Simulation-based solution of stochastic mathematical programs with complementarity constraints: Sample-path analysis

We consider a class of stochastic mathematical programs with complementarity constraints, in which both the objective and the constraints involve limit functions or expectations that need to be estimated or approximated. Such programs can be used for modeling \\average" or steady-state behavior of complex stochastic systems. Recently, simulation-based methods have been successfully used for solving challenging stochastic optimization problems and equilibrium models. Here we broaden the applicability of so-called the sample-path method to include the solution of certain stochastic mathematical programs with equilibrium constraints. The convergence analysis of sample-path methods rely heavily on stability conditions. We first review necessary sensitivity results, then describe the method, and provide sufficient conditions for its almost-sure convergence. Alongside we provide a complementary sensitivity result for the corresponding deterministic problems. In addition, we also provide a unifying discussion on alternative set of sufficient conditions, derive a complementary result regarding the analysis of stochastic variational inequalities, and prove the equivalence of two different regularity conditions

The effect of transport time, season and position on the truck on stress response in rabbits

[EN] The present study analyzed the effect of transport time, season and position on the truck on physiological stress response of commercial rabbits in Aragón (Spain). A total of 156 animals were sampled in a 2x2x3 factorial design testing two transport times: short, 1 hour (1hT) and long, 7 hours (7hT), in two different seasons: hot, during summer (HT) and cold during winter (CT), and three different positions on the truck: upper, middle or lower decks in multi-floor cages on rolling stands (MFRS-top, MFRS-middle and MFRS-bottom). Three replicates were performed per treatment. Blood samples were taken at sticking during slaughter to compare hematocrite, corticosterone, glucose, lactate and Creatine Kinase (CK) levels as well as the ultimate pH of the carcass (pH24). Corticosterone and CK levels were highest in 1hT rabbits. With respect to season, colder temperatures increased corticosterone, while warmer temperatures increased CK (P<0.001). Regarding position on the truck, MFRS-middle and bottom rabbits had higher levels of glucose, corticosterone and CK. The pH24 values were within normal ranges for all treatments but slightly higher for animals transported in winter. In general, transport time and season were significant stressors for commercial rabbits, due to the effects on their physiological states. Position on the truck seems to have an effect on stress response to transport in rabbits. However, pH24, which is considered one of the main parameters of welfare measurements, was not affected by transport time or position on the truck.Our project was financed by the Spanish Ministry of Science and Technology (CICYT AGL-2002-01346). The authors wish to thank CUIN S.L. in Villanueva de Gállego and the associations MADECUN and ASESCU for their collaboration.Liste, M.; María, GA.; García-Belenguer, S.; Chacón, G.; Gazzola, P.; Villarroel, M. (2008). The effect of transport time, season and position on the truck on stress response in rabbits. World Rabbit Science. 16(4). doi:10.4995/wrs.2008.618SWORD16

Influence of transport duration and season on sensory meat quality in rabbits

Little is known about the effect that journey duration and position on the vehicle have on the sensory aspects of meat quality in rabbits. In this study, 156 rabbits were transported by road in a commercial truck for 1 h or 7 h in one of three replicates in summer or winter. After slaughter, slices from the left side of the longissimus dorsi muscle were vacuum-packaged and chilled at -18 ºC until the sensory analysis to assess odour, tenderness, juiciness, fibrousity, greasiness, and flavour intensity. Overall, the journey duration had a significant effect (P<0.05) on tenderness, fi brousity and overall liking of the meat, being better the results of the meat samples from the short transport treatment. Season had a significant effect (P<0.05) on the intensity of off-odours, being obtained the highest scores in summer transports. There was a significant interaction effect (P<0.05) of journey time and season on tenderness and meat odour. Therefore, meat from short journeys in summer was the most tender, and meat from long journeys in winter was the toughest. The position on the truck (in multi-layered cages) do not influence sensory meat quality. Therefore, rabbit sensory meat quality can be affected by transport time.Funded by CICYT Ministry of Science and Technology of Spain. Project AGL 2002-01346 COTRANSMaría, GA.; Liste, G.; Campo, M.; Villarroel, M.; Sañudo, C.; Olleta, J.; Alierta, S. (2010). Influence of transport duration and season on sensory meat quality in rabbits. World Rabbit Science. 16(2). doi:10.4995/wrs.2008.63016

Global optimization in systems biology: stochastic methods and their applications

Mathematical optimization is at the core of many problems in systems biology: (1) as the underlying hypothesis for model development, (2) in model identification, or (3) in the computation of optimal stimulation procedures to synthetically achieve a desired biological behavior. These problems are usually formulated as nonlinear programing problems (NLPs) with dynamic and algebraic constraints. However the nonlinear and highly constrained nature of systems biology models, together with the usually large number of decision variables, can make their solution a daunting task, therefore calling for efficient and robust optimization techniques. Here, we present novel global optimization methods and software tools such as cooperative enhanced scatter search (eSS), AMIGO, or DOTcvpSB, and illustrate their possibilities in the context of modeling including model identification and stimulation design in systems biology.This work was supported by the Spanish MICINN project ”MultiSysBio” (ref. DPI2008-06880-C03-02), and by CSIC intramural project ”BioREDES” (ref. PIE-201170E018).Peer reviewe

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

Understanding the molecular programs of the generation of human dopaminergic neurons (DAn) from their ventral mesencephalic (VM) precursors is of key importance for basic studies, progress in cell therapy, drug screening and pharmacology in the context of Parkinson's disease. The nature of human DAn precursors in vitro is poorly understood, their properties unstable, and their availability highly limited. Here we present positive evidence that human VM precursors retaining their genuine properties and long-term capacity to generate A9 type Substantia nigra human DAn (hVM1 model cell line) can be propagated in culture. During a one month differentiation, these cells activate all key genes needed to progress from pro-neural and prodopaminergic precursors to mature and functional DAn. For the first time, we demonstrate that gene cascades are correctly activated during differentiation, resulting in the generation of mature DAn. These DAn have morphological and functional properties undistinguishable from those generated by VM primary neuronal cultures. In addition, we have found that the forced expression of Bcl-XL induces an increase in the expression of key developmental genes (MSX1, NGN2), maintenance of PITX3 expression temporal profile, and also enhances genes involved in DAn long-term function, maintenance and survival (EN1, LMX1B, NURR1 and PITX3). As a result, Bcl-XL anticipates and enhances DAn generation

Human cortical organoids expose a differential function of GSK3 on cortical neurogenesis

The regulation of the proliferation and polarity of neural progenitors is crucial for the development of the brain cortex. Animal studies have implicated glycogen synthase kinase 3 (GSK3) as a pivotal regulator of both proliferation and polarity, yet the functional relevance of its signaling for the unique features of human corticogenesis remains to be elucidated. We harnessed human cortical brain organoids to probe the longitudinal impact of GSK3 inhibition through multiple developmental stages. Chronic GSK3 inhibition increased the proliferation of neural progenitors and caused massive derangement of cortical tissue architecture. Single-cell transcriptome profiling revealed a direct impact on early neurogenesis and uncovered a selective role of GSK3 in the regulation of glutamatergic lineages and outer radial glia output. Our dissection of the GSK3-dependent transcriptional network in human corticogenesis underscores the robustness of the programs determining neuronal identity independent of tissue architecture

CMEMS downscaled wave operational forecast system

This document describes the numerical modelling work for waves done in wp5.2. needed to implement OSPA

CMEMS downscaled circulation operational forecast system

This document describes the numerical modelling work done in task 5.2 needed to implement OSPA

Clonal human fetal ventral mesencephalic dopaminergic neuron precursors for cell therapy research

A major challenge for further development of drug screening procedures, cell replacement therapies and developmental studies is the identification of expandable human stem cells able to generate the cell types needed. We have previously reported the generation of an immortalized polyclonal neural stem cell (NSC) line derived from the human fetal ventral mesencephalon (hVM1). This line has been biochemically, genetically, immunocytochemically and electrophysiologically characterized to document its usefulness as a model system for the generation of A9 dopaminergic neurons (DAn). Long-term in vivo transplantation studies in parkinsonian rats showed that the grafts do not mature evenly. We reasoned that diverse clones in the hVM1 line might have different abilities to differentiate. In the present study, we have analyzed 9 hVM1 clones selected on the basis of their TH generation potential and, based on the number of v-myc copies, v-myc down-regulation after in vitro differentiation, in vivo cell cycle exit, TH+ neuron generation and expression of a neuronal mature marker (hNSE), we selected two clones for further in vivo PD cell replacement studies. The conclusion is that homogeneity and clonality of characterized NSCs allow transplantation of cells with controlled properties, which should help in the design of long-term in vivo experimentsThis work was supported by grants from the Spanish Ministry of Economy and Competitiveness (formerly Science and Innovation; PLE2009-0101, SAF2010-17167), Comunidad Autónoma Madrid (S2011-BMD-2336), Instituto Salud Carlos III (RETICS TerCel, RD06/0010/0009) and European Union (Excell, NMP4-SL-2008-214706). This work was also supported by an institutional grant from Foundation Ramón Areces to the Center of Molecular Biology Severo Ocho

High Frequency of Copy Number Variations and Sequence Variants at CYP21A2 Locus: Implication for the Genetic Diagnosis of 21-Hydroxylase Deficiency

BACKGROUND: The systematic study of the human genome indicates that the inter-individual variability is greater than expected and it is not only related to sequence polymorphisms but also to gene copy number variants (CNVs). Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (21OHD) is the most common autosomal recessive disorder with a carrier frequency of 1:25 to 1:10. The gene that encodes 21-hydroxylase enzyme, CYP21A2, is considered to be one of the most polymorphic human genes. Copy number variations, such as deletions, which are severe mutations common in 21OHD patients, or gene duplications, which have been reported as rare events, have also been described. The correct characterization of 21OHD alleles is important for disease carrier detection and genetic counselling METHODOLOGY AND FINDINGS: CYP21A2 genotyping by sequencing has been performed in a random sample of the Spanish population, where 144 individuals recruited from university students and employees of the hospital were studied. The frequency of CYP21A2 mutated alleles in our sample was 15.3% (77.3% were mild mutations, 9% were severe mutations and 13.6% were novel variants). Gene dosage assessment was also performed when CYP21A2 gene duplication was suspected. This analysis showed that 7% of individuals bore a chromosome with a duplicated CYP21A2 gene, where one of the copies was mutated. CONCLUSIONS: As far as we know, the present study has shown the highest frequency of 21OHD carriers reported by a genotyping analysis. In addition, a high frequency of alleles with CYP21A2 duplications, which could be misinterpreted as 21OHD alleles, was found. Moreover, a high frequency of novel genetic variations with an unknown effect on 21-hydroxylase activity was also found. The high frequency of gene duplications, as well as novel variations, should be considered since they have an important involvement in carrier testing and genetic counseling