Outside-in signaling in the chondrocyte. Nitric oxide disrupts fibronectin-induced assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling complex

Elevated levels of fibronectin (Fn) in articular cartilage have been linked to the progression of both rheumatoid and osteoarthritis. In this study, we examined intracellular events which follow ligation of Fn to its receptor, the integrin alpha5beta1. In addition, we examined the regulatory influence of nitric oxide on these events, since this free radical has been implicated in cartilage degradation. Exposure of chondrocytes to Fn-coated beads resulted in the circumferential clustering of the alpha5beta1 integrin receptor, which was accompanied by the subplasmalemmal assembly of a focal activation complex comprised of F-actin, the tyrosine kinase, focal adhesion kinase (FAK), the ras related G protein rho A, as well as tyrosine-phosphorylated proteins. Treatment with exogenous nitric oxide (NO) or catabolic cytokines which induce nitric oxide synthase blocked the assembly of F-actin, FAK, rho A and tyrosine-phosphorylated proteins while not affecting the total number of beads bound per cell nor the clustering of alpha5beta1 integrin. Use of a cGMP antagonist (Rp-8-Br cGMPS) or cGMP agonist (Sp-cGMPS) either abolished or mimicked the NO effect, respectively. Adherence of chondrocytes to fibronectin enhanced proteoglycan synthesis by twofold (vs. albumin). In addition, basic fibroblast growth factor (FGF) and insulin growth factor (IGF-1) induced proteoglycan synthesis in chondrocytes adherent to Fn but not albumin suggesting a costimulatory signal transduced by alpha5betal and the FGF receptor. Both constitutive and FGF stimulated proteoglycan synthesis were completely inhibited by nitric oxide. These data indicate that the ligation of alpha5beta1 in the chondrocyte induced the intracellular assembly of an activation complex comprised of the cytoplasmic tail of alpha5beta1 integrin, actin, and the signaling molecules rho A and FAK. We show that NO inhibits the assembly of the intracellular activation complex and the synthesis of proteoglycans, but has no effect on the extracellular aggregation of alpha5beta1 integrin. These observations provide a basis by which nitric oxide can interfere with chondrocyte functions by affecting chondrocyte-matrix interactions.     

Performance of standards: intercomparison, treatment of correlations, detection of laboratory offsets and outliers, and long-term assessment of an ensemble of standards

This paper discusses some techniques for judging the performance of artefact standards. In order of increasing time scales, these are: a cross-comparison design, a means of removing reference-induced correlations, detection of laboratory offsets by travelling standards and a graphical means of assessment in the long term.     

Pediatric AIDS prognosis using somatic growth velocity

OBJECTIVE: To describe the natural history of somatic growth in HIV infection by constructing age-specific growth velocity norms and to assess specific prognostic information available using these norms. DESIGN: Observations on 1338 HIV-infected children aged 3 months to 15 years who participated in one of four US clinical trials of pediatric anti-HIV therapies were pooled; baseline growth velocity data were obtained using the first 6 months of observation for each child. METHODS: Distributions of physical growth velocities in HIV-infected children in the Pediatric AIDS Clinical Trials Group were computed. Statistical smoothing of growth histories was employed to derive velocity estimates, and quantile regression analysis of growth velocities was performed to allow comparisons of growth rates in age- and gender-heterogeneous cohorts in the context of HIV infection. The quantile regressions provide corrected z-scores for growth velocity that appropriately compare HIV-infected children with one another for the purpose of distinguishing more from less favorable prognoses. RESULTS: Consistent deficits in growth velocity amongst HIV-infected children were revealed when compared with the Fels Institute velocity standards. Approximately 33% of height (and 20% of weight) age- and sex-corrected velocity measurements obtained in the first 6 months of clinical trial participation lay beneath the corresponding third percentiles of the Fels reference distributions, which are commonly regarded as critical indicators of growth failure. Proportional hazards regression tests indicated that both weight and height velocity contributed significant information on the risk of death among children with AIDS after adjusting for antiretroviral therapy received, CD4 cell counts, and age at trial enrollment. Comparing subjects who differ in initial weight velocity by one age- and sex-corrected SD, the relative hazard of death was 0.63 (95% confidence interval, 0.55-0.72; P < or = 0.0001) in favor of the child with greater weight velocity, controlling for antiretroviral therapy received, age and CD4 cell count at baseline. The analogous hazard ratio for height velocity was 0.68 (95% confidence interval, 0.57-0.79; P < or = 0.0001). CONCLUSIONS: Suitably normalized growth velocities are informative and inexpensive criteria for pediatric AIDS prognosis; the growth velocity distributions presented will be useful for comparing growth effects of new therapeutic strategies to those of single and combination antiretrovirals employed for maintenance of pediatric HIV infection in the mid-1990s.     

Web Thermo Tables – an On-Line Version of the TRC Thermodynamic Tables

It has long been understood that availability of thermophysical and thermochemical property data is vital to scientific research and industrial design. For over 65 years, the Thermodynamics Research Center (TRC) has been publishing tables of critically evaluated data covering physical and thermodynamic properties of pure compounds, TRC Tables-Hydrocarbons and TRC Tables-Non-Hydrocarbons. Over their long history, the TRC Tables have always been valued as a reputable source of evaluated thermophysical and thermodynamic data. To facilitate more flexible, convenient, and up-to-date access to the data, here, we present the release of the on-line version of the TRC tables, Web Thermo Tables (WTT). Presently, WTT contains data for 7838 compounds and over 950,000 evaluated data points. The tabulated information includes critical properties, vapor pressures and boiling temperatures, phase transition properties, volumetric properties, heat capacities and derived properties, transport properties, reaction state-change properties, as well as index of refraction, surface tension, and speed of sound. Various search options and data plotting capabilities are provided via the Web interface. WTT are distributed through the NIST Standard Reference Data Program [1].     

Local milieu and innovations: Some empirical results

. Industrial innovations constitute a major factor in fostering the expansion of industrial activities and, consequently, regional growth. Innovations are closely tied to variables both internal and external to the structure and operation of the firm. The latter variables have hardly ever been investigated empirically. The current study utilizes data collected by means of a thorough personal interview of a representative sample of firms belonging to the three fastest-growing industries in Israel: Electronics, Plastics and Metals. All the firms are located in the Northern region of Israel and cover three different sub-regions: metropolitan core, intermediate zone and periphery. The paper reports an attempt to identify and quantify external factors clustered under the term, “local innovation milieu,” and to analyze their effect on the rate of industrial innovation. More specifically, the present study describes the construction of alternative measures of industrial agglomeration economies and their effect on the probability of a firm‘s belonging to different industrial branches when it comes to innovation. The results show that the size of the industry, as measured by the total number of employees, is the best explanatory measure of agglomeration economies in a particular sub-region. Agglomeration economies are significantly responsible for the increase in the rate of a firm‘s innovation potential in the Electronics industry. In the Plastics industry, however, no significant effect of agglomeration economies on the rate of innovation is detected; and in the Metals industry, only a marginal effect is felt.     

Hematopoiesis during Ontogenesis,Adult Life,and Aging

In the bone marrow of vertebrates, two types of stem cells coexist—hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the mature blood cells, while MSCs give rise to stromal cells that form a niche for HSCs and regulate the process of hematopoiesis. The studies of hematopoiesis were initially based on morphological observations, later extended by the use of physiological methods, and were subsequently augmented by massive application of sophisticated molecular techniques. The combination of these methods produced a wealth of new data on the organization and functional features of hematopoiesis in the ontogenesis of mammals and humans. This review summarizes the current views on hematopoiesis in mice and humans, discusses the development of blood elements and hematopoiesis in the embryo, and describes how the hematopoietic system works in the adult organism and how it changes during aging.     

Zero-state Markov switching count-data models: An empirical assessment

In this study, a two-state Markov switching count-data model is proposed as an alternative to zero-inflated models to account for the preponderance of zeros sometimes observed in transportation count data, such as the number of accidents occurring on a roadway segment over some period of time. For this accident-frequency case, zero-inflated models assume the existence of two states: one of the states is a zero-accident count state, which has accident probabilities that are so low that they cannot be statistically distinguished from zero, and the other state is a normal-count state, in which counts can be non-negative integers that are generated by some counting process, for example, a Poisson or negative binomial. While zero-inflated models have come under some criticism with regard to accident-frequency applications - one fact is undeniable - in many applications they provide a statistically superior fit to the data. The Markov switching approach we propose seeks to overcome some of the criticism associated with the zero-accident state of the zero-inflated model by allowing individual roadway segments to switch between zero and normal-count states over time. An important advantage of this Markov switching approach is that it allows for the direct statistical estimation of the specific roadway-segment state (i.e., zero-accident or normal-count state) whereas traditional zero-inflated models do not. To demonstrate the applicability of this approach, a two-state Markov switching negative binomial model (estimated with Bayesian inference) and standard zero-inflated negative binomial models are estimated using five-year accident frequencies on Indiana interstate highway segments. It is shown that the Markov switching model is a viable alternative and results in a superior statistical fit relative to the zero-inflated models.