ELECTRONIC-STRUCTURE OF V- CENTER IN MGO

The authors have investigated in detail the two models of the V- centre, where a hole is trapped at a cation vacancy. These are the model of Bartram, Swenberg and Fourn (1965), where optical transitions occur within an O- ion, and the model of Schirmer, Koidl and Reik (1974), which involves a hole hopping from one oxygen ion to another. The calculations show (i) that the hole should be self-trapped on a single oxygen, as observed, (ii) that the predictions of ground-state ionization energy and of elastic and electrical dipole moments (apart from some uncertainties in local-field corrections) agree adequately with measurements, (iii) that the transitions within an O- ion appear to account for observed structure at around 1.5 eV, both in energy and oscillator strength, and (iv) that the observed 2.3 eV band corresponds to the transition suggested by Schirmer et al. Calculations are also given for some centres related to the V- centre, V0, V(Al)- and (Na)0, again predicting optical absorption in good agreement with experiment

The ground state of two-hole centres in oxides

The nature of the ground state of the V centre in ionic oxides is discussed, where two holes are trapped by a cation vacancy. Experiment appears to indicate an S=1 ground state for BeO and Al 2 O 3 and possibly ZnO, with S=0 in MgO and CaO. Simple theoretical arguments suggest S=0. It is shown that a weak mixture of (O 0 O 2- ) configurations into the dominant (O - O - ) configuration can explain the observations. Quantitative calculations are given for MgO, and suggest the singlet state is lowest by about 30 cm -1

Three-Dimensional Imaging of the Mouse Neurovasculature with Magnetic Resonance Microscopy

Knowledge of the three-dimensional (3D) architecture of blood vessels in the brain is crucial because the progression of various neuropathologies ranging from Alzheimer's disease to brain tumors involves anomalous blood vessels. The challenges in obtaining such data from patients, in conjunction with development of mouse models of neuropathology, have made the murine brain indispensable for investigating disease induced neurovascular changes. Here we describe a novel method for “whole brain” 3D mapping of murine neurovasculature using magnetic resonance microscopy (μMRI). This approach preserves the vascular and white matter tract architecture, and can be combined with complementary MRI contrast mechanisms such as diffusion tensor imaging (DTI) to examine the interplay between the vasculature and white matter reorganization that often characterizes neuropathologies. Following validation with micro computed tomography (μCT) and optical microscopy, we demonstrate the utility of this method by: (i) combined 3D imaging of angiogenesis and white matter reorganization in both, invasive and non-invasive brain tumor models; (ii) characterizing the morphological heterogeneity of the vascular phenotype in the murine brain; and (iii) conducting “multi-scale” imaging of brain tumor angiogenesis, wherein we directly compared in vivo MRI blood volume measurements with ex vivo vasculature data

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Sensitivity of MRI Tumor Biomarkers to VEGFR Inhibitor Therapy in an Orthotopic Mouse Glioma Model

MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI) and a slight decrease in the water apparent diffusion coefficient (ADC) were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV), relative microvascular blood volume (rMBV), transverse relaxation time (T2), blood vessel permeability (Ktrans), and extravascular-extracellular space (νe). The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology

Characterisation of tumour vasculature in mouse brain by USPIO contrast-enhanced MRI

To enhance the success rate of antiangiogenic therapies in the clinic, it is crucial to identify parameters for tumour angiogenesis that can predict response to these therapies. In brain tumours, one such parameter is vascular leakage, which is a response to tumour-derived vascular endothelial growth factor-A and can be measured by Gadolinium-DTPA (Gd-DTPA)-enhanced magnetic resonance imaging (MRI). However, as vascular permeability and angiogenesis are not strictly coupled, tumour blood volume may be another potentially important parameter. In this study, contrast-enhanced MR imaging was performed in three orthotopic mouse models for human brain tumours (angiogenic melanoma metastases and E34 and U87 human glioma xenografts) using both Gd-DTPA to detect vascular leakage and ultrasmall iron oxide particles (USPIO) to measure blood volume. Pixel-by-pixel maps of the enhancement in the transverse relaxation rates (ΔR2 and ΔR2*) after injection of USPIO provided an index proportional to the blood volume of the microvasculature and macrovasculature, respectively, for each tumour. The melanoma metastases were characterised by a blood volume and vessel leakage higher than both glioma xenografts. The U87 glioblastoma xenografts displayed higher permeability and blood volume in the rim than in the core. The E34 glioma xenografts were characterised by a relatively high blood volume, accompanied by only a moderate blood–brain barrier disruption. Delineation of the tumour was best assessed on post-USPIO gradient-echo images. These findings suggest that contrast-enhanced MR imaging using USPIOs and, in particular, ΔR2 and ΔR2* quantitation, provides important additional information about tumour vasculature

Multimodality Imaging of Abnormal Vascular Perfusion and Morphology in Preclinical 9L Gliosarcoma Model

This study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone.One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65 ± .13) as compared to the fifth day during treatment (1.26 ±.19, p < 0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89 ±.13, 1.00 ± .21, 1.13 ± .23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32 ± 2.34 branches/mm(3), p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29 ± 3.51 branches/mm(3)). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45 ± 1.36 µm(2)) as compared to saline treated tumor regions (30.83 ± 4.31 µm(2), p<0.001) and non-tumor regions (22.80 ± 1.11 µm(2), p<0.01).Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment