Princípio da Insignificância

O princípio da insignificância pode ser considerado como um meio de recuperar a legitimidade do Direito Penal, com a soma de seus valores à qualidade dos fatos que visam, de maneira abstrata ou concreta, a reprimir. O presente trabalho teve como objetivo observar as situações em que o Princípio da Insignificância pode ser aplicado. O Estado Democrático de Direito tem por finalidade tutelar os bens jurídicos mais importantes para a proteção da sociedade, e não é toda conduta humana que merece reprovação pelo Direito Penal, pois ele está voltado a resguardar e proteger as garantias e direitos fundamentais dos cidadãos, alicerçado nos princípios da dignidade das pessoas humana e da intervenção mínima. Para a aplicação do Princípio da Insignificância, deve-se observar requisitos objetivos, ou seja a mínima ofensividade da conduta; ausência de periculosidade social da ação; reduzido grau de reprovabilidade do comportamento; e inexpressividade da lesão jurídica, além dos quesitos subjetivos, que levam em conta a situação do fato, apreciando as condições subjetivas do sujeito ativo do crime e do sujeito passivo a qual se relaciona com a vítima do crime. No âmbito dos crimes contra o patrimônio, não há um valor máximo a limitar a incidência do Princípio da Insignificância, assim, sua análise há de ser efetuada levando-se em conta o contexto em que se deu a prática da conduta, especialmente a importância do objeto material, a condição econômica da vítima e o resultado produzido. O Princípio da Insignificância atua como excludente de tipicidade, pois os crimes de bagatela, considerados insignificantes, configuram-se incapazes de provocar lesão ou perigo de lesão efetiva, o que torna inexistente a tipicidade conglobante e, sem ela, o fato deixa de ser típico e, consequentemente de ser crime. Porém, percebe-se que a melhor solução para os crimes de bagatela é a criação de sanções alternativas, proporcionais ao ato praticado, na tentativa de educar a sociedade, para que haja uma diminuição na taxa de criminalidade, ao invés de tornar atípico um fato ilícito, descaracterizando o crime, pois dessa forma o infrator não receberá o aval do Estado para praticar pequenos delitos, evitando a punição exacerbada e ao mesmo tempo, a banalização dessas ações. Palavras-chave: Principio da Insignificância. Direito Penal. Criminalidad

Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma

High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and beta 1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics. Timp1 downregulation resulted in decreased anoikis resistance, clonogenicity, dacarbazine resistance, and in vivo tumor growth and lung colonization. In metastatic cells, pAKT(Thr308) is highly expressed, contributing to anoikis resistance. We showed that PDK1(Ser241) and PKC beta IISer660 are activated by Timp1 in different stages of melanoma progression, contributing to colony formation and anoikis resistance. Moreover, simultaneous inhibition of Timp1 and AKT in metastatic cells resulted in more effective anoikis inhibition. Our findings demonstrate that Timp1 promotes cell survival with the participation of PDK1 and PKC in melanoma. In addition, Timp1 and AKT act synergistically to confer anoikis resistance in advanced tumor stages. This study brings new insights about the mechanisms by which Timp1 promotes cell survival in melanoma, and points to novel perspectives for therapeutic approaches.Fundacao de Amparo a Pesquisa do Estado de Sao PauloConselho Nacional de Desenvolvimento Cientifico e TecnologicoUniv Fed Sao Paulo, Dept Pharmacol, BR-04039032 Sao Paulo, BrazilUniv Sao Paulo, Sch Med, Canc Inst Sao Paulo, Ctr Translat Invest Oncol LIM 24, BR-01246000 Sao Paulo, BrazilFac Med Santa Casa Sao Paulo, BR-01221020 Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Pharmacol, BR-04039032 Sao Paulo, Brazil|FAPESP: 2010/18715-8FAPESP: 2011/12306-1FAPESP: 2014/13663-0CNPq: 470681/2012-8Web of Scienc

The C-terminal tail of ribosomal protein Rps15 is engaged in cytoplasmic pre-40S maturation

The small ribosomal subunit protein Rps15/uS19 is involved in early nucleolar ribosome biogenesis and subsequent nuclear export of pre-40S particles to the cytoplasm. In addition, the C-terminal tail of Rps15 was suggested to play a role in mature ribosomes, namely during translation elongation. Here, we show that Rps15 not only functions in nucleolar ribosome assembly but also in cytoplasmic pre-40S maturation, which is indicated by a strong genetic interaction between Rps15 and the 40S assembly factor Ltv1. Specifically, mutations either in the globular or C-terminal domain of Rps15 when combined with the non-essential ltv1 null allele are lethal or display a strong growth defect. However, not only rps15 ltv1 double mutants but also single rps15 C-terminal deletion mutants exhibit an accumulation of the 20S pre-rRNA in the cytoplasm, indicative of a cytoplasmic pre-40S maturation defect. Since in pre-40S particles, the C-terminal tail of Rps15 is positioned between assembly factors Rio2 and Tsr1, we further tested whether Tsr1 is genetically linked to Rps15, which indeed could be demonstrated. Thus, the integrity of the Rps15 C-terminal tail plays an important role during late pre-40S maturation, perhaps in a quality control step to ensure that only 40S ribosomal subunits with functional Rps15 C-terminal tail can efficiently enter translation. As mutations in the C-terminal tail of human RPS15 have been observed in connection with chronic lymphocytic leukaemia, it is possible that apart from defects in translation, an impaired late pre-40S maturation step in the cytoplasm could also be a reason for this disease.Austrian science fund (FWF) P27996- B21, P28874-B21Ministerio de Ciencia e Innovación PID2019–103850-GB-I00Agencia Estatal de Investigación AEI/10.13039/ 501100011033Junta de Andalucía P20_00581, BIO-27

Analysis of mitochondrial enzymatic activity in blood lymphomonocyte fractions during infection with different Trypanosoma cruzi strains

Proinflammatory and inflammatory mediators induced by Trypanosoma cruzi infection increase the oxidative stress, generating toxicity for cells targeting mitochondria of different tissues. We studied the activity of citrate synthase and complexes I-IV of respiratory chain in mitochondria of blood lymphomonocyte fraction, from albino Swiss mice infected with different isolates of T. cruzi, during Chagas disease evolution. Complexes I-IV were modified in infected groups (p<0.05) in all the stages, and an inflammatory process of different magnitudes was detected in the heart and skeletal muscle according to the isolate. The citrate synthase activity presented modifications in the SGO Z12 and the Tulahuen group (p<0.05). Hearts showed fiber fragmentation and fibrosis; skeletal muscle presented inflammatory infiltrates and in the Tulahuen infected group, there were also amastigote nests. The inflammatory processes produced an oxidative stress that induced different alterations of mitochondrial enzymes activities in the lymphomonocyte fraction that can be detected by a simple blood extraction, suggesting that they could be used as disease markers, especially in the indeterminate phase of Chagas disease

Schulinterne Aushandlung der Anforderung, Lernende partizipieren zu lassen: welche Schulentwicklungschancen entstehen?

Im Beitrag wird der Frage nachgegangen, wie Partizipation von Schülerinnen und Schülern – als Qualitätsmerkmal – in Schulen ausgehandelt wird. Vor dem Hintergrund der Praxistheorie wird die Erweiterung von Partizipationsmöglichkeiten als Anlass für Schulentwicklung thematisiert, die sich in den verschiedenen Praktiken der Schule zeigt. Mit Hilfe der Dokumentarischen Methode wurden Gruppendiskussionen mit Lehrpersonen analysiert, wobei zwei Typen anhand der Vergleichsdimension Bild der Lernenden ausgearbeitet wurden. Im Beitrag wird gezeigt, wie diese Vergleichsdimension mit dem Verständnis der eigenen Rolle der Lehrpersonen zusammenhängt und daraus unterschiedliche Räume für Partizipation für Schülerinnen und Schüler entstehen. Im Anschluss an die Analyse wird diskutiert, wie aus der Dokumentarischen Methode, mit besonderem Fokus auf das Gespräch als Teamperformanz und Praktik, Hinweise auf relevante Fragestellungen an die schulische Partizipations- und Schulentwicklungsforschung abgeleitet werden können

Activation of endogenous p53 by combined p19Arf gene transfer and nutlin-3 drug treatment modalities in the murine cell lines B16 and C6

<p>Abstract</p> <p>Background</p> <p>Reactivation of p53 by either gene transfer or pharmacologic approaches may compensate for loss of p19Arf or excess mdm2 expression, common events in melanoma and glioma. In our previous work, we constructed the pCLPG retroviral vector where transgene expression is controlled by p53 through a p53-responsive promoter. The use of this vector to introduce p19Arf into tumor cells that harbor p53wt should yield viral expression of p19Arf which, in turn, would activate the endogenous p53 and result in enhanced vector expression and tumor suppression. Since nutlin-3 can activate p53 by blocking its interaction with mdm2, we explored the possibility that the combination of p19Arf gene transfer and nutlin-3 drug treatment may provide an additive benefit in stimulating p53 function.</p> <p>Methods</p> <p>B16 (mouse melanoma) and C6 (rat glioma) cell lines, which harbor p53wt, were transduced with pCLPGp19 and these were additionally treated with nutlin-3 or the DNA damaging agent, doxorubicin. Viral expression was confirmed by Western, Northern and immunofluorescence assays. p53 function was assessed by reporter gene activity provided by a p53-responsive construct. Alterations in proliferation and viability were measured by colony formation, growth curve, cell cycle and MTT assays. In an animal model, B16 cells were treated with the pCLPGp19 virus and/or drugs before subcutaneous injection in C57BL/6 mice, observation of tumor progression and histopathologic analyses.</p> <p>Results</p> <p>Here we show that the functional activation of endogenous p53wt in B16 was particularly challenging, but accomplished when combined gene transfer and drug treatments were applied, resulting in increased transactivation by p53, marked cell cycle alteration and reduced viability in culture. In an animal model, B16 cells treated with both p19Arf and nutlin-3 yielded increased necrosis and decreased BrdU marking. In comparison, C6 cells were quite susceptible to either treatment, yet p53 was further activated by the combination of p19Arf and nutlin-3.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first study to apply both p19Arf and nutlin-3 for the stimulation of p53 activity. These results support the notion that a p53 responsive vector may prove to be an interesting gene transfer tool, especially when combined with p53-activating agents, for the treatment of tumors that retain wild-type p53.</p

Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma

HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed similar to 60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed similar to 60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC-PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), BrazilFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil [2010/17668-6]Univ Fed Sao Paulo, UNIFESP, Dept Clin & Expt Oncol, Discipline Hematol & Hemotherapy, Sao Paulo, SP, BrazilUniv Sao Paulo, Fac Med, Canc Inst State Sao Paulo, Ctr Translat Invest Oncol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, UNIFESP, Dept Pathol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, UNIFESP, Dept Biochem, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, UNIFESP, Dept Clin & Expt Oncol, Discipline Hematol & Hemotherapy, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, UNIFESP, Dept Pathol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, UNIFESP, Dept Biochem, Sao Paulo, SP, BrazilFAPESP [2010/17668-6]Web of Scienc

Insights into the evolutionary conserved regulation of Rio ATPase activity

Department of Biochemistry III ‘House of the Ribosome’ and by the DFG Collaborative Research Center [SFB960-AP1] ‘Ribosome formation: principles of RNP biogenesis and control of their function’ (to S.F.-C.).; Work in the MacNeill laboratory was funded by Forskningsrådet for Natur og Univers (FNU) [sagsnr. 272-05-0446]; Scottish Universities Life Sciences Alliance (SULSA); Research in the Medenbach laboratory is supported by the Bavarian Research Network for Molecular Biosystems (BioSysNet); German Research Foundation (DFG) [ME4238/1-1]; DFG Collaborative Research Center [SFB960-B11] ‘Ribosome formation: principles of RNP biogenesis and control of their function’; German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept [01ZX1401D]; Work in the Siebers laboratory was funded by a grant from the German Science Foundation (DFG) [SI642/10-1] from the Federal Ministry of Education and Research (BMBF) [0316188A]; Work in the LaRonde laboratory was funded by National Science Foundation [MCB0953493]; Publishing of this work was supported by the German Research Foundation (DFG) within the funding program Open Access Publishing. Funding for open access charge: DFG—Open Access program.Eukaryotic ribosome biogenesis is a complex dynamic process which requires the action of numerous ribosome assembly factors. Among them, the eukaryotic Rio protein family members (Rio1, Rio2 and Rio3) belong to an ancient conserved atypical protein kinase/ ATPase family required for the maturation of the small ribosomal subunit (SSU). Recent structure-function analyses suggested an ATPase-dependent role of the Rio proteins to regulate their dynamic association with the nascent pre-SSU. However, the evolutionary origin of this feature and the detailed molecular mechanism that allows controlled activation of the catalytic activity remained to be determined. In this work we provide functional evidence showing a conserved role of the archaeal Rio proteins for the synthesis of the SSU in archaea. Moreover, we unravel a conserved RNA-dependent regulation of the Rio ATPases, which in the case of Rio2 involves, at least, helix 30 of the SSU rRNA and the P-loop lysine within the shared RIO domain. Together, our study suggests a ribosomal RNA-mediated regulatory mechanism enabling the appropriate stimulation of Rio2 catalytic activity and subsequent release of Rio2 from the nascent pre- 40S particle. Based on our findings we propose a unified release mechanism for the Rio proteins.Publisher PDFPeer reviewe

Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26

The TRIM-NHL protein Meiotic P26 (Mei-P26) acts as a regulator of cell fate in Drosophila. Its activity is critical for ovarian germline stem cell maintenance, differentiation of oocytes, and spermatogenesis. Mei-P26 functions as a post-transcriptional regulator of gene expression; however, the molecular details of how its NHL domain selectively recognizes and regulates its mRNA targets have remained elusive. Here, we present the crystal structure of the Mei-P26 NHL domain at 1.6 Å resolution and identify key amino acids that confer substrate specificity and distinguish Mei-P26 from closely related TRIM-NHL proteins. Furthermore, we identify mRNA targets of Mei-P26 in cultured Drosophila cells and show that Mei-P26 can act as either a repressor or activator of gene expression on different RNA targets. Our work reveals the molecular basis of RNA recognition by Mei-P26 and the fundamental functional differences between otherwise very similar TRIM-NHL proteins

Determinants of female sexual function in inflammatory bowel disease: a survey based cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>Sexual function is impaired in women with inflammatory bowel disease (IBD) as compared to normal controls. We examined disease specific determinants of different aspects of low sexual function.</p> <p>Methods</p> <p>Women with IBD aged 18 to 65 presenting to the university departments of internal medicine and surgery were included. In addition, a random sample from the national patients organization was used (separate analyses). Sexual function was assessed by the Brief Index of Sexual Function in Women, comprising seven different domains of sexuality. Function was considered impaired if subscores were < -1 on a z-normalized scale. Results are presented as age adjusted odds ratios with 95% CI based on multiple logistic regression.</p> <p>Results</p> <p>336 questionnaires were included (219 Crohn's disease, 117 ulcerative colitis). Most women reported low sexual activity (63%; 17% none at all, 20% moderate or high activity). Partnership satisfaction was high in spite of low sexual interest in this group. Depressed mood was the strongest predictor of low sexual function scores in all domains. Urban residency and higher socioecomic status had a protective effect. Disease activity was moderately associated with low desire (OR 1.8, 95% CI 1.0 to 3.2). Severity of the disease course impacted most on intercourse frequency (OR 2.3, 95% CI 1.4 to 4.7). Lubrication problems were more common in smokers (OR 2.5, 95% CI 1.3 to 5.1).</p> <p>Conclusion</p> <p>Mood disturbances and social environment impacted more on sexual function in women with IBD than disease specific factors. Smoking is associated with lubrication problems.</p