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1
Raitio, M. (Maarit). "Caries risk determination and cost-effectiveness of targeted prevention in adolescents." Doctoral thesis, University of Oulu, 2005. http://urn.fi/urn:isbn:9514266366.
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Abstract
The aim of this study was to assess a series of caries risk indicators to find a suitable model for
screening adolescents for risk cases, and to evaluate the long-term efficacy and cost-effectiveness of an
one-year intervention programme provided for the resulting risk groups.
To reduce the spread of infectious diseases at 20 day-care centres, risk factors for the occurrence of
salivary mutans streptococci were surveyed in 345 children before and after 8 months of intervention, i.e.
withdrawal of tooth brushing in 10 centres. Dental health habits were evaluated by means of questionnaires.
Four clinical and six salivary tests were related to 11-month caries increment in 181 adolescents. The 109
high-risk subjects presenting four or more risk factors were provided either with chlorhexidine or fluoride
treatment, the low-risk group receiving basic prevention. An age and sex-matched control group was chosen.
Life-long data on all 390 subjects were collected from their dental records. Survival analysis was applied,
taking as the starting point the time of tooth eruption and as the event the first filling due to caries.
The costs of the intervention and the number of fillings were compared between the groups.
The dental health of the risk groups tended to approach the average level for the control group. One
tooth surface per subject was saved from filling. The costs of fillings for the control group were twice as great
as those for the risk groups at the end of the intervention, but only slightly more after the five-year
follow-up period.
The model (DFS, Candida and sucrase) offers additive information for finding adolescents at risk
of caries, and for targeting preventive measures at the individual level and for the motivation of patients. The results stress the importance of dental age and of
providing preventive procedures at the time of tooth eruption. The present risk-based strategy proved to be
of moderate benefit to dental health by comparison with the costs of normal preventive and restorative care
and cannot be recommended as such for a target population with a high risk of caries.
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Bourgeois, Karine. "Towards in vitro Pharmacokinetic Assessment of Novel Targeted Covalent Inhibitors for Human Tissue Transglutaminase." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39472.
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Human tissue transglutaminase (TG2) is a calcium-dependent multifunctional enzyme that natively catalyzes the post-translational modification of proteins, namely by the formation of isopeptide bonds between protein- or peptide-bound glutamine and lysine residues. This ubiquitously expressed enzyme plays important roles in cellular differentiation, extracellular matrix stabilization, and apoptosis, to name a few. However, its unregulated activity has been associated with many pathologies such as fibrosis, cancer, neurodegenerative disorders and celiac disease. Most of these disorders are associated with unregulated acyl-transferase activity. As such, the Keillor group has directed its efforts towards the development of TG2 inhibitors.
Over the years, the Keillor group has synthesized large libraries of targeted covalent inhibitors against TG2. These compounds have undergone pharmacodynamic testing in order to examine their kinetic parameters of inhibition. Having gained knowledge of their enzyme kinetics, the logical next step was to consider their pharmacokinetic profiles. In the context of this thesis, we considered two important pharmacokinetic properties: membrane permeability and off-target reactivity.
Firstly, we aimed to evaluate our inhibitors for their ability to permeate the cell membrane. In efforts to do so, we were able to adapt, optimize, and validate a parallel artificial membrane permeability assay (PAMPA) utilizing hexadecane as our artificial membrane. We were able to test a few of our own inhibitors and found that compounds NC9, VA4 and AA9 possess Log Pe values of -5.26 ± 0.01, -4.66 ± 0.04 and -6.5 ± 0.5 respectively.
Secondly, we sought to investigate the susceptibility of our inhibitors to glutathione addition reactions under physiological conditions. We adapted and optimized a colorimetric assay using Ellman’s reagent (DTNB) and found that our inhibitors are minimally reactive with glutathione.
The methods developed over the course of this work provide protocols that can be adopted for the characterization of future inhibitors in the Keillor group, along the process of developing TG2 inhibitors into drug candidates.
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Clark, Paul Ivor. "CDM regulations : safety targeted assessment through gateway evaluation (stage) approach." Thesis, University of the West of England, Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.573115.
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It has been well published that employment within the construction industry, particularly in manual roles, is a dangerous occupation. Within the United Kingdom (UK) some 2.2 million people are employed within this sector and during the last 25 years, over 2,800 people have died with many more injured or suffering ill health as a result of this occupation. Further to this, many more people have indirectly been killed or suffered injury or ill health by poorly designed and constructed workplaces. As a consequence, much research on occupational health and safety within this sector has been undertaken to establish root causes of accidents and ill health. One attributor identified by research is ineffective consideration of health and safety by construction designers during the design development stages. Legislation via the Construction (Design and Management) Regulations 2007 (CDM2007) has been introduced in the UK to provide clear responsibilities on construction designers towards occupational health and safety. This responsibility requires construction designers to consider the impact of their design on the health and safety of those affected by the construction and end use, including end users, maintenance staff and future demolition workers. However, recent research has repeatability shown that CDM has not achieved the desired effect and that many construction designers are failing to fulfil their statutory designer duty obligations as defined by CDM2007 This research explores the established link between poor design and accident causation and the reported failures of construction designers to effectively manage their legal and moral obligations by considering health and safety implications of their designs. It uses data from existing studies, interviews, focus groups, online forums, questionnaires and case study observations, using a mixed method approach, targeting registered Architects. The research uncovers a number of underlying barriers that potentially hinder designer consideration of Health and Safety, proposes a number of influencing factors that act as triggers for design team involvement and suggests a framework to utilize these factors. The developed framework, called STAGE, establishes a series of structured design reviews throughout the design and construction phases of a project and provides tools to encourage and support collective consideration of health and safety risks. This method supports development of a safety culture with focus on collective knowledge sharing and encouragement of holistic and pre planned structured safety reviews. As pointed out by Walker (1989), disasters of all kinds occur with monotonous regularity in humanly devised systems. This impresses upon us the fact that good design is not simply a question of taste or style; it is literally a matter of life and death.
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Chajnacki, Gregory M. "An assessment of human resource career development programs within targeted city governments." Instructions for remote access. Click here to access this electronic resource. Access available to Kutztown University faculty, staff, and students only, 1995. http://www.kutztown.edu/library/services/remote_access.asp.
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Thesis (M.P.A.)--Kutztown University of Pennsylvania, 1995.Source: Masters Abstracts International, Volume: 45-06, page: 2936. Abstract precedes thesis as preliminary leaves i-iv. Typescript. Includes bibliographical references (leaves 80-84).
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Matlebjane, Dikeledi M. A. "In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design." Diss., University of Pretoria, 2017. http://hdl.handle.net/2263/63045.
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Malaria is a major public health problem that affects millions of lives globally. The increased
burden of malaria requires new interventions that will address the eradication of the disease.
Current interventions include vector control by using insecticide-treated bed nets and indoor
residual spraying, and antimalarial drugs to control the parasite. Parasite resistance has
been reported for the currently used effective antimalarial drugs. To pre-empt the impact of
parasite resistance a continued development of new antimalarial drugs that have novel
mechanisms of action should be pursued. Antimalarial drug discovery requires that potential
antimalarial drugs should have different drug targets to those already targeted, to lower the
chances of resistance. Potential antimalarial drugs should preferably provide a single radical
cure to prevent reproduction at all life cycle stages.
This study tested the effects of in silico designed compounds targeting plasmodial Ca2+-
dependent protein kinases (CDPK) 1 & 4, FIKK kinases and bromodomain proteins on the
Plasmodium parasite. These enzymes are involved in gene regulation and are important
factors during gene transcription. In P. falciparum the gatekeeper kinases contain small
hydrophobic pockets near the ATP-binding site. These hydrophobic pockets allow for
selective inhibition of these proteins at the ATP-binding site. The compounds were tested in
vitro to determine their antiplasmodial activity. These compounds are shown to be potential
inhibitors of the intra-erythrocytic P. falciparum parasites as three of the compounds showed
selective cytotoxic activity at less than 1 μM against the chloroquine sensitive laboratory
strains (3D7 and NF54). Even though the proteins targeted by these compounds have been
previously indicated to play a role at specific stages during the parasite’s life cycle, the
compounds tested here were not able to target the sexual gametocyte stages of the
Plasmodium parasite. Further optimisation of these compounds should be performed to
improve activity against both the asexual and sexual stages of the parasites.Dissertation (MSc)--University of Pretoria, 2017.
Pharmacology
MSc
Unrestricted
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Hurlbut, Madeleine A. "Deconstructing 'Empowerment' in Nike's 2010 Campaign: A Critical Assessment of Female-Targeted Sports Advertising." Scholarship @ Claremont, 2015. http://scholarship.claremont.edu/scripps_theses/567.
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This paper explores the ways in which Nike's 2010 'Make Yourself' campaign claims to promote 'female empowerment', when in actuality it supports beauty standards that serve to disempower and devalue women. This paper uses various semiotic and deconstructive techniques to explore this issue, including close readings of both the film and photographic texts of the campaign.
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Berry, Michael CSE UNSW. "Assessment of software measurement." Awarded by:University of New South Wales. CSE, 2006. http://handle.unsw.edu.au/1959.4/25134.
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Background and purpose. This thesis documents a program of five studies concerned with the assessment of software measurement. The goal of this program is to assist the software industry to improve the information support for managers, analysts and software engineers by providing evidence of where opportunities for improving measurement and analysis exist. Methods. The first study examined the assessment of software measurement frameworks using models of best practice based on performance/success factors. The software measurement frameworks of thirteen organisations were surveyed. The association between a factor and the outcome experienced with the organisations' frameworks was then evaluated. The subsequent studies were more info-centric and investigated using models of information quality to assess the support provided for software processes. For these studies, information quality models targeting specific software processes were developed using practitioner focus groups. The models were instantiated in survey instruments and the responses were analysed to identify opportunities to improve the information support provided. The final study compared the use of two different information quality models for the assessing and improving information support. Assessments of the same quantum of information were made using a targeted model and a generic model. The assessments were then evaluated by an expert panel in order to identify which information quality model was more effective for improvement purposes. Results. The study of performance factors for software measurement frameworks confirmed the association of some factors with success and quantified that association. In particular, it demonstrated the importance of evaluating contextual factors. The conclusion is that factor-based models may be appropriately used for risk analysis and for identifying constraints on measurement performance. Note, however, that a follow-up study showed that some initially successful frameworks subsequently failed. This implied an instability in the dependent variable, success, that could reduce the value of factor-based models for predicting success. The studies of targeted information quality models demonstrated the effectiveness of targeted assessments for identifying improvement opportunities and suggest that they are likely to be more effective for improvement purposes than using generic information quality models. The studies also showed the effectiveness of importance-performance analysis for prioritizing improvement opportunities.
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Engelhardt, Kerstin. "Assessment of the antibiotic production potential of marinederived actinomycetes via bioactivity screening and targeted genetic analysis." Doctoral thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for bioteknologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-11793.
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Drug discovery from marine organisms is gaining momentum and research focusing on marine actinomycete diversity has yielded numerous novel secondary metabolites with unique chemical structures. This study was based on targeted analyses of marine actinobacteria selected from a library of ca. 10.000 isolates cultivated from sediment- and sponge-samples in the Trondheim fjord, Norway. The two small sub-collections used in this study consisted of 35 shallow-water sediment-derived actinomycetes (“sub-library I”) and 27 deep-water sediment- and sponge-derived actinobacterial isolates (“sub-library II”). The isolates in these collections were analyzed for: (i) the influence of seawater on growth; (ii) their phylogenetic diversity based on molecular taxonomy, and (iii) their antibiotic production potential. The presence of seawater had different effects on the growth of the studied isolates. A preference for seawater or an obligatory requirement indicated the presence of indigenous marine actinomycetes in sub-library I and was used as a criterion for selection of isolates in sub-library II. The preliminary classification of isolates was performed by 16S rRNA gene sequence analysis which revealed significant biodiversity. Representatives of 11 different actinomycete genera were identified in sublibrary I and members of 8 genera confirmed in sub-library II. The results of a PCR screening for poly ketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) genes demonstrated the genetic potential to produce secondary metabolites with poly ketide and/or non-ribosomal peptide backbones for the majority of isolates in both sub-libraries. Whole-cell based antimicrobial assays involving microtitre cultivations and multiple fermentation media were performed using isolates of sub-library II with the objective to find producers of new antibacterial or antifungal compounds. Extracts with antibacterial or antifungal activity were identified for more than 50% of the isolates subjected to this screening. Nine isolates produced compounds with activity against multi-resistant bacterial and/or fungal strains. Fermentation extracts of isolate Nocardiopsis sp. TFS65-07 from sub-library II displayed high activity against vancomycin-resistant Enterococcus faecium. The active antibacterial compound was purified from fermentation extracts of TFS65-07 and structure elucidation identified it as a new member of the thiopeptide antibiotic family. The gene cluster for biosynthesis of the new thiopeptide, TP-1161, was identified by mining a draft genome sequence obtained for the producing organism. The proposed identity of the cluster was confirmed by gene inactivation experiments. Bioinformatics analyses of genes constituting the cluster and their products allowed proposition of the biosynthetic pathway for TP-1161. A cosmid containing the TP-1161 cluster (tpa) was isolated from a genomic cosmid library constructed for TFS65-07 and used for further studies of tpa gene functions. For heterologous expression, the cosmid was modified inserting the ΦC31 integration function and a selective marker, and successfully introduced into the genome of Streptomyces coelicolor M512. Heterologous production of TP-1161, however, could not be detected in M512. Further studies involving e.g. alternative hosts could pave the way for a systematic functional analysis of all genes involved in the TP-1161 biosynthesis.
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Harbor, Aderonke Omolola. "Assessment of the monitoring and evaluation tools for transversal training management agency for targeted community based organizations." Thesis, University of Fort Hare, 2014. http://hdl.handle.net/10353/1172.
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The purpose of this study was to determine if monitoring and evaluation tools at a local level could help bring about sustainability of rural projects of the community based organizations thereby making the livelihoods of community members better in the Eastern Cape Province. To accomplish this objective, a case study of the training provided by Transversal Training Management Agency (TTMA) was assessed within the concept of the practice of evaluation and seeking to answer four research questions: To what extent should capacity development create sustainable managerial competencies for rural projects? Are monitoring and evaluation tools the key to sustainable projects? How will knowledge and application of M&E tools improve capacity development of CBOs? What are the policy lessons that can be derived from the application of M&E tools for the grass roots groups? The research design was in two parts namely the literature review which focuses on the roles of social change theory and program theory approaches of evaluation which is best applicable for the grassroots, then the case study of TTMA. This was a qualitative research whereby secondary data source was mainly used. The researcher was an employee of TTMA within the period of study, therefore, was able to validate information. Multiple community projects were studied using the secondary data analysis. This was necessary because of the geographic spread of the CBOs that were trained all around the Eastern Cape province and the language barrier would have pose a challenge to the researcher if all project members were to be interviewed. The main findings of the study shows that training was well conducted and project members gave positive feedback about training but what was absent in the training is a study of a monitoring and evaluation framework for the projects‘ members as one of the necessary managerial competencies in order for them to track progress and warning signals in the project cycle before it is too late. In conclusion some recommendations have been made amongst which is a practical handbook of M&E for the grassroots. This provides variety of tools that can best suit the literacy levels of project members that this study targeted. TTMA can therefore, adopt this as part of the training courses for project sustainability.
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Klingler, Stefan [Verfasser]. "Combination of geophysical and hydrogeological methods for the targeted assessment of fine-grained valley fills / Stefan Klingler." Tübingen : Universitätsbibliothek Tübingen, 2021. http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1182889.
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Lamendella, Regina. "Assessment of Fecal Source Pollution in Plum Creek Watershed, Nebraska Using Bacteroidetes-Targeted PCR Assays and Phylogenetic Analysis." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1141427143.
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McCormick, Deirdre. "The development and evaluation of an integrated nursing approach to delivering targeted interventions based on health needs assessment." Thesis, Glasgow Caledonian University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486488.
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The aim of this Action Research study was to evaluate the development of an integrated nursing team delivering targeted interventions based on Health Needs Assessment in one primary health care team. The study was located within a Local Health Care Cooperative in an urban area of Scotland. Participants included 6 general practitioners, 2 health visitors, 3 district nurses, 2 practice nurses, 2 nursing auxiliaries and a treatment room nurse. The introduction of the integrated community nursing approach was mapped across a four Cycle design which took place over two years and two months. This included illumination of the integrated nursing team concept and the nature of the change required for its introduction drawing on a normative re-educative model of change. Data collection approaches included 18 focus groups, 20 individual interviews, participant observation, nursing diaries, and the Team Climate Inventory Questionnaire. Although effort was taken to progress in the collaborative spirit of action research, evidence of team ownership of integrated nursing did not emerge until the fourth and final action cycle. The study illuminates the complexities of achieving integrated nursing approaches and determinants for success. For example, role differences and the differing underlying philosophies for each of the nursing disciplines presented specific challenges. Health needs assessment used as a tool to support the development of integrated nursing, has proved to be of value as a means to overcome boundary issues and securing commitment to integrated working. The findings suggest that for integrated nursing to be effective greater emphasis needs to be placed on the identification of priority areas using a comprehensive health needs assessment where nurses are motivated and can lead developments. The study has demonstrated that the integrated nursing approach may involve complete role overlap or the contribution of specific expertise in the delivery of targeted interventions. The complexity of achieving integrated approaches however demands resources, appropriate facilitation, protected time for key stakeholders to engage in the change process and to optimise opportunities for interprofessional learning.
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Ullrich, Roland Tillmann [Verfasser], Jürgen [Akademischer Betreuer] Wolf, and Peter [Akademischer Betreuer] Kloppenburg. "Molecular imaging for the quantitative assessment of tumor proliferation, progression and the early assessment of molecular targeted treatment response / Roland Tillmann Ullrich. Gutachter: Jürgen Wolf ; Peter Kloppenburg." Köln : Universitäts- und Stadtbibliothek Köln, 2010. http://d-nb.info/1037851145/34.
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Ullrich, Roland [Verfasser], Jürgen [Akademischer Betreuer] Wolf, and Peter [Akademischer Betreuer] Kloppenburg. "Molecular imaging for the quantitative assessment of tumor proliferation, progression and the early assessment of molecular targeted treatment response / Roland Tillmann Ullrich. Gutachter: Jürgen Wolf ; Peter Kloppenburg." Köln : Universitäts- und Stadtbibliothek Köln, 2010. http://nbn-resolving.de/urn:nbn:de:hbz:38-33173.
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Vinayan, Anup. "Targeted anti-angiogenic therapy in metastatic renal cell carcinoma and methodological improvements in assessment of therapeutic response with imaging biomarkers." Thesis, University of Hertfordshire, 2018. http://hdl.handle.net/2299/20960.
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Background: Drugs targeting angiogenic pathway remain the mainstay of treatment for metastatic renal cell carcinoma (mRCC). Tyrosine Kinase Inhibitors (TKI) as Sunitinib, Pazopanib as single agents and humanised monoclonal antibody bevacizumab (Bev) in combination with Interferon- α2a (IFN) have established as the first-line therapy for mRCC. Despite improvements in treatment, there are multiple questions which remain unanswered. In the combination of Bev and IFN, the respective role of each drug and whether any additional anti-angiogenic activity is gained by adding IFN to Bev remains unknown. As the clinical benefit obtained with these cytostatic agents does not always correlate with the conventional response assessment techniques as RECIST, it is necessary to reconsider the methods by which we assess benefit from these therapies. In this thesis, I report three studies aiming to answer these questions. Methods: With the clinical trial reported here, I explore whether Bev induced changes in vascular parameters measured by Dynamic Contrast Enhanced MRI (DCE-MRI) is significantly enhanced by the addition of IFN. In a phase II, randomised, open labelled, multicentre trial, treatment naïve mRCC patients were randomised to receive Bev on its own or in combination with a low dose (3MU) or standard dose (9MU) IFN. DCE-MRI was used to assess the changes in vascularity with the primary endpoint being, changes in transfer coefficient (Ktrans) after six weeks of treatment. I also report two retrospective imaging-based studies, using contrast-enhanced CT scans, performed to improve the methodology of response assessment for these antiangiogenic therapeutics. Here I explore the use of a) combining changes in size and arterial phase contrast enhancement measured using CT scan and b) changes in CT texture as methods of therapeutic response assessment in mRCC patients treated with TKI. Results: With the phase 2 clinical trial, we faced significant difficulty in recruitment as a result of restrictions in access to treatment in NHS, other competing studies and restrictions proposed by the DCE-MRI inclusion criteria. With slow recruitment, an unplanned analysis was performed after 21 patients were recruited. Analysis of primary endpoint showed no trend in the difference between arms with no correlation found between change in Ktrans and addition of IFN to bevacizumab. Effect size analysis performed due to the small numbers recruited failed to show any significance in the observed difference in Ktrans. Change in Ktrans and Kep may identify a group of patients likely to have PFS > 6 months, but this observation needs to evaluation in a larger sample size. Measuring size and change in arterial phase enhancement retrospectively using CT, a new criterion "modified" Choi, which prerequisite a combination of a decrease in arterial phase density by 15% and a decrease in size by 10% for response was proposed. Response assessment was measured with RECIST, Choi and modified Choi individually in 20 evaluable patients retrospectively and clinical benefit compared with Kaplan-Meier statistics and Log-Rank test. Response assessment as defined by the modified Choi criteria successfully identified patients who received clinical benefit from the treatment. Time to progression (TTP) was 448 days for the partial response and 89 days for stable disease as per the new criteria which were statistically significant with a p-value of 0.002. The second retrospective analysis explored the textural changes in enhanced CT scan. Performed in collaboration with researchers from Brighton University who developed the software algorithm used to assess changes in entropy and uniformity, 87 metastases from 39 patients with mRCC were analysed at baseline and after two cycles of TKI treatment. Textural parameters and response assessment criteria were correlated with TTP. After two cycles of TKI, the decrease in tumour entropy was 3%-45%, and increase in uniformity was 5%-21%. At a threshold change of -2% with uniformity, on a coarse scale of 2.5, the textural change was able to separate responders from non-responders. With Kaplan-Meier analysis comparing all four criteria, the percentage change in uniformity was statistically more significant than for RECIST, Choi, and Modified Choi criteria. Cox regression analysis showed that texture uniformity was an independent predictor of time to progression. Discussion: With the studies reported here, I was able to demonstrate the importance of improving the methodology in assessment of therapeutic response to targeted anti-angiogenic therapy in metastatic renal cell carcinoma. Even though the clinical trial, terminated early due to slow recruitment, did not reach its primary endpoint, changes in other vascular parameters as Kep combined with changes Ktrans showed tendency towards identifying a group of patients who derived clinical benefit of >6months with these therapies. This is particularly exciting as given the vascular stabilisation effect proposed for bevacizumab, the effusion parameter Kep may be a better tool in assessing response rather than Ktrans and warrants further assessment in a larger cohort. Modified choi criterion and textural analysis are two important methodological improvements in response assessment of cytostatic anti-angiogenic therapy. In the analyses reported here, both techniques have shown superiority over RECIST in response assessment and differentiating mRCC patients who is likely to gain clinical benefit by TKI therapy. Validation of these criteria on a larger patient cohort is important. As these criterions are assessed on standard enhanced CT scans, incorporating these criteria, especially modified choi criterion, as part of standard CT assessment could be performed and will provide a real world validation. Retrospective assessment using larger cohort of patients from previous phase 3 trials or inclusion of these parameters prospectively in phase 3 trials would also help us in evaluating these modalities further.
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Walsh, John Barry. "The Effects Of Targeted, Connectivism-Based Information Literacy Instruction On Latino Students Information Literacy Skills And Library Usage Behavior." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/312502.
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The United States is experiencing a socio-demographic shift in population and education. Latinos are the fastest growing segment of the population on the national level and in higher education. The Latino student population growth rate and Latino college completion rate are not reciprocal. While Latino students are the fastest growing demographic group in higher education, they continue to have the lowest persistence and retention rates. Latino students are more at risk for dropping out of college than any other ethnic group. Latinos decreasing persistence rates have caused an academic achievement gap in higher education (Long, 2011). Literature has correlated the gap with Latinos limited IL competency and low library usage (Long, 2011).This quasi-experimental research examined the effects of a targeted information literacy (IL) instructional method on Latino community college students IL skills and library usage. The study also introduced the idea of using a connectivism based targeted instruction to influence Latinos IL skills and library usage. The intent of the study was to investigate the development of information literacy instruction (ILI) which targets Latino students and uses the principles of connectivism. Connectivism posits that students' learn by connecting to information along their personal learning networks (Siemens, 2005). Connectivism helps position the library within Latino students' personal learning networks. This positioning may increase their library usage and by extension their IL skills. Specifically, this quantitative study assessed the effect of the instruction on IL skills and library usage behavior of Latino community college students. A pretest/posttest control group design was used for this study. A sample of 92 Latino male and female students completed the pretest and posttest. They were recruited from a diverse population of community college students who were registered for Introductory English classes. Data was collected through instrumentation that included an Information Literacy Rubric, an Information Literacy Skills Test, a Library Usage Survey/Demographic Identification Form, and a Citation Analysis Form. Though two of the hypotheses were not supported, the data collected allowed the researcher to accomplish two of the purposes of this study, to design and assess a targeted ILI that increases Latino students' IL skills and library usage, and to advance the research that grounds the emerging learning theory of connectivism. The more connections students made to information sources the higher their overall IL skill score were. This data suggests that as students make connections to information resources they are learning IL skills and the more sources they connect to, the more they learn. Though TI did not emerge as the more effective method, it is effective at increasing library usage and IL skills in Latino community college students'. The results of this study may lead to a better understanding of how students acquire IL skills. Instruction has become increasingly important in librarianship and recently has even eclipsed traditional reference service. (Grassian & Kaplowitz, xix, 2009). More and more academic libraries are being held accountable for their contribution to student learning. The findings of this study provide evidence that the instructional efforts of the library are influencing student learning outcomes.
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Davis, Adreana A. "A Case Study of Mathematics Teachers' Use of Short-Cycle Formative Assessment Strategies." Thesis, University of North Texas, 2017. https://digital.library.unt.edu/ark:/67531/metadc1011817/.
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A single case study was used to examine two middle grades mathematics teachers' use of short-cycle formative assessment strategies. Data was collected using multiple sources to provide a description of this single case. Participant change in knowledge of short-cycle formative assessment strategies was collected and analyzed through participant pre- and post-interviews and targeted instructional support was provided through professional development sessions designed to meet diverse needs of participants. Participant change in use of short-cycle formative assessment strategies was collected and analyzed through classroom observations using Assess Today observation protocol and targeted instructional support was provided through post-observation conferences with written feedback. Findings from the study verified that changes in teachers' use of short-cycle formative assessment strategies were positively influenced by the targeted instructional support provided to each participant during the study. The study further indicated that an assessment of teacher's present knowledge and use of short-cycle formative assessment strategies should be considered before providing targeted instructional support to maximize the learning potential for each teacher. Future research is needed regarding the importance of building student self-efficacy through teacher use of short-cycle formative assessment, as well as the importance of involving students in the formative assessment process.
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Vital, Heather Stacey Tomkinson. "Opportunities and challenges in oncology targeted drug development : an assessment of the use of prevalence and companion diagnostic performance thresholds to guide clinical trial strategies." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/78156.
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Thesis (S.M. in Health Sciences and Technology)--Harvard-MIT Program in Health Sciences and Technology, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 67-70).
Targeted, especially stratified or biomarker-guided, therapies offer significant advantages over traditional oncology therapies in certain settings. Selecting patients most likely to respond to a drug increases the therapeutic efficacy while reducing toxicities and may accelerate regulatory approval since smaller clinical trials are needed to demonstrate benefit. Several drugs, including vemurafenib and crizotinib have demonstrated these benefits along with commercial success. However, significant risk exists for the drug developer since approval may be threatened if they fail to meet unclear and differing yet parallel requirements for both the drug and the required companion diagnostic. Tumor biology is also increasingly complex since recent studies suggest that there are limited numbers of individual driver mutations, complicated interactions throughout signaling pathways as well as extensive tumor heterogeneity, all of which will challenge the effectiveness of targeted therapies. Clinical trial strategy decisions can greatly impact the success of a targeted therapy due to these challenges. While therapeutic efficacy is considered important, biomarker prevalence and companion diagnostic performance have been shown to be as important, yet more informative at the time decisions are made. I hypothesized that common prevalence and companion diagnostic performance thresholds are being used to guide biomarker-guided clinical trial strategy decisions for targeted oncology therapies. Seventeen interviews with preclinical, clinical or translational leads were conducted across a focused set of ten "pathway-modifying" cancer drug programs (CDK4/6, MDM2 and P13KP inhibitors) that reflect the biological complexity of future targeted therapies. These interviews provided empirical data as to how biomarkers are being incorporated into current clinical trial decisions. All respondents were planning to use a companion diagnostic for their program, however, the use of biomarkers varied significantly. For those programs with ongoing clinical trials in phase I and II, 54% (n=7/13) were pursuing a biomarker-guided strategy while 46% (n=6/13) were using an initial all-comers strategy. This fairly equal split separated when compared by phase where trials in phase I and 1/11, 60% (n=6/10) were using an all-comers strategy but for those trials in phase II (n=3), all were using biomarker-guided strategies. A key finding of the interviews was that 66.7% (n=4/6) were planning biomarker enrichment as part of expansion plans. Disproving my hypothesis, however, common thresholds for neither biomarker prevalence nor companion diagnostic performance were being used to guide these decisions. Biomarker prevalences of 50-100% were stated as potentially appropriate for an all-comers strategy. Companion diagnostic performance thresholds were even less influential as only a few respondents provided a general range of desired sensitivity and specificity. This study found that actions of drug developers are not necessarily following the emerging recommendations for targeted therapies due to the significant challenges of biomarker and companion diagnostic development.
by Heather Stacey Tomkinson Vital.
S.M.in Health Sciences and Technology
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Sargeant, Aaron Matthew. "Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876.
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Bennett-Perro, Whitney Rae. "How Elementary Teachers Determine Meaningful Homework Assignments." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/7365.
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A self-study at a local elementary school revealed that homework assignments appeared to be at lower levels of Bloom’s taxonomy, and students were inadequately prepared for summative assessments that required the application and critical thinking levels of Bloom’s taxonomy. Formative assessment data, ideally, drives teachers’ instructional decisions in the classroom. The purpose of this qualitative case study was to better understand the formative assessment processes that drive instructional decision making. The conceptual framework by Chappuis and influenced by Black and Wiliam includes the strategic process for successful formative assessment teaching and learning. The research questions explored the use of homework as a formative assessment in classrooms. In this intrinsic case study, data collection included face to face interviews with 10 general education Grade 3-5 teachers in 2 different schools within the same, a 2- week document analysis of homework assigned in language arts and mathematics, and a focus group of participants. The data were analyzed with open coding followed by axial coding to determine themes. Member checking and triangulation were used to ensure validity and accuracy. The themes that emerged from the coded data identified ineffective teacher use of feedback, self-assessment, and learning targets—essential practices of the formative assessment process. Improving the formative assessment process for teaching and learning may encourage positive social change through promoting teacher selfefficacy and collaboration through a professional development paired with a professional learning community. This study may also lead teachers to change their formative assessment processes and provide guided instruction that enhances student learning outcomes.
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Diaz, Saez Laura. "Assessment of potential antibacterial drug targets." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/4c3fe03b-5ddc-40c9-962c-8c38f811f6ea.
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The alarming increase in antibacterial drug resistance indicates an urgent need to develop new drugs. This project aimed to assess and select potential antibacterial targets and carry out initial biochemical characterisation concentrating on enzymes from biowarfare agents Bacillus anthracis, Burkholderia pseudomallei, Francisella tularensis and Yersinia pestis. The overall objective is to combine genetic and chemical studies to validate, or not, targets for early stage drug discovery. In collaboration with the Dstl (Defence Science and Technology Laboratory), a series of potential targets were selected. This was carried out using essentiality prediction data from the Dstl labs, information at AEROPATH and ChEMBL databases, and the literature. Once ten different targets were selected, recombinant protein production was carried out to support structural and biochemical characterisation. Seven proteins were successfully purified and four of them prioritised for further studies. These are kynurenine formamidase (KynB), D-alanine—D-alanine ligase (Ddl), caseinolytic protease subunit P (ClpP), and the dihydrofolate synthase:folyl-poly-glutamate synthase (bifunctional protein FolC). X-ray crystallography was used to determine protein structures of KynB, Ddl and ClpP from various bacteria. Additionally, different enzymatic and binding assays were applied to assess kinetic parameters of KynB, Ddl and FolC, and compound library screenings were carried out for Ddl. In parallel, the genetic validation of these targets was being carried out by the Dstl. KynB is an important enzyme in tryptophan metabolism and predicted to be essential in Pseudomonas aeruginosa. The B. anthracis, B. cenocepacia and P. aeruginosa KynB structures showed an amidase fold not previously described, with a distinctive binuclear Zn2+ catalytic site that indicated a distinct reaction mechanism. Whilst the characterisation of the enzyme was ongoing, the Dstl lab reported the gene as non-essential and so no additional chemical validation was pursued. Ddl generates a precursor for the peptidoglycan layer and appears to be an essential protein in several Gram-negative bacteria. The structure of B. pseudomallei Ddl (BpDdl) in the presence of the co-factor and the reaction product D-alanyl-D-alanine (1.5 Å resolution) gives information about the substrate-binding site. Biolayer interferometry (BLI) and high-throughput (HTP) assay protocols were developed and applied. Despite testing around 22,000 compounds no inhibitors or suitable hits were found. This suggests BpDdl is a challenging target and a different approach for drug discovery might have to be considered. Fourteen ClpP subunits form a proteolytic complex which presents two different conformations; open and compressed. Structures of F. turalensis ClpP (FtClpP) with open and compressed conformations have been determined indicating this major conformational change is caused by a loop rearrangement at the proteasome inner canal that leads to the protease active site. FolC is an essential protein for the synthesis of folyl-poly-glutamates, a reference pathway for drug development. A new enzymatic assay, using malachite green, has been identified and used to confirm Y. pestis FolC activity. Such an assay could be used to determine kinetic parameters and to develop a HTP assay. The studies carried out informed about potential antibacterial target structures and biochemical properties. Protocols have been developed for protein recombinant expression, purification, crystallisation and structure determination as well as enzymatic assay development and compound library screens.
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Poon, E. C. C. "Assessment of TWIST1 as an immunotherapeutic target of cancer." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1333306/.
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CD8+ T lymphocytes are key mediators of anti-tumour immunity, eliminating tumour cells through the recognition of tumour antigens. Increasing the number of characterised tumour antigens, especially those with highly specific tumour expression, may enable the development of more effective immunotherapy of cancers. TWIST1 is a basic-helix-loop-helix transcription factor (bHLB) with an important role in cell lineage determination and differentiation. It is expressed by a number of carcinomas where it functions as a pro-metastatic oncogene, but is absent or expressed at low levels in normal tissues. The main aim of this study was to investigate whether anti-TWIST1 immune responses could be generated and used to target cancer cells. Two potential HLA-A0201 restricted TWIST1-derived epitopes, SLNEAFAAL and KLAARYIDFL (referred to as SLN and KLA) were identified by in silico prediction methods and their binding to HLA-A*0201 confirmed in vitro. The peptides were assessed for their capacity to induce specific immune responses by generating cytotoxic T lymphocyte (CTL) lines from the peripheral blood of HLA-A2-positive healthy donors. SLN peptide-specific CTLs were detected in 1 out of 5 healthy donors by peptide/MHC class I pentamers and the CTL line generated showed specific cytotoxicity and the release of interferon-γ on recognition of T2 target cells pulsed with SLN. KLA peptide-specific CTLs were not detected in the four healthy HLA-A2-positive donors tested. The immunogenicity of KLA was also assessed by peptide immunisation of HLA-A*0201 transgenic mice and the in vitro stimulation of alloreactive peptide-specific CD8+ T cells from HLA-A2-negative healthy blood donors. CTLs capable of specifically killing T2 cells pulsed with KLA peptide were isolated from an alloreactive CTL bulk line using peptide/HLA-A*0201 pentamer reagents and magnetic cell sorting. The data presented here shows the existence of functional anti-TWIST1 CTL precursors within the autologous and allogeneic HLA-A*0201-restricted T cell repertoires of healthy donors, and therefore merits the further evaluation of SLN and KLA as target epitopes for the treatment of TWIST1+ tumours.
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Cusumano, Carl Joseph. "Assessment of Residual Nonuniformity on Hyperspectral Target Detection Performance." University of Dayton / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1565137429596905.
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Leung, Man Ching. "Identification of human hair follicle antigens targeted in the presumptive autoimmune hair follicle disorder Alopecia Areata and their potential functional relevance In Vitro. Methods development for isolation and identification of Alopecia Areata-relevant human hair follicle antigens using a proteomics approach and their functional assessment using an Ex Vivo hair follicle organ culture model." Thesis, University of Bradford, 2008. http://hdl.handle.net/10454/4330.
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Alopecia areata (AA) is a putative autoimmune hair loss disorder. It mainly affects the scalp hair but can also involve body hair, and can also affect the nail and the eye. While there are may be several lines of evidence to support the autoimmune basis of AA, there is still very little information on the hair follicle autoantigen(s) involved in its pathogenesis. In this project, serum antibodies (AA=10, control=10) were used to immunoprecipitate AA-relevant target antigens from normal human scalp hair follicle extracts. These immunoprecipitates were analysed by LC-MALDI-TOF/TOF mass spectrometry for target protein identification. This part of the project involved substantial methods development. Trichohyalin was immunoprecipitated by all AA sera, but by only 5 normal sera. Importantly, the mean Mascot scores of the AA group was significantly higher than the normal group (p=0.005). Keratin 16 was also identified from immunoprecipitates as another potential AA-relevant target antigen. Functional studies by ex vivo whole hair follicle organ culture using commercial antibodies to trichohyalin and keratin 16 significantly inhibited hair fibre elongation compared to controls. Indirect immunofluorescence studies revealed that AA sera contained higher immunoreactivity against normal human scalp anagen hair follicles compared to normal sera. Immunoreactivities were mainly in the outer root sheath and inner root sheath, and less so to the medulla and hair bulb matrix. Double immunofluorescence studies of AA and normal serum with anti-trichohyalin antibody (AE15) revealed co-localisation of 9 of the AA sera antibodies with trichohyalin in the inner root sheath (mostly in Henle's, less in Huxley's/inner root sheath cuticle), but only weakly in 3 normal sera. This study supports the involvement of an antibody response to anagen-specific hair follicles antigens in AA. Moreover, there may be some evidence that these antibodies may have a pathogenic role.
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Grant, Eugene. "INTERCEPTOR TARGET MISSILE TELEMETRY." International Foundation for Telemetering, 1997. http://hdl.handle.net/10150/607598.
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International Telemetering Conference Proceedings / October 27-30, 1997 / Riviera Hotel and Convention Center, Las Vegas, NevadaA target missile is a unique piece of test hardware. This test tool must be highly reliable, low cost and simple and must perform any task that the developing interceptor missile planners require. The target missile must have ample power and guidance resources to put the target in a specified place in the sky at a desired time. The telemetry and measurement system for the target missile must have the same requirements as its interceptor missile but must be flexible enough to accept new requirements as they are applied to the target and its interceptor. The United States Army has tasked Coleman Aerospace to design and build this type of target missile. This paper describes and analyzes the telemetry and instrumentation system that a Hera target missile carries. This system has been flying for the past two years, has completed seven out of seven successful test flights and has accomplished all test objectives to date. The telemetry and instrumentation system is an integral part of the missile self-test system. All preflight checks and flight simulations are made with the on-board three-link telemetry system through a radio frequency (RF) link directly through the missile antenna system to a ground station antenna. If an RF transmission path is not available due to test range restrictions, a fiber-optic cable links the pulse code modulator (PCM) encoder to the receiving ground stations which include the bitsync, decommutator and recorders. With this capability, alternative testing is not limited by RF test range availability. The ground stations include two mobile stations and a factory station for all testing including preflight testing of the missile system prior to flight test launches. These three ground stations are built in a single configuration with additional equipment in the mobile units for use at remote locations. The design, fabrication, testing and utilization of these ground stations are reviewed. The telemetry system is a modification of the classical PCM system and will operate with its interceptor missile at least into the first decade from the year 2000.
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Gui, Chen. "Autonomous science target detection and touchability assessment for planetary exploration." Thesis, Aberystwyth University, 2015. http://hdl.handle.net/2160/1e065532-23c4-4690-81fd-e94523834f23.
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One of the goals of planetary exploration is to cache rock samples for subsequent return to the Earth in future Mars Sample Return missions. Rocks on the Martian surface are one of the most interesting science targets for geologists and planetary scientists. Hence, it is essential to develop a method for the accurate segmentation of Martian rocks in Mars images. This thesis introduces a new approach to segmenting Mars images captured by the NASA Mars Exploration Rover (MER). An improved OTSU and Canny operator are utilized for detecting rock regions and their space relations, respectively. The closed contours of detected rocks are gained by the use of template dilatation edge linking for a given set of images. These images have been obtained from MER Navcam and Pancam. Experimental results of six representative images (with different illumination levels, spectral bands and scenes) including a total of 128 rocks are shown. In these experiments qualitative and quantitative comparisons are accomplished. The results demonstrate that the proposed approach is consistent with human perception and is the best in terms of the average values over the performance indices such as Precision, Recall and misclassification error in comparison to the existing approaches. Additionally, a method is proposed for computing the size of a detected rock through the stereo triangulation technique. Experimental results also show that this proposed method offers better accuracy than the standard disparity algorithm. Currently, science target selection, and whether or not it is possible for a robot arm to touch the target, is accomplished by human operators and scientists on the Earth. The use of onboard autonomy would greatly reduce the human intervention, and it would be advantageous if the rover could evaluate autonomously whether the robot arm could place an instrument against an identified science target. In this thesis a fuzzy logic-based system is presented to address the problem of autonomous science target touchability evaluation. The touchability of a potential science target is assessed in terms of its size (the bounding area of the rock), SV (the science value of the target), distance (the reachable distance of the arm between its base and the science target), and orientation (the angular regions of the arm's shoulder azimuth). In particular, the plane in front of the arm is divided into a number of partitions, which are ranked with the different touchability levels by the use of a fuzzy rule-based system. Simulations on the rank of science object touchability are carried out, via hardware implementation. Based on the real data gathered from the cameras and the Schunk arm experimental results successfully verify the validity of the proposed touchability approach and associated software and hardware implementations.
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Plym, Forshell Linus. "Assessment of therapeutic targets in experimental models of Myc-induced lymphoma." Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-46534.
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The Myc transcription factor activates expression of genes that promote cellular functions such as proliferation and cell growth. The deregulated Myc expression, characteristic for the tumor cell, also activates apoptosis, which selects for additional genetic changes deactivating the induced cell death. However, the continuous overexpression of Myc can also be a liability for a tumor, which can be taken advantage of in cancer treatment. In Paper I, we describe a new way of using the DNA methyltransferase inhibitor Decitabine, in treating Myc overexpressing tumors. We show that Decitabine treatment activates cell death by reactivating silenced tumor suppressors such as Puma, but also by inducing DNA damage. Decitabine treatment of Myc driven lymphomas is also shown to prolong disease free survival in mouse models. Myc driven transformation requires a collaborative deregulation of genes. The family of Pim kinases has been shown to collaborate with Myc in tumorigenesis. In Paper II, we show that the Pim-3 kinase protein is highly expressed in many Myc overexpressing lymphomas from Myc transgenic mice as well as human Burkitt Lymphoma samples. The Pim-3 locus is shown to interact with the Myc protein and be a direct target for Myc activated transcription. Additionally, we demonstrate that the Pim kinase inhibitor, Pimi, targeting the Pim kinase family (Pim-1, Pim-2 and Pim-3), induce a cell death that is mediated by, but not dependent on caspase activity. The Pimi induced cell death was potentiated when combined with RNAi knockdown of the casein kinase II (CK2) protein. In paper III, we describe the development of a somatic mouse model for lymphomagenesis, utilizing the RCAS-tva technology. We show that primary B cells from these mice are transducible and transformed when infected with a combination of RCAS- HA tagged Myc, KRasV12D and human Bcl-XL virus. In conclusion, we show that the labile milieu created by the deregulated expression of Myc facilitates new approaches in treatment of Myc overexpressing tumors. Also, our new tva mouse model show promise in modeling lymphomagenesis.
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Janssen, Marcus Alexander. "Meeting targets tools to support integrated assessment modelling of global change /." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1996. http://arno.unimaas.nl/show.cgi?fid=6702.
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Hill, Johan C. "Structural characterisation of calnexin cycle components and assessment as antiviral targets." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:49322df0-e182-41a1-97ce-34aac70150fc.
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N-glycosylated proteins that traverse the endoplasmic reticulum (ER) can make use of the calnexin cycle to attain their correct fold. The calnexin cycle modifies the N-glycan structure and allows for association of the glycoprotein with the ER lectins calnexin and calreticulin, which in turn recruit further chaperones that assist folding. Most enveloped viruses encode glycoproteins, which, upon infection of a host cell, crucially depend on the calnexin cycle to aid their folding. This includes diverse families such as Flaviviridae, Retroviridae and Orthomyxoviridae. We studied the calnexin cycle components with the ultimate aim of developing broad-spectrum antivirals. X-ray crystallography was used to structurally characterise the murine ER α-glucosidase I, which controls entry into the calnexin cycle, with a number of inhibitory antiviral iminosugars. These data reveal flexibility in the ligands' alkyl tails and may act as a basis for the discovery of enzyme specific inhibitors. UDP-glucose: glycoprotein glucosyltransferase (UGGT) is the quality control checkpoint of the calnexin cycle whose full-length structure from the thermophilic fungus Chaetomium thermophilum was recently determined. Presented here are a higher resolution structure in addition to SAXS studies of UGGT's interaction with Sep15, a protein that enhances UGGT activity. UGGT's reaction releases into the ER lumen UDP, which is the only known small molecule inhibitor of UGGT. An ER-resident UDPase, ENTPD5, breaks down UDP into UMP. Enzymatic characterisation of ENTPD5 reveals its substrate specificities; in addition we show a paralog, ENTPD6, possesses similar activities. Presented here is work towards crystallisation of these two proteins and a test of the anti-Zika activity of ENTPD5 inhibitors. Finally, CRISPR/Cas9 knock-out cells were generated to test, in principle, whether modulation of the activity of proteins involved in the calnexin cycle could be antiviral. The data confirm that the ER glucosidases are likely the best targets of those studied.
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Al, Khathami Ali Gaithan. "Towards gastric cancer immunotherapy : assessment of cancer immunity and potential immune targets." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8855/.
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Gastric cancer (GC), the fourth most common malignancy worldwide, has poor prognosis and treatment innovation is needed. The aims of this project were to investigate immune targets and treatment strategies for GC. I identified new T-cell epitopes in three Epstein-Barr virus (EBV) tumor antigens, LMP1, LMP2 and BARF1, expressed in the 10% of GC cases positive for EBV. T-cell clones showed that a BARF1-specific CD4 T-cell epitope restricted by HLA-DR51, an allele common in the population, was presented by an EBV-positive epithelial cancer cell line. Analysing blood and fresh tumor from newly diagnosed GC patients, I detected T-cell responses to MAGEA1, MAGEA4 and NY-ESO-1 tumour antigens in blood but not tumor. Compared to healthy donors, patients had: higher frequencies of LAG3 or CTLA4 positive CD8 T-cells, TIM-3 or CTLA4 CD4+ T-cells, T-regs, NKT-cells and gamma-delta T-cells in blood and tissue. Patients also had high granulocytic MDSC frequencies in PBMC. The CD4:CD8 ratio was low in some patients' blood, potentially indicating immunosenesence, but was always higher in tumor tissue. I successfully generated tumour infiltrating lymphocytes (TILs) from nine patients' tumors. These comprised high T-cells and NK-cells and low T-reg and MDSC. LAG-3 was increased, but PD1, was decreased on TIL T-cells. Using 3-dimensional organoids established from two patients, I showed that TIL NK-cells, but not TIL T-cells, recognized autologous tumor organoids. My results are the first proof of principle that TILs can readily be generated from gastric tumors, can target tumors cells and therefore be used to treat gastric cancer.
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Rao, Vincenzo A. "Structure of T6SS components and assessment of potential Gram-ve drug targets." Thesis, University of Dundee, 2012. https://discovery.dundee.ac.uk/en/studentTheses/ec37df62-b65a-4f10-ba48-e8edde10e454.
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The structure and potential function of two components of the type VI secretion system in Serratia marcescens have been investigated by X-ray crystallography. Chapters 1 and 2 describe the background of the type VI secretion system and experimental methods respectively. In chapter 3, the solution of the structure of S. marcescens Lip is presented. This is an essential outer membrane lipoprotein that is conserved among bacterial species. It is part of a membrane-spanning sub-assembly that is thought to anchor the remaining components to the cell envelope. The crystal structure of SmLip was determined using single-wavelength anomalous dispersion methods targeting iodides that were present in the crystallisation solution. The structure was refined to 1.92 Å and displays a fold similar to that of transthyretin; a protein that binds the hormone thyroxine. Despite the sequence identity between the two proteins being low, SmLip can be considered a new member of the transthyretin-like protein family. A role is suggested for loop 1 being involved in protein-protein interactions with other components of the type VI secretion system and therefore a potential drug target.In chapter 4, the structure of S. marcescens Rap1b is described. This protein is thought to be part of a set of periplasmic resistance proteins that protect S. marcescens from succumbing to the effects of its own secreted toxins. The crystal structure of Rap1b was determined using single-wavelength anomalous dispersion methods targeting both iodides from a halide soak and endogenous sulfurs. The structure was refined to 1.88 Å and displays a helical rich fold not previously characterised. This structure is described and is suggested to represent this family of resistance proteins. In addition to determining the structure of components of the type VI secretion system, the assessment of two drug targets have been investigated by biochemical techniques. The need for new antimicrobials and the importance of target selection in the drug discovery process is described in chapter 5. PBP3 from both Pseudomonas aeruginosa and Burkholderia pseudomallei is the focus of chapter 6. This protein is essential in bacteria as it catalyses the cross-linking of peptidoglycan. Peptidoglycan provides bacteria with structural rigidity and strength to withstand pressures that would otherwise rupture the cell. Sequence identity between the two homologues is approximately 40 %, with the catalytic residues conserved. The production of soluble protein and the results of screening for novel chemical fragments using several techniques are presented. The characterisation of P. aeruginosa IMPDH, an essential protein that is present in nearly all living organisms is described in chapter 7. This protein controls the pool of guanine nucleotides within cells. Fragments were identified using bio-layer interterformetry, a label free optical analytical technique that monitors biomolecular interactions in real time. Fragments were assessed for inhibitory effects using enzyme kinetics. The crystal structure of PaIMPDH was determined by molecular replacement and refined to 2.25 Å. This structure displays the catalytic domain with the active site loop fully ordered and in a conformation rarely observed.
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Williams, A. Lynn. "Assessment, Target Selection, and Intervention: Dynamic Interactions Within a Systemic Perspective." Digital Commons @ East Tennessee State University, 2005. https://dc.etsu.edu/etsu-works/2002.
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There are a number of clinical options available for speech-language pathologists to choose from to analyze a child's phonological system, select treatment targets, and design intervention. Frequently, each of these areas of clinical options is viewed independently of one another or approached within an eclectic framework. In this article, an integrated and systemic approach is presented which assumes that a dynamic interaction exists among assessment, target selection, and intervention. Systemic Phonological Assessment of Child Speech, the distance metric approach to target selection, and the multiple oppositions treatment approach are described, with examples provided for each component. Finally, a case study is presented that examines the systemic approach of multiple oppositions relative to the approach of minimal pairs.
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Hernandez, Jerome H. "Operational assessment of Target Acquisitions Weapons Software (TAWS) prediction performance at Nellis AFB, NV." Thesis, Monterey, California. Naval Postgraduate School, 2006. http://hdl.handle.net/10945/2884.
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Target Acquisition Weapons Software (TAWS) Version 3.4 is a joint Tactical Decision Aid (TDA) used to predict performance of electro-optic and electro-magnetic (EM/EO) munitions and navigation systems. TAWS is the USAF and USN mission-planning standard for laser-guided, infrared, and TV munitions and navigation systems TDAs. As TAWS continues to deploy through the mission planning community there is a need to establish a systematic approach to assessing TAWS accuracy. This study was an operational assessment of TAWS Infrared (IR) model performance and consisted of two parts: a comparison of model predictions to pilot observations of IR detection range of a static tank target and an assessment of physical temperature predictions. Limiting factors of this project are similar to those encountered in real world utilization of TAWS mission planning TDAs. This evaluation found TAWS predicted detection ranges and target scene model output were representative forecasts of observed values. The TDA provided a good description of background thermal behavior and highlighted the necessity of careful evaluation of the target scene because of component facet complexity and the geometry of facets exposed to the sensor view. The resulting component analysis illuminated the benefit of focusing new TAWS development on improving the target physical model.
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Lee, Siu-fan. "An investigation of teacher's interpretations of target oriented assessment in English language." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21160855.
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Lee, Siu-fan, and 李少芬. "An investigation of teacher's interpretations of target oriented assessment in English language." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31945090.
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Jorge, Carlos Alexandre Fructuoso. "Received radiation dose assessment for nuclear plants personnel by video-based surveillance." Instituto de Engenharia Nuclear, 2015. http://carpedien.ien.gov.br:8080/handle/ien/1463.
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This work proposes the development of a system to evaluate received radiation dose for nuclear plants personnel. The system is conceived to operate in a complementary form to the existing approaches for radiological protection, thus o ering redundancy, what is desirable for critical plants operation. The proposed system must operate in an independent form on the actions to be performed by the operators under evaluation. Therefore, it was decided it would be based on methods used for video surveillance. The nuclear plant used as example is Argonauta Nuclear Research Reactor, belonging to Instituto de Engenharia Nuclear, Comiss~ao Nacional de Energia Nuclear (Nuclear Engineering Institute, National Nuclear Energy Commission). During this thesis research, both radiation dose rate distribution and video databases were obtained. Methods available in the literature, for targets detection and/or tracking, were evaluated for this database. From these results, a new system was proposed, with the purpose of meeting the requisites for this particular application. Given the tracked positions of each worker, the radiation dose received by each one during tasks execution is estimated, and may serve as part of a decision support system.
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Miehling, Erik J. "Stochastic target scheduling for radar resource management : threat assessment and optimal threshold policies." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/37417.
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This thesis formulates a stochastic scheduler for use in adaptive resource management of a single Ground Moving Target Indicator (GMTI) radar when faced with tracking multiple, weakly maneuvering targets. The general problem involves first determining a priority allocation of the L targets, then determining the optimal time to spend using the specified allocation. We present a framework for computing the threat estimate and associated priority of each target in a surveillance environment, termed the radar macro-manager. The threat level of each target is computed based on its heading and proximity relative to a set of user-specified static assets. We present a weight assignment algorithm based on the geography of the surveillance region and use eigenvector centrality to assign vulnerability weights to each asset. The error in the threat level is computed based on the error-covariance matrix of each target, provided by a Kalman filter. Both the threat level and threat error are used to compute the respective priority rank distributions. From the priority distributions of each target we specify a queue of tasks to maximize a reward function associated with processing the queue. The queue is determined with the aid of structural results from the field of optimal issuing which involves ordering the priority rank distributions with respect to the monotone likelihood ratio. In particular, we compute an optimal queue which specifies the order in which we observe individual targets. The length of each target observation is controlled by an external stochastic process, termed the radar micro-manager. The problem of determining this optimal stopping time is formulated as a sequential decision process, a type of Markov decision process. We provide conditions such that the optimal policy is characterized by a monotone threshold policy on the partially ordered set of positive definite error covariance matrices of each target. Given that the optimal policy is monotone, we can efficiently approximate its form with an affine hyperplane using a hybrid random search - Simultaneous Perturbation Stochastic Approximation (SPSA) algorithm. Detailed numerical simulations evaluate the performance of both the radar macro-manager and radar micro-manager.
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Xu, Cong. "Multi-objective optimization approaches to efficiency assessment and target setting for bank branches." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/multiobjective-optimization-approaches-to-efficiency-assessment-and-target-setting-for-bank-branches(eef70a4a-359d-40ed-9b6c-3eeb98fe477a).html.
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This thesis focuses on combining data envelopment analysis (DEA) and multi-objective linear programming (MOLP) methods to set targets by referencing peers' performances and decision-makers' (DMs) preferences. A large number of past papers have proven the importance of a company having a target; however, obtaining a feasible but challenging target has always been a difficult topic for companies. Since DEA was proposed in 1978, it has become one of the most popular performance assessment tools. The performance possibility set and efficient frontier established by DEA provide solid and scientific reference information for managers to evaluate an individual's efficiency. Based on the successful experience of DEA in performance assessment, many scholars have mentioned that DEA can be used to set appropriate targets as well; however, traditional DEA models do not include DMs' preference information that is crucial to a target-setting process. Therefore, several MOLP methods have been introduced to include DMs' preferences in the target-setting process based on the DEA efficient frontier and performance possibility set. The trade-off-based method is one of the most popular interactive methods that have been incorporated with DEA. However, there are several gaps in the current research: (1) the trade-off-based method could take so many interactions that no DMs could finish the interactive process; (2) DMs might find it very difficult to provide the preference information required by MOLP models; and (3) DMs cannot have an intuitive view in terms of the efficient frontier. Regarding the gaps above, this thesis proposes three new trade-off-based interactive target-setting models based on the DEA performance possibility set and efficient frontier to improve DMs' experience when setting targets. The three models can work independently or can be combined during the decision-making process. The piecewise linear model uses a piecewise linear assumption to simulate DMs' real utility function. It gradually narrows down the region that could contain DMs' most-preferred solution (MPS) until it reaches an acceptable range. This model could help DMs who have limited time for interaction but want to have a global view of the entire efficient frontier. This model has also been proven very helpful when DMs are not sensitive to close efficient solutions. The prioritized trade-off model provides a new way for a DM to know about the efficient frontier, which allows the DM to explore the efficient frontier following the preferred direction with a series of trade-off tables and trade-off figures as visual aids. The stepwise trade-off model focuses on situations where the number of objectives (outputs/inputs for the DEA model) is quite large and DMs cannot provide all indifference trade-offs between all the objectives simultaneously. To release the DMs' burden, the stepwise model starts from two objectives and gradually includes new objectives in the decision-making process, with the assumption that the indifference trade-offs between previous objectives are fixed, until all objectives are included. All three models have been validated through numerical examples and case studies of a Chinese state-owned bank to help DMs to explore their MPS in the DEA production possibility set.
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Thys, An. "Assessment of new potential therapeutic targets in murine and cellular models of gastrointestinal stromal tumors." Doctoral thesis, Universite Libre de Bruxelles, 2015. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/220502.
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The present thesis project focused on the preclinical study of Neurotensin receptor 1 (Ntsr1), Endoglin/CD105 (Eng), Glypican 6 (Gpc6) and Sprouty homolog 4 (Spry4) as potential markers or molecular targets for future therapeutic interventions of gastrointestinal stromal tumors (GIST). Ntsr1 expression was characterized was reported in a paper that I co-authored entitled “Neurotensin receptor 1 is expressed in gastrointestinal stromal tumors but not in interstitial cells of Cajal.” by Gromova et al. PLOS ONE, 2009. As radio-labeled NTSR1 ligand analogues have already been reported for whole-body imaging and therapeutic interventions, prompting us to investigate NTSR1 as a target for in vivo imaging of GIST.Next, expression of Eng was characterized in the KitK641E murine GIST model, human GIST, GIST882 and BaF3 cells. This study has been reported in “Endoglin/CD105 is expressed in KIT positive cells in the gut and gastrointestinal stromal tumors” by Gromova et al. JCMM, 2011, a paper I co-authored. As result, an American start-up approached us to assess their proprietary compound targeting ENG on GIST882 cells. However, concerns were raised about possible non-selective action and the project was stalled by the company.Subsequently, GIST tissue microarrays were examined by immunohistochemistry using the sole commercially available GPC6 antibody. No statistical correlation could be found between GPC6-ir and GIST clinic-pathological features and concerns were raised about the reliability of the GPC6 antibody used. Ultimately, Spry4 was investigated in the last part of my thesis. In vitro, we have demonstrated that Spry4 is specifically upregulated by the ERK pathway in GIST882 cells. In vivo, Spry4 deficient mice showed an ICC hyperplasia in antrum and colon, using a new ICC quantification method developed in the lab, which was reminiscent of the oncogenic GIST murine model KitK641E. Similarities between Spry4 KO and KitK641E heterozygous animals were even further emphasized by functional studies, as both genotypes showed a delay in transit time. This study lead to the publication “Hyperplasia of interstitial cells of Cajal in Sprouty homolog 4 deficient mice” by Thys et al. 2015, PLOS ONE.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
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Hernandez, Jerome H. "Operational Assessment of Target Acquisition Weapons Software (TAWS) Prediction Performance at Nellis AFB, NV." Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2006. http://library.nps.navy.mil/uhtbin/hyperion/06Mar%5FHernandez.pdf.
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Thesis (M.S. in Meteorology)--Naval Postgraduate School, March 2006.Thesis Advisor(s): Kenneth L. Davidson, Andreas K. Goroch. "March 2006." Includes bibliographical references (p.75). Also available online.
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Rose, Robyn Ilene. "An ecological risk assessment of BT transgenic sweet corn on non-target arthropod communities." College Park, Md. : University of Maryland, 2005. http://hdl.handle.net/1903/2451.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2005.Thesis research directed by: Entomology. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Ramos, Nicole R. "Assessment of vision-based target detection and classification solutions using an indoor aerial robot." Thesis, Monterey, California: Naval Postgraduate School, 2014. http://hdl.handle.net/10945/43984.
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Approved for public release; distribution is unlimitedThe role of unmanned aerial vehicles (UAVs) in military, commercial and recreational applications is continuously evolving as devel-opments in technology increase capabilities. The research herein presents an inexpensive computer-vision-based solution for detection and classification of a stationary target with a mobile aerial sensor as a prototyping platform. The main goal of this system is to use commercial-off-the-shelf and open-source components to reduce design complexity to provide a legacy product for future develop-ment of specific capabilities. Color imagery collected during flight using a low-resolution camera is used to test the application of a simple algorithm against a commercially available and low cost sensor. Original image processing algorithms that leverage the existing body of works in the open-source community are developed and tested within the Systems Engineering construct. System architec-ture leverages a modular approach that can be easily modified and adapted to changing requirements and objectives. Conclusions are drawn and recommendations for further study and system development are presented.
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Durokifa, Anuoluwapo Abosede. "An assessment of the Millennium Development Goal's poverty reduction target in Ogun State, Nigeria." Thesis, University of Fort Hare, 2017. http://hdl.handle.net/10353/4649.
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Nigeria, like many nations of the world, is confronted with a high level of poverty. Over the years the country has taken several initiatives to reduce the incidence of poverty. Nigeria was one of the earliest countries to adopt the Millennium Development Goals [MDGs] as a strategy in reducing poverty and promoting development across the vast nation. The federating states have also rolled out a number of poverty reduction programmes tailored along the millennium development goals. This study, therefore, evaluates the achievement of the millennium development poverty reduction target in Ogun State, South west Nigeria. The study seeks to ascertain whether the state was able to significantly reduce poverty with the introduction of the MDGs. The study also attempts to establish difference or similarity (if any) between past poverty reduction policies in the state and the MDGs poverty reduction strategies. In carrying out this study, related literature on poverty, development and poverty reduction efforts (strategies and programmes) implemented in the state were extensively reviewed and relevant information retrieved for the study. This study employed the mixed method research, comprising both the quantitative and qualitative data. Quantitative data through the administration of a questionnaire was obtained from 232 respondents. While in-depth interview with seven participants provided the qualitative data. Quantitative data was analyzed using Descriptive statistics, and chi-square statistical technique was used to analyze the quantitative data while qualitative data analysis was carried out using transcription and thematic clusters. The findings of the study, in general, revealed that the MDG poverty reduction strategy did not make any significant contribution in reducing poverty in the state. The MDG strategy was not any different from past poverty reduction strategies implemented in the state. The findings of the research also strongly indicated that there was low awareness regarding the MDGs poverty reduction strategies set up amongst the citizens of the state. The low awareness emerged as a major hindrance to the success of the MDG programme. Based on the findings of this study, a sustainable development poverty reduction model was developed. The model gives room for programme awareness; people’s consultation and participation. It emphasizes the need to consider the community setting or environment factors in the planning and execution of poverty reduction programme. This model contend that aligning strategies to the peculiar need of each environment is a critical component for the sustenance of any poverty reduction programme.
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Wegener, Duane Theodore. "The flexible correction model : using naive theories of bias to correct assessments of targets." Connect to resource, 1994. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1234615264.
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Eidehall, Andreas. "Tracking and threat assessment for automotive collision avoidance." Doctoral thesis, Linköping : Department of Electrical Engineering, Linköpings universitet, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-8338.
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Thorngren, Jordan L. "Fate, transport, and relative risk of atrazine and sulfentrazone to non-target species at an agricultural site." OpenSIUC, 2015. https://opensiuc.lib.siu.edu/theses/1687.
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The risk associated with the application and co-occurrence of atrazine and sulfentrazone, two herbicides applied to a corn and soybean rotational field, was evaluated in the current study. Peak field concentrations were found in the soil matrix, with atrazine and sulfentrazone values of 144 ng/g dry weight (dw), and 318 ng/g dw, respectively; however, due to the physicochemical properties of the compounds, the two herbicides were also transported to field water matrices. The highest mean runoff water concentrations for atrazine and sulfentrazone were 4.72 µg/L and 10.3 µg/L, respectively. A direct spray event of atrazine to the runoff water sampler caused concentrations as high as 1.6 mg/L, effectively becoming a worst case scenario concentration. Individual and mixture laboratory bioassays were also conducted to determine the effects of atrazine and sulfentrazone on the survival of D. magna, and P. promelas. Sub-lethal effects including germination of L. sativa, and growth of P. promelas, S. capricornutum and L. minor were also evaluated. Results showed that S. capricornutum and L. minor were the most susceptible non-target species tested, and synergistic effects were observed for both species when equipotent mixtures were tested. Margin of safety of 10% (MOS10) values were calculated for each species using field concentrations and bioassay benchmark concentrations. Atrazine MOS10 values, calculated with environmental concentrations not including the direct spray event, were 0.83 and 0.10 for S. capricornutum and L. minor, respectively. The MOS10 value for sulfentrazone effects on S. capricornutum was 0.31, and effects on L. minor was 1.39. There was a slight risk to S. capricornutum and L. minor growth associated with exposure to atrazine and sulfentrazone in an agricultural field. Although the co-occurrence of atrazine and sulfentrazone was observed, and synergistic effects were observed in the equipotent binary mixture bioassays for S. capricornutum and L. minor, it is believed that there is minimal increase in risk potential due to the co-occurrence, because field concentrations do not proportionally mimic the concentrations that produced synergism in the plant species.
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Machado, Brenda I. "Characterization and cytotoxic assessment of ballistic aerosolized particulates for tungsten alloy penetrators interfacing with steel targets." To access this resource online via ProQuest Dissertations and Theses @ UTEP, 2009. http://0-proquest.umi.com.lib.utep.edu/login?COPT=REJTPTU0YmImSU5UPTAmVkVSPTI=&clientId=2515.
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Angelstam, Per, Jean-Michel Roberge, Robert Axelsson, Marine Elbakidze, Karl-Olof Bergman, Anders Dahlberg, Erik Degerman, et al. "Evidence-Based Knowledge Versus Negotiated Indicators for Assessment of Ecological Sustainability : The Swedish Forest Stewardship Council Standard as a Case Study." Linköpings universitet, Biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-90236.
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Assessing ecological sustainability involves monitoring of indicators and comparison of their states with performance targets that are deemed sustainable. First, a normative model was developed centered on evidence-based knowledge about (a) forest composition, structure, and function at multiple scales, and (b) performance targets derived by quantifying the habitat amount in naturally dynamic forests, and as required for presence of populations of specialized focal species. Second, we compared the Forest Stewardship Council (FSC) certification standards’ ecological indicators from 1998 and 2010 in Sweden to the normative model using a Specific, Measurable, Accurate, Realistic, and Timebound (SMART) indicator approach. Indicator variables and targets for riparian and aquatic ecosystems were clearly under-represented compared to terrestrial ones. FSC’s ecological indicators expanded over time from composition and structure towards function, and from finer to coarser spatial scales. However, SMART indicators were few. Moreover, they poorly reflected quantitative evidence-based knowledge, a consequence of the fact that forest certification mirrors the outcome of a complex social negotiation process.
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Strain, Katherine E. "Fate and transport of Cry1Ab from transgenic Bacillus thuringiensis corn in an agricultural field and aquatic microcosms." OpenSIUC, 2014. https://opensiuc.lib.siu.edu/theses/1596.
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AN ABSTRACT OF THE THESIS OF Katherine E. Strain, for the Master's degree in Zoology, presented on October 21, 2014, at Southern Illinois University Carbondale. TITLE: FATE AND TRANSPORT OF CRY1AB FROM TRANSGENIC BACILLUS THURINGIENSIS CORN IN AN AGRICULTURAL FIELD AND AQUATIC MICROCOSMS MAJOR PROFESSOR: Dr. Michael Lydy, Ph.D. Genetically-modified crops expressing insecticidal crystalline proteins derived from a soil bacterium, Bacillus thuringiensis (Bt), were commercialized almost two decades ago as a means to combat agricultural pests. The Bt proteins are highly specific and only lethal upon ingestion, limiting the scope of toxicity to target insects. However, evidence for risk to non-target organisms and negative public perceptions on the use of Bt crops has caused controversy surrounding their use. The objective of this research was to monitor the fate and transport of a Bt protein, Cry1Ab, in a large-scale agricultural field and in aquatic microcosms. Quantitative methods were validated using enzyme-linked immunosorbent assay (ELISA) and then used to evaluate field and laboratory samples. The highest environmental concentrations of the Cry1Ab protein were found in runoff water and sediment, up to 130 ng/L and 143 ng/g dry weight, respectively, with the Cry1Ab protein detected in both Bt and non-Bt fields. As surface runoff and residual crop debris can transport Bt proteins to waterways adjacent to agricultural fields, a series of laboratory experiments were conducted to determine the potential risk to non-target aquatic organisms. The results showed that sediment type and temperature can influence the degradation of the Cry1Ab protein in an aquatic system and that the Cry1Ab protein can persist for two months. While Cry1Ab protein concentrations measured in the field soil indicate little risk to terrestrial organisms, the consistent input of Bt-contaminated runoff and crop debris into agricultural waterways impart chronic risk to non-target aquatic species.
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Roberts, Adam. "Assessment of N-myristoyltransferase and the N-myristoylomeas : a potential chemotherapeutic target in Trypanosoma cruzi." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/0751872a-abe8-4de0-86f6-5f26fe9ab6e4.
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As there is a need for fully validated drug targets in Trypanosoma cruzi, the genetic andbiochemical essentiality of N-myristoyltransferase (NMT) was assessed. The geneticrequirement was assessed using a classical gene replacement strategy, attempting tosequentially replace the endogenous alleles with drug resistance genes to generate anNMT null parasite. It was only possible to achieve this in the presence of an ectopiccopy of NMT under constitutive expression, providing the strongest evidence that thisgene is essential for the proliferation of the epimastigote. While both NMT and N-myristoylationwere detected in all lifecycle stages, there were subtle differences in theexpression of several myristoylated proteins. However, at least ~10 myristoylatedproteins were common throughout the lifecycle. In addition, N-myristoylation in thisparasite was found to be primarily associated with nascent protein synthesis, astreatment with cycloheximide reduced the number of N-myristoylated proteins detected. The sensitivity of epimastigotes to the inhibitor DDD85646 correlated with theexpression of NMT, suggesting it to be the target in the parasite. This was confirmedby the dose-dependent depletion of N-myristoylated proteins detected in parasitestreated with this compound. Mechanism of action studies revealed a cytokinesis defectcaused by the inhibition of N-myristoylation and NMT. Overexpression of NMT wasable to rescue these cells from this phenotype confirming that it is NMT mediated. TheN-myristoylated proteins comprising the N-myristoylome of the epimastigote wereidentified using the myristic acid analog, azidomyristate and a chemical proteomicsapproach. Combining label-free and SILAC methodologies, 38 proteins were enrichedfrom azidomyristate labelled cells, 35 of which were predicted to have a glycine afterthe initial methionine. The findings from these experiments have led to the mostcomprehensive N-myristoylome of T. cruzi studied to date and provide severalhypotheses, by which the inhibition of NMT leads to the observed cytokinesis defect.