Comparison of particle image velocimetry and phase contrast MRI in a patient-specific extracardiac total cavopulmonary connection

Particle image velocimetry (PIV) and phase contrast magnetic resonance imaging (PC-MRI) have not been compared in complex biofluid environments. Such analysis is particularly useful to investigate flow structures in the correction of single ventricle congenital heart defects, where fluid dynamic efficiency is essential. A stereolithographic replica of an extracardiac total cavopulmonary connection (TCPC) is studied using PIV and PC-MRI in a steady flow loop. Volumetric two-component PIV is compared to volumetric three-component PC-MRI at various flow conditions. Similar flow structures are observed in both PIV and PC-MRI, where smooth flow dominates the extracardiac TCPC, and superior vena cava flow is preferential to the right pulmonary artery, while inferior vena cava flow is preferential to the left pulmonary artery. Where three-component velocity is available in PC-MRI studies, some helical flow in the extracardiac TCPC is observed. Vessel cross sections provide an effective means of validation for both experiments, and velocity magnitudes are of the same order. The results highlight similarities to validate flow in a complex patient-specific extracardiac TCPC. Additional information obtained by velocity in three components further describes the complexity of the flow in anatomic structures.     

Small molecule antagonists of CCR8 inhibit eosinophil and T cell migration

In this study, we demonstrate that in addition to T lymphocytes, human naïve eosinophils and the differentiated eosinophil-like cell line, AML14.3D10 express CCR8 and respond to CCL1 through CCR8 engagement. The responsiveness of cells was dependent on maturation stage, since CCL1 induced pronounced chemotaxis only in differentiated CCR8 positive AML14.3D10 cells. Despite the low CCR8 surface expression, human naïve eosinophils respond with a chemotaxis to high concentration CCL1. We further describe that Th2 clones in a maturation dependent fashion produce autocrine CCL1, which renders them unresponsive to further stimulation. An innovative method to enrich primary CCR8 reactive T cells was developed which demonstrates that primary peripheral CCR8 expressing T cells respond significantly to CCL1.We have developed novel small molecule CCR8 antagonists that are effective in inhibiting calcium mobilization and chemotaxis in differentiated AML cells as well as in human primary CCR8 positive T cells. Importantly, we demonstrate that the compounds can be divided into two subgroups: (i) compounds that are functional agonists for calcium mobilization and chemotaxis (ii) compounds that are pure antagonists. We demonstrate that agonism of these compounds does not correlate with their antagonistic potency. Taken together, we have identified a novel set of CCR8 compounds with antagonistic properties that inhibit CCL1 driven chemotaxis in both CCR8 expressing eosinophils as well as primary human T cells.     

Spatial correlations of trabecular bone microdamage with local stresses and strains using rigid image registration

Although microdamage is known to accumulate in trabecular bone with overloading and aging, the tissue-level stresses and strains associated with local bone failure are not well known. Local correlation of microdamage with microstructural stresses and strains requires methods to accurately register histological sections with micro-computed tomography (micro-CT) based finite element models. In addition, the resolution of correlation (i.e., grid size) selected for analysis may affect the observed results. Therefore, an automated, repeatable, and accurate image registration algorithm was developed to determine the range of local stresses and strains associated with microdamage initiation. Using a two-dimensional rigid registration algorithm, bone structures from histology and micro-CT imaging were aligned. Once aligned, microdamaged regions were spatially correlated with local stresses and strains obtained from micro-CT based finite element analysis. Using this more sophisticated registration technique, we were able to analyze the effects of varying spatial grid resolution on local stresses and strains initiating microdamage. The results indicated that grid refinement to the individual pixel level (pixel-by-pixel method) more precisely defined the range of microdamage initiation compared to manually selected individual damaged and undamaged trabeculae. Using the pixel-by-pixel method, we confirmed that trabecular bone from younger cows sustained higher local strains prior to microdamage initiation compared to older bone.     

DFT study of the Lewis acid mediated synthesis of 3-acyltetramic acids

The recent emergence and re-emergence of alphaviruses, in particular the chikungunya virus (CHIKV), in numerous countries has invoked a worldwide threat to human health, while simultaneously generating an economic burden on affected countries. There are currently no vaccines or effective drugs available for the treatment of the CHIKV, and with few lead compounds reported, the vital medicinal chemistry is significantly more challenging. This study reports on the discovery of potential inhibitors for the nsP3 macro domain of CHIKV using molecular docking, virtual screening, and molecular dynamics simulations, as well as work done to evaluate and confirm the active site of nsP3. Virtual screening was carried out based on blind docking as well as focused docking, using the database of 1541 compounds from NCI Diversity Set II, to identify hit compounds for nsP3. The top hit compounds were further subjected to molecular dynamic simulations, yielding a greater understanding of the dynamic behavior of nsP3 and its complexes with various ligands, concurrently confirming the outcomes of docking, and establishing in silico lead compounds which target the CHIKV nsP3 enzyme.