Automatic granularity-aware parallelization of programs with predicates, functions, and constraints

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Chemical Modification of a Dehydratase Enzyme Involved in Bacterial Virulence by an Ammonium Derivative: Evidence of its Active Site Covalent Adduct

The first example of an ammonium derivative that causes a specific modification of the active site of type I dehydroquinase (DHQ1), a dehydratase enzyme that is a promising target for antivirulence drug discovery, is described. The resolution at 1.35 Å of the crystal structure of DHQ1 from Salmonella typhi chemically modified by this ammonium derivative revealed that the ligand is covalently attached to the essential Lys170 through the formation of an amine. The detection by mass spectroscopy of the reaction intermediates, in conjunction with the results of molecular dynamics simulations, allowed us to explain the inhibition mechanism and the experimentally observed differences between S. typhi and Staphylococcus aureus enzymes. The results presented here reveal that the replacement of Phe225 in St-DHQ1 by Tyr214 in Sa-DHQ1 and its hydrogen bonding interaction with the conserved water molecule observed in several crystal structures protects the amino adduct against further dehydration/aromatization reactions. In contrast, for the St-DHQ1 enzyme, the carboxylate group of Asp114, with the assistance of this water molecule, would trigger the formation of a Schiff base that can undergo further dehydration reactions until full aromatization of the cyclohexane ring is achieved. Moreover, in vitro antivirulence studies showed that the reported compound is able to reduce the ability of Salmonella Enteritidis to kill A459 respiratory cells. These studies have identified a good scaffold for the design of irreversible inhibitors that can be used as drugs and has opened up new opportunities for the development of novel antivirulence agents by targeting the DHQ1 enzymeFinancial support from the Spanish Ministry of Science and Innovation (SAF2013-42899-R), Xunta de Galicia (GRC2013-041), and the European Regional Development Fund (ERDF) is gratefully acknowledged. E.L. thanks the Xunta de Galicia for his postdoctoral fellowship. A.B. thanks the Miguel Servet Programme ISCIII-FEDER (CP13/00226) and the ISCIIIGeneral Subdirection of Assesment and Promotion of the Research (PI14/00059) for financial supportS

Cadomian metabasites of the Eastern Pyrenees revisited

This study presents a new geochemical, petrological, and geochronological U–Pb dataset from Ediacaran metabasites of the Canigó and Cap de Creus massifs, Eastern Pyrenees. The rocks are composed of calcic amphibole + plagioclase + chlorite + epidote ± quartz plus titanite + apatite + ilmenite ± biotite ± rutile as accessory phases and show relict igneous textures. Peak pressure-temperature determinations share common conditions, ranging 452–482ºC and 5.2–7.7kbar. These intermediate P-T conditions suggest Barrovian-type metamorphism, most likely related to a collisional setting. The metabasites correspond to evolved basaltic rocks (Mg#<0.55) with moderate TiO2 content (up to 2.08wt.%) and relatively low Cr (43–416ppm). The rocks are moderately enriched in light rare earth elements (LREE) relative to heavy rare earth elements (HREE) (average (La/Lu)n of 2.7) and the N-MORB normalized multi-element patterns show negative slopes, with prominent negative Nb anomalies ((Nb/La)NMORB=0.33–0.78). These variations are akin to island arc tholeiites generated in back-arc basins and to other metabasites described in the Eastern Pyrenees with a putative Ediacaran age, and they differ from the Ordovician tholeiitic metabasites from the Canigó massif, which derived from a contaminated E-MORB source. The positive ƐNd(T) values (0.82–3.05) of the studied metabasites preclude a notable contribution from an older continental crust. U-Pb dating (LA-ICP-MS) of one chlorite-rich schist sample in contact with the metabasites from the Canigó massif yielded a main peak at ca. 632Ma. We argue that the Cadomian metabasites from the Pyrenees formed during back-arc extension in the continental margin of Gondwana and were later affected by (probably early Variscan) medium-P metamorphism before the HT-LP metamorphism classically described in the Pyrenees

Cadomian metabasites of the Eastern Pyrenees revisited

This study presents a new geochemical, petrological, and geochronological U–Pb dataset from Ediacaran metabasites of the Canigó and Cap de Creus massifs, Eastern Pyrenees. The rocks are composed of calcic amphibole + plagioclase + chlorite + epidote ± quartz plus titanite + apatite + ilmenite ± biotite ± rutile as accessory phases and show relict igneous textures. Peak pressure-temperature determinations share common conditions, ranging 452–482ºC and 5.2–7.7kbar. These intermediate P-T conditions suggest Barrovian-type metamorphism, most likely related to a collisional setting. The metabasites correspond to evolved basaltic rocks (Mg#<0.55) with moderate TiO2 content (up to 2.08wt.%) and relatively low Cr (43–416ppm). The rocks are moderately enriched in light rare earth elements (LREE) relative to heavy rare earth elements (HREE) (average (La/Lu)n of 2.7) and the N-MORB normalized multi-element patterns show negative slopes, with prominent negative Nb anomalies ((Nb/La)NMORB=0.33–0.78). These variations are akin to island arc tholeiites generated in back-arc basins and to other metabasites described in the Eastern Pyrenees with a putative Ediacaran age, and they differ from the Ordovician tholeiitic metabasites from the Canigó massif, which derived from a contaminated E-MORB source. The positive ƐNd(T) values (0.82–3.05) of the studied metabasites preclude a notable contribution from an older continental crust. U-Pb dating (LA-ICP-MS) of one chlorite-rich schist sample in contact with the metabasites from the Canigó massif yielded a main peak at ca. 632Ma. We argue that the Cadomian metabasites from the Pyrenees formed during back-arc extension in the continental margin of Gondwana and were later affected by (probably early Variscan) medium-P metamorphism before the HT-LP metamorphism classically described in the Pyrenees.This research was financially supported by the Spanish Projects CGL2017-87631-P and PGC2018-093903-B-C22, Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación/Fondo Europeo de Desarrollo Regional, Unión Europea. Additional funding was provided by a Margarita Salas grant to NPS by the Universitat de Barcelona with funds from the Ministerio de Universidades/NextGenerationEU/PRTR/Plan de recuperación, transformación y resiliencia

Cadomian metabasites of the Eastern Pyrenees revisited

This study presents a new geochemical, petrological, and geochronological U-Pb dataset from Ediacaran metabasites and associated rocks of the Canigó and Cap de Creus massifs, Eastern Pyrenees. Metabasites are composed of calcic amphibole + plagioclase + chlorite + epidote ± quartz plus titanite + apatite + ilmenite ± biotite ± rutile as accessory phases and show relict igneous textures. Peak pressure-temperature determinations share common conditions, ranging 452-482ºC and 5.2-7.7kbar, which suggest Barrovian-type metamorphism, most likely related to a collisional setting. The metabasites correspond to evolved basaltic rocks (Mg#&lt;0.55) with moderate TiO2 content (up to 2.08wt.%) and relatively low Cr (43-416ppm). The rocks are moderately enriched in Light Rare Earth Elements (LREE) relative to Heavy Rare Earth Elements (HREE) (average (La/Lu)n of 2.7) and the N-MORB normalized multi-element patterns show negative slopes, with prominent negative Nb anomalies ((Nb/La)NMORB=0.33–0.78). These variations are akin to island arc tholeiites generated in back-arc basins and to other metabasites described in the Eastern Pyrenees with a putative Ediacaran age, and they differ from the Ordovician tholeiitic metabasites from the Canigó massif, which derived from a contaminated E-MORB source. The positive ƐNd(T) values (0.82-3.05) of the studied metabasites preclude a notable contribution from an older continental crust. Detrital zircon U-Pb dating Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS) of one chlorite-rich schist sample in contact with the metabasites from the Canigó massif yielded a main peak at ca. 632Ma and apparent maximum age of deposition at ca. 550Ma. We argue that the Cadomian metabasites from the Pyrenees formed during back-arc extension in the continental margin of Gondwana and were later affected by (probably early Variscan) medium-P metamorphism before the Low-Pressure High-Temperature (LP-HT) metamorphism classically described in the Pyrenees

Exploring the Water-Binding Pocket of the Type II Dehydroquinase Enzyme in the Structure-Based Design of Inhibitors

Structural and computational studies to explore the WAT1 binding pocket in the structure-based design of inhibitors against the type II dehydroquinase (DHQ2) enzyme are reported. The crystal structures of DHQ2 from M. tuberculosis in complex with four of the reported compounds are described. The electrostatic interaction observed between the guanidinium group of the essential arginine and the carboxylate group of one of the inhibitors in the reported crystal structures supports the recently suggested role of this arginine as the residue that triggers the release of the product from the active site. The results of the structural and molecular dynamics simulation studies revealed that the inhibitory potency is favored by promoting interactions with WAT1 and the residues located within this pocket and, more importantly, by avoiding situations where the ligands occupy the WAT1 binding pocket. The new insights can be used to advantage in the structure-based design of inhibitorsFinancial support from the Spanish Ministry of Science and Innovation (Grant SAF2010-15076) and the Xunta de Galicia (Grant GRC2013/041) is gratefully acknowledged. B.B. and A.P. thank the Spanish Ministry of Education for their respective FPU fellowships. A.S. thanks the Spanish Ministry of Economy and Competitiveness for her FPI fellowship. J.M.O. thanks the Xunta de Galicia for a Plan I2C postdoctoral fellowshipS

Static Analysis-based Debugging, Certification, Testing, and Optimization with CiaoPP

Facilitate the development of safe, efficient programs. Approach: •Next-generation, higher-level, multiparadigm prog. languages. •Improved program development environments. •A framework (CiaoPP) which integrates: •Debugging. •Verification and certification. •Testing. •Optimization (optimized compilation, parallelization, ...

Cambios en el perfil bioquímico hepático de alpacas positivas a huevos de Fasciola hepática

The aim of this study was to determine changes in the liver biochemical profile in alpacas with presence of F. hepatica eggs. We used serum and feces samples of 35 male alpaca between 2-5 years old, 18 were positives and 17 were negatives in coproparasitologic analysis for F. hepatica eggs. Differences are showed (p&lt;0.05) in the values of ALT, GGT and direct bilirubin between positives y negatives animals. We concluded that there is relationship between presence of F. hepatica eggs and high levels in the liver biochemical profile, maybe due to alterations in the hepatic parenchyma by chronic infection in alpacas.El objetivo del presente estudio fue determinar cambios en el perfil bioquímico hepático en alpacas con presencia de huevos de F. hepatica en heces. Se utilizaron muestras de suero y heces de 35 alpacas machos de entre 2 y 5 años de edad, de los cuales 18 fueron positivos y 17 negativos al examen coproparasitológico (sedimentación) para identificación de huevos de F. hepática. Se observó diferencia significativa (p&lt;0.05) entre los valores de ALT, GGT y bilirrubina directa entre los animales positivos y negativos. Concluimos que la presencia de huevos de Fasciola hepatica guarda relación con la elevación de algunos parámetros del perfil hepática posiblemente por alguna alteración en el parénquima producto de una infección crónica en alpacas