281 research outputs found
A Numerical Study of Coulomb Interaction Effects on 2D Hopping Transport
We have extended our supercomputer-enabled Monte Carlo simulations of hopping
transport in completely disordered 2D conductors to the case of substantial
electron-electron Coulomb interaction. Such interaction may not only suppress
the average value of hopping current, but also affect its fluctuations rather
substantially. In particular, the spectral density of current
fluctuations exhibits, at sufficiently low frequencies, a -like increase
which approximately follows the Hooge scaling, even at vanishing temperature.
At higher , there is a crossover to a broad range of frequencies in which
is nearly constant, hence allowing characterization of the current
noise by the effective Fano factor F\equiv S_I(f)/2e \left. For
sufficiently large conductor samples and low temperatures, the Fano factor is
suppressed below the Schottky value (F=1), scaling with the length of the
conductor as . The exponent is significantly
affected by the Coulomb interaction effects, changing from when such effects are negligible to virtually unity when they are
substantial. The scaling parameter , interpreted as the average
percolation cluster length along the electric field direction, scales as when Coulomb interaction effects are negligible
and when such effects are substantial, in
good agreement with estimates based on the theory of directed percolation.Comment: 19 pages, 7 figures. Fixed minor typos and updated reference
Spacelike distance from discrete causal order
Any discrete approach to quantum gravity must provide some prescription as to
how to deduce continuum properties from the discrete substructure. In the
causal set approach it is straightforward to deduce timelike distances, but
surprisingly difficult to extract spacelike distances, because of the unique
combination of discreteness with local Lorentz invariance in that approach. We
propose a number of methods to overcome this difficulty, one of which
reproduces the spatial distance between two points in a finite region of
Minkowski space. We provide numerical evidence that this definition can be used
to define a `spatial nearest neighbor' relation on a causal set, and conjecture
that this can be exploited to define the length of `continuous curves' in
causal sets which are approximated by curved spacetime. This provides evidence
in support of the ``Hauptvermutung'' of causal sets.Comment: 32 pages, 16 figures, revtex4; journal versio
BRCA1 and BRCA2 mutations in a population-based study of male breast cancer
Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC)
in the United Kingdom is not known, and the importance of these genes in the increased risk of female
breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear.
Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We
screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these
cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the
contribution of BRCA1 and BRCA2 to this risk.
Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also
had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4
times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation
carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a
mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8%
(95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or
pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast
cancer in female first-degree relatives.
Conclusion: These data suggest that other genes that confer an increased risk for both female and
male breast cancer have yet to be found
High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II
Abstract not availableAaron L. Sverdlov, Aly Elezaby, Jessica B. Behring, Markus M. Bachschmid, Ivan Luptak, Vivian H. Tu, Deborah A. Siwik, Edward J. Miller, Marc Liesa, Orian S. Shirihai, David R. Pimentel, Richard A. Cohen, Wilson S. Colucc
Mitochondrial reactive oxygen species mediate cardiac structural, functional, and mitochondrial consequences of diet-induced metabolic heart disease
Mitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD.Mice fed a high-fat high-sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild-type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS-fed wild-type mice had a 3-fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate-driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate-driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet-induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS-fed wild-type mice complex II substrate-driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site-directed mutation of complex II subunit B Cys100 or Cys103 to redox-insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium.Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103.Aaron L. Sverdlov, Aly Elezaby, Fuzhong Qin, Jessica B. Behring, Ivan Luptak, Timothy D. Calamaras, Deborah A. Siwik, Edward J. Miller, Marc Liesa, Orian S. Shirihai, David R. Pimentel, Richard A. Cohen, Markus M. Bachschmid, Wilson S. Colucc
Stable Homology as an Indicator of Manifoldlikeness in Causal Set Theory
We present a computational tool that can be used to obtain the "spatial"
homology groups of a causal set. Localisation in the causal set is seeded by an
inextendible antichain, which is the analog of a spacelike hypersurface, and a
one parameter family of nerve simplicial complexes is constructed by
"thickening" this antichain. The associated homology groups can then be
calculated using existing homology software, and their behaviour studied as a
function of the thickening parameter. Earlier analytical work showed that for
an inextendible antichain in a causal set which can be approximated by a
globally hyperbolic spacetime region, there is a one parameter sub-family of
these simplicial complexes which are homological to the continuum, provided the
antichain satisfies certain conditions. Using causal sets that are approximated
by a set of 2d spacetimes our numerical analysis suggests that these conditions
are generically satisfied by inextendible antichains. In both 2d and 3d
simulations, as the thickening parameter is increased, the continuum homology
groups tend to appear as the first region in which the homology is constant, or
"stable" above the discreteness scale. Below this scale, the homology groups
fluctuate rapidly as a function of the thickening parameter. This provides a
necessary though not sufficient criterion to test for manifoldlikeness of a
causal set.Comment: Latex, 46 pages, 43 .eps figures, v2 numerous changes to content and
presentatio
Partial Liver Kinase B1 (LKB1) Deficiency Promotes Diastolic Dysfunction, De Novo Systolic Dysfunction, Apoptosis, and Mitochondrial Dysfunction with Dietary Metabolic Challenge
Background - Myocardial hypertrophy and dysfunction are key features of metabolic heart disease due to dietary excess. Metabolic heart disease manifests primarily as diastolic dysfunction but may progress to systolic dysfunction, although the mechanism is poorly understood. Liver kinase B1 (LKB1) is a key activator of AMP-activated protein kinase and possibly other signaling pathways that oppose myocardial hypertrophy and failure. We hypothesized that LKB1 is essential to the heart's ability to withstand the metabolic stress of dietary excess. Methods and Results - Mice heterozygous for cardiac LKB1 were fed a control diet or a high-fat, high-sucrose diet for 4 months. On the control diet, cardiac LKB1 hearts had normal structure and function. After 4 months of the high-fat, high-sucrose diet, there was left ventricular hypertrophy and diastolic dysfunction in wild-type mice. In cardiac LKB1 (versus wild-type) mice, high-fat, high-sucrose feeding caused more hypertrophy (619 versus 553 μm(2), P<0.05), the de novo appearance of systolic dysfunction (left ventricular ejection fraction; 41% versus 59%, P<0.01) with left ventricular dilation (3.6 versus 3.2 mm, P<0.05), and more severe diastolic dysfunction with progression to a restrictive filling pattern (E/A ratio; 5.5 versus 1.3, P=0.05). Myocardial dysfunction in hearts of cardiac LKB1 mice fed the high-fat, high-sucrose diet was associated with evidence of increased apoptosis and apoptotic signaling via caspase 3 and p53/PUMA (p53 upregulated modulator of apoptosis) and more severe mitochondrial dysfunction. Conclusions - Partial deficiency of cardiac LKB1 promotes the adverse effects of a high-fat, high-sucrose diet on the myocardium, leading to worsening of diastolic function and the de novo appearance of systolic dysfunction. LKB1 plays a key role in protecting the heart from the consequences of metabolic stress.Edward J. Miller, Timothy Calamaras, Aly Elezaby, Aaron Sverdlov, Fuzhong Qin, Ivan Luptak, Ke Wang, Xinxin Sun, Andrea Vijay, Dominique Croteau, Markus Bachschmid, Richard A. Cohen, Kenneth Walsh, Wilson S. Colucc
European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment.
AIMS: To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. CONCLUSION: We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes
Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction
Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1−/−) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3–6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct
- …