Elevated formation of pyridinoline cross-links by profibrotic cytokines is associated with enhanced lysyl hydroxylase 2b levels

AbstractThe hallmark of fibrosis is the excessive accumulation of collagen. The deposited collagen contains increased pyridinoline cross-link levels due to an overhydroxylation of lysine residues within the collagen telopeptides. Lysyl hydroxylase 2b (LH2b) is the only lysyl hydroxylase consistently up-regulated in several forms of fibrosis, suggesting that an enhanced LH2b level is responsible for the overhydroxylation of collagen telopeptides. The present paper reports the effect of profibrotic cytokines on the expression of collagen, lysyl hydroxylases and lysyl oxidase in normal human skin fibroblasts, as well as the effect on pyridinoline formation in the deposited matrix. All three isoforms of TGF-β induce a substantial increase in LH2b mRNA levels, also when expressed relatively to the mRNA levels of collagen type I α2 (COL1A2). The TGF-β isoforms also clearly influence the collagen cross-linking pathway, since higher levels of pyridinoline cross-links were measured. Similar stimulatory effects on LH2b/COL1A2 mRNA expression and pyridinoline formation were observed for IL-4, activin A, and TNF-α. An exception was BMP-2, which has no effect on LH2b/COL1A2 mRNA levels nor on pyridinoline formation. Our data show for the first time that two processes, i.e., up-regulation of LH2b mRNA levels and increased formation of pyridinoline cross-links, previously recognized to be inherent to fibrotic processes, are induced by various profibrotic cytokines

Quantum Locality

It is argued that while quantum mechanics contains nonlocal or entangled states, the instantaneous or nonlocal influences sometimes thought to be present due to violations of Bell inequalities in fact arise from mistaken attempts to apply classical concepts and introduce probabilities in a manner inconsistent with the Hilbert space structure of standard quantum mechanics. Instead, Einstein locality is a valid quantum principle: objective properties of individual quantum systems do not change when something is done to another noninteracting system. There is no reason to suspect any conflict between quantum theory and special relativity.Comment: Introduction has been revised, references added, minor corrections elsewhere. To appear in Foundations of Physic

Automatic runtime validation and correction of the navigational design of web sites

Essential to an audience driven website design philosophy is the organization of information and functionality according to the requirements of the different audience classes. However, at design time, it is often difficult to correctly assess the different needs and requirements of the different prospective users of a website. This may result in a non-optimal navigation structure, which will decrease the usability of the website. In this paper, we describe how to correct, at run-time and automatically, possible flaws in the design resulting from incomplete requirement assessment, using adaptive behavior. By observing the browsing behavior of the users, the requirements for the different users are validated and the website is adapted according to adaptation specifications made by the designer. These specifications express when and how the website needs to be adapted and are expressed using an Adaptation Specification Language. The work is presented in the context of an audience driven design method but we also elaborate shortly on the applicability of the technique in general

Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon

Fibrosis is characterized by an excessive accumulation of collagen which contains increased levels of pyridinoline cross-links. The occurrence of pyridinolines in the matrix is an important criterion in assessing the irreversibility of fibrosis, which suggests that collagen containing pyridinoline cross-links significantly contributes to the unwanted collagen accumulation. Pyridinoline cross-links are derived from hydroxylated lysine residues located within the collagen telopeptides (hydroxyallysine pathway). Here, we have investigated whether the increase in hydroxyallysine-derived cross-links in fibrotic conditions can be ascribed to an increased expression of one of the lysyl hydroxylases (LH1, LH2 with its splice variants LH2a and LH2b, or LH3) and/or to an increased expression of lysyl oxidase (LOX). In fibroblast cultures of hypertrophic scars, keloid and palmar fascia of Dupuytren's patients, as well as in activated hepatic stellate cells, increased levels of LH2b mRNA expression were observed. Only minor amounts of LH2a were present. In addition, no consistent increase in the mRNA expression levels of LH1, LH3 and LOX could be detected, suggesting that LH2b is responsible for the overhydroxylation of the collagen telopeptides and the concomitant formation of pyridinolines as found in the collagen matrix deposited in long-term cultures by the same fibrotic cells. This is consistent with our previous observation that LH2b is a telopeptide lysyl hydroxylase. We conclude that the increased expression of LH2b, leading to the increased formation of pyridinoline cross-links, is present in a wide variety of fibrotic disorders and thus represents a general fibrotic phenomenon

On the Discrepancy Measures for the Optimal Equal Probability Partitioning in Bayesian Multivariate Micro-Aggregation

Asymptotic theory, Convex partition, Discrepancy measures, Identity protection, Multivariate micro-aggregation, Probabilistic distances,