A Square Peg in a Circular Hole: Choosing the Right Ansatz for Isolated Black Holes in Generic Gravitational Theories

The metric of a spacetime can be greatly simplified if the spacetime is circular. We prove that in generic effective theories of gravity, the spacetime of a stationary, axisymmetric and asymptotically flat solution must be circular if the solution can be obtained perturbatively from a solution in the General Relativity limit. This result applies to a broad class of gravitational theories, that include arbitrary scalars and vectors in their light sector, so long as their non-standard kinetic terms and non-mininal couplings to gravity are treated perturbatively.Comment: 7+5 pages, 1 figure, submitted to PR

A Prediction Algorithm For Drug Response In Patients With Mesial Temporal Lobe Epilepsy Based On Clinical And Genetic Information

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms ( SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy. For this, we divided 237 patients into two groups: 75 responsive and 162 refractory to antiepileptic drug therapy. We genotyped 119 SNPs in ABCB1, ABCC2, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 genes. We used 98 additional SNPs to evaluate population stratification. We assessed a first scenario using only clinical variables and a second one including SNP information. The random forests algorithm combined with leave-one-out cross-validation was used to identify the best predictive model in each scenario and compared their accuracies using the area under the curve statistic. Additionally, we built a variable importance plot to present the set of most relevant predictors on the best model. The selected best model included the presence of hippocampal sclerosis and 56 SNPs. Furthermore, including SNPs in the model improved accuracy from 0.4568 to 0.8177. Our findings suggest that adding genetic information provided by SNPs, located on drug transport and metabolism genes, can improve the accuracy for predicting which patients with mesial temporal lobe epilepsy are likely to be refractory to drug treatment, making it possible to identify patients who may benefit from epilepsy surgery sooner.121FAPESP [2013/07559-3]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Genetically Modifying the Insect Gut Microbiota to Control Chagas Disease Vectors through Systemic RNAi

Technologies based on RNA interference may be used for insect control. Sustainable strategies are needed to control vectors of Chagas disease such as Rhodnius prolixus. The insect microbiota can be modified to deliver molecules to the gut. Here, Escherichia coli HT115(DE3) expressing dsRNA for the Rhodnius heme-binding protein (RHBP) and for catalase (CAT) were fed to nymphs and adult triatomine stages. RHBP is an egg protein and CAT is an antioxidant enzyme expressed in all tissues by all developmental stages. The RNA interference effect was systemic and temporal. Concentrations of E. coli HT115(DE3) above 3.35 × 107 CFU/mL produced a significant RHBP and CAT gene knockdown in nymphs and adults. RHBP expression in the fat body was reduced by 99% three days after feeding, returning to normal levels 10 days after feeding. CAT expression was reduced by 99% and 96% in the ovary and the posterior midgut, respectively, five days after ingestion. Mortality rates increased by 24-30% in first instars fed RHBP and CAT bacteria. Molting rates were reduced by 100% in first instars and 80% in third instars fed bacteria producing RHBP or CAT dsRNA. Oviposition was reduced by 43% (RHBP) and 84% (CAT). Embryogenesis was arrested in 16% (RHBP) and 20% (CAT) of laid eggs. Feeding females 105 CFU/mL of the natural symbiont, Rhodococcus rhodnii, transformed to express RHBP-specific hairpin RNA reduced RHBP expression by 89% and reduced oviposition. Modifying the insect microbiota to induce systemic RNAi in R. prolixus may result in a paratransgenic strategy for sustainable vector control

An Intracellular Arrangement of Histoplasma capsulatum Yeast-Aggregates Generates Nuclear Damage to the Cultured Murine Alveolar Macrophages

Histoplasma capsulatum is responsible for a human systemic mycosis that primarily affects lung tissue. Macrophages are the major effector cells in humans that respond to the fungus, and the development of respiratory disease depends on the ability of Histoplasma yeast cells to survive and replicate within alveolar macrophages. Therefore, the interaction between macrophages and H. capsulatum is a decisive step in the yeast dissemination into host tissues. Although the role played by components of cell-mediated immunity in the host's defense system and the mechanisms used by the pathogen to evade the host immune response are well understood, knowledge regarding the effects induced by H. capsulatum in host cells at the nuclear level is limited. According to the present findings, H. capsulatum yeast cells display a unique architectural arrangement during the intracellular infection of cultured murine alveolar macrophages, characterized as a formation of aggregates that seem to surround the host cell nucleus, resembling a crown. This extranuclear organization of yeast-aggregates generates damage on the nucleus of the host cell, producing DNA fragmentation and inducing apoptosis, even though the yeast cells are not located inside the nucleus and do not trigger changes in nuclear proteins. The current study highlights a singular intracellular arrangement of H. capsulatum yeast near to the nucleus of infected murine alveolar macrophages that may contribute to the yeast’s persistence under intracellular conditions, since this fungal pathogen may display different strategies to prevent elimination by the host's phagocytic mechanisms

Avaliação eletroforética, cromatográfica e molecular da Hb D Los Angeles no Brasil

A variante de hemoglobina (Hb) D mais comum, Hb D Los Angeles ou D Punjab, é originada de uma transversão GAA->CAA no códon 121 da globina beta; essa mutação resulta na substituição do ácido glutâmico por glutamina na proteína. É a terceira variante de hemoglobina mais freqüente da população brasileira. Como as hemoglobinas D apresentam migração similar à hemoglobina S em pH alcalino, e com a hemoglobina A em pH ácido, são necessários vários testes para o correto diagnóstico. No presente estudo objetivou-se relacionar os diferentes procedimentos laboratoriais de rotina diagnóstica, além da análise molecular, para estabelecer o perfil de Hb D Los Angeles no Brasil. Foram analisados 47 indivíduos da população brasileira com provável Hb D Los Angeles, por vários procedimentos eletroforéticos em diferentes condições de pH, além da cromatografia líquida de alta pressão, e testes moleculares para confirmação da mutação. Foram encontrados quatro tipos de combinações de hemoglobinas: 42 indivíduos portadores de hemoglobina AD Los Angeles, dois indivíduos com doença de Hb S/D Los Angeles, dois indivíduos com Hb D Los Angeles e talassemia beta e um indivíduo com Hb D Los Angeles e Hb Lepore. Os indivíduos heterozigotos para D Los Angeles são assintomáticos, entretanto, em associação com outras variantes e talassemias podem apresentar graus variáveis de manifestações clínicas. Os resultados apresentados enfatizaram a necessidade da associação de várias metodologias para a identificação da Hb D Los Angeles, além de auxiliar na elucidação de combinações raras.<br>The most common Hb D variant, the Hb D-Los Angeles, also know as Hb D-Punjab, originates through a GAA->CAA change at the 121 codon of the beta globin gene; this mutation results in the replacement of glutamic acid for glutamine in the protein. It is the third most common hemoglobin variant in the Brazilian population. This variant has electrophoretic migration in alkaline pHs similar to Hb S and identical migration to hemoglobin A in acidic pHs. Thus, several techniques are necessary for its correct diagnosis. The purpose of this work was to relate the different laboratorial techniques and molecular analyses to determine the profile of Hb D Los Angeles in Brazil. Forty-seven individuals from the Brazilian population with Hb D Los Angeles were studied. Multiple electrophoresis in several experimental conditions were carried out, in addition to high performance liquid chromatography (HPLC) and molecular analysis to confirm this mutation. Four compound heterozygotes were observed: 42 individuals heterozygous Hb AD Los Angeles, two with Hb S/D Los Angeles disease, two individuals with Hb D Los Angeles and beta-thalassemia and one with Hb D Los Angeles and Hb Lepore. The heterozygous hemoglobin D Los Angeles is asymptomatic, even though its association with other variants and thalassemias may present varying degrees of clinical manifestations. The results presented emphasize the significance of the association of different laboratorial techniques for D Los Angeles diagnosis, and help to elucidate rare combinations

Re-annotation of the Theileria parva genome refines 53% of the proteome and uncovers essential components of N-glycosylation, a conserved pathway in many organisms

The apicomplexan parasite Theileria parva causes a livestock disease called East coast fever (ECF), with millions of animals at risk in sub-Saharan East and Southern Africa, the geographic distribution of T. parva. Over a million bovines die each year of ECF, with a tremendous economic burden to pastoralists in endemic countries. Comprehensive, accurate parasite genome annotation can facilitate the discovery of novel chemotherapeutic targets for disease treatment, as well as elucidate the biology of the parasite. However, genome annotation remains a significant challenge because of limitations in the quality and quantity of the data being used to inform the location and function of protein-coding genes and, when RNA data are used, the underlying biological complexity of the processes involved in gene expression. Here, we apply our recently published RNAseq dataset derived from the schizont life-cycle stage of T. parva to update structural and functional gene annotations across the entire nuclear genome.; The re-annotation effort lead to evidence-supported updates in over half of all protein-coding sequence (CDS) predictions, including exon changes, gene merges and gene splitting, an increase in average CDS length of approximately 50 base pairs, and the identification of 128 new genes. Among the new genes identified were those involved in N-glycosylation, a process previously thought not to exist in this organism and a potentially new chemotherapeutic target pathway for treating ECF. Alternatively-spliced genes were identified, and antisense and multi-gene family transcription were extensively characterized.; The process of re-annotation led to novel insights into the organization and expression profiles of protein-coding sequences in this parasite, and uncovered a minimal N-glycosylation pathway that changes our current understanding of the evolution of this post-translational modification in apicomplexan parasites

Pleiotropic antifibrotic actions of aspirin-triggered resolvin D1 in the lungs

Introduction: Pulmonary fibrosis is a destructive, progressive disease that dramatically reduces life quality of patients, ultimately leading to death. Therapeutic regimens for pulmonary fibrosis have shown limited benefits, hence justifying the efforts to evaluate the outcome of alternative treatments. Methods: Using a mouse model of bleomycin (BLM)-induced lung fibrosis, in the current work we asked whether treatment with pro-resolution molecules, such as pro-resolving lipid mediators (SPMs) could ameliorate pulmonary fibrosis. To this end, we injected aspirin-triggered resolvin D1 (7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E19Z-docosahexaenoic acid; ATRvD1; i.v.) 7 and 10 days after BLM (intratracheal) challenge and samples were two weeks later. Results and discussion: Assessment of outcome in the lung tissues revealed that ATRvD1 partially restored lung architecture, reduced leukocyte infiltration, and inhibited formation of interstitial edema. In addition, lung tissues from BLM-induced mice treated with ATRvD1 displayed reduced levels of TNF-α, MCP-1, IL-1-β, and TGF-β. Of further interest, ATRvD1 decreased lung tissue expression of MMP-9, without affecting TIMP-1. Highlighting the beneficial effects of ATRvD1, we found reduced deposition of collagen and fibronectin in the lung tissues. Congruent with the anti-fibrotic effects that ATRvD1 exerted in lung tissues, α-SMA expression was decreased, suggesting that myofibroblast differentiation was inhibited by ATRvD1. Turning to culture systems, we next showed that ATRvD1 impaired TGF-β-induced fibroblast differentiation into myofibroblast. After showing that ATRvD1 hampered extracellular vesicles (EVs) release in the supernatants from TGF-β-stimulated cultures of mouse macrophages, we verified that ATRvD1 also inhibited the release of EVs in the bronco-alveolar lavage (BAL) fluid of BLM-induced mice. Motivated by studies showing that BLM-induced lung fibrosis is linked to angiogenesis, we asked whether ATRvD1 could blunt BLM-induced angiogenesis in the hamster cheek pouch model (HCP). Indeed, our intravital microscopy studies confirmed that ATRvD1 abrogates BLM-induced angiogenesis. Collectively, our findings suggest that treatment of pulmonary fibrosis patients with ATRvD1 deserves to be explored as a therapeutic option in the clinical setting.Fil: Guilherme, Rafael F.. Universidade Federal do Rio de Janeiro; BrasilFil: Silva, José Bruno N.F.. Universidade Federal do Rio de Janeiro; Brasil. Universidade Federal do Tocantins; BrasilFil: Waclawiack, Ingrid. Universidade Federal do Rio de Janeiro; BrasilFil: Fraga Junior, Vanderlei S.. Universidade Federal do Rio de Janeiro; BrasilFil: Nogueira, Thaís O.. Universidade Federal do Rio de Janeiro; BrasilFil: Pecli, Cyntia. Universidade Federal do Rio de Janeiro; BrasilFil: Araújo Silva, Carlla A.. Universidade Federal do Rio de Janeiro; BrasilFil: Magalhães, Nathalia S.. Ministerio de Salud de Brasil. Fundación Oswaldo Cruz. Instituto Oswaldo Cruz;Fil: Lemos, Felipe S.. Ministerio de Salud de Brasil. Fundación Oswaldo Cruz. Instituto Oswaldo Cruz;Fil: Bulant, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Blanco, Pablo Javier. Laboratório Nacional para Computação Científica; BrasilFil: Serra, Rafaela. Universidade Federal do Rio de Janeiro; BrasilFil: Svensjö, Erik. Universidade Federal do Rio de Janeiro; BrasilFil: Scharfstein, Júlio. Universidade Federal do Rio de Janeiro; BrasilFil: Moraes, João A.. Universidade Federal do Rio de Janeiro; BrasilFil: Canetti, Claudio. Universidade Federal do Rio de Janeiro; BrasilFil: Benjamim, Claudia F.. Universidade Federal do Rio de Janeiro; Brasi

Synthesis of Selenium-Quinone Hybrid Compounds with Potential Antitumor Activity via Rh-Catalyzed C-H Bond Activation and Click Reactions

In continuation of our quest for new redox-modulating catalytic antitumor molecules, selenium-containing quinone-based 1,2,3-triazoles were synthesized using rhodium-catalyzed C-H bond activation and click reactions. All compounds were evaluated against five types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), SF295 (human glioblastoma cells), NCIH-460 (human lung cells) and PC3 (human prostate cancer cells). Some compounds showed good activity with IC50 values below 1 µM. The cytotoxic potential of the naphthoquinoidal derivatives was also evaluated in non-tumor cells, exemplified by L929 cells. Overall, these compounds represent promising new lead derivatives and stand for a new class of chalcogenium-containing derivatives with potential antitumor activity

Transcriptome profiling of grapevine seedless segregants during berry development reveals candidate genes associated with berry weight

Indexación: Web of Science; PubMedBackground Berry size is considered as one of the main selection criteria in table grape breeding programs. However, this is a quantitative and polygenic trait, and its genetic determination is still poorly understood. Considering its economic importance, it is relevant to determine its genetic architecture and elucidate the mechanisms involved in its expression. To approach this issue, an RNA-Seq experiment based on Illumina platform was performed (14 libraries), including seedless segregants with contrasting phenotypes for berry weight at fruit setting (FST) and 6–8 mm berries (B68) phenological stages. Results A group of 526 differentially expressed (DE) genes were identified, by comparing seedless segregants with contrasting phenotypes for berry weight: 101 genes from the FST stage and 463 from the B68 stage. Also, we integrated differential expression, principal components analysis (PCA), correlations and network co-expression analyses to characterize the transcriptome profiling observed in segregants with contrasting phenotypes for berry weight. After this, 68 DE genes were selected as candidate genes, and seven candidate genes were validated by real time-PCR, confirming their expression profiles. Conclusions We have carried out the first transcriptome analysis focused on table grape seedless segregants with contrasting phenotypes for berry weight. Our findings contributed to the understanding of the mechanisms involved in berry weight determination. Also, this comparative transcriptome profiling revealed candidate genes for berry weight which could be evaluated as selection tools in table grape breeding programs.http://bmcplantbiol.biomedcentral.com/articles/10.1186/s12870-016-0789-