Knowledge dimensions in prototyping: investigating the what, when and how of knowledge generation during product development

Prototyping is a knowledge generation activity facilitating improved understanding of problem and solution spaces. This knowledge can be generated across a range of dimensions, termed knowledge dimensions (KDs), via a range of methods and media, each with their own inherent properties. This article investigates and characterises the relationships between prototypes and knowledge generated from prototyping activities during the design process, by establishing how different methods and media contribute across KDs. In so doing, it provides insights into prototyping activity, as well as affording a means by which prototyping knowledge generation may be studied in detail. The investigation considers sets of prototypes from eight parallel 16-week design projects, with subsequent investigation of the knowledge contributions that each prototype provides and at what stage of the design process. Results showed statistical significance supporting three inferences: i) teams undertaking the same design brief create similar knowledge profiles; ii) prototyping fidelity impacts KD contribution and iii) KDs align with the different phases of the project. This article demonstrates a means to describe and potentially prescribe knowledge generation activities through prototyping. Correspondingly, the article contends that consideration of KDs offers potential to improve aspects of the design process through better prototyping method selection and sequencing

Pesticide risk assessment and management in a globally changing world—report from a European interdisciplinary workshop

[Departement_IRSTEA]Eaux [TR1_IRSTEA]BELCA [Axe_IRSTEA]DTAM-QT2-ADAPTATION [TR2_IRSTEA]ARCEAU [TR2_IRSTEA]DTAMGlobal climate change will affect worldwide agriculture in many ways. The anticipated or already occurring changes raise concerns about the sustainability of production and the ability of agriculture to feed human populations. This appeals to sustainable agriculture providing ecosystem services more efficiently than today, and accordingly to substantial evolutions of pesticide risk assessment (RA) and risk management (RM). The RA/RM issues were discussed by two European research networks in a 2011 workshop. The RA-RM-monitoring conceptual cycle tends to be virtual, with poor connections between certain steps. The design of more comprehensive emissions scenarios could improve the accuracy of predicted runoff transport, while the microcosm/mesocosm approach could help establish causal relationships between fate / exposure and populations / communities. Combined with ecological modelling, effects can be extrapolated to higher spatial and temporal scales. Risk management of diffuse sources should be designed simultaneously at the watershed and individual plot scales. Monitoring is key to assessing the effectiveness of risk reduction measures reduce and evaluate the overall quality of the aquatic compartment. More flexible monitoring strategies clearly linked to RM decisions are therefore needed. Although some technical questions remain, it is time to apply passive samplers more routinely. A set of research and development needs covering the whole RA/RM cycle is listed in conclusion

The PNPLA3 Genetic Variant rs738409 Influences the Progression to Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients

Contradictory data about the impact of the rs738409 steatosis-related polymorphism within PNPLA3 gene on liver fibrosis progression in HIV/hepatitis C virus (HIV/HCV)-coinfected patients have been reported. Our objective was to test whether this, and other polymorphisms previously related to fatty liver disease in HIV infection linked to SAMM50 or LPPR4 genes, influence liver fibrosis progression in HIV/HCV-coinfected individuals. Three hundred and thirty two HIV/HCV-coinfected patients who consecutively attended four Spanish university hospitals from November 2011 to July 2013 were included. A liver stiffness cut-off of 14.6 kPa, as determined by transient elastography, was used to diagnose cirrhosis. Liver stiffness progression was studied in 171 individuals who had two available LS determinations without anti-HCV treatment between them. Moreover, 28 HIV/HCV-coinfected patients who underwent liver transplant, as well as 19 non-cirrhotic coinfected individuals used as controls, were included in an additional study. Only rs738409 was associated with cirrhosis: 45 (29.6%) of 152 G allele carriers versus 36 (20.0%) of 180 CC carriers showed cirrhosis (multivariate p = 0.018; adjusted odds ratio = 1.98; 95% confidence interval = 1.12-3.50). Also, 21 (30.4%) of 69 G allele carriers versus 16 (15.7%) of 102 CC patients showed significant liver stiffness progression (adjusted p-value = 0.015; adjusted odds ratio = 2.89; 95% confidence interval = 1.23-6.83). Finally, the proportion of rs738409 G allele carriers was significantly higher in transplanted individuals than in controls (p = 0.044, odds ratio = 3.43; 95% confidence interval = 1.01-11.70). Our results strongly suggest that the rs738409 polymorphism is associated with liver fibrosis progression in HIV/HCV-coinfected patients

Co-occurrence of cohesin complex and Ras signaling mutations during progression from myelodysplastic syndromes to secondary acute myeloid leukemia

Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. To elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic transformation. The study showed that MDS progression to sAML is characterized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing (STAG2) and newly-acquired (NRAS and FLT3) mutations. Moreover, we observed cooperation between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their progression to sAML.This work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias FIS PI18/01500, PI17/01741, Instituto de Salud Carlos III (ISCIII), Fondo de Investigación Sanitaria (Instituto de Salud Carlos III – Contratos Río Hortega (CM17/0017), European Regional Development Fund (ERDF), Una manera de hacer Europa, European Union Seventh Framework Programme [FP7/2007-2013] under Grant Agreement nº306242-NGS-PTL, SYNtherapy: Synthetic Lethality for Personalized Therapy-based Stratification in Acute Leukemia (ERAPERMED2018-275); ISCIII (AC18/00093), Proyectos de Investigación del SACYL, Gerencia Regional de Salud de Castilla y León: GRS1850/A18, GRS1653/A17, and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC CB16/12/00233). MMI is supported by a predoctoral grant from the Junta de Castilla y León, and by the Fondo Social Europeo (JCYL-EDU/556/2019 PhD scholarship) and JMHS is supported by a research grant from Fundación Española de Hematología y Hemoterapia

Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5-9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10-13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target

Anacreonte, Safo y Tirteo

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2009-2010Las h. pleg. son partiturasContiene: Odas de Anacreonte. Fragmentos de Safo. Poesías de Tirteo

Participation of the Cell Polarity Protein PALS1 to T-Cell Receptor-Mediated NF-κB Activation

BACKGROUND: Beside their established function in shaping cell architecture, some cell polarity proteins were proposed to participate to lymphocyte migration, homing, scanning, as well as activation following antigen receptor stimulation. Although PALS1 is a central component of the cell polarity network, its expression and function in lymphocytes remains unknown. Here we investigated whether PALS1 is present in T cells and whether it contributes to T Cell-Receptor (TCR)-mediated activation. METHODOLOGY/PRINCIPAL FINDINGS: By combining RT-PCR and immunoblot assays, we found that PALS1 is constitutively expressed in human T lymphocytes as well as in Jurkat T cells. siRNA-based knockdown of PALS1 hampered TCR-induced activation and optimal proliferation of lymphocyte. We further provide evidence that PALS1 depletion selectively hindered TCR-driven activation of the transcription factor NF-κB. CONCLUSIONS: The cell polarity protein PALS1 is expressed in T lymphocytes and participates to the optimal activation of NF-κB following TCR stimulation

The role of parasites in the invasion success of the exotic brine shrimp Artemia Franciscana in the Meditarranean region

Trabajo presentado en el Symposium for European Freshwater Science, celebardo en Girona del 27 de junio al 1 de julio de 2011.Biological invasions are main threats to biodiversity at global scale and increasing numbers of studies suggest that parasites may have a role. However, the mechanism through which parasites may influence the outcome of the invasion is poorly understood. Here we provide evidence supporting the role of parasites as potential agents mediating the competitive exclusion of Mediterranean brine shrimps Artemia (A. parthenogenetica and A. salina) by the exotic American A. franciscana, using different native and invasive populations from South Spain and South France. Our results revealed high rates of infection by cestodes in native brine shrimps, sometimes with extreme prevalences of up to 100%. In contrast, A. franciscana populations showed very low diversity, prevalence and burden of cestodes. The effect of parasites in native populations was multiple, ranging from reproduction and survival, to life history traits, microhabitat selection and diet. Infection strongly reduced host fitness by both, reducing fecundity (parasite castration) and indirectly increasing predation by birds final hosts as revealed by prey choice experiments. We found evidence that high rate of parasitism (particularly the castrating parasite Flamingolepis liguloides, the most prevalent cestode in natives but nearly absent in the exotic Artemia), indirectly affected the life-history strategy of non infected individuals, inducing for example earlier maturation. Moreover cestodes influenced spatial (vertical and horizontal) distribution of the host, altering the diet as revealed by isotopic analysis. Contrasting with the strong impact of parasites in native populations, we have never observed any pathology (castration, behavioural alteration, etc) associated with infection in the exotic species. Overall, the results of this study suggest that the large impact of cestode on the native, but not the invading species, is likely to confer a decisive competitive advantage to the invader, contributing to explain the demographic success of A. franciscana in the Mediterranean region.Peer reviewe