Rational Attenuation of a Morbillivirus by Modulating the Activity of the RNA-Dependent RNA Polymerase

Negative-strand RNA viruses encode a single RNA-dependent RNA polymerase (RdRp) which transcribes and replicates the genome. The open reading frame encoding the RdRp from a virulent wild-type strain of rinderpest virus (RPV) was inserted into an expression plasmid. Sequences encoding enhanced green fluorescent protein (EGFP) were inserted into a variable hinge of the RdRp. The resulting polymerase was autofluorescent, and its activity in the replication/transcription of a synthetic minigenome was reduced. We investigated the potential of using this approach to rationally attenuate a virus by inserting the DNA sequences encoding the modified RdRp into a full-length anti-genome plasmid from which a virulent virus (rRPV(KO)) can be rescued. A recombinant virus, rRPV(KO)L-RRegfpR, which grew at an indistinguishable rate and to an identical titer as rRPV(KO) in vitro, was rescued. Fluorescently tagged polymerase was visible in large cytoplasmic inclusions and beneath the cell membrane. Subcutaneous injection of 10(4) TCID(50) of the rRPV(KO) parental recombinant virus into cattle leads to severe disease symptoms (leukopenia/diarrhea and pyrexia) and death by 9 days postinfection. Animals infected with rRPV(KO)L-RRegfpR exhibited transient leukopenia and mild pyrexia, and the only noticeable clinical signs were moderate reddening of one eye and a slight ocular-nasal discharge. Viruses that expressed the modified polymerase were isolated from peripheral blood lymphocytes and eye swabs. This demonstrates that a virulent morbillivirus can be attenuated in a single step solely by modulating RdRp activity and that there is not necessarily a correlation between virus growth in vitro and in vivo.

Factores explicativos de las actitudes hacia el castigo juvenil. Evidencias de un diseño factorial

El rol desempeñado por la opinión pública en el desarrollo de la política criminal actual justifica el incremento de investigaciones destinadas a evaluar las actitudes de los ciudadanos hacia el castigo. No obstante, los avances en este ámbito han sido limitados debido a la utilización de rudimentarios instrumentos de medida. Por ello, el presente trabajo tiene como propósito explorar el efecto que generan en la opinión ciudadana ciertas variables referidas al hecho delictivo y al infractor, precisando su contribución relativa y la interacción existente entre ellas. Para satisfacer este objetivo se recurrió a un diseño factorial de la encuesta, creando una población de 256 casos-escenario fruto de la combinación de cuatro factores: la edad del joven, su historial delictivo, el grado de implicación en el hecho y el tipo de delito cometido. Los mismos fueron distribuidos en grupos de ocho casos ordenados aleatoriamente y fueron suministrados a 32 sujetos. Posteriormente se aplicaron análisis de regresión logística binaria. Los resultados obtenidos revelan que la naturaleza violenta de los hechos, la implicación activa de los jóvenes y el historial delictivo son predictores importantes de las condenas punitivas. Sin embargo la edad, una variable fundamental en la configuración de la justicia juvenil, no resulta significativa. De este modo, el trabajo muestra el potencial explicativo de este conjunto de factores y debate sus implicaciones teóricas y metodológicas para la investigación futura en este terreno.

Antioxidants and periodontitis in 60-70 year- old men

Objective: The aim was to investigate the association between periodontal health and the serum levels of various antioxidants including carotenoids, retinol and vitamin E in a homogenous group of Western European men.
Materials and Methods: A representative sample of 1258 men aged 60-70 years, drawn from the population of Northern Ireland, was examined between 2001 and 2003. Each participant had six or more teeth, completed a questionnaire and underwent a clinical periodontal examination. Serum lipid-soluble antioxidant levels were measured by high-performance liquid chromatography with diode array detection. Multivariable analysis was carried out using logistic regression with adjustment for possible confounders. Models were constructed using two measures of periodontal status (low- and high-threshold periodontitis) as dependent variables and the fifths of each antioxidant as a predictor variable.
Results: The levels of a- and ß-carotene, ß-cryptoxanthin and zeaxanthin were highly significantly lower in the men with low-threshold periodontitis (p<0.001). These carotenoids were also significantly lower in high-threshold periodontitis. There were no significant differences in the levels of lutein, lycopene, a- and ?-tocopherol or retinol in relation to periodontitis. In fully adjusted models, there was an inverse relationship between a number of carotenoids (a- and ß-carotene and ß-cryptoxanthin) and low-threshold periodontitis. ß-Carotene and ß-cryptoxanthin were the only antioxidants that were associated with an increased risk of high-threshold severe periodontitis. The adjusted odds ratio for high-threshold periodontitis in the lowest fifth relative to the highest fifth of ß-cryptoxanthin was 4.02 (p=0.003).
Conclusion: It is concluded that low serum levels of a number of carotenoids, in particular beta-cryptoxanthin and beta-carotene, were associated with an increased prevalence of periodontitis in this homogenous group of 60-70-year-old Western European men.

Modeling Frequency-Dependent Boundaries as Digital Impedance Filters in FDTD and K-DWM Room Acoustics Simulations

A new method for modeling-frequency-dependent boundaries in finite-difference time-domain (FDTD) and Kirchhoff variable digital waveguide mesh (K-DWM) room acoustics simulations is presented. The proposed approach allows the direct incorporation of a digital impedance filter (DIF) in the Multidimensional (2D or 3D) FDTD boundary model of a locally reacting surface. An explicit boundary update equation is obtained by carefully constructing a Suitable recursive formulation. The method is analyzed in terms of pressure wave reflectance for different wall impedance filters and angles of incidence. Results obtained from numerical experiments confirm the high accuracy of the proposed digital impedance filter boundary model, the reflectance of which matches locally reacting surface (LRS) theory closely. Furthermore a numerical boundary analysis (NBA) formula is provided as a technique for an analytic evaluation of the numerical reflectance of the proposed digital impedance filter boundary formulation.

Impaired endothelium-dependent vasodilatation is a novel predictor of mortality in intensive care

Objective: Endothelial function may be impaired in critical illness. We hypothesized that impaired endothelium-dependent vasodilatation is a predictor of mortality in critically ill patients.
Design: Prospective observational cohort study.
Setting: Seventeen-bed adult intensive care unit in a tertiary referral university teaching hospital. Patients: Patients were recruited within 24 hrs of admission to the intensive care unit.
Interventions: The SphygmoCor Mx system was used to derive the aortic augmentation index from radial artery pulse pressure waveforms. Endothelium-dependent vasodilatation was calculated as the change in augmentation index in response to an endothelium-dependent vasodilator (salbutamol).
Measurements and Main Results: Demographics, severity of illness scores, and physiological parameters were collected. Statistically significant predictors of mortality identified using single regressor analysis were entered into a multiple logistic regression model. Receiver operator characteristic curves were generated. Ninety-four patients completed the study. There were 80 survivors and 14 nonsurvivors. The Simplified Acute Physiology Score II, the Sequential Organ Failure Assessment score, leukocyte count, and endothelium-dependent vasodilatation conferred an increased risk of mortality. In logistic regression analysis, endothelium-dependent vasodilatation was the only predictor of mortality with an adjusted odds ratio of 26.1 (95% confidence interval [CI], 4.3-159.5). An endothelium-dependent vasodilatation value of 0.5% or less predicted intensive care unit mortality with a sensitivity of 79% (CI, 59-88%) and specificity of 98% (CI, 94-99%).
Conclusions: In vivo bedside assessment of endothelium-dependent vasodilatation is an independent predictor of mortality in the critically ill. We have shown it to be superior to other validated severity of illness scores with high sensitivity and specificity.

Dietary intake of fruits and vegetables improves microvascular function in hypertensive subjects in a dose-dependent manner

Background— Observational evidence has consistently linked increased fruit and vegetable consumption with reduced cardiovascular morbidity; however, there is little direct trial evidence to support the concept that fruit and vegetable consumption improves vascular function. This study assessed the dose-dependent effects of a fruit and vegetable intervention on arterial health in subjects with hypertension.

Methods and Results— After a 4-week run-in period during which fruit and vegetable intake was limited to 1 portion per day, participants were randomized to consume either 1, 3, or 6 portions daily for the next 8 weeks. Endothelium-dependent and -independent arterial vasodilator responses were assessed by venous occlusion plethysmography in the brachial circulation before and after intervention. Compliance was monitored with serial contemporaneous 4-day food records and by measuring concentrations of circulating dietary biomarkers. A total of 117 volunteers completed the 12-week study. Participants in the 1-, 3-, and 6-portions/d groups reported consuming on average 1.1, 3.2, and 5.6 portions of fruit and vegetables, respectively, and serum concentrations of lutein and ß-cryptoxanthin increased across the groups in a dose-dependent manner. For each 1-portion increase in reported fruit and vegetable consumption, there was a 6.2% improvement in forearm blood flow responses to intra-arterial administration of the endothelium-dependent vasodilator acetylcholine (P=0.03). There was no association between increased fruit and vegetable consumption and vasodilator responses to sodium nitroprusside, an endothelium-independent vasodilator.

Conclusions— The present study illustrates that among hypertensive volunteers, increased fruit and vegetable consumption produces significant improvements in an established marker of endothelial function and cardiovascular prognosis.

An efficient feature selection method for mobile devices with application to activity recognition

This paper presents a feature selection method for data classification, which combines a model-based variable selection technique and a fast two-stage subset selection algorithm. The relationship between a specified (and complete) set of candidate features and the class label is modelled using a non-linear full regression model which is linear-in-the-parameters. The performance of a sub-model measured by the sum of the squared-errors (SSE) is used to score the informativeness of the subset of features involved in the sub-model. The two-stage subset selection algorithm approaches a solution sub-model with the SSE being locally minimized. The features involved in the solution sub-model are selected as inputs to support vector machines (SVMs) for classification. The memory requirement of this algorithm is independent of the number of training patterns. This property makes this method suitable for applications executed in mobile devices where physical RAM memory is very limited. An application was developed for activity recognition, which implements the proposed feature selection algorithm and an SVM training procedure. Experiments are carried out with the application running on a PDA for human activity recognition using accelerometer data. A comparison with an information gain based feature selection method demonstrates the effectiveness and efficiency of the proposed algorithm.

ON THE UNIVERSALITY OF 2-DIMENSIONAL DIFFUSION-LIMITED DEPOSITION

A history dependent stick probability is introduced to the diffusion-limited deposition model. The exponents in the scaling laws are calculated. The universality class is also discussed.

How Porosity and Permeability Vary Spatially With Grain Size, Sorting, Cement Volume, and Mineral Dissolution In Fluvial Triassic Sandstones: The Value of Geostatistics and Local Regression

Although it is well known that sandstone porosity and permeability are controlled by a range of parameters such as grain size and sorting, amount, type, and location of diagenetic cements, extent and type of compaction, and the generation of intergranular and intragranular secondary porosity, it is less constrained how these controlling parameters link up in rock volumes (within and between beds) and how they spatially interact to determine porosity and permeability. To address these unknowns, this study examined Triassic fluvial sandstone outcrops from the UK using field logging, probe permeametry of 200 points, and sampling at 100 points on a gridded rock surface. These field observations were supplemented by laser particle-size analysis, thin-section point-count analysis of primary and diagenetic mineralogy, quantitiative XRD mineral analysis, and SEM/EDAX analysis of all 100 samples. These data were analyzed using global regression, variography, kriging, conditional simulation, and geographically weighted regression to examine the spatial relationships between porosity and permeability and their potential controls. The results of bivariate analysis (global regression) of the entire outcrop dataset indicate only a weak correlation between both permeability porosity and their diagenetic and depositional controls and provide very limited information on the role of primary textural structures such as grain size and sorting. Subdividing the dataset further by bedding unit revealed details of more local controls on porosity and permeability. An alternative geostatistical approach combined with a local modelling technique (geographically weighted regression; GWR) subsequently was used to examine the spatial variability of porosity and permeability and their controls. The use of GWR does not require prior knowledge of divisions between bedding units, but the results from GWR broadly concur with results of regression analysis by bedding unit and provide much greater clarity of how porosity and permeability and their controls vary laterally and vertically. The close relationship between depositional lithofacies in each bed, diagenesis, and permeability, porosity demonstrates that each influences the other, and in turn how understanding of reservoir properties is enhanced by integration of paleoenvironmental reconstruction, stratigraphy, mineralogy, and geostatistics.

Increasing the accuracy of Nitrogen Dioxide (NO2) pollution mapping using geographically weighted regression (GWR) and geostatistics.

Nitrogen Dioxide (NO2) is known to act as an environmental trigger for many respiratory illnesses. As a pollutant it is difficult to map accurately, as concentrations can vary greatly over small distances. In this study three geostatistical techniques were compared, producing maps of NO2 concentrations in the United Kingdom (UK). The primary data source for each technique was NO2 point data, generated from background automatic monitoring and background diffusion tubes, which are analysed by different laboratories on behalf of local councils and authorities in the UK. The techniques used were simple kriging (SK), ordinary kriging (OK) and simple kriging with a locally varying mean (SKlm). SK and OK make use of the primary variable only. SKlm differs in that it utilises additional data to inform prediction, and hence potentially reduces uncertainty. The secondary data source was Oxides of Nitrogen (NOx) derived from dispersion modelling outputs, at 1km x 1km resolution for the UK. These data were used to define the locally varying mean in SKlm, using two regression approaches: (i) global regression (GR) and (ii) geographically weighted regression (GWR). Based upon summary statistics and cross-validation prediction errors, SKlm using GWR derived local means produced the most accurate predictions. Therefore, using GWR to inform SKlm was beneficial in this study.

Defective B cell response to TLR9 ligand (CpG-ODN), Streptococcus pneumoniae and Haemophilus influenzae extracts in common variable immunodeficiency patients

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinaemia and antibody deficiency to both T dependent and independent antigens. Patients suffer from recurrent sinopulmonary infections mostly caused by Streptococcus pneumoniae and Haemophilus influenzae, but also gastrointestinal or autoimmune symptoms. Their response to vaccination is poor or absent. In this study we investigated B cell activation induced by the TLR9 specific ligand (CpG-ODN) and bacterial extracts from S. pneumoniae and H. influenzae known to stimulate several TLR. We found that B cells from CVID patients express lower levels of CD86 after stimulation with CpG-ODN, S. pneumoniae and H. influenzae extracts in combination with anti-IgM antibody and also display a lower proliferative index when stimulated with bacterial extracts. Our results point to a broad TLR signalling defect in B lymphocytes from CVID patients that may be related to the hypogammaglobulinaemia and poor response to vaccination characteristic of these patients.

THE CUE-RESPONSIVITY PHENOMENON IN DEPENDENT DRINKERS - PERSONALITY VULNERABILITY AND ANXIETY AS INTERVENING VARIABLES

The cue-responsivity phenomenon to alcohol-associated stimuli in dependent drinkers was examined. In accordance with previous research, significant differences on both physiological and subjective cue-responsivity variables, between dependent and non-dependent drinkers were found. The unique contribution of this paper is two-fold. Firstly, evidence is presented which suggests that the Eysenckian personality traits of introversion and neuroticism are more predictive of cue-responsivity variance in the dependent drinkers than either severity of dependence or number of years' drinking. Secondly, within this dependent group, the relationship between cue-responsivity and 'craving' was seen to be less straightforward than traditionally thought. Specifically, it suggested that it was the extent to which autonomic cue-responsivity elicited increases in self-reported anxiety, which predicted most of the variance on the 'craving' variable. Taken together, these results raise the interesting possibility that a personality disposition akin to trait anxiety, and the degree to which cue exposure elicits state anxiety, mediated the relationship between cue-responsivity and 'craving' in dependent drinkers.

Robust Multimodal Person Identification With Limited Training Data

This paper presents a novel method of audio-visual feature-level fusion for person identification where both the speech and facial modalities may be corrupted, and there is a lack of prior knowledge about the corruption. Furthermore, we assume there are limited amount of training data for each modality (e.g., a short training speech segment and a single training facial image for each person). A new multimodal feature representation and a modified cosine similarity are introduced to combine and compare bimodal features with limited training data, as well as vastly differing data rates and feature sizes. Optimal feature selection and multicondition training are used to reduce the mismatch between training and testing, thereby making the system robust to unknown bimodal corruption. Experiments have been carried out on a bimodal dataset created from the SPIDRE speaker recognition database and AR face recognition database with variable noise corruption of speech and occlusion in the face images. The system's speaker identification performance on the SPIDRE database, and facial identification performance on the AR database, is comparable with the literature. Combining both modalities using the new method of multimodal fusion leads to significantly improved accuracy over the unimodal systems, even when both modalities have been corrupted. The new method also shows improved identification accuracy compared with the bimodal systems based on multicondition model training or missing-feature decoding alone.

The C-Terminal Variable Region Specifies the Dynamic Properties of Arabidopsis Microtubule-Associated Protein MAP65 Isotypes

The microtubule-associated protein, MAP65, is a member of a family of divergent microtubule-associated proteins from different organisms generally involved in maintaining the integrity of the central spindle in mitosis. The dicotyledon Arabidopsis thaliana and the monocotyledon rice (Oryza sativa) genomes contain 9 and 11 MAP65 genes, respectively. In this work, we show that the majority of these proteins fall into five phylogenetic clades, with the greatest variation between clades being in the C-terminal random coil domain. At least one Arabidopsis and one rice isotype is within each clade, indicating a functional specification for the C terminus. In At MAP65-1, the C-terminal domain is a microtubule binding region (MTB2) harboring the phosphorylation sites that control its activity. The At MAP65 isotypes show differential localization to microtubule arrays and promote microtubule polymerization with variable efficiency in a MTB2-dependent manner. In vivo studies demonstrate that the dynamics of the association and dissociation of different MAP65 isotypes with microtubules can vary up to 10-fold and that this correlates with their ability to promote microtubule polymerization. Our data demonstrate that the C-terminal variable region, MTB2, determines the dynamic properties of individual isotypes and suggest that slower turnover is conditional for more efficient microtubule polymerization.

A multiconfigurational time-dependent Hartree-Fock method for excited electronic states. I. General formalism and application to open-shell states

The solution of the time-dependent Schrodinger equation for systems of interacting electrons is generally a prohibitive task, for which approximate methods are necessary. Popular approaches, such as the time-dependent Hartree-Fock (TDHF) approximation and time-dependent density functional theory (TDDFT), are essentially single-configurational schemes. TDHF is by construction incapable of fully accounting for the excited character of the electronic states involved in many physical processes of interest; TDDFT, although exact in principle, is limited by the currently available exchange-correlation functionals. On the other hand, multiconfigurational methods, such as the multiconfigurational time-dependent Hartree-Fock (MCTDHF) approach, provide an accurate description of the excited states and can be systematically improved. However, the computational cost becomes prohibitive as the number of degrees of freedom increases, and thus, at present, the MCTDHF method is only practical for few-electron systems. In this work, we propose an alternative approach which effectively establishes a compromise between efficiency and accuracy, by retaining the smallest possible number of configurations that catches the essential features of the electronic wavefunction. Based on a time-dependent variational principle, we derive the MCTDHF working equation for a multiconfigurational expansion with fixed coefficients and specialise to the case of general open-shell states, which are relevant for many physical processes of interest. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3600397]