Mito-Nuclear Communication in Hepatocellular Carcinoma Metabolic Rewiring

As the main metabolic and detoxification organ, the liver constantly adapts its activity to fulfill the energy requirements of the whole body. Despite the remarkable adaptive capacity of the liver, prolonged exposure to noxious stimuli such as alcohol, viruses and metabolic disorders results in the development of chronic liver disease that can progress to hepatocellular carcinoma (HCC), which is currently the second leading cause of cancer-related death worldwide. Metabolic rewiring is a common feature of cancers, including HCC. Altered mito-nuclear communication is emerging as a driving force in the metabolic reprogramming of cancer cells, affecting all aspects of cancer biology from neoplastic transformation to acquired drug resistance. Here, we explore relevant aspects (and discuss recent findings) of mito-nuclear crosstalk in the metabolic reprogramming of hepatocellular carcinoma

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC

Frames e fala espontânea

Os estudos baseados em dados que tratam da noção de frame e do seu uso na análise da linguagem adotam unidades de análise que variam desde unidades lexicais até estruturas construcionais, sintáticas e textuais. Os mesmos princípios são utilizados em aplicações de processamento de linguagem natural. Neste artigo discutimos o porquê de se fazer necessária a inclusão das noções de unidade informacional e enunciado nas propostas de tratamento, via frames, da linguagem falada espontânea. A Teoria da Língua em Ato - TLA (CRESTI, 2000), que propõe o estudo da fala através da interface pragmática-prosódica e da sua segmentação em enunciados e unidades tonais, será brevemente apresentada, assim como sua aplicação a e validação através dos estudos de corpora aplicados a línguas românicas europeias (C-ORAL-ROM) e ao português brasileiro (C-ORAL-BRASIL).  Possíveis consequências para a incorporação do nível pragmático como a base analítica na constituição de frames para análise da fala espontânea serão discutidas

Illocution, Modality, Attitude, Information Patterning and Speech Annotation

Most of the papers collected in this book resulted from presentations and discussions undertaken during the V Lablita Workshop that took place at the Federal University of Minas Gerais, Brazil, on August 23-25, 2011. The workshop was held in conjunction with the II Brazilian Seminar on Pragmatics and Prosody. The guiding themes for the joint event were illocution, modality, attitude, information patterning and speech annotation. Thus, all papers presented here are concerned with theoretical and methodological issues related to the study of speech. Among the papers in this volume, there are different theoretical orientations, which are mirrored through the methodological designs of studies pursued. However, all papers are based on the analysis of actual speech, be it from corpora or from experimental contexts trying to emulate natural speech. Prosody is the keyword that comes out from all the papers in this publication, which indicates the high standing of this category in relation to studies that are geared towards the understanding of major elements that are constitutive of the structuring of speech

Para a compilação do C-ORAL-ANGOLA: um corpus de fala espontânea informal do português angolano

The paper introduces the architecture and compilation criteria for an Angolan Portuguese spontaneous speech corpus. After a brief introduction about the linguistic scenario in Angola, we present an in-depth description of the recording modalities and treatment related to the multiple sociolinguistic variations documented, with special attention to diaphasic variation. The first twenty-seven recorded texts are then detailed. These will make up a minicorpus, portraying at least 30,000 words. The minicorpus will be prosodically segmented and will display text-to-speech alignment. The last part of the article is dedicated to the methodological steps taken for the corpus compilation: acoustic quality definition, transcription criteria, prosodic segmentation procedures, revision, alignment and statistic validation.O trabalho apresenta a arquitetura e os critérios de compilação de um corpus de fala espontânea do português angolano. Após uma breve contextualização da realidade linguística de Angola, são apresentados em detalhe as modalidades de gravação e o tratamento das diferentes variações sociolinguísticas documentadas, destacando-se a atenção à variação diafásica. Em seguida, são detalhados os primeiros 27 textos gravados, que formarão um minicorpus de pelo menos 30.000 palavras, segmentado prosodicamente e oferecendo o texto alinhado ao sinal sonoro. A última parte do artigo é dedicada à discussão dos passos metodológicos da compilação do corpus: definição da qualidade acústica, critérios de transcrição, procedimento de segmentação prosódica, revisão, alinhamento e validação estatística

Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory

The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30 min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object–place learning and recall. Furthermore, our results are in accordance with previous reports that selective molecular mechanisms underlie either short term memory, long term memory, or both. Furthermore, our discovery that administration of rapamycin increased the activation of mTORC2 in microglial cells supports a reappraisal of the beneficial/adverse effects of rapamycin administration

Oxidative Stress in the Healthy and Wounded Hepatocyte: A Cellular Organelles Perspective

Accurate control of the cell redox state is mandatory for maintaining the structural integrity and physiological functions. This control is achieved both by a fine-tuned balance between prooxidant and anti-oxidant molecules and by spatial and temporal confinement of the oxidative species. The diverse cellular compartments each, although structurally and functionally related, actively maintain their own redox balance, which is necessary to fulfill specialized tasks. Many fundamental cellular processes such as insulin signaling, cell proliferation and differentiation and cell migration and adhesion, rely on localized changes in the redox state of signal transducers, which is mainly mediated by hydrogen peroxide (H2O2). Therefore, oxidative stress can also occur long before direct structural damage to cellular components, by disruption of the redox circuits that regulate the cellular organelles homeostasis. The hepatocyte is a systemic hub integrating the whole body metabolic demand, iron homeostasis and detoxification processes, all of which are redox-regulated processes. Imbalance of the hepatocyte’s organelles redox homeostasis underlies virtually any liver disease and is a field of intense research activity. This review recapitulates the evolving concept of oxidative stress in the diverse cellular compartments, highlighting the principle mechanisms of oxidative stress occurring in the healthy and wounded hepatocyte