T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors.

Normative Topographic ERP Analyses of Speed of Speech Processing and Grammar Before and After Grammatical Treatment.

Typically developing (TD) preschoolers and age-matched preschoolers with specific language impairment (SLI) received event-related potentials (ERPs) to four monosyllabic speech sounds prior to treatment and, in the SLI group, after 6 months of grammatical treatment. Before treatment, the TD group processed speech sounds faster than the SLI group. The SLI group increased the speed of their speech processing after treatment. Posttreatment speed of speech processing predicted later impairment in comprehending phrase elaboration in the SLI group. During the treatment phase, change in speed of speech processing predicted growth rate of grammar in the SLI group.

Impingement jet cooling of end windings in a high-speed electric machine

The rotational speed of high-speed electric machines is over 15 000 rpm. These machines are compact in size when compared to the power rate. As a consequence, the heat fluxes are at a high level and the adequacy of cooling becomes an important design criterion. In the high-speed machines, the air gap between the stator and rotor is a narrow flow channel. The cooling air is produced with a fan and the flow is then directed to the air gap. The flow in the gap does not provide sufficient cooling for the stator end windings, and therefore additional cooling is required. This study investigates the heat transfer and flow fields around the coil end windings when cooling jets are used. As a result, an innovative and new assembly is introduced for the cooling jets, with the benefits of a reduced amount of hot spots, a lower pressure drop, and hence a lower power need for the cooling fan. The gained information can also be applied to improve the cooling of electric machines through geometry modifications. The objective of the research is to determine the locations of the hot spots and to find out induced pressure losses with different jet alternatives. Several possibilities to arrange the extra cooling are considered. In the suggested approach cooling is provided by using a row of air jets. The air jets have three main tasks: to cool the coils effectively by direct impingement jets, to increase and cool down the flow that enters the coil end space through the air gap, and to ensure the correct distribution of the flow by forming an air curtain with additional jets. One important aim of this study is the arrangement of cooling jets in such manner that hot spots can be avoided to wide extent. This enables higher power density in high-speed motors. This cooling system can also be applied to the ordinary electric machines when efficient cooling is needed. The numerical calculations have been performed using a commercial Computational Fluid Dynamics software. Two geometries have been generated: cylindrical for the studied machine and Cartesian for the experimental model. The main parameters include the positions, arrangements and number of jets, the jet diameters, and the jet velocities. The investigated cases have been tested with two widely used turbulence models and using a computational grid of over 500 000 cells. The experimental tests have been made by using a simplified model for the end winding space with cooling jets. In the experiments, an emphasis has been given to flow visualisation. The computational analysis shows good agreement with the experimental results. Modelling of the cooling jet arrangement enables also a better understanding of the complex system of heat transfer at end winding space.

Local adaptation and life history traits evolution in heterogeneous environment : an empirical example in the freshwater snail, Galba truncatula

Abstract: To understand the processes of evolution, biologists are interested in the ability of a population to respond to natural or artificial selection. The amount of genetic variation is often viewed as the main factor allowing a species to answer to selection. Many theories have thus focused on the maintenance of genetic variability. Ecologists and population geneticists have long-suspected that the structure of the environment is connected to the maintenance of diversity. Theorists have shown that diversity can be permanently and stably maintained in temporal and spatial varying environment in certain conditions. Moreover, varying environments have been also theoretically demonstrated to cause the evolution of divergent life history strategies in the different niches constituting the environment. Although there is a huge number of theoretical studies selection and on life history evolution in heterogeneous environments, there is a clear lack of empirical studies. The purpose of this thesis was to. empirically study the evolutionary consequences of a heterogeneous environment in a freshwater snail Galba truncatula. Indeed, G. truncatula lives in two habitat types according the water availability. First, it can be found in streams or ponds which never completely dry out: a permanent habitat. Second, G. truncatula can be found in pools that freeze during winter and dry during summer: a temporary habitat. Using a common garden approach, we empirically demonstrated local adaptation of G. truncatula to temporary and permanent habitats. We used at first a comparison of molecular (FST) vs. quantitative (QST) genetic differentiation between temporary and permanent habitats. To confirm the pattern QST> FST between habitats suggesting local adaptation, we then tested the desiccation resistance of individuals from temporary and permanent habitats. This study confirmed that drought resistance seemed to be the main factor selected between habitats, and life history traits linked to the desiccation resistance were thus found divergent between habitats. However, despite this evidence of selection acting on mean values of traits between habitats, drift was suggested to be the main factor responsible of variation in variances-covariances between populations. At last, we found life history traits variation of individuals in a heterogeneous environment varying in parasite prevalence. This thesis empirically demonstrated the importance of heterogeneous environments in local adaptation and life history evolution and suggested that more experimental studies are needed to investigate this topic. Résumé: Les biologistes se sont depuis toujours intéressés en l'aptitude d'une population à répondre à la sélection naturelle. Cette réponse dépend de la quantité de variabilité génétique présente dans cette population. Plus particulièrement, les théoriciens se sont penchés sur la question du maintient de la variabilité génétique au sein d'environnements hétérogènes. Ils ont alors démontré que, sous certaines conditions, la diversité génétique peut se maintenir de manière stable et permanente dans des environnements variant au niveau spatial et temporel. De plus, ces environments variables ont été démontrés comme responsable de divergence de traits d'histoire de vie au sein des différentes niches constituant l'environnement. Cependant, malgré ce nombre important d'études théoriques portant sur la sélection et l'évolution des traits d'histoire de vie en environnement hétérogène, les études empiriques sont plus rares. Le but de cette thèse était donc d'étudier les conséquences évolutives d'un environnement hétérogène chez un esgarcot d'eau douce Galba truncatula. En effet, G. truncatula est trouvé dans deux types d'habitats qui diffèrent par leur niveau d'eau. Le premier, l'habitat temporaire, est constitué de flaques d'eau qui peuvent s'assécher pendant l'été et geler pendant l'hiver. Le second, l'habitat permanent, correspond à des marres ou à des ruisseaux qui ont un niveau d'eau constant durant toute l'année. Utilisant une approche expérimentale de type "jardin commun", nous avons démontré l'adaptation locale des individus à leur type d'habitat, permanent ou temporaire. Nous avons utilisé l'approche Fsr/QsT qui compare la différentiation génétique moléculaire avec la différentiation génétique quantitative entre les 2 habitats. Le phénomène d'adapation locale démontré par QsT > FsT, a été testé experimentalement en mesurant la résistance à la dessiccation d'individus d'habitat temporaire et permanent. Cette étude confirma que la résistance à la sécheresse a été sélectionné entre habitats et que les traits responsables de cette resistance sont différents entre habitats. Cependant si la sélection agit sur la valeur moyenne des traits entre habitats, la dérive génétique semble être le responsable majeur de la différence de variances-covariances entre populations. Pour finir, une variation de traits d'histoire de vie a été trouvée au sein d'un environnement hétérogène constitué de populations variants au niveau de leur taux de parasitisme. Pour conclure, cette thèse a donc démontré l'importance d'un environnement hétérogène sur l'adaptation locale et l'évolution des traits d'histoire de vie et suggère que plus d'études empiriques sur le sujet sont nécessaires.

Utilisation of Statistics in Intelligent Web Applications

Web-portaalien aiheenmukaista luokittelua voidaan hyödyntää tunnistamaan käyttäjän kiinnostuksen kohteet keräämällä tilastotietoa hänen selaustottumuksistaan eri kategorioissa. Tämä diplomityö käsittelee web-sovelluksien osa-alueita, joissa kerättyä tilastotietoa voidaan hyödyntää personalisoinnissa. Yleisperiaatteet sisällön personalisoinnista, Internet-mainostamisesta ja tiedonhausta selitetään matemaattisia malleja käyttäen. Lisäksi työssä kuvaillaan yleisluontoiset ominaisuudet web-portaaleista sekä tilastotiedon keräämiseen liittyvät seikat.

High speed release -mittausmenetelmän käyttäminen tarralaminaattiprosessin ohjaukses

Työn tavoitteena oli tutkia HSR(High Speed Release)-mittausmenetelmän käyttämistä tarralaminaattiprosessin ohjauksessa UPM Raflatacissa. Nykyisin käytössä olevaan LSR(Low Speed Release)-menetelmään verrattuna HSR-menetelmä kuvaa paremmin tarralaminaatin jatkojalostuksessa sekä etiketöinnissä tapahtuvaa irrotustyötä. Lisäksi työssä tutkittiin irrotusnopeuden vaikutusta HSR-arvoon. Työn kirjallisuusosassa perehdyttiin tarralaminaatin rakenteeseensekä valmistusprosessiin. Koska silikonin valinnalla on merkittävä vaikutus tarralaminaatin releasearvoon, kirjallisessa osassa syvennytään tarkastelemaan tarralaminaatin valmistuksessa käytettyjä silikoneja sekänäiden rakennetta. Kirjallisuusosassa on myös käsitelty muita releasetasoon vaikuttavia tekijöitä. Työn kokeellisessa osassa oli tarkoituksena tutkia HSR-mittausmenetelmän käytettävyyttä tarralaminaatin prosessinohjauksessa. Tätä tutkittiin selvittämällä nykyisin käytössä olevan LSR-menetelmän sekä HSR-menetelmän välistä korreloituvuutta. Mikäli näidenvälillä olisi korreloituvuutta, voitaisiin prosessinohjauksessa ajatella siirtyvän HSR-mittaukseen. Korrelaatiota näiden kahden menetelmän välille ei kuitenkaan löydetty. Työssä tutkittiin myös irrotusnopeuden vaikutusta tuotteen HSR-arvoon. Testeihin valittiin useita eri tuotteita useilta tuotantolaitoksilta. Kaikilla näillä tuotteilla releasearvo kasvoi irrotusnopeutta lisättäessä. Lisäksi työssä määritettiin uudet HSR-spesifikaatiot tietyille tuotteille. Kaikille UPM Raflatacin tuotteille on määritetty LSRspesifikaatiot, HSR-spesifikaatiot on asetettu vain tietyille tuotteille.

La dépression majeure en hôpital général: adaptation et mise en oeuvre de recommandations pour la pratique clinique [Major depression in the general hospital: adaptation and implementation of guidelines]

Major depression IMD) is highly prevalent in the general hospital and adds a considerable burden to affected patients, but remains under detected and under treated. In an attempt to improve this situation, existing guidelines on MD were retrieved, systematically evaluated with the instrument AGREE (Appraisal of guidelines for research and evaluation), and adapted to the needs of the general hospital. These guidelines were made available on intranet, and actively implemented in two wards, where their impact on clinical practice was evaluated.

The French adaptation of the Health of the Nation Outcome Scale for Children and Adolescents Self-Rated Form (F-HoNOSCA-SR): Validation and clinical routine use.

The current study aimed to explore the validity of an adaptation into French of the self-rated form of the Health of the Nation Outcome Scales for Children and Adolescents (F-HoNOSCA-SR) and to test its usefulness in a clinical routine use. One hundred and twenty nine patients, admitted into two inpatient units, were asked to participate in the study. One hundred and seven patients filled out the F-HoNOSCA-SR (for a subsample (N=17): at two occasions, one week apart) and the strengths and difficulties questionnaire (SDQ). In addition, the clinician rated the clinician-rated form of the HoNOSCA (HoNOSCA-CR, N=82). The reliability (assessed with split-half coefficient, item response theory (IRT) models and intraclass correlations (ICC) between the two occasions) revealed that the F-HoNSOCA-SR provides reliable measures. The concurrent validity assessed by correlating the F-HoNOSCA-SR and the SDQ revealed a good convergent validity of the instrument. The relationship analyses between the F-HoNOSCA-SR and the HoNOSCA-CR revealed weak but significant correlations. The comparison between the F-HoNOSCA-SR and the HoNOSCA-CR with paired sample t-tests revealed a higher score for the self-rated version. The F-HoNSOCA-SR was reported to provide reliable measures. In addition, it allows us to measure complementary information when used together with the HoNOSCA-CR.

Early, low-level auditory-somatosensory multisensory interactions impact reaction time speed.

Several lines of research have documented early-latency non-linear response interactions between audition and touch in humans and non-human primates. That these effects have been obtained under anesthesia, passive stimulation, as well as speeded reaction time tasks would suggest that some multisensory effects are not directly influencing behavioral outcome. We investigated whether the initial non-linear neural response interactions have a direct bearing on the speed of reaction times. Electrical neuroimaging analyses were applied to event-related potentials in response to auditory, somatosensory, or simultaneous auditory-somatosensory multisensory stimulation that were in turn averaged according to trials leading to fast and slow reaction times (using a median split of individual subject data for each experimental condition). Responses to multisensory stimulus pairs were contrasted with each unisensory response as well as summed responses from the constituent unisensory conditions. Behavioral analyses indicated that neural response interactions were only implicated in the case of trials producing fast reaction times, as evidenced by facilitation in excess of probability summation. In agreement, supra-additive non-linear neural response interactions between multisensory and the sum of the constituent unisensory stimuli were evident over the 40-84 ms post-stimulus period only when reaction times were fast, whereas subsequent effects (86-128 ms) were observed independently of reaction time speed. Distributed source estimations further revealed that these earlier effects followed from supra-additive modulation of activity within posterior superior temporal cortices. These results indicate the behavioral relevance of early multisensory phenomena.

Development of Paperboard Forming Tools with a Focus on Intelligent Manufacturing

Tämä diplomityö käsittelee kartonginmuovaukseen käytettävien puristintyökalujen kehittämistä. Työntavoitteina oli kehittää työkalutekniikan suunnittelua ja valmistusta edullisemmaksi, nopeammaksi ja työkaluja toiminnoiltaan tehokkaammiksi. Työn tuli sisältää myös ohjeet työkalujen suunnittelemiseksi ja valmistamiseksi jatkoa ajatellen. Työn aikana selvitettiin mahdollisia työkalurakennevaihtoehtoja, valmistusmateriaaleja sekä niiden käsittelymenetelmiä ja lastuamista sekä sen tarjoamia mahdollisuuksia valmistusmenetelmänä. Työkalupari suunniteltiin modulaariseksi siten, että uusia työkaluja varten vain osa komponenteista täytyy valmistaa uudelleen, samalla työkalun osien lukumäärää pienennettiin merkittävästi. Valmistusmateriaaliksi valittiin hyvin lastuttava työkaluteräs ja sen koneistaminen tapahtui vaakakaraisessa koneistuskeskuksessa. Työn loppuvaiheessa työkalukokonaisuudelle tehtiin kustannuslaskelma jaoteltuna eri työvaiheille sekä komponenteittain. Työkalu asennettiin puristimeen ja sille suoritettiin käyttötestaus. Työn aikana karttuneen kokemuksen sekä koekäytön perusteella tehtiin jatkokehitysehdotuksia.

Guideline adaptation: an approach to enhance efficiency in guideline development and improve utilisation.

BACKGROUND: Developing and updating high-quality guidelines requires substantial time and resources. To reduce duplication of effort and enhance efficiency, we developed a process for guideline adaptation and assessed initial perceptions of its feasibility and usefulness. METHODS: Based on preliminary developments and empirical studies, a series of meetings with guideline experts were organised to define a process for guideline adaptation (ADAPTE) and to develop a manual and a toolkit made available on a website (http://www.adapte.org). Potential users, guideline developers and implementers, were invited to register and to complete a questionnaire evaluating their perception about the proposed process. RESULTS: The ADAPTE process consists of three phases (set-up, adaptation, finalisation), 9 modules and 24 steps. The adaptation phase involves identifying specific clinical questions, searching for, retrieving and assessing available guidelines, and preparing the draft adapted guideline. Among 330 registered individuals (46 countries), 144 completed the questionnaire. A majority found the ADAPTE process clear (78%), comprehensive (69%) and feasible (60%), and the manual useful (79%). However, 21% found the ADAPTE process complex. 44% feared that they will not find appropriate and high-quality source guidelines. DISCUSSION: A comprehensive framework for guideline adaptation has been developed to meet the challenges of timely guideline development and implementation. The ADAPTE process generated important interest among guideline developers and implementers. The majority perceived the ADAPTE process to be feasible, useful and leading to improved methodological rigour and guideline quality. However, some de novo development might be needed if no high quality guideline exists for a given topic.

Role of mutations in the phosphoprotein on RNA polymerase activity of canine distemper virus following cell culture adaptation

Abstract: The canine distemper virus A75/17 wild-type strain, which is unable to replicate in cell lines, was adapted to growth in Vero cells. Sequence comparison between the A75/17 and the Vero cell-adapted A75/17-V virus revealed 7 amino acid differences between the 2 viruses. Three of these were located in the matrix protein, three in the phosphoprotein also changing the V protein but not the C protein and one in the large protein. The phosphoprotein and the large protein constituted the viral RNA polymerase whose activity was studied by transfection experiments using a reverse genetic system with a plasmid encoding a minireplicon and expression plasmids encoding the nucleocapsid protein and the viral RNA polymerase subunits. Surprinsingly, the enzyme of A75/17 CDV was significantly more active in cell lines compared to the polymerase of A75/17-V CDV. The decrease in overall enzyme activity was found to be due to both decreased replication and transcription activity. This polymerase attenuation was confirmed in CHO cells infection stably expressing the dog SLAM receptor mainly found in dog's lymphoid organs and allowing both virus strains to enter these cells at the same efficiency. A75/17-V CDV replicated more slowly in CHODogSLAM cells than A75/17 CDV and syncytium formation was significantly decreased compared to A75/17 infected CHODogSLAM cells.. Cell culture adaptation lead to an attenuated virus strain both in vitro and in vivo with decreased polymerase activity and syncytium forming capability showing an important role of the polymerase in determining the phenoytpe of the virus. In addition, this reduced phenotype of A75/17-V CDV was shown to be due to the P mutations in the P protein only, showing an important function of the polycistronic P gene in the adaptation process. The role of the matrix protein was found not to have any effect on polymerase activity, however its participation in the adaptation process still needs to be elucidated. The accessory proteins V and C were shown to act on polymerase activity, but their functions in virus pathogenicity and in inhibiting the interferon system have not been studied in this thesis. The V proteins have an activating effect on the polymerase of both the A75/17 and the A75/17-V CDV strains. Although the C protein amino acid sequence was not changed during adaptation of wild-type canine distemper virus in Vero cells, the C protein was demonstrated to have opposite effects on polymerase activity of both virus strains suggesting a different interaction of the C protein with the proteins forming the polymerase complex, which could modulate polymeras activity. These effects were demonstrated by transfection experiments and studying recombinant viruses not expressing the C protein. Thus, the abrogation of the C protein decrease the activity of the wild-type polymerase. In contrast, the polymerase activity of the Vero cell- adapted virus is enhanced in the absence of the C protein and this has also been demonstrated with a recombinant virus, which grew faster in the first 48 hours of infection. Future studies will focus on the generation of recombinant wild-type viruses, which should be very helpful in understanding the molecular mechanisms underlying the adaptation process and the loss of pathogenicity.