Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia

Cleft lip, with or without cleft palate (CL/P), is one of the most common birth defects, occurring in 0.4 to 2.0 per 1,000 infants born alive. Approximately 70% of CL/P cases are non-syndromic (MIM 119530), but CL/P also occurs in many single-gene syndromes, each affecting a protein critical for orofacial development. Here we describe positional cloning of the gene responsible for an autosomal recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously ED4; ref. 2), which we identify as PVRL1, encoding nectin-1, an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system. Nectin-1 is also the principal cell surface receptor for alpha-herpesviruses (HveC; ref. 7), and the high frequency of CLPED1 on Margarita Island in the Caribbean Sea might result from resistance of heterozygotes to infection by these viruses.     

致第三届中国国际毛纺织会议组织者和参加者

祝贺大会召开 !这次不能如邀访问西安 ,我感到遗憾。祝第三届中国国际毛纺织会议圆满成功。着手研究羊毛及产品的性能与结构之间关系 ,正值此时。大约在 1 92 0到 1 970年这段时期 ,有一批扎实的实验研究项目 ,为研究羊毛结构和机械性能提供了大量资料信息。同时 ,开始了理论模拟研究。这些研究结果请参见由 W.S.Simpson和 G.H.Crawshaw主编、Woodhead Publishing出版社的书 :《Wool:Science and Technology》。尽管这些研究为发展羊毛技术提供了有用的基本信息 ,但是对工业界的直接影响甚小。相比之下 ,羊毛化学的知识为羊毛化学处理…     

A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis

Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting approximately 2% of the Western population. It occurs more frequently in individuals with human immunodeficiency virus, and 20-30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, and previous linkage analysis by our group identified a second psoriasis locus at 17q24-q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets. Additional loci have also been proposed to be associated with psoriasis. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.     

Association analyses identify six new psoriasis susceptibility loci in the Chinese population

We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10??) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10?21) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10?3 and P = 7.9 × 10?3, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10?3 and P = 1.5 × 10?3, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.     

Complex hybrid origin of genetic caste determination in harvester ants

Caste differentiation and division of labour are the hallmarks of insect societies and at the root of their ecological success. Kin selection predicts that caste determination should result from environmentally induced differences in gene expression, a prediction largely supported by empirical data. However, two exceptional cases of genetically determined caste differentiation have recently been found in harvester ants. Here we show that genetic caste determination evolved in these populations after complex hybridization events. We identified four distinct genetic lineages, each consisting of unique blends of the genomes of the parental species, presumably Pogonomyrmex barbatus and P. rugosus. Crosses between lineages H1 and H2 and between J1 and J2 give rise to workers, whereas queens develop from within-lineage matings. Although historical gene flow is evident, genetic exchange among lineages and between lineages and the parental species no longer occurs. This unusual system of caste determination seems to be evolutionarily stable.     

Cranial skeletal biology

To artists, the face is a mirror of the soul. To biologists, the face reflects remarkable structural diversity--think of bulldogs and wolfhounds or galapagos finches. How do such variations in skeletal form arise? Do the same mechanisms control skeletogenesis elsewhere in the body? The answers lie in the molecular machinery that generates neural crest cells, controls their migration, and guides their differentiation to cartilage and bone.     

Transforming growth factor-beta induces development of the T(H)17 lineage

A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (T(H)17) lineage, was recently described based on developmental and functional features distinct from those of classical T(H)1 and T(H)2 lineages. Like T(H)1 and T(H)2, T(H)17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant T(H)17 responses have been implicated in a growing list of autoimmune disorders. T(H)17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rbeta1, that pairs with unique, inducible components, IL-23R and IL-12Rbeta2, to confer receptor responsiveness. Here we identify transforming growth factor-beta (TGF-beta) as a cytokine critical for commitment to T(H)17 development. TGF-beta acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-beta on naive T cells is antagonized by interferon-gamma and IL-4, thus providing a mechanism for divergence of the T(H)1, T(H)2 and T(H)17 lineages.     

Rapid cloning of high-affinity human monoclonal antibodies against influenza virus

Pre-existing neutralizing antibody provides the first line of defence against pathogens in general. For influenza virus, annual vaccinations are given to maintain protective levels of antibody against the currently circulating strains. Here we report that after booster vaccination there was a rapid and robust influenza-specific IgG+ antibody-secreting plasma cell (ASC) response that peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells. These ASCs could be distinguished from influenza-specific IgG+ memory B cells that peaked 14-21 days after vaccination and averaged 1% of all B cells. Importantly, as much as 80% of ASCs purified at the peak of the response were influenza specific. This ASC response was characterized by a highly restricted B-cell receptor (BCR) repertoire that in some donors was dominated by only a few B-cell clones. This pauci-clonal response, however, showed extensive intraclonal diversification from accumulated somatic mutations. We used the immunoglobulin variable regions isolated from sorted single ASCs to produce over 50 human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains with high affinity. This strategy demonstrates that we can generate multiple high-affinity mAbs from humans within a month after vaccination. The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine. However, we found that most of the influenza-virus-specific mAbs showed the highest affinity for the current vaccine strain. Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination.