RESUMO
Socio-emotional and motivational skills are routinely measured using self-reports in large-scale educational assessments. Measures exploiting test-takers' behaviour during the completion of questionnaires or cognitive tests are increasingly used as alternatives to self-reports in the economics of education literature. We compute behavioural measures of socio-emotional and motivational skills using data from the Programme for International Student Assessment (PISA). We find that these measures capture important aspects of students' academic profiles: some are importantly associated with contemporaneous performance and educational attainment and most measures have a high degree of stability over time. However, these measures are only limitedly correlated among themselves and have low correlations with self-report measures of the same constructs. This is likely a reflection of the fact that behavioural measures are representations of the test taker current 'state', rather than descriptions of the participant view of their own 'trait' like the self-report measures. Moreover, the low correlation across measures suggests that they capture different behavioural responses to the test-taking situation. These differences are still limitedly understood because the measures are constructed ex-post using collateral information collected during the administration of assessments rather than developed ex ante in line with theoretical models of human cognition and affect.
Assuntos
Emoções , Motivação , Humanos , Avaliação Educacional , Estudantes , EscolaridadeRESUMO
BACKGROUND: Kicking a ball is a very frequent action in sport and leisure time activities and a low proficiency in this skill could limit the participation in recreational sport activities. This issue is emphasised in individuals with Down syndrome (IDS) for which data about motor competence in kicking are limited to children. Here, we aim at evaluating the kicking competence of IDS combining a qualitative and a quantitative method. METHODS: Twenty-three adult IDS and 21 typically developed individuals (ITD) volunteered to participate in the study. Peak-to-peak 3D linear acceleration and angular velocity were recorded at 200 samples/s using two inertial measurement units placed on the lower back and lateral malleolus of the dominant limb during kicking. Motor competence in kicking was assessed according to the criteria proposed in the test of gross motor development version 3 (TGMD-3). RESULTS: Individuals with Down syndrome showed lower motor competence (ITD: 5.9 ± 1.2; IDS: 3.2 ± 2.0) and lower angular velocities about the cranio-caudal (ITD: 3.0 ± 1.8; IDS: 2.1 ± 1.1 rad/s) and medio-lateral axes (ITD: 4.5 ± 1.5; IDS: 3.0 ± 1.1 rad/s) of the trunk compared with ITD. Shank angular velocity about the medio-lateral axis was lower in IDS (ITD: 14.3.6 ± 4.0; IDS: 9.9 ± 2.8 rad/s). CONCLUSIONS: The lower trunk angular velocity in IDS may limit the possibility to rely on the proximal-to-distal sequencing commonly observed in kicking and generate high shank angular velocity upon ball impact. The lower trunk angular velocity may result from orthopaedic features of the pelvic girdle and possibly from a poorer neuromuscular control of core muscles.
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Síndrome de Down , Esportes , Dispositivos Eletrônicos Vestíveis , Adulto , Fenômenos Biomecânicos , Criança , Humanos , Extremidade Inferior/fisiologiaRESUMO
BACKGROUND: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. OBJECTIVES: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-ß signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. METHODS: Immunohistochemistry was used to analyse AMBRA1 and TGF-ß2 in a cohort of 109 AJCC all-stage melanomas, and TGF-ß2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-ß2 signalling evaluated in primary keratinocytes. RESULTS: Increased tumoral TGF-ß2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-ß2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). CONCLUSIONS: Collectively, these data suggest a paracrine mechanism whereby TGF-ß2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.
Assuntos
Melanoma , Neoplasias Cutâneas , Fator de Crescimento Transformador beta2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Epiderme/metabolismo , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores/metabolismoRESUMO
INTRODUCTION: Educational attainment is associated with important life outcomes including labour market performance, health status, well-being, civic and political participation. An important question is whether it is possible to identify early those students who lack the achievement motivation that is needed to complete a higher education degree. METHODS: Longitudinal follow-ups of representative samples of participants in the 2000 and 2003 Programme for International Student Assessment (PISA) from Australia, Denmark and Switzerland (N = 3110; 1130; and 1962; age = 15 to 27; % females 51%, 51%, 49%; ethnicity/race unknown) were used to identify the association between a measure of effort on a cognitively demanding low-stake task at age 15 - performance decline during the test - and educational attainment at age 25-27. RESULTS: A one SD difference in performance decline was associated with a 5-6 percentage point difference in the probability of obtaining tertiary-level qualifications (r = -0.15 in Australia; -0.11 in Denmark and -0.11 in Switzerland). We find no evidence of differences in this relationship across genders, socio-economic status and baseline levels of ability in the three countries. The association between performance decline and educational attainment is homogeneous across these groups. Self-reported measures of achievement motivation were not predictive of educational attainment in the three countries. CONCLUSIONS: Our work contributes new longitudinal evidence to the body of research in education employing behavioural measures of motivation and engagement. It can be used to understand the potential long-term consequences of disparities in students' preparation to sustain effort over cognitively demanding tasks.
Assuntos
Sucesso Acadêmico , Motivação , Adolescente , Adulto , Escolaridade , Feminino , Nível de Saúde , Humanos , Masculino , Classe Social , Adulto JovemRESUMO
OBJECTIVE: To predict the occult tumor involvement of nipple-areola complex (NAC) using preoperative MR imaging and to investigate whether the intraoperative histopathological examination of the subareolar tissue is still necessary. PATIENTS AND METHODS: Out of 712 patients submitted to nipple-sparing mastectomy (NSM) between 2014 and 2019, we selected 188 patients who underwent preoperative breast MRI. Breast MRI and intraoperative histopathological examination of the subareolar tissue were performed to predict NAC involvement at permanent pathology. All parameters were correlated with final pathological NAC assessment by univariate and multivariate analysis. RESULTS: Forty-three patients (22.9%) had tumor involvement of the NAC. At univariate analysis, non-mass enhancement type (p = 0.009), multifocality/multicentricity (p = 0.002), median tumor size (p < 0.001), median tumor-NAC distance measured by MRI (p < 0.001), tumor-NAC distance ≤ 10 mm (p < 0.001) and tumor-NAC distance ≤ 20 mm (p < 0.001), and lymphovascular invasion (p = 0.001) were significantly correlated with NAC involvement. At multivariate analysis, only tumor-NAC distance ≤ 10 mm retained statistical significance. The sensitivity and specificity of MRI tumor-NAC distance ≤ 10 mm were 79.1% and 97.2% and those of intraoperative pathologic assessment were 74,4% and 100%, respectively. CONCLUSIONS: Tumor-NAC distance is the only reliable MRI characteristic that can predict NAC involvement in breast cancer patients. Although several cut-offs showed promising performances, intraoperative pathologic assessment is still mandatory.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Imageamento por Ressonância Magnética , Mamilos/diagnóstico por imagem , Biópsia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Análise Multivariada , Mamilos/cirurgiaRESUMO
INTRODUCTION: The purpose of our work was to evaluate the feasibility of prostate multiparametric MR imaging at 1.5-T without endorectal coil using an 8 channel pelvic phased array coil. MATERIAL AND METHODS: A total of 154 patients who underwent mp-MRI were retrospectively included. Patients received a standardized mp-MRI, compliant with 2012 European Society of Uro-Radiology guidelines, with 1·5 T magnetic field strength and an 8 channel pelvic phased-array coil. Two blinded readers graded the image quality of mp-MRI on a three-point scale and they scored the prostate lesions according to PI-RADS v2. All PI-RADS of 4 or 5 underwent biopsy. A third radiologist and a pathologist verified the correspondence between the MRI images and the results of the biopsy. RESULTS: 64 (41.6%) patients showed a Pi-rads of 4 or 5. At biopsy, 79.7% showed a Gleason score ≥7, 12.5% showed a Gleason score of 6 and 7.8% showed a negative biopsy. In the group of Pi-rads ≤ 3, 12 patients underwent a biopsy with the following results: negative biopsy in 33.3%, atypical Small Acinar Proliferation in 16.7%, prostatic intraepithelial neoplasia in 25% and indolent PCa 25%. Mp-MRI in the identification of clinically significant cancer provided a low percentage of false positive (7.8%) while in 79.7% of cases it was capable to detect clinically significant prostate cancer. In 92.2% of patients mp-MRI identified a prostate cancer with a Gleason score ≥6. The inter-reader agreement was excellent in defining both the quality of the examination and the PI-RADS category (k = 0.83 and k = 0.70, respectively). CONCLUSIONS: mp-MRI at 1.5-T without endorectal coil using an 8 channel phased array is an appropriate tool for early detection of clinically significant prostate cancer. IMPLICATIONS FOR PRACTICE: 8 channel pelvic phased array is still an appropriate tool for early detection of clinically significant prostate cancer and for obtaining a reduction in overdiagnosis of indolent PCa.
Assuntos
Imageamento por Ressonância Magnética , Neoplasias da Próstata , Humanos , Biópsia Guiada por Imagem , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Type 2 transglutaminase (TG2) is a multifunctional protein involved in various biological processes playing a key regulatory role in cell homeostasis such as cell death and autophagy. New evidence is emerging that support an important role of autophagy in regulating normal hematopoiesis. Prompted by these findings, in this study we investigated in vivo involvement of TG2 in mouse hematopoiesis under normal or nutrient deprivation conditions. We found that the number and rate of differentiation of bone marrow hematopoietic stem cell was decreased in the TG2 knockout mice. We present evidence showing that these effects on hematopoietic system are very likely due to the TG2-dependent impairment of autophagy. In fact, stimulation of autophagy by starvation is able to rescue the block of the differentiation of stem cells progenitors in the TG2 KO mice. It was also shown that the RhoA/ERK½ pathway, known to be essential for regulation of the bone marrow progenitor cells homeostasis, was significantly impaired in the absence of TG2. Hence, this study expanded our knowledge about TG2 discovering a role of this enzyme in regulation of hematopoiesis.
Assuntos
Autofagia , Proteínas de Ligação ao GTP/fisiologia , Células-Tronco Hematopoéticas , Transglutaminases/fisiologia , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Hematopoese , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 2 Glutamina gama-GlutamiltransferaseRESUMO
Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.
Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Ubiquitina-Proteína Ligases/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Transdiferenciação Celular , Humanos , Lisina/metabolismo , Camundongos , Camundongos Knockout , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Mioblastos/citologia , Mioblastos/metabolismo , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Mycobacterium tuberculosis (MTB), the aetiological agent of tuberculosis (TB), is capable of interfering with the phagosome maturation pathway, by inhibiting phagosome-lysosome fusion and the autophagic process to ensure survival and replication in macrophages. Thus, it has been proposed that the modulation of autophagy may represent a therapeutic approach to reduce MTB viability by enhancing its clearance. OBJECTIVE: The aim of this study was to investigate whether transglutaminase type 2 (TG2) is involved in the pathogenesis of MTB. RESULTS: We have shown that either genetic or pharmacological inhibition of TG2 leads to a marked reduction in MTB replicative capacity. Infection of TG2 knockout mice demonstrated that TG2 is required for MTB intracellular survival in macrophages and host tissues. The same inhibitory effect can be reproduced in vitro using Z-DON, a specific inhibitor of the transamidating activity of TG2. Massive cell death observed in macrophages that properly express TG2 is hampered by the absence of the enzyme and can be largely reduced by the treatment of wild-type macrophages with the TG2 inhibitor. Our data suggest that reduced MTB replication in cells lacking TG2 is due to the impairment of LC3/autophagy homeostasis. Finally, we have shown that treatment of MTB-infected murine and human primary macrophages with cystamine, a TG2 inhibitor already tested in clinical studies, causes a reduction in intracellular colony-forming units in human macrophages similar to that achieved by the anti-TB drug capreomycin. CONCLUSION: These results suggest that inhibition of TG2 activity is a potential novel approach for the treatment of TB.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , Mycobacterium tuberculosis/patogenicidade , Transglutaminases/metabolismo , Tuberculose/metabolismo , Animais , Autofagia , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Proteína 2 Glutamina gama-Glutamiltransferase , Tuberculose/microbiologia , Tuberculose/patologiaRESUMO
The human transglutaminases (TGases) are a widely distributed and peculiar group of enzymes that catalyze the posttranslational modification of proteins by the formation of isopeptide bonds. Tissue or type 2 transglutaminase (TG2) represents the most ubiquitous isoform belonging to TGases family. The vast array of biochemical functions catalyzed by TG2 distinguishes it from the other members of the TGase family. In the presence of high calcium levels TG2 catalyzes a vast array of protein posttranslational modifications, including protein-protein cross-linking, incorporation of primary amines into proteins, as well as glutamine deamination. In the last few years, it has become evident that TG2 is involved in the final maturation of autolysosomes. The TG2 regulation of autophagy occurs by its transamidating activity and its inhibition results in the intracellular increase of ubiquitinated protein aggregates. In this chapter, we describe the methods used in our laboratories to assess the catalytic activity of TG2 in the autophagic process.
Assuntos
Autofagia/fisiologia , Biologia Molecular/métodos , Transglutaminases/metabolismo , Animais , Proteínas de Ligação ao GTP/metabolismo , Humanos , Camundongos , Proteína 2 Glutamina gama-Glutamiltransferase , Proteínas de Ligação a RNA/metabolismo , Transglutaminases/análiseRESUMO
The aim of autophagy is to re-establish homeostasis in response to a variety of stress conditions. By forming double-membrane vesicles, autophagy engulfs damaged or superfluous cytoplasmic material and recycles degradation products for new synthesis or energy production. Of note, the same mechanism is used to capture pathogens and has important implications in both innate and adaptive immunity. To establish a chronic infection, pathogens have therefore evolved multiple mechanisms to evade autophagy-mediated degradation. HIV infection represents one of the best characterized systems in which autophagy is disarmed by a virus using multiple strategies to prevent the sequestration and degradation of its proteins and to establish a chronic infection. HIV alters autophagy at various stages of the process in both infected and bystander cells. In particular, the HIV proteins TAT, NEF and ENV are involved in this regulation by either blocking or stimulating autophagy through direct interaction with autophagy proteins and/or modulation of the mTOR pathway. Although the roles of autophagy during HIV infection are multiple and vary amongst the different cell types, several lines of evidence point to a potential beneficial effect of stimulating autophagy-mediated lysosomal degradation to potentiate the immune response to HIV. Characterization of the molecular mechanisms regulating selective autophagy is expected to be valuable for developing new drugs able to specifically enhance the anti-HIV response.
Assuntos
Autofagia/fisiologia , Infecções por HIV/imunologia , Proteínas Relacionadas à Autofagia/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções do Sistema Nervoso Central/imunologia , Células Dendríticas/imunologia , HIV/imunologia , HIV/fisiologia , Humanos , Imunidade Celular/imunologia , Macrófagos/imunologia , Replicação Viral/fisiologiaRESUMO
Hepatitis C virus (HCV) is a major leading cause of hepatocellular carcinoma (HCC). HCV-induced hepatocarcinogenesis is a multistep process resulting from a combination of pathway alterations that are either caused directly by viral factors or immune mediated as a consequence of a chronic state of inflammation. Host genetic variation is now emerging as an additional element that contribute to increase the risk of developing HCC. The advent of direct-acting antiviral agents foresees a rapid decline of HCC rate in HCV patients. However, a full understanding of the HCV-mediated tumourigenic process is required to elucidate if pro-oncogenic signatures may persist after virus clearance, and to identify novel tools for HCC prevention and therapy. In this review, we summarize the current knowledge of the molecular mechanisms responsible for HCV-induced hepatocarcinogenesis.
Assuntos
Carcinoma Hepatocelular/virologia , Hepatite C/genética , Neoplasias Hepáticas/virologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Carcinogênese , Carcinoma Hepatocelular/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Neoplasias Hepáticas/genéticaRESUMO
Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Doença pelo Vírus Ebola/patologia , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Anticorpos Monoclonais/uso terapêutico , Apoptose , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Ebolavirus/fisiologia , ELISPOT , Citometria de Fluxo , Antígenos HLA-DR/metabolismo , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/imunologia , Humanos , Imuno-Histoquímica , Interferon gama/análise , Estudos Longitudinais , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Receptor fas/metabolismoRESUMO
Infection by human immunodeficiency virus-1 (HIV-1) is associated with a progressive decrease in CD4 T-cell numbers and the consequent collapse of host immune defenses. The major pathogenic mechanism of AIDS is the massive apoptotic destruction of the immunocompetent cells, including uninfected cells. The latter process, also known as by-stander killing, operates by various mechanisms one of which involves the formation of syncytia which undergo cell death by following a complex pathway. We present here a detailed and curated map of the syncytial apoptosis signaling network, aimed at simplifying the whole mechanism that we have characterized at the molecular level in the last 15 years. The map was created using Systems Biology Graphical Notation language with the help of CellDesigner software and encompasses 36 components (proteins/genes) and 54 interactions. The simplification of this complex network paves the way for the development of novel therapeutic strategies to eradicate HIV-1 infection. Agents that induce the selective death of HIV-1-elicited syncytia might lead to the elimination of viral reservoirs and hence constitute an important complement to current antiretroviral therapies.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Células Gigantes/metabolismo , Proteína gp160 do Envelope de HIV/metabolismo , Infecções por HIV/metabolismo , HIV-1/metabolismo , Transdução de Sinais/genética , Apoptose/genética , Efeito Espectador/genética , Antígenos CD4/genética , Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/patologia , Fusão Celular , Regulação da Expressão Gênica , Células Gigantes/patologia , Proteína gp160 do Envelope de HIV/genética , Infecções por HIV/genética , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/genética , Humanos , Mapeamento de Interação de Proteínas , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Receptores Purinérgicos/genética , Receptores Purinérgicos/metabolismoRESUMO
Ebola virus (EBOV) belongs to the Filoviridae family and is responsible for a severe disease characterized by the sudden onset of fever and malaise accompanied by other non-specific signs and symptoms; in 30-50% of cases hemorrhagic symptoms are present. Multiorgan dysfunction occurs in severe forms with a mortality up to 90%. The EBOV first attacks macrophages and dendritic immune cells. The innate immune reaction is characterized by a cytokine storm, with secretion of numerous pro-inflammatory cytokines, which induces a huge number of contradictory signals and hurts the immune cells, as well as other tissues. Other highly pathogenic viruses also trigger cytokine storms, but Filoviruses are thought to be particularly lethal because they affect a wide array of tissues. In addition to the immune system, EBOV attacks the spleen and kidneys, where it kills cells that help the body to regulate its fluid and chemical balance and that make proteins that help the blood to clot. In addition, EBOV causes liver, lungs and kidneys to shut down their functions and the blood vessels to leak fluid into surrounding tissues. In this review, we analyze the molecular mechanisms at the basis of Ebola pathogenesis with a particular focus on the cell death pathways induced by the virus. We also discuss how the treatment of the infection can benefit from the recent experience of blocking/modulating cell death in human degenerative diseases.
Assuntos
Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/virologia , Morte Celular/fisiologia , Células Dendríticas/metabolismo , Humanos , Macrófagos/metabolismoRESUMO
AIM: The aim of the present study was to investigate the stress--related changes of a TeamGym competition considering both physiological [i.e. salivary cortisol (sC) and alpha--amylase (sAA)] and psychological (i.e. state anxiety) responses in relation to exercise intensity and competition outcomes. METHODS: Eleven (5 males and 6 females) elite TeamGym athletes (age: 21--28 yrs) were administered the State--Trait Anxiety Inventory before an official international TeamGym competition. sAA and sC samples were collected 15 minutes prior to competition, after each apparatus, 10--min and 30--min after competition. Exercise intensity was estimated by heart rate (HR) recording and performance was evaluated by three international judges. All these parameters were correlated with competition outcomes. RESULTS: TeamGym competition posed a low exercise load (most of exercise was performed below 85% of the individual HR max ). Significant increases (P<0.004) in sAA (3.53 fold induction) and state anxiety (P=0.045) were observed, with respect to baseline values. Conversely, sC remained stable throughout the competition. Significant (P=0.029) correlation between sAA, state anxiety and competition outcomes emerged. CONCLUSIONS: Present findings provide the first evidence that the psycho--physiological stress response prior to and during competition can affect performance outcome, especially in a technical sport such as TeamGym.
RESUMO
The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF(V600E) mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAF(V600E) induces a chronic ER stress status directly increasing basal cell autophagy. BRAF(V600E)-mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAF(V600E)-mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAF(V600E) melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma.
Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Melanoma/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Apoptose/genética , Apoptose/fisiologia , Autofagia/genética , Autofagia/fisiologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/genética , Humanos , Lentivirus/genética , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas , Melanoma Maligno CutâneoRESUMO
AIM: The aim of the present study was to investigate heart rate (HR), salivary cortisol (sC) alpha-amylase (sAA) and rating of perceived exertion (RPE) in relation to competition outcome during a half marathon. METHODS: HR was monitored and salivary samples were collected during an official half marathon in five Master endurance runners (age 47 ± 7 years). RPE was collected using a 100-mm Visual Analogue Scale (VAS) 30 minutes after the end of competition. RESULTS: Performance corresponded to 94% of their personal best (PB). Athletes spent 53.7% of total race time at intensities above 95% HRmax. RPE showed values of 68 ± 8 mm. With respect to pre-competition values (25.54 ± 6.39 nmol/L), sC concentrations significantly increased (P=0.043) by 59% immediately after the race (40.54 ± 3.95 nmol/L) and remained elevated until 1 h post exercise. Pre-competition sAA concentrations (90.59 ± 42.86 U/mL) were 118% higher (P=0.043) with respect to time-matched baseline values (197.92 ± 132 U/mL). sAA increased (192%; P=0.043) immediately after the race and was higher than time-matched resting samples. The better each athlete performed the greater cortisol increase during exercise (P<0.001). Performance was not correlated to the anticipatory sAA (the percent difference between pre-competition values and time-matched baseline ones) or to the sAA increase during exercise. CONCLUSION: This is the first attempt to study the stress-related responses during official endurance competitions in master runners. Although the strict criteria of inclusion might have limited the statistical significance, the present findings indicate that endurance competition is a remarkable stressor for psycho-physiological aspects of master athletes.