The role of Jade-1 in DNA mismatch damage and repair in renal cancer

The von Hippel-Lindau (VHL) tumor suppressor pVHL is lost in 90% of clear-cell renal-cell carcinomas (ccRCCs). Jade-1 is a renal tumor suppressor that is normally stabilized by pVHL. MutS Homolog2 (MSH2) is a key initiator in DNA mismatch repair (MMR). Defects in MMR are associated with genome-wide instability and predisposition to certain types of cancer. Mass spectrometry data of immunoprecipitated Flag-tagged Jade-1 lysates showed signal for MSH2, suggesting Jade-1 may participate in MMR. Here, we confirmed an interaction between endogenous MSH2 and endogenous Jade-1 by coimmunoprecipitation. Using cell fractionation, we found that MSH2 and Jade-1 translocated to the nucleus in response to alkylating agent MNNG in kidney proximal tubule cells. We also visualized the translocation of Jade-1 by immunofluorescence. Silencing JADE1 also influenced the kinetics of MSH2 translocation. In addition, by colony forming assay, JADE1-silenced cells were resistant to mismatch damage induced by MNNG, which is a feature of cells with an MMR defect. Furthermore, reintroducing pVHL into renal cancer cells also changed the amount of translocated MSH2 and Jade-1. In contrast to wild-type mice, Jade1 heterozygous mice got spontaneous tumors, and those tumors continued to show heterozygosity for Jade1. Taken together, our results identify a mechanism for Jade-1 regulation of MMR through its nuclear translocation. pVHL may also contribute to MSH2 and Jade-1 translocation by increasing Jade-1 abundance. These findings establish an early role for Jade-1 in MMR, provide further indication that Jade-1 helps maintain genomic stability in the kidney and support that Jade-1 is a haploinsufficient renal tumor suppressor

Quantifying the Evidential Value of Celebrity Endorsement: A p-Curve Analysis

Celebrity endorsements have long been used as a promotional tool in marketing communication. However, literature has documented inconsistent findings on the effects of celebrity endorsements compared to no endorsement or noncelebrity endorsements, suggesting a close examination about the reliability and robustness of celebrity endorsements is needed. This study conducted a p-curve analysis among two sets of published studies based on different comparison groups (celebrity endorsements vs. no celebrity endorsement; celebrity endorsements vs. noncelebrity endorsements) to investigate if both sets of studies contain an evidential value. The significantly right-skewed p curve suggests that both sets of published studies have some integrity. However, the studies that compared celebrity endorsements with no celebrity endorsements showed low statistical power. Theoretical and methodological implications for celebrity endorsement research were discussed

The Global Landscape of Neural Networks: An Overview

One of the major concerns for neural network training is that the non-convexity of the associated loss functions may cause bad landscape. The recent success of neural networks suggests that their loss landscape is not too bad, but what specific results do we know about the landscape? In this article, we review recent findings and results on the global landscape of neural networks. First, we point out that wide neural nets may have sub-optimal local minima under certain assumptions. Second, we discuss a few rigorous results on the geometric properties of wide networks such as "no bad basin", and some modifications that eliminate sub-optimal local minima and/or decreasing paths to infinity. Third, we discuss visualization and empirical explorations of the landscape for practical neural nets. Finally, we briefly discuss some convergence results and their relation to landscape results.Comment: 16 pages. 8 figure

Additive Manufacturing of Complexly Shaped SiC with High Density Via Extrusion-Based Technique – Effects of Slurry Thixotropic Behavior and 3D Printing Parameters

Additive manufacturing of dense SiC parts was achieved via an extrusion-based process followed by electrical-field assisted pressure-less sintering. The aim of this research was to study the effect of the rheological behavior of SiC slurry on the printing process and quality, as well as the influence of 3D printing parameters on the dimensions of the extruded filament, which are directly related to the printing precision and quality. Different solid contents and dispersant- Darvan 821A concentrations were studied to optimize the viscosity, thixotropy and sedimentation rate of the slurry. The optimal slurry was composed of 77.5 wt% SiC, Y2O3 and Al2O3 powders, 0.25 wt% dispersant and 0.01 wt% defoamer. The printing parameters studied included extrusion pressure, nozzle size, layer height and printing speed; the one that had the most prominent effect on filament width and height was indicated as layer height. The nozzle inner diameter of 1.04 mm, speed of 350 mm/min, layer height of 0.7 mm and extrusion air pressure of 0.31 MPa were the optimal printing parameters. Furthermore, the relationship between the printing parameters and the filament dimensions was successfully predicted by using machine learning and grey system theory. Finally, the relative density of the printed SiC parts sintered at 1900 oC reached 94.7±1.5%

Fine-mapping within eQTL credible intervals by expression CROP-seq

The majority of genome-wide association study (GWAS)-identified SNPs are located in noncoding regions of genes and are likely to influence disease risk and phenotypes by affecting gene expression. Since credible intervals responsible for genome-wide associations typically consist of ≥100 variants with similar statistical support, experimental methods are needed to fine map causal variants. We report here a moderate-throughput approach to identifying regulatory GWAS variants, expression CROP-seq, which consists of multiplex CRISPR-Cas9 genome editing combined with single-cell RNAseq to measure perturbation in transcript abundance. Mutations were induced in the HL60/S4 myeloid cell line nearby 57 SNPs in three genes, two of which, rs2251039 and rs35675666, significantly altered CISD1 and PARK7 expression, respectively, with strong replication and validation in single-cell clones. The sites overlap with chromatin accessibility peaks and define causal variants for inflammatory bowel disease at the two loci. This relatively inexpensive approach should be scalable for broad surveys and is also implementable for the fine mapping of individual genes

Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call “meta-loci”, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci

A facile one-pot synthesis of CaO/CuO hollow microspheres featuring highly porous shells for enhanced CO2 capture in combined Ca-Cu looping process via a template-free synthesis approach

The preparation of bifunctional CaO/CuO composites with high performance is essential for the development of the combined Ca–Cu looping process, in which the exothermic reduction of CuO with methane is used in situ to provide the heat required to calcine CaCO3. However, the rapid decline in CO2 uptake of CaO/CuO composites remains an important problem to be solved, despite their excellent redox characteristic. Herein we report a facile one-pot template-free synthesis approach to yield CaO/CuO hollow microspheres, aimed at enhancing the CO2 capture performance of CaO/CuO composites. CaO/CuO hollow microspheres feature highly porous shells and a homogeneous elemental distribution, and demonstrate significantly enhanced CO2 capture performance. After ten repeated cycles in a fixed-bed reactor, the CO2 uptake capacity of the best-performing CaO/CuO hollow microspheres exceeded that of the reference materials, i.e., CaO/CuO composites synthesized via wet mixing or a co-precipitation method, by 222% and 114%, respectively. Moreover, from cycle number eight onwards, the CO2 uptake was very stable over the tested 20 cycles, suggesting good cyclic stability of CaO/CuO hollow microspheres. Oxidation was always fast with O2 uptake capacities greater than 0.13 gO2 gmaterial−1. On the basis of N2 adsorption, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) characterizations, the significantly enhanced CO2 capture performance of the CaO/CuO hollow microspheres resulted from the unique hollow microsphere structure with highly porous shells, which were retained throughout the cyclic operations