Articles de revista
http://hdl.handle.net/2117/3942
2017-12-14T21:06:51ZIdentification of interleukin-27 (IL-27)/IL-27 receptor subunit alpha as a critical immune axis for in vivo hiv control
http://hdl.handle.net/2117/111542
Identification of interleukin-27 (IL-27)/IL-27 receptor subunit alpha as a critical immune axis for in vivo hiv control
Ruiz-Riol, M.; Berdnik, D.; Llano, A.; Mothe, Beatriz; Gálvez, C.; Pérez Alvarez, Susana; Oriol Tordera, B.; Olvera Van der Stoep, Alex; Silva Arrieta, S.; Meulbroek, M.; Salvat Pujol, Francesc; Coll, J.; Martínez Picado, Javier; Ganoza, Carmela; Sánchez, J.; Gómez Melis, Guadalupe; Coray, Wyss; Brander, Christian
Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (> 50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/beta-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.
IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach (
2017-12-04T14:41:37ZRuiz-Riol, M.Berdnik, D.Llano, A.Mothe, BeatrizGálvez, C.Pérez Alvarez, SusanaOriol Tordera, B.Olvera Van der Stoep, AlexSilva Arrieta, S.Meulbroek, M.Salvat Pujol, FrancescColl, J.Martínez Picado, JavierGanoza, CarmelaSánchez, J.Gómez Melis, GuadalupeCoray, WyssBrander, ChristianIntact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (> 50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/beta-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.
IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach (Heuristic solucions to the facility location problem with general Bernoulli demands
http://hdl.handle.net/2117/111476
Heuristic solucions to the facility location problem with general Bernoulli demands
Albareda Sambola, Maria; Fernández Aréizaga, Elena; Saldanha da Gama, Francisco
In this paper, a heuristic procedure is proposed for the facility location problem with general Bernoulli demands. This is a discrete facility location problem with stochastic demands that can be formulated as a two-stage stochastic program with recourse. In particular, facility locations and customer assignments must be decided here and now, i.e., before knowing the customers who will actually require to be served. In a second stage, service decisions are made according to the actual requests. The heuristic proposed consists of a greedy randomized adaptive search procedure followed by a path relinking. The heterogeneous Bernoulli demands make prohibitive the computational effort for evaluating feasible solutions. Thus the expected cost of a feasible solution is simulated when necessary. The results of extensive computational tests performed for evaluating the quality of the heuristic are reported, showing that high-quality feasible solutions can be obtained for the problem in fairly small computational times.
2017-12-01T15:29:15ZAlbareda Sambola, MariaFernández Aréizaga, ElenaSaldanha da Gama, FranciscoIn this paper, a heuristic procedure is proposed for the facility location problem with general Bernoulli demands. This is a discrete facility location problem with stochastic demands that can be formulated as a two-stage stochastic program with recourse. In particular, facility locations and customer assignments must be decided here and now, i.e., before knowing the customers who will actually require to be served. In a second stage, service decisions are made according to the actual requests. The heuristic proposed consists of a greedy randomized adaptive search procedure followed by a path relinking. The heterogeneous Bernoulli demands make prohibitive the computational effort for evaluating feasible solutions. Thus the expected cost of a feasible solution is simulated when necessary. The results of extensive computational tests performed for evaluating the quality of the heuristic are reported, showing that high-quality feasible solutions can be obtained for the problem in fairly small computational times.On the testing of Hardy-Weinberg proportions and equality of allele frequencies in males and females at biallelic genetic markers
http://hdl.handle.net/2117/111053
On the testing of Hardy-Weinberg proportions and equality of allele frequencies in males and females at biallelic genetic markers
Graffelman, Jan; Weir, B.S.
Standard statistical tests for equality of allele frequencies in males and females and tests for Hardy-Weinberg equilibrium are tightly linked by their assumptions. Tests for equality of allele frequencies assume Hardy-Weinberg equilibrium, whereas the usual chi-square or exact test for Hardy-Weinberg equilibrium assume equality of allele frequencies in the sexes. In this paper, we propose ways to break this interdependence in assumptions of the two tests by proposing an omnibus exact test that can test both hypotheses jointly, as well as a likelihood ratio approach that permits these phenomena to be tested both jointly and separately. The tests are illustrated with data from the 1000 Genomes project.
2017-11-22T10:07:59ZGraffelman, JanWeir, B.S.Standard statistical tests for equality of allele frequencies in males and females and tests for Hardy-Weinberg equilibrium are tightly linked by their assumptions. Tests for equality of allele frequencies assume Hardy-Weinberg equilibrium, whereas the usual chi-square or exact test for Hardy-Weinberg equilibrium assume equality of allele frequencies in the sexes. In this paper, we propose ways to break this interdependence in assumptions of the two tests by proposing an omnibus exact test that can test both hypotheses jointly, as well as a likelihood ratio approach that permits these phenomena to be tested both jointly and separately. The tests are illustrated with data from the 1000 Genomes project.Interventions to improve adherence to reporting guidelines in health research: a scoping review protocol
http://hdl.handle.net/2117/111049
Interventions to improve adherence to reporting guidelines in health research: a scoping review protocol
Blanco de Tena Davila, David; Kirkham, Jamie; Altman, D.G.; Moher, David; Boutron, Isabelle; Cobo Valeri, Erik
There is evidence that the use of some reporting guidelines, such as the Consolidated Standards for Reporting Trials, is associated with improved completeness of reporting in health research. However, the current levels of adherence to reporting guidelines are suboptimal. Over the last few years, several actions aiming to improve compliance with reporting guidelines have been taken and proposed. We will conduct a scoping review of interventions to improve adherence to reporting guidelines in health research that have been evaluated or suggested, in order to inform future interventions.
2017-11-22T09:27:02ZBlanco de Tena Davila, DavidKirkham, JamieAltman, D.G.Moher, DavidBoutron, IsabelleCobo Valeri, ErikThere is evidence that the use of some reporting guidelines, such as the Consolidated Standards for Reporting Trials, is associated with improved completeness of reporting in health research. However, the current levels of adherence to reporting guidelines are suboptimal. Over the last few years, several actions aiming to improve compliance with reporting guidelines have been taken and proposed. We will conduct a scoping review of interventions to improve adherence to reporting guidelines in health research that have been evaluated or suggested, in order to inform future interventions.The use of a binary composite endpoint and sample size requirement: influence of endpoints overlap
http://hdl.handle.net/2117/110928
The use of a binary composite endpoint and sample size requirement: influence of endpoints overlap
Ramon Marsal, Josep; Ferreira González, Ignacio; Bertrán, Sandra; Ribera, Aida; Permanyer-Miralda, Gaietà; Garcia Dorado, Antonio David; Gómez Melis, Guadalupe
Although composite endpoints (CE) are common in clinical trials, the impact of the relationship between the components of a binary CE on the sample size requirement (SSR) has not been addressed. We performed a computational study considering 2 treatments and a CE with 2 components: the relevant endpoint (RE) and the additional endpoint (AE). We assessed the strength of the components’ interrelation by the degree of relative overlap between them, which was stratified into 5 groups. Within each stratum, SSR was computed for multiple scenarios by varying the events proportion and the effect of the therapy. A lower SSR using CE was defined as the best scenario for using the CE. In 25 of 66 scenarios the degree of relative overlap determined the benefit of using CE instead of the RE. Adding an AE with greater effect than the RE leads to lower SSR using the CE regardless of the AE proportion and the relative overlap. The influence of overlapping decreases when the effect on RE increases. Adding an AE with lower effect than the RE constitutes the most uncertain situation. In summary, the interrelationship between CE components, assessed by the relative overlap, can help to define the SSR in specific situations and it should be considered for SSR computation.
2017-11-20T15:21:50ZRamon Marsal, JosepFerreira González, IgnacioBertrán, SandraRibera, AidaPermanyer-Miralda, GaietàGarcia Dorado, Antonio DavidGómez Melis, GuadalupeAlthough composite endpoints (CE) are common in clinical trials, the impact of the relationship between the components of a binary CE on the sample size requirement (SSR) has not been addressed. We performed a computational study considering 2 treatments and a CE with 2 components: the relevant endpoint (RE) and the additional endpoint (AE). We assessed the strength of the components’ interrelation by the degree of relative overlap between them, which was stratified into 5 groups. Within each stratum, SSR was computed for multiple scenarios by varying the events proportion and the effect of the therapy. A lower SSR using CE was defined as the best scenario for using the CE. In 25 of 66 scenarios the degree of relative overlap determined the benefit of using CE instead of the RE. Adding an AE with greater effect than the RE leads to lower SSR using the CE regardless of the AE proportion and the relative overlap. The influence of overlapping decreases when the effect on RE increases. Adding an AE with lower effect than the RE constitutes the most uncertain situation. In summary, the interrelationship between CE components, assessed by the relative overlap, can help to define the SSR in specific situations and it should be considered for SSR computation.Comparison of production strategies and degree of postponement when incorporating additive manufacturing to product supply chains
http://hdl.handle.net/2117/110899
Comparison of production strategies and degree of postponement when incorporating additive manufacturing to product supply chains
Minguella Canela, Joaquim; Muguruza Blanco, Asier; Ramón Lumbierres, Daniel Jacobo; Heredia, F.-Javier (Francisco Javier); Gimeno Feu, Robert; Guo, Ping; Hamilton, Mary; Shastry, Kiron; Webb, Sunny
The best-selling products manufactured nowadays are made in long series along rigid product value chains. Product repetition and continuous/stable manufacturing is seen as a chance for achieving economies of scale. Nevertheless, these speculative strategies fail to meet special customer demands, thus reducing the effective market share of a product in a range.
Additive Manufacturing technologies open promising product customization opportunities; however, to achieve it, it is necessary to delay the production operations in order to incorporate the customer’s inputs in the product materialization.
The study offered in the present paper compares different possible production strategies for a product (via conventional technologies and Additive Manufacturing) and assesses the degree of postponement that it would be recommended in order to meet a certain demand distribution. The problem solving is calculated by a program containing a stochastic mathematical model which incorporates extensive information on costs and lead times for the required manufacturing operations.
2017-11-20T08:13:49ZMinguella Canela, JoaquimMuguruza Blanco, AsierRamón Lumbierres, Daniel JacoboHeredia, F.-Javier (Francisco Javier)Gimeno Feu, RobertGuo, PingHamilton, MaryShastry, KironWebb, SunnyThe best-selling products manufactured nowadays are made in long series along rigid product value chains. Product repetition and continuous/stable manufacturing is seen as a chance for achieving economies of scale. Nevertheless, these speculative strategies fail to meet special customer demands, thus reducing the effective market share of a product in a range.
Additive Manufacturing technologies open promising product customization opportunities; however, to achieve it, it is necessary to delay the production operations in order to incorporate the customer’s inputs in the product materialization.
The study offered in the present paper compares different possible production strategies for a product (via conventional technologies and Additive Manufacturing) and assesses the degree of postponement that it would be recommended in order to meet a certain demand distribution. The problem solving is calculated by a program containing a stochastic mathematical model which incorporates extensive information on costs and lead times for the required manufacturing operations.A bayesian test for Hardy-Weinberg equilibrium of bi-allelic X-chromosomal markers
http://hdl.handle.net/2117/110646
A bayesian test for Hardy-Weinberg equilibrium of bi-allelic X-chromosomal markers
Puig Oriol, Xavier; Ginebra Molins, Josep; Graffelman, Jan
The X chromosome is a relatively large chromosome, harboring a lot of genetic information. Much of the statistical analysis of X-chromosomal information is complicated by the fact that males only have one copy. Recently, frequentist statistical tests for Hardy–Weinberg equilibrium have been proposed specifically for dealing with markers on the X chromosome. Bayesian test procedures for Hardy–Weinberg equilibrium for the autosomes have been described, but Bayesian work on the X chromosome in this context is lacking. This paper gives the first Bayesian approach for testing Hardy–Weinberg equilibrium with biallelic
markers at the X chromosome. Marginal and joint posterior distributions for the inbreeding coefficient in females and the male to female allele frequency ratio are computed, and used for statistical inference. The paper gives a detailed account of the proposed Bayesian test, and illustrates it with data from the 1000 Genomes project. In that implementation, a novel approach to tackle multiple testing from a Bayesian perspective through posterior predictive checks is used.
2017-11-15T09:21:37ZPuig Oriol, XavierGinebra Molins, JosepGraffelman, JanThe X chromosome is a relatively large chromosome, harboring a lot of genetic information. Much of the statistical analysis of X-chromosomal information is complicated by the fact that males only have one copy. Recently, frequentist statistical tests for Hardy–Weinberg equilibrium have been proposed specifically for dealing with markers on the X chromosome. Bayesian test procedures for Hardy–Weinberg equilibrium for the autosomes have been described, but Bayesian work on the X chromosome in this context is lacking. This paper gives the first Bayesian approach for testing Hardy–Weinberg equilibrium with biallelic
markers at the X chromosome. Marginal and joint posterior distributions for the inbreeding coefficient in females and the male to female allele frequency ratio are computed, and used for statistical inference. The paper gives a detailed account of the proposed Bayesian test, and illustrates it with data from the 1000 Genomes project. In that implementation, a novel approach to tackle multiple testing from a Bayesian perspective through posterior predictive checks is used.Identification of Interleukin-27 (IL-27)/IL- 27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control
http://hdl.handle.net/2117/110221
Identification of Interleukin-27 (IL-27)/IL- 27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control
Ruiz-Riol, M.; Berdnik, D.; Llano, A.; Mothe, Beatriz; Gálvez Montón, Carolina; Pérez Alvarez, Susana; Oriol Tordera, B.; Olvera Van der Stoep, Alex; Silva Arrieta, S.; Meulbroek, M.; Pujol, F.; Coll, J.; Martínez Picado, Javier; Ganoza, Carmela; Sánchez, J.; Gómez Melis, Guadalupe; Coray, Wyss; Brander, Christian
Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/ß-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.
2017-11-10T10:03:13ZRuiz-Riol, M.Berdnik, D.Llano, A.Mothe, BeatrizGálvez Montón, CarolinaPérez Alvarez, SusanaOriol Tordera, B.Olvera Van der Stoep, AlexSilva Arrieta, S.Meulbroek, M.Pujol, F.Coll, J.Martínez Picado, JavierGanoza, CarmelaSánchez, J.Gómez Melis, GuadalupeCoray, WyssBrander, ChristianIntact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/ß-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.Nonlinear loads model for harmonics flow prediction, using multivariate regression
http://hdl.handle.net/2117/108748
Nonlinear loads model for harmonics flow prediction, using multivariate regression
Lamich Arocas, Manuel; Balcells Sendra, Josep; Corbalán Fuertes, Montserrat; Griful Ponsati, Eulàlia
This paper describes a method for obtaining a model of a single or a set of nonlinear loads (NLL) connected to a certain point of an electrical network. The basic assumption is that the network supplying the NLL has significant series impedances and is disturbed by other parallel, random, and unknown neighbor loads, sharing part of the supply system with the NLL. The main interest for obtaining the model is its further use to predict the amount and flow of harmonic currents generated by the NLL, in the case of adding a filter to reduce the harmonics distortion. The modeling technique used in the paper is based on multivariate multiple outputs regression and leads to a set of equations giving the NLL behavior (one for each of the harmonic currents). The model is obtained from data taken at measuring point and is only valid to predict the NLL behavior when new loads are connected at this point. The modeling method was first tested with V, I data coming from simulations using a MATLAB-Simulink SimPowerSystems toolbox. Finally, the method has been validated using V, I data taken in a real installation with different neighbor loads and under different load conditions.
2017-10-17T12:00:15ZLamich Arocas, ManuelBalcells Sendra, JosepCorbalán Fuertes, MontserratGriful Ponsati, EulàliaThis paper describes a method for obtaining a model of a single or a set of nonlinear loads (NLL) connected to a certain point of an electrical network. The basic assumption is that the network supplying the NLL has significant series impedances and is disturbed by other parallel, random, and unknown neighbor loads, sharing part of the supply system with the NLL. The main interest for obtaining the model is its further use to predict the amount and flow of harmonic currents generated by the NLL, in the case of adding a filter to reduce the harmonics distortion. The modeling technique used in the paper is based on multivariate multiple outputs regression and leads to a set of equations giving the NLL behavior (one for each of the harmonic currents). The model is obtained from data taken at measuring point and is only valid to predict the NLL behavior when new loads are connected at this point. The modeling method was first tested with V, I data coming from simulations using a MATLAB-Simulink SimPowerSystems toolbox. Finally, the method has been validated using V, I data taken in a real installation with different neighbor loads and under different load conditions.Choosing the most relevant level sets for depicting a sample of densities
http://hdl.handle.net/2117/108716
Choosing the most relevant level sets for depicting a sample of densities
Delicado Useros, Pedro Francisco; Vieu, Philippe
When exploring a sample composed with a set of bivariate density functions, the question of the visualisation of the data has to front with the choice of the relevant level set(s). The approach proposed in this paper consists in defining the optimal level set(s) as being the one(s) allowing for the best reconstitution of the whole density. A fully data-driven procedure is developed in order to estimate the link between the level set(s) and their corresponding density, to construct optimal level set(s) and to choose automatically the number of relevant level set(s). The method is based on recent advances in functional data analysis when both response and predictors are functional. After a wide description of the methodology, finite sample studies are presented (including both real and simulated data) while theoretical studies are reported to a final appendix.
The final publication is available at link.springer.com
2017-10-16T11:23:54ZDelicado Useros, Pedro FranciscoVieu, PhilippeWhen exploring a sample composed with a set of bivariate density functions, the question of the visualisation of the data has to front with the choice of the relevant level set(s). The approach proposed in this paper consists in defining the optimal level set(s) as being the one(s) allowing for the best reconstitution of the whole density. A fully data-driven procedure is developed in order to estimate the link between the level set(s) and their corresponding density, to construct optimal level set(s) and to choose automatically the number of relevant level set(s). The method is based on recent advances in functional data analysis when both response and predictors are functional. After a wide description of the methodology, finite sample studies are presented (including both real and simulated data) while theoretical studies are reported to a final appendix.