Due to the rapid development of technology, quality control charts have attracted more attention from manufacturing industries in order to monitor quality characteristics of interest more effectively. Among many control charts, my research work has focused on the multivariate exponentially weighted moving average (MEWMA) and the univariate exponentially weighted moving average (EWMA) control charts by using the Markov chain method. The performance of the chart is measured by the optimal average run length (ARL). My Ph.D. thesis is composed of the following three contributions. My first research work is about differential smoothing. The MEWMA control chart proposed by Lowry et al. (1992) has become one of the most widely used charts to monitor multivariate processes. Its simplicity, combined with its high sensitivity to small and moderate process mean jumps, is at the core of its appeal. Lowry et al. (1992) advocated equal smoothing of each quality variable unless there is an a priori reason to weigh quality characteristics differently. However, one may have situations where differential smoothing may be justified. For instance: (a) departures in process mean may be different across quality variables, (b) some variables may evolve over time at a much different pace than other variables, and (c) the level of correlation between variables could vary substantially. For these reasons, I focus on and assess the performance of the differentially smoothed MEWMA chart. The case of two quality variables (BEWMA) is discussed in detail. A bivariate Markov chain method that uses conditional distributions is developed for average run length (ARL) calculations. The proposed chart is shown to perform at least as well as Lowry et al. (1992)'s chart, and noticeably better in most other mean jump directions. Comparisons with the recently introduced double-smoothed BEWMA chart and the univariate charts for the independent case show that the proposed differentially smoothed BEWMA chart has superior performance. My second research work is about monitoring skewed multivariate processes. Recently, Xie et al. (2011) studied monitoring bivariate exponential quality measurements using the standard MEWMA chart originally developed to monitor multivariate normal quality data. The focus of my work is on situations where, marginally, the quality measurements may follow not only exponential distributions but also other skewed distributions such as Gamma or Weibull, in any combination. The joint distribution is specified using the Gumbel copula function thus allowing for varying degrees of correlation among the quality measurements. In addition to the standard MEWMA chart, charts based on the largest or smallest of the measurements and on the joint cumulative distribution function or the joint survivor function, are studied in detail. The focus is on the case of two quality measurements, i.e., on skewed bivariate processes. The proposed charts avoid an undesirable feature encountered by Xie et al. (2011) for the standard MEWMA chart where in some cases the off-target average run length turns out to be larger than the on-target one. Using the optimal average run length, our extensive numerical results show that the proposed methods provide an overall good detection performance in most directions. Simulations were performed to obtain the optimal ARL results but the Markov chain method using the empirical CDF of the statistics involved verified the accuracy of the ARL results. In addition, an examination of the effect of correlation on chart performance was undertaken numerically. The methods are easily extendable to more than two variables. Final study is about a new ARL criterion for univariate processes studied in detail in this thesis. The traditional ARL is calculated assuming a given fixed process mean jump and a given time point where the jump occurs, usually taken to be from the very beginning in most chart performance studies. However, Ryu et al. (2010) demonstrated that the assumption of a fixed mean shift might lead to poor performance of control charts when the actual size of the mean shift is significantly different and therefore suggested a new ARL-based performance measure, called expected weighted run length (EWRL), by assuming that the size of the mean shift is not specified but rather it follows a probability distribution. The EWRL becomes the expected value of the weighted ordinary ARL with respect to this distribution. My methods generalize this criterion by allowing the time at which the mean shift occurs to also vary according to a probability distribution. This leads to a joint distribution for the size of the mean shift and the time the shift takes place, then the EWRL is calculated as the weighted expected value with respect to this joint distribution. The benefit of the generalized EWRL is that one can assess the performance of control charts more realistically when the process starts on-target and then the mean shift occurs at some later random time. Moreover, I also propose the effective EWRL, which measures the number of additional process runs that on average are needed to detect a jump in the mean after it happens. I evaluate several well-known univariate control charts based on their EWRL and effective EWRL performance. The numerical results show that the choice of control chart depends on the additional information on the transition point of the mean shift. The methods can readily be extended to other control charts, including multivariate charts. / Thesis / Doctor of Philosophy (PhD) / Since the introduction of the standard multivariate exponentially weighted moving average (MEWMA) procedure (Lowry et al. 1992), equal smoothing on all quality variables has been conveniently adopted. In this thesis, a bivariate exponentially weighted moving average (BEWMA) control statistic with unequal smooth- ing parameters is introduced with the aim of improving performance over the standard BEWMA chart. Extensive numerical comparisons reveal that the proposed chart enhances the efficiency and flexibility of the control chart in many mean-shift directions. Recently, Xie et al. (2011) proposed a chart for bivariate Exponential data when the quality measures follow Gumbel’s bivariate Exponential distribution (Gumbel 1960). However, when the process means experience a downward shift (D-D shift), the control charts are shown to break down. In other words, we encounter the strange situation where the out-of-control ARL becomes larger than the in-control ARL. To address this issue, we have proposed two methods, the MAX-MIN and CDF methods and applied them to the univariate EWMA chart. Our numerical results show that not only do our proposed methods prevent the undesirable behaviour from happening, but they also offer substantial improvement in the ARL over the approach proposed by Xie et al. (2011) in many mean shifts. Finally, in general, when it comes to designing a control chart, it is assumed that the size of the mean shift is fixed and known. However, Ryu et al. (2010) proposed a new general performance measure, EWRL, by modelling the size of the mean shift with a probability distribution function. We further generalize the measure by introducing a new random variable, T, which is the transition point of the mean shift. Based on that, we propose several ARL-based criteria to measure the chart performance and try them on several univariate control charts.

Shewhart X bar control charts with estimated control limits are widely used in practice. When the sample size is not fixed,we propose seven statistics to estimate the standard deviation sigma . These estimators are applied to estimate the control limits of Shewhart X bar control chart. The estimated results through simulated computation are given and discussed. Finally, we investigate the performance of the Shewhart X bar control charts based on the seven estimators of sigma via its simulated average run length (ARL).

Organelles within the endomembrane system of all eukaryotic cells exchange membrane lipids and proteins using membrane-bound transport vesicles. This highly conserved vesicular transport process is essential for life and is highly regulated. Much of this regulation is provided by small monomeric GTP-binding proteins such as Arf and Arl that act as molecular switches, cycling between inactive GDP-bound and active GTP-bound states. This cycle of GTP binding and hydrolysis is controlled by guanine-nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), respectively. I have investigated regulatory interactions involving two ArfGAPs, Age1 and Gcs1, involved in post-Golgi vesicular transport in the budding yeast Saccharomyces cerevisiae. In yeast, the Age2 + Gcs1 ArfGAP pair is essential and facilitates post-Golgi transport. I found that overexpression of either the poorly characterized ArfGAP Age1 or the Sfh2 phosphatidylinositol-transfer protein can bypass the requirement for Age2 and Gcs1. Indeed, endogenous Age1 is required for efficient Sfh2-bypass. Moreover, the yeast phospholipase D protein, Spo14, which is activated by Sfh2 and regulates membrane lipid composition, is required for Age1 to effectively alleviate the deleterious effects of defective Age2 + Gcs1 function. My findings suggest that Age1 is regulated by membrane lipid composition and can provide ArfGAP function for post-Golgi transport. Gcs1 is involved in multiple vesicular transport stages, is a dual-specificity GAP for both Arf and Arl1 proteins and, as shown here, also has functions independent of its GAP activity. The absence of Gcs1 causes cold sensitivity for growth and endocytic transport. The cold sensitivity of cells lacking Gcs1 is alleviated by the elimination of either the Arl1 or Ypt6 vesicle-tethering pathway at the trans-Golgi, or by overexpression of Imh1, an effector of the Arl1 pathway. I found elimination of the Ypt6 pathway also prevents Arl1 activation and membrane localization, that Arl1 binding by Imh1 is necessary and sufficient for alleviation, and that the Gcs1 function required for growth and transport in the cold is independent of any GAP activity. My findings suggest that in the absence of this GAP-independent function of Gcs1 the resulting dysregulated Arl1 causes the gcs1? defects through the sequestration of a yet-to-be-determined cellular factor.

Human Systems Integration Capstone / Approved for public release;distribution is unlimited / MANPRINT efforts have the greatest impact when initiated early in the acquisition process, when changes to a system can be made most easily. At this point in time, MANPRINT activities are funded directly by the Program Manager (PM)/Program Executive Office (PEO), who do not tend to allocate appropriate funding for early MANPRINT efforts. For this reason, HRED FE personnel must become MANPRINT salesmen and promote the value of their inclusion and market themselves to the acquisition managers. As support of acquisition programs early in their lifecycle has the greatest need for guidance, this document will largely discuss methods for moving MANPRINT â to the leftâ that can be undertaken at the HRED FE working level. Specifically, this document will detail how to become part of the PMâ s team and what activities would best support the PM once included.

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Candida albicans est une levure pathogène opportuniste de l’homme. La capacité de C. albicans à changer de forme en réponse à des stimuli externes, passant d’une croissance bourgeonnante à filamenteuse, est associée à sa virulence. Cette morphogenèse requiert une réorganisation du cytosquelette d’actine et un trafic membranaire ciblé. Chez Saccharomyces cerevisiae, les petites protéines G de type Arf jouent un rôle important dans le trafic membranaire et la polarité cellulaire. Le rôle de ces protéines chez C. albicans est largement méconnu. C. albicans a 3 protéines Arf, Arf1-Arf3 et 2 Arf-like, Arl1 et Arl3. Nos résultats indiquent que seule Arf2 est nécessaire à la viabilité et à la résistance aux antifongiques, et qu’Arf2 et Arl1 sont critiques pour la croissance filamenteuse hyphale; le mutant arl1/arl1 en particulier forme des hyphes 2 fois plus courtes que la souche sauvage. Les mutants Δ/pTetARF2 et arl1/arl1 ont un défaut de virulence dramatique et ARL1 est particulièrement critique pour la candidose oropharyngée. Nos résultats indiquent que les défauts du mutant Δ/pTetARF2 seraient dus à une altération du Golgi, et ceux d’arl1/arl1 de l’incapacité de ce mutant à restreindre sa croissance à un site unique. Ce défaut de croissance polarisée du mutant arl1/arl1 n’est pas lié à la mislocalisation de son effecteur Imh1, ni à une misrégulation de la phosphatidylsérine flippase Drs2. Par contre, nos données suggèrent que le défaut de croissance hyphale de ce mutant résulterait d’une hypersécrétion. Cette étude nous a permis d’identifier Arf2 et Arl1 comme protéines clés du trafic membranaire, critiques pour la croissance filamenteuse et la virulence de C. albicans. / The human fungal pathogen Candida albicans switches from budding to filamentous growth. This dramatic morphogenesis is critical for its virulence and requires sustained polarized growth, via exocytosis and endocytosis, as well as reorganization of intracellular compartments. In the yeast Saccharomyces cerevisiae, Arf G-proteins and their regulators function at the interface of membrane traffic and cell polarity. The roles of this class of proteins during the transition to filamentous growth and virulence in C. albicans are largely unknown. In C. albicans there are 3 Arf proteins, Arf1-Arf3 and 2 Arf-like proteins, Arl1 and Arl3. Our results reveal that only Arf2 is required for viability and sensitivity to antifungal drugs and that both Arf2 and Arl1 are required for hyphal growth, with arl1/arl1 hyphal filaments being 2-fold shorter than that of the wild-type strain. Furthermore, both Δ/pTetARF2 and arl1/arl1 mutants have drastically reduced virulence, with ARL1 particularly critical for oropharyngeal candidiasis. We show that the defects in Δ/pTetARF2 is due to an alteration of Golgi integrity, while the defects in the arl1 mutant are likely to result from the inability of this mutant to restrict growth to a single site. Further analyses of the arl1/arl1 mutant revealed that this defect does not result from a misregulation of the GRIP-domain golgin coiled-coil tethering protein Imh1 nor of the phosphatidylserine flippase Drs2. Rather, our results suggest that the arl1/arl1 hyphal growth defect results from increased secretion. Together our work identifies Arf2 and Arl1 as key regulators of membrane traffic, critical for hyphal growth and virulence.

Candida albicans est un organisme commensal présent dans le microbiote, qui peut cependant provoquer des infections superficielles mais aussi systémiques, engageant alors le pronostic vital chez les patients immunodéprimés. La transition entre forme bourgeonnante et forme filamenteuse hyphale hautement polarisée, ce qui nécessite une réorganisation du cytosquelette et un trafic membranaire soutenu, est associée à la virulence. Chez les eucaryotes, les GTPases de la famille Rab (Ras related protein in the brain) et leurs régulateurs jouent un rôle central dans le trafic membranaire. L'objectif de ce travail est de comprendre le rôle de ces protéines, en particulier de Ypt6, l'homologue de Rab6 humain, dans la transition morphologique et la virulence de C. albicans. Dans ce but, j'ai construit des mutants « perte de fonction » et déterminé que YPT6 n'est pas essentiel à la viabilité, mais est critique pour l'intégrité de la paroi cellulaire et la croissance hyphale invasive ; les hyphes du mutant ypt6 sont plus courtes que celles de la souche sauvage. En outre, YPT6 est critique pour la virulence dans deux modèles murins de candidose. Lors de la croissance hyphale, Ypt6 est co-localisé avec Arl1, une GTPase de la famille Arf (ADP Ribosylation Factor), également nécessaire pour la croissance hyphale et la virulence de C. albicans. De plus, la surexpression de YPT6 compense spécifiquement le défaut de croissance hyphale du mutant de délétion arl1, mais pas l'inverse. La délétion de YPT6 résulte également en une augmentation du nombre de citernes Golgiennes, suggérant que l'intégrité du Golgi est altérée dans ce mutant. Utilisant de l'imagerie sur cellules vivantes, j'ai montré que la distribution d’Abp1 (Actin binding protein 1), qui est un rapporteur des sites d’endocytose, est aussi altérée dans le mutant ypt6, en ceci qu’elle n’est plus restreinte à l’apex de l’hyphe, comme observé dans les cellules sauvages. Ces données suggèrent que le défaut de maintien de la croissance hyphale du mutant ypt6 est au moins en partie associé à une altération de la distribution des sites d’endocytose. En résumé, j’ai identifié le rôle de Ypt6 dans la croissance hyphale invasive et la virulence du pathogène fongique opportuniste de l’homme C. albicans, et mis en évidence une interaction entre deux GTPases, Ypt6 et Arl1, lors du processus de croissance hyphale. / Candida albicans is a harmless constituent of the human microbiota that causes superficial infections as well as life threatening infections in immune compromised individuals. The transition from a budding form to the highly polarized hyphal form is associated with virulence and requires cytoskeleton reorganization and sustained membrane trafficking. In a range of eukaryotes, Ras related protein in the brain (Rab) G proteins and their regulators have been shown to play a central role in membrane traffic. The objective of this work is to understand the role of Rab proteins, in particular Ypt6, the homolog of Human Rab6, in the morphological transition and virulence of C. albicans. To this aim, I generated loss of function mutants and found that YPT6 is not essential for viability, yet was critical for cell wall integrity and invasive hyphal growth, with ypt6 hyphal filaments shorter compared to that of the wild type (WT). Furthermore, YPT6 was important for virulence in two murine candidiasis models. I determined that Ypt6 was localized at the late Golgi compartment during hyphal growth, where it co-localized with Arl1, a small GTPase of the Arf (ADP Ribosylation Factor) family, also required for hyphal growth and virulence. Interestingly, overexpression of YPT6 specifically rescued the hyphal growth defect of the arl1 mutant, but not the converse. Further characterization of the ypt6 deletion mutant showed that the number of Golgi cisternae is increased in this mutant compared to that of WT strain, suggesting an alteration of Golgi integrity. In addition, using live cell imaging I showed that the distribution of Actin binding protein 1 (Abp1), which is a reporter for actin patches, was altered in the ypt6 mutant, in that it was no longer restricted to the tip of the filament, as is observed in WT cells. These data suggest that the defect in hyphal growth maintenance of the ypt6 deletion mutant is at least partly associated with an alteration of the distribution of endocytic sites. Thus, I identified a critical role of Ypt6 during invasive hyphal growth and virulence in the human fungal opportunistic pathogen C. albicans and revealed an interaction between Ypt6 and Arl1 in the hyphal growth process.

<p>The distribution of asset returns may lead to structural breaks. Thesebreaks may result in changes of the optimal portfolio weights. For a port-folio investor, the ability of timely detection of any systematic changesin the optimal portfolio weights is of a great interest.In this master thesis work, the use of the Shewhart method, as amethod for detecting a sudden parameter change, the implied changein the multivariate portfolio weights and its performance is reviewed.</p><p> </p>

The distribution of asset returns may lead to structural breaks. Thesebreaks may result in changes of the optimal portfolio weights. For a port-folio investor, the ability of timely detection of any systematic changesin the optimal portfolio weights is of a great interest.In this master thesis work, the use of the Shewhart method, as amethod for detecting a sudden parameter change, the implied changein the multivariate portfolio weights and its performance is reviewed.