CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas-Fas ligand interactions

Better understanding of tolerance and autoimmunity toward melanocyte-specific Ags is needed to develop effective treatment for vitiligo and malignant melanoma; yet, a systematic assessment of these mechanisms has been hampered by the difficulty in tracking autoreactive T cells. To address this issue, we have generated transgenic mice that express hen egg lysozyme as a melanocyte-specific neoantigen. By crossing these animals to a hen egg lysozyme-specific CD4 TCR transgenic line we have been able to track autoreactive CD4+ T cells from their development in the thymus to their involvement in spontaneous autoimmune disease with striking similarity to human vitiligo vulgaris and Vogt-Koyanagi-Harada syndrome. Our findings show that CD4-dependent destruction of melanocytes is partially inhibited by blocking Fas-Fas ligand interactions and also highlights the importance of local control of autoimmunity, as vitiligo remains patchy and never proceeds to confluence even when Ag and autoreactive CD4+ T cells are abundant. Immune therapy to enhance or suppress melanocyte-specific T cells can be directed at a series of semiredundant pathways involving tolerance and cell death.     

The Relationship of DNA Methylation with Age,Gender and Genotype in Twins and Healthy Controls

Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease.     

Quantifying Primate Food Distribution and Abundance for Socioecological Studies: An Objective Consumer-centered Method

Food abundance and distribution have played a central role in the conceptual theory of primate socioecology. This theory predicts that agonistic (contest) competition should occur when food is distributed in discrete, defensible patches; in contrast, when food sources are distributed uniformly or randomly, nonagonistic (scramble) competition is expected. Primatologists usually measure resource density and patchiness from a botanical perspective, without an explicit link to the biology of the animal being studied. Such an approach may be irrelevant to how the animals view the dispersion of resources. For studies related to feeding competition, we suggest the use of a method that provides a consumer-based index of food distribution. We then describe such an approach and apply it to understand agonistic behavior in white-faced capuchins (Cebus capucinus), at Lomas Barbudal. Instead of choosing sample plots at random, we use each actual feeding tree of a group as the center of a sample plot and we use the monkey species’ average group spread as the sampling area. This focal tree method allows us to evaluate the resource availability both within and outside of the feeding tree during a particular feeding bout. To summarize the spatial distribution of food at the level of a foraging group, we define and use an extension of Lloyd’s Dispersion Index, Lloyd’s Extended Index (LEI), designed to allow the inclusion of resources of diverse sizes and species in a single measure. We evaluate if LEI can be used to predict the frequency of aggression, if changing the area of the plot alters these results, and if calculating LEI based on fruit abundance or fruit biomass better predicts the frequency of aggression in this population of capuchins. In support of socioecological predictions, our results show that the frequency of agonism in a focal tree declines as LEI increases. This relationship is significant when LEI is calculated using a 20-m plot size and weighting tree size by fruit counts, but not when using larger plot sizes, unweighted tree counts, or weighting by fruit biomass. Our approach demonstrates the importance of carefully considering plot size and different measures of food availability when testing socioecological models relating resource distribution and quality to aggression in nonhuman primates.     

The intra-annual variability of soft-bottom macrobenthos abundance patterns in the North Channel of the Seine estuary

Temporal and spatial variability of the Abra alba–Pectinaria koreni and Macoma balthica communities was examined in the northern part of the Seine estuary (North Channel) over different space and time scales in order to assess the role that the hydrologic regime and/or anthropogenic influences play in defining benthic communities over time. Sediment in the North Channel displayed strong spatial and temporal variability, sustained by intense sediment transport episodes. Total macrobenthic abundances ranged widely on the course of the year and there was no evidence of a seasonal signal for the density fluctuations, whatever the spatial scale considered. The bio-sedimentary dynamics can be divided into two periods: the first corresponds to the high flow rate period (January–May) during which fauna is influenced by fine silt/clay deposition, and the second to the low flow rate period (June–December) during which sandy deposits prevail. Despite the absence of significant correlations between sediment composition and abundance, episodes of sediment transport seem to be an important structuring mechanism in the Seine estuary. As a consequence, the faunal composition varied throughout the year. The winter and spring fauna, characterised by species living on muddy fine-sands or muds, were enriched during the summer and autumn by species living in clean fine sand, such as Donax vittatus, Nephtys cirrosa or Spio decoratus, mainly represented by adult individuals. Secondary settlement of drifters may explain the rapid structuration of assemblages a few days after the sandy deposits. Our results suggest the importance of the bentho-pelagic coupling, primarily induced by the sedimentary instability, on the macrobenthic fauna dynamics. The intra-annual variability of assemblages at the mouth of the Seine river and the silted situation of the North Channel might simply be the result of the silting up and alteration of the inner estuary, generated by several decades of man-made modifications and natural processes.     

Stringent and reproducible tetracycline-regulated transgene expression by site-specific insertion at chromosomal loci with pre-characterised induction characteristics

Background  

The ability to regulate transgene expression has many applications, mostly concerning the analysis of gene function. Desirable induction characteristics, such as low un-induced expression, high induced expression and limited cellular heterogeneity, can be seriously impaired by chromosomal position effects at the site of transgene integration. Many clones may therefore need to be screened before one with optimal induction characteristics is identified. Furthermore, such screens must be repeated for each new transgene investigated, and comparisons between clones with different transgenes is complicated by their different integration sites.     

Force generation by dynamic microtubules

The assembly and disassembly of microtubules can generate pushing and pulling forces that, together with motor proteins, contribute to the correct positioning of chromosomes, mitotic spindles and nuclei in cells. In vitro experiments combined with modeling have shed light on the intrinsic capability of dynamic microtubules to generate force, and various observations of positioning processes in cells and model systems have shown how pushing and pulling forces are used in different situations. A sophisticated set of microtubule-end-binding proteins is responsible for steering dynamic microtubules toward their cellular target and regulating the pushing and/or pulling forces that are generated once contact is established.     

Decoding the research exemption

While debate continues as to whether genetic sequences, which many argue represent natural phenomena rather than inventions, should be subject to standard patent protections, issuance of patents that claim DNA sequences remains common practice. In an attempt to insulate researchers from patent claims that could hinder scientific progress, many countries have provided general exemptions for scientific research. However, there is no international consensus about the extent of required protections, and even existing exemptions vary widely in clarity and are limited in practical application. We believe that gene patents raise several unique issues that are inadequately handled by the current research exemptions.     

Primate socioecology at the crossroads: Past, present, and future

Attempts to explain differences in the size and structure of primate groups have argued that they are a consequence of variation in the intensity of feeding competition caused by contrasts in food distribution. However, although feeding competition can limit the size of female groups, many other factors affect the costs and the benefits of sociality to females and contribute to differences in group size. Moreover, interspecific differences in social relationships between females, in female philopatry, and in kinship between group members appear to be more closely associated with variation in life‐history parameters, reproductive strategies, and phylogeny than with contrasts in food distribution or feeding competition. The mismatch between predictions of socioecological theory and observed variation in primate social behavior has led to protracted arguments about the future of primate socioecology. We argue that future attempts to understand the diversity of primate societies need to be based on an approach that explores separate explanations for different components of social organization, combines ecological and phylogenetic information, and integrates research on primates with similar studies of other groups of mammals. © 2012 Wiley Periodicals, Inc.     

Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner

ABSTRACT: BACKGROUND: Chromosome 17q21.31 contains a common inversion polymorphism of approximately 900 kb in populations with European ancestry. Two divergent MAPT haplotypes, H1 and H2 are described with distinct linkage disequilibrium patterns across the region reflecting the inversion status at this locus. The MAPT H1 haplotype has been associated with progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and Alzheimer's disease, while the H2 is linked to recurrent deletion events associated with the 17q21.31 microdeletion syndrome, a disease characterized by developmental delay and learning disability. RESULTS: In this study, we investigate the effect of the inversion on the expression of genes in the 17q21.31 region. We find the expression of several genes in and at the borders of the inversion to be affected; specific either to whole blood or different regions of the human brain. The H1 haplotype was found to be associated with an increased expression of LRRC37A4, PLEKH1M and MAPT. In contrast, a decreased expression of MGC57346, LRRC37A and CRHR1 was associated with H1. CONCLUSIONS: Studies thus far have focused on the expression of MAPT in the inversion region. However, our results show that the inversion status affects expression of other genes in the 17q21.31 region as well. Given the link between the inversion status and different neurological diseases, these genes may also be involved in disease pathology, possibly in a tissue-specific manner.