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Recent progress in targeting KRAS G12C has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS G12D inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS G12D with K D and IC 50 values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS G12D as compared to KRAS WT . MRTX1133 also demonstrated potent inhibition of activated KRAS G12D based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS G12D -mutant cell lines, with median IC 50 values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS WT cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS G12D -mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS G12D with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS G12D mutation-positive tumors on mutant KRAS for tumor cell growth and survival. A potent and selective inhibitor of KRAS G12D , the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

A failure of the glymphatic pathway to clear brain byproducts implicated in neurodegeneration may contribute to the pathophysiology of Parkinson’s disease. The glymphatic pathway relies on vasomotion (rhythmic constriction and dilation of blood vessels) to drive cerebrospinal fluid through the interstitial space and clear waste from the brain. The current study demonstrated that intermittent hypercapnia, exposure to low levels of CO 2 in ON-OFF cycles, elicited vasomotion-induced cerebrospinal fluid inflow in both healthy controls and individuals with Parkinson’s disease. The magnitude of the vasomotion-induced cerebrospinal fluid inflow in patients with Parkinson’s disease was reduced relative to healthy controls. However, intermittent hypercapnia, administered in three 10-minute sessions totaling approximately 30 minutes, increased the appearance of total α-synuclein, neurofilament light, glial fibrillary acidic protein, amyloid β 1-42 , amyloid β 1-40 , and phosphorylated tau 217 in the plasma of both healthy controls and individuals with Parkinson’s disease. This suggests that intermittent hypercapnia can be used to clear potentially toxic brain byproducts from the brain, highlighting its potential use as a disease modifying treatment.

Leadership teams are responsible for optimum staffing according to the current economic situation. Due to a recent economic downturn, service occupation leaders were found struggling with human resource and budgetary reductions. Employee absences cost organizations millions of dollars annually from lost productivity and training expenses. This study was completed to provide quantitative data to service occupation leadership teams to determine possible relationships between the state of the economy per the unemployment rate and the number of reported absences as presented by the Bureau of Labor Statistics data. The analyses conducted were on service occupation employee absence data released by the U.S. Bureau of Labor Statistics from 2004 through 2011. Leadership teams may use the results of this study to inspire company changes resulting in attaining optimum staffing levels with budgetary constraints while avoiding gaps in customer service due to absent employees. The findings indicated that there was a moderate positive relationship between service occupation employee absence rates and the unemployment rates during those years. Leadership understanding the possibility of existing correlational relationships among service occupation employee absence rates and the unemployment rates during the years 2004 through 2011 may make organizational leadership teams more aware that any future economic situation may relate to employee absence rates. The existing relationship does not indicate causation but provides service occupation leadership teams with another tool to assist in attaining a common organizational goal of an even balance between staffing levels and available organizational resources during certain economic conditions.

Recent progress in targeting KRAS has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS with K and IC values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS as compared to KRAS . MRTX1133 also demonstrated potent inhibition of activated KRAS based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in KRAS -mutant cell lines, with median IC values of ~5 nM, and demonstrated >1,000-fold selectivity compared to KRAS cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of KRAS -mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of KRAS mutation-positive tumors on mutant KRAS for tumor cell growth and survival.

Your first decision is to decide between a CRT or LCD screen. Most monitors sold today are standard CRT (cathode-ray tube) monitors. A more expensive option is a flat panel LCD (liquid-crystal display) monitor. LCD monitors are much more expensive, but they can be very handy if desk space is an issue. They also can be easier on the eyes, because they do not flicker and are less likely to cause eye fatigue. Moving on in the decision process, dot pitch is one of the most important and least looked at statistics to consider when choosing a monitor. All CRT monitors use tiny red, green and blue dots to produce what we see as a single dot of any particular color. Thousands of these dots make up the image that we see on the screen.

Finding the right people to staff a microcomputer consulting practice can be very challenging. Depending on the services the practice offers, the ideal consultant may need to wear many hats. The consultant should have some characteristics of an accountant, bookkeeper, teacher, student, programmer, graphic designer, author, public speaker, salesperson, marketing professional and a data entry clerk, to name a few. A good computer consultant should possess the following basic knowledge: 1. accounting theory, 2. microcomputer operating systems, 3. hardware components, and 4. software basics.

It was with much chagrin that we learned that the National Symphony Board had turned down the plans of Serge Koussevitzky, the eminent leader of the Boston Symphony. He proposed building a much-needed conservatory and opera house and also to mold a top-ranking symphony orchestra here in Washington.

Projected increases in greenhouse gas emissions could suppress marine biological productivity for a thousand years or more. As the climate warms, westerly winds in the Southern Hemisphere will strengthen and shift poleward, surface waters will warm, and sea ice will disappear. Moore et al. suggest that one effect of these changes will be a dramatic decrease in marine biological productivity (see the Perspective by Laufkötter and Gruber). This decrease will result from a global-scale redistribution of nutrients, with a net transfer to the deep ocean. By 2300, this could drive declines in fisheries yields by more than 20% globally and by nearly 60% in the North Atlantic. Science , this issue p. 1139 ; see also p. 1103 Multicentury climate warming could suppress marine biological productivity for a millennium. Climate change projections to the year 2100 may miss physical-biogeochemical feedbacks that emerge later from the cumulative effects of climate warming. In a coupled climate simulation to the year 2300, the westerly winds strengthen and shift poleward, surface waters warm, and sea ice disappears, leading to intense nutrient trapping in the Southern Ocean. The trapping drives a global-scale nutrient redistribution, with net transfer to the deep ocean. Ensuing surface nutrient reductions north of 30°S drive steady declines in primary production and carbon export (decreases of 24 and 41%, respectively, by 2300). Potential fishery yields, constrained by lower–trophic-level productivity, decrease by more than 20% globally and by nearly 60% in the North Atlantic. Continued high levels of greenhouse gas emissions could suppress marine biological productivity for a millennium.

The AMP-activated protein kinase (AMPK) is a heterotrimeric complex with central roles in cellular energy sensing and the regulation of metabolism and exercise adaptations. AMPK regulatory β subunits contain a conserved carbohydrate-binding module (CBM) that binds glycogen, the major tissue storage form of glucose. Research over the past two decades has revealed that the regulation of AMPK is impacted by glycogen availability, and glycogen storage dynamics are concurrently regulated by AMPK activity. This growing body of research has uncovered new evidence of physical and functional interactive roles for AMPK and glycogen ranging from cellular energy sensing to the regulation of whole-body metabolism and exercise-induced adaptations. In this review, we discuss recent advancements in the understanding of molecular, cellular, and physiological processes impacted by AMPK-glycogen interactions. In addition, we appraise how novel research technologies and experimental models will continue to expand the repertoire of biological processes known to be regulated by AMPK and glycogen. These multidisciplinary research advances will aid the discovery of novel pathways and regulatory mechanisms that are central to the AMPK signaling network, beneficial effects of exercise and maintenance of metabolic homeostasis in health and disease.

The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders are unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells, to evaluate the effects of schizophrenia (SZ)-associated common variants predicted to function as SZ expression quantitative trait loci (eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ eQTL ( FURIN rs4702) and four top-ranked SZ eQTL genes ( FURIN , SNAP91 , TSNARE1 and CLCN3 ), our platform resolves pre- and postsynaptic neuronal deficits, recapitulates genotype-dependent gene expression differences and identifies convergence downstream of SZ eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders. Combinatorial perturbation of schizophrenia risk loci in human induced pluripotent stem cell–derived neuronal cells demonstrates a synergistic effect converging on synaptic function.