Lymphangiogenesis in development and human disease

The lymphatic vasculature forms a vessel network that drains interstitial fluid from tissues and returns it to the blood. Lymphatic vessels are also an essential part of the body's immune defence. They have an important role in the pathogenesis of several diseases, such as cancer, lymphoedema and various inflammatory conditions. Recent biological and technological developments in lymphatic vascular biology will lead to a better understanding and treatment of these diseases.     

ADVANCES IN DECISION ANALYSIS AND SYSTEMS ENGINEERING FOR MANAGING LARGE-SCALE ENTERPRISES IN A VOLATILE WORLD： INTEGRATING BENEFITS, OPPORTUNITIES, COSTS AND RISKS （BOCR） WITH THE BUSINESS MOTIVATION MODEL （BMM）

1. Introduction Recent advances in Information and Communication Technologies (ICT) have occurred in a number of areas includinginformation quality (Chutimaskul and Wangpipatwong 2004), strategy (Sha, Hung and Lin 2004) organization (Crowne 2004), technological change (Mitchell 2004), and utility1. Introduction Recent advances in Information and Communication Technologies (ICT) have occurred in a number of areas includinginformation quality (Chutimaskul and Wangpipatwong 2004), strateg…     

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.     

Recombination of mitochondrial DNA in skeletal muscle of individuals with multiple mitochondrial DNA heteroplasmy

Experimental evidence for human mitochondrial DNA (mtDNA) recombination was recently obtained in an individual with paternal inheritance of mtDNA and in an in vitro cell culture system. Whether mtDNA recombination is a common event in humans remained to be determined. To detect mtDNA recombination in human skeletal muscle, we analyzed the distribution of alleles in individuals with multiple mtDNA heteroplasmy using single-cell PCR and allele-specific PCR. In all ten individuals who carried a heteroplasmic D-loop mutation and a distantly located tRNA point mutation or a large deletion, we observed a mixture of four allelic combinations (tetraplasmy), a hallmark of recombination. Twelve of 14 individuals with closely located heteroplasmic D-loop mutation pairs contained a mixture of only three types of mitochondrial genomes (triplasmy), consistent with the absence of recombination between adjacent markers. These findings indicate that mtDNA recombination is common in human skeletal muscle.     

Formation of a functional thymus initiated by a postnatal epithelial progenitor cell

The thymus is essential for the generation of self-tolerant effector and regulatory T cells. Intrathymic T-cell development requires an intact stromal microenvironment, of which thymic epithelial cells (TECs) constitute a major part. For instance, cell-autonomous genetic defects of forkhead box N1 (Foxn1) and autoimmune regulator (Aire) in thymic epithelial cells cause primary immunodeficiency and autoimmunity, respectively. During development, the thymic epithelial rudiment gives rise to two major compartments, the cortex and medulla. Cortical TECs positively select T cells, whereas medullary TECs are involved in negative selection of potentially autoreactive T cells. It has long been unclear whether these two morphologically and functionally distinct types of epithelial cells arise from a common bi-potent progenitor cell and whether such progenitors are still present in the postnatal period. Here, using in vivo cell lineage analysis in mice, we demonstrate the presence of a common progenitor of cortical and medullary TECs after birth. To probe the function of postnatal progenitors, a conditional mutant allele of Foxn1 was reverted to wild-type function in single epithelial cells in vivo. This led to the formation of small thymic lobules containing both cortical and medullary areas that supported normal thymopoiesis. Thus, single epithelial progenitor cells can give rise to a complete and functional thymic microenvironment, suggesting that cell-based therapies could be developed for thymus disorders.     

ClustNails:Visual Analysis of Subspace Clusters

Subspace clustering addresses an important problem in clustering multi-dimensional data.In sparse multi-dimensional data,many dimensions are irrelevant and obscure the cluster boundaries.Subspace clustering helps by mining the clusters present in only locally relevant subsets of dimensions.However,understanding the result of subspace clustering by analysts is not trivial.In addition to the grouping information,relevant sets of dimensions and overlaps between groups,both in terms of dimensions and records,need to be analyzed.We introduce a visual subspace cluster analysis system called ClustNails.It integrates several novel visualization techniques with various user interaction facilities to support navigating and interpreting the result of subspace clustering.We demonstrate the effectiveness of the proposed system by applying it to the analysis of real world data and comparing it with existing visual subspace cluster analysis systems.     

New data on isotopic composition of Jurassic-Early Cretaceous cephalopods

The aim of this paper is to reconstruct the Jurassic-Early Cretaceous climatic conditions using new isotopic data. Paleobotanical data indicate that a cooling occurred gradually just after Late Triassic, and a temperature minimum was reached in the Pliensbachian. This was followed by a climatic optimum in the early Toarcian, cooling in the late Toarcian and a second climatic optimum in the Oxfordian. Published isotopic thermometry data and our new results on isotopic composition of some Jurassic invertebrate shells from the Russian Platform, Poland, Germany and England generally confirm this pattern, and also indicate a third climatic optimum in the Middle Callovian. Middle-Late Mesozoic adult belemnites apparently lived during their spawning phase, in shallow waters similar to extant Nautilus. However, at least juvenile belemnoids, unlike ammonoids, engaged in significant short-term vertical migrations in the water column, reaching colder waters of the upper bathyal zone.     

The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein

The antimicrobial defence of Drosophila relies largely on the challenge-induced synthesis of an array of potent antimicrobial peptides by the fat body. The defence against Gram-positive bacteria and natural fungal infections is mediated by the Toll signalling pathway, whereas defence against Gram-negative bacteria is dependent on the Immune deficiency (IMD) pathway. Loss-of-function mutations in either pathway reduce the resistance to corresponding infections. The link between microbial infections and activation of these two pathways has remained elusive. The Toll pathway is activated by Gram-positive bacteria through a circulating Peptidoglycan recognition protein (PGRP-SA). PGRPs appear to be highly conserved from insects to mammals, and the Drosophila genome contains 13 members. Here we report a mutation in a gene coding for a putative transmembrane protein, PGRP-LC, which reduces survival to Gram-negative sepsis but has no effect on the response to Gram-positive bacteria or natural fungal infections. By genetic epistasis, we demonstrate that PGRP-LC acts upstream of the imd gene. The data on PGRP-SA with respect to the response to Gram-positive infections, together with the present report, indicate that the PGRP family has a principal role in sensing microbial infections in Drosophila.     

Patterns of somatic mutation in human cancer genomes

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.