Meta-analysis of genetic variants associated with human exceptional longevity

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population

Targeting Hypoxia in Cancer Cells by Restoring Homeodomain Interacting Protein-Kinase 2 and p53 Activity and Suppressing HIF-1α

BACKGROUND:The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) by phosphorylating serine 46 (Ser46) is a crucial regulator of p53 apoptotic function. HIPK2 is also a transcriptional co-repressor of hypoxia-inducible factor-1alpha (HIF-1alpha) restraining tumor angiogenesis and chemoresistance. HIPK2 can be deregulated in tumors by several mechanisms including hypoxia. Here, we sought to target hypoxia by restoring HIPK2 function and suppressing HIF-1alpha, in order to provide evidence for the involvement of both HIPK2 and p53 in counteracting hypoxia-induced chemoresistance. METHODOLOGY/PRINCIPAL FINDINGS:Upon exposure of colon and lung cancer cells to hypoxia, by either low oxygen or cobalt, HIPK2 function was impaired allowing for increased HIF-1alpha expression and inhibiting the p53-apoptotic response to drug. Cobalt suppressed HIPK2 recruitment onto HIF-1alpha promoter. Hypoxia induced expression of the p53 target MDM2 that downregulates HIPK2, thus MDM2 inhibition by siRNA restored the HIPK2/p53Ser46 response to drug. Zinc supplementation to hypoxia-treated cells increased HIPK2 protein stability and nuclear accumulation, leading to restoration of HIPK2 binding to HIF-1alpha promoter, repression of MDR1, Bcl2, and VEGF genes, and activation of the p53 apoptotic response to drug. Combination of zinc and ADR strongly suppressed tumor growth in vivo by inhibiting HIF-1 pathway and upregulating p53 apoptotic target genes. CONCLUSIONS/SIGNIFICANCE:We show here for the first time that hypoxia-induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment

Precipitation products from the hydrology SAF

Abstract. The EUMETSAT Satellite Application Facility on Support to Operational Hydrology and Water Management (H-SAF) was established by the EUMETSAT Council on 3 July 2005, starting activity on 1 September 2005. The Italian Meteorological Service serves as Leading Entity on behalf of twelve European member countries. H-SAF products include precipitation, soil moisture and snow parameters. Some products are based only on satellite observations, while other products are based on the assimilation of satellite measurements/products into numerical models. In addition to product development and generation, H-SAF includes a product validation program and a hydrological validation program that are coordinated, respectively, by the Italian Department of Civil Protection and by the Polish Institute of Meteorology and Water Management. The National Center of Aeronautical Meteorology and Climatology (CNMCA) of the Italian Air Force is responsible for operational product generation and dissemination. In this paper we describe the H-SAF precipitation algorithms and products, which have been developed by the Italian Institute of Atmospheric Sciences and Climate (in collaboration with the international community) and by CNMCA during the Development Phase (DP, 2005–2010) and the first Continuous Development and Operations Phase (CDOP-1, 2010–2012). The precipitation products are based on passive microwave measurements obtained from radiometers onboard different sun-synchronous low-Earth-orbiting satellites (especially, the SSM/I and SSMIS radiometers onboard DMSP satellites and the AMSU-A + AMSU-B/MHS radiometer suites onboard EPS-MetOp and NOAA-POES satellites), as well as on combined infrared/passive microwave measurements in which the passive microwave precipitation estimates are used in conjunction with SEVIRI images from the geostationary MSG satellite. Moreover, the H-SAF product generation and dissemination chain and independent product validation activities are described. Also, the H-SAF program and its associated activities that currently are being carried out or are planned to be performed within the second CDOP phase (CDOP-2, 2012–2017) are presented in some detail. Insofar as CDOP-2 is concerned, it is emphasized that all algorithms and processing schemes will be improved and enhanced so as to extend them to satellites that will be operational within this decade – particularly the geostationary Meteosat Third Generation satellites and the low-Earth-orbiting Core Observatory of the international Global Precipitation Measurement mission. Finally, the role of H-SAF within the international science and operations community is explained.</p

Butyrate as bioactive human milk protective component against food allergy

Background: Food allergy (FA) is a growing health problem worldwide. Effective strategies are advocated to limit the disease burden. Human milk (HM) could be considered as a protective factor against FA, but its mechanisms remain unclear. Butyrate is a gut microbiota-derived metabolite able to exert several immunomodulatory functions. We aimed to define the butyrate concentration in HM, and to see whether the butyrate concentration detected in HM is able to modulate the mechanisms of immune tolerance. Methods: HM butyrate concentration from 109 healthy women was assessed by GS-MS. The effect of HM butyrate on tolerogenic mechanisms was assessed in in vivo and in vitro models. Results: The median butyrate concentration in mature HM was 0.75&nbsp;mM. This butyrate concentration was responsible for the maximum modulatory effects observed in all experimental models evaluated in this study. Data from mouse model show that in basal condition, butyrate up-regulated the expression of several biomarkers of gut barrier integrity, and of tolerogenic cytokines. Pretreatment with butyrate significantly reduced allergic response in three animal models of FA, with a stimulation of tolerogenic cytokines, inhibition of Th2 cytokines production and a modulation of oxidative stress. Data from human cell models show that butyrate stimulated human beta defensin-3, mucus components and tight junctions expression in human enterocytes, and IL-10, IFN-γ and FoxP3 expression through epigenetic mechanisms in PBMCs from FA children. Furthermore, it promoted the precursors of M2 macrophages, DCs and regulatory T cells. Conclusion: The study's findings suggest the importance of butyrate as a pivotal HM compound able to protect against FA

Goal Commitment And Competition As Drivers For Group Productivity In Business Process Modeling

Many studies have looked at the factors that control the productivity of collaborative work. We claim that goal commitment and competition have a strong impact on group productivity in collaborative modelling. To substantiate this claim we first take a look at existing factor models to identify the factors that potentially mediate the effect on group productivity. We then investigate the relation between the factors with the help of controlled field experiments in five different organisations. We confirm the theoretical results with the help of structured equation modelling

The validation service of the hydrological SAF geostationary and polar satellite precipitation products

Abstract. The development phase (DP) of the EUMETSAT Satellite Application Facility for Support to Operational Hydrology and Water Management (H-SAF) led to the design and implementation of several precipitation products, after 5 yr (2005–2010) of activity. Presently, five precipitation estimation algorithms based on data from passive microwave and infrared sensors, on board geostationary and sun-synchronous platforms, function in operational mode at the H-SAF hosting institute to provide near real-time precipitation products at different spatial and temporal resolutions. In order to evaluate the precipitation product accuracy, a validation activity has been established since the beginning of the project. A Precipitation Product Validation Group (PPVG) works in parallel with the development of the estimation algorithms with two aims: to provide the algorithm developers with indications to refine algorithms and products, and to evaluate the error structure to be associated with the operational products. In this paper, the framework of the PPVG is presented: (a) the characteristics of the ground reference data available to H-SAF (i.e. radar and rain gauge networks), (b) the agreed upon validation strategy settled among the eight European countries participating in the PPVG, and (c) the steps of the validation procedures. The quality of the reference data is discussed, and the efforts for its improvement are outlined, with special emphasis on the definition of a ground radar quality map and on the implementation of a suitable rain gauge interpolation algorithm. The work done during the H-SAF development phase has led the PPVG to converge into a common validation procedure among the members, taking advantage of the experience acquired by each one of them in the validation of H-SAF products. The methodology is presented here, indicating the main steps of the validation procedure (ground data quality control, spatial interpolation, up-scaling of radar data vs. satellite grid, statistical score evaluation, case study analysis). Finally, an overview of the results is presented, focusing on the monthly statistical indicators, referred to the satellite product performances over different seasons and areas

Acetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogen

Recent studies demonstrate that acetylation of the transcription factor, p53 on lysine(373) leads to its enhanced stabilization/activity and increased susceptibility of cells to stress. However, it is not known whether acetylation of p53 is altered in the hippocampus following global cerebral ischemia (GCI) or is regulated by the hormone, 17β-estradiol (17β-E(2)), and thus, this study examined these issues.The study revealed that Acetyl p53-Lysine(373) levels were markedly increased in the hippocampal CA1 region after GCI at 3 h, 6 h and 24 h after reperfusion, an effect strongly attenuated by 17β-E(2). 17β-E(2) also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its down-regulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys(382)) at 3 h after reperfusion, and 17β-E(2) also markedly attenuated this effect. Furthermore, administration of an inhibitor of CBP/p300 acetyltransferase, which acetylates p53, was strongly neuroprotective of the CA1 region following GCI. In long-term estrogen deprived (LTED) animals, the ability of 17β-E(2) to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine(373) levels were markedly elevated in sham (non-ischemic) LTED animals. Finally, intracerebroventricular injections of Gp91ds-Tat, a specific NADPH oxidase (NOX2) inhibitor, but not the scrambled tat peptide control (Sc-Tat), attenuated acetylation of p53 and reduced levels of Puma following GCI.The studies demonstrate that p53 undergoes enhanced acetylation in the hippocampal CA1 region following global cerebral ischemia, and that the neuroprotective agent, 17β-E(2), markedly attenuates the ischemia-induced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17β-E(2) on p53 acetylation is lost, and p53 acetylation increases in the hippocampus, which may explain previous reports of increased sensitivity of the hippocampus to ischemic stress following LTED