Mice with hyper-long telomeres show less metabolic aging and longer lifespans

Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.S

Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations

Although telomere length is genetically determined, mouse embryonic stem (ES) cells with telomeres of twice the normal size have been generated. Here, we use such ES cells with 'hyper-long' telomeres, which also express green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We show that chimaeric mice contain GFP-positive cells in all mouse tissues, display normal tissue histology and normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells retain longer telomeres as mice age. Chimaeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. In highly renewing compartments, such as the blood, cells with hyper-long telomeres are longitudinally maintained or enriched with age. We further show that wound-healing rates in the skin are increased in chimaeric mice. Our work demonstrates that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as TERT overexpression.M. A. Blasco’s laboratory is funded by the Spanish Ministry of Economy and Competitiveness Project SAF2013-45111RETOS, the European Union FP7 Project EUROBATS, the European Research Council (ERC) Project TEL STEM CELL (GA#232854), the Regional Government of Madrid 2þ2 ReCaRe, the AXA Research Fund and the Fundacion BotınS

Alguns caràcters del margall (lolium multiflorum var. westerwoldicum) correlacionats amb la producció

Peer Reviewe

Alguns caràcters del margall (Lolium multiflorum var. westerwoldicum). Correlacionats amb la producció

Peer Reviewe

Anchoring Inflation Expectations in the Face of Oil Shocks & in the Proximity of ZLB : A Tale of Two Targeters

This paper applies a N-ARDL framework to two longstanding inflation targeting policy regimes in order to assess the relation between oil prices dynamics and inflation expectations and the further consequences created by a proximal ZLB situation. The application is based on data from January 1994 to June 2018 for New Zealand and the UK. We focus on oil price shocks as a variable of interest and this was found to have an asymmetric effect on inflation expectations. One further key finding is that the real effective exchange rate has significant impacts on inflation expectations and this is indicative of an exchange rate pass-through to inflation via an inflation expectations channel. In general, we find that inflation, exchange rate, money supply, output growth, unemployment and fiscal deficit/surplus have significant implications for inflation expectations. Inflation expectations are also influenced by their past behaviour indicating adaptive inflation expectations. This study contributes to the debate on the inflation targeting at ZLB

Substrate-controlled Michael additions of titanium enolates from chiral α-benzyloxy ketones to conjugated nitroalkenes

Lewis acid-mediated substrate-controlled reactions of the titanium(IV) enolates of chiral a-benzyloxy ketones with conjugated nitroalkenes give the 2,4-anti-4,5-syn Michael adducts in good yields and diastereomeric ratios. The supplementary Lewis acid plays a key role in the outcome of these transformations, probably as a consequence of the formation of bimetallic enolates that increase the reactivity of the enolate and direct the approach of the nitroalkene. Importantly, the most appropriate Lewis acid depends on the electrophilic partner: TiCl4 is the most suitable Lewis acid for b-aryl nitroalkenes while the best results for b-alkyl nitroalkenes are obtained with SnCl4. Finally, the nitro group of the resultant compounds can be converted into the corresponding amino, oxime, and nitrile groups under mild conditions, which permits the synthesis of a variety of enantiomerically pure derivatives with excellent yields

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

OBJECTIVES: RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. METHODS: We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. RESULTS: Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). CONCLUSION: Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states

Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial

Background & Aims: Histamine intolerance is a disorder in the homeostasis of histamine due to a reduced intestinal degradation of this amine, mainly caused by a deficiency in the enzyme diamine oxidase (DAO). Among histamine related symptoms, headache is one of the most recorded. Current clinical strategies for the treatment of the symptomatology related to this disorder are based on the exclusion of foods with histamine or other bioactive amines and/or exogenous DAO supplementation. The aim of this study was to assess the efficacy of a food supplement consisting of DAO enzyme as a preventive treatment of migraine in patients with DAO deficiency through a randomized double-blind trial. Methods: 100 patients with confirmed episodic migraine according to current International Headache Society (IHS) criteria and DAO deficiency (levels below 80 HDU/ml) were randomized in two groups. One group received DAO enzyme supplementation and the other received placebo for one month. Clinical outcomes assessed were duration and number of attacks, perception of pain intensity and adverse effects during treatment. The use of triptans was also recorded. Results: Great variability was found in the duration of migraine attacks reported by placebo and DAO groups. A significant reduction (p=0.0217) in hours of pain was achieved in patients treated with DAO supplement, with mean durations of 6.14 (±3.06) and 4.76 (±2.68) hours before and after treatment, respectively. A smaller reduction without statistical signification was also observed for this outcome in the placebo group, from 7.53 (±4.24) to 6.68 (±4.42) hours. Only in DAO group, a decrease in the percentage of patients taking triptans was observed. The number of attacks and the scores of pain intensity showed a similar reduction in both groups. No adverse effects were registered in patients treated with DAO enzyme. Conclusions: Migranous patients supplemented with DAO enzyme during one month significantly reduced the duration of their migraine attacks by 1.4 hours. No statistically significant reduction was found in placebo group before and after treatment. The reduction of pain hours observed in placebo group (0.9 hours) could explain the lack of significant differences between both study groups. One month of DAO supplementation has demonstrated a positive trend in the improvement of migraine but more studies with a longer treatment period are needed to better assess the efficacy of DAO supplementation. Clinical trial registration number ISRCTN10091019; www.isrctn.org