Directed selection of recombinant human monoclonal antibodies to herpes simplex virus glycoproteins from phage display libraries.

Human monoclonal antibodies have considerable potential in the prophylaxis and treatment of viral disease. However, only a few such antibodies suitable for clinical use have been produced to date. We have previously shown that large panels of human recombinant monoclonal antibodies against a plethora of infectious agents, including herpes simplex virus types 1 and 2, can be established from phage display libraries. Here we demonstrate that facile cloning of recombinant Fab fragments against specific viral proteins in their native conformation can be accomplished by panning phage display libraries against viral glycoproteins "captured" from infected cell extracts by specific monoclonal antibodies immobilized on ELISA plates. We have tested this strategy by isolating six neutralizing recombinant antibodies specific for herpes simplex glycoprotein gD or gB, some of which are against conformationally sensitive epitopes. By using defined monoclonal antibodies for the antigen-capture step, this method can be used for the isolation of antibodies to specific regions and epitopes within the target viral protein. For instance, monoclonal antibodies to a nonneutralizing epitope can be used in the capture step to clone antibodies to neutralizing epitopes, or antibodies to a neutralizing epitope can be used to clone antibodies to a different neutralizing epitope. Furthermore, by using capturing antibodies to more immunodominant epitopes, one can direct the cloning to less immunogenic ones. This method should be of value in generating antibodies to be used both in the prophylaxis and treatment of viral infections and in the characterization of the mechanisms of antibody protective actions at the molecular level.

Light alloy castings for automotive applications: The case of Al vs Mg

The economical and environmental effects of mass reduction through Al and Mg primary alloys substitutions for cast iron and steel in automotive components are discussed using MF. Ashby's penalty functions method The viability of Mg alloy substitutions for existing Al alloy cast components is also considered. The cost analysis shows that direct, equal-volume, Al alloy substitutions for cast iron and steel are the most feasible in terms of the CAFE liability, followed by substitutions involving flat panels of prescribed stiffness. When the creation of CO2 associated to the production of Al and Mg is considered, the potential gasoline savings over the lifespan of the car compensate for the intrinsic environmental burden of Al in all applications, while electrolytic Mg substitutions for cast iron and steel are feasible for equal volume and panels only. Magnesium produced by the Pidgeon thermal process appears to be too primary energy intensive to be competitive in structural applications. Magnesium substitutions for existing Al alloy beams and panels are generally unviable. The current higher recycling efficiency of Al casting alloys confers Al a significant advantage over Mg alloys.

Density forecasts of crude-oil prices using option-implied and ARCH-type models

The predictive accuracy of competing crude-oil price forecast densities is investigated for the 1994–2006 period. Moving beyond standard ARCH type models that rely exclusively on past returns, we examine the benefits of utilizing the forward-looking information that is embedded in the prices of derivative contracts. Risk-neutral densities, obtained from panels of crude-oil option prices, are adjusted to reflect real-world risks using either a parametric or a non-parametric calibration approach. The relative performance of the models is evaluated for the entire support of the density, as well as for regions and intervals that are of special interest for the economic agent. We find that non-parametric adjustments of risk-neutral density forecasts perform significantly better than their parametric counterparts. Goodness-of-fit tests and out-of-sample likelihood comparisons favor forecast densities obtained by option prices and non-parametric calibration methods over those constructed using historical returns and simulated ARCH processes. © 2010 Wiley Periodicals, Inc. Jrl Fut Mark 31:727–754, 2011

Hilbert Space Valued Signal Plus Noise Models: Analysis of Structural Breaks under High Dimensionality and Temporal Dependence

This thesis is concerned with change point analysis for time series, i.e. with detection of structural breaks in time-ordered, random data. This long-standing research field regained popularity over the last few years and is still undergoing, as statistical analysis in general, a transformation to high-dimensional problems. We focus on the fundamental »change in the mean« problem and provide extensions of the classical non-parametric Darling-Erdős-type cumulative sum (CUSUM) testing and estimation theory within highdimensional Hilbert space settings. In the first part we contribute to (long run) principal component based testing methods for Hilbert space valued time series under a rather broad (abrupt, epidemic, gradual, multiple) change setting and under dependence. For the dependence structure we consider either traditional m-dependence assumptions or more recently developed m-approximability conditions which cover, e.g., MA, AR and ARCH models. We derive Gumbel and Brownian bridge type approximations of the distribution of the test statistic under the null hypothesis of no change and consistency conditions under the alternative. A new formulation of the test statistic using projections on subspaces allows us to simplify the standard proof techniques and to weaken common assumptions on the covariance structure. Furthermore, we propose to adjust the principal components by an implicit estimation of a (possible) change direction. This approach adds flexibility to projection based methods, weakens typical technical conditions and provides better consistency properties under the alternative. In the second part we contribute to estimation methods for common changes in the means of panels of Hilbert space valued time series. We analyze weighted CUSUM estimates within a recently proposed »high-dimensional low sample size (HDLSS)« framework, where the sample size is fixed but the number of panels increases. We derive sharp conditions on »pointwise asymptotic accuracy« or »uniform asymptotic accuracy« of those estimates in terms of the weighting function. Particularly, we prove that a covariance-based correction of Darling-Erdős-type CUSUM estimates is required to guarantee uniform asymptotic accuracy under moderate dependence conditions within panels and that these conditions are fulfilled, e.g., by any MA(1) time series. As a counterexample we show that for AR(1) time series, close to the non-stationary case, the dependence is too strong and uniform asymptotic accuracy cannot be ensured. Finally, we conduct simulations to demonstrate that our results are practically applicable and that our methodological suggestions are advantageous.

Helping someone with problem drinking: Mental health first aid guidelines - a Delphi expert consensus study

Background Alcohol is a leading risk factor for avoidable disease burden. Research suggests that a drinker's social network can play an integral role in addressing hazardous (i.e., high-risk) or problem drinking. Often however, social networks do not have adequate mental health literacy (i.e., knowledge about mental health problems, like problem drinking, or how to treat them). This is a concern as the response that a drinker receives from their social network can have a substantial impact on their willingness to seek help. This paper describes the development of mental health first aid guidelines that inform community members on how to help someone who may have, or may be developing, a drinking problem (i.e., alcohol abuse or dependence). Methods A systematic review of the research and lay literature was conducted to develop a 285-item survey containing strategies on how to help someone who may have, or may be developing, a drinking problem. Two panels of experts (consumers/carers and clinicians) individually rated survey items, using a Delphi process. Surveys were completed online or via postal mail. Participants were 99 consumers, carers and clinicians with experience or expertise in problem drinking from Australia, Canada, Ireland, New Zealand, the United Kingdom, and the United States. Items that reached consensus on importance were retained and written into guidelines. Results The overall response rate across all three rounds was 68.7% (67.6% consumers/carers, 69.2% clinicians), with 184 first aid strategies rated as essential or important by ≥80% of panel members. The endorsed guidelines provide guidance on how to: recognize problem drinking; approach someone if there is concern about their drinking; support the person to change their drinking; respond if they are unwilling to change their drinking; facilitate professional help seeking and respond if professional help is refused; and manage an alcohol-related medical emergency. Conclusion The guidelines provide a consensus-based resource for community members seeking to help someone with a drinking problem. Improving community awareness and understanding of how to identify and support someone with a drinking problem may lead to earlier recognition of problem drinking and greater facilitation of professional help seeking.

O'Neill Building Nudgee College

This project involved the complete refurbishment and extension of a 1980’s two-storey domestic brick building, previously used as a Boarding House (Class 3), into Middle School facilities (Class 9b) on a heritage listed site at Nudgee College secondary school, Brisbane. The building now accommodates 12 technologically advanced classrooms, computer lab and learning support rooms, tuckshop, art room, mini library/reading/stage area, dedicated work areas for science and large projects with access to water on both floors, staff facilities and an undercover play area suitable for assemblies and presentations. The project was based on a Reggio Emilia approach, in which the organisation of the physical environment is referred to as the child’s third teacher, creating opportunities for complex, varied, sustained and changing relationships between people and ideas. Classrooms open to a communal centre piazza and are integrated with the rest of the school and the school with the surrounding community. In order to achieve this linkage of the building with the overall masterplan of the site, a key strategy of the internal planning was to orientate teaching areas around a well defined active circulation space that breaks out of the building form to legibly define the new access points to the building and connect up to the pathway network of the campus. The width of the building allowed for classrooms and a generous corridor that has become ‘breakout’ teaching areas for art, IT, and small group activities. Large sliding glass walls allow teachers to maintain supervision of students across all areas and allow maximum light penetration through small domestic window openings into the deep and low-height spaces. The building was also designed with an effort to uphold cultural characteristics from the Edmund Rice Education Charter (2004). Coherent planning is accompanied by a quality fit-out, creating a vibrant and memorable environment in which to deliver the upper primary curriculum. Consistent with the Reggio Emilia approach, materials, expressive of the school’s colours, are used in a contemporary, adventurous manner to create panels of colour useful for massing and defining the ‘breakout’ teaching areas and paths of travel, and storage elements are detailed and arranged to draw attention to their aesthetic features. Modifications were difficult due to the random placement of load bearing walls, minimum ceiling heights, the general standard of finishes and new fire and energy requirements, however the reuse of this building was assessed to be up to 30% cheaper than an equivalent new building, The fit out integrates information technology and services at a level not usually found in primary school facilities. This has been achieved within the existing building fabric through thoughtful detailing and co-ordination with allied disciplines.

Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Using simplified peer review processes to fund research: A prospective study

Objective: To prospectively test two simplified peer review processes, estimate the agreement between the simplified and official processes, and compare the costs of peer review. Design, participants and setting: A prospective parallel study of Project Grant proposals submitted in 2013 to the National Health and Medical Research Council (NHMRC) of Australia. The official funding outcomes were compared with two simplified processes using proposals in Public Health and Basic Science. The two simplified processes were: panels of 7 reviewers who met face-to-face and reviewed only the nine-page research proposal and track record (simplified panel); and 2 reviewers who independently reviewed only the nine-page research proposal (journal panel). The official process used panels of 12 reviewers who met face-to-face and reviewed longer proposals of around 100 pages. We compared the funding outcomes of 72 proposals that were peer reviewed by the simplified and official processes. Main outcome measures: Agreement in funding outcomes; costs of peer review based on reviewers’ time and travel costs. Results: The agreement between the simplified and official panels (72%, 95% CI 61% to 82%), and the journal and official panels (74%, 62% to 83%), was just below the acceptable threshold of 75%. Using the simplified processes would save $A2.1–$A4.9 million per year in peer review costs. Conclusions: Using shorter applications and simpler peer review processes gave reasonable agreement with the more complex official process. Simplified processes save time and money that could be reallocated to actual research. Funding agencies should consider streamlining their application processes.

Generalized model for infrared perception from an engine exhaust

A comprehensive scheme has been developed for the prediction of radiation from engine exhaust and its incidence on an arbitrarily located sensor. Existing codes have been modified for the simulation of flows inside nozzles and jets. A novel view factor computation scheme has been applied for the determination of the radiosities of the discrete panels of a diffuse and gray nozzle surface. The narrowband model has been used to model the radiation from the gas inside the nozzle and the nonhomogeneous jet. The gas radiation from the nozzle inclusive of nozzle surface radiosities have been used as boundary conditions on the jet radiation. Geometric modeling techniques have been developed to identify and isolate nozzle surface panels and gas columns of the nozzle and jet to determine the radiation signals incident on the sensor. The scheme has been validated for intensity and heat flux predictions, and some useful results of practical importance have been generated to establish its viability for infrared signature analysis of jets.

Packing in molten globules and native states

Close packing of hydrophobic residues in the protein interior is an important determinant of protein stability. Cavities introduced by large to small substitutions are known to destabilize proteins. Conversely, native states of proteins and protein fragments can be stabilized by filling in existing cavities. Molten globules (MGs) were initially used to describe a state of protein which has well-defined secondary structure but little or no tertiary packing. Subsequent studies have shown that MGs do have some degree of native-like topology and specific packing. Wet molten globules (WMGs) with hydrated cores and considerably decreased packing relative to the native state have been studied extensively. Recently there has been renewed interest in identification and characterization of dry molten globules (DMGs). These are slightly expanded forms of the native state which show increased conformational flexibility, native-like main-chain hydrogen bonding and dry interiors. The generality of occurrence of DMGs during protein unfolding and the extent and nature of packing in DMGs remain to be elucidated. Packing interactions in native proteins and MGs can be probed through mutations. Next generation sequencing technologies make it possible to determine relative populations of mutants in a large pool. When this is coupled to phenotypic screens or cell-surface display, it becomes possible to rapidly examine large panels of single-site or multi-site mutants. From such studies, residue specific contributions to protein stability and function can be estimated in a highly parallelized fashion. This complements conventional biophysical methods for characterization of packing in native states and molten globules.

A propósito de una posible escena ritual de caza en el abrigo de Legteitira 5 (Agüenit, Sahara Occidental)

[ES] La presencia de unos personajes humanos con grandes cabezas pintadas en uno de los paneles artísticos del abrigo de Legteitira 5 genera diversas impresiones sobre su significado. A lo extraño de la composición, hay que añadir que se trata, por el momento, de un caso único en el repertorio iconográfico del Occidente del Sahara. La hipótesis de una posible relación con cabezas enmascaradas, en el contexto simbólico de una escena ritual cinegética, pudiera acaso retenerse como argumento explicativo.

Visualização dos dados estatísticos da Uerj: proposta de dashboards baseados no trabalho de Jacques Bertin

Os painéis de gráficos estatísticos conhecidos como dashboards são utilizados comumente naárea de Business Intelligence (BI) para a visualização de grandes sistemas organizados de dados. A presente dissertação propõe embasar o projeto de dashboards pelas teorias de Jacques Bertin, formuladas nas obras Sémiologie Graphique e La Graphique et le Traitement Graphique de linformation. Considerando este referencial, e ainda parâmetros do design de informação e da visualização de dados, foram desenvolvidos dashboards que apresentam dados sobre a política de reserva de vagas da Universidade do Estado do Rio de Janeiro, sistematizados pelo projeto de BI dessa instituição. O objetivo foi não apenas o de atender aos requisitos convencionais de um dashboard, mas sobretudo o de apresentar outras perspectivas informativas. Nesse sentido, investigam-se as especificidades dos métodos de Bertin e sua expansão para o domínio dos sistemas interativos.

Assembleia de aves consumidoras de frutos de sub-bosque em diferentes altitudes em uma área de Mata Atlântica no estado do Rio de Janeiro

Neste estudo, investigamos a distribuição altitudinal da composição, riqueza, abundância das espécies de aves consumidoras de frutos em cinco altitudes e avaliamosa influência da estrutura da vegetação nas diversidades de aves. O estudo foi realizado na Reserva Ecológica de Guapiaçu (REGUA) contígua ao Parque Estadual dos Três Picos (PEPT), no município de Cachoeiras de Macacu, RJ. Coletamos os dados das aves em 24 excursões a campo, incluindo seis bimensais (jul./2010 a maio/2011) e 18 mensais (jul./2011 a dez./2012). Para amostragem das aves, utilizamos o método de captura-marcação-recaptura com redes de neblina, expostas durante sete h/dia em cinco altitudesao longo de uma variação altitudinal de 1000 m. O esforço amostral foi de 8400 h-rede. Para amostragem da estrutura da vegetação, sorteamos três parcelas de 100 m2 adjacentes às linhas das redes em cada altitude, nas quais foram analisadas as densidades de diferentes hábitos de vida. Das árvores, arvoretas e arbustos coletamos as medidas de altura total e diâmetro da altura (no caso dos arbustos, o diâmetro foi coletado a 50 cm do solo). Capturamos 448 indivíduos correspondentes a 35 espécies de aves, distribuídas em 16 famílias. Destas, 26% são endêmicas de Mata Atlântica, incluindo quatro espécies categorizadas com algum grau de vulnerabilidade. Dezesseis espécies foram classificadas como frugívoras enquanto 19 como insetívoras-frugívoras. Leptopogon amaurocephalus, Mionectes rufiventris, Lanio melanops, Chiroxiphia caudata foram capturadas nas cinco altitudes, sendo as últimas duas espécies as mais abundantes. Registramos maior riqueza e abundância de aves nas altitudes de 370 e 770 m. A composição de aves diferiu entre as altitudes, sendo 170 e 1000 m as mais dissimilares. As espécies de aves insetívoras-frugívoras predominaram nos sub-bosques das cinco altitudes. Registramos deslocamento altitudinal de cinco espécies de aves, sendo o maior deslocamento realizado por um indivíduo de Attilarufus, capturado a 770 m e, recapturado a 370 m. Encontramos maior densidade de plantas no sub-bosque nas altitudes 170, 370 e 1000 m. Bambus foram registrados apenas a 1000 m, enquanto que as ervas foram limitadas às altitudes de 170 e 370 m. A estrutura da vegetação apresentou baixa similaridade entre as altitudes, principalmente devido a diferentes densidades das formas de vida e altura das plantas. Três altitudes, 170, 370 e 1000 m, apresentaram alta densidade de indivíduos no sub-bosque, sendo que esta última evidenciou uma estrutura da vegetação relativamente mais simples devido ao alto número de árvores de baixa altura, ao maior número de arvoretas e à presença de bambus. A diversidade de aves foi sensível à estrutura da vegetação, em especial à altura das árvores que apresentou um decréscimo da altura com o aumento da altitude. Esta relação entre a diversidade de aves e a estruturada da vegetação destaca a importância da preservação da estrutura da vegetação para a manutenção da diversidade de aves consumidoras de frutos da REGUA e do PETP

毛竹茎木质化过程的组织细胞学研究

应用光学显微镜和透射电子显微镜，并结合组织化学和细胞化学方法，研究了毛竹（Phyllostachys pubescens Mazel）茎各组织中细胞壁的木质化过程、木质素异质性、酚酸类成分的分布、木质素在细胞壁中的沉积方式以及过氧化物酶的组织、细胞化学定位等。 研究结果表明：毛竹茎的原生木质部导管在维管束发育早期就已木质化;后生木质部导管和纤维细胞在维管束分化完成后，自胞间层和细胞角隅处开始木质化;基本薄壁组织细胞木质化的发生较晚，通常在茎的节间完成伸长生长后才开始，但也有少数薄壁组织细胞始终保持非木质化的薄壁状态。根据可见光显微分光光度的分析结果，纤维细胞壁在木质化的早期，主要形成愈创木基木质素（guaiacyl lignin）, 随着木质化过程的发展，紫丁得基木质素（syringyl lignin）含量不断增加，最后成为纤维细胞壁木质素的主要组成成分。导管分子的木质素主要成分为愈创木基木质素，基本薄壁组织细胞壁为愈创木基与紫丁香基两种。 毛竹茎各组织在紫外光激发下自发荧光的荧光显微分光光度分析表明，氨水处理可以有效地识别阿魏酸的分布，如在竹笋各种幼嫩组织中均分布有阿魏酸;而用过氧化氢／冰醋酸混合液处理，则可以区分木素与结合于半纤维素中的阿魏酸和对－香豆酸，随着毛竹茎的生长和细胞壁木质化的增加，阿魏酸的含量下降。 通过对毛竹茎纤维细胞壁木质化过程中超微结构的观察表明，高尔基体、高尔基小泡、内质网、壁旁体细胞器在木质素前体的形成和运输等方面均起着重要作用，而周质微管在细胞壁木质化过程中的具体作用方式尚不明确。木质素在细胞壁中的沉积方式分别为：胞间层的木质素呈分散的颗粒状沉积方式，导管次生壁的木质素为片层状沉积方式，而在纤维细胞次生壁Sl层中，木质素为团块状的沉积方式。木质素沉积方式与纤维素微纤丝的排列有密切关系。 在毛竹茎各组织的细胞壁尚未木质化之前，过氧化物酶仅分布于细胞角隅处，随着细胞次生壁的增厚和木质化的增强，过氧化物酶可大量出现在次生壁中;在纤维细胞次生壁中，木质素含量较高的St各层，过氧化物酶活性也较强，而木质素含量较低的Sl各层，过氧化物酶活性则较弱。由此表明，过氧化物酶直接参与了细胞壁木质素的合成。另外，在茎的部分基本薄壁组织细胞和韧皮部等未木质化的细胞壁中，过氧化物酶也同样表现出较强的活性，这说明在茎的不同组织中分布的这种酶，可能是几种不同功能的同工酶形式。

Experiments with fibre-glass sheathing as a protection against marine wood-boring organisms

Wooden test panels of different species of wood sheathed with fibre-glass reinforced plastic were subjected to immersion tests along with corresponding controls in Cochin Port area and the effect of the protective coating studied.