DOSSIÊ DO CENTRO ACADÊMICO DE ADMINISTRAÇÃO PÚBLICA UFPR: UMA CRÔNICA DOS FATOS

O presente artigo tem por objetivo realizar um relato de experiência por meio da análise da trajetória do Centro Acadêmico de Administração Pública (CAAP) UFPR, buscando reconhecer avanços e entraves à sua consolidação. Para tanto, valeu-se de textos que retratam da trajetória do Campo de Públicas como base teórica fundante. Quanto aos aspectos metodológicos parte-se de uma abordagem predominantemente qualitativa, cuja coleta e análise dos dados baseiam-se em documentos, registros e conversas com os membros que compuseram o CAAP no período de 2016-2020. Os resultados do estudo destacam os processos macro-políticos e o microcosmo que envolveram a força motriz do primeiro intento de criação em 2016. O presente relato presenta a fundação, a instituição de uma alma mater e a sinergia marcantes em 2017; os progressos da gestão de 2018 e os desafios de 2019. Discute-se as transições esperadas e inesperadas em 2020, no contexto da pandemia Covid-19. Por fim, destaca o legado do CAAP e reflete sobre o movimento estudantil no Campo de Públicas

ER shaping proteins regulate mitochondrial fission, outer membrane permeabilization and apoptosis

The mitochondrial fission machinery, comprising a dynamin-related GTPase, DRP-1, is crucial for the regulation of mitochondrial membrane dynamics. Recent reports suggest that the tubular architecture of the endoplasmic reticulum (ER) marks the constriction sites on the mitochondria to facilitate DRP-1-mediated mitochondrial fission. However, the role of several ER shaping proteins that maintain the elaborate network of tubes and sheets in mitochondrial constriction and fission is not yet known. In this report, we demonstrate that modulation of the expression levels of key ER shaping proteins, namely Reticulon1 (RTN-1), Reticulon 4 (RTN-4), Lunapark-1 (LNP-1) and CLIMP-63, markedly decreased the extent of mitochondrial fission mediated by BH3 mimetics, despite no detectable changes in DRP-1 recruitment to the mitochondria. Furthermore, modulation of ER shaping proteins significantly decreased other hallmarks of apoptosis, such as mitochondrial outer membrane permeabilization, caspase activation and phosphatidylserine externalization, and functioned independently of mitochondrial cristae remodeling, thus demonstrating a requirement of ER shaping proteins and ER structural integrity for the efficient execution of the instrinsic apoptotic pathway

Maritoclax and Dinaciclib inhibit MCL-1 activity and induce apoptosis in both a MCL-1-dependent and -independent manner

The anti-apoptotic BCL-2 family proteins are important targets for cancer chemotherapy. Specific and potent inhibitors of the BCL-2 family, such as ABT-263 (navitoclax) and ABT-199, are only effective against some members of the BCL-2 family but do not target MCL-1, which is commonly amplified in tumors and associated with chemoresistance. In this report, the selectivity and potency of two putative MCL-1 inhibitors, dinaciclib and maritoclax, were assessed. Although both compounds induced Bax/Bak- and caspase-9-dependent apoptosis, dinaciclib was more potent than maritoclax in downregulating MCL-1 and also in inducing apoptosis. However, the compounds induced apoptosis, even in cells lacking MCL-1, suggesting multiple mechanisms of cell death. Furthermore, maritoclax induced extensive mitochondrial fragmentation, and a Bax/Bak- but MCL-1-independent accumulation of mitochondrial reactive oxygen species (ROS), with an accompanying loss of complexes I and III of the electron transport chain. ROS scavengers, such as MitoQ, could not salvage maritoclax-mediated effects on mitochondrial structure and function. Taken together, our data demonstrate that neither dinaciclib nor maritoclax exclusively target MCL-1. Although dinaciclib is clearly not a specific MCL-1 inhibitor, its ability to rapidly downregulate MCL-1 may be beneficial in many clinical settings, where it may reverse chemoresistance or sensitize to other chemotherapeutic agents

Nesting Behaviour of a Neotropical Social Wasp Mischocyttarus saussurei Zikán, 1949 (Hymenoptera, Vespidae)

Mischocyttarus saussurei nests show a curious architectural pattern which could be related to colony camouflage. Since information on that species is scarce in literature, this study aimed to record ecological data on M. saussurei, as well as morphometric data on its nests. Data was collected at the Parque Estadual do Ibitipoca state park and at the municipalities of Barroso and Inconfidentes, Minas Gerais state, Southeastern Brazil. Seven colonies were located, exclusively in conserved environments. Five nests were dissected for morphometric analysis and for the assessment of the vegetal matter incorporated to comb walls. Nests showed comb cells opening towards the substrate and covered by vegetal layers, in which three families of mosses and three of liverworts could be identified. We deduct that the nests’ morphometry and the incorporation of vegetal layers to the combs are related to the camouflaging of colonies amidst their substrate

DRP-1 is required for BH3 mimetic-mediated mitochondrial fragmentation and apoptosis

The concept of using BH3 mimetics as anticancer agents has been substantiated by the efficacy of selective drugs, such as Navitoclax and Venetoclax, in treating BCL-2-dependent haematological malignancies. However, most solid tumours depend on MCL-1 for survival, which is highly amplified in multiple cancers and a major factor determining chemoresistance. Most MCL-1 inhibitors that have been generated so far, while demonstrating early promise in vitro, fail to exhibit specificity and potency in a cellular context. To address the lack of standardised assays for benchmarking the in vitro binding of putative inhibitors before analysis of their cellular effects, we developed a rapid differential scanning fluorimetry (DSF)-based assay, and used it to screen a panel of BH3 mimetics. We next contrasted their binding signatures with their ability to induce apoptosis in a MCL-1 dependent cell line. Of all the MCL-1 inhibitors tested, only A-1210477 induced rapid, concentration-dependent apoptosis, which strongly correlated with a thermal protective effect on MCL-1 in the DSF assay. In cells that depend on both MCL-1 and BCL-XL, A-1210477 exhibited marked synergy with A-1331852, a BCL-XL specific inhibitor, to induce cell death. Despite this selectivity and potency, A-1210477 induced profound structural changes in the mitochondrial network in several cell lines that were not phenocopied following MCL-1 RNA interference or transcriptional repression, suggesting that A-1210477 induces mitochondrial fragmentation in an MCL-1-independent manner. However, A-1210477-induced mitochondrial fragmentation was dependent upon DRP-1, and silencing expression levels of DRP-1 diminished not just mitochondrial fragmentation but also BH3 mimetic-mediated apoptosis. These findings provide new insights into MCL-1 ligands, and the interplay between DRP-1 and the anti-apoptotic BCL-2 family members in the regulation of apoptosis

DRP-1 functions independently of mitochondrial structural perturbations to facilitate BH3 mimetic-mediated apoptosis.

Maintenance of mitochondrial integrity is critical for normal cellular homoeostasis. Most cells respond to stress stimuli and undergo apoptosis by perturbing mitochondrial structure and function to release proteins, such as cytochrome c, which are essential for the execution of the intrinsic apoptotic cascade. Cancer cells evade these events by overexpressing the anti-apoptotic BCL-2 family of proteins on mitochondrial membranes. Inhibitors of the anti-apoptotic BCL-2 family proteins, also known as BH3 mimetics, antagonise the pro-survival functions of these proteins and result in rapid apoptosis. Although the precise mechanism by which BH3 mimetics induce apoptosis has been well characterised, not much is known in terms of the structural changes that occur in mitochondria during apoptosis. Using a panel of highly selective BH3 mimetics and a wide range of cell lines, we demonstrate that BH3 mimetics induce extensive mitochondrial fission, accompanied by swelling of the mitochondrial matrix and rupture of the outer mitochondrial membrane. These changes occur in a BAX/ BAK-dependent manner. Although a major mitochondrial fission GTPase, DRP-1, has been implicated in mitochondrial apoptosis, our data demonstrate that DRP-1 might function independently/downstream of BH3 mimetic-mediated mitochondrial fission to facilitate the release of cytochrome c and apoptosis. Moreover, downregulation of DRP-1 prevented cytochrome c release and apoptosis even when OPA1, a protein mediating mitochondrial fusion, was silenced. Although BH3 mimetic-mediated displacement of BAK and other BH3-only proteins from BCL-XL and MCL-1 was unaffected by DRP-1 downregulation, it prevented BAK activation significantly, thus placing DRP-1 as one of the most critical players, along with BAX and BAK, that governs BH3 mimetic-mediated cytochrome c release and apoptosis

Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis

The recruitment of DRP1 to mitochondrial membranes prior to fission is facilitated by the wrapping of endoplasmic reticulum (ER) membranes around the mitochondria. To investigate the complex interplay between the ER membranes and DRP1 in the context of mitochondrial structure and function, we downregulate two key ER shaping proteins, RTN4 and CLIMP-63, and demonstrate pronounced mitochondrial hyperfusion and reduced ER-mitochondria contacts, despite their differential regulation of ER architecture. Although mitochondrial recruitment of DRP1 is unaltered in cells lacking RTN4 or CLIMP-63, several aspects of mitochondrial function, such as mtDNA-encoded translation, respiratory capacity and apoptosis are significantly hampered. Further mechanistic studies reveal that CLIMP-63 is required for cristae remodeling (OPA1 proteolysis) and DRP1-mediated mitochondrial fission, whereas both RTN4 and CLIMP-63 regulate the recruitment of BAX to ER and mitochondrial membranes to enable cytochrome c release and apoptosis, thereby performing novel and distinct roles in the regulation of mitochondrial structure and function

Targeting Intermediary Metabolism Enhances The Efficacy Of BH3 Mimetic Therapy In Haematological Malignancies

BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-X-L (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy

Como as mães colocam seus bebês no berço para dormir? : um estudo sobre conhecimentos e hábitos quanto ao posicionamento de lactentes no berço e uma estratégia educativa associada (projeto piloto)

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