The hepatitis C virus NS3 serine proteinase and NS4A cofactor: establishment of a cell-free trans-processing assay.

The hepatitis C virus RNA genome encodes a long polyprotein that is proteolytically processed into at least 10 products. The order of these cleavage products in the polyprotein is NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B -COOH. A serine proteinase domain located in the N-terminal one-third of nonstructural protein NS3 mediates cleavage at four downstream sites (the 3/4A, 4A/4B, 4B/5A, and 5A/5B sites). In addition to the proteinase catalytic domain, the NS4A protein is required for processing at the 4B/5A site but not at the 5A/5B site. These cleavage events are likely to be essential for virus replication, making the serine proteinase an attractive antiviral target. Here we describe an in vitro assay where the NS3-4A polyprotein, NS3, the serine proteinase domain (the N-terminal 181 residues of NS3), and the NS4A cofactor were produced by cell-free translation and tested for trans-processing of radiolabeled substrates. Polyprotein substrates, NS4A-4B or truncated NS5A-5B, were cleaved in trans by all forms of the proteinase, whereas NS4A was also required for NS4B-5A processing. Proteolysis was abolished by substitution mutations previously shown to inactivate the proteinase or block cleavage at specific sites in vivo. Furthermore, N-terminal sequence analysis established that cleavage in vitro occurred at the authentic 4A/4B site. Translation in the presence of microsomal membranes enhanced processing for some, but not all, proteinase-substrate combinations. Trans-processing was both time and temperature dependent and was eliminated by treatment with a variety of detergents above their critical micelle concentrations. Among many common proteinase inhibitors tested, only high (millimolar) concentrations of serine proteinase inhibitors tosyllysyl chloromethyl ketone and 4-(2-aminoethyl)benzenesulfonyl fluoride inactivated the NS3 proteinase. This in vitro assay should facilitate purification and further characterization of the viral serine proteinase and identification of molecules which selectively inhibit its activity.

The law of charitable uses : argument of Wm. Curtis Noyes, before the Court of Appeals of the State of New York, in the case of Beekman, administrator, &c., against the people, &c., and others, in behalf of Thomas Beekman, one of the respondents, with an appendix containing the will.

W. Barthrop's will and codicils: p. 93-102.

Hampton and its students /

Songs (with music): p. [171]-255.

Jubilee of the Royal Museum and Library, Peel Park. Salford and the inauguration of the public free libraries movement. Together with a short history of the museum and libraries ...

Cover-title: The Royal Museum & Libraries, Salford: their inception & development.

The preacher : a collection of sermons from various authors, doctrinal and practical.

C. Le Fevre. Omniscience of the deity.--W. Whittaker. The certainty of punishment.--C. Le Fevre. Christian resignation.--T. Smith. Self-righteousness reproved.--D. Ackley. Christian revivalism.--C. Hammond. Triumph of the Gospel.--T. Sawyer. Mans̓ littleness and dignity.--B. Hallock. The seasons of life.--M. Smith. Universal paternity of God.--W. Manley. Free will--free agency--necessity.--H. Fitz. The destruction of the wicked.--T. Sawyer. Humility.--G. Quinby. The certainty of punishment.--R. Williams. Candor in the investigation of religious truth.--M. Ballou. Seeking God.--B. Hallock. The Christians̓ triumph.--E. Chapin. The Christian name and the Christian spirit.--T. Sawyer. Blessed are the merciful.

Access to the environment : a series of reference documents on the design and development of site facilities to make them barrier free to the physically handicapped and disabled /

Prepared under contract (H-2002-R) with the Office of Policy Development and Research, Dept. of Housing and Urban Development, and Architectural and Transportation Barriers Compliance Board.

Synapses, quantum theory and panpsychism

The introduction situates the ‘hard problem’ in its historical context and argues that the problem has two sides: the output side (the Kant-Eccles problem of the freedom of the Will) and the input side (the problem of qualia). The output side ultimately reduces to whether quantum mechanics can affect the operation of synapses. A discussion of the detailed molecular biology of synaptic transmission as presently understood suggests that such affects are unlikely. Instead an evolutionary argument is presented which suggests that our conviction of free agency is an evolutionarily induced illusion and hence that the Kant-Eccles problem is itself illusory. This conclusion is supported by well-known neurophysiology. The input side, the problem of qualia, of subjectivity, is not so easily outflanked. After a brief review of the neurophysiological correlates of consciousness (NCC) and of the Penrose-Hameroff microtubular neuroquantology it is again concluded that the molecular neurobiology makes quantum wave-mechanics an unlikely explanation. Instead recourse is made to an evolutionarily- and neurobiologically-informed panpsychism. The notion of an ‘emergent’ property is carefully distinguished from that of the more usual ‘system’ property used by most dual-aspect theorists (and the majority of neuroscientists) and used to support Llinas’ concept of an ‘oneiric’ consciousness continuously modified by sensory input. I conclude that a panpsychist theory, such as this, coupled with the non-classical understanding of matter flowing from quantum physics (both epistemological and scientific) may be the default and only solution to the problem posed by the presence of mind in a world of things.

A földrajzi távolság, a kulturális hasonlóság és a szabadkereskedelem hatása a borkereskedelemre = Effects on the global wine trade of geographical distance, cultural and linguistic similarity, and free trade

A globalizálódó világgazdaságban a vezető bortermelő országok egyre jelentősebb borkereskedelmet bonyolítanak le egymás között. Míg Európában a fogyasztók egyre kevesebb bort vásárolnak, addig Amerikában és Ázsiában a bor iránti kereslet folyamatosan bővül: a borkereskedelem földrajzi átrendeződése zajlik. A kulturális hasonlóság és a földrajzi távolság kereskedelemre gyakorolt hatását gyakran a kereskedelemelméletek gravitációs modelljével elemzik. E tanulmány azt vizsgálja, hogy a fő borexportáló országok közötti földrajzi távolság, kulturális hasonlóság és szabadkereskedelem milyen hatással van a nemzetközi borkereskedelemre, annak költségeire. A regressziós becslés eredményei alátámasztják, hogy a borkereskedelem költségei alacsonyabbak, ha a kereskedelmi partnerek kulturálisan hasonlók, földrajzilag közel helyezkednek el egymáshoz, vagy van tengeri kikötőjük, tagjai a WTO-nak, illetve ha kötöttek egymással regionális kereskedelmi megállapodást. Ezenkívül megállapítható, hogy az angolszász, a latin-amerikai és az európai kulturális klaszterek elsősorban egymással kereskednek. A kutatás számos kulturális változó alkalmazásával és több ökonometriai modell, illetve becslési eljárás nagymintás tesztelésével gazdagítja a szakirodalmat. ____ In a globalizing world, major wine-producing countries export considerable quantities to the global wine market and turn over a notable trade, but in what happens European wine regions differ markedly from the New World. Here major wine producers suffered a remarkable fall in domestic wine consumption in recent decades, while New World wine producers increased their production potential and generated new foreign demand. The changes have been joined by geographical relocation of wine consumption and exports. The gravity equation can be derived from demand-side or supply-side theory-consistent estimation methods that suggest relationships between the size of the economies, geographical distances, cultural similarities, and size of their trade. The paper analyses the effects of cultural and geographical proximity, free trade, and linguistic similarity on bilateral trade in the main wine-producing countries, using a cross-section gravity model for 2012. The results suggest that larger countries export more wine, while transport costs rise in line with geographical distance and are higher for landlocked trading partners. Wine export costs are lower if trading partners are culturally similar, share a dominant religion, or are both WTO members with regional trade agreements. Anglo-Saxon, Germanic, Latin American and Latin European countries mainly trade wines within their groups. The paper looks to extend the number of trading partners, investigate the effect of language clusters, and confirm that the results are robust by different econometric methodologies.

Perkins+Will Meeting Agendas and 15 Campus Plans

Meeting agenda and documents from Meeting # 5 between the memebers of Perkins+Will and the FIU-AHSCMP Executive Planning Committee. Includes plans and blueprints detailing facility goals and assumptions for the Academic Health Sciences facility over a 5, 10, and 20 year planning period, as well as future goals. Blueprints include a Campus Plan and 5, 10, and 20 year plans for the Program, Space, Service, and Access, as well as a Site Plan, and Perspective View of the facilities.

A New Method for Modeling Free Surface Flows and Fluid-structure Interaction with Ocean Applications

The computational modeling of ocean waves and ocean-faring devices poses numerous challenges. Among these are the need to stably and accurately represent both the fluid-fluid interface between water and air as well as the fluid-structure interfaces arising between solid devices and one or more fluids. As techniques are developed to stably and accurately balance the interactions between fluid and structural solvers at these boundaries, a similarly pressing challenge is the development of algorithms that are massively scalable and capable of performing large-scale three-dimensional simulations on reasonable time scales. This dissertation introduces two separate methods for approaching this problem, with the first focusing on the development of sophisticated fluid-fluid interface representations and the second focusing primarily on scalability and extensibility to higher-order methods.

We begin by introducing the narrow-band gradient-augmented level set method (GALSM) for incompressible multiphase Navier-Stokes flow. This is the first use of the high-order GALSM for a fluid flow application, and its reliability and accuracy in modeling ocean environments is tested extensively. The method demonstrates numerous advantages over the traditional level set method, among these a heightened conservation of fluid volume and the representation of subgrid structures.

Next, we present a finite-volume algorithm for solving the incompressible Euler equations in two and three dimensions in the presence of a flow-driven free surface and a dynamic rigid body. In this development, the chief concerns are efficiency, scalability, and extensibility (to higher-order and truly conservative methods). These priorities informed a number of important choices: The air phase is substituted by a pressure boundary condition in order to greatly reduce the size of the computational domain, a cut-cell finite-volume approach is chosen in order to minimize fluid volume loss and open the door to higher-order methods, and adaptive mesh refinement (AMR) is employed to focus computational effort and make large-scale 3D simulations possible. This algorithm is shown to produce robust and accurate results that are well-suited for the study of ocean waves and the development of wave energy conversion (WEC) devices.

Organic functionalisation, doping and characterisation of semiconductor surfaces for future CMOS device applications

Organic Functionalisation, Doping and Characterisation of Semiconductor Surfaces for Future CMOS Device Applications Semiconductor materials have long been the driving force for the advancement of technology since their inception in the mid-20th century. Traditionally, micro-electronic devices based upon these materials have scaled down in size and doubled in transistor density in accordance with the well-known Moore’s law, enabling consumer products with outstanding computational power at lower costs and with smaller footprints. According to the International Technology Roadmap for Semiconductors (ITRS), the scaling of metal-oxide-semiconductor field-effect transistors (MOSFETs) is proceeding at a rapid pace and will reach sub-10 nm dimensions in the coming years. This scaling presents many challenges, not only in terms of metrology but also in terms of the material preparation especially with respect to doping, leading to the moniker “More-than-Moore”. Current transistor technologies are based on the use of semiconductor junctions formed by the introduction of dopant atoms into the material using various methodologies and at device sizes below 10 nm, high concentration gradients become a necessity. Doping, the controlled and purposeful addition of impurities to a semiconductor, is one of the most important steps in the material preparation with uniform and confined doping to form ultra-shallow junctions at source and drain extension regions being one of the key enablers for the continued scaling of devices. Monolayer doping has shown promise to satisfy the need to conformally dope at such small feature sizes. Monolayer doping (MLD) has been shown to satisfy the requirements for extended defect-free, conformal and controllable doping on many materials ranging from the traditional silicon and germanium devices to emerging replacement materials such as III-V compounds This thesis aims to investigate the potential of monolayer doping to complement or replace conventional doping technologies currently in use in CMOS fabrication facilities across the world.

Shiftwork, sleep disturbance and the metabolic syndrome among female hospital workers

Background: Shiftwork is associated with increased sleep disturbance and cardiovascular and metabolic disease risk. This thesis will focus on shiftwork-related sleep disturbance and the potential mediating role of reduced sleep duration in the relationship between a current rotational shiftwork schedule and the metabolic syndrome among female hospital employees. Objectives: 1) To describe sleep patterns in relation to different shiftwork exposure metrics (current status, cumulative exposure, number of consecutive night shifts); 2) To assess the association between shiftwork metrics and sleep duration; 3) To determine whether sleep duration on work shifts mediates the relationship between a current rotational shiftwork pattern and the metabolic syndrome; and 4) To assess whether cumulative shiftwork exposure and the number of consecutive night shifts are associated with the metabolic syndrome. Methods: 294 female hospital employees (142 rotating shiftworkers, 152 dayworkers) participated in a cross-sectional study. Shiftwork parameters were determined through self-report. Sleep was measured for one week with the ActiGraph GT3X+, a tri-axial accelerometer. The metabolic syndrome was defined according to the Joint Interim Studies Consensus Statement. Sleep was described by shiftwork exposure parameters, and multivariable linear regression was used to determine associations between shiftwork variables and sleep duration. Regression path analysis was used to assess whether sleep duration was a mediator between a current shiftwork schedule and the metabolic syndrome, and the significance of the indirect (mediating) effect was tested with bootstrap confidence intervals. Logistic regression was used to determine associations between cumulative shiftwork exposure, number of consecutive night shifts, and the metabolic syndrome. Results: Current shiftworkers slept less on work shifts, more on free days, and were more likely to nap compared to dayworkers. Sleep duration on work shifts was a strong intermediate in the relationship between a current shiftwork pattern and the metabolic syndrome. Cumulative shiftwork exposure and the number of consecutive night shifts did not affect sleep or the metabolic syndrome. Conclusions: A current shiftwork pattern disrupts sleep, and reduced sleep duration is an important intermediate between shiftwork and the metabolic syndrome among female hospital employees.

The Internet as opportunity and challenge in contemporary social movements

This paper explores the relationship between the rise of “new” social movements (15-M and Occupy) and the Internet. The new social media gives rise to new kinds of social movements  which embed this technology from the moment of conception. The future of social movements will be characterised by movinets, which will have the effect of developing new efficient ways of activism. The movinets, with their embedded technology and capacity to circulate ideas among different spheres of reality, have a potential to alter the dynamics of social mobilisation.

Pulling Back the Veil: The Characterization and Habitability of Enshrouded Worlds

Thesis (Ph.D.)--University of Washington, 2016-08

A study of ignorance: suffering and freedom in early Buddhist teachings and parallels in modern neuroscience

What might early Buddhist teachings offer neuroscience and how might neuroscience inform contemporary Buddhism? Both early Buddhist teachings and cognitive neuroscience suggest that the conditioning of our cognitive apparatus and brain plays a role in agency that may be either efficacious or non-efficacious. Both consider internal time to play a central role in the efficacy of agency. Buddhism offers an approach that promises to increase the efficacy of agency. This approach is found in five early Buddhist teachings that are re-interpreted here with a view to explaining how they might be understood as a dynamic basis for ‘participatory will’ in the context of existing free will debates and the neuroscientific work of Patrick Haggard (et al.). These perspectives offer Buddhism and neuroscience a basis for informing each other as the shared themes of: (1) cognition is dynamic and complex/aggregate based, (2) being dynamic, cognition lacks a fixed basis of efficacy, and (3) efficacy of cognition may be achieved by an understanding of the concept of dynamic: as harmony and efficiency and by means of Buddha-warranted processes that involve internal time.