The cell motility modulator Slit2 is a potent inhibitor of platelet function.

Vascular injury and atherothrombosis involve vessel infiltration by inflammatory leukocytes, migration of medial vascular smooth muscle cells to the intimal layer, and ultimately acute thrombosis. A strategy to simultaneously target these pathological processes has yet to be identified. The secreted protein, Slit2, and its transmembrane receptor, Robo-1, repel neuronal migration in the developing central nervous system. More recently, it has been appreciated that Slit2 impairs chemotaxis of leukocytes and vascular smooth muscle cells toward diverse inflammatory attractants. The effects of Slit2 on platelet function and thrombus formation have never been explored. We detected Robo-1 expression in human and murine platelets and megakaryocytes and confirmed its presence via immunofluorescence microscopy and flow cytometry. In both static and shear microfluidic assays, Slit2 impaired platelet adhesion and spreading on diverse extracellular matrix substrates by suppressing activation of Akt. Slit2 also prevented platelet activation on exposure to ADP. In in vivo studies, Slit2 prolonged bleeding times in murine tail bleeding assays. Using intravital microscopy, we found that after mesenteric arteriolar and carotid artery injury, Slit2 delayed vessel occlusion time and prevented the stable formation of occlusive arteriolar thrombi. These data demonstrate that Slit2 is a powerful negative regulator of platelet function and thrombus formation. The ability to simultaneously block multiple events in vascular injury may allow Slit2 to effectively prevent and treat thrombotic disorders such as myocardial infarction and stroke

SLIT/ROBO Signaling in Monocyte Chemotaxis and Function: A Role in Vascular Inflammation

Vascular inflammation and associated leukocyte influx is a hallmark in the pathogenesis of atherosclerosis. In both animal models and human subjects, inhibiting monocyte recruitment is beneficial in preventing atherosclerosis and its clinical manifestations. The trafficking signals that recruit cells to areas of inflammation are provided by small secreted proteins called chemokines. Chemokines play a major role in the pathogenesis of inflammation, and redundancy among the chemokine signaling pathways means that blocking one pathway could result in another assuming its function. Therefore, we aim to block a cell’s response to a range of chemokine-induced directional migration signals. Slit2 treatment inhibits monocyte migration in vitro using transwell migration assays, and in vivo, using a murine peritonitis model of inflammatory cell influx. This inhibition is shown to be dose- and time- dependent. Furthermore, Slit2 inhibits monocyte adhesion to activated endothelial cell monolayers. These data may suggest a therapeutic role for Slit2 in atherosclerosis.MAS

Clinical and immunological characteristic and immuno-modulating therapy of brucellosis

Available from VNTIC / VNTIC - Scientific & Technical Information Centre of RussiaSIGLERURussian Federatio

Slit2/Robo-1 Signaling in Monocyte and Macrophage Function: A Role in Vascular Inflammation

Atherosclerosis is a maladaptive inflammatory response initiated by the retention of cholesterol-rich low-density lipoproteins. These are rendered pro-inflammatory upon oxidation, leading to activation of endothelial cells and recruitment of monocyte-derived macrophages. While the clearance of oxidized low-density lipoprotein (oxLDL) by macrophages is initially beneficial, excessive accumulation results in cholesterol-laden foam cells that drive disease progression. The uptake of oxLDL is largely mediated by the scavenger receptor CD36 and requires dynamic actin reorganization driven by Rac GTPases. The Slit family of secreted proteins, together with their transmembrane receptor Robo, inhibit the migration of a variety of cell types, in part by inactivating Rac and blocking dynamic actin rearrangement. We show that Slit2 inhibited adhesion of monocytic cells to activated human endothelial cells, and to immobilized ICAM-1 and VCAM-1. Microfluidic live cell imaging showed that Slit2 inhibited the ability of monocytes tethered to endothelial cells to stabilize their actin-associated anchors and to resist detachment in response to increasing shear forces. Transfection of plasmids encoding constitutively-active Rac1 revealed that Slit2 inhibited post-adhesion stabilization of monocytes on endothelial cells by preventing activation of Rac1. Slit2 also inhibited chemotaxis of monocytes towards the chemokines, CXCL12 and CCL2, and administration of Slit2 to atherosclerosis-prone LDL receptor-deficient mice inhibited monocyte recruitment to nascent atherosclerotic lesions. The role of Slit2 in foam cell formation was investigated using a neutral lipid probe, BODIPY 497/503, and quantified by immunofluorescence microscopy and flow cytometry, revealing a decrease in cholesterol ester accumulation in Slit2 treated cells. The binding and uptake of oxLDL was investigated using fluorescently (DiI)-labeled oxLDL, and quantified by microscopy and flow cytometry. Slit2 decreased oxLDL-mediated foam cell formation in human and murine macrophages, by blocking Rac-dependent uptake of oxLDL by CD36. Thus, Slit2 may represent a powerful new tool to inhibit pathologic monocyte recruitment in vascular inflammation, and block foam cell formation in progressive atherosclerosis.Ph.D.2018-07-08 00:00:0

Topical AHA in Dermatology: Formulations, Mechanisms of Action, Efficacy, and Future Perspectives

The utilization of topical formulations containing alpha hydroxy acids (AHAs) has garnered considerable attention. This review summarizes the effectiveness of the most common topical AHA formulations, including mechanisms of action and future research directions. AHAs have a dramatic impact on diverse skin conditions, enhancing texture and stimulating collagen synthesis. Uncertainties persist regarding optimal concentration, pH, and vehicle for maximum efficacy. Advancements in formulation technologies offer opportunities for AHA penetration and stability. Understanding mechanisms is vital for skincare optimization. The review covers AHAs, their concentrations, formulation considerations, safety measures, and future directions.Medicine, Faculty ofNon UBCDermatology and Skin Science, Department ofReviewedFacult

The Role of Human Herpesvirus 6 Infection in Alzheimer’s Disease Pathogenicity—A Theoretical Mosaic

Alzheimer’s disease (AD), a neurodegenerative disorder generally affecting older adults, is the most common form of dementia worldwide. The disease is marked by severe cognitive and psychiatric decline and has dramatic personal and social consequences. Considerable time and resources are dedicated to the pursuit of a better understanding of disease mechanisms; however, the ultimate goal of obtaining a viable treatment option remains elusive. Neurodegenerative disease as an outcome of gene–environment interaction is a notion widely accepted today; a clear understanding of how external factors are involved in disease pathogenesis is missing, however. In the case of AD, significant effort has been invested in the study of viral pathogens and their role in disease mechanisms. The current scoping review focuses on the purported role HHV-6 plays in AD pathogenesis. First, early studies demonstrating evidence of HHV-6 cantonment in either post-mortem AD brain specimens or in peripheral blood samples of living AD patients are reviewed. Next, selected examples of possible mechanisms whereby viral infection can directly or indirectly contribute to AD pathogenesis are presented, such as autophagy dysregulation, the interaction between miR155 and HHV-6, and amyloid-beta as an antimicrobial peptide. Finally, closely related topics such as HHV-6 penetration in the CNS, HHV-6 involvement in neuroinflammation, and a brief discussion on HHV-6 epigenetics are examined.Medicine, Faculty ofNon UBCDermatology and Skin Science, Department ofReviewedFacultyResearche

Transmission of Onychomycosis and Dermatophytosis between Household Members: A Scoping Review

Onychomycosis is a common fungal infection of the nail, caused by dermatophytes, non-dermatophytes, and yeasts. Predisposing factors include older age, trauma, diabetes, immunosuppression, and previous history of nail psoriasis or tinea pedis. Though many biological risk factors have been well characterized, the role of the environment has been less clear. Studies have found evidence of transmission in 44% to 47% of households with at least one affected individual, but the underlying mechanisms and risk factors for transmission of onychomycosis between household members are incompletely understood. A scoping literature review was performed to characterize and summarize environmental risk factors involved in the transmission of onychomycosis within households. A total of 90 papers met the inclusion criteria, and extracted data was analyzed in an iterative manner. Shared household surfaces may harbor dermatophytes and provide sources for infection. Shared household equipment, including footwear, bedding, and nail tools, may transmit dermatophytes. The persistence of dermatophytes on household cleaning supplies, linen, and pets may serve as lasting sources of infection. Based on these findings, we provide recommendations that aim to interrupt household transmission of onychomycosis. Further investigation of the specific mechanisms behind household spread is needed to break the cycle of transmission, reducing the physical and social impacts of onychomycosis.Medicine, Faculty ofAlumniNon UBCDermatology and Skin Science, Department ofMedicine, Department ofReviewedFacultyOthe

AGING OF FRESH AND USED CA-SR-CUPRATE-BASED CATALYSTS

An ageing degeneration process was observed in a Ca-Sr-cuprate catalyst, both unused and after use in an NO decomposition reaction. The formation of strongly interacting dipoles (SIDs) by Cu2+ and oxygen ions perturbs the layerlike structure, which is typical of Sr3Cu5O8 species and is also characteristic of the present catalyst when it is fresh. This phenomenon was observed with both unused and used aged samples. Furthermore, in the case of the used catalysts, the degeneration process lead to the disappearance of both the layerlike crystal structure and of the SID systems. However, the samples recover their properties when recalcined

Structural effects of interaction between lanthanum cuprate and cerium dioxide

In the present work the structural effects of La2CuO4 doping with CeO2, or of supporting the former on the latter, have been investigated. It was found that lanthanum oxide possesses a very good solubility in cerium dioxide in the presence of copper oxide, forming a solid solution. According to our experimental data, at 1050 degrees C and in the presence of copper oxide (over 1.5% mass), the boundary for the existence of the Ce1-zLazO2-z/2-delta phase falls between z = 0.398 and z = 0.462. Copper oxide itself has a very low, but appreciable solubility in this system. The excess of CuO strongly increases the rate of formation of the solid oxides solution, due to its relatively low melting point