Genetic and clinical characterization of familial renal glucosuria.

Background: Familial renal glucosuria (FRG) is a hereditary disorder caused by variants in SLC5A2 encoding sodium-glucose cotransporter 2 (SGLT2). In this study, we aimed to characterize proximal tubule solute transport, glucagon secretion and the genotype-phenotype relationship in FRG patients. Methods: We sequenced SLC5A2 and PDZK1IP1 in 21 FRG patients and measured the renal threshold of glucose (RTG) in 15 patients. We built an open-source online calculator of RTG, evaluated the proximal tubule transport of amino acid, uric acid and phosphate, and explored glucagon secretion after glucose ingestion in FRG patients. Results: We identified 12 novel SLC5A2 variants (G484D, R564W, A212S, c.574+1G>C, W649*, S592Cfs*6, Q579*, Y339*, V39F, G491E, A464E and G360D) in our cohort and yielded 111 SLC5A2 variants from literature review. RTG in our cohort ranged from 1.0 to 9.2 mmol/L. Patients with two SLC5A2 variants had lower RTG (3.9 vs 6.2 mmol/L) and higher 24-h urinary glucose excretion (24hUG) than single-variant carriers (291.0 vs 40.0 mmol/1.73 m2). Patients with homozygous missense or in-frame indels had mean 24hUG of 457.2 mmol/1.73 m2, comparable to those with homozygous truncating variants (445.0 mmol/1.73 m2) and significantly more than those with homozygous splicing variants (196.6 mmol/1.73 m2). Patients with homozygous missense variants involving conservative residues (582.0 mmol/1.73 m2) had more 24hUG than those with variants at non-conservative residues (257.6 mmol/1.73 m2). Four out of 14 tested patients had mild aminoaciduria. The RTG of FRG patients had no significant correlation to phosphate reabsorption but a potential negative correlation to the fractional excretion of uric acid. Postprandial suppression of glucagon secretion was absent in most FRG patients. Conclusions: We built a comprehensive map showing the impact of SLC5A2 variant type and variant location on glucosuria severity. Our results highlighted the role of key residues in maintaining the transport function of SGLT2 and the functional link between glucosuria and reabsorption of amino acid and uric acid in FRG patients.

Containing anti-PLA2R IgG antibody induces podocyte injury in idiopathic membranous nephropathy.

Background: Idiopathic membranous nephropathy is widely recognized as an autoimmune kidney disease that is accompanied by the discovery of several autoantibodies, and the antibody subclass in the circulation of patients with iMN is mainly IgG. However, the direct pathogenic effect of the containing anti-PLA2R IgG antibody on podocytes is not clear.Method: A protein G affinity chromatography column was used to purify serum IgG antibodies. Containing anti-PLA2R IgG antibodies from iMN patients and IgG from healthy controls were also obtained. Based on the established in vitro podocyte culture system, purified IgG antibodies from the two groups were used to stimulate podocytes, and the expression of essential podocyte proteins (podocin), the levels of inflammatory cytokines in the cell supernatant, cytoskeletal disorders, and podocyte apoptosis were analyzed.Results: Compared with that in the normal IgG group, the expression of podocin and podocin mRNA was reduced (p = 0.016 and p = 0.005, respectively), the fluorescence intensity of podocin on the surface of podocytes was reduced, the cytoskeleton of podocytes was disordered and reorganized, and the ratio of podocyte apoptosis was increased in the iMN group (p = 0.008).Conclusion: The containing anti-PLA2R IgG antibody might have a direct damaging effect on podocytes in idiopathic membranous nephropathy.

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.

Rainbow-Colored Carbon Nanotubes via Rational Surface Engineering for Smart Visualized Sensors.

Surface engineering is effective for developing materials with novel properties, multifunctionality, and smart features that can enable their use in emerging applications. However, surface engineering of carbon nanotubes (CNTs) to add color properties and functionalities has not been well established. Herein, a new surface engineering strategy is developed to achieve rainbow-colored CNTs with high chroma, high brightness, and strong color travel for visual hydrogen sensing. This approach involved constructing a bilayer structure of W and WO3 on CNTs (CNT/W/WO3 ) and a trilayer structure of W, WO3 , and Pd on CNTs (CNT/W/WO3 /Pd) with tunable thicknesses. The resulting CNT/W/WO3 composite film exhibits a wide range of visible colors, including yellow, orange, magenta, violet, blue, cyan, and green, owing to strong thin-film interference. This coloring method outperforms other structural coloring methods in both brightness and chroma. The smart CNT/W/WO3 /Pd films with porous characteristics quickly and precisely detect the hydrogen leakage site. Furthermore, the smart CNT/W/WO3 /Pd films allow a concentration as low as 0.6% H2 /air to be detected by the naked eye in 58 s, offering a very practical and safe approach for the detection and localization of leaks in onboard hydrogen tanks.

Update of dialysis initiation timing in end stage kidney disease patients: is it a resolved question? A systematic literature review.

BACKGROUND: The exact optimal timing of dialysis for ESKD patients remains unknown. This study systematically reviewed the available evidence with regard to the optimal initiation of maintenance dialysis in ESKD patients. METHODS: An electronic search was performed in Embase, PubMed and the Cochrane Library in order to find studies investigating associations between variables reference to "start of dialysis" and outcomes. Quality assessment and bias assessment were performed by the Newcastle-Ottawa scale and the ROBINSI tool. Due to the heterogeneity of studies, a meta-analysis could not be performed. RESULTS: Thirteen studies were included; four studies included only haemodialysis patients, three peritoneal dialysis, six both; study outcomes included mortality, cardiovascular events, technique failure, quality of life and others. Nine studies mainly focused on the optimal GFR of maintenance dialysis initiation; five studies showed none association between GFR and mortality or other adverse outcomes, two studies showed dialysis initiation at higher GFR levels were with poor prognosis, and 2 studies showed higher GFR levels with better prognosis. Three studies paid attention to comprehensive assessment of uremic signs and/or symptoms for optimal dialysis initiation; uremic burden based on 7 uremic indicators (hemoglobin, serum albumin, blood urea nitrogen, serum creatinine, potassium, phosphorus, and bicarbonate) were not associated with mortality; another equation (combination of sex, age, serum creatinine, blood urea nitrogen, serum albumin, haemoglobin, serum phosphorus, diabetes mellitus, and heart failure) based on fuzzy mathematics to assess the timing of haemodialysis initiation was accuracy to prognose 3-year survival; the third study found that volume overload or hypertension was associated with the highest risk for subsequent mortality. Two studies compared urgent or optimal start in dialysis, a study reported increased survival in optimal start patients, another reported no differences between Urgent-Start-PD and Early-Start-PD regarding 6-month outcomes. LIMITATIONS: Heterogeneity among the studies was quite high, with differences in sample size, variable and group characteristics; no RCT studies were included, which weakened the strength of evidences. CONCLUSIONS: The criteria for dialysis initiation were varied. Most studies proved that GFR at dialysis initiation was not associated with mortality, timing of dialysis initiation should not be based on GFR, assessments of volume load and patient's tolerance to volume overload are prospective approaches.

Colorful Electrochromic Displays with High Visual Quality Based on Porous Metamaterials.

The introduction of metamaterials into electrochromic (EC) displays has recently inspired a great breakthrough in the EC field, as this can offer a variety of new attractive features, from a very wide gamut of colors to very fast switching times. However, such metamaterial-based EC displays still face significant constraints when developing from single electrodes to full devices, because other supportive components in devices, such as counter electrodes and electrolytes, significantly affect light propagation and the subsequent perceived color quality in metamaterial-based EC devices. Herein, a new, cost-effective device design structured around a new type of porous metamaterial is reported to circumvent the critical problem in metamaterial-based EC displays. Owing to its unique design, the metamaterial-based EC device achieves good color quality with no drop in brightness or shift in color chromaticity when compared with a single electrode. Moreover, the porous-metamaterial-based EC device can exhibit non-iridescence and be viewed from a wide range of angles (5°-85°) and has fast switching response (2.4 and 2.5 s for coloration and bleaching, respectively), excellent cycling performance (at least 2000 cycles), and extremely low power consumption (4.0 mW cm-2 ).

Genetic dissection of the impact of lncRNA AI662270 during the development of atherosclerosis.

BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. METHODS: Apolipoprotein E deficiency (ApoE-/-) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA-protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. RESULTS: The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. CONCLUSION: These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

In Situ Electrochemically Oxidative Activation Inducing Ultrahigh Rate Capability of Vanadium Oxynitride/Carbon Cathode for Zinc-Ion Batteries.

As a promising candidate for large-scale energy storage, aqueous zinc-ion batteries (ZIBs) still lack cathode materials with large capacity and high rate capability. Herein, a spherical carbon-confined nanovanadium oxynitride with a polycrystalline feature (VNxOy/C) was synthesized by the solvothermal reaction and following nitridation treatment. As a cathode material for ZIBs, it is interesting that the electrochemical performance of the VNxOy/C cathode is greatly improved after the first charging process viain situ electrochemically oxidative activation. The oxidized VNxOy/C delivers a greatly enhanced reversible capacity of 556 mAh g-1 at 0.2 A g-1 compared to the first discharge capacity of 130 mAh g-1 and a high capacity of 168 mAh g-1 even at 80 A g-1. The ex situ characterizations verify that the insertion/extraction of Zn2+ does not affect the crystal structure of oxidized VNxOy/C to promise a stable cycle life (retain 420 mAh g-1 after 1000 cycles at 10 A g-1). The experimental analysis further elucidates that charging voltage and H2O in the electrolyte are curial factors to activate VNxOy/C in that the oxygen replaces the partial nitrogen and creates abundant vacancies, inducing a conversion from VNxOy/C to VNx-mOy+2m/C and then resulting in considerably strengthened rate performance and improved Zn2+ storage capability. The study broadens the horizons of fast ion transport and is exceptionally desirable to expedite the application of high-rate ZIBs.

lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis.

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of atherosclerosis. Here, we investigated the role of the lncRNA growth arrest-specific 5 (lncR-GAS5) in atherogenesis. We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis, which presented as increased plaque size and reduced collagen content. Moreover, impaired autophagy was observed, as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells. By contrast, lncR-GAS5 knockdown promoted autophagy. Moreover, serine/arginine-rich splicing factor 10 (SRSF10) knockdown increased the LC3II/LC3I ratio and decreased the P62 level, thus enhancing the formation of autophagic vacuoles, autolysosomes, and autophagosomes. Mechanistically, lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium, which was reversed by the knockdown of SRSF10. Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene, SRSF10. Notably, miR-193-5p overexpression decreased plaque size and increased collagen content. Altogether, these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy. In conclusion, lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway. Thus, miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis.

Semiconductor SERS on Colourful Substrates with Fabry-Pérot Cavities.

Non-metallic materials have emerged as a new family of active substrates for surface-enhanced Raman scattering (SERS), with unique advantages over their metal counterparts. However, owing to their inefficient interaction with the incident wavelength, the Raman enhancement achieved with non-metallic materials is considerably lower with respect to the metallic ones. Herein, we propose colourful semiconductor-based SERS substrates for the first time by utilizing a Fabry-Pérot cavity, which realize a large freedom in manipulating light. Owing to the delicate adjustment of the absorption in terms of both frequency and intensity, resonant absorption can be achieved with a variety of non-metal SERS substrates, with the sensitivity further enhanced by ≈100 times. As a typical example, by introducing a Fabry-Pérot-type substrate fabricated with SiO2 /Si, a rather low detection limit of 10-16  M for the SARS-CoV-2S protein is achieved on SnS2 . This study provides a realistic strategy for increasing SERS sensitivity when semiconductors are employed as SERS substrates.

M6A RNA methylation-mediated RMRP stability renders proliferation and progression of non-small cell lung cancer through regulating TGFBR1/SMAD2/SMAD3 pathway.

Non-small cell lung cancer (NSCLC) has the highest mortality rate among all malignancies worldwide. The role of long noncoding RNAs (lncRNAs) in the progression of cancers is a contemporary research hotspot. Based on an integrative analysis of The Cancer Genome Atlas database, we identified lncRNA-RNA Component of Mitochondrial RNA Processing Endoribonuclease (RMRP) as one of the most highly upregulated lncRNAs that are associated with poor survival in NSCLC. Furthermore, N(6)-methyladenosine (m6A) was highly enriched within RMRP and enhanced its RNA stability. In vitro and in vivo experiments showed that RMRP promoted NSCLC cell proliferation, invasion, and migration. In terms of mechanism, RMRP recruited YBX1 to the TGFBR1 promotor region, leading to upregulation of the transcription of TGFBR1. The TGFBR1/SMAD2/SMAD3 pathway was also regulated by RMRP. In addition, RMRP promoted the cancer stem cells properties and epithelial mesenchymal transition, which promote the resistance to radiation therapy and cisplatin. Clinical data further confirmed a positive correlation between RMRP and TGFBR1. In short, our work reveals that m6A RNA methylation-mediated RMRP stability renders proliferation and progression of NSCLC through regulating TGFBR1/SMAD2/SMAD3 pathway.

Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.

Heart aging is characterized by left ventricular hypertrophy and diastolic dysfunction, which in turn induces a variety of cardiovascular diseases. There is still no therapeutic drug to ameliorate cardiac abnormities in heart aging. In this study we investigated the protective effects of berberine (BBR) and its derivative tetrahydroberberrubine (THBru) against heart aging process. Heart aging was induced in mice by injection of D-galactose (D-gal, 120 mg · kg-1 · d-1, sc.) for 12 weeks. Meanwhile the mice were orally treated with berberine (50 mg · kg-1 · d-1) or THBru (25, 50 mg · kg-1 · d-1) for 12 weeks. We showed that BBR and THBru treatment significantly mitigated diastolic dysfunction and cardiac remodeling in D-gal-induced aging mice. Furthermore, treatment with BBR (40 µM) and THBru (20, 40 µM) inhibited D-gal-induced senescence in primary neonatal mouse cardiomyocytes in vitro. Overall, THBru exhibited higher efficacy than BBR at the same dose. We found that the levels of mitophagy were significantly decreased during the aging process in vivo and in vitro, THBru and BBR promoted mitophagy with different potencies. We demonstrated that the mitophagy-inducing effects of THBru resulted from increased mRNA stability of prohibitin 2 (PHB2), a pivotal factor during mitophagy, thereby upregulating PHB2 protein expression. Knockdown of PHB2 effectively reversed the antisenescence effects of THBru in D-gal-treated cardiomyocytes. On the contrary, overexpression of PHB2 promoted mitophagy and retarded cardiomyocyte senescence, as THBru did. In conclusion, this study identifies THBru as a potent antiaging medicine that induces PHB2-mediated mitophagy and suggests its clinical application prospects.

Prognostic significance of the extent of tubulointerstitial lesions in patients with IgA nephropathy.

PURPOSE: IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. However, the effect of the degree of tubulointerstitial lesions (TIL) on the renal prognosis of these patients is uncertain. METHODS: All biopsy-proven primary IgAN patients from a single center (≥ 14 years old) were retrospectively examined from January 2006 to December 2011. According to the Oxford classification for tubulointerstitial lesions in IgAN, eligible patients were assigned to T0 or T1/2 groups. The clinicopathological features of these groups were compared and multivariate models were used to identify the effect of tubulointerstitial lesions on renal prognosis. The composite endpoint was end-stage renal disease or doubling of serum creatinine. RESULTS: We initially identified 1570 patients with IgAN and examined 988 patients who completed follow-up examinations (mean: 49 months). There were 506 patients in the T0 group (51.2%) and 482 in the T1/2 group (48.8%). The 1-year, 3-year, and 5-year incidences of the composite endpoint were 0.2%, 1.5%, 7.7% in the T0 group, and 1.9%, 9.9%, 18.1% in the T1/2 group. An adjusted multivariate model indicated the hazard ratio for reaching the composite endpoint was 9.3 for patients with T1/2 rather than T0 (reference group). A multivariate logistic analysis of the T1/2 group indicated the independent risk factors for reaching the composite endpoint were decreased eGFR, hypertension, hyperlipidemia, proteinuria, global glomerulosclerosis, and segmental glomerulosclerosis. CONCLUSION: More severe tubulointerstitial lesions (> 25%, T1/2) were an independent predictor of poor renal prognosis in patients with IgAN.

Elucidating the cation hydration ratio in water-in-salt electrolytes for carbon-based supercapacitors.

The solvation of cations is one of the important factors that determine the properties of electrolytes. Rational solvation structures can effectively improve the performance of various electrochemical energy storage devices. Water-in-Salt (WIS) electrolytes with a wide electrochemically stable potential window (ESW) have been proposed to realize high cell potential aqueous electrochemical energy storage devices relying on the special solvation structures of cations. The ratio of H2O molecules participating in the primary solvation structure of a cation (a cation hydration ratio) is the key factor for the kinetics and thermodynamics of the WIS electrolytes under an electric field. Here, acetates with different cations were used to prepare WIS electrolytes. And, the effect of different cation hydration ratios on the properties of WIS electrolytes was investigated. Various WIS electrolytes exhibited different physicochemical properties, including the saturated concentration, conductivity, viscosity, pH values and ESW. The WIS electrolytes with a low cation hydration ratio (<100%, an NH4-based WIS electrolyte) or a high cation hydration ratio (>100%, a K-based WIS electrolyte and a Cs-based WIS electrolyte) exhibit more outstanding conductivity or a wide ESW, respectively. SCs constructed from active carbon (AC) and these WIS electrolytes exhibited distinctive electrochemical properties. A SC with an NH4-based WIS electrolyte was characterized by higher capacity and better rate capability. SCs with a K-based WIS electrolyte and a Cs-based WIS electrolyte were characterized by a wider operating cell potential, higher energy density and better ability to suppress self-discharge and gas production. These results show that a WIS electrolyte with a low cation hydration ratio or a high cation hydration ratio is suitable for the construction of power-type or energy-type aqueous SCs, respectively. This understanding provides the foundation for the development of novel WIS electrolytes for the application of SCs.

PRRT2 gene mutations associated with infantile convulsions induced by sucking and the genotype-phenotype correlation.

Introduction: PRRT2 is a major causative gene for self-limited familial neonatal-infantile epilepsy, paroxysmal kinesigenic dyskinesia, and paroxysmal kinesigenic dyskinesia with infantile convulsions. Voluntary movement trigger is prominent in adolescence and adulthood, but the triggers are unknown in infants. Methods: A gene panel designed for targeted next-generation sequencing (NGS) was used to screen genetic abnormalities in a cohort of 45 cases with infantile convulsions. The copy number variation was detected by a computational method based on the normalized depth of coverage and validated by a quantitative real-time polymerase chain reaction (RT-qPCR) method. The genotype-phenotype correlation of the PRRT2 mutation gene was analyzed. Results: A de novo heterozygous PRRT2 deletion was identified in a child who had infantile convulsions induced by vigorous sucking. Seizures happened during the change of feeding behavior from breast to formula, which led to hungry and vigorous sucking. Ictal electroencephalograms recorded seizures with focal origination, which provided direct evidence of epileptic seizures in infants with PRRT2 mutations. Seizures stopped soon after the feeding behavior was changed by reducing feeding interval time and extending feeding duration. Data reanalysis on our previously reported cases with PRRT2 mutations showed that six of 18 (33.3%) patients had infantile convulsions or infantile non-convulsion seizures during feeding. The mutations included two truncating mutations (c.579dupA/p.Glu194Argfs*6, and c.649dupC/p.Arg217Profs*8) that were identified in each of the three affected individuals. Conclusions: This study suggests that feeding, especially vigorous sucking, is potentially a trigger and highlights the significance of feeding behavior in preventing seizures in infants with PRRT2 mutations. Identification of PRRT2 haploinsufficiency mutations in the patients with infantile convulsions induced by sucking suggested a potential genotype-phenotype correlation.

Clinicopathological Patterns and Outcomes in Patients with Lupus Nephritis and Hyperuricemia.

A limited number of large cohort studies have reported the clinicopathological characteristics and prognosis of patients with lupus nephritis (LN) and hyperuricemia (HUA). In this retrospective cohort study, 1297 LN patients were enrolled from January 1996 to December 2011 in the First Affiliated Hospital of Sun Yat-Sen University, and HUA occurred in 649 (50.04%) of these 1297 LN patients. Compared to patients without HUA, those with HUA presented with higher blood pressure and triglyceride levels, lower hemoglobin and serum albumin levels, worse renal function, more severe hematuria and proteinuria, higher lupus activity, and more positive antiphospholipid antibody. Pathologically, HUA cases presented more crescents, a higher degree of mesangial matrix, endothelial cell proliferation, and inflammatory cell infiltration. During the 52-month follow-up, the 5-year and 10-year incidence rates of renal endpoint events were 11.1% and 19.5% in the HUA group, and 8.3% and 13.8% in the non-HUA group, respectively (p = 0.073). In addition, the 5-year and 10-year mortality rates did not differ significantly between the HUA (12.0% and 18.2%) and non-HUA (12.2% and 17.5%) groups, respectively. This study verified that HUA was not an independent risk for poor clinical outcomes, and steroids that delay the deterioration of renal function did not affect the survival of these patients.

Posttranslational modifications in GPCR internalization.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors that serve as the most important drug targets. Classically, GPCR internalization has been considered to lead to receptor desensitization. However, many studies over the past decade have reported that internalized membrane receptors can trigger distinct signal activation. The "internalized activation" provides a completely new understanding for the receptor internalization, the mechanism of physiology/pathology and novel drug targets for precision medicine. GPCR internalization undergoes a series of strict regulations, especially by posttranslational modifications (PTMs). Here, this review summarizes different PTMs in GPCR internalization and analyzes their significance in GPCR internalization dynamics, internalization routes, postinternalization fates, and related diseases, which will offer new insights into the regulatory mechanism of GPCR signaling and novel drug targets for precision medicine.

CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications.

Purpose: Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity. Methods: Trio-based whole-exome sequencing was performed in 318 cases with partial epilepsy and 150 cases with generalized epilepsy. We then reviewed all previously reported CACNA1A mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications. Results: We identified 12 CACNA1A mutations in ten unrelated cases of epilepsy, including four de novo null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G > A, c.4755 + 1G > T, and c.6340-1G > A), four de novo missense mutations (c.203G > T/p.Arg68Leu, c.3965G > A/p.Gly1322Glu, c.5032C > T/p.Arg1678Cys, and c.5393C > T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu and c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys). The eight de novo mutations were evaluated as pathogenic or likely pathogenic mutations according to the criteria of American College of Medical Genetics and Genomics (ACMG). The frequencies of the compound heterozygous CACNA1A mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (P = 7.30 × 10-4, P = 2.53 × 10-4). All of the ten cases were ultimately seizure-free after antiepileptic treatment, although frequent epileptic seizures were observed in four cases. Further analysis revealed that episodic ataxia type 2 (EA2) had a tendency of higher frequency of null mutations than epilepsies. The missense mutations in severe epileptic phenotypes were more frequently located in the pore region than those in milder epileptic phenotypes (P = 1.67 × 10-4); de novo mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (P = 1.92 × 10-3). Conclusion: This study suggested that CACNA1A mutations were potentially associated with pure epilepsy and the spectrum of epileptic phenotypes potentially ranged from the mild form of epilepsies such as absence epilepsy or partial epilepsy, to the severe form of developmental epileptic encephalopathy. The clinical phenotypes variability is potentially associated with the molecular sub-regional of the mutations.

Optimal targets of chronic kidney disease-mineral and bone disorder markers for Chinese patients with maintenance peritoneal dialysis: a single-center retrospective cohort study.

BACKGROUND: The chronic kidney disease-mineral and bone disorder（CKD-MBD) is known to be associated with increased mortality in dialysis patients, but whether current global guidelines for CKD-MBD, which were primarily developed from hemodialysis, are suitable for peritoneal dialysis (PD) patients practice require further investigation. METHODS: This is a single-center retrospective cohort study. In total 491 prevalent PD patients (median follow-ups: 34 months) from Peking Union Medical College Hospital (PUMCH) from January 2004 to December 2017 were included and followed until 30 June 2018. In the first dialysis year, the average levels of serum calcium, albumin-corrected calcium (CorCa), phosphorus, and parathyroid hormone (PTH) levels were the interested predictors in Cox proportional regression model. RESULTS: Of these PD patients (age 58 ± 17 years), 52% were male and 36% had diabetic nephropathy. In Cox regression over first-year mean parameters, PTH <100 pg/mL (HR = 1.97, 95% CI 1.32 to 2.94, p < 0.001) and ≥300 pg/mL (HR = 2.24, 95% CI 1.32 to 3.81, p = 0.003) were associated with increased all-cause mortality than that of PTH 100-200 pg/mL. Patients with albumin-corrected serum calcium level < 2.13 mmol/L also had higher risk of death than patients with level of 2.13 to 2.38 mmol/L (HR = 2.06, 95% CI 1.06 to 4.01, p = 0.02). Serum phosphorus ≥1.45 mmol/L were associated with increased all-cause mortality. However, lacking of data on 25-hydroxy vitamin D, alkaline phosphatase, and activated vitamin-D are limitations of our analysis. CONCLUSIONS: As one of the largest PD cohort study focusing on CKD-MBD, we demonstrated that the level of CKD-MBD markers in the first PD year are independent predictors of all-cause mortality. PTH 100-300 pg/mL might be the best target for Chinese PD patients.