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Interplay between ADAMTS13 and von Willebrand factor in inherited and acquired thrombotic microangiopathies.

The presence of unusually large multimers of von Willebrand factor (VWF) is thought to be a major pathogenic factor for thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is a protease that regulates the multimeric size and function of VWF by cleaving VWF. Hence, congenital or acquired deficiency of ADAMTS13 causes life-threatening illness of TTP. Mutations in the ADAMTS13 gene cause inherited TTP, and the development of autoantibodies that inhibit ADAMTS13 activity frequently are associated with acquired TTP. ADAMTS13 consists of 1,427 amino acid residues and is composed of multiple structural and functional domains, containing a signal peptide, a propeptide, a reprolysin-like metalloprotease domain, a disintegrin-like domain, a thrombospondin type-1 (Tsp1) motif, a cysteine-rich domain, a spacer domain, seven additional Tsp1 repeats, and two CUB domains. In particular, the cysteine-rich/spacer domains are essential for VWF cleavage and are the principal epitopes recognized by autoantibodies in patients with acquired TTP. Therefore, it is likely that these domains are involved in the recognition and binding of ADAMTS13 to VWF. ADAMTS13 circulates in the blood in an active state, and efficiently cleaves unfold form of VWF induced under shear stress caused by blood flow, preventing the accumulation of pathogenic unusually large VWF multimers (ULVWF). Thus, ADAMTS13 helps maintain vascular homeostasis by preventing the excess thrombus formation.

ADAM Proteins↗

Bulimia Nervosa and Diabetes Mellitus: A Dangerous Interplay Producing Accelerated Complications.

A combination of bulimia and diabetes represents special clinical circumstances for both the patient and clinician. This chapter addresses the complicated interactions that exist between these two conditions and reviews the literature regarding effects on worsening of both the bulimia and diabetes by the concommitant condition and the impact that these two diseases have on each other relative to outcome. Specific treatment interventions and systems for control of blood sugar are reviewed, as are the psychological issues experienced by bulimic patients who also suffer from Type 1 diabetes mellitus.

Journal Article↗

[Coronaro-myocardial interplay determining the instantaneous mean ventricular shape (author's transl)].

A working hypothesis on the mechanism of diastolic chamber expansion based on functional anatomy and physiology is developed. It should be a major determinant of the momentary average chamber width. The sum of all intramyocardial fluid-filled spaces and the myocardium itself are considered in the working hypothesis as the hydraulic medium of a process which can be summarised under the term "cavernous body mechanism". The most important factor of this hydraulic system should represent the intramural fluid volume (hydraulic medium) and the contractile-elastic tension development in the transmural direction of the chamber wall. Morphological analysis of myocardial structure shows that an endoepicardial direction of force in the myocardial net can be recognised. The "motor" of circular fibres of the middle layer is surrounded by the spiral course of the fibres of the inner and outer layers of the chamber wall (uvula mechanism). It is interwoven by very dense bifurcating myocardial fibres (structural principle of the tongue). By these means, the width of the chamber cone is influenced decisively by an active decrease in wall thickness. The coronary perfusion pressure is thought to have a chamber dilating influence in the sense of a "cavernous body mechanism". The hypothesis presented helps us to understand pathological chamber dilation secondary to transmural myocardial fibrosis. Such a narrow functional coronary-myocardial interaction gives the myocardium two functions; besides haemodynamic pumping, the cardial muscle must function as an internal antagonist to favour diastolic chamber dilation.

Animals↗

The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia.

Recently, high-dose factor VIIa has been used to correct bleeding in patients with various thrombocytopathias including Glanzmann's thrombasthenia, Bernard-Soulier syndrome, and uremia. High-dose factor VIIa is postulated to act on platelets in the absence of tissue factor to activate factors IX and X and thus enhance thrombin generation. This enhanced thrombin generation might help provide hemostasis in patients with thrombocytopathias through several mechanisms. Enhanced thrombin generation would provide a strong signal for recruitment of other platelets. Also, enhanced fibrin deposition might provide mechanisms for bypassing the specific defect in thrombocytopathias. Thus, platelets from a patient with Bernard-Soulier syndrome might associate with fibrin by a glycoprotein IIb-IIIa-mediated mechanism. Also, platelets from a patient with Glanzmann's thrombasthenia might associate with fibrin through von Willebrand factor-mediated interactions with glycoprotein Ib-V-IX. Finally, enhanced thrombin generation on platelets would mean that fewer platelets are required for hemostasis.

Blood Platelet Disorders↗

Exercise as a stress model and the interplay between the hypothalamus-pituitary-adrenal and the hypothalamus-pituitary-thyroid axes.

Exercise represents a physical stress that challenges homeostasis. In response to this stressor, the autonomic nervous system and hypothalamus-pituitary-adrenal axis are known to react and participate in the maintenance of homeostasis and the development of physical fitness. This includes elevation of cortisol and catecholamines in plasma. However, physical conditioning is associated with a reduction in pituitary-adrenal activation in response to exercise. On the other hand, highly trained athletes exhibit chronic mild hypercortisolism at baseline that may be an adaptive change to chronic exercise. In addition the proinflammatory cytokine, IL-6 is also activated, probably via catecholamines. On the other hand, the stress of chronic exercise induces certain changes to the thyroid axis. Peripheral thyroid hormone metabolism suppression is observed, and the result is a hormonal status similar to that of euthyroid sick syndrome (ESS), with suppression of T3 and elevation of rT3 plasma levels. One mechanism proposed involves exercise-activated pathways participating in the pathogenesis of ESS. This is realized through norepinephrine's activation of NF-kappaB. Neuroendocrine response to exercise stress involves activation of NF-kappaB resulting in inactivation of T3-dependent 5'-deiodinase gene expression and enzyme activity. Thus, ESS is generated in the periphery. On the other hand, activation and nuclear translocation of NF-kappaB leads to increased transcription of proinflammatory genes responsible for the expression of proinflammatory cytokines such as TNF-alpha and IL-6. These cytokines could activate cortisol, which in turn inhibits NF-kappaB activation through IkappaB and finally shuts down this cycle.

Animals↗

Interplay of ionic and structural heterogeneity on functional action potential duration gradients: Implications for arrhythmogenesis.

Action potential duration (APD) dispersion in the heart is governed by the underlying cellular architecture and the spatial distribution of the membrane properties. Understanding the contribution of each factor is important in designing more effective methods for the control of arrhythmias. Recent experimental studies have shown that the insertion of structural barriers in ionically heterogeneous tissue facilitates the formation of unidirectional block and discordant alternans. In this work, computational modeling is used to examine the effect of internal obstacles on the formation of functional APD gradients in ionically heterogeneous tissue. Intrinsic APD differences are introduced by assigning two discrete cell types to each half of a square domain. The combined effect of structural and ionic heterogeneities is shown to produce gradients in APD that are oblique to both the intrinsic gradients in APD and the physical boundary. Simulation results are presented that show that the magnitude and spatial extent of the subsequent APD gradients are modulated by the size and orientation of the obstacle, the degree of anisotropy, and the location of the pacing site. Long, thin internal obstacles are found to produce the greatest dispersion in APD. The combination of internal obstacles and ionic heterogeneities is shown to produce a substrate for re-entrant excitation following a pair of near threshold point stimuli. (c) 2002 American Institute of Physics.

Journal Article↗

Interplay between shear flow and elastic deformations in liquid crystals.

We study shear flow in liquid crystal cells with elastic deformations using a lattice Boltzmann scheme that solves the full, three-dimensional Beris-Edwards equations of hydrodynamics. We consider first twisted and hybrid aligned nematic cells, in which the deformation is imposed by conflicting anchoring at the boundaries. We find that backflow renders the velocity profile non Newtonian, and that the director profile divides into two regions characterized by different director orientations. We next consider a cholesteric liquid crystal, in which a twist deformation is naturally present. We confirm the presence of secondary flow for small shear rates, and are able to follow the dynamical pathway of shear-induced unwinding, for higher shear rates. Finally, we analyze how the coupling between shear and elastic deformation can affect shear banding in an initially isotropic phase. We find that for a nematic liquid crystal, elastic distortions may cause an asymmetry in the dynamics of band formation, whereas for a cholesteric, shear can induce twist in an initially isotropic sample.

Journal Article↗

Interplay of secondary structures and side-chain contacts in the denatured state of BBA1.

The denatured state of a miniprotein BBA1 is studied under the native condition with the AMBER/Poisson-Boltzmann energy model and with the self-guided enhanced sampling technique. Forty independent trajectories are collected to sample the highly diversified denatured structures. Our simulation data show that the denatured BBA1 contains high percentage of native helix and native turn, but low percentage of native hairpin. Conditional population analysis indicates that the native helix formation and the native hairpin formation are not cooperative in the denatured state. Side-chain analysis shows that the native hydrophobic contacts are more preferred than the non-native hydrophobic contacts in the denatured BBA1. In contrast, the salt-bridge contacts are more or less nonspecific even if their populations are higher than those of hydrophobic contacts. Analysis of the trajectories shows that the native helix mostly initiates near the N terminus and propagates to the C terminus, and mostly forms from 3(10)-helix/turn to alpha helix. The same analysis shows that the native turn is important but not necessary in its formation in the denatured BBA1. In addition, the formations of the two strands in the native hairpin are rather asymmetric, demonstrating the likely influence of the protein environment. Energetic analysis shows that the native helix formation is largely driven by electrostatic interactions in denatured BBA1. Further, the native helix formation is associated with the breakup of non-native salt-bridge contacts and the accumulation of native salt-bridge contacts. However, the native hydrophobic contacts only show a small increase upon the native helix formation while the non-native hydrophobic contacts stay essentially the same, different from the evolution of hydrophobic contacts observed in an isolated helix folding.

Biophysical Phenomena↗

Polymer adsorption onto random planar surfaces: interplay of polymer and surface correlations.

We study the adsorption of homogeneous or heterogeneous polymers onto heterogeneous planar surfaces with exponentially decaying site-site correlations, using a variational reference system approach. As a main result, we derive simple equations for the adsorption-desorption transition line. We show that it is preferable to have a small amount of strongly adsorbing sites or monomers rather than a greater amount of weakly adsorbing ones. The results are discussed with respect to their implications for the physics of molecular recognition.

Journal Article↗

Remarkable interplay of electron correlation and relativity in the photodetachment spectrum of PtCl(6)2-.

In this work we calculate the photoelectron spectrum of the PtCl(6) (2-) dianion by application of the recently developed third-order Dirac-Hartree-Fock implementation of the one-particle propagator technique allowing for a consistent treatment of spin-orbit and scalar relativistic effects together with electron correlation. For PtCl(6) (2-) a gas phase photoelectron spectrum is available showing clearly discernible structures not reproducible by a nonrelativistic or purely scalar-relativistic computation. A population analysis of the valence orbitals allows for an assignment of the photoelectron peaks and reveals the strong influence of relativity in combination with electron correlation.

Journal Article↗

Simulation of a complex spectrum: interplay of five electronic states and 21 vibrational degrees of freedom in C5H4 +.

Using a five-state, all-mode vibronic coupling model Hamiltonian derived in a previous publication [A. Markmann et al., J. Chem. Phys. 122, 144320 (2005)], we have calculated the photoelectron spectrum of the pentatetraene cation in the neighborhood of the B (2)E state, which can be represented with charge-localized components. To this end, quantum nuclear dynamics calculations were performed using the multiconfiguration time-dependent Hartree method, taking all 21 vibrational normal modes into account. Compared to experiment, the main features are reproduced but higher accuracy experiments are necessary to gauge the accuracy of the predictions for the vibronic progressions at the rising flank of the spectrum.

Journal Article↗

Frustration and hydrophobicity interplay in protein folding and protein evolution.

A lattice model is used to study mutations and compacting effects on protein folding rates and folding temperature. In the context of protein evolution, we address the question regarding the best scenario for a polypeptide chain to fold: either a fast nonspecific collapse followed by a slow rearrangement to form the native structure or a specific collapse from the unfolded state with the simultaneous formation of the native state. This question is investigated for optimized sequences, whose native state has no frustrated contacts between monomers, and also for mutated sequences, whose native state has some degree of frustration. It is found that the best scenario for folding may depend on the amount of frustration of the native structure. The implication of this result on protein evolution is discussed.

Algorithms↗

The interplay between discrete noise and nonlinear chemical kinetics in a signal amplification cascade.

We used various analytical and numerical techniques to elucidate signal propagation in a small enzymatic cascade which is subjected to external and internal noises. The nonlinear character of catalytic reactions, which underlie protein signal transduction cascades, renders stochastic signaling dynamics in cytosol biochemical networks distinct from the usual description of stochastic dynamics in gene regulatory networks. For a simple two-step enzymatic cascade which underlies many important protein signaling pathways, we demonstrated that the commonly used techniques such as the linear noise approximation and the Langevin equation become inadequate when the number of proteins becomes too low. Consequently, we developed a new analytical approximation, based on mixing the generating function and distribution function approaches, to the solution of the master equation that describes nonlinear chemical signaling kinetics for this important class of biochemical reactions. Our techniques work in a much wider range of protein number fluctuations than the methods used previously. We found that under certain conditions the burst phase noise may be injected into the downstream signaling network dynamics, resulting possibly in unusually large macroscopic fluctuations. In addition to computing first and second moments, which is the goal of commonly used analytical techniques, our new approach provides the full time-dependent probability distributions of the colored non-Gaussian processes in a nonlinear signal transduction cascade.

Cytosol↗