Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome

X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein–Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.

Kinetics of formation of hypoxanthine containing base pairs by HIV-RT: RNA template effects on the base substitution frequencies

Hypoxanthine (H), the deamination product of adenine, has been implicated in the high frequency of A to G transitions observed in retroviral and other RNA genomes. Although H·C base pairs are thermodynamically more stable than other H·N pairs, polymerase selection may be determined in part by kinetic factors. Therefore, the hypoxanthine induced substitution pattern resulting from replication by viral polymerases may be more complex than that predicted from thermodynamics. We have examined the steady-state kinetics of formation of base pairs opposite template H in RNA by HIV-RT, and for the incorporation of dITP during first- and second-strand synthesis. Hypoxanthine in an RNA template enhances the k2app for pairing with standard dNTPs by factors of 10–1000 relative to adenine at the same sequence position. The order of base pairing preferences for H in RNA was observed to be H·C >> H·T > H·A > H·G. Steady-state kinetics of insertion for all possible mispairs formed with dITP were examined on RNA and DNA templates of identical sequence. Insertion of dITP opposite all bases occurs 2–20 times more frequently on RNA templates. This bias for higher insertion frequencies on RNA relative to DNA templates is also observed for formation of mispairs at template A. This kinetic advantage afforded by RNA templates for mismatches and pairing involving H suggests a higher induction of mutations at adenines during first-strand synthesis by HIV-RT.

Mutations in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein.

A series of mutant human and yeast copper-zinc superoxide dismutases has been prepared, with mutations corresponding to those found in familial amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease). These proteins have been characterized with respect to their metal-binding characteristics and their redox reactivities. Replacement of Zn2+ ion in the zinc sites of several of these proteins with either Cu2+ or Co2+ gave metal-substituted derivatives with spectroscopic properties different from those of the analogous derivative of the wild-type proteins, indicating that the geometries of binding of these metal ions to the zinc site were affected by the mutations. Several of the ALS-associated mutant copper-zinc superoxide dismutases were also found to be reduced by ascorbate at significantly greater rate than the wild-type proteins. We conclude that similar alterations in the properties of the zinc binding site can be caused by mutations scattered throughout the protein structure. This finding may help to explain what is perhaps the most perplexing question in copper-zinc superoxide dismutase-associated familial ALS-i.e., how such a diverse set of mutations can result in the same gain of function that causes the disease.

CD4+ blood lymphocytes are rapidly killed in vitro by contact with autologous human immunodeficiency virus-infected cells.

We have investigated the ability of human immunodeficiency virus (HIV)-infected cells to kill uninfected CD4+ lymphocytes. Infected peripheral blood mononuclear cells were cocultured with autologous 51Cr-labeled uninfected cells. Rapid death of the normal CD4-expressing target population was observed following a brief incubation. Death of blood CD4+ lymphocytes occurred before syncytium formation could be detected or productive viral infection established in the normal target cells. Cytolysis could not be induced by free virus, was dependent on gp120-CD4 binding, and occurred in resting, as well as activated, lymphocytes. CD8+ cells were not involved in this phenomenon, since HIV-infected CEMT4 cells (CD4+, CD8- cells) mediated the cytolysis of uninfected targets. Reciprocal isotope-labeling experiments demonstrated that infected CEMT4 cells did not die in parallel with their targets. The uninfected target cells manifested DNA fragmentation, followed by the release of the 51Cr label. Thus, in HIV patients, infected lymphocytes may cause the depletion of the much larger population of uninfected CD4+ cells without actually infecting them, by triggering an apoptotic death.

Inside the living cell; some secrets of life.

1959

At a court of admiralty held at Boston ... the 22d day of 1704 was condemned the briggantine Charles whereof John Quelch was late commander ... , 1704

Attestation regarding the trial of Quelch and other defendants, who were convicted of piracy. Signed: John Valentine, registrar.

New York, N.Y. and vicinity, 1860 (Raster Image) (Image 2 of 2)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the five cities of New York, Brooklyn, Jersey City, Hoboken & Hudson City : Plate no. 2, prepared by M. Dripps for Valentine's Manuel [sic] of the Corporation of the city of New York. It was published by Common Council in 1860. Scale not given. This layer is image 2 of 2 total images of the two sheet source map, representing the southern portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, railroads, drainage, city wards, parks, cemeteries, pier and bulkhead lines, selected public buildings, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York, N.Y. and vicinity, 1860 (Raster Image) (Image 2 of 2)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the five cities of New York, Brooklyn, Jersey City, Hoboken & Hudson City : Plate no. 1, prepared by M. Dripps for Valentine's Manuel [sic] of the Corporation of the city of New York. It was published by Common Council in 1860. Scale not given. This layer is image 1 of 2 total images of the two sheet source map, representing the northern portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, railroads, drainage, city wards, parks, cemeteries, pier and bulkhead lines, selected public buildings, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Lower Manhattan, New York, N.Y., 1730 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: A plan of the city of New York from an actual survey, made by James Lyne. It was reproduced by Henry Dunreath Tyler ca. 1890. Scale [ca. 1:3,200]. Covers lower Manhattan below Worth St. Facsimile of an original map made in 1728 appearing in various eds. of Valentine's Manual of New York. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, selected public buildings (churches, markets, etc.), city wards, wharves, and more. Relief is shown by hachures. Includes index to points of interest. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Lower Manhattan, New York, N.Y., 1778 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This plan of the city of New York (within the palisades which were erected in the year 1745) was made for the purpose of shewing the progress and extent of the Great Fire which happened in the year 1776, the number of houses that was consumed, and also the Fire of 1778. It was published by Common Council for Valentine's Manual of the corporation of the city of New York, for the years ... 1866. Scale not given. Copy of a manuscript map. Covers Manhattan below Chambers St. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, fire areas (1776, 1778), drainage, selected public buildings (churches, markets, etc.) and more. Relief is shown by hachures. Includes ill. and index to points of interest. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Gulistān : manuscript, 1727?

Written in one column (in black and red ink) and two columns (in red ink), 29 lines per page.

L'immigrazione algerina in Francia. Proposta di traduzione del libro per bambini Le cahier de Leïla. De l'Algérie à Billancourt

Il presente elaborato è diviso in quattro capitoli e ha l'obiettivo di presentare la proposta di traduzione del libro per bambini Le cahier de Leïla. De l'Algérie à Billancourt, scritto da Valentine Goby. Il primo capitolo si propone di definire il concetto di letteratura per l'infanzia e di ripercorrere le origini della traduzione per l'infanzia. Il secondo capitolo illustra brevemente la storia dell'Algeria, dalla colonizzazione francese iniziata nel 1870 all'indipendenza nel 1962, e l'immigrazione algerina in Francia, soprattutto negli anni Sessanta. Il terzo capitolo presenta la proposta di traduzione del libro. Infine, il quarto capitolo si focalizza sul commento alla traduzione, analizzando in modo approfondito i principali problemi incontrati.

(Table 1) Age determination of sediment cores MD925-2002 and MD03-2690

The compilation of results obtained on three giant piston cores from the Whittard, Shamrock and Guilcher turbidite levees reveals a high-resolution stratigraphic record for the Bay of Biscay. Due to the abundance of reworked sediments in these sedimentary environments, a specific methodological approach, based on an X-ray-assisted subsampling phase associated with sedimentological, geochemical and micropalaeontological analyses, was implemented. With an accurate chronological framework, this multi-proxy investigation provides observations on the 'Fleuve Manche' palaeoriver and the British-Irish Ice Sheet (BIS) histories over the last 20,000 years. The results obtained highlight the direct influence of the decay of the BIS on the Bay of Biscay deep-sea clastic sedimentation during the last European deglacial phase. During this period, the annual BIS cycle of meltwater seems enough to generate seasonal turbidity currents associated with exceptional sedimentation rates in all the Celtic and Armorican turbidite systems. With very high sedimentation rates, the turbidite levees represent the main deep-sea clastic depositional area. Long coring combined with a very careful subsampling method can provide continuous high-resolution palaeoenvironmental signals.