59 research outputs found
Shutdown of achaete-scute homolog-1 expression by heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 in hypoxia
The basic helix-loop-helix transcription factor hASH1, encoded by the ASCL1 gene, plays an important role in neurogenesis and tumor development. Recent findings indicate that the local oxygen tension is a critical determinant for the progression of neuroblastomas. Here we investigated the molecular mechanisms underlying the oxygen-dependent expression of hASH1 in neuroblastoma cells. Exposure of human neuroblastoma-derived Kelly cells to 1% O2 significantly decreased ASCL1 mRNA and hASH1 protein levels. Using reporter gene assays, we show that the response of hASH1 to hypoxia is mediated mainly by post-transcriptional inhibition via the ASCL1 mRNA 5'- and 3'-UTRs, while additional inhibition of the ASCL1 promoter was observed under prolonged hypoxia. By RNA pull-down experiments followed by MALDI/TOF-MS analysis, we identified heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 and hnRNP-R as interactors binding directly to the ASCL1 mRNA 5'- and 3'-UTRs and influencing its expression. We further demonstrate that hnRNP-A2/B1 is a key positive regulator of ASCL1, findings that were also confirmed by analysis of a large compilation of gene expression data. Our data suggest that a prominent down-regulation of hnRNP-A2/B1 during hypoxia is associated with the post-transcriptional suppression of hASH1 synthesis. This novel post-transcriptional mechanism for regulating hASH1 levels will have important implications in neural cell fate development and disease
Tunable variation of optical properties of polymer capped gold nanoparticles
Optical properties of polymer capped gold nanoparticles of various sizes
(diameter 3-6 nm) have been studied. We present a new scheme to extract size
dependent variation of total dielectric function of gold nanoparticles from
measured UV-Vis absorption data. The new scheme can also be used, in principle,
for other related systems as well. We show how quantum effect, surface atomic
co - ordination and polymer - nanoparticle interface morphology leads to a
systematic variation in inter band part of the dielectric function of gold
nanoparticles, obtained from the analysis using our new scheme. Careful
analysis enables identification of the possible changes to the electronic band
structure in such nanoparticles.Comment: 13 pages,7 figures, 1 tabl
Structure Formation, Melting, and the Optical Properties of Gold/DNA Nanocomposites: Effects of Relaxation Time
We present a model for structure formation, melting, and optical properties
of gold/DNA nanocomposites. These composites consist of a collection of gold
nanoparticles (of radius 50 nm or less) which are bound together by links made
up of DNA strands. In our structural model, the nanocomposite forms from a
series of Monte Carlo steps, each involving reaction-limited cluster-cluster
aggregation (RLCA) followed by dehybridization of the DNA links. These links
form with a probability which depends on temperature and particle
radius . The final structure depends on the number of monomers (i. e. gold
nanoparticles) , , and the relaxation time. At low temperature, the
model results in an RLCA cluster. But after a long enough relaxation time, the
nanocomposite reduces to a compact, non-fractal cluster. We calculate the
optical properties of the resulting aggregates using the Discrete Dipole
Approximation. Despite the restructuring, the melting transition (as seen in
the extinction coefficient at wavelength 520 nm) remains sharp, and the melting
temperature increases with increasing as found in our previous
percolation model. However, restructuring increases the corresponding link
fraction at melting to a value well above the percolation threshold. Our
calculated extinction cross section agrees qualitatively with experiments on
gold/DNA composites. It also shows a characteristic ``rebound effect,''
resulting from incomplete relaxation, which has also been seen in some
experiments. We discuss briefly how our results relate to a possible sol-gel
transition in these aggregates.Comment: 12 pages, 10 figure
Age impairs soluble guanylyl cyclase function in mouse mesenteric arteries
Endothelial dysfunction (ED) comes with age, even without overt vessel damage such as that which occurs in atherosclerosis and diabetic vasculopathy. We hypothesized that aging would affect the downstream signalling of the endothelial nitric oxide (NO) system in the vascular smooth muscle (VSM). With this in mind, resistance mesenteric arteries were isolated from 13-week (juvenile) and 40-week-old (aged) mice and tested under isometric conditions using wire myography. Acetylcholine (ACh)-induced relaxation was reduced in aged as compared to juvenile vessels. Pretreatment with L-NAME, which inhibits nitrix oxide synthases (NOS), decreased ACh-mediated vasorelaxation, whereby differences in vasorelaxation between groups disappeared. Endothelium-independent vasorelaxation by the NO donor sodium nitroprusside (SNP) was similar in both groups; however, SNP bolus application (10(-6) mol L(-1)) as well as soluble guanylyl cyclase (sGC) activation by runcaciguat (10(-6) mol L(-1)) caused faster responses in juvenile vessels. This was accompanied by higher cGMP concentrations and a stronger response to the PDE5 inhibitor sildenafil in juvenile vessels. Mesenteric arteries and aortas did not reveal apparent histological differences between groups (van Gieson staining). The mRNA expression of the α1 and α2 subunits of sGC was lower in aged animals, as was PDE5 mRNA expression. In conclusion, vasorelaxation is compromised at an early age in mice even in the absence of histopathological alterations. Vascular smooth muscle sGC is a key element in aged vessel dysfunction
SARS-CoV-2 effects on the renin-angiotensin-aldosterone system, therapeutic implications
Angiotensin converting enzyme-2 (ACE-2) is the cell-surface receptor enabling viral uptake of corona virus 2019 (SARS-CoV-2), thus ACE-2 is a first step towards COVID-19 disease. ACE-2 is a metalloenzyme located primarily on the apical surface, and serves as the entry point also for other coronaviruses, including HCoV-NL63 and SARS-CoV. Throughout evolution, ACE-2 precedes renin, suggesting that ACE-2's role changed over time
Expression of smooth muscle MyHC B in blood vessels of hypertrophied heart in experimentally hypertensive rats
We demonstrated recently a significantly lower fraction of cardiac precapillary arterioles that expressed smooth muscle myosin heavy chain (MyHC) B (SMB) in spontaneously hypertensive rats. To clarify whether this reduction of SMB expression is of genetic origin, we investigated SMB expression in cardiac precapillary arterioles of normotensive and experimentally hypertensive rats (one clip, one kidney or ANG II minipump). We observed similar SMB expression patterns in precapillary arterioles of experimentally hypertensive rats compared with normotensive controls. These observations suggest that the downregulation of SMB in spontaneously hypertensive rats is of genetic origin rather than an adaptive response to chronically enhanced blood pressure and cardiac hypertrophy
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