Simulation of discontinuous dynamic recrystallization in pure Cu using a probabilistic cellular automaton

A cellular automaton algorithm with probabilistic cell switches is employed in the simulation of dynamic discontinuous recrystallization. Recrystallization kinetics are formulated on a microlevel where, once nucleated, new grains grow under the driving pressure available from the competing processes of stored energy minimization and boundary energy reduction. Simulations of the microstructural changes in pure Cu under hot compression are performed where the influence of different thermal conditions are studied. The model is shown to capture both the microstructural evolution in terms of grain size and grain shape changes and also the macroscopic flow stress behavior of the material. The latter gives the expected transition from single- to multiple-peak serrated flow with increasing temperature. Further, the effects on macroscopic flow stress by varying the initial grain size is analyzed and the model is found to replicate the shift towards more serrated flow as the initial grain size is reduced. Conversely, the flow stress is stabilized by larger initial grain sizes. The extent of recrystallization as obtained from simulations are compared to classical JMAK theory and proper agreement with theory is established. In addition, by tracing the strain state during the simulations, a post-processing step is devised to obtain the macroscopic deformation of the cellular automaton domain, giving the expected deformation of the equiaxed recrystallized grains due to the macroscopic compression

Modeling of continuous dynamic recrystallization in commercial-purity aluminum

A constitutive model for polycrystalline metals is established within a micromechanical framework. The inelastic deformation is defined by the formation and annihilation of dislocations together with grain refinement due to continuous dynamic recrystallization. The recrystallization studied here occurs due to plastic deformation without the aid of elevated temperatures. The grain refinement also influences the evolution of the dislocation density since the recrystallization introduces a dynamic recovery as well as additional grain and subgrain boundaries, hindering the movement of dislocations through the material microstructure. In addition, motivated by experimental evidence, the rate dependence of the material is allowed to depend on the grain size. Introducing a varying grain size into the evolution of the dislocation density and in the rate dependence of the plastic deformation are believed to be important and novel features of the present model. The proposed constitutive model is implemented in a numerical scheme allowing calibration against experimental results, which is shown using commercial-purity aluminum as example material. The model is also employed in macroscale simulations of grain refinement in this material during extensive inelastic deformation. (C) 2009 Elsevier B.V. All rights reserved

Discovery of Inhibitors of Insulin-Regulated Aminopeptidase as Cognitive Enhancers

The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins

Direct angiotensin AT2 receptor stimulation using a novel AT2 receptor agonist, compound 21, evokes neuroprotection in conscious hypertensive rats

Background: In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents. Methods and Results: Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury. Conclusion: These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development

Angiotensin II, a Neuropeptide at the Frontier between Endocrinology and Neuroscience: Is There a Link between the Angiotensin II Type 2 Receptor and Alzheimer’s Disease?

Amyloid-β peptide deposition, abnormal hyperphosphorylation of tau, as well as inflammation and vascular damage, are associated with the development of Alzheimer’s disease (AD). Angiotensin II (Ang II) is a peripheral hormone, as well as a neuropeptide, which binds two major receptors, namely the Ang II type 1 receptor (AT1R) and the type 2 receptor (AT2R). Activation of the AT2R counteracts most of the AT1R-mediated actions, promoting vasodilation, decreasing the expression of pro-inflammatory cytokines, both in the brain and in the cardiovascular system. There is evidence that treatment with AT1R blockers (ARBs) attenuates learning and memory deficits. Studies suggest that the therapeutic effects of ARBs may reflect this unopposed activation of the AT2R in addition to the inhibition of the AT1R. Within the context of AD, modulation of AT2R signaling could improve cognitive performance not only through its action on blood flow/brain microcirculation but also through more specific effects on neurons. This review summarizes the current state of knowledge and potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2R activation by non-peptide and highly selective agonists, acting on neuronal plasticity, could represent new pharmacological tools that may help improve impaired cognitive performance in AD and other neurological cognitive disorders

The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system

<p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P_1-7(SP_1-7) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP_1-7and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice.</p> <p>Results</p> <p>Intrathecal treatment with the dipeptide increased the tail-flick latency in both diabetic and non-diabetic mice. This effect of Phe-Phe amide was significantly greater in diabetic mice than non-diabetic mice. The Phe-Phe amide-induced antinociceptive effect in both diabetic and non-diabetic mice was reversed by the σ₁receptor agonist (+)-pentazocine. Moreover, Phe-Phe amide attenuated mechanical allodynia in diabetic mice, which was reversible by (+)-pentazocine. The expression of spinal σ1 receptor mRNA and protein did not differ between diabetic mice and non-diabetic mice. On the other hand, the expression of phosphorylated extracellular signal-regulated protein kinase 1 (ERK1) and ERK2 proteins was enhanced in diabetic mice. (+)-Pentazocine caused phosphorylation of ERK1 and ERK2 proteins in non-diabetic mice, but not in diabetic mice.</p> <p>Conclusions</p> <p>These results suggest that the spinal σ₁receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.</p

Anabolic Androgenic Steroids : Effects on Neuropeptide Systems in the Rat Brain

Anabolic-androgenic steroids (AAS) have been used in clinics for decades. The misuse of AAS has previously been attributed merely to sport athletes, taking AAS with intentions to increase muscle mass, enhance physical performance and to improve results in competitions. Today, the misuse of AAS has spread to adolescents and young adults not connected to sports. Alarmingly, many reports are pointing at severe psychiatric adverse effects among AAS abusers, which include mood swings, mania, anxiety, depression and aggression. Numerous examples of severe and often unprovoked violence and brutal crimes have been connected to AAS abuse and there is a strong need for a better understanding of the underlying biochemical events that might account for the adverse behaviors induced by AAS. The general aim of this thesis was to study the effect of chronic AAS administration on neuropeptide circuits in the rat brain associated with the regulation of rewarding effects, memory, anxiety, depression and aggression, using nandrolone decanoate as a prototype AAS. Results demonstrated that daily administration of AAS to rats in doses comparable to those taken by AAS abusers, in certain brain structures significantly affected, a) the levels of the opioid peptides dynorphin B and Met-enkephalin-Arg6Phe7, b) the levels of the tachykinin substance P (SP), c) the density of the SP neurokinin 1 (NK1) receptor, d) the level of the SP metabolite SP1-7 that frequently exerts opposite effects to SP, e) the SP1-7 generating enzyme substance P endopeptidase (SPE) and finally, f) the levels of the neuropeptide calcitonin gene-related peptide (CGRP) often co-localized with SP. The alterations seen in the levels and activities of these neurochemical components are in many aspects compatible with behaviors typified among AAS abusers

From Angiotensin IV to Small Peptidemimetics Inhibiting Insulin-Regulated Aminopeptidase

It was reported three decades ago that intracerebroventricular injection of angiotensin IV (Ang IV, Val-Tyr-Ile-His-Pro-Phe) improved memory and learning in the rat. There are several explanations for these positive effects of the hexapeptide and related analogues on cognition available in the literature. In 2001, it was proposed that the insulin-regulated aminopeptidase (IRAP) is a main target for Ang IV and that Ang IV serves as an inhibitor of the enzyme. The focus of this review is the efforts to stepwise transform the hexapeptide into more drug-like Ang IV peptidemimetics serving as IRAP inhibitors. Moreover, the discovery of IRAP inhibitors by virtual and substance library screening and direct design applying knowledge of the structure of IRAP and of related enzymes is briefly presented

Modeling of continuous dynamic recrystallization in commercial-purity aluminum

Abstract A constitutive model for polycrystalline metals is established within a micromechanical framework. The inelastic deformation is defined by the formation and annihilation of dislocations together with grain refinement due to continuous dynamic recrystallization. The recrystallization studied here occurs due to plastic deformation without the aid of elevated temperatures. The grain refinement also influences the evolution of the dislocation density since the recrystallization introduces a dynamic recovery as well as additional grain and subgrain boundaries, hindering the movement of dislocations through the material microstructure. In addition, motivated by experimental evidence, the rate dependence of the material is allowed to depend on the grain size. Introducing a varying grain size into the evolution of the dislocation density and in the rate dependence of the plastic deformation are believed to be important and novel features of the present model. The proposed constitutive model is implemented in a numerical scheme allowing calibration against experimental results, which is shown using commercial-purity aluminum as example material. The model is also employed in macroscale simulations of grain refinement in this material during extensive inelastic deformation