Designs and model effects definitions in the initial stage of a plant breeding program

The objective of this work was to compare the relative efficiency of initial selection and genetic parameter estimation, using augmented blocks design (ABD), augmented blocks twice replicated design (DABD) and group of randomised block design experiments with common treatments (ERBCT), by simulations, considering fixed effect model and mixed model with regular treatment effects as random. For the simulations, eight different conditions (scenarios) were considered. From the 600 simulations in each scenario, the mean percentage selection coincidence, the Pearsons´s correlation estimates between adjusted means for the fixed effects model, and the heritability estimates for the mixed model were evaluated. DABD and ERBCT were very similar in their comparisons and slightly superior to ABD. Considering the initial stages of selection in a plant breeding program, ABD is a good alternative for selecting superior genotypes, although none of the designs had been effective to estimate heritability in all the different scenarios evaluated.

Cancer chronotherapeutics: experimental, theoretical, and clinical aspects.

The circadian timing system controls cell cycle, apoptosis, drug bioactivation, and transport and detoxification mechanisms in healthy tissues. As a consequence, the tolerability of cancer chemotherapy varies up to several folds as a function of circadian timing of drug administration in experimental models. Best antitumor efficacy of single-agent or combination chemotherapy usually corresponds to the delivery of anticancer drugs near their respective times of best tolerability. Mathematical models reveal that such coincidence between chronotolerance and chronoefficacy is best explained by differences in the circadian and cell cycle dynamics of host and cancer cells, especially with regard circadian entrainment and cell cycle variability. In the clinic, a large improvement in tolerability was shown in international randomized trials where cancer patients received the same sinusoidal chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed chronotherapy. However, sex, genetic background, and lifestyle were found to influence optimal chronotherapy scheduling. These findings support systems biology approaches to cancer chronotherapeutics. They involve the systematic experimental mapping and modeling of chronopharmacology pathways in synchronized cell cultures and their adjustment to mouse models of both sexes and distinct genetic background, as recently shown for irinotecan. Model-based personalized circadian drug delivery aims at jointly improving tolerability and efficacy of anticancer drugs based on the circadian timing system of individual patients, using dedicated circadian biomarker and drug delivery technologies.

Local and Regional Scale Determinants of Biodiversity Patterns in Boreal Agricultural Landscapes

This thesis examines the local and regional scale determinants of biodiversity patterns using existing species and environmental data. The research focuses on agricultural environments that have experienced rapid declines of biodiversity during past decades. Existing digital databases provide vast opportunities for habitat mapping, predictive mapping of species occurrences and richness and understanding the speciesenvironment relationships. The applicability of these databases depends on the required accuracy and quality of the data needed to answer the landscape ecological and biogeographical questions in hand. Patterns of biodiversity arise from confounded effects of different factors, such as climate, land cover and geographical location. Complementary statistical approaches that can show the relative effects of different factors are needed in biodiversity analyses in addition to classical multivariate models. Better understanding of the key factors underlying the variation in diversity requires the analyses of multiple taxonomic groups from different perspectives, such as richness, occurrence, threat status and population trends. The geographical coincidence of species richness of different taxonomic groups can be rather limited. This implies that multiple geographical regions should be taken into account in order to preserve various groups of species. Boreal agricultural biodiversity and in particular, distribution and richness of threatened species is strongly associated with various grasslands. Further, heterogeneous agricultural landscapes characterized by moderate field size, forest patches and non-crop agricultural habitats enhance the biodiversity of rural environments. From the landscape ecological perspective, the major threats to Finnish agricultural biodiversity are the decline of connected grassland habitat networks, and general homogenization of landscape structure resulting from both intensification and marginalization of agriculture. The maintenance of key habitats, such as meadows and pastures is an essential task in conservation of agricultural biodiversity. Furthermore, a larger landscape context should be incorporated in conservation planning and decision making processes in order to respond to the needs of different species and to maintain heterogeneous rural landscapes and viable agricultural diversity in the future.

Early selection in open-pollinated Eucalyptus families based on competition covariates

The objetive of this work was to evaluate the influence of intergenotypic competition in open-pollinated families of Eucalyptus and its effects on early selection efficiency. Two experiments were carried out, in which the timber volume was evaluated at three ages, in a randomized complete block design. Data from the three years of evaluation (experiment 1, at 2, 4, and 7 years; and experiment 2, at 2, 5, and 7 years) were analyzed using mixed models. The following were estimated: variance components, genetic parameters, selection gains, effective number, early selection efficiency, selection gain per unit time, and coincidence of selection with and without the use of competition covariates. Competition effect was nonsignificant for ages under three years, and adjustment using competition covariates was unnecessary. Early selection for families is effective; families that have a late growth spurt are more vulnerable to competition, which markedly impairs ranking at the end of the cycle. Early selection is efficient according to all adopted criteria, and the age of around three years is the most recommended, given the high efficiency and accuracy rate in the indication of trees and families. The addition of competition covariates at the end of the cycle improves early selection efficiency for almost all studied criteria.

European climate variations over the past half-millennium reconstructed from groundwater

Temperature reconstructions for recent centuries are the basis of estimations of the natural variability in the climate system before and during the onset of anthropogenic perturbation. Here we present, for the first time, an independent and physically based reconstruction of mean annual temperature over the past half millennium obtained from groundwater in France. The reconstructed noble gas temperature (NGT) record suggests cooler than present climate conditions throughout the 16th-19th centuries. Periods of warming occur in the 17th-18th and 20th century, while cooling is reconstructed in the 19th century. A noticeable coincidence with other temperature records is demonstrated. Deuterium excess varies in parallel with the NGT, and indicates variation in the seasonality of the aquifer recharge; whereas high excess air in groundwater indicates periods with high oscillations of the water table.

Neurobiology of addiction: the role of transcription factors CREB and C/EBP as well as that of their coactivators

Résumé Le présent travail de thèse a fait face au défi de lier les changements transcriptionnels dans les neurones du système nerveux central au développement de l'addiction aux drogues. I1 est connu que l'apprentissage induit des modifications au niveau de la structure du cerveau, principalement en changeant la manière dont les neurones sont interconnectés par des synapses. De plus en plus d'évidences soutiennent un scénario selon lequel l'activité neuronale déclenche des cascades de signalisation intracellulaire qui ciblent des facteurs de transcription. Ces derniers peuvent activer la transcription de gènes spécifiques qui codent pour des protéines nécessaires au renforcement des synapses mémorisant ainsi la nouvelle information. Puisque l'addiction peut être considérée comme une forme aberrante d'apprentissage, et que les modifications synaptiques sont connues pour être impliquées dans le processus d'addiction, nous essayons de décrire des mécanismes transcriptionels étant à la base des changements synaptiques induits par les drogues. Comme modèle nous utilisons des cultures primaires des neurones de striatum, d'hippocampe et de cortex de souris ainsi que des tranches de cerveau de rat. Une des caractéristiques communes de quasiment toutes les substances addictives est de pouvoir activer le système mésolimbique dopaminergique provoquant la libération de dopamine sur les neurones du striatum (du noyau accumbens). Dans ce travail de thèse nous démontrons que dans des cultures du striatum, la dopamine induit le facteur de transcription C/EBPβ qui, à son tour, provoque l'expression du gène codant pour la substance P. Ce mécanisme pourrait potentiellement contribuer à la tolérance envers les drogues puisqu'il fait partie d'une rétroaction (feed-back) sur les cellules produisant la dopamine. Etant donné que ces résultats montrent l'importance de C/EBPβ dans la psychopathologie de l'addiction, nous avons également décidé d'étudier les mécanismes fondamentaux de l'activation de la transcription par C/EBPβ. Nos expériences démontrent que trois isoformes activatrices de la famille C/EBP recrutent le coactivateur CBP et provoquent en même temps sa phosphorylation. Enfin, nous montrons que les coactivateurs nommés TORC, nouvellement découverts et clonés, sont capables de détecter la coïncidence d'un signal cAMP et d'une entrée de calcium dans des neurones. Par conséquent les TORCs pourraient contribuer à détecter la coïncidence d'un signal glutamate et d'un signal dopamine dans les neurones de striatum, ce qui pourrait être important pour associer les effets hédonistes de la drogue à l'information contextuelle (par exemple à l'environnement où la drogue a été consommée). Nous sommes les premiers à observer que les TORCs sont nécessaires pour la potentiation à long terme dans l'hippocampe. Summary The present thesis work faced the challenge to link the development of drug addiction to transcriptional changes in the neurons of the central nervous system. Experience and learning are known to induce structural modifications in the brain, and these changes are thought to occur mainly in the way neurons are interconnected by synapses. More and more evidences point to a scenario in which neuronal activity would activate signalization cascades that impinge on transcription factors, which, in turn, would activate genes necessary for the reinforcement of synapses coding for new informations. Given that drug addiction can be considered as an aberrant form of learning and is thought to involve synaptic modifications, we try to elucidate some of the transcriptional mechanisms that could underlie drug-induced synaptic changes. As a model system, we use primary cultures of striatal, cortical and hippocampal neurons dissected from mouse embryos as well as brain slices from rats. One of the common features of virtually all drugs of abuse is to activate the mesocorticolimbic dopaminergic system that results in the release of dopamine onto the neurons of the striatum (nucleus accumbens). In this thesis work we show that in striatal cultures, dopamine induces the transcription factor C/EBPβ that in turn drives the expression of the gene coding for substance P. This mechanism is likely to be important for the drug-induced tolerance in the brain since it might be a part of a feedback acting on dopaminergic neurons. Given the suspected importance of C/EBPβ in drug addiction, we also try to elucidate some aspects of the basic mechanisms by which the C/EBP family activates transcription. We show that three activating members of the C/EBP family recruit the coactivator CBP and trigger its phosphorylation. Finally, we demonstrate that the newly discovered and cloned transcriptional coactivators, named TORCs (transducers of regulated CREB activity) are able to detect the coincidence of a calcium and a cAMP signal in the central nervous system. This way, TORCs could contribute to the detection of a coincidence between a glutamate and a dopamine signal in striatal neurons - a process that is suggested to be important for an association between the rewarding effect of a drug and contextual information (such as the environment where the drug had been taken). We demonstrate that TORCs are required for hippocampal LTP.

Semantic domain and grammatical class effects in the picture-word interference paradigm

The role of grammatical class in lexical access and representation is still not well understood. Grammatical effects obtained in picture-word interference experiments have been argued to show the operation of grammatical constraints during lexicalization when syntactic integration is required by the task. Alternative views hold that the ostensibly grammatical effects actually derive from the coincidence of semantic and grammatical differences between lexical candidates. We present three picture-word interference experiments conducted in Spanish. In the first two, the semantic relatedness (related or unrelated) and the grammatical class (nouns or verbs) of the target and the distracter were manipulated in an infinitive form action naming task in order to disentangle their contributions to verb lexical access. In the third experiment, a possible confound between grammatical class and semantic domain (objects or actions) was eliminated by using action-nouns as distracters. A condition in which participants were asked to name the action pictures using an inflected form of the verb was also included to explore whether the need of syntactic integration modulated the appearance of grammatical effects. Whereas action-words (nouns or verbs), but not object-nouns, produced longer reaction times irrespective of their grammatical class in the infinitive condition, only verbs slowed latencies in the inflected form condition. Our results suggest that speech production relies on the exclusion of candidate responses that do not fulfil task-pertinent criteria like membership in the appropriate semantic domain or grammatical class. Taken together, these findings are explained by a response-exclusion account of speech output. This and alternative hypotheses are discussed.

Effects of solar activity and climate variability on large floods in Switzerland

The paper presents the variability of major floods in Switzerland for the period 1800-2008 from a summer index (INU). The index is constructed from the damage caused by flooding, with the aim of establishing the possible influence of the solar and climate variability on the major floods. The coincidence of flood-rich periods with those observed in other regions of different climate and fluvial regimes suggests that climate forcings and changes in the general circulation of the atmosphere are those who govern the appearance of these high-frequency temporal clusters.

La importancia de las emociones en los períodos sensibles del desarrollo = The importance of emotions in sensitive developmental periods

Investigaciones recientes sugieren que en la adolescencia tienen lugar importantes cambios en la estructura,bioquímica y fisiología del cerebro que podrían explicar la dificultad que experimentan los adolescentes en elcontrol de sus emociones así como también otros rasgos de su comportamiento inestable. En este artículo presentamosalgunas investigaciones que establecen, asimismo, una correlación entre las reorganizaciones cerebrales quetienen lugar en el primer año de vida con signos de irritabilidad y desazón emocional que muestra el bebédurante este periodo. En ambos casos la dificultad de controlar los impulsos emocionales es susceptible de afectarla relación de los padres con el niño o joven. Discutimos la posible relevancia de esta coincidencia dentro de unaperspectiva evolucionista así como la posible vulnerabilidad de estos períodos. Finalmente, apuntamos la necesidadde una teoría integradora del desarrollo humano y ofrecemos algunos puntos de debate

Alueellisen innovaatiojärjestelmän kehityspolku - case Kouvolan seutu

Tutkimus on esiselvitystyö, jonka tavoitteena oli selvittää miten luoda innovaatiojärjestelmä Kouvolan seudulle. Lisäksi tavoitteena oli selvittää alueen innovaatiojärjestelmän nykytila, tutkia miten toimijat saadaan sitoutumaan ja toimimaan kohti yhteistä päämäärää sekä kuvata prosessi kehitystyölle. Kouvolan seudulla on tapahtunut lähiaikoina runsaasti muutoksia, jotka vaikuttavat myös innovaatiotoimintaan. Kehitystä on tapahtunut, mutta kehitystä on kiihdytettävä, jotta alue on tulevaisuudessa elinvoimainen seutu asua ja yrittää. Suoritettujen kahdeksan asiantuntijahaastattelun pohjalta voidaan todeta, että Kouvolan seudulla ei nykyisellään ole innovaatiojärjestelmää. Kouvolan seudulla on innovaatiojärjestelmän osia, mutta toiminta on hajanaista ja toimijoilla ei ole selkeää kuvaa omasta roolistaan osana kokonaisuutta. Innovaatioiden syntyä ei voi jättää sattuman käsiin, vaan uusien innovaatioiden syntyminen vaatii yhteistyötä ja vuorovaikutusta eri yritysten ja organisaatioiden välillä. Innovaatiojärjestelmän luomiseen Kouvolan seudulle ei ole yhtä oikeaa ja helppoa tietä. Harmaakorven alueellinen kehitysalustamenetelmä tarjoaa selkeän prosessin kehitystyöhön, mutta onko Kouvolassa tarvittavia resursseja ja osaamista prosessin läpivientiin? Tulisiko lähteä liikkeelle pienistä asioista, yhteisesti määritellyistä käsitteistä, päämääristä ja rooleista. Yhtenä ratkaisuna on Kouvolan seudun innovaatio-ohjelman rakentaminen, jossa nämä määritellään. Ohjelman kehittämisessä on syytä olla mukana mahdollisimman laajalti innovaatiojärjestelmän toimijoita, mutta kehittämisprosessin on syytä olla kevyt. Jo ohjelmaa kehittäessä tarvitaan erilaisia pilot-projekteja ja foorumeita, joiden kautta Kouvolan seudun innovaatiojärjestelmää saadaan kehitettyä ja pikku hiljaa rakennettua luottamusta ja yhteistyötä. Tekemisen kautta tietoisuus toiminnasta ja sen eduista leviää, ja Kouvolan seudun saadaan luotua toimiva alueellinen innovaatiojärjestelmä.

Uraohjaus ja urasuunnittelu ammattikorkeakoulussa

Tutkimuksen tarkoituksena oli selvittää, millaista uraohjausta ammattikorkeakoulun tuutoriopettajat antavat ja millaista uraohjausta opiskelijat haluavat. Lisäksi tavoitteena oli selvittää, löytyykö opiskelijoiden koulutusalavalinnan perusteista yhteyttä uran suunnittelutaitoihin ja ohjauksen tarpeeseen, ja tunnistavatko tuutoriopettajat opiskelijoiden erilaiset uraohjauksen tarpeet. Tutkimuksen teoreettisissa rakenteissa hyödynnettiin kolmea postmodernia urateoriaa, jotka olivat Hodkinsonin ja Sparkesin (1997) uranvalinnan päätöksentekoteoria, Mitchellin, Lewinin ja Krumbolzin (1999) suunnitellun sattuman teoria ja Savickasin (2005) uran rakentamisteoria. Tutkimusympäristönä oli Satakunnan ammattikorkeakoulu. Tutkimus oli kaksivaiheinen. Ensimmäisessä vaiheessa kerättiin harkinnanvaraisesti valituilta tuutoriopettajilta (n=14) ja opintojensa eri vaiheissa olevilta opiskelijoilta (n=65) kirjoitettu aineisto. Kvalitatiivinen aineisto analysoitiin sisällönanalyysillä. Aineiston perusteella löydettiin kolmenlaisia urasuunnittelijoita: epävarmat, uteliaat ja tietoiset. Aineiston perusteella laadittiin kyselylomake tutkimuksen toisen vaiheen tiedonkeruuta varten. Tutkimuksen toisessa vaiheessa kerättiin opintojen eri vaiheissa olevilta opiskelijoilta kyselylomakekyselynä kvantitatiivinen aineisto (n=903), joka analysoitiin tilastollisin menetelmin. Koulutusalavalinnan perusteista elämäntilanne, alan mahdollisuudet, oma toive, kutsumus, aktiivinen tiedonhaku ja halu opiskella ammattikorkeakoulussa olivat yhteydessä opiskelijan hyvään urasuunnittelukykyyn. Näillä perusteilla koulutusalansa valinneita tietoisiksi luokiteltuja urasuunnittelijoita oli 72 % vastanneista. Alavalinnan perusteista sattuman, kavereiden, sukulaisten, lukion opinto-ohjauksen ja paikkakunnan perusteella koulutusalansa valinneet luokiteltiin epävarmoiksi urasuunnittelijoiksi, ja heitä oli 28 % vastanneista. Tulokset antavat ohjaajille tukea epävarman ja muita enemmän uraohjausta tarvitsevan opiskelijan tunnistamiseen ja heidän hops-prosessinsa tehostamiseen opintojen alusta asti. Lisäksi tulosten perusteella esitetään seuraavia suosituksia: tuutoriopettajille tulisi asettaa pätevyysvaatimukseksi ohjausalan opintojen suorittaminen; opiskelijoita tulisi ohjata tunnistamaan erilaisia satunnaisesti avautuvia mahdollisuuksia ja tietoisesti hyödyntämään niitä elämässään; uraohjaukseen tulisi kytkeä mukaan työelämäyhteistyö; ohjaajien tulisi tiivistää yhteistyötä toisen asteen ohjaajien kanssa, jotta opiskelijoiden koulutusalavalinnat onnistuisivat paremmin; uraohjausta tulisi antaa tulevaisuuden kvalifikaatioiden ennakoinnin ja elinikäisten oppimisvalmiuksien näkökulmasta.

Att tala om det osägbara : Nicolaus Cusanus cirkulära filosofi i verket De coniecturis med särskild hänsyn till Nelson Pikes tankar om unio mystica

In my dissertation called Speaking of the unsayable: The circular philosophy of Nicholas of Cusa in his work De coniecturis, I presuppose an internal (conceptual) relation between the personal experience of God of Nicholas of Cusa (1401-64) in 1438 and, on the other hand, his philosophy. I hence try to describe the precise character of this relation. Referring to the Norwegian scholars Egil Wyller and Viggo Rossvær, I assume that there is a circularity in Cusanus’ philosophy which appears as self-references (= a sentence refers to itself: A is explained by B and B is explained by A). Wyller finds three phases in the thought of Cusanus (1. De docta ignorantia I-III, 2. De coniecturis I-II, 3. all subsequent works). Rossvær finds it impossible to presuppose certain phases, as the philosophy of Cusanus continuously proceeds and remains open to new ideas. As Cusanus however treats his experience of God far more consciously in his second work De coniecturis than in De docta ignorantia, I find it possible to distinguish between the earlier Cusanus (De docta ignorantia including his earlier works) and the later Cusanus (De coniecturis, about 1444, as well as the following works). Cusanus creates a philosophy of language in outline expressed in De coniecturis, in which he presents two concepts of necessity, i.e. absolute necessity and logical, or reasonable, necessity. These are interrelated in the sense that the mind, or the self, logically affirms the absolute, or unsayable, necessity, which shows itself in the mind and which the mind affirms conjecturally. The endeavour conceptually to understand absolute necessity implies intuitive (or intellectual) contemplation, or vision (investigatio symbolica), in which the four mental unities (the absolute, the intellectual, the rational and the sensuous) work together according to the rules described in De coniecturis. In De coniecturis Cusanus obviously turns from a negative concept of the unsayable to a paradigmatic, which implies that he looks for principles of speaking of the unsayable and presents the idea of a divine language (divinaliter). However, he leaves this idea behind after De coniecturis, although he continues to create new concepts of the unsayable and incomprehensible. The intellectual language of absolute seeing is expressed in the subjunctive, i.e. conditionally. In order to describe the unsayable, Cusanus uses tautologies, the primary one of which is a concept of God, i.e. non aliud est non aliud quam non aliud (the non-other is non-other than the nonother). Wyller considers this the crucial point of the philosophy of Cusanus (De non aliud), described by the latter as the definition of definitions, i.e. the absolute definition. However, this definition is empty regarding its content. It demonstrates that God surpasses the coincidence of opposites (coincidentia oppositorum) and that he is “superunsayable” (superineffabilis), i.e. he is beyond what can be conceived or said. Nothing hence prevents us from speaking of him, provided that he is described as unsayable (= the paradigmatic concept of the unsayable). Here the mode of seeing is decisive. Cusanus in this context (and especially in his later literary production) uses modalities which concern possibility and necessity. His aim is to conduct any willing reader ahead on the way of life (philosophia mentalis). In De coniecturis II he describes the notion of human self-consciousness as the basis of spiritual mutuality in accordance with the humanistic tradition of his time. I mainly oppose the negatively determined concept of Christian mysticism presented by the German philosopher Kurt Flasch and prefer the presentation of Burkhard Mojsisch of the translogical and conjectural use of language in De coniecturis. In particular, I take account of the Scandinavian research, basically that of Johannes Sløk, Birgit H. Helander, Egil Wyller and Viggo Rossvær, who all consider the personal experience of God described by Cusanus a tacit precondition of his philosophy.

An acid-sensing ion channel that detects ischemic pain

Ischemic pain occurs when there is insufficient blood flow for the metabolic needs of an organ. The pain of a heart attack is the prototypical example. Multiple compounds released from ischemic muscle likely contribute to this pain by acting on sensory neurons that innervate muscle. One such compound is lactic acid. Here, we show that ASIC3 (acid-sensing ion channel #3) has the appropriate expression pattern and physical properties to be the detector of this lactic acid. In rats, it is expressed only in sensory neurons and then only on a minority (~40%) of these. Nevertheless, it is expressed at extremely high levels on virtually all dorsal root ganglion sensory neurons that innervate the heart. It is extraordinarily sensitive to protons (Hill slope 4, half-activating pH 6.7), allowing it to readily respond to the small changes in extracellular pH (from 7.4 to 7.0) that occur during muscle ischemia. Moreover, both extracellular lactate and extracellular ATP increase the sensitivity of ASIC3 to protons. This final property makes ASIC3 a "coincidence detector" of three molecules that appear during ischemia, thereby allowing it to better detect acidosis caused by ischemia than other forms of systemic acidosis such as hypercapnia.

Overview of Zika virus (ZIKV) infection in regards to the Brazilian epidemic

Zika virus (ZIKV), a mosquito-borne flavivirus, belongs to the Flaviviridae family, genus Flavivirus. ZIKV was initially isolated in 1947 from a sentinel monkey in the Zika forest, Uganda. Little clinical importance was attributed to ZIKV, once only few symptomatic cases were reported in some African and Southeast Asiatic countries. This situation changed in 2007, when a large outbreak was registered on the Yap Island, Micronesia, caused by the Asian ZIKV lineage. Between 2013 and 2014, ZIKV spread explosively and caused many outbreaks in different islands of the Southern Pacific Ocean and in 2015 autochthonous transmission was reported in Brazil. Currently, Brazil is the country with the highest number of ZIKV-positive cases in Latin America. Moreover, for the first time after the discovery of ZIKV, the Brazilian scientists are studying the possibility for the virus to cause severe congenital infection related to microcephaly and serious birth defects due to the time-spatial coincidence of the alarming increase of newborns with microcephaly and the Brazilian ZIKV epidemic. The present review summarizes recent information for ZIKV epidemiology, clinical picture, transmission, diagnosis and the consequences of this emerging virus in Brazil.