Red deer in Iberia: Molecular ecological studies in a southern refugium and inferences on European postglacial colonization history.

The red deer (Cervus elaphus) is a widespread wild ungulate in Europe that has suffered strong anthropogenic impacts over their distribution during the last centuries, but also at the present time, due its economic importance as a game species. Here we focus on the evolutionary history of the red deer in Iberia, one of the three main southern refugial areas for temperate species in Europe, and addressed the hypothesis of a cryptic refugia at higher latitudes during the Last Glacial Maximum (LGM). A total of 911 individuals were sampled, genotyped for 34 microsatellites specifically developed for red deer and sequenced for a fragment of 670 bp of the mitochondrial (mtDNA) D-loop. The results were combined with published mtDNA sequences, and integrated with species distribution models and historical European paleo-distribution data, in order to further examine the alternative glacial refugial models and the influence of cryptic refugia on European postglacial colonization history. Clear genetic differentiation between Iberian and European contemporary populations was observed at nuclear and mtDNA levels, despite the mtDNA haplotypes central to the phylogenetic network are present across western Europe (including Iberia) suggesting a panmictic population in the past. Species distribution models, fossil records and genetic data support a timing of divergence between Iberian and European populations that overlap with the LGM. A notable population structure was also found within the Iberian Peninsula, although several populations displayed high levels of admixture as a consequence of recent red deer translocations. Five D-loop sub-lineages were found in Iberia that belong to the Western European mtDNA lineage, while there were four main clusters based on analysis of nuclear markers. Regarding glacial refugial models, our findings provide detailed support for the hypothesis that red deer may have persisted in cryptic northern refugia in western Europe during the LGM, most likely in southern France, southern Ireland, or in a region between them (continental shelf), and these regions were the source of individuals during the European re-colonization. This evidence heightens the importance of conserving the high mitochondrial and nuclear diversity currently observed in Iberian populations

Structure-Guided Discovery of Phenyl-diketo Acids as Potent Inhibitors of M. tuberculosis Malate Synthase

SummaryThe glyoxylate shunt plays an important role in fatty acid metabolism and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and overexpression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors guided optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics

O estatuto variável de construções com e sem Alçamento: uma abordagem sociofuncionalista

RESUMO Constituintes argumentais de oração encaixada podem assumir comportamento típico de Sujeito ou de Objeto em uma predicação matriz, fenômeno conhecido como Alçamento. Sob perspectiva sociofuncionalista, discutimos o estatuto variável de construções com e sem Alçamento, sob a hipótese de que tais construções podem ser concebidas como variantes de mesma variável sintática. Independentemente de ajustes morfossintáticos prototípicos do Alçamento, analisamos dados de uma variedade falada do português brasileiro envolvendo casos de Alçamento a Sujeito. Na consideração de variáveis linguísticas e sociais, os resultados apontam, no condicionamento da regra variável: (i) maior produtividade de Alçamento de Sujeito a Sujeito do que de Objeto a Sujeito; (ii) maior relevância de variáveis semântico-pragmáticas; (iii) irrelevância de variáveis sociais. A conclusão é a de que um tratamento satisfatório do fenômeno sob perspectiva sociofuncionalista requer mesmo que critérios morfossintáticos sejam abrandados, em favor da inclusão de critérios discursivo-pragmáticos