CK2b regulates thrombopoiesis and Ca21-Triggered platelet activation in arterial thrombosis

© 2017 by The American Society of Hematology. Platelets, anucleated megakaryocyte (MK)-derived cells, play a major role in hemostasis and arterial thrombosis. Although protein kinase casein kinase 2 (CK2) is readily detected in MKs and platelets, the impact of CK2-dependent signaling on MK/platelet (patho-) physiology has remained elusive. The present study explored the impact of the CK2 regulatory b-subunit on platelet biogenesis and activation. MK/platelet-specific genetic deletion of CK2β (ck2β-/-) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with an enhanced proportion of premature platelets. Although platelet life span was only mildly affected, ck2β-/- MK displayed an abnormal microtubule structure with a drastically increased fragmentation within bone marrow and a significantly reduced proplatelet formation in vivo. In ck2β-/- platelets, tubulin polymerization was disrupted, resulting in an impaired thrombopoiesis and an abrogated inositol 1,4,5-Triphosphate receptor-dependent intracellular calcium (Ca21) release. Presumably due to a blunted increase in the concentration of cytosolic Ca21, activation-dependent increases of a and dense-granule secretion and integrin aIIbb3 activation, and aggregation were abrogated in ck2β-/- platelets. Accordingly, thrombus formation and stabilization under high arterial shear rates were significantly diminished, and thrombotic vascular occlusion in vivo wassignificantly blunted in ck2β-/- mice, accompanied by a slight prolongation of bleeding time. Following transient middle cerebral artery occlusion, ck2b-/- mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits, and showed significantly better outcomes after ischemic stroke than ck2βfl/fl mice. The present observations reveal CK2b as a novel powerful regulator of thrombopoiesis, Ca2+-dependent platelet activation, and arterial thrombosis in vivo

Too Hot to Handle: An Evaluation of the Effect of Thermal Visual Representation on User Grasping Interaction in Virtual Reality

Influence of interaction fidelity and rendering quality on perceived user experience have been largely explored in Virtual Reality (VR). However, differences in interaction choices triggered by these rendering cues have not yet been explored. We present a study analysing the effect of thermal visual cues and contextual information on 50 participants' approach to grasp and move a virtual mug. This study comprises 3 different temperature cues (baseline empty, hot and cold) and 4 contextual representations; all embedded in a VR scenario. We evaluate 2 different hand representations (abstract and human) to assess grasp metrics. Results show temperature cues influenced grasp location, with the mug handle being predominantly grasped with a smaller grasp aperture for the hot condition, while the body and top were preferred for baseline and cold conditions

Aberrant Receptor-Mediated Endocytosis of Schistosoma mansoni Glycoproteins on Host Lipoproteins

BACKGROUND: Bilharzia is one of the major parasitic infections affecting the public health and socioeconomic circumstances in (sub) tropical areas. Its causative agents are schistosomes. Since these worms remain in their host for decades, they have developed mechanisms to evade or resist the immune system. Like several other parasites, their surface membranes are coated with a protective layer of glycoproteins that are anchored by a lipid modification. METHODS AND FINDINGS: We studied the release of glycosyl-phosphatidylinositol (GPI)-anchored proteins of S. mansoni and found them in the circulation associated with host lipoprotein particles. Host cells endocytosed schistosomal GPI-anchored proteins via their lipoprotein receptor pathway, resulting in disturbed lysosome morphology. In patients suffering from chronic schistosomiasis, antibodies attacked the parasite GPI-anchored glycoproteins that were associated with the patients' own lipoprotein particles. These immunocomplexes were endocytosed by cells carrying an immunoglobulin-Fc receptor, leading to clearance of lipoproteins by the immune system. As a consequence, neutral lipids accumulated in neutrophils of infected hamsters and in human neutrophils incubated with patient serum, and this accumulation was associated with apoptosis and reduced neutrophil viability. Also, Trypanosoma brucei, the parasite that causes sleeping sickness, released its major GPI-anchored glycoprotein VSG221 on lipoprotein particles, demonstrating that this process is generalizable to other pathogens/parasites. CONCLUSIONS: Transfer of parasite antigens to host cells via host lipoproteins disrupts lipid homeostasis in immune cells, promotes neutrophil apoptosis, may result in aberrant antigen presentation in host cells, and thus cause an inefficient immune response against the pathogen

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

with a Virtual Control Panel

We present a haptic feedback technique that combines feedback from a portable force-feedback glove with feedback from direct contact with rigid passive objects. This approach is a haptic analogue of visual mixed reality, since it can be used to haptically combine real and virtual elements in a single display. We discuss device limitations that motivated this combined approach and summarize technological challenges encountered. We present three experiments to evaluate the approach for interactions with buttons and sliders on a virtual control panel. In our first experiment, this approach resulted in better task performance and better subjective ratings than the use of only a force-feedback glove. In our second experiment, visual feedback was degraded and the combined approach resulted in better performance than the glove-only approach and in better ratings of slider interactions than both glove-only and passive-only approaches. A third experiment allowed subjective comparison of approaches and provided additional evidence that the combined approach provides the best experience.

Overview and Assessment of Unity Toolkits for Rapid Development of an Educational VR Application

As the interest in Virtual Reality (VR) increases, so does the number of software toolkits available for various&nbsp;VR applications. Given that more games are being made with the Unity game engine than any other game&nbsp;technology, several of these toolkits are developed to be directly imported into Unity. A feature and interaction&nbsp;comparison of the toolkits is needed by Unity developers to properly suit one for a specific application. This&nbsp;paper presents an overview and comparison of several virtual reality toolkits available for developers using the Unity game engine. getReal3D, MiddleVR, and Reality-based User Interface System (RUIS) are analysed for VR&nbsp;interaction and display on multi-projection immersive environments like Cave Automatic Virtual Environments&nbsp;(CAVE)s. MiddleVR was found to have the highest performance and most versatile toolkit for CAVE display and&nbsp;interaction. However, taking cost into account, RUIS is the clear winner as it is available for free under the&nbsp;Lesser General Public License (LGPL) Version 3 license