The Effects of an Inflammasome Inhibitor OLT1177 on the Development of Ischemic Heart Failure

Thesis Abstract THE EFFECTS OF AN INFLAMMASOME INHIBITOR OLT1177 ON THE DEVELOPMENT OF ISCHEMIC HEART FAILURE By Joseph S. Aliaga, BS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. Virginia Commonwealth University, 2020 Background: Evidence suggests that prolonged and enhanced pro-inflammatory signaling, modulated by the NLRP3 inflammasome, plays a crucial role in the pathophysiology of several different types of cardiovascular diseases such as acute myocardial infarction (AMI), adverse ventricular remodeling, and heart failure (HF). Consequently, we hypothesize that attenuating the enhanced inflammatory response using a pharmacological NLRP3 inflammasome inhibitor would decrease cell death, improve cardiac function, limit adverse cardiac remodeling, and overall reduce the risk of developing ischemic heart failure. We investigated the role of the NLRP3 inflammasome after a nonreperfused AMI, by studying the effects of inhibiting the NLRP3 inflammasome. Methods: In this study we used a mouse model of acute myocardial infarction (AMI) due to permanent coronary artery ligation. We assessed cardiac function in mice using transthoracic echocardiography 3 days after inducing a large nonreperfused AMI, via permanent ligation of the LAD coronary artery, and select mice with large nonreperfused anterior infarct (\u3e 4 akinetic segments involving the anterior wall) as well as an enlarged ventricle (left ventricular end-diastolic diameter [LVEDD] \u3e 4.4 mm) and systolic dysfunction (left ventricular ejection fraction [LVEF] \u3c 40%). The mice were then randomly assigned to one of four groups. Group 1 (n=8) consisted of mice with an AMI and were fed OLT1177, a NLRP3 inflammasome inhibitor admixed with the chow in the diet (3.75 gr/kg) for 10 weeks. Group 2 (n=7) consisted of mice with an AMI and were fed OLT1177, a NLRP3 inflammasome inhibitor admixed with the chow in the diet (7.5 gr/kg) for 10 weeks. Group 3 (n=7) consisted of mice with AMI that were fed a standard diet (without OLT1177) for 10 weeks. Group 4 (n=6) consisted of mice that underwent a sham operation and had no AMI and were fed a standard diet for 10 weeks. We repeated transthoracic echocardiography assessments 4-weeks and 10-weeks after coronary artery ligation surgery with an assessment of changes in LVEF, along with isoproterenol challenge in order to measure contractile reserve, a surrogate for cardiorespiratory fitness. The surviving mice underwent LV catheterization, a terminal procedure, in order to evaluate left ventricular diastolic function in vivo by measuring left ventricular end-diastolic pressure. Results: At the end of 10 weeks, 2 of 10 mice (20%) had died in OLT 3.75 gr/kg group, as compared with 2 of 9 (22%) in the OLT 7.50 gr/kg group, 3 of 10 mice (30%) in the control diet group, and 0 of 6 mice (0%) in the sham-operated group. Treatment with OLT 3.75 gr/kg or 7.50 gr/kg led to preservation of contractile reserve (percent increase in LVEF after isoproterenol challenge [+33±11% or +40±6% vs +9±7 % in standard diet; P Conclusions/implications: The results presented in this study show that NLRP3 inhibition with OLT1177 can preserve ß-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in large nonreperfused anterior AMI thereby reducing the risk of developing post-infarct heart failure. Keywords: Acute myocardial infarction, cardiac remodeling, heart failure, NLRP3 inflammasome, NLRP3 inflammasome inhibitor, OLT117

Paleontología y ambientes del Triásico Medio en el sector noroccidental de la cordillera ibérica (provs. de Soria y Guadalajara, España)

El Triásico Medio del sector noroccidental de la Cordillera Ibérica está compuesto por dos formaciones carbonáticas, que se corresponden con la unidad carbonática superior del Muschelkalk, y que hacia el NW pasan lateralmente a una formación terrígena. El registro fósil se encuentra en ambos tipos de formaciones. Tanto el estudio tafonómico como sedimentológico, permiten inferir la presencia de elementos acumulados que podrían corresponder a asociaciones autóctonas, compuestas en su mayoría por bivalvos infaunales de medios marinos someros y sometidos a fuerte influencia de terrígenos. Se caracterizan en la zona tres asociaciones faunísticas: 1. Asociación CostatoriaLyriomyophoria, que aparece tanto en la formación carbonática inferior como en la formación terrígena equivalente; 2. Asociación «Fauna de Terue!», que aparece en la formación carbonática superior, y 3. Asociación Lingula-Pseudocorbula, que aparece también en la formación carbonática superior, pero en niveles más altos. La «Fauna de Terue!» es característica de la Formación «Dolomías, Margas y Calizas de Royuela», y está bien representada en toda la Cordillera Ibérica. La presencia de la misma en nuestra zona constituye el registro más noroccidental de esta asociación en la misma. Por tanto, significa la penetración más occidental en la península de las faunas endémicas del «Dominio Sefardí» durante el Ladiniense.The Triassic of the NW Iberian Ranges consists of two carbonatic formations equivalent to the Upper Carbonatic Formation of the Muschelkalk Facies and pass laterally into siliciciastic deposits to the NW. Fossillocalities have been found in both formations. Taphonomic and sedimentologic studies allow for the interpretation as autochthonous associations of the infaunal Bivalves of shallow water marine environments with siliciciastic input. Three faunal associations have been distinguished: 1. Costatoria-Lyriomyophoria association, found in the lower carbonatic formation and the equivalent siliciciastic formation; 2. «Teruel Fauna» association, found in the upper carbonatic formation; 3. Lingula-Pseudocorbula association, found near the top of the upper carbonatic Formation. The «Teruel Fauna» is well represented in the Iberian Ranges, and always occur in the «Royuela Marls and Limestones» Formation, and our fossil localities are its most Northwestern record in the Iberian Ranges up to now, thus extending the presence of the endemic «Sephardic Faunas» during the [email protected]

An efficient GPU version of the preconditioned GMRES method

[EN] In a large number of scientific applications, the solution of sparse linear systems is the stage that concentrates most of the computational effort. This situation has motivated the study and development of several iterative solvers, among which preconditioned Krylov subspace methods occupy a place of privilege. In a previous effort, we developed a GPU-aware version of the GMRES method included in ILUPACK, a package of solvers distinguished by its inverse-based multilevel ILU preconditioner. In this work, we study the performance of our previous proposal and integrate several enhancements in order to mitigate its principal bottlenecks. The numerical evaluation shows that our novel proposal can reach important run-time reductions.Aliaga, JI.; Dufrechou, E.; Ezzatti, P.; Quintana-Orti, ES. (2019). An efficient GPU version of the preconditioned GMRES method. The Journal of Supercomputing. 75(3):1455-1469. https://doi.org/10.1007/s11227-018-2658-1S14551469753Aliaga JI, Badia RM, Barreda M, Bollhöfer M, Dufrechou E, Ezzatti P, Quintana-Ortí ES (2016) Exploiting task and data parallelism in ILUPACK’s preconditioned CG solver on NUMA architectures and many-core accelerators. Parallel Comput 54:97–107Aliaga JI, Bollhöfer M, Dufrechou E, Ezzatti P, Quintana-Ortí ES (2016) A data-parallel ILUPACK for sparse general and symmetric indefinite linear systems. In: Lecture Notes in Computer Science, 14th Int. Workshop on Algorithms, Models and Tools for Parallel Computing on Heterogeneous Platforms—HeteroPar’16. SpringerAliaga JI, Bollhöfer M, Martín AF, Quintana-Ortí ES (2011) Exploiting thread-level parallelism in the iterative solution of sparse linear systems. Parallel Comput 37(3):183–202Aliaga JI, Bollhöfer M, Martín AF, Quintana-Ortí ES (2012) Parallelization of multilevel ILU preconditioners on distributed-memory multiprocessors. Appl Parallel Sci Comput LNCS 7133:162–172Aliaga JI, Dufrechou E, Ezzatti P, Quintana-Ortí ES (2018) Accelerating a preconditioned GMRES method in massively parallel processors. In: CMMSE 2018: Proceedings of the 18th International Conference on Mathematical Methods in Science and Engineering (2018)Bollhöfer M, Grote MJ, Schenk O (2009) Algebraic multilevel preconditioner for the Helmholtz equation in heterogeneous media. SIAM J Sci Comput 31(5):3781–3805Bollhöfer M, Saad Y (2006) Multilevel preconditioners constructed from inverse-based ILUs. SIAM J Sci Comput 27(5):1627–1650Dufrechou E, Ezzatti P (2018) A new GPU algorithm to compute a level set-based analysis for the parallel solution of sparse triangular systems. In: 2018 IEEE International Parallel and Distributed Processing Symposium, IPDPS 2018, Canada, 2018. IEEE Computer SocietyDufrechou E, Ezzatti P (2018) Solving sparse triangular linear systems in modern GPUs: a synchronization-free algorithm. In: 2018 26th Euromicro International Conference on Parallel, Distributed and Network-Based Processing (PDP), pp 196–203. https://doi.org/10.1109/PDP2018.2018.00034Eijkhout V (1992) LAPACK working note 50: distributed sparse data structures for linear algebra operations. Tech. rep., Knoxville, TN, USAGolub GH, Van Loan CF (2013) Matrix computationsHe K, Tan SXD, Zhao H, Liu XX, Wang H, Shi G (2016) Parallel GMRES solver for fast analysis of large linear dynamic systems on GPU platforms. Integration 52:10–22 http://www.sciencedirect.com/science/article/pii/S016792601500084XLiu W, Li A, Hogg JD, Duff IS, Vinter B (2017) Fast synchronization-free algorithms for parallel sparse triangular solves with multiple right-hand sides. Concurr Comput 29(21)Saad Y (2003) Iterative methods for sparse linear systems, 2nd edn. SIAM, PhiladelphiaSchenk O, Wächter A, Weiser M (2008) Inertia revealing preconditioning for large-scale nonconvex constrained optimization. SIAM J Sci Comput 31(2):939–96

The sexual identity of adult intestinal stem cells controls organ size and plasticity

Sex differences in physiology and disease susceptibility are commonly attributed to developmental and/or hormonal factors, but there is increasing realization that cell-intrinsic mechanisms play important and persistent roles. Here we use the Drosophila melanogaster intestine to investigate the nature and importance of cellular sex in an adult somatic organ in vivo. We find that the adult intestinal epithelium is a cellular mosaic of different sex differentiation pathways, and displays extensive sex differences in expression of genes with roles in growth and metabolism. Cell-specific reversals of the sexual identity of adult intestinal stem cells uncovers the key role this identity has in controlling organ size, reproductive plasticity and response to genetically induced tumours. Unlike previous examples of sexually dimorphic somatic stem cell activity, the sex differences in intestinal stem cell behaviour arise from intrinsic mechanisms that control cell cycle duration and involve a new doublesex- and fruitless-independent branch of the sex differentiation pathway downstream of transformer. Together, our findings indicate that the plasticity of an adult somatic organ is reversibly controlled by its sexual identity, imparted by a new mechanism that may be active in more tissues than previously recognized

Dinámica de aguas superficiales de tres períodos continuos de Landsat; diferencias subregionales en llanuras argentinas

[EN] The Pampean region in Argentina is an extensive plain characterized by abundant shallow lakes that fulfill many environmental, ecological, and social functions. This study aims to detect the multiannual lake area changes in this region during 2001-2009 using remote sensing, including lakes as small as ≥10,000 m2 or 1 ha. Landsat scenes of the wet (2008-2009), normal (2006), and dry (2008-2009) seasons were obtained, and using remote sensing techniques, the number and area of shallow lakes were calculated. The spatiotemporal variation of shallow lakes was studied in different climate periods in eight singular subregions. Spatial associations between annual precipitation and lake number and area were analyzed through the development of a Geographic Information System (GIS) at a subregional scale. During the study period the total lake area in the Pampean region decreased by 5257.39 km2 (62 %), but each subregion showed different responses to climatic events. In seven of them, the differences between climate periods prove to be statistically significant (P>0.01). The relationship between precipitation and lake number and area revealed the domain of positive association. We conclude that climate factors play a dominant role in lake changes across the Pampean plains. However, other factors such as origin, topographic and edaphic characteristics intensify or mitigate changes in surface hydrology.[ES] La Región Pampeana en Argentina es una extensa planicie caracterizada por abundantes lagunas que cumplen numerosas funciones ambientales, ecológicas y sociales. Este estudio tiene como objetivo detectar los cambios plurianuales del área lagunar en esta región durante el período 2001-2009 utilizando la teledetección, incluidos lagos tan pequeños como ≥ 10.000 m2 o 1 ha. Se obtuvieron escenas Landsat de las estaciones húmeda (2008-2009), normal (2006) y seca (2008-2009) y, mediante técnicas de teledetección, se calculó el número y el área de las lagunas. Se estudió su variación espacio-temporal en diferentes períodos climáticos en ocho subregiones singulares. Se analizaron las correlaciones espaciales entre la precipitación anual y el número y el área de los lagos mediante el desarrollo de un Sistema de Información Geográfica (SIG). Durante el período de estudio el área total de lagos en la región pampeana disminuyó en 5.257,39  km2 (62 %), pero cada subregión mostró diferentes respuestas a los eventos climáticos. En siete de ellos, las diferencias entre periodos climáticos resultan estadísticamente significativas (P>0,01). La relación entre la precipitación con el número y área de las lagunas reveló el dominio de asociaciones positivas. Si bien el clima juega un papel dominante en los cambios en las lagunas de planicie, otros factores, como el origen, las características topográficas y edáficas, intensifican o mitigan los cambios en la hidrología superficial.Authors would like to thank the Consejo Nacional de Investigaciones Científicas y Técnicas for supporting this study. Besides, to the United States Geological Survey for supplying the information analyzed in this study. This work was carried out with the aid of a grant from the Inter-American Institute for Global Change Research (IAI) CRN3038, which is supported by the US National Science Foundation (Grant GEO-1128040)Aliaga, VS.; Piccolo, M.; Perillo, G. (2021). Surface water extent dynamics from three periods of continuous Landsat time series; subregional differences across Argentine plains. Revista de Teledetección. 0(58):131-145. http://hdl.handle.net/10251/169769OJS13114505

Characterization of Multicore Architectures using Task-Parallel ILU-type Preconditioned CG Solvers

Ponència presentada al 2nd Workshop on Power-Aware Computing (PACO 2017) Ringberg Castle, Germany, July, 5-8 2017We investigate the eficiency of state-of-the-art multicore processors using a multi-threaded task-parallel implementation of the Conjugate Gradient (CG) method, accelerated with an incomplete LU (ILU) preconditioner. Concretely, we analyze multicore architectures with distinct designs and market targets to compare their parallel performance and energy eficiency

Goodness-of-Fit Tests to study the Gaussianity of the MAXIMA data

Goodness-of-Fit tests, including Smooth ones, are introduced and applied to detect non-Gaussianity in Cosmic Microwave Background simulations. We study the power of three different tests: the Shapiro-Francia test (1972), the uncategorised smooth test developed by Rayner and Best(1990) and the Neyman's Smooth Goodness-of-fit test for composite hypotheses (Thomas and Pierce 1979). The Smooth Goodness-of-Fit tests are designed to be sensitive to the presence of ``smooth'' deviations from a given distribution. We study the power of these tests based on the discrimination between Gaussian and non-Gaussian simulations. Non-Gaussian cases are simulated using the Edgeworth expansion and assuming pixel-to-pixel independence. Results show these tests behave similarly and are more powerful than tests directly based on cumulants of order 3, 4, 5 and 6. We have applied these tests to the released MAXIMA data. The applied tests are built to be powerful against detecting deviations from univariate Gaussianity. The Cholesky matrix corresponding to signal (based on an assumed cosmological model) plus noise is used to decorrelate the observations previous to the analysis. Results indicate that the MAXIMA data are compatible with Gaussianity.Comment: MNRAS, in pres