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Telomeres cap the ends of eukaryotic chromosomes and distinguish them from broken DNA ends to suppress DNA damage response, cell cycle arrest and genomic instability. Telomeres are elongated by telomerase to compensate for incomplete replication and nuclease degradation and to extend the proliferation potential of germ and stem cells and most cancers. However, telomeres in somatic cells gradually shorten with age, ultimately leading to cellular senescence. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and diverse symptoms including bone marrow failure, immunodeficiency, and neurodevelopmental defects. HHS is caused by germline mutations in telomerase subunits, factors essential for its biogenesis and recruitment to telomeres, and in the helicase RTEL1. While diverse phenotypes were associated with RTEL1 deficiency, the telomeric role of RTEL1 affected in HHS is yet unknown. Inducible ectopic expression of wild-type RTEL1 in patient fibroblasts rescued the cells, enabled telomerase-dependent telomere elongation and suppressed the abnormal cellular phenotypes, while silencing its expression resulted in gradual telomere shortening. Our observations reveal an essential role of the RTEL1 C-terminus in facilitating telomerase action at the telomeric 3' overhang. Thus, the common etiology for HHS is the compromised telomerase action, resulting in telomere shortening and reduced lifespan of telomerase positive cells.G protein-coupled receptors are critical mediators of platelet activation whose signaling can be modulated by members of the Regulator of G protein Signaling (RGS) family. The two most abundant RGS proteins in human and mouse platelets are RGS10 and RGS18. While each has been studied individually, critical questions remain about the overall impact of this mode of regulation in platelets. Here we report that mice missing both proteins show reduced platelet survival and a 40% decrease in platelet count that can be partially reversed with aspirin and a P2Y12 antagonist. Their platelets have increased basal TLT-1 expression, a leftward shift in the dose/response for a thrombin receptor activating peptide, an increased maximum response to ADP and TxA2, and a greatly exaggerated response to penetrating injuries in vivo. Neither of the individual knockout displays this constellation of findings. RGS10-/- platelets have an enhanced response to agonists in vitro, but platelet count and survival is normal. RGS18-/- mice have a 15% reduction in platelet count that is not affected by antiplatelet agents, nearly-normal responses to platelet agonists and normal platelet survival. Megakaryocyte number and ploidy are normal in all 3 mouse lines, but platelet recovery from severe acute thrombocytopenia is slower in RGS18-/- and RGS10-/-18-/- mice. Collectively, these results show that RGS10 and RGS18 have complementary roles in platelets. Removing both at the same time discloses the extent to which this regulatory mechanism normally controls platelet reactivity in vivo, modulates the hemostatic response to injury, promotes platelet production and prolongs platelet survival.The management of frail older people is a key component of aged care. selleck inhibitor There has been a plethora of tools developed for the diagnosis and screening of frailty. Some of these tools are entering routine clinical practice at a time when the higher healthcare costs involved in caring for older people who are frail have become a potential target for cost-cutting. Yet there is still only limited evidence to support the widespread adoption of frailty tools, and foundational factors impact on their accuracy and validity. Despite the acceptance of frailty as a valid term in research and clinical practice, older people believe the term carries stigma. Such issues indicate that there may be a need to reconsider current approaches to frailty. Recent advances in the science of ageing biology can provide a new framework for reconfiguring how we screen, diagnose, treat and prevent frailty. Frailty can be considered to be a multisystem ageing syndrome of decreased physiological and functional reserve, where the biological changes of ageing are seen in most tissues and organs and are the pathogenic mechanism for frailty. Likewise age-related chronic disease and multimorbidity are syndromes where ageing changes occur in one or multiple systems, respectively. This model focusses diagnostic criteria for frailty onto the biomarkers of ageing and generates new targets for the prevention and treatment of frailty based on interventions that influence ageing biology.Different root zones have distinct capacities for nitrate (NO3-) uptake in Populus species, but the underlying physiological and microRNA (miRNA) regulatory mechanisms remain largely unknown. To address this question, two root zones of P. × canescens with contrasting capacities for NO3- uptake were investigated. The region of 0 to 40 mm (root zone I) to the root apex displayed net influxes, whereas the region of 40 to 80 mm (root zone II) exhibited net effluxes. Concentrations of NO3- and ammonium (NH4+) as well as nitrate reductase (NR) activity were lower in zone II than in zone I. Forty one upregulated and twenty three downregulated miRNAs, and 576 targets of these miRNAs were identified in zone II in comparison with zone I. Particularly, growth-regulating factor 4 (GRF4), a target of upregulated ptc-miR396g-5p and ptc-miR396f_L + 1R-1, was downregulated in zone II in comparison with zone I, probably contributing to lower NO3- uptake rates and assimilation in zone II. Furthermore, several miRNAs and their targets, members of C2H2 zinc finger family and APETALA2/ethylene-responsive element binding protein family, were found in root zones, which probably play important roles in regulating NO3- uptake. These results indicate that differentially expressed miRNA-target pairs play key roles in regulation of distinct NO3- uptake rates and assimilation in different root zones of poplars.Performance evaluation is typically assessed as part of the approval procedure to verify that a dosimetry system fulfils specified national or international type-test requirements under representative exposure conditions that are expected to mimic workplace fields from the radiological activities being monitored. The International Atomic Energy Agency Radiation Safety Technical Services Laboratory has recently implemented an integrated radiophotoluminescence (RPL) personal dosimetry system developed by Chiyoda Technol Corporation. This paper reports on the successful verification of dosimetric performance properties of the RPL dosimetry system to IEC 623872020, in which the badges were exposed to a range of radiation energies and angles of incidence as well as other influence parameters. Characteristics under test included the coefficient of variation, non-linearity of response due to dose dependence as well as the energy and angular response to photon and beta radiation.