Transformation kinetics of alloys under non-isothermal conditions

The overall solid-to-solid phase transformation kinetics under non-isothermal conditions has been modeled by means of a differential equation method. The method requires provisions for expressions of the fraction of the transformed phase in equilibrium condition and the relaxation time for transition as functions of temperature. The thermal history is an input to the model. We have used the method to calculate the time/temperature variation of the volume fraction of the favored phase in the alpha-to-beta transition in a zirconium alloy under heating and cooling, in agreement with experimental results. We also present a formulation that accounts for both additive and non-additive phase transformation processes. Moreover, a method based on the concept of path integral, which considers all the possible paths in thermal histories to reach the final state, is suggested.Comment: 16 pages, 7 figures. To appear in Modelling Simul. Mater. Sci. En

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps

Altered Metabolism of Growth Hormone Receptor Mutant Mice: A Combined NMR Metabonomics and Microarray Study

Growth hormone is an important regulator of post-natal growth and metabolism. We have investigated the metabolic consequences of altered growth hormone signaling in mutant mice that have truncations at position 569 and 391 of the intracellular domain of the growth hormone receptor, and thus exhibit either low (around 30% maximum) or no growth hormone-dependent STATS signaling respectively. These mutants result in altered liver metabolism, obesity and insulin resistance

CONSTRUCTIVE DISMISSAL: A TRICKY HORSE TO RIDE Jordaan v CCMA 2010 31 ILJ 2331 (LAC)

The concept of constructive dismissal is flexible because the circumstances that may give rise to it are “so infinitely various” (Minister of Home Affairs v Hambidge 1999 20 ILJ 2632 (LC) par 12). As such, there are no clear rules defining precisely when a constructive dismissal has taken place. The facts of each case must be established, interpreted and measured against general principles to determine whether the requirements for constructive dismissal have been met. The Labour Appeal Court (LAC), in the case of Jordaan v CCMA (2010 31 ILJ 2331 (LAC) 2335), made the point that the law has attained more certainty since Hambidge’s case. This is partially true. However, this case note shows that it remains difficult to set down hard and fast rules to determine the existence of a constructive dismissal. The Supreme Court of Appeal (SCA) has held that very strict proof of constructive dismissal is required, and it has not readily found that circumstances complained of by employees constitute such a dismissal. In the case of Old Mutual Group Schemes v Dreyer (1999 20 ILJ 2030 (LAC)) Conradie JA cautioned that constructive dismissal is not for the asking. He held that generally it will be difficult for an employee who resigns to show that he has actually been constructively dismissed, because the onus of proof on the employee in this regard is a heavy one. Jordaan’s case highlights just how hard it is to establish a viable claim of constructive dismissal. It shows that even where an employee experiences a loss of job security as a result of attempts by the employer to protect his business, and this leads to the employee’s resignation, it will not rise to the standard of constructive dismissal. The LAC saw Jordaan’s case as an attempt to “stretch the law relating to constructive dismissal” and held that this was not only inappropriate but that such an attempt “should not be contemplated” by future courts

A simple device to rapidly prepare whole mounts of murine intestine.

Many mouse models of neoplasia and pre-neoplasia require the examination of whole mounts of the gastrointestinal tract. A simple device has been produced to facilitate the rapid preparation of mouse intestines for subsequent quantification of tumours and pre-neoplastic lesions such as aberrant crypt foci. The device greatly speeds up the production of whole mounts and also provides far more consistent and better-quality preparations

Intranasal immunization with an Apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces Atherosclerosis

OBJECTIVE: Atherosclerosis is an inflammatory disease. Autoimmune responses to low-density lipoproteins (LDL) contribute to its progression, whereas immunization with LDL may induce atheroprotective or proatherogenic responses. The objective of this study was to develop an atheroprotective vaccine by targeting a peptide of the LDL protein constituent apolipoprotein B-100 (apoB-100) to the nasal mucosa to induce a protective mucosal immune response. METHODS AND RESULTS: A peptide comprising amino acids 3136 to 3155 of apoB-100 (p210) was fused to the B subunit of cholera toxin (CTB), which binds to a ganglioside on mucosal epithelia. The effect of nasal administration of the p210-CTB fusion protein on atherogenesis was compared with that of an ovalbumin peptide fused to CTB and with untreated controls. Immunization with p210-CTB for 12 weeks caused a 35% reduction in aortic lesion size in Apoe(-/-) mice. This effect was accompanied by induction regulatory T cells that markedly suppressed effector T cells rechallenged with apoB-100 and increased numbers of interleukin (IL)-10(+) CD4(+) T cells. Furthermore, a peptide-specific antibody response was observed. Atheroprotection was also documented in apoe(-/-) mice lacking functional transforming growth factor-beta receptors on T cells. CONCLUSIONS: Nasal administration of an apoB-100 peptide fused to CTB attenuates atherosclerosis and induces regulatory Tr1 cells that inhibit T effector responses to apoB-100

Attacking the supply wagons to starve cancer cells to death

The constitutive anabolism of cancer cells supports proliferation but also addicts tumor cells to a steady influx of exogenous nutrients. Limiting access to metabolic substrates could be an effective and selective means to block cancer growth. In this review, we define the pathways by which cancer cells acquire the raw materials for anabolism, highlight the actionable proteins in each pathway, and discuss the status of therapeutic interventions that disrupt nutrient acquisition. Critical open questions to be answered before apical metabolic inhibitors can be successfully and safely deployed in the clinic are also outlined. In summary, recent studies provide strong support that substrate limitation is a powerful therapeutic strategy to effectively, and safely, starve cancer cells to death