91 research outputs found
Studies on terrein as a new class of proteasome inhibitors
The proteasome is an intracellular multicatalytic protease involved in the cell cycle regulation, signaling response, antigen presentation and apoptosis. Since proteasome inhibitors promote cell death by apoptosis, they have been proposed as new anti-tumoral drugs. Terrein, a secondary metabolite secreted by the fungus Aspergillus terreus, was firstly described in 1935. In the present work we report that terrein isolated through the screening for inhibitors of the 20S proteasome showed inhibitory effect upon both chymotrypsin- and trypsin-like activities of the multicatalytic core particle, the 20S proteasome. Despite of the high inhibitory concentration determined in vitro, that verified by incubating cells (fibroblasts and a pulmonary tumor cell line) in the presence of terrein was 4-fold lower indicating the proteasome as a selective intracellular target. Moreover, terrein promoted apoptotic cell death on both fibroblasts and pulmonary tumor cell line tested. Although terrein concentrations (mM range) necessary to elicit apoptosis in the cellular models herein tried were high when compared to those (μM and nM range) of other inhibitors recently described, its chemical structure is not correlated to any other inhibitor reported thus far. Therefore, the present results point out for the possibility of exploring terrein as a new molecular fragment for the development of synthetic proteasome inhibitors
Radial Basis Functions collocation and a Unified Formulation for bending, vibration and buckling analysis of laminated plates, according to a variation of Murakami's zig-zag theory
In this paper, we propose to use the Murakami's zig-zag theory for the static and vibration analysis of laminated plates, by local collocation with radial basis functions in a finite differences framework. The equations of motion and the boundary conditions are obtained by the Carrera's Unified Formulation, and further interpolated by a local collocation with radial basis functions and finite differences. This paper considers the analysis of static deformations, free vibrations and buckling loads on laminated composite plates
Non equilibrium steady states: fluctuations and large deviations of the density and of the current
These lecture notes give a short review of methods such as the matrix ansatz,
the additivity principle or the macroscopic fluctuation theory, developed
recently in the theory of non-equilibrium phenomena. They show how these
methods allow to calculate the fluctuations and large deviations of the density
and of the current in non-equilibrium steady states of systems like exclusion
processes. The properties of these fluctuations and large deviation functions
in non-equilibrium steady states (for example non-Gaussian fluctuations of
density or non-convexity of the large deviation function which generalizes the
notion of free energy) are compared with those of systems at equilibrium.Comment: 35 pages, 9 figure
Gene and protein expression of glucose transporter 1 and glucose transporter 3 in human laryngeal cancer—the relationship with regulatory hypoxia-inducible factor-1α expression, tumor invasiveness, and patient prognosis
Increased glucose uptake mediated by glucose
transporters and reliance on glycolysis are common features
of malignant cells. Hypoxia-inducible factor-1α supports the
adaptation of hypoxic cells by inducing genes related to
glucose metabolism. The contribution of glucose transporter
(GLUT) and hypoxia-inducible factor-1α (HIF-1α) activity to
tumor behavior and their prognostic value in head and neck
cancers remains unclear. The aim of this study was to examine
the predictive value of GLUT1, GLUT3, and HIF-1α messenger
RNA (mRNA)/protein expression as markers of tumor
aggressiveness and prognosis in laryngeal cancer. The level of
hypoxia/metabolic marker genes was determined in 106 squamous
cell laryngeal cancer (SCC) and 73 noncancerous
matched mucosa (NCM) controls using quantitative realtime
PCR. The related protein levels were analyzed by
Western blot. Positive expression of SLC2A1, SLC2A3, and
HIF-1α genes was noted in 83.9, 82.1, and 71.7 % of SCC
specimens and in 34.4, 59.4, and 62.5 % of laryngeal cancer
samples. Higher levels of mRNA/protein for GLUT1 and
HIF-1α were noted in SCC compared to NCM (p<0.05).
SLC2A1 was found to have a positive relationship with grade,
tumor front grading (TFG) score, and depth and mode of
invasion (p<0.05). SLC2A3 was related to grade and invasion
type (p<0.05). There were also relationships of HIF-1α with
pTNM, TFG scale, invasion depth and mode, tumor recurrences,
and overall survival (p<0.05). In addition, more advanced
tumors were found to be more likely to demonstrate
positive expression of these proteins. In conclusion, the
hypoxia/metabolic markers studied could be used as molecular
markers of tumor invasiveness in laryngeal cancer.This work was supported, in part, by the statutory
fund of the Department of Cytobiochemistry, University of Łódź, Poland
(506/811), and by grant fromtheNational Science Council, Poland (N403
043 32/2326)
A pedestrian's view on interacting particle systems, KPZ universality, and random matrices
These notes are based on lectures delivered by the authors at a Langeoog
seminar of SFB/TR12 "Symmetries and universality in mesoscopic systems" to a
mixed audience of mathematicians and theoretical physicists. After a brief
outline of the basic physical concepts of equilibrium and nonequilibrium
states, the one-dimensional simple exclusion process is introduced as a
paradigmatic nonequilibrium interacting particle system. The stationary measure
on the ring is derived and the idea of the hydrodynamic limit is sketched. We
then introduce the phenomenological Kardar-Parisi-Zhang (KPZ) equation and
explain the associated universality conjecture for surface fluctuations in
growth models. This is followed by a detailed exposition of a seminal paper of
Johansson that relates the current fluctuations of the totally asymmetric
simple exclusion process (TASEP) to the Tracy-Widom distribution of random
matrix theory. The implications of this result are discussed within the
framework of the KPZ conjecture.Comment: 52 pages, 4 figures; to appear in J. Phys. A: Math. Theo
Proteasome Activator Enhances Survival of Huntington's Disease Neuronal Model Cells
In patients with Huntington's disease (HD), the proteolytic activity of the ubiquitin proteasome system (UPS) is reduced in the brain and other tissues. The pathological hallmark of HD is the intraneuronal nuclear protein aggregates of mutant huntingtin. We determined how to enhance UPS function and influence catalytic protein degradation and cell survival in HD. Proteasome activators involved in either the ubiquitinated or the non-ubiquitinated proteolysis were overexpressed in HD patients' skin fibroblasts or mutant huntingtin-expressing striatal neurons. Following compromise of the UPS, overexpression of the proteasome activator subunit PA28γ, but not subunit S5a, recovered proteasome function in the HD cells. PA28γ also improved cell viability in mutant huntingtin-expressing striatal neurons exposed to pathological stressors, such as the excitotoxin quinolinic acid and the reversible proteasome inhibitor MG132. These results demonstrate the specific functional enhancements of the UPS that can provide neuroprotection in HD cells
Meta-analysis of Outcomes Following Aneurysm Repair in Patients with Synchronous Intra-abdominal Malignancy
Pneumonia eosinofílica crônica secundária ao uso prolongado de nitrofurantoína: achados da tomografia computadorizada de alta resolução do tórax
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