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Because a cell must adapt to different stresses and growth rates, its proteostasis system must too. How do cells detect and adjust proteome folding to different conditions? Here, we explore a biophysical cost-benefit principle, namely that the cell should keep its proteome as folded as possible at the minimum possible energy cost. This can be achieved by differential expression of chaperones-balancing foldases (which accelerate folding) against holdases (which act as parking spots). The model captures changes in the foldase-holdase ratio observed both within organisms during aging and across organisms of varying metabolic rates. This work describes a simple biophysical mechanism by which cellular proteostasis adapts to meet the needs of a changing growth environment.

Elevated levels of the protease inhibitor PAI-1 are well-known molecular markers of the Metabolic Syndrome. A hypothesis is presented those PAI-1 acts as a causative factor in the development of Metabolic Syndrome and its clinical sequelae.

Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance ([sup.1]H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows [greater than] 90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of [greater than] 90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins., Author(s): Joanne T. Brindle [1]; Henrik Antti [1]; Elaine Holmes [1]; George Tranter [1]; Jeremy K. Nicholson [1]; Hugh W.L. Bethell [2]; Sarah Clarke [2]; Peter M. Schofield [2]; Elaine [...]

The presence of active transforming growth factor (TGF)-beta in the vessel wall and in the circulation maintains the architecture of the vessel wall and prevent the migration and proliferation of smooth muscle cells (SMCs) that may cause atherogenesis. As long as there is TGF-beta activity, the vessel wall is protected from other independent risk factors. When TGF-beta activity is minimal, however, the brake on atherogenesis is released and the vascular SMCs will abate their gene expression pattern and develop susceptibility to inflammation and lipid uptake.

An inhibitory autocrine loop and the release of active transforming growth factor-beta (TGF-beta) result in the long population doubling time of vascular smooth muscle cells (VSMC). This was observed when a population doubling time of 70-85 hours for VSMC from adult human aortas were compared with 35 plus or minus hours for VSMC obtained from adult rat aortas. The population doubling time for human VSMC, reduced to 46 plus or minus 6 hours when neutralizing antibody, was added to TGF-beta.

Abstract Background Cellular infection with human immunodeficiency virus (HIV) both in vitro and in vivo requires a member of the chemokine receptor family to act as a co-receptor for viral entry. However, it is presently unclear to what extent the interaction of HIV proteins with chemokine receptors generates intracellular signals that are important for productive infection. Results In this study we have used a recently described family of chemokine inhibitors, termed BSCIs, which specifically block chemokine-induced chemotaxis without affecting chemokine ligands binding to their receptors. The BSCI termed Peptide 3 strongly inhibited CCR5 mediated HIV infection of THP-1 cells (83 ± 7% inhibition assayed by immunofluoresence staining), but had no effect on gp120 binding to CCR5. Peptide 3 did not affect CXCR4-dependent infection of Jurkat T cells. Conclusion These observations suggest that, in some cases, intracellular signals generated by the chemokine coreceptor may be required for a productive HIV infection.

Apolipoprotein(a) suppression of plasminogen activation inhibits the stimulation of transforming growth factor-beta (TGF-beta) in the aortic wall and serum of mice expressing human apolipoprotein(a) gene. The pathway of inhibition of the activation of TGF-beta, an autocrine inhibitor of human vascular smooth muscle cells (hVSMC), is vital for atherogenesis. These inhibitory effects are associated with VSMC activation.

Author(s): Joanne T. Brindle; Henrik Antti; Elaine Holmes; George Tranter; Jeremy K. Nicholson; Hugh W.L. Bethell; Sarah Clarke; Peter M. Schofield; Elaine McKilligin; David E. Mosedale; David J. Grainger Nat. [...]