985 research outputs found
Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6
Background: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV.
Methods:
We investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619.
Results:
OAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV.
Conclusion:
These findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG
The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation
Abstract
Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster ortholog of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here, we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell-cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in oligodendrogliomas prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.
Significance: Inactivation of CIC inhibits its direct repression of MAPK pathway genes, leading to their increased expression and mitogen-independent growth.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4114/F1.large.jpg. Cancer Res; 78(15); 4114–25. ©2018 AACR.</jats:p
One- and many-body effects on mirages in quantum corrals
Recent interesting experiments used scanning tunneling microscopy to study
systems involving Kondo impurities in quantum corrals assembled on Cu or noble
metal surfaces. The solution of the two-dimensional one-particle Schrodinger
equation in a hard wall corral without impurity is useful to predict the
conditions under which the Kondo effect can be projected to a remote location
(the quantum mirage). To model a soft circular corral, we solve this equation
under the potential W*delta(r-r0), where r is the distance to the center of the
corral and r0 its radius. We expand the Green's function of electron surface
states Gs0 for r<r0 as a discrete sum of contributions from single poles at
energies epsilon_i-I*delta_i. The imaginary part delta_i is the half-width of
the resonance produced by the soft confining potential, and turns out to be a
simple increasing function of epsilon_i. In presence of an impurity, we solve
the Anderson model at arbitrary temperatures using the resulting expression for
Gs0 and perturbation theory up to second order in the Coulomb repulsion U. We
calculate the resulting change in the differential conductance Delta dI/dV as a
function of voltage and space, in circular and elliptical corrals, for
different conditions, including those corresponding to recent experiments. The
main features are reproduced. The role of the direct hybridization between
impurity and bulk, the confinement potential, the size of the corral and
temperature on the intensity of the mirage are analyzed. We also calculate
spin-spin correlation functions.Comment: 13 pages, 12 figures, accepted for publication in Phys. Rev. B.
Calculations of spin correlations within an additional approximation adde
Simple model for scanning tunneling spectroscopy of noble metal surfaces with adsorbed Kondo impurities
A simple model is introduced to describe conductance measurements between a
scanning tunneling microscope (STM) tip and a noble metal surface with adsorbed
transition metal atoms which display the Kondo effect. The model assumes a
realistic parameterization of the potential created by the surface and a
d3z2-r2 orbital for the description of the adsorbate. Fano lineshapes
associated with the Kondo resonance are found to be sensitive to details of the
adsorbate-substrate interaction. For instance, bringing the adsorbate closer to
the surface leads to more asymmetric lineshapes while their dependence on the
tip distance is weak. We find that it is important to use a realistic surface
potential, to properly include the tunnelling matrix elements to the tip and to
use substrate states which are orthogonal to the adsorbate and tip states. An
application of our model to Co adsorbed on Cu explains the difference in the
lineshapes observed between Cu(100) and Cu(111) surfaces.Comment: 11 pages, 8 eps figure
Eplerenone attenuates pathological pulmonary vascular rather than right ventricular remodeling in pulmonary arterial hypertension
BACKGROUND: Aldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation. Although pharmacological aldosterone antagonism reduces mortality and morbidity among patients with severe left-sided heart failure, the contribution of aldosterone to the pathobiology of pulmonary arterial hypertension (PAH) and right ventricular (RV) heart failure is not fully understood. METHODS: The effects of Eplerenone (0.1% Inspra® mixed in chow) on pulmonary vascular and RV remodeling were evaluated in mice with pulmonary hypertension (PH) caused by Sugen5416 injection with concomitant chronic hypoxia (SuHx) and in a second animal model with established RV dysfunction independent from lung remodeling through surgical pulmonary artery banding. RESULTS: Preventive Eplerenone administration attenuated the development of PH and pathological remodeling of pulmonary arterioles. Therapeutic aldosterone antagonism - starting when RV dysfunction was established - normalized mineralocorticoid receptor gene expression in the right ventricle without direct effects on either RV structure (Cardiomyocyte hypertrophy, Fibrosis) or function (assessed by non-invasive echocardiography along with intra-cardiac pressure volume measurements), but significantly lowered systemic blood pressure. CONCLUSIONS: Our data indicate that aldosterone antagonism with Eplerenone attenuates pulmonary vascular rather than RV remodeling in PAH
Interaction between Kondo impurities in a quantum corral
We calculate the spectral densities for two impurities inside an elliptical
quantum corral using exact diagonalization in the relevant Hilbert subspace and
embedding into the rest of the system. For one impurity, the space and energy
dependence of the change in differential conductance observed
in the quantum mirage experiment is reproduced. In presence of another
impurity, is very sensitive to the hybridization between
impurity and bulk. The impurities are correlated ferromagnetically between
them. A hopping eV between impurities destroy the Kondo
resonance.Comment: 4 pages, 4 figure
Oxidative injury of the pulmonary circulation in the perinatal period: Short- and long-term consequences for the human cardiopulmonary system
Development of the pulmonary circulation is a complex process with a spatial pattern that is tightly controlled. This process is vulnerable for disruption by various events in the prenatal and early postnatal periods. Disruption of normal pulmonary vascular development leads to abnormal structure and function of the lung vasculature, causing neonatal pulmonary vascular diseases. Premature babies are especially at risk of the development of these diseases, including persistent pulmonary hypertension and bronchopulmonary dysplasia. Reactive oxygen species play a key role in the pathogenesis of neonatal pulmonary vascular diseases and can be caused by hyperoxia, mechanical ventilation, hypoxia, and inflammation. Besides the well-established short-term consequences, exposure of the developing lung to injurious stimuli in the perinatal period, including oxidative stress, may also contribute to the development of pulmonary vascular diseases later in life, through so-called ‘‘fetal or perinatal programming.’’ Because of these long-term consequences, it is important to develop a follow-up program tailored to adolescent survivors of neonatal pulmonary vascular diseases, aimed at early detection of adult pulmonary vascular diseases, and thereby opening the possibility of early intervention and interfering with disease progression. This review focuses on pathophysiologic events in the perinatal period that have been shown to disrupt human normal pulmonary vascular development, leading to neonatal pulmonary vascular diseases that can extend even into adulthood. This knowledge may be particularly important for expremature adults who are at risk of the long-term consequences of pulmonary vascular diseases, thereby contributing disproportionately to the burden of adult cardiovascular disease in the future
Theory of the Fano Resonance in the STM Tunneling Density of States due to a Single Kondo Impurity
The conduction electron density of states nearby single magnetic impurities,
as measured recently by scanning tunneling microscopy (STM), is calculated,
taking into account tunneling into conduction electron states only. The Kondo
effect induces a narrow Fano resonance in the conduction electron density of
states, while scattering off the d-level generates a weakly energy dependent
Friedel oscillation. The line shape varies with the distance between STM tip
and impurity, in qualitative agreement with experiments, but is very sensitive
to details of the band structure. For a Co impurity the experimentally observed
width and shift of the Kondo resonance are in accordance with those obtained
from a combination of band structure and strongly correlated calculations.Comment: 4 pages, ReVTeX + 4 figures (Encapsulated Postscript), submitted to
PR
- …