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30 (1.15, 1.47), the hsCRP-based score was 1.35 (1.19, 1.53), and the hsCRP, C-peptide, and HbA1c-based score was 1.35 (1.19, 1.52). The latter score was associated with non-CIMP tumors (HRQ4vsQ1 1.59; 95% CI 1.17, 2.16) but not CIMP-positive tumors (pheterogeneity=0.04). CONCLUSIONS These results further support hypotheses that systemic biomarkers of metabolic health -inflammation and abnormal glucose homeostasis- mediate part of the relationship between several energy balance-related modifiable factors and CRC risk. IMPACT Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors. Copyright ©2020, American Association for Cancer Research.This work addresses the challenge of underactuated pattern generation in continuous multistable structures. The examined configuration is a slender membrane which can concurrently sustain two different equilibria states, separated by transition regions, and is actuated by a viscous fluid. We first demonstrate the formation and motion of a single transition region and then sequencing of several such moving transition regions to achieve arbitrary patterns by controlling the inlet pressure of the actuating fluid. Finally, we show that nonuniform membrane properties, along with transient dynamics of the fluid, can be leveraged to directly snap through any segment of the membrane.Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SCniche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.A critical problem in the fight against bacterial infection is the rising rates of resistance and the lack of new antibiotics. The discovery of new targets or new antibacterial mechanisms is a potential solution but is becoming more difficult. Here we report an antibacterial mechanism that safeguards intestine cells from enteropathogenic Escherichia coli (EPEC) by shutting down an infection-responsive signal of the host intestine cell. A key step in EPEC infection of intestinal cells involves Tir-induced actin reorganization. Nck mediates this event by binding with Tir through its SH2 domain (Nck-SH2) and with WIP through its second SH3 domain (Nck-SH3.2). selleck chemicals Here we report the design of a synthetic peptide that reacts precisely with a unique cysteine of the Nck-SH3.2 domain, blocks the binding site of the Nck protein, and prevents EPEC infection of Caco-2 cells. Oral update of this nontoxic peptide before EPEC administration safeguards mice from EPEC infection and diarrhea. This study demonstrates domain-specific blockage of an SH3 domain of a multidomain adaptor protein inside cells and the inhibition of Tir-induced rearrangement of the host actin cytoskeleton as a previously unknown antibacterial mechanism.Chimeric antigen receptor (CAR)-T immunotherapy has yielded impressive results in several B cell malignancies, establishing itself as a powerful means to redirect the natural properties of T lymphocytes. In this strategy, the T cell genome is modified by the integration of lentiviral vectors encoding CAR that direct tumor cell killing. However, this therapeutic approach is often limited by the extent of CAR-T cell expansion in vivo. A major outstanding question is whether or not CAR-T integration itself enhances the proliferative competence of individual T cells by rewiring their regulatory landscape. To address this question, it is critical to define the identity of an individual CAR-T cell and simultaneously chart where the CAR-T vector integrates into the genome. Here, we report the development of a method called EpiVIA (https//github.com/VahediLab/epiVIA) for the joint profiling of the chromatin accessibility and lentiviral integration site analysis at the population and single-cell levels. We validate our technique in clonal cells with previously defined integration sites and further demonstrate the ability to measure lentiviral integration sites and chromatin accessibility of host and viral genomes at the single-cell resolution in CAR-T cells. We anticipate that EpiVIA will enable the single-cell deconstruction of gene regulation during CAR-T therapy, leading to the discovery of cellular factors associated with durable treatment. Copyright © 2020 the Author(s). Published by PNAS.Traditionally, precipitates in a material are thought to serve as obstacles to dislocation glide and cause hardening of the material. This conventional wisdom, however, fails to explain recent discoveries of ultrahigh-strength and large-ductility materials with a high density of nanoscale precipitates, as obstacles to dislocation glide often lead to high stress concentration and even microcracks, a cause of progressive strain localization and the origin of the strength-ductility conflict. Here we reveal that nanoprecipitates provide a unique type of sustainable dislocation sources at sufficiently high stress, and that a dense dispersion of nanoprecipitates simultaneously serve as dislocation sources and obstacles, leading to a sustainable and self-hardening deformation mechanism for enhanced ductility and high strength. The condition to achieve sustainable dislocation nucleation from a nanoprecipitate is governed by the lattice mismatch between the precipitate and matrix, with stress comparable to the recently reported high strength in metals with large amount of nanoscale precipitates.