Liver fat metabolism, obesity and diabetes in Psammomys obesis

Defects in fat metabolism are central to the aetiology and pathogenesis of obesity and type II diabetes. The liver plays a central role in these disease states via its regulation of glucose and fat metabolism. In addition, accumulation of fat within the liver has been associated with changes in key pathways of carbohydrate and fat metabolism. However a number of questions remain. It is hypothesised that fat accumulation within the liver is a primary defect in the aetiology and pathogenesis of obesity and type II diabetes. Fat accumulating in the liver is the result of changes in the gene expression of key enzymes and proteins involved with fat uptake, fat transport, fat oxidation, fat re-esterification or storage and export of fat from the liver and these changes are regulated by key lipid responsive transcription factors. To study these questions Psammomys obesus was utilised. This polygenic rodent model of obesity and type II diabetes develops obesity and diabetes in a similar pattern to susceptible human populations. In addition dietary and environmental changes to Psammomys obesus were employed to create different states of energy balance, which allowed the regulation of liver fat gene expression to be examined. These investigations include: 1) Measurement of fat accumulation and fatty acid binding proteins in lean, obese and diabetic Psammomys obesus. 2) Characterisation of hepatic lipid enzymes, transport protein and lipid responsive transcription factor gene expression in lean, obese and diabetic Paammomys obesus. 3) The effect of acute and chronic energy restriction on hepatic lipid metabolism in Psammomys obesus. 4) The effect of sucrose feeding on the development of obesity and type II diabetes in Psammomys obesus. 5) The effect of nicotine treatment in lean and obese Psammomys obesus, 6) The effect of high dose leptin administration on hepatic fat metabolism in Psammomys obesus. The results of these studies demonstrated that fat accumulation within the liver was not a primary defect in the aetiology and pathogenesis of obesity and type II diabetes. Fat accumulating in the liver was not the result of changes in the gene expression of key enzymes and proteins involved in hepatic fat metabolism. However changes in the mRNA level of the transcription factors PPAR∝ and SREBP-1C was associated with the development of diabetes and the gene expression of these two transcription factors was associated with changes in diabetic status.

Role of leptin receptors in the development of obesity

The focus of this dissertation was leptin and the leptin receptor, and the role of these genes (OB and OB-R) in the development of obesity and type 2 diabetes in humans and Psammomys obesus, a polygenic rodent model of obesity and type 2 diabetes. Studies in humans showed that circulating leptin concentrations were positively associated with adiposity, and independently associated with circulating insulin and triglyceride concentrations. Analysis of two leptin receptor sequence polymorphisms in a Caucasian Australian population and a population of Nauruan males, with very high prevalence rates of obesity, showed no associations between sequence variation within the OB-R gene and obesity- or diabetes-related phenotypic measures. In addition, these two OB-R polymorphisms were not associated with longitudinal changes in body mass or composition in either of the populations examined. A unique analysis of the effects of multiple gene defects in the Nauruan population, demonstrated that the presence of sequence alterations in both the OB and OB-R genes were associated with insulin resistance. Psammomys obesus is regarded as an excellent rodent model in which to study the development of obesity and type 2 diabetes in humans. Examination of circulating leptin concentrations in Psammomys revealed that, as in humans, leptin concentrations were associated with adiposity, and independently associated with circulating insulin concentrations. This animal model was utilised to examine expression of OB-R, and the regulation of expression of this gene after dietary manipulation. OB-R is known to have several isoforms, and in particular, OB-RA and OB-RB gene expression were examined. OB-RB is the main signalling isoform of the leptin receptors. It has a long intracellular domain and has previously been shown to play an important role in energy balance and body weight regulation in rodents and humans. OB-RA is a much shorter isoform of OB-R, and although it lacks the long intracellular domain necessary to activate the JAK/STAT pathway, OB-RA is also capable of signalling, although to a lesser degree than OB-RB. OB-RA is found to be expressed almost ubiquitously throughout the body, and this isoform may be involved in transport of leptin into the cell, although its role remains unclear. OB-RA and OB-RB were both found to be expressed in a large number of tissues in Psammomys obesus. Interestingly, obese Psammomys were found to have lower levels of expression of OB-RA and OB-RB in the hypothalamus, compared to lean animals. This finding raises the possibility that decreased leptin signalling in the brain of obese, hyperleptinemic Psammomys obesus may contribute to the leptin resistance previously described in this animal model. However, the primary defect is unclear, as alternatively, increased circulating leptin concentrations may lead to down-regulation of leptin receptors. The effect of fasting on leptin concentrations and gene expression of OB-RA and OB-RB was also examined. A 24-hour fast resulted in no change in body weight, but a reduction in circulating leptin concentrations, and an increase in hypothalamic OB-RB gene expression in lean Psammomys. In obese animals, fasting again did not alter body weight, but resulted in an increase in both circulating leptin concentrations and hypothalamic OB-RB gene expression. In the liver, fasting resulted in a large increase in OB-RA gene expression in both lean and obese animals. These results highlighted the fact that regulation of leptin receptor gene expression in polygenic models of obesity and type 2 diabetes is complex, and not solely under the control of circulating leptin concentrations. Sucrose-feeding is an established method of inducing obesity and type 2 diabetes in rodents, and this experimental paradigm was utilised to examine the effects of longer term perturbations of energy balance on the leptin signalling pathway in Psammomys obesus. Addition of a 5% sucrose solution to the diet of lean and obese Psammomys resulted in increased body weight in both groups of animals, however only obese Psammomys showed increased fat mass and the development of type 2 diabetes. The changes in body mass and composition with sucrose-feeding were accompanied by decreased circulating leptin concentrations in both groups of animals, as well as a range of changes in leptin receptor gene expression. Sucrose-feeding increased hypothalamic OB-RB gene expression in obese Psammomys only, while in the liver there was evidence of a reduction in OB-RA and OB-RB gene expression in both lean and obese animals. The direct effects of sucrose on the leptin signalling pathway are unclear, however it is possible to speculate that the effect of sucrose to decrease leptin concentrations may have been involved in the exacerbation of obesity and the development of type 2 diabetes in obese Psammomys, From these studies, it appears that sequence variation in the OB and OB-R genes is unlikely to be a major factor in the etiology of obesity in human populations. The ability to examine regulation of expression of these genes in Psammomys obesus, however, has demonstrated that the effects of nutritional modifications on leptin receptor gene expression need closer attention. The role of the OB and OB-R genes in metabolism and the development of type 2 diabetes also warrants further examination, with particular attention on the differential effects of dietary modifications on leptin receptor gene expression across a range of tissues.

Identification of genes in the liver of Psammomys obesus associated with Type II diabetes

Type II diabetes is characterised by hyperglycemia and disturbances of fat, carbohydrate and protein metabolism. It occurs mainly in adults, with obesity being the most modifiable risk factor. This project utilised the Israeli Sand Rat (Psammomys obesus) and some of the latest molecular biology technology including differential display, membrane microarray and real-time PCR to detect genes in the liver that may be associated with the development of Type II diabetes and/or obesity. This study showed calpain, a proteolytic inhibitor and calpastatin, its natural inhibitor to be disregulated in the liver during the diabetic state.

Microstructural development in Al/MgAl2O4 in situ metal matrix composite using value-added silica sources

Al/MgAl2O4 in situ metal matrix composites have been synthesized using value-added silica sources (microsilica and rice husk ash) containing ~97% SiO2 in Al-5 wt.% Mg alloy. The thermodynamics and kinetics of MgAl2O4 formation are discussed in detail. The MgO and MgAl2O4 phases were found to dominate in microsilica (MS) and rice husk ash (RHA) value-added composites, respectively, during the initial stage of holding the composites at 750 °C. A transition phase between MgO and MgAl2O4 was detected by the scanning electron microscopy and energy-dispersive spectroscopy (SEM–EDS) analysis of the particles extracted from the composite using 25% NaOH solution. This confirms that MgO is gradually transformed to MgAl2O4 by the reaction 3SiO2(s)+2MgO(s)+4Al(l)→2MgAl2O4(s)+3Si(l). The stoichiometry of MgAl2O4, n, computed by a new methodology is between 0.79 and 1.18. The reaction between the silica sources and the molten metal stopped after 55% of the silica source was consumed. A gradual increase in mean MgAl2O4 crystallite size, D, from 24 to 36 nm was observed in the samples held for 10 h.

Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient

Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by computer-assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2-45), correlating with Ishak stage (stage 6 range, 13%-45%), and with HVPG (r = 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more [odds ratio, 1.206; 95% confidence interval (CI), 1.094-1.331; P < 0.001], or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026-1.191; P = 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. Conclusion: CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis.

A new rodent model to assess blood stage immunity to the plasmodium falciparum antigen merozoite surface protein 119 reveals a protective role for invasion inhibitory antibodies

Antibodies capable of inhibiting the invasion of Plasmodium merozoites into erythrocytes are present in individuals that are clinically immune to the malaria parasite. Those targeting the 19-kD COOH-terminal domain of the major merozoite surface protein (MSP)-119 are a major component of this inhibitory activity. However, it has been difficult to assess the overall relevance of such antibodies to antiparasite immunity. Here we use an allelic replacement approach to generate a rodent malaria parasite (Plasmodium berghei) that expresses a human malaria (Plasmodium falciparum) form of MSP-119. We show that mice made semi-immune to this parasite line generate high levels of merozoite inhibitory antibodies that are specific for P. falciparum MSP-119. Importantly, protection from homologous blood stage challenge in these mice correlated with levels of P. falciparum MSP-119–specific inhibitory antibodies, but not with titres of total MSP-119–specific immunoglobulins. We conclude that merozoite inhibitory antibodies generated in response to infection can play a significant role in suppressing parasitemia in vivo. This study provides a strong impetus for the development of blood stage vaccines designed to generate invasion inhibitory antibodies and offers a new animal model to trial P. falciparum MSP-119 vaccines.

Inflammatory pseudotumour of the liver : the residuum of a biliary cystadenoma?

Inflammatory pseudotumour is a rare form of a liver mass. We report the case of a 28-year-old man presenting with obstructive jaundice, in whom an inflammatory pseudotumour arose with the resolution of a mucus secreting cystic liver lesion. The initial features suggested an intrahepatic cystadenoma or cystadenocarcinoma, which on its involution left a solid mass. Histopathology showed an inflammatory pseudotumour with no evidence of malignancy. A similar case has been reported recently, with the development of an inflammatory pseudotumour following collapse of a liver cyst seen on imaging. These two cases may shed some light on the origins of these rare liver lesions.

Development of a contact probe incorporating a bragg grating strain sensor for nano coordinate measuring machines

This paper presents a novel optical fibre based micro contact probe system with high sensitivity and repeatability. In this optical fibre probe with a fused spherical tip, a fibre Bragg grating has been utilized as a strain sensor in the probe stem. When the probe tip contacts the surface of the part, a strain will be induced along the probe stem and will produce a Bragg wavelength shift. The contact signal can be issued once the wavelength shift signal is produced and demodulated. With the fibre grating sensor element integrated into the probe directly, the probe system shows a high sensitivity. In this work, the strain distributions along the probe stem with the probe under axial and lateral load are analysed. A simulation of the strain distribution was performed using the finite element package ANSYS 11. Performance tests using a piezoelectric transducer stage with a displacement resolution of 1.5 nm yielded a measurement resolution of 60 nm under axial loading.

The use of control systems in new product development innovation : advancing the 'help or hinder' debate

New Product Development (NPD) innovation is a critical activity in the current economic environment. In order to manage their NPD innovation projects, firms use Management Controls Systems (MCS). However, the effect that these systems have on NPD innovation is not clear. One stream of research suggests that MCS help NPD innovation while another stream suggests MCS hinder NPD innovation. Past research has shown that the role and style of MCS used may offer explanations on why MCS can both help and hinder NPD innovation. This paper adds another explanation by examining the relationship between three models (divisional, activity/decision and conversion/response) of a commonly used MCS, known as the Stage-Gate Process1 in the NPD innovation literature, and three types of NPD innovation projects (incremental, semi-radical and radical). The insights from an ethnomethodology informed field study are used to understand how and why the firms may use a different MCS (Stage-Gate Process models) for different NPD innovation project types.

Customer-product interaction : a model for new product development in entrepreneurial firms

Use of New Product Development (NPD) methods may benefit New Zealand SMEs and entrepreneurial firms in gaining greater market share. In this paper we review the literature on New Product Development, NPD theory and methods for early stage product design and development. Our reading suggests that product design has greater success when the customer is involved in the design effort. It also recommends methods of approach to new markets in the (NPD) life cycle. The literature further elucidates methods for identification of product design criteria based on customer needs identification. In essence, customer-product interaction in the early stages of product development is important to product success in new markets for entrepreneurial firms and SMEs. Of particular interest are early-stage NPD research methods and their influence on the company’s marketing strategy.

The transformation of development strategy in Korea : a 'risk society' perspective

After undergoing rapid socio-economic and political transformation, the Republic of Korea has arrived at the stage of development which Beck refers to as a risk society. Korea has experienced both sides of the risks which accompany modernity: the wealth associated with an advanced economy and also the hazards which are by-products of industrial society. However the Korean case is distinctive, this article argues, due to the state’s role in calibrating and managing risk. Whereas prior to the financial crisis of 1997–98 state elites privileged big business and exposed workers to higher levels of risk, calculations of the costs and benefits of risk have changed since the financial crisis. A notable outcome has been the straining of traditionally close ties between the state and the chaebŏl.

Pubertal stage and the prevalence of violence and social/relational aggression

OBJECTIVE We examined associations between pubertal stage and violent adolescent behavior and social/relational aggression.

METHODS The International Youth Development Study comprises statewide representative student samples in grades 5, 7, and 9 (N = 5769) in Washington State and Victoria, Australia, drawn as a 2-stage cluster sample in each state. We used a school-administered, self-report student survey to measure previous-year violent behavior (ie, attacking or beating up another person) and social/relational aggression (excluding peers from the group, threatening to spread lies or rumors), as well as risk and protective factors and pubertal development. Cross-sectional data were analyzed.

RESULTS Compared with early puberty, the odds of violent behavior were approximately threefold higher in midpuberty (odds ratio [OR]: 2.87 [95% confidence interval (CI): 1.81–4.55]) and late puberty (OR: 3.79 [95% CI: 2.25–6.39]) after adjustment for demographic factors. For social/relational aggression, there were weaker overall associations after adjustment, but these associations included an interaction between pubertal stage and age, and stronger associations with pubertal stage at younger age were shown (P = .003; midpuberty OR: 1.78 [95% CI: 1.20–2.63]; late puberty OR: 3.00 [95% CI: 1.95–4.63]). Associations between pubertal stage and violent behavior and social/relational aggression remained after the inclusion of social contextual mediators in the analyses.

CONCLUSIONS Pubertal stage was associated with higher rates of violent behavior and social/relational aggression, with the latter association seen only at younger ages. Puberty is an important phase at which to implement prevention programs to reduce adolescent violent and antisocial behaviors.

Texture and substructure development during post-dynamic softening in Ni-30%Fe austenite

The texture and substructure development during post-dynamic annealing of an austenitic Ni-30%Fe model alloy after complete dynamic recrystallization was investigated using electron back-scattered diffraction (EBSD) and transmission electron microscopy (TEM). A novel mechanism of metadynamic softening is proposed based on the experimental investigation of the grain structure, crystallographic texture and dislocation substructure evolution. The initial softening stage involved rapid growth of the dynamically formed nuclei and migration of the mobile boundaries. The subboundaries within DRX grains progressively disintegrated through dislocation climb and dislocation annihilation, which ultimately led to the formation of dislocation-free grains, while the grain boundary migration gradually became slower. As a result, the DRX texture was largely preserved throughout the annealing process.

Development of plastids in pollen and tapetum of rye-grass, Lolium perenne L

Proplastids of both tapetal cells and microsporocytes were present early in anther development. Tapetal proplastids differentiated—probably into elaioplasts—at late microspore stage. The tapetal cytoplasm was completely resorbed by early tricellular pollen stage. Microspore proplastids differentiated into amyloplasts at early bicellular stage, and were present in both vegetative and generative cells. In the generative cell, the amyloplasts were ephemeral and apparently degenerated within autophagic vacuoles. Plastids were absent from sperm cells. Vegetative cell amyloplasts increased in number apparently by fission such that one amyloplast produced one amyloplast and one proplastid per division. Mature pollen grains were estimated to contain between 550 and 820 amyloplasts with only one starch granule per plastid.

Suppressor of cytokine signaling 1 regulates embryonic myelopoiesis independently of its effects on T cell development

Suppressor of cytokine signaling 1 (SOCS1) has been shown to play important roles in the immune system. It acts as a key negative regulator of signaling via receptors for IFNs and other cytokines controlling T cell development, as well as Toll receptor signaling in macrophages and other immune cells. To gain further insight into SOCS1, we have identified and characterized the zebrafish socs1 gene, which exhibited sequence and functional conservation with its mammalian counterparts. Initially maternally derived, the socs1 gene showed early zygotic expression in mesodermal structures, including the posterior intermediate cell mass, a site of primitive hematopoiesis. At later time points, expression was seen in a broad anterior domain, liver, notochord, and intersegmental vesicles. Morpholino-mediated knockdown of socs1 resulted in perturbation of specific hematopoietic populations prior to the commencement of lymphopoiesis, ruling out T cell involvement. However, socs1 knockdown also lead to a reduction in the size of the developing thymus later in embryogenesis. Zebrafish SOCS1 was shown to be able to interact with both zebrafish Jak2a and Stat5.1 in vitro and in vivo. These studies demonstrate a conserved role for SOCS1 in T cell development and suggest a novel T cell-independent function in embryonic myelopoiesis mediated, at least in part, via its effects on receptors using the Jak2-Stat5 pathway.