Lifelongα-tocopherol supplementation increases the median life span of C57BL/6 mice in the cold but has only minor effects on oxidative damage

The effects of dietary antioxidant supplementation on oxidative stress and life span are confused. We maintained C57BL/6 mice at 7 ± 2°C and supplemented their diet with α-tocopherol from 4 months of age. Supplementation significantly increased (p = 0.042) median life span by 15% (785 days, n = 44) relative to unsupplemented controls (682 days, n = 43) and also increased maximum life span (oldest 10%, p = 0.028). No sex or sex by treatment interaction effects were observed on life span, with treatment having no effect on resting or daily metabolic rate. Lymphocyte and hepatocyte oxidative DNA damage and hepatic lipid peroxidation were unaffected by supplementation, but hepatic oxidative DNA damage increased with age. Using a cDNA macroarray, genes associated with xenobiotic metabolism were significantly upregulated in the livers of female mice at 6 months of age (2 months supplementation). At 22 months of age (18 months supplementation) this response had largely abated, but various genes linked to the p21 signaling pathway were upregulated at this time. We suggest that α-tocopherol may initially be metabolized as a xenobiotic, potentially explaining why previous studies observe a life span extension generally when lifelong supplementation is initiated early in life. The absence of any significant effect on oxidative damage suggests that the life span extension observed was not mediated via any antioxidant properties of α-tocopherol. We propose that the life span extension observed following α-tocopherol supplementation may be mediated via upregulation of cytochrome p450 genes after 2 months of supplementation and/or upregulation of p21 signaling genes after 18 months of supplementation. However, these signaling pathways now require further investigation to establish their exact role in life span extension following α-tocopherol supplementation

Effects of dietary protein intake on lactation performance of the laboratory mouse, Mus musculus

Laboratory mice (strain MF1) were used to investigate the effects of dietary protein content on lactation performance to test the heat dissipation limit hypothesis. The specific dynamic action (SDA) for high protein (HP) and high carbohydrate (HC) diets was measured using open-flow respirometry at 9.4% and 6.1%, respectively. The same two diets were fed ad libitum to mice during lactation. Mice fed on HP and HC diets at 21 ºC reached a plateau in their daily food intake at 12.3±0.2 g day-1 and 16.6±0.2 g day-1, respectively between days 12-17 of lactation. HP-fed mice had a significantly higher daily energy expenditure (DEE) measured by doubly labelled water and higher water turnover than HC-fed mice but the energy they exported as milk was significantly lower than that of HC-fed mice and therefore resulted in poor growth rate of their offspring. The urea production of HP-fed mice from their daily protein intake of 7.1 g was estimated at 1994 mg which required 10.2 mls of water per day to be cleared. The mice increased their urine production by 14.4 mls probably to eliminate this urea. High protein diet had negative effects on lactation, indicating the growth of pups in previous studies was not protein limited. The negative effects of the HP diet were due to the high DEE that greatly reduced the energy available for milk production, rather than a toxicity effect of the urea production. The different DEE of the two diets suggests that other factors were involved in the delivery of energy to the offspring.KEY WORDS: Laboratory mouse, dietary protein, specific dynamic action, and daily energy expenditur

Effects of feeding fat on lactation performance of the laboratory mouse, Mus musculus

Laboratory mice (strain MF1) were used to investigate the effects of dietary fat intake on lactation performance. The specific dynamic action (SDA) for high fat (HF), medium fat (MF) and a low fat (LF) diets was measured using open-flow respirometry at 4.5%, 3.9% and 6.1%, respectively. The same three diets were fed ad libitum to mice between days 4 and 18 of lactation. Mice fed HF, MF and LF diets reached plateau in their daily food intake at 14.95±1.14 g day-1, 16.30±0.61 g day-1 and 16.57±0.26 g day-1, respectively between days 12-17 of lactation. At weaning, litters from HF and MF-fed mice were significantly heavier than pups on LF diet. This was because the HF and MF-fed mice not only consumed more energy at peak lactation but also delivered more milk energy to their pups than the LF-fed mice. Evidence suggested that the positive effects of feeding fat to mice were in part due to the low SDA and probably low heat production for milk synthesis. Probably, the ability of the HF and MF-fed mice to directly transfer absorbed fat into the milk might have reduced the heat production of lactogenesis. The HF and MF diets had beneficial effects on lactation because they increased the capacity of mice to generate milk more efficiently and wean heavier offspring than mice fed LF diet. The daily energy expenditure (DEE) of mice in the three dietary groups was fixed.KEY WORDS: Laboratory mouse, dietary fat, specific dynamic action, doubly labelled water, daily energy expenditure, milk energy output, reproductive performanc

Elevated O-GlcNAc levels activate epigenetically repressed genes and delay mouse ES cell differentiation without affecting naive to primed cell transition

The differentiation of mouse embryonic stem (ES) cells is controlled by the interaction of multiple signaling pathways, typically mediated by post-translational protein modifications. The addition of O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of nuclear and cytoplasmic proteins is one such modification (O-GlcNAcylation), whose function in ES cells is only now beginning to be elucidated. Here we demonstrate that the specific inhibition of O-GlcNAc hydrolase (Oga) causes increased levels of protein O-GlcNAcylation and impairs differentiation of mouse ES cells both in serum-free monolayer and in embryoid bodies (EBs). Use of reporter cell lines demonstrates that Oga inhibition leads to a reduction in the number of Sox1-expressing neural progenitors generated following induction of neural differentiation, as well as maintained expression of the ES cell marker Oct4 (Pou5f1). In EBs expression of mesodermal and endodermal markers is also delayed. However, the transition of naïve cells to primed pluripotency indicated by Rex1 (Zfp42), Nanog, Esrrb and Dppa3 downregulation and Fgf5 upregulation remains unchanged. Finally, we demonstrate that increased O-GlcNAcylation results in upregulation of genes normally epigenetically silenced in ES cells, supporting the emerging role for this protein modification in the regulation of histone modifications and DNA methylation. Stem Cells 2014

The Global academic research organization network: Data sharing to cure diseases and enable learning health systems.

Introduction:Global data sharing is essential. This is the premise of the Academic Research Organization (ARO) Council, which was initiated in Japan in 2013 and has since been expanding throughout Asia and into Europe and the United States. The volume of data is growing exponentially, providing not only challenges but also the clear opportunity to understand and treat diseases in ways not previously considered. Harnessing the knowledge within the data in a successful way can provide researchers and clinicians with new ideas for therapies while avoiding repeats of failed experiments. This knowledge transfer from research into clinical care is at the heart of a learning health system. Methods:The ARO Council wishes to form a worldwide complementary system for the benefit of all patients and investigators, catalyzing more efficient and innovative medical research processes. Thus, they have organized Global ARO Network Workshops to bring interested parties together, focusing on the aspects necessary to make such a global effort successful. One such workshop was held in Austin, Texas, in November 2017. Representatives from Japan, Taiwan, Singapore, Europe, and the United States reported on their efforts to encourage data sharing and to use research to inform care through learning health systems. Results:This experience report summarizes presentations and discussions at the Global ARO Network Workshop held in November 2017 in Austin, TX, with representatives from Japan, Korea, Singapore, Taiwan, Europe, and the United States. Themes and recommendations to progress their efforts are explored. Standardization and harmonization are at the heart of these discussions to enable data sharing. In addition, the transformation of clinical research processes through disruptive innovation, while ensuring integrity and ethics, will be key to achieving the ARO Council goal to overcome diseases such that people not only live longer but also are healthier and happier as they age. Conclusions:The achievement of global learning health systems will require further exploration, consensus-building, funding aligned with incentives for data sharing, standardization, harmonization, and actions that support global interests for the benefit of patients

Assigning stranded bottlenose dolphins to source stocks using stable isotope ratios following the Deepwater Horizon oil spill

The potential for stranded dolphins to serve as a tool for monitoring free-ranging populations would be enhanced if their stocks of origin were known. We used stable isotopes of carbon, nitrogen, and sulfur from skin to assign stranded bottlenose dolphins Tursiops truncatus to different habitats, as a proxy for stocks (demographically independent populations), following the Deepwater Horizon oil spill. Model results from biopsy samples collected from dolphins from known habitats (n = 205) resulted in an 80.5% probability of correct assignment. These results were applied to data from stranded dolphins (n = 217), resulting in predicted assignment probabilities of 0.473, 0.172, and 0.355 to Estuarine, Barrier Island (BI), and Coastal stocks, respectively. Differences were found west and east of the Mississippi River, with more Coastal dolphins stranding in western Louisiana and more Estuarine dolphins stranding in Mississippi. Within the Estuarine East Stock, 2 groups were identified, one predominantly associated with Mississippi and Alabama estuaries and another with western Florida. δ15N values were higher in stranded samples for both Estuarine and BI stocks, potentially indicating nutritional stress. High probabilities of correct assignment of the biopsy samples indicate predictable variation in stable isotopes and fidelity to habitat. The power of δ34S to discriminate habitats relative to salinity was essential. Stable isotopes may provide guidance regarding where additional testing is warranted to confirm demographic independence and aid in determining the source habitat of stranded dolphins, thus increasing the value of biological data collected from stranded individuals.Publisher PDFPeer reviewe

Limits to sustained energy intake XXIV : impact of suckling behaviour on the body temperatures of lactating female mice

We would like to thank the animal house staff and all members of the Energetics group for their invaluable help at various stages throughout the project. This work was supported by Natural Environment Research Council grant (NERC, NE/C004159/1). YG was supported by a scholarship from the rotary foundation. LV was supported by a Rubicon grant from the Netherlands Scientific Organisation (NWO).Peer reviewedPublisher PD

Limits to sustained energy intake XXVIII : Beneficial effects of high dietary fat on lactation performance in mice

JKA was supported by a scholarship from the government of the Republic of Ghana. LMV was supported by a Rubicon grant from the Netherlands Organisation for Scientific Research (NWO).Peer reviewedPublisher PD

Attitudes of People in the UK with HIV Who Are Antiretroviral (ART) Naïve to Starting ART at High CD4 Counts for Potential Health Benefit or to Prevent HIV Transmission

Objective To assess if a strategy of early ART to prevent HIV transmission is acceptable to ART naïve people with HIV with high CD4 counts. Design ASTRA is a UK multicentre, cross sectional study of 3258 HIV outpatients in 2011/12. A self-completed questionnaire collected sociodemographic, behavioral and health data, and attitudes to ART; CD4 count was recorded from clinical records. Methods ART naïve participants with CD4 ≥350 cells/µL (n = 281) were asked to agree/disagree/undecided with the statements (i) I would want to start treatment now if this would slightly reduce my risk of getting a serious illness, and (ii) I would want to start treatment now if this would make me less infectious to a sexual partner, even if there was no benefit to my own health. Results Participants were 85% MSM, 76% white, 11% women. Of 281 participants, 49.5% and 45.2% agreed they would start ART for reasons (i) and (ii) respectively; 62.6% agreed with either (i) or (ii); 12.5% agreed with neither; 24.9% were uncertain. Factors independently associated (p<0.1) with agreement to (i) were: lower CD4, more recent HIV diagnosis, physical symptoms, not being depressed, greater financial hardship, and with agreement to (ii) were: being heterosexual, more recent HIV diagnosis, being sexually active. Conclusions A strategy of starting ART at high CD4 counts is likely to be acceptable to the majority of HIV-diagnosed individuals. Almost half with CD4 >350 would start ART to reduce infectiousness, even if treatment did not benefit their own health. However a significant minority would not like to start ART either for modest health benefit or to reduce infectivity. Any change in approach to ART initiation must take account of individual preferences. Transmission models of potential benefit of early ART should consider that ART uptake may be lower than that seen with low CD4 counts

B Physics at the Tevatron: Run II and Beyond

This report provides a comprehensive overview of the prospects for B physics at the Tevatron. The work was carried out during a series of workshops starting in September 1999. There were four working groups: 1) CP Violation, 2) Rare and Semileptonic Decays, 3) Mixing and Lifetimes, 4) Production, Fragmentation and Spectroscopy. The report also includes introductory chapters on theoretical and experimental tools emphasizing aspects of B physics specific to hadron colliders, as well as overviews of the CDF, D0, and BTeV detectors, and a Summary.Comment: 583 pages. Further information on the workshops, including transparencies, can be found at the workshop's homepage: http://www-theory.lbl.gov/Brun2/. The report is also available in 2-up http://www-theory.lbl.gov/Brun2/report/report2.ps.gz or chapter-by-chapter http://www-theory.lbl.gov/Brun2/report