219 research outputs found
Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue
The Insulin/IGF-1 signalling (IIS) pathway plays an essential role in the regulation of glucose and
lipid homeostasis. At the same time, a reduction in the IIS pathway activity can extend lifespan and
healthspan in various model organisms. Amongst a number of body organs that sense and respond to
insulin/IGF-1, the adipose tissue has a central role in both the metabolic and lifespan efects of IIS at
the organismal level. Genetic inactivation of IIS components specifcally in the adipose tissue has been
shown before to improve metabolic profle and extend lifespan in various model organisms. We sought
to identify conserved molecular mechanisms that may underlie the benefcial efects of IIS inhibition
in the adipose tissue, specifcally at the level of phosphoinositide 3-kinase (PI3K), a key IIS efector
molecule. To this end, we inactivated PI3K by genetic means in the fy fat body and by pharmacological
inhibition in mammalian adipocytes. Gene expression studies revealed changes to metabolism and
upregulation of mitochondrial activity in mouse adipocytes and fy fat bodies with downregulated
PI3K, which were confrmed by biochemical assays in mammalian adipocytes. These data suggest that
PI3K inactivation has a conserved efect of upregulating mitochondrial metabolism in both fy and
mammalian adipose tissue, which likely contributes to the health- and life-span extending efect of IIS
pathway downregulation
Implementation of standard testbeds for numerical relativity
We discuss results that have been obtained from the implementation of the
initial round of testbeds for numerical relativity which was proposed in the
first paper of the Apples with Apples Alliance. We present benchmark results
for various codes which provide templates for analyzing the testbeds and to
draw conclusions about various features of the codes. This allows us to sharpen
the initial test specifications, design a new test and add theoretical insight.Comment: Corrected versio
Potential role of the geriatric nutritional risk index as a novel risk factor for the development of non-valvular atrial fibrillation in patients with heart failure
PURPOSE: The geriatric nutritional risk index (GNRI) is a simple and objective nutritional assessment tool for elderly patients. Lower GNRI values are associated with a worse prognosis in heart failure with reduced ejection fraction (HFrEF). Our aim is to investigate the relationship between malnutrition and follow-up cardiovascular (CV) events in HFrEF.
METHODS: A retrospective study was performed on 362 patients with HFrEF. The baseline GNRI was calculated at the first visit. The patients were divided into three groups according to the GNRI: >98, no-risk group; 92 to <= 98, low risk group; 82 to <92, moderate-to-high-risk group. The study endpoint was a composite of follow-up CV events, including all-cause mortality, non-valvular atrial fibrillation (NVAF) , need for cardioverter defibrillator (ICD) therapy, HfrEF-related hospitalizations and need for percutaneous coronary interventions (PCIs).
RESULTS: Follow-up data showed that the group with moderate-to-high risk had a significantly higher incidence of NVAF, PCIs and all-cause mortality compared to other groups (p0.05). Mean GNRI value was 83.3 in NVAF patients and 101.1 in patients without NVAF (p<0.001). Kaplan Meier survival analysis showed that patients from the group with moderate-to-high risk had a significantly worse survival rate (p < 0.001). In the multivariate Cox regression analysis, the group with moderate-to-high risk (HR =3.872) and ICD implantations (HR = 4.045) were associated with increased mortality.
CONCLUSION: The GNRI value may have a potential role for predicting future events, especially NVAF in patients with HfrEF
Radiofrequency localization of nonpalpable breast cancer in a multicentre prospective cohort study:feasibility, clinical acceptability, and safety
Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan
The genetic pathways that modulate ageing in multicellular organisms are typically highly conserved across wide evolutionary distances. Recently RNA polymerase III (Pol III) was shown to promote ageing in yeast, C. elegans and D. melanogaster. In this study we investigated the role of Pol III in mammalian ageing using C57BL/6N mice heterozygous for Pol III (Polr3b+/−). We identified sexually dimorphic, organ-specific beneficial as well as detrimental effects of the Polr3b+/− mutation on health. Female Polr3b+/− mice displayed improved bone health during ageing, but their ability to maintain an effective gut barrier function was compromised and they were susceptible to idiopathic dermatitis (ID). In contrast, male Polr3b+/− mice were lighter than wild-type (WT) males and had a significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b+/− mice were long-lived compared to WT controls. Overall, we find no evidence that a reduced Pol III activity extends mouse lifespan but we do find some potential organ- and sex-specific benefits for old-age health
Three little pieces for computer and relativity
Numerical relativity has made big strides over the last decade. A number of
problems that have plagued the field for years have now been mostly solved.
This progress has transformed numerical relativity into a powerful tool to
explore fundamental problems in physics and astrophysics, and I present here
three representative examples. These "three little pieces" reflect a personal
choice and describe work that I am particularly familiar with. However, many
more examples could be made.Comment: 42 pages, 11 figures. Plenary talk at "Relativity and Gravitation:
100 Years after Einstein in Prague", June 25 - 29, 2012, Prague, Czech
Republic. To appear in the Proceedings (Edition Open Access). Collects
results appeared in journal articles [72,73, 122-124
Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells
Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly
Drosophila melanogaster
. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans
Error-analysis and comparison to analytical models of numerical waveforms produced by the NRAR Collaboration
The Numerical-Relativity-Analytical-Relativity (NRAR) collaboration is a
joint effort between members of the numerical relativity, analytical relativity
and gravitational-wave data analysis communities. The goal of the NRAR
collaboration is to produce numerical-relativity simulations of compact
binaries and use them to develop accurate analytical templates for the
LIGO/Virgo Collaboration to use in detecting gravitational-wave signals and
extracting astrophysical information from them. We describe the results of the
first stage of the NRAR project, which focused on producing an initial set of
numerical waveforms from binary black holes with moderate mass ratios and
spins, as well as one non-spinning binary configuration which has a mass ratio
of 10. All of the numerical waveforms are analysed in a uniform and consistent
manner, with numerical errors evaluated using an analysis code created by
members of the NRAR collaboration. We compare previously-calibrated,
non-precessing analytical waveforms, notably the effective-one-body (EOB) and
phenomenological template families, to the newly-produced numerical waveforms.
We find that when the binary's total mass is ~100-200 solar masses, current EOB
and phenomenological models of spinning, non-precessing binary waveforms have
overlaps above 99% (for advanced LIGO) with all of the non-precessing-binary
numerical waveforms with mass ratios <= 4, when maximizing over binary
parameters. This implies that the loss of event rate due to modelling error is
below 3%. Moreover, the non-spinning EOB waveforms previously calibrated to
five non-spinning waveforms with mass ratio smaller than 6 have overlaps above
99.7% with the numerical waveform with a mass ratio of 10, without even
maximizing on the binary parameters.Comment: 51 pages, 10 figures; published versio
Supermassive Black Hole Binaries: The Search Continues
Gravitationally bound supermassive black hole binaries (SBHBs) are thought to
be a natural product of galactic mergers and growth of the large scale
structure in the universe. They however remain observationally elusive, thus
raising a question about characteristic observational signatures associated
with these systems. In this conference proceeding I discuss current theoretical
understanding and latest advances and prospects in observational searches for
SBHBs.Comment: 17 pages, 4 figures. To appear in the Proceedings of 2014 Sant Cugat
Forum on Astrophysics. Astrophysics and Space Science Proceedings, ed.
C.Sopuerta (Berlin: Springer-Verlag
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