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Background Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified. Methods Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes. Results Two variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3β, resulting in dysregulated calcineurin activity and apoptosis. Conclusions These data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3β, in the treatment of FSGS.

Heavy metal concentrations were measured in 150 human hairs samples collected from five provinces in China to investigate heavy metal exposure levels and influencing factors. The gender, age, diet and lifestyle habits of the volunteers were investigated through questionnaires to analyze their effects on hair element concentrations. Metal concentrations in hair were 1.62 μg/g (Mn), 0.99 μg/g (Co), 0.22 μg/g (Cd) and 8.49 μg/g (Pb), which were low compared with those reported in mine contaminated areas. Cd concentration was higher in females than males, Pb concentration was lower in the elder group and the younger group. No difference of Cd and Co concentrations among rice consumers and/or wheat consumers was found. Pb concentration in rice consumers were higher than those in rice and/or wheat consumers. Fish consumption were a factor affecting hair Cd and Pb levels, while smoking was not one main pathway of hair Cd and Pb exposure.

Epichloë endophytes can not only affect the growth and resistance of the host plant but also change the biotic and abiotic properties of the soil where the host is situated. Here, we used endophyte-infected (EI) and endophyte-free (EF) Leymus chinensis as plant materials, to study the microbial diversity and composition in the host root endosphere and rhizosphere soil under both pot and field conditions. The results showed that endophyte infection did not affect the diversity of either bacteria or fungi in the root zone. There were significant differences in both bacterial and fungal communities between the root endosphere and the rhizosphere, and between the field and the pot, while endophytes only affected root endosphere microbial communities. The bacterial families affected by endophyte infection changed from 29.07% under field conditions to 40% under pot conditions. In contrast, the fungal families affected by endophyte infection were maintained at nearly 50% under both field and pot conditions. That is to say, bacterial communities in the root endosphere were more strongly affected by environmental conditions, and in comparison, the fungal communities were more strongly affected by species specificity. Endophytes significantly affected the fungal community composition of the host root endosphere in both potted and field plants, only the effect was more obvious in potted plants. Endophyte infection increased the abundance of three fungal families (Thelebolaceae, Herpotrichiellaceae and Trimorphomycetaceae) under both field and potted conditions. In potted plants, endophytes also altered the dominant fungi from pathogenic Pleosporales to saprophytic Chaetomiaceae. Endophyte infection increased the relative abundance of arbuscular mycorrhizal fungi and saprophytic fungi, especially under potted conditions.Overall, endophytes significantly affected the fungal community composition of the host root endosphere in both potted and field plants. Endophytes had a greater impact on root endosphere microorganisms than the rhizosphere, a greater impact on fungal communities than bacteria, and a greater impact on root endosphere microorganisms under potted conditions than at field sites.

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.

BACKGROUND: Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified. METHODS: Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes. RESULTS: Two variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3β, resulting in dysregulated calcineurin activity and apoptosis. CONCLUSIONS: These data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3β, in the treatment of FSGS.

Background We previously reported that mutations in the anillin ( ANLN ) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP. Methods We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLN R431C and ANLN G618C during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN ( ANLN WT ) or ANLN R431C . Results Experiments in anln -deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLN R431C increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLN R431C -expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLN R431C -expressing podocytes. Inhibition of mTOR, GSK-3 β , Rac1, or calcineurin ameliorated the effects of ANLN R431C . Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR. Conclusions The ANLN R431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes.

A tide gate was built in 2010 to prevent seawater from moving upstream into the Yongdingxin River estuary in Bohai Bay, Northern China. We analysed the concentrations of Hg, Cd, Pb, TOC, TN, δ13C and δ15N and studied their variations in the surface layer and vertical profiles of sediment cores collected from the Yongdingxin River estuary. Contamination factors and geo-accumulation indices were calculated for each metal, which revealed high levels of contamination for Hg and Cd in the sediments, likely from anthropogenic sources. δ13C and δ15N were used as natural tracers to determine the sources of TOC and TN. The results revealed that sewage was the main source of TOC, while TN may have more than one source in the Yongdingxin River estuary. Sewage dominated trace metal pollution in the Yongdingxin River estuary. Our results provide a baseline for trace metal contamination in an estuary facing a large water project.

Trends in annual precipitation and river discharge (1956–2012) were analyzed using the Mann–Kendall test and Sen's method to evaluate the impact of climate variation and human activities on the Haihe River discharge to Bohai Bay. Compared to observations before 1965, two obvious decreases in annual river discharge occurred after 1965 and after 1980. Considering 1956–1965 as the baseline period, it was established that the reduction in Haihe River discharge to the Bohai Sea was 52.9% and 81.9% during 1966–1980 and 1981–2012, respectively. Compared to the baseline period, the reductions in annual precipitation in 1966–1980 and 1981–2012 were 7.1% and 14.2%, respectively. Following the increase in population, industrial activity, and irrigated areas, water consumption has increased rapidly, from 51.9 mm in 1965 to 124.8 mm in 1980 and 126.4 mm in 2000. These results indicate that the reduction in discharge in the Haihe River basin during 1966–1980 and 1981–2000 could be attributed to climatic variations (33.2% and 41.4%, respectively) and human activities (66.8% and 58.6%, respectively). The results also indicate that salinity in Bohai Bay increased following the decrease in discharge from the Haihe River.

In this paper, a class of nonlinear p-Laplace diffusion BAM Cohen-Grossberg neural networks (BAM CGNNs) with time delays is investigated. In the case of p>1 with p≠2, the authors construct novel Lyapunov functional to overcome the mathematical difficulties of nonlinear p-Laplace diffusion time-delay model with parameter uncertainties, deriving the LMI-based robust stability criterion applicable to computer MATLAB LMI toolbox and deleting the boundedness of the amplification functions. And in the case of p=2, LMI-based sufficient conditions are also inferred for robust input-to-state stability of reaction-diffusion Markovian jumping BAM CGNNs with the event-triggered control, which is different from those of many previous related literature. In particular, the role of diffusion can be reflected in newly acquired criteria. Finally, numerical examples verify the effectiveness of the proposed methods.

This study aimed to determine sediment contamination in the Beidagang Wetland Nature Reserve to describe atmospheric deposition of trace metals. We analyzed Hg, Cd, Pb, TOC, TN, TP, δ13C, and δ15N, and studied their variations in surface sediments and in the vertical profiles of sediment cores collected from the reserve. Evaluation of environmental trace metal contamination using sediment quality guidelines and geochemical background values indicated that the risk of metal pollution in the reserve sediments was relatively low. Concentrations of Hg, Cd, and Pb in the sediments were much lower than concentrations in sediment samples from Bohai Bay and polluted rivers in Tianjin. Enrichment factors indicate that samples are moderately contaminated with Hg, Cd, and Pb; whereas the geo-accumulation index results classify the sediments as uncontaminated to moderately contaminated with Hg, Cd, and Pb. The distribution patterns of trace metal concentrations in the three core samples were uniform. δ13C and δ15N were used to track the sources of TOC and TN in sediments. Results show that TOC mainly originated from the residue and decaying matter of aquatic plants (e.g., algae, reeds, and Typha), while TN was derived from soil N and elevated atmospheric N deposition. Because domestic and industrial waste is not discharged into the Beidagang Wetland Nature Reserve, trace metals found in sediments mainly originate from atmospheric deposition. The results provide baseline data for analysis of trace metal accumulation in Beijing-Tianjin-Hebei, a region subject to atmospheric deposition in northern China.

Hợp tác quốc tế trong Tố tụng hình sự được pháp luật Trung Quốc qui định từ khá sớm. Những qui định về hợp tác quốc tế trong Tố tụng hình sự đã góp phần tích cực vào việc đấu tranh, xử lý tội phạm có yếu tố nước ngoài, tội phạm có tổ chức, tội phạm xuyên quốc gia… và thúc đẩy quan hệ hợp tác quốc tế sâu rộng của Trung Quốc với các quốc gia khác trong lĩnh vực Tư pháp Hình sự. Bài viết này sẽ giới thiệu một số nội dung cơ bản về hợp tác quốc tế trong tố tụng hình sự của Trung quốc và những vấn đề đặt ra.

BACKGROUND: We previously reported that mutations in the anillin (ANLN) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP. METHODS: We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLN(R431C) and ANLN(G618C) during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN (ANLN(WT)) or ANLN(R431C). RESULTS: Experiments in anln-deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLN(R431C) increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLN(R431C)-expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLN(R431C)-expressing podocytes. Inhibition of mTOR, GSK-3β, Rac1, or calcineurin ameliorated the effects of ANLN(R431C). Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR. CONCLUSIONS: The ANLN(R431C) mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes.

Regions that have large coal consumption could be prone to elevated concentrations of atmospheric trace metals. Snow samples were collected at two sites in Tianjin, northern China, during three heating seasons and analyzed for major and trace elements. Concentrations were assessed for compliance with Chinese and US EPA Water Quality Standards for Surface Waters, and it was established that trace metals except Cd were present at concentrations below these standards. Enrichment factors showed that, in comparison with local top soils, Se, Hg, Cd, and Zn were highly enriched and As, Cu, Ni, and Pb were moderately enriched, suggesting that these metals were contributed primarily via anthropogenic activities. Concentrations of Mn, Co, Cr, V, and Al were not enriched and were mostly of crustal origin. Backward trajectories were calculated for each snow event using the NOAA HYSPLIT model. The transport characteristics and origins of the air masses were examined, which indicated that the elevated concentrations of Hg, Se, Cd, Zn, and As were influenced mainly by coal burning activities in northern China during the heating season. The results of this study revealed that anthropogenic activities have significant effect on snow water quality and thus, heavy metal emissions from coal consumption should be regulated more tightly.

The impact of tide gate on heavy metal mobility in Haihe River sediments was studied in a laboratory leaching simulation experiment. The results indicated that seawater promoted a higher release of Cd and Cu than deionized water and river water, and river water extracts high amounts of Zn. This release may be a result of both the formation of chloride complexes and ion exchange. However, the salinity induced by seawater did not significantly enhance the mobility of Pb. This implied that the mobility of Cd and Cu can be reduced by the insufficiency of the salinity when constructing tide gates in the brackish zones of an estuary. In the acidification processes, Cd and Zn were not, but Cu and Pb were, affected by an increase of salinity and ionic strength.

Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene (TNXB) as a cause of PVUR with joint hypermobility. To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants inTNXB and the tenascin C gene (TNC) after excluding mutations in ROBO2 and SOX17. The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9 %) families had FPVUR and 2/55 (4 %) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12 %) families (9 % in TNXB and 3 % in ROBO2). In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.

Mutations in the LIM homeobox transcription factor 1-beta (LMX1B) are a cause of nail patellar syndrome, a condition characterized by skeletal changes, glaucoma and focal segmental glomerulosclerosis. Recently, a missense mutation (R246Q) in LMX1B was reported as a cause of glomerular pathologies without extra-renal manifestations, otherwise known as nail patella-like renal disease (NPLRD). We have identified two additional NPLRD families with the R246Q mutation, though the mechanisms by which LMX1BR246Q causes a renal-specific phenotype is unknown. In this study, using human podocyte cell lines overexpressing either myc-LMX1BWT or myc-LMX1BR246Q, we observed dominant negative and haploinsufficiency effects of the mutation on the expression of podocyte genes such as NPHS1, GLEPP1, and WT1. Specifically, we observed a novel LMX1BR246Q-mediated downregulation of WT1(−KTS) isoforms in podocytes. In conclusion, we have shown that the renal-specific phenotype associated with the LMX1BR246Q mutation may be due to a dominant negative effect on WT1(−KTS) isoforms that may cause a disruption of the WT1 (−KTS):(+KTS) isoform ratio and a decrease in the expression of podocyte genes. Full delineation of the LMX1B gene regulon is needed to define its role in maintenance of glomerular filtration barrier integrity.

The emerging role of the transient receptor potential cation channel isotype 6 (TRPC6) as a central contributor to various pathological processes affecting podocytes has generated interest in the development of therapeutics to modulate its function. Recent insights into the regulation of TRPC6 have revealed PKG as a potent negative modulator of TRPC6 conductance and associated signaling via its phosphorylation at two highly conserved amino acid residues: Thr69/Thr70 (Thr69 in mice and Thr70 in humans) and Ser321/Ser322 (Ser321 in mice and Ser322 in humans). Here, we tested the role of PKG in modulating TRPC6-dependent responses in primary and conditionally immortalized mouse podocytes. TRPC6 was phosphorylated at Thr69 in nonstimulated podocytes, but this declined upon ANG II stimulation or overexpression of constitutively active calcineurin phosphatase. ANG II induced podocyte motility in an in vitro wound assay, and this was reduced 30–60% in cells overexpressing a phosphomimetic mutant TRPC6 (TRPC6T70E/S322E) or activated PKG ( P < 0.05). Pretreatment of podocytes with the PKG agonists S-nitroso- N-acetyl-dl-penicillamine (nitric oxide donor), 8-bromo-cGMP, Bay 41–2772 (soluble guanylate cyclase activator), or phosphodiesterase 5 (PDE5) inhibitor 4-{[3′,4′-(methylenedioxy)benzyl]amino}[7]-6-methoxyquinazoline attenuated ANG II-induced Thr69 dephosphorylation and also inhibited TRPC6-dependent podocyte motility by 30–60%. These data reveal that PKG activation strategies, including PDE5 inhibition, ameliorate ANG II-induced podocyte dysmotility by targeting TRPC6 in podocytes, highlighting the potential therapeutic utility of these approaches to treat hyperactive TRPC6-dependent glomerular disease.

Concentrations, distributions, and potential sources of DDTs and HCHs in seawater, sediments, soils, and atmosphere were collected to review their pollution statuses in the Bohai Sea and its coastal areas. In comparison to various sediment and seawater quality standards, DDTs and HCHs in sediments and seawater were at low levels in the entire Bohai Sea and might not cause adverse biological effects. However, DDTs and HCHs levels in various sea areas were closely associated with local pesticides production and application as well as hydrodynamic. DDTs and HCHs showed an obvious spatial distribution pattern. High levels were found in the Bohai Bay, Haihe River and Yellow River estuary. DDTs and HCHs concentrations in river and estuary sediments were higher than sea sediments and a seaward decreasing trend was observed. Although HCHs and DDTs residues in the Bohai Sea primarily originated from river runoffs (pesticide factory wastewater, historical applications and residues of technical HCH and DDT, etc.), additional sources of lindane and dicofol existed. Runoff from the demolished old pesticide factories might be another source. Further researches are highly recommended on pollution hotpots of DDTs and HCHs and investigate their migration and transformation at sediment-water interface and pollution history from sediment depth profiles.

The polysaccharides extracted by hot water and precipitated by 50% ethanol from the fruiting bodies of cultured Cordyceps militaris (W-CBP50) were introduced. Antioxidant activities of W-CBP50, W-CBP50 I (obtained from W-CBP50 purified by Sephadex G-100 chromatography) and W-CBP50 II (obtained from W-CBP50I purified by Sephadex G-200 chromatography) were evaluated and structural features of W-CBP50 II were analyzed. The polysaccharide W-CBP50 II was able to scavenge the stable free radical 1,1-diphenyl-2-picrylhyrazyl (DPPH), while W-CBP50 and W-CBP50I could scavenge DPPH, hydroxyl and superoxide radical. Structural characteristics of W-CBP50 II were investigated using GPC, GC–MS, 1H NMR and IR. The results showed that it was mainly composed of α-glucose, α-mannose, α-galactose and α-arabinose with α-type glycosidic linkage and the molecular weight of its main component was 8.97 kD.

Samples of class F coal fly ash (levels I, II, and III), slag, coal, atmospheric deposition, and soils collected from Tianjin, China, were analyzed using U.S. Environmental Protection Agency (U.S. EPA) Method 3052 and a sequential extraction procedure, to investigate the pollution status and mobility of Hg. The results showed that total mercury (HgT) concentrations were higher in level I fly ash (0.304 µg/g) than in level II and level III fly ash and slag (0.142, 0.147, and 0.052 µg/g, respectively). Total Hg in the atmospheric deposition was higher during the heating season (0.264 µg/g) than the nonheating season (0.135 µg/g). Total Hg contents were higher in suburban area soils than in rural and agricultural areas. High HgT concentrations in suburban area soils may be a result of the deposition of Hg associated with particles emitted from coal-fired power plants. Mercury in fly ash primarily existed as elemental Hg, which accounted for 90.1, 85.3, and 90.6% of HgT in levels I, II, and III fly ash, respectively. Mercury in the deposition existed primarily as sulfide Hg, which accounted for 73.8% (heating season) and 74.1% (nonheating season) of HgT. However, Hg in soils existed primarily as sulfide Hg, organo-chelated Hg and elemental Hg, which accounted for 37.8 to 50.0%, 31.7 to 41.8%, and 13.0 to 23.9% of HgT, respectively. The percentage of elemental Hg in HgT occurred in the order fly ash > atmospheric deposition > soils, whereas organo-chelated Hg and sulfide Hg occurred in the opposite order. The present approach can provide a window for understanding and tracing the source of Hg in the environment in Tianjin and the risk associated with Hg bioaccessibility. Environ. Toxicol. Chem. 2011;30:1997–2003. © 2011 SETAC

Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.

Considering the highly stochastic nature of the hydrological process, wavelet transform was used to analyse the characteristics, trends and causes of variations in annual run-off (1917–2006) into Tianjin in the Haihe River Basin. Run-off was steadily declining due to climate change and human activity and a significant decrease in run-off along the time series was discovered around the 1960s; however, the change in precipitation was insignificant. The time series of run-off was heavily influenced by a nonlinear feature and mainly influenced by the natural climate before the 1960s, but after the 1970s the change remained steady, with an annual run-off that fluctuated between 0·2 and 48·4 mm and was maintained at a low level (9·3 mm). The main cause of the run-off decline in the 1960s was that more than 1900 reservoirs with a total holding capacity of up to 83 mm were constructed in the upper and middle reaches, which controlled 85% of the total run-off. These projects have played an active role in the reservoir action and water conservation since they were implemented. At the beginning of the 1980s, the demand for water resources increased with the rapid growth of the population and the large-scale development of industry and agriculture in the Haihe River Basin, which caused a reduction in run-off into Tianjin. Overall, the hydrological effects of water storage projects regulating river run-off were beneficial to flood control, but might cause a serious reduction in river run-off into Tianjin and the lower reaches of the basin. In addition, a decrease in annual precipitation and changes in temperature in Northern China have also had an adverse effect on natural run-off, which caused a greater decline in water resources, but this did not have a powerful influence on the overall decline in the run-off. Copyright © 2011 John Wiley & Sons, Ltd.

FSGS is a clinicopathologic entity characterized by nephrotic syndrome and progression to ESRD. Although the pathogenesis is unknown, the podocyte seems to play a central role in this disorder. Here, we present six kindreds with hereditary FSGS that did not associate with mutations in known causal genes, and we report a new locus for the disease on chromosome 2p15 in one kindred. We performed genome-wide linkage analysis and refined the linkage area with microsatellite markers and haplotype analysis to define the minimal candidate region. Genome-wide linkage analysis yielded a maximum two-point logarithm of odds (LOD) score of 3.6 for the six families on chromosome 2p. One family contributed the largest proportion of the additive score (LOD 2.02) at this locus. Multipoint parametric LOD score calculation in this family yielded a significant LOD score of 3.1 at markers D2S393 and D2S337, and fine mapping of this region with microsatellite markers defined a minimal candidate region of 0.9 Mb with observed recombinations at markers D2S2332 and RS1919481. We excluded the remaining five families from linkage to this region by haplotype analysis. These data support a new gene locus for familial FSGS on chromosome 2p15. Identification of the mutated gene at this locus may provide further insight into the disease mechanisms of FSGS.

Batch experiments were conducted to test the effects of various solution properties, such as pH, temperature, initial concentration and anoxic and aerobic atmosphere, on Cd removal by nanoscale zerovalent iron (nZVI) supported on industrial coal fly ash. Cd (II) could be removed by adsorption on fly ash-nZVI in a very short time (5 min) with high removal rates (greater than 99.9%) over a wide range of concentration (5–100 mg l −1 ). Cd (II) was physically adsorbed on the surface of fly ash-nZVI. The preparation of fly ash-nZVI can incorporate the use of waste media, making the overall adsorbent more removal efficient and low cost.

We investigated the concentrations of Hg, Cd, Pb and As in samples of irrigation water, sediment, soil and groundwater from a field in Tianjin that was irrigated with wastewater. The results showed that the concentrations (Hg, 0.82 microg/L; Cd, 0.18 microg/L; Pb, 1.5 microg/L; As, 8.02 microg/L) in the irrigation water did not exceed the China Surface Water Quality Standard or the maximum concentrations in irrigation water recommended by the FAO. The concentrations of metals in the groundwater of wells (Hg, 0.016 microg/L; Cd, 0.128 microg/L; Pb, 0.25 microg/L; As, 4.65 microg/L) were lower than China Groundwater Quality Standard and the WHO guideline values for drinking water. The groundwater had not yet been contaminated through vertical infiltration-induced leaching. However, a substantial buildup of Hg and Cd in river sediments (I(geo) for Hg and Cd; 5.24 and 3.04, respectively) and wastewater-irrigated soils (I(geo) for Hg and Cd; 2.50 and 3.09, respectively) was observed. Taken together, these results indicated that irrigation with wastewater damaged the soil quality over the long term and that metals more easily accumulated in vegetable fields than rice fields.

Pentachlorophenol (PCP) concentrations were determined in 55 samples of fish, shrimp, crabs, frogs and turtles collected in Jiangsu Province and 55 freshwater shrimp samples collected from the Huiming Fish Market, Nanjing, China between 2003 and 2004. PCP concentrations ranged from less than the method detection limit (MDL: 0.5 microg/kg ww) to 61 microg/kg ww, with a mean of 5.2 microg/kg ww in 55 samples collected across Jiangsu Province and a mean of 0.5 microg/kg ww for freshwater shrimp collected from the Huiming Fish Market. Concentrations of PCP in common carp (Carassius auratus) were significantly greater than concentrations of PCP in other species from all of the areas studied. Grass carp (Ctenopharyngodon idella) contained the second greatest concentrations and crustacean species contained the least concentrations. Concentrations of PCP were greater in samples collected from Southern Jiangsu than those collected from other areas of Jiangsu Province. Concentrations of PCP in the freshwater shrimp (Macrobrachium nipponense) from the Huiming Fish Market were greater in March and September than those collected in June and December. Based on the allowable daily intake (ADI) set by the US National Academy of Science, current concentrations of PCP measured in aquatic products from Jiangsu Province presented minimus health risks to humans.

Qompsell are extracts of several traditional Chinese medicines: Astragalus membranaceus, Portulaca oleracea L, Flavescent sophora and Andrographis paniculata, etc. The macrophage phagocytic activity, macrophage ROS (reactive oxygen species), activity of serum lysozyme, SOD (superoxide dismutase), NOS (nitric oxide synthetase) and levels of total serum protein, globulin, and albumin were measured in carp that had been fed diets containing Qompsell at 0.3 g kg−1 for 60 days. The results showed that Qompsell had increased the macrophage phagocytic activity, macrophage ROS and the content of total protein, globulin, lysozyme in serum significantly (P 0.05). These results indicate that the Qompsell formula might elevate the immunity function of carp (Cyprinus carpio).

Surface soil samples were collected from 52 sites around Guanting Reservoir in Beijing, China, and contents of 'total' metals (Cu, Zn, Pb, Cd, As, Ni and Cr) were determined. The results indicate that the degree of heavy metal pollution in the soils declines in the order of Cd>Cr>Zn>As>Cu>Ni>Pb. Based on the results of a combination of multivariate statistics and geostatiscal analyses, it was concluded that land application of phosphate fertilizer, wastewater and sludge were the primary sources of Cd and Zn in soils. Whereas As, Cu, Cr and Ni in some soils were due to natural rock weathering. The sources of Pb in soils only partially originated from land application of phosphate fertilizer, but mainly from vehicle exhaust. The greatest concentrations of all metals, except for Pb, were found in Huailai County and the towns of Yanghedaqiao and Guanting.

The herbal immunoregulation mixture (HIRM) were extracts of several traditional Chinese medicines (TCMs): Astragalus membranaceus (from the root and stem), Polygonum multiflorum Thunb. (from the root), Isatis tinctoria L. (from the root), Glycyrrhiza glabra (from the stem). Immune parameters, which included macrophage phagocytic activity, macrophage reactive oxygen species (ROS), activity of serum lysozyme, nitric oxide synthetase (NOS) and superoxide dismutase (SOD), levels of total serum protein, globulin, albumin, triglyceride and cholesterol, were determined in carp that had been fed diets containing HIRM at 0.5% or 1% for 30 days. The results showed that, compared with those in the control group, the diets with 0.5% and 1% HIRM resulted in significant increase in macrophage phagocytic activity, macrophage ROS and the levels of total protein, globulin, albumin and NOS activity in serum (P 0.05). On the other hand, 0.5% HIRM led to evident enhancement of NOS activity and cholesterol level compared to 1% HIRM. These results indicated that HIRM might elevate the function of immunity in carp (Cyprinus carpio).

The pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin were investigated in the Chinese mitten-handed crab after a single intramuscular injection of enrofloxacin at 5.0mg/kg body weight. The tissue concentrations of enrofloxacin and ciprofloxacin were determined simultaneously by a high-performance liquid chromatography (HPLC) method. The data were analyzed with Practical Pharmacokinetic Program 3P97. The highest average concentrations of enrofloxacin in liver, muscle, gill, and hemolymph were 3.93, 12.42, 16.73, and 11.04 microg/g (ml), respectively. The elimination half-lives (t(1/2beta)) for enrofloxacin were 92.42, 64.86, 38.80, and 52.39 h, respectively. The AUC(0-infinity) values for enrofloxacin were 304.80, 260.74, 288.30, and 269.24 microg h/ml, respectively. Ciprofloxacin could be detected in all four tissues. The respective values of main pharmacokinetics parameters Cmax, t(1/2beta), and AUC(0-infinity) were 0.52 microg/g (ml), 38.38 h, and 35.06 microg h/ml for liver; 0.24 microg/g (ml), 65.36 h, and 25.64 microg h/ml for muscle; 0.10 microg/g (ml), 112.88 h, and 11.57 microg h/ml for gill; and 0.30 microg/g (ml), 93.33 h, and 39.99 microg h/ml for hemolymph.

Huntington's disease results from expansion of the polyglutamine (PolyQ) domain in the huntingtin protein. Although the cellular mechanism by which pathologic-length PolyQ protein causes neurodegeneration is unclear, mitochondria appear central in pathogenesis. We demonstrate in isolated mitochondria that pathologic-length PolyQ protein directly inhibits ADP-dependent (state 3) mitochondrial respiration. Inhibition of mitochondrial respiration by PolyQ protein is not due to reduction in the activities of electron transport chain complexes, mitochondrial ATP synthase, or the adenine nucleotide translocase. We show that pathologic-length PolyQ protein increases the production of reactive oxygen species in isolated mitochondria. Impairment of state 3 mitochondrial respiration by PolyQ protein is reversed by addition of the antioxidants N-acetyl-L-cysteine or cytochrome c. We propose a model in which pathologic-length PolyQ protein directly inhibits mitochondrial function by inducing oxidative stress.

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.

FSGS is characterized by segmental scarring of the glomerulus and is a leading cause of kidney failure. Identification of genes causing FSGS has improved our understanding of disease mechanisms and points to defects in the glomerular epithelial cell, the podocyte, as a major factor in disease pathogenesis. Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS. We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS. We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1-associated nephropathy. Overexpression of R431C mutant ANLN in immortalized human podocytes results in enhanced podocyte motility. The mutant anillin displays reduced binding to the slit diaphragm-associated scaffold protein CD2AP. Knockdown of the ANLN gene in zebrafish morphants caused a loss of glomerular filtration barrier integrity, podocyte foot process effacement, and an edematous phenotype. Collectively, these findings suggest that anillin is important in maintaining the integrity of the podocyte actin cytoskeleton.

Concentrations of heavy metals in river water and sediment were investigated in nine estuaries along the coast of Bohai Bay, Northern China. Multivariate statistical techniques such as principal component analysis and cluster analysis, in combination with metal concentration analysis and correlation analysis, were used to identify the possible sources of the metals and the pollution pattern in nine estuaries along the coast of Bohai Bay. The environmental risks of metals, evaluated by sediment quality guidelines and background values, revealed Hg contamination in the estuaries. However, levels of Cd in estuarine sediments were low, and they were less than those levels in river sediments, partly due to the high mobility and dilution of river or seawater. Cd did not contribute to sediment deposits in estuaries. High organic matter from effluents from large municipal sewage treatment plants was predominantly responsible for restricting Hg mobility from the river to Bohai Bay.