Coping with cyclic oxygen availability: evolutionary aspects

Both the gradual rise in atmospheric oxygen over the Proterozoic Eon as well as episodic fluctuations in oxygen over several million-year time spans during the Phanerozoic Era, have arguably exerted strong selective forces on cellular and organismic respiratory specialization and evolution. The rise in atmospheric oxygen, some 2 billion years after the origin of life, dramatically altered cell biology and set the stage for the appearance of multicelluar life forms in the Vendian (Ediacaran) Period of the Neoproterozoic Era. Over much of the Paleozoic, the level of oxygen in the atmosphere was near the present atmospheric level (21%). In the Late Paleozoic, however, there were extended times during which the level of atmospheric oxygen was either markedly lower or markedly higher than 21%. That these Paleozoic shifts in atmospheric oxygen affected the biota is suggested by the correlations between: (1) Reduced oxygen and the occurrences of extinctions, a lowered biodiversity and shifts in phyletic succession, and (2) During hyperoxia, the corresponding occurrence of phenomena such as arthropod gigantism, the origin of insect flight, and the evolution of vertebrate terrestriality. Basic similarities in features of adaptation to hyopoxia, manifest in living organisms at levels ranging from genetic and cellular to physiological and behavioral, suggest the common and early origin of a suite of adaptive mechanisms responsive to fluctuations in ambient oxygen. Comparative integrative approaches addressing the molecular bases of phenotypic adjustments to cyclic oxygen fluctuation provide broad insight into the incremental steps leading to the early evolution of homeostatic respiratory mechanisms and to the specialization of organismic respiratory functio

Pyrotechnic Actuator for Retracting Tubes Between MSL Subsystems

An apparatus, denoted the "retractuator" (a contraction of "retracting actuator"), was designed to help ensure clean separation between the cruise stage and the entry-vehicle subsystem of the Mars Science Laboratory (MSL) mission. The retractuator or an equivalent mechanism is needed because of tubes that (1) transport a heat-transfer fluid between the stages during flight and (2) are cut immediately prior to separation of the stages retractuator. The role of the retractuator is to retract the tubes, after they are cut and before separation of the subsystem, so that cut ends of the tubes do not damage thermal-protection coats on the entry vehicle and do not contribute to uncertainty of drag and consequent uncertainty in separation velocity

Age-related molecular genetic changes of murine bone marrow mesenchymal stem cells

<p>Abstract</p> <p>Background</p> <p>Mesenchymal stem cells (MSC) are pluripotent cells, present in the bone marrow and other tissues that can differentiate into cells of all germ layers and may be involved in tissue maintenance and repair in adult organisms. Because of their plasticity and accessibility these cells are also prime candidates for regenerative medicine. The contribution of stem cell aging to organismal aging is under debate and one theory is that reparative processes deteriorate as a consequence of stem cell aging and/or decrease in number. Age has been linked with changes in osteogenic and adipogenic potential of MSCs.</p> <p>Results</p> <p>Here we report on changes in global gene expression of cultured MSCs isolated from the bone marrow of mice at ages 2, 8, and 26-months. Microarray analyses revealed significant changes in the expression of more than 8000 genes with stage-specific changes of multiple differentiation, cell cycle and growth factor genes. Key markers of adipogenesis including lipoprotein lipase, FABP4, and Itm2a displayed age-dependent declines. Expression of the master cell cycle regulators p53 and p21 and growth factors HGF and VEGF also declined significantly at 26 months. These changes were evident despite multiple cell divisions in vitro after bone marrow isolation.</p> <p>Conclusions</p> <p>The results suggest that MSCs are subject to molecular genetic changes during aging that are conserved during passage in culture. These changes may affect the physiological functions and the potential of autologous MSCs for stem cell therapy.</p

Profiling Disease-Selective Drug Targets: From Proteomics to Ligandomics

Despite advancements in omics technologies, including proteomics and transcriptomics, identification of therapeutic targets remains challenging. Ligandomics recently emerged as a unique technology of functional proteomics for global profiling of cell-binding protein ligands. When applied to diseased versus healthy vasculatures, comparative ligandomics systematically maps novel disease-restricted ligands that allow selective targeting of pathological but not physiological pathways, providing high efficacy with intrinsic safety. In this review, we discuss the potential of cellular ligands as therapeutic targets and summarize the development of ligandomics. We further compare the advantages and limitations of different omics technologies for drug target discovery and discuss target selection criteria to improve drug R&D success rates

Sorl1 as an Alzheimer's disease predisposition gene?

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) epsilon4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval

Characterisation of a Wheat Breeders’ Array suitable for high throughput SNP genotyping of global accessions of hexaploid bread wheat (<i>Triticum aestivium</i>)

Targeted selection and inbreeding have resulted in a lack of genetic diversity in elite hexaploid bread wheat accessions. Reduced diversity can be a limiting factor in the breeding of high yielding varieties and crucially can mean reduced resilience in the face of changing climate and resource pressures. Recent technological advances have enabled the development of molecular markers for use in the assessment and utilization of genetic diversity in hexaploid wheat. Starting with a large collection of 819 571 previously characterized wheat markers, here we describe the identification of 35 143 single nucleotide polymorphism-based markers, which are highly suited to the genotyping of elite hexaploid wheat accessions. To assess their suitability, the markers have been validated using a commercial high-density Affymetrix Axiom® genotyping array (the Wheat Breeders' Array), in a high-throughput 384 microplate configuration, to characterize a diverse global collection of wheat accessions including landraces and elite lines derived from commercial breeding communities. We demonstrate that the Wheat Breeders' Array is also suitable for generating high-density genetic maps of previously uncharacterized populations and for characterizing novel genetic diversity produced by mutagenesis. To facilitate the use of the array by the wheat community, the markers, the associated sequence and the genotype information have been made available through the interactive web site 'CerealsDB'

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Resveratrol augments ER stress and the cytotoxic effects of glycolytic inhibition in neuroblastoma by downregulating Akt in a mechanism independent of SIRT1

Cancer cells typically display increased rates of aerobic glycolysis that are correlated with tumor aggressiveness and a poor prognosis. Targeting the glycolytic pathway has emerged as an attractive therapeutic route mainly because it should spare normal cells. Here, we evaluate the effects of combining the inhibition of glycolysis with application of the polyphenolic compound resveratrol (RSV) in neuroblastoma (NB) cancer cell lines. Inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) significantly reduced NB cell viability and was associated with increased endoplasmic reticulum (ER) stress and Akt activity. Administration of 2-DG increased the expression of the ER molecular chaperones GRP78 and GRP94, the prodeath protein C/EBP homology protein (CHOP) and the phosphorylation of Akt at S473, T450 and T308. Combined treatment with both RSV and 2-DG reduced GRP78, GRP94 and Akt phosphorylation but increased CHOP and NB cell death when compared with the administration of 2-DG alone. The selective inhibition of Akt activity also decreased 2-DG-induced GRP78 and GRP94 expression and increased CHOP expression, suggesting that Akt can modulate ER stress. Protein phosphatase 1 alpha (PP1 alpha) was activated by RSV, as indicated by a reduction in PP1 alpha phosphorylation at T320. Pretreatment of cells with tautomycin, a selective PP1 alpha inhibitor, prevented the RSV-mediated decrease in Akt phosphorylation, suggesting that RSV enhances 2-DG-induced cell death by activating PP1 and downregulating Akt. The RSV-mediated inhibition of Akt in the presence of 2-DG was not prevented by the selective inhibition of SIRT1, a known target of RSV, indicating that the effects of RSV on this pathway are independent of SIRT1. We propose that RSV inhibits Akt activity by increasing PP1 alpha activity, thereby potentiating 2-DG-induced ER stress and NB cell death