Cobbkumar4940

Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.Low-coverage whole-genome sequencing followed by imputation has been proposed as a cost-effective genotyping approach for disease and population genetics studies. However, its competitiveness against SNP arrays is undermined because current imputation methods are computationally expensive and unable to leverage large reference panels. read more Here, we describe a method, GLIMPSE, for phasing and imputation of low-coverage sequencing datasets from modern reference panels. We demonstrate its remarkable performance across different coverages and human populations. GLIMPSE achieves imputation of a genome for less than US$1 in computational cost, considerably outperforming other methods and improving imputation accuracy over the full allele frequency range. As a proof of concept, we show that 1× coverage enables effective gene expression association studies and outperforms dense SNP arrays in rare variant burden tests. Overall, this study illustrates the promising potential of low-coverage imputation and suggests a paradigm shift in the design of future genomic studies.Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.In cross-platform analyses of 174 metabolites, we identify 499 associations (P  less then  4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.Introduction The objectives were to characterise the particle size distribution of aerosols generated by standard dental aerosol generating procedures (AGPs) and to assess the impact of aerosol-management interventions on 'fallow time'. Interventions included combinations of high-volume intraoral suction (HVS[IO]), high-volume extraoral suction (HVS[EO]) and an air cleaning system (ACS).Method A sequence of six AGPs were performed on a phantom head. Real-time aerosol measurements (particle size range 0.0062-9.6 μm) were acquired from six locations within a typical dental treatment room (35 m3).Results The majority (>99%) of AGP particles were less then 0.3 μm diameter and remained at elevated levels around the dental team during the AGPs. With no active aerosol-management interventions, AGP particles were estimated to remain above the baseline range for up to 30 minutes from the end of the sequence of procedures.Conclusions The results emphasise the importance of personal protection equipment, particularly respiratory protection. Use of HVS(IO), either alone or in combination with the ACS, reduced particle concentrations to baseline levels on completion of AGPs. These data indicate potential to eliminate fallow time. The study was performed using a phantom head so confirmatory studies with patients are required.