RESUMO
In this article we seek to explain how safety mechanisms and risks evolve over time. The article focuses on a sociotechnical system, that of a polar traverse (a transport operation in a polar environment). In the study spanning a period of 27 years data were collected with ethnographic participative observations on three of the 56 traverses already achieved. Activities were traced from the whole 1398 daily reports and scale models of the convoy vehicles were used to reconstruct events during the traverses. Self-confrontation interviews were also conducted. A traverse feedback process was carried out which revealed that (1) whereas proactive safety is aimed at maintaining the continuous improvement of a system, reactive safety makes it possible to maintain the system's level of safety; (2) the development of redundancy and mixed technology contribute positively to the safety system. Improvements made to the safety system, its dynamics, and embodied resilience are discussed as well as the study limitations and implications. Practitioner summary: This article seeks to understand how safety has been ensured in logistical transport in extreme conditions in a case study extending over a period of more than 27 years. The study investigates how risks and safety mechanisms have evolved and the benefits of developing a traverse feedback process to improve safety. Abbreviations: IPEV: French Polar Institute (Institut Polaire Francais); DDU: Dumont d'Urville (French coastal antarctic station).
Assuntos
Ambientes Extremos , Gestão da Segurança/métodos , Gestão da Segurança/tendências , Meios de Transporte/métodos , Idoso , Regiões Antárticas , Humanos , Masculino , Medição de RiscoRESUMO
NG2-glia are known to proliferate in the adult brain, however the extent of their mitotic and regenerative capacity and particularly their adult origin is uncertain. By employing a paradigm of mitotic blockade in conjunction with genetic fate tracing we demonstrate that intracerebroventricular mitotic blocker infusion leads to wide-spread and complete ablation of NG2-glial cells in the hypothalamus and other periventricular brain regions. However, despite the extensive glia loss, parenchymal NG2-glia coverage is fully restored to pretreatment levels within two weeks. We further reveal that in response to mitotic blocker treatment, NG2-glia bordering the ablated territories start to express the stem cell marker nestin, divide and migrate to replace the lost cells. Importantly, the migration front of repopulating NG2-glia invariably proceeds from the distal parenchyma towards the ventricles, ruling out contributions of the subventricular zone neurogenic niche or the corresponding area of the third ventricle as source of new NG2-glia. NG2-CreER-based fate tracing further substantiates that NG2-glia which have been spared from mitotic blockade are the sole source of regenerating NG2-glia. Collectively, our data reveals that all adult NG2-glia retain the ability to divide and that they are capable of fully restoring parenchymal NG2-glia coverage after wide-spread NG2 cell loss, indicating complete self-sufficiency in maintaining NG2-glia population levels in the adult brain.
Assuntos
Antígenos/metabolismo , Diferenciação Celular/fisiologia , Neuroglia/fisiologia , Proteoglicanas/metabolismo , Regeneração/fisiologia , Animais , Antígenos/genética , Bromodesoxiuridina , Antígenos CD13/metabolismo , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/efeitos dos fármacos , Citarabina/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Nestina/metabolismo , Proteoglicanas/genética , RNA Mensageiro/metabolismo , Regeneração/efeitos dos fármacos , Regeneração/genética , Tamoxifeno/toxicidade , Fatores de TempoRESUMO
Female athletes have garnered considerable attention in the last few years as more and more women participate in sports events. However, despite the well-known repercussions of female sex hormones, few studies have investigated the specificities of elite female athletes. In this review, we present the current but still limited data on how normal menstrual phases, altered menstrual phases, and hormonal contraception affect both physical and cognitive performances in these elite athletes. To examine the implicated mechanisms, as well as the potential performances and health risks in this population, we then take a broader multidisciplinary approach and report on the causal/reciprocal relationships between hormonal status and mental and physical health in young (18-40 years) healthy females, both trained and untrained. We thus cover the research on both physiological and psychological variables, as well as on the Athlete Biological Passport used for anti-doping purposes. We consider the fairly frequent discrepancies and summarize the current knowledge in this new field of interest. Last, we conclude with some practical guidelines for eliciting improvements in physical and cognitive performance while minimizing the health risks for female athletes.
RESUMO
Two-dimensional color-coded pulsed Doppler ultrasonography (US) with a 12-MHz linear transducer was used to follow tumor growth and neoangiogenesis development in 12 transgenic mice developing a whole liver hepatocellular carcinoma (HCC) induced by the expression of SV40-T antigen. In this model, male mice developed HCC at various temporal and histologic stages (hyperplastic, four-eight wk; nodular, 12 wk; diffuse carcinoma, 16-20 wk), whereas female mice remained tumor free. Seven age-matched tumor-free mice were used as controls. Liver volume was calculated from B-mode images of the abdomen. Blood flow waveforms were recorded from the hepatic tumor-feeding artery upstream from the tumor vessels, allowing quantitative blood flow velocity measurements. Measurements were performed every four weeks from four to 20 weeks. As early as the hyperplastic stage (eight weeks), liver volume was increased by 2.7-fold, hepatic artery peak-systolic blood flow velocities (BFV) by 1.5-fold, end-diastolic BFV by 1.6-fold and mean BFV by 2.0-fold compared with control values (p < 0.001). Differences increased until 20 weeks and peak-systolic reached 90 +/- 6, end-diastolic 54 +/- 5 and mean BFV 48 +/- 5 cm s(-1). Successive measurements of BFV were reproducible and intraobserver repeatability coefficient values were <3 cm s(-1). In contrast, mesenteric artery BFV, which did not supply tumor region, did not show any significant difference with respect to control values. Thus, an increase in BFV constitutes a functional evaluation of tumor vascularity. In preclinical studies in small animals, measurements of liver volume and blood flow velocities in hepatic tumor-feeding artery provide a useful, reproducible, noninvasive, easy-to-repeat tool to monitor tumor growth and neoangiogenesis in hepatocellular carcinoma in mice.
Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Neovascularização Patológica/diagnóstico por imagem , Processamento de Sinais Assistido por Computador , Animais , Volume Sanguíneo , Feminino , Fígado/irrigação sanguínea , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Radiografia , Ultrassonografia Doppler em Cores , Ultrassonografia Doppler de PulsoRESUMO
The functioning of the genome is tightly related to its architecture. Therefore, understanding the relationship between different regulatory mechanisms and the organization of chromosomal domains is essential for understanding genome regulation. The majority of imprinted genes are assembled into clusters, share common regulatory elements, and, hence, represent an attractive model for studies of regulation of clusters of non-paralogous genes. Here, we investigated the relationship between genomic imprinting and diurnal regulation of genes from the imprinted domain of mouse chromosome 12. We compared gene expression patterns in C57BL/6 mice and congenic mice that carry the imprinted region from a Mus musculus molossinus strain MOLF/Ei. In the C57BL/6 mice, a putative enhancer/oscillator regulated the expression of only Mico1/Mico1os, whereas in the congenic mice its influence was spread onto Rtl1as, Dio3 and Dio3os, i.e. the distal part of the imprinted domain, resulting in coordinated diurnal variation in expression of five genes. Using additional congenic strains we determined that in C57BL/6 the effect of the putative enhancer/oscillator was attenuated by a linked dominant trans-acting factor located in the distal portion of chromosome 12. Our data demonstrate that (i) in adult organs, mRNA levels of several imprinted genes vary during the day, (ii) genetic variation may remove constraints on the influence of an enhancer and lead to spreading of its effect onto neighboring genes, thereby generating genotype-dependent expression patterns and (iii) different regulatory mechanisms within the same domain act independently and do not seem to interfere with each other.
Assuntos
Ritmo Circadiano/genética , Impressão Genômica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Iodeto Peroxidase/genética , Animais , Sítios de Ligação/genética , Proteínas de Ligação ao Cálcio , Córtex Cerebral/metabolismo , Elementos Facilitadores Genéticos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Atividade Motora/genética , Família Multigênica , Reação em Cadeia da Polimerase , Gravidez , RNA/genética , RNA/metabolismo , Especificidade da EspécieRESUMO
Vascular endothelial growth factor (VEGF) and Delta-like 4 ligand (DLL4) are the only genes whose haploinsufficiency results in vascular abnormalities. Although many common pathways are up-regulated in both vascular development and tumor angiogenesis and in vascular remodeling, the role of the Delta/Notch pathway has not been clearly defined in tumor angiogenesis. In this study, we assessed the expression of DLL4, Notch4, and ephrin B2 in transgenic mice developing hepatocarcinoma characterized by a strong remodeling of the tumor sinusoids. We also investigated the role of VEGF in the expression and biological functions of these molecules on human venous endothelial cells. In transgenic livers, we showed that DLL4, active Notch4, and ephrin B2 were gradually up-regulated within the hepatocarcinoma progression and expressed on tumor sinusoidal endothelial cells. In venous endothelial cells, we showed that VEGF up-regulates DLL4 and presenilin, and increased the activation of Notch4, leading to an up-regulation of ephrin B2 with a down-regulation of Eph B4. We also showed that the activation of Notch4 is required for VEGF-induced up-regulation of ephrin B2 and the differentiation of human venous endothelial cells in vitro. Accordingly, the disruption of Notch4 signaling by pharmacologic inhibition of presenilin or addition of soluble DLL4 inhibited the effect of VEGF on human venous endothelial cell migration and differentiation. Our study strongly suggests that a coordinated activation of DDL4/Notch4 and ephrin B2 pathways downstream of VEGF plays a key role in the abnormal remodeling of tumor vessels.
Assuntos
Endotélio Vascular/fisiologia , Efrina-B2/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Notch/fisiologia , Veias Umbilicais/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Ligação ao Cálcio , Carcinoma/patologia , Carcinoma Hepatocelular/patologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor Notch4 , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Sarco/endoplasmic reticulum Ca(2+)ATPases (SERCAs) pump free Ca(2+) from the cytosol into the endoplasmic reticulum. The human SERCA3 family counts six members named SERCA3a to 3f. However, the exact role of these different isoforms in cellular physiology remains undetermined. In this study, we compared some physiological consequences of SERCA3b and SERCA3f overexpression in HEK-293 cells. We observed that overexpression of SERCA3b affected cell adhesion capacity associated with a major disorganization of F-actin and a decrease in focal adhesion. Furthermore, we found that SERCA3f overexpression resulted in an increase in endoplasmic reticulum stress markers (including processing of X-box-binding protein-1 (XBP-1) mRNA and expression of chaperone glucose-regulated protein 78 (GRP78)). This was associated with the activation of caspase cascade and a higher spontaneous cell death. In conclusion, these data point for the first time to distinct physiological roles of SERCA3 isoforms in cell functions.
Assuntos
ATPases Transportadoras de Cálcio/metabolismo , Caspases/metabolismo , Isoenzimas/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Western Blotting , ATPases Transportadoras de Cálcio/genética , ATPases Transportadoras de Cálcio/fisiologia , Caspase 3 , Inibidores de Caspase , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Inibidores de Cisteína Proteinase/farmacologia , Proteínas de Ligação a DNA/genética , Chaperona BiP do Retículo Endoplasmático , Ativação Enzimática/efeitos dos fármacos , Expressão Gênica , Humanos , Isoenzimas/genética , Isoenzimas/fisiologia , Proteínas Nucleares/genética , Oligopeptídeos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição de Fator Regulador X , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/fisiologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Fatores de Tempo , Fatores de Transcrição , Transfecção , Proteína 1 de Ligação a X-BoxRESUMO
BACKGROUND/AIMS: The hypervascularity described in hepatocellular carcinoma varies according to the progression and the differentiation of the tumor, suggesting an angiogenic switch during tumor development. METHODS: We used a transgenic mouse model of hepatocellular carcinoma induced by the expression of SV40-T antigen, in which male mice developed hepatic tumors at various temporal and histological stages, whereas female mice remained tumor-free. We analyzed, by immunostaining and reverse transcription-polymerase chain reaction, factors involved in tumoral angiogenesis. RESULTS: We demonstrated that tumoral angiogenesis occurred before the development of diffuse hepatocarcinoma. We showed that some SV40-T-positive cells with an endothelial phenotype are involved in angiogenic processes, suggesting a partial vasculogenic mimicry. This tumoral angiogenesis is associated with platelet activation due to tissue factor expression in endothelial cells and invading macrophages. Normal and transgenic livers exhibited different pattern of expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) mRNA. CONCLUSIONS: This model of hepatocellular carcinoma displays marked tumoral angiogenesis, with proliferation, remodeling and arterialization of hepatic sinusoids, probably associated with a partial vasculogenic mimicry. Abnormal angiogenesis observed in hepatocarcinoma was associated with platelet activation by tissue factor (TF) produced by endothelial cells and invading macrophages. In this transgenic model, HIF-1alpha, VEGF, and TF play a crucial role in tumoral angiogenesis.
Assuntos
Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Neovascularização Patológica , Tromboplastina/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Progressão da Doença , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/sangue , Neovascularização Patológica/metabolismo , Ativação Plaquetária , RNA Mensageiro/metabolismo , Distribuição Tecidual , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Human T-cell leukemia virus I is the etiologic agent of adult T-cell leukemia (ATL), an aggressive T-cell malignancy. The viral oncoprotein Tax, through the activation of nuclear factorkappaB (NF-kappaB), CCAAT-enhancer binding protein (CREB), and activated protein-1 (AP-1) pathways, is a transcriptional regulator of critical genes for T-cell homeostasis. In ATL cells, activated AP-1 complexes induce the production of transforming growth factor beta1 (TGF-beta1). TGF-beta1 is an inhibitor of T-cell proliferation and cytotoxicity. Here we show that, in contrast to normal peripheral T cells, ATL cells are resistant to TGF-beta1-induced growth inhibition. The retroviral transduction of the Tax protein in peripheral T cells resulted in the loss of TGF-beta1 sensitivity. Transient transfection of Tax in HepG2 cells specifically inhibited Smad/TGF-beta1 signaling in a dose-dependent manner. In the presence of Tax transfection, increasing amounts of Smad3 restored TGF-beta1 signaling. Tax mutants unable to activate NF-kappaB or CREB pathways were also able to repress Smad3 transcriptional activity. Next we have demonstrated that Tax inhibits TGF-beta1 signaling by reducing the Smad3 DNA binding activity. However, Tax did not decrease the expression and the nuclear translocation of Smad3 nor did it interact physically with Smad3. Rather, Tax induced c-Jun N-terminal kinase (JNK) activity and c-Jun phosphorylation, leading to the formation of Smad3/c-Jun complexes. Whereas c-Jun alone abrogates Smad3 DNA binding, cotransfection of Tax and of a dominant-negative form of JNK or a c-Jun antisense-restored Smad3 DNA binding activity and TGF-beta1 responsiveness. In ATL and in normal T cells transduced by Tax, c-Jun was constitutively phosphorylated. Thus, we describe a new function of Tax, as a repressor of TGF-beta1 signaling through JNK/c-Jun constitutive activation, which may play a critical role in ATL leukemogenesis.