In this study, we examined the effect of disrupting the function of the VSMC adhesion molecule, N-cadherin, using antagonists, neutralizing antibodies, and a dominant negative, on VSMC migration and intimal thickening. Migration was assessed by the scratch-wound assay of human saphenous vein VSMCs and in a human saphenous vein ex vivo organ culture model of intimal thickening.

Results: Inhibition of cadherin function using a pan-cadherin antagonist, significantly reduced migration by 53% +/- 8% compared with the control peptide (n = 3; P < .05). Furthermore, inhibition

of N-cadherin function with an N-cadherin antagonist, neutralizing antibodies, and adenoviral expression of dominant negative N-cadherin (RAd dn-N-cadherin), significantly reduced

migration by 31% +/- 2%, 23% +/- 1% and 32% +/- 7% compared CAL-101 with controls, respectively (n = 3; P < .05). Inhibition of cadherin function significantly increased apoptosis by between 1.5- and 3.3-fold at the wound edge. In an ex vivo model of intimal thickening, inhibition of N-cadherin function by infection of human saphenous vein segments with RAd dn-N-cadherin significantly reduced VSMC migration by 55% and increased VSMC apoptosis by 2.7-fold. As a result, intimal thickening was significantly suppressed by 54% +/- 14%. Importantly, there was no detrimental effect of dn-N-cadherin on endothelial coverage; in fact, it was significantly increased, as was survival BMS-777607 manufacturer of cultured human saphenous vein endothelial cells.

Conclusions: Under the condition of this study, cell-cell adhesion mediated by N-cadherin regulates VSMC migration via modulation of viability. Interestingly, inhibition of N-cadherin function significantly retards intimal thickening via inhibition of VSMC migration and promotion of endothelial cell survival. We suggest that disruption of N-cadherin-mediated cell-cell contacts is a potential strategy for reducing VSMC migration and intimal thickening. (J Vase Surg 2010;52:1301-9.)

Clinical

Relevance: Intimal thickening occurs in a large number of coronary Oxalosuccinic acid artery vein grafts, lower extremity vein grafts, and stented arteries and is therefore a significant clinical problem. Intimal thickening is caused by migration of vascular smooth muscle cells (VSMC) from the intima to the media where they proliferate. In this study, we have shown that inhibition of the function of N-cadherin (a cell-cell contact protein) significantly retards VSMC migration and intimal thickening, while promoting endothelial coverage, and may therefore be clinically useful for treating intimal thickening.”
“The production of membrane proteins in cellular systems is besieged by several problems due to their hydrophobic nature which often causes misfolding, protein aggregation and cytotoxicity, resulting in poor yields of stable proteins.

No currently available test can formally prove that the leukaemic clone is eradicated. Here we discuss the sensitive measurement of minimal residual disease, and speculate on the biology of BCR-ABL-positive cells that may persist after effective therapy of CML. Leukemia (2011) 25, 193-200; doi:10.1038/leu.2010.197; published online 16 September 2010″
“Introduction: No direct proof

has been brought to light in a link between hypoxic changes in glioma models and the effects of antiangiogenic treatments. Here, we assessed the sensitivity of the detection of hypoxia through the use of (18)F-fluoromisonidazole positron emission tomography ([(18)]-FMISO PET) in response to the evolution of the tumor and its vasculature.

Methods: Orthotopic glioma tumors were induced in rats after implantation of C6 or 9L cells. Sunitinib this website was administered from day (D) 17 to D24. At D17 and D24, multiparametric magnetic

resonance imaging was performed to characterize tumor growth and vasculature. Hypoxia was assessed by [(18)F]-FMISO PET.

Results: We showed that brain hypoxic volumes are related to glioma volume and its vasculature and that an antiangiogenic treatment, leading to an increase in cerebral selleck screening library blood volume and a decrease in vessel permeability, is accompanied by a decrease in the degree of hypoxia.

Conclusions: We propose that [(18)F]-FMISO PET and multiparametric magnetic resonance imaging are pertinent complementary tools in the evaluation of the effects of an antiangiogenic treatment in glioma. (C) 2011 Elsevier Inc. All rights reserved.”
“BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) constitute the cornerstone of treatment for chronic myeloid leukemia. Although these agents are normally safe and effective, they can cause side effects that lead to intolerance and necessitate selleck compound switching to an alternative treatment. In this review, we describe side

effects that occur during treatment with imatinib, nilotinib or dasatinib-the currently approved TKI treatments for chronic myeloid leukemia-including class effects and key differences in safety profiles. We also describe how common side effects can be effectively managed and offer a working definition of intolerance that may be useful to clinicians when they consider switching between TKIs. Leukemia (2011) 25, 201-210; doi:10.1038/leu.2010.215; published online 23 September 2010″
“Introduction: Interleukin (IL)-1 and IL-18 are potent proinflammatory cytokines in inflammation-related diseases. Their actions are regulated by IL-1 receptor antagonist (IL-1ra) and IL-18 binding protein (IL-18bp). This study was designed to (99m)Tc-radiolabel an IL-1ra and IL-18bp dual-domain cytokine ligand, IL-18bp-Fc-IL-1ra, for specific inflammation targeting.

Methods: The (99m)Tc-IL-18bp-Fc-IL-1ra was obtained by direct labeling via 2-iminothiolane reduction.

This review article provides a concise incursion into the current and future applications of nano-enabled drug delivery systems for the treatment of NDs, in particular Alzheimer’s and Parkinson’s diseases, and explores the application of nanotechnology in clinical neuroscience to develop innovative therapeutic modalities for the treatment of NDs. (C) 2009 Elsevier Ltd. All rights reserved.”
“Recent findings document numerous interactions between neuronal and glial systems that likely play a role in the pathophysiology of depression. These findings suggest that glia-derived neurotrophic protein S100B may play

a significant role in developing depression. To test the relationship between S100B and depressive symptoms we designed cross-sectional clinical study including S100B serum and CSF levels in neurological patients with non-inflammatory disorders Anlotinib mouse (NIND), who undergone cerebrospinal fluid assessment mTOR inhibitor for diagnostic

purposes. The present study was focused on psychometric testing of depression (BDI-II). anxiety (SAS) and alexithymia (TAS-20), and neurochemical measure of cerebrospinal fluid (CSF) and serum levels of S100B in 40 NIND inpatients [mean age 41.67]. The main result shows that S100B in CSF is significantly negatively correlated with BDI-II (Spearman R=-0.51, p < 0.0009) but not with SAS and TAS-20. The finding indicates that decreased level of Si COB in CSF is related to increased symptoms of depression in the NIND patients. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular Batimastat in vivo consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor

2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions.

(C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“The hypothalamic neuropeptide, orexin-A has a number of regulatory effects in humans and pre-clinical evidence suggests a link to neuroendocrine

systems known to be pathophysiologically related to posttraumatic stress disorder (PTSD). However, there are no reports of central nervous system (CNS) or peripheral orexin-A concentrations in patients with PTSD, or any anxiety disorder. Cerebrospinal fluid (CSF) and plasma levels selleck chemicals of orexin-A were serially determined in patients with PTSD and healthy comparison subjects to characterize the relationships between orexin-A (in the CNS and peripheral circulation) and central indices of monoaminergic selleck kinase inhibitor neurotransmission and to determine the degree to which CNS orexin-A concentrations reflect those in the circulating blood. CSF and plasma samples were

obtained serially over a 6-h period in 10 male combat veterans with chronic PTSD and 10 healthy male subjects through an indwelling subarachnoid catheter. Orexin-A concentrations were determined in plasma and CSF and CSF levels of the serotonin metabolite, 5-hydroxyindolacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid (HVA), were determined over the sampling period. CSF and plasma orexin-A concentrations were significantly lower in the patients with PTSD as compared with healthy comparison subjects at all time points. In addition, CSF orexin-A concentrations strongly and negatively correlated with PTSD severity as measured by the Clinician-Administered PTSD Scale (CAPS) in patients with PTSD. Peripheral

Selleckchem PS-341 and CNS concentrations of orexin-A were correlated in the healthy comparison subjects and peripheral orexin-A also correlated with CNS serotonergic tone. These findings suggest low central and peripheral orexin-A activity in patients with chronic PTSD are related to symptom severity and raise the possibility that orexin-A is part of the pathophysiological mechanisms of combat-related PTSD. (C) 2010 Elsevier Ltd. All rights reserved.”
“Coxsackievirus A1 (CVA1) belongs to human enterovirus species C within the family Picornaviridae, order Picornavirales. Two Chinese CVA1 isolates, HT-THLH02F/XJ/CHN/2011 and KS-ZPH01F/XJ/CHN/2011, were isolated from stool specimens of two healthy children in the Xinjiang Uygur autonomous region of China. They were found to elicit cytopathic effects in a human rhabdomyosarcoma cell line, and complete genome sequences of these two CVA1 isolates revealed that natural intertypic recombination events occurred between CVA1 and CVA22.”
“Transcranial direct current stimulation (tDCS) is a non-invasive technique that moderates cognitive and motor function. The effects of tDCS on cognitive and motor tasks vary among individuals. However, the source of the inter-individual variability remains unknown.

The aim of the study was to close this

Cl-amidine chemical structure gap and to explore the therapeutical potential of dermal nitric oxide application. We characterized with human skin in vitro and in vivo the capacity of NO, applied in a NO-releasing acidified form of nitrite-containing liniments, to penetrate the epidermis and to influence local as well as systemic hemodynamic parameters. We found that dermal application of NO led to a very rapid and significant transepidermal translocation of NO into the underlying tissue. Depending on the size of treated skin area, this translocation manifests itself through a significant systemic increase of the NO derivates nitrite and nitroso compounds, respectively. In parallel, this translocation Tucidinostat cell line was accompanied by an increased systemic vasodilatation and blood flow as well as reduced blood pressure. We here give evidence that in humans dermal application of NO has a therapeutic potential for systemic hemodynamic disorders that might arise from local or systemic insufficient

availability of NO or its bio-active NO derivates, respectively. (c) 2012 Elsevier Inc. All rights reserved.”
“Hemoglobin-based oxygen carriers (HBOCs) have been studied for decades as red blood cell substitutes. Profound vasoconstrictor effects have limited the clinical utility of HBOCs and are attributable to avid scavenging of nitric oxide (NO). Inhaling NO can charge the body’s stores of NO metabolites without producing hypotension and can prevent systemic hypertension induced https://www.selleck.cn/products/isrib-trans-isomer.html when HBOCs are subsequently infused. Concurrent breathing of low NO doses can prevent pulmonary vasoconstriction after HBOC infusion without augmenting plasma methemoglobinemia. (Trends Cardiovasc Med 2009; 19:103-107) (C) 2009, Elsevier Inc.”
“Background: Negative mood symptoms remain one of the major reasons for discontinuation of oral contraceptive pills. The aim of this study was to compare acoustic startle response and prepulse inhibition

(PPI) in women with different experience of oral contraceptive pills.

Methods: Thirty women currently on combined oral contraceptives (COCs) with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects from treatment, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 32 women who had discontinued COC use due to adverse mood effects were included.

The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of musculus Orbicularis Oculi. Twenty pulse-alone trials (115dB 40 ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40 ms noise burst preceded at a 100 ms interval by 20 ms prepulses that were 72, 74, 78, or 86 dB.

Successful tumor implantation was confirmed by transabdominal micro-ultrasound imaging on post-implantation day 11. Contrast enhanced micro-ultrasound imaging was done on days 14 and 21. Vascular endothelial growth factor receptor 2 targeted contrast agent was prepared by adding biotinylated anti-vascular endothelial growth factor receptor 2 monoclonal antibodies to streptavidin coated microbubbles. The targeted contrast agents were

injected via the retro-orbital route. We quantified intratumor perfusion, vascular endothelial growth factor receptor 2 endothelial expression and blood volume in real time.

Results: In the initial study intratumor perfusion data and vascular endothelial growth factor receptor 2 expression could only be measured in 10 of 14 mice (71%) due to motion artifact. We modified our technique by applying an elastic band over selleck inhibitor Selleck BAY 1895344 the lower abdomen to minimize body wall movement. After the modification complete images were acquired in all mice at 2 consecutive imaging sessions. Measurements were made of intratumor perfusion and in vivo vascular endothelial growth factor receptor 2 expression. No adverse effects occurred due to anesthesia or the ultrasound contrast agent.

Conclusions: Targeted

contrast enhanced micro-ultrasound imaging enables investigators to detect and monitor vascular changes in orthotopic bladder tumors. It may be useful for direct, noninvasive, in vivo evaluation of novel anti-angiogenesis therapeutic agents. With the modified technique target enhanced contrast ultrasound can be applied in an orthotopic bladder cancer model.”
“The tonically active neurons (TANS) are a population of neurons scattered sparsely throughout the striatum that show intriguing patterns

of firing activity during reinforcement learning. Following repeated pairings of a neutral stimulus with a primary reward, TANs develop a transient cessation of firing activity in response to the stimulus, termed the “”conditioned pause response.”" In tasks where specific cues are arranged to signal the probability of particular outcomes, the pause response to both cue and outcome may differ in ways that suggest the involvement of different inputs to the same neuron. Here we review the cellular properties of E7080 order cholinergic interneurons and describe the response to their afferents in terms of inducing TAN-like pauses in tonic firing. Recent work has shown that thalamostriatal inputs to cholinergic neurons transiently suppress firing activity via dopamine release. Because these pauses are initiated by subcortical pathways with limited sensory processing abilities, we propose that they are an ideal correlate for the pauses observed in TANs in response to cues signaling trial initiation. On the other hand, pauses that accompany outcome presentation contain higher-level information, including an apparent sensitivity to reward prediction error. Thus, these pauses may be mediated by cortical inputs to cholinergic interneurons.

OGD-induced free radical production, a contributing factor in cell swelling, was significantly reduced by both myricetin and quercetin. However, depolarization of the inner mitochondrial membrane potential (Delta Psi(m)), the blockade of which generally reduces swelling, was significantly diminished by myricetin,

but not quercetin. This indicated that quercetin could reduce swelling despite its inability to prevent depolarization of Delta Psi(m) possibly through other signaling pathways. Increased intracellular calcium ([Ca(2+)](i)) is an important characteristic of ischemic selleck products injury and is implicated in swelling. Both myricetin and quercetin attenuated the increase in [Ca(2+)](i). Further, a reduction in [Ca(2+)](i), through the use of nifedipine, nimodipine, verapamil, dantrolene, or BAPTA-AM, significantly reduced www.selleckchem.com/products/sbe-b-cd.html OGD-induced cell swelling indicating that one possible mechanism by which such flavonoids attenuate cell swelling may be through regulating [Ca(2+)](i). OGD-induced decrease in glutamate uptake was attenuated by myricetin, but not quercetin. Cyclosporin A, a blocker of the mitochondrial permeability transition (mPT)

pore, but not FK506 (that does not block the mPT), attenuated the decline in glutamate uptake after OGD, indicating the involvement of the mPT in glutamate uptake. Our results indicated that while blockade of Delta Psi(m) may be sufficient to reduce swelling,

it may not be a necessary factor, and that flavonoids reduce cell swelling by regulating [Ca(2+)](i). The differential effects of myricetin and quercetin on OGD-induced reduction on glutamate uptake may be due to their differential Calpain effects on mitochondria. Published by Elsevier Ltd on behalf of IBRO.”
“It has been hypothesized that corticotropin-releasing factor (CRF) and its related neuropeptide urocortin 1 (Ucn1) play different roles in the initiation and adaptive phases of the stress response, which implies different temporal dynamics of these neuropeptides in response to stressors. We have tested the hypothesis that acute pain stress (APS) differentially changes the dynamics of CRF expression in the paraventricular nucleus of the hypothalamus (PVN), oval subdivision of the bed nucleus of the stria terminalis (BSTov) and central amygdala (CeA), and the dynamics of Ucn1 expression in the midbrain non-preganglionic Edinger Westphal nucleus (npEW). Thirty minutes after APS, induced by a formalin injection into the left hind paw, PVN, BSTov, CeA and npEW all showed a peak in cFos mRNA expression that was followed by a robust increase in cFos protein-immunoreactivity, indicating a rapid increase in (immediate early) gene expression in all four brain nuclei.

Characterization of their binding to IL-15R alpha and their ability to stimulate the T-cell growth response showed that M38 binds as strongly as native IL-15 to IL-15R alpha and acts as an effective agonist of IL-15.”
“While a large number of mosquito-transmitted alphaviruses are known to cause serious human diseases, there are no licensed vaccines that protect against alphavirus JSH-23 price infections. The alphavirus chikungunya virus (CHIKV) has caused multiple recent outbreaks of chikungunya fever. This virus has the potential to cause a worldwide epidemic and has generated strong interest

in development of a prophylactic CHIKV vaccine. We report here on the development of a potent experimental vaccine for CHIKV based on a chimeric vesicular stomatitis virus (VSV) expressing the entire CHIKV envelope polyprotein (E3-E2-6K-E1) in place of the VSV glycoprotein (G). These VSV Delta G-CHIKV chimeras incorporated functional CHIKV glycoproteins into the viral envelope in place of VSV G. The chimeric viruses YM155 cell line were attenuated for growth in tissue culture but could be propagated to high titers without VSV G complementation. They also generated robust neutralizing antibody and cellular immune responses to CHIKV in mice after a single dose and protected mice against CHIKV infection. VSV Delta G-alphavirus chimeras could have general applicability as alphavirus

vaccines.”
“In human populations, there is a well-defined sequence of involvement in drugs of abuse, in which the use of nicotine or alcohol precedes the use of marijuana, which in turn, precedes the use of cocaine. The term “”Gateway Hypothesis”" describes this developmental sequence of drug involvement. In prior work, we have developed a mouse model to

study the underlying metaplastic behavioral, cellular and molecular mechanisms by which exposure to one drug, namely nicotine, Alisertib purchase affects the response to another drug, namely cocaine. We found that nicotine enhances significantly the changes in synaptic plasticity in the striatum induced by cocaine (Levine et al., 2011). Here we ask: does the metaplastic effect of nicotine on cocaine also apply in the amygdala, a brain region that is involved in the orchestration of emotions and in drug addiction? We find that pretreatment with nicotine enhances long-term synaptic potentiation (LTP) in response to cocaine in the amygdala. Both short-term (1 day) and long-term (7 days) preexposure to nicotine facilitate the induction of LTP by cocaine. The effect of nicotine on LTP is unidirectional; exposure to nicotine following treatment with cocaine is ineffective. This metaplastic effect of nicotine on cocaine is long lasting but reversible. The facilitation of LTP can be obtained for 24 but not 40 days after cessation of nicotine. As is the case in the striatum, pretreatment with Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, simulates the priming effect of nicotine.

The previous studies demonstrated that these

four proteins may function in the cell migration process. This method will provide insights into the molecular details of pseudopodia and a further understanding of malignant phenotypes of tumor cells and novel therapeutic strategies. Laboratory Investigation (2012) 92, 1374-1385; doi:10.1038/labinvest.2012.98; published online 2 July 2012″
“Oxytocin (OT) is a peptide increasingly studied in relation to human social interactions, affiliation, and clinical disorders. Studies are constrained by use of invasive blood draws and would benefit from a reliable salivary OT assay. Our goals were to examine feasibility of salivary OT measurement, compare salivary to plasma OT responses in 12 breast- and 8 formula-feeding mothers, and assess the degree of correlation between plasma and salivary OT. Using a commercial CX-6258 EIA kit, we measured Evofosfamide ic50 OT in 5 saliva and 7 plasma samples in a protocol designed to elicit changes in OT (Rest, Infant Interaction, Stress, Feeding). Breast-feeders had higher OT levels than formula-feeders across all conditions in plasma (+36%) and saliva (+23%). OT levels and ranges were similar in saliva and plasma, with slightly

greater variance in saliva. Concurrently sampled plasma and salivary OT were correlated at end of Baseline Rest (r=+.59, p=.022) and Post-Stress Recovery (r=+.59, p=.025). Liproxstatin-1 supplier These data suggest that salivary OT assay is feasible, and will be of value where plasma samples are not possible. Validation with larger samples is needed.”
“Most consensus leukemia & lymphoma antibody panels consist of lists of

markers based on expert opinions, but they have not been validated. Here we present the validated EuroFlow 8-color antibody panels for immunophenotyping of hematological malignancies. The single-tube screening panels and multi-tube classification panels fit into the EuroFlow diagnostic algorithm with entries defined by clinical and laboratory parameters. The panels were constructed in 2-7 sequential design-evaluation-redesign rounds, using novel Infinicyt software tools for multivariate data analysis. Two groups of markers are combined in each 8-color tube: (i) backbone markers to identify distinct cell populations in a sample, and (ii) markers for characterization of specific cell populations. In multi-tube panels, the backbone markers were optimally placed at the same fluorochrome position in every tube, to provide identical multidimensional localization of the target cell population(s). The characterization markers were positioned according to the diagnostic utility of the combined markers. Each proposed antibody combination was tested against reference databases of normal and malignant cells from healthy subjects and WHO-based disease entities, respectively.

Here we describe the spatio-temporal distribution of activated MMP-2 and MMP-9 in the brain of rats subjected to 2 h middle cerebral artery occlusion (MCAo) followed by different periods of reperfusion (15 min, 2 h, 6 h and 22 h). By in situ zymography we have observed that gelatinases become activated 15 min and 2 h after the beginning of reperfusion in the ischemic core and

penumbra, respectively.

In situ zymography signal broadly co-localized with NeuN-positive cells, thus suggesting that proteolysis mainly occurs in neurons. Gelatinolytic activity was mainly detected in cell nuclei, marginally appearing in the cytosol only at later selleck screening library stages following the insult; we did not detect variations in gelatinolysis in the extracellular matrix. Finally, we report that pharmacological inhibition of MMPs by N-[(2R)-2-(hydroxamidocarbonyl-methyl)-L-methylpenthanoyi]-L-tryptophan methylamide (GM6001) significantly Stem Cells & Wnt inhibitor reduces brain infarct volume induced

by transient MCAo. Taken together our data underscore the crucial role of gelatinases during the early stages of reperfusion and further extend previous observations documenting the detrimental role of these enzymes in the pathophysiology of brain ischemia. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“We develop a genetic algorithm (GA) approach to a selleck kinase inhibitor well-known model of vigilance behaviour in a group of animals. We first demonstrate that the GA approach can provide a good match to analytic solutions to the original model. We demonstrate that

a GA can be used to find the evolutionarily stable strategies in a model relevant to behavioural ecology where the fitness of each strategy is determined by the frequencies of different strategies in the population. We argue that the GA implementation demonstrates the combination of assumptions used to generate analytic solution to the original model can only be simultaneously satisfied under relatively restrictive conditions on the ecology of the species involved; specifically that group membership is very fluid but group size is conserved over timescales of individual foraging bouts. We further explore the sensitivity of model predictions to alternative choices in the implementation of the GA, and present advice for implementation and presentation of similar models. In particular, we emphasise the need for care in measuring the predictions of such models, so as to capture the intrinsic behaviour of the system and not the remnant of often arbitrarily chosen initial conditions. We also emphasise the potential for GA models to be more transparent about model assumptions regarding underlying biology than analytic models. (c) 2007 Elsevier Ltd. All rights reserved.