Altered serological and cellular reactivity to H-2 antigens after target cell infection with vaccinia virus

MICE generate cytotoxic T lymphocytes (CTL) which are able to lyse virus infected target cells in vitro after infection with lymphocytic choriomeningitis virus (LCMV) and pox-viruses1−3. CTL kill syngeneic and semiallogenic infected cells but not allogenic infected targets. Target cell lysis in these systems seems to be restricted by H-2 antigens, especially by the K or D end of the major histocompatibility complex (MHC). In experiments where virus specific sensitised lymphocytes kill virus infected allogenic target cells4 the effector lymphocytes have not been characterised exactly. Recent investigations suggest that the active cell in this assay, at least in the measles infection, is a non-thymus derived cell (H. Kreth, personal communication). An H-2 restriction of cell mediated cytolysis (CMC) to trinitrophenol (TNP)-modified lymphocytes has also been described5. Zinkernagel and Doherty6 postulated that the CTL is directed against syngeneic H-2 antigens and viral antigens and they suggested an alteration of H-2 induced by the LCMV infection. Earlier7 we found a close topological relationship between H-2 antigens and the target antigen(s) responsible for CMC in the vaccinia system. Here we report experiments which were carried out to prove alteration of H-2 after infection of L-929 fibroblasts with vaccinia virus

Functional claudication distance: a reliable and valid measurement to assess functional limitation in patients with intermittent claudication

BACKGROUND: Disease severity and functional impairment in patients with intermittent claudication is usually quantified by the measurement of pain-free walking distance (intermittent claudication distance, ICD) and maximal walking distance (absolute claudication distance, ACD). However, the distance at which a patient would prefer to stop because of claudication pain seems a definition that is more correspondent with the actual daily life walking distance. We conducted a study in which the distance a patient prefers to stop was defined as the functional claudication distance (FCD), and estimated the reliability and validity of this measurement. METHODS: In this clinical validity study we included patients with intermittent claudication, following a supervised exercise therapy program. The first study part consisted of two standardised treadmill tests. During each test ICD, FCD and ACD were determined. Primary endpoint was the reliability as represented by the calculated intra-class correlation coefficients. In the second study part patients performed a standardised treadmill test and filled out the Rand-36 questionnaire. Spearman's rho was calculated to assess validity. RESULTS: The intra-class correlation coefficients of ICD, FCD and ACD were 0.940, 0.959, and 0.975 respectively. FCD correlated significantly with five out of nine domains, namely physical function (rho = 0.571), physical role (rho = 0.532), vitality (rho = 0.416), pain (rho = 0.416) and health change (rho = 0.414). CONCLUSION: FCD is a reliable and valid measurement for determining functional capacity in trained patients with intermittent claudication. Furthermore it seems that FCD better reflects the actual functional impairment. In future studies, FCD could be used alongside ICD and ACD

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

A Dominated Coupling From The Past algorithm for the stochastic simulation of networks of biochemical reactions

<p>Abstract</p> <p>Background</p> <p>In recent years, stochastic descriptions of biochemical reactions based on the Master Equation (ME) have become widespread. These are especially relevant for models involving gene regulation. Gillespie’s Stochastic Simulation Algorithm (SSA) is the most widely used method for the numerical evaluation of these models. The SSA produces exact samples from the distribution of the ME for finite times. However, if the stationary distribution is of interest, the SSA provides no information about convergence or how long the algorithm needs to be run to sample from the stationary distribution with given accuracy. </p> <p>Results</p> <p>We present a proof and numerical characterization of a Perfect Sampling algorithm for the ME of networks of biochemical reactions prevalent in gene regulation and enzymatic catalysis. Our algorithm combines the SSA with Dominated Coupling From The Past (DCFTP) techniques to provide guaranteed sampling from the stationary distribution. The resulting DCFTP-SSA is applicable to networks of reactions with uni-molecular stoichiometries and sub-linear, (anti-) monotone propensity functions. We showcase its applicability studying steady-state properties of stochastic regulatory networks of relevance in synthetic and systems biology.</p> <p>Conclusion</p> <p>The DCFTP-SSA provides an extension to Gillespie’s SSA with guaranteed sampling from the stationary solution of the ME for a broad class of stochastic biochemical networks.</p

Perspective from a Younger Generation -- The Astro-Spectroscopy of Gisbert Winnewisser

Gisbert Winnewisser's astronomical career was practically coextensive with the whole development of molecular radio astronomy. Here I would like to pick out a few of his many contributions, which I, personally, find particularly interesting and put them in the context of newer results.Comment: 14 pages. (Co)authored by members of the MPIfR (Sub)millimeter Astronomy Group. To appear in the Proceedings of the 4th Cologne-Bonn-Zermatt-Symposium "The Dense Interstellar Medium in Galaxies" eds. S. Pfalzner, C. Kramer, C. Straubmeier, & A. Heithausen (Springer: Berlin

Body image, body dissatisfaction and weight status in south asian children: a cross-sectional study

Background Childhood obesity is a continuing problem in the UK and South Asian children represent a group that are particularly vulnerable to its health consequences. The relationship between body dissatisfaction and obesity is well documented in older children and adults, but is less clear in young children, particularly South Asians. A better understanding of this relationship in young South Asian children will inform the design and delivery of obesity intervention programmes. The aim of this study is to describe body image size perception and dissatisfaction, and their relationship to weight status in primary school aged UK South Asian children. Methods Objective measures of height and weight were undertaken on 574 predominantly South Asian children aged 5-7 (296 boys and 278 girls). BMI z-scores, and weight status (underweight, healthy weight, overweight or obese) were calculated based on the UK 1990 BMI reference charts. Figure rating scales were used to assess perceived body image size (asking children to identify their perceived body size) and dissatisfaction (difference between perceived current and ideal body size). The relationship between these and weight status were examined using multivariate analyses. Results Perceived body image size was positively associated with weight status (partial regression coefficient for overweight/obese vs. non-overweight/obese was 0.63 (95% CI 0.26-0.99) and for BMI z-score was 0.21 (95% CI 0.10-0.31), adjusted for sex, age and ethnicity). Body dissatisfaction was also associated with weight status, with overweight and obese children more likely to select thinner ideal body size than healthy weight children (adjusted partial regression coefficient for overweight/obese vs. non-overweight/obese was 1.47 (95% CI 0.99-1.96) and for BMI z-score was 0.54 (95% CI 0.40-0.67)). Conclusions Awareness of body image size and increasing body dissatisfaction with higher weight status is established at a young age in this population. This needs to be considered when designing interventions to reduce obesity in young children, in terms of both benefits and harms

Robust Detection of Hierarchical Communities from Escherichia coli Gene Expression Data

Determining the functional structure of biological networks is a central goal of systems biology. One approach is to analyze gene expression data to infer a network of gene interactions on the basis of their correlated responses to environmental and genetic perturbations. The inferred network can then be analyzed to identify functional communities. However, commonly used algorithms can yield unreliable results due to experimental noise, algorithmic stochasticity, and the influence of arbitrarily chosen parameter values. Furthermore, the results obtained typically provide only a simplistic view of the network partitioned into disjoint communities and provide no information of the relationship between communities. Here, we present methods to robustly detect coregulated and functionally enriched gene communities and demonstrate their application and validity for Escherichia coli gene expression data. Applying a recently developed community detection algorithm to the network of interactions identified with the context likelihood of relatedness (CLR) method, we show that a hierarchy of network communities can be identified. These communities significantly enrich for gene ontology (GO) terms, consistent with them representing biologically meaningful groups. Further, analysis of the most significantly enriched communities identified several candidate new regulatory interactions. The robustness of our methods is demonstrated by showing that a core set of functional communities is reliably found when artificial noise, modeling experimental noise, is added to the data. We find that noise mainly acts conservatively, increasing the relatedness required for a network link to be reliably assigned and decreasing the size of the core communities, rather than causing association of genes into new communities.Comment: Due to appear in PLoS Computational Biology. Supplementary Figure S1 was not uploaded but is available by contacting the author. 27 pages, 5 figures, 15 supplementary file

The interplay of intrinsic and extrinsic bounded noises in genetic networks

After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a genetic network. The influence of intrinsic and extrinsic noises on genetic networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: $(i)$ the Michaelis-Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, $(ii)$ a model of enzymatic futile cycle and $(iii)$ a genetic toggle switch. In $(ii)$ and $(iii)$ we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possibile functional role of bounded noises

Stress related epigenetic changes may explain opportunistic success in biological invasions in Antipode mussels

Different environmental factors could induce epigenetic changes, which are likely involved in the biological invasion process. Some of these factors are driven by humans as, for example, the pollution and deliberate or accidental introductions and others are due to natural conditions such as salinity. In this study, we have analysed the relationship between different stress factors: time in the new location, pollution and salinity with the methylation changes that could be involved in the invasive species tolerance to new environments. For this purpose, we have analysed two different mussels’ species, reciprocally introduced in antipode areas: the Mediterranean blue mussel Mytilus galloprovincialis and the New Zealand pygmy mussel Xenostrobus securis, widely recognized invaders outside their native distribution ranges. The demetylathion was higher in more stressed population, supporting the idea of epigenetic is involved in plasticity process. These results can open a new management protocols, using the epigenetic signals as potential pollution monitoring tool. We could use these epigenetic marks to recognise the invasive status in a population and determine potential biopollutants