383 research outputs found
Scaling of energy spreading in strongly nonlinear disordered lattices
To characterize a destruction of Anderson localization by nonlinearity, we
study the spreading behavior of initially localized states in disordered,
strongly nonlinear lattices. Due to chaotic nonlinear interaction of localized
linear or nonlinear modes, energy spreads nearly subdiffusively. Based on a
phenomenological description by virtue of a nonlinear diffusion equation we
establish a one-parameter scaling relation between the velocity of spreading
and the density, which is confirmed numerically. From this scaling it follows
that for very low densities the spreading slows down compared to the pure power
law.Comment: 4 pages, 4 figure
Introduction of Macromolecules into Bovine Adrenal Medullary Chromaffin Cells and Rat Pheochromocytoma Cells (PC12) by Permeabilization with Streptolysin O: Inhibitory Effect of Tetanus Toxin on Catecholamine Secretion
Conditions are described for controlled plasma membrane permeabilization of rat pheochromocytoma cells (PC12) and cultured bovine adrenal chromaffin cells by Streptolysin O (SLO). The transmembrane pores created by SLO invoke rapid efflux of intracellular 86Rb+ and ATP, and also permit passive diffusion of proteins, including immunoglobulins, into the cells. SLO-permeabilized PC12 cells release [3H]dopamine in response to micromolar concentrations of free Ca2+. Permeabilized adrenal chromaffin cells present a similar exocytotic response to Ca2+ in the presence of Mg2+/ ATP. Permeabilized PC12 cells accumulate antibodies against synaptophysin and calmodulin, but neither antibody reduces the Ca2+-dependent secretory response. Reduced tetanus toxin, although ineffective when applied to intact chromaffin cells, inhibits Ca2+-induced exocytosis by both types of permeabilized cells studied. Omission of dithiothreitol, toxin inactivation by boiling, or preincubation with neutralizing antibodies abolishes the inhibitory effect. The data indicate that plasma membrane permeabilization by Streptolysin O is a useful tool to probe and define cellular components that are involved in the final steps of exocytosis
GTP and Ca2+ Modulate the Inositol 1,4,5-Trisphosphate-Dependent Ca2+ Release in Streptolysin O-Permeabilized Bovine Adrenal Chromaffin Cells
The inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release was studied using streptolysin O-permeabilized bovine adrenal chromaffin cells. The IP3-induced Ca2+ release was followed by Ca2+ reuptake into intracellular compartments. The IP3-induced Ca2+ release diminished after sequential applications of the same amount of IP3. Addition of 20 ÎŒM GTP fully restored the sensitivity to IP3. Guanosine 5'-O-(3-thio)triphosphate (GTPÎłS) could not replace GTP but prevented the action of GTP. The effects of GTP and GTPÎłS were reversible. Neither GTP nor GTPÎłS induced release of Ca2+ in the absence of IP3. The amount of Ca2+ whose release was induced by IP3 depended on the free Ca2+ concentration of the medium. At 0.3 ÎŒM free Ca2+, a half-maximal Ca2+ release was elicited with âŒ0.1 ÎŒM IP3. At 1 ÎŒM free Ca2+, no Ca2+ release was observed with 0.1 ÎŒM IP3; at this Ca2+ concentration, higher concentrations of IP3 (0.25 ÎŒM) were required to evoke Ca2+ release. At 8 ÎŒM free Ca2+, even 0.25 ÎŒM IP3 failed to induce release of Ca2+ from the store. The IP3-induced Ca2+ release at constant low (0.2 ÎŒM) free Ca2+ concentrations correlated directly with the amount of stored Ca2+. Depending on the filling state of the intracellular compartment, 1 mol of IP3 induced release of between 5 and 30 mol of Ca2+
Further Characterization of Dopamine Release by Permeabilized PC 12 Cells
Rat pheochromocytoma cells (PC 12) permeabilized with staphylococcal α-toxin release [3H]dopamine after addition of micromolar Ca2+. This does not require additional Mg2+-ATP (in contrast to bovine adrenal medullary chromaffin cells). We also observed Ca2+-dependent [3H]-dopamine release from digitonin-permeabilized PC 12 cells. Permeabilization with α-toxin or digitonin and stimulation of the cells were done consecutively to wash out endogenous Mg2+-ATP. During permeabilization, ATP was removed effectively from the cytoplasm by both agents but the cells released [3H]dopamine in response to micromolar Ca2+ alone. Replacement by chloride of glutamate, which could sustain mitochondrial ATP production in permeabilized cells, does not significantly alter catecholamine release induced by Ca2+. However, Mg2+ without ATP augments the Ca2+-induced release. The release was unaltered by thiol-, hydroxyl-, or calmodulin-interfering substances. Thus Mg2+-ATP, calmodulin, or proteins containing -SH or -OH groups are not necessary for exocytosis in permeabilized PC 12 cells
Molecular Aspects of Secretory Granule Exocytosis by Neurons and Endocrine Cells
Neuronal communication and endocrine signaling are fundamental for integrating
the function of tissues and cells in the body. Hormones released by endocrine
cells are transported to the target cells through the circulation. By contrast, transmitter
release from neurons occurs at specialized intercellular junctions, the synapses.
Nevertheless, the mechanisms by which signal molecules are synthesized,
stored, and eventually secreted by neurons and endocrine cells are very similar.
Neurons and endocrine cells have in common two different types of secretory
organelles, indicating the presence of two distinct secretory pathways. The synaptic
vesicles of neurons contain excitatory or inhibitory neurotransmitters, whereas the
secretory granules (also referred to as dense core vesicles, because of their electron
dense content) are filled with neuropeptides and amines. In endocrine cells, peptide
hormones and amines predominate in secretory granules. The function and content
of vesicles, which share antigens with synaptic vesicles, are unknown for most
endocrine cells. However, in B cells of the pancreatic islet, these vesicles contain
GABA, which may be involved in intrainsular signaling.'
Exocytosis of both synaptic vesicles and secretory granules is controlled by
cytoplasmic calcium. However, the precise mechanisms of the subsequent steps,
such as docking of vesicles and fusion of their membranes with the plasma membrane,
are still incompletely understood. This contribution summarizes recent observations
that elucidate components in neurons and endocrine cells involved in
exocytosis. Emphasis is put on the intracellular aspects of the release of secretory
granules that recently have been analyzed in detail
Dynamical Thermalization of Disordered Nonlinear Lattices
We study numerically how the energy spreads over a finite disordered
nonlinear one-dimensional lattice, where all linear modes are exponentially
localized by disorder. We establish emergence of dynamical thermalization,
characterized as an ergodic chaotic dynamical state with a Gibbs distribution
over the modes. Our results show that the fraction of thermalizing modes is
finite and grows with the nonlinearity strength.Comment: 5 pages, 5 figure
Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
CLR457; Inhibidor Pan-PI3K; Fase ICLR457; Inhibidor Pan-PI3K; Fase ICLR457; Pan-PI3K inhibitor; Phase IBackground CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110ÎČ, p110ÎŽ and p110Îł isoforms with an IC50 of 89â±â29 nM, 56â±â35 nM, 39â±â10 nM and 230â±â31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (nâ=â11), 3 (27.3%) patients had DLTs and all patients (100%) experienced â„ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicitiesâ51.6% patients experienced â„ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.Novartis Pharmaceuticals Corporation
Genetic-Algorithm-based Light Curve Optimization Applied to Observations of the W UMa star BH Cas
I have developed a procedure utilizing a Genetic-Algorithm-based optimization
scheme to fit the observed light curves of an eclipsing binary star with a
model produced by the Wilson-Devinney code. The principal advantages of this
approach are the global search capability and the objectivity of the final
result. Although this method can be more efficient than some other comparably
global search techniques, the computational requirements of the code are still
considerable. I have applied this fitting procedure to my observations of the W
UMa type eclipsing binary BH Cassiopeiae. An analysis of V-band CCD data
obtained in 1994/95 from Steward Observatory and U- and B-band photoelectric
data obtained in 1996 from McDonald Observatory provided three complete light
curves to constrain the fit. In addition, radial velocity curves obtained in
1997 from McDonald Observatory provided a direct measurement of the system mass
ratio to restrict the search. The results of the GA-based fit are in excellent
agreement with the final orbital solution obtained with the standard
differential corrections procedure in the Wilson-Devinney code.Comment: 9 pages, 2 figures, 2 tables, uses emulateapj.st
Strong and weak chaos in weakly nonintegrable many-body Hamiltonian systems
We study properties of chaos in generic one-dimensional nonlinear Hamiltonian
lattices comprised of weakly coupled nonlinear oscillators, by numerical
simulations of continuous-time systems and symplectic maps. For small coupling,
the measure of chaos is found to be proportional to the coupling strength and
lattice length, with the typical maximal Lyapunov exponent being proportional
to the square root of coupling. This strong chaos appears as a result of
triplet resonances between nearby modes. In addition to strong chaos we observe
a weakly chaotic component having much smaller Lyapunov exponent, the measure
of which drops approximately as a square of the coupling strength down to
smallest couplings we were able to reach. We argue that this weak chaos is
linked to the regime of fast Arnold diffusion discussed by Chirikov and
Vecheslavov. In disordered lattices of large size we find a subdiffusive
spreading of initially localized wave packets over larger and larger number of
modes. The relations between the exponent of this spreading and the exponent in
the dependence of the fast Arnold diffusion on coupling strength are analyzed.
We also trace parallels between the slow spreading of chaos and deterministic
rheology.Comment: 15 pages, 14 figure
Genetic structure and molecular diversity of cacao plants established as local varieties for more than two centuries: the genetic history of cacao plantations in Bahia, Brazil
ahia is the most important cacao-producing state in Brazil, which is currently the sixth-largest country worldwide to produce cacao seeds. In the eighteenth century, the Comum, ParĂĄ and MaranhĂŁo varieties of cacao were introduced into southern Bahia, and their descendants, which are called âBahian cacaoâ or local Bahian varieties, have been cultivated for over 200 years. Comum plants have been used to start plantations in African countries and extended as far as countries in South Asia and Oceania. In Brazil, two sets of clones selected from Bahian varieties and their mutants, the Agronomic Institute of East (SIAL) and Bahian Cacao Institute (SIC) series, represent the diversity of Bahian cacao in germplasm banks. Because the genetic diversity of Bahian varieties, which is essential for breeding programs, remains unknown, the objective of this work was to assess the genetic structure and diversity of local Bahian varieties collected from farms and germplasm banks. To this end, 30 simple sequence repeat (SSR) markers were used to genotype 279 cacao plants from germplasm and local farms. The results facilitated the identification of 219 cacao plants of Bahian origin, and 51 of these were SIAL or SIC clones. Bahian cacao showed low genetic diversity. It could be verified that SIC and SIAL clones do not represent the true diversity of Bahian cacao, with the greatest amount of diversity found in cacao trees on the farms. Thus, a core collection to aid in prioritizing the plants to be sampled for Bahian cacao diversity is suggested. These results provide information that can be used to conserve Bahian cacao plants and applied in breeding programs to obtain more productive Bahian cacao with superior quality and tolerance to major diseases in tropical cacao plantations worldwide1012CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTĂFICO E TECNOLĂGICO - CNPQCOORDENAĂĂO DE APERFEIĂOAMENTO DE PESSOAL DE NĂVEL SUPERIOR - CAPESFUNDAĂĂO DE AMPARO Ă PESQUISA DO ESTADO DE SĂO PAULO - FAPESP620239/2008-5; 555432/2009-2PROCAD-NF20082008/52197-4; 2010/50033-4; 2013/08086-
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