Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice.

Alterations of specific genes can modulate aging. Myc, a transcription factor that regulates the expression of many genes involved in critical cellular functions was shown to have a role in controlling longevity. Decreased expression of Myc inhibited many of the deleterious effects of aging and increased lifespan in mice. Without altering Myc expression, reduced levels of Mtbp, a recently identified regulator of Myc, limit Myc transcriptional activity and proliferation, while increased levels promote Myc-mediated effects. To determine the contribution of Mtbp to the effects of Myc on aging, we studied a large cohort of Mtbp heterozygous mice and littermate matched wild-type controls. Mtbp haploinsufficiency significantly increased longevity and maximal survival in mice. Reduced levels of Mtbp did not alter locomotor activity, litter size, or body size, but Mtbp heterozygous mice did exhibit elevated markers of metabolism, particularly in the liver. Mtbp(+/-) mice also had a significant delay in spontaneous cancer development, which was most prominent in the hematopoietic system, and an altered tumor spectrum compared to Mtbp(+/+) mice. Therefore, the data suggest Mtbp is a regulator of longevity in mice that mimics some, but not all, of the properties of Myc in aging

A pipeline for targeted metagenomics of environmental bacteria.

BackgroundMetagenomics and single cell genomics provide a window into the genetic repertoire of yet uncultivated microorganisms, but both methods are usually taxonomically untargeted. The combination of fluorescence in situ hybridization (FISH) and fluorescence activated cell sorting (FACS) has the potential to enrich taxonomically well-defined clades for genomic analyses.MethodsCells hybridized with a taxon-specific FISH probe are enriched based on their fluorescence signal via flow cytometric cell sorting. A recently developed FISH procedure, the hybridization chain reaction (HCR)-FISH, provides the high signal intensities required for flow cytometric sorting while maintaining the integrity of the cellular DNA for subsequent genome sequencing. Sorted cells are subjected to shotgun sequencing, resulting in targeted metagenomes of low diversity.ResultsPure cultures of different taxonomic groups were used to (1) adapt and optimize the HCR-FISH protocol and (2) assess the effects of various cell fixation methods on both the signal intensity for cell sorting and the quality of subsequent genome amplification and sequencing. Best results were obtained for ethanol-fixed cells in terms of both HCR-FISH signal intensity and genome assembly quality. Our newly developed pipeline was successfully applied to a marine plankton sample from the North Sea yielding good quality metagenome assembled genomes from a yet uncultivated flavobacterial clade.ConclusionsWith the developed pipeline, targeted metagenomes at various taxonomic levels can be efficiently retrieved from environmental samples. The resulting metagenome assembled genomes allow for the description of yet uncharacterized microbial clades. Video abstract

Smoking, environmental tobacco smoke, and risk of renal cell cancer: a population-based case-control study

<p>Abstract</p> <p>Background</p> <p>Kidney and renal pelvis cancers account for 4% of all new cancer cases in the United States, among which 85% are renal cell carcinomas (RCC). While cigarette smoking is an established risk factor for RCC, little is known about the contribution of environmental tobacco smoke (ETS) to RCC incidence. This study assesses the role of smoking and ETS on RCC incidence using a population-based case-control design in Florida and Georgia.</p> <p>Methods</p> <p>Incident cases (n = 335) were identified from hospital records and the Florida cancer registry, and population controls (n = 337) frequency-matched by age (+/- 5 years), gender, and race were identified through random-digit dialing. In-person interviews assessed smoking history and lifetime exposure to ETS at home, work, and public spaces. Home ETS was measured in both years and hours of exposure. Odds ratios and 95% confidence intervals were calculated using logistic regression, controlled for age, gender, race, and BMI.</p> <p>Results</p> <p>Cases were more likely to have smoked 20 or more pack-years, compared with never-smokers (OR: 1.35, 95% CI: 0.93 – 1.95). A protective effect was found for smoking cessation, beginning with 11–20 years of cessation (OR: 0.39, 95% CI: 0.18–0.85) and ending with 51 or more years of cessation (OR: 0.11, 95% CI: 0.03–0.39) in comparison with those having quit for 1–10 years. Among never-smokers, cases were more likely to report home ETS exposure of greater than 20 years, compared with those never exposed to home ETS (OR: 2.18; 95% CI: 1.14–4.18). Home ETS associations were comparable when measured in lifetime hours of exposure, with cases more likely to report 30,000 or more hours of home ETS exposure (OR: 2.37; 95% CI: 1.20–4.69). Highest quartiles of combined home/work ETS exposure among never-smokers, especially with public ETS exposure, increased RCC risk by 2 to 4 times.</p> <p>Conclusion</p> <p>These findings confirm known associations between smoking and RCC and establish a potential etiologic role for ETS, particularly in the home. Differences in methods of retrospective measurement of lifetime smoking and ETS exposure may contribute to discrepancies in measures of associations across studies, and should be addressed in future research.</p

Potential Environmental Impacts of Hydrogen-based Transportation and Power Systems

Hydrogen (H2) offers advantages as an energy carrier: minimal discharge of pollutants, production from multiple sources, increased thermodynamic efficiencies compared to fossil fuels, and reduced dependence on foreign oil. However, potential impacts from the H2 generation processes, transport and distribution of H2, and releases of H2 into the atmosphere have been proposed. The goal of this project was to analyze the effects of emissions of hydrogen, the six criteria pollutants and greenhouse gases on climate, human health, materials and structures. This project was part of a larger effort by DOE to assess the life-cycle costs and benefits and environmental impacts to inform decisions regarding future hydrogen research. Technical Approach: A modeling approach was developed and used to evaluate the potential environmental effects associated with the conversion of the on-road vehicle fleet from fossil-fuel vehicles to hydrogen fuel cell vehicles. GATOR-GCMOM was the primary tool used to predict atmospheric concentrations of gases and aerosols for selected scenarios. This model accounts for all feedbacks among major atmospheric processes based on first principles. The future scenarios and the emission rates selected for this analysis of hydrogen environmental effects are based on the scenarios developed by IPCC. The scenarios selected for the model simulations are a 2000 and 2050 A1B base cases, and a 2050 A1B case with hydrogen fuel cell vehicles (HFCVs). The hydrogen fuel cell scenario assumed conversion of 90% of fossil-fuel on-road vehicles (FFOV) in developed countries and 45% of FFOVs vehicles in other countries to HFCVs, with the H2 produced by steam-reforming of natural gas (SHFCVs). Simulations were conducted to examine the effect of converting the worldâÂÂs FFOVs to HFCVs, where the H2 is produced by wind-powered electrolysis (WHFCVs). In all scenarios a 3% leakage of H2 consumed was assumed. Two new models were developed that provide the ability to evaluate a wider range of conditions and address some of the uncertainties that exist in the evaluation of hydrogen emissions. A simplified global hydrogen cycle model that simulates hydrogen dynamics in the troposphere and stratosphere was developed. A Monte Carlo framework was developed to address hydrogen uptake variability for different types of ecosystems. Findings 1.Converting vehicles worldwide in 2050 to SHFCVs at 90% penetration in developed countries and 45% penetration in other countries is expected to reduce NOx, CO, CO2, CH4, some other organic gases, ozone, PAN, black carbon, and other particle components in the troposphere, but may increase some other organic gases, depending on emissions. Conversion to SHFCVs is also expected to cool the troposphere and warm the stratosphere, but to a lesser extent than WHFCVs. Finally, SHFCVs are expected to increase UTLS ozone while decreasing upper stratospheric ozone, but to a lesser extent than WHFCVs. 2.The predicted criteria pollutant concentrations from the GATOR-GCMOM simulations indicated that near-surface annual mean concentrations in the US are likely to increase from the 2000 base case to the 2050 A1B base case for CO2 and ozone due to the increased economic activity, but to decrease for CO, NO2, SO2, and PM10 due to improved pollution control equipment and energy efficiencies. The shift to SHFCVs in 2050 was predicted to result in decreased concentrations for all the criteria pollutants, except for SO2 and PM10. The higher predicted concentrations for SO2 and PM10 were attributed to increased emissions using the steam-reforming method to generate H2. If renewable methods such as wind-based electrolysis were used to generate H2, the emissions of SO2 and PM10 would be lower. 3.The effects on air quality, human health, ecosystem, and building structures were quantified by comparing the GATOR-GCMOM model output and accepted health and ecosystem effects levels and ambient air quality criteria. Shifting to HFCVs is expected to result in improved air quality and benefits to human health. Shifting to HFCVs is unlikely to result in damage to buildings. 4.Results are thought to be robust for larger leakage rates of H2 and for greater penetrations of HFCVs, since the controlling factor for stratospheric ozone impacts is the reduction in fossil-fuel greenhouse gases and the resulting surface cooling, which reduces water vapor emissions and stratospheric warming, which increases tropopause stability reducing water vapor transport to the stratosphere. 5.The supplemental modeling results were generally supportive of the results from the GATOR-GCMOM simulations, and recommendations for additional analyses were made. Extending the duration of the simulation to coincide with the time required for hydrogen mixing ratios to attain a steady state condition was recommended. Further evaluation of algorithms to describe hydrogen uptake in the model was also recommended

MiniBooNE Results and Neutrino Schemes with 2 sterile Neutrinos: Possible Mass Orderings and Observables related to Neutrino Masses

The MiniBooNE and LSND experiments are compatible with each other when two sterile neutrinos are added to the three active ones. In this case there are eight possible mass orderings. In two of them both sterile neutrinos are heavier than the three active ones. In the next two scenarios both sterile neutrinos are lighter than the three active ones. The remaining four scenarios have one sterile neutrino heavier and another lighter than the three active ones. We analyze all scenarios with respect to their predictions for mass-related observables. These are the sum of neutrino masses as constrained by cosmological observations, the kinematic mass parameter as measurable in the KATRIN experiment, and the effective mass governing neutrinoless double beta decay. It is investigated how these non-oscillation probes can distinguish between the eight scenarios. Six of the eight possible mass orderings predict positive signals in the KATRIN and future neutrinoless double beta decay experiments. We also remark on scenarios with three sterile neutrinos. In addition we make some comments on the possibility of using decays of high energy astrophysical neutrinos to discriminate between the mass orderings in presence of two sterile neutrinos.Comment: 33 pages, 8 figures. Comments added, to appear in JHE

Stabilizing Soybean Production in Northeast Texas with Early Planting of Early-Maturing Soybean Varieties.

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Synthesis of diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups by Buchwald–Hartwig C–N coupling

Diarylamines in the benzo[b]thiophene series bearing electron donating or withdrawing groups, were prepared by Buchwald– Hartwig C–N coupling in moderate to high yields. The conditions used were Pd(OAc)2 (3 mol%), BINAP as ligand (4 mol%) and Cs2CO3 as base (1.4 equiv.), in toluene at 1008C, being 6-bromo or amino benzo[b]thiophenes coupled, respectively, with substituted anilines or phenylbromides. The 6-aminobenzo[b]thiophene derivatives were also prepared by palladium catalyzed C–N coupling of the corresponding 6-bromo compounds with benzophenone imine, followed by acidic hydrolysis of the imino derivatives. When 4-nitrobromobenzene and 4-bromobenzonitrile were used as coupling components, triarylamines were also isolated in small amounts. The presence of a fluorine atom on the phenylbromide highly increases the diarylamine yield

Tryptophan pathway abnormalities in a murine model of hereditary glaucoma

Background: It has been shown that a possible pathogenetic mechanism of neurodegenera-tion in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina. Methods: Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio. Results: TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains. Conclusions: Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma

Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes

Kynurenines, products of tryptophan (TRP) metabolism, display neurotoxic (e.g., 3-hydroxykynurenine; 3-HK), or neuroprotective (e.g., kynurenic acid; KYNA) properties. Imbalance between the enzymes constituting the kynurenine pathway (KP) plays a role in several disease, including neurodegeneration. In this study, we track changes in concentrations of tryptophan and its selected metabolites after damage to retinal ganglion cells and link this data with expression of KP enzymes. Brown-Norway rats were subjected to intravitreal N-methyl-D-aspartate (NMDA) injection or partial optic nerve crush (PONC). Retinas were collected 2 and 7 days after the completion of PONC or NMDA injection. Concentrations of TRP, kynurenine (KYN), and KYNA were determined by high performance liquid chromatography (HPLC). Data on gene expression in the rat retina were extracted from GEO, public microarray experiments database. Two days after NMDA injection concentration of TRP decreased, while KYN and KYNA increased. At day 7 compared to day 2 decrease of KYN, KYNA and further reduction of TRP concentration were observed, but on day 7 KYN concentration was still elevated when compared to controls. At day 2 and 7 after NMDA injection no statistically significant alterations of 3-HK were observed. TRP and 3-HK concentration was higher in PONC group than in controls. However, both KYN and KYNA were lower. At day seven concentration of TRP, 3-HK, and KYN was higher, whereas concentration of KYNA declined. In vivo experiments showed that retinal damage or optic nerve lesion affect TRP metabolism via KP. However, the pattern of changes in metabolite concentrations was different depending on the model. In particular, in PONC KYNA and KYN levels were decreased and 3-HK elevated. These observations correspond with data on expression of genes encoding KP enzymes assessed after optic nerve crush or transection. After intraorbital optic nerve crush downregulation of KyatI and KyatIII between 24 h and 3 days after procedure was observed. Kmo expression was transiently upregulated (12 h after the procedures). After intraorbital optic nerve transsection (IONT) Kmo expression was upregulated after 48 h and 7 days, KyatI and KyatIII were downregulated after 12, 48 h, 7 days and upregulated after 15 days. Collected data point to the conclusion that development of therapeutic strategies targeting the KP could be beneficial in diseases involving retinal neurodegeneration