Structure-Guided Design and Biophysical Characterization of Novel Anti-HIV Reagents

Despite over 30 years of effort, an HIV-1 vaccine that elicits protective antibodies still does not exist. Recent clinical studies have identified that during natural infection about 20% of the population is capable of mounting a potent and protective antibody response. Closer inspection of these individuals reveal that a subset of these antibodies, recently termed potent VRC01-like (PVL), derive exclusively from a single human germline heavy chain gene. Induced clonal expansion of the B cell encoding this gene is the first step through which PVL antibodies may be elicited. Unfortunately, naturally occurring HIV gp120s fail to bind to this germline, and as a result cannot be used as the initial prime for a vaccine regimen. We have determined the crystal structure of an important germline antibody that is a promising target for vaccine design efforts, and have set out to engineer a more likely candidate using computationally-guided rational design.

In addition to prevention efforts on the side of vaccine design, recently characterized broadly neutralizing anti-HIV antibodies have excellent potential for use in gene therapy and passive immunotherapy. The separation distance between functional Fabs on an antibody is important due to the sparse distribution of envelop spikes on HIV compared to other viruses. We set out to build and characterize novel antibody architectures by incorporating structured linkers into the hinge region of an anti-HIV antibody b12. The goal was to observe whether these linkers increased the arm-span of the IgG dimer. When incorporated, flexible Gly4Ser repeats did not result in detectable extensions of the IgG antigen binding domains, by contrast to linkers including more rigid domains such as β2-microglobulin, Zn-α2-glycoprotein, and tetratricopeptide repeats (TPRs). This study adds an additional set of linkers with varying lengths and rigidities to the available linker repertoire, which may be useful for the modification and construction of antibodies and other fusion proteins.

First principles based multiparadigm modeling of electronic structures and dynamics

Electronic structures and dynamics are the key to linking the material composition and structure to functionality and performance.

An essential issue in developing semiconductor devices for photovoltaics is to design materials with optimal band gaps and relative positioning of band levels. Approximate DFT methods have been justified to predict band gaps from KS/GKS eigenvalues, but the accuracy is decisively dependent on the choice of XC functionals. We show here for CuInSe₂ and CuGaSe₂, the parent compounds of the promising CIGS solar cells, conventional LDA and GGA obtain gaps of 0.0-0.01 and 0.02-0.24 eV (versus experimental values of 1.04 and 1.67 eV), while the historically first global hybrid functional, B3PW91, is surprisingly the best, with band gaps of 1.07 and 1.58 eV. Furthermore, we show that for 27 related binary and ternary semiconductors, B3PW91 predicts gaps with a MAD of only 0.09 eV, which is substantially better than all modern hybrid functionals, including B3LYP (MAD of 0.19 eV) and screened hybrid functional HSE06 (MAD of 0.18 eV).

The laboratory performance of CIGS solar cells (> 20% efficiency) makes them promising candidate photovoltaic devices. However, there remains little understanding of how defects at the CIGS/CdS interface affect the band offsets and interfacial energies, and hence the performance of manufactured devices. To determine these relationships, we use the B3PW91 hybrid functional of DFT with the AEP method that we validate to provide very accurate descriptions of both band gaps and band offsets. This confirms the weak dependence of band offsets on surface orientation observed experimentally. We predict that the CBO of perfect CuInSe₂/CdS interface is large, 0.79 eV, which would dramatically degrade performance. Moreover we show that band gap widening induced by Ga adjusts only the VBO, and we find that Cd impurities do not significantly affect the CBO. Thus we show that Cu vacancies at the interface play the key role in enabling the tunability of CBO. We predict that Na further improves the CBO through electrostatically elevating the valence levels to decrease the CBO, explaining the observed essential role of Na for high performance. Moreover we find that K leads to a dramatic decrease in the CBO to 0.05 eV, much better than Na. We suggest that the efficiency of CIGS devices might be improved substantially by tuning the ratio of Na to K, with the improved phase stability of Na balancing phase instability from K. All these defects reduce interfacial stability slightly, but not significantly.

A number of exotic structures have been formed through high pressure chemistry, but applications have been hindered by difficulties in recovering the high pressure phase to ambient conditions (i.e., one atmosphere and room temperature). Here we use dispersion-corrected DFT (PBE-ulg flavor) to predict that above 60 GPa the most stable form of N₂O (the laughing gas in its molecular form) is a 1D polymer with an all-nitrogen backbone analogous to cis-polyacetylene in which alternate N are bonded (ionic covalent) to O. The analogous trans-polymer is only 0.03-0.10 eV/molecular unit less stable. Upon relaxation to ambient conditions both polymers relax below 14 GPa to the same stable non-planar trans-polymer, accompanied by possible electronic structure transitions. The predicted phonon spectrum and dissociation kinetics validate the stability of this trans-poly-NNO at ambient conditions, which has potential applications as a new type of conducting polymer with all-nitrogen chains and as a high-energy oxidizer for rocket propulsion. This work illustrates in silico materials discovery particularly in the realm of extreme conditions.

Modeling non-adiabatic electron dynamics has been a long-standing challenge for computational chemistry and materials science, and the eFF method presents a cost-efficient alternative. However, due to the deficiency of FSG representation, eFF is limited to low-Z elements with electrons of predominant s-character. To overcome this, we introduce a formal set of ECP extensions that enable accurate description of p-block elements. The extensions consist of a model representing the core electrons with the nucleus as a single pseudo particle represented by FSG, interacting with valence electrons through ECPs. We demonstrate and validate the ECP extensions for complex bonding structures, geometries, and energetics of systems with p-block character (C, O, Al, Si) and apply them to study materials under extreme mechanical loading conditions.

Despite its success, the eFF framework has some limitations, originated from both the design of Pauli potentials and the FSG representation. To overcome these, we develop a new framework of two-level hierarchy that is a more rigorous and accurate successor to the eFF method. The fundamental level, GHA-QM, is based on a new set of Pauli potentials that renders exact QM level of accuracy for any FSG represented electron systems. To achieve this, we start with using exactly derived energy expressions for the same spin electron pair, and fitting a simple functional form, inspired by DFT, against open singlet electron pair curves (H₂ systems). Symmetric and asymmetric scaling factors are then introduced at this level to recover the QM total energies of multiple electron pair systems from the sum of local interactions. To complement the imperfect FSG representation, the AMPERE extension is implemented, and aims at embedding the interactions associated with both the cusp condition and explicit nodal structures. The whole GHA-QM+AMPERE framework is tested on H element, and the preliminary results are promising.

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.

At Your Convenience: Facilitating Voting and Registration

This work proposes answers to methodological and substantive questions related to convenience voting. The first analytical chapter surveys the various research designs that have been proposed within this literature, and concludes that the field benefits from using all in conjunction. The next chapter uses matching to identify the relationship between disability status and political participation, and considers whether any forms of convenience voting mediate in the relationship. The final two analytical chapters examine how online voter registration, one of the most recent policy innovations, affects participation and vote share in American elections. The concluding chapter summarizes the findings presented herein, and briefly discusses the natural extensions of this work.

Death or taxes? The political economy of sanitation expenditure in nineteenth-century Britain

This thesis consists of three papers studying the relationship between democratic reform, expenditure on sanitation public goods and mortality in Britain in the second half of the nineteenth century. During this period decisions over spending on critical public goods such as water supply and sewer systems were made by locally elected town councils, leading to extensive variation in the level of spending across the country. This dissertation uses new historical data to examine the political factors determining that variation, and the consequences for mortality rates.

The first substantive chapter describes the spread of government sanitation expenditure, and analyzes the factors that determined towns' willingness to invest. The results show the importance of towns' financial constraints, both in terms of the available tax base and access to borrowing, in limiting the level of expenditure. This suggests that greater involvement by Westminster could have been very effective in expediting sanitary investment. There is little evidence, however, that democratic reform was an important driver of greater expenditure.

Chapter 3 analyzes the effect of extending voting rights to the poor on government public goods spending. A simple model predicts that the rich and the poor will desire lower levels of public goods expenditure than the middle class, and so extensions of the right to vote to the poor will be associated with lower spending. This prediction is tested using plausibly exogenous variation in the extent of the franchise. The results strongly support the theoretical prediction: expenditure increased following relatively small extensions of the franchise, but fell once more than approximately 50% of the adult male population held the right to vote.

Chapter 4 tests whether the sanitary expenditure was effective in combating the high mortality rates following the Industrial Revolution. The results show that increases in urban expenditure on sanitation-water supply, sewer systems and streets-was extremely effective in reducing mortality from cholera and diarrhea.

Experimental and theoretical studies of the electrothermal instability in a nonequilibrium plasma

Experimental and theoretical studies have been made of the electrothermal waves occurring in a nonequilibrium MHD plasma. These waves are caused by an instability that occurs when a plasma having a dependence of conductivity on current density is subjected to crossed electric and magnetic fields. Theoretically, these waves were studied by developing and solving the equations of a steady, one-dimensional nonuniformity in electron density. From these nonlinear equations, predictions of the maximum amplitude and of the half width of steady waves could be obtained. Experimentally, the waves were studied in a nonequilibrium discharge produced in a potassium-seeded argon plasma at 2000°K and 1 atm. pressure. The behavior of such a discharge with four different configurations of electrodes was determined from photographs, photomultiplier measurements, and voltage probes. These four configurations were chosen to produce steady waves, to check the stability of steady waves, and to observe the manifestation of the waves in a MHD generator or accelerator configuration.

Steady, one-dimensional waves were found to exist in a number of situations, and where they existed, their characteristics agreed with the predictions of the steady theory. Some extensions of this theory were necessary, however, to describe the transient phenomena occurring in the inlet region of a discharge transverse to the gas flow. It was also found that in a discharge away from the stabilizing effect of the electrodes, steady waves became unstable for large Hall parameters. Methods of prediction of the effective electrical conductivity and Hall parameter of a plasma with nonuniformities caused by the electrothermal waves were also studied. Using these methods and the values of amplitude predicted by the steady theory, it was found that the measured decrease in transverse conductivity of a MHD device, 50 per cent at a Hall parameter of 5, could be accounted for in terms of the electrothermal instability.

Large plane deformations of thin elastic sheets of neo-hookean material

Large plane deformations of thin elastic sheets of neo-Hookean material are considered and a method of successive substitutions is developed to solve problems within the two-dimensional theory of finite plane stress. The first approximation is determined by linear boundary value problems on two harmonic functions, and it is approached asymptotically at very large extensions in the plane of the sheet. The second and higher approximations are obtained by solving Poisson equations. The method requires modification when the membrane has a traction-free edge.

Several problems are treated involving infinite sheets under uniform biaxial stretching at infinity. First approximations are obtained when a circular or elliptic inclusion is present and when the sheet has a circular or elliptic hole, including the limiting cases of a line inclusion and a straight crack or slit. Good agreement with exact solutions is found for circularly symmetric deformations. Other examples discuss the stretching of a short wide strip, the deformation near a boundary corner which is traction-free, and the application of a concentrated load to a boundary point.

Detecção e classificação de VTCDs em sistemas de distribuição de energia elétrica usando redes neurais artificiais.

O objetivo deste trabalho é conhecer e compreender melhor os imprevistos no fornecimento de energia elétrica, quando ocorrem as variações de tensão de curta duração (VTCD). O banco de dados necessário para os diagnósticos das faltas foi obtido através de simulações de um modelo de alimentador radial através do software PSCAD/EMTDC. Este trabalho utiliza um Phase-Locked Loop (PLL) com o intuito de detectar VTCDs e realizar a estimativa automática da frequência, do ângulo de fase e da amplitude das tensões e correntes da rede elétrica. Nesta pesquisa, desenvolveram-se duas redes neurais artificiais: uma para identificar e outra para localizar as VTCDs ocorridas no sistema de distribuição de energia elétrica. A técnica aqui proposta aplica-se a alimentadores trifásicos com cargas desequilibradas, que podem possuir ramais laterais trifásicos, bifásicos e monofásicos. No desenvolvimento da mesma, considera-se que há disponibilidade de medições de tensões e correntes no nó inicial do alimentador e também em alguns pontos esparsos ao longo do alimentador de distribuição. Os desempenhos das arquiteturas das redes neurais foram satisfatórios e demonstram a viabilidade das RNAs na obtenção das generalizações que habilitam o sistema para realizar a classificação de curtos-circuitos.

Modeling habits as self-sustaining patterns of sensorimotor behavior

In the recent history of psychology and cognitive neuroscience, the notion of habit has been reduced to a stimulus-triggered response probability correlation. In this paper we use a computational model to present an alternative theoretical view (with some philosophical implications), where habits are seen as self-maintaining patterns of behavior that share properties in common with self-maintaining biological processes, and that inhabit a complex ecological context, including the presence and influence of other habits. Far from mechanical automatisms, this organismic and self-organizing concept of habit can overcome the dominating atomistic and statistical conceptions, and the high temporal resolution effects of situatedness, embodiment and sensorimotor loops emerge as playing a more central, subtle and complex role in the organization of behavior. The model is based on a novel "iterant deformable sensorimotor medium (IDSM)," designed such that trajectories taken through sensorimotor-space increase the likelihood that in the future, similar trajectories will be taken. We couple the IDSM to sensors and motors of a simulated robot, and show that under certain conditions, the IDSM conditions, the IDSM forms self-maintaining patterns of activity that operate across the IDSM, the robot's body, and the environment. We present various environments and the resulting habits that form in them. The model acts as an abstraction of habits at a much needed sensorimotor "meso-scale" between microscopic neuron-based models and macroscopic descriptions of behavior. Finally, we discuss how this model and extensions of it can help us understand aspects of behavioral self-organization, historicity and autonomy that remain out of the scope of contemporary representationalist frameworks.

Motivações e experiências de alunos em Projeto de Extensão Universitária em hospital pediátrico: o projeto Alunos Contadores de Histórias do IPPMG/ UFRJ

Este estudo investigou as motivações de alunos da Universidade Federal do Rio de Janeiro (UFRJ) para participar de um projeto de Extensão Universitária em um hospital pediátrico, assim como as contribuições percebidas pelos estudantes em relação às suas trajetórias pessoais e profissionais relacionadas à participação no projeto. O Projeto de Extensão Universitária Alunos Contadores de Histórias é desenvolvido no Instituto de Puericultura e Pediatria Martagão Gesteira (IPPMG) há quatro anos e visa à melhoria do cuidado junto à clientela, através da oferta de uma atividade lúdica, a contação de histórias, que representa algo de positivo num momento de muitas perdas e sofrimento. A cada semestre é realizada uma seleção e, após a capacitação, os alunos passam a contar histórias para as crianças, os adolescentes e seus familiares, nos diversos setores assistenciais da instituição durante duas horas por semana, por no mínimo seis meses. Foi realizado um estudo exploratório usando os métodos quantitativo e qualitativo. Os dados utilizados foram provenientes da análise de registros existentes em documentos do projeto e de dois grupos focais realizados com alunos. A análise dos dados apontou que os alunos participantes buscam o projeto no intuito de poder realizar uma atividade solidária, junto às crianças. Suas percepções sobre a experiência e suas contribuições, de uma maneira geral, são muito positivas, e revelam amadurecimento e redimensionamento de valores com ampliação da visão social, através de uma atividade a qual referem ser prazerosa. As principais dificuldades observadas foram a falta de flexibilização curricular e o desconhecimento das propostas da Extensão Universitária por grande parte do corpo discente e também dos docentes e técnico administrativos dos diversos cursos. O projeto está sintonizado com as propostas da Política Nacional de Extensão Universitária e o presente estudo espera contribuir para o aprimoramento das atividades de Extensão Universitária em ambientes institucionais análogos.

The Ragfish, Icosteus aenigmaticus Lockington, 1880: A Synthesis of Historical and Recent Records From the North Pacific Ocean and the Bering Sea

Knowledge of the distribution and biology of the ragfish, Icosteus aenigmaticus, an aberrant deepwater perciform of the North Pacific Ocean, has increased slowly since the first description of the species in the 1880’s which was based on specimens retrieved from a fish monger’s table in San Francisco, Calif. As a historically rare, and subjectively unattractive appearing noncommercial species, ichthyologists have only studied ragfish from specimens caught and donated by fishermen or by the general public. Since 1958, I have accumulated catch records of >825 ragfish. Specimens were primarily from commercial fishermen and research personnel trawling for bottom and demersal species on the continental shelves of the eastern North Pacific Ocean, Gulf of Alaska, Bering Sea, and the western Pacific Ocean, as well as from gillnet fisheries for Pacific salmon, Oncorhynchus spp., in the north central Pacific Ocean. Available records came from four separate sources: 1) historical data based primarily on published and unpublished literature (1876–1990), 2) ragfish delivered fresh to Humboldt State University or records available from the California Department of Fish and Game of ragfish caught in northern California and southern Oregon bottom trawl fisheries (1950–99), 3) incidental catches of ragfish observed and recorded by scientific observers of the commercial fisheries of the eastern Pacific Ocean and catches in National Marine Fisheries Service trawl surveys studying these fisheries from 1976 to 1999, and 4) Japanese government research on nearshore fisheries of the northwestern Pacific Ocean (1950–99). Limited data on individual ragfish allowed mainly qualitative analysis, although some quantitative analysis could be made with ragfish data from northern California and southern Oregon. This paper includes a history of taxonomic and common names of the ragfish, types of fishing gear and other techniques recovering ragfish, a chronology of range extensions into the North Pacific and Bering Sea, reproductive biology of ragfish caught by trawl fisheries off northern California and southern Oregon, and topics dealing with early, juvenile, and adult life history, including age and growth, food habits, and ecology. Recommendations for future study are proposed, especially on the life history of juvenile ragfish (5–30 cm FL) which remains enigmatic.

A U.S. Perspective on Access to Fisheries Resources

The passage of the Magnuson Fishery Conservation and Management Act of 1976 (MFCMA) and the establishment of a 200-mile exclusive economic zone (EEZ) in 1983 have resulted in a radical change in the pattern of foreign fishing operations off the U. S. coasts. Likewise, the extensions of 200-mile EEZ's by other nations have impacted U.S. distant-water fisheries. The result has been that a new international framework for fisheries is emerging and is continuing to evolve.

Review of discharge consents. River Irwell catchment report

This is the Review of discharge consents, River Irwell catchment report produced by the North West Water Authority (NWWA) in 1979. The purpose of this Report is to make recommendations for the revision of consents for discharges within the catchment of the River Irwell, downstream and including the River Medlock in Manchester. This revision has the sole objective of recognising the present effluent and river water quality - proposals for long term river water quality objectives are to be put forward in other Reports. The report identifies the existing situation regarding the legal status of effluent discharges from Authority and non-Authority owned installations within the catchment, details the determinant concentration limits included in existing discharge consents (where appropriate) and proposes the limits to be included in the reviewed consents. The reviewed consents will reflect the quality of effluent achievable by good operation of the existing plant based on 1977 effluent quality data but taking into account any improvements, extensions etc. that have been or are about to be carried out and any known further industrial and/or housing development in the works drainage area.

A guide to the deep-water sponges of the Aleutian Island Archipelago

The first dedicated collections of deep-water (>80 m) sponges from the central Aleutian Islands revealed a rich fauna including 28 novel species and geographical range extensions for 53 others. Based on these collections and the published literature, we now confirm the presence of 125 species (or subspecies)of deep-water sponges in the Aleutian Islands. Clearly the deep-water sponge fauna of the Aleutian Islands is extraordinarily rich and largely understudied. Submersible observations revealed that sponges, rather than deep-water corals, are the dominant feature shaping benthic habitats in the region and that they provide important refuge habitat for many species of fish and invertebrates including juvenile rockfish (Sebastes spp.) and king crabs (Lithodes sp). Examination of video footage collected along 127 km of the seafloor further indicate that there are likely hundreds of species still uncollected from the region, and many unknown to science. Furthermore, sponges are extremely fragile and easily damaged by contact with fishing gear. High rates of fishery bycatch clearly indicate a strong interaction between existing fisheries and sponge habitat. Bycatch in fisheries and fisheries-independent surveys can be a major source of information on the location of the sponge fauna, but current monitoring programs are greatly hampered by the inability of deck personnel to identify bycatch. This guide contains detailed species descriptions for 112 sponges collected in Alaska, principally in the central Aleutian Islands. It addresses bycatch identification challenges by providing fisheries observers and scientists with the information necessary to adequately identify sponge fauna. Using that identification data, areas of high abundance can be mapped and the locations of indicator species of vulnerable marine ecosystems can be determined. The guide is also designed for use by scientists making observations of the fauna in situ with submersibles, including remotely operated vehicles and autonomous underwater vehicles.

An experimental model of relay deployment planning tool for a wireless sensor network system to monitor civil engineering structures

It is essential to monitor deteriorated civil engineering structures cautiously to detect symptoms of their serious disruptions. A wireless sensor network can be an effective system for monitoring civil engineering structures. It is fast to deploy sensors especially in difficult-to-access areas, and it is extendable without any cable extensions. Since our target is to monitor deteriorations of civil engineering structures such as cracks at tunnel linings, most of the locations of sensors are known, and sensors are not required to move dynamically. Therefore, we focus on developing a deployment plan of a static network in order to reduce the value of a cost function such as initial installation cost and summation of communication distances of the network. The key issue of the deployment is the location of relays that forward sensing data from sensors to a data collection device called a gateway. In this paper, we propose a relay deployment-planning tool that can be used to design a wireless sensor network for monitoring civil engineering structures. For the planning tool, we formalize the model and implement a local search based algorithm to find a quasi-optimal solution. Our solution guarantees two routings from a sensor to a gateway, which can provide higher reliability of the network. We also show the application of our experimental tool to the actual environment in the London Underground.