Micrornas In The Host-apicomplexan Parasites Interactions: A Review Of Immunopathological Aspects

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)MicroRNAs (miRNAs), a class of small non-coding regulatory RNAs, have been detected in a variety of organisms ranging from ancient unicellular eukaryotes to mammals. They have been associated with numerous molecular mechanisms involving developmental, physiological and pathological changes of cells and tissues. Despite the fact that miRNA-silencing mechanisms appear to be absent in some Apicomplexan species, an increasing number of studies have reported a role for miRNAs in host-parasite interactions. Host miRNA expression can change following parasite infection and the consequences can lead, for instance, to parasite clearance. In this context, the immune system signaling appears to have a crucial role.6Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/16525-2]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)FAPESPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients

Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses and ex vivo assays. Patterns of clinical features, parasite burden and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients' signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, in particular in the hematopoietic niche of bone marrow and spleen

Identification of differentially expressed genes in queen and worker castes of Melipona quadrifasciata

Orientador: Gonçalo Amarante Guimarães PereiraTese (doutorado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: O polifenismo de castas é um fenômeno multifacetado, sendo mais evidente em diferenças na capacidade reprodutiva e na longevidade entre rainhas e operárias. No presente estudo, a abelha sem ferrão Melipona quadrifasciata anthidioides foi escolhida para a investigação de diferenças na expressão gênica entre rainhas e operárias recém nascidas. Este estudo foi focalizado em adultos recém nascidos pois esse estágio representa o ponto final do desenvolvimento embrionário e o ponto inicial para o desempenho de tarefas casta-específicas. Inicialmente, foi empregada a metodologia do ¿differential display reverse transcription (DDRT)-PCR¿ e podendo ser detectada a expressão diferenciada de 14 genes entre rainhas e operárias. As diferenças no perfil de expressão foram posteriormente analisadas através de duas bibliotecas subtrativas de cDNA: uma representando genes muito expressos ou induzidos em operárias quando em comparação com rainhas, e a outra representando genes mais expressos na casta rainha. Embora o número total de seqüências geradas não tenha permitido uma compreensão completa dos transcriptomas das castas, foi possível detectar em rainhas a predominância de genes envolvidos na regulação transcricional e no metabolismo, em relação à ampla diversidade de categorias funcionais das ESTs encontradas na casta operária. Um outro grupo representando seqüências de funções desconhecidas apresentou elevada similaridade a seqüências de Apis mellifera, podendo, portanto, conter genes candidatos para investigações em processos específicos das abelhas sociais ou do desenvolvimento de castas de maneira geral. Além disso, este estudo questionou se rainhas induzidas pelo tratamento com hormônio juvenil (HJ) durante a fase larval poderiam apresentar níveis de expressão gênica similares aos de uma rainha produzida de modo natural. Curiosamente, os dados preliminares sugerem que a rainha artificial não apresenta o mesmo transcriptoma de uma rainha natural, indicando que o HJ pode induzir a diferenciação, mas não em todos os aspectosAbstract: Caste polyphenism is a multifaceted phenomenon, most evident in the marked differences in reproductive capacity and longevity between queens and workers. In the present study, the stingless bee Melipona quadrifasciata anthidioides was chosen to investigate differences in gene expression between newly emerged adult queens and workers. This study has focused on newly emerged adults since this stage represents the endpoint of post-embryonic development and the starting point for caste-specific task performance.Initially, the methodology of differential display reverse transcription (DDRT)-PCR was employed and the differential expression for 14 M. quadrifasciata genes could be detected between queens and workers. The differences in the expression profile of the castes were further analysed through two subtractive cDNA libraries: one representing the genes that are overexpressed in workers, when compared with queens and the other representing genes which are overexpressed in queens.Although the total number of sequence does not allow a comprehensive picture of the caste transcriptomes, there seems to exist a predominance of genes involved in transcriptional regulation and metabolism in the queen ESTs, versus a much broader spectrum of categories in the worker ESTs. Another group representing sequences with unknown function displayed significant matches only with the Apis database and, therefore, may contain candidates for further investigations on processes specific to social bees or caste development in general.In addition, this study addressed the question of whether queens induced by treatment with juvenile hormone (JH) during the larval phase display genes with similar expression levels as naturally produced queens. Remarkably, our preliminary data suggest that the artificial queen does not present the same transcriptome of a natural queen, indicating that JH may not induce all aspects of the differentiation processDoutoradoGenetica Animal e EvoluçãoDoutor em Genetica e Biologia Molecula

Micrornas In The Host-apicomplexan Parasites Interactions: A Review Of Immunopathological Aspects.

MicroRNAs (miRNAs), a class of small non-coding regulatory RNAs, have been detected in a variety of organisms ranging from ancient unicellular eukaryotes to mammals. They have been associated with numerous molecular mechanisms involving developmental, physiological and pathological changes of cells and tissues. Despite the fact that miRNA-silencing mechanisms appear to be absent in some Apicomplexan species, an increasing number of studies have reported a role for miRNAs in host-parasite interactions. Host miRNA expression can change following parasite infection and the consequences can lead, for instance, to parasite clearance. In this context, the immune system signaling appears to have a crucial role

MicroRNAs in the host-apicomplexan parasites interactions: a review of immunopathological aspects

MicroRNAs (miRNAs), a class of small non-coding regulatory RNAs, have been detected in a variety of organisms ranging from ancient unicellular eukaryotes to mammals. They have been associated with numerous molecular mechanisms involving developmental, physiological and pathological changes of cells and tissues. Despite the fact that miRNA-silencing mechanisms appear to be absent in some Apicomplexan species, an increasing number of studies have reported a role for miRNAs in host-parasite interactions. Host miRNA expression can change following parasite infection and the consequences can lead, for instance, to parasite clearance. In this context, the immune system signaling appears to have a crucial role6CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2012/16525-

Physiological and genetic mechanisms underlying caste development, reproduction and division of labor in stingless bees

Investigations on physiological and molecular mechanisms underlying developmental and reproductive differentiation in social bees center on the question of how different patterns of larval nutrition can affect hormonal dynamics and how these drive differential gene expression. Differential expression analyses and the generation of AFLP markers now enable us to re-examine the question of genetic caste determination in the genus Melipona. The comparison of vitellogenin expression in three species of stingless bees suggests divergence in regulatory mechanisms that directly relate to the mode of worker reproduction. As in honey bees, this indicates alternative functions for vitellogenin in the life cycle of adult workers. The diversity in life histories and their associated specific physiologies make the stingless bees a rich resource for information on evolutionary trajectories that have generated phenotypic plasticity in social Hymenoptera

Bax And Bcl-2 Expression And Tunel Labeling In Lumbar Enlargement Of Neonatal Rats After Sciatic Axotomy And Melatonin Treatment.

Peripheral axotomy in neonatal rats induces neuronal death. We studied the anti-apoptotic protein Bcl-2 and cell death promoter Bax in spinal cord of neonatal rats after sciatic transection and treatment with melatonin, a neuroprotective substance. Pups were unilaterally axotomized at P2 and received melatonin (1 mg/kg; sc) or vehicle 1 h prior to lesion, immediately after, at 1 h, 2 h and then once daily. Rats were sacrificed at 3 h, 6 h, 24 h, 72 h and 5 days postaxotomy. Intact animals were used as controls. Lumbar enlargement was processed for Nissl staining, immunohistochemistry and RT-PCR for Bax or Bcl-2 and TUNEL reaction. Motoneurons (MN) of lesioned (L) and normal (N) sides were counted, and MN survival ratio (MSR=L/N) was calculated. Bax and Bcl-2 showed cytoplasmic immunoreactivity (IR). Bax IR was noticeable in small cells but less evident in MN. In unlesioned pups, some Bax-positive small cells (B+) and TUNEL-positive nuclei (T+) were mainly seen in the dorsal horn. In lesioned animals given vehicle, Bax mRNA levels and numbers of B+ and T+ were increased in comparison with intact controls at 24 h postaxotomy. The basal IR for Bax in MN was not changed by axotomy. Bcl-2 IR was noted in all cells and, like Bcl-2 mRNA, was unaltered after lesion. Melatonin reduced MN loss at 24 h, 72 h and 5 days and T+ at 24 h after lesion but did not interfere with Bax or Bcl-2 expression. These results suggest that (1) sciatic transection at P2 increases Bax mRNA and the amount of B+ and T+ in the lumbar enlargement, (2) Bax IR in immature MN is not altered by axotomy and (3) melatonin protects MN and dorsal horn cells through a mechanism independent of Bax and Bcl-2.111280-9

The A-Z of Zika drug discovery

Submitted by Sandra Infurna ([email protected]) on 2018-08-02T12:28:34Z No. of bitstreams: 1 PHM_torres_etal_IOC_2018.pdf: 2136278 bytes, checksum: 0c319e8dd6057f423b6a61ea6b50d413 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-08-02T12:47:52Z (GMT) No. of bitstreams: 1 PHM_torres_etal_IOC_2018.pdf: 2136278 bytes, checksum: 0c319e8dd6057f423b6a61ea6b50d413 (MD5)Made available in DSpace on 2018-08-02T12:47:52Z (GMT). No. of bitstreams: 1 PHM_torres_etal_IOC_2018.pdf: 2136278 bytes, checksum: 0c319e8dd6057f423b6a61ea6b50d413 (MD5) Previous issue date: 2018Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ. Brasil / University of Cambridge. Department of Biochemistry. London, UK.Universidade de Campinas. Instituto de Biologia. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacintho da Silva. Campinas, SP, Brasil.Universidade de Campinas. Instituto de Biologia. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacintho da Silva. Campinas, SP, Brasil.Universidade de Campinas. Instituto de Biologia. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacintho da Silva. Campinas, SP, Brasil.Universidade de Campinas. Instituto de Biologia. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacintho da Silva. Campinas, SP, Brasil.Collaborations Pharmaceuticals, Inc. Raleigh, NC 27606, USA.Rutgers University–New Jersey Medical School. Department of Pharmacology, Physiology and Neuroscience. Newark, NJ, USA.Universidade Federal de Goias. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil / Universidade de Campinas. Instituto de Biologia. Departamento de Genética, Evolução, Microbiologia e Imunologia. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacintho da Silva. Campinas, SP, Brasil.Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond

MEF2C Silencing Attenuates Load-Induced Left Ventricular Hypertrophy by Modulating mTOR/S6K Pathway in Mice

Background: The activation of the members of the myocyte enhancer factor-2 family (MEF2A, B, C and D) of transcription factors promotes cardiac hypertrophy and failure. However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear. Methodology/Principal Findings: In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1a and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice. Conclusion/Significance: These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertroph