Intestinal barrier tightening by a cell-penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis.

Patients afflicted with ulcerative colitis (UC) are at increased risk of colorectal cancer. While its causes are not fully understood, UC is associated with defects in colonic epithelial barriers that sustain inflammation of the colon mucosa caused by recruitment of lymphocytes and neutrophils into the lamina propria. Based on genetic evidence that attenuation of the bridging integrator 1 (Bin1) gene can limit UC pathogenicity in animals, we have explored Bin1 targeting as a therapeutic option. Early feasibility studies in the dextran sodium sulfate mouse model of experimental colitis showed that administration of a cell-penetrating Bin1 monoclonal antibody (Bin1 mAb 99D) could prevent lesion formation in the colon mucosa in part by preventing rupture of lymphoid follicles. In vivo administration of Bin1 mAb altered tight junction protein expression and cecal barrier function. Strikingly, electrophysiology studies in organ cultures showed that Bin1 mAb could elevate resistance and lowe

Accuracy of phase-contrast velocimetry in systems with skewed intravoxel velocity distributions

Phase contrast velocimetry (PCV) has been widely used to investigate flow properties in numerous systems. Several authors have reported errors in velocity measurements and have speculated on the sources, which have ranged from eddy current effects to acceleration artefacts. An often overlooked assumption in the theory of PCV, which may not be met in complex or unsteady flows, is that the intravoxel displacement distributions (propagators) are symmetric. Here, the effect of the higher moments of the displacement distribution (variance, skewness and kurtosis) on the accuracy of PCV is investigated experimentally and theoretically. Phase and propagator measurements are performed on tailored intravoxel distributions, achieved using a simple phantom combined with a single large voxel. Asymmetric distributions (Skewness ≠ 0) are shown to generate important phase measurement errors that lead to significant velocimetry errors. Simulations of the phase of the spin vector sum, based on experimentally measured propagators, are shown to quantitatively reproduce the relationship between measured phase and experimental parameters. These allow relating the observed velocimetry errors to a discrepancy between the average phase of intravoxel spins considered in PCV theory and the vector phase actually measured by a PFG experiment. A theoretical expression is derived for PCV velocimetry errors as a function of the moments of the displacement distribution. Positively skewed distributions result in an underestimation of the true mean velocity, while negatively skewed distributions result in an overestimation. The magnitude of these errors is shown to increase with the variance and decrease with the kurtosis of the intravoxel displacement distribution

Biotransformation of Silver Released from Nanoparticle Coated Titanium Implants Revealed in Regenerating Bone

Antimicrobial silver nanoparticle coatings have attracted interest for reducing prosthetic joint infection. However, few studies report in vivo investigations of the biotransformation of silver nanoparticles within the regenerating tissue and its impact on bone formation. We present a longitudinal investigation of the osseointegration of silver nanoparticle-coated additive manufactured titanium implants in rat tibial defects. Correlative imaging at different time points using nanoscale secondary ion mass spectrometry, transmission electron microscopy (TEM), histomorphometry, and 3D X-ray microcomputed tomography provided quantitative insight from the nano- to macroscales. The quality and quantity of newly formed bone is comparable between the uncoated and silver coated implants. The newly formed bone demonstrates a trabecular morphology with bone being located at the implant surface, and at a distance, at two weeks. Nanoscale elemental mapping of the bone−implant interface showed that silver was present primarily in the osseous tissue and colocalized with sulfur. TEM revealed silver sulfide nanoparticles in the newly regenerated bone, presenting strong evidence that the previously in vitro observed biotransformation of silver to silver sulfide occurs in vivo

Polychlorinated Biphenyls and Biotransformation Enzymes in Three Species of Sea Turtles from the Baja California Peninsula of Mexico

Concentrations of polychlorinated biphenyls (PCBs) as well as the expression patterns of cytochrome P450 (CYP) enzymes and glutathione-S-transferase (GST) activities were measured in livers of loggerhead (Caretta caretta), green (Chelonia mydas), and olive ridley (Lepidocheyls olivacea) sea turtles from the Baja California peninsula of Mexico. The mean concentrations of total PCBs were 18.1, 10.5, and 15.2 ng/g wet weight (ww) respectively for the three species and PCB 153 was the dominant congener in all samples. Total PCB concentrations were dominated by penta- and hexa-chlorinated biphenyls. The mean estimated TEQs were 42.8, 22.9, and 10.4 pg/g (ww) for loggerhead, green, and olive ridley, respectively, and more than 70% was accounted for by non-ortho PCBs. Western blots revealed the presence of hepatic microsomal proteins that cross-reacted with anti-CYP2K1 and anti-CYP3A27 antibodies but not with anti-CYP1A antibody. There were no significant differences in GST activities between species. Grouping congeners based on structure–activity relationships for CYP isoenzymes suggested limited activity of CYP1A contribution to PCB biotransformation in sea turtles. These results suggest potential accumulation of PCBs that are CYP1A substrates and provide evidence for biotransformation capacity, which differs from known animal models, highlighting the need for further studies in reptiles, particularly those threatened with extinction