Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand activated transcription factors. There are three identified isotypes: PPAR alpha, PPAR gamma and PPAR delta, together controlling the expression of genes involved in inflammation, cell differentiation, proliferation, lipid and carbohydrate metabolism and energy homeostasis. The PPARs are potential targets for the treatment of dyslipidaemia, type II diabetes mellitus and the metabolic syndrome. This thesis uses a multi-platform metabolomics approach, 13C-isotope substrate flux analysis, respirometry and transcriptomics to determine the role PPAR delta and PPAR gamma play in metabolic control both in adipose tissue and systemically. To achieve this, the metabolic phenotype of the 3T3-L1 adipocyte cell line was defined to generate a metabolically phenotyped in vitro model of adipose tissue. The importance of fatty acid alpha-oxidation in the differentiation of adipocytes was emphasised The effects of PPAR delta and PPAR gamma activation in white adipose tissue from the ob/ob mouse model of insulin resistance, and in the phenotyped 3T3-L1 adipocyte model, were investigated. PPAR delta activation was distinguished by oxidative catabolism of fatty acids and citric acid cycle intermediates. Conversely, PPAR gamma activation was identified by the sequestration of lipids into adipose tissue. Moreover, to address the systemic influence of PPAR activation, with a focus on the Cori cycle and the interactions of the liver and skeletal muscle, the metabolic changes that occur in these tissues following PPAR delta and PPAR gamma activation in the ob/ob mouse were examined. PPAR delta activation was characterised by the mobilisation and release of triacylglycerols (TAGs) into circulation as an energy source for peripheral tissues whereas PPAR gamma activation was defined by a reduction and sequestration of circulating TAGs. This thesis has better characterised the role of the PPARs as master regulators of metabolism and emphasised their potential as therapeutic targets for metabolic diseases of global importance.

O diabetes mellitus (DM) é caracterizado por uma deficiência no transporte de glicose da corrente sanguínea para o interior da célula, elevando os níveis de glicose no sangue. Isso ocorre pela deficiência e até mesmo resistência à insulina, e é controlada por agentes hipoglicêmicos orais e/ou dieta, associada a exercícios físicos. É classificada em tipo I e II, sendo que o segundo é a forma mais comum da doença e tem a idade como um dos fatores predisponentes. O periodonto é formado por estruturas de suporte e proteção ao elemento dentário e seu aspecto de saúde tem uma importância significante na cavidade bucal. A doença periodontal (DP) é um processo inflamatório crônico caracterizado por inflamação do tecido gengival e/ou perda de estruturas que compõem o periodonto, causando danos à estrutura dentária ou até perda do dente. É reconhecida como a sexta maior complicação do diabetes. Esse estudo teve como objetivo comparar as alterações periodontais em indivíduos diabéticos tipo II e não diabéticos residentes no município de Araguaína Tocantins (TO). Para isso, foram examinados 34 pacientes divididos em dois grupos: diabéticos e não diabéticos, que foram submetidos a exames periodontais para determinar a Profundidade de Sondagem (PS), Perda de Inserção Clínica (PIC), Índice Gengival (IG), Índice de Placa (IP), Índice de Higiene Oral (IHO) e exames laboratoriais para os diabéticos tipo II. Para a análise estatística foi usado o teste t no intuito de obter as correlações dos índices entre os diabéticos e o teste U para analisar as alterações periodontais entre os grupos. Foram encontrados PIC e IHO maiores em diabéticos, sendo os demais índices maiores no grupo dos não diabéticos. Só IP não apresentou diferença estatística significante (p>0,05). Também foi verificada uma correlação entre IP e IG, não ocorrendo entre os demais índices. Concluiu-se que os diabéticos têm doença periodontal mais severa que os não diabéticos. / Diabetes Melitus (DM) is characterized by a deficiency in the glicose transport from the blood stream to the inside of cells, raising the glicose leves in the blood. This occurs due to the deficiency or even resistance to insulin, and it is controlled by oral hypoglicemic agents and/or diet, associated with physical exercises. It is classified in types I and II, in such a way the second type in the most common and its predisponent factor is age. The periodonto is made of structures that support and protect the dental element and its health aspect has a significant importance to the bucal cavity. The periodontal disease (PD) is a chronic inflammatory process characterized by inflammation of the gingival tissue and /or loss of structures that compose the periodonto, causing damage to the dental structure or even loss of teeth. Its known as the sixth biggest complication derived from diabetes. This work had the purpose of comparing periodontal modifications in diabetic type II and non diabetic patients who lived in Araguaína Tocantins (TO). Therefore, 34 patients were examined and separated in two groups with PD: diabetics and non diabetics. They were submitted to periodontal examination in order to measure the Depth Proof (PPD), Clinical Attachment Loss (CAL), Gingival Index (GI), Plaque Index (PII), Oral Hygiene Index (OHI) indices. Also, laboratorial tests were made for type II - diabetic patients. The statistical analysis was made using the t-test to obtain the indices of correlation in diabetic group and the u-test to evaluate periodontal modifications between the groups. The CAL and the indices were higher in diabetic group and the other indices were higher in non diabetic group. Only the PII index show no significant statistic difference (p>0,05). It was also verified a correlation between PII and GI indices, yet it was not true in other indices. It was possible the conclude that the diabetics have more severe periodontal disease than the non diabetics.

Avaliou-se a velocidade da onda de pulso (VOP) carótido-femoral (CF) e carótido-radial (CR), por meio de técnica não-invasiva, em 14 indivíduos diabéticos do tipo 2 normotensos, A sensibilidade do barorreflexo (SBR) foi avaliada pela manobra de Valsalva e por testes com nitroglicerina e fenilefrina, durante monitorização não-invasiva batimento-a-batimento da pressão arterial. Os resultados foram comparados aos obtidos em 13 indívíduos saudáveis pareados por idade, índice de massa corporal e sexo. O grupo diabetes apresentou maiores níveis de glicose de jejum e HbA1c. As VOP CF e CR foram mais elevadas no grupo diabetes. A SBR estava reduzida nos diabéticos, nos testes com nitroglicerina, fenilefrina e, no reflexo de taquicardia da fase II da manobra de Valsalva. O aumento da VOP CF foi significativamente correlacionado à redução da SBR. Os resultados demonstram que em diabéticos do tipo 2 há maior rigidez arterial e a SBR está reduzida. A SBR é inversamente correlacionada ao aumento da rigidez arterial / Fourteen normotensive diabetic subjects were submitted to carotid-femoral (CF) and carotid-radial (CR) pulse wave velocity (PWV) analysis by non-invasive automatic device. The baroreflex sensitivity (BRS) was evaluated by Valsalva manoeuvre, phenylephrine and nitroglycerin tests during non-invasive beat-to-beat blood pressure monitoring. The data were compared with those obtained in 13 age, body mass index and sex-matched healthy subjects. The diabetes group showed a higher fasting glucose level and HbA1c. The CF PWV and CR PWV were higher in diabetic patients. The BRS was impaired in diabetic individuals in nitroglycerine and phenylephrine tests and, also, in the tachycardic reflex in phase II of Valsalva manoeuvre. The increase of CF PWV was significantly correlated to the decrease of BRS. The data demonstrated that, in diabetic normotensive individuals, arterial stiffness is increased and the BRS is impaired. The BRS is inverselly correlated to increase of aortic stiffness

La prévalence du diabète de type 2 augmente à travers le monde du fait de l’obésité et du vieillissement de la population. En France, cette prévalence est estimée à 14 % chez les plus de 65 ans et à 25 % pour les plus de 75 ans. Les médecins généralistes sont les médecins de premier recours dans la prise en charge du diabète. Les récentes recommandations de prise en charge du diabète de type 2 chez les sujets âgés préconisent d’ajuster la cible thérapeutique (niveau d’HbA1c) à l’état de santé du patient. Cependant, il peut s’avérer difficile pour les médecins généralistes d’estimer cet état de santé dans leur pratique courante. Une façon de faire est d’estimer l’âge apparent des patients par rapport à leur âge chronologique (font-ils plus vieux ou plus jeunes que leur âge, font-ils leur âge ?).Les objectifs de ce travail étaient 1) d’analyser la prise en charge médicale en soins primaires de sujets âgés diabétiques, en particulier l’association entre l’atteinte de la cible d’HbA1C personnalisée recommandée et la survenue d'événements cliniques majeurs ; 2) de déterminer si l’estimation de l'âge apparent est prédictive de la mortalité sur 3 ans de suivi.La cohorte S. AGES est une étude prospective multicentrique de patients de plus de 65 ans non institutionnalisés ayant une fibrillation auriculaire, un diabète de type 2 ou des douleurs chroniques. Trois ans de suivi étaient prévus. Des modèles logistiques mixtes ont été utilisés pour la plupart des analyses.D'avril 2009 à juin 2011, 760 médecins généralistes ont inclus 3434 patients : 1379, 983, 1072 dans la sous-cohorte douleurs chroniques, diabète et fibrillation auriculaire respectivement. Leur âge moyen était de 77,6 ± 6,2 ans et 56,6 % étaient des femmes. La plupart étaient autonomes, 70% n’avaient pas de troubles cognitifs et 20% des patients avaient un niveau d'études supérieur au baccalauréat.Dans la sous-cohorte diabète, la durée du diabète était de 11,3 ± 8,7 ans avec un taux d'HbA1c moyen de 6,9± 1,0% ; 20 % des patients avaient une complication macrovasculaire, 33 % une insuffisance rénale. La metformine était le premier traitement antidiabétique utilisé et 18 % des patients étaient sous insuline.Parmi les 747 patients analysés à l’inclusion, 551 (76,8 %) atteignaient leur cible d'HbA1C personnalisée recommandée. Au cours du suivi, 391 (52,3%) ont présenté un événement majeur. Parmi les patients qui n'ont pas atteint leur cible d'HbA1C personnalisée (par rapport à ceux qui l'ont atteint), le risque (OR) d'un événement clinique majeur était de 0,95 [IC 95% 0,69 - 1,31], p = 0,76. Les risques de décès, d'événements artériels et d'hospitalisations étaient respectivement de 0,88 [IC à 95% 0,40-1,94], p = 0,75, 1,14 [IC à 95% 0,71-1,83], p = 0,59 et 0,84 [IC à 95% 0,60 - 1,18], p = 0,32.Nos résultats n'ont montré aucune différence, de risque d’événement clinique majeur au cours du suivi entre les patients, qu'ils aient ou non atteint leur cible d’HbA1c recommandée.Parmi les 3434 patients inclus dans les 3 sous-cohortes, 3427 ont été classés en 3 catégories : faire leur âge, faire plus âgés ou plus jeunes. La dépression, la perte d’autonomie, l’insuffisance cardiaque et l’obésité était associés à un risque plus élevé de faire plus âgé, alors que l’absence de dépression, une autonomie conservée et un niveau d’études élevé était associé à un risque plus élevé de faire plus jeune. L'âge apparent était associé au risque de décès au cours du suivi de trois ans : les patients faisant leur âge ou plus âgés avaient un risque de décès plus élevé que ceux faisant plus jeunes : HR=1,27 (0,93-1,73) et 1,79 (1,16-2,76), respectivement (p = 0,008).Nos résultats soutiennent l'hypothèse qu'une stratégie plus permissive pour traiter le diabète de type 2 chez les patients âgés peut être mise en œuvre sans augmenter le risque d'événement clinique majeur. L'âge apparent peut être considéré comme un marqueur de l'état de santé rapide et facile en soins primaires. / Prevalence of type 2 diabetes mellitus is increasing worldwide and this trend is projected to persist because of the demographic shift (ageing population) and the obesity pandemic. Diabetes prevalence increases with age attaining 14% in people aged 65 years and over. Recent guidelines for the management of type 2 diabetes in the elderly recommend adjusting the therapeutic targets according to the patients’ health status. General practitioners (GPs) are the leading health professionals in charge of people with diabetes. In order to deliver appropriate medical care, GPs need to accurately assess the health status of their patients. However, in clinical practice it might be difficult for GPs to assess the health status of their patients routinely and they often rely on their intuitive clinical impression. The aim of this work was to describe the medical management of people aged 65 and older with type 2 diabetes followed up in the primary care. We particularly sought to assess the association between achieving the recommended personalized glycaemic targets (HbA1C) and the occurrence of major clinical events. Also, we sought to explore the relationship between GP estimation of the patient’ apparent age, as a simple tool to assess health status, and the risk of death in the next three years.Average age of all patients was 77.6±6.2 years and 56.6% were women. Most patients were independent and without cognitive impairment. Around 20% of patients had a high level of education. In the diabetes sub-cohort, the duration of diabetes was 11.3±8.7 years and the average HbA1c was 6.9±1.0%; 20% of patients had macrovascular complications and 33% had renal failure at baseline. Metformin was the most commonly used medication (62%) while insulin was used in 18% of patients. Concerning the association between glycaemic targets and major clinical events, data were available for 747 patients of whom 551 (76.8%) were in their recommended target. During the 3-year follow-up, 391 patients (52.3%) experienced a major clinical event but there was no difference between those who did not achieve their target and those who achieved it: odds ratio 0.95, 95% CI 0.69-1.31, p=0.76. These results suggest that a more permissive strategy to treat diabetes in the elderly could be implemented without increasing the risk of major clinical events. Among the 3434 included, 3427 patients were classified into one of three categories according to whether they looked their age or older or younger than their chronologic age. Depression, poor functional ability, heart failure and obesity were associated with a higher risk to look older whereas absence of depression, normal functional ability, higher educational level were associated with a higher risk of looking younger. Patients who looked their age or older had a higher risk of death than those who looked younger: hazard ratios 1.27 (95% CI 0.93–1.73) and 1.79 (95% CI 1.16–2.76), respectively (p=0.008). These results suggest that GPs integrate past medical history and deep knowledge of their patients to ascertain an apparent age, which may be considered as a marker of health status.

The current study empirically tested four models of type II diabetic patient adherence, including wellness, screening, medication, and treatment adherence. Four mediators were proposed patient understanding, agreement, trust, and motivation were tested for each model. The current study is grounded in patient-centered communication, responding to Street’s (2013) call to model pathways between communication and patient health outcomes. Moreover, the study argues that adherence, for type II diabetic patients should be conceptualized as four distinct clusters of behavior (wellness, screening, medication, and treatment). A sample of (n=817) type II diabetes patients from the U.S. under the care of a medical provider and taking medication for their type II diabetes were surveyed. Findings from the present study indicate that the relationship between patient-centered communication and patient-health outcomes is mediated by proximal outcomes. The results contribute to our understanding or patient-centered communication, patient understanding, agreement, trust, and motivation, and adherence behaviors. Resulted indicated that while three of the four proposed hypotheses were supported, the most commonly studied type of adherence (medication), the relationship between patient-centered communication and medication adherence was not mediated. The current study ends with a discussion and implication of the findings as well as directions for future research

abstract: The first part of this dissertation reports the study of the vertical carrier transport and device application in InAs/InAs1-xSbx strain-balanced type-II superlattice. It is known that the low hole mobility in the InAs/InAs1-xSbx superlattice is considered as the main reason for the low internal quantum efficiency of its mid-wave and long-wave infrared photodetectors, compared with that of its HgCdTe counterparts. Optical measurements using time-resolved photoluminescence and steady-state photoluminescence spectroscopy are implemented to extract the diffusion coefficients and mobilities of holes in the superlattices at various temperatures from 12 K to 210 K. The sample structure consists of a mid-wave infrared superlattice absorber region grown atop a long-wave infrared superlattice probe region. An ambipolar diffusion model is adopted to extract the hole mobility. The results show that the hole mobility first increases from 0.2 cm2/Vs at 12 K and then levels off at ~50 cm2/Vs as the temperature exceeds ~60 K. An InAs/InAs1-xSbx type-II superlattice nBn long-wavelength barrier infrared photodetector has also been demonstrated with a measured dark current density of 9.5×10-4 A/cm2 and a maximum resistance-area product of 563 Ω-cm2 at 77 K under a bias of -0.5 V. The Arrhenius plot of the dark current density reveals a possible high-operating-temperature of 110 K.The second part of the dissertation reports a lift-off technology using a water-soluble sacrificial MgTe layer grown on InSb. This technique enables the seamless integration of materials with lattice constants near 6.5 Å, such as InSb, CdTe, PbTe, HgTe and Sn. Coherently strained MgTe with a lattice constant close to 6.5 Å acts as a sacrificial layer which reacts with water and releases the film above it. Freestanding CdTe/MgxCd1-xTe double-heterostructures resulting from the lift-off process show increased photoluminescence intensity due to enhanced extraction efficiency and photon-recycling effect. The lifted-off thin films show smooth and flat surfaces with 6.7 Å root-mean-square roughness revealed by atomic-force microscopy profiles. The increased photoluminescence intensity also confirms that the CdTe/MgxCd1-xTe double-heterostructures maintain the high optical quality after epitaxial lift-off. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2020

This work details the inhibition of BACE1, BACE2, and SARS-CoV-2 3CLpro through several novel and potent protease inhibitors. Nanomolar potency of BACE1 and BACE2 is achieved with all tested inhibitors, and the S2 subsite has been identified as a BACE2 selectivity determinant. This is supported by the observation that the novel BACE2 mutant, BACE2 L246N, displays increased potency and selectivity over BACE1 against this peptidomimetic scaffold. Nanomolar to micromolar potency of SARS-CoV-2 3CLpro is achieved with the compounds tested in this study. Kinetic data illustrates the allowed substitutions at the P1’, P1, P2, and P4 positions on two scaffolds: ML188 and GC376. Finally, this work presents the high-resolution crystal structures of four inhibitors bound to BACE1 and 12 inhibitors bound to SARS-CoV-2 3CLpro. These structural data help to explain the selectivity determinants of BACE1 and BACE2 and further enable structure-based drug design against these two enzymes for the treatments of Alzheimer's Disease and Type II Diabetes, respectively. Additionally, these structural data illustrate the flexibility of the GC376 scaffold at the P3/P4 position, providing a structural rationale for the observed differences in potency across the different analogs. These structural data further enable structure-based drug design against SARS-CoV-2 3CLpro for the treatment of COVID-19.

This study focuses on the development of a generalised multivariate beta type II distribution as well as the noncentral and bimatrix counterparts with positive domain. These models emanate from a sequential quality monitoring procedure with the normal and multivariate normal distributions as the underlying process distributions. Three different scenarios are considered, namely: 1. The variance is monitored from a normal process and the mean remains unchanged; 2. The above-mentioned scenario but the known mean also encounters a sustained shift; 3. The covariance structure of a multivariate normal distribution is monitored with the known mean vector unchanged. The statistics originating from the above-mentioned scenarios considered are constructed from different dependent chi-squared or Wishart ratios. Exact expressions are derived for the probability density functions of these statistics. These new distributions contribute to the statistical discipline in the sense that it can serve as alternatives to existing probability models, and can be used in determining the performance of the quality monitoring procedure. / Thesis (PhD)--University of Pretoria, 2013. / gm2014 / Statistics / unrestricted

Type II diabetes is a significant problem in the United States that had affected almost 10% of the American population and over 13% of African Americans. Although culturally competent diabetes education and treatment programs have been significantly more successful, little is known about the cultural factors affecting type II diabetes in African Americans of Caribbean descent (AACD). The purpose of this qualitative, phenomenological study was to explore the cultural factors relevant to the treatment and prevention of type II diabetes among AACD. The theoretical framework for the study consisted of cultural adaptation theory and the transtheoretical model. Data collection consisted of in-depth, qualitative semistructured interviews. For the first research question, findings indicated that AACD viewed dietary and exercise regimens as challenging to implement. For the second question, findings indicated that AACD viewed medical advice related to diabetes as valuable and helpful, and AACD fully appreciated and perhaps even exaggerated the seriousness of diabetes, a factor that might incentivize preventative behaviors. Findings from the present study could inform new diabetes treatment and education for AACD that addresses specific cultural factors, which could lead to lower diabetes rates for this population.

The incidence of diabetes mellitus and cardiovascular diseases is increasing at a worrisome rate globally. Diabetes mellitus is known to occur due to high blood glucose levels, caused by defects in insulin levels. Adult on-set type II diabetes, which is closely associated with obesity, is reported to be 90-95% of all diabetic cases and linked to diet and lifestyle factors. A large population of the developed and developing countries is now being effected by this epidemic. Natural sources of phenolic antioxidants and inhibitors of digestive enzymes from food sources have potential for low cost dietary management of type II diabetes. Therefore, the main focus of this study was to evaluate, develop and design effective dietary strategies based on a combination of Chilean potatoes and herb synergies for the management of hyperglycemia and hypertension linked to type II diabetes. Antioxidant, antihypertensive and anti-hyperglycemic potentials of Chilean potato (Solanum tuberosum ssp. tuberosum L.), herbs from the Apiaceae (Dill, Ajowan, Fennel, Caraway, Coriander and Anise) and Lamiaceae (Sage and Marjoram) families were evaluated, with a goal to target a new dietary management strategy for early stages of type II diabetes through lowering of hyperglycemia and related complications of hypertension The results indicated a high correlation between total phenolic content and total antioxidant activity in several Chilean potato varieties evaluated, which indicates that certain phenolic compounds may be responsible for high antioxidant activity. Also, certain varieties of Chilean potato had antihypertensive potentials, with ACE inhibition upto 88%. The -glucosidase inhibition relevant for hyperglycemia management for Apiaceae family ranged upto 50% (Dill) for aqueous extracts. A high correlation (r = 0.86) was observed between -glucosidase inhibition and total phenolic content for aqueous extracts of all species investigated in the Apiaceae family. A high rosmarinic acid activity was observed in aqueous extracts of Lamiaceae family, which ranged upto 39.7 mg/g of sample dry weight (DW). This suggests that high phenolic content and associated antioxidant activity found in sage and marjoram is dominated by rosmarinic acid. High enzyme inhibitory activities, reflecting in vitro anti-hyperglycemic and anti-hypertensive potentials indicates that consumption of these food sources in our diet would prove to be beneficial towards our health. Further in vivo studies for type II diabetes-linked functionalities of these natural sources of antioxidants and inhibitors would confirm the human health benefits achieved through dietary intake.