Multiscale phylogeography: glacial history and autopolyploidy of Biscutella laevigata L. (Brassicaceae) in the Western Alps

Résumé Les changements climatiques du Quaternaire ont eu une influence majeure sur la distribution et l'évolution des biota septentrionaux. Les Alpes offrent un cadre spatio-temporel bien étudié pour comprendre la réactivité de la flore et le potentiel d'adaptation d'une espèce végétale face aux changements climatiques. Certaines hypothèses postulent une diversification des espèces en raison de la disparition complète de la flore des Alpes et d'un isolement important des espèces dans des refuges méridionaux durant les dernières glaciations (Tabula Rasa). Une autre hypothèse stipule le maintien de poches de résistance pour la végétation au coeur des Alpes (Nunataks). Comme de nombreuses espèces végétales présentant un grand succès écologique semblent avoir réagi aux glaciations par la multiplication de leur génome (autopolyploïdie), leur étude en milieu naturel devrait permettre de comprendre les avantages inhérents à la polyploïdie. Biscutella laevigata est un modèle emblématique de biogéographie historique, diverses études ayant montré que des populations diploïdes sont actuellement isolées dans les zones restées déglacées durant le dernier maximum glaciaire, alors que des tétraploïdes ont recolonisé l'ensemble des zones alpines mises à nu par le retrait des glaciers. Si le contexte périglaciaire semble avoir favorisé ce jeune complexe autopolyploïde, les circonstances et les avantages de cette mutation génomique ne sont pas encore clairs. Y a-t-il eu de multiples événements de polyploïdisation ? Dans quelle mesure affecte(nt)il(s) la diversité génétique et le potentiel évolutif des polyploïdes ? Les polyploïdes ont-ils une grande flexibilité génomique, favorisant une radiation adaptative, ou doivent-ils leur succès à une grande plasticité écologique ? Cette étude aborde ces questions à différentes échelles spatiales et temporelles. L'échelle régionale des Alpes occidentales permet d'aborder les facteurs distaux (aspects historiques), alors que l'échelle locale cherche à appréhender les facteurs proximaux (mécanismes évolutifs). Dans les Alpes occidentales, des populations ont été densément échantillonnées et étudiées grâce à (1) leur cytotype, (2) leur appartenance taxonomique, (3) leur habitat et (4) des marqueurs moléculaires de l'ADN chloroplastique, en vue d'établir leurs affinités évolutives. Á l'échelle locale, deux systèmes de population ont été étudiés : l'un où les populations persistent en périphérie de l'aire de distribution et l'autre au niveau du front actif de colonisation, en marge altitudinale. Les résultats à l'échelle des Alpes occidentales révèlent les sites d'intérêt (refuges glaciaires, principales barrières et voies de recolonisation) pour une espèce représentative des pelouses alpines, ainsi que pour la biodiversité régionale. Les Préalpes ont joué un rôle important dans le maintien de populations à proximité immédiate des Alpes centrales et dans l'évolution du taxon, voire de la végétation. Il est aussi démontré que l'époque glaciaire a favorisé l'autopolyploïdie polytopique et la recolonisation des Alpes occidentales par des lignées distinctes qui s'hybrident au centre des Alpes, influençant fortement leur diversité génétique et leur potentiel évolutif. L'analyse de populations locales en situations contrastées à l'aide de marqueurs AFLP montre qu'au sein d'une lignée présentant une grande expansion, la diversité génétique est façonnée par des forces évolutives différentes selon le contexte écologique et historique. Les populations persistant présentent une dispersion des gènes restreinte, engendrant une diversité génétique assez faible, mais semblent adaptées aux conditions locales de l'environnement. À l'inverse, les populations colonisant la marge altitudinale sont influencées par les effets de fondation conjugués à une importante dispersion des gènes et, si ces processus impliquent une grande diversité génétique, ils engendrent une répartition aléatoire des génotypes dans l'environnement. Les autopolyploïdes apparaissent ainsi comme capables de persister face aux changements climatiques grâce à certaines facultés d'adaptation locale et de grandes capacités à maintenir une importante diversité génétique lors de la recolonisation post-glaciaire. Summary The extreme climate changes of the Quaternary have had a major influence on species distribution and evolution. The European Alps offer a great framework to investigate flora reactivity and the adaptive potential of species under changing climate. Some hypotheses postulate diversification due to vegetation removal and important isolation in southern refugia (Tabula Rasa), while others explain phylogeographic patterns by the survival of species in favourable Nunataks within the Alps. Since numerous species have successfully reacted to past climate changes by genome multiplication (autopolyploidy), studies of such taxa in natural conditions is likely to explain the ecological success and the advantages of autopolyploidy. Early cytogeographical surveys of Biscutella laevigata have shed light on the links between autopolyploidy and glaciations by indicating that diploids are now spatially isolated in never-glaciated areas, while autotetraploids have recolonised the zones covered by glaciers- during the last glacial maximum. A periglacial context apparently favoured this young autopolyploid complex but the circumstances and the advantages of this genomic mutation remain unclear. What is the glacial history of the B. laevigata autopolyploid complex? Are there multiple events of polyploidisation? To what extent do they affect the genetic diversity and the evolutionary potential of polyploids? Is recolonisation associated with adaptive processes? How does long-term persistence affect genetic diversity? The present study addresses these questions at different spatiotemporal scales. A regional survey at the Western Alps-scale tackles distal factors (evolutionary history), while local-scale studies explore proximal factors (evolutionary mechanisms). In the Western Alps, populations have been densely sampled and studied from the (1) cytotypic, (2) morphotaxonomic, (3) habitat point of views, as well as (4) plastid DNA molecular markers, in order to infer their relationships and establish the maternal lineages phylogeography. At the local scale, populations persisting at the rear edge and populations recolonising the attitudinal margin at the leading edge have been studied by AFLPs to show how genetic diversity is shaped by different evolutionary forces across the species range. The results at the regional scale document the glacial history of a widespread species, representative of alpine meadows, in a regional area of main interest (glacial refugia, main barriers and recolonisation routes) and points out to sites of interest for regional biodiversity. The external Alps have played a major role in the maintenance of populations near the central Alps during the Last Glacial Maximum and influenced the evolution of the species, and of vegetation. Polytopic autopolyploidy in different biogeographic districts is also demonstrated. The species has had an important and rapid radiation because recolonisation took place from different refugia. The subsequent recolonisation of the Western Alps was achieved by independent lineages that are presently admixing in the central Alps. The role of the Pennic summit line is underlined as a great barrier that was permeable only through certain favourable high-altitude passes. The central Alps are thus viewed as an important crossroad where genomes with different evolutionary histories are meeting and admixing. The AFLP analysis and comparison of local populations growing in contrasted ecological and historical situations indicate that populations persisting in the external Alps present restricted gene dispersal and low genetic diversity but seem in equilibrium with their environment. On the contrary, populations colonising the attitudinal margin are mainly influenced by founder effects together with great gene dispersal and genotypes have a nearly random distribution, suggesting that recolonisation is not associated with adaptive processes. Autopolyploids that locally persist against climate changes thus seem to present adaptive ability, while those that actively recolonise the Alps are successful because of their great capacity to maintain a high genetic diversity against founder effects during recolonisation.

Innate and adaptive effects of inflammasomes on T cell responses.

Inflammasomes are protein complexes that form in response to pathogen-derived or host-derived stress signals. Their activation leads to the production of inflammatory cytokines and promotes a pyrogenic cell death process. The massive release of inflammatory mediators that follows inflammasome activation is a key event in alarming innate immune cells. Growing evidence also highlights the role of inflammasome-dependent cytokines in shaping the adaptive immune response, as exemplified by the capacity of IL-1β to support Th17 responses, or by the finding that IL-18 evokes antigen-independent IFN-γ secretion by memory CD8(+) T cells. A deeper understanding of these mechanisms and on how to manipulate this powerful inflammatory system therefore represents an important step forward in the development of improved vaccine strategies.

Adaptive learning in models with lagged variables

In this work I study the stability of the dynamics generated by adaptivelearning processes in intertemporal economies with lagged variables. Iprove that determinacy of the steady state is a necessary condition for the convergence of the learning dynamics and I show that the reciprocal is not true characterizing the economies where convergence holds. In the case of existence of cycles I show that there is not, in general, a relationship between determinacy and convergence of the learning process to the cycle. I also analyze the expectational stability of these equilibria.

Characterization of the effects of radiation therapy on the tumour microenvironment and their consequences on cancer progression

RESUME La radiothérapie est utilisée avec succès pour le traitement d'un grand nombre de pathologies tumorales (1). Cependant, les récidives post-actiniques sont associées à un risque accru de développer des métastases régionales et à distance (2, 3). La prise en charge de ce type de patients demeure insatisfaisante à l'heure actuelle, principalement parce que les mécanismes physio-pathologiques sous- sous-jacents restent mal compris. Etant donné le rôle primordial du stroma dans la progression tumorale (4) et l'importance des effets de la radiothérapie sur le micro-environnement des tumeurs (5), nous avons émis l'hypothèse que la radiothérapie pouvait engendrer des modifications stromales susceptibles de contribuer à l'émergence d'un phénotype tumoral plus agressif. Nous avons observé que l'exposition préalable d'un environnement tumoral à des radiations ionisantes engendre une inhibition locale et à long terme de l'angiogenèse. Cette inhibition conduit à la création d'un environnement tumoral hypoxique favorisant l'invasion et la métastatisation tumorale. Les mécanismes sous-jacents impliquent l'activation de gènes prométastatiques sous le contrôle du facteur de transcription HIF-1, ainsi que la sélection hypoxique de cellules hautement invasives et métastatiques. Par des analyses de profile d'expression génétique ainsi que par des analyses fonctionnelles, nous avons identifié la protéine matri-cellulaire CYR61 ainsi que ses partenaires d'interaction, les intégrines aVb5/aVb3, comme médiateurs importants de ces effets. De plus, une corrélation significative a également été trouvée entre le niveau d'expression de CYR61 et le taux d'hypoxie dans un grand nombre de carcinomes mammaires chez l'humain. Une association a aussi été observée entre le niveau d'expression de CYR61 et le pronostic de patientes souffrant d'un cancer du sein traité par chimiothérapie adjuvante. Globalement ces résultats identifient l'interaction entre la protéine CYR61 et ses récepteurs aVb5/aVb3 comme un mécanisme important du processus de métastatisation et en font une cible thérapeutique potentielle pour le traitement de patients souffrant d'une récidive tumorale après un traitement de radiothérapie. Finalement, bien que l'inhibition de l'angiogenèse soit locale dans ce cas particulier, nos résultats justifient une surveillance particulière des patients souffrant d'une pathologie tumorale et étant au bénéfice d'un traitement inhibiteur de l'angiogenèse. SUMMARY Radiotherapy is successfully used to treat a large variety of tumours (1 ). However, cancer patients experiencing local recurrent disease after radiation therapy are at increased risk of developing regional and distant metastasis (2, 3). The clinical management of this condition represents a difficult and challenging issue, mainly because the underlying physio-pathological mechanisms remain poorly understood. Given the well established role of the tumour stroma in promoting cancer progression (4) and since radiotherapy is known to persistently alter the tumour microenvironment (5), we hypothesized that ionising radiations may generate stromal modifications contributing to the metastatic spread of relapsing tumours. Here, we report that irradiation of the prospective tumour microenvironment promotes tumour invasion and metastasis through a mechanism of local and sustained impairment of angiogenesis leading to both HIF-1 dependent activation of pro-metastatic genes and hypoxia-mediated selection of highly metastatic tumour cell variants. Through gene expression profiling and functional experiments, we identified the matricellular signalling protein CYR61 and its interaction partners aVb5/ aVb3 integrins as critical mediators of these effects. Furthermore, we found a significant correlation between CYR61 expression and the hypoxic status of a large number of human mammary carcinomas. A positive correlation between increased levels of CYR61 expression and shorter relapse free survival was also identified in breast cancer patients treated with adjuvant chemotherapy. Together, these results identify CYR61 and aVb5/aVb3 integrins as critical mediators of metastasis and potential therapeutic targets to improve outcome in patients with post-radiation tumour recurrences. Finally, although inhibition of angiogenesis is local in this setting, our data warrant close monitoring of tumour progression in patients under anti-angiogenic therapy.

An experimental study of adaptive behavior in an oligopolistic market game

We consider an oligopolistic market game, in which the players are competing firm in the same market of a homogeneous consumption good. The consumer side is represented by a fixed demand function. The firms decide how much to produce of a perishable consumption good, and they decide upon a number of information signals to be sent into the population in order to attract customers. Due to the minimal information provided, the players do not have a well--specified model of their environment. Our main objective is to characterize the adaptive behavior of the players in such a situation.

Late Onset Cystoid Macular Oedema Following Surgery for Radiation Induced Cataract in Patient With Retinoblastoma

Purpose: Cystoid macular oedema (CMO) is a very rare condition following cataract surgery in paediatric population. Nevertheless, we report a case series of patients with radiation induced cataract after retinoblastoma (Rb) treatment that underwent cataract surgery and developed subsequently late onset CMO. Methods: Between January 1984 and December 2009, 25 consecutive eyes (25 patients) with Rb presented with radiation induced cataract surgery at the Jules Gonin Eye Hospital. Sixteen eyes (16 patients) had prior radiation induced retinopathy and maculopathy (IRM). Out of these, 3 eyes (3 patients) developed CMO after cataract surgery. Results: One eye had Rb stage B, and 2 eyes had stage D International classification. All of them developed IRM following brachytherapy and/or external beam irradiation. Patients underwent phako-aspiration and in bag intraocular lens implantation after IRM had resolved. Mean age at cataract surgery was 10.7 ± 2.8 (SEM) (range 5-14) years old. Mean time between resolution of IRM and cataract surgery was 76.0 ± 27.2 (SEM) (range 24-116) months. Mean time of onset CMO after cataract surgery was 81.0 ± 34.4 (SEM) (range 13-124) months. There was no other underlying vascular or tractional factor for CMO development. All of them were treated with a combination of oral carbonic anhydrase inhibitor, topical steroid and topical non-steroid. Mean macular thickness pre-, during-, and post CMO were 134.0 ± 10.3, 298.0 ± 37.1, and 154.0 ± 4.0 (SEM) µm, respectively. Mean best corrected visual acuity pre-, during-, and post CMO were 0.31 ± 0.19, 0.46 ± 0.12, and 0.34 ± 0.18 (SEM) LogMAR, respectively. Mean time for CMO reabsorption was 17.0 ± 9.8 (SEM) months. Conclusions: To the best of our knowledge, CMO following paediatric cataract surgery is a very uncommon condition. Moreover, late onset CMO after phako-aspiration for radiation induced cataract in Rb patients has never been described. It is a rare complication but can be treated successfully.

A simple adaptive procedure leading to correlated equilibrium

We propose a simple adaptive procedure for playing a game. In thisprocedure, players depart from their current play with probabilities thatare proportional to measures of regret for not having used other strategies(these measures are updated every period). It is shown that our adaptiveprocedure guaranties that with probability one, the sample distributionsof play converge to the set of correlated equilibria of the game. Tocompute these regret measures, a player needs to know his payoff functionand the history of play. We also offer a variation where every playerknows only his own realized payoff history (but not his payoff function).

Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.

Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.

EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach.

PURPOSE: The Gastro-Intestinal Working Party of the EORTC Radiation Oncology Group (GIWP-ROG) developed guidelines for target volume definition in neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction (GEJ) and the stomach. METHODS AND MATERIALS: Guidelines about the definition of the clinical target volume (CTV) are based on a systematic literature review of the location and frequency of local recurrences and lymph node involvement in adenocarcinomas of the GEJ and the stomach. Therefore, MEDLINE was searched up to August 2008. Guidelines concerning prescription, planning and treatment delivery are based on a consensus between the members of the GIWP-ROG. RESULTS: In order to support a curative resection of GEJ and gastric cancer, an individualized preoperative treatment volume based on tumour location has to include the primary tumour and the draining regional lymph nodes area. Therefore we recommend to use the 2nd English Edition of the Japanese Classification of Gastric Carcinoma of the Japanese Gastric Cancer Association which developed the concept of assigning tumours of the GEJ and the stomach to anatomically defined sub-sites corresponding respectively to a distinct lymphatic spread pattern. CONCLUSION: The GIWP-ROG defined guidelines for preoperative irradiation of adenocarcinomas of the GEJ and the stomach to reduce variability in the framework of future clinical trials.

Adaptive approach heuristics for the generalized assignment problem

The Generalized Assignment Problem consists in assigning a setof tasks to a set of agents with minimum cost. Each agent hasa limited amount of a single resource and each task must beassigned to one and only one agent, requiring a certain amountof the resource of the agent. We present new metaheuristics forthe generalized assignment problem based on hybrid approaches.One metaheuristic is a MAX-MIN Ant System (MMAS), an improvedversion of the Ant System, which was recently proposed byStutzle and Hoos to combinatorial optimization problems, and itcan be seen has an adaptive sampling algorithm that takes inconsideration the experience gathered in earlier iterations ofthe algorithm. Moreover, the latter heuristic is combined withlocal search and tabu search heuristics to improve the search.A greedy randomized adaptive search heuristic (GRASP) is alsoproposed. Several neighborhoods are studied, including one basedon ejection chains that produces good moves withoutincreasing the computational effort. We present computationalresults of the comparative performance, followed by concludingremarks and ideas on future research in generalized assignmentrelated problems.

Rational reasoning or adaptive behavior? Evidence from two-person beauty contest games

Many experiments have shown that human subjects do not necessarily behave in line with game theoretic assumptions and solution concepts. The reasons for this non-conformity are multiple. In this paper we study the argument whether a deviation from game theory is because subjects are rational, but doubt that others are rational as well, compared to the argument that subjects, in general, are boundedly rational themselves. To distinguish these two hypotheses, we study behavior in repeated 2-person and many-person Beauty-Contest-Games which are strategically different from one another. We analyze four different treatments and observe that convergence toward equilibrium is driven by learning through the information about the other player s choice and adaptation rather than self-initiated rational reasoning.

Adaptive model selection using empirical complexities

Given $n$ independent replicates of a jointly distributed pair $(X,Y)\in {\cal R}^d \times {\cal R}$, we wish to select from a fixed sequence of model classes ${\cal F}_1, {\cal F}_2, \ldots$ a deterministic prediction rule $f: {\cal R}^d \to {\cal R}$ whose risk is small. We investigate the possibility of empirically assessingthe {\em complexity} of each model class, that is, the actual difficulty of the estimation problem within each class. The estimated complexities are in turn used to define an adaptive model selection procedure, which is based on complexity penalized empirical risk.The available data are divided into two parts. The first is used to form an empirical cover of each model class, and the second is used to select a candidate rule from each cover based on empirical risk. The covering radii are determined empirically to optimize a tight upper bound on the estimation error. An estimate is chosen from the list of candidates in order to minimize the sum of class complexity and empirical risk. A distinguishing feature of the approach is that the complexity of each model class is assessed empirically, based on the size of its empirical cover.Finite sample performance bounds are established for the estimates, and these bounds are applied to several non-parametric estimation problems. The estimates are shown to achieve a favorable tradeoff between approximation and estimation error, and to perform as well as if the distribution-dependent complexities of the model classes were known beforehand. In addition, it is shown that the estimate can be consistent,and even possess near optimal rates of convergence, when each model class has an infinite VC or pseudo dimension.For regression estimation with squared loss we modify our estimate to achieve a faster rate of convergence.

Building adaptive capacity and resilience to climate change in the water sector in Cape Verde

Purpose of the evaluation This is a scheduled standard mid-term evaluation (MTR) of a UNDP implemented GEF LDCF co-financed project. It is conducted by a team of an international and a national independent evaluator. The objective of the MTR, as set out in the Terms of Reference (TORs; Annex 1), is to provide an independent analysis of the progress of the project so far. The MTR aims to:  identify potential project design problems,  assess progress towards the achievement of the project objective and outcomes,  identify and document lessons learned (including lessons that might improve design and implementation of other projects, including UNDP-GEF supported projects), and  make recommendations regarding specific actions that should be taken to improve the project. The MTR is intended to assess signs of project success or failure and identify the necessary changes to be made. The project commenced its implementation in the first half of 2010 with the recruitment of project staff. According to the updated project plan, it is due to close in July 201410 with operations scaling down in December 2013 due to funding limits. Because of a slow implementation start, the mid-term evaluation was delayed to July 201311 The intended target audience of the evaluation are:  The project team and decision makers in the INGRH  The GEF and UNFCCC Operational Focal Points  The project partners and beneficiaries  UNDP in Cape Verde as well as the regional and headquarter (HQ) office levels  The GEF Secretariat.