Regional brain development analysis through registration using anisotropic similarity, a constrained affine transformation

We propose a novel method to quantify brain growth in 3 arbitrary orthogonal directions of the brain or its sub-regions through linear registration. This is achieved by introducing a 9 degrees of freedom (dof) transformation called anisotropic similarity which is an affine transformation with constrained scaling directions along arbitrarily chosen orthogonal vectors. This gives the opportunity to extract scaling factors describing brain growth along those directions by registering a database of subjects onto a common reference. This information about directional growth brings insights that are not usually available in longitudinal volumetric analysis. The interest of this method is illustrated by studying the anisotropic regional and global brain development of 308 healthy subjects betwen 0 and 19 years old. A gender comparison of those scaling factors is also performed for four age-intervals. We demonstrate through these applications the stability of the method to the chosen reference and its ability to highlight growth differences accros regions and gender

Physical Structure of Planetary Nebulae. I. The Owl Nebula

The Owl Nebula is a triple-shell planetary nebula with the outermost shell being a faint bow-shaped halo. We have obtained deep narrow-band images and high-dispersion echelle spectra in the H-alpha, [O III], and [N II] emission lines to determine the physical structure of each shell in the nebula. These spatio-kinematic data allow us to rule out hydrodynamic models that can reproduce only the nebular morphology. Our analysis shows that the inner shell of the main nebula is slightly elongated with a bipolar cavity along its major axis, the outer nebula is a filled envelope co-expanding with the inner shell at 40 km/s, and the halo has been braked by the interstellar medium as the Owl Nebula moves through it. To explain the morphology and kinematics of the Owl Nebula, we suggest the following scenario for its formation and evolution. The early mass loss at the TP-AGB phase forms the halo, and the superwind at the end of the AGB phase forms the main nebula. The subsequent fast stellar wind compressed the superwind to form the inner shell and excavated an elongated cavity at the center, but has ceased in the past. At the current old age, the inner shell is backfilling the central cavity.Comment: 10 pages, 6 figures, 1 table, to appear in the Astronomical Journa

Perinatal grief following neonatal comfort care for lethal fetal condition

BACKGROUND: The objective of the study was to assess perinatal grief experienced after continuing pregnancy and comfort care in women diagnosed with lethal fetal condition compared with termination of pregnancy for fetal anomaly (TOPFA). METHODS: This was a retrospective observational study which included women who chose to continue their pregnancy after the diagnosis of lethal fetal condition with comfort care support at birth at the Prenatal Diagnosis Center of Rennes Hospital from January 2007 to January 2017. Women were matched with controls who underwent TOPFA for the same type of fetal anomaly, gestational age at diagnosis and year. Women were evaluated by a questionnaire including the Perinatal Grief Scale. RESULTS: There were 28 patients in the continuing pregnancy group matched with 56 patients in the TOPFA group. Interval between fetal loss and completion of questionnaire was 6±3 years. Perinatal grief score was similar at 61±22 vs 58±18 (p = 0.729) in the continuing pregnancy and TOPFA groups, respectively. Women in the TOPFA group expressed more guilt. The cesarean-section rate in the continuing pregnancy group was 25% . CONCLUSION: Perinatal grief experienced by women opting for continuing pregnancy and comfort care after diagnosis of a potentially lethal fetal anomaly is not more severe than for those choosing TOPFA

Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects

Up-regulation of the folding machinery of the heat-shock protein 90 (Hsp90) chaperone protein is crucial for cancer progression. The two Hsp90 isoforms (α and β) play different roles in response to chemotherapy. To identify isoform-selective inhibitors of Hsp90(α/β)/cochaperone p23 interactions, we developed a dual-luciferase (Renilla and Firefly) reporter system for high-throughput screening (HTS) and monitoring the efficacy of Hsp90 inhibitors in cell culture and live mice. HTS of a 30,176 small-molecule chemical library in cell culture identified a compound, N-(5-methylisoxazol-3-yl)-2-[4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-ylthio]acetamide (CP9), that binds to Hsp90(α/β) and displays characteristics of Hsp90 inhibitors, i.e., degradation of Hsp90 client proteins and inhibition of cell proliferation, glucose metabolism, and thymidine kinase activity, in multiple cancer cell lines. The efficacy of CP9 in disrupting Hsp90(α/β)/p23 interactions and cell proliferation in tumor xenografts was evaluated by non-invasive, repetitive Renilla luciferase and Firefly luciferase imaging, respectively. At 38 h posttreatment (80 mg/kg × 3, i.p.), CP9 led to selective disruption of Hsp90α/p23 as compared with Hsp90β/p23 interactions. Small-animal PET/CT in the same cohort of mice showed that CP9 treatment (43 h) led to a 40% decrease in 18F-fluorodeoxyglucose uptake in tumors relative to carrier control-treated mice. However, CP9 did not lead to significant degradation of Hsp90 client proteins in tumors. We performed a structural activity relationship study with 62 analogs of CP9 and identified A17 as the lead compound that outperformed CP9 in inhibiting Hsp90(α/β)/p23 interactions in cell culture. Our efforts demonstrated the power of coupling of HTS with multimodality molecular imaging and led to identification of Hsp90 inhibitors

Natural and anthropogenic changes to mangrove distributions in the Pioneer River Estuary (QLD, Australia)

We analyzed a time series of aerial photographs and Landsat satellite imagery of the Pioneer River Estuary (near Mackay, Queensland, Australia) to document both natural and anthropogenic changes in the area of mangroves available to filter river runoff between 1948 and 2002. Over 54 years, there was a net loss of 137 ha (22%) of tidal mangroves during four successive periods that were characterized by different driving mechanisms: (1) little net change (1948– 1962); (2) net gain from rapid mangrove expansion (1962–1972); (3) net loss from clearing and tidal isolation (1972–1991); and (4) net loss from a severe species-specific dieback affecting over 50% of remaining mangrove cover (1991–2002). Manual digitization of aerial photographs was accurate for mapping changes in the boundaries of mangrove distributions, but this technique underestimated the total loss due to dieback. Regions of mangrove dieback were identified and mapped more accurately and efficiently after applying the Normalized Difference Vegetation Index (NDVI) to Landsat Thematic Mapper satellite imagery, and then monitoring changes to the index over time. These remote sensing techniques to map and monitor mangrove changes are important for identifying habitat degradation, both spatially and temporally, in order to prioritize restoration for management of estuarine and adjacent marine ecosystems

Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

<p>Abstract</p> <p>Background</p> <p>Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated.</p> <p>Results</p> <p>The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 Å of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method.</p> <p>Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed.</p> <p>Conclusion</p> <p>Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.</p

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic–pharmacodynamic (PK–PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition

Bidirectional texture function of high resolution optical images of tropical forest : an approach using LiDAR hillshade simulations

Quantifying and monitoring the structure and degradation of tropical forests over regional to global scales is gaining increasing scientific and societal importance. Reliable automated methods are only beginning to appear; for instance, through the recent development of textural approaches applied to high resolution optical imagery. In particular, the Fourier Transform Textural Ordination (FOTO) method shows some potential to provide non-saturating estimates of tropical forest structure, including for large scale applications. However, we need to understand more precisely how canopy structure interacts with physical signals (light) to produce a given texture, notably to assess the method's sensitivity to varying sun-view acquisition conditions. In this study, we take advantage of the detailed description of canopy topography provided by airborne small footprint LiDAR data acquired over the Paracou forest experimental station in French Guiana. Using hillshade models and a range of sun-view angles identical to the actual parameter distributions found for Quickbird (TM) images over the Amazon, we study noise and bias in texture estimation induced by the changing configurations. We introduce the bidirectional texture function, which summarizes these effects, and in particular the existence of a textural 'hot spot', similar to a well-known feature of bidirectional reflectance studies. For texture, this effect implies that coarseness decreases in configurations for which shadows are concealed to the observer. We also propose a method, termed partitioned standardization, that allows mitigating acquisition effects and discuss the potential for an operational use of VHR optical imagery and the FOTO method in the current context of international decisions to reduce CO2 emissions due to deforestation and forest degradation