About a decade ago, Adam Elga introduced philosophers to an intriguing puzzle. In it, Sleeping Beauty, a perfectly rational agent, undergoes an experiment in which she becomes ignorant of what time it is. This situation is puzzling for two reasons: First, because there are two equally plausible views about how she will change her degree of belief given her situation and, second, because the traditional rules for updating degrees of belief don't seem to apply to this case. In this dissertation, my goals are to settle the debate concerning this puzzle and to offer a new rule for updating some types of degrees of belief. Regarding the puzzle, I will defend a view called "the Lesser view," a view largely favorable to the Thirders' position in the traditional debate on the puzzle. Regarding the general rule for updating, I will present and defend a rule called "Shifted Jeffrey Conditionalization." My discussions of the above view and rule will complement each other: On the one hand, I defend the Lesser view by making use of Shifted Jeffrey Conditionalization. On the other hand, I test Shifted Jeffrey Conditionalization by applying it to various credal transitions in the Sleeping Beauty problem and revise that rule in accordance with the results of the test application. In the end, I will present and defend an updating rule called "General Shifted Jeffrey Conditionalization," which I suspect is the general rule for updating one's degrees of belief in so-called tensed propositions.

Yes / When lying supine, due to the reaction force from the mattress acting mostly through the heel, an external knee-extension joint-torque is induced that keeps the knee fully extended. This torque becomes zero if the feet are hung over the end of the support. This study investigated, in patients with knee-osteoarthritis (knee-OA) who routinely sleep supine, whether a change to such a sleeping position would ameliorate the knee pain and associated physical problems they suffer. Patients were recruited (General-Practitioners Centre, UK) over a 9-month period; those eligible (51/70) were randomly allocated to an intervention (65% female; age 71.5 [11.3] yrs; BMI, 29.20 [5.54] kg/m2; knee-OA severity, 20 mild–mod/3 severe) or control group (63% female; age, 68.3 [9.7] yrs; BMI, 28.69 [5.51] kg/m2; knee-OA severity, 17 mild–mod/2 severe). The primary outcome was improvements (0 [worst] to 100 [best]) in knee pain at 3 months and was rated in the Knee-Injury-and-Osteoarthritis-Outcome-Score questionnaire (KOOS). Secondary outcomes were improvements (0–100) in the other four KOOS-subscales. There were no differences between groups in KOOS outcomes at baseline, and there were no changes in KOOS outcomes in the control group at 3 months. Relative to the baseline KOOS values in Knee-Pain (50.1), Symptoms (52.5), Activities-of-Daily-Living (53.8) and Quality-of-Life (31.5), were all seen to improve at 3 months in the intervention group (by between 11.9 and 12.9); however, when comparing to controls, only the improvements in the subscale Activities-of-Daily-Living (which improved by 12.2) were statistically significant. Findings indicate that for those with knee-OA who routinely sleep supine, sleeping with the feet over the end of the mattress (to prevent the knee being pushed into/held in full extension) can help ameliorate the physical problems they suffer.

No / The alkaloid cryptolepine (1) and eight synthetic analogues (2-8) were assessed for in vitro activities against Trypanosoma brucei. Four of the analogues were found to be highly potent with IC50 values of less than 3 nM and three of these were assessed against T. brucei brucei infection in rats. The most effective compound was 2,7-dibromocryptolepine (7); a single oral dose of 20 mg/Kg suppressed parasitaemia and increased the mean survival time to 13.6 days compared with 8.4 days for untreated controls. In addition, four huperzine derivatives (9-12) were shown to have in vitro antitrypanosomal activities with IC50 values from 303-377 nM.

Sleeping Beauty (SB) Transposon-basierte Vektoren werden als Alternative zu viralen Vektoren für T-Zell-Gentherapie erforscht und ermöglichen eine schnelle und kostengünstige Genmanipulation von T-Zellen. Die Verwendung von Transposon-Vektoren erfordert jedoch die DNA-Elektroporation von T-Zellen, die sich schädlich auf T-Zellen auswirkt. DNA-elektroporierte T-Zellen weisen eine verringerte Lebensfähigkeit und eine verzögerte Aktivierung nach Stimulation des T-Zell-Rezeptors (TCR) auf. Um die Nachteile der Transposon-basierten T-Zell-Genmanipulation zu überwinden, haben wir neuartige SB-Vektoren entwickelt. Durch die Kombination von SB Transposon-basierten Minicircle-Vektoren mit SB100X Transposase-mRNA konnten T-Zellen effizient genmodifiziert werden. Unser Ansatz reduzierte die T-Zell-Mortalität und steigerte gleichzeitig die Transfektionseffizienz. Mit diesen neuartigen Vektoren wurde die stabile Expression verschiedener TCRs und CARs in über 50% der eingesetzten T-Zellen erreicht. Gentechnisch manipulierte T-Zellen konnten Antigen-spezifisch stimuliert werden und zeigten effiziente Zytokin-Sekretion und Tumorzell-Lyse. Weiterhin haben wir miRNAs entwickelt, die die Expression der endogenen TCR-Ketten unterdrücken. Der Einbau dieser miRNAs in die TCR-Expressionskassette erhöhte die Oberflächenexpression des therapeutischen TCRs, verringerte die Fehlpaarung mit endogenen TCR-Ketten und erhöhte die T-Zell-Funktionalität. Ein direkter Vergleich von SB- und Virus-modifizierten T-Zellen zeigte sowohl in vitro als auch in vivo eine vergleichbare Wirksamkeit der modifizierten T-Zellen hinsichtlich Zytokin-Sekretion, Tumorzell-Lyse und Tumorkontrolle. In dieser Arbeit konnte gezeigt werden, dass SB Minicircle-Vektoren die Herstellung von genetisch modifizierten T-Zellen ermöglichen und diese Tumor-spezifische Wirksamkeit aufweisen. Dieser Ansatz könnte die Herstellung therapeutischer T-Zellen für die personalisierte T-Zell-Gentherapie vereinfachen und beschleunigen. / Sleeping Beauty (SB) transposon-based vectors have entered clinical trials as an alternative to viral vectors for T cell gene therapy, offering time- and cost-efficient engineering of therapeutic T cells. However, transposon vectors require DNA electroporation into T cells, which we found to cause adverse effects. T cell viability was decreased, and DNA-transfected T cells showed delayed activation upon T cell receptor (TCR) stimulation regarding blast formation and proliferation. To overcome the limitations of transposon-based T cell engineering, we investigated the effect of DNA electroporation on T cells and developed novel SB vectors. T cells could efficiently be engineered with Sleeping Beauty vectors by combining SB transposon minicircles and SB100X transposase mRNA. Our approach reduced T cell mortality and substantially enhanced transfection efficiency. We achieved stable expression of several TCRs and CARs in more than 50% of the transfected T cells compared to 15% when conventional plasmids were used. T cells engineered to express a tumor-specific TCR mediated effective tumor cell lysis and cytokine secretion upon antigen-specific stimulation. Furthermore, we developed miRNAs to silence the expression of the endogenous TCR chains. Incorporation of these miRNAs into the TCR expression cassette increased surface expression of the therapeutic TCR, diminished mispairing with endogenous TCR chains, and enhanced T cell functionality. Importantly, a direct comparison of SB minicircle- and RV-engineered T cells in vitro as well as in vivo demonstrated equal T cell efficacy with regards to cytokine release, tumor cell lysis and tumor control. We demonstrated that SB minicircles enable the generation of gene-modified T cells with tumor-specific reactivity. Our approach facilitates the manufacturing of therapeutic T cells with superior biosafety and accelerates the generation of patient-specific T cell products for personalized T cell gene therapy.

In October 2006 an intervention was initiated to arrest the northerly advance through Uganda of the zoonotic parasite Trypanosoma brucei rhodesiense. This is a protozoal infection that is vectored by the tsetse fly. It is the aim of this thesis to review the impact of this large scale treatment programme in terms of animal health and human disease. The Stamp Out Sleeping Sickness (SOS) campaign was designed to target the cattle reservoir of T. b. rhodesiense in these newly affected areas by block treating >180,000 head of cattle. This was achieved in collaboration with final year vet students from the University of Makerere, Uganda. Farmers were also encouraged to spray their animals with deltamethrin in order to suppress the tsetse population. In order to monitor the impact of this intervention a base line survey was carried out. Evaluation of the logistics and implementation of the SOS campaign was assessed through interviews with personnel involved. Analysis by PCR revealed the prevalence of T. brucei s.l. as 15.57% (T. b. rhodesiense as 0.81%) within the cattle reservoir prior to SOS treatment. Follow up sampling was carried out at 23 locations at three, nine and 18 months. The prevalence of T. brucei s.l. was reduced post treatment, but in the absence of sustained vector control infections amongst the animals returned by nine months and subsequently exceeded the base line findings (P=<0.0001). It was observed that across most of the SOS area, T. b. rhodesiense did not re-establish following treatment. However, a significant cluster was identified where cases of both human and animal disease were continually reported. This cluster was noted to include the area immediately surrounding the Otuboi cattle market. This link between cattle movement and the spread of T. b. rhodesiense is an established one and is addressed by Ugandan governmental policy which states that ‘cattle traded at market must be treated with trypanocidal drugs prior to movement’. The findings presented here suggest that this policy may not be strictly enforced. The risk of spread is compounded at the northern districts of Uganda restock their domestic livestock following years of civil conflict. The majority of animals are traded in a northward direction – transporting infected animals from the endemic south. The scale of this trade is assessed through questionnaires, analysis of trade records and animal screening. Specific consideration is given to the implications of this cattle trade and impact this may have on the sustainability of the SOS campaign.

Trypanosoma brucei is a protozoan parasite that is the causative agent of sleeping sickness in sub-Saharan Africa. T. brucei has a complex life cycle involving passage between a mammalian host and the tsetse fly. The parasite evades the mammalian immune system via expression of Variant Surface Glycoprotein (VSG) on the cell surface. VSG genes are expressed at telomeric expression sites and at these sites are a number of Expression Site Associated Genes (ESAGs). One unusual ESAG, ESAG9, is developmentally regulated: RNA for these genes accumulates during the transition from slender to stumpy cells in the mammalian bloodstream and cellassociated protein is only detected transiently in stumpy and differentiating cells. Transgenic cell lines were generated which ectopically express one or more members of the ESAG9 gene family. Biochemical and cytological analyses using these cell lines indicated that some members of this family are glycosylated and GPI-anchored, and also that one gene, ESAG9-K69, is secreted. ESAG9-K69 is also secreted by wild-type stumpy parasites. In vivo experiments with tsetse flies did not conclusively show whether ESAG9 proteins play a role in the establishment of a tsetse fly mid-gut infection by transgenic trypanosomes. However, In vivo and ex vivo experiments using the mouse model of trypanosomiasis indicated that expression of ESAG9 proteins may alter parasitaemia in the mouse and results in a significant decrease in the proportion of CD4+ T cells in the mouse spleen.

Over the past two decades movement of cattle towards the north of Uganda has enabled the Trypanosoma brucei rhodesiense focus in south-eastern Uganda to spread into previously unaffected districts. This thesis brings together important epidemiological data regarding the impact of mass cattle drug treatment on the point prevalence of several different species of trypanosome in a newly endemic area of human sleeping sickness. Crucially the findings illustrate mass drug treatment is effective in reducing the prevalence of T. b. rhodesiense in cattle, thus minimising the reservoir potential of these animals in the epidemiology of human disease. During 2006 a control programme was launched to halt the northward spread of this zoonotic parasite. This programme, entitled ‘Stamping Out Sleeping Sickness’ (SOS) proposed to reduce the prevalence of Human African Trypanosomiasis (HAT) in the newly affected districts by reducing the prevalence of this parasite in the main animal reservoir of infection – domestic cattle. Cattle were mass treated using trypanocides to clear infections. Previous work demonstrated the prevalence of T. brucei s. l. and T. b. rhodesiense in cattle was higher in the districts of Dokolo and Kaberamaido than in the other SOS intervention districts (Selby 2011). To determine whether animals in these areas were also exposed to pathogenic cattle trypanosomes samples were screened for the presence of T. vivax and T. congolense savannah using PCR. Chapter three of this thesis determined the prevalence of these trypanosomes in cattle in these districts. Before treatment had taken place the prevalence of T. vivax was 2% (4/200, 95% CI 3.57 – 0.12%) in Dokolo and 7.3% (21/310, 95% CI 10.17 - 4.24 %) in Kaberamaido. The prevalence of T. congolense savannah at baseline was 3.5% (7/200, 95% CI 7.08–1.42 %) in Dokolo and 9.1% (21/230, 95% CI13.6–5.7 %) in Kaberamaido. Monitoring was conducted three, nine and 18 months post treatment and both pathogens were detected at all time points. The impact the treatment had on point prevalence varied by trypanosome species and between the two districts. Several clusters of villages in Dokolo and Kaberamaido continued to report cases of HAT after the initial SOS intervention due in part to their proximity to livestock markets (Batchelor et al., 2009). In 2008 re-treatment of these ‘high risk’ areas was undertaken. Monitoring was performed before and six months after treatment. Cattle blood samples were collected at 20 village sites from ten ‘case-positive villages’ (from which human sleeping sickness cases had been reported six months prior to June 2007) and from ten ‘case-negative villages’ (no reported human sleeping sickness cases six months prior to June 2007). These samples were screened for all of the aforementioned trypanosomes using species specific PCR protocols. Chapter five details the results of this screening, and assessed whether re-treatment in Dokolo and Kaberamaido was effective in reducing the prevalence of trypanosomiasis. The re-treatment had a dramatic effect, significantly reducing the point prevalence of overall trypanosomiasis in the 20 villages screened from 38.1% (95% CI = 40.5 – 35.79%) at baseline to 26.9% (95% CI 28.96 – 24.97, p < 0.0001) at six months. Looking at each species separately, point prevalence of three out of four detected species of trypanosome fell significantly, including T. b. rhodesiense, which was reduced to 25% of its baseline prevalence. Finally the two SOS treatment cycles were compared both statistically and spatially with emphasis on trends at village level and the occurrence of mixed infections.

Stress är en riskfaktor och en fråga som blivit alltmer aktuell för barnhälsovården då forskningen ser att vuxna och barn kan påverkas negativt till ohälsa. Vanligt förekommande frågor på BVC är de som handlar om föräldrars stress och barns sömnproblem och det är därför angeläget att fördjupa sig i dessa frågor. I den här uppsatsen undersöks eventuella samband mellan föräldrastress och barns sömnproblem med hjälp av en tvärsnittstudie där föräldrar besvarade enkätfrågor. Resultatet visade ett samband mellan föräldrastress orsakat av problem i parrelation och barns sömnsvårighet. Däremot fanns inget belägg i det totala resultatet för något samband mellan barns sömnsvårigheter och stress i föräldraskap. Även om resultatet i denna studie inte kunde påvisa starka samband är frågan inte mindre intressant eftersom det finns annan forskning som tyder på att stress i familjen orsakar hälsoproblem hos både barn och vuxna. BVC har ett stort ansvar för att främja hälsa hos barn och stödja föräldrarna och behöver tydliga arbetsredskap för att kunna utföra uppdraget effektivt. / Program: Fristående kurs

O presente trabalho tem como objetivo analisar as transformacoes da producao artesanal de redes de dormir, no nordeste brasileiro, e as repercussoes dessas transformacoes onde essa atividade e exercida. Para se atingir tal objetivo, parte-se do pressuposto de que as transformacoes ocorridas decorrem de processos relacionados com a incorporacao de materias-primas industriais e de ampliacao do mercado de consumo, sobretudo quando a rede passa a ser considerada como um bem de lazer e decoracao. Este estudo procura abranger os diferentes segmentos relacionados com essa problematica em algumas cidades nordestinas. Numa pesquisa direta, coletaram-se informacoes sobre as materias-primas, os instrumentos, as tecnicas e as relacoes sociais inerentes a atividade. Este estudo mostra que as transformacoes verificadas abrangem a reorganizacao da producao de redes e o aproveitamento das tecnicas de tecelagem das redes para a producao de outros bens, contribuindo, assim para a reproducao do espaco. / This study has the objective to analyze changes in handcraft of sleeping hammocks in Brazilian Northeast and implications of these transformations upon developed activities. In order to achieve this end, the premise is that occurred changes are caused by processes related to incorporation of industrial raw materials and expansion of consumption market, mainly when hammock becomes a leisure and decorative article. This research covers different segments related to this problem in some northeast cities. On direct research, it was collected information about raw material, instruments, techniques and social relations inherent to the activity. This study demonstrates that verified changes comprises reorganization of hammock production and utilization of hammock weaving techniques on other goods manufacturing and so contributing space reproduction.

The aim of this doctoral thesis is to investigate the practices of rough sleeping and inhabiting public space, with a focus on the modern city of Rome. By inhabiting public spaces, people who are homeless expose their private sphere to public view. Paradoxically, this public exposure of the private becomes a means of exclusion according to Judith Butler and Athena Athanasiou (2013). Scholars acknowledge public space as constructed by the actions that people carry out in public (Lefebvre 1991; Tschumi 1996; Harvey 2012; Jon Goodbun et al. 2014). People who are homeless certainly contribute to the construction of public space (Petty 2016). However, as asserted by architectural scholar Gill Doron, certain practices 'reveal how the public space is restricted to a very small spectrum of activities, and how many other activities are not permitted' (Doron 2000, p.254). These practices put into question what public these spaces are designed and designated for, questioning why only some activities are regarded as public and why some others take place only at night when spaces are temporary urban voids. Rough sleeping in Rome takes place mostly at night, exposing the city to its own fragilities and contradictions. Public space emerges as precarious. It is defned by social and cultural boundaries, within which urban practices alternate one with the other. These are irreconcilable poles within a parallax gap (Žižek 2009). The theoretical scaffolding of the thesis is structured alongside two other transgressive case studies: Pussy Riot's occupation in Moscow and my interviews with parkour practitioners. These cases have been investigated in comparison with homelessness in order to highlight aspects concerning occupation of space as a performative action under precarious circumstances (precarity). The literary review is combined with auto-ethnographical studies I conducted with a community of rough sleepers, comprising 20-40 members who inhabit a portico area nearby St Peter's Square in Rome. I also ran focus groups, individual interviews and project presentations to people who either are involved in charitable bodies that deal with homelessness or are part of the general public, such as passers-by in St Peter's Square. This study has revealed a series of aspects concerning the negotiation of public space and the role of agency and mediation. This study has stimulated questions concerning the role design can play in discourses of social innovation and inclusion. The research conducted has also outlined diffculties concerning the range of data and the possible response to the many voices heard. How can design re-imagine the centre ground between alternative practices in space? By highlighting the centre as precarious, is it possible to fnd a way of re-thinking the centre? On the basis of this study, the aim of the research has been to look at the state of the gap between these alternative poles, investigating and exploring the concept of precarity. This suggests the possibility of redefning concepts of mediation, social inclusion and architectural activism, articulated further through a series of speculative projects, concluding with the presentation of a 'precarious' object I designed together with the community of rough sleepers in St Peter's Square and COTRAD onlus (a charitable body based in Rome).