The growth of vertebrate animals from neonatal to adult size depends upon the proper functioning of the hypothalamic/pituitary/end organ system known as the growth hormone axis. In Laron-type dwarves, in whom growth hormone (GH) insensitivity results from the absence of GHR signalling, increased growth velocity can be stimulated with the injection of insulin-like growth factor-I, although hypoglycaemia is a common side effect. The complexity of the hypothalamic/pituitary growth axis can be further appreciated by consideration of the variety of growth dynamics among species. At one extreme are animals such as rats and pigs, which continue somatic growth indefinitely into adulthood. In addition, an ever increasing number of animal model systems, both naturally occurring and transgenic, have facilitated the in vivo study of animal growth. The most severe form of growth deficiency, called isolated GH deficiency, type IA, is caused by mutation or deletion of GH-N.
The major hormonal regulators of glucose homeostasis are glucagon and insulin. Defects in the mechanism controlling glucose homeostasis are relatively common in humans, the most widespread of these being diabetes. The endocrine pancreas is made up of four major cell types and the regulated secretion of peptide hormones from these cells provides the main mechanism by which the body achieves glucose homeostasis. The effects of insulin on glucose homeostasis are largely mediated through a reduction in hepatic glucose output with simultaneous stimulation of glucose uptake into muscle and adipose tissue. The importance of hepatic glycogenolysis and glucose-6-phosphatase in regulating whole body glucose homeostasis is illustrated by the pathophysiology of type-1 glycogen storage disease. The close links between obesity and insulin resistance suggest that events occurring in adipose tissue may influence whole body glucose homeostasis. The insulin receptor has a crucial role in glucose homeostasis and decreasing levels of insulin receptor function are inversely related to the degree of insulin resistance.
The discovery of parathyroid hormone-related protein (PTHrP) resulted from investigations of the mechanisms by which certain cancers cause hypercalcaemia without necessarily metastasizing to bone. PTHrP and IL-1 can synergistically stimulate bone resorption in vitro and increase the serum calcium concentration in mice in vivo. Elevated PTHrP levels have also been found in a proportion of patients with haematological malignancies and hypercalcaemia. The marked species conservation of the PTHrP sequence over these 111 amino acids indicates that important functions are likely to reside in this region. The existence of multiple PTHrP mRNA species as shown by Northern blot analysis and the demonstration of 5' and 3' divergent cDNA clones indicated that PTHrP transcripts may be alternatively spliced or that the transcripts result from a multigene family. The properties outlined suggest that PTHrP should be considered as a cytokine and support the proposal that PTHrP is a member of the early response gene family.
The biosynthesis of steroid hormones is the result of sequential hydroxylation and isomerization reactions which convert cholesterol to the physiologically active mineralocorticoids, glucocorticoids, androgens and oestrogens. The major sites of steroidogenesis are the ovaries, testes, adrenal glands and placenta although other organs such as the brain, liver and adipose tissue can play a significant role. A number of factors determine whether a steroid molecule will remain on the single active site of CYP17 and undergo cleavage of the 17,20 bond to produce androgens. Cholesterol can be synthesized from acetate in all steroidogenic tissues but the favoured route is to obtain the steroid from dietary sources via low density lipoprotein. The mechanism by which steroidogenesis is limited to a small number of tissues is not understood. The first line of tissue specificity must be the presence or absence of receptors for the various trophic hormones.
The great majority of point mutations found to be responsible for human disease to date result in aberrant splicing of primary gene transcripts or alteration of the protein coding region of the mRNA. Reporter gene assays allow DNA fragments to be tested for their ability to regulate transcription. To generate transgenic mice by microinjection, female mice are first induced to superovulate and then mated. Once a homozygous mutant strain has been derived, both copies of the target gene will be disrupted in every cell of the mice. One application of targeted gene disruption is the creation of mouse strains carrying mutations responsible for human disease. Homologous recombination in ES cells can be used to produce transgenic mice carrying the Cre gene, and with lox sites inserted at each end of the target gene. Downstream of the mouse gene sequence is another selectable marker gene, encoding the herpes simplex virus thymidine kinase gene.
This chapter consider fertility as the end product of two major complex phenomena. The first is a cascade of events that ensures sexual dimorphism and gonadal development. The second is a hormonal feedback system that controls gamete production and presentation. GnRH is released, under the influence of central neurotransmitters and gonadal feedback, in a pulsatile fashion at 90 min intervals resulting in concomitant pulsatile release of gonadotrophins. Raised gonadotrophin concentrations may result from primary gonadal failure or from insensitivity to glycoprotein hormones. Defects in the pituitary/gonadal axis include abnormalities of the structure of the hormone or of its receptor and come under the heading of hormone resistance syndromes. The reproductive axes, however, have lagged behind others in the molecular definition of hormone resistance. Mild resistance to hormone action is rarely detectable in relatives who are heterozygote for receptor mutations which are inherited in a recessive pattern.
This chapter focuses on both the common and divergent features of peptide hormone action and includes representative examples of the major signalling pathways. Each peptide hormone interacts with a specific high affinity receptor which is an integral protein spanning the plasma membrane. A number of novel approaches are being taken to facilitate the design of a new generation of non-peptide peptide mimetics. Polypeptides corresponding to regions of the intracellular domains of receptors have also been used to study their effect on G-protein activation in the absence of intact receptor. An additional way in which the magnitude and duration of G-protein-mediated signals can be controlled is by downregulation of the particular G-protein itself. The identification of multiple protein isoforms at each step of each signal transduction pathway has advanced an explanation for the diverse effects which can be elicited by a particular hormone in a given cell/tissue context.
Hypertension is a significant underlying cause of cardio- and cerebrovascular morbidity and mortality and much effort has been devoted to identifying genetic risk factors for its development. The gene for angiotensinogen is linked to the development of essential hypertension, whereas mutations in regulatory subunits of the sodium channel itself, or in any of several steroid-metabolizing enzymes, cause syndromes of hypertension inherited as monogenic traits. The most important regulator of sodium resorption is the renin—angiotensin-aldosterone system. Plasma renin activity is usually suppressed and levels of aldosterone are consequently low even though the ability to synthesize aldosterone is actually unimpaired. Absolute levels of aldosterone secretion are usually moderately elevated in the untreated state but may be within normal limits. Plasma renin activity is strongly suppressed, so that the ratio of aldosterone secretion to renin activity is always abnormally high.
The mechanism controlling tissue-specific expression of estrogen receptor 1 (ESR1) is unclear. In other genes, DNA methylation of a region called the tissue-dependent and differentially methylated region (T-DMR) has been associated with tissue-specific gene expression. This study investigated whether human ESR1 has a T-DMR and whether DNA methylation of the T-DMR regulates its expression. ESR1 expression was tissue-specific, being high in the endometrium and mammary gland and low/nil in the placenta and skin. Therefore, DNA methylation profiles of the promoter of ESR1 were analyzed in these tissues and in breast cancer tissues. In all of the normal tissues, the proximal promoter regions were unmethylated. On the other hand, the distal regions (T-DMR) were unmethylated in the endometrium and mammary gland, but were moderately methylated and hypermethylated in the placenta and skin, respectively. T-DMR-methylated reporter assay was performed to examine whether DNA methylation at the T-DMR suppresses ESR1 transcription. T-DMR, but not the promoter region, had transcriptional activities and DNA methylation of the T-DMR suppressed ESR1 transcription. Early growth response protein 1 was shown to be a possible transcription factor to bind the T-DMR and up-regulate ESR1 expression. ESR1 has several upstream exons, and each upstream exon, Exon-A/Exon-B/Exon-C, had its own T-DMR. In some breast cancer cases and breast cancer cell lines, ESR1 expression was not regulated by DNA methylation at T-DMR as it is in normal tissues. In conclusion, ESR1 has a T-DMR. DNA methylation status at the T-DMR is involved in tissue-specific ESR1 expression in normal tissues but not always in breast cancer.
CHAPTER 4: FAMILY GROUP DECISION-MAKING STUDY (FGDM) 4.1 General Research Design 1 4.2 Process Study 9 4.2.1 FGDM Process Study Purpose 9 4.2.2 Methodology 9 4.2.3 Results 12 4.2.4 Discussion 35 4.3 Fidelity Study 37 4.3.1 Purpose 37 4.3.2 General methodology and research questions 37 4.3.3 Components: methods and results 39 4.3.4 Discussion 67 4.4 Impact Study 71 4.4.1 Purpose 71 4.4.2 Methodology 71 4.4.3 Results 76 4.4.4 Discussion 83 4.5 Fresno Cost Study 86 4.5.1 Purpose 86 4.5.2 Methodology 86 4.5.3 Results 89 4.5.4 Discussion 99
This paper explores the functions and definitions of Supply Chain Management (SCM) and explains how Market Intelligence overlaps with a firm’s SCM goals. We look at how MI offerings can better match the needs of SCM professionals. The better information that is available, the more efficiently the SCM function can be accomplished, enabling strategic decision-making for all levels of corporate supply chain management. ExEcutIvE SummAry Supply chain management experts claim that properly focused efforts to manage a firm’s supply chain create cost savings, which are better than any money spent on creating profits – think of this as 100% ROI. It is thus in every firm’s interest to constantly keep costs in check. As well, firms need to focus on relationships with suppliers and the movement and storage of goods to maximize profitable outcomes while minimizing risks and costs. This subject is as important today as ever before.
Foreword.......................................................................................................................................................x Organizing Committee................................................................................................................................xi Program Committee...................................................................................................................................xii Steering Committee ..................................................................................................................................xiv Reviewers ...................................................................................................................................................xv Tutorials .....................................................................................................................................................xvi Keynote Addresses.................................................................................................................................xviii Invited Talk...............................................................................................................................................xxiv Sponsors..................................................................................................................................................xxvi
The dissertation of Javid J. Huseynov is approved and is acceptable in quality and form for publication on microfilm and in digital formats: ii DEDICATION To my mother and to all others that are dear to me...
About half of U.S. farm workers are not authorized to work in the United States. Pending immigration reforms aim to prevent the entry and employment of more unauthorized foreigners, but they differ on what to do about unauthorized workers already in the United States. These unauthorized workers are not likely to disappear overnight, and agricultural adjustments to a legal work force are likely to be determined by enforcement patterns, the structure of new guest worker programs, and the speed at which current farm workers find nonfarm jobs.
Foreword.......................................................................................................................................................x Organizing Committee................................................................................................................................xi Program Committee...................................................................................................................................xii Steering Committee ..................................................................................................................................xiv Reviewers ...................................................................................................................................................xv Tutorials .....................................................................................................................................................xvi Keynote Addresses.................................................................................................................................xviii Invited Talk...............................................................................................................................................xxiv Sponsors..................................................................................................................................................xxvi
Zinc transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells, where it mediates zinc (Zn2+) uptake into secretory granules. Although a common nonsynonymous polymorphism (R325W), which lowers activity, is associated with increased type 2 diabetes (T2D) risk, rare inactivating mutations in SLC30A8 have been reported to protect against T2D. Here, we generate and characterize new mouse models to explore the impact on glucose homeostasis of graded changes in ZnT8 activity in the β-cell. Firstly, Slc30a8 was deleted highly selectively in these cells using the novel deleter strain, Ins1Cre. The resultant Ins1CreZnT8KO mice displayed significant (P < .05) impairments in glucose tolerance at 10 weeks of age vs littermate controls, and glucose-induced increases in circulating insulin were inhibited in vivo. Although insulin release from Ins1CreZnT8KO islets was normal, Zn2+ release was severely impaired. Conversely, transgenic ZnT8Tg mice, overexpressing the transporter inducibly in the adult β-cell using an insulin promoter-dependent Tet-On system, showed significant (P < .01) improvements in glucose tolerance compared with control animals. Glucose-induced insulin secretion from ZnT8Tg islets was severely impaired, whereas Zn2+ release was significantly enhanced. Our findings demonstrate that glucose homeostasis in the mouse improves as β-cell ZnT8 activity increases, and remarkably, these changes track Zn2+ rather than insulin release in vitro. Activation of ZnT8 in β-cells might therefore provide the basis of a novel approach to treating T2D.
