Drosophila nonclaret disjunctional (Ncd) is a kinesin-like C-terminal motor protein that is involved in spindle assembly in oocytes during meiosis and in spindle maintenance in early embryos during mitosis. Ncd interacts with both "highway" and "cargo" microtubules (MTs) in meiotic and mitotic spindles through the action of ATP-dependent and ATP-independent MT binding sites in the head and tail domains, respectively. Through the action of these binding sites, Ncd bundles and, perhaps, slides MTs relative to each other. These functions are important for the in vivo role of Ncd in the formation of the bipolar spindle and maintenance of the spindle assembly. Despite the high homology of the Ncd head domain to the kinesin head domain, the Ncd tail domain is unique among kinesin-like motor proteins. Characterization of ATP-independent interactions of Ncd with cargo MTs and identification of MT binding sites (located in amino acid residues 83-100 and 115-187) in the tail region by MT co-sedimentation assays revealed that the Ncd tail has functional similarities to microtubule-associated proteins, especially to tau and MAP2, that regulate MT assembly. Like tau MT binding motifs, MT binding sites of the tail domain are rich in basic amino acids that are flanked by proline residues. Cross-linking and MT co-sedimentation assays with subtilisin-digested MTs demonstrated that Ncd tail binding sites (located at the extreme C-terminus and in the H11-H12 loop / H12 helix of each tubulin monomer) on tubulin correspond to tau binding sites. Further, the Ncd tail domain, like tau, can promote and stabilize MT assembly under conditions that induce MT disassembly. Taken together, these results suggest that the Ncd tail functions both in the transport of cargo MTs to spindle poles for the formation of the spindle assembly during meiosis, and in maintenance of spindle assembly during mitosis. How these different functions of Ncd are regulated still remains unknown, however further understanding of the regulation of Ncd function should contribute to our knowledge of cell cycle regulation in both meiotic and mitotic cells. / Ph. D.

Chemical modification is a powerful technique for probing functionally important amino acids. N-ethylmaleimide (NEM) reacts readily with exposed sulfhydryl groups, and has previously been shown to inhibit the activity of MT-motor proteins and tubulin assembly. This project seeks to investigate the mechanisms by which NEM affects motor function and inhibits MT minus end assembly. Recombinant motor domains of Drosophila kinesin (DK350 and DK375), Ncd (MC1), and squid kinesin (p181) were modified by NEM. NEM treatment was shown to affect the binding of MC1, but not recombinant kinesin proteins to MTs in the co-sedimentation assay. NEM treatment decreased the MT-stimulated ATPase rates of MC1 and DK350 in an NEM-concentration dependent manner, but did not affect the rate of DK375. Observed effects with DK375, p181, and MC1 were correlated with the number of labeled cysteines determined with [3H]NEM. As previously known, when NEM-treated tubulin was combined with untreated tubulin at certain ratios, assembly occurred only at the MT plus end. To investigate the mechanism by which NEM affects the polarity of tubulin assembly, tubulin was treated with NEM and assembly was analyzed using video-enhanced differential interference contrast microscopy. [3H]NEM was used to follow the time course of modification and to determine the number of modified sites per tubulin subunit. After 10 minutes, one cysteine was labeled on both a and b tubulin and this was sufficient to inhibit minus end assembly. Additionally, having one subunit labeled out of five tubulin subunits was sufficient to observe this effect. Protein digestion methods were used to aid in elimination of cysteines, to characterize potential critical cysteines in MC1, a, and b tubulin. / Master of Science

The aim of this study is to investigate knowledge, perceptions and attitudes towards cardiovascular diseases and obesity among men and women and current health strategies in Babati, Tanzania. The results of this study can contribute to answers about where focus needs to be added for preventive health interventions. In order to answer the research questions of this study, a qualitative field study was conducted in Babati town, Tanzania during three weeks in February and March 2017. The theoretical framework used in this study is the Theory of planned behavior, a psychological theory that explains human behavior that is used to understand people’s behavior and decision making. The findings of this study shows that people in Babati have a substantial knowledge, which shows that knowledge does not play an important role in the fight against NCDs since it is increasing anyway. People have a negative attitude towards these diseases but claims that there is still people that has a positive attitude. This study conclude that the main problem is people’s behavior and accepting a lifestyle change rather than lack of knowledge as previous research claims.

OBJECTIVE: To examine associations and trends between chronic diseases and tooth loss using BRFSS 2012-2018. METHODS: Self-reported permanent tooth loss from tooth decay/gum disease and several self-reported chronic disease diagnoses were analyzed by cycle (2012, 2014, 2016, 2018) to explore associations and trends. Chi-square analyses were performed for the primary outcome of one or more teeth lost with the following ailments: physical health, mental health, weight, diabetes, myocardial infarction, coronary heart disease, stroke, asthma, cancer, respiratory diseases, arthritis, and kidney disease. Multivariate logistic regressions were performed to estimate the odds for tooth-loss for each disease using gender, age, race, insurance, income, education and smoking as covariates. Effects of one or more concurrent chronic disease diagnoses on tooth loss were calculated and 2012-2018 results compared. Interaction between disease and year were used in the multivariate regression aanalyses to find differences in tooth loss from 2012- 2018. All calculations were performed using SAS 9.4. RESULTS: Tooth loss has declined from 45% - in 2012 to 39% - in 2018 in individuals with one chronic disease. A similar decline in tooth loss is seen in those with two, three, four or more chronic diseases. Increased tooth-loss was significantly associated with each chronic disease, with adjusted odds of tooth-loss ranging from 1.08-1.72. Diabetics, had an increased and significant odds of tooth loss with time: 1.36 (2012)-1.54 (2018). The odds of tooth-loss increased as number of concurrent chronic diseases increased -1.2 (one chronic disease)-2.4 (four or more chronic diseases). CONCLUSION: Fewer people are losing teeth, but those with chronic disease experience higher odds of tooth-loss. Having more concurrent diseases is associated with increased tooth-loss. Oral health is essential for overall health, therefore access to oral health care and educating the public and health professionals about these associations is vital. / 2021-07-29T00:00:00Z

Yes / Background: Non-communicable diseases (NCDs) affect a growing share of the population in Kosovo. The country faces challenges with NCDs management, specifically detecting, screening, and treating people with NCDs. Objective: To assess the management of NCDs, including the inputs that influence the provision of NCDs and outcomes of NCD management. Eligibility criteria: Studies had to report NCD management in Kosovo. Sources of evidence: We systematically searched Google Scholar, PubMed, Scopus, and Web of Science. Charting methods: The data were charted by two researchers. We extracted data on general study details and design and information on the management and outcomes of NCDs in Kosovo. Synthesis of results: For the mix of studies that were included in the review, thematic narrative synthesis was used. We developed a conceptual framework based on health production core components to analyze the data. Results: Kosovo's health care system is available to provide basic care for patients with NCDs. However, there are serious limitations in the availability of key inputs providing care, i.e., funding, medicines, supplies, and medical staff. Additionally, in terms of the management of NCDs, there are areas for improvement, such as limited application of clinical pathways and guidelines and issues with referrals of patients among levels and sectors of care. Finally, it is worth noting that there is overall limited information on NCD management and outcomes. Conclusions: Kosovo provides only basic services and treatment of NCDs. The data reporting the existing situation on NCD management are limited. The inputs from this review are helpful for existing policy efforts by the government aimed to enhance NCD care in Kosovo. / This study is part of the research done for a World Bank review of the state of NCDs in Kosovo and APC was funded through the Access Accelerated Trust Fund (P170638).

Du fait de leurs excellentes propriétés mécaniques et de leurs faibles masses spécifiques, l’utilisation des matériaux composites, au sein des structures mécaniques, est en plein essor. Cependant, leur usinage entraine une usure prématurée et aléatoire des outils de coupes en cermet WC-Co. L’origine de cette étude provient de la nécessité de protéger leur surface par un revêtement dur et résistant comme, par exemple, le diamant NCD. Toutefois, le cobalt présent dans le carbure cémenté favorise la formation de graphite au niveau de l’interface avec le film de diamant, ce qui nuit à son adhérence. La méthode retenue afin d’isoler ce métal de la surface a été de réaliser des systèmes interfaciaux multicouches. Ces derniers sont composés d’une barrière de diffusion au cobalt en nitrure de tantale et/ou en nitrure de zirconium et d’une couche favorisant la germination du diamant en acier inoxydable ou en molybdène. Les protocoles de dépôt élaborés au cours de ce travail ont la particularité d’utiliser une polarisation négative et séquencée du substrat durant l’étape de croissance. Cela induit une morphologie originale au revêtement de diamant breveté sous le nom de PyrNCD (Brevet N° :FR0807181). Les objectifs de cette étude sont la compréhension de l’ensemble des mécanismes (influence de la solubilité du carbone sur la germination du diamant, l’effet de la polarisation sur le substrat revêtu et sur la croissance du diamant,…) intervenant durant le dépôt de diamant et l’optimisation du procédé. / The combination of good mechanical properties and low specific mass ensures the increasing use of composite materials to reduce the weight of mechanical structures. However, their machining induces premature and random wear of WC-Co cermet cutting-tools. The origin of this study comes from the necessity to protect cutting-tools surfaces by hard and resistant coatings like NCD diamond. Unfortunately, the cobalt found in these cemented carbides catalyses graphite formation at the interface with the diamond layer and harms the grip of the diamond film. The method used to isolate this metal from the surface has been to form interfacial multilayer systems. These are composed of a tantalum nitride and/or zirconium nitride diffusion barrier for cobalt and a layer promoting the diamond nucleation in molybdenum or stainless steel. The deposit protocols developed during this PhD work have the particularity of using a negative and sequenced substrate bias during the growth stage. This leads to an original morphology of the diamond coating which is patented under the name PyrNCD (International Patent N°: WO/2010/076423). The goal of this study is to understand all the mechanisms (like the impact of the carbon solubility on the diamond nucleation, the effects of negative bias on the coated substrate and the diamond growth,...) occurring during diamond deposition and process optimization.

Philosophiae Doctor - PhD / Background: Non-communicable diseases (NCDs) continue to rise in South Africa, accounting for 43% of total deaths in 2012. Smoking and a diet high in salt are among the major modifiable risk factors for NCDs that can be addressed through cost-effective policy interventions in the form of regulation or legislation and active multisectoral engagement. Population-based prevalence and mortality data are necessary for monitoring and evaluation such interventions. South Africa has developed a National Strategic Plan for NCDs but there is limited evaluation of NCD policies. Furthermore, there is a need to explore the availability of population-based data and the role that it can play to monitor interventions. Aim: The overall aim of the thesis is to assess the implementation of policies for reducing risk factors for chronic NCDs in South Africa, and to explore the role of population-based data in supporting environmental and policy approaches to prevent NCDs. The thesis will also examine whether there are differences in urban and rural settings in the implementation of tobacco control and salt reduction regulation as well as the barriers to implement the National Strategic Plan for prevention of NCDs. Methods: Multiple methods of data collection were used. A desk review of policies to address NCDs in South Africa was undertaken and semi-structured interviews with the NCD policymakers and managers in two provinces (the Eastern Cape and Western Cape) were undertaken, to explore challenges and successes of implementation of the NSP. The Cross-sectional baseline questionnaire and quantified food frequency data from the PURE study were used to determine the prevalence of smoking and the intakes of sodium and potassium in a selected urban and a rural community. Data collected using a validated community audit tool was used to assess the physical environment related to tobacco as well as questionnaire data from face-to-face interviews about perceptions about tobacco use in the urban and rural communities. Trends in mortality from tobacco related and high salt consumption related conditions together with prevalence data from national health surveys were reviewed to assess the health impact.

Philosophiae Doctor - PhD / Non-communicable diseases (NCD) continue to be a public health concern globally and contribute to the burden of disease. The formal health system in developing countries lacks the capacity to deal with these NCD as it is overburdened by communicable diseases. Thus, community health workers (CHWs) have been suggested as a solution for alleviating the burden for primary health facilities, by extending NCD care to the community. This thesis aims to develop an integrated model of care for CHWs working with patients with non-communicable diseases by describing and exploring current CHW roles, knowledge and practices in relation to community-based NCD care. The specific objectives for this study included 1) the exploration of the NCD roles of generalist CHWs in the context of a limited resource urban setting; 2) determining the NCD-related knowledge of CHWs, and factors influencing this in a limited resource urban setting and 3) a comparison of actual and envisaged roles in the management and prevention of NCD using the integrated chronic diseases management model (ICDM) as a benchmark, and propose key competencies and systems support for NCD functions of CHWs in South Africa Mixed methods were used to achieve the objectives of this study. First, a qualitative enquiry was conducted using observations to respond to the first objective. A quantitative cross-sectional design was then used to achieve the second objective, and a questionnaire was used to interview CHWs. A comparison of findings from both the quantitative and qualitative studies with policy guidelines was undertaken to address the third objective.

Alpha-helical coiled-coils are common protein structural motifs with varied mechanical roles, such as, tropomyosin in muscle contraction or neck-stalks of kinesins and myosins, in motor proteins. Using computer simulations, we characterized elastic properties of coiled-coils both, globally and locally. Normal mode analysis for global elastic properties revealed a buckling instability due to inherently present weak non-bonded forces. We characterized this using a critical buckling length (lc). For coiled-coils, lc was significantly less than their persistence length thereby governing the filament conformation. We also found that mutations to the hydrophobic residues at the knob-into-hole interface affect elasticity of coiled-coils significantly. We built a flexibility map of tropomyosin using a local fluctuation analysis and found regional variations in flexibilities due to such breaks in the knob-into-hole packing. Overall, flexibility varies by more than twofold and increases towards the C-terminal region of the molecule. Actin binding sites in zones and broken core regions due to acidic residues at the hydrophobic face such as, the Asp137 and the Glu218, are found to be the most labile with moduli for splay and broad face bending as 70 nm and 116 nm, respectively. Such variations in flexibility could be relevant to the tropomyosin function, especially for moving across the non-uniform surface of F-actin to regulate myosin binding. Non-claret disjunction (Ncd), is a Kinesin-14 family protein that walks to the microtubule's minus end. Although available structures show its alpha-helical coiled-coil neck in either pre- or post-stroke orientations, little is known about the transition between these two states. Using a combination of molecular dynamics simulations and structural analyses, we find that the neck travel is a guided diffusion involving sequential intermediate contacts with the motor head. The post-stroke is at a higher free-energy minimum than the pre-stroke. The importance of intermediate contacts correlates with the existing motility data including those of mutant Ncds and other members of the kinesin-14 family. While the forward motion has a ~4.5 kBT (kB: Boltzmann constant, T = 300 K) free energy barrier, recovery stroke goes nearly downhill in free energy. The hysteresis in forward and reverse neck motion energetics arises from the mechanical compliance of the protein, and together with guided diffusion, it may be key for the directed motility of Ncd. Although it is known that neighboring Ncds on a microtubule (MT) have an attractive interaction and a group of Ncds act cooperatively, the physical basis of neither this attraction nor the cooperativity is known. From structural analysis of Ncd neighbors on an MT lattice we find that steric hindrances between the coiled-coil neck-stalks of longitudinal neighbors drive synchrony among a group of Ncds on a single protofilament. Across lateral dimers, surface loop L2 of the motor-head (MH) that is not bound to the MT (unbound-MH) in a pre-stroke dimer, is seen to have strong attraction to the nucleotide pocket in the MH that is bound to MT (bound-MH) of its off-axis neighbor. Such an attraction will however impede the motility in both the dimers. We hence propose rules that drive motor binding to an MT site in the presence of immediate neighbors such that motility of the group is not compromised. The unbound-MH, whose role in the walking step of an Ncd was unclear, is thus seen to regulate MT decoration.

Background: Non communicable diseases (NCD) are recognized as a major burden of human health globally, especially in low and middle-income countries including Indonesia. This thesis addresses a community intervention program utilizing a community empowerment approach to study whether this is a reasonable strategy to control NCD. Objective: To explore possible opportunities, common pitfalls, and barriers in the process of developing a pilot community intervention program to prevent NCD in an urban area of a middle-income country. Methods: The study was conducted in Yogyakarta Municipality. The baseline risk factor survey in 2004 (n=3205) describes the pattern of NCD risk factors (smoking, physical inactivity and low fruit and vegetable intake) and demographic characteristics using STEPwise instrument. A qualitative study was conducted in order to illustrate peoples’ perceptions about NCD risk factors and how NCD might be prevented. A pilot intervention was developed based on the baseline survey and the qualitative data. The pilot intervention was conducted in four intervention communities while one community served as the referent area. The intervention was evaluated using quantitative and qualitative approaches. Finally, a second cross-sectional survey conducted in 2009 (n= 2467) to measure NCD risk factor changes during the five year period. Results: Baseline qualitative data showed that people in the high SES (Socio Economic Status) group preferred individual activities, whereas people in the low SES group preferred collective activities. Baseline survey data showed that the prevalence of all NCD risk factors were high. The community intervention was designed to promote passive smoking protection, promote healthy diet and physical activity, improve people’s knowledge of NCD, and provide a supporting environment. A mutual understanding between the Proriva team and community leadership was bargained. Several interactive group discussions were performed to increase NCD awareness. A working team was assigned to set goals and develop programs, and the programs were delivered to the community. There were more frequent activities and higher participation rates in the low SES group than in high SES group. The repeated cross-sectional surveys showed that the percentage of men predicted to be at high risk of getting an NCD event had significantly increased in 2009 compared to 2004. Conclusion: The community empowerment model was a feasible choice as a “moderate”strategy to accommodate with people’s need when implementing a community intervention that also interacts with the service provided by the existing health system. A community empowerment approach may improve program acceptance among the people.