Object-oriented inheritance of statecharts for control applications

This paper discusses how object-oriented iuheritance can be re-interpreted if statecharts are used for modelling the dynamic behaviour of an object. The support of inheritance of statecharts allows the improvement of systems' development by easing the reutilization of parts of already developed euccessful systems, aad by promoting the iterative and continuous models' refinement advocated by the operatioaal approach. Statechart is the formalism used within UML to specify reactive state.based behaviours. This paper covers the use of statecharts within the modelling of embedded systems for industrial control applxications, where performance and memory usage are main concerns.

Estudio de los modos de vida e historia biológica de las poblaciones humanas de la región central de argentina desde el registro bioarqueológico. Lifestyles and biological history of human populations of the central region of argentina from bioarchaeological record.

Se pretende aportar al estudio de la estructura, historia biológica y estilos de vida de las poblaciones que habitaron la región central de Argentina durante el Holoceno, desde una perspectiva que combina los aportes teóricos y metodológicos de la Genética del paisaje y la Bioarqueología. Interesa a) identificar barreras de diferenciación morfológica entre poblaciones, b) poner a prueba modelos poblacionales para explicar la variación observada e identificar las variables que contribuyan a dicha diferenciación, c) evaluar la congruencia de los resultados obtenidos, d) reconstruir los patrones de movilidad residencial de las poblaciones, e) estudiar sus patrones dietarios considerando diferencias temporales y espaciales, f) identificar indicadores de diversos tipos de estrés (nutricional, funcional), así como traumas, g) estudiar las historias tafonómicas del registro bioarqueológico regional, y h) proponer un modelo para explicar el poblamiento y la evolución local de las poblaciones que habitaron esta región, a partir de la información arqueológica y bioantropológica. Para el análisis de los patrones espaciales de variación biológica se trabajará a partir del registro de rasgos epigenéticos craneales, medidas lineales y datos obtenidos a partir de morfometría geométrica sobre fotografías en 2D sobre muestras arqueológicas procedentes de esta región y de otras regiones geográficas de la Argentina. Para el análisis de la estructura de la población se trabajará a partir del cálculo de la matriz R para datos morfológicos y sus estimaciones derivadas (distancia D², Fst, coordenadas principales) y la aplicación del modelo de Harpending y Ward. Desde la genética del paisaje, se realizarán análisis de autocorrelación espacial, barreras genéticas y análisis geoestadísticos (kriging). Para el estudio de los modos de vida a partir del registro bioarqueológico se relevarán patologías dento-alveolares y alteraciones vinculadas con la salud bucal tales como desgaste dental –a nivel micro y macroscópico- caries, abscesos, pérdidas dentales antemortem, cálculos, hipoplasias, marcadores esqueletales de salud y lesiones traumáticas. Se analizarán isótopos estables (δ13C, δ15N, 86Sr y 87Sr) en restos óseos humanos de diversos sitios arqueológicos con el objetivo de reconstruir patrones dietarios y analizar la movilidad residencial y migración de las poblaciones. Paralelamente, se establecerán procedimientos de control tafonómico de los restos óseos, y se harán análisis específicos para estudiar las historias tafonómicas y evaluar el grado de integridad de los contextos de depositación y de las colecciones en general. Estimamos que el análisis de los patrones espaciales y temporales de variabilidad morfológica craneofacial, así como el estudio de las dietas a partir de información isotópica y bioarqueológica, de las migraciones y la movilidad residencial de las poblaciones a partir de isótopos de estroncio, la reconstrucción de comportamientos y actividades cotidianas a partir de marcadores de estrés músculo-esqueletal, en un marco cronológico y espacial constituye un aporte novedoso y eficaz que permitirá incrementar de manera substancial la información sobre la evolución de las poblaciones originarias del centro del territorio argentino. The aim of this project is to study the structure, biological history and lifestyles of the people that inhabitated the central region of Argentina during the Holocene, from a perspective that combines theoretical and methodological contributions of Landscape Genetics and Bioarchaeology. To analyze the spatial patterns of biological variation we consider epigenetic cranial traits, linear measurements and data obtained from geometric morphometric on 2D photographs. Morphological variation will be focused on landscape genetics (autocorrelation, genetic barriers and geostatistical analysis –kriging-) and population structure (matrix R, D², Fst, principal coordinates, Harpendig and Ward model). For the study of lifestyles from bioarchaeological record we consider alveolar pathologies and disorders related to oral health such as tooth wear, micro and macroscopic level, caries, abscesses, antemortem tooth loss, hypoplasia, markers skeletal health and traumatic injuries, as well as taphonomic processes. Stable isotopes will be analyzed (δ13C, d15N, 86Sr and 87Sr) in human skeletal remains from various archaeological sites in order to reconstruct and analyze dietary patterns of residential mobility and migration of populations. It will be established procedures of taphonomic control on skeletal remains, analysis to study taphonomic histories and assess the degree of completeness of depositional context and collection, in general terms. We consider that analysis of spatial and temporal patterns of variability in craniofacial morphology and the study of health and diets from isotopic and bioarchaeological data, migration and residential mobility patterns from strontium isotopes, as well as activity patterns from stress markers is a novel and effective contribution that will substantially increase the information about the local evolution of populations that inhabitated the center of Argentina.

Population dynamics of 0-group flounder (Platichthys flesus L.) in Galway Bay, West of Ireland and the value of flounder from shore angling tourism in Ireland

The economic value of flounder from shore angling around Ireland was assessed. Flounder catches from shore angling tournaments around Ireland were related to domestic and overseas shore angling expenditure in order to determine an economic value for the species. Temporal trends in flounder angling catches, and specimen (trophy) flounder reports were also investigated. Flounder was found to be the most caught shore angling species in competitions around Ireland constituting roughly one third of the shore angling competition catch although this did vary by area. The total value of flounder from shore angling tourism was estimated to be of the order of €8.4 million. No significant temporal trends in flounder angling catches and specimen reports were found. Thus there is no evidence from the current study for any decline in flounder stocks. The population dynamics of 0-group flounder during the early benthic stage was investigated at estuarine sites in Galway Bay, west of Ireland. Information was analysed from the March to June sampling period over five years (2002 to 2006). Spatial and temporal variations in settlement and population length structure were analysed between beach and river habitats and sites. Settlement of flounder began from late March to early May of each year, most commonly in April. Peak settlement was usually in April or early May. Settlement was recorded earlier than elsewhere, although most commonly was similar to the southern part of the UK and northern France. Settlement was generally later in tidal rivers than on sandy beaches. Abundance of 0-group flounder in Galway Bay did not exhibit significant inter -annual variability. 0-group flounder were observed in dense aggregations of up to 105 m'2, which were patchy in distribution. Highest densities of 0-group flounder were recorded in limnetic and oligohaline areas as compared with the lower densities in polyhaline and to a lesser extent mesohaline areas. Measurements to of salinity allowed the classification of beaches, and tidal river sections near the mouth, into a salinity based scheme for length comparisons. Beaches were classified as polyhaline,the lower section of rivers as mesohaline, and the middle and upper sections as oligohaline. Over the March to June sampling period 0-group flounder utilised different sections at different length ranges and were significantly larger in more upstream sections. During initial settlement in April, 0-group flounder of 8-10 mm (standard length, SL) were present in abundance on polyhaline sandy beaches. By about 10mm (SL), flounder were present in all polyhaline, mesohaline and (oligohaline) sections. 0-group flounder became absent or in insignificant numbers in polyhaline and mesohaline sections in a matter of weeks after first appearance. From April to June, 0-group flounder of 12-30mm (SL) were found in more upstream locations in the oligohaline sections. About one month (May or June) after initial settlement, 0-group flounder became absent from the oligohaline sections. Concurrently, flounder start to reappear in mesohaline and polyhaline areas at approximately 30mm (SL) in June. The results indicate 0-group flounder in the early benthic stage are associated with low salinity areas, but as they grow, this association diminishes. Results strongly suggest that migration of 0-group flounder between habitats takes place during the early benthic phase.

A Model of Video Traffic Transmission in IP Networks

Telecommunications and network technology is now the driving force that ensures continued progress of world civilization. Design of new and expansion of existing network infrastructures requires improving the quality of service(QoS). Modeling probabilistic and time characteristics of telecommunication systems is an integral part of modern algorithms of administration of quality of service. At present, for the assessment of quality parameters except simulation models analytical models in the form of systems and queuing networks are widely used. Because of the limited mathematical tools of models of these classes the corresponding parameter estimation of parameters of quality of service are inadequate by definition. Especially concerning the models of telecommunication systems with packet transmission of multimedia real-time traffic.

Temporal variability of benthic macrofauna on Cassino beach, southernmost Brazil

The temporal variability of benthic macrofauna on Cassino beach, southernmost Brazil, was studied for a period of one year (June 2004 to May 2005) based on monthly sampling. Three sites were selected distant 50m from each other. At each site, 3 transects were established, 2m equidistant from one another. Each transect extended from the base of the primary dunes to the inner surf zone at approximately 1m in depth, with 7 or 8 sampling levels. Within transects, the distance between the levels was 20m until the upper swash zone, from which distance was 10m until the 1-meter isobath. The temporal variation in the abundance of benthic macrofauna observed in the present study can be attributed to (1) the positive effects of the recruitment peaks and migration of particular species to the swash zone and (2) negative effects of the migration of some species to deeper waters, as well (3) as mortality through natural causes (stranding and action of predators) and (4) human causes (harvesting and vehicle transit). We attribute the expressive abundance increase of benthic macrofauna to recruitment. The stranding, that is, the trapping of the organisms on the upper parts of the beach, is likely the main cause of abrupt drops in benthic macrofauna abundance.

A comparison of simian rotavirus SA11 preparations maintained in different laboratories

Preparations of simian SA11 maintained in different laboratories were compared with each other by polyacrylamide gel electrophoresis of genomic RNA. Differences in the migration of genome segments 4,5 and 7 allowed the classification of eight virus preparations into four electrophoretic types.

Point-occurrence self-similarity in crackling-noise systems and in other complex systems

It has been recently found that a number of systems displaying crackling noise also show a remarkable behavior regarding the temporal occurrence of successive events versus their size: a scaling law for the probability distributions of waiting times as a function of a minimum size is fulfilled, signaling the existence on those systems of self-similarity in time-size. This property is also present in some non-crackling systems. Here, the uncommon character of the scaling law is illustrated with simple marked renewal processes, built by definition with no correlations. Whereas processes with a finite mean waiting time do not fulfill a scaling law in general and tend towards a Poisson process in the limit of very high sizes, processes without a finite mean tend to another class of distributions, characterized by double power-law waiting-time densities. This is somehow reminiscent of the generalized central limit theorem. A model with short-range correlations is not able to escape from the attraction of those limit distributions. A discussion on open problems in the modeling of these properties is provided.

Mecanismes de reacció de sistemes catalítics amb èmfasi en carbens de Fischer i quantificació de l'aromaticitat en petites molècules inorgàniques cícliques i planes.

El tema principal del treball és sobre l'estudi teòric de l'estructura i reactivitat en carbens de Fischer de la forma (CO)5Cr=C(X)R (X= OH, NH2, OMe, NMe2 i R= CHCH2 i Ph). Particularment, el nostre interès va sorgir del tipus de reaccions de cicloadicció que donen lloc a la síntesi de productes naturals i fàrmacs de gran valor afegit. Hem estudiat els mecanismes de reacció dels casos més comuns de cicloanul•lació: la reacció de benzanul•lació de Dötz i ciclopentanulacions que es troben en competència amb el primer cas, derivats de l'inserció de acetilè i fenilacetilè. En l'últim pas de les reaccions que comporten la formació d'un sistema de més d'un anell, hi tenim una migració del complex metàl•lic de crom d'un extrem a un altre anomenat com rearranjament haptotròpic. Aleshores, hem investigat sobre els mecanismes de migració haptotròpica de Cr(CO)3 sobre hidrocarburs aromàtics policíclics analitzant l'efecte de la mida i la curvatura del sistema així com la complexació d'un segon fragment metàl•lic a la manera de coordinació als anells. D'una altre banda, vam estudiar l'aromaticitat en 54 cúmuls cíclics de molecules inorgàniques mitjançant metodologia desenvolupada al nostre grup de recerca i altres. Vam proposar la tècnica del scan-NICS com nova mesura quantitativa d'aromaticitat i reportar l'escassa correlació entre els distints índexs d'aromaticitat a la literatura. Finalment, com resultat de col•laboracions en estades de recerca, he desenvolupat propostes de mecanismes de reacció en sistemes catalítics de isonitrils i fosfinetà-amides i en dímers de gassos nobles.

Migration and trade: Theory with an Application to the Eastern- Western European Integration

The remarkable increase in trade flows and in migratory flows of highly educated people are two important features of globalization of the last decades. This paper extends a two-country model of inter- and intraindustry trade to a rich environment featuring technological differences, skill differences and the possibility of international labor mobility. The model is used to explain the patterns of trade and migration as countries remove barriers to trade and to labor mobility. We parameterize the model to match the features of the Western and Eastern European members of the EU and analyze first the effects of the trade liberalization which occured between 1989 and 2004, and then the gains and losses from migration which are expected to occur if legal barriers to labor mobility are substantially reduced. The lower barriers to migration would result in significant migration of skilled workers from Eastern European countries. Interestingly, this would not only benefit the migrants and most Western European workers but, via trade, it would also benefit the workers remaining in Eastern Europe. Key Words: Skilled Migration, Gains from Variety, Real Wages, Eastern-Western Europe. JEL Codes: F12, F22, J61.

The role of Pten in the Hematopoietic System and the Hematopoietic Stem Cells

Résumé Identification, localisation et activation des cellules souches hématopoiétiques dormantes in vivo Les cellules souches somatiques sont présentes dans la majorité des tissus régénératifs comme la peau, l'épithélium intestinal et le système hématopoiétique. A partir d'une seule cellule, elles ont les capacités de produire d'autres cellules souches du même type (auto-renouvellement) et d'engendrer un ensemble défini de cellules progénitrices différenciées qui vont maintenir ou réparer leur tissu hôte. Les cellules souches adultes les mieux caractérisées sont les cellules souches hématopoiétiques (HSC), localisées dans la moelle osseuse. Un des buts de mon travail de doctorat était de caractériser plus en profondeur la localisation des HSCs endogènes in vivo. Pour ce faire, la technique "label retaining assay", se basant sur la division peu fréquentes et sur la dormance des cellules souches, a été utilisée. Après un marquage des souris avec du BrdU (analogue à l'ADN) suivi d'une longue période sans BrdU, les cellules ayant incorporés le marquage ("label retaining cells" LCRs) ont pu être identifiées dans la moelle osseuse. Ces cellules LCRs étaient enrichies 300 fois en cellules de phenotype HSC et, en utilisant de la cytofluorométrie, il a pu être montré qu'environ 15% de toutes les HSCs d'une souris restent dormantes durant plusieures semaines. Ces HSCs dormantes à long terme ne sont probablement pas impliquées dans la maintenance de 'hématopoièse. Par contre, on assiste à l'activation rapide de ces HSCs dormantes lors d'une blessure, comme une ablation myéloide. Elles re-entrent alors en cycle cellulaire et sont essentielles pour une génération rapide des cellules progénitrices et matures qui vont remplacer les cellules perdues. De plus, la détection des LCRs, combinée avec l'utilisation du marqueur de HSCs c-kit, peut être utilisée pour la localisation des HSCs dormantes présentes dans la paroi endostéale de la cavité osseuse. De manière surprenante, les LCRs c-kit+ ont surtout étés trouvées isolées en cellule unique, suggérant que le micro-environement spécifique entourant et maintenant les HSCs, appelé niche, pourrait être très réduit et abriter une seule HSC par niche. Rôles complexes du gène supresseur de tumeur Pten dans le système hématopoiétique La phosphatase PTEN disparaît dans certains cancers héréditaires ou sporadiques humains, comme les gliomes, les cancers de l'utérus ou du sein. Pten inhibe la voie de signalisation de la PI3-kinase et joue un rôle clé dans l'apoptose, la croissance, la prolifération et la migration cellulaire. Notre but était d'étudier le rôle de Pten dans les HSC normale et durant la formation de leucémies. Pour ce faire, nous avons généré un modèle murin dans lequel le gène Pten peut être supprimé dans les cellules hématopoiétiques, incluant les HSCs. Ceci a été possible en croissant l'allèle conditionnelle ptenflox soit avec le transgène MxCre inductible par l'interféron α soit avec le transgène Scl-CreERt inductible par le tamoxifen. Ceci permet la conversion de l'allèle ptenflox en l'allèle nul PtenΔ dans les HSCs et les autres types cellulaires hématopoiétiques. Les souris mutantes Pten développent une splénomégalie massive causée par une expansion dramatiques de toutes les cellules myéloides. De manière interessante, alors que le nombre de HSCs dans la moelle osseuse diminue progressivement, le nombre des HSCs dans la rate augmente de manière proportionnelle. Etrangement, les analyses de cycle cellulaire ont montrés que Pten n'avait que peu ou pas d'effet sur la dormance des HSCs ou sur leur autorenouvellement. En revanche, une augmentation massive du niveau de la cytokine de mobilisation G-CSF a été détéctée dans le serum sanguin, suggérant que la suppression de Pten stimulerait la mobilisation et la migration des HSC de la moelle osseuse vers la rate. Finallement, la transplantation de moelle osseuse délétée en Pten dans des souris immuno-déficientes montre que Pten fonctionnerait comme un suppresseur de tumeur dans le système hématopoiétique car son absence entraîne la formation rapide de leucémies lymphocytaires. Summary Identification, localization and activation of dormant hematopoietic stun cells in vivo Somatic stem cells are present in most self-renewing tissues including the skin, the intestinal epithelium and the hematopoietic system. On a single cell basis they have the capacity to produce more stem cells of the same phenotype (self-renewal) and to give rise to a defined set of mature differentiated progeny, responsible for the maintenance or repair of the host tissue. The best characterized adult stem cell is the hematopoietic stem cell (HSC) located in the bone marrow. One goal of my thesis work was to further characterize the location of endogenous HSCs in vivo. To do this, a technique called "label retaining assay» was used which takes advantage of the fact that stem cells (including HSCs) divide very infrequently and can be dormant for months. After labeling mice with the DNA analogue BrdU followed by a long BrdU free "chase", BrdU "label retaining cells" (CRCs) could be identified in the bone marrow. These CRCs were 300-fold enriched for phenotypic HSCs and by using flow cytometry analysis it could be shown that about 15% of all HSCs in the mouse are dormant for many weeks. Our results suggest that these long-term dormant HSCs are unlikely to be involved in homeostatic maintenance. However they are rapidly activated and reenter the cell cycle in response to injury signals such as myeloid ablation. In addition, detection of LRCs in combination with the HSC marker c-Kit could be used to locate engrafted dormant HSCs close to the endosteal lining of the bone marrow cavities. Most surprisingly, c-Kit+LRCs were found predominantly as single cells suggesting that the specific stem cell maintaining microenvironment, called niche, has limited space and may house only single HSCs. Complex roles of the tumor suppressor gene Pten in the hematopoietic system. The phosphatase PTEN is lost in hereditary and sporadic forms of human cancers, including gliomas, endometrial and breast cancers. Pten inhibits the PI3-kina.se pathway and plays a key role in apoptosis, cell growth, proliferation and migration. Our aim was to study the role of Pten in normal HSCs and during leukemia formation. To do this, we generated a mouse model in which the Pten gene can be deleted in hematopoietic cells including HSCs. This was achieved by crossing the conditional ptenflox allele with either the interferona inducible MxCre or the tamoxifen inducible Scl-CreERT transgene. This allowed the conversion of the ptenflox allele into a pterr' null allele in HSCs and other hematopoietic cell types. As a result Pten mutant mice developed massive splenomegaly due to a dramatic expansion of all myeloid cells. Interestingly, while the number of bone marrow HSCs progressively decreased, the number of HSCs in the spleen increased to a similar extent. Unexpectedly, extensive cell cycle analysis showed that Pten had little or no effect on HSC dormancy or HSC self-renewal. Instead, dramatically increased levels of the mobilizing cytokine G-CSF were detected in the blood serum suggesting that loss-of Pten stimulates mobilization and migration of HSC from the BM to the spleen. Finally, transplantation of Pten deficient BM cells into immuno-compromised mice showed that Pten can function as a tumor suppressor in the hematopoietic system and that its absence leads to the rapid formation of T cell leukemia.

SYSGENET: a meeting report from a new European network for systems genetics.

The first scientific meeting of the newly established European SYSGENET network took place at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, April 7-9, 2010. About 50 researchers working in the field of systems genetics using mouse genetic reference populations (GRP) participated in the meeting and exchanged their results, phenotyping approaches, and data analysis tools for studying systems genetics. In addition, the future of GRP resources and phenotyping in Europe was discussed.

Sedimentology, geochemistry and mineralogy of the Paleocene-Eocene thermal maximum (PETM) : sediment records from Egypt, India and Spain

A gradual increase in Earth's surface temperatures marking the transition from the late Paleocene to early Eocene (55.8±0.2Ma), represents an extraordinary warming event known as Paleocene-Eocene Thermal Maximum (PETM). Both marine and continental sedimentary records during this period reveal evidences for the massive injection of isotopically light carbon. The carbon dioxide injection from multiple potential sources may have triggered the global warming. The importance of the PETM studies is due to the fact that the PETM bears some striking resemblances to the human-caused climate change unfolding today. Most notably, the culprit behind it was a massive injection of heat-trapping greenhouse gases into the atmosphere and oceans, comparable in volume to what our persistent burning of fossil fuels could deliver in coming centuries. The exact knowledge of what went on during the PETM could help us to foresee the future climate change. The response of the oceanic and continental environments to the PETM is different. Many factors might control the response of the environments to the PETM such as paleogeography, paleotopography, paleoenvironment, and paleodepth. To better understand the mechanisms triggering PETM events, two different environments were studied: 1) shallow marine to inner shelf environment (Wadi Nukhul, Sinai; and the Dababiya GSSP, Luxor, Egypt), and 2) terrestrial environments (northwestern India lignite mines) representing wetland, and fluvial environments (Esplugafreda, Spain) both highlighting the climatic changes observed in continental conditions. In the marine realm, the PETM is characterized by negative ö13Ccar and ô13Corg excursions and shifts in Ô15N to ~0%o values above the P/E boundary and persisting along the interval suggesting a bloom and high production of atmospheric N2-fixers. Decrease in carbonate contents could be due to dissolution and/or dilution by increasing detrital input. High Ti, K and Zr and decreased Si contents at the P/E boundary indicate high weathering index (CIA), which coincides with significant kaolinite input and suggests intense chemical weathering under humid conditions at the beginning of the PETM. Two anoxic intervals are observed along the PETM. The lower one may be linked to methane released from the continental shelf with no change in the redox proxies, where the upper anoxic to euxinic conditions are revealed by increasing U, Mo, V, Fe and the presence of small size pyrite framboids (2-5fim). Productivity sensitive elements (Cu, Ni, and Cd) show their maximum concentrated within the upper anoxic interval suggesting high productivity in surface water. The obtained data highlight that intense weathering and subsequent nutrient inputs are crucial parameters in the chain of the PETM events, triggering productivity during the recovery phase. In the terrestrial environments, the establishment of wetland conditions and consequence continental climatic shift towards more humid conditions led to migration of modern mammals northward following the extension of the tropical belts. Relative ages of this mammal event based on bio-chemo- and paleomagnetic stratigraphy support a migration path originating from Asia into Europe and North America, followed by later migration from Asia into India and suggests a barrier to migration that is likely linked to the timing of the India-Asia collision. In contrast, at Esplugafereda, northeastern Spain, the terrestrial environment reacted differently. Two significant S13C shifts with the lower one linked to the PETM and the upper corresponding to the Early Eocene Thermal Maximum (ETM2); 180/160 paleothermometry performed on two different soil carbonate nodule reveal a temperature increase of around 8°C during the PETM. The prominent increase in kaolinite content within the PETM is linked to increased runoff and/or weathering of adjacent and coeval soils. These results demonstrate that the PETM coincides globally with extreme climatic fluctuations and that terrestrial environments are very likely to record such climatic changes. - La transition Paléocène-Eocène (55,8±0,2 Ma) est marquée par un réchauffement extraordinaire communément appelé « Paleocene-Eocene Thermal Maximum » (PETM). Les données géochimiques caractérisant les sédiments marins et continentaux de cette période indiquent que ce réchauffement a été déclenché par une augmentation massive de CO2 lié à la déstabilisation des hydrates de méthane stockés le long des marges océaniques. L'étude des événements PETM constitue donc un bon analogue avec le réchauffement actuel. Le volume de CO2 émis durant le PETM est comparable avec le CO2 lié à l'activité actuelle humaine. La compréhension des causes du réchauffement du PETM peut être cruciale pour prévoir et évaluer les conséquences du réchauffement anthropogénique, en particulier les répercussions d'un tel réchauffement sur les domaines continentaux et océaniques. De nombreux facteurs entrent en ligne de compte dans le cas du PETM, tels que la paléogéographie, la paléotopographie et les paléoenvironnement. Pour mieux comprendre les réponses environnementales aux événements du PETM, 2 types d'environnements ont été choisis : (1) le domaine marin ouvert mais relativement peu profond (Wadi Nukhul. Sinai, Dababiya, Luxor, Egypte), (2) le milieu continental marécageux humide (mines de lignite, Inde) et fluviatile, semi-aride (Esplugafreda, Pyrénées espagnoles). Dans le domaine marin, le PETM est caractérisé par des excursions négatives du ô13Ccar et ô13Corg et un shift persistant des valeurs de 815N à ~ 0 %o indiquant une forte activité des organismes (bactéries) fixant l'azote. La diminution des carbonates observée durant le PETM peut-être due à des phénomènes de dissolution ou une augmentation des apports terrigènes. Des taux élevés en Ti, K et Zr et une diminution des montants de Si, reflétés par des valeurs des indices d'altération (CIA) qui coïncident avec une augmentation significative des apports de kaolinite impliquent une altération chimique accrue, du fait de conditions plus humides au début du PETM. Deux événements anoxiques globaux ont été mis en évidence durant le PETM. Le premier, situé dans la partie inférieur du PETM, serait lié à la libération des hydrates de méthane stockés le long des talus continentaux et ne correspond pas à des variations significatives des éléments sensibles aux changements de conditions redox. Le second est caractérisé par une augmentation des éléments U, Mo, V et Fe et la présence de petit framboids de pyrite dont la taille varie entre 2 et 5pm. Le second épisode anoxique est caractérisé par une forte augmentation des éléments sensibles aux changements de la productivité (Cu, Ni et Co), indiquant une augmentation de la productivité dans les eaux de surface. Les données obtenues mettent en évidence le rôle crucial joué par l'altération et les apports en nutriments qui en découlent. Ces paramètres sont cruciaux pour la succession des événements qui ont conduit au PETM, et plus particulièrement l'augmentation de la productivité dans la phase de récupération. Durant le PETM, le milieu continental est caractérisé par l'établissement de conditions humides qui ont facilité voir provoqué la migration des mammifères modernes qui ont suivi le déplacement de ces ceintures climatiques. L'âge de cette migration est basé sur des arguments chimiostratigraphiques (isotopes stables), biostratigraphiques et paléomagnétiques. Les données bibliographiques ainsi que celles que nous avons récoltées en Inde, montrent que les mammifères modernes ont d'abord migré depuis l'Asie vers l'Europe, puis dans le continent Nord américain. Ces derniers ne sont arrivés en Inde que plus tardivement, suggérant que le temps de leur migration est lié à la collision Inde-Asie. Dans le Nord-Est de l'Espagne (Esplugafreda), la réponse du milieu continental aux événements PETM est assez différente. Comme en Inde, deux excursions signicatives en ô13C ont été observées. La première correspond au PETM et la seconde est corrélée avec l'optimum thermique de l'Eocène précoce (ETM2). Les isotopes stables de l'oxygène mesurés 2 différents types de nodules calcaires provenant de paléosols suggère une augmentation de 10°C pendant le PETM. Une augmentation simultanée des taux de kaolinite indique une intensification de l'altération chimique et/ou de l'érosion de sols adjacents. Ces résultats démontrent que le PETM coïncide globalement avec des variations climatiques extrêmes qui sont très aisément reconnaissables dans les dépôts continentaux.

Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells.

Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies. Cancer Immunol Res; 2(8); 741-55. ©2014 AACR.

In vitro infection of human dendritic cells by Aspergillus fumigatus conidia triggers the secretion of chemokines for neutrophil and Th1 lymphocyte recruitment.

Given the role played by chemokines in the selective homing of immune cells, we sought to characterize the profile of chemokines produced by human dendritic cells (DC) following in vitro Aspergillus fumigatus infection and their ability to recruit cells involved in the antifungal defense. At the onset of A. fumigatus infection, DC released elevated amounts of CXCL8 that promote the migration of polymorphonuclear cells (PMN). Moreover, soluble factors released from A. fumigatus-infected DC increased also the surface expression of two activation markers, CD11b and CD18, on PMN. A. fumigatus infection resulted also in CCL3, CCL4, CXCL10 and CCL20 productions that induce the migration of effector memory Th1 cells. Moreover, the late expression of CCL19 suggests that A. fumigatus-infected DC could be implicated in the migration of CCR7+ naïve T cells and mature DC in lymph nodes. Together these results suggested the involvement of human DC in the regulation of innate and adaptive immunity against A. fumigatus through the recruitment of cells active in the fungal destruction.

Contribution of NFI-C to TGF-β1 signalling and tissue regeneration

Summary : Platelet Derived Growth Factor (PDGF) and Transforming Growth Factor-ß (TGF-ß) are two crucial growth factors in tissue repair and regeneration. They control migration and proliferation of macrophages and fibroblasts, as well as myofibroblast differentiation and synthesis of the new connective tissue. The transcription factor Nuclear Factor I-C (NFI-C) has been implicated in the TGF-ß pathway and regulation of extracellular matrix proteins in vitro. This suggests a possible implication of NFI-C in tissue repair. In this study, our purpose was to identify the NFI-C target genes in TGF-ß1 pathway activation and define the relationship between these two factors in cutaneous wound healing process. High-throughput genomic analysis in wild-type and NFI-C knock-out embryonic fibroblasts indicated that NFI-C acts as a repressor of the expression of genes which transcriptional activity is enhanced by TGF-ß. Interestingly, we found an over representation of genes involved in connective tissue inflammation and repair. In accordance with the genomic analysis, NFI-C-/- mice showed an improvement of skin healing during the inflammatory stage. Analysis of this new phenotype indicated that the expression of PDGFA and PDGF-Ra genes were increased in the wounds of NFI-C-/- mice resulting in early recruitment of macrophages and fibroblasts in the granulation tissue. In correlation with the stimulation effect of TGF-ß on myofibroblast differentiation we found an increased differentiation of these cells in null mice, providing a rationale for rapid wound closure. Thus, in the absence of NFI-C, both TGF-ß and PDGF pathways may be activated, leading to enhanced healing process. Therefore, the inhibition of NFI-C expression could constitute a suitable therapy for healing improvement. In addition, we identified a delay of hair follicle cycle initiation in NFI-C-/- mice. This prompted us to investigate the role of NFI-C in skin appendage. The transition from a quiescent to a proliferative phase requires a perfect timing of signalling modulation, leading to stem cell activation. As a consequence of cycle initiation delay in null mice, the activation of signalling involved in cell proliferation was also retarded. Interestingly, at the crucial moment of cell fate determination, we identified a decrease of CD34 gene in mutant mice. Since CD34 protein is involved in migration of multipotent cells, we suggest that NFI-C may be involved in stem cell mobilisation required for hair follicle renewal. Further investigations of the role of NFI-C in progenitor cell activation will lead to a better understanding of tissue regeneration and raise the possibility of treating alopecia with NFI-C-targeting treatment. In summary, this study demonstrates new regenerative functions of NFI-C in adult mice, which regulates skin repair and hair follicle renewal. Résumé : PDGF et TGF-ß sont des facteurs important du mécanisme de défense immunitaire. Ils influencent la prolifération et migration des macrophages et des fibroblastes, ainsi que la différenciation des myofibroblastes et la formation du nouveau tissu conjonctif. Le facteur de transcription NFI-C a été impliqué dans la voie de signalisation de TGF-ß et dans 1a régulation de l'expression des protéines de la matrice extracellulaire in vitro. Ces études antérieures laissent supposer que NFI-C serait un facteur important du remodelage tissulaire. Cependant le rôle de NFI-C dans un tissu comme la peau n'a pas encore été étudié. Dans ce travail, le but a été de d'identifier la relation qu'il existe entre I~1FI-C et TGF-ßl à un niveau transcriptionnel et dans le processus de cicatrisation cutanée in vivo. Ainsi, une analyse génétique à grande échelle, a permis d'indiquer que NFI-C agit comme un répresseur sur l'expression des gènes dont l'activité transcriptionnelle est activée par TGF-ß. De plus nous avons identifié un groupe de gènes qui controlent le développement et l'inflammation du tissue conjonctif. En relation avec ce résultat, l'absence de NFI-C dans la peau induit une cicatrisation plus rapide pendant la phase inflammatoire. Durant cette période, nous avons montré que les expressions de PDGFA et PDGFRa seraient plus élevées en absence de NFI-C. En conséquence, l'activation de la voie de PDGF induit une infiltration plus importante des macrophages et fibroblastes dans le tissue granuleux des souris mutantes. De plus, en corrélation avec le rôle de TGF-ßl dans la différenciation des myofibroblasts, nous avons observé une différenciation plus importante de ces cellules chez les animaux knock-out, ce qui peut expliquer une contraction plus rapide de la plaie. De plus, nous avons découvert que NFI-C est impliqué dans l'initiation du cycle folliculaire. La caractérisation de ce nouveau phénotype a montré un ralentissement de la transition telogène-anagène des souris NFI-C-/-. Or, un événement clé de cette transition est la modulation de plusieurs signaux moléculaires aboutissant à' l'activation des cellules souches. En corrélation avec le decalage du cycle, l'activation de ces signaux est également décalée dans les souris NFI-C-/-. Ainsi, au commencement de l'anagène, la prolifération des keratinocytes,NFI-C-/- est retardée et corrèle avec une diminution de l'expression de CD34, une protéine responsable de la détermination du migration des cellules multipotentes. Ainsi, NFI-C semble être impliqué dans la mobilisation des cellules souches qui sont nécessaires au renouvellement folliculaire. En résumé, NFI-C est impliqué dans la régulation des signaux moléculaires nécessaires à la réparation tissulaire et son inhibition pourrait constituer un traitement de la cicatrisation. L'analyse de son rôle dans l'activation des cellules souches permettrait de mieux comprendre le renouvellement tissulaire et, à long terme, d'améliorer les techniques de greffe des cellules souches épithéliales ou consituter une cible pour le traitement de l'alopecie.