京都大学 / 新制・課程博士 / 博士(理学) / 甲第25143号 / 理博第5050号 / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 本川 雅治, 准教授 中野 隆文, 教授 森 哲 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Hybridization between closely related species of mammals is often accompanied by abnormal growth of placentas and fetuses. From the perspective of evolutionary biology, our knowledge about the contribution of such interspecies incompatibilities in speciation is still insufficient. In my thesis, I was finding out if abnormal placental and fetal growth contributes to reproductive isolation of two subspecies of house mouse, Mus musculus musculus and M. m. domesticus, which are at an early phase of speciation and in nature they still hybridize. Using two inbred strains derived from M. m. musculus (PWD/Ph, STUS) and two inbred strains derived from M. m. domesticus (C57BL6/J, SCHEST) we performed four different intrasubspecies and four different intersubspecies crosses. We found out that the size of the placenta in hybrids is more influenced by father, while the size of the fetus is more influenced by mother. After elimination influence of weight of mother and father we have not recorded a significant difference in the size of placentas and fetuses in intrasubspecies and intersubspecies crosses. Our results show that hybridization between subspecies of house mouse does not produce abnormalities in prenatal development, as was observed in hybrids between distant species of mice. It is thus possible that...

O surgimento e a evolução da vida na terra foram possíveis graças ao desenvolvimento de mecanismos temporais precisos capazes de ajustar os processos fisiológicos que ocorriam no interior do organismo com os ciclos ambientais, promovendo assim, ganhos na capacidade adaptativa e reprodutiva dos indivíduos. Neste contexto, luz e temperatura são as duas pistas temporais mais relevantes para resetar o relógio endógeno e, aparentemente, esses dois zeitgebers trabalham juntos para manter os ritmos circadianos. Uma ampla gama de fotorreceptores e fotopigmentos evoluiu no sentido de perceber com alta sensibilidade a informação fótica fornecida pelo ambiente e, recentemente, foi demonstrado que a detecção de temperatura também pode ser exercida pelos fotopigmentos rodopsina e melanopsina, sendo mediada por canais TRP (Shen et al., 2011). Consideramos as células B16-F10 Per1::Luc como um modelo promissor para o estudo de luz e temperatura em relógios periféricos, uma vez que essa linhagem expressa os dois fotopigmentos apontados com função de termorreceptores em Drosophila. Nossos estudos nos permitiram verificar que a luz não atua como um agente sincronizador nessas células, que se mantiveram em livre curso mesmo após um pulso de 10 min de luz azul (650 lux). Por outro lado, um pulso de temperatura de 2,5º C acima da temperatura de manutenção por 1h atuou ajustando a expressão do gene Per1, imprimindo um ritmo circadiano, diferentemente do observado no controle. Com base nessas informações, hipotetizamos que a informação de luz, percebida via melanopsina na retina de mamíferos, levaria a regulação da temperatura circadiana pelo NSQ, e a temperatura corporal, por sua vez, poderia atuar como uma pista interna para a sincronização dos tecidos periféricos, tendo os canais TRP como mediadores. Para responder esta questão, utilizamos camundongos WT e TrpV1 KO submetidos a diferentes protocolos de luz e avaliamos a expressão de genes do relógio Per1, Per2, Clock e Bmal1 e dos canais TrpV1 e TrpA1 em tecidos periféricos. Identificamos que a glândula suprarrenal, fígado e tecido adiposo marrom possuem uma maquinaria do relógio tipicamente ativa e acreditamos que a oscilação dos genes de relógio observada nesses tecidos é expressiva. Interessantemente, vimos também que o TrpV1, além de ser expresso nos tecidos analisados em animais WT, apresenta uma transcrição rítmica no fígado e tecido adiposo marrom de animais em LD, corroborando nossa hipótese de que canais TRP atuam como mediadores da informação de luz aos tecidos periféricos. Dadas as diferenças encontradas entre os animais WT e TrpV1 KO, sugerimos que a presença do canal TRPV1 pode ser essencial, embora seu grau de envolvimento varie de acordo com o tecido. No que diz respeito ao canal TRPA1, encontramos dois resultados que merecem ser destacados. Primeiramente, identificamos no fígado de camundongos TrpV1 KO mantidos em LD uma provável compensação da expressão de TrpA1 na ausência de TrpV1 e, curiosamente, que o tecido adiposo marrom não expressa o canal TrpA1. Considerando os resultados deste trabalho sobre o envolvimento dos canais TRP em resposta à luz e temperatura, acreditamos ter fortalecido nossa hipótese inicial, principalmente após demonstrarmos o papel do canal TRPV1 e que tecidos periféricos são sincronizados por alterações de temperatura. / The life emergence and evolution on Earth were made possible by the development of precise temporal mechanisms able to adjust the physiological processes within an organism with environmental cycles, thus promoting gains in the adaptive and reproductive capacity of the individuals. In this context, light and temperature are the two most relevant time cues to reset the endogenous clock; apparently these two zeitgebers work together to keep the circadian rhythms. A wide variety of photoreceptors and photopigments evolved in order to precisely perceive the photic information provided by the environment, and recently it has been shown that the temperature detection can also be exerted by the photopigments rhodopsin and melanopsin, being mediated by TRP channels (Shen et al., 2011). We have identified B16-F10 Per1::Luc cells as a promising model for the study of light and temperature effects on peripheral clocks, since this cell line expresses both photopigments pointed as thermoreceptors in Drosophila. Our studies allowed us to demonstrate that light does not act as a synchronizing agent on those cells, which remained in free running after a 10 min pulse of blue light (650 lux). On the other hand, a temperature pulse of 2.5º C above the maintenance temperature, for 1h, adjusted Per1 gene expression, imprinting a circadian rhythm, which was not observed in the control. Based on this information, we hypothesized that the light perceived via melanopsin by the mammalian retina would lead to the regulation of the circadian temperature by the SCN, and the body temperature, in turn, could act as an inner cue for the synchronization of the peripheral tissues, having the TRP channels as mediators. To answer this question, we have used WT and TrpV1 KO mice under different light protocols and evaluated the expression of clock genes Per1, Per2, Clock and Bmal1 and TrpV1 and TrpA1 channels in peripheral tissues. We found that the adrenal gland, liver and brown adipose tissue have a typically active clock machinery, and the oscillation of clock genes observed in these tissues is significant. Interestingly, we observed that TrpV1 is expressed in those tissues, and presents a rhythmic transcription in the liver and brown adipose tissue of LD maintained animals, confirming our hypothesis that TRP channels act as mediators of light information to peripheral tissues. In face of the differences between WT and trpV1 KO animals, we suggest that the presence of the TRPV1 channel may be essential, although its degree of involvement may vary according to the tissue. In terms of TRPA1 channel, we found two results that deserve to be highlighted. Firstly, we identified in the liver of TrpV1 KO mice maintained in LD a presumable compensation of TrpA1 expression in the absence of TrpV1 and, interestingly, the brown adipose tissue does not express TrpA1 channel. Considering the findings of this study on the participation of TRP channels in responses to light and temperature, we believe we have strengthened our initial hypothesis, especially after we have demonstrated the role of TRPV1 channel, and that peripheral tissues may be synchronized by temperature changes.

Submitted by Lara Oliveira (lara@ufersa.edu.br) on 2017-08-08T21:28:55Z No. of bitstreams: 1 EdigleyceLC_DISSERT.pdf: 1495589 bytes, checksum: 331e814fbf35fd0903ce95ef191653df (MD5) / Approved for entry into archive by Vanessa Christiane (referencia@ufersa.edu.br) on 2017-08-17T22:39:03Z (GMT) No. of bitstreams: 1 EdigleyceLC_DISSERT.pdf: 1495589 bytes, checksum: 331e814fbf35fd0903ce95ef191653df (MD5) / Approved for entry into archive by Vanessa Christiane (referencia@ufersa.edu.br) on 2017-08-17T22:41:07Z (GMT) No. of bitstreams: 1 EdigleyceLC_DISSERT.pdf: 1495589 bytes, checksum: 331e814fbf35fd0903ce95ef191653df (MD5) / Made available in DSpace on 2017-08-17T22:41:14Z (GMT). No. of bitstreams: 1 EdigleyceLC_DISSERT.pdf: 1495589 bytes, checksum: 331e814fbf35fd0903ce95ef191653df (MD5) Previous issue date: 2015-02-12 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The Aspidosperma pyrifolium Mart species. it is used in feed for farm ani-mals. However, there are few studies on the toxicity of this plant. This study aimed to iden-tify the existence of toxic effect, cytotoxic and mutagenic leaves of A. pyrifolium the test system Allium cepa and mice. It was made growth analysis of roots, inhibition relative and mitotic index with the Allium cepa test. For the LD50 they were used of groups mice were observed for 14 days to determine the number of dead and surviving animals. For the mi-cronucleus test and binucleated cells was done extracting bone marrow of animals. Bioas-says performed with the Allium cepa revealed that the aqueous extract of dried leaves showed no toxic effects, however, stimulated cell division in a concentration of 50 mg/L, is indicative of formation of tumor cells. The fresh leaves were toxic at the concentration of 300 mg/L and had a effect toxic sublethal on concentration of 5 mg/L.. In mice, the median lethal dose was 750.63 mg/kg with the aqueous extract of fresh leaves, and lethal concen-trations tested from the concentration 900 mg/kg in males and females. The evaluated ani-mals showed behavioral changes in the nervous system and change in average total weight. The concentrations tested indicated are not mutagenic or not cytotoxic in the overall analy-sis of micronucleus frequency and binucleated cells, respectively. But, this work provides data toxicity; cytotoxicity and mutagenicity still have not investigated for the species A. pyrifolium / A espécie Aspidosperma pyrifolium Mart. é utilizada na alimentação por animais de produção. No entanto, são escassos os estudos sobre a toxicidade dessa planta. Este trabalho objetivou identificar a existência de efeito tóxico, citotóxico e mutagênico de folhas de A. pyrifolium no sistema teste Allium cepa e em camundongos. Foi feita a análise de crescimento de raízes, inibição relativa e índice mitótico com o teste Allium cepa. Para a DL50 foram utilizados grupos de camundongos, observados por 14 dias para determinar a quantidade de mortos, doentes e sobreviventes. Para o teste de micronúcleo e células binucleadas foi feita a extração da medula óssea dos animais. Os bioensaios com o Allium cepa realizados revelaram que o extrato aquoso das folhas secas não mostrou efeito tóxico, contudo, estimulou a divisão celular na concentração de 50 mg/L, sendo indicativo de formação de células tumorais. As folhas frescas foram tóxicas na concentração de 300 mg/L e teve efeito tóxico subletal na concentração de 5 mg/L. Nos camundongos, a dose letal mediana foi de 750,63 mg/Kg com o extrato aquoso de folhas frescas, sendo letal nas concentrações testadas a partir da concentração de 900 mg/Kg em machos e fêmeas. Os animais avaliados apresentaram alterações comportamentais no sistema nervoso e alteração no peso médio total. As concentrações testadas indicaram não serem mutagênicas e nem citotóxicas na análise geral das frequências de micronúcleo e células binucleadas, respectivamente. Mas, este trabalho fornece dados de toxicidade, citotoxicidade e mutagenicidade ainda não investigados para a espécie A. pyrifolium / 2017-08-08

O surgimento e a evolução da vida na terra foram possíveis graças ao desenvolvimento de mecanismos temporais precisos capazes de ajustar os processos fisiológicos que ocorriam no interior do organismo com os ciclos ambientais, promovendo assim, ganhos na capacidade adaptativa e reprodutiva dos indivíduos. Neste contexto, luz e temperatura são as duas pistas temporais mais relevantes para resetar o relógio endógeno e, aparentemente, esses dois zeitgebers trabalham juntos para manter os ritmos circadianos. Uma ampla gama de fotorreceptores e fotopigmentos evoluiu no sentido de perceber com alta sensibilidade a informação fótica fornecida pelo ambiente e, recentemente, foi demonstrado que a detecção de temperatura também pode ser exercida pelos fotopigmentos rodopsina e melanopsina, sendo mediada por canais TRP (Shen et al., 2011). Consideramos as células B16-F10 Per1::Luc como um modelo promissor para o estudo de luz e temperatura em relógios periféricos, uma vez que essa linhagem expressa os dois fotopigmentos apontados com função de termorreceptores em Drosophila. Nossos estudos nos permitiram verificar que a luz não atua como um agente sincronizador nessas células, que se mantiveram em livre curso mesmo após um pulso de 10 min de luz azul (650 lux). Por outro lado, um pulso de temperatura de 2,5º C acima da temperatura de manutenção por 1h atuou ajustando a expressão do gene Per1, imprimindo um ritmo circadiano, diferentemente do observado no controle. Com base nessas informações, hipotetizamos que a informação de luz, percebida via melanopsina na retina de mamíferos, levaria a regulação da temperatura circadiana pelo NSQ, e a temperatura corporal, por sua vez, poderia atuar como uma pista interna para a sincronização dos tecidos periféricos, tendo os canais TRP como mediadores. Para responder esta questão, utilizamos camundongos WT e TrpV1 KO submetidos a diferentes protocolos de luz e avaliamos a expressão de genes do relógio Per1, Per2, Clock e Bmal1 e dos canais TrpV1 e TrpA1 em tecidos periféricos. Identificamos que a glândula suprarrenal, fígado e tecido adiposo marrom possuem uma maquinaria do relógio tipicamente ativa e acreditamos que a oscilação dos genes de relógio observada nesses tecidos é expressiva. Interessantemente, vimos também que o TrpV1, além de ser expresso nos tecidos analisados em animais WT, apresenta uma transcrição rítmica no fígado e tecido adiposo marrom de animais em LD, corroborando nossa hipótese de que canais TRP atuam como mediadores da informação de luz aos tecidos periféricos. Dadas as diferenças encontradas entre os animais WT e TrpV1 KO, sugerimos que a presença do canal TRPV1 pode ser essencial, embora seu grau de envolvimento varie de acordo com o tecido. No que diz respeito ao canal TRPA1, encontramos dois resultados que merecem ser destacados. Primeiramente, identificamos no fígado de camundongos TrpV1 KO mantidos em LD uma provável compensação da expressão de TrpA1 na ausência de TrpV1 e, curiosamente, que o tecido adiposo marrom não expressa o canal TrpA1. Considerando os resultados deste trabalho sobre o envolvimento dos canais TRP em resposta à luz e temperatura, acreditamos ter fortalecido nossa hipótese inicial, principalmente após demonstrarmos o papel do canal TRPV1 e que tecidos periféricos são sincronizados por alterações de temperatura. / The life emergence and evolution on Earth were made possible by the development of precise temporal mechanisms able to adjust the physiological processes within an organism with environmental cycles, thus promoting gains in the adaptive and reproductive capacity of the individuals. In this context, light and temperature are the two most relevant time cues to reset the endogenous clock; apparently these two zeitgebers work together to keep the circadian rhythms. A wide variety of photoreceptors and photopigments evolved in order to precisely perceive the photic information provided by the environment, and recently it has been shown that the temperature detection can also be exerted by the photopigments rhodopsin and melanopsin, being mediated by TRP channels (Shen et al., 2011). We have identified B16-F10 Per1::Luc cells as a promising model for the study of light and temperature effects on peripheral clocks, since this cell line expresses both photopigments pointed as thermoreceptors in Drosophila. Our studies allowed us to demonstrate that light does not act as a synchronizing agent on those cells, which remained in free running after a 10 min pulse of blue light (650 lux). On the other hand, a temperature pulse of 2.5º C above the maintenance temperature, for 1h, adjusted Per1 gene expression, imprinting a circadian rhythm, which was not observed in the control. Based on this information, we hypothesized that the light perceived via melanopsin by the mammalian retina would lead to the regulation of the circadian temperature by the SCN, and the body temperature, in turn, could act as an inner cue for the synchronization of the peripheral tissues, having the TRP channels as mediators. To answer this question, we have used WT and TrpV1 KO mice under different light protocols and evaluated the expression of clock genes Per1, Per2, Clock and Bmal1 and TrpV1 and TrpA1 channels in peripheral tissues. We found that the adrenal gland, liver and brown adipose tissue have a typically active clock machinery, and the oscillation of clock genes observed in these tissues is significant. Interestingly, we observed that TrpV1 is expressed in those tissues, and presents a rhythmic transcription in the liver and brown adipose tissue of LD maintained animals, confirming our hypothesis that TRP channels act as mediators of light information to peripheral tissues. In face of the differences between WT and trpV1 KO animals, we suggest that the presence of the TRPV1 channel may be essential, although its degree of involvement may vary according to the tissue. In terms of TRPA1 channel, we found two results that deserve to be highlighted. Firstly, we identified in the liver of TrpV1 KO mice maintained in LD a presumable compensation of TrpA1 expression in the absence of TrpV1 and, interestingly, the brown adipose tissue does not express TrpA1 channel. Considering the findings of this study on the participation of TRP channels in responses to light and temperature, we believe we have strengthened our initial hypothesis, especially after we have demonstrated the role of TRPV1 channel, and that peripheral tissues may be synchronized by temperature changes.

Les invasions biologiques sont de plus en plus fréquentes, avec des conséquences importantes sur la biodiversité et la santé humaine. Étudier les mécanismes qui les expliquent permet simultanément (i) d’envisager des stratégies efficaces de contrôle et de prévention et (ii) d’étudier divers processus écologiques et évolutifs sur des échelles de temps contemporaines. Plusieurs hypothèses basées sur le parasitisme et l’immunité des hôtes sont proposées pour expliquer le succès des espèces envahissantes. Ainsi, au cours de l’invasion, les hôtes exotiques (1) perdraient leurs parasites naturels (Enemy Release, ER), (2) transfèreraient leurs parasites exotiques aux hôtes natifs (Spill-Over, SO) et/ou (3) amplifieraient les cycles des parasites natifs au sein des hôtes locaux (Spill-Back, SB). En relation avec ces changements dans les interactions hôtes-parasites, l’hypothèse EICA (Evolution of Increased Competitive Ability) prédit une modulation des ressources de l’hôte envahissant via un investissement moins important dans les réponses immunitaires coûteuses (inflammation) au profit de réponses immunitaires beaucoup moins coûteuses (réponses médiées par les anticorps) et de capacités de reproduction et de dispersion des populations sur le front d’invasion. Le but de ma thèse est de tester ces prédictions dans le cadre de deux invasions actuellement en cours au Sénégal : celles du rat noir Rattus rattus et de la souris domestique Mus musculus domesticus, deux espèces envahissantes majeures tant par leurs impacts (économique, sanitaire, écologique) que par leur distribution quasiment mondiale. Mes travaux se basent sur un dispositif d’échantillonnage en populations naturelles et sur le développement d’approches comparatives le long d’un gradient d’invasion pour chacune des deux espèces exotiques. Les patrons de structure (prévalence, abondance, richesse) de deux communautés de parasites (helminthes gastro-intestinaux, bactéries pathogènes) et les profils immunitaires (réponses médiées par les anticorps naturels, inflammation) des rongeurs commensaux exotiques (M. m. domesticus, R. rattus) et/ou natifs (Mastomys spp.) ont été comparés pour des localités situées dans des régions anciennement envahies (depuis plus de 100 ans), récemment envahies (depuis moins de 30 an : front d’invasion), et non envahies. Mes résultats montrent des variations dans la structure des communautés de parasites et les réponses immunitaires des hôtes natifs et exotiques. Les tendances observées, aussi bien pour les communautés de parasites que pour les composantes immunitaires étudiées le long des deux routes d’invasion, attestent de patrons globalement plus complexes qu’attendu sous les hypothèses de départ, suggérant l’existence de relations complexes entre caractéristiques des communautés d’hôtes et de parasites, investissement immunitaire, conditions environnementales et invasions biologiques. Des approches expérimentales doivent être envisagées afin de déterminer les conséquences et les mécanismes sous-jacents aux différents phénomènes observés. / Biological invasions are increasingly phenomenon worldwide having deleterious impacts on biodiversity and human health. Studying the mechanisms explaining them allows both (i) to define efficient strategies for controlling and preventing invaders and (ii) to study ecological and evolutionary processes at contemporary scales. Some major hypotheses rely on parasitism and host immunity to explain invasion success. Thus, exotic host populations (1) may benefit of an " Enemy Release " (ER) through impoverishment of their original parasite communities, and may affect native hosts by (2) transferring exotic parasites (Spill-Over, SO) and/or (3) by increasing transmission risk of native parasites (Spill-Back, SB). In turn, according to the refined “Evolution of Increased Competitive Ability” (EICA) theory, invasive populations should experience immune trade-offs by favouring less expensive antibody-mediated responses over costly inflammation, to increase their competitive ability (dispersion, reproduction). The aim of my thesis is to test these predictions along the invasion routes of two commensal exotic species in Senegal, the domestic mouse (Mus musculus domesticus) and the black rat (Rattus rattus). These rodent species are considered to be major invasive species worldwide inducing high economic, sanitary and ecological damages. My research is based on comparative analyses along one invasion route for each invasive species. We focused on gastrointestinal helminths and pathogenic bacteria as parasite communities, and inflammation and natural antibody-mediated responses as immune estimates. Comparisons were performed for invasive and/or native (Mastomys spp.) rodents between localities of long-established invasion (100-200 years ago), recent invasion (10-30 years ago; invasion front), and non-invaded localities. My findings showed variations along both invasion routes in parasite community structure and immune patterns, but in a more complex way than expected under the initial predictions. The heterogeneity of changes observed highlights the existence of particular relations between host and parasite traits, host immune investment, environmental conditions and biological invasions. Further experimental works are needed to assess the consequences and mechanisms underlying the changes observed along both invasion routes.

The contact zone between subspecies of house mouse Mus musculus musculus and Mus musculus domesticus is one of the most intensively studied hybrid zones. It is also due to extensive introgression of the Y chromosome of M. m. musculus subspecies to the genetic background of M. m. domesticus. One theory of the origin of the introgression explains it by intragenomic conflict between the sexes. With a set of variable microsatellite markers on the Y chromosome, I have examined the validity of this theory by simple approaches revealing the history of the introgression area. It turned out that overly big variability of our markers makes the revelation of this theory impossible. Our markers have been found suitable for use in the analysis of population structure of house mouse. Thanks to them, we can identify migrants between localities and estimate the level of closeness of the population structure in relation to migrants from the neighborhood. Populations in our analysis proved to be relatively closed and resistant to the influx of migrants. Despite the conclusions of previous research where the dispersion of males ran up to one kilometer, I have discovered a relatively large number of migrations to a distance of thirty kilometers. Keywords Mus musculus musculus, Mus musculus domesticus, Y chromosome,...

Transcription factors (TFs) are key regulatory proteins that regulate transcriptionthrough precise, but highly variable binding events to cis-regulatory elements.The complexity of their regulatory patterns makes it difficult to determinethe roles of different TFs, a task which the field is still struggling with.Experimental procedures for this purpose, such as knock out experiments, arehowever costly and time consuming, and with the ever-increasing availabilityof sequencing data, computational methods for inferring the activity of TFsfrom such data have become of great interest. Current methods are howeverlacking in several regards, which necessitates further exploration of alternatives. A novel tool for estimating the activity of individual TFs over time fromlongitudinal mRNA expression data was in this project therefore put togetherand tested on data from Mus musculus liver and brain. The tool is based onprincipal component analysis, which is applied to data subsets containing theexpression data of genes likely regulated by a specific TF to acquire an estimationof its activity. Though initial tests on 17 selected TFs showed issues withunspecific trends in the estimations, further testing is required for a statementon the potential of the estimator. / Transcriptionsfaktorer (TFer) är viktiga regulatoriska protein som reglerar transkriptiongenom att binda till cis-regulatoriska element på precisa, menmycketvarierande vis. Komplexiteten i deras regulatoriska mönster gör det svårt attavgöra vilka roller olika TFer har, vilket är en uppgift som fältet fortfarandebrottas med. Experimentella procedurer i detta syfte, till exempel "knockout"experiment, är dock kostsamma och tidskrävande, och med den evigt ökandetillgången på sekvenseringsdata har metoder för att beräkna TFers aktivitetfrån sådan data fått stort intresse. De beräkningsmetoder som finns idag bristerdock på flera punker, vilket erfordrar ett fortsatt sökande efter alternativ. Ett nytt vektyg för att upskatta aktiviteten hos individuella TFer över tidmed hjälp av longitunell mRNA-uttrycksdata utvecklades därför i det här projektetoch testades på data från Mus musculus lever och hjärna. Verktyget ärbaserat på principalkomponentsanalys, som applicerades på set med uttrycksdatafrån gener sannolikt reglerade av en specifik TF för att erhålla en uppskattningav dess aktivitet. Trots att de första testerna för 17 utvalda TFer påvisadeproblem med ospecifika trender i upskattningarna krävs forsatta tester för attkunna ge ett tydligt svar på vilken potential estimatorn har.

Background: Alongside experiencing physical symptoms with no identifiable organic cause, patients with MUS commonly experience comorbid anxiety and depression. They also have high health utilisation costs, which has implications for the health service. Interventions which target these symptoms in a cost effective way need to be developed and evaluated. Objective: To develop and evaluate a self-help mindfulness-based stress reduction (MBSR) intervention for patients with medically unexplained symptoms (MUS). Methods: A systematic review of the literature was carried out to evaluate the effectiveness of MBSR for reducing psychological distress in people with MUS. Study 1 developed and evaluated a self-help MBSR intervention in a clinical setting. Fifteen participants were recruited from eight practice, however only five completed post-intervention measures. A combination of t-tests and descriptive statistics were used to compare changes in levels of psychological distress, quality of life, symptoms and mindfulness at post-intervention. Pearson‘s correlations were used to identify relationships between improvements in mindfulness and improvements in outcomes. Study 2, exploring the reasons for the difficulties recruiting participants to Study 1, was then carried out through questionnaires to GPs. Results: Though more evidence is needed, the systematic review found MBSR to have moderate effects on psychological distress, which are largely maintained or improved at follow-up. Study 1 found symptom frequency and levels of acceptance to have improved at post-intervention. Study 2 found that the main reasons for GPs not recruiting participants was that they were busy and found it difficult to prioritise given other demands. Conclusions: Evidence to date suggests that MBSR is an effective intervention for patients with MUS. Future studies may benefit from recruiting participants from relevant organisations or using alternative methods such as database searches. No firm conclusions can be made about the self-help MBSR intervention‘s efficacy due to the study‘s limitations, however changes seen in the completer group suggest that further research would be warranted.

The human-abetted introduction of commensal species (i.e. those that opportunistically exploit the anthropogenic environment for food and shelter, e.g. rats, cockroaches etc.) to new areas has occurred throughout history. This has resulted in detrimental ecological changes worldwide but, from a viewpoint of human knowledge, a beneficial corollary of these translocations is that the species in question can be used as proxies to study the movement of the humans who transported them. I reconstruct colonisation histories of three widespread commensal mammalian species in the Western Indian Ocean, the black rat Rattus rattus, house mouse Mus musculus and Asian house shrew Suncus murinus, through phylogeographic studies (the geographic distribution of genetic lineages) of maternally-inherited mitochondrial markers, and zooarchaeological data. The DNA analyses are conducted on samples largely derived from museum specimens collected up to 110 years ago, and from archaeological bones (in the case of rats). I show considerable cryptic diversity in all three species, particularly in mice for which we find a potential major new lineage. Certain lineages within each species predominantly reveal long-distance translocations within the Indian Ocean, but high resolution geographic and genetic clustering is also evident, particularly in Asian house shrews. Phylogeographic structuring of the three species in East Africa and the southern Indian Ocean region (e.g. Madagascar, Reunion, etc.) indicate connections with Arabia, the Middle East, and India in the Islamic period from the first millennium AD, and later European connections during the Age of Exploration. Closer to the origins of the three species (the Indian subcontinent in all cases), range expansions in Eurasia and nearby islands relate to early to mid Holocene human populations, but also with signals of later secondary colonisations. Through ancient DNA studies I found genetic continuity between temporally separated populations of black rats suggesting population persistence, and high levels of diversity in Songo Mnara, a Swahili stonetown in Tanzania. Knowledge of the colonisation history and genetic diversity of an introduced species is essential to understand their resilience in novel landscapes, and to identify pathways of invasion and, by proxy, human trade and exchange networks that facilitated their dispersal. My research contributes significantly to that end for three socially, economically and ecologically important species that are well-established in the Indian Ocean region and beyond.