Transient receptor potential channel 1 deficiency impairs host defense and proinflammatory responses to bacterial infection by regulating protein kinase Cα signaling

Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca2+ homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1-/- mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca2+ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca2+ entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cγ (PLC-γ), TRPC1 mediated Ca2+ entry and triggered protein kinase Cα (PKC-α) activity to facilitate nuclear translocation of NF-kB/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKCγ signaling circuit.Fil: Zhou, Xikun. University Of North Dakota; Estados Unidos. West China Hospital Of Sichuan University; ChinaFil: Ye, Yan. University Of North Dakota; Estados UnidosFil: Sun, Yuyang. University Of North Dakota; Estados UnidosFil: Li, Xuefeng. West China Hospital Of Sichuan University; China. University Of North Dakota; Estados UnidosFil: Wang, Wenxue. University Of North Dakota; Estados UnidosFil: Privratsky, Breanna. University Of North Dakota; Estados UnidosFil: Tan, Shirui. University Of North Dakota; Estados UnidosFil: Zhou, Zongguang. West China Hospital Of Sichuan University; ChinaFil: Huang, Canhua. West China Hospital Of Sichuan University; ChinaFil: Wei, Yu-Quan. West China Hospital Of Sichuan University; ChinaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute Of Environmental Health Sciences; Estados UnidosFil: Singh, Brij B.. University Of North Dakota; Estados UnidosFil: Wu, Min. University Of North Dakota; Estados Unido

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

Identification of Glycine Receptor α3 as a Colchicine-Binding Protein

Colchicine (Col) is considered a kind of highly effective alkaloid for preventing and treating acute gout attacks (flares). However, little is known about the underlying mechanism of Col in pain treatment. We have previously developed a customized virtual target identification method, termed IFPTarget, for small-molecule target identification. In this study, by using IFPTarget and ligand similarity ensemble approach (SEA), we show that the glycine receptor alpha 3 (GlyRα3), which play a key role in the processing of inflammatory pain, is a potential target of Col. Moreover, Col binds directly to the GlyRα3 as determined by the immunoprecipitation and bio-layer interferometry assays using the synthesized Col-biotin conjugate (linked Col and biotin with polyethylene glycol). These results suggest that GlyRα3 may mediate Col-induced suppression of inflammatory pain. However, whether GlyRα3 is the functional target of Col and serves as potential therapeutic target in gouty arthritis requires further investigations

IMI - Myopia Genetics Report

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

Background High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ −6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. Methods The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. Findings In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17–21%), 2% (1–3%), 8% (7–10%) and 6% (3–9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75–0.81), 0.58 (0.53–0.64), 0.71 (0.69–0.74) and 0.67 (0.62–0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92–1.24). Interpretation Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted fo

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

The Future Change in Evaporation Based on the CMIP6 Merged Data Generated by Deep-Learning Method in China

Land evaporation (LET) is an important variable in climate change, water cycle and water resources management. Mastering the projected changes in LET is significant for crop water requirements and the energy cycle. The global climate model (GCM) is a vital tool for future climate change research. However, the GCMs have low spatial resolution and relatively high errors. We use a deep learning (DL)-based model to deal with this problem. The DL approach can downscale the model data and merge simultaneously. We applied the DL approach to a suit of models from the Coupled Model Intercomparison Project 6th edition (CMIP6) LET data. From the result of all the evaluation metrics, the DL merged data greatly improved in both spatial and time dimensions. The mean RMSE is 5.85 mm and the correlation is 0.95 between the DL merged data and reference data (historical reliable evaporation data). The future LET evidently increases in four scenarios (SSP1–2.6, SSP2–4.5, SSP3–7.0, and SSP5–8.5), and the upward intensity rises from the low to high emission scenarios. The highest increasing regions are in the Tibet Plateau and the south of China and the trend is larger than 10 mm/decade in the high scenarios. From the seasonal point of view, the increasing trend in spring and summer is far larger than for autumn and winter. The Tibet Plateau and the northeast of China have the largest upward trend in the spring of SSP5–8.5, higher than 1.6 mm/decade

Study on Height Development Characteristics of Water-Conducting Fracture Zone in Fully Mechanized Mining of Shallow Thick Coal Seam under Water

The height of water-conducting fracture zone (HWCFZ) is one of the important technical parameters for water-preserved coal mining. The purpose of this paper is to acquire information about the height development characteristics of water-conducting fracture zone (WCFZ) in fully mechanized mining of shallow thick coal seam under water body in western mining area of China. The 91,105 fully mechanized mining face of Daheng coal mine under composite water body was taken as the research object, the development height, morphological characteristics, development and evolution process of WCFZ in working face mining were studied through underground up-hole water injection method by intervals, borehole TV and numerical simulation. The results show that the HWCFZ in 91,105 fully mechanized mining face is 52.7~53.6 m, and the fracture mining ratio is 12.55~12.76. The final development form is saddle-shaped with “large at both ends and small in the middle”. It is accurate and reliable to determine the development characteristics of overburden fractures and the HWCFZ by the field measurement of the combination of underground upward hole segmented water injection method and borehole TV. The development height of the water-conducting fracture zone obtained by numerical simulation is consistent with the field measured results. The development and evolution of the height of WCFZ presents four stages: “development–slow increase–sudden increase–stability”. When the WCFZ develops to a certain layer, the cracks generated by the weak strata in the fracture zone of overlying strata on the working face will automatically close with the advancement of the working face, resulting in “bridging phenomenon”, which inhibits the further development of the WCFZ. That is, the existence of soft rock with a certain thickness in overburden will become the key inhibiting layer for the development of WCFZ, effectively blocking the communication between water-conducting fracture and overlying aquifer. The research results are intended to provide guidance for the implementation of water preserving mining and ecological environment protection in ecologically fragile areas in western China