A sequence-based variation map of 8.27 million SNPs in inbred mouse strains

A dense map of genetic variation in the laboratory mouse genome will provide insights into the evolutionary history of the species and lead to an improved understanding of the relationship between inter-strain genotypic and phenotypic differences. Here we resequence the genomes of four wild-derived and eleven classical strains. We identify 8.27 million high-quality single nucleotide polymorphisms (SNPs) densely distributed across the genome, and determine the locations of the high (divergent subspecies ancestry) and low (common subspecies ancestry) SNP-rate intervals for every pairwise combination of classical strains. Using these data, we generate a genome-wide haplotype map containing 40,898 segments, each with an average of three distinct ancestral haplotypes. For the haplotypes in the classical strains that are unequivocally assigned ancestry, the genetic contributions of the Mus musculus subspecies--M. m. domesticus, M. m. musculus, M. m. castaneus and the hybrid M. m. molossinus--are 68%, 6%, 3% and 10%, respectively; the remaining 13% of haplotypes are of unknown ancestral origin. The considerable regional redundancy of the SNP data will facilitate imputation of the majority of these genotypes in less-densely typed classical inbred strains to provide a complete view of variation in additional strains.     

Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4+ T-cells

This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG₁ simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG₁ was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG₁ short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG₁ before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG₁ anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders).     

What is the environment in environmental health research? Perspectives from the ethics of science

Environmental health research produces scientific knowledge about environmental hazards crucial for public health and environmental justice movements that seek to prevent or reduce exposure to these hazards. The environment in environmental health research is conceptualized as the range of possible social, biological, chemical, and/or physical hazards or risks to human health, some of which merit study due to factors such as their probability and severity, the feasibility of their remediation, and injustice in their distribution. This paper explores the ethics of identifying the relevant environment for environmental health research, as judgments involved in defining an environmental hazard or risk, judgments of that hazard or risk's probability, severity, and/or injustice, as well as the feasibility of its remediation, all ought to appeal to non-epistemic as well as epistemic values. I illustrate by discussing the case of environmental lead, a housing-related hazard that remains unjustly distributed by race and class and is particularly dangerous to children. Examining a controversy in environmental health research ethics where researchers tested multiple levels of lead abatement in lead-contaminated households, I argue that the broader perspective on the ethics of environmental health research provided in the first part of this paper may have helped prevent this controversy.     

Experimental study on dehydration melting of natural biotite-plagioclase gneiss from High Himalayas and implications for Himalayan crust anatexis

Here we present the results of dehydration melting, melt morphology and fluid migration based on the dehydration melting experiments on natural biotite-plagioclase gneiss performed at the pressure of 1.0—1.4 GPa, and at the temperature of 770—1028℃. Experimental results demonstrate that: (ⅰ) most of melt tends to be distributed along mineral boundaries forming “melt film” even the amount of melt is less than 5 vol%; melt connectivity is controlled not only by melt topology but also by melt fraction; (ⅱ) dehydration melting involves a series of subprocesses including subsolidus dehydration reaction, fluid migration, vapor-present melting and vapor-absent melting; (ⅲ) experiments produce peraluminous granitic melt whose composition is similar to that of High Himalayan leucogranites (HHLG) and the residual phase assemblage is Pl+Qz+ Gat+Bio+Opx± Cpx+Ilm/Rut± Kfs and can be comparable with granulites observed in Himalayas. The experiments provide the evidence that biotite-plagioclase gneiss is one of source rocks of HHLG and dehydration melting is an important way to form HHLG and the granulites. Additionally, experimental results provide constraints on determining the P-T conditions of Himalayan crustal anatexis.     

Gap analysis of the vegetation of the Intermountain Semi-Desert ecoregion

A conservation gap analysis was conducted for the Intermountain Semi-Desert ecoregion to assess the representation of land-cover types within areas managed primarily for biodiversity objectives. Mapped distributions of plant communities were summarized by land-management status categories. The total amount of land permanently protected in the ecoregion is < 4%, and most types that are characteristic of the region have < 10%. Of 48 land-cover types, 20 were found to be particularly vulnerable to potential loss or degradation because of low level of representation in biodiversity management areas and the impact of expected land-use activities. Gap analysis data and findings will be useful in providing a regional perspective in project impact assessment and future conservation planning within this ecoregion.     

Family of disulphide-linked dimers containing the zeta and eta chains of the T-cell receptor and the gamma chain of Fc receptors

Stimulation of T cells by antigen activates many signalling pathways. The capacity for this range of biochemical responses may reside in the complex structure of the seven-chain T-cell antigen receptor (TCR). In addition to the complexity shared by all TCRs, coexpression of zeta (zeta) and the distinct but related eta (eta) chains creates structural diversity among the TCR complexes expressed on a given cell. In most murine T cells that we have studied, about 90% of the heptameric receptor complexes contain a zeta zeta disulphide homodimer, whereas 10% contain a zeta eta disulphide heterodimer. Recent studies suggest that zeta has a critical role in allowing antigen to activate the cell, whereas eta expression has been correlated with the capacity for antigen-induced phosphoinositide turnover. A third zeta-related protein, the gamma (gamma) chain of the Fc epsilon and some Fc gamma receptors, exists as a disulphide homodimer in those complexes. The structural relatedness of zeta and gamma is emphasized by the recent demonstration of zeta zeta in association with CD16 in TCR-negative natural killer cells. Here we identify T cells lacking Fc receptors but coexpressing zeta, gamma, and eta, document the formation of novel heterodimers between zeta and gamma and between eta and gamma and show their association with the TCR. A greater range of homologous coupling structures than previously thought may be one way of achieving the variety of TCR-mediated (and possibly Fc receptor-mediated) biochemical responses and effector functions.     

A preliminary study of optimal variable weighting in k-means clustering

Recently, algorithms for optimally weighting variables in non-hierarchical and hierarchical clustering methods have been proposed. Preliminary Monte Carlo research has shown that at least one of these algorithms cross-validates extremely well.The present study applies a k-means, optimal weighting procedure to two empirical data sets and contrasts its cross-validation performance with that of unit (i.e., equal) weighting of the variables. We find that the optimal weighting procedure cross-validates better in one of the two data sets. In the second data set its comparative performance strongly depends on the approach used to find seed values for the initial k-means partitioning.The authors would like to acknowledge the support of the Citibank Fellowship from the Sol C. Snider Entrepreneurial Center at the Wharton School. The authors would like to express their appreciation to J. Douglas Carroll and Abba M. Kreiger for comments on an earlier version of the paper.