Intramolecular hydrogen bond activation: Thiourea-organocatalyzed enantioselective 1,3-dipolar cycloaddition of salicylaldehyde-derived azomethine ylides with nitroalkenes

An organocatalytic strategy for the synthesis of tetrasubstituted pyrrolidines with monoactivated azomethine ylides in high enantiomeric excess and excellent exo/endo selectivity is presented. The key to success is the intramolecular activation via hydrogen bonding through an o-hydroxy group, which allows the dipolar cycloaddition to take place in the presence of azomethine ylides bearing only one activating group. The intramolecular hydrogen bond in the azomethine ylide and the intermolecular hydrogen bond with the catalyst have been demonstrated by DFT calculations and mechanistic proofs to be crucial for the reaction to proceedThe Spanish Government (CTQ2015-64561-R, CTQ2016- 76061-P) and the European Research Council (ERC-CG, contract number 647550) are acknowledged. We acknowledge the generous allocation of computing time at the CCC (UAM). S.D.-T. gratefully acknowledges the “Ramón y Cajal” program (RYC-2010-07019). Financial support from the Spanish Ministry of Economy and Competitiveness, through the “Maria de Maeztu” Program of Excellence in R&D (MDM- 2014-0377

Outcomes of Trypanosoma cruzi and Trypanosoma evansi infections on health of Southern coati (Nasua nasua), crab-eating fox (Cerdocyon thous), and ocelot (Leopardus pardalis) in the Brazilian Pantanal.

The occurrence of Trypanosoma spp. in wild carnivore populations has been intensively investigated during the last decades. However, the impact of these parasites on the health of free-living infected animals has been largely neglected. The Pantanal biome is the world's largest seasonal wetland, harboring a great diversity of species and habitats. This includes 174 species of mammals, of which 20 belong to the order Carnivora. The present study aimed to investigate the effect of Trypanosoma evansi and Trypanosoma cruzi infections and coinfections on the health of the most abundant carnivores in the Pantanal: coati (Nasua nasua), crab-eating fox (Cerdocyon thous), and ocelot (Leopardus pardalis). We captured 39 coatis, 48 crab-eating foxes, and 19 ocelots. Diagnostic tests showed T. cruzi infection in 7 crab-eating foxes and 5 coatis. Additionally, 7 crab-eating foxes, 10 coatis, and 12 ocelots were positive for T. evansi. We observed coinfections in 9 crab-eating foxes, 8 coatis, and 2 ocelots. This is the first report of T. evansi and T. cruzi infection on the health of free-living ocelots and crab-eating foxes. We showed that single T. evansi or T. cruzi infection, as well as coinfection, caused some degree of anemia in all animals, as well as an indirect negative effect on body condition in coatis and crab-eating foxes via anemia indicators and immune investment, respectively. Furthermore, the vigorous immune investment observed in sampled coatis, crab-eating foxes and ocelots infected by T. evansi, T. cruzi and coinfected can be highly harmful to their health. Overall, our results indicate that single and combined infection with T. evansi and T. cruzi represent a severe risk to the health of wild carnivores in the Pantanal region

Statement of Foliar Fertilization Impact on Yield, Composition, and Oxidative Biomarkers in Rice

In rice crops, fertilization is a naturalized practice, although inefficient, that could be improved by applying foliar fertilization. Phytoprostanes (PhytoPs) and phytofurans (PhytoFs) are products of α-linolenic acid peroxidation, useful as biomarkers of oxidative degradation in higher plants. The objective was to determine the effect of the foliar fertilization on the concentration of PhytoPs and PhytoFs and its relationships with modifications of yield and quality of rice productions. It was described that the concentration of biomarkers of stress decreased with the application of foliar fertilization, being the response significantly different depending the genotypes and compound monitored. Moreover, fertilization did not modify significantly the parameters of yield (961.2 g m−2), 1000 whole-grain (21.2 g), and protein content (10.7% dry matter). Therefore, this is the first work that describes the effect of fertilization on PhytoPs and PhytoFs in rice genotypes and reinforces the capacity of these compounds as biomarkers to monitor specific abiotic stress, in this case, represented by nutritional stress.Facultad de Ciencias Agrarias y Forestale

Presencia de polifenoles, fitoprostanos y fitofuranos bioactivos en cultivares de arroz tipo largo fino

El consumo de granos enteros de arroz proporciona efectos protectores frente a enfermedades crónicas como diabetes tipo 2, cáncer, hipercolesterolemia y enfermedades cardiovasculares. Por otro lado, la actividad de los polifenoles en relación con la captación de radicales libres, sugiere valiosas funciones biológicas tales como la antimutagénica, anticancerígena y antienvejecimiento (Velioglu et al, 1998). Recientemente, se ha demostrado que el salvado de arroz contiene una mezcla compleja de compuestos fitoquímicos biológicamente activos tales como tocoferoles, tocotrienoles, ƴ-orizanol, y polifenoles, a los que se han atribuido actividades funcionales relacionadas con su capacidad antioxidante (Huang and Ng, 2012). En mamíferos, el estrés oxidativo está asociado a la incidencia y severidad de diversas enfermedades crónicas. Los altos niveles de especies reactivas de oxígeno (ROS) conducen a daños oxidativos en lípidos, proteínas y ácidos nucleicos. Por este motivo, la identificación de matrices vegetales que presenten compuestos con actividad antioxidante ha sido promovida como una vía para la reducción de la prevalencia de enfermedades relacionadas con altos niveles de ROS. Además, estos compuestos son de relevancia para la industria alimentaria debido a su impacto en la calidad de los alimentos. En numerosas especies vegetales, el ácido α-linolénico (ALA, 18: 3ω-3) es el punto final de la biosíntesis de ácidos grasos, constituyendo un sustrato altamente reactivo en frente a ROS que dan lugar a reacciones de peroxidación no enzimática. Como consecuencia, en primer término se producen los fitoprostanos (FPs), en tanto que la adición de oxígeno molecular después de la ciclación inicial conduce a la generación de estructuras furánicas llamadas fitofuranos (FFs). Dadas la característica de sus rutas de síntesis y su analogía estructural con los derivados del ácido araquidónico, estos compuestos podrían tener un gran potencial como nuevos compuestos bioactivos. Tanto el perfil de FPs y FFs como su contenido cuantitativo son fuertemente dependientes de factores genéticos, de manejo, almacenamiento y procesamiento. Varios autores han estudiado el comportamiento de los fitoprostanos en las plantas sometidas a estrés hídrico (González-Collado et al. 2015) o térmico (Yonny et al., 2016). Dado que el arroz es el alimento básico más importante del mundo, es probable que represente una fuente dietética significativa de estos compuestos para una gran proporción de la población. El objetivo de este trabajo fue evaluar las características de distintos tipos de harina (de grano pulido, integral y salvado) obtenida de cuatro variedades de arroz en relación a su contenido en polifenoles, FPs y FFs, así como el efecto del tipo de procesado del arroz en los citados compuestos.Centro de Investigación y Desarrollo en Criotecnología de Alimento

c-Rel Controls Multiple Discrete Steps in the Thymic Development of Foxp3+ CD4 Regulatory T Cells

The development of natural Foxp3+ CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25+GITRhiFoxp3−CD4+ nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-κB transcription factor required for nTreg differentiation, we establish that c-Rel regulates both of these developmental steps. c-Rel controls the generation of nTreg precursors via a haplo-insufficient mechanism, indicating that this step is highly sensitive to c-Rel levels. However, maintenance of c-Rel in an inactive state in nTreg precursors demonstrates that it is not required for a constitutive function in these cells. While the subsequent IL-2 induction of Foxp3 in nTreg precursors requires c-Rel, this developmental transition does not coincide with the nuclear expression of c-Rel. Collectively, our results support a model of nTreg differentiation in which c-Rel generates a permissive state for foxp3 transcription during the development of nTreg precursors that influences the subsequent IL-2 dependent induction of Foxp3 without a need for c-Rel reactivation

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function

Excavations at Azoria, 2003–2004, Part 2: The Final Neolithic, Late Prepalatial, and Early Iron Age Occupation

This article constitutes the second of two reports on fieldwork conducted at Azoria in eastern Crete during the 2003 and 2004 excavation seasons. Evidence of Final Neolithic and Early Iron Age occupation and traces of Late Prepalatial activity were found underlying the Archaic civic buildings on the South Acropolis, particularly along the southwest terrace. The recovery of substantial Final Neolithic architectural and habitation remains contributes to our understanding of the 4th millennium in eastern Crete. Stratigraphic excavations have also clarified the spatial extent of the settlement from Late Minoan IIIC to the Late Geometric period, and brought to light evidence for the transition from the Early Iron Age to the Archaic period, and the transformation of the site in the 7th century B.C

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.Genetics of disease, diagnosis and treatmen