Restriction site-associated DNA sequencing, genotyping error estimation and de novo assembly optimization for population genetic inference.

Restriction site-associated DNA sequencing (RADseq) provides researchers with the ability to record genetic polymorphism across thousands of loci for nonmodel organisms, potentially revolutionizing the field of molecular ecology. However, as with other genotyping methods, RADseq is prone to a number of sources of error that may have consequential effects for population genetic inferences, and these have received only limited attention in terms of the estimation and reporting of genotyping error rates. Here we use individual sample replicates, under the expectation of identical genotypes, to quantify genotyping error in the absence of a reference genome. We then use sample replicates to (i) optimize de novo assembly parameters within the program Stacks, by minimizing error and maximizing the retrieval of informative loci; and (ii) quantify error rates for loci, alleles and single-nucleotide polymorphisms. As an empirical example, we use a double-digest RAD data set of a nonmodel plant species, Berberis alpina, collected from high-altitude mountains in Mexico.

In Search of a theory of debt management

A growing literature integrates theories of debt management into models of optimal fiscal policy. One promising theory argues that the composition of government debt should be chosen so that fluctuations in the market value of debt offset changes in expected future deficits. This complete market approach to debt management is valid even when the government only issues non-contingent bonds. A number of authors conclude from this approach that governments should issue long term debt and invest in short term assets. We argue that the conclusions of this approach are too fragile to serve as a basis for policy recommendations. This is because bonds at different maturities have highly correlated returns, causing the determination of the optimal portfolio to be ill-conditioned. To make this point concrete we examine the implications of this approach to debt management in various models, both analytically and using numerical methods calibrated to the US economy. We find the complete market approach recommends asset positions which are huge multiples of GDP. Introducing persistent shocks or capital accumulation only worsens this problem. Increasing the volatility of interest rates through habits partly reduces the size of these simulations we find no presumption that governments should issue long term debt ? policy recommendations can be easily reversed through small perturbations in the specification of shocks or small variations in the maturity of bonds issued. We further extend the literature by removing the assumption that governments every period costlessly repurchase all outstanding debt. This exacerbates the size of the required positions, worsens their volatility and in some cases produces instability in debt holdings. We conclude that it is very difficult to insulate fiscal policy from shocks by using the complete markets approach to debt management. Given the limited variability of the yield curve using maturities is a poor way to substitute for state contingent debt. The result is the positions recommended by this approach conflict with a number of features that we believe are important in making bond markets incomplete e.g allowing for transaction costs, liquidity effects, etc.. Until these features are all fully incorporated we remain in search of a theory of debt management capable of providing robust policy insights.

Stochastic Search Variable Selection in Vector Error Correction Models with an Application to a Model of the UK Macroeconomy

This paper develops methods for Stochastic Search Variable Selection (currently popular with regression and Vector Autoregressive models) for Vector Error Correction models where there are many possible restrictions on the cointegration space. We show how this allows the researcher to begin with a single unrestricted model and either do model selection or model averaging in an automatic and computationally efficient manner. We apply our methods to a large UK macroeconomic model.

Codex Search: propuesta e implementación de un sistema de recuperación de información de ámbito local basado en casos

CODEX SEARCH es un motor de recuperación de información especializado en derecho de extranjería que está basado en herramientas y conocimiento lingüísticos. Un motor o Sistema de Recuperación de Información (SRI) es un software capaz de localizar información en grandes colecciones documentales (entorno no trivial) en formato electrónico. Mediante un estudio previo se ha detectado que la extranjería es un ámbito discursivo en el que resulta difícil expresar la necesidad de información en términos de una consulta formal, objeto de los sistemas de recuperación actuales. Por lo tanto, para desarrollar un SRI eficiente en el dominio indicado no basta con emplear un modelo tradicional de RI, es decir, comparar los términos de la pregunta con los de la respuesta, básicamente porque no expresan implicaciones y porque no tiene que haber necesariamente una relación 1 a 1. En este sentido, la solución lingüística propuesta se basa en incorporar el conocimiento del especialista mediante la integración en el sistema de una librería de casos. Los casos son ejemplos de procedimientos aplicados por expertos a la solución de problemas que han ocurrido en la realidad y que han terminado en éxito o fracaso. Los resultados obtenidos en esta primera fase son muy alentadores pero es necesario continuar la investigación en este campo para mejorar el rendimiento del prototipo al que se puede acceder desde &http://161.116.36.139/~codex/&.

The antecedents and innovation consequences of organizational search: empirical evidence for Spain

This paper examines the antecedents and innovation consequences of the methods firms adopt in organizing their search strategies. From a theoretical perspective, organizational search is described using a typology that shows how firms implement exploration and exploitation search activities that span their organizational boundaries. This typology includes three models of implementation: ambidextrous, specialized, and diversified implementation. From an empirical perspective, the paper examines the performance consequences when applying these models, and compares their capacity to produce complementarities. Additionally, since firms' choices in matters of organizational search are viewed as endogenous variables, the paper examines the drivers affecting them and identifies the importance of firms' absorptive capacity and diversified technological opportunities in determining these choices. The empirical design of the paper draws on new data for manufacturing firms in Spain, surveyed between 2003 and 2006.

Diffusion-weighted MR imaging of the spine at 3-T: feasibility, optimization of b-value and utility to differentiate benign from pathological vertebral compression fractures

Purpose: To evaluate the feasibility, determine the optimal b-value, and assess the utility of 3-T diffusion-weighted MR imaging (DWI) of the spine in differentiating benign from pathologic vertebral compression fractures.Methods and Materials: Twenty patients with 38 vertebral compression fractures (24 benign, 14 pathologic) and 20 controls (total: 23 men, 17 women, mean age 56.2years) were included from December 2010 to May 2011 in this IRB-approved prospective study. MR imaging of the spine was performed on a 3-T unit with T1-w, fat-suppressed T2-w, gadolinium-enhanced fat-suppressed T1-w and zoomed-EPI (2D RF excitation pulse combined with reduced field-of-view single-shot echo-planar readout) diffusion-w (b-values: 0, 300, 500 and 700s/mm2) sequences. Two radiologists independently assessed zoomed-EPI image quality in random order using a 4-point scale: 1=excellent to 4=poor. They subsequently measured apparent diffusion coefficients (ADCs) in normal vertebral bodies and compression fractures, in consensus.Results: Lower b-values correlated with better image quality scores, with significant differences between b=300 (mean±SD=2.6±0.8), b=500 (3.0±0.7) and b=700 (3.6±0.6) (all p<0.001). Mean ADCs of normal vertebral bodies (n=162) were 0.23, 0.17 and 0.11×10-3mm2/s with b=300, 500 and 700s/mm2, respectively. In contrast, mean ADCs were 0.89, 0.70 and 0.59×10-3mm2/s for benign vertebral compression fractures and 0.79, 0.66 and 0.51×10-3mm2/s for pathologic fractures with b=300, 500 and 700s/mm2, respectively. No significant difference was found between ADCs of benign and pathologic fractures.Conclusion: 3-T DWI of the spine is feasible and lower b-values (300s/mm2) are recommended. However, our preliminary results show no advantage of DWI in differentiating benign from pathologic vertebral compression fractures.

Restriction site-associated DNA sequencing, genotyping error estimation and de novo assembly optimization for population genetic inference.

Restriction site-associated DNA sequencing (RADseq) provides researchers with the ability to record genetic polymorphism across thousands of loci for nonmodel organisms, potentially revolutionizing the field of molecular ecology. However, as with other genotyping methods, RADseq is prone to a number of sources of error that may have consequential effects for population genetic inferences, and these have received only limited attention in terms of the estimation and reporting of genotyping error rates. Here we use individual sample replicates, under the expectation of identical genotypes, to quantify genotyping error in the absence of a reference genome. We then use sample replicates to (i) optimize de novo assembly parameters within the program Stacks, by minimizing error and maximizing the retrieval of informative loci; and (ii) quantify error rates for loci, alleles and single-nucleotide polymorphisms. As an empirical example, we use a double-digest RAD data set of a nonmodel plant species, Berberis alpina, collected from high-altitude mountains in Mexico.

Molecular characterisation of intermediate snail hosts and the search for resistance genes

The relationship between schistosomes and their intermediate hosts is an extremely intricate one with strains and species of the parasite depending on particular species of snail, which in turn may vary in their susceptibility to the parasites. In order to gain a better understanding of the epidemiology of the disease we have been investigating the use of molecular markers for snail identification and for studying host-parasite relationships. In this paper we will draw on examples concerning schistosomiasis in West and East Africa to illustrate how a molecular analysis can be used as part of a "total evidence" approach to characterisation of Bulinus species and provide insights into parasite transmission. Particular emphasis is given to ribosomal RNA genes (rRNA), random amplified polymorphic DNA (RAPDs) and the mitochondrial gene cytochrome oxidase I (COI). Snails resistant to infection occur naturally and there is a genetic basis for this resistance. In Biomphalaria glabrata resistance to Schistosoma mansoni is known to be a polygenic trait and we have initiated a preliminary search for snail genomic regions linked to, or involved in, resistance by using a RAPD based approach in conjunction with progeny pooling methods. We are currently characterising a variety of STSs (sequence tagged sites) associated with resistance. These can be used for local linkage and interval mapping to define genomic regions associated with the resistance trait. The development of such markers into simple dot-blot or specific PCR-based assays may have a direct and practical application for the identification of resistant snails in natural populations.

Optimization of spatial resolution for peripheral magnetic resonance angiography.

RATIONALE AND OBJECTIVES: To determine optimum spatial resolution when imaging peripheral arteries with magnetic resonance angiography (MRA). MATERIALS AND METHODS: Eight vessel diameters ranging from 1.0 to 8.0 mm were simulated in a vascular phantom. A total of 40 three-dimensional flash MRA sequences were acquired with incremental variations of fields of view, matrix size, and slice thickness. The accurately known eight diameters were combined pairwise to generate 22 "exact" degrees of stenosis ranging from 42% to 87%. Then, the diameters were measured in the MRA images by three independent observers and with quantitative angiography (QA) software and used to compute the degrees of stenosis corresponding to the 22 "exact" ones. The accuracy and reproducibility of vessel diameter measurements and stenosis calculations were assessed for vessel size ranging from 6 to 8 mm (iliac artery), 4 to 5 mm (femoro-popliteal arteries), and 1 to 3 mm (infrapopliteal arteries). Maximum pixel dimension and slice thickness to obtain a mean error in stenosis evaluation of less than 10% were determined by linear regression analysis. RESULTS: Mean errors on stenosis quantification were 8.8% +/- 6.3% for 6- to 8-mm vessels, 15.5% +/- 8.2% for 4- to 5-mm vessels, and 18.9% +/- 7.5% for 1- to 3-mm vessels. Mean errors on stenosis calculation were 12.3% +/- 8.2% for observers and 11.4% +/- 15.1% for QA software (P = .0342). To evaluate stenosis with a mean error of less than 10%, maximum pixel surface, the pixel size in the phase direction, and the slice thickness should be less than 1.56 mm2, 1.34 mm, 1.70 mm, respectively (voxel size 2.65 mm3) for 6- to 8-mm vessels; 1.31 mm2, 1.10 mm, 1.34 mm (voxel size 1.76 mm3), for 4- to 5-mm vessels; and 1.17 mm2, 0.90 mm, 0.9 mm (voxel size 1.05 mm3) for 1- to 3-mm vessels. CONCLUSION: Higher spatial resolution than currently used should be selected for imaging peripheral vessels.

Version brève du DISCERN, une voie d'amélioration de la recherche d'information médicale sur le net [Brief-DISCERN, a possible way to improve patient's search on the health-related web]

Internet is increasingly used as a source of information on health issues and is probably a major source of patients' empowerment. This process is however limited by the frequently poor quality of web-based health information designed for consumers. A better diffusion of information about criteria defining the quality of the content of websites, and about useful methods designed for searching such needed information, could be particularly useful to patients and their relatives. A brief, six-items DISCERN version, characterized by a high specificity for detecting websites with good or very good content quality was recently developed. This tool could facilitate the identification of high-quality information on the web by patients and may improve the empowerment process initiated by the development of the health-related web.

Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria

Background. A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation. METHODS: Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN beta1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years. RESULTS: We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m - last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m - last visit; CH: 0.29, NCH: 0.13). CONCLUSION: Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.

Towards Direct Policy Search Reinforcement Learning for Robot Control

This paper proposes a high-level reinforcement learning (RL) control system for solving the action selection problem of an autonomous robot. Although the dominant approach, when using RL, has been to apply value function based algorithms, the system here detailed is characterized by the use of direct policy search methods. Rather than approximating a value function, these methodologies approximate a policy using an independent function approximator with its own parameters, trying to maximize the future expected reward. The policy based algorithm presented in this paper is used for learning the internal state/action mapping of a behavior. In this preliminary work, we demonstrate its feasibility with simulated experiments using the underwater robot GARBI in a target reaching task

Route optimization and customization using real geographical data in Android mobile devices

Nowadays, there are several services and applications that allow users to locate and move to different tourist areas using a mobile device. These systems can be used either by internet or downloading an application in concrete places like a visitors centre. Although such applications are able to facilitate the location and the search for points of interest, in most cases, these services and applications do not meet the needs of each user. This paper aims to provide a solution by studying the main projects, services and applications, their routing algorithms and their treatment of the real geographical data in Android mobile devices, focusing on the data acquisition and treatment to improve the routing searches in off-line environments.

Low-dose multidetector computed tomography of the cervical spine: optimization of iterative reconstruction strength levels.

BACKGROUND: Iterative reconstruction (IR) techniques reduce image noise in multidetector computed tomography (MDCT) imaging. They can therefore be used to reduce radiation dose while maintaining diagnostic image quality nearly constant. However, CT manufacturers offer several strength levels of IR to choose from. PURPOSE: To determine the optimal strength level of IR in low-dose MDCT of the cervical spine. MATERIAL AND METHODS: Thirty consecutive patients investigated by low-dose cervical spine MDCT were prospectively studied. Raw data were reconstructed using filtered back-projection and sinogram-affirmed IR (SAFIRE, strength levels 1 to 5) techniques. Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured at C3-C4 and C6-C7 levels. Two radiologists independently and blindly evaluated various anatomical structures (both dense and soft tissues) using a 4-point scale. They also rated the overall diagnostic image quality using a 10-point scale. RESULTS: As IR strength levels increased, image noise decreased linearly, while SNR and CNR both increased linearly at C3-C4 and C6-C7 levels (P < 0.001). For the intervertebral discs, the content of neural foramina and dural sac, and for the ligaments, subjective image quality scores increased linearly with increasing IR strength level (P ≤ 0.03). Conversely, for the soft tissues and trabecular bone, the scores decreased linearly with increasing IR strength level (P < 0.001). Finally, the overall diagnostic image quality scores increased linearly with increasing IR strength level (P < 0.001). CONCLUSION: The optimal strength level of IR in low-dose cervical spine MDCT depends on the anatomical structure to be analyzed. For the intervertebral discs and the content of neural foramina, high strength levels of IR are recommended.

When should clinicians search for GLUT1 deficiency syndrome in childhood generalized epilepsies?

UNLABELLED: GLUT1 deficiency (GLUT1D) has recently been identified as an important cause of generalized epilepsies in childhood. As it is a treatable condition, it is crucial to determine which patients should be investigated. METHODS: We analyzed SLC2A1 for mutations in a group of 93 unrelated children with generalized epilepsies. Fasting lumbar puncture was performed following the identification of a mutation. We compared our results with a systematic review of 7 publications of series of patients with generalized epilepsies screened for SLC2A1 mutations. RESULTS: We found 2/93 (2.1%) patients with a SLC2A1 mutation. One, carrying a novel de novo deletion had epilepsy with myoclonic-atonic seizures (MAE), mild slowing of head growth, choreiform movements and developmental delay. The other, with a paternally inherited missense mutation, had childhood absence epilepsy with atypical EEG features and paroxysmal exercise-induced dyskinesia (PED) initially misdiagnosed as myoclonic seizures. Out of a total of 1110 screened patients with generalized epilepsies from 7 studies, 2.4% (29/1110) had GLUT1D. This rate was higher (5.6%) among 303 patients with early onset absence epilepsy (EOAE) from 4 studies. About 50% of GLUT1D patients had abnormal movements and 41% a family history of seizures, abnormal movements or both. CONCLUSION: GLUT1D is most likely to be found in MAE and in EOAE. The probability of finding GLUT1D in the classical idiopathic generalized epilepsies is very low. Pointers to GLUT1D include an increase in seizures before meals, cognitive impairment, or PED which can easily be overlooked.