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In our fast-paced, hectic time, which is stamped by an ever-increasing degree of nervousness, unrest, and unsteadiness it has become customary for mankind to relax for a shorter or longer period of time from the habits of everyday life and recreation. To search for strength somewhere on earth that is away from the place of business, that invites you to rest from everyday worries and toils. So lures the Black Forest. With these words, the Sommerberg-Hotel was advertised already over 100 years ago. Nowadays stress has become a fashionable term in our modern and digital world. For many, it is almost a status symbol - because those who are stressed have a lot on their plate and are therefore important. This attitude is leading to increasing health issues and to a society that is not able to breathe anymore because they have to be in working order. After decades of being empty and unused, the Sommerberg-Hotel occupies a unique location on top of the mountain in the Black Forest. Following its rich past and responding to society's needs it becomes once more a refuge to escape the rush. In close dialogue with the existing, this project investigates a possible transformation and a repurposing of the old structures of the Sommerberg-Hotel. Making it to The Mental Wellbeing Place.

Pharmaceutical industry is today struggling with its productivity as products keep failing after long and expensive development programs. The protability is further threatened by erce competition from cheaper product copies. As an attempt to increase the pipeline output, pharmaceutical companies have lately turned to the strategy of drug repositioning. By applying an already developed drug in new disease areas the lifetime of the product is prolonged and return time on already made investments elongated.  Such development is imbued by less risk than a de novo development and has proven to be a faster and cheaper way to meet the medical demand. With limited company budgets and the often many repositioning possibilities, an informed repositioning selection must be made. As such theoretical model is not publicly available this thesis takes on the task to determine which parameters to take into consideration and how these should be weighted in relation to each other in order to evaluate di erent drug repositioning possibilities. Six main topics are identied to a ect the repositioning success, these are: medical need, economic return, scientic support, timing, life cycle extenders and external relations. These ndings are derived from empirics collected during interviews with employees from ve di erent competence areas involved in repositioning initiatives, na mely: research & development, clinical studies, regulatory a airs, pricing, and commercial. By further support from literature within the elds of drug repositioning and R&D project selection a three-step repositioning model was developed. The first step in the three-step repositioning model consists of primary parameters, these are essential parameters that have to be fullled in order to perform a repositioning strategy. If any of the primary parameters are not fullled, the repositioning opportunity should be killed in a go/no-go decision. In a second step, the secondary parameters are evaluated in a scoring model in order to determine the economical outlook of each repositioning opportunity. The opportunities showing greatest economical outlook should further be evaluated in the third and nal step in the three-step repositioning model. In this nal step the di erent repositioning opportunities are evaluated by their coherence with an overall corporate strategy. By applying this repositioning model to a repositioning selection scarce company resources  ay be focused on the repositioning opportunities showing best future prospect. Evaluating the potential of repositioning opportunities in a structured way should also increase chances to succeed. If successful, a repositioning initiative may a ect both company and society as the company improves return on earlier investments, while more patients in need of treatment will receive access to it. However, the three-step repositioning model presented in this thesis should be tested for more cases and perhaps be complemented with additional parameters or di erent gradings in order to optimize the selection.

Several Fungal species have the potential to cause a broad spectrum of diseases in humans, ranging from mild superficial to disseminated invasive infections that involve the bloodstream and vital organs. Invasive fungal infections are severe, life-threatening diseases that result in the deaths of 1.5 million patients each year. The most common fungal species responsible for the majority of invasive fungal infections include Candida, Cryptococcus, and Aspergillus. The current treatment options for invasive fungal infections are restricted to three classes of antifungals: Azoles, polyenes, and echinocandins. The emergence of new fungal species, especially C. auris, marked by high resistance profiles and increased mortality rates (30-60%), has further exacerbated the limitations in its therapeutic options. This emphasizes the urgent need for effective alternatives to combat these deadly pathogens. C. auris isolates exhibited high resistance capability especially against azole (fluconazole) and polyene (amphotericin B) antifungals. Here, we utilized the combinatorial strategy to screen ~3400 FDA-approved drugs and clinical compounds to identify hits that can enhance/restore the antifungal activity of azoles and amphotericin B against resistant C. auris. The HIV protease inhibitors (lopinavir and ritonavir) were identified as potent enhancers to the antifungal activity of azole drugs (fluconazole, voriconazole and itraconazole). We confirmed that lopinavir and ritonavir have the capability to interfere with fungal efflux pump machinery. The in vivo efficacy of the combination of azole antifungals and HIV protease inhibitors was also evaluated to discover the best combination of itraconazole, lopinavir and ritonavir. Three drugs (lansoprazole, rolapitant and idebenone) were identified to effectively enhance the antifungal effects of amphotericin B and overcome its resistance in C. auris. Furthermore, the synergistic interactions of these combinations were applied on other medically important Candida, Cryptococcus, and Aspergillus species. In a comprehensive mechanistic study, we discovered that lansoprazole interferes with an essential target in the fungal mitochondrial cytochrome system, cytochrome bc1. This interference induces oxidative stress in fungal cells and subsequently enhances the antifungal activity of amphotericin B. For rolapitant, a transcriptomic analysis along with ATP luminescence assays confirmed that rolapitant at sub-inhibitory concentrations significantly interferes with ATP production in C. auris. For idebenone, checkerboard assays confirmed the synergistic interactions between amphotericin B and idebenone against a diversity of medically important fungal species. This combination exhibited a rapid fungicidal activity within 4 hours. Additionally, the cytotoxicity of this combination was assessed in a cell line model of kidney cells. Based on the potent in vitro and in vivo synergistic relationships observed for the identified combinations, it can be concluded that our approach offers a new hope to restore the antifungal activity of the existing antifungal drugs, even against resistant fungal infections. Additionally, it provides valuable insights into identifying novel targets to overcome resistance in multidrug-resistant fungal pathogens. / Doctor of Philosophy / Fungi comprise a diverse group of organisms that interact with humans in many good and bad aspects. Candida auris, a recently identified fungus, poses a significant threat to patients with weak immune systems. Infections with C. auris can be associated with mortality rates of up to 60%. Notably, this fungus is characterized by its powerful spreading capability and displays extraordinary resistance to antifungal agents, rendering many existing antifungal drugs ineffective. As a result, there is an unmet need to find efficient treatments for such deadly fungal infections. In this study, several drugs were identified with the potential to restore the activity of traditional antifungal drugs. The study identified four promising drugs (lopinavir, lansoprazole, rolapitant, and idebenone) with the potential to enhance the activity of the antifungal drugs against C. auris. lopinavir showed great potential to enhance the activity of azole antifungals, including fluconazole, voriconazole, and itraconazole. Furthermore, three other drugs (lansoprazole, rolapitant, and idebenone) were identified for their potential to enhance the activity of amphotericin B, which is considered a last-line antifungal therapy. We clarified the mechanisms by which these drugs could restore the activity of antifungal agents. Finally, we confirmed the effectiveness of these combinations in animal models, providing valuable insights into their potential for clinical applications. In summary, our research has opened promising avenues to overcome resistance and develop new treatments for hard-to-treat fungal infections.

Investigating novel treatment approaches to combat Clostridioides difficile Rusha Pal ABSTRACT Clostridioides difficile is the leading cause of antibiotic-induced diarrhea and colitis in hospitals and communities worldwide. The enteric pathogen, classified to be an "urgent threat" by the United States Center for Disease Control and Prevention (CDC), capitalizes on disrupted intestinal microbiome to establish infection with disease symptoms ranging from mild diarrhea to potentially fatal conditions. Disruption of the intestinal microbiome, caused mostly by antibiotic use, enables C. difficile to colonize and proliferate within the host. Paradoxically, antibiotics are used to treat C. difficile infection. These antibiotics decimate the gut microbial community further, thus priming the gastrointestinal tract to become more prone to recurrence of infection. To tackle this clinical setback, we utilized a combination of traditional and non-traditional drug discovery approaches and identified chemical entities and targeted treatment options effective against this toxin-producing intestinal pathogen. Herein, we exploited the strategy of high-throughput screening to identify leads that harbor anticlostridial activity. Our primary phenotypic screen of FDA-approved drugs and natural product libraries led to the identification of novel molecules that were further characterized for their anticlostridial efficacy both in vitro and in vivo. The most potent scaffolds identified were those of mitomycin C, mithramycin A, aureomycin, NP-003875, NAT13-338148, NAT18-355531, and NAT18-355768. Of these, mithramycin A, aureomycin, and NP-003875 were also found to harbor anti-virulence properties as they inhibited toxin production by the pathogen. Furthermore, natural product NP-003875 could confer protection to 100% of the infected mice from clinical manifestations of the disease in a primary infection model of C. difficile. Our final approach has been to develop targeted therapeutics called peptide nucleic acids (PNAs). PNAs are antisense agents capable of inhibiting gene expression in bacteria. In this study, antisense inhibition of the RNA polymerase  subunit gene (rpoA) of C. difficile was found to be bactericidal for the pathogen and could also inhibit the expression of its virulence factors. Additionally, antisense inhibition of the C. difficile rpoA gene was found to be non-deleterious for the tested commensal microflora strains. Given their intriguing anticlostridial properties, it can be concluded that our research opened exciting possibilities that can be further evaluated to uncover new treatments for CDI. / Doctor of Philosophy / Investigating novel treatment approaches to combat Clostridioides difficile Rusha Pal LAYMAN LANGUAGE ABSTRACT Clostridioides difficile is a prominent human pathogen that can colonize the gut and cause fatal infections. C. difficile is the most common cause of microbial healthcare-associated infection and results in substantial morbidity and mortality. The "most urgent worldwide public health threat" label has been assigned to C. difficile by the United States Centers for Disease Control and Prevention (CDC). There is a pressing need to develop new classes of antibiotics with improved efficacy to treat C. difficile infections (CDI). To address the need for novel strategies to combat the growing problem of CDI, we screened FDA-approved drugs and natural products library in search of novel drugs that possess potent and specific anticlostridial activity. Several promising hits were identified and evaluated successfully both in vitro and in vivo. The most potent and novel hits that displayed exceptional activity were mitomycin C, mithramycin A, aureomycin, NP-003875, NAT13-338148, NAT18-355531, and NAT18-355768. Furthermore, a murine model of C. difficile infection revealed that compound NP-003875 conferred 100% protection to the infected mice from clinical manifestations of the disease. Interestingly, these compounds were non-toxic to the gut microflora and human cells. Our final approach has been to develop non-traditional therapeutics to target specific genes in C. difficile. These novel therapeutics are called peptide nucleic acids (PNA). Herein, we designed a PNA targeting RNA polymerase  subunit gene (rpoA) of C. difficile. The designed PNA could successfully inhibit the growth of the pathogen and expression of its virulence factors. In conclusion, our research opened exciting possibilities that can be further evaluated to uncover new treatments for CDI.

Historical hydroelectric stations are part of an aging industrial heritage that is still extremely relevant today through its form of generating energy. Many stations built in the 20th c. are categorized as architectural heritage, therefore protected against demolition or radical change, thus also a radical expansion that would allow to modernize the station and allow for bigger energy output. Viskafors power station in Borås (Sweden) built in 1917 for the former local textile factory,  is a small-scale power station that is marked as architectural heritage, currently owned by Vattenfall.  The town of Viskafors is one of many factory towns along the river and as the industry went bankrupt in the 1970-ties it has become a suburb to the city of Borås. The only public buildings in Viskafors are schools. The town once defined by the industry is now left with an inaccessible waterfront and plenty of unused and unattainable space.The former factory grounds and the restricted area around the hydroelectric station, railway and regional road block the waterfront.The latest station renovation happened in 2013, leaving the second floor and the lift tower empty. Forming another void in the total space that Viskafors has to offer.Can this void be used as leverage to explore the potential of formerly unattainable space within the station and in connection to the waterfront? Keeping this in mind, this thesis aims to find meaningful ways to inhabit and repurpose formerly unattainable space as it is today; to find methods of organizing complex landscapes; initiate a discussion of new thinking of potential hybrid scenarios for the complexities of our future settlements.Can the future be a link to the past and vice versa?The project space stretches from the street level approaching the building to the rooftop, extends into the empty space of the station's second floor, and continues over the other side of the river. The existing second-floor space dimensions are  33 m x 11m x 5.5 m forming a box space. In theory, a box space this size holds infinite potential as long as it remains empty and has no walls, this project aims to explore the method of placing programmed pavilions/interventions as a space-organizing method of work and extending the approach to the rest of the project site area.The aim is to keep the hydroelectric station running while inhabiting the empty space surrounding it, and learning how to live with it.

The site of this diploma project is the small hilltop village of Poggio Aquilone. The village, situated in the region of Umbria in central Italy, lies roughly halfway between Rome and Florence. The Region of Umbria is one of the least populated in Italy, characterized by its hills, river valleys and historical towns such as Assisi, Terni, Todi, Orvieto and the regional capital of Perugia with its 160.000 inhabitants. It is the only landlocked region in central Italy, bordered by Lazio to the south, Marche to the east and Tuscany to the west and north. Primary industries include agriculture, textile, and steel. Tourism has, historically, been relatively modest in Umbria compared to its neighboring regions. Poggio Aquilone, traces its ancestry centuries back, but similar to countless small villages and settlements across Italy and other rural parts of Europe, Poggio Aquilone’s population is dwindling. The youth, in particular, are migrating to larger urban conurbations such as Perugia or Rome. Within the next few decades, two-thirds of the world’s population will live in urban areas, and with urbanization comes large challenges for rural communities. In the specific case of Italy, many of the affected places are of great cultural- and historical value. Old buildings are oftentimes left abandoned and in a state of disrepair, while the rate of new developments and resource waste continue to soar. However, there is a lot of untapped potential in many countryside towns and villages – both social, economic, and cultural – that larger cities lack. The proximity to nature, an affordable cost of living and a peaceful and quiet environment to name a few. An increasing number of city dwellers are missing these valuable factors.  The project strives to explore how architectural strategies can be utilized to strengthen the independence of Poggio Aquilone through means of rural tourism – safeguarding its character and history while improving conditions for long term survival. The project consists of two distinct phases; the first includes an extensive survey and site analysis, the second a proposal for the repurposing of select derelict buildings into dwellings. The survey phase and following processing of the findings are integral parts of this project in their own right, as they have allowed for the exploration of current technology for efficiently and accurately measuring a site, as well as approaching an existing, sensitive environment.

No description available.

No description available.

The site of this diploma project is the small hilltop village of Poggio Aquilone. The village, situated in the region of Umbria in central Italy, lies roughly halfway between Rome and Florence. The Region of Umbria is one of the least populated in Italy, characterized by its hills, river valleys and historical towns such as Assisi, Terni, Todi, Orvieto and the regional capital of Perugia with its 160.000 inhabitants. It is the only landlocked region in central Italy, bordered by Lazio to the south, Marche to the east and Tuscany to the west and north. Primary industries include agriculture, textile, and steel. Tourism has, historically, been relatively modest in Umbria compared to its neighboring regions. Poggio Aquilone, traces its ancestry centuries back, but similar to countless small villages and settlements across Italy and other rural parts of Europe, Poggio Aquilone’s population is dwindling. The youth, in particular, are migrating to larger urban conurbations such as Perugia or Rome. Within the next few decades, two-thirds of the world’s population will live in urban areas, and with urbanization comes large challenges for rural communities. In the specific case of Italy, many of the affected places are of great cultural- and historical value. Old buildings are oftentimes left abandoned and in a state of disrepair, while the rate of new developments and resource waste continue to soar. However, there is a lot of untapped potential in many countryside towns and villages – both social, economic, and cultural – that larger cities lack. The proximity to nature, an affordable cost of living and a peaceful and quiet environment to name a few. An increasing number of city dwellers are missing these valuable factors.  The project strives to explore how architectural strategies can be utilized to strengthen the independence of Poggio Aquilone through means of rural tourism – safeguarding its character and history while improving conditions for long term survival. The project consists of two distinct phases; the first includes an extensive survey and site analysis, the second a proposal for the repurposing of select derelict buildings into dwellings. The survey phase and following processing of the findings are integral parts of this project in their own right, as they have allowed for the exploration of current technology for efficiently and accurately measuring a site, as well as approaching an existing, sensitive environment.