Engineered discoidin domain from factor VIII binds αvβ3 integrin with antibody-like affinity

Alternative scaffolds are non-antibody proteins that can be engineered to bind new targets. They have found useful niches in the therapeutic space due to their smaller size and the ease with which they can be engineered to be bispecific. We sought a new scaffold that could be used for therapeutic ends and chose the C2 discoidin domain of factor VIII, which is well studied and of human origin. Using yeast surface display, we engineered the C2 domain to bind to αvβ3 integrin with a 16 nM affinity while retaining its thermal stability and monomeric nature. We obtained a crystal structure of the engineered domain at 2.1 Å resolution. We have christened this discoidin domain alternative scaffold the “discobody.”

Chesapeake and Delaware Canal Affects Environmental: presented at American Society of Civil Engineers National Water Resources Engineering Meeting, Phoenix, Arizona, 14 January 1971

The Chesapeake and Delaware Canal is a man-made waterway connecting the upper Chesapeake Bay with the Delaware Bay. It started in 1829 as a private barge canal with locks, two at the Delaware end, and one at the Chesapeake end. For the most part, natural tidal and non-tidal waterways were connected by short dredged sections to form the original canal. In 1927, the C and D Canal was converted to a sea-level canal, with a controlling depth of 14 feet, and a width of 150 feet. In 1938 the canal was deepened to 27 feet, with a channel width of 250 feet. Channel side slopes were dredged at 2.5:1, thus making the total width of the waterway at least 385 feet in those segments representing new cuts or having shore spoil area dykes rising above sea level. In 1954 Congress authorized a further enlargement of the Canal to a depth of 35 feet and a channel width of 450 feet. (pdf contains 27 pages)

Some constructions, related to noncommutative tori; Fredholm modules and the Beilinson-Bloch regulator

A noncommutative 2-torus is one of the main toy models of noncommutative geometry, and a noncommutative n-torus is a straightforward generalization of it. In 1980, Pimsner and Voiculescu in [17] described a 6-term exact sequence, which allows for the computation of the K-theory of noncommutative tori. It follows that both even and odd K-groups of n-dimensional noncommutative tori are free abelian groups on 2^n-1 generators. In 1981, the Powers-Rieffel projector was described [19], which, together with the class of identity, generates the even K-theory of noncommutative 2-tori. In 1984, Elliott [10] computed trace and Chern character on these K-groups. According to Rieffel [20], the odd K-theory of a noncommutative n-torus coincides with the group of connected components of the elements of the algebra. In particular, generators of K-theory can be chosen to be invertible elements of the algebra. In Chapter 1, we derive an explicit formula for the First nontrivial generator of the odd K-theory of noncommutative tori. This gives the full set of generators for the odd K-theory of noncommutative 3-tori and 4-tori.

In Chapter 2, we apply the graded-commutative framework of differential geometry to the polynomial subalgebra of the noncommutative torus algebra. We use the framework of differential geometry described in [27], [14], [25], [26]. In order to apply this framework to noncommutative torus, the notion of the graded-commutative algebra has to be generalized: the "signs" should be allowed to take values in U(1), rather than just {-1,1}. Such generalization is well-known (see, e.g., [8] in the context of linear algebra). We reformulate relevant results of [27], [14], [25], [26] using this extended notion of sign. We show how this framework can be used to construct differential operators, differential forms, and jet spaces on noncommutative tori. Then, we compare the constructed differential forms to the ones, obtained from the spectral triple of the noncommutative torus. Sections 2.1-2.3 recall the basic notions from [27], [14], [25], [26], with the required change of the notion of "sign". In Section 2.4, we apply these notions to the polynomial subalgebra of the noncommutative torus algebra. This polynomial subalgebra is similar to a free graded-commutative algebra. We show that, when restricted to the polynomial subalgebra, Connes construction of differential forms gives the same answer as the one obtained from the graded-commutative differential geometry. One may try to extend these notions to the smooth noncommutative torus algebra, but this was not done in this work.

A reconstruction of the Beilinson-Bloch regulator (for curves) via Fredholm modules was given by Eugene Ha in [12]. However, the proof in [12] contains a critical gap; in Chapter 3, we close this gap. More specifically, we do this by obtaining some technical results, and by proving Property 4 of Section 3.7 (see Theorem 3.9.4), which implies that such reformulation is, indeed, possible. The main motivation for this reformulation is the longer-term goal of finding possible analogs of the second K-group (in the context of algebraic geometry and K-theory of rings) and of the regulators for noncommutative spaces. This work should be seen as a necessary preliminary step for that purpose.

For the convenience of the reader, we also give a short description of the results from [12], as well as some background material on central extensions and Connes-Karoubi character.

Investigation of competitive antagonist binding to the nicotinic acetylcholine receptor using voltage-jump and light-flash techniques

1. The effect of 2,2’-bis-[α-(trimethylammonium)methyl]azobenzene (2BQ), a photoisomerizable competitive antagonist, was studied at the nicotinic acetycholine receptor of Electrophorus electroplaques using voltage-jump and light-flash techniques.

2. 2BQ, at concentrations below 3 μΜ, reduced the amplitude of voltage-jump relaxations but had little effect on the voltage-jump relaxation time constants under all experimental conditions. At higher concentrations and voltages more negative than -150 mV, 2BQ caused significant open channel blockade.

3. Dose-ratio studies showed that the cis and trans isomers of 2BQ have equilibrium binding constants (K _ᵢ) of .33 and 1.0 μΜ, respectively. The binding constants determined for both isomers are independent of temperature, voltage, agonist concentration, and the nature of the agonist.

4. In a solution of predominantly cis-2BQ, visible-light flashes led to a net cis→trans isomerization and caused an increase in the agonist-induced current. This increase had at least two exponential components; the larger amplitude component had the same time constant as a subsequent voltage-jump relaxation; the smaller amplitude component was investigated using ultraviolet light flashes.

5. In a solution of predominantly trans-2BQ, UV-light flashes led to a net trans→cis isomerization and caused a net decrease in the agonist-induced current. This effect had at least two exponential components. The smaller and faster component was an increase in agonist-induced current and had a similar time constant to the voltage-jump relaxation. The larger component was a slow decrease in the agonist-induced current with rate constant approximately an order of magnitude less than that of the voltage-jump relaxation. This slow component provided a measure of the rate constant for dissociation of cis-2BQ (k_ = 60/s at 20°C). Simple modelling of the slope of the dose-rate curves yields an association rate constant of 1.6 x 10⁸/M/s. This agrees with the association rate constant of 1.8 x 10⁸/M/s estimated from the binding constant (K_i). The Q₁₀ of the dissociation rate constant of cis-2BQ was 3.3 between 6° and 20°C. The rate constants for association and dissociation of cis-28Q at receptors are independent of voltage, agonist concentration, and the nature of the agonist.

6. We have measured the molecular rate constants of a competitive antagonist which has roughly the same K _ᵢ as d-tubocurarine but interacts more slowly with the receptor. This leads to the conclusion that curare itself has an association rate constant of 4 x 10⁹/M/s or roughly as fast as possible for an encounter-limited reaction.

Investigating the Role of the GET3-GET4/GET5 Interaction During Tail-Anchor Protein Targeting

The proper targeting of membrane proteins is essential to the viability of all cells. Tail-anchored (TA) proteins, defined as having a single transmembrane helix at their C-terminus, are post-translationally targeted to the endoplasmic reticulum (ER) membrane by the GET pathway (Guided Entry of TA proteins). In the yeast pathway, the handover of TA substrates is mediated by the heterotetrameric Get4/Get5 (Get4/5) complex, which tethers the co-chaperone Sgt2 to the central targeting factor, the Get3 ATPase. Although binding of Get4/5 to Get3 is critical for efficient TA targeting, the mechanisms by which Get4 regulates Get3 are unknown. To understand the molecular basis of Get4 function, we used a combination of structural biology, biochemistry, and cell biology. Get4/5 binds across the Get3 dimer interface, in an orientation only compatible with a closed Get3, providing insight into the role of nucleotide in complex formation. Additionally, this structure reveals two functionally distinct binding interfaces for anchoring and ATPase regulation, and loss of the regulatory interface leads to strong defects in vitro and in vivo. Additional crystal structures of the Get3-Get4/5 complex give rise to an alternate conformation, which represents an initial binding interaction mediated by electrostatics that facilitates the rate of subsequent inhibited complex formation. This interface is supported by an in-depth kinetic analysis of the Get3-Get4/5 interaction confirming the two-step complex formation. These results allow us to generate a refined model for Get4/5 function in TA targeting.

Geomorphology of a Portion of the Easternmost Ventura Basin

The Humphreys Quadrangle is a portion of the easternmost Ventura Basin underlain by a thick series of Tertiary sedimentary rocks. On these rocks a great variety of geomorphic forms have been molded by the processes of running water typical of a semi-arid climate and by several types of mass movement. Among the different categories of mass movement present, a new type, the siltflow, was observed.

The geomorphic forms of special interest present in the quadrangle are rock cones, open canyonheads, asymmetric canyons, and stream terraces and straths. The author urges the adoption of the definition of strath as that part of an old dissected valley floor, including the floors of tributary valleys, which was not part of the floodplain of the main valley stream.

An old erosion surface, the Puckett Mesa Surface, is present in the Humphreys Quadrangle which is correlative with certain of the older stream terraces. By correlating the variation of gradient and of fill of the stream terraces with post –Wisconsin climatic fluctuations the age of the Puckett Mesa Surface is set at approximately 6000 B.C. This correlation sets the probable age of the older Rancho La Brea deposits at 6000 to 8000 B. C. and the probable age of the Carpenteria brea deposits at 1000 to 1 B. C.

A Geologic Report on the Pacoima Area

The region treated in the following report is a small area of about one square mile near Pacoima, California. It consists of a group of small hills that that form the western abutment of the Hansen Dam. It is underlain by a section of intrusives, sediments, and extrusives, which may be subdivided into four groups.

The oldest rocks form the Dimebere complex of Jurassic (?) plutonic rocks, pegmatites, and schists. Lying uncomformably on this is a series of alternating terrestrial sandstones and bassalts of Tertiary age. These are unconformably overlain in turn by the Hansen Dam formation, a series of marine shales and sandstone correlated with the Temblor by the fossil contact. Finally into these strata was intruded the Munglish andesite.

These strata form a shallow, plunging anticline, whose axis trends slightly east of north and lies in the center of the hills. The unconformities have been offset in several places by a series of faults apparently related to the anticline.

A complete outline of the geologic history is included in the report.

Energy transfer in molecular collisions

Two general, numerically exact, quantum mechanical methods have been developed for the calculation of energy transfer in molecular collisions. The methods do not treat electronic transitions because of the exchange symmetry of the electrons. All interactions between the atoms in the system are written as potential energies.

The first method is a matrix generalization of the invariant imbedding procedure, ^{17, 20} adapted for multi-channel collision processes. The second method is based on a direct integration of the matrix Schrödinger equation, with a re-orthogonalization transform applied during the integration.

Both methods have been applied to a collinear collision model for two diatoms, interacting via a repulsive exponential potential. Two major studies were performed. The first was to determine the energy dependence of the transition probabilities for an H₂ on the H₂ model system. Transitions are possible between translational energy and vibrational energy, and from vibrational modes of one H₂ to the other H₂. The second study was to determine the variation of vibrational energy transfer probability with differences in natural frequency of two diatoms similar to N₂.

Comparisons were made to previous approximate analytical solutions of this same problem. For translational to vibrational energy transfer, the previous approximations were not adequate. For vibrational to vibrational energy transfer of one vibrational quantum, the approximations were quite good.

Aprimorando a raça brasileira: uma análise dos discursos da psiquiatria no início do século XX no Brasil

O presente trabalho tem por objetivo analisar a noção de causalidade biológica da doença mental através dos discursos eugênicos e higiênicos nas décadas de 1920 e 1930 no Brasil. Para tanto, selecionamos a revista Archivos Brasileiros de Hygiene Mental. Esta revista foi escolhida por ser produzida pela Liga Brasileira de Hygiene Mental, uma instituição bastante representativa destes discursos neste período, e também por ser uma revista editada no Rio de Janeiro, nosso recorte geográfico. A revista foi produzida de 1925 a 1947 e o período selecionado para sua análise foi o de 1925 a 1935. Para tal propósito, utilizamos um referencial teórico foucaultiano, especialmente no que tange às discussões em torno do tema do biopoder. Acreditamos que uma análise histórica, necessariamente desnaturalizante, dos discursos psiquiátricos desse período no Brasil, possa contribuir para a compreensão de certas peculiaridades dos discursos psiquiátricos atuais, a fim de possibilitar uma revisão das concepções estabelecidas de tratamento, incitando a ressignificação das experiências de saúde e adoecimento e, conseqüentemente, de propostas terapêuticas.

Economía de la salud, modalidades de evaluación económica

La salud es un aspecto muy importante en la vida de cualquier persona, de forma que, al ocurrir cualquier contingencia que merma el estado de salud de un individuo o grupo de personas, se debe valorar estrictamente y en detalle las distintas alternativas destinadas a combatir la enfermedad. Esto se debe a que, la calidad de vida de los pacientes variará dependiendo de la alternativa elegida. La calidad de vida relacionada con la salud (CVRS) se entiende como el valor asignado a la duración de la vida, modificado por la oportunidad social, la percepción, el estado funcional y la disminución provocadas por una enfermedad, accidente, tratamiento o política (Sacristán et al, 1995). Para determinar el valor numérico asignado a la CVRS, ante una intervención, debemos beber de la teoría económica aplicada a las evaluaciones sanitarias para nuevas intervenciones. Entre los métodos de evaluación económica sanitaria, el método coste-utilidad emplea como utilidad, los años de vida ajustado por calidad (AVAC), que consiste, por un lado, tener en cuenta la calidad de vida ante una intervención médica, y por otro lado, los años estimados a vivir tras la intervención. Para determinar la calidad de vida, se emplea técnicas como el Juego Estándar, la Equivalencia Temporal y la Escala de Categoría. Estas técnicas nos proporcionan un valor numérico entre 0 y 1, siendo 0 el peor estado y 1 el estado perfecto de salud. Al entrevistar a un paciente a cerca de la utilidad en términos de salud, puede haber riesgo o incertidumbre en la pregunta planteada. En tal caso, se aplica el Juego Estándar con el fin de determinar el valor numérico de la utilidad o calidad de vida del paciente ante un tratamiento dado. Para obtener este valor, al paciente se le plantean dos escenarios: en primer lugar, un estado de salud con probabilidad de morir y de sobrevivir, y en segundo lugar, un estado de certeza. La utilidad se determina modificando la probabilidad de morir hasta llegar a la probabilidad que muestra la indiferencia del individuo entre el estado de riesgo y el estado de certeza. De forma similar, tenemos la equivalencia temporal, cuya aplicación resulta más fácil que el juego estándar ya que valora en un eje de ordenadas y abscisas, el valor de la salud y el tiempo a cumplir en esa situación ante un tratamiento sanitario, de forma que, se llega al valor correspondiente a la calidad de vida variando el tiempo hasta que el individuo se muestre indiferente entre las dos alternativas. En último lugar, si lo que se espera del paciente es una lista de estados de salud preferidos ante un tratamiento, empleamos la Escala de Categoría, que consiste en una línea horizontal de 10 centímetros con puntuaciones desde 0 a 100. La persona entrevistada coloca la lista de estados de salud según el orden de preferencia en la escala que después es normalizado a un intervalo entre 0 y 1. Los años de vida ajustado por calidad se obtienen multiplicando el valor de la calidad de vida por los años de vida estimados que vivirá el paciente. Sin embargo, ninguno de estas metodologías mencionadas consideran el factor edad, siendo necesario la inclusión de esta variable. Además, los pacientes pueden responder de manera subjetiva, situación en la que se requiere la opinión de un experto que determine el nivel de discapacidad del aquejado. De esta forma, se introduce el concepto de años de vida ajustado por discapacidad (AVAD) tal que el parámetro de utilidad de los AVAC será el complementario del parámetro de discapacidad de los AVAD Q^i=1-D^i. A pesar de que este último incorpora parámetros de ponderación de edad que no se contemplan en los AVAC. Además, bajo la suposición Q=1-D, podemos determinar la calidad de vida del individuo antes del tratamiento. Una vez obtenido los AVAC ganados, procedemos a la valoración monetaria de éstos. Para ello, partimos de la suposición de que la intervención sanitaria permite al individuo volver a realizar las labores que venía realizando. De modo que valoramos los salarios probables con una temporalidad igual a los AVAC ganados, teniendo en cuenta la limitación que supone la aplicación de este enfoque. Finalmente, analizamos los beneficios derivados del tratamiento (masa salarial probable) si empleamos la tabla GRF-95 (población femenina) y GRM-95 (población masculina).

Arquitetura de uma rede de interconexão com memória compartilhada baseada na topologia crossbar

Multi-Processor System-on-Chip (MPSoC) possui vários processadores, em um único chip. Várias aplicações podem ser executadas de maneira paralela ou uma aplicação paralelizável pode ser particionada e alocada em cada processador, a fim de acelerar a sua execução. Um problema em MPSoCs é a comunicação entre os processadores, necessária para a execução destas aplicações. Neste trabalho, propomos uma arquitetura de rede de interconexão baseada na topologia crossbar, com memória compartilhada. Esta arquitetura é parametrizável, possuindo N processadores e N módulos de memórias. A troca de informação entre os processadores é feita via memória compartilhada. Neste tipo de implementação cada processador executa a sua aplicação em seu próprio módulo de memória. Através da rede, todos os processadores têm completo acesso a seus módulos de memória simultaneamente, permitindo que cada aplicação seja executada concorrentemente. Além disso, um processador pode acessar outros módulos de memória, sempre que necessite obter dados gerados por outro processador. A arquitetura proposta é modelada em VHDL e seu desempenho é analisado através da execução paralela de uma aplicação, em comparação à sua respectiva execução sequencial. A aplicação escolhida consiste na otimização de funções objetivo através do método de Otimização por Enxame de Partículas (Particle Swarm Optimization - PSO). Neste método, um enxame de partículas é distribuído igualmente entre os processadores da rede e, ao final de cada interação, um processador acessa o módulo de memória de outro processador, a fim de obter a melhor posição encontrada pelo enxame alocado neste. A comunicação entre processadores é baseada em três estratégias: anel, vizinhança e broadcast. Essa aplicação foi escolhida por ser computacionalmente intensiva e, dessa forma, uma forte candidata a paralelização.

The Great Albatross Philippine Expedition and Its Fishes

The Philippine Expedition of 1907-10 was the longest and most extensive assignment of the Albatross's 39-year career. It came about because the United States had acquired the Philippines following the Spanish-American War of 1898 and the bloody Philippine Insurection of 1899-1902. The purpose of the expedition was to surbey and assess the aquatic resources of the Philippine Islands. Dr. Hugh M. Smith, the Deputy Commissioner of the U.S. Bureau of Fisheries, was the Director of the Expedition. Other scientific participants were Frederick M. Chamberlain, Lewis Radcliffe, Paul Bartsch, Harry C. Fasset, Clarence Wells, Albert Burrows, Alvin Seale, and Roy Chapman Andrews. The expedition consisted of a series of cruises, each beginning and ending in Manila and exploring a different part of the island group. In addition to the Philippines proper, the ship also explored parts of the Dutch East Indies and areas around Hong Kong and Taiwan. The expedition returned great quantities of fish and invertebrate speciments as well as hydrographic and fisheries data; most of the material was eventually deposited in the Smithsonian Institution's National Museum of Natural History. The fisehs were formally accessioned into the museum in 1922 and fell under the car of Barton A. Bean, Assistant Curator of Fishes, who then recruited Henry W. Fowler to work up the material. Fowler completed his studies of the entire collection, but only part of it was ever published, due in part to the economic constraints caused by the Depression. The material from the Philippine Expedition constituted the largest single accession of fishes ever received by the museum. These speciments are in good condition today and are still being used in scientific research.

A Review of Interactions Between Hawaii's Fisheries and Protected Species

Several fisheries in Hawaii are known to have interactions with protected cetaceans, seabirds, marine turtles, or seals. Handline fisheries for bottomfish, tuna, and mackerel scad lose bait and catch to bottlenose dolphins, rough-toothed dolphins, and Hawaiian monk seals. Troll fisheries for billfish lose live bait to bottlenose dolphins, rough-toothed dolphins, albatrosses, and boobies; these fisheries may also lose catch to false killer whales. A longline fishery for tuna and billfish has burgeoned in Hawaii since 1987, resulting in interactions with protected species; marine turtles, seabirds, and monk seals take bait and are known to become hooked, and false killer whales may take catch. Research on deterrents or alternative fishing methods has been limited, and interactions have been reduced primarily through management and regulatory actions. These include area closures and gear requirements. An observer program has also been established for the bottomfish and longline fisheries.

DistributedCL: middleware de processamento distribuído em GPU com interface da API OpenCL.

Este trabalho apresenta a proposta de um middleware, chamado DistributedCL, que torna transparente o processamento paralelo em GPUs distribuídas. Com o suporte do middleware DistributedCL uma aplicação, preparada para utilizar a API OpenCL, pode executar de forma distribuída, utilizando GPUs remotas, de forma transparente e sem necessidade de alteração ou nova compilação do seu código. A arquitetura proposta para o middleware DistributedCL é modular, com camadas bem definidas e um protótipo foi construído de acordo com a arquitetura, onde foram empregados vários pontos de otimização, incluindo o envio de dados em lotes, comunicação assíncrona via rede e chamada assíncrona da API OpenCL. O protótipo do middleware DistributedCL foi avaliado com o uso de benchmarks disponíveis e também foi desenvolvido o benchmark CLBench, para avaliação de acordo com a quantidade dos dados. O desempenho do protótipo se mostrou bom, superior às propostas semelhantes, tendo alguns resultados próximos do ideal, sendo o tamanho dos dados para transmissão através da rede o maior fator limitante.

Breeding populations of seabirds in California, 1989-1991. Volume I - population estimates

In 1989-1991, the U.S. Fish and Wildlife Service surveyed breeding populations of seabirds on the entire California coast. This study was sponsored by the Minerals Management Service in relation to outer continental shelf oil and gas leasing. At 483 nesting sites (excluding terns and skimmers in southern California), we estimated 643,307 breeding birds of 21 seabird species including: 410 Fork-tailed Storm-petrel (Oceanodroma furcata); 12,551 Leach's Storm-petrel (O. leucorhoa); 7,209 Ashy Storm-petrel (O. homochroa); 274 Black Storm-petrel (O. melania); 11,916 Brown Pelican (Pelecanus occidentalis); 10,037 Double-crested Cormorant (Phalacrocorax auritus); 83,394 Brandt's Cormorant (P. penicillatus); 14,345 Pelagic Cormorant (P. pelagicus); 888 Black Oystercatcher (Haemotopus bachmani); 4,764 California Gull (Larus californicus); 61,760 Western Gull (L. occidentalis); 2,838 Caspian Tern (Sterna caspia) (excluding southern California); 3,550 Forster's Tern (S. forsteri) (excluding southern California); 272 Least Tern (S. albifrons) (excluding southern California); 351,336 Common Murre (Uria aalge); 15,470 Pigeon Guillemot (Cepphus columba); 1,821 Marbled Murrelet (Brachyramphus marmoratus); 1,760 Xantus' Murrelet (Endomychura hypoleuca); 56,562 Cassin's Auklet (Ptychoramphus aleuticus); 1,769 Rhinoceros Auklet (Cerorhinca monocerata); and 276 Tufted Puffin (Fratercula cirrhata). The inland, historical or hybrid breeding status of American White Pelican (P. erythrorynchus), American Oystercatcher (H. palliatus), Heermann's Gull (L. heermanni), Ring-billed Gull (L. delawarensis), Glaucous-winged Gull (L. glaucescens) and Black Tern (Chlidonias niger) are discussed. Estimates for Gull-billed Tern (S. nilotica), Royal Tern (S. maxima), Elegant Tern (S. elegans) and Black Skimmer (Rhynchops niger) will be included in the final draft of this report. Overall numbers were slightly lower than reported in 1975-1980 surveys (summarized in Sowls et al. 1980. Catalog of California seabird colonies. U.S. Dept. Int., Fish Wildl. Serv., Biol. Serv. Prog., FWS/OBS 37/80). Recent declines were found or suspected for Fork-tailed Storm-petrel, Leach's Storm-petrel, White Pelican, Black Tern, Caspian Tern, Least Tern, Common Murre and Marbled Murrelet. Recent increases were found or suspected for Brown Pelican, Double-crested cormorant, California Gull, Western Gull, Forster's Tern and Rhinoceros Auklet. Similar numbers were found for other species or trends could not be determined without additional surveys, studies and/or more in-depth comparisons with previous surveys. The status of terns and skimmers in southern California has not yet been finalized.