Compared to making a city solely out of one building, it is rather important for people to understand what roles a building can play in a city; especially within urban condition. How a building could actually react and respond to certain human perceptions and functions as an element of a city has become a significant issue. From place to place, the city mutates in several different phases, such as usage, terrain, orientation and material. Therefore, to embrace the urban situation and to optimize the space emerged as the main element of the whole thesis. The particular character of the site starts this program as a mix-usage building from the beginning. Whether it is the usage or orientation that mutates along the city, they should finally come to a concord of optimization and solution that represents the city either on the street or in the sky. / Master of Architecture

In this thesis, we present a new register-transfer level (RTL) test generation method that makes use of two coverage metrics, Branch Coverage, and Mutation Coverage across two stages, to cover hard-to-reach points previously unreached. We start with a preprocessing stage by converting the RTL source to a C++ equivalent using a modified Verilator, which also automatically creates mutants and the corresponding mutated C++ design, based on arithmetic, logical and relational operators during conversion. With the help of extracted Data Dependency and Control Flow Graphs, in every <golden, mutation> pair, branches containing variables dependent on the mutated statement are instrumented to track them. The first stage uses Evolutionary algorithms with Ant Colony Optimization to generate test vectors with mutation coverage as the metric. Two new filtering techniques are also proposed which optimize the first stage by eliminating the need for generating tests for redundant mutants. The next stage is the original BEACON which now takes the generated mutation test vectors as the initial population unlike random vectors, and output final test vectors. These test vectors succeed in improving the coverage up to 70%, compared to the previous approaches for most of the ITC99 benchmarks. With the application of filtering techniques, we also observed a speedup by 85% in the test generation runtime and also up to 78% reduction in test vector size when compared with those generated by the previous techniques. / MS / In the recent years, Verification has become one of the major bottlenecks in integrated circuit design process, which is exacerbated by the increasing design complexities today. Today designers start the design process by abstracting the initial design in a manner similar to software programming language using a higher abstraction language called Hardware Descriptive Language(HDL). Hence, an HDL based design also contains a number of case statements and if-else statements, also called branches, similar to a software design. Branches indicate decision points in the design and high branch coverage based tests can give us an assurance that the design is properly exercised as compared to those given by randomly generated tests. In this thesis, we introduce a new test generation methodology which generates tests using the help of user introduced mutants to ensure higher branch coverage. Mutation testing is similar to a fault testing method, in which an error or a fault is deliberately introduced into the design and we check if the tests generated are able to detect the fault. An important property of a mutant is that: when a mutant is applied and if the mutated part of the design is exercised by the given test suite, then the following data and control flow path taken can be different from that taken on the original design. This important property along with proper guidance is used in our work to reach some branches which are difficult to cover by random test vectors, and this is the main basis of this thesis. Applying this method, we observed that the branch coverage increased with a decrease in test generation runtime and test vector length when compared to previously proposed techniques.

Das Trichorhinophalangeale Syndrom (TRPS) ist eine autosomal-dominant vererbbare Erkrankung, die in drei Subtypen unterteilt wird. Das für alle Typen veränderte TRPS-Gen kodiert einen Zinkfinger-Transkriptionsfaktor, der eine zentrale Rolle im Mineralisierungsprozess des Knochens und im Parathormon-Signalweg spielt. Ziel der vorliegenden monozentrischen Querschnittsstudie war es, die Symptome und Beschwerden der Patienten umfassend zu charakterisieren, die subjektive Lebensqualität zu bewerten, den diagnostischen und therapeutischen Verlauf zu rekonstruieren, potenzielle Veränderungen in den Laborparametern des Knochenstoffwechsels sowie der Knochendichte zu identifizieren und den Bekanntheitsgrad der Erkrankung, insbesondere unter ärztlichen Kollegen in Deutschland, zu erhöhen. Für die Datenerhebung wurde ein speziell auf die Symptome der TRPS-Patienten zugeschnittener Fragebogen entwickelt und ausgewertet. Zusätzlich wurde die Lebensqualität der Teilnehmer mittels standardisierter Fragebögen erfasst. Die vorhandenen Daten zu laborchemischen Parametern, Knochendichte und muskuloskelettalen Defiziten wurden genutzt, um einen umfassenden Überblick über mögliche Einschränkungen bei TRPS-Patienten zu erhalten. Die Analyse der Daten von 13 Patienten mit TRPS Typ 1 ergab, dass die Patienten in zahlreichen Bereichen erhebliche Symptome und Beschwerden aufweisen. Besonders betroffen sind der muskuloskelettale Apparat, der durch Knochenschmerzen, Gelenkschmerzen und Bewegungseinschränkungen beeinträchtigt ist. Interessanterweise zeigte sich, dass nicht die subjektive Schmerzintensität, sondern die Häufigkeit der Beschwerden in direkter Korrelation zu den objektiv messbaren Einschränkungen in der Funktionsdiagnostik steht. In Bezug auf die Rolle des TRPS-Transkriptionsfaktors im Knochenstoffwechsel konnte bei einigen Patienten eine reduzierte Knochendichte nachgewiesen werden. Eine allgemeine Tendenz zur Osteopenie oder Osteoporose nach WHO-Kriterien konnte jedoch nicht bestätigt werden. Dermatologische und faziale Auffälligkeiten, die für die Patienten ebenfalls belastend sind, wurden in ähnlichem Maße wie in der aktuellen Literatur beschrieben. Die Versorgungsstruktur der Betroffenen weist noch erhebliche Verbesserungspotenziale auf. Während die Mehrheit der Patienten in orthopädischer Betreuung steht, wurden bei den wenigsten die Knochendichte oder der Knochenstoffwechsel jemals überprüft. Viele Patienten gaben an, regelmäßig Schmerzmedikamente einzunehmen. Eine spezifische Osteoporosetherapie wurde selten angewandt oder als nicht notwendig erachtet. Trotz des relativ jungen Alters mussten sich viele Patienten bereits operativen Eingriffen unterziehen. Die Mehrheit erhielt jedoch eine unterstützende physiotherapeutische Betreuung zur Linderung der muskuloskelettalen Beschwerden. Der Austausch in Selbsthilfegruppen wie der AG TRPS & MHE wurde nur begrenzt genutzt. Die Auswertung der radiologischen Bilddaten offenbarte hohe Raten der krankheitstypischen Veränderungen, wie Coxa plana, Brachydaktylie und Zapfenepiphysen, die den bisherigen Literaturberichten entsprechen. In den Laborparametern des Knochenstoffwechsels konnten keine generellen Tendenzen zu spezifischen Parametern festgestellt werden. Diese Befunde könnten jedoch auf die Rolle des TRPS-Gens im Mineralisierungsprozess des Knochens hinweisen. Die durchgeführten funktionellen Tests zeigten, dass die Patienten in einigen Bereichen, insbesondere durch körperliche Veränderungen wie den Minderwuchs, alltägliche Einschränkungen erfahren. Dennoch haben sich die meisten Teilnehmer gut an ihre Situation angepasst und erreichten insgesamt durchgehend recht gute Testwerte. Zusammenfassend zeigt diese Studie, dass das Trichorhinophalangeale Syndrom erhebliche Einschränkungen für die Betroffenen mit sich bringt, jedoch insbesondere unter medizinischen Fachkollegen noch weitgehend unbekannt ist. Daher ist es dringend erforderlich, sowohl die molekulargenetischen Grundlagen der Erkrankung als auch die Behandlungs- und Betreuungssituation der Patienten weiter zu erforschen und zu verbessern. / Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant hereditary disease that is divided into three subtypes. The TRPS gene, which is altered for all types, encodes a zinc finger transcription factor that plays a central role in the bone mineralisation process and the parathyroid hormone signalling pathway. The aim of this monocentric cross-sectional study was to comprehensively characterise the symptoms and complaints of the patients, to assess the subjective quality of life, to reconstruct the diagnostic and therapeutic course, to identify potential changes in the laboratory parameters of bone metabolism and bone density and to increase awareness of the disease, particularly among medical colleagues in Germany. A questionnaire specially tailored to the symptoms of TRPS patients was developed and analysed for the data collection. In addition, the participants' quality of life was recorded using standardised questionnaires. The available data on laboratory chemical parameters, bone density and musculoskeletal deficits were used to obtain a comprehensive overview of possible limitations in TRPS patients. The analysis of the data from 13 patients with TRPS type 1 revealed that the patients have significant symptoms and complaints in numerous areas. The musculoskeletal system is particularly affected, with bone pain, joint pain and restricted movement. Interestingly, it was found that it is not the subjective intensity of pain but the frequency of complaints that correlates directly with the objectively measurable limitations in functional diagnostics. With regard to the role of the TRPS transcription factor in bone metabolism, reduced bone density was demonstrated in some patients. However, a general tendency towards osteopenia or osteoporosis according to WHO criteria could not be confirmed. Dermatological and facial abnormalities, which are also stressful for the patients, were described to a similar extent as in the current literature. There is still considerable potential for improvement in the care structure for those affected. While the majority of patients receive orthopaedic care, very few have ever had their bone density or bone metabolism checked. Many patients stated that they regularly take pain medication. Specific osteoporosis therapy was rarely used or not considered necessary. Despite their relatively young age, many patients had already undergone surgery. However, the majority received supportive physiotherapy to alleviate musculoskeletal complaints. The exchange in self-help groups such as the AG TRPS & MHE was only utilised to a limited extent. The evaluation of the radiological image data revealed high rates of changes typical of the disease, such as coxa plana, brachydactyly and cone epiphyses, which correspond to previous literature reports. No general tendencies towards specific parameters could be identified in the laboratory parameters of bone metabolism. However, these findings could indicate the role of the TRPS gene in the bone mineralisation process. The functional tests carried out showed that the patients experience everyday limitations in some areas, particularly due to physical changes such as short stature. Nevertheless, most of the participants adapted well to their situation and achieved very good test scores overall. In summary, this study shows that trichorhinophalangeal syndrome causes considerable limitations for those affected, but is still largely unknown, particularly among medical specialists. There is therefore an urgent need to further research and improve both the molecular genetic basis of the disease and the treatment and care situation for patients.

No description available.

While mutation testing is an effective fault-based testing technique, it has its challenges such as being computationally expensive and requiring a large amount of effort to review surviving mutants. These problems have resulted in mutation testing mostly being restricted to academic research and not as widely adopted in the industry. In the academic context, the focus has been on maximizing the mutation score and while a high mutation score might increase the quality of the software, it is not feasible to kill all the mutants. Moreover, all mutants are not as equally important, and some can not or should not be killed. Instead, the focus should be shifted to prioritizing the productive mutants, those that further improve the test suite or the source code. This thesis investigated if some mutation operators are more suitable for certain types of software by using selective mutation. The mutation operators were evaluated based on their ability to generate productive mutants. Moreover, the mutation operators were analyzed to identify how they could be improved to reduce the number of unproductive mutants generated by them. Dextool Mutate was used to conduct mutation testing on four open-source C/C++ software that were all different types of software. It was concluded that some mutation operators are more suitable for certain types of software resulting in the proposal of a set of mutation operators for each software type. Moreover, various improvements for the mutation operators were identified that reduce the number of unproductive mutants generated. Lastly, it may be helpful to customize the implementation of mutation operators for each type of software and some software types may require additional specialized mutation operators.

HIV-1 protease (PR) inhibitors (PIs) are important anti-HIV drugs for the treatment of AIDS and have shown great success in reducing mortality and prolonging the life of HIV-infected individuals. However, the rapid development of drug resistance is one of the major factors causing the reduced effectiveness of PIs. Consequently, various drug resistant mutants of HIV-1 PR have been extensively studied to gain insight into the mechanisms of drug resistance. In this study, the crystal structures, dimer stabilities, and kinetics data have been analyzed for wild type PR and over 10 resistant mutants including PRL24I, PRI32V, PRM46L, PRG48V, PRI50V, PRF53L, PRI54V, PRI54M, PRG73S and PRL90M. These mutations lie in varied structural regions of PR: adjacent to the active site, in the inhibitor binding site, the flap or at protein surface. The enzymatic activity and inhibition were altered in mutant PR to various degrees. Crystal structures of the mutants complexed with a substrate analog inhibitor or drugs indinavir, saquinavir and darunavir were determined at resolutions of 0.84 – 1.50 Å. Each mutant revealed distinct structural changes, which are usually located at the mutated residue, the flap and inhibitor binding sites. Moreover, darunavir was shown to bind to PR at a new site on the flap surface in PRI32V and PRM46L. The existence of this additional inhibitor binding site may explain the high effectiveness of darunavir on drug resistant mutants. Moreover, the unliganded structure PRF53L had a wider separation at the tips of the flaps than in unliganded wild type PR. The absence of flap interactions in PRF53L suggests a novel mechanism for drug resistance. Therefore, this study enhanced our understanding of the role of individual residues in the development of drug resistance and the structural basis of drug resistance mechanisms. Atomic resolution crystal structures are valuable for the design of more potent protease inhibitors to overcome the drug resistance problem.

Mutation testing is a powerful, but resource intense technique for asserting software quality. This report investigates two claims about one of the mutation operators on procedural logic, the relation operator replacement (ROR). The constrained ROR mutant operator is a type of constrained mutation, which targets to lower the number of mutants as a “do smarter” approach, making mutation testing more suitable for industrial use. The findings in the report shows that the hypothesis on subsumption is rejected if mutants are to be detected on function return values. The second hypothesis stating that a test case can only detect a single top-level mutant in a subsumption graph is also rejected. The report presents a comprehensive overview on the domain of mutation testing, displays examples of the masking behaviour previously not described in the field of mutation testing, and discusses the importance of the granularity where the mutants should be detected under execution. The contribution is based on literature survey and experiment. The empirical findings as well as the implications are discussed in this master dissertation.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Pheochromocytomas and paragangliomas are neuroendocrine tumors that arise from neural crest-derived cells of the adrenal medulla and the extra-adrenal paraganglia. They cause hypertension due to an abnormally high production of catecholamines (mainly adrenaline and noradrenaline), with symptoms including recurrent episodes of headache, palpitations and sweating, and an increased risk of cardiovascular disease. Malignancy in the form of distant metastases occurs in 10-15% of the patients. The malignant cases are difficult to predict and cure, and have a poor prognosis. About a third of pheochromocytomas and paragangliomas are caused by hereditary mutations in a growing list of known susceptibility genes. However, the cause of the remaining, sporadic, tumors is still largely unknown. The aim of this thesis project has been to further characterize the genetic background of pheochromocytomas and paragangliomas, with a focus on the sporadic tumors. First, we investigated the role of the genes known from the familial tumors in the sporadic form of the disease. By studying mutations, copy number variations, DNA methylation and gene expression, we found that many of the known susceptibility genes harbor somatic alterations in sporadic pheochromocytomas. Particularly, we found that the NF1 gene, which plays an important role in suppressing cell growth and proliferation by regulating the RASMAPK pathway, was inactivated by mutations in more than 20% of the cases. The mutations occurred together with deletions of the normal allele and were associated with a reduced NF1 gene expression and a specific hormone profile. We also detected activating mutations in the gene EPAS1, which encodes HIF-2α, in a subset of sporadic cases. Microarray analysis of gene expression showed that several genes involved in angiogenesis and cell metabolism were upregulated in EPAS1-mutated tumors, which is in agreement with the role of HIF-2α in the cellular response to hypoxia. In order to comprehensively investigate all the known susceptibility genes in a larger patient cohort, we designed a targeted next-generation sequencing approach and could conclude that it was fast and cost-efficient for genetic testing of pheochromocytomas and paragangliomas. The results showed that about 40% of the sporadic cases had mutations in the tested genes. The majority of the mutations were somatic, but some apparently sporadic cases in fact carried germline mutations. Such knowledge of the genetic background can be of importance to facilitate early detection and correct treatment of pheochromocytomas, paragangliomas and potential co-occurring cancers, and also to identify relatives that might be at risk. By sequencing all the coding regions of the genome, the exome, we then identified recurrent activating mutations in a novel gene, in which mutations have previously only been reported in subgroups of brain tumors. The identified mutations are proposed to cause constitutive activation of the encoded receptor tyrosine kinase, resulting in the activation of downstream kinase signaling pathways that promote cell growth and proliferation. In summary, the studies increase our biological understanding of pheochromocytoma and paraganglioma, and possibly also co-occurring cancers in which the same genes and pathways are involved. Together with the findings of other scientific studies, our results may contribute to the development of future treatment options.

Early events occurring during induction of the SOS response in Escherichia coli are poorly understood. In order to understand the early steps in SOS induction more fully, we have isolated several mutations which constitutively express the SOS regulon. Using a Mud(Apᴿ,lac) fusion to the SOS regulated gene sulA, we isolated Lac⁺ colonies as mutants in which RecA protein is constitutively activated for repressor cleavage. The mutations map to four loci: dam, lig, uvrD and recA. The extent of constitutive SOS induction in these mutants varied greatly, indicating different levels or types of signal in the cell. The mutations isolated demonstrate two early steps in SOS induction. The first step in SOS induction is signal generation and includes mutations found in dam, lig and uvrD genes. The mutant gene products presumably alter DNA metabolism to produce an inducing signal. These non-lethal mutations lead to sub-induction and probably generate very specific signals, such as abnormally unwound DNA in the case of DNA helicase II mutants or unsealed DNA nicks that result from deficient ligation in lig mutants. Greater induction may require quantitatively more signal or different types of signal generated by severe defects leading to cell death. These mutations also show that signal is a variable quantity, allowing the cell to fine tune the levels of SOS repair activity according to the amount or type of signal (damage) perceived. In some cases (such as dam mutations), blocking the SOS response by lexA(Ind⁻) alleles leads to cell death. In this type of constitutively activated strain, the increased level of repair from SOS induction is required to allow the cell to tolerate potentially lethal DNA structures generated by the mutant gene product. The second step in induction is the interaction of signal with RecA protein and is shown by isolating 8 recA mutants. Mutant recA alleles caused the strongest SOS induction in any mutants obtained, similar to the level found in strains lacking repressor (lexA(Def) mutants). This full induction in the absence of lethal DNA damage underscores the pivotal role of RecA protein in regulating the SOS response.