abstract: Efforts to treat prostate cancer have seen an uptick, as the world’s most commoncancer in men continues to have increasing global incidence. Clinically, metastatic prostate cancer is most commonly treated with hormonal therapy. The idea behind hormonal therapy is to reduce androgen production, which prostate cancer cells require for growth. Recently, the exploration of the synergistic effects of the drugs used in hormonal therapy has begun. The aim was to build off of these recent advancements and further refine the synergistic drug model. The advancements I implement come by addressing biological shortcomings and improving the model’s internal mechanistic structure. The drug families being modeled, anti-androgens, and gonadotropin-releasing hormone analogs, interact with androgen production in a way that is not completely understood in the scientific community. Thus the models representing the drugs show progress through their ability to capture their effect on serum androgen. Prostate-specific antigen is the primary biomarker for prostate cancer and is generally how population models on the subject are validated. Fitting the model to clinical data and comparing it to other clinical models through the ability to fit and forecast prostate-specific antigen and serum androgen is how this improved model achieves validation. The improved model results further suggest that the drugs’ dynamics should be considered in adaptive therapy for prostate cancer. / Dissertation/Thesis / Masters Thesis Mathematics 2020

[pt] Escoamentos intermitentes gás-líquido são encontrados em diversas aplicações de engenharia, como em linhas de produção de petróleo e em sistemas de refrigeração de reatores nucleares. O conhecimento detalhado deste padrão de escoamento é indispensável para a construção de modelos matemáticos representativos deste fenômeno físico complexo. No presente trabalho, foi desenvolvido um estudo experimental com o objetivo de fornecer informações que possibilitem a melhoria dos modelos existentes para o escoamento bifásico intermitente em duto horizontal. A técnica de velocimetria por imagem de partículas estereoscópica (SPIV) de alta frequência foi empregada, em conjunto com a técnica de fluorescência induzida por laser (LIF), permitindo a obtenção de campos de velocidade na região do pistão de líquido, a jusante da bolha alongada, e na região do filme líquido, a montante da bolha. O arranjo experimental possibilitou a medição das três componentes do vetor velocidade do escoamento bifásico água-glicerina e ar na seção transversal de uma tubulação horizontal de 40mm de diâmetro interno. Os resultados obtidos, originais na literatura, mostraram a evolução detalhada das três componentes dos campos médios do vetor velocidade ao longo da passagem da bolha alongada durante o escoamento intermitente. / [en] Gas-liquid intermittent flows can be found in many engineering applications, such as oil production lines and nuclear reactors cooling systems. The detailed knowledge of this flow pattern is necessary for the development of accurate mathematical models of this complex phenomenon. In this work, an experimental study was developed with the goal to provide data that could be used to improve the existing models for two-phase intermittent flow in horizontal pipes. The high-frequency stereoscopic particle image velocimetry (SPIV) technique was employed along with the laser induced fluorescence (LIF) technique, allowing the measurement of velocity fields in the liquid slug, downstream of the elongated bubble, and in the liquid film, upstream of the elongated bubble. The experimental arrangement allowed the measurement of the three components of the velocity vector in an intermittent two-phase water-glycerine and air flow, in a transversal sections of a 40mm internal diameter horizontal pipe. The results obtained revealed original detailed information on the evolution of the three components of the averaged velocity field associated with the passage of the elongated bubble characteristic of the intermittent flow.

Orientador: Marla Andréia Garcia de Avila / Resumo: Trata-se do levantamento de vídeos sobre o cateterismo intermitente limpo no YouTube e avaliação dos acessos de conteúdos voltados do website Cateterismo Digital nas redes sociais. Estudo metodológico dividido em duas etapas com abordagem quantitativa e descritiva para avaliar os conteúdos existentes no YouTube que abordam o cateterismo intermitente limpo e na segunda etapa avaliar os acessos de tecnologias educativas disponibilizadas em redes sociais acerca da temática. Na primeira etapa a amostra constituiu-se por 07 vídeos que descreviam a técnica do cateterismo intermitente limpo com disponibilização gratuita no YouTube. O material foi avaliado por enfermeiros baseado nas recomendações da Sociedade Brasileira de Urologia. A segunda etapa constituiu-se pela avaliação dos acessos das redes sociais Cateterismo Digital, sendo o YouTube a rede social com maior média de visitas ao perfil e impressão de conteúdos. De acordo a avaliação dos acessos das redes sociais Cateterismo Digital pode concluir que os perfis responderam positivamente às expectativas de divulgação dos conteúdos do website aos usuários. Nesse contexto, é importante considerar o potencial que as redes sociais desenvolvidas por profissionais de saúde apresentam como ferramentas tecnológicas educativas, podem ser utilizadas tanto pelos usuários quanto por demais profissionais para nortear a busca por informações seguras online colaborando com a promoção da saúde. / Abstract: This involves surveying videos about clean intermittent catheterization on YouTube and evaluating access to content on the Cateterismo Digital website on social networks. Methodological study divided into two stages with a quantitative and descriptive approach to evaluate the existing content on YouTube that address clean intermittent catheterization and in the second stage to assess the access of educational technologies available on social networks on the subject. In the first stage, the sample consisted of 07 videos that described the technique of clean intermittent catheterization with free availability on YouTube. The material was evaluated by nurses based on the recommendations of the Brazilian Society of Urology. The second stage consisted of assessing the accesses of the social networks Cateterismo Digital, with YouTube being the social network with the highest average number of visits to the profile and content printing. According to the evaluation of the accesses of the social networks Cateterismo Digital can conclude that the profiles responded positively to the expectations of disclosing the contents of the website to users. In this context, it is important to consider the potential that social networks developed by health professionals present as educational technological tools, which can be used by both users and other professionals to guide the search for safe information online, collaborating with health promotion. / Mestre

Les fumeurs consomment des cigarettes de façon intermittente, inhalant chaque cigarette par intermittence, et consommant aussi des cigarettes par intermittence durant la journée. Toutefois, les modèles animaux utilisés pour étudier les effets de la nicotine impliquent un accès continu à la nicotine durant chaque session d’auto-administration. Ici, nous avons donné à des rats un accès intermittent versus continu à la nicotine durant des sessions d’auto-administration. Nous avons ensuite comparé les groupes sur des comportements de consommation caractéristiques de la toxicomanie. Des rats mâles se sont auto-administrés de la nicotine (0.015 ou 0.03 mg/kg/infusion) durant 14 sessions (7h/session). Un groupe avait un accès continu à la nicotine durant chaque session (Long Access, LgA). L’autre groupe avait un accès intermittent (IntA; 12 minutes d’accès à la nicotine par heure). Nous avions donc 4 groupes; LgA-0.015, LgA-0.03, IntA-0.015 et IntA-0.03. Nous avons mesuré la consommation de nicotine et la motivation à consommer différentes doses de nicotine (0.0075, 0.015, 0.03, 0.06mg/kg/infusion), tel que mesuré par l’auto-administration de nicotine sous un horaire de ratio progressif. Après ~15–38 jours d’abstinence, nous avons aussi mesuré la rechute à la consommation induite par une réexposition soit à des stimuli distincts associés à la nicotine, soit à la nicotine elle-même (0.075, 0.15, 0.3 mg/kg, sous-cutané) ou du salin par injection sous-cutanée. Durant les 14 sessions d’auto-administration, les rats LgA-0.03 ont consommé le plus de nicotine. Cependant, après ces 14 sessions, les groupes IntA ont démontré autant de motivation à obtenir la nicotine que les groupes LgA. Les deux groupes avaient aussi une vulnérabilité équivalente à la rechute après la période d’abstinence. L’auto-administration de nicotine par intermittence chez le rat est davantage analogue au mode de consommation de la drogue chez l’humain. De plus, les rats consommant de la nicotine par intermittence prennent nettement moins de drogue que les rats consommant en continu, mais les deux procédures sont tout aussi efficaces pour produire des signes d’addiction à la nicotine. Ceci a des implications pour le raffinement des modèles animaux utilisés dans l’étude des changements neurobiologiques, psychologiques et comportementaux impliqués dans le tabagisme. / Although cigarette smokers consume nicotine and other tobacco products found in cigarettes intermittently throughout each day, procedures to study nicotine effects in laboratory animals involve continuous nicotine access during self-administration sessions. Here, we compared the effects of intermittent versus continuous nicotine self-administration on behavioural features relevant to drug addiction, using an animal model. Four groups of male rats self-administered different doses of nicotine (i.e., 0.015 or 0.03 mg/kg/infusion) during 14 sessions (7 h/session) either as continuous nicotine access (Long Access, or LgA) or intermittent access (IntA; 12 minutes of access to nicotine per hour). We assessed group differences in nicotine intake, as well as nicotine seeking under a progressive ratio schedule of reinforcement (a measure of incentive motivation for drugs). Following nicotine withdrawal, we also measured the susceptibility to cue (withdrawal days 15-30) as well as nicotine-primed (0.075–0.15–3 mg/kg, subcutaneous; withdrawal days 30–38) reinstatement of nicotine-seeking behaviour (measures of relapse). LgA-0.03 rats consumed the most nicotine across the 14 self-administration sessions; however, despite taking much less nicotine than LgA groups, IntA groups showed similar levels of responding for nicotine under a progressive ratio schedule. After nicotine withdrawal, all groups also showed equivalent levels of cue and nicotine induced reinstatement behaviour. IntA nicotine self-administration results in much less drug intake than LgA self-administration, yet the two procedures are equally effective in producing behavioural signs relevant to tobacco addiction. Also, IntA nicotine self-administration serves as a better model of the intermittency of cigarette smoking in humans. Our findings have important implications for preclinical studies investigating the behavioural, psychological, and neurobiological processes involved in tobacco addiction.

Neural synchrony in the brain at rest is usually variable and intermittent, thus intervals of predominantly synchronized activity are interrupted by intervals of desynchronized activity. Prior studies suggested that this temporal structure of the weakly synchronous activity might be functionally significant: many short desynchronizations may be functionally different from few long desynchronizations, even if the average synchrony level is the same. In this thesis, we use computational neuroscience methods to investigate the effects of (i) spike-timing dependent plasticity (STDP) and (ii) noise on the temporal patterns of synchronization in a simple model. The model is composed of two conductance-based neurons connected via excitatory unidirectional synapses. In (i) these excitatory synapses are made plastic, in (ii) two different types of noise implementation to model the stochasticity of membrane ion channels is considered. The plasticity results are taken from our recently published article, while the noise results are currently being compiled into a manuscript.<br><br>The dynamics of this network is subjected to the time-series analysis methods used in prior experimental studies. We provide numerical evidence that both STDP and channel noise can alter the synchronized dynamics in the network in several ways. This depends on the time scale that plasticity acts on and the intensity of the noise. However, in general, the action of STDP and noise in the simple network considered here is to promote dynamics with short desynchronizations (i.e. dynamics reminiscent of that observed in experimental studies) over dynamics with longer desynchronizations.

NR 20140805

Chickpea (Cicer arietinum) is an important legume crop globally ranked third after dry bean (Phaseolus vulgaris) and field pea (Pisum sativum). It constitutes 20% of the total global pulse production and around 95% of its production and consumption takes place in developing countries. Major constraints to chickpea production in sub Saharan Africa (SSA) have broadly been related to abiotic stresses, particularly drought and heat stresses, predicted to increase due to the global climatic changes.Dueto the imperativeness of research for identifying heat tolerance markers for potential chickpea genotype selection, in chapter two of the thesis, the response of four chickpea genotypes to a natural temperature gradient in the field was assessed using chlorophyll fluorescence, non-structural carbohydrate, gas exchange and grain yield. Field experiments were carried out in two winter seasons at three locations with known differences in temperature in NE South Africa. Results showed two genotypes (Acc#3 and Acc#7) were tolerant to heat stress with an Fᵥ/Fₘ of 0.83-0.85 at the warmer site, while the two sensitive genotypes (Acc#RR-2 and Acc#8) showed lower Fᵥ/Fₘ of 0.78-0.80. Both chlorophyll fluorescence measurements: dark-adapted Fᵥ/Fₘ and Fq'/Fₘ' (where Fq' =Fₘ'–F) measured at comparable high light levels correlated positively with grain yield. The two tolerant genotypes also showed higher photosynthetic rates,starch, sucrose and grain yield than the sensitive genotypes at the warmer site. However, these parameters were consistently higher at the cooler than at the warmer sites. It was concluded that genotypes Acc#RR-3 and Acc#7 are heat tolerant and chlorophyll fluorescence and leaf carbohydrates are suitable tools for selection of heat tolerant chickpea genotypes under field conditions. The coolest site of Polokwane showed favourable conditions for chickpea production.Heat and drought stresses are two abioticfactors that often occur simultaneously and are predicted to increase, consequently hampering plant growth. Response of different species to either stresses is well documented but information on the response of the same genotypes to both stresses in chickpea is limited. We aimed to determine whether previously noted heat stress tolerant genotype (Acc#7) is drought tolerant and the heat sensitive (Acc#8) is drought sensitive, and whether intermittent moisture supply at vegetative stage would induce priming effect to later drought at flowering. At vegetative stage, plants were divided into three groups, non-stressed (watered to 75% field capacity (FC), severe water stress (moisture-withholding for 14 days) and treated to 40% FC throughout the experiment (mild-stress), with recovery for the severely stressed plants after which they were stressed (double-stress) at flowering. Drought treatments at vegetative and flowering growth stages decreased physiological parameters and biomass accumulation in both genotypesexcept low water supply at 40% FC that decreased biomass in Acc#7 but not Acc#8. Double drought stress resulted in priming effect in Acc#7, having higher biomass, chlorophyll fluorescence, stomatal conductance, net photosynthesis, and relative water content in comparison to the introduction of stress only at flowering growth stage, as well as in comparison to Acc#8. These results showed that both Acc#7 and Acc#8 are sensitive to drought whereas after priming Acc#7 is better acclimated to drought than Acc#8 associated with osmotic adjustment on leaf relative water content (RWC) and higher capacity to protect photosynthetic activity, making Acc#7 potentially ideal for areas associated with intermittent drought spells. This observation, however, disapproved the hypothesis that Acc#7 is more drought tolerant than Acc#8 but is rather better acclimated than Acc#8, because of its superiority only in primed plants and not those stressed only at either vegetative or flowering stages. The findings emphasise the importance of matching chickpea physiological performance to expected rainfall amounts and distribution in drought prone areas during genotype selection. Chapter four of the thesis was an interrogative proteome analysis of the differences in the heat tolerant and sensitive chickpea (Cicer arietinumL.; Fabaceae) genotypes along a temperature gradient under field conditions which will help in identifying the molecular mechanisms involved in the crop's tolerance. Few studies have thus far combined chickpea physiological and proteome analysis to elucidate the changes in abundance and/or activity of relevant enzymes and expression of heat responsive proteins. In this study, analyses of chlorophyll concentrations, gas exchange, flavonoids and anthocyanin concentrations from a chamber experiment, as well as proteomic parameters from field studies in both the heat tolerant and sensitive genotypes are presented. The heat tolerant genotype Acc#7 maintained unaltered physiological performance at flowering growth stage when exposed to high (35/30°C) and moderate (30/25°C) heat stress, under climate chamber conditions compared to the two heat susceptible genotypes (Acc#RR-2 and Acc#8). Results from the proteomic studies showed an up-regulation in proteins related to protein synthesis (e.g. ribulose bisphosphate carboxylase/oxygenase activase), intracellular traffic (e.g. mitochondrial dicarboxylate/tricarboxylate transporter DTC), defence (e.g. HSP70) and transport (e.g. GTP-binding protein SAR1A-like) in heat tolerant Acc#7 compared to the susceptible Acc#8. Results from KEGG analyses support the involvement of probable sucrose-phosphate synthase and sucrose-phosphate phosphatase proteins in the starch and sucrose pathway,that were up-regulated in the heat tolerant genotype Acc#7. This result was in support of our earlier report where tolerant genotype Acc#7 had higher leaf starch and sucrose concentrations in comparison to the susceptible genotype Acc#8. The presence of these differentially regulated proteins including HSP70, ribulose bisphosphate carboxylase/oxygenase activase, plastocyanin and protoporphyrinogen oxidase shows their potential role in field grown chickpea tolerance to heat stress at flowering growth stage. In conclusion, chlorophyll fluorescence (both Fᵥ/Fₘ and Fq'/Fₘ') and leaf carbohydrates were identified as selection markers that can potentially be used for chickpea phenotyping for heat stress under field conditions with the chlorophyll fluorescence parameters correlating positively with seed yield. Due to its higher biomass, chlorophyll fluorescence (Fᵥ/Fₘ), stomatal conductance, net photosynthesis and RWC, heat tolerant genotype Acc#7 was identified to have better adaptive tolerance to drought stress after priming through exposure to intermittent dry spells than Acc#8. Furthermore, under controlled climate chamber conditions, Acc#7 consistently showed characteristics of tolerance to heat stress while Acc#RR-2 and Acc#8 were heat susceptible. Higher chlorophyll fluorescence, grain yield, chlorophyll concentrations, gas exchange, flavonoids and anthocyanin concentrations for Acc#7 compared to Acc#8 in the climate chamber was further validated by the higher up-regulation of proteins involved in protein synthesis, intracellular traffic, defence and transport in Acc#7 compared to Acc#8. The incorporation of proteomics in heat and drought stress studies will potentially help further the understanding of mechanisms by which the crop responds to these stresses.

Variable mortality of Pyrenophora semeniperda--infected Bromus tectorum seeds has been referred to as a "race for survival", stating that seeds that germinate quickly are more likely to escape pathogen-caused mortality. Dormancy status is not the only variable determining outcomes within the Bromus-Pyrenophora pathosystem. Varying temperature and exposure to water may strongly influence germination outcomes of B. tectorum when in the presence of P. semeniperda. Low water potentials characteristic of semi-arid soils are often over-looked in the context of seed pathogens, and are ecologically relevant- especially for plant species that inhabit intermittently dry environments. To adequately characterize the Bromus tectorum-Pyrenophora semeniperda pathosystem, four studies were conducted to address the following questions: (1) do temperature, water potential, and dormancy status influence germination outcomes in the Bromus-Pyrenophora pathosystem, (2) do repeated wetting-drying scenarios influence germination outcomes of infected B. tectorum seeds following dehydration at low water potentials similar to those found in the field (i.e., -4 through -150 MPa), (3) can we accurately characterize the asexual life cycle of P. semeniperda on a dormant B. tectorum seed, determining when infection takes place, and what occurs during disease development in continuously hydrated conditions, and (4) how does disease development of P. semeniperda influence the B. tectorum seed embryo and endosperm. All studies were conducted using dormant and/or non-dormant B. tectorum seeds and an intermediate strain of P. semeniperda. Study one used varying temperatures (5-20°C), and five water potentials (0, -0.5, -1, -1.5, -2 MPa) (achieved using PEG 8000). Inoculated seeds were exposed to low water potentials at various temperatures for 7, 14, 21, or 28 days then re-hydrated for 28 days. In the second study, seeds were incubated at 20°C at four nominal water potentials (-4, -10, -40, or -150 MPa) following 8 or 24 hours of initial hydration. Seeds were dehydrated for 1, 7, 14, or 21 days, then re-hydrated. In study three, inoculated seeds were chemically fixed between days 0 and 21 and viewed with a scanning electron microscope. In the fourth study, infected seeds were frozen with liquid nitrogen following 3, 8, and 14 days of disease development, then cross sectioned longitudinally and laterally prior to chemical fixation. Results indicate that non-dormant seeds escape death by germinating rapidly under favorable conditions, that incubation at low water potentials greatly increases seed mortality, that -10 MPa is near the threshold for full pathogen activity, and at water potentials lower than -40 MPa, P. semeniperda may successfully survive severe dehydration if previous hydration resulting in infection has occurred. SEM images indicate that mycelia penetration occurs within 8-24 hours, and that mycelium may penetrate all opening in the seed (i.e., stomata, cracks). Development of P. semeniperda is shown to cause significant damage to the endosperm and embryo within 8 days. As starch is consumed, the endosperm collapses leaving a hollow middle. The embryo is more resilient, but gradually deforms and deteriorates.

In this project an experimental setup is designed to investigate the effect of intermittent load patterns in combination with moisture content on cellulose ageing. It is done by exposing groups of samples to different intermittent load patterns with varying frequency. A literature review is done on transformer insulation system and cellulose degradation. Various technical solutions to different aspects of the experimental design are reviewed. The final experimental setup is explained with the primary focus being on the hardware and programming of the controlling system. The controlling system consists of a Data Acquisition (DAQ) system from National Instruments and is programmed in LabVIEW. The controlling system is examined in two investigative tests where it performed satisfactorily. Three load patterns are developed. This project suggests how to prepare the samples and what direct- and indirect tests to apply to the insulation system for future analysis.Over the years, a considerable amount of scientific work has been devoted to understanding paper ageing in order to improve transformer diagnostics and investments for utility owners. However, transformer loading guidelines of today do not take intermittent load in combination with moisture content into account [1] [2]. Previous work suggests that the thermal models may be improved by looking into the effects of moisture content [3].The primary aim of the proposed experimental setup is to investigate whether an intermittent load pattern in combination with moisture content have a considerable detrimental effect on cellulose ageing. The intent is to contribute with new knowledge about transformer diagnostics and long-term possibly improve the current thermal models used for Dynamic Transformer Rating (DTR) which do not take this phenomenon into account. This would in particular benefit transformers with typically intermittent load patterns, e.g. a transformer connected to a wind farm or photovoltaic panels. Increasing renewable energy installations increase the need for developing the thermal models in the transformer loading guidelines to take unconventional load profiles into account. / I det här projektet utformas ett experiment för att undersöka inverkan av intermittenta lastmönster i kombination med fukthalt på åldrande av cellulosa. Detta görs genom att utsätta provgrupper för olika lastmönster med varierande frekvens. En litteraturgenomgång görs på transformatorisoleringssystem och nedbrytning av cellulosa. Olika tekniska lösningar för olika aspekter av experimentets design ses över. Den slutliga utformningen av experimentet förklaras med fokus på hårdvara och programmering av kontrollsystemet. Kontrollsystemet består av ett system för datainsamling från National Instruments och programmeras i LabVIEW. Kontrollsystemet utvärderas i två undersökande test där det förfor på ett tillfredsställande sätt. Tre lastmönster till experimentet har tagits fram. Det här projektet föreslår hur man förbereder proverna och vilka direkta och indirekta test som kan göras för framtida analyser.Under åren har en betydande mängd vetenskapligt arbete ägnats åt att förstå pappersåldring för att förbättra transformatordiagnostik och investeringsunderlaget för nätägare. De industriella standarderna tar dock inte hänsyn till intermittent belastning i kombination med fukthalt [1] [2]. Tidigare arbete föreslår att de termiska modellerna möjligen kan förbättras genom att undersöka effekterna av fukthalt [3].Det huvudsakliga målet med den föreslagna experimentella uppställningen är att undersöka huruvida ett intermittent belastningsmönster i kombination med fukthalt har en betydande inverkan på pappersåldrandet. Föresatsen är att bidra med ny kunskap om transformatordiagnostik och för att om möjligt långsiktigt förbättra de nuvarande termiska modellerna som används till dynamiska lastbarhetsmodeller för transformatorer. Detta skulle särskilt gynna transformatorer med typiskt intermittenta belastningsmönster, t ex en transformator ansluten till en vindkraftpark eller solcellspaneler. Ökande antal av anläggningar för förnybar energi ökar behovet av att utveckla de termiska modellerna för att ta hänsyn till okonventionella lastprofiler.

As we move deep into nanometer regime of CMOS VLSI (45nm node and below), the device noise margin gets sharply eroded because of continuous lowering of device threshold voltage together with ever increasing rate of signal transitions driven by the consistent demand for higher performance. Sharp erosion of device noise margin vastly increases the likelihood of intermittent failures (also known as parametric failures) during device operation as opposed to permanent failures caused by physical defects introduced during manufacturing process. The major sources of intermittent failures are capacitive crosstalk between neighbor interconnects, abnormal drop in power supply voltage (also known as droop), localized thermal gradient, and soft errors caused by impact of high energy particles on semiconductor surface. In nanometer technology, these intermittent failures largely outnumber the permanent failures caused by physical defects. Therefore, it is of paramount importance to come up with efficient test generation and test application methods to accurately detect and characterize these classes of failures. Soft error rate (SER) is an important design metric used in semiconductor industry and represented by number of such errors encountered per Billion hours of device operation, known as Failure-In-Time (FIT) rate. Soft errors are rare events. Traditional techniques for SER characterization involve testing multiple devices in parallel, or testing the device while keeping it in a high energy neutron bombardment chamber to artificially accelerate the occurrence of single events. Motivated by the fact that measurement of SER incurs high time and cost overhead, in this thesis, we propose a two step approach: hii a new filtering technique based on amplitude of the noise pulse, which significantly reduces the set of soft error susceptible nodes to be considered for a given design; followed by hiii an Integer Linear Program (ILP)-based pattern generation technique that accelerates the SER characterization process by 1-2 orders of magnitude compared to the current state-of-the-art. During test application, it is important to distinguish between an intermittent failure and a permanent failure. Motivated by the fact that most of the intermittent failures are temporally sparse in nature, we present a novel design-for-testability (DFT) architecture which facilitates application of the same test vector twice in a row. The underlying assumption here is that a soft fail will not manifest its effect in two consecutive test cycles whereas the error caused by a physical defect will produce an identically corrupt output signature in both test cycles. Therefore, comparing the output signature for two consecutive applications of the same test vector will accurately distinguish between a soft fail and a hard fail. We show application of this DFT technique in measuring soft error rate as well as other circuit marginality related parametric failures, such as thermal hot-spot induced delay failures. A major contribution of this thesis lies on investigating the effect of multiple sources of noise acting together in exacerbating the noise effect even further. The existing literature on signal integrity verification and test falls short of taking the combined noise effects into account. We particularly focus on capacitive crosstalk on long signal nets. A typical long net is capacitively coupled with multiple aggressors and also tend to have multiple fanout gates. Gate leakage current that originates in fanout receivers, flows backward and terminates in the driver causing a shift in driver output voltage. This effect becomes more prominent as gate oxide is scaled more aggressively. In this thesis, we first present a dynamic simulation-based study to establish the significance of the problem, followed by proposing an automatic test pattern generation (ATPG) solution which uses 0-1 Integer Linear Program (ILP) to maximize the cumulative voltage noise at a given victim net due to crosstalk and gate leakage loading in conjunction with propagating the fault effect to an observation point. Pattern pairs generated by this technique are useful for both manufacturing test application as well as signal integrity verification for nanometer designs. This research opens up a new direction for studying nanometer noise effects and motivates us to extend the study to other noise sources in tandem including voltage drop and temperature effects.