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Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has Ki values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 A resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide ...

Purpose To compare mono- and bi-exponential relaxation model equations to discriminate between normal and fatty liver disease. Materials and Methods Six rats on a choline deficient amino acid modified (CDAA) diet and six on normal chow were studied. Multiple spin echo images with increasing echo times (TEs) were collected at 9.4T. Pixel-wise T2 maps were generated using mono-exponential decay function to calculate T2M, and a bi-exponential to calculate, short T2 component (T2S), long T2 component (T2L), and fractions of these components (ρS, ρL), respectively. Statistical F-tests and Akaike's information criterion (AIC) were used to assess the relative performance of the two models. Results F-test and AIC showed that in the CDAA group, T2 bi-exponential model described the signal of T2 weighted imaging of the liver better than the mono-exponential model. Controls were best described by the mono-exponential model. Mean values for T2M, T2L, T2S, ρS, ρL were 31.2 ± 0.7 ms, 72.8 ± 3.3 ms, 8.2 ± 0.6 ms,71.2 ± 2.1%, 30.4 ± 1.3%, respectively, in CDAA rats, compared with 18.8 ± 0.5 ms, 32.3 ± 0.7 ms, 9.2 ± 1.8 ms, 79 ± 2%, 21.0 ± 1.1% in controls. Conclusion In the fatty liver of CDAA rats we have shown that T2 weighted images fit the bi-exponential model better than mono-exponential decays thus providing a better description of the data. Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:468–476.

Background Atorvastatin and metformin are known energy restricting mimetic agents that act synergistically to produce molecular and metabolic changes in advanced prostate cancer (PCa). This trial seeks to determine whether these drugs favourably alter selected parameters in men with clinically-localized, aggressive PCa. Methods/design This prospective phase II randomized, controlled window trial is recruiting men with clinically significant PCa, confirmed by biopsy following multiparametric MRI and intending to undergo radical prostatectomy. Ethical approval was granted by the Royal Brisbane and Women's Hospital Human and The University of Queensland Medical Research Ethics Committees. Participants are being randomized into four groups: metformin with placebo; atorvastatin with placebo; metformin with atorvastatin; or placebo alone. Capsules are consumed for 8 weeks, a duration selected as the most appropriate period in which histological and biochemical changes may be observed while allowing prompt treatment with curative intent of clinically significant PCa. At recruitment and prior to RP, participants provide blood, urine and seminal fluid. A subset of participants will undergo 7Tesla magnetic resonance spectroscopy to compare metabolites in-vivo with those in seminal fluid and biopsied tissue. The primary end point is biochemical evolution, defined using biomarkers (serum prostate specific antigen; PCA3 and citrate in seminal fluid and prostatic tissue). Standard pathological assessment will be undertaken. Discussion This study is designed to assess the potential synergistic action of metformin and atorvastatin on PCa tumour biology. The results may determine simple methods of tumour modulation to reduce disease progression.

We present a combined PET/7 T MR imaging and 16.4 T microscopic MR imaging dual-modality imaging approach enabling quantification of the amyloid load at high sensitivity and high resolution, and of regional cerebral blood flow (rCBF) in the brain of transgenic APP23 mice. Moreover, we demonstrate a novel, voxel-based correlative data analysis method for in-depth evaluation of amyloid PET and rCBF data. Methods: We injected C-11-Pittsburgh compound B (PIB) intravenously in transgenic and control APP23 mice and performed dynamic PET measurements. rCBF data were recorded with a flow-sensitive alternating inversion recovery approach at 7 T. Subsequently, the animals were sacrificed and their brains harvested for ex vivo microscopic MR imaging at 16.4 T with a T-2*-weighted gradient-echo sequence at 30-mu m spatial resolution. Additionally, correlative amyloid histology was performed. The C-11-PIB PET data were quantified to nondisplaceable binding potentials (BPND) using the Logan graphical analysis; flow-sensitive alternating inversion recovery data were quantified with a simplified version of the Bloch equation. Results: Amyloid load assessed by both C-11-PIB PET and amyloid histology was highest in the frontal cortex of transgenic mice (C-11-PIB BPND: 0.93 +/- 0.08; amyloid histology: 15.1% +/- 1.5%), followed by the temporoparietal cortex (C-11-PIB BPND: 0.75 +/- 0.08; amyloid histology: 13.9% +/- 0.7%) and the hippocampus (C-11-PIB BPND: 0.71 +/- 0.09; amyloid histology: 9.2% +/- 0.9%), and was lowest in the thalamus (C-11-PIB BPND: 0.40 +/- 0.07; amyloid histology: 6.6% +/- 0.6%). However, C-11-PIB BPND and amyloid histology linearly correlated (R-2 = 0.82, P < 0.05) and were significantly higher in transgenic animals (P < 0.01). Similarly, microscopic MR imaging allowed quantifying the amyloid load, in addition to the detection of substructures within single amyloid plaques correlating with amyloid deposition density and the measurement of hippocampal atrophy. Finally, we found an inverse relationship between C-11-PIB BPND and rCBF MR imaging in the voxel-based analysis that was absent in control mice (slope(tg): -0.11 +/- 0.03; slope.: 0.004 +/-. 0.005; P = 0.014). Conclusion: Our dual-modality imaging approach using C-11-PIB PET/7 T MR imaging and 16.4 T microscopic MR imaging allowed amyloid-load quantification with high sensitivity and high resolution, the identification of substructures within single amyloid plaques, and the quantification of rCBF.

Bruising of the mesocarp in avocado fruit is an important postharvest issue for the industry. Proton magnetic resonance imaging (H-1-MRI) was used as a non-destructive tool to monitor bruise expression over time in avocado cv. Hass fruit. H-1-MRI clearly identified fruit morphological features and bruised mesocarp tissue. The pixel intensity value of T-2 weighted spin echo H-1-MRI images of avocado fruit pericarp changed over time with fruit softening. Bruised mesocarp tissue in impacted fruit appeared relatively hyperintense (brighter) in T-2 weighted H-1-MRI images. For firm ripe fruit impacted from 25 cm drop height (0.38 J +/- 0.004) and for firm ripe fruit impacted from 50 cm drop height (0.81 J +/- 0.011), hyper-intensity in the mesocarp beneath the impact point was evident immediately after impact. However, visible symptoms of bruising in the form of flesh browning did not appear in parallel serial destructive assessments until after day 1 following impact on day 0. The brown, bruised mesocarp volume in ripe fruit increased progressively over the assessment period of 3 days. This trend was evident in destructive assessments as well as in H-1-MRI images. In hard green mature fruit impacted from 100 cm drop height (1.68 J +/- 0.020), contrast between mesocarp tissue beneath the impact site and surrounding sound mesocarp was evident in T-2 weighted H-1-MRI images from day 0. However, no bruise symptoms were evident as flesh browning upon serial destructive assessments of fruit over the 3 days assessment period. The average pixel intensity values at the impact site in T-2 weighted H-1-MRI images for both firm ripe and hard green mature fruit decreased over the period of assessment. In contrast, the pixel intensities in the T-2 weighted H-1-MRI images of diseased flesh increased over time. (C) 2014 Elsevier B.V. All rights reserved.

Magnetic Resonance Imaging (MRI) of the rodent brain at ultra-high magnetic fields (> 9.4 Tesla) offers a higher signal-to-noise ratio that can be exploited to reduce image acquisition time or provide higher spatial resolution. However, significant challenges are presented due to a combination of longer T 1 and shorter T 2/T2* relaxation times and increased sensitivity to magnetic susceptibility resulting in severe local-field inhomogeneity artefacts from air pockets and bone/brain interfaces. The Stejskal-Tanner spin echo diffusion-weighted imaging (DWI) sequence is often used in high-field rodent brain MRI due to its immunity to these artefacts. To accurately determine diffusion-tensor or fibre-orientation distribution, high angular resolution diffusion imaging (HARDI) with strong diffusion weighting (b >3000 s/mm2) and at least 30 diffusion-encoding directions are required. However, this results in long image acquisition times unsuitable for live animal imaging. In this study, we describe the optimization of HARDI acquisition parameters at 16.4T using a Stejskal-Tanner sequence with echo-planar imaging (EPI) readout. EPI segmentation and partial Fourier encoding acceleration were applied to reduce the echo time (TE), thereby minimizing signal decay and distortion artefacts while maintaining a reasonably short acquisition time. The final HARDI acquisition protocol was achieved with the following parameters: 4 shot EPI, b = 3000 s/mm2, 64 diffusion-encoding directions, 125×150 μm2 in-plane resolution, 0.6 mm slice thickness, and 2h acquisition time. This protocol was used to image a cohort of adult C57BL/6 male mice, whereby the quality of the acquired data was assessed and diffusion tensor imaging (DTI) derived parameters were measured. High-quality images with high spatial and angular resolution, low distortion and low variability in DTI-derived parameters were obtained, indicating that EPI-DWI is feasible at 16.4T to study animal models of white matter (WM) diseases.