Dengue is a highly endemic infectious disease of the tropical countries and is rapidly becoming a global burden. It is caused by any of the 4 serotypes of dengue virus and is transmitted within humans through female Aedes mosquitoes. Dengue disease varies from mild fever to severe conditions of dengue hemorrhagic fever and shock syndrome. Globalization, increased air travel, and unplanned urbanization have led to increase in the rate of infection and helped dengue to expand its geographic and demographic distribution. Dengue vaccine development has been a challenging task due to the existence of four antigenically distinct dengue virus serotypes, each capable of eliciting cross-reactive and disease-enhancing antibody response against the remaining three serotypes. Recently, Sanofi Pasteur's chimeric live-attenuated dengue vaccine candidate has been approved in Mexico, Brazil, and Philippines for usage in adults between 9 and 45 years of age. The impact of its limited application to the public health system needs to be evaluated. Simultaneously, the restricted application of this vaccine candidate warrants continued efforts in developing a dengue vaccine candidate which is additionally efficacious for infants and naïve individuals. In this context, alternative strategies of developing a designed vaccine candidate which does not allow production of enhancing antibodies should be explored, as it may expand the umbrella of efficacy to include infants and naïve individuals.

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Objective Von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes, is known to worsen stroke outcome. In vitro studies suggest that platelet-derived VWF is biochemically different from the endothelial cell-derived VWF. However, little is known about relative contribution of different pools of VWF in stroke. Approach and Results Using bone marrow transplantation, we generated chimeric platelet derived-VWF mice (Plt-VWF), platelet derived-VWF mice that lack ADAMTS13 in platelets and plasma (Plt-VWF/Adamts13−/−), and endothelial cell derived-VWF mice (EC-VWF) to determine relative contribution of different pools of VWF in stroke. In brain ischemia/reperfusion injury model, we found that infarct size, post-ischemic intracerebral thrombo-inflammation (fibrin(ogen) deposition, neutrophil infiltration, IL-1β and TNF-α levels) within lesions were comparable between EC-VWF and WT mice. Infarct size and post-ischemic thrombo-inflammation were comparable between Plt-VWF and Plt-VWF/Adamts13−/− mice, but decreased compared to EC-VWF and/or WT mice (P<0.05) and increased compared to Vwf −/− mice (P<0.05). Susceptibility to FeCl3 injury-induced carotid artery thrombosis was comparable between WT and EC-VWF mice, whereas Plt-VWF and Plt-VWF/Adamts13−/− mice exhibited defective thrombosis. Although most of the injured vessels did not occlude, slope over time showed that thrombus growth rate was increased in both Plt-VWF and Plt-VWF/Adamts13−/− mice compared to Vwf −/− mice (P<0.05), but decreased compared to WT or EC-VWF mice. Conclusions Platelet-derived VWF, either in presence or absence of ADAMTS13, partially contributes to VWF-dependent injury and post-ischemic thrombo-inflammation following stroke. Endothelial cell-derived VWF is the major determinant that mediates VWF-dependent ischemic stroke by promoting post-ischemic thrombo-inflammation.

Background: Dengue has emerged as the most significant of arboviral diseases in the 21st century. It is endemic to >100 tropical and sub-tropical countries around the world placing an estimated 3.6 billion people at risk. It is caused by four genetically similar but antigenically distinct, serotypes of dengue viruses. There is neither a vaccine to prevent nor a drug to treat dengue infections, at the present time. The major objective of this work was to explore the possibility of identifying a small molecule inhibitor of the dengue virus protease and assessing its ability to suppress viral replication in cultured cells. Methods: We cloned, expressed and purified recombinant dengue virus type 2 protease. Using an optimized and validated fluorogenic peptide substrate cleavage assay to monitor the activity of this cloned dengue protease we randomly screened~1000 small molecules from an 'in-house' library to identify potential dengue protease inhibitors.

BackgroundHemiparesis after stroke often leads to impaired ankle motor control that impacts gait function. In recent studies, robotic devices have been developed to address this impairment. While capable of imparting forces to assist during training and gait, these devices add mass to the paretic leg which might encumber patients' gait pattern. The purpose of this study was to assess the effects of the added mass of one of these robots, the MIT's Anklebot, while unpowered, on gait of chronic stroke survivors during overground and treadmill walking.MethodsNine chronic stroke survivors walked overground and on a treadmill with and without the anklebot mounted on the paretic leg. Gait parameters, interlimb symmetry, and joint kinematics were collected for the four conditions. Repeated-measures analysis of variance (ANOVA) tests were conducted to examine for possible differences across four conditions for the paretic and nonparetic leg.ResultsThe added inertia and friction of the unpowered anklebot had no statistically significant effect on spatio-temporal parameters of gait, including paretic and nonparetic step time and stance percentage, in both overground and treadmill conditions. Noteworthy, interlimb symmetry as characterized by relative stance duration was greater on the treadmill than overground regardless of loading conditions. The presence of the unpowered robot loading reduced the nonparetic knee peak flexion on the treadmill and paretic peak dorsiflexion overground (p < 0.05).ConclusionsOur results suggest that for these subjects the added inertia and friction of this backdriveable robot did not significantly alter their gait pattern.