Model for signal sequence recognition from amino-acid sequence of 54K subunit of signal recognition particle

Protein targeting to the endoplasmic reticulum in mammalian cells is catalysed by signal recognition particle (SRP). Cross-linking experiments have shown that the subunit of relative molecular mass 54,000 (Mr 54K; SRP54) interacts directly with signal sequences as they emerge from the ribosome. Here we present the sequence of a complementary DNA clone of SRP54 which predicts a protein that contains a putative GTP-binding domain and an unusually methionine-rich domain. The properties of this latter domain suggest that it contains the signal sequence binding site. A previously uncharacterized Escherichia coli protein has strong homology to both domains. Closely homologous GTP-binding domains are also found in the alpha-subunit of the SRP receptor (SR alpha, docking protein) in the endoplasmic reticulum membrane and in a second E. coli protein, ftsY, which resembles SR alpha. Recent work has shown that SR alpha is a GTP-binding protein and that GTP is required for the release of SRP from the signal sequence and the ribosome on targeting to the endoplasmic reticulum membrane. We propose that SRP54 and SR alpha use GTP in sequential steps of the targeting reaction and that essential features of such a pathway are conserved from bacteria to mammals.     

Expression of human adenosine deaminase in murine haematopoietic progenitor cells following retroviral transfer

Adenosine deaminase (ADA) deficiency, an autosomal recessive inborn error of metabolism, leads to severe combined immune deficiency in man. This enzyme, although constitutively expressed in most tissues, is expressed at high level in immature T cells, and study of the pathophysiology of the disorder indicates that increased deoxyadenosine or altered methylation capacity have toxic effects on T-cell maturation. Although bone marrow transplantation can correct the immune deficiency, this therapy is associated with graft-versus-host disease and incomplete immune restoration, and so our laboratory and others have sought to develop a method of gene replacement as a possible treatment for the disease. Moreover, characterization of the complementary DNA of the human ADA gene and some of its mutants makes it possible to design gene transfer strategies. We have now subcloned a human adenosine deaminase cDNA into the retrovirus shuttle vector pZIP-SV(B), and in this way have isolated a cell line, 4.2T, which produces high titres of replication-defective retrovirus which have been used to transfer the gene for human ADA to mouse bone marrow cells. Transfer and expression of the neomycin-resistance gene (neo) and the ADA gene in murine bone marrow colony-forming units (CFU) was demonstrated by in vitro colony formation in the presence of the antibiotic G418 or 9-xylofuranosyladenine plus deoxycoformycin, respectively. Isoenzyme analysis also showed human ADA expression in the cultured mouse bone marrow.     

Detection of weak gravitational lensing distortions of distant galaxies by cosmic dark matter at large scales

Most of the matter in the Universe is not luminous, and can be observed only through its gravitational influence on the appearance of luminous matter. Weak gravitational lensing is a technique that uses the distortions of the images of distant galaxies as a tracer of dark matter: such distortions are induced as the light passes through large-scale distributions of dark matter in the foreground. The patterns of the induced distortions reflect the density of mass along the line of sight and its distribution, and the resulting 'cosmic shear' can be used to distinguish between alternative cosmologies. But previous attempts to measure this effect have been inconclusive. Here we report the detection of cosmic shear on angular scales of up to half a degree using 145,000 galaxies and along three separate lines of sight. We find that the dark matter is distributed in a manner consistent with either an open universe, or a flat universe that is dominated by a cosmological constant. Our results are inconsistent with the standard cold-dark-matter model.     

Ant compound eye: Size-related ommatidium differences within a single wood ant nest

Résumé Pour compter le nombre de facettes de l'il composé de la fourmi, une nouvelle méthode a été mise au point en utilisant des photographies d'empreintes de collodion. Dans une population d'ouvrières provenant d'un seul nid de fourmis rouges lignicoles, le nombre et le diamètre des facettes augmentent avec la grosseur de l'il et de la tête. Pour une telle population il y a une relation entre la grosseur des tissus neuraux et sensoriels, l'il composé inclus, et l'efficacité avec laquelle une fourmi ouvrière parcourt le terrain en cherchant de la nourriture.

---

---

This work was supported by U.S. Public Health Service Research Scientist Development Award Type I No. 5K01 MH 15475 to S.B. Computing assistance was obtained from the Health Sciences Computing Facility, UCLA, sponsored by NIH Special Research Resources Grant No. RR-3.     

C16-methyl derivatives of progesterone and 17α-acetoxyprogesterone: Preparation and biological activities

Zusammenfassung Mehrere Derivate des 16-Methyl-progesteron wurden synthetisiert und biologisch geprüft. Die Einführung einer C16-Methylgruppe ergab keine gesteigerte Progesteronaktivität in den getesteten Verbindungen.     

Mapping and analysis of chromatin state dynamics in nine human cell types

Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.     

Initial genome sequencing and analysis of multiple myeloma

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.     

Identity of the proliferating cell nuclear antigen and cyclin

Studies of growth regulation and cellular transformation will be assisted by the identification of proteins that are preferentially synthesized in dividing cells. The 'proliferating cell nuclear antigen' ( PCNA ), distinguished by its apparent association with cell division, is defined by reaction with an antibody found in the autoimmune disease systemic lupus erythematosus (SLE). This antibody reacts with proliferating cells including tumour cells but gives weak or undetectable immunofluorescence with resting cells of normal tissues. Peripheral blood lymphocytes are devoid of PCNA until activated by mitogen in vitro. In synchronized cultures its level and distribution fluctuate through the cell cycle, with a striking accumulation in the nucleolus late in the G1 phase and early in the S phase. Many of these properties are shared by ' cyclin '. This nuclear protein, identified by its position in a two-dimensional separation of cell proteins, is also transformation-sensitive and is preferentially synthesized in the S phase. We establish here that PCNA and cyclin are identical, and show that PCNA is an acidic nuclear protein of apparent molecular weight 35,000.     

Synaptic boutons in the hippocampus: Changes are produced by age and experience

Zusammenfassung Erstmaliger morphometrischer Nachweis bei 2 Gruppen reifer, altersunterschiedlicher Ratten, dass die Zahl der Synapsen im Hippocampus mit dem Alter zunimmt, wobei die effektive Steigerungsrate auch mit Umwelteinflüssen zusammenhängen könnte.

---

---

This work was supported by grants from the U.S. National Institutes of Health to JJB (No. NS-06164) and to LEW,Jr., (No. NS-09358) and funds from the Center for Neurobiological Sciences of the University of Florida (No. NIH-MH-10320).