Generation of a human iPSC line (CIBi013-A) from a patient with young-onset Parkinson's disease carrying a novel homozygous PARK7 (DJ-1) mutation.

Mutations in PARK7 and the resulting alterations in its production protein (DJ-1) are tightly associated with Parkinson's disease. We generated a human induced pluripotent stem cell (iPSC) line (CIBi013-A) from a patient with young-onset Parkinson's disease (YOPD) who carried a novel homozygous PARK7 (DJ-1) mutation (chr1:8037723, c.334C>G). The generated iPSCs will be used for investigating phenotype and underlying molecular mechanisms in patient-derived cells.

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus.

Background: Alpha-klotho (α-KL) is not only related to the regulation of calcium-phosphorus metabolism, and fibrosis in chronic kidney disease (CKD), it is also involved in the regulation of many cognitive disorders. We conducted this study to investigate the effects of CKD on cognitive dysfunction and α-KL. Methods: Doxorubicin was used to induce a CKD model, which was validated by weight, 24-hour urine protein quantification, serum creatinine (Cr), blood urea nitrogen (BUN), and kidney hematoxylin-eosin (HE) staining. The Morris water maze (MWM) paradigm was used to assess the effects of CKD on cognitive behavior. The expression of α-KL in the hippocampus was detected using real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry (IHC). Results: (I) In the CKD group, the weight of the rats increased slowly (P<0.001), 24-hour urine protein increased (P<0.05), and Cr (P=0.026) and BUN levels (P=0.003) increased; (II) HE staining showed that in the CKD group there were changes in the structure, fibrosis, and inflammatory infiltration of the renal tissues, and changes in the structure, cell necrosis, and neuronal degeneration of the hippocampus; (III) in the MWM experiment, the escape latency of the CKD group was prolonged compared to that of the control group (P=0.043, 0.023), and the number of crossing the platform was reduced (P=0.003); (IV) in the CKD group, the expressions of α-KL messenger ribonucleic acid (P=0.0005) and α-KL protein (P=0.0005) in the hippocampus were downregulated. The IHC results showed that the expression of α-KL protein in the hippocampal region III cornus ammonis (CA3) of the CKD group region was also downregulated, and the α-KL-positive cells (P=0.019) and mean optical density (P=0.015) were decreased. Conclusions: The expression of α-KL appears to effect the cognitive function of CKD rats; thus, it may be a valuable target in the treatment of CKD with cognitive impairment.

Managing Methane Emissions in Abandoned Coal Mines: Comparison of Different Recovery Technologies by Integrating Techno-Economic Analysis and Life-Cycle Assessment.

Methane emissions from worldwide increasing abandoned coal mines have posed multiple challenges of global warming, energy waste, and explosion risk. This study first profiles the dynamic patterns of coal mine methane emissions in different recovery technologies, methane extraction with drainage (MEWD, mine-water concurrently extracted and treated) and direct methane extraction (DME, noncontrol on mine-water), in two abandoned mines from Ningxia and Inner Mongolia as China's leading coal provinces. Then, we conducted a techno-economic analysis and life-cycle assessment to quantify their comprehensive benefits. The key findings are as follows: (1) MEWD can long recover methane, although the economic profits decrease with declining methane extraction volume. DME can only work for ∼5 years, after which the mine is flooded, where methane is sealed underground and not recoverable. (2) MEWD drains and further treats the mine-water with an additional 29.4-35.9 million CNY cost compared with DME, while MEWD can achieve greater life-cycle environmental benefits with more cumulative methane recovery, whose CO2-eq (GWP-100) and SO2 reductions are 64.4 and 53.4% higher than those of DME. (3) MEWD is more promising for large-scale implementation, where feed-in tariffs and carbon market measures can improve the economics for sustainable management of incremental abandoned mine methane.

Tumor-Infiltrated CD8+ T Cell 10-Gene Signature Related to Clear Cell Renal Cell Carcinoma Prognosis.

Clear cell renal cell carcinoma (ccRCC) usually affects multiple organs (e.g., bone and brain), and patient prognosis is usually poor. Although it is known that CD8+ T cell infiltration can potentially alleviate ccRCC progression, few studies have concentrated on the correlation between CD8+ T cell infiltration and ccRCC prognosis. In this study, ten genes expressed by infiltrated CD8+ T cells (i.e., AMD1, CCSER2, CIB1, DRAP1, HMGB2, HMGN1, NPIPB5, PTP4A2, RORA, and SAP18) were suggested as potential ccRCC prognostic biomarkers, by using next-generation sequencing (i.e. bulk sequencing and single-cell sequencing) of ccRCC, papillary renal cell carcinoma (papRCC), and control kidney biopsies. Specifically, we identified four genes (i.e., CCSER2, DRAP1, NPIPB5, and SAP18) as potential novel prognostic biomarkers for ccRCC. It is noteworthy that SAP18 derived from CD8+ T cells negatively correlates to Atg7+ neutrophils in ccRCC, compared with papRCC, indicating a potential decreased neutrophil metabolic function in autophagy and fatty acids. This study elucidated the protective role of infiltrated CD8+ T cells in ccRCC and identified ten candidate genes related to an improved prognosis in patients with ccRCC.

Expression of LncRNA KCNQ1Ot1 in diabetic nephropathy and its correlation with MEK/ERK signaling pathway.

OBJECTIVE: To explore the expression of LncRNA KCNQ1OT1 in diabetic nephropathy (DN), and its correlation with MEK/ERK signaling pathway. METHODS: 148 patients with type 2 diabetes in our hospital were selected as research subjects, including 83 patients with simple type 2 diabetes (T2D group) and 65 patients with type 2 diabetes with DN (DN group). Another 50 non-diabetic patients were enrolled as the control group. The expressions of LncRNA KCNQ1OT1 and MEK/ERK signaling pathway related molecules in peripheral blood mononuclear cells (PBMCs) of the three groups of subjects were detected and their correlations were analyzed. In addition, 30 Wistar rats were divided into a control group, diabetes group and DN model group, and the expression of LncRNA KCNQ1OT1 and MEK/ERK signal pathway-related molecules in kidney tissue of the three groups was detected and compared. RESULTS: The relative expression of LncRNA KCNQ1OT1, MEK-5 and ERK2 in the control group was lower than that of the T2D group and DN group (P<0.05), and the relative expression of LncRNA KCNQ1OT1 in T2D group was lower than that of DN group (P<0.05). The expression of LncRNA KCNQ1OT1 was positively-correlated with MEK-5 and ERK2 (P<0.05). The relative expression of LncRNA KCNQ1OT1, MEK-5, and ERK2 in renal tissues of the DN group was higher than those in the control group and diabetes group (P<0.05). CONCLUSION: The expression of LncRNA KCNQ1OT1 in PBMCs of DN patients is abnormally increased, and may be a biomarker for the diagnosis and treatment of the disease. In addition, an abnormal increase of LncRNA KCNQ1OT1 is associated with the activation of the MEK/ERK signaling pathway.

Correlation of Carotid Artery Intima-Media Thickness with Calcium and Phosphorus Metabolism, Parathyroid Hormone, Microinflammatory State, and Cardiovascular Disease.

The internal thickness of the carotid artery is the vertical distance between the intima of the carotid artery and the middle mold. Its normal thickness is less than 1 mm. It can be used to judge the degree of arteriosclerosis. Under normal circumstances, the change of the internal thickness of the carotid artery is caused by cardiovascular disease. The purpose of this article is to study the relationship between the thickness of the carotid artery and the metabolism of calcium and phosphorus, parathyroid hormone, microinflammatory state, and cardiovascular disease. This article uses ultrasound measurement to measure the IMT of ESRD patients and carotid arteries with normal renal function. The analysis includes blood pressure, blood phosphorus, blood calcium, blood creatinine, blood urea nitrogen, blood sugar, glycosylated hemoglobin, blood lipids, parathyroid hormone, and C reaction. The correlation between clinical indicators includes protein and carotid IMT in ESRD patients which can be used in designing a diagnostic plan for patients through correlation research. The results showed that the carotid artery IMT of ESRD nondialysis patients was 13% thicker than that of those with normal renal function, and it was significantly positively correlated with age, blood pressure, blood phosphorus, glycosylated hemoglobin, and C-reactive protein. The correlation ratio with calcium and phosphorus was about 0.1.

The Identification of a Tumor Infiltration CD8+ T-Cell Gene Signature That Can Potentially Improve the Prognosis and Prediction of Immunization Responses in Papillary Renal Cell Carcinoma.

BACKGROUND: CD8+ T cells, vital effectors pertaining to adaptive immunity, display close relationships to the immunization responses to kill tumor cells. Understanding the effect exerted by tumor infiltration CD8+ T cells in papillary renal cell carcinoma (papRCC) is critical for assessing the prognosis process and responses to immunization therapy in cases with this disease. MATERIALS AND APPROACHES: The single-cell transcriptome data of papRCC were used for screening CD8+ T-cell-correlated differentially expressed genes to achieve the following investigations. On that basis, a prognosis gene signature associated with tumor infiltration CD8+ T cell was built and verified with The Cancer Genome Atlas data set. Risk scores were determined for papRCC cases and categorized as high- or low-risk groups. The prognosis significance for risk scores was assessed with multiple-variate Cox investigation and Kaplan-Meier survival curves. In addition, the possible capability exhibited by the genetic profiles of cases to assess the response to immunization therapy was further explored. RESULTS: Six hundred twenty-one cell death-inhibiting RNA genes were screened using single-cell RNA sequencing. A gene signature consisting of seven genes (LYAR, YBX1, PNRC1, TCF25, MYL12B, MINOS1, and LINC01420) was then identified, and this collective was considered to be an independent prognosis indicator that could strongly assess overall survival in papRCC. In addition, the data allowed papRCC cases to fall to cohorts at high and low risks, exhibiting a wide range of clinically related features as well as different CD8+ T-cell immunization infiltration and immunization therapy responses. CONCLUSIONS: Our work provides a possible explanation for the limited response of current immunization checkpoint-inhibiting elements for combating papRCC. Furthermore, the researchers built a novel genetic signature that was able to assess the prognosis and immunotherapeutic response of cases. This may also be considered as a promising therapeutic target for the disease.

Road freight emission in China: From supply chain perspective.

Freight emissions management has entered the deep-water zone. This study evaluated road freight emissions from supply chain perspective using China's 2007, 2010 and 2012 multiregional input-output table. For the first time, we quantified road freight emission based on sectors in China. Heavy industries, mining, agriculture and light industry contributed 71%,14%, 12% and 3% of total NOx emissions in 2012 from production perspective. Construction was the largest consumption sector (43%) responsible for road freight emission from consumption perspective. Upstream transport and final product transport emitted 3.04 Tg (80%) and 0.77 Tg (20%) NOx in 2012. Huge disparities of road freight emissions flows and allocation patterns were found across provinces in China in terms of resource endowments, geographical position and economic development. The road freight emission increased rapidly from 2007 to 2012, and economic growth effect outpaced emission control effect caused by emission standard upgrade and thus dominated the emission growth. The production structure and consumption pattern changes also promoted the emission growth. It is thus important to mitigate freight emissions with different strategies based on a certain sector's freight emissions features from the whole supply chain.

S3-2, a novel long-lasting oxyntomodulin derivative, exerts improvement on diabesity and renal injury through activating GLP-1 and glucagon receptors.

AIMS: To prolong the short lifespan of oxyntomodulin (OXM) for treating obesity and diabetes, we designed a novel fused OXM analog, containing an albumin-binding sequence, a protease cleavable tetrapeptide, and a mutated OXM. MAIN METHODS: We screened two albumin-binding sequences (S3 and S6) to construct OXM derivatives, termed S3-2 (with two cysteines) and S6-0 (without cysteine). After peptides were synthesized, isothermal titration calorimetry (ITC) was applied to assess binding-affinity for HSA. Further in vivo acute efficacies evaluation and candidate selection were performed in diabetic db/db mice via oral glucose tolerance test (OGTT) and glucose-lowering duration test. Chronic efficacy test of selected candidate was also performed in diabetic mice. RESULTS: Firstly, S3-2 and S6-0 with purity over 99% were prepared. ITC measurements demonstrated that S3-2 and S6-0 associate with HSA with high-affinity (Kd = 12.81 ± 1.11 nM and 26.98 ± 2.39 nM, respectively). Then hypoglycemic efficacies showed deoxidation S3-2 (S3-2re) showed longer hypoglycemic duration than the oxidation one (S3-2ox), and better blood glucose level (BGL) control effect than S6-0. OGTTs in diabetic mice revealed the glucose-lowering efficacies of S3-2re were similar to Liraglutide. The protracted antidiabetic effects of S3-2re were further confirmed by multiple OGTTs in db/db mice. Furthermore, twice weekly injection of S3-2re to db/db mice achieved beneficial effects on body weight gain, glucose tolerance, postprandial BGL and obesity. Moreover, S3-2 produces significantly protective effects on the impaired renal functions of the diabetic mice. CONCLUSION: S3-2re exhibits outstanding therapeutical potential as a candidate drug for treating the obesity and diabetes.

Profiling the Resident and Infiltrating Monocyte/Macrophages during Rejection following Kidney Transplantation.

Immune tolerance research is essential for kidney transplantation. Other than antibody and T cell-mediated immune rejection, macrophage-mediated innate immunity plays an important role in the onset phase of transplantation rejection. However, due to the complexity of the kidney environment as well as its diversity and low abundance, studies pertaining to monocyte/macrophages in kidney transplantation require further elucidation. In this study, kidney samples taken from healthy human adults and biopsy specimens from patients undergoing rejection following kidney transplantation were analysed and studied. By conducting a single-cell RNA analysis, the type and status of monocyte/macrophages in kidney transplantation were described, in which monocyte/macrophages were observed to form two different subpopulations: resident and infiltrating monocyte/macrophages. Furthermore, previously defined genes were mapped to all monocyte/macrophage types in the kidney and enriched the differential genes of the two main subpopulations using gene expression databases. Considering that various cases of rejection may be of the monocyte/macrophage type, the present data may serve as a reference for studies regarding immune tolerance following kidney transplantation.

PM2.5 concentration estimation using convolutional neural network and gradient boosting machine.

Surface monitoring, vertical atmospheric column observation, and simulation using chemical transportation models are three dominant approaches for perception of fine particles with diameters less than 2.5 micrometers (PM2.5) concentration. Here we explored an image-based methodology with a deep learning approach and machine learning approach to extend the ability on PM2.5 perception. Using 6976 images combined with daily weather conditions and hourly time data in Shanghai (2016), trained by hourly surface monitoring concentrations, an end-to-end model consisting of convolutional neural network and gradient boosting machine (GBM) was constructed. The mean absolute error, the root-mean-square error and the R-squared for PM2.5 concentration estimation using our proposed method is 3.56, 10.02, and 0.85 respectively. The transferability analysis showed that networks trained in Shanghai, fine-tuned with only 10% of images in other locations, achieved performances similar to ones from trained on data from target locations themselves. The sensitivity of different regions in the image to PM2.5 concentration was also quantified through the analysis of feature importance in GBM. All the required inputs in this study are commonly available, which greatly improved the accessibility of PM2.5 concentration for placed and period with no surface observation. And this study makes an exploratory attempt on pollution monitoring using graph theory and deep learning approach.

Intermediate-Volatility Organic Compound Emissions from Nonroad Construction Machinery under Different Operation Modes.

Intermediate-volatility organic compounds (IVOCs) have been found as important sources for secondary organic aerosol (SOA) formation. IVOC emissions from nonroad construction machineries (NRCMs), including two road rollers and three motor graders, were characterized under three operation modes using an improved portable emission measurement system. The fuel-based IVOC emission factors (EFs) of NRCMs varied from 245.85 to 1802.19 mg/kg·fuel, which were comparable at magnitudes to the reported results of an ocean-going ship and on-road diesel vehicles without filters. The discrepancy of IVOC EFs is significant within different operation modes. IVOC EFs under the idling mode were 1.24-3.28 times higher than those under moving/working modes. Unspeciated b-alkanes and cyclic compounds, which were the unresolved components in IVOCs at the molecular level, accounted for approximately 91% of total IVOCs from NRCMs. The SOA production potential analysis shows that IVOCs dominated SOA formation of NRCMs. Our results demonstrate that IVOC emissions from NRCMs are non-negligible. Thus, an accurate estimation of their IVOC emissions would benefit the understanding of SOA formation in the urban atmosphere.

[Correlation between TGF-B gene promoter-509C/T polymorphism and IgA nephropathy in core families in Guangxi Zhuang Autonomous Region and the therapeutic effect of dendrobium].

OBJECTIVE: To investigate the correlation between transformation growth factor (TGF- B) polymorphisms and IgA nephropathy and the therapeutic effect of dendrobium on IgA nephropathy. METHODS: Polymerase chain reaction- restriction fragment length polymorphism (PCR- RFLP) and direct sequencing were used for analysis of 118 patients with IgA nephropathy from core families in Guangxi Zhuang Autonomous Region. The imbalanced transfer of TGF iso1-509 C/T in the affected offsprings was observed by transfer imbalance test and HRR analysis. The TGF-B genotype of the patients and the core family members were detected. The therapeutic effects of Dendrobium candidum combined with hormone and ACEI/ARB treatments were evaluated by observing the patient's urine protein (24 hUpr), serum albumin (ALB), creatinine (Scr) and urea nitrogen (BUN) levels. RESULTS: In the 118 patients with IgA nephropathy, we identified TGF-B 1 promoter -509C/T genotype CC in 32 (27.1%) cases, CT in 58 (49.2%) cases, and TT in 28 (23.7%) cases. In the core family of the patients, CC genotype was found in 33 (28.0%) cases, CT in 55 (46.6%) cases, and TT in 30 (28.0%) cases. The treatments significantly lowered 24 hUpr, Scr, and BUN levels (P > 0.05) in patients with CC genotype, significantly lowered 24 hUpr and BUN levels in patients with CT genotype (P < 0.05), and significantly lowered 24 hUpr and BUN level and increased (P < 0.05) ALB level (P < 0.01) in patients with TT genotype. CONCLUSIONS: There is no significant correlation between TGF-B promoter - 509C/T polymorphism and IgA nephropathy. The patients with CC genotype are sensitive to the treatments with hormone and ACEI/ ARB and show a stronger response to combined treatments with dendrobium.

The impact of marine shipping and its DECA control on air quality in the Pearl River Delta, China.

Marine trade has significantly expanded over the past decades aiding to the economic development of the maritime countries, yet, this has been associated with a considerable increase in pollution emission from shipping operation. This study aims at considering both sides of the spectrum at the same time, which is including both public and shipping business. Of the key significance would be to optimize the operation of the shipping industry, such that its impact on air pollution is minimized, without, however, significant escalation of its cost, and therefore to protect the whole seaborne trade. To do this, we considered the impacts of three control strategies, including the current emission control area (ECA) design, as well two additional ones. Thus the first scenario (DECA1) was based on the China's domestic emission control area (DECA), which was set up in 2016. The DECA1 scale was only 12 nautical miles, which was much smaller than the emission control areas in US or Europe. We defined the second scenario (DECA2), by stretching the zone to 200 nautical miles towards the ocean, modeling it on the ECA in North America. The third scenario (DECA3), on the other hand, expanded the 12 nautical miles control zone along the whole coastline. To investigate the impact of shipping emissions on air quality, a shipping emission calculation model and an air quality simulation model were used, and Pearl River Delta (PRD), China was chosen to serve as a case study. The study demonstrated that in 2013 marine shipping emissions contributed on average 0.33 and 0.60µg·m-3, respectively to the land SO2 and PM2.5 concentrations in the PRD, and that the concentrations were high along the coastline. The DECA1 policy could effectively reduce SO2 and PM2.5 concentrations in the port regions, and the average reduction in the land area were 9.54% and 2.7%, respectively. Compared with DECA1, DECA2 would not measurably improve the air quality, while DECA3 would effectively decrease the pollution in the entire coast area. Thus, instead of expanding emission control area far to the ocean, it is more effective to control emissions along the coastline to secure the best air quality and lower the health impacts. By doing this, 19 million dollars of fuel cost could be saved per year. The saved cost could help the ship owners to endure, considering the current low profits of the seaborne trade, and thus to protect the overall growth of the economy.

Inhibition of TRPC6 Signal Pathway Alleviates Podocyte Injury Induced by TGF-ß1.

BACKGROUND/AIMS: Transforming growth factor beta 1 (TGF-ß1) plays a critical role in the pathogenesis of glomerulosclerosis. The purpose of this study was to examine the effects of inhibition of transient receptor potential cation channel C6 (TRPC6) on podocyte injury induced by TGF-ß1 via nephrin and desmin mechanisms. METHODS: A rat model of nephropathy was first induced by intravenous injections of adriamycin to determine TRPC6 signal pathway engaged in glomerulosclerosis in vivo. Conditionally immortalized podocytes were cultured in vitro and they were divided into four groups: control; TGF-ß1 treatment; TGF-ß1 with TRPC6 knockdown and TGF-ß1 without TRPC6 knockdown. Real time RT-PCR and Western blot analysis were employed to determine the mRNA and protein of expression of nephrin, desmin and caspase-9, respectively. Flow cytometry was used to examine the apoptotic rate of podocytes and DAPI fluorescent staining was used to determine apoptotic morphology. RESULTS: In vivo experiment, adriamycin significantly upregulated the protein expression of TGF-ß1, TRPC6, desmin and caspase-9, and decreased nephrin. Consistent with the latter results, in vitro experiment mRNA and protein expression of desmin and caspase-9 was increased in cultured TGF-ß1-treated podocytes, whereas nephrin was declined as compared with the control group. Importantly, TRPC6 knockdown significantly attenuated the upregulated desmin and caspase-9, and alleviated impairment of nephrin induced by TGF-ß1. Moreover, typical morphologic features were presented in apoptotic podocytes. The number of apoptotic podocytes was increased after exposure to TGF-ß1 and this was alleviated after TRPC6 knockdown. TRPC6 knockdown also decreased an apoptosis rate of TGF-ß1-treated podocytes. Note that negative TRPC6 transfection control failed to alter an increase of the apoptosis rate in TGF-ß1-treated podocytes. CONCLUSIONS: TGF-ß1 induced by glomerulosclerosis impairs the protein expression of nephrin and amplifies the protein expression of desmin and caspase -9 via TRPC6 signal pathway. Inhibition of TRPC6 alleviates these changes in podocytes-treated with TGF-ß1 and attenuated apoptosis of podocytes. Our data suggest that TRPC6 signal plays an important role in mediating TGF-ß1-induced podocyte injury via nephrin, desmin and caspase-9. Results of the current study also indicate that blocking TRPC6 signal pathway has a protective effect on podocyte injury. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of podocyte injury observed in glomerulosclerosis.