies is synthesised via a hydrothermal and annealing procedure. Density functional theory (DFT) calculations reveal that the incorporation of copper vacancies significantly boosts electrical conductivity by reducing the energy barrier for ion diffusion, thereby promoting efficient electron/ion transport. Moreover, the presence of copper vacancies creates ample active sites for the integration of sodium ions, streamlines charge transfer, boosts electronic conductivity, and, ultimately, significantly enhances the overall performance of SIBs. This novel anode material, Cu1.96 S@NC, demonstrates a reversible capacity of 339 mAh g-1 after 2000 cycles at a rate of 5 A g-1 . In addition, it maintains a noteworthy reversible capacity of 314 mAh g-1 with an exceptional capacity retention of 96% even after 2000 cycles at 20 A g-1 . The results demonstrate that creating cationic vacancies is a highly effective strategy for engineering anode materials with high capacity and rapid reactivity.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study.

OBJECTIVE: The aim of this study is to identify whether low lupus disease activity status (LLDAS) and clinical remission (CR) of belimumab plus standard of care (SoC) therapy are achievable goals in childhood-onset SLE (cSLE). METHODS: This multicentre, one arm pre-post intervention study was conducted at 15 centers in China. The primary end point was to describe the proportion of patients who achieved LLDAS and CR after 3, 6, and 12 months after treatment with belimumab plus SoC therapy. A multiple regression model was used to impute missing data. A Poisson regression model was used to calculate the effect of belimumab treatment on the reduced risk of serious diseases and the incidence of new damage. RESULT: 193 (92.2% female) with active cSLE from 15 centers were included. At 3, 6 and 12 months, the proportion of LLDAS (CR) was 12.4% (1.0%), 25.6% (4.5%) and 70.3% (29.7%), respectively. The mean SELENA-SLEDAI score decreased from 11.0 at baseline to 3.7, 2.9 and 1.7 at 3, 6, and 12 months. At baseline, all patients received steroids at a mean (SD) prednisone equivalent dose of 31.0 (18.2) mg/day, which decreased to 19.4 (10.8) mg/day at month 3, 12.6 (7.2) mg/day at month 6 and 6.7 (5.3) mg/day at month 12. The symptoms and immunological indicators were also significantly improved. CONCLUSION: This is the first and largest sample size prospective clinical intervention study of cSLE patients treated with belimumab in China. LLDAS and CR were attainable treat-to-target of belimumab plus SoC therapy in cSLE.

Synthesis, characterization, anticancer efficacy evaluation of ruthenium(II) and iridium(III) polypyridyl complexes toward A549 cells.

A new ligand DFIP (2-(dibenzo[b,d]furan-3-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its two complexes iridium(III) [Ir(ppy)2(DFIP)](PF6) (ppy = 2-phenylpyridine, Ir1) and ruthenium(II) [Ru(bpy)2(DFIP)](PF6)2 (bpy = 2,2'-bipyridine, Ru1) were synthesized and characterized. The anticancer effects of the two complexes on A549, BEL-7402, HepG2, SGC-7901, HCT116 and normal LO2 cells were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complex Ir1 shows high cytotoxic activity on A549, BEL-7402, SGC-7901 and HepG2, Ru1 exhibits moderate anticancer activity toward A549, BEL-7402 and SGC-7901 cells. The IC50 values of Ir1 and Ru1 toward A549 are 7.2 ± 0.1 and 22.6 ± 1.4 µM, respectively. The localization of complexes Ir1 and Ru1 in the mitochondrial, intracellular accumulation of reactive oxygen species (ROS) levels, and the changes of mitochondrial membrane potential (MMP) and cytochrome c (cyto-c) were investigated. Apoptosis and cell cycle were detected by flow cytometry. Immunogenic cell death (ICD) was used to detect the effects of Ir1 and Ru1 on the A549 using a confocal laser scanning microscope. The expression of apoptosis-related proteins was detected by western blotting. Ir1 and Ru1 can increase the intracellular ROS levels and release cyto-c, reduce the MMP, leading to the apoptosis of A549 cells and blocking the A549 cells at the G0/G1 phase. Additionally, the complexes caused a decrease of the expression of polyADP-ribose polymerase (PARP), caspase 3, Bcl-2 (B-cell lymphoma-2), PI3K (phosphoinositide-3 kinase) and upregulated the expression of Bax. All these findings indicated that the complexes exert anticancer efficacy to induce cell death through immunogenic cell death, apoptosis, and autophagy.

Induction of apoptosis in SGC-7901 cells by iridium(III) complexes via endoplasmic reticulum stress-mitochondrial dysfunction pathway.

This study was intended to evaluate the anticancer activity of three newly synthesized iridium(III) complexes [Ir(ppy)2(PEIP)](PF6) (1) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(SIP)](PF6) (2) (SIP = (E)-2-styryl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(PEYIP)](PF6) (3) (PEYIP = 2-phenethynyl-1H-imidazo[4,5-f][1,10]phenanthroline). The cytotoxic activity in vitro against A549, SGC-7901, HepG2, HeLa and normal NIH3T3 cells was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. We found that the complexes 1, 2 and 3 significantly inhibited cell proliferation, in particular, complexes 2 and 3 show high cytotoxic effect on SGC-7901 cells with an IC50 value of 5.8 ± 0.7 and 4.4 ± 0.1 µM. Moreover, cell cycle assay revealed that the complexes could block G2/M phase of the cell cycle. Apoptotic evaluation by Annexin V/PI staining indicated that complexes 1-3 can induce apoptosis in SGC-7901 cells. In addition, microscopy detection suggested that disruption of mitochondrial functions, characterized by increased generation of intracellular ROS and Ca2+ as well as decrease of mitochondrial membrane potential. Western blot analysis shows that the complexes upregulate the expression of pro-apoptotic Bax and downregulate the expression of anti-apoptotic Bcl-2, which further activates caspase-3 and prompts the cleavage of PARP. Taken together, these results demonstrated that complexes 1-3 exert a potent anticancer effect on SGC-7901 cells via ROS-mediated endoplasmic reticulum stress-mitochondrial apoptotic pathway and have a potential to be developed as novel chemotherapeutic agents for human gastric cancer. Three new iridium(III) complexes [Ir(ppy)2(PEIP)](PF6) (1) (ppy = 2-phenylpyridine, PEIP = 2-phenethyl-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(SIP)](PF6) (2) (SIP = 2-styryl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(PEYIP)](PF6) (3) (PEYIP = 2-phenethynyl-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The anticancer activity in vitro was investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results show that the complexes induce apoptosis via ROS-mediated endoplasmic reticulum stress-mitochondrial dysfunction pathway.

In vivo and in vitro impact of miRNA-153 on the suppression of cell growth apoptosis through mTORC2 signaling pathway in breast cancer.

PURPOSE: To investigate the effects and mechanism of miRNA-153 on breast cancer cells in vitro and in vivo. MATERIAL AND METHODS: The cells and mice were divided into five groups: miRNA-153 mimic, miRNA-153 NC, miRNA-153 inhibitor, miRNA-153 inhibitor-NC, and blank control groups. The real-time PCR and western blot were used to detect the rictor expression regulated by miRNA-153. The western blot was used to explore the expression levels of p-Akt Ser473, p-SGK1 Ser422, and p-FOXO1 Thr24 regulated by miRNA-153. The H&E stain was used to detect the morphology and vitality of tumor cells. Flow cytometry analysis or TUNEL detection was used to evaluate the apoptosis of tumor cells. RESULTS: MiRNA-153 was significantly reduced in breast cancer cell lines. The real-time PCR and western blot assay suggested that the miRNA-153 downregulation of rictor expression, which was correlated with the antitumor effects both in vitro and in vivo. The western blot assay also showed that the expression levels of p-Akt Ser473, p-SGK1 Ser422, and p-FOXO1 Thr24 were largely reduced in miRNA-153 treated group, which indicated that miRNA-153 inhibited breast cancer growth by regulation of mTORC2 signaling pathway. The H&E stain demonstrated that the morphology and vitality of tumor cells in tumor tissues were influenced in miRNA-153 mimic treated group. The TUNEL detection also showed a great quantity of apoptotic cells in the miRNA-153 mimic group. CONCLUSIONS: All these results uncovering that the miRNA-153 inhibited breast cancer growth via regulation of mTORC2 signaling pathway, which provided breast cancer treatment a novel direction.

Safety and efficacy of telitacicept in refractory childhood-onset systemic lupus erythematosus: A self-controlled before-after trial.

OBJECTIVE: To observe the efficacy and safety of telitacicept in refractory childhood-onset systemic lupus erythematosus (cSLE). METHODS: A self-controlled before-after trial. Children with active SLE, aged 5-18 years, who cannot tolerate side effects of glucocorticoid, were enrolled in our study. Patients received subcutaneous injection of telitacicept weekly based on the standard treatment. SLE responder index-4 (SRI-4) was assessed before the first administration and at least 4 weeks after the first administration. RESULTS: Among the 15 cases of refractory cSLE, three were males (20%) and 12 were females (80%). The median age and weight were 13 years old and 52 kg, respectively. The median duration of disease was 30 months. 5-26 weeks (80 or 160 mg per week) after administration of telitacicept, 66.7% (n=10) reached SRI-4 response. 12 cases reduced their glucocorticoid intake from 40 mg/d to 17.5 mg/d. The urinary protein after treatment declined in 8 cases whose 24-h proteinuria was >0.5 g at baseline. The urinary protein in two of the eight cases turned negative and plasma albumin in five of the eight cases rose to normal. In addition, three of these eight cases demonstrated varying degrees of improvement in renal impairment, whose estimated glomerular filtration rate (eGFR, ml/min·1.73 m2) rose from 17.4 to 26.6, 40.7 to 48.2, and 63.2 to 146.0, respectively. There were mild to moderate adverse events after treatment. CONCLUSION: Telitacicept combined with the standard treatment may significantly increase the SRI-4 response rate and reduce the glucocorticoid dosage in refractory cSLE, and also shown efficacy on lupus nephritis. The related adverse drug events were controllable.

Synthesis of 3-Trifluoromethyl-1,2,4-triazolines and 1,2,4-Triazoles via Tandem Addition/Cyclization of Trifluoromethyl N-Acylhydrazones with Cyanamide.

A tandem addition/cyclization reaction between trifluoromethyl N-acylhydrazones and cyanamide is described, which provides a novel and efficient process for the synthesis of polysubstituted 3-trifluoromethyl-1,2,4-triazolines and their derivatives. The method has the advantages of mild reaction conditions, a broad substrate scope, good product yields, and atom economy.

PPARα agonist exerts protective effects in podocyte injury via inhibition of the ANGPTL3 pathway.

Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exert protective effects on podocytes, whereas angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on these cells. This study aimed to investigate the link between the protective effects of PPARα activation and the pathogenic effects of ANGPTL3 in podocytes. Both PPARα and ANGPTL3 were expressed in cultured podocytes. PPARα mRNA and protein levels decreased whereas ANGPTL3 mRNA and protein levels increased in a time-dependent manner in podocytes treated with puromycin aminonucleoside (PAN). Gemfibrozil, a pharmacological agonist of PPARα, increased PPARα levels and activity in podocytes. The drug also decreased ANGPTL3 levels by potentially weakening ANGPTL3 promoter activity in both normal and PAN-treated podocytes. Furthermore, gemfibrozil significantly decreased PAN-induced apoptosis and F-actin rearrangement. Primary podocytes from Angptl3-knockout mice were cultured. There was no significant difference between Angptl3-/- podocytes treated with or without gemfibrozil in the lamellipodia numbers after PAN treatment. The results suggested that the protective effects of gemfibrozil on podocytes were not exerted following knockout of the Angptl3 gene. This study identified a novel mechanism of the PPARα agonist gemfibrozil that exerts its protective effects by inhibiting PAN-induced apoptosis and cytoskeleton rearrangements through inhibition of ANGPTL3 expression.

A Therapeutic Play Program for Children Undergoing Kidney Biopsy With Local Anesthesia: Construction and Feasibility Evaluation.

PURPOSE: To construct a therapeutic play program for children undergoing preparation for kidney biopsy under local anesthesia and explore the feasibility of the program from stakeholders' perspectives. DESIGN: The program was constructed by a multidisciplinary team and the feasibility and acceptability of the program were explored by a descriptive qualitative study. METHODS: Based on Lazarus & Folkman's stress-coping model and Piaget's theory of play, and using on-site participatory field observation, a multidisciplinary team constructed a therapeutic play program for children undergoing kidney biopsy under local anesthesia. The feasibility and acceptability of the program were evaluated by interviewing children, their caregivers, and physicians. FINDINGS: The main tools constructed for the intervention were a 15-page picture book titled Kidney Biopsy Treasure Hunt and a homemade kidney biopsy play package. The therapeutic play intervention for kidney biopsy under local anesthesia was led by nurses and followed the steps of kidney biopsy, using the picture book, and group play simulation. Through informed in-depth interviews with 10 children and their caregivers, we showed that the therapeutic play program materials were accessible, clinically feasible, and necessary for kidney biopsy under local anesthesia in children. The children and their caregivers had high acceptance of the content of the picture book, the format of the play, and high satisfaction with the overall program. CONCLUSIONS: The therapeutic play program we constructed for children undergoing kidney biopsy with local anesthesia was simple, feasible, and well accepted in the clinical setting.

Sodium-Ion Battery with a Wide Operation-Temperature Range from -70 to 100 °C.

Sodium-ion batteries (SIBs), as one of the potential candidates for grid-scale energy storage systems, are required to tackle extreme weather conditions. However, the all-weather SIBs with a wide operation-temperature range are rarely reported. Herein, we propose a wide-temperature range SIB, which involves a carbon-coated Na4 Fe3 (PO4 )2 P2 O7 (NFPP@C) cathode, a bismuth (Bi) anode, and a diglyme-based electrolyte. We demonstrate that solvated Na+ can be directly stored by the Bi anode via an alloying reaction without the de-solvent process. Furthermore, the NFPP@C cathode exhibits a high Na+ diffusion coefficient at low temperature. As a result, the Bi//NFPP@C battery exhibits perfect low-temperature behavior. Even at -70 °C, this battery still delivers 70.19 % of the room-temperature capacity. Furthermore, benefitting from the high boiling point of the electrolyte, this battery also works well at a high temperature of up to 100 °C. These results are encouraging for the further exploration of wide-temperature range SIBs.

Genetic heterogeneity in Chinese children with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with extreme clinical heterogeneity and significant differences between populations. Here, we performed whole exome sequencing (WES) in 52 children with SLE from China. METHODS: The patients all fulfilled the 2012 SLICC criteria for the classification of SLE. Patients were enrolled if they met one of the following criteria: 1. age of disease onset under 5 years; 2. family history of autoimmune disease; 3. syndromic SLE; and 4. complicated conditions, such as life-threatening and refractory SLE. RESULTS: 52 out of 281 newly diagnosed pSLE patients met the inclusion criteria. We identified causative mutations in 12 patients in five different genes: SLC7A7, NRAS, TNFAIP3, PIK3CD, and IDS. The age of onset was under five years in eight patients (8/15, p=0.003) with mutations. Two of 5 patients had a family history of autoimmune disease, with family members developing different autoimmune diseases. Causal mutations were identified in five patients who presented with syndromic SLE (5/5 p=0.000) and in another five patients who presented with primary immunodeficiency diseases (5/5, p=0.000). Causal mutations were detected in 12 of 36 patients with SLEDAI scores>14 (12/36, p=0.023) and in 9 of 17 patients with haematological and renal involvement (9/17, p=0.048). CONCLUSIONS: We revealed a significant fraction of monogenic SLE aetiologies using WES (12/52, 23.1%). WES should perform in patients with very early onset SLE (<5 years of age), syndromic SLE, severe SLE (SLEDAI score>14), family history of autoimmune disease, primary immunodeficiency disease and renal and haematological involvement.

Resveratrol Stimulates the Na+-Ca2+ Exchanger on the Plasma Membrane to Reduce Cytosolic Ca2+ in Rat Aortic Smooth Muscle Cells.

Resveratrol is well known to exhibit vascular relaxant and antihypertensive effects. In this study, we determined the effects of resveratrol on the modulation of cytosolic [Ca] level and adenosine 5'-triphosphate-induced Ca release from the sarcoplasmic reticulum (SR) in rat aortic smooth muscle cells (ASMCs) and explored its underlying mechanisms. In this article, cytosolic [Ca] and SR [Ca] in ASMCs were determined by Fluo-4/acetoxymethyl and Mag-Fluo-4/acetoxymethyl respectively. Resveratrol (20, 50, and 100 µM) caused a rapid and substantial reduction in cytosolic [Ca] in ASMCs bathed in normal Hank's Balanced Salt Solution or Ca-free Hank's Balanced Salt Solution. Pretreatment with resveratrol reduced adenosine 5'-triphosphate-induced SR Ca release and SR Ca content. In the cells bathed in Na-free physiological saline, which favors the reverse mode of the Na-Ca exchanger (NCX), resveratrol induced an increase in cytosolic [Ca] and SR [Ca]. However, its effect on cytosolic [Ca] was inhibited by the selective NCX inhibitor, SEA0400. Our findings suggest that resveratrol reduces cytosolic [Ca] and SR [Ca] in ASMCs in normal physiological saline, which might be, at least in part, mediated by the NCX.

Phenotypic variability in a child with Felty's syndrome: a case report.

BACKGROUND: Felty's syndrome (FS) is characterized by the triad of rheumatoid arthritis (RA), splenomegaly and neutropenia. The arthritis is typically severe and virtually always associated with high-titer rheumatoid factor. The presence of persistent neutropenia is generally required to make the diagnosis. Most patients diagnosed with FS are aged 50-70 years and have had RA for more than 10 years. It is rarely seen in patients with juvenile idiopathic arthritis (JIA), with only five cases having been reported throughout the world. CASE PRESENTATION: The present study describes the case of a 14-year-old female with a seven-year history of polyarticular JIA, presenting with splenomegaly, hepatomegaly, cholestasis and thrombocytopenia. However, she occasionally developed neutropenia. Titers of rheumatoid factor and anti-CCP were persistently high, and the antinuclear antibody titer was 1:320, while the antibody results for anti-dsDNA and anti-Sm were negative. Serum levels of IgA, IgG, IgM and IgE were all persistently elevated, and the ratio of CD19+ lymphocytes in the subgroups of lymphocytes was persistently high. The level of complements was normal. No STAT3 and STAT5B mutations were found by next-generation sequencing. The patient did not respond to methotrexate, prednisolone, hydroxychloroquine (HCQ), sulfasalazine and etanercept but was responsive to rituximab. CONCLUSIONS: JIA, thrombocytopenia and splenomegaly are the most common and important features in six children with FS, while persistent neutropenia is not seen in all these patients. No complement deficiency has been found in children with FS so far. Manifestations of FS without neutropenia may be extremely rare. There are differences between adults and children in the clinical and laboratory features of FS.

Anti-proteinuria effect of antibody against ANGPTL3 coil-coiled domain on adriamycin-induced nephropathy in mice.

Proteinuria is an important marker and is closely related to the progressive decline of renal function. Our previous research showed that angiopoietin-like-3 (ANGPTL3) plays a crucial role in proteinuria. In this study, we prepared an antibody against ANGPTL3 coil-coiled domain (ANGPTL3-CCD) and investigated the protective effect of anti-ANGPTL3-CCD antibody in mice with adriamycin-induced nephropathy. Nephropathy was established by adriamycin injection at a dose of 25 mg per kg in 8-12 week-old male mice in the ADR group. Blockade of ANGPTL3 by anti-ANGPTL3-CCD antibody (20 mg per kg) was performed every three days nine times after adriamycin injection in the ADR plus anti-angptl3-antibody group. The anti-ANGPTL3-CCD antibody can specifically recognize ANGPTL3. After anti-ANGPTL3-CCD antibody intervention, the urinary protein level in the ADR plus anti-angptl3-antibody group was significantly lower than that in the ADR group. Serum albumin was higher and triglyceride and total cholesterol were lower in the ADR plus anti-angptl3-antibody group than in the ADR group. The levels of serum creatinine did not significantly differ among the groups. Focal sclerotic glomeruli and podocyte foot processes extensive fusion were found in the renal tissue of the ADR group, whereas no sclerotic glomeruli and only partial fusion were found in the ADR plus anti-angptl3-antibody group. This study demonstrated that the anti-ANGPTL3-CCD antibody ameliorated proteinuria and podocyte dysfunction in adriamycin-induced nephropathy in mice.

Expanding the spectrum of A20 haploinsufficiency in two Chinese families: cases report.

BACKGROUND: The association between mutations in the TNFAIP3 gene and a new autoinflammatory disease (called A20 haploinsufficiency, HA20) has recently been recognized. Here, we describe four patients with HA20 from two unrelated Chinese families. CASE PRESENTATION: A total of four patients from two families were included. The average age at onset was 5.9 years. All patients had no signs of eye or skin problems, such as uveitis, rash, folliculitis and dermal abscess. Prior to the recognition of HA20, P1 was diagnosed with SLE, liver fibrosis and hypothyroidism. She also had no oral, genital or perineal ulcers. P2 was diagnosed with Crohn's disease and inflammatory bowel disease-related arthritis (IBD-RA). He had a perianal abscess but no oral or genital ulcers. P3, the father of P1 and P2, only had mild oral ulcers, arthralgia, and archosyrinx. P4 was diagnosed with polyarticular juvenile idiopathic arthritis (JIA), macrophage activation syndrome (MAS) and interstitial lung disease (ILD). Whole exome sequencing (WES) was performed in two families. WES revealed heterozygous c.559C > T in the TNFAIP3 gene in P1, P2 and P3, while the c.259C > T mutation in the TNFAIP3 gene was identified in P4. The c.259C > T mutations is novel. CONCLUSION: HA20 had a different phenotype between families and even between family members with the same mutation. Liver fibrosis, hypothyroidism, ILD and MAS in the patients with HA20 were first reported in this study. Our results expanded the phenotype and genotype spectrum of A20 haploinsufficiency.

The new complement inhibitor CRIg/FH ameliorates lupus nephritis in lupus-prone MRL/lpr mice.

BACKGROUNDS: The aberrant activation of complement system is critically involved in lupus nephropathy. Recent study showed complement C3 inhibitor was effective in the treatment of lupus nephropathy. In this study, we investigate the effect of a novel complement C3 inhibitor, CRIg/FH, in the treatment of lupus nephropathy in MRL/lpr lupus mice. METHODS: We treated MRL/lpr female mice with a dose escalation of CRIg/FH (10, 5 and 2 mg/kg) by intraperitoneal injection twice weekly since 12 weeks age. In addition, MRL/lpr mice treated with intraperitoneal injection of normal saline or oral prednisone, along with C57BL/6 J healthy mice were maintained to serve as controls. We started 8-h urine collection weekly to screen proteinuria by measuring the levels of urine urea/creatinine. Serum samples was collected at week 16 and 20 to measure levels of urea nitrogen, creatinine, and immunological markers (C3, C4, A-ds-DNA) before the mice were sacrificed at 20 weeks age to collect kidneys for histopathological examinations. RESULTS: Overt skin lesions were observed in MRL/lpr mice treated with normal saline, while skin lesion was not observed in CRIg/FH treated MRL/lpr mice. There was no overt proteinuria observed in MRL/lpr mice treated with CRIg/FH. Serum creatinine and BUN levels in MRL/lpr mice was maintained in highest CRIg/FH dose (10 mg/kg twice a week) to be significantly lower than that in prednisone treated MRL/lpr mice at 20 weeks age. In addition, CRIg/FH treatment in MRL/lpr mice results in a significantly elevated serum C3 and C4 levels when compared to prednisone treatment at both 16 and 20 weeks. Furthermore, our study identified that serum level of A-ds-DNA was also significantly lower in CRIg/FH treatment than that in predisone treated MRL/lpr mice. Renal pathology confirmed that kidneys from CRIg/FH treated MRL/lpr mice suffered less from nephritis and complement disposition. CONCLUSION: Our results showed that the complement inhibitor CRIg/FH can protect MRL/lpr mice from lupus nephropathy by preserving renal function and glomerulus complement activation. Our findings support the positive effect of complement inhibitors in the treatment of lupus nephropathy.

Angiopoietin-like-3 knockout protects against glomerulosclerosis in murine adriamycin-induced nephropathy by attenuating podocyte loss.

BACKGROUND: Angiopoietin-like-3 (Angptl3) knockout is known for its protective effects on podocyte injury and proteinuria in the early stage of adriamycin (ADR) nephropathy. The current study re-evaluated the renoprotective effect of Angptl3 knockout in chronic ADR nephropathy and attempted to explore the mechanism underlying the effect associated with Angptl3 knockout in glomerulosclerosis. METHODS: B6; 129S5 mice were injected with ADR to induce nephropathy. Kidney structure and serum and urine parameters were observed during long-term follow-up. Cultured primary mouse podocytes were exposed to ADR and analyzed for the expression of some relative proteins. Podocyte loss was analyzed in both in vivo and in vitro experiments. RESULTS: Angptl3 knockout attenuated proteinuria and hypoproteinemia, protected renal structure and function, and improved the survival of mice over the whole process of ADR nephropathy. Furthermore, Angptl3 knockout reduced the numbers of the detached and apoptotic cells in the renal tissue and alleviated podocyte loss in mice with ADR chronic nephropathy, thereby, delaying the glomerulosclerosis formation. Additional results in vitro showed that Angptl3 knockout attenuated ADR-induced primary podocyte loss, including podocyte detachment and apoptosis. CONCLUSION: In addition to serving a renoprotective role in the early stage of ADR nephropathy, Angptl3 knockout contributed to disease amelioration throughout the ADR nephropathy process. Angptl3 knockout effectively delayed glomerulosclerosis formation by attenuating podocyte loss through rescuing podocytes from detachment and apoptosis. Angptl3 antagonists or inhibitors might have therapeutic potential in the occurrence and progression of nephropathy.

pH-mediated upregulation of AQP1 gene expression through the Spi-B transcription factor.

BACKGROUND: Bicarbonate-based peritoneal dialysis (PD) fluids enhance the migratory capacity and damage-repair ability of human peritoneal mesothelial cells by upregulating AQP1. However, little is known about the underlying molecular mechanisms. RESULTS: Here we used HEK-293T cells to investigate the effect of pH on AQP1 gene transcription levels. We found that AQP1 mRNA levels increases with pH. Transfection of HEK-293T cells with luciferase reporter vectors containing different regions of the AQP1 promoter identified an upstream region in the AQP1 gene between - 2200 and - 2300 bp as an enhancer required for pH-mediated regulation of AQP1 expression. Site-directed mutagenesis of this specific promoter region revealed a critical region between - 2257 and - 2251 bp, and gene knock-down experiments and ChIP assays suggested that the Spi-B transcription factor SPIB is involved in pH-mediated regulation of AQP1 expression. CONCLUSIONS: We identified an upstream region in the AQP1 gene and the transcription factor SPIB that are critically involved in pH-mediated regulation of AQP1 expression. These findings provide the basis for further studies on the pH- and buffer-dependent effects of PD fluids on peritoneal membrane integrity and function.

Gene mutation analysis in 12 Chinese children with congenital nephrotic syndrome.

BACKGROUND: Congenital nephrotic syndrome (CNS) is characterised by increased proteinuria, hypoproteinemia, and edema beginning in the first 3 months of life. Recently, molecular genetic studies have identified several genes involved in the pathogenesis of CNS. A systematic investigation of the genes for CNS in China has never been performed; therefore, we conducted a mutational analysis in 12 children with CNS,with the children coming from 10 provinces and autonomous regions in China. METHODS: Twelve children with CNS were enrolled from 2009 to 2016. A mutational analysis was performed in six children by Sanger sequencing in eight genes (NPHS1, NPHS2, PLCE1, WT1, LAMB2, LMXIB, COQ6 and COQ2) before 2014, and whole-exome sequencing was used from 2014 to 2016 in another six children. Significant variants that were detected by next generation sequencing were confirmed by conventional Sanger sequencing in the patients' families. RESULTS: Of the 12 children, eight patients had a compound heterozygous NPHS1 mutation, one patient had a de novo mutation in the WT1 gene, and another patient with extrarenal symptoms had a homozygous mutation in the COQ6 gene. No mutations were detected in genes NPHS2, PLCE1, LAMB2, LMXIB, and COQ2 in the 12 patients. CONCLUSIONS: This study demonstrates that the majority of CNS cases (67%, 8/12 patients) are caused by genetic defects, and the NPHS1 mutation is the most common cause of CNS in Chinese patients. A mutational analysis of NPHS1 should be recommended in Chinese patients with CNS in all exons of NPHS1 and in the intron-exon boundaries.