Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.     

Ionomycin-regulated phosphorylation of the myeloid calcium-binding protein p14

Two associated calcium-binding proteins (CaBPs) have recently been identified specifically in cells of myeloid origin. These proteins have relative molecular masses (Mr) of 8,000 and 14,000 and are variously referred to as the cystic fibrosis antigen, the L1 light chain, MRP-8 or p8, and the L1 heavy chain, MRP14 or p14, respectively. The expression of p8 and p14 seems to be confined to a specific stage of myeloid cell differentiation, because both proteins are expressed in circulating neutrophils and monocytes but not in normal tissue macrophages. In chronic inflammatory conditions, however, such as rheumatoid arthritis, macrophages in affected tissues express both p8 and p14. These proteins are members of a family of CaBPs of low Mr, which include S-100 alpha and beta proteins, calcyclin (2A9), intestinal CaBP and p11. All the proteins have an Mr of approximately 10,000 with the exception of p14 which has a longer C-terminal sequence after the second calcium-binding domain. Little is known about their function, although by analogy with calmodulin they could be molecules involved in intracellular signalling that are activated by an increase in the intracellular Ca2+ concentration ([Ca2+]). Here we report that p14 is phosphorylated in both monocytes and neutrophils. The level of p14 phosphorylation can be increased by elevating the [Ca2+]i using the ionophore ionomycin, but is not affected by activation of protein kinase C using phorbol 12,13-dibutyrate. The phosphorylated residue is threonine at position 113, which is the penultimate amino acid in p14 and contained in the longer 'tail' sequence. Part of this sequence is identical to the neutrophil immobilizing factors NIF-1 and NIF-2, indicating that the phosphorylation event could have a role in the generation of NIF activity in the p14 protein.     

Male sexual differentiation in mice lacking H-Y antigen

The sexual phenotype of an adult mammal depends on whether the fetal gonad has differentiated as a testis or as an ovary. Because individuals of XY or XXY sex chromosome constitution develop as males, while XX and XO individuals develop as females, the presence of a Y chromosome seems normally to be required for testis differentiation and its absence to be necessary for differentiation of an ovary. The nature of the hypothetical Y-dependent substance responsible for masculinization of the indifferent gonad has been a matter for debate. A male-specific transplantation antigen, H-Y, has been known for many years and more recently a serologically detected antigen, also male-specific, has been reported. Those who believe that the two are antigenically distinct refer to the latter as SDM (serologically detected male) antigen, but many refer to both as H-Y antigen. The hypothesis that H-Y is itself the Y-dependent testis inducer, although supported by little or no direct evidence, is economical and hence attractive. H-Y antigen is frequently stated to be the substance responsible for primary sex determination (for example, see ref. 11). We report here that H-Y is absent from certain mice that develop testes and are of indisputably male phenotype, hence this transplantation antigen is unlikely to be responsible for testis determination.     

Filtered Backprojection Reconstruction with Depth-Dependent Filtering

A direct filtered-backprojection(FBP) reconstruction algorithm is presented for circular cone-beam computed tomography(CB-CT) that allows the filter operation to be applied efficiently with shift-variant band-pass characteristics on the kernel function.Our algorithm is derived from the ramp-filter based FBP method of Feldkamp et al.and obtained by decomposing the ramp filtering into a convolution involving the Hilbert kernel(global operation) and a subsequent differentiation operation(local operation).The d...     

Cotransfection of ICAM-1 and HLA-DR reconstitutes human antigen-presenting cell function in mouse L cells

The initiation of a specific immune response is believed to require not only activation through antigen-specific receptors on T cells and B cells but also antigen-independent interactions between accessory molecules. One such molecule is LFA-1, which enhances the avidity of interactions between T cells and antigen-presenting cells, and is possibly involved in signal transduction across the T-cell membrane. Intercellular adhesion molecule-1 (ICAM-1), a surface glycoprotein of relative molecular mass (Mr) 80,000-110,000, has been defined as a ligand for LFA-1, and has been shown to participate in the interaction between T cells and monocytes. The determination of the precise contribution of such accessory molecules to antigen presentation, however, is complicated by the need to analyse against a background of multiple molecular interactions. We have investigated the role of LFA-1/ICAM-1 interactions in antigen presentation directly by quantifying the contribution of ICAM-1 expression to T-cell stimulation using L-cell transfectants that co-express ICAM-1 and HLA-DR. In the case of transfectants expressing modest levels of HLA-DR, co-expression of ICAM-1 is critical for effective HLA class II-restricted and allospecific T-cell activation, pointing to an important role for ICAM-1 in the induction of T-cell responses.