The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.
As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded ∼0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of ∼81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs.de novo genome sequence | genome expansion | Solanaceae evolution
Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1–/– phenotype. Here we demonstrate that cells derived from Bmi1–/– mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1–/– mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.
High-quality two-dimensional atomic layered p–n heterostructures are essential for high-performance integrated optoelectronics. The studies to date have been largely limited to exfoliated and restacked flakes, and the controlled growth of such heterostructures remains a significant challenge. Here we report the direct van der Waals epitaxial growth of large-scale WSe2/SnS2 vertical bilayer p–n junctions on SiO2/Si substrates, with the lateral sizes reaching up to millimeter scale. Multi-electrode field-effect transistors have been integrated on a single heterostructure bilayer. Electrical transport measurements indicate that the field-effect transistors of the junction show an ultra-low off-state leakage current of 10−14 A and a highest on–off ratio of up to 107. Optoelectronic characterizations show prominent photoresponse, with a fast response time of 500 μs, faster than all the directly grown vertical 2D heterostructures. The direct growth of high-quality van der Waals junctions marks an important step toward high-performance integrated optoelectronic devices and systems.
Talin is a large dimeric protein that couples integrins to cytoskeletal actin. Here, we report the structure of the C-terminal actin-binding domain of talin, the core of which is a five-helix bundle linked to a C-terminal helix responsible for dimerisation. The NMR structure of the bundle reveals a conserved surface-exposed hydrophobic patch surrounded by positively charged groups. We have mapped the actin-binding site to this surface and shown that helix 1 on the opposite side of the bundle negatively regulates actin binding. The crystal structure of the dimerisation helix reveals an antiparallel coiled-coil with conserved residues clustered on the solvent-exposed face. Mutagenesis shows that dimerisation is essential for filamentous actin (F-actin) binding and indicates that the dimerisation helix itself contributes to binding. We have used these structures together with small angle X-ray scattering to derive a model of the entire domain. Electron microscopy provides direct evidence for binding of the dimer to F-actin and indicates that it binds to three monomers along the long-pitch helix of the actin filament.
Impaired or deficient autophagy is believed to cause or contribute to aging, as well as a number of age-related pathologies. The exact mechanism through which alterations in autophagy induce these various pathologies is not well understood. Here we describe the creation of two in vivo mouse models that allow for the characterization of the alteration in mitochondrial function and the contribution of the corresponding oxidative stress following deletion of Atg7. Using these models we demonstrate that isolated mitochondria obtained from Atg7-/- skeletal muscle exhibit a significant defect in mitochondrial respiration. We further show that cells derived from Atg7-/- mice have an altered metabolic profile characterized by decreased resting mitochondrial oxygen consumption and a compensatory increase in basal glycolytic rates. Atg7-/-cells also exhibit evidence for increased steady state levels of reactive oxygen species. The observed mitochondrial dysfunction and oxidative stress is also evident in a mouse model where Atg7 is deleted within the pancreatic β cell. In this model, the simple administration of an antioxidant can significantly ameliorate the physiological impairment in glucose-stimulated insulin secretion. Taken together, these results demonstrate the potential role of mitochondrial dysfunction and oxidative stress in autophagy related pathology.
Abstract-Reactive oxygen species contribute to the pathogenesis of a number of disparate disorders including tissue inflammation, heart failure, hypertension, and atherosclerosis. In response to oxidative stress, cells activate expression of a number of genes, including those required for the detoxification of reactive molecules as well as for the repair and maintenance of cellular homeostasis. In many cases, these induced genes are regulated by transcription factors whose structure, subcellular localization, or affinity for DNA is directly or indirectly regulated by the level of oxidative stress. This review summarizes the recent progress on how cellular redox status can regulate transcription-factor activity and the implications of this regulation for cardiovascular disease. O xidative stress represents a common threat and danger for all aerobic organisms. Any enzyme capable of metabolizing oxygen also carries with it the intentional or accidental capability of generating reactive oxygen species (ROS). Once formed, these radical species can damage a number of essential cellular components including lipid membranes, DNA, and proteins. In addition, there exists a growing body of evidence that acting at lower concentrations, ROS can be purposely made within cells to serve as signaling molecules. 1 The response of a cell or organism to an increase in superoxide, hydrogen peroxide, or related ROS often involves the activation of numerous intracellular signaling pathways. These cytosolic pathways can, in turn, regulate a host of transcriptional changes that allow the cell to respond appropriately to the perceived oxidative stress. In addition to the regulation achieved by classical cytosolic signaling pathways, such as the family of mitogen-activated protein kinases (eg, mitogen-activated protein kinase, c-Jun N-terminal kinase, and p38 kinase family), evidence suggests that certain transcription factors can directly or indirectly alter their activity, depending on cellular redox conditions. Numerous studies have implicated oxidative or nitrosative stress in the progression of atherosclerosis and heart failure as well as the regulation of angiogenesis and other cardiovascular conditions. 2-5 Although the evidence for an oxidative stress component to disease initiation or progression has been well documented, the precise and relevant molecular targets of ROS remain less well understood. One clear mechanism through which ROS might alter the vessel wall or the myocardium would be through a redox-dependent change in transcriptional outputs. Clearly, this is not the only mechanism one could envision because the ROS-mediated oxidation of low-density lipoprotein cholesterol represents a transcription-independent mechanism through which oxidants could obviously contribute to atherosclerosis. Nonetheless, understanding how changes in intracellular oxidants might affect transcriptional activity represents an important avenue in understanding how ROS contribute to numerous disease states.In this review, we have decided to pres...
Vinculin plays a pivotal role in cell adhesion and migration by providing the link between the actin cytoskeleton and the transmembrane receptors, integrin and cadherin. We used a combination of electron microscopy, computational docking, and biochemistry to provide an atomic model of how the vinculin tail binds actin filaments. The vinculin tail actin binding site comprises two distinct regions. One of these regions is exposed in the full-length autoinhibited conformation of vinculin, whereas the second site is sterically occluded by vinculin's N-terminal domain. The partial accessibility of the F-actin binding site in the autoinhibited full-length vinculin structure suggests that F-actin can act as part of a combinatorial input framework with other binding partners such as alpha-catenin or talin to induce vinculin head-tail dissociation, thus promoting vinculin activation. Furthermore, binding to F-actin potentiates a local rearrangement in the vinculin tail that in turn promotes vinculin dimerization and, hence, formation of actin bundles.
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