Granzyme B Cleaves Decorin, Biglycan and Soluble Betaglycan, Releasing Active Transforming Growth Factor-β1

Objective: Granzyme B (GrB) is a pro-apoptotic serine protease that contributes to immune-mediated target cell apoptosis. However, during inflammation, GrB accumulates in the extracellular space, retains its activity, and is capable of cleaving extracellular matrix (ECM) proteins. Recent studies have implicated a pathogenic extracellular role for GrB in cardiovascular disease, yet the pathophysiological consequences of extracellular GrB activity remain largely unknown. The objective of this study was to identify proteoglycan (PG) substrates of GrB and examine the ability of GrB to release PG-sequestered TGF-b1 into the extracellular milieu. Methods/Results: Three extracellular GrB PG substrates were identified; decorin, biglycan and betaglycan. As all of these PGs sequester active TGF-b1, cytokine release assays were conducted to establish if GrB-mediated PG cleavage induced TGF-b1 release. Our data confirmed that GrB liberated TGF-b1 from all three substrates as well as from endogenous ECM and this process was inhibited by the GrB inhibitor 3,4-dichloroisocoumarin. The released TGF-b1 retained its activity as indicated by the induction of SMAD-3 phosphorylation in human coronary artery smooth muscle cells. Conclusion: In addition to contributing to ECM degradation and the loss of tissue structural integrity in vivo, increase

Serpina3n attenuates granzyme B-mediated decorin cleavage and rupture in a murine model of aortic aneurysm

Granzyme B (GZMB) is a proapoptotic serine protease that is released by cytotoxic lymphocytes. However, GZMB can also be produced by other cell types and is capable of cleaving extracellular matrix (ECM) proteins. GZMB contributes to abdominal aortic aneurysm (AAA) through an extracellular, perforin-independent mechanism involving ECM cleavage. The murine serine protease inhibitor, Serpina3n (SA3N), is an extracellular inhibitor of GZMB. In the present study, administration of SA3N was assessed using a mouse Angiotensin II-induced AAA model. Mice were injected with SA3N (0–120 μg/kg) before pump implantation. A significant dose-dependent reduction in the frequency of aortic rupture and death was observed in mice that received SA3N treatment compared with controls. Reduced degradation of the proteoglycan decorin was observed while collagen density was increased in the aortas of mice receiving SA3N treatment compared with controls. In vitro studies confirmed that decorin, which regulates collagen spacing and fibrillogenesis, is cleaved by GZMB and that its cleavage can be prevented by SA3N. In conclusion, SA3N inhibits GZMB-mediated decorin degradation leading to enhanced collagen remodelling and reinforcement of the adventitia, thereby reducing the overall rate of rupture and death in a mouse model of AAA

Thresholds for adding degraded tropical forest to the conservation estate

Logged and disturbed forests are often viewed as degraded and depauperate environments compared with primary forest. However, they are dynamic ecosystems1 that provide refugia for large amounts of biodiversity2,3, so we cannot afford to underestimate their conservation value4. Here we present empirically defined thresholds for categorizing the conservation value of logged forests, using one of the most comprehensive assessments of taxon responses to habitat degradation in any tropical forest environment. We analysed the impact of logging intensity on the individual occurrence patterns of 1,681 taxa belonging to 86 taxonomic orders and 126 functional groups in Sabah, Malaysia. Our results demonstrate the existence of two conservation-relevant thresholds. First, lightly logged forests (68%) of their biomass removed, and these are likely to require more expensive measures to recover their biodiversity value. Overall, our data confirm that primary forests are irreplaceable5, but they also reinforce the message that logged forests retain considerable conservation value that should not be overlooked

Drag resistance of ship hulls: effects of surface roughness of newly applied fouling control coatings, coating water absorption, and welding seams

Fouling control coatings (FCCs) and irregularities (e.g. welding seams) on ship hull surfaces have significant effects on the overall drag performance of ships. In this work, skin frictions of four newly applied FCCs were compared using a pilot-scale rotary setup. Particular attention was given to the effects of coating water absorption on skin friction. Furthermore, to investigate the effects of welding seam height and density (number of welding seams per five meters of ship side) on drag resistance, a new flexible rotor was designed and used for experimentation.It was found, under the conditions selected, that a so-called fouling release (FR) coating caused approximately 5.6 % less skin friction (torque) over time than traditional biocide-based antifouling (AF) coatings at a tangential speed of 12 knots. Furthermore, results of immersion experiments and supporting “standard” water absorption experiments showed that water absorption of the FR coating did not result in any significant impacts on skin friction. On the other hand, water absorption was found to actually lower the skin friction of AF coatings. This may be attributed to a smoothening of the coating surface.The effects of welding seam height and density on drag resistance were found to be substantial when welding seam height is above 5 mm, especially at high tangential speeds (above 15 knots). Using an interpolation approach, the pilot-scale welding seam drag data could be used to estimate the drag resistance at approximated full-scale conditions, equivalent to about one welding seam per five meters of ship side. It was shown, in this case, that the contribution of welding seams to ship skin friction could very well be less significant than those of FCCs when the welding seam height is below 5 mm, a representative value for full-scale welding seam height

Luxation injuries in primary teeth: a retrospective study in children assisted at an emergency service

The purpose of this study was to analyze luxation injuries in children between the ages of 0 and 5 years treated at an emergency service department. A total of 1,703 records, corresponding to a period of 10 years at the Emergency Center of the Baby Clinic at Londrina State University, Brazil, were analyzed. The age, gender, etiologic factors, type of injury, injured teeth, treatment and time interval between injury and treatment were determined for each patient. Of the examined records, 409 patients met the study criteria and included a total of 679 injured teeth. Statistical analyses were carried out using the chi-square test with the level of significance set at 5%. Trauma incidence was higher in boys (57.0%) and in children less than two years of age (40.3%). Falling while walking or running was the most predominant etiologic factor (37.7%), and the most prevalent type of injury was subluxation (32.6%). Luxation injuries decreased with increasing age (p = 0.045). Treatment usually occurred within the first 1-15 days and was significantly associated with the type of trauma (p = 0.041). "Monitor only" was the treatment most frequently observed (74.0%). In conclusion, more luxation injuries were found in younger children, predominantly in boys. Falls resulting from walking or running were the etiologic factor most observed, with subluxation as the most common type of trauma. Treatment usually occurred within the first 15 days after the injury. Despite the severity of these injuries, "monitor only" was the eligible treatment