1,044 research outputs found
Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling
Background: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K‐ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K‐ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway.
Methods and Results: Biosynthesis of MBG by cultured human JEG‐3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 μmol/L of rapamycin inhibited production of MBG in human JEG‐2 cells. Male Sprague‐Dawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025±60 vs 377±53 pmol/L; PPP
Conclusions: Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG‐mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy
Gender differences in the development of uremic cardiomyopathy following partial nephrectomy: Role of progesterone
Gender difference has been suggested as a risk factor for developing cardiovascular and renal diseases in humans and experimental animals. As a major sex hormone, progesterone was reported to compete with cardiotonic steroid binding to Na/K-ATPase. Our previous publication demonstrated that cardiotonic steroids (e.g., marinobufagenin) play an important role in the development of experimental uremic cardiomyopathy. We also observed that the putative mineralocorticoid antagonists, spironolactone and its major metabolite canrenone, antagonize binding of cardiotonic steroids to Na/K-ATPase in a competitive manner and also ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy. In the following studies, we noted that progesterone displayed competitive inhibition of cardiotonic steroid binding to Na/K-ATPase and partially inhibited collagen synthesis induced by marinobufagenin in cultured cardiac fibroblasts. Therefore, we sought to examine whether female rats displayed less uremic cardiomyopathy than male rats when subjected to partial nephrectomy. Although partial nephrectomy caused the induction of smaller increases in blood pressure of female rats, they appeared to be similarly susceptible to cardiac remodeling induced by partial nephrectomy in terms of hypertrophy and fibrosis as age-matched male rats. The possible explanations for our findings are therefore discussed
Uniform electron gases
We show that the traditional concept of the uniform electron gas (UEG) --- a
homogeneous system of finite density, consisting of an infinite number of
electrons in an infinite volume --- is inadequate to model the UEGs that arise
in finite systems. We argue that, in general, a UEG is characterized by at
least two parameters, \textit{viz.} the usual one-electron density parameter
and a new two-electron parameter . We outline a systematic
strategy to determine a new density functional across the
spectrum of possible and values.Comment: 8 pages, 2 figures, 5 table
Von Bezold assimilation effect reverses in stereoscopic conditions
Lightness contrast and lightness assimilation are opposite phenomena: in contrast,
grey targets appear darker when bordering bright surfaces (inducers) rather than dark ones; in
assimilation, the opposite occurs. The question is: which visual process favours the occurrence
of one phenomenon over the other? Researchers provided three answers to this question. The
first asserts that both phenomena are caused by peripheral processes; the second attributes their
occurrence to central processes; and the third claims that contrast involves central processes,
whilst assimilation involves peripheral ones. To test these hypotheses, an experiment on an IT
system equipped with goggles for stereo vision was run. Observers were asked to evaluate the
lightness of a grey target, and two variables were systematically manipulated: (i) the apparent
distance of the inducers; and (ii) brightness of the inducers. The retinal stimulation was kept
constant throughout, so that the peripheral processes remained the same. The results show that
the lightness of the target depends on both variables. As the retinal stimulation was kept constant, we
conclude that central mechanisms are involved in both lightness contrast and lightness assimilation
Protein Carbonylation of an Amino Acid Residue of the Na/K‐ATPase α1 Subunit Determines Na/K‐ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells
Background We have demonstrated that cardiotonic steroids, such as ouabain, signaling through the Na/K‐ATPase, regulate sodium reabsorption in the renal proximal tubule. By direct carbonylation modification of the Pro222 residue in the actuator (A) domain of pig Na/K‐ATPase α1 subunit, reactive oxygen species are required for ouabain‐stimulated Na/K‐ATPase/c‐Src signaling and subsequent regulation of active transepithelial 22Na+ transport. In the present study we sought to determine the functional role of Pro222 carbonylation in Na/K‐ATPase signaling and sodium handling.
Methods and Results Stable pig α1 knockdown LLC‐PK1‐originated PY‐17 cells were rescued by expressing wild‐type rat α1 and rat α1 with a single mutation of Pro224 (corresponding to pig Pro222) to Ala. This mutation does not affect ouabain‐induced inhibition of Na/K‐ATPase activity, but abolishes the effects of ouabain on Na/K‐ATPase/c‐Src signaling, protein carbonylation, Na/K‐ATPase endocytosis, and active transepithelial 22Na+ transport.
Conclusions Direct carbonylation modification of Pro224 in the rat α1 subunit determines ouabain‐mediated Na/K‐ATPase signal transduction and subsequent regulation of renal proximal tubule sodium transport
The Dawn of Open Access to Phylogenetic Data
The scientific enterprise depends critically on the preservation of and open
access to published data. This basic tenet applies acutely to phylogenies
(estimates of evolutionary relationships among species). Increasingly,
phylogenies are estimated from increasingly large, genome-scale datasets using
increasingly complex statistical methods that require increasing levels of
expertise and computational investment. Moreover, the resulting phylogenetic
data provide an explicit historical perspective that critically informs
research in a vast and growing number of scientific disciplines. One such use
is the study of changes in rates of lineage diversification (speciation -
extinction) through time. As part of a meta-analysis in this area, we sought to
collect phylogenetic data (comprising nucleotide sequence alignment and tree
files) from 217 studies published in 46 journals over a 13-year period. We
document our attempts to procure those data (from online archives and by direct
request to corresponding authors), and report results of analyses (using
Bayesian logistic regression) to assess the impact of various factors on the
success of our efforts. Overall, complete phylogenetic data for ~60% of these
studies are effectively lost to science. Our study indicates that phylogenetic
data are more likely to be deposited in online archives and/or shared upon
request when: (1) the publishing journal has a strong data-sharing policy; (2)
the publishing journal has a higher impact factor, and; (3) the data are
requested from faculty rather than students. Although the situation appears
dire, our analyses suggest that it is far from hopeless: recent initiatives by
the scientific community -- including policy changes by journals and funding
agencies -- are improving the state of affairs
Resource Modelling: The Missing Piece of the HTA Jigsaw?
Within health technology assessment (HTA), cost-effectiveness analysis and budget impact analyses have been broadly accepted as important components of decision making. However, whilst they address efficiency and affordability, the issue of implementation and feasibility has been largely ignored. HTA commonly takes place within a deliberative framework that captures issues of implementation and feasibility in a qualitative manner. We argue that only through a formal quantitative assessment of resource constraints can these issues be fully addressed. This paper argues the need for resource modelling to be considered explicitly in HTA. First, economic evaluation and budget impact models are described along with their limitations in evaluating feasibility. Next, resource modelling is defined and its usefulness is described along with examples of resource modelling from the literature. Then, the important issues that need to be considered when undertaking resource modelling are described before setting out recommendations for the use of resource modelling in HTA
The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation
PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry
<p>Abstract</p> <p>Background</p> <p>Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry.</p> <p>Methods</p> <p>Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15<sup>th </sup>percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin<sup>® </sup>or Prolastin<sup>®</sup>], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.</p> <p>Results</p> <p>Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.</p> <p>Conclusions</p> <p>The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.</p> <p>Trial registration</p> <p>The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.</p
Tendinopathy—from basic science to treatment
Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy
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