Studies on the response to, and recovery from, rapamycin in Saccharomyces cerevisiae

The Target of Rapamycin Complex 1 (TORC1) is a key and conserved regulator of cell growth and proliferation. The xenobiotic compound rapamycin is a potent inhibitor of TORC1 in yeast. The EGO complex, a non-essential activator of TORC1 is required for recovery of cells following rapamycin treatment. Why? Here, we find that rapamycin is in fact only a partial inhibitor of yeast TORC1; wild-type cells are able to maintain slow proliferation in the presence of high concentrations of the drug (i.e. concentrations multiple times the minimum inhibitory concentration). We find that this residual, rapamycin-insensitive, proliferation is dependent on the EGO complex and on TORC1 activity. We show that the ability of cells to maintain slow proliferation in the presence of rapamycin dictates their ability to recover. We find that rapamycin is not actively detoxified in yeast; instead, rapamycin is cleared by dilution-by-proliferation. The cell-associated intracellular pool of rapamycin is stable, decreasing only very slowly following washout of the drug and only diminishing at the rate of cell proliferation. The rapamycin-insensitive growth rate also persists long after rapamycin washout, indeed, until cells recover from the drug. The rapamycin-insensitive growth rate is not only able to quantitatively account for the observed kinetics of recovery from the drug in wild-type cultures, but also explains the severity of the ego- recovery defect. We contributed to a large-scale genetic screen seeking mutants that, like ego- mutants, fail to recover from rapamycin treatment. We find that loss of any one of 10 proteins identified results in a rapamycin recovery defect and a slow rapamycin-insensitive growth rate. Our data propose important or novel roles of the core HOPS/CORVET complex, threonine biosynthesis, Vps15p, Vsp34p, Ccr4p and Dhh1p activities in modulating the activity or efficiency of TORC1. Overall our results reveal that rapamycin is only a partial inhibitor of yeast TORC1, that persistence of the drug within the cell limits recovery and that rapamycin is not actively detoxified in yeast. Instead, recovery occurs due to dilution-by-proliferation and distribution of the drug among an increasing number of progeny cells. We also identify a set of potentially novel regulators of TORC1 activity

Spectrum of excess mortality due to carbapenem-resistant Klebsiella pneumoniae infections

Patients infected or colonized with carbapenem-resistant Klebsiella pneumoniae (CRKp) are often chronically and acutely ill, which results in substantial mortality unrelated to infection. Therefore, estimating excess mortality due to CRKp infections is challenging. The Consortium on Resistance against Carbapenems in K. pneumoniae (CRACKLE) is a prospective multicenter study. Here, patients in CRACKLE were evaluated at the time of their first CRKp bloodstream infection (BSI), pneumonia, or urinary tract infection (UTI). A control cohort of patients with CRKp urinary colonization without CRKp infection was constructed. Excess hospital mortality was defined as mortality in cases after subtracting mortality in controls. In addition, the adjusted hazard ratios (aHR) for time-to-hospital-mortality censored at 30 days associated with infection as compared to colonization were calculated in Cox proportional hazard models. In the study period, 260 patients with CRKp infections were included in the BSI (90), pneumonia (49), and UTI (121) groups, who were compared to 223 controls. All-cause hospital mortality in controls was 12%. Excess hospital mortality was 27% and 27% in patients with BSI and pneumonia, respectively. Excess hospital mortality was not observed in patients with UTI. In multivariable analyses, BSI and pneumonia as compared to controls was associated with an aHR of 2.59 (95% CI 1.52–4.50, p<0.001) and 3.44 (95% CI 1.80–6.48, p<0.001), respectively. In conclusion, in patients with CRKp infection, pneumonia is associated with the highest excess hospital mortality. Patients with BSI have slightly lower excess hospital mortality rates, whereas excess hospital mortality was not observed in hospitalized patients with UTI

Simulations and Measurements of the Background Encountered by a High-Altitude Balloon-Borne Experiment for Hard X-ray Astronomy

We have modelled the hard X-ray background expected for a high-altitude balloon flight of the Energetic X-ray Telescope Experiment (EXITE2), an imaging phoswich detector/telescope for the 20--600 keV energy range. Photon and neutron-induced contributions to the background are considered. We describe the code and the results of a series of simulations with different shielding configurations. The simulated hard X-ray background for the actual flight configuration agrees reasonably well (within a factor of $\sim$ 2) with the results measured on the first flight of EXITE2 from Palestine, Texas. The measured background flux at 100 keV is $\sim$ 4 $\times$ 10$^{-4}$ counts cm$^{-2}$ s$^{-1}$ keV$^{-1}$.Comment: 17 pages Latex (uses aaspp4.sty) plus 7 postscript figures: available in file figs.tar.g

The impact of obesity and timely antiviral administration on severe influenza outcomes among hospitalized adults

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141541/1/jmv24946.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141541/2/jmv24946_am.pd

Practice-based arts research in repositories: how do we better engage with researchers to capture, manage and enable discoverability of this research?

This panel session brought together a range of experts including a practice-based arts researcher, repository managers, software developer and a representation of Jisc to discuss the challenges in capturing non-text outputs in repositories and how these could be made more discoverable

The 2 × 2 model of perfectionism and school‐ and community‐based sport participation.

The authors adopted the 2 × 2 model of perfectionism to examine the unique and interactive effects of two dimensions of perfectionism (personal standards perfectionism PSP and evaluative concerns perfectionism ECP) on personal and interpersonal indicators of participant experience in youth sport (enjoyment, physical self‐worth, and friendship quality). Participants (N = 219, M age = 15.12, SD = 2.02) were recruited from various school‐ and community‐based sports and completed a multi‐section questionnaire. Consideration of main and interaction effects indicated that pure PSP (high PSP/low ECP) was associated with the most positive sport experience and pure ECP (low PSP/high ECP) was associated with the least positive sport experience. The findings suggest that subtypes of perfectionism from the 2 × 2 model are predictive of differing experiences in youth sport participation. (PsycINFO Database Record (c) 2015 APA, all rights reserved). (journal abstract

Providing information for young people in sexual health clinics: getting it right

Background. The need to improve the quality and availability of information on sexual health is identified as a key element in achieving the aims set out in the National Strategy for Sexual Health and HIV. Providing information about sexual health to young people poses particular challenges because of the sensitive nature of the issues and because of the difficulties that young people may face in sourcing information and asking questions of professionals. Objective. To explore the views of young people attending sexual health services on several aspects of service delivery, including provision of information. Method. Twenty-five in-depth qualitative interviews were conducted with a purposive sample of young people attending a range of different outlets for sexual health care. Results. This research revealed important information about the ways in which the type, format, tone and design of health promotion materials and the methods used to impart information to young people has a strong impact on client satisfaction during visits to sexual health services. Conclusions. Young people vary greatly in their needs for sexual health information in terms of level, extent and manner of provision. Passive acceptance of information should not be taken to indicate tacit satisfaction with level and complexity. Written information needs to be used in conjunction with face-to-face discussion. Effective provision of sexual health information impacts notably on client satisfaction. Pitched at the right level, sexual health information has considerable potential to enhance sexual health status

Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo's potential, affecting adult health

Periconceptional environment may influence embryo development, ultimately affecting adult health. Here, we review the rodent model of maternal low-protein diet specifically during the preimplantation period (Emb-LPD) with normal nutrition during subsequent gestation and postnatally. This model, studied mainly in the mouse, leads to cardiovascular, metabolic and behavioural disease in adult offspring, with females more susceptible. We evaluate the sequence of events from diet administration that may lead to adult disease. Emb-LPD changes maternal serum and/or uterine fluid metabolite composition, notably with reduced insulin and branched-chain amino acids. This is sensed by blastocysts through reduced mammalian target of rapamycin complex 1 signalling. Embryos respond by permanently changing the pattern of development of their extra-embryonic lineages, trophectoderm and primitive endoderm, to enhance maternal nutrient retrieval during subsequent gestation. These compensatory changes include stimulation in proliferation, endocytosis and cellular motility, and epigenetic mechanisms underlying them are being identified. Collectively, these responses act to protect fetal growth and likely contribute to offspring competitive fitness. However, the resulting growth adversely affects long-term health because perinatal weight positively correlates with adult disease risk. We argue that periconception environmental responses reflect developmental plasticity and 'decisions' made by embryos to optimise their own development, but with lasting consequences