Branched-chain amino acid biosynthesis in Salmonella typhimurium: a quantitative analysis

We report here the first quantitative study of the branched-chain amino acid biosynthetic pathway in Salmonella typhimurium LT2. The intracellular levels of the enzymes of the pathway and of the 2-keto acid intermediates were determined under various physiological conditions and used for estimation of several of the fluxes in the cells. The results led to a revision of previous ideas concerning the way in which multiple acetohydroxy acid synthase (AHAS) isozymes contribute to the fitness of enterobacteria. In wild-type LT2, AHAS isozyme I provides most of the flux to valine, leucine, and pantothenate, while isozyme II provides most of the flux to isoleucine. With acetate as a carbon source, a strain expressing AHAS II only is limited in growth because of the low enzyme activity in the presence of elevated levels of the inhibitor glyoxylate. A strain with AHAS I only is limited during growth on glucose by the low tendency of this enzyme to utilize 2-ketobutyrate as a substrate; isoleucine limitation then leads to elevated threonine deaminase activity and an increased 2-ketobutyrate/2-ketoisovalerate ratio, which in turn interferes with the synthesis of coenzyme A and methionine. The regulation of threonine deaminase is also crucial in this regard. It is conceivable that, because of fundamental limitations on the specificity of enzymes, no single AHAS could possibly be adequate for the varied conditions that enterobacteria successfully encounter.     

G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins

G-protein-coupled receptors (GPCRs) represent a large family of proteins that transduce extracellular signals to the interior of cells. Signalling through these receptors rapidly desensitized primarily as the consequence of receptor phosphorylation, but receptor sequestration and downregulation can also contribute to this process. Two families of serine/threonine kinases, second messenger dependent protein kinases and receptor-specific G-protein-coupled receptor kinases (GRKs), phosphorylate GPCRs and thereby contribute to receptor desensitization. Receptor-specific phosphorylation of GPCRs promotes the binding of cytosolic proteins referred to as arrestins, which function to further uncouple GPCRs from their heterotrimeric G-proteins. To date, the GRK protein family consists of six members, which can be further classified into subgroups according to sequence homology and functional similarities. The arrestin protein family also comprises six members, which are subgrouped on the basis of sequence homology and tissue distribution. While the molecular mechanisms contributing to GPCR desensitization are fairly well characterized, little is known about the mechanism(s) by which GPCR responsiveness is reestablished, other than that receptor sequestration (internalization) might be involved. The goal of the present review is to overview current understanding of the regulation of GPCR responsiveness. In particular, we will review new evidence suggesting a pleiotropic role for GRKs and arrestins in the regulation of GPCR responsiveness. GRK-mediated phosphorylation and arrestin binding are not only involved in the functional uncoupling of GPCRs but they are also intimately involved in promoting GPCR sequestration and as such likely play an important role in mediating the subsequent resensitization of GPCRs.     

Counselor and therapist gender bias? More questions than answers.

Examined inconsistent evidence for counselor and therapist gender bias in empirical investigations and literature reviews. Three sets of possible explanations for inconsistent findings are proposed and illustrated with examples: conceptual and definitional problems with the concept of gender bias; methodological shortcomings in key studies in this area; and the influence of researchers' beliefs and values on interpretation of research findings. We suggest that any conclusions about counselor and therapist gender bias are premature, that existing research must be reevaluated in light of the limitations that have been identified, and that future research that avoids these pitfalls must be conducted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

InterPlay: Horizontal Scale-Up and Transition to Design in Scenario-Based Programming

We describe InterPlay, a simulation engine coordinator that supports cooperation and interaction of multiple simulation and execution tools, thus helping to scale up the design and development cycle of reactive systems. InterPlay involves a number of related ideas. In the first, we concentrate on the interobject design approach involving live sequence charts (LSCs) and its support tool, the Play-Engine, enabling multiple Play-Engines to run in cooperation. This makes possible the distributed design of large-scale systems by different teams, as well as the refinement of parts of a system using different Play-Engines. The second idea concerns combining the interobject approach with the more conventional intraobject approach, involving, for example, statecharts and Rhapsody. InterPlay makes it possible to run the Play-Engine in cooperation with Rhapsody, and is very useful when some system objects have clear and distinct internal behavior, or in an iterative development process where the design is implementation-oriented and the ultimate goal is to end up with an intraobject implementation. Finally, we have expanded the Play-Engine's ability to delegate some of the system's functionality to complex GUIs. This enables beneficial interaction with "smart” GUIs that have built-in behavior of their own, and which are more naturally implemented in code.     

A lower bound on the integral of the nonlinear filtering error

A lower bound on the nonlinear filtering error derived on the basis of information theoretic considerations will be proposed. The tightness of this bound will be shown in an example.     

Immunomodulation of murine experimental SLE-like disease by interferon-gamma

The objective of this study was to assess the impact of murine recombinant IFN-gamma and anti-IFN-gamma monoclonal antibody on the BALB/c mice experimental model of lupus. BALB/c female mice were immunized with a human anti-DNA antibody that carries the 16/6 idiotype. These mice were divided into several therapeutic groups according to different treatment strategies; injection with mouse recombinant IFN-gamma, anti-IFN-gamma mAb, phosphate-buffered saline (PBS), irrelevant mouse IgG and control groups that were neither treated nor immunized with the human anti-DNA antibody. The administration of IFN-gamma, intensified the degree of clinical, histological and serological parameters in this model of BALB/c murine lupus. This immunomanipulation decreased the mice longevity. All the laboratory parameters reflected acceleration of the disease in the IFN-gamma treated group as an elevated sedimentation rate, decreased white blood cell count and the development of massive proteinuria. One month after the boost injection, all the mice that were immunized with the anti-DNA antibody, developed high titers of autoantibodies; however, following an additional month, their levels declined in the IFN-gamma treated group. These findings were in concordance with an increased glomerular deposition of immune complexes in the IFN-gamma treated mice. IFN-gamma upregulated the levels of IL-4 and increased the number of IL-4 and IL-6 secreting splenocytes. In conclusion IFN-gamma administration can aggravate the clinical and laboratory outcome of 16/6 id induced lupus in BALB/c mice.     

Tiefenorientierte Pumpversuche zur Bestimmung der hydraulischen Anisotropie in einem geschichteten Grundwasserleiter

Grundwasser - Die horizontale Schichtung von Sedimentkörpern bewirkt, dass die effektive hydraulische Durchlässigkeit eines sedimentären Grundwasserleiters in horizontaler Richtung...