No description available.

No description available.

Incretins are gastric hormones released by intestinal K-cells in response to food consumption and stimulate insulin secretion from pancreatic beta cells. One of these hormones, glucose-dependent insulinotropic peptide (GIP) is also anabolic in bone. Individuals with diabetes experience diminished bone quality caused by a low bone formation osteopenia. The present study seeks to identify a mechanism for diabetic osteopenia in which diabetes interferes with GIP-stimulated increases in the collagen cross-linking enzyme lysyl oxidase (LOX) in osteoblasts, leading to decreased collagen integrity and the trabecular abnormalities seen in diabetic bone. Micro-CT analysis and picrosirius red histology of long bones from LOX +/- and wild type mice made diabetic by low dose streptozotocin induction revealed a profound exacerbation of the decreased bone volume, impaired trabecular structure, and disorganized collagen matrix seen in diabetic mice when the mice were also haploinsufficient for LOX. Furthermore, qPCR of RNA isolated from diabetic long bones revealed a more than 20 fold decrease in LOX expression in diabetic bone from wild type mice. Treatment of wild type osteoblasts in culture with GIP results in a significant increase in LOX transcript and protein levels. Interestingly in our diabetic mice there is a decrease in osteoblast derived LOX and an abnormal increase in serum levels of the anti-incretin gut-derived dopamine, which is known to inhibit the effects of GIP in the pancreas. Therefore the ability of dopamine to inhibit GIP-stimulated signaling in osteoblasts was examined. Data indicate a strong dose-dependent inhibition of GIP-stimulated LOX expression when primary osteoblast cultures are pretreated with dopamine. Finally, pretreatment of primary osteoblasts with the dopamine receptor inhibitor amisulpride restored the impaired GIP stimulated increases in LOX expression in osteoblasts isolated from diabetic mice. This study defines a potential mechanism for diabetic bone disease and suggests that interference with dopamine signaling would likely restore bone health in diabetes.

We study the interplay between dependent types and computational effects, two important areas of modern programming language research. On the one hand, dependent types underlie proof assistants such as Coq and functional programming languages such as Agda, Idris, and F*, providing programmers a means for encoding detailed specifications of program behaviour using types. On the other hand, computational effects, such as exceptions, nondeterminism, state, I/O, probability, etc., are integral to all widely-used programming languages, ranging from imperative languages, such as C, to functional languages, such as ML and Haskell. Separately, dependent types and computational effects both come with rigorous mathematical foundations, dependent types in the effect-free setting and computational effects in the simply typed setting. Their combination, however, has received much less attention and no similarly exhaustive theory has been developed. In this thesis we address this shortcoming by providing a comprehensive treatment of the combination of these two fields, and demonstrating that they admit a mathematically elegant and natural combination. Specifically, we develop a core effectful dependently typed language, eMLTT, based on Martin-L¨of’s intensional type theory and a clear separation between (effect-free) values and (possibly effectful) computations familiar from simply typed languages such as Levy’s Call-By-Push-Value and Egger et al.’s Enriched Effect Calculus. A novel feature of our language is the computational S-type, which we use to give a uniform treatment of type-dependency in sequential composition. In addition, we define and study a class of category-theoretic models, called fibred adjunction models, that are suitable for defining a sound and complete interpretation of eMLTT. Specifically, fibred adjunction models naturally combine standard category-theoretic models of dependent types (split closed comprehension categories) with those of computational effects (adjunctions). We discuss and study various examples of these models, including a domain-theoretic model so as to extend eMLTT with general recursion. We also investigate a dependently typed generalisation of the algebraic treatment of computational effects by showing how to extend eMLTT with fibred algebraic effects and their handlers. In particular, we specify fibred algebraic effects using a dependently typed generalisation of Plotkin and Pretnar’s effect theories, enabling us to capture precise notions of computation such as state with location-dependent store types and dependently typed update monads. For handlers, we observe that their conventional term-level definition leads to unsound program equivalences becoming derivable in languages that include a notion of homomorphism, such as eMLTT. To solve this problem, we propose a novel type-based treatment of handlers via a new computation type, the user-defined algebra type, which pairs a value type (the carrier) with a family of value terms (the operations). This type internalises Plotkin and Pretnar’s insight that handlers denote algebras for a given equational theory of computational effects. We demonstrate the generality of our type-based treatment of handlers by showing that their conventional term-level presentation can be routinely derived, and this treatment provides a useful mechanism for reasoning about effectful computations. Finally, we show that these extensions of eMLTT can be soundly interpreted in a fibred adjunction model based on the families of sets fibration and models of Lawvere theories.

No description available.

Genome wide association studies (GWAS) have transformed the study of the heritability of complex diseases such as type 2 diabetes (T2D), with the current tally of established risk loci close to ninety. Each of these loci has the potential to offer novel insights into the biology of this disease, and opportunities for clinical exploitation. However, the complexity of T2D has often frustrated efforts to achieve these functional and translational advances. This thesis aims to delve into the functional characterisation of two known susceptibility loci, KLF14 and ADCY5, and describe findings relevant to disease pathology. KLF14 and ADCY5 are two loci associated with T2D predisposition working through disparate mechanisms. Variants at the maternally imprinted KLF14 locus are associated with measures of insulin resistance and expression data has implicated KLF14 as a master regulator of genes in adipose tissue. In contrast, variation at the ADCY5 locus is associated with impaired beta cell function, high fasting glucose, and low birth weight suggesting ADCY5 is having an effect on insulin secretion. In this thesis, ENU mouse models of these two genes are investigated functionally to elucidate more about the pathology of common human variation at these loci. A mouse model was derived with an ENU point mutation at Adcy5 Y1064C. Phenotyping of this model revealed improved oral glucose tolerance, and secretion studies from isolated islet cells demonstrated impaired glucagon secretion from mice homozygous for the Y1064C mutation in the presence of adrenaline. These results suggest that Adcy5 is involved in glucagon regulation in the alpha cell. The Adcy5 Y1064C confers a protective effect against hyperglycaemia in mouse indicating that the T2D risk allele at the ADCY5 locus in humans may have the opposite direction of effect. A mouse model containing the ENU point mutation Klf14 R238L predicted to be disruptive to KLF14 protein function showed no significant difference in body weight, measures of insulin resistance, or blood cholesterol. However, expression of several genes associated in trans with variation near KLF14 in humans was changed in adipose tissue and skeletal muscle when the R238L mutation was inherited maternally compared to mice which had inherited the mutation paternally or carried two wild type alleles. This result suggests a mechanism by which Klf14 is regulating genes across metabolic tissues.

A linguagem C não provê segurança espacial de memória: não garante que a memória acessada através de um ponteiro para um objeto, tal como um vetor, de fato pertence ao objeto em questão. Em vez disso, o programador é responsável por gerenciar informações de alocações e limites, e garantir que apenas acessos válidos à memória são realizados pelo programa. Por um lado, isso provê flexibilidade: o programador tem controle total sobre o layout dos dados em memória, e sobre o momento em que verificações são realizadas. Por outro lado, essa é uma fonte frequente de erros e vulnerabilidades de segurança em programas C. Diversas técnicas já foram propostas para prover segurança de memória em C. Tipicamente tais sistemas mantêm suas próprias informações de limites e instrumentam o programa para garantir que a segurança de memória não seja violada. Isso causa uma série de inconvenientes, tais como mudanças no layout de memória de estruturas de dados, quebrando assim a compatibilidade binária com bibliotecas externas, e/ou um aumento no consumo de memória. Uma abordagem diferente consiste em usar tipos dependentes para descrever a informação de limites já latente em programas C e assim permitir que o compilador use essa informação para garantir a segurança espacial de memória. Embora tais sistemas tenham sido propostos no passado, eles estão atrelados especificamente à linguagem C. Outras linguagens, como C++, sofrem de problemas similares de segurança de memória, e portanto poderiam se beneficiar de uma abordagem mais independente de linguagem. Este trabalho propõe Týr, uma transformação de código baseada em tipos dependentes para garantir a segurança espacial de memória de programas C ao nível LLVM IR. O sistema permite que o programador descreva no nível dos tipos as relações entre pointeiros e informação de limites já presente em programas C. Dessa maneira, Týr provê segurança espacial de memória verificando o uso consistente desses metadados pré-existentes, através de verificações em tempo de execução inseridas no programa guiadas pela informação de tipos dependentes. Ao trabalhar no nível mais baixo do LLVM IR, Týr tem por objetivo ser usável como uma fundação para segurança espacial de memória que possa ser facilmente estendida no futuro para outras linguagens compiláveis para LLVM IR, tais como C++ e Objective C. Demonstramos que Týr é eficaz na proteção contra violações de segurança espacial de memória, com um overhead de tempo de execução relativamente baixo e de consumo de memória próximo de zero, atingindo assim um desempenho competitivo com outros sistemas para segurança espacial de memória de uma maneira mais independente de linguagem. / The C programming language does not enforce spatial memory safety: it does not ensure that memory accessed through a pointer to an object, such as an array, actually belongs to that object. Rather, the programmer is responsible for keeping track of allocations and bounds information and ensuring that only valid memory accesses are performed by the program. On the one hand, this provides flexibility: the programmer has full control over the layout of data in memory, and when checks are performed. On the other hand, this is a frequent source of bugs and security vulnerabilities in C programs. A number of techniques have been proposed to provide memory safety in C. Typically such systems keep their own bounds information and instrument the program to ensure that memory safety is not violated. This has a number of drawbacks, such as changing the memory layout of data structures and thus breaking binary compatibility with external libraries and/or increased memory usage. A different approach is to use dependent types to describe the bounds information already latent in C programs and thus allow the compiler to use that information to enforce spatial memory safety. Although such systems have been proposed before, they are tied specifically to the C programming language. Other languages such as C++ suffer from similar memory safety problems, and thus could benefit from a more language-agnostic approach. This work proposes Týr, a program transformation based on dependent types for ensuring spatial memory safety of C programs at the LLVM IR level. It allows programmers to describe at the type level the relationships between pointers and bounds information already present in C programs. In this way, Týr ensures spatial memory safety by checking the consistent usage of this pre-existing metadata, through run-time checks inserted in the program guided by the dependent type information. By targeting the lower LLVM IR level, Týr aims to be usable as a foundation for spatial memory which could be easily extended in the future to other languages that can be compiled to LLVM IR, such as C++ and Objective C. We show that Týr is effective at protecting against spatial memory safety violations, with a reasonably low execution time overhead and nearly zero memory consumption overhead, thus achieving performance competitive with other systems for spatial memory safety, in a more language-agnostic way.

abstract: One solution to mitigating global climate change is using cyanobacteria or single-celled algae (collectively microalgae) to replace petroleum-based fuels and products, thereby reducing the net release of carbon dioxide. This work develops and evaluates a mechanistic kinetic model for light-dependent microalgal growth. Light interacts with microalgae in a variety of positive and negative ways that are captured by the model: light intensity (LI) attenuates through a microalgal culture, light absorption provides the energy and electron flows that drive photosynthesis, microalgae pool absorbed light energy, microalgae acclimate to different LI conditions, too-high LI causes damage to the cells’ photosystems, and sharp increases in light cause severe photoinhibition that inhibits growth. The model accounts for all these phenomena by using a set of state variables that represent the pooled light energy, photoacclimation, PSII photo-damage, PSII repair inhibition and PSI photodamage. Sets of experiments were conducted with the cyanobacterium Synechocystis sp. PCC 6803 during step-changes in light intensity and flashing light. The model was able to represent and explain all phenomena observed in the experiments. This included the spike and depression in growth rate following an increasing light step, the temporary depression in growth rate following a decreasing light step, the shape of the steady-state growth-irradiance curve, and the “blending” of light and dark periods under rapid flashes of light. The LI model is a marked improvement over previous light-dependent growth models, and can be used to design and interpret future experiments and practical systems for generating renewable feedstock to replace petroleum. / Dissertation/Thesis / Doctoral Dissertation Civil and Environmental Engineering 2017

Thesis (MSc (Biomedical Technology))--Cape Peninsula University of Technology, 2016. / The early detection of individuals who are at risk of developing type 2 diabetes mellitus (T2DM) would decrease the morbidity and mortality associated with this disease. DNA methylation, the most widely studied epigenetic mechanism, offers unique opportunities in this regard. Aberrant DNA methylation is associated with disease pathogenesis and is observed during the asymptomatic stage of disease. DNA methylation has therefore attracted increasing attention as a potential biomarker for identifying individuals who have an increased risk of developing T2DM. The identification of high risk biomarkers for T2DM could facilitate risk stratification and lifestyle interventions, which could ultimately lead to better ways to prevent, manage and control the T2DM epidemic that is rampant worldwide. The aim of the study was to investigate global DNA methylation as a potential risk factor for T2DM by studying the association between the global DNA methylation levels and hyperglycaemic states. A cross-sectional, quantitative study design, involving 564 individuals of mixed ancestry descent, residing in Bellville South, South Africa was used. Participants were classified as normal, pre-diabetic (impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)) or diabetic (screen detected diabetic and known diabetics) according to WHO criteria of 1998. DNA was extracted from whole blood using the salt extraction method. The percentage global DNA methylation was measured by an enzyme-linked immunosorbent assay (ELISA). The association between global DNA methylation and hyperglycaemia, as well as other biochemical markers of T2DM was tested in a robust linear regression analysis adjusted for age, gender and smoking.

Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2016. / The early detection of individuals who are at risk of developing type 2 diabetes mellitus (T2DM) would decrease the morbidity and mortality associated with this disease. DNA methylation, the most widely studied epigenetic mechanism, offers unique opportunities in this regard. Aberrant DNA methylation is associated with disease pathogenesis and is observed during the asymptomatic stage of disease. DNA methylation has therefore attracted increasing attention as a potential biomarker for identifying individuals who have an increased risk of developing T2DM. The identification of high risk biomarkers for T2DM could facilitate risk stratification and lifestyle interventions, which could ultimately lead to better ways to prevent, manage and control the T2DM epidemic that is rampant worldwide. The aim of the study was to investigate global DNA methylation as a potential risk factor for T2DM by studying the association between the global DNA methylation levels and hyperglycaemic states. A cross-sectional, quantitative study design, involving 564 individuals of mixed ancestry descent, residing in Bellville South, South Africa was used. Participants were classified as normal, pre-diabetic (impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)) or diabetic (screen detected diabetic and known diabetics) according to WHO criteria of 1998. DNA was extracted from whole blood using the salt extraction method. The percentage global DNA methylation was measured by an enzyme-linked immunosorbent assay (ELISA). The association between global DNA methylation and hyperglycaemia, as well as other biochemical markers of T2DM was tested in a robust linear regression analysis adjusted for age, gender and smoking.