Ricerca di nuove strategie differenziative: Analisi degli effetti di stimoli fisici e molecolari su cellule mesenchimali umane isolate da tessuto adiposo

Introduzione. Le cellule mesenchimali derivate dal tessuto adiposo (hASC) rappresentano un importante strumento per la terapia cellulare, in quanto derivano da un tessuto adulto abbondante e facilmente reperibile. Con il dispositivo medico Lipogems l’isolamento di tali cellule è eseguito esclusivamente mediante sollecitazioni meccaniche. Il prodotto ottenuto è quindi minimamente manipolato e subito utilizzabile. Ad oggi, il condizionamento pro-differenziativo delle staminali è per lo più attuato mediante molecole di sintesi. Tuttavia, altri fattori possono modulare la fisiologia cellulare, come gli stimoli fisici e molecole naturali. Onde elettromagnetiche hanno indotto in modelli cellulari staminali l’espressione di alcuni marcatori di differenziamento e, in cellule adulte, una riprogrammazione, mentre estratti embrionali di Zebrafish sono risultati antiproliferativi sia in vitro che in vivo. Metodi. La ricerca di nuove strategie differenziative sia di natura fisica che molecolare, nel particolare onde acustiche ed estratti embrionali di Zebrafish, è stata condotta utilizzando come modello cellulare le hASC isolate con Lipogems. Onde acustiche sono state somministrate mediante l’utilizzo di due apparati di trasduzione, un generatore di onde meccaniche e il Cell Exciter . I trattamenti con gli estratti embrionali sono stati effettuati utilizzando diverse concentrazioni e diversi tempi sperimentali. Gli effetti sull’espressione dei marcatori di staminalità e differenziamento relativi ai trattamenti sono stati saggiati in RT-PCR quantitativa relativa e/o in qPCR. Per i trattamenti di tipo molecolare è stata valutata anche la proliferazione. Risultati e conclusioni. La meta-analisi dei dati delle colture di controllo mostra la stabilità d’espressione genica del modello. I trattamenti con i suoni inducono variazioni dell’espressione genica, suggerendo un ruolo regolatorio di tali stimoli, in particolare del processo di commitment cardiovascolare. Due degli estratti embrionali di Zebrafish testati inibiscono la proliferazione alle 72 ore dalla somministrazione. L’analisi d’espressione associata ai trattamenti antiproliferativi suggerisce che tale effetto abbia basi molecolari simili ai processi di differenziamento.

Expressionsunterschiede verschiedener miRNAs bei chronisch-entzündlichen Darmerkrankungen

Chronisch-entzündliche Darmerkrankungen konfrontieren unsere heutige Gesellschaft mit hohen Inzidenzraten in der westlichen Welt und zunehmend steigenden Inzidenzraten im asiatischen Raum. Die Folgen für die Patienten sind eine starke Beeinträchtigung der Lebensqualität, mit sozialen und wirtschaftlichen Folgen sowie ein erhöhtes Risiko für die Entwicklung kolorektaler Karzinome. Durch die Entdeckung von 22 nt langen, regulierenden RNAs, auch genannt miRNAs, wurde ein neuer Baustein im Verständnis zellulärer Regelprozesse und der Differenzierung und Aktivierung von Antworten etwa des Immunsystems entdeckt. Somit stellt sich die Frage nach der Bedeutung von miRNAs im Rahmen von chronisch-entzündlichen Darmerkrankungen. Hierzu wurden in dieser Arbeit über ein miRNA-Array System 12 miRNAs als potentiell relevante Ziele identifiziert und an einem Kollektiv aus insgesamt 131 Patienten und 163 Biopsien aus dem Bereich des Darmes überprüft. Es zeigte sich hierbei, dass im Rahmen eines Morbus Crohn mit Befall des Dickdarms die miRNAs let-7d und miR-22 in gesteigerter Expression vorlagen. Da im terminalen Ileum eine gesonderte Immunsituation vorliegt, wurde dieser Bereich zusätzlich bei der Erkrankung Morbus Crohn untersucht. Es zeigten sich Expressionsveränderungen für die miRNAs miR-30e, miR-185, miR-374b und miR-424. Bei Patienten mit einer Colitis ulcerosa waren die miRNAs let-7d, miR-185 und miR-424 in ihrem Expressionsverhalten verändert. Zusätzlich konnte gezeigt werden, dass in Abhängigkeit vom Entzündungsgrad bei bestehender Colitis ulcerosa eine zunehmenden Überexpression der miRNAs let-7d, miR-185 und miR-424 erfolgte. Die miRNAs miR-18a und miR-185 wiesen unter Remissionsbedingungen Expressionsveränderungen auf und lassen somit den Verdacht eines protektiven Effektes aufkommen. Mit Hilfe von computerbasierten Datenbankanalysen konnten gemeinsam regulierenden miRNAs Proteine und Pathways zugeordnet werden, welche einen Zusammenhang mit bereits pathogenetisch bestätigten Signalwegen wie etwa dem nF-ĸB und MAPK-Signalweg nahelegen. Auch konnte herausgearbeitet werden, dass einige, der von diesen miRNAs regulierten Proteine, bereits in veröffentlichten Arbeiten als fehlreguliert festgestellt wurden, jedoch blieb die Ursache dieser Fehlregulation gänzlich unbekannt. Mit den in dieser Arbeit erhobenen Daten konnte gezeigt werden, dass eine Kongruenz der Befunde vorliegt, welche einen Zusammenhang der miRNA-Expression mit der Fehlregulation bestimmter Proteine nicht nur nahelegt, sondern darüber hinaus auch noch einige weitere potentielle Proteinziele für weitere Untersuchungen aufführt. Dazu ist es jedoch notwendig, die Relevanz der hier entdeckten, computerbasierten Proteine in zukünftigen Untersuchungen einer genauen Prüfung zu unterziehen.

The Role of Features and Context in Recognition of Novel Melodies

WE INVESTIGATED HOW WELL STRUCTURAL FEATURES such as note density or the relative number of changes in the melodic contour could predict success in implicit and explicit memory for unfamiliar melodies. We also analyzed which features are more likely to elicit increasingly confident judgments of "old" in a recognition memory task. An automated analysis program computed structural aspects of melodies, both independent of any context, and also with reference to the other melodies in the testset and the parent corpus of pop music. A few features predicted success in both memory tasks, which points to a shared memory component. However, motivic complexity compared to a large corpus of pop music had different effects on explicit and implicit memory. We also found that just a few features are associated with different rates of "old" judgments, whether the items were old or new. Rarer motives relative to the testset predicted hits and rarer motives relative to the corpus predicted false alarms. This data-driven analysis provides further support for both shared and separable mechanisms in implicit and explicit memory retrieval, as well as the role of distinctiveness in true and false judgments of familiarity.

Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update

Objectives: To update the 2006 systematic review of the comparative benefits and harms of erythropoiesis-stimulating agent (ESA) strategies and non-ESA strategies to manage anemia in patients undergoing chemotherapy and/or radiation for malignancy (excluding myelodysplastic syndrome and acute leukemia), including the impact of alternative thresholds for initiating treatment and optimal duration of therapy. Data sources: Literature searches were updated in electronic databases (n=3), conference proceedings (n=3), and Food and Drug Administration transcripts. Multiple sources (n=13) were searched for potential gray literature. A primary source for current survival evidence was a recently published individual patient data meta-analysis. In that meta-analysis, patient data were obtained from investigators for studies enrolling more than 50 patients per arm. Because those data constitute the most currently available data for this update, as well as the source for on-study (active treatment) mortality data, we limited inclusion in the current report to studies enrolling more than 50 patients per arm to avoid potential differential endpoint ascertainment in smaller studies. Review methods: Title and abstract screening was performed by one or two (to resolve uncertainty) reviewers; potentially included publications were reviewed in full text. Two or three (to resolve disagreements) reviewers assessed trial quality. Results were independently verified and pooled for outcomes of interest. The balance of benefits and harms was examined in a decision model. Results: We evaluated evidence from 5 trials directly comparing darbepoetin with epoetin, 41 trials comparing epoetin with control, and 8 trials comparing darbepoetin with control; 5 trials evaluated early versus late (delay until Hb ≤9 to 11 g/dL) treatment. Trials varied according to duration, tumor types, cancer therapy, trial quality, iron supplementation, baseline hemoglobin, ESA dosing frequency (and therefore amount per dose), and dose escalation. ESAs decreased the risk of transfusion (pooled relative risk [RR], 0.58; 95% confidence interval [CI], 0.53 to 0.64; I2 = 51%; 38 trials) without evidence of meaningful difference between epoetin and darbepoetin. Thromboembolic event rates were higher in ESA-treated patients (pooled RR, 1.51; 95% CI, 1.30 to 1.74; I2 = 0%; 37 trials) without difference between epoetin and darbepoetin. In 14 trials reporting the Functional Assessment of Cancer Therapy (FACT)-Fatigue subscale, the most common patient-reported outcome, scores decreased by −0.6 in control arms (95% CI, −6.4 to 5.2; I2 = 0%) and increased by 2.1 in ESA arms (95% CI, −3.9 to 8.1; I2 = 0%). There were fewer thromboembolic and on-study mortality adverse events when ESA treatment was delayed until baseline Hb was less than 10 g/dL, in keeping with current treatment practice, but the difference in effect from early treatment was not significant, and the evidence was limited and insufficient for conclusions. No evidence informed optimal duration of therapy. Mortality was increased during the on-study period (pooled hazard ratio [HR], 1.17; 95% CI, 1.04 to 1.31; I2 = 0%; 37 trials). There was one additional death for every 59 treated patients when the control arm on-study mortality was 10 percent and one additional death for every 588 treated patients when the control-arm on-study mortality was 1 percent. A cohort decision model yielded a consistent result—greater loss of life-years when control arm on-study mortality was higher. There was no discernible increase in mortality with ESA use over the longest available followup (pooled HR, 1.04; 95% CI, 0.99 to 1.10; I2 = 38%; 44 trials), but many trials did not include an overall survival endpoint and potential time-dependent confounding was not considered. Conclusions: Results of this update were consistent with the 2006 review. ESAs reduced the need for transfusions and increased the risk of thromboembolism. FACT-Fatigue scores were better with ESA use but the magnitude was less than the minimal clinically important difference. An increase in mortality accompanied the use of ESAs. An important unanswered question is whether dosing practices and overall ESA exposure might influence harms.

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2-8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56-1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4-0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8-55·9) in the immediate treatment group and 31·8% (24·2-39·6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.

Interannual Variability in Timing of Bloom Initiation in the California Current System

In the California Current System the spring transition from poleward to equatorward alongshore wind stress heralds the beginning of upwelling-favorable conditions. The phytoplankton response to this transition is investigated using 8 years ( 1998-2005) of daily, 4-km resolution, Sea-viewing Wide Field of view Sensor ( SeaWiFS) chlorophyll a concentration data. Cluster analysis of the chlorophyll a time series at each location is used to separate the inshore upwelling region from offshore and oligotrophic areas. An objective method for estimating the timing of bloom initiation is used to construct a map of the mean bloom start date. Interannual variability in bloom timing and magnitude is investigated in four regions: 45 degrees N - 50 degrees N, 40 degrees N - 45 degrees N, 35 degrees N - 40 degrees N and 20 degrees N - 35 degrees N. Daily satellite derived wind data ( QuikSCAT) allow the timing of the first episode of persistently upwelling favorable winds to be estimated. Bloom initiation generally coincides with the onset of upwelling winds ( +/- 15 days). South of similar to 35 degrees N, where winds are southward year-round, the timing of increased chlorophyll concentration corresponds closely to timing of the seasonal increase in upwelling intensity. A 1-D model and satellite derived photosynthetically available radiation data are used to estimate time series of depth- averaged irradiance. In the far north of the region (> 46 degrees N) light is shown to limit phytoplankton growth in early spring. In 2005 the spring bloom in the northern regions (> 35 degrees N) had a "false start''. A sharp increase in chl a in February quickly receded, and a sustained increase in biomass was delayed until July. We hypothesize that this resulted in a mismatch in timing of food availability to higher trophic levels.

The illness narratives of Hispanic American women with coronary heart disease (CHD): An ethnographic approach

Purpose. To provide a descriptive representation of the illness narratives described by Hispanic American women with CHD. ^ Design. Focused ethnographic design. ^ Setting. One outpatient general medicine clinic, one nurse-managed health promotion clinic, and informants' homes in a large metropolitan city located in southeast Texas. ^ Sample. Purposeful sampling from two different sites resulted in 17 interviews being conducted with 14 informants. ^ Method. Focused ethnographic techniques were employed in the designation of participants for the study, data collection, analysis and re-presentation. Audiotaped interviews and fieldwork were transcribed verbatim and analyzed through an iterative process of data reduction, data display, drawing conclusions and verification. ^ Findings. The developing conceptual framework that emerged from the data is labeled after the overarching experience described by informants, the experience of Embodied Exhaustion. Embodied Exhaustion, as described in this study, refers to an ongoing, dynamic, indeterminate experience of mind-body exhaustion resulting from a complex constellation of biologic, psychological and social distresses occurring over the life course. The experience consists of three categories: Taking Care of Others, Wearing Down and Hurting Hearts. Two stabilizing forces were identified: Collective Self and Believing in God. ^ Conclusions. The findings of this study emphasize the importance of framing all research, theory and practice targeting Hispanic women with CHD within a sociocentric paradigm. Nursing is challenged to provide care that extends beyond the physical body of the patient to include the social context of illness, especially the family. ^

THE IMPACT OF FAMILY HISTORY ON MEDULLARY THYROID CANCER IN MEN2A PATIENTS

The American Thyroid Association recently classified all MEN2A-associated codons into increasing risk levels A-C and stated that some patients may delay prophylactic thyroidectomy if certain criteria are met. One criterion is a less aggressive family history of MTC but whether families with the same mutated codon have variable MTC aggressiveness is not well described. We developed several novel measures of MTC aggressiveness and compared families with the same mutated codon to determine if there is significant inter-familial variability. Pedigrees of families with MEN2A were reviewed for codon mutated and proportion of RET mutation carriers with MTC. Individuals with MTC were classified as having local or distant MTC and whether they had progressive MTC. MTC status and age were assessed at diagnosis and most advanced MTC stage. For those without MTC, age was recorded at prophylactic thyroidectomy or last follow-up if the patient did not have a thyroidectomy. For each pedigree, the mean age of members without MTC, with MTC, and the proportion of RET mutation carriers with local or distant and progressive MTC were calculated. We assessed differences in these variables using ANOVA and the Fisher’s exact test. Sufficient data for analysis were available for families with mutated codons 609 (92 patients from 13 families), 618 (41 patients from 7 families), and 634 (152 patients from 13 families). The only significant differences found were the mean age of patients without MTC between families with codon 609 and 618 mutations even after accounting for prophylactic thyroidectomy (p=0.006 and 0.001, respectively), and in the mean age of MTC diagnosis between families with codon 618 and 634 mutations even after accounting for symptomatic presentation (p=0.023 and 0.014, respectively). However, these differences may be explained by generational differences in ascertainment of RET carriers and the availability of genetic testing when the proband initially presented.

Caracterización por contenido de β-carotenos de ocho cultivares de zanahoria (Daucus carota L.) y su relación con el color

El objetivo fue determinar, durante dos años, el contenido de β-caroteno y su relación con el Índice de Color (IC), de ocho cultivares comerciales del tipo 'Flakkee' cultivadas en el INTA La Consulta. El diseño experimental a campo utilizado fue en bloques al azar con 3 repeticiones. Se evaluó β-caroteno (espectrofotometría a 450 nm) y se calculó el IC, mediante captación de imagen digital con PC y escáner, midiendo L, a y b del Sistema CIELAB. Los datos fueron analizados por ACP (análisis de componentes principales), la visualización de la variabilidad, por cartografiado de datos, análisis de varianza, pruebas de diferencia de medias y correlaciones. Los contenidos de β-carotenos y el IC de los cultivares se mantuvieron constantes durante los dos años estudiados, resultando las cultivares Natasha, Flakesse y Colmar las de mayor valor nutricional en cuanto a aporte de β-carotenos. En el rango de valores menores de 18 mg%g de β-carotenos, se observó una correlación positiva significativa en las cultivares Supreme, Spring y Laval. No se encontró una correlación alta lineal entre el IC y el contenido de β-carotenos. El uso del IC resulta adecuado para predecir, en un intervalo de valores, el contenido de β-carotenos en cultivares de zanahoria.

Probability inundation map for a scenario combining storm surge and sea-level rise

Coastal managers require reliable spatial data on the extent and timing of potential coastal inundation, particularly in a changing climate. Most sea level rise (SLR) vulnerability assessments are undertaken using the easily implemented bathtub approach, where areas adjacent to the sea and below a given elevation are mapped using a deterministic line dividing potentially inundated from dry areas. This method only requires elevation data usually in the form of a digital elevation model (DEM). However, inherent errors in the DEM and spatial analysis of the bathtub model propagate into the inundation mapping. The aim of this study was to assess the impacts of spatially variable and spatially correlated elevation errors in high-spatial resolution DEMs for mapping coastal inundation. Elevation errors were best modelled using regression-kriging. This geostatistical model takes the spatial correlation in elevation errors into account, which has a significant impact on analyses that include spatial interactions, such as inundation modelling. The spatial variability of elevation errors was partially explained by land cover and terrain variables. Elevation errors were simulated using sequential Gaussian simulation, a Monte Carlo probabilistic approach. 1,000 error simulations were added to the original DEM and reclassified using a hydrologically correct bathtub method. The probability of inundation to a scenario combining a 1 in 100 year storm event over a 1 m SLR was calculated by counting the proportion of times from the 1,000 simulations that a location was inundated. This probabilistic approach can be used in a risk-aversive decision making process by planning for scenarios with different probabilities of occurrence. For example, results showed that when considering a 1% probability exceedance, the inundated area was approximately 11% larger than mapped using the deterministic bathtub approach. The probabilistic approach provides visually intuitive maps that convey uncertainties inherent to spatial data and analysis.

Accumulation, velocities, fluxes and mass balance of glacial tributaries to the Lambert Glacier-Amery Ice Shelf system, Antarctica

By incorporating recently available remote sensing data, we investigated the mass balance for all individual tributary glacial basins of the Lambert Glacier-Amery Ice Shelf system, East Antarctica. On the basis of the ice flow information derived from SAR interferometry and ICESat laser altimetry, we have determined the spatial configuration of eight tributary drainage basins of the Lambert-Amery glacial system. By combining the coherence information from SAR interferometry and the texture information from SAR and MODIS images, we have interpreted and refined the grounding line position. We calculated ice volume flux of each tributary glacial basin based on the ice velocity field derived from Radarsat three-pass interferometry together with ice thickness data interpolated from Australian and Russian airborne radio echo sounding (RES) surveys and inferred from ICESat laser altimetry data. Our analysis reveals that three tributary basins have a significant net positive imbalance, while five other subbasins are slightly positive or close to zero balance. Overall, in contrast to previous studies, we find that the grounded ice in Lambert Glacier-Amery Ice Shelf system has a positive mass imbalance of 22.9 ± 4.4 Gt/a. The net basal melting for the entire Amery Ice Shelf is estimated to be 27.0 ± 7.0 Gt/a. The melting rate decreases rapidly from the grounding zone to the ice shelf front. Significant basal refreezing is detected in the downstream section of the ice shelf. The mass balance estimates for both the grounded ice sheet and the ice shelf mass differ substantially from other recent estimates.

Effectiveness of abstract interpretation in automatic parallelization: a case study in logic programming

We report on a detailed study of the application and effectiveness of program analysis based on abstract interpretation to automatic program parallelization. We study the case of parallelizing logic programs using the notion of strict independence. We first propose and prove correct a methodology for the application in the parallelization task of the information inferred by abstract interpretation, using a parametric domain. The methodology is generic in the sense of allowing the use of different analysis domains. A number of well-known approximation domains are then studied and the transformation into the parametric domain defined. The transformation directly illustrates the relevance and applicability of each abstract domain for the application. Both local and global analyzers are then built using these domains and embedded in a complete parallelizing compiler. Then, the performance of the domains in this context is assessed through a number of experiments. A comparatively wide range of aspects is studied, from the resources needed by the analyzers in terms of time and memory to the actual benefits obtained from the information inferred. Such benefits are evaluated both in terms of the characteristics of the parallelized code and of the actual speedups obtained from it. The results show that data flow analysis plays an important role in achieving efficient parallelizations, and that the cost of such analysis can be reasonable even for quite sophisticated abstract domains. Furthermore, the results also offer significant insight into the characteristics of the domains, the demands of the application, and the trade-offs involved.

Análisis estático de sistemas de membranas para la determinación de reglas activas

Esta tesis doctoral se enmarca dentro de la computación con membranas. Se trata de un tipo de computación bio-inspirado, concretamente basado en las células de los organismos vivos, en las que se producen múltiples reacciones de forma simultánea. A partir de la estructura y funcionamiento de las células se han definido diferentes modelos formales, denominados P sistemas. Estos modelos no tratan de modelar el comportamiento biológico de una célula, sino que abstraen sus principios básicos con objeto de encontrar nuevos paradigmas computacionales. Los P sistemas son modelos de computación no deterministas y masivamente paralelos. De ahí el interés que en los últimos años estos modelos han suscitado para la resolución de problemas complejos. En muchos casos, consiguen resolver de forma teórica problemas NP-completos en tiempo polinómico o lineal. Por otra parte, cabe destacar también la aplicación que la computación con membranas ha tenido en la investigación de otros muchos campos, sobre todo relacionados con la biología. Actualmente, una gran cantidad de estos modelos de computación han sido estudiados desde el punto de vista teórico. Sin embargo, el modo en que pueden ser implementados es un reto de investigación todavía abierto. Existen varias líneas en este sentido, basadas en arquitecturas distribuidas o en hardware dedicado, que pretenden acercarse en lo posible a su carácter no determinista y masivamente paralelo, dentro de un contexto de viabilidad y eficiencia. En esta tesis doctoral se propone la realización de un análisis estático del P sistema, como vía para optimizar la ejecución del mismo en estas plataformas. Se pretende que la información recogida en tiempo de análisis sirva para configurar adecuadamente la plataforma donde se vaya a ejecutar posteriormente el P sistema, obteniendo como consecuencia una mejora en el rendimiento. Concretamente, en esta tesis se han tomado como referencia los P sistemas de transiciones para llevar a cabo el estudio de dicho análisis estático. De manera un poco más específica, el análisis estático propuesto en esta tesis persigue que cada membrana sea capaz de determinar sus reglas activas de forma eficiente en cada paso de evolución, es decir, aquellas reglas que reúnen las condiciones adecuadas para poder ser aplicadas. En esta línea, se afronta el problema de los estados de utilidad de una membrana dada, que en tiempo de ejecución permitirán a la misma conocer en todo momento las membranas con las que puede comunicarse, cuestión que determina las reglas que pueden aplicarse en cada momento. Además, el análisis estático propuesto en esta tesis se basa en otra serie de características del P sistema como la estructura de membranas, antecedentes de las reglas, consecuentes de las reglas o prioridades. Una vez obtenida toda esta información en tiempo de análisis, se estructura en forma de árbol de decisión, con objeto de que en tiempo de ejecución la membrana obtenga las reglas activas de la forma más eficiente posible. Por otra parte, en esta tesis se lleva a cabo un recorrido por un número importante de arquitecturas hardware y software que diferentes autores han propuesto para implementar P sistemas. Fundamentalmente, arquitecturas distribuidas, hardware dedicado basado en tarjetas FPGA y plataformas basadas en microcontroladores PIC. El objetivo es proponer soluciones que permitan implantar en dichas arquitecturas los resultados obtenidos del análisis estático (estados de utilidad y árboles de decisión para reglas activas). En líneas generales, se obtienen conclusiones positivas, en el sentido de que dichas optimizaciones se integran adecuadamente en las arquitecturas sin penalizaciones significativas. Summary Membrane computing is the focus of this doctoral thesis. It can be considered a bio-inspired computing type. Specifically, it is based on living cells, in which many reactions take place simultaneously. From cell structure and operation, many different formal models have been defined, named P systems. These models do not try to model the biological behavior of the cell, but they abstract the basic principles of the cell in order to find out new computational paradigms. P systems are non-deterministic and massively parallel computational models. This is why, they have aroused interest when dealing with complex problems nowadays. In many cases, they manage to solve in theory NP problems in polynomial or lineal time. On the other hand, it is important to note that membrane computing has been successfully applied in many researching areas, specially related to biology. Nowadays, lots of these computing models have been sufficiently characterized from a theoretical point of view. However, the way in which they can be implemented is a research challenge, that it is still open nowadays. There are some lines in this way, based on distributed architectures or dedicated hardware. All of them are trying to approach to its non-deterministic and parallel character as much as possible, taking into account viability and efficiency. In this doctoral thesis it is proposed carrying out a static analysis of the P system in order to optimize its performance in a computing platform. The general idea is that after data are collected in analysis time, they are used for getting a suitable configuration of the computing platform in which P system is going to be performed. As a consequence, the system throughput will improve. Specifically, this thesis has made use of Transition P systems for carrying out the study in static analysis. In particular, the static analysis proposed in this doctoral thesis tries to achieve that every membrane can efficiently determine its active rules in every evolution step. These rules are the ones that can be applied depending on the system configuration at each computational step. In this line, we are going to tackle the problem of the usefulness states for a membrane. This state will allow this membrane to know the set of membranes with which communication is possible at any time. This is a very important issue in determining the set of rules that can be applied. Moreover, static analysis in this thesis is carried out taking into account other properties such as membrane structure, rule antecedents, rule consequents and priorities among rules. After collecting all data in analysis time, they are arranged in a decision tree structure, enabling membranes to obtain the set of active rules as efficiently as possible in run-time system. On the other hand, in this doctoral thesis is going to carry out an overview of hardware and software architectures, proposed by different authors in order to implement P systems, such as distributed architectures, dedicated hardware based on PFGA, and computing platforms based on PIC microcontrollers. The aim of this overview is to propose solutions for implementing the results of the static analysis, that is, usefulness states and decision trees for active rules. In general, conclusions are satisfactory, because these optimizations can be properly integrated in most of the architectures without significant penalties.

Políticas de esfuerzo combinado económico-laboral en la retención y atracción del conocimiento científico: un estudio del caso español

El objetivo de este trabajo es la aportación de un caso que evidencie la importancia de realizar esfuerzos tanto en el terreno económico como en el laboral para conseguir una adecuada retención y atracción del conocimiento científico. Para ello, se analizan los datos de un estudio que destaca estas cuestiones para un país como España, que necesita urgentemente mejorar su balance de movilidad investigadora. Los resultados confirman la importancia de la aplicación de estas medidas y las debilidades que presenta en este tipo de políticas el sistema nacional de investigación, desarrollo e innovación (I+D+i). Abstract: The goal of this paper is to disclose a case study which highlights the impor tance of realising effor ts at an economic and labour scale in order to reach an adequate retention and attraction of scientific knowledge. Although science has evolved during different periods through the flow of mankind and ideas, studies about international mobility of scientists are recent in time. It started mid XXth century with the brain drain phenomenon. To alleviate the loss of scientists, countries have disclosed different politics. Some countries like Singapore, Southern Korea, India and China have been successful in bringing scientists back home. Those countries have made huge effor ts in human resources investments and scientific infrastructures, so as to enforce their national R&D&I systems. Despite such experiences and despite the increasement in terms of evidences related with international scientific mobility, few studies and figures have been disclosed. The goal of this current work is to disclose data, which backs up the liability of such kind of politics that combine effor ts in economic and labour terms. For that reason, data has been analyzed from a study which highlights these key aspects for a country like Spain and which recently established a wide range of politics in order to attract scientists. Despite the increasement of financial resources, such politics have turned out unable to reach a proper balance in terms of mobility research. Such data as well as it analysis comes from the development of an annual survey to Spanish scientists during the period 2008- 2011. Based on sample data and analysis an expectations index for the coming year has been constructed. This compares the level of confidence which related the support and prestige of their national R&D&I systems in which they operate. Two groups where surveyed: young researchers which currently work in Spain and as a group are more likely to go working abroad and Spanish scientists who are currently working abroad. Samples were obtained for young researchers were the following: 2008 (217), 2009 (270), 2010 (390) and 2011 (610). In the case of Spanish scientists abroad, the following data were obtained: 2008 (218), 2009 (250), 2010 (241) and 2011 (167). Both groups assume simple random sampling, with a level of confidence of 95%. The results obtained confirm the importance of this combined effor t of labor and economic policies which presents weaknesses of Spanish national R&D&I systems and its application, so that Spain becomes a pole of excellence in terms of attraction and retention of scientific knowledge.

A visual framework to accelerate knowledge discovery based on dimensionality reduction minimizing degradation of quality

Tradicionalmente, el uso de técnicas de análisis de datos ha sido una de las principales vías para el descubrimiento de conocimiento oculto en grandes cantidades de datos, recopilados por expertos en diferentes dominios. Por otra parte, las técnicas de visualización también se han usado para mejorar y facilitar este proceso. Sin embargo, existen limitaciones serias en la obtención de conocimiento, ya que suele ser un proceso lento, tedioso y en muchas ocasiones infructífero, debido a la dificultad de las personas para comprender conjuntos de datos de grandes dimensiones. Otro gran inconveniente, pocas veces tenido en cuenta por los expertos que analizan grandes conjuntos de datos, es la degradación involuntaria a la que someten a los datos durante las tareas de análisis, previas a la obtención final de conclusiones. Por degradación quiere decirse que los datos pueden perder sus propiedades originales, y suele producirse por una reducción inapropiada de los datos, alterando así su naturaleza original y llevando en muchos casos a interpretaciones y conclusiones erróneas que podrían tener serias implicaciones. Además, este hecho adquiere una importancia trascendental cuando los datos pertenecen al dominio médico o biológico, y la vida de diferentes personas depende de esta toma final de decisiones, en algunas ocasiones llevada a cabo de forma inapropiada. Ésta es la motivación de la presente tesis, la cual propone un nuevo framework visual, llamado MedVir, que combina la potencia de técnicas avanzadas de visualización y minería de datos para tratar de dar solución a estos grandes inconvenientes existentes en el proceso de descubrimiento de información válida. El objetivo principal es hacer más fácil, comprensible, intuitivo y rápido el proceso de adquisición de conocimiento al que se enfrentan los expertos cuando trabajan con grandes conjuntos de datos en diferentes dominios. Para ello, en primer lugar, se lleva a cabo una fuerte disminución en el tamaño de los datos con el objetivo de facilitar al experto su manejo, y a la vez preservando intactas, en la medida de lo posible, sus propiedades originales. Después, se hace uso de efectivas técnicas de visualización para representar los datos obtenidos, permitiendo al experto interactuar de forma sencilla e intuitiva con los datos, llevar a cabo diferentes tareas de análisis de datos y así estimular visualmente su capacidad de comprensión. De este modo, el objetivo subyacente se basa en abstraer al experto, en la medida de lo posible, de la complejidad de sus datos originales para presentarle una versión más comprensible, que facilite y acelere la tarea final de descubrimiento de conocimiento. MedVir se ha aplicado satisfactoriamente, entre otros, al campo de la magnetoencefalografía (MEG), que consiste en la predicción en la rehabilitación de lesiones cerebrales traumáticas (Traumatic Brain Injury (TBI) rehabilitation prediction). Los resultados obtenidos demuestran la efectividad del framework a la hora de acelerar y facilitar el proceso de descubrimiento de conocimiento sobre conjuntos de datos reales. ABSTRACT Traditionally, the use of data analysis techniques has been one of the main ways of discovering knowledge hidden in large amounts of data, collected by experts in different domains. Moreover, visualization techniques have also been used to enhance and facilitate this process. However, there are serious limitations in the process of knowledge acquisition, as it is often a slow, tedious and many times fruitless process, due to the difficulty for human beings to understand large datasets. Another major drawback, rarely considered by experts that analyze large datasets, is the involuntary degradation to which they subject the data during analysis tasks, prior to obtaining the final conclusions. Degradation means that data can lose part of their original properties, and it is usually caused by improper data reduction, thereby altering their original nature and often leading to erroneous interpretations and conclusions that could have serious implications. Furthermore, this fact gains a trascendental importance when the data belong to medical or biological domain, and the lives of people depends on the final decision-making, which is sometimes conducted improperly. This is the motivation of this thesis, which proposes a new visual framework, called MedVir, which combines the power of advanced visualization techniques and data mining to try to solve these major problems existing in the process of discovery of valid information. Thus, the main objective is to facilitate and to make more understandable, intuitive and fast the process of knowledge acquisition that experts face when working with large datasets in different domains. To achieve this, first, a strong reduction in the size of the data is carried out in order to make the management of the data easier to the expert, while preserving intact, as far as possible, the original properties of the data. Then, effective visualization techniques are used to represent the obtained data, allowing the expert to interact easily and intuitively with the data, to carry out different data analysis tasks, and so visually stimulating their comprehension capacity. Therefore, the underlying objective is based on abstracting the expert, as far as possible, from the complexity of the original data to present him a more understandable version, thus facilitating and accelerating the task of knowledge discovery. MedVir has been succesfully applied to, among others, the field of magnetoencephalography (MEG), which consists in predicting the rehabilitation of Traumatic Brain Injury (TBI). The results obtained successfully demonstrate the effectiveness of the framework to accelerate and facilitate the process of knowledge discovery on real world datasets.