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Responsible Mechanism (responsible + mechanism)

Distribution by Scientific Domains

Life Sciences	50%

Selected Abstracts

Antigenic Variation in Ciliates: Antigen Structure, Function, Expression,

THE JOURNAL OF EUKARYOTIC MICROBIOLOGY, Issue 1 2007
MARTIN C. SIMON
ABSTRACT. In the past decades, the major focus of antigen variation research has been on parasitic protists. However, antigenic variation occurs also in free-living protists. The antigenic systems of the ciliates Paramecium and Tetrahymena have been studied for more than 100 yr. In spite of different life strategies and distant phylogenetic relationships of free-living ciliates and parasitic protists, their antigenic systems have features in common, such as the presence of repeated protein motifs and multigene families. The function of variable surface antigens in free-living ciliates is still unknown. Up to now no detailed monitoring of antigen expression in free-living ciliates in natural habitats has been performed. Unlike stochastic switching in parasites, antigen expression in ciliates can be directed, e.g. by temperature, which holds great advantages for research on the expression mechanism. Regulated expression of surface antigens occurs in an exclusive way and the responsible mechanism is complex, involving both transcriptional and post-transcriptional features. The involvement of homology-dependent effects has been proposed several times but has not been proved yet. [source]

Parsing the Effects of Binding, Signaling, and Trafficking on the Mitogenic Potencies of Granulocyte Colony-Stimulating Factor Analogues

BIOTECHNOLOGY PROGRESS, Issue 3 2003
Casim A. Sarkar
The pharmacodynamic potency of a therapeutic cytokine interacting with a cell-surface receptor can be attributed primarily to three central properties: [1] cytokine/receptor binding affinity, [2] cytokine/receptor endocytic trafficking dynamics, and [3] cytokine/receptor signaling. Thus, engineering novel or second-generation cytokines requires an understanding of the contribution of each of these to the overall cell response. We describe here an efficient method toward this goal in demonstrated application to the clinically important cytokine granulocyte colony-stimulating factor (GCSF) with a chemical analogue and a number of genetic mutants. Using a combination of simple receptor-binding and dose-response proliferation assays we construct an appropriately scaled plot of relative mitogenic potency versus ligand concentration normalized by binding affinity. Analysis of binding and proliferation data in this manner conveniently indicates which of the cytokine properties,binding, trafficking, and/or signaling,are contributing substantially to altered potency effects. For the GCSF analogues studied here, two point mutations as well as a poly(ethylene glycol) chemical conjugate were found to have increased potencies despite comparable or slightly lower affinities, and trafficking was predicted to be the responsible mechanism. A third point mutant exhibiting comparable binding affinity but reduced potency was predicted to have largely unchanged trafficking properties. Surprisingly, another mutant possessing an order-of-magnitude weaker binding affinity displayed enhanced potency, and increased ligand half-life was predicted to be responsible for this net beneficial effect. Each of these predictions was successfully demonstrated by subsequent measurements of depletion of these five analogues from cell culture medium. Thus, for the GCSF system we find that ligand trafficking dynamics can play a major role in regulating mitogenic potency. Our results demonstrate that cytokine analogues can exhibit pharmacodynamic behaviors across a diverse spectrum of "binding-potency space" and that our analysis through normalization can efficiently elucidate hypotheses for the underlying mechanisms for further dedicated testing. We have also extended the Black-Leff model of pharmacological agonism to include trafficking effects along with binding and signaling, and this model provides a framework for parsing the effects of these factors on pharmacodynamic potency. [source]

Identifying the Bond Responsible for the Fluorescence Modulation in an Amyloid Fibril Sensor

CHEMISTRY - A EUROPEAN JOURNAL, Issue 30 2010
Anvita Srivastava
Abstract An ultrafast intramolecular bond twisting process is known to be the responsible mechanism for the sensing activity of the extensively used amyloid fibril sensor thioflavin,T (ThT). However, it is not yet known which one of the two possible single bonds in ThT is actually involved in the twisting process. To resolve this fundamental issue, two derivatives of ThT have been designed and synthesized and subsequently their photophysical properties have been studied in different solvents. It is understood from the present study that the rotation around the central CC single bond, and not that around the CN single bond, is primarily responsible for the sensor activity of ThT. Detailed viscosity-dependent fluorescence studies revealed that the ThT derivative with restricted CN bond rotation acts as a better sensor than the derivative with free CN bond rotation. The better sensory activity is directly correlated with a shorter excited-state lifetime. Results obtained from the photophysical studies of the ThT derivatives have also been supported by the results obtained from quantum chemical calculations. [source]

Loeffler endocarditis: What have we learned?

AMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2007
Juan Benezet-Mazuecos
Loeffler endocarditis, eosinophilic endomyocardial disease or fibroplastic endocarditis appears to be a subcategory of the Hypereosinophilic syndrome in which the heart is predominantly involved. It is an uncommon myocardial disease, thought to be secondary to eosinophils damage, characterized by fibrous thickening of the endocardium of one or both ventricles, leading to apical obliteration and multiple cardiovascular complications. Despite all the efforts, the ultimate responsible mechanisms of this entity remain unresolved. Many theories have been raised trying to explain this phenomenon, but nowadays the enigma in relation to the different patterns of evolution continues. In this concise review we discuss the different pathophysiologic theories postulated and the management of the cardiovascular complications. Perhaps it will serve to assist in recognition of patients with the same condition around the world. Am. J. Hematol. 82:861,862, 2007. © 2007 Wiley-Liss, Inc. [source]