Phthalazinone inhibitors of inosine-5?-monophosphate dehydrogenase from Cryptosporidium parvum

Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5?-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure–activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented

Selective and potent urea inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase

Cryptosporidium parvum and related species are zoonotic intracellular parasites of the intestine. Cryptosporidium is a leading cause of diarrhea in small children around the world. Infection can cause severe pathology in children and immunocompromised patients. This waterborne parasite is resistant to common methods of water treatment and therefore a prominent threat to drinking and recreation water even in countries with strong water safety systems. The drugs currently used to combat these organisms are ineffective. Genomic analysis revealed that the parasite relies solely on inosine-5?-monophosphate dehydrogenase (IMPDH) for the biosynthesis of guanine nucleotides. Herein, we report a selective urea-based inhibitor of C. parvum IMPDH (CpIMPDH) identified by high-throughput screening. We performed a SAR study of these inhibitors with some analogues exhibiting high potency (IC50 1000-fold versus human IMPDH type 2 and good stability in mouse liver microsomes. A subset of inhibitors also displayed potent antiparasitic activity in a Toxoplasma gondii model

Forced Symmetry Breaking from SO(3) to SO(2) for Rotating Waves on the Sphere

We consider a small SO(2)-equivariant perturbation of a reaction-diffusion system on the sphere, which is equivariant with respect to the group SO(3) of all rigid rotations. We consider a normally hyperbolic SO(3)-group orbit of a rotating wave on the sphere that persists to a normally hyperbolic SO(2)-invariant manifold $M(\epsilon)$. We investigate the effects of this forced symmetry breaking by studying the perturbed dynamics induced on $M(\epsilon)$ by the above reaction-diffusion system. We prove that depending on the frequency vectors of the rotating waves that form the relative equilibrium SO(3)u_{0}, these rotating waves will give SO(2)-orbits of rotating waves or SO(2)-orbits of modulated rotating waves (if some transversality conditions hold). The orbital stability of these solutions is established as well. Our main tools are the orbit space reduction, Poincare map and implicit function theorem

Plasma microRNAs are Associated with Atrial Fibrillation (the miRhythm Study) and Change After Catheter-ablation

Background: Atrial fibrillation (AF) is the most common dysrhythmia in the U.S. and Europe. Few biomarkers exist to identify individuals at risk for AF. Cardiac microRNAs (miRNAs) have been implicated in susceptibility to AF and are detectable in the circulation. Nevertheless, data are limited on how circulating levels of miRNAs relate to AF or change over time after catheter- ablation. Methods: In 211 miRhythm participants (112 with paroxysmal or persistent AF; 99 without AF), we quantified plasma expression of 86 miRNAs associated with cardiac remodeling or disease by high-throughput quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We used qRT-PCR to examine change in plasma miRNA expression from baseline to 1-month after ablation in 47 participants. We also quantified expression of the 20 most variable miRNAs in atrial tissue in 31 participants undergoing cardiac surgery. Results: The mean age of the miRhythm cohort was 59 years and 58% of participants were men. 21 miRNAs differed significantly between participants with AF and those with no AF in regression models adjusting for known AF risk factors (p value of ≤ 0.0006). Several miRNAs associated with AF, including miR-21, miR-29a, miR-122, miR-150, miR-320, and miR-92a, regulate expression of genes implicated in the pathogenesis of AF. Levels of 33 miRNAs, including 14 associated with AF, changed significantly between baseline and 1-month after catheter ablation (p value of ≤ 0.0006). Although all AF-related plasma miRNAs were expressed in atrial tissue, only miR-21 and miR-411 differed significantly with respect to preoperative AF status. Conclusions: Plasma levels of miRNAs associated with heart disease and cardiac remodeling were related to AF and changed after catheter-ablation. Our study suggests that AF has a unique circulating miRNA profile and that this profile is influenced by catheter-ablation

EO-ALERT: A Novel Architecture for the Next Generation of Earth Observation Satellites Supporting Rapid Civil Alerts

The EO-ALERT project proposes the definition and development of the next-generation Earth Observation (EO) data processing chain, based on a novel flight segment architecture that moves opti-mised key EO data processing elements from the ground segment to on-board the satellite, with the aim of delivering EO products to the end user with very low latency. EO-ALERT achieves, globally, latencies below five minutes for EO products delivery, and below 1 minute in some scenarios. The proposed archi-tecture combines innovations in the on-board elements of the data chain and the communications, namely: on-board reconfigurable data handling, on-board image generation and processing for the generation of alerts (EO products) using Artificial Intelligence (AI), on-board AI-based data compression and encryption, high-speed on-board avionics, and reconfigurable high data rate communication links to ground, including a separate chain for alerts with minimum latency and global coverage. This paper pre-sents the proposed architecture, its performance and hardware, considering two different user scenarios: ship detection and extreme weather nowcasting. The results show that, when implemented using COTS components and available communication links, the proposed architecture can deliver alerts to ground with latency below five minutes, for both SAR and Optical missions, demonstrating the viability of the EO-ALERT concept

A Novel Satellite Architecture for the Next Generation of Earth Observation Satellites Supporting Rapid Alerts

The EO-ALERT European Commission H2020 project proposes the definition, development, and verification and validation through ground hardware testing, of a next-generation Earth Observation (EO) data processing chain. The proposed data processing chain is based on a novel flight segment architecture that moves EO data processing elements traditionally executed in the ground segment to on-board the satellite, with the aim of delivering EO products to the end user with very low latency. EO-ALERT achieves, globally, latencies below five minutes for EO products delivery, and below one minute in realistic scenarios. The proposed EO-ALERT architecture is enabled by on-board processing, recent improvements in processing hardware using Commercial Off-The-Shelf (COTS) components, and persistent space-to-ground communications links. EO-ALERT combines innovations in the on-board elements of the data chain and the communications, namely: on-board reconfigurable data handling, on-board image generation and processing for the generation of alerts (EO products) using Machine Learning (ML) and Artificial Intelligence (AI), on-board AI-based data compression and encryption, high-speed on-board avionics, and reconfigurable high data rate communication links to ground, including a separate chain for alerts with minimum latency and global coverage. This paper presents the proposed architecture, its hardware realization for the ground testing in a representative environment and its performance. The architecture’s performance is evaluated considering two different user scenarios where very low latency (almost-real-time) EO product delivery is required: ship detection and extreme weather monitoring/nowcasting. The hardware testing results show that, when implemented using COTS components and available communication links, the proposed architecture can deliver alerts to the end user with a latency below five minutes, for both SAR and Optical missions, demonstrating the viability of the EO-ALERT architecture. In particular, in several test scenarios, for both the TerraSAR-X SAR and DEIMOS-2 Optical Very High Resolution (VHR) missions, hardware testing of the proposed architecture has shown it can deliver EO products and alerts to the end user globally, with latency lower than one-point-five minutes

Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements

Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely

A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship

The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface.This work was partially supported by the Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, Ministerio de Ciencia e Innovacion of Spain (TEC2008-02090), by the Plan Avanza (Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion), Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), by the Programa Prometeo 2012 of the Generalitat Valenciana and by the Programa de Apoyo a la Investigacion y Desarrollo de la Universitat Politecnica de Valencia (PAID-06-11-2002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Tobón Zuluaga, C.; Ruiz Villa, CA.; Heidenreich, E.; Romero Pérez, L.; Hornero, F.; Saiz Rodríguez, FJ. (2013). A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship. PLoS ONE. 8(2):1-13. https://doi.org/10.1371/journal.pone.0050883S11382Ho SY, Sanchez-Quintana D, Anderson RH (1998) Can anatomy define electric pathways? In: International Workshop on Computer Simulation and Experimental Assessment of Electrical Cardiac Function, Lausanne, Switzerland. 77–86.Tobón C (2009) Evaluación de factores que provocan fibrilación auricular y de su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Master Thesis Universitat Politècnica de València.Ruiz C (2010) Estudio de la vulnerabilidad a reentradas a través de modelos matemáticos y simulación de la aurícula humana. Doctoral Thesis Universitat Politècnica de València.Tobón C (2010) Modelización y evaluación de factores que favorecen las arritmias auriculares y su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Doctoral Thesis Universitat Politècnica de València.Henriquez, C. S., & Papazoglou, A. A. (1996). Using computer models to understand the roles of tissue structure and membrane dynamics in arrhythmogenesis. Proceedings of the IEEE, 84(3), 334-354. doi:10.1109/5.486738Grimm, R. A., Chandra, S., Klein, A. L., Stewart, W. J., Black, I. W., Kidwell, G. A., & Thomas, J. D. (1996). Characterization of left atrial appendage Doppler flow in atrial fibrillation and flutter by Fourier analysis. American Heart Journal, 132(2), 286-296. doi:10.1016/s0002-8703(96)90424-xMaleckar, M. M., Greenstein, J. L., Giles, W. R., & Trayanova, N. A. (2009). K+ current changes account for the rate dependence of the action potential in the human atrial myocyte. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1398-H1410. doi:10.1152/ajpheart.00411.200

Mapping human genetic diversity in Asia

Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations