Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo

<p>Abstract</p> <p>Background</p> <p>Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD⁺-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation.</p> <p>Results</p> <p>Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR <it>in vivo</it>, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet.</p> <p>Conclusion</p> <p>CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting <it>in vitro </it>and <it>in vivo </it>data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation <it>in vivo</it>. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.</p

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

VLTI/Hi-5: detection yield predictions for young giant exoplanets

The Hi-5 instrument, a proposed high-contrast L' band (3.5-4.0 μm) nulling interferometer for the visitor focus of the Very Large Telescope Interferometer (VLTI), will characterize young extra-solar planetary systems and exozodiacal dust around nearby main-sequence stars. Thanks to VLTI's angular resolution (λ=B = 5 mas for the longest UT baseline), it will fill the gap between young giant exoplanets discovered by ongoing single-aperture direct imaging surveys and exoplanet populations discovered by radial velocity surveys. In this paper, we investigate the exoplanet detection yield of Hi-5. First, we present the latest catalog of stars identified as members of young stellar associations within 150 pc of the Sun thanks to the BANYAN algorithm and other searches for young moving group members. Realistic exoplanet populations are then generated around these stars and processed with the SCIFYsim tool, the end-to-end simulator for the Hi-5 instrument. Then, two formation models are used to estimate the giant planet's luminosity. The first is the New Generation Planetary Population Synthesis (NGPPS), also known as the Bern model, and the second is a statistical model based on gravitational instability (hot-start model - AMES-Dusty model). We show that Hi-5 is insensitive to cold-start planets but can detect giant hot-start planets. With ATs, more than 40 planets could be detected assuming 20 nights of observations. With its unique capabilities, Hi-5 is also able to constrain in mass the observed systems. Hi-5 is sensitive to planets with a mass &gt; 2 Mjup around the snow line

VLTI/Hi-5: detection yield predictions for young giant exoplanets

The Hi-5 instrument, a proposed high-contrast L' band (3.5-4.0 μm) nulling interferometer for the visitor focus of the Very Large Telescope Interferometer (VLTI), will characterize young extra-solar planetary systems and exozodiacal dust around nearby main-sequence stars. Thanks to VLTI's angular resolution (λ=B = 5 mas for the longest UT baseline), it will fill the gap between young giant exoplanets discovered by ongoing single-aperture direct imaging surveys and exoplanet populations discovered by radial velocity surveys. In this paper, we investigate the exoplanet detection yield of Hi-5. First, we present the latest catalog of stars identified as members of young stellar associations within 150 pc of the Sun thanks to the BANYAN algorithm and other searches for young moving group members. Realistic exoplanet populations are then generated around these stars and processed with the SCIFYsim tool, the end-to-end simulator for the Hi-5 instrument. Then, two formation models are used to estimate the giant planet's luminosity. The first is the New Generation Planetary Population Synthesis (NGPPS), also known as the Bern model, and the second is a statistical model based on gravitational instability (hot-start model - AMES-Dusty model). We show that Hi-5 is insensitive to cold-start planets but can detect giant hot-start planets. With ATs, more than 40 planets could be detected assuming 20 nights of observations. With its unique capabilities, Hi-5 is also able to constrain in mass the observed systems. Hi-5 is sensitive to planets with a mass &gt; 2 Mjup around the snow line.Spaceborne Instrumentatio

Investigating the biology, husbandry and health of non-salmonid finfish

NRC publication: Ye

Cryogenic High-Reynolds Turbulence Experiment at CERN

The potential of cryogenic helium flows for studying high-Reynolds number turbulence in the laboratory has been recognized for a long time and implemented in several small-scale hydrodynamic experiments. With its large superconducting particle accelerators and detector magnets, CERN, the European Laboratory for Particle Physics, has become a major world center in helium cryogenics, with several large helium refrigerators having capacities up to 18 kW @ 4.5 K. Combining a small fraction of these resources with the expertise of three laboratories at the forefront of turbulence research, has led to the design, swift implementation, and successful operation of GReC (Grands Reynolds Cryogéniques) a large axisymmetric turbulent-jet experiment. With flow-rates up to 260 g/s of gaseous helium at ≈5 K and atmospheric pressure, Reynolds numbers up to 10 7 have been achieved in a 4.6 m high, 1.4 m diameter cryostat. This paper presents the results of the first runs and describes the experimental set-up comprehensively equipped with “hot” wire micro-anemometers, acoustic scattering vorticity measurements and a large-bandwidth data acquisition system