Tertiary structure of an amyloid immunoglobulin light chain protein: a proposed model for amyloid fibril formation.

An immunoglobulin light chain protein was isolated from the urine of an individual (BRE) with systemic amyloidosis. Complete amino acid sequence of the variable region of the light chain (VL) protein established it as a kappa I, which when compared with other kappa I amyloid associated proteins had unique residues, including Ile-34, Leu-40, and Tyr-71. To study the tertiary structure, BRE VL was expressed in Escherichia coli by using a PCR product amplified from the patient BRE's bone marrow DNA. The PCR product was ligated into pCZ11, a thermal-inducible replication vector. Recombinant BRE VL was isolated, purified to homogeneity, and crystallized by using ammonium sulfate as the precipitant. Two crystal forms were obtained. In crystal form I the BRE VL kappa domain crystallizes as a dimer with unit cell constants isomorphous to previously published kappa protein structures. Comparison with a nonamyloid VL kappa domain from patient REI, identified significant differences in position of residues in the hypervariable segments plus variations in framework region (FR) segments 40-46 (FR2) and 66-67 (FR3). In addition, positional differences can be seen along the two types of local diads, corresponding to the monomer-monomer and dimer-dimer interfaces. From the packing diagram, a model for the amyloid light chain (AL) fibril is proposed based on a pseudohexagonal spiral structure with a rise of approximately the width of two dimers per 360 degree turn. This spiral structure could be consistent with the dimensions of amyloid fibrils as determined by electron microscopy.

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

Operational RNA code for amino acids: species-specific aminoacylation of minihelices switched by a single nucleotide.

The genetic code is based on aminoacylation reactions where specific amino acids are attached to tRNAs bearing anticodon trinucleotides. However, the anticodon-independent specific aminoacylation of RNA minihelix substrates by bacterial and yeast tRNA synthetases suggested an operational RNA code for amino acids whereby specific RNA sequences/structures in tRNA acceptor stems correspond to specific amino acids. Because of the possible significance of the operational RNA code for the development of the genetic code, we investigated aminoacylation of synthetic RNA minihelices with a human enzyme to understand the sequences needed for that aminoacylation compared with those needed for a microbial system. We show here that the species-specific aminoacylation of glycine tRNAs is recapitulated by a species-specific aminoacylation of minihelices. Although the mammalian and Escherichia coli minihelices differ at 6 of 12 base pairs, two of the three nucleotides essential for aminoacylation by the E. coli enzyme are conserved in the mammalian minihelix. The two conserved nucleotides were shown to be also important for aminoacylation of the mammalian minihelix by the human enzyme. A simple interchange of the differing nucleotide enabled the human enzyme to now charge the bacterial substrate and not the mammalian minihelix. Conversely, this interchange made the bacterial enzyme specific for the mammalian substrate. Thus, the positional locations (if not the actual nucleotides) for the operational RNA code for glycine appear conserved from bacteria to mammals.

Identification of mutations in the Wiskott-Aldrich syndrome gene and characterization of a polymorphic dinucleotide repeat at DXS6940, adjacent to the disease gene.

The Wiskott-Aldrich syndrome (WAS) is an X-chromosome-linked recessive disease characterized by eczema, thrombocytopenia, and immunodeficiency. The disease gene has been localized to the proximal short arm of the X chromosome and recently isolated through positional cloning. The function of the encoded protein remains undetermined. In this study we have characterized mutations in 12 unrelated patients to confirm the identity of the disease gene. We have also revised the coding sequence and genomic structure for the WAS gene. To analyze further the transmittance of the disease gene, we have characterized a polymorphic microsatellite at the DXS6940 locus within 30 kb of the gene and demonstrate the inheritance of the affected alleles in families with a history of WAS.

Análise elastoplástica bidimensional de meios reforçados com fibras

De modo a satisfazer aspectos de resistência, custo ou conforto, o aperfeiçoamento do desempenho das estruturas é uma meta sempre almejada na Engenharia. Melhorias têm sido alcançadas dado ao crescente uso de materiais compósitos, pois estes apresentam propriedades físicas diferenciadas capazes de atender as necessidades de projeto. Associado ao emprego de compósitos, o estudo da plasticidade demonstra uma interessante alternativa para aumentar o desempenho estrutural ao conferir uma capacidade resistente adicional ao conjunto. Entretanto, alguns problemas podem ser encontrados na análise elastoplástica de compósitos, além das próprias dificuldades inerentes à incorporação de fibras na matriz, no caso de compósitos reforçados. A forma na qual um compósito reforçado por fibras e suas fases têm sua representação e simulação é de extrema importância para garantir que os resultados obtidos sejam compatíveis com a realidade. À medida que se desenvolvem modelos mais refinados, surgem problemas referentes ao custo computacional, além da necessidade de compatibilização dos graus de liberdade entre os nós das malhas de elementos finitos da matriz e do reforço, muitas vezes exigindo a coincidência das referidas malhas. O presente trabalho utiliza formulações que permitem a representação de compósitos reforçados com fibras sem que haja a necessidade de coincidência entre malhas. Além disso, este permite a simulação do meio e do reforço em regime elastoplástico com o objetivo de melhor estudar o real comportamento. O modelo constitutivo adotado para a plasticidade é o de von Mises 2D associativo com encruamento linear positivo e a solução deste modelo foi obtida através de um processo iterativo. A formulação de elementos finitos posicional é adotada com descrição Lagrangeana Total e apresenta as posições do corpo no espaço como parâmetros nodais. Com o intuito de averiguar a correta implementação das formulações consideradas, exemplos para validação e apresentação das funcionalidades do código computacional desenvolvido foram analisados.

South America, 1807 (Image 2 of 7) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Colombia Prima or South America : in which it has been attempted to delineate the extent of our knowledge of that continent, extracted chiefly from the original manuscript maps of ... Pinto, likewise fom those of João Joaquin da Rocha, João da Costa Ferreira ... Francisco Manuel Sobreviela &c. and from the most authentic edited accounts of those countries, digested & constructed by ... Louis Stanislas D'Arcy Delarochette. It was published by William Faden geographer to His Majesty and to His Royal Highness the Prince of Wales in June 4th, 1807. Scale [ca. 1:3,000,000]. This layer is image 2 of 7 total images of the eight sheet 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 South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, roads, territorial boundaries, shoreline features, mines, tribes, and more. Relief shown by hachures. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1807 (Image 3 of 7) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Colombia Prima or South America : in which it has been attempted to delineate the extent of our knowledge of that continent, extracted chiefly from the original manuscript maps of ... Pinto, likewise fom those of João Joaquin da Rocha, João da Costa Ferreira ... Francisco Manuel Sobreviela &c. and from the most authentic edited accounts of those countries, digested & constructed by ... Louis Stanislas D'Arcy Delarochette. It was published by William Faden geographer to His Majesty and to His Royal Highness the Prince of Wales in June 4th, 1807. Scale [ca. 1:3,000,000]. This layer is image 3 of 7 total images of the eight sheet map, representing the eastern portion of the map.The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, roads, territorial boundaries, shoreline features, mines, tribes, and more. Relief shown by hachures. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1807 (Image 4 of 7) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Colombia Prima or South America : in which it has been attempted to delineate the extent of our knowledge of that continent, extracted chiefly from the original manuscript maps of ... Pinto, likewise fom those of João Joaquin da Rocha, João da Costa Ferreira ... Francisco Manuel Sobreviela &c. and from the most authentic edited accounts of those countries, digested & constructed by ... Louis Stanislas D'Arcy Delarochette. It was published by William Faden geographer to His Majesty and to His Royal Highness the Prince of Wales in June 4th, 1807. Scale [ca. 1:3,000,000]. This layer is image 4 of 7 total images of the eight sheet map, representing the northeast portion of the map.The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, roads, territorial boundaries, shoreline features, mines, tribes, and more. Relief shown by hachures. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1807 (Image 5 of 7) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Colombia Prima or South America : in which it has been attempted to delineate the extent of our knowledge of that continent, extracted chiefly from the original manuscript maps of ... Pinto, likewise fom those of João Joaquin da Rocha, João da Costa Ferreira ... Francisco Manuel Sobreviela &c. and from the most authentic edited accounts of those countries, digested & constructed by ... Louis Stanislas D'Arcy Delarochette. It was published by William Faden geographer to His Majesty and to His Royal Highness the Prince of Wales in June 4th, 1807. Scale [ca. 1:3,000,000]. This layer is image 5 of 7 total images of the eight sheet map, representing the southwest portion of the map.The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, roads, territorial boundaries, shoreline features, mines, tribes, and more. Relief shown by hachures. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1807 (Image 6 of 7) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Colombia Prima or South America : in which it has been attempted to delineate the extent of our knowledge of that continent, extracted chiefly from the original manuscript maps of ... Pinto, likewise fom those of João Joaquin da Rocha, João da Costa Ferreira ... Francisco Manuel Sobreviela &c. and from the most authentic edited accounts of those countries, digested & constructed by ... Louis Stanislas D'Arcy Delarochette. It was published by William Faden geographer to His Majesty and to His Royal Highness the Prince of Wales in June 4th, 1807. Scale [ca. 1:3,000,000]. This layer is image 6 of 7 total images of the eight sheet map, representing the western portion of the map.The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, roads, territorial boundaries, shoreline features, mines, tribes, and more. Relief shown by hachures. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1807 (Image 7 of 7) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Colombia Prima or South America : in which it has been attempted to delineate the extent of our knowledge of that continent, extracted chiefly from the original manuscript maps of ... Pinto, likewise fom those of João Joaquin da Rocha, João da Costa Ferreira ... Francisco Manuel Sobreviela &c. and from the most authentic edited accounts of those countries, digested & constructed by ... Louis Stanislas D'Arcy Delarochette. It was published by William Faden geographer to His Majesty and to His Royal Highness the Prince of Wales in June 4th, 1807. Scale [ca. 1:3,000,000]. This layer is image 7 of 7 total images of the eight sheet 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 South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, roads, territorial boundaries, shoreline features, mines, tribes, and more. Relief shown by hachures. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1819 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: South America : from the latest Spanish and Portuguese surveys. It was published by W. Faden in Jany. 1, 1819. Scale [ca. 1:77,500,000]. The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, territorial boundaries, shoreline features, and more. Relief shown by hachures and pictorially.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1825 (Image 1 of 2) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: General-Charte von Süd-America = Carte générale de L'Amerique Méridionale : en deux grandes feuilles. d'après les observations et les cartes spéciales, rapportées du Voyage dans l'intérieur du Brèsil, pendant les années 1817-1820..., par les Docteurs de Spix et de Martius, Chevaliers de L'Ordre civil de la Couronne de Bavière, membres de L'Académie Royale de Munich ; gestochen von Joh. Bapt. Seitz, Kupferstecher im topographischen Bureau des Kön. baier. General-Quartiermeister Stab. It was published by [M. Lindauer] in 1825. Scale [ca. 1:7,000,000]. This layer is image 1 of 2 total images of the two sheet source map, representing the southern portion of the map. Map in German and French. The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, territorial boundaries, roads, shoreline features, and more. Relief shown by hachures.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

South America, 1825 (Image 2 of 2) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: General-Charte von Süd-America = Carte générale de L'Amerique Méridionale : en deux grandes feuilles. d'après les observations et les cartes spéciales, rapportées du Voyage dans l'intérieur du Brèsil, pendant les années 1817-1820..., par les Docteurs de Spix et de Martius, Chevaliers de L'Ordre civil de la Couronne de Bavière, membres de L'Académie Royale de Munich ; gestochen von Joh. Bapt. Seitz, Kupferstecher im topographischen Bureau des Kön. baier. General-Quartiermeister Stab. It was published by [M. Lindauer] in 1825. Scale [ca. 1:7,000,000]. This layer is image 2 of 2 total images of the two sheet source map, representing the northern portion of the map. Map in German and French.The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, territorial boundaries, roads, shoreline features, and more. Relief shown by hachures.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Ecuador, 1892 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Carta geográfica del Ecuador, por Teodoro Wolf ; publicada por órden del supremo gobierno de la república y trabajada bajo las presidencias de los EE. señores D.J.M. Plácido Caamaño y D. Antonio Flores. It was published by Instituto geográfica de H. Wagner & E. Debes in 1892. Scale 1:445,000. Covers coastal Ecuador and portions of Colombia and Peru. Map in Spanish. The image inside the map neatline is georeferenced to the surface of the earth and fit to the South America Lambert Conformal Conic projected coordinate system. 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 drainage, cities and other human settlements, railroads, roads, territorial boundaries, shoreline features, and more. Relief shown by shading and spot heights. Includes also insets: La region oriental del Ecuador -- Archipiélago de Galápagos, and table of altitudes of cities, villages and other inhabited spots, and, a table administrative divisions and subdivisions of Ecuador. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.