Crystalline

Crystalline is a fast action arena shooter with a focus on gunplay. The core objective of this project was to create a fun multiplayer First Person Shooter. To achieve this goal as a team we had to best leverage the tools and technology available to us. As First Person Shooter games typically have teams far larger than our own, we had to work hard and smart on Crystalline. Unreal Engine 4 was used in lieu of Unity or an in-house engine, saving hours of development time and allowing us to focus on gameplay and assets more. Thanks to Unreal Engine 4, we were able to produce a game that, based on playtesting, appears to meet our core objective. Due to the limited time available for the project, there are still far more designed features to be implemented. However, the core gameplay has been completed leaving opportunity for expansion and future work. This document is divided into nine chapters and an appendix. Chapter 1 will introduce readers to the core concepts of Crystalline. Market analysis and background research are covered in Chapters 2 and 3 respectively. The prototypes and general process that took Crystalline from concept to game are outlined in Chapter 4. Chapters 5 and 6 outline the core design of the final iteration of Crystalline, technical or otherwise. Chapter 7 describes overall visual designs of the game, both 2D and 3D. Playtesting data is reported and assessed in Chapter 8, and a post mortem is detailed in Chapter 9. This document concludes with an appendix containing an asset bible

Circumnuclear Gas in Seyfert 1 Galaxies: Morphology, Kinematics, and Direct Measurement of Black Hole Masses

(Abridged) The two-dimensional distribution and kinematics of the molecular, ionized, and highly ionized gas in the nuclear regions of Seyfert 1 galaxies have been measured using high spatial resolution (~0''.09) near-infrared spectroscopy from NIRSPEC with adaptive optics on the Keck telescope. Molecular hydrogen, H2, is detected in all nine Seyfert 1 galaxies and, in the majority of galaxies, has a spatially resolved flux distribution. In contrast, the narrow component of the BrG emission has a distribution consistent with that of the K-band continuum. In general, the kinematics of H2 are consistent with thin disk rotation, with a velocity gradient of over 100 km/s measured across the central 0''.5 in three galaxies, and across the central 1''.5 in two galaxies. The kinematics of BrG are in agreement with the H2 rotation, except in all four cases the central 0''.5 is either blue- or redshifted by more than 75 km/s. The highly ionized gas, measured with the [Ca VIII] and [Si VII] coronal lines, is spatially and kinematically consistent with BrG in the central 0''.5. Dynamical models have been fitted to the two-dimensional H2 kinematics, taking into account the stellar mass distribution, the emission line flux distribution, and the point spread function. For NGC 3227 the modeling indicates a black hole mass of Mbh = 2.0{+1.0/-0.4} x 10^7 Msun, and for NGC 4151 Mbh = 3.0{+0.75/-2.2} x 10^7 Msun. In NGC 7469 the best fit model gives Mbh < 5.0 x 10^7 Msun. In all three galaxies, modeling suggests a near face-on disk inclination angle, which is consistent with the unification theory of active galaxies. The direct black hole mass estimates verify that masses determined from the technique of reverberation mapping are accurate to within a factor of three with no additional systematic errors.Comment: 43 pages, including 47 figures; Accepted for publication in ApJ. All 2-D maps (in high resolution) are available at http://www.astro.ucla.edu/~ehicks . Minor changes to the text and updated reverberation mapped black hole mass estimates; the conclusions are unchange

Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation.

Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis. We used small molecule inhibitors of Trx (PMX 464 and PX-12) to determine whether Trx activity influences platelet function, as well as an unbiased proteomics approach to identify potential Trx substrates on the surface of platelets that might contribute to platelet reactivity and function. Using LC-MS/MS we found that PMX 464 and PX-12 affected the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation were affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. To experimentally validate these findings we assessed platelet function in the presence of PMX 464, PX-12, and rutin (a selective inhibitor of the related protein disulphide isomerase). In agreement with the proteomics data, small molecule inhibitors of thioredoxin selectively inhibited GPVI-mediated platelet activation, and attenuated ristocetin-induced GPIb-vWF-mediated platelet agglutination, thus validating the findings of the proteomics study. These data reveal a novel role for thioredoxin in regulating platelet reactivity via proteins required for early platelet responses at sites of vessel injury (GPVI and GPIb). This work also highlights a potential opportunity for repurposing of PMX 464 and PX-12 as antiplatelet agents.CM is funded by Medical Research Council Grant No G9826026. AR was funded by a British Heart Foundation Centre of Research Excellence-funded Vacation Studentship. CHC is funded by British Heart Foundation Fellowship FS/11/49/28751.This is the final version of the article. It first appeared from PLOS via https://doi.org/10.1371/journal.pone.016300

Protease-activated receptor 4 variant p.Tyr157Cys reduces platelet functional responses and alters receptor trafficking

OBJECTIVE—: Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect on platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms. APPROACH AND RESULTS—: We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cysteine substitution (Y157C) was predicted computationally to affect most on PAR4 structure. Y157C platelets from 3 cases showed reduced responses to PAR4-activating peptide and to α-thrombin compared with controls, but no reduction in responses to PAR1-activating peptide. Pretreatment with the PAR1 antagonist vorapaxar caused lower residual α-thrombin responses in Y157C platelets than in controls, indicating greater platelet inhibition. HEK293 cells transfected with a PAR4 Y157C expression construct had reduced PAR4 functional responses, unchanged total PAR4 expression but reduced surface expression. PAR4 Y157C was partially retained in the endoplasmic reticulum and displayed an expression pattern consistent with defective N-glycosylation. Mutagenesis of Y322, which is the putative hydrogen bond partner of Y157, also reduced PAR4 surface expression in HEK293 cells. CONCLUSIONS—: Reduced PAR4 responses associated with Y157C result from aberrant anterograde surface receptor trafficking, in part, because of disrupted intramolecular hydrogen bonding. Characterization of PAR4 Y157C establishes that rare F2RL3 variants have the potential to markedly alter platelet PAR4 reactivity particularly after exposure to therapeutic PAR1 antagonists

Platelet reactivity influences clot structure as assessed by fractal analysis of viscoelastic properties

<p>Despite the interwoven nature of platelet activation and the coagulation system in thrombosis, few studies relate both analysis of protein and cellular parts of coagulation in the same population. In the present study, we use matched ex vivo samples to determine the influences of standard antiplatelet therapies on platelet function and use advanced rheological analyses to assess clot formation. Healthy volunteers were recruited following fully informed consent then treated for 7 days with single antiplatelet therapy of aspirin (75 mg) or prasugrel (10 mg) or with dual antiplatelet therapy (DAPT) using aspirin (75 mg) plus prasugrel (10 mg) or aspirin (75 mg) plus ticagrelor (90 mg). Blood samples were taken at day 0 before treatment and at day 7 following treatment. We found that aspirin plus prasugrel or aspirin plus ticagrelor inhibited platelet responses to multiple agonists and reduced P-selectin expression. Significant platelet inhibition was coupled with a reduction in fractal dimension corresponding to reductions in mean relative mass both for aspirin plus prasugrel (−35 ± 16% change, p = 0.04) and for aspirin plus ticagrelor (−45 ± 14% change, p = 0.04). Aspirin alone had no effect upon measures of clot structure, whereas prasugrel reduced fractal dimension and mean relative mass. These data demonstrate that platelets are important determinants of clot structure as assessed by fractal dimension (d_<i>f</i>) and that effective platelet inhibition is associated with a weaker, more permeable fibrin network. This indicates a strong association between the therapeutic benefits of antiplatelet therapies and their abilities to reduce thrombus density that may be useful in individual patients to determine the functional relationship between platelet reactivity, eventual clot quality, and clinical outcome. d_<i>f</i> could represent a novel risk stratification biomarker useful in individualizing antiplatelet therapies.</p

A Linear Domain for Analyzing the Distribution of Numerical Values 1 by

Abstract. This paper explores the abstract domain of grids, a domain that is able to represent sets of equally spaced points and hyperplanes over an n-dimensional vector space. Such a domain is useful for the static analysis of the patterns of distribution of the values program variables can take. Besides the bare abstract domain, we present a complete set of operations on grids that includes all that is necessary to define the abstract semantics and the widening operators required to compute it in a finite number of steps. The definition of the domain and its operations exploit well-known techniques from linear algebra as well as a dual representation that allows, among other things, for a concise and efficient implementation.

Grids: A domain for analyzing the distribution of numerical values

This paper explores the abstract domain of grids, a domain that is able to represent sets of equally spaced points and hyperplanes over an n-dimensional vector space. Such a domain is useful for the static analysis of the patterns of distribution of the values program variables can take. We present the domain, its representation and the basic operations on grids necessary to define the abstract semantics. We show how the definition of the domain and its operations exploit well-known techniques from linear algebra as well as a dual representation that allows, among other things, for a concise and efficient implementation

Alternating magnetic fields drive stimulation of gene expression via generation of reactive oxygen species

Summary: Magnetogenetics represents a method for remote control of cellular function. Previous work suggests that generation of reactive oxygen species (ROS) initiates downstream signaling. Herein, a chemical biology approach was used to elucidate further the mechanism of radio frequency-alternating magnetic field (RF-AMF) stimulation of a TRPV1-ferritin magnetogenetics platform that leads to Ca2+ flux. RF-AMF stimulation of HEK293T cells expressing TRPV1-ferritin resulted in ∼30% and ∼140% increase in intra- and extracellular ROS levels, respectively. Mutations to specific cysteine residues in TRPV1 responsible for ROS sensitivity eliminated RF-AMF driven Ca2+-dependent transcription of secreted embryonic alkaline phosphatase (SEAP). Using a non-tethered (to TRPV1) ferritin also eliminated RF-AMF driven SEAP production, and using specific inhibitors, ROS-activated TRPV1 signaling involves protein kinase C, NADPH oxidase, and the endoplasmic reticulum. These results suggest ferritin-dependent ROS activation of TRPV1 plays a key role in the initiation of magnetogenetics, and provides relevance for potential applications in medicine and biotechnology