Modelling the Human Immune System by Combining Bioinformatics and Systems Biology Approaches

Over the past decade a number of bioinformatics tools have been developed that use genomic sequences as input to predict to which parts of a microbe the immune system will react, the so-called epitopes. Many predicted epitopes have later been verified experimentally, demonstrating the usefulness of such predictions. At the same time, simulation models have been developed that describe the dynamics of different immune cell populations and their interactions with microbes. These models have been used to explain experimental findings where timing is of importance, such as the time between administration of a vaccine and infection with the microbe that the vaccine is intended to protect against. In this paper, we outline a framework for integration of these two approaches. As an example, we develop a model in which HIV dynamics are correlated with genomics data. For the first time, the fitness of wild type and mutated virus are assessed by means of a sequence-dependent scoring matrix, derived from a BLOSUM matrix, that links protein sequences to growth rates of the virus in the mathematical model. A combined bioinformatics and systems biology approach can lead to a better understanding of immune system-related diseases where both timing and genomic information are of importance.     

Targeting head and neck tumoral stem cells: From biological aspects to therapeutic perspectives

Head and neck squamous cell cancer(HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of the disease. In most cases, treatment fails to obtain total cancer cure. In recent years, it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells(CSCs) that escape currently available therapies. CSCs form a small portion of the total tumor burden but may play a disproportionately important role in determining outcomes. CSCs have stem features such as self-renewal, high migration capacity, drug resistance, high proliferation abilities. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In HNSCC, CSCs have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis and treatment resistance. In the light of such observations, the present review summarizes biological characteristics of CSCs in HNSCC, outlines targeted strategies for the successful eradication of CSCs in HNSCC including targeting the self-renewal controlling pathways, blocking epithelial mesenchymal transition, niche targeting, immunotherapy approaches and highlights the need to better understand CSCs biology for new treatments modalities.     

Identification of target antigens of antiendothelial cell antibodies in healthy individuals: A proteomic approach

In order to identify target antigens of anti-endothelial cell (anti-EC) antibodies (AECA) in healthy individuals, we have used a proteomic approach combining 2-DE and immunoblotting. Whole cell protein extracts obtained from human umbilical vein EC (HUVEC) cultures were used as a source of antigens. Serum IgG from 12 healthy blood donors were tested at a concentration of 200 microg/mL. Targeted spots were identified by MS. The HUVEC proteome was composed of 884 protein spots. Among these, 61 +/- 25.8 (mean +/- SD) spots were recognized by serum IgG from healthy individuals, with marked differences from one individual to another. Among these spots, 11 were recognized by serum IgG from all healthy individuals tested. These spots corresponded to six different proteins with several spots corresponding to different isoforms of the same protein. Target antigens were: cytoskeletal proteins (beta-actin, alpha-tubulin, and vimentin); glycolytic enzymes (glucose-3-phosphate-deshydrogenase and alpha-enolase); and prolyl-4-hydroxylase beta subunit, a member of the disulfide isomerase family. This study shows that the repertoire of IgG AECA is heterogeneous among healthy individuals. IgG from all of the healthy individuals tested recognized a restricted set of highly conserved ubiquitous proteins playing key roles in cell biology and maintenance of homeostasis.     

How life‐history traits affect ecosystem properties: effects of dispersal in meta‐ecosystems

The concept of life‐history traits and the study of these traits are the hallmark of population biology. Acknowledging their variability and evolution has allowed us to understand how species adapt in response to their environment. The same traits are also involved in how species alter ecosystems and shape their dynamics and functioning. Some theories, such as the metabolic theory of ecology, ecological stoichiometry or pace‐of‐life theory, already recognize this junction, but only do so in an implicitly non‐spatial context. Meanwhile, for a decade now, it has been argued that ecosystem properties have to be understood at a larger scale using meta‐ecosystem theory because source–sink dynamics, community assembly and ecosystem stability are all modified by spatial structure. Here, we argue that some ecosystem properties can be linked to a single life‐history trait, dispersal, i.e. the tendency of organisms to live, compete and reproduce away from their birth place. By articulating recent theoretical and empirical studies linking ecosystem functioning and dynamics to species dispersal, we aim to highlight both the known connections between life‐history traits and ecosystem properties and the unknown areas, which deserve further empirical and theoretical developments.     

Reciprocal influence of connexins and apical junction proteins on their expressions and functions

Membranes of adjacent cells form intercellular junctional complexes to mechanically anchor neighbour cells (anchoring junctions), to seal the paracellular space and to prevent diffusion of integral proteins within the plasma membrane (tight junctions) and to allow cell-to-cell diffusion of small ions and molecules (gap junctions). These different types of specialised plasma membrane microdomains, sharing common adaptor molecules, particularly zonula occludens proteins, frequently present intermingled relationships where the different proteins co-assemble into macromolecular complexes and their expressions are co-ordinately regulated. Proteins forming gap junction channels (connexins, particularly) and proteins fulfilling cell attachment or forming tight junction strands mutually influence expression and functions of one another.     

A half a century of measuring ungulate body condition using indices: is it time for a change?

From a literature review of five wildlife ecology journals since 1937, we document how using indices to monitor ungulate body condition is common practice, with the kidney fat index (KFI = weight of fat around the kidneys/weight of kidneys without fat × 100) as the favoured tool (82% of studies). In this context, we highlight the problems of using indices when underlying statistical assumptions are not met (isometry, parallel slopes between treatments). We show, with real and simulated data for two cervids with contrasting fat storage strategies, how results from analysis of variance of KFI values differ from analysis of covariance (ANCOVA) of raw data. We conclude that the KFI is affected by the restrictions typically associated with derived index values, and as a consequence, statistical analysis of the KFI could generate spurious results leading to erroneous interpretations concerning variation in body condition of ungulate populations. Thus, we recommend analysing fat weight as an untransformed variable in ANCOVA (kidney weight as covariate) to describe body condition variation in ungulates. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Risks of Avian Influenza Transmission in Areas of Intensive Free-Ranging Duck Production with Wild Waterfowl

For decades, southern China has been considered to be an important source for emerging influenza viruses since key hosts live together in high densities in areas with intensive agriculture. However, the underlying conditions of emergence and spread of avian influenza viruses (AIV) have not been studied in detail, particularly the complex spatiotemporal interplay of viral transmission between wild and domestic ducks, two major actors of AIV epidemiology. In this synthesis, we examine the risks of avian influenza spread in Poyang Lake, an area of intensive free-ranging duck production and large numbers of wild waterfowl. Our synthesis shows that farming of free-grazing domestic ducks is intensive in this area and synchronized with wild duck migration. The presence of juvenile domestic ducks in harvested paddy fields prior to the arrival and departure of migrant ducks in the same fields may amplify the risk of AIV circulation and facilitate the transmission between wild and domestic populations. We provide evidence associating wild ducks migration with the spread of H5N1 in the spring of 2008 from southern China to South Korea, Russia, and Japan, supported by documented wild duck movements and phylogenetic analyses of highly pathogenic avian influenza H5N1 sequences. We suggest that prevention measures based on a modification of agricultural practices may be implemented in these areas to reduce the intensity of AIV transmission between wild and domestic ducks. This would require involving all local stakeholders to discuss feasible and acceptable solutions.     

A mixed relaxed clock model

Over recent years, several alternative relaxed clock models have been proposed in the context of Bayesian dating. These models fall in two distinct categories: uncorrelated and autocorrelated across branches. The choice between these two classes of relaxed clocks is still an open question. More fundamentally, the true process of rate variation may have both long-term trends and short-term fluctuations, suggesting that more sophisticated clock models unfolding over multiple time scales should ultimately be developed. Here, a mixed relaxed clock model is introduced, which can be mechanistically interpreted as a rate variation process undergoing short-term fluctuations on the top of Brownian long-term trends. Statistically, this mixed clock represents an alternative solution to the problem of choosing between autocorrelated and uncorrelated relaxed clocks, by proposing instead to combine their respective merits. Fitting this model on a dataset of 105 placental mammals, using both node-dating and tip-dating approaches, suggests that the two pure clocks, Brownian and white noise, are rejected in favour of a mixed model with approximately equal contributions for its uncorrelated and autocorrelated components. The tip-dating analysis is particularly sensitive to the choice of the relaxed clock model. In this context, the classical pure Brownian relaxed clock appears to be overly rigid, leading to biases in divergence time estimation. By contrast, the use of a mixed clock leads to more recent and more reasonable estimates for the crown ages of placental orders and superorders. Altogether, the mixed clock introduced here represents a first step towards empirically more adequate models of the patterns of rate variation across phylogenetic trees.This article is part of the themed issue ‘Dating species divergences using rocks and clocks’.     

Exosomes surf on filopodia to enter cells at endocytic hot spots,traffic within endosomes,and are targeted to the ER

Exosomes are nanovesicles released by virtually all cells, which act as intercellular messengers by transfer of protein, lipid, and RNA cargo. Their quantitative efficiency, routes of cell uptake, and subcellular fate within recipient cells remain elusive. We quantitatively characterize exosome cell uptake, which saturates with dose and time and reaches near 100% transduction efficiency at picomolar concentrations. Highly reminiscent of pathogenic bacteria and viruses, exosomes are recruited as single vesicles to the cell body by surfing on filopodia as well as filopodia grabbing and pulling motions to reach endocytic hot spots at the filopodial base. After internalization, exosomes shuttle within endocytic vesicles to scan the endoplasmic reticulum before being sorted into the lysosome as their final intracellular destination. Our data quantify and explain the efficiency of exosome internalization by recipient cells, establish a new parallel between exosome and virus host cell interaction, and suggest unanticipated routes of subcellular cargo delivery.     

Graphene Doping Induced Tunability of Nanoparticles Plasmonic Resonances

Interest in graphene has been widely increasing since its discovery in 2004. Research on graphene for plasmonic applications has also boomed due to the high potential of these systems. In this article, we discuss the possible interaction between metallic NPs and graphene monolayer. We show how the contact between metallic NPs and graphene results in graphene doping. More importantly, we experimentally put into evidence the possible modulation of the plasmonic resonance of NPs by graphene doping. Understanding and evidencing this interaction is highly important both from a fundamental point of view and for specific applications such as active plasmonic devices.

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