QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni.

Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure-activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents

Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity

Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF- B-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF- B signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Systemic mastocytosis with terminal leukemic manifestation in two dogs

Systemic mastocytosis (SM) with leukemic manifestation is rarely reported in veterinary patients. Here, we describe two cases of systemic mastocytosis with leukemic spread of neoplastic mast cells in adult dogs, including their clinical signs, clinical and anatomic pathology, and immunohistochemical analysis of c-KIT as a diagnostic tool. In both cases, hematologic examination revealed normocytic and normochromic anaemia, leucocytosis with segmented neutrophils, and mastocytosis. Cytological analyses of the peritoneal fluid revealed many neoplastic mast cells. Case 1 was associated with a subcutaneous mast cell tumor and Case 2 was not associated with a cutaneous or subcutaneous mast cell tumor. Neoplastic mast cells were found in the lymph nodes, spleen, liver, and kidneys, and a diagnosis of visceral mastocytosis was established. SM with terminal leukemic manifestation was confirmed by the mastocythemia intensity associated with the morphological changes of the mast cells in the blood and bone marrow.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superio

Perfil socioeconômico dos produtores do Assentamento Indaiá, Itaquiraí, MS.

Localizacao e caracterizacao da area; Metodos e procedimentos utilizados; Resultados; O produtor; Uso de tecnologia; Algumas conclusoes sobre o perfil dos produtores do Assentamento Indaia; Sugestoes para intervencao.bitstream/item/65624/1/DOC17-00-perfil.pd

Comparação entre dois programas na análise de dados obtidos por meio de marcadores dominantes ISSR.

O presente trabalho teve como objetivo avaliar as divergências entre dois programas quanto aos resultados das análises de uma matriz binária de dados, baseada em presença ou ausência de bandas amplificadas por marcadores dominantes do tipo ISSR

Ten relevant questions for applying biodiversity offsetting in the Pantanal wetland.

Abstract : In Brazil, biodiversity offsetting operates in an ad hoc manner while biodiversity equivalence has mainly been overlooked by public policies. Despite being mandatory since 1965s Forest Code (Law 4.771), we fail to have a robust offsetting framework. The revision of the forest code in 2012 (i.e., Native Vegetation Protection Law—NVPL—Law n° 12,651/2012), maintained the obligation for landowners to set aside a biome-specific percentage of their native vegetation for preservation. Known as Legal Reserves, these set-asides are a precondition for compliance with NVPL's regularization procedure called CAR (Rural Environmental Cadaster). Despite enthusiasm about biodiversity offsetting opportunities following the NVPL enactment in 2012, uncertainties around its implementation remains. Here, we formulated 10 questions that discuss and illustrate how offsetting can be applied to maintain wetland integrity, economic fairness and biodiversity conservation in the Pantanal and Upper Paraguay River basin (UPRB). The aim is to stimulate robust public policies and stimulate wetland offsetting research opportunities. We provided examples of implementation opportunities of the NVPL in integrating the floodplain and highland in Pantanal at UPRB, analyze spatial compliance deficits, and illustrate opportunities that require harmonized legislation and policies between Mato Grosso and Mato Grosso do Sul states in Brazil. No Brasil, a compensação da biodiversidade tem sido implementada de forma não sistematizada, enquanto a equivalência da biodiversidade permanece amplamente negligenciada pelas políticas públicas. Embora sua obrigatoriedade esteja prevista desde o Código Florestal de 1965 (Lei nº 4.771), ainda não há um arcabouço regulatório consolidado para a compensação ambiental. A revisão do Código Florestal em 2012, por meio da Lei de Proteção da Vegetação Nativa (LPVN, Lei nº 12.651/2012), manteve a exigência de que os proprietários rurais destinem um percentual específico de suas propriedades à preservação da vegetação nativa. Essas áreas, denominadas Reservas Legais, constituem um requisito essencial para a regularização ambiental no âmbito do Cadastro Ambiental Rural (CAR). Resumo: Apesar das perspectivas promissoras geradas pela LPVN quanto à compensação da biodiversidade, sua implementação ainda enfrenta desafios e incertezas. Neste estudo, são apresentadas e discutidas dez questões fundamentais que abordam o potencial da compensação ambiental para assegurar a integridade dos ecossistemas úmidos, promover a equidade econômica e fomentar a conservação da biodiversidade no Pantanal e na Bacia do Alto Paraguai (BAP). O objetivo é contribuir para o aprimoramento das políticas públicas e incentivar pesquisas sobre compensação ambiental em ecossistemas úmidos. Adicionalmente, são fornecidos exemplos de oportunidades para a aplicação da LPVN, com foco na integração entre a planície de inundação e as áreas de maior altitude no Pantanal, além da análise de déficits espaciais de conformidade. Por fim, são discutidas oportunidades que demandam a harmonização da legislação e das políticas ambientais entre os estados de Mato Grosso e Mato Grosso do Sul, no Brasil

Appraisal of MC2010 shear resistance approaches coupled with a residual flexural strength prediction model

In the present work the predictive performance of the two approaches proposed by Model Code 2010 for the evaluation of the shear capacity of fiber reinforced concrete (FRC) elements flexurally reinforced with conventional steel bars is assessed considering a database (DBs) constituted by 80 FRC beams do not including conventional transverse reinforcements. The accuracy of these shear models is evaluated by statistical analysis of the prediction ratio between the experimental and estimated shear capacity of the beams of the DBs, and applying the Demerit Points Classification approach for further information about the reliability of the two approaches in design context. Due to the absence of the post-cracking experimental characterization of the FRC used in several beams considered in the DBs, an approach was developed for estimating the residual flexural strength parameters from the most relevant known variables of steel fiber reinforcement mechanisms for concrete, namely the fiber volume and aspect ratio, and the concrete compressive and tensile strength. The residual flexural strength prediction model is assessed and its influence on the performance of the shear resistance models is evaluatedSFRH/BDE/96381/2013 co-funded by CiviTest - Pesquisa de Novos Materiais para a Engenharia Civil, Lda. and by FCT - Portuguese Foundation for Science and Technology. The authors also acknowledge the support provided by the FCT project PTDC/ECM-EST/2635/201

The use of Open Reading frame ESTs (ORESTES) for analysis of the honey bee transcriptome

BACKGROUND: The ongoing efforts to sequence the honey bee genome require additional initiatives to define its transcriptome. Towards this end, we employed the Open Reading frame ESTs (ORESTES) strategy to generate profiles for the life cycle of Apis mellifera workers. RESULTS: Of the 5,021 ORESTES, 35.2% matched with previously deposited Apis ESTs. The analysis of the remaining sequences defined a set of putative orthologs whose majority had their best-match hits with Anopheles and Drosophila genes. CAP3 assembly of the Apis ORESTES with the already existing 15,500 Apis ESTs generated 3,408 contigs. BLASTX comparison of these contigs with protein sets of organisms representing distinct phylogenetic clades revealed a total of 1,629 contigs that Apis mellifera shares with different taxa. Most (41%) represent genes that are in common to all taxa, another 21% are shared between metazoans (Bilateria), and 16% are shared only within the Insecta clade. A set of 23 putative genes presented a best match with human genes, many of which encode factors related to cell signaling/signal transduction. 1,779 contigs (52%) did not match any known sequence. Applying a correction factor deduced from a parallel analysis performed with Drosophila melanogaster ORESTES, we estimate that approximately half of these no-match ESTs contigs (22%) should represent Apis-specific genes. CONCLUSIONS: The versatile and cost-efficient ORESTES approach produced minilibraries for honey bee life cycle stages. Such information on central gene regions contributes to genome annotation and also lends itself to cross-transcriptome comparisons to reveal evolutionary trends in insect genomes