Local optima networks of hard combinatorial landscapes

Combinatorial optimization involves finding an optimal solution in a finite set of options; many everyday life problems are of this kind. However, the number of options grows exponentially with the size of the problem, such that an exhaustive search for the best solution is practically infeasible beyond a certain problem size. When efficient algorithms are not available, a practical approach to obtain an approximate solution to the problem at hand, is to start with an educated guess and gradually refine it until we have a good-enough solution. Roughly speaking, this is how local search heuristics work. These stochastic algorithms navigate the problem search space by iteratively turning the current solution into new candidate solutions, guiding the search towards better solutions. The search performance, therefore, depends on structural aspects of the search space, which in turn depend on the move operator being used to modify solutions. A common way to characterize the search space of a problem is through the study of its fitness landscape, a mathematical object comprising the space of all possible solutions, their value with respect to the optimization objective, and a relationship of neighborhood defined by the move operator. The landscape metaphor is used to explain the search dynamics as a sort of potential function. The concept is indeed similar to that of potential energy surfaces in physical chemistry. Borrowing ideas from that field, we propose to extend to combinatorial landscapes the notion of the inherent network formed by energy minima in energy landscapes. In our case, energy minima are the local optima of the combinatorial problem, and we explore several definitions for the network edges. At first, we perform an exhaustive sampling of local optima basins of attraction, and define weighted transitions between basins by accounting for all the possible ways of crossing the basins frontier via one random move. Then, we reduce the computational burden by only counting the chances of escaping a given basin via random kick moves that start at the local optimum. Finally, we approximate network edges from the search trajectory of simple search heuristics, mining the frequency and inter-arrival time with which the heuristic visits local optima. Through these methodologies, we build a weighted directed graph that provides a synthetic view of the whole landscape, and that we can characterize using the tools of complex networks science. We argue that the network characterization can advance our understanding of the structural and dynamical properties of hard combinatorial landscapes. We apply our approach to prototypical problems such as the Quadratic Assignment Problem, the NK model of rugged landscapes, and the Permutation Flow-shop Scheduling Problem. We show that some network metrics can differentiate problem classes, correlate with problem non-linearity, and predict problem hardness as measured from the performances of trajectory-based local search heuristics.

GENCODE: producing a reference annotation for ENCODE.

BACKGROUND: The GENCODE consortium was formed to identify and map all protein-coding genes within the ENCODE regions. This was achieved by a combination of initial manual annotation by the HAVANA team, experimental validation by the GENCODE consortium and a refinement of the annotation based on these experimental results. RESULTS: The GENCODE gene features are divided into eight different categories of which only the first two (known and novel coding sequence) are confidently predicted to be protein-coding genes. 5' rapid amplification of cDNA ends (RACE) and RT-PCR were used to experimentally verify the initial annotation. Of the 420 coding loci tested, 229 RACE products have been sequenced. They supported 5' extensions of 30 loci and new splice variants in 50 loci. In addition, 46 loci without evidence for a coding sequence were validated, consisting of 31 novel and 15 putative transcripts. We assessed the comprehensiveness of the GENCODE annotation by attempting to validate all the predicted exon boundaries outside the GENCODE annotation. Out of 1,215 tested in a subset of the ENCODE regions, 14 novel exon pairs were validated, only two of them in intergenic regions. CONCLUSION: In total, 487 loci, of which 434 are coding, have been annotated as part of the GENCODE reference set available from the UCSC browser. Comparison of GENCODE annotation with RefSeq and ENSEMBL show only 40% of GENCODE exons are contained within the two sets, which is a reflection of the high number of alternative splice forms with unique exons annotated. Over 50% of coding loci have been experimentally verified by 5' RACE for EGASP and the GENCODE collaboration is continuing to refine its annotation of 1% human genome with the aid of experimental validation.

Association of electrocardiogram abnormalities and incident heart failure events.

Unless effective preventive strategies are implemented, aging of the population will result in a significant worsening of the heart failure (HF) epidemic. Few data exist on whether baseline electrocardiographic (ECG) abnormalities can refine risk prediction for HF. METHODS: We examined a prospective cohort of 2,915 participants aged 70 to 79 years without preexisting HF, enrolled between April 1997 and June 1998 in the Health, Aging, and Body Composition (Health ABC) study. Minnesota Code was used to define major and minor ECG abnormalities at baseline and at year 4 follow-up. Using Cox models, we assessed (1) the association between ECG abnormalities and incident HF and (2) the incremental value of adding ECG to the Health ABC HF Risk Score using the net reclassification index. RESULTS: At baseline, 380 participants (13.0%) had minor, and 620 (21.3%) had major ECG abnormalities. During a median follow-up of 11.4 years, 485 participants (16.6%) developed incident HF. After adjusting for the Health ABC HF Risk Score variables, the hazard ratio (HR) was 1.27 (95% CI 0.96-1.68) for minor and 1.99 (95% CI 1.61-2.44) for major ECG abnormalities. At year 4, 263 participants developed new and 549 had persistent abnormalities; both were associated with increased subsequent HF risk (HR 1.94, 95% CI 1.38-2.72 for new and HR 2.35, 95% CI 1.82-3.02 for persistent ECG abnormalities). Baseline ECG correctly reclassified 10.5% of patients with HF events, 0.8% of those without HF events, and 1.4% of the overall population. The net reclassification index across the Health ABC HF risk categories was 0.11 (95% CI 0.03-0.19). CONCLUSIONS: Among older adults, baseline and new ECG abnormalities are independently associated with increased risk of HF. The contribution of ECG screening for targeted prevention of HF should be evaluated in clinical trials.

Data-parallel computation in parallel and distributed environments

The past few decades have seen a considerable increase in the number of parallel and distributed systems. With the development of more complex applications, the need for more powerful systems has emerged and various parallel and distributed environments have been designed and implemented. Each of the environments, including hardware and software, has unique strengths and weaknesses. There is no single parallel environment that can be identified as the best environment for all applications with respect to hardware and software properties. The main goal of this thesis is to provide a novel way of performing data-parallel computation in parallel and distributed environments by utilizing the best characteristics of difference aspects of parallel computing. For the purpose of this thesis, three aspects of parallel computing were identified and studied. First, three parallel environments (shared memory, distributed memory, and a network of workstations) are evaluated to quantify theirsuitability for different parallel applications. Due to the parallel and distributed nature of the environments, networks connecting the processors in these environments were investigated with respect to their performance characteristics. Second, scheduling algorithms are studied in order to make them more efficient and effective. A concept of application-specific information scheduling is introduced. The application- specific information is data about the workload extractedfrom an application, which is provided to a scheduling algorithm. Three scheduling algorithms are enhanced to utilize the application-specific information to further refine their scheduling properties. A more accurate description of the workload is especially important in cases where the workunits are heterogeneous and the parallel environment is heterogeneous and/or non-dedicated. The results obtained show that the additional information regarding the workload has a positive impact on the performance of applications. Third, a programming paradigm for networks of symmetric multiprocessor (SMP) workstations is introduced. The MPIT programming paradigm incorporates the Message Passing Interface (MPI) with threads to provide a methodology to write parallel applications that efficiently utilize the available resources and minimize the overhead. The MPIT allows for communication and computation to overlap by deploying a dedicated thread for communication. Furthermore, the programming paradigm implements an application-specific scheduling algorithm. The scheduling algorithm is executed by the communication thread. Thus, the scheduling does not affect the execution of the parallel application. Performance results achieved from the MPIT show that considerable improvements over conventional MPI applications are achieved.

Particularités du variant logopénique au sein des aphasies progressives primaires [Specificities of the logopenic variant of primary progressive aphasia].

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved.

Genes outside The Hla Region affecting Susceptibility to Type 1 Diabetes - The Role of Iddm2 and Iddm9 in the Finnish Population

Tyypin 1 diabeteksen perinnöllinen alttius Suomessa - HLA-alueen ulkopuolisten alttiuslokusten IDDM2 ja IDDM9 rooli taudin periytymisessä HLA-alue, joka sijaitsee kromosomissa 6p21.3, vastaa noin puolesta perinnöllisestä alttiudesta sairastua tyypin 1 diabetekseen. Myös HLA-alueen ulkopuolisten lokusten on todettu liittyvän sairausalttiuteen. Näistä kolmen lokuksen on varmistettu olevan todellisia alttiuslokuksia ja lisäksi useiden muiden, vielä varmistamattomien lokusten, on todettu liittyvän sairausalttiuteen. Tässä tutkimuksessa 12:n HLA-alueen ulkopuolisen alttiuslokuksen kytkentä tyypin 1 diabetekseen tutkittiin käyttäen 107:aa suomalaista multiplex-perhettä. Jatkotutkimuksessa analysoitiin IDDM9-alueen kytkentä ja assosiaatio sairauteen laajennetuissa perhemateriaaleissa sekä IDDM2-alueen mahdollinen interaktio HLA-alueen kanssa sairauden muodostumisessa. Lisäksi suoritettiin IDDM2-alueen suojaavien haplotyyppien alatyypitys tarkoituksena tutkia eri haplotyyppien käyttökelpoisuutta sairastumisriskin tarkempaa ennustamista varten. Ensimmäisessä kytkentätutkimuksessa ei löytynyt koko genomin tasolla merkitsevää tai viitteellistä kytkentää tutkituista HLA-alueen ulkopuolisista lokuksista. Voimakkain havaittu nimellisen merkitsevyyden tavoittava kytkentä nähtiin IDDM9-alueen markkerilla D3S3576 (MLS=1.05). Tutkimuksessa ei kyetty varmistamaan tai sulkemaan pois aiempia kytkentähavaintoja tutkituilla lokuksilla, mutta IDDM9-alueen jatkotutkimuksessa havaittu voimakas kytkentä (MLS=3.4) ja merkitsevä assosiaatio (TDT p=0.0002) viittaa vahvasti siihen, että 3q21-alueella sijaitsee todellinen tyypin 1 diabeteksen alttiusgeeni, jolloin alueen kattava assosiaatiotutkimus olisi perusteltu jatkotoimenpide. Sairauteen altistava IDDM2-alueen MspI-2221 genotyyppi CC oli nimellisesti yleisempi matalan tai kohtalaisen HLA-sairastumisriskin diabeetikoilla, verrattuna korkean HLA-riskin potilaisiin (p=0.05). Myös genotyyppijakauman vertailu osoitti merkitsevää eroa ryhmien välillä (p=0.01). VNTR-haplotyyppitutkimus osoitti, että IIIA/IIIA-homotsygootin sairaudelta suojaava vaikutus on merkitsevästi voimakkaampi kuin muiden luokka III:n genotyypeillä. Nämä tulokset viittaavat IDDM2-HLA -vuorovaikutukseen sekä siihen että IDDM2-alueen haplotyyppien välillä esiintyy etiologista heterogeniaa. Tämän johdosta IDDM2-alueen haplotyyppien tarkempi määrittäminen voisi tehostaa tyypin 1 diabeteksen riskiarviointia.

Intrinsic ROS-production capacity of nanoparticles

Engineered nanomaterials (ENMs) exhibit special physicochemical properties and thus are finding their way into an increasing number of industries, enabling products with improved properties. Their increased use brings a greater likelihood of exposure to the nanoparticles (NPs) that could be released during the life cycle of nano-abled products. The field of nanotoxicology has emerged as a consequence of the development of these novel materials, and it has gained ever more attention due to the urgent need to gather information on exposure to them and to understand the potential hazards they engender. However, current studies on nanotoxicity tend to focus on pristine ENMs, and they use these toxicity results to generalize risk assessments on human exposure to NPs. ENMs released into the environment can interact with their surroundings, change characteristics and exhibit toxicity effects distinct from those of pristine ENMs. Furthermore, NPs' large surface areas provide extra-large potential interfaces, thus promoting more significant interactions between NPs and other co-existing species. In such processes, other species can attach to a NP's surface and modify its surface functionality, in addition to the toxicity in normally exhibits. One particular occupational health scenario involves NPs and low-volatile organic compounds (LVOC), a common type of pollutant existing around many potential sources of NPs. LVOC can coat a NP's surface and then dominate its toxicity. One important mechanism in nanotoxicology is the creation of reactive oxygen species (ROS) on a NP's surface; LVOC can modify the production of these ROS. In summary, nanotoxicity research should not be limited to the toxicity of pristine NPs, nor use their toxicity to evaluate the health effects of exposure to environmental NPs. Instead, the interactions which NPs have with other environmental species should also be considered and researched. The potential health effects of exposure to NPs should be derived from these real world NPs with characteristics modified by the environment and their distinct toxicity. Failure to suitably address toxicity results could lead to an inappropriate treatment of nano- release, affect the environment and public health and put a blemish on the development of sustainable nanotechnologies as a whole. The main objective of this thesis is to demonstrate a process for coating NP surfaces with LVOC using a well-controlled laboratory design and, with regard to these NPs' capacity to generate ROS, explore the consequences of changing particle toxicity. The dynamic coating system developed yielded stable and replicable coating performance, simulating an important realistic scenario. Clear changes in the size distribution of airborne NPs were observed using a scanning mobility particle sizer, were confirmed using both liquid nanotracking analyses and transmission electron microscopy (TEM) imaging, and were verified thanks to the LVOC coating. Coating thicknesses corresponded to the amount of coating material used and were controlled using the parameters of the LVOC generator. The capacity of pristine silver NPs (Ag NPs) to generate ROS was reduced when they were given a passive coating of inert paraffin: this coating blocked the reactive zones on the particle surfaces. In contrast, a coating of active reduced-anthraquinone contributed to redox reactions and generated ROS itself, despite the fact that ROS generation due to oxidation by Ag NPs themselves was quenched. Further objectives of this thesis included development of ROS methodology and the analysis of ROS case studies. Since the capacity of NPs to create ROS is an important effect in nanotoxicity, we attempted to refine and standardize the use of 2'7-dichlorodihydrofluorescin (DCFH) as a chemical tailored for the characterization of NPs' capacity for ROS generation. Previous studies had reported a wide variety of results, which were due to a number of insufficiently well controlled factors. We therefore cross-compared chemicals and concentrations, explored ways of dispersing NP samples in liquid solutions, identified sources of contradictions in the literature and investigated ways of reducing artificial results. The most robust results were obtained by sonicating an optimal sample of NPs in a DCFH-HRP solution made of 5,M DCFH and 0.5 unit/ml horseradish peroxidase (HRP). Our findings explained how the major reasons for previously conflicting results were the different experimental approaches used and the potential artifacts appearing when using high sample concentrations. Applying our advanced DCFH protocol with other physicochemical characterizations and biological analyses, we conducted several case studies, characterizing aerosols and NP samples. Exposure to aged brake wear dust engenders a risk of potential deleterious health effects in occupational scenarios. We performed microscopy and elemental analyses, as well as ROS measurements, with acellular and cellular DCFH assays. TEM images revealed samples to be heterogeneous mixtures with few particles in the nano-scale. Metallic and non-metallic elements were identified, primarily iron, carbon and oxygen. Moderate amounts of ROS were detected in the cell-free fluorescent tests; however, exposed cells were not dramatically activated. In addition to their highly aged state due to oxidation, the reason aged brake wear samples caused less oxidative stress than fresh brake wear samples may be because of their larger size and thus smaller relative reactive surface area. Other case studies involving welding fumes and differently charged NPs confirmed the performance of our DCFH assay and found ROS generation linked to varying characteristics, especially the surface functionality of the samples. Les nanomatériaux manufacturés (ENM) présentent des propriétés physico-chimiques particulières et ont donc trouvés des applications dans un nombre croissant de secteurs, permettant de réaliser des produits ayant des propriétés améliorées. Leur utilisation accrue engendre un plus grand risque pour les êtres humains d'être exposés à des nanoparticules (NP) qui sont libérées au long de leur cycle de vie. En conséquence, la nanotoxicologie a émergé et gagné de plus en plus d'attention dû à la nécessité de recueillir les renseignements nécessaires sur l'exposition et les risques associés à ces nouveaux matériaux. Cependant, les études actuelles sur la nanotoxicité ont tendance à se concentrer sur les ENM et utiliser ces résultats toxicologiques pour généraliser l'évaluation des risques sur l'exposition humaine aux NP. Les ENM libérés dans l'environnement peuvent interagir avec l'environnement, changeant leurs caractéristiques, et montrer des effets de toxicité distincts par rapport aux ENM originaux. Par ailleurs, la grande surface des NP fournit une grande interface avec l'extérieur, favorisant les interactions entre les NP et les autres espèces présentes. Dans ce processus, d'autres espèces peuvent s'attacher à la surface des NP et modifier leur fonctionnalité de surface ainsi que leur toxicité. Un scénario d'exposition professionnel particulier implique à la fois des NP et des composés organiques peu volatils (LVOC), un type commun de polluant associé à de nombreuses sources de NP. Les LVOC peuvent se déposer sur la surface des NP et donc dominer la toxicité globale de la particule. Un mécanisme important en nanotoxicologie est la création d'espèces réactives d'oxygène (ROS) sur la surface des particules, et les LVOC peuvent modifier cette production de ROS. En résumé, la recherche en nanotoxicité ne devrait pas être limitée à la toxicité des ENM originaux, ni utiliser leur toxicité pour évaluer les effets sur la santé de l'exposition aux NP de l'environnement; mais les interactions que les NP ont avec d'autres espèces environnementales doivent être envisagées et étudiées. Les effets possibles sur la santé de l'exposition aux NP devraient être dérivés de ces NP aux caractéristiques modifiées et à la toxicité distincte. L'utilisation de résultats de toxicité inappropriés peut conduire à une mauvaise prise en charge de l'exposition aux NP, de détériorer l'environnement et la santé publique et d'entraver le développement durable des industries de la nanotechnologie dans leur ensemble. L'objectif principal de cette thèse est de démontrer le processus de déposition des LVOC sur la surface des NP en utilisant un environnement de laboratoire bien contrôlé et d'explorer les conséquences du changement de toxicité des particules sur leur capacité à générer des ROS. Le système de déposition dynamique développé a abouti à des performances de revêtement stables et reproductibles, en simulant des scénarios réalistes importants. Des changements clairs dans la distribution de taille des NP en suspension ont été observés par spectrométrie de mobilité électrique des particules, confirmé à la fois par la méthode dite liquid nanotracking analysis et par microscopie électronique à transmission (MET), et a été vérifié comme provenant du revêtement par LVOC. La correspondance entre l'épaisseur de revêtement et la quantité de matériau de revêtement disponible a été démontré et a pu être contrôlé par les paramètres du générateur de LVOC. La génération de ROS dû aux NP d'argent (Ag NP) a été diminuée par un revêtement passif de paraffine inerte bloquant les zones réactives à la surface des particules. Au contraire, le revêtement actif d'anthraquinone réduit a contribué aux réactions redox et a généré des ROS, même lorsque la production de ROS par oxydation des Ag NP avec l'oxygène a été désactivé. Les objectifs associés comprennent le développement de la méthodologie et des études de cas spécifique aux ROS. Etant donné que la capacité des NP à générer des ROS contribue grandement à la nanotoxicité, nous avons tenté de définir un standard pour l'utilisation de 27- dichlorodihydrofluorescine (DCFH) adapté pour caractériser la génération de ROS par les NP. Des etudes antérieures ont rapporté une grande variété de résultats différents, ce qui était dû à un contrôle insuffisant des plusieurs facteurs. Nous avons donc comparé les produits chimiques et les concentrations utilisés, exploré les moyens de dispersion des échantillons HP en solution liquide, investigué les sources de conflits identifiées dans les littératures et étudié les moyens de réduire les résultats artificiels. De très bon résultats ont été obtenus par sonication d'une quantité optimale d'échantillons de NP en solution dans du DCFH-HRP, fait de 5 nM de DCFH et de 0,5 unité/ml de Peroxydase de raifort (HRP). Notre étude a démontré que les principales raisons causant les conflits entre les études précédemment conduites dans la littérature étaient dues aux différentes approches expérimentales et à des artefacts potentiels dus à des concentrations élevées de NP dans les échantillons. Utilisant notre protocole DCFH avancé avec d'autres caractérisations physico-chimiques et analyses biologiques, nous avons mené plusieurs études de cas, caractérisant les échantillons d'aérosols et les NP. La vielle poussière de frein en particulier présente un risque élevé d'exposition dans les scénarios professionnels, avec des effets potentiels néfastes sur la santé. Nous avons effectué des analyses d'éléments et de microscopie ainsi que la mesure de ROS avec DCFH cellulaire et acellulaire. Les résultats de MET ont révélé que les échantillons se présentent sous la forme de mélanges de particules hétérogènes, desquels une faible proportion se trouve dans l'échelle nano. Des éléments métalliques et non métalliques ont été identifiés, principalement du fer, du carbone et de l'oxygène. Une quantité modérée de ROS a été détectée dans le test fluorescent acellulaire; cependant les cellules exposées n'ont pas été très fortement activées. La raison pour laquelle les échantillons de vielle poussière de frein causent un stress oxydatif inférieur par rapport à la poussière de frein nouvelle peut-être à cause de leur plus grande taille engendrant une surface réactive proportionnellement plus petite, ainsi que leur état d'oxydation avancé diminuant la réactivité. D'autres études de cas sur les fumées de soudage et sur des NP différemment chargées ont confirmé la performance de notre test DCFH et ont trouvé que la génération de ROS est liée à certaines caractéristiques, notamment la fonctionnalité de surface des échantillons.

Contrast : a concept in language and its development in Medieval Spanish

The purpose of this PhD thesis is to investigate a semantic relation present in the connection of sentences (more specifically: propositional units). This relation, which we refer to as contrast, includes the traditional categories of adversatives - predominantly represented by the connector but in English and pero in Modern Spanish - and concessives, prototypically verbalised through although / aunque. The aim is to describe, analyse and - as far as possible - to explain the emergence and evolution of different syntactic schemes marking contrast during the first three centuries of Spanish (also referred to as Castilian) as a literary language, i.e., from the 13th to the 15th century. The starting point of this question is a commonplace in syntax, whereby the semantic and syntactic complexity of clause linkage correlates with the degree of textual elaboration. In historical linguistics, i.e., applied to the phylogeny of a language, it is commonly referred to as the parataxis hypothesis A crucial part of the thesis is dedicated by the definition of contrast as a semantic relation. Although the label contrast has been used in this sense, mainly in functional grammar and text linguistics, mainstream grammaticography and linguistics remain attached to the traditional categories adversatives and concessives. In opposition to this traditional view, we present our own model of contrast, based on a pragma-semantic description proposed for the analysis of adversatives by Oswald Ducrot and subsequently adopted by Ekkehard König for the analysis of concessives. We refine and further develop this model in order for it to accommodate all, not just the prototypical instances of contrast in Spanish, arguing that the relationship between adversatives and concessives is a marked opposition, i.e., that the higher degree of semantic and syntactic integration of concessives restricts some possible readings that the adversatives may have, but that this difference is almost systematically neutralised by contextual factors, thus justifying the assumption of contrast as a comprehensive onomasiological category. This theoretical focus is completed by a state-of-the-question overview attempting to account for all relevant forms in which contrast is expressed in Medieval Spanish, with the aid of lexicographic and grammaticographical sources, and an empirical study investigating the expression of corpus in a corpus study on the textual functions of contrast in nine Medieval Spanish texts: Cantar de Mio Cid, Libro de Alexandre, Milagros de Nuestra Sehora, Estoria de Espana, Primera Partida, Lapidario, Libro de buen amor, Conde Lucanor, and Corbacho. This corpus is analysed using quantitative and qualitative tools, and the study is accompanied by a series of methodological remarks on how to investigate a pragma-semantic category in historical linguistics. The corpus study shows that the parataxis hypothesis fails to prove from a statistical viewpoint, although a qualitative analysis shows that the use of subordination does increase over time in some particular contexts.

Assessment of the role of LASER-Doppler in the treatment of port-wine stains in infants.

BACKGROUND: Port-wine stains (PWS) are malformations of capillaries in 0.3% of newborn children. The treatment of choice is by pulsed dye LASER (PDL), and requires several sessions. The efficacy of this treatment is at present evaluated on the basis of clinical inspection and of digital photographs taken throughout the treatment. LASER-Doppler imaging (LDI) is a noninvasive method of imaging the perfusion of the tissues by the microcirculatory system (capillaries). The aim of this paper is to demonstrate that LDI allows a quantitative, numerical evaluation of the efficacy of the PDL treatment of PWS. METHOD: The PDL sessions were organized according to the usual scheme, every other month, from September 1, 2012, to September 30, 2013. LDI imaging was performed at the start and at the conclusion of the PDL treatment, and simultaneously on healthy skin in order to obtain reference values. The results evidenced by LDI were analyzed according to the "Wilcoxon signed-rank" test before and after each session, and in the intervals between the three PDL treatment sessions. RESULTS: Our prospective study is based on 20 new children. On average, the vascularization of the PWS was reduced by 56% after three laser sessions. Compared with healthy skin, initial vascularization of PWS was 62% higher than that of healthy skin at the start of treatment, and 6% higher after three sessions. During the 2 months between two sessions, vascularization of the capillary network increased by 27%. CONCLUSION: This study shows that LDI can demonstrate and measure the efficacy of PDL treatment of PWS in children. The figures obtained when measuring the results by LDI corroborate the clinical assessments and may allow us to refine, and perhaps even modify, our present use of PDL and thus improve the efficacy of the treatment.

Une délicate rencontre entre savoirs autochtones "experts" : enjeux politiques interculturelles dans le domaine de la prévention de la violence à l'égard des femmes kichwa en Amazonie équatorienne

Cette thèse porte sur l'élaboration et la mise en pratique de politiques interculturelles dans le champ de la santé internationale, en se basant sur une ethnographie d'un programme de préven¬tion de la violence de genre dans le canton de Loreto, en Amazonie équatorienne, mis en place par la Croix-Rouge suisse et aujourd'hui géré de concert avec l'Etat équatorien et une organisation kichwa locale. Suivant une approche qui fait varier les échelles d'analyses pour articuler le niveau local, national et international, elle met en évidence les lieux d'intersection et les hiatus entre l'idéal d'interculturalité tel qu'il est conçu «par le haut» et les pratiques qui sont mises en oeuvre au quotidien par des professionnels de la santé et du développement métis équatoriens. Elle révèle ainsi qu'au-delà de l'idéal du respect des « différences culturelles autochtones » et de la symétrie entre les « cultures », les discours et les pratiques de ces professionnels consistent en une entreprise de normalisation et de moralisation des comportements des destinataires kichwa en matière de rapports de genre. Pour affiner ces analyses et dépasser une approche critique de la santé publique, cette thèse explore également les représentations et les pratiques des destinataires - femmes agents de santé et « bénéficiaires » kichwa du programme - en matière de violence et de rapports de genre. Elle montre ainsi que le transfert de normes et de valeurs via la santé publique fait l'objet de mul¬tiples processus d'appropriations, et explore les différentes d'interprétations, de négociations et d'instrumentalisations de la part des destinataires, tant au niveau individuel que collectif. -- Intercultural politics and the prevention of violence against kichwa women in the Ecuadorian Amazon This PhD thesis focuses on the development and application of intercultural policies in the field of international health. It is drawn on an ethnographic fieldwork conducted in canton Loreto, in the Ecuadorian Amazon, about a gender violence prevention program which was set up by the Swiss Red Cross and which is now managed in cooperation with the Ecuadorian State and a local kichwa organization. Following a multiple-scale analysis in order to articulate the local, national and international dynamics, it highlights the intersections and the gaps between, on the one hand, the the institutional prescriptions about the ideal of interculturality and on the other hand, the daily practices of Ecuadorian mestizo health and development profesionals. It reveals that beyond the ideal of respect for «indigenous cultural differences» and of symmetry between «cultures», the discourses and practices of these professionals consist of a normalizing and moralizing enter¬prise concerning the gendered and, more broadly, social behaviors of kichwa «beneficiaries». In order to refine the analysis and to go beyond a critical approach of public health, this thesis also explores the violence and gender relations representations and practices of kichwa women health workers and «beneficiaries», men and women. Thus it shows that the transfer of norms via public health is the subject of multiple processes of appropriation, interpretation, negotiation and instru¬mentalisation both on individual and collective levels by the «beneficiaries».

Intracranial Aneurysms: Wall Motion Analysis for Prediction of Rupture.

Intracranial aneurysms are a common pathologic condition with a potential severe complication: rupture. Effective treatment options exist, neurosurgical clipping and endovascular techniques, but guidelines for treatment are unclear and focus mainly on patient age, aneurysm size, and localization. New criteria to define the risk of rupture are needed to refine these guidelines. One potential candidate is aneurysm wall motion, known to be associated with rupture but difficult to detect and quantify. We review what is known about the association between aneurysm wall motion and rupture, which structural changes may explain wall motion patterns, and available imaging techniques able to analyze wall motion.

A inovação por sustração : contribução para a sociología do distanciamento

To develop the understanding of innovation processes conceptualized in terms of association through the "sociology of translation" (cf. actor-network theory) studies, this article analyses innovation processes in terms of dissociation and detachment mechanisms, examining innovation through "withdrawal"; that is, innovation based on reducing or withdrawing use of a practice - "subtracting", "detaching" - a given artefact. Specifically, it focuses on the shift to farming techniques that have eliminated ploughing, bringing to light four major mechanisms constitutive of dissociation : centrifugal association ; making entities and associations visible ; making other entities and associations invisible; bringing together or " associating " new entities. The study helps refine our understanding of the detachment processes at work in innovation.

Attracting cavities for docking. Replacing the rough energy landscape of the protein by a smooth attracting landscape.

Molecular docking is a computational approach for predicting the most probable position of ligands in the binding sites of macromolecules and constitutes the cornerstone of structure-based computer-aided drug design. Here, we present a new algorithm called Attracting Cavities that allows molecular docking to be performed by simple energy minimizations only. The approach consists in transiently replacing the rough potential energy hypersurface of the protein by a smooth attracting potential driving the ligands into protein cavities. The actual protein energy landscape is reintroduced in a second step to refine the ligand position. The scoring function of Attracting Cavities is based on the CHARMM force field and the FACTS solvation model. The approach was tested on the 85 experimental ligand-protein structures included in the Astex diverse set and achieved a success rate of 80% in reproducing the experimental binding mode starting from a completely randomized ligand conformer. The algorithm thus compares favorably with current state-of-the-art docking programs. © 2015 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.

A cast of shadow on adjuvant radiotherapy for prostate cancer: A critical review based on a methodological perspective.

OBJECTIVE: To perform a critical review focusing on the applicability in clinical daily practice of data from three randomized controlled trials (RCTs): SWOG 8794, EORTC 22911, and ARO/AUO 96-02. METHODS AND MATERIALS: An analytical framework, based on the identified population, interventions, comparators, and outcomes (PICO) was used to refine the search of the evidence from the three large randomized trials regarding the use of radiation therapy after prostatectomy as adjuvant therapy (ART). RESULTS: With regard to the inclusion criteria: (1) POPULATION: in the time since they were designed, in two among three trial (SWOG 8794 and EORTC 22911) patients had a detectable PSA at the time of randomization, thus representing de facto a substantial proportion of patients who eventually received salvage RT (SRT) at non-normalised PSA levels rather than ART. (2) INTERVENTIONS: although all the trials showed the benefit of postoperative ART compared to a wait-and-see approach, the dose herein employed would be now considered inadequate; (3) COMPARATORS: the comparison arm in all the 3 RCTs was an uncontrolled observation arm, where patients who subsequently developed biochemical failure were treated in various ways, with up to half of them receiving SRT at PSA well above 1ng/mL, a level that would be now deemed inappropriate; (4) OUTCOMES: only in one trial (SWOG 8794) ART was found to significantly improve overall survival compared to observation, with a ten-year overall survival rate of 74% vs. 66%, although this might be partly the result of imbalanced risk factors due to competing event risk stratification. CONCLUSIONS: ART has a high level of evidence due to three RCTs with at least 10-year follow-up recording a benefit in biochemical PFS, but its penetrance in present daily clinics should be reconsidered. While the benefit of ART or SRT is eagerly expected from ongoing randomized trials, a dynamic risk-stratified approach should drive the decisions making process.

High connectivity in a long-lived High-Arctic seabird, the ivory gull Pagophila eburnea

Species may cope with rapid habitat changes by distribution shifts or adaptation to new conditions. A common feature of these responses is that they depend on how the process of dispersal connects populations, both demographically and genetically. We analyzed the genetic structure of a near-threatened high-Arctic seabird, the ivory gull (Pagophila eburnea) in order to infer the connectivity among gull colonies. We analyzed 343 individuals sampled from 16 localities across the circumpolar breeding range of ivory gulls, from northern Russia to the Canadian Arctic. To explore the roles of natal and breeding dispersal, we developed a population genetic model to relate dispersal behavior to the observed genetic structure of worldwide ivory gull populations. Our key finding is the striking genetic homogeneity of ivory gulls across their entire distribution range. The lack of population genetic structure found among colonies, in tandem with independent evidence of movement among colonies, suggests that ongoing effective dispersal is occurring across the Arctic Region. Our results contradict the dispersal patterns generally observed in seabirds where species movement capabilities are often not indicative of dispersal patterns. Model predictions show how natal and breeding dispersal may combine to shape the genetic homogeneity among ivory gull colonies separated by up to 2800 km. Although field data will be key to determine the role of dispersal for the demography of local colonies and refine the respective impacts of natal versus breeding dispersal, conservation planning needs to consider ivory gulls as a genetically homogeneous, Arctic-wide metapopulation effectively connected through dispersal.