Tuning immune tolerance with vasoactive intestinal peptide: a new therapeutic approach for immune disorders

The induction of immune tolerance is essential for the maintenance of immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure self-tolerance, including central clonal deletion, cytokine deviation and induction of regulatory T cells. Identifying the factors that regulate these processes is crucial for the development of new therapies of autoimmune diseases and transplantation. The vasoactive intestinal peptide (VIP) is a well-characterized endogenous anti-inflammatory neuropeptide with therapeutic potential for a variety of immune disorders. Here, we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors.     

Path tortuosity of Eurasian badgers (<Emphasis Type="Italic">Meles meles</Emphasis>) in a heterogeneous Mediterranean landscape

Movement is the process by which individual organisms are displaced over time to eat, reproduce and defend resources. Fractal analysis is a technique used to study animal movement that measures spatial complexity of path tortuosity; here, we apply it to characterize the movement patterns of the Eurasian badger (Meles meles) in a Mediterranean landscape. We calculated path tortuosity overall and seasonally, and for individuals of different sexes and social groups. The influence of variables related to badgers’ resources (food, shelter, water), human infra-structures and weather conditions were analysed with respect to the tortuosity of each badger’s path. A total of 55 search paths from six badgers were considered for this study. Although badgers generally displayed convoluted movement, there were two exceptions: (a) males overall and (b) all badgers in summer; for both, movements had a lower fractal value, i.e. were less tortuous. The convoluted movement pattern generally observed is probably adapted to the clumped distribution of food in the study area. Nevertheless, our results suggest that the use of dens and latrines were the principal determinants of tortuosity of badgers’ paths while foraging.     

Malleable applications for scalable high performance computing

Iterative applications are known to run as slow as their slowest computational component. This paper introduces malleability, a new dynamic reconfiguration strategy to overcome this limitation. Malleability is the ability to dynamically change the data size and number of computational entities in an application. Malleability can be used by middleware to autonomously reconfigure an application in response to dynamic changes in resource availability in an architecture-aware manner, allowing applications to optimize the use of multiple processors and diverse memory hierarchies in heterogeneous environments. The modular Internet Operating System (IOS) was extended to reconfigure applications autonomously using malleability. Two different iterative applications were made malleable. The first is used in astronomical modeling, and representative of maximum-likelihood applications was made malleable in the SALSA programming language. The second models the diffusion of heat over a two dimensional object, and is representative of applications such as partial differential equations and some types of distributed simulations. Versions of the heat application were made malleable both in SALSA and MPI. Algorithms for concurrent data redistribution are given for each type of application. Results show that using malleability for reconfiguration is 10 to 100 times faster on the tested environments. The algorithms are also shown to be highly scalable with respect to the quantity of data involved. While previous work has shown the utility of dynamically reconfigurable applications using only computational component migration, malleability is shown to provide up to a 15% speedup over component migration alone on a dynamic cluster environment. This work is part of an ongoing research effort to enable applications to be highly reconfigurable and autonomously modifiable by middleware in order to efficiently utilize distributed environments. Grid computing environments are becoming increasingly heterogeneous and dynamic, placing new demands on applications’ adaptive behavior. This work shows that malleability is a key aspect in enabling effective dynamic reconfiguration of iterative applications in these environments.

A Single Mutation in the Gene Responsible for the Mucoid Phenotype of Bifidobacterium animalis subsp. lactis Confers Surface and Functional Characteristics

Exopolysaccharides (EPS) are extracellular carbohydrate polymers synthesized by a large variety of bacteria. Their physiological functions have been extensively studied, but many of their roles have not yet been elucidated. We have sequenced the genomes of two isogenic strains of Bifidobacterium animalis subsp. lactis that differ in their EPS-producing phenotype. The original strain displays a nonmucoid appearance, and the mutant derived thereof has acquired a mucoid phenotype. The sequence analysis of their genomes revealed a nonsynonymous mutation in the gene Balat_1410, putatively involved in the elongation of the EPS chain. By comparing a strain from which this gene had been deleted with strains containing the wild-type and mutated genes, we were able to show that each strain displays different cell surface characteristics. The mucoid EPS synthesized by the strain harboring the mutation in Balat_1410 provided higher resistance to gastrointestinal conditions and increased the capability for adhesion to human enterocytes. In addition, the cytokine profiles of human peripheral blood mononuclear cells and ex vivo colon tissues suggest that the mucoid strain could have higher anti-inflammatory activity. Our findings provide relevant data on the function of Balat_1410 and reveal that the mucoid phenotype is able to alter some of the most relevant functional properties of the cells.     

GMP synthase is essential for viability and infectivity of Trypanosoma brucei despite a redundant purine salvage pathway

The causative agent of human African trypanosomiasis, Trypanosoma brucei, lacks de novo purine biosynthesis and depends on purine salvage from the host. The purine salvage pathway is redundant and contains two routes to guanosine‐5′‐monophosphate (GMP) formation: conversion from xanthosine‐5′‐monophosphate (XMP) by GMP synthase (GMPS) or direct salvage of guanine by hypoxanthine‐guanine phosphoribosyltransferase (HGPRT). We show recombinant T. brucei GMPS efficiently catalyzes GMP formation. Genetic knockout of GMPS in bloodstream parasites led to depletion of guanine nucleotide pools and was lethal. Growth of gmps null cells was only rescued by supraphysiological guanine concentrations (100 μM) or by expression of an extrachromosomal copy of GMPS. Hypoxanthine was a competitive inhibitor of guanine rescue, consistent with a common uptake/metabolic conversion mechanism. In mice, gmps null parasites were unable to establish an infection demonstrating that GMPS is essential for virulence and that plasma guanine is insufficient to support parasite purine requirements. These data validate GMPS as a potential therapeutic target for treatment of human African trypanosomiasis. The ability to strategically inhibit key metabolic enzymes in the purine pathway unexpectedly bypasses its functional redundancy by exploiting both the nature of pathway flux and the limited nutrient environment of the parasite's extracellular niche.     

The galactose‐binding lectin isolated from Bauhinia bauhinioides Mart seeds inhibits neutrophil rolling and adhesion via primary cytokines

In this study, the amino acid sequence and anti‐inflammatory effect of Bauhinia bauhinioides (BBL) lectin were evaluated. Tandem mass spectrometry revealed that BBL possesses 86 amino acid residues. BBL (1 mg/kg) intravenously injected in rats 30 min prior to inflammatory stimuli inhibited the cellular edema induced by carrageenan in only the second phase (21% – 3 h, 19% – 4 h) and did not alter the osmotic edema induced by dextran. BBL also inhibited carrageenan peritoneal neutrophil migration (51%), leukocyte rolling (58%) and adhesion (68%) and the neutrophil migration induced by TNF‐α (64%). These effects were reversed by the association of BBL with galactose, demonstrating that the carbohydrate‐binding domain is essential for lectin activity. In addition, BBL reduced myeloperoxidase activity (84%) and TNF‐α (68%) and IL1‐β (47%) levels. In conclusion, the present investigation demonstrated that BBL contains highly homologous isolectins, resulting in a total of 86 amino acid residues, and exhibits anti‐inflammatory activity by inhibiting neutrophil migration by reducing TNF‐α and IL1‐β levels via the lectin domain. Copyright © 2015 John Wiley & Sons, Ltd.     

Sex‐biased dispersal,kin selection and the evolution of sexual conflict

There is growing interest in resolving the curious disconnect between the fields of kin selection and sexual selection. Rankin's (2011, J. Evol. Biol. 24 , 71–81) theoretical study of the impact of kin selection on the evolution of sexual conflict in viscous populations has been particularly valuable in stimulating empirical research in this area. An important goal of that study was to understand the impact of sex‐specific rates of dispersal upon the coevolution of male‐harm and female‐resistance behaviours. But the fitness functions derived in Rankin's study do not flow from his model's assumptions and, in particular, are not consistent with sex‐biased dispersal. Here, we develop new fitness functions that do logically flow from the model's assumptions, to determine the impact of sex‐specific patterns of dispersal on the evolution of sexual conflict. Although Rankin's study suggested that increasing male dispersal always promotes the evolution of male harm and that increasing female dispersal always inhibits the evolution of male harm, we find that the opposite can also be true, depending upon parameter values.     

Differential effects of temperature change and human impact on European Late Quaternary mammalian extinctions

Species that inhabited Europe during the Late Quaternary were impacted by temperature changes and early humans, resulting in the disappearance of half of the European large mammals. However, quantifying the relative importance that each factor had in the extinction risk of species has been challenging, mostly due to the spatio‐temporal biases of fossil records, which complicate the calibration of realistic and accurate ecological niche modeling. Here, we overcome this problem by using ecotypes, and not real species, to run our models. We created 40 ecotypes with different temperature requirements (mean temperature from ?20 °C to 25 °C and temperature range from 10 °C to 40 °C) and used them to quantify the effect of climate change and human impact. Our results show that cold‐adapted ecotypes would have been highly affected by past temperature changes in Europe, whereas temperate and warm‐adapted ecotypes would have been positively affected by temperature change. Human impact affected all ecotypes negatively, and temperate ecotypes suffered the greatest impacts. Based on these results, the extinction of cold‐adapted species like Mammuthus primigenius may be related to temperature change, while the extinction of temperate species, like Crocuta crocuta, may be related to human impact. Our results suggest that temperature change and human impact affected different ecotypes in distinct ways, and that the interaction of both impacts may have shaped species extinctions in Europe.