Academic literature on the topic 'AP-4 Complex'
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Journal articles on the topic "AP-4 Complex"
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Hirst, Jennifer, Nicholas A. Bright, Brian Rous, and Margaret S. Robinson. "Characterization of a Fourth Adaptor-related Protein Complex." Molecular Biology of the Cell 10, no. 8 (August 1999): 2787–802. http://dx.doi.org/10.1091/mbc.10.8.2787.
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Adaptor protein complexes (APs) function as vesicle coat components in different membrane traffic pathways; however, there are a number of pathways for which there is still no candidate coat. To find novel coat components related to AP complexes, we have searched the expressed sequence tag database and have identified, cloned, and sequenced a new member of each of the four AP subunit families. We have shown by a combination of coimmunoprecipitation and yeast two-hybrid analysis that these four proteins (ε, β4, μ4, and ς4) are components of a novel adaptor-like heterotetrameric complex, which we are calling AP-4. Immunofluorescence reveals that AP-4 is localized to ∼10–20 discrete dots in the perinuclear region of the cell. This pattern is disrupted by treating the cells with brefeldin A, indicating that, like other coat proteins, the association of AP-4 with membranes is regulated by the small GTPase ARF. Immunogold electron microscopy indicates that AP-4 is associated with nonclathrin-coated vesicles in the region of the trans-Golgi network. The μ4 subunit of the complex specifically interacts with a tyrosine-based sorting signal, indicating that, like the other three AP complexes, AP-4 is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs. AP-4 is of relatively low abundance, but it is expressed ubiquitously, suggesting that it participates in a specialized trafficking pathway but one that is required in all cell types.
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Salazar, G., B. Craige, M. L. Styers, K. A. Newell-Litwa, M. M. Doucette, B. H. Wainer, J. M. Falcon-Perez, et al. "BLOC-1 Complex Deficiency Alters the Targeting of Adaptor Protein Complex-3 Cargoes." Molecular Biology of the Cell 17, no. 9 (September 2006): 4014–26. http://dx.doi.org/10.1091/mbc.e06-02-0103.
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Mutational analyses have revealed many genes that are required for proper biogenesis of lysosomes and lysosome-related organelles. The proteins encoded by these genes assemble into five distinct complexes (AP-3, BLOC-1-3, and HOPS) that either sort membrane proteins or interact with SNAREs. Several of these seemingly distinct complexes cause similar phenotypic defects when they are rendered defective by mutation, but the underlying cellular mechanism is not understood. Here, we show that the BLOC-1 complex resides on microvesicles that also contain AP-3 subunits and membrane proteins that are known AP-3 cargoes. Mouse mutants that cause BLOC-1 or AP-3 deficiencies affected the targeting of LAMP1, phosphatidylinositol-4-kinase type II alpha, and VAMP7-TI. VAMP7-TI is an R-SNARE involved in vesicle fusion with late endosomes/lysosomes, and its cellular levels were selectively decreased in cells that were either AP-3- or BLOC-1–deficient. Furthermore, BLOC-1 deficiency selectively altered the subcellular distribution of VAMP7-TI cognate SNAREs. These results indicate that the BLOC-1 and AP-3 protein complexes affect the targeting of SNARE and non-SNARE AP-3 cargoes and suggest a function of the BLOC-1 complex in membrane protein sorting.
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Dell’Angelica, Esteban C., Chris Mullins, and Juan S. Bonifacino. "AP-4, a Novel Protein Complex Related to Clathrin Adaptors." Journal of Biological Chemistry 274, no. 11 (March 12, 1999): 7278–85. http://dx.doi.org/10.1074/jbc.274.11.7278.
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Ponsankarar, Lalitha, A. Sinthiya, and V. Rashmi. "Hydrogen-bonding interaction of 4-AP metal complex with proteins." Acta Crystallographica Section A Foundations and Advances 73, a2 (December 1, 2017): C402. http://dx.doi.org/10.1107/s2053273317091719.
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Behne, Robert, Julian Teinert, Miriam Wimmer, Angelica D’Amore, Alexandra K. Davies, Joseph M. Scarrott, Kathrin Eberhardt, et al. "Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking." Human Molecular Genetics 29, no. 2 (January 9, 2020): 320–34. http://dx.doi.org/10.1093/hmg/ddz310.
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Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.
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BAROIS, Nicolas, and Oddmund BAKKE. "The adaptor protein AP-4 as a component of the clathrin coat machinery: a morphological study." Biochemical Journal 385, no. 2 (January 7, 2005): 503–10. http://dx.doi.org/10.1042/bj20041010.
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The four members of the AP (adaptor protein) family are heterotetrameric cytosolic complexes that are involved in the intracellular trafficking of cargo proteins between different organelles. They interact with motifs present in the cytoplasmic tails of their specific cargo proteins at different intracellular locations. While AP-1, AP-2 and AP-3 have been investigated extensively, very few studies have focused on the fourth member, AP-4. In the present study, we report on the intracellular localization of AP-4 in the MDCK (Madin–Darby canine kidney) and MelJuSo cell lines after immunogold labelling of ultrathin cryosections. We find that AP-4 is localized mainly in the Golgi complex, as well as on endosomes and transport vesicles. Interestingly, we show for the first time that AP-4 is localized with the clathrin coat machinery in the Golgi complex and in the endocytic pathway. Furthermore, we find that AP-4 is localized with the CI-MPR (cation-independent mannose 6-phosphate receptor), but not with the transferrin receptor, LAMP-2 (lysosomal-associated membrane protein-2) or invariant chain. The difference in morphology between CI-MPR/AP-4-positive vesicles and CI-MPR/AP-1-positive vesicles raises the possibility that AP-4 acts at a location different from that of AP-1 in the intracellular trafficking pathway of CI-MPR.
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Mattera, Rafael, Chad D. Williamson, Xuefeng Ren, and Juan S. Bonifacino. "The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A." Molecular Biology of the Cell 31, no. 9 (April 15, 2020): 963–79. http://dx.doi.org/10.1091/mbc.e19-11-0658.
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In this study, we identify the dynein–dynactin adaptor FTS-Hook-FHIP (FHF) complex as an accessory factor for the TGN-associated adaptor protein 4 (AP-4) coat. We show that FHF is required for distribution of AP-4 and its cargo ATG9A to the perinuclear area, highlighting a novel mechanism for coupling of transport vesicles to microtubule motors.
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Schneider, Helga, Margarita Martin, Fernando A. Agarraberes, Li Yin, Iris Rapoport, Tomas Kirchhausen, and Christopher E. Rudd. "Cytolytic T Lymphocyte-Associated Antigen-4 and the TCRζ/CD3 Complex, But Not CD28, Interact with Clathrin Adaptor Complexes AP-1 and AP-2." Journal of Immunology 163, no. 4 (August 15, 1999): 1868–79. http://dx.doi.org/10.4049/jimmunol.163.4.1868.
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Abstract The negative signaling receptor cytolytic T lymphocyte-associated Ag-4 (CTLA-4) resides primarily in intracellular compartments such as the Golgi apparatus of T cells. However, little is known regarding the molecular mechanisms that influence this accumulation. In this study, we demonstrate binding of the clathrin adaptor complex AP-1 with the GVYVKM motif of the cytoplasmic domain of CTLA-4. Binding occurred primarily in the Golgi compartment of T cells, unlike with AP-2 binding that occurs mostly with cell surface CTLA-4. Although evidence was not found to implicate AP-1 binding in the retention of CTLA-4 in the Golgi, AP-1 appears to play a role in shuttling of excess receptor from the Golgi to the lysosomal compartments for degradation. In support of this, increased CTLA-4 synthesis resulted in an increase in CTLA-4/AP-1 binding and a concomitant increase in the appearance of CTLA-4 in the lysosomal compartment. At the same time, the level of intracellular receptor was maintained at a constant level, suggesting that CTLA-4/AP-1 binding represents one mechanism to ensure steady state levels of intracellular CTLA-4 in T cells. Finally, we demonstrate that the TCRζ/CD3 complex (but not CD28) also binds to AP-1 and AP-2 complexes, thus providing a possible link between these two receptors in the regulation of T cell function.
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Mattera, Rafael, Sang Yoon Park, Raffaella De Pace, Carlos M. Guardia, and Juan S. Bonifacino. "AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation." Proceedings of the National Academy of Sciences 114, no. 50 (November 27, 2017): E10697—E10706. http://dx.doi.org/10.1073/pnas.1717327114.
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AP-4 is a member of the heterotetrameric adaptor protein (AP) complex family involved in protein sorting in the endomembrane system of eukaryotic cells. Interest in AP-4 has recently risen with the discovery that mutations in any of its four subunits cause a form of hereditary spastic paraplegia (HSP) with intellectual disability. The critical sorting events mediated by AP-4 and the pathogenesis of AP-4 deficiency, however, remain poorly understood. Here we report the identification of ATG9A, the only multispanning membrane component of the core autophagy machinery, as a specific AP-4 cargo. AP-4 promotes signal-mediated export of ATG9A from the trans-Golgi network to the peripheral cytoplasm, contributing to lipidation of the autophagy protein LC3B and maturation of preautophagosomal structures. These findings implicate AP-4 as a regulator of autophagy and altered autophagy as a possible defect in AP-4–deficient HSP.
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Szurmak, Blanka, Aleksandra Wysłouch-Cieszyńska, Małgorzata Wszelaka-Rylik, Wojciech Bal, and Marta Dobrzańska. "A diadenosine 5',5''-P1P4 tetraphosphate (Ap4A) hydrolase from Arabidopsis thaliana that is activated preferentially by Mn2+ ions." Acta Biochimica Polonica 55, no. 1 (March 13, 2008): 151–60. http://dx.doi.org/10.18388/abp.2008_3173.
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Asymmetrical diadenosine 5',5''-P(1)P(4) tetraphosphate (Ap(4)A) hydrolases are key enzymes controlling the in vivo concentration of Ap(4)A--an important signaling molecule involved in regulation of DNA replication and repair, signaling in stress response and apoptosis. Sequence homologies indicate that the genome of the model plant Arabidopsis thaliana contains at least three open reading frames encoding presumptive Ap(4)A hydrolases: At1g30110, At3g10620, and At5g06340. In this work we present efficient overexpression and detailed biochemical characteristics of the AtNUDX25 protein encoded by the At1g30110 gene. Aided by the determination of the binding constants of Mn(Ap(4)A) and Mg(Ap(4)A) complexes using isothermal titration calorimetry (ITC) we show that AtNUDX25 preferentially hydrolyzes Ap(4)A in the form of a Mn(2+) complex.
Dissertations / Theses on the topic "AP-4 Complex"
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Davies, Alexandra Katherine. "An investigation of the function of adaptor protein complex 4 (AP-4)." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289777.
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Vesicle trafficking provides the solution to the 'sorting problem' - how the eukaryotic cell maintains the distinct identities, and thus functional properties, of its membrane-bound organelles. During vesicle trafficking, proteins are selectively sorted into membrane bound transport intermediates by vesicle adaptors, which include those of the highly conserved adaptor protein (AP) complex family. Each AP complex has a distinct subcellular localisation and functions in the sorting of a specific subset of transmembrane cargo proteins. Adaptor protein complex 4 (AP-4) is one of the more recently identified AP complexes, whose function has largely remained elusive. In humans, AP-4 deficiency causes a severe neurological disorder, suggesting an important role in neuronal development and homeostasis. However, the pathomechanisms that underly the neuronal pathology in AP-4 deficiency are currently unknown. AP-4 is proposed to function in protein sorting at the trans-Golgi network (TGN), so AP-4 deficiency can be thought of as a disease of missorting. The aim of this study was to apply unbiased global proteomic approaches to define the composition of AP-4 vesicles and to identify physiological cargo proteins of the AP-4 pathway. Using 'Dynamic Organellar Maps' and comparative analysis of vesicle-enriched fractions from wild-type and AP-4-depleted cells, three ubiquitously expressed transmembrane cargo proteins, ATG9A, SERINC1 and SERINC3, were found to be mislocalised in AP-4-deficient cells. Two novel cytosolic AP-4 accessory proteins, RUSC1 and RUSC2, were also identified. Further proteomic analyses confirmed the interactions between these proteins. AP-4 deficiency was found to cause missorting of ATG9A in diverse cell types, including patient derived cells, as well as dysregulation of autophagy. RUSC2 facilitates the transport of AP-4-derived, ATG9A and SERINC-positive vesicles from the TGN to the cell periphery. These vesicles cluster in close association with autophagosomes, suggesting they are the 'ATG9 reservoir' required for autophagosome biogenesis. This study uncovers ATG9A trafficking as a ubiquitous function of the AP-4 pathway. Furthermore, it provides a potential molecular pathomechanism of AP-4 deficiency, through dysregulated spatial control of autophagy.
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Angelica, D'Amore. "Next Generation Molecular Studies of Hereditary Spastic Paraplegias in Men and Zebrafish." Doctoral thesis, Università di Siena, 2020. http://hdl.handle.net/11365/1105261.
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The term Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that NGS facilitates the diagnostic approach to HSP, but the power of this method as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity— there are over 80 potential disease-associated genes— and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming.
In a single-center, cross-sectional study, spanning 5 years, 242 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP or syndromic conditions. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation
pathogenicity, we gathered a positive diagnostic yield of 30% (73/242), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 (34%) cases remained unsolved. This study is among the largest screening of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern,
first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy. Interestingly, we identified new unreported mutations in the AP4S1 gene (SPG52), the smallest of the four subunits that form the AP-4 complex, a heterotetrameric protein complex which participates in membrane sorting between the trans-Golgi network and the endosomes, and plays a key role in signal-mediated tracking of integral membrane proteins.
Mutations in AP4 subunits have been associated with alterations in neurodevelopment, epilepsy and complicated spastic paraplegia and the relative rarity of patients with mutations in subunits of the AP4 complex makes useful to report additional cases. In this study we described clinical presentations of three additional unrelated patients and their mutations. To improve our understating on to how AP4S1 operates during neurodevelopment, we knocked-down ap4s1 in zebrafish (Danio rerio), using morpholino antisense oligonucleotide technique. Our results showed that morphant embryos displayed an impairment of the neuronal excitability, locomotor defects, development delay, and altered neurogenesis, which are also phenotypic traits of AP4-HSP patients. Whilst we expanded the allelic heterogeneity in AP4-related diseases, we modeled in the simple vertebrate system zebrafish the early steps of abnormal neurodevelopment associated with AP4S1 defects offering a new tool for future therapeutic opportunities. Importantly, AP-complex served as an example for similar strategies in genes associated with HSP.
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Müdsam, Christina [Verfasser], Norbert [Akademischer Betreuer] Sauer, and Norbert [Gutachter] Sauer. "Dissecting the role of adaptor protein complex 4 (AP-4) on development and protein sorting in Arabidopsis thaliana / Christina Müdsam ; Gutachter: Norbert Sauer ; Betreuer: Norbert Sauer." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2017. http://d-nb.info/1156780926/34.
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Tavares, Lucas Alves. "O envolvimento da proteína adaptadora 1 (AP-1) no mecanismo de regulação negativa do receptor CD4 por Nef de HIV-1." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17136/tde-06012017-113215/.
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O Vírus da Imunodeficiência Humana (HIV) é o agente etiológico da Síndrome da Imunodeficiência Adquirida (AIDS). A AIDS é uma doença de distribuição mundial, e estima-se que existam atualmente pelo menos 36,9 milhões de pessoas infectadas com o vírus. Durante o seu ciclo replicativo, o HIV promove diversas alterações na fisiologia da célula hospedeira a fim de promover sua sobrevivência e potencializar a replicação. A rápida progressão da infecção pelo HIV-1 em humanos e em modelos animais está intimamente ligada à função da proteína acessória Nef. Dentre as diversas ações de Nef está a regulação negativa de proteínas importantes na resposta imunológica, como o receptor CD4. Sabe-se que esta ação resulta da indução da degradação de CD4 em lisossomos, mas os mecanismos moleculares envolvidos ainda são totalmente elucidados. Nef forma um complexo tripartite com a cauda citosólica de CD4 e a proteína adaptadora 2 (AP-2), em vesículas revestidas por clatrina nascentes, induzindo a internalização e degradação lisossomal de CD4. Pesquisas anteriores demonstraram que o direcionamento de CD4 aos lisossomos por Nef envolve a entrada do receptor na via dos corpos multivesiculares (MVBs), por um mecanismo atípico, pois, embora não necessite da ubiquitinação de carga, depende da ação de proteínas que compõem os ESCRTs (Endosomal Sorting Complexes Required for Transport) e da ação de Alix, uma proteína acessória da maquinaria ESCRT. Já foi reportado que Nef interage com subunidades dos complexos AP-1, AP-2, AP-3 e Nef não parece interagir com subunidades de AP-4 e AP-5. Entretanto, o papel da interação de Nef com AP-1 e AP-3 na regulação negativa de CD4 ainda não está totalmente elucidado. Ademais, AP-1, AP-2 e AP-3 são potencialmente heterogêneos devido à existência de isoformas múltiplas das subunidades codificadas por diferentes genes. Todavia, existem poucos estudos para demonstrar se as diferentes combinações de isoformas dos APs são formadas e se possuem propriedades funcionais distintas. O presente trabalho procurou identificar e caracterizar fatores celulares envolvidos na regulação do tráfego intracelular de proteínas no processo de regulação negativa de CD4 induzido por Nef. Mais especificamente, este estudo buscou caracterizar a participação do complexo AP-1 na modulação negativa de CD4 por Nef de HIV-1, através do estudo funcional das duas isoformas de ?-adaptina, subunidades de AP-1. Utilizando a técnica de Pull-down demonstramos que Nef é capaz de interagir com ?2. Além disso, nossos dados de Imunoblot indicaram que a proteína ?2-adaptina, e não ?1-adaptina, é necessária no processo de degradação lisossomal de CD4 por Nef e que esta participação é conservada para degradação de CD4 por Nef de diferentes cepas virais. Ademais, por citometria de fluxo, o silenciamento de ?2, e não de ?1, compromete a diminuição dos níveis de CD4 por Nef da membrana plasmática. A análise por imunofluorêsncia indireta também revelou que a diminuição dos níveis de ?2 impede a redistribuição de CD4 por Nef para regiões perinucleares, acarretando no acúmulo de CD4, retirados por Nef da membrana plasmática, em endossomos primários. A depleção de ?1A, outra subunidade de AP-1, acarretou na diminuição dos níveis celulares de ?2 e ?1, bem como, no comprometimento da eficiente degradação de CD4 por Nef. Além disso, foi possível observar que, ao perturbar a maquinaria ESCRT via super-expressão de HRS (uma subunidade do complexo ESCRT-0), ocorreu um acumulo de ?2 em endossomos dilatados contendo HRS-GFP, nos quais também detectou-se CD4 que foi internalizado por Nef. Em conjunto, os resultados indicam que ?2-adaptina é uma importante molécula para o direcionamento de CD4 por Nef para a via ESCRT/MVB, mostrando ser uma proteína relevante no sistema endo-lisossomal. Ademais, os resultados indicaram que as isoformas ?-adaptinas não só possuem funções distintas, mas também parecem compor complexos AP-1 com diferentes funções celulares, já que apenas a variante AP-1 contendo ?2, mas não ?1, participa da regulação negativa de CD4 por Nef. Estes estudos contribuem para o melhor entendimento dos mecanismos moleculares envolvidos na atividade de Nef, que poderão também ajudar na melhor compreensão da patogênese do HIV e da síndrome relacionada. Em adição, este trabalho contribui para o entendimento de processos fundamentais da regulação do tráfego de proteínas transmembrana no sistema endo-lisossomal.The Human Immunodeficiency Virus (HIV) is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). AIDS is a disease which has a global distribution, and it is estimated that there are currently at least 36.9 million people infected with the virus. During the replication cycle, HIV promotes several changes in the physiology of the host cell to promote their survival and enhance replication. The fast progression of HIV-1 in humans and animal models is closely linked to the function of an accessory protein Nef. Among several actions of Nef, one is the most important is the down-regulation of proteins from the immune response, such as the CD4 receptor. It is known that this action causes CD4 degradation in lysosome, but the molecular mechanisms are still incompletely understood. Nef forms a tripartite complex with the cytosolic tail of the CD4 and adapter protein 2 (AP-2) in clathrin-coated vesicles, inducing CD4 internalization and lysosome degradation. Previous research has demonstrated that CD4 target to lysosomes by Nef involves targeting of this receptor to multivesicular bodies (MVBs) pathway by an atypical mechanism because, although not need charging ubiquitination, depends on the proteins from ESCRTs (Endosomal Sorting Complexes Required for Transport) machinery and the action of Alix, an accessory protein ESCRT machinery. It has been reported that Nef interacts with subunits of AP- 1, AP-2, AP-3 complexes and Nef does not appear to interact with AP-4 and AP-5 subunits. However, the role of Nef interaction with AP-1 or AP-3 in CD4 down-regulation is poorly understood. Furthermore, AP-1, AP-2 and AP-3 are potentially heterogeneous due to the existence of multiple subunits isoforms encoded by different genes. However, there are few studies to demonstrate if the different combinations of APs isoforms are form and if they have distinct functional properties. This study aim to identify and characterize cellular factors involved on CD4 down-modulation induced by Nef from HIV-1. More specifically, this study aimed to characterize the involvement of AP-1 complex in the down-regulation of CD4 by Nef HIV-1 through the functional study of the two isoforms of ?-adaptins, AP-1 subunits. By pull-down technique, we showed that Nef is able to interact with ?2. In addition, our data from immunoblots indicated that ?2- adaptin, not ?1-adaptin, is required in Nef-mediated targeting of CD4 to lysosomes and the ?2 participation in this process is conserved by Nef from different viral strains. Furthermore, by flow cytometry assay, ?2 depletion, but not ?1 depletion, compromises the reduction of surface CD4 levels induced by Nef. Immunofluorescence microscopy analysis also revealed that ?2 depletion impairs the redistribution of CD4 by Nef to juxtanuclear region, resulting in CD4 accumulation in primary endosomes. Knockdown of ?1A, another subunit of AP-1, resulted in decreased cellular levels of ?1 and ?2 and, compromising the efficient CD4 degradation by Nef. Moreover, upon artificially stabilizing ESCRT-I in early endosomes, via overexpression of HRS, internalized CD4 accumulates in enlarged HRS-GFP positive endosomes, where co-localize with ?2. Together, the results indicate that ?2-adaptin is a molecule that is essential for CD4 targeting by Nef to ESCRT/MVB pathway, being an important protein in the endo-lysosomal system. Furthermore, the results indicate that ?-adaptins isoforms not only have different functions, but also seem to compose AP-1 complex with distinct cell functions, and only the AP-1 variant comprising ?2, but not ?1, acts in the CD4 down-regulation induced by Nef. These studies contribute to a better understanding on the molecular mechanisms involved in Nef activities, which may also help to improve the understanding of the HIV pathogenesis and the related syndrome. In addition, this work contributes with the understanding of primordial process regulation on intracellular trafficking of transmembrane proteins.
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Ku, Wei-Chi, and 辜韋智. "Complementary Quantitative Proteomics Reveals that Transcription Factor AP-4 Mediates E-Box-Dependent Complex Formation for Transcriptional Repression of HDM2." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/86812726367946597857.
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博士國立清華大學
生物資訊與結構生物研究所
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Transcription factor activating enhancer binding protein 4 (AP-4) is a basic helix-loop-helix protein that binds to E-box elements. AP-4 has received increasing attention for its regulatory role in cell growth and development, including transcriptional repression of the human homolog of murine double minute 2 (HDM2), an important oncoprotein controlling cell growth and survival, by an unknown mechanism. Here we demonstrate that AP-4 binds to an E-box located in the HDM2-P2 promoter in vitro and in vivo as demonstrated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Luciferase assay further revealed that AP-4 represses HDM2 transcription in a p53-independent manner. In addition, incremental truncations of AP-4 showed that the C-terminal glutamine/proline-rich domain is essential for transcriptional repression of HDM2. To further delineate the molecular mechanism(s) of AP-4 transcriptional control and its potential implications, we performed single-step DNA-affinity purification followed by complementary quantitative proteomics, cICAT and iTRAQ labeling methods, to identify a previously unknown E-box-bound AP-4 protein complex. The two labeling methods complementarily quantified 75 putative components in AP-4 protein complex, including the most significant recruitment of DNA damage–responsive proteins, followed by transcription factors, transcription repressors/corepressors, and histone-modifying proteins. Using AP-4 truncation mutants and DNA pull-down assay, specific interaction of AP-4 with CTCF, SP1, and histone deacetylase 1 (an AP-4 corepressor) was validated. Although AP-4 may repress HDM2 transcripion by recruiting HDAC, inclusion of HDAC specific inhibitor, trichostatin A, did not alleviate AP-4-mediated repression of HDM2 transcription. Taken together the data suggest a previously unidentified histone deacetylase-independent repression mechanism. Alternatively, the complementary quantitative proteomics study suggests that transcription repression occurs via coordination of AP-4 with other transcription factors, histone methyltransferases, and/or a nucleosome remodeling SWI/SNF complex. In addition to previously known functions of AP-4, our data suggest that AP-4 participates in a transcriptional regulating complex at the HDM2 promoter in response to DNA damage. In conclusion, we successfully demonstrate how AP-4 regulates HDM2 transcription via binding to the previously unknown AP-4 binding site. By taking the advantage of the complementary quantitative proteomics, we identify a DNA bound AP-4 protein complex from single-step DNA afftinity purification from crude nuclear extracts. By analyzing the components and functions of the AP-4 protein complex, we are able to deduce the possible repressive mechanisms on HDM2 transcription and the potential role of AP-4 in DNA damaging response. Our findling may shed a light in better understanding the physiological role of AP-4. Finally, we also develop a strategy combining single-step purification and complementary quantitative proteomics for target proteomics study, which provides an alternative MS-based way to study protein complex in the future.
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Burgess, Jason. "The Clathrin Adaptor AP-1 and Type II Phosphatidylinositol 4-Kinase are Required for Glue Granule Biogenesis in Drosophila." Thesis, 2012. http://hdl.handle.net/1807/33847.
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Regulated secretion of hormones, digestive enzymes and other biologically active molecules requires formation of secretory granules. However, the molecular machinery required for secretory granule biogenesis is incompletely understood. I used powerful genetic approaches available in the fruit fly Drosophila melanogaster to investigate the factors required for biogenesis of mucin-containing ‘glue granules,’ which form within epithelial cells of the third-instar larval salivary gland. I discovered that clathrin and the clathrin adaptor protein complex (AP-1), as well the enzyme type II phosphatidylinositol 4-kinase (PI4KII), are indispensable for glue granule biogenesis.
Clathrin and AP-1 are necessary for maturation of exocrine, endocrine and neuroendocrine secretory granules in mammalian cells. I found that Drosophila clathrin and AP-1 colocalize at the TGN and that clathrin recruitment requires AP-1. I further showed that clathrin and AP-1 colocalize with secretory cargo at the TGN and on glue granules. Finally, I demonstrated that loss of clathrin or AP-1 leads to a profound block in secretory granule biogenesis. These findings establish a novel role for AP-1/clathrin-dependent trafficking in the formation of mucin-containing secretory granules.
Type II phosphatidylinositol 4-kinase (PI4KII) generates the membrane lipid phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi network and is required to recruit cargo to endosomes in mammalian cells. I generated null mutations in the sole Drosophila PI4KII and demonstrated a role for PI4KII in both glue granule and pigment granule biogenesis. PI4KII mutant salivary gland cells exhibit small glue granules and mislocalize glue protein to abnormally large late endosomes. Additionally, PI4KII mutants exhibit altered distribution of the granule specific SNARE, SNAP-24. These data point to a crucial role for PI4KII in sorting of regulated secretory products during granule biogenesis. Together, my results indicate that the larval salivary gland is a valuable system for investigating molecular mechanisms involved in secretory granule biogenesis, and provide a framework for future studies using this system.
Book chapters on the topic "AP-4 Complex"
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Sergeevna Ageeva, Liliya, Nikolai Alekseevich Borsch, and Nikolay Vladimirovich Kuvardin. "2(4)-Aminopyridines as Ligands in the Coordination and Extraction Chemistry of Platinum Metals." In Exploring Chemistry with Pyridine Derivatives. IntechOpen, 2023. http://dx.doi.org/10.5772/intechopen.106376.
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The specific behavior of aromatic amines in the coordination and extraction processes of isolation and separation of platinum and other metals is discussed using the example of 2(4)-aminopyridines (2(4)-AP). As intrasphere ligands, 2(4)-AP have a high electron-donor capacity due to the pumping of an easily polarizable π-electron density. The chemistry of the extraction of platinum metals, iridium in particular, is considered: depending on the conditions, ion associates, coordination-solvated compounds or compounds containing an amine in the inner and outer coordination sphere of the metal are extracted. In the extraction of simple singly charged anions, there is a violation of the exchange-extraction series established for a large set of aliphatic amines. Soft anions (according to Pearson), for example, SCN- and I-, are best extracted, while for aliphatic amines such an anion is hard СlO4−. In the coordination compounds of platinum metals, 2(4)-AP acts as an electron donor, is coordinated by heterocyclic nitrogen with a redistribution of electron density not only to the accepting metal-complexing agent, but also further along the N-Me-X chain (X is an acido ligand in the composition of the complex), which leads to even greater covalence of the molecule as a whole.
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Makhlouf, Amel Meddeb, and Noureddine Boudriga. "Intrusion and Anomaly Detection in Wireless Networks." In Handbook of Research on Wireless Security, 78–94. IGI Global, 2008. http://dx.doi.org/10.4018/978-1-59904-899-4.ch006.
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The broadcast nature of wireless networks and the mobility features created new kinds of intrusions and anomalies taking profit of wireless vulnerabilities. Because of the radio links and the mobile equipment features of wireless networks, wireless intrusions are more complex because they add to the intrusions developed for wired networks, a large spectrum of complex attacks targeting wireless environment. These intrusions include rogue or unauthorized access point (AP), AP MAC spoofing, and wireless denial of service and require adding new techniques and mechanisms to those approaches detecting intrusions targeting wired networks. To face this challenge, some researchers focused on extending the deployed approaches for wired networks while others worked to develop techniques suitable for detecting wireless intrusions. The efforts have mainly addressed: (1) the development of theories to allow reasoning about detection, wireless cooperation, and response to incidents; and (2) the development of wireless intrusion and anomaly detection systems that incorporate wireless detection, preventive mechanisms and tolerance functions. This chapter aims at discussing the major theories, models, and mechanisms developed for the protection of wireless networks/systems against threats, intrusions, and anomalous behaviors. The objectives of this chapter are to: (1) discuss security problems in a wireless environment; (2) present the current research activities; (3) study the important results already developed by researchers; and (4) discuss the validation methods proposed for the protection of wireless networks against attacks.
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"Language and Communication Skills A child's competence withlanguage is highly likely to affect the extent and quality of her/his social relationships. As significant conversational ability develops at approximately 2Vi years, social interaction increases simultaneously (Holmberg, Note 2). Children whose language and comprehension skills are limited may be hampered in their ability to communicate and interact with •their peers. Certainly, the relationship between language com-petence and competence in other areas has been documented (Ap-pleton, Clifton, & Goldberg, 1975). Social play requires at least some level of adequate communi-cation skills (Asher, Oden, & Gottman, 1977), e.g., the ability to share a theme of an activity and develop it (Garvey, 1976). Little is known yet about the relative importance of deficits in specific com-munication skills, and further, few effects have been noted as a function of training. It is probable that children with less verbal ability, e.g., younger or handicapped, are less likely to profit from skills training involving verbal instruction or complex language per-formance. And. whereas language skills may not be related to social competence among prelingual toddlers, as the child develops, lan-guage may play a more crucial role. Preliminary analyses of our data show a significant but low correlation between measures of listener vocabulary and knowledge of basic concepts in preschool children and both teacher ratings of social behavior and peer popularity. It appears, then, that language has some role to play in a child's social competence, and the practitioner would be wise to consider the socially withdrawn child's language capabilities before at-tempting remediations which otherwise may prove ineffective. Motor Skills A series of studies of elementary school children from 4th through 7th grades found consistent and significant relationships between their performance on physical measures and social status as measured by socio-metrics (Broekhoff, 1976, 1977, in press). Com-parisons of high and low status contrast groups indicated that signifi-cant differences were maintained over the three years on physical fitness and indices of muscular strength. Thus, it seems logical to." In Social Skills Training for Children and Youth, 45–50. Routledge, 2014. http://dx.doi.org/10.4324/9781315059167-4.
Full textConference papers on the topic "AP-4 Complex"
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Alecu, Julian E., Marvin Ziegler, Barbara Brechmann, Kathrin Eberhardt, Hellen Jumo, Angelica D’Amore, Afshin Saffari, et al. "High-Throughput Imaging of ATG9A Distribution as a Diagnostic Functional Assay for Adaptor Protein Complex 4: Associated Hereditary Spastic Paraplegia (AP-4-HSP)." In Abstracts of the 46th Annual Meeting of the Society for Neuropediatrics. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1739686.
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Holmes, W. E., H. R. Lijnen, and D. Collen. "CHARACTERIZATION OFα2-ANTIPLASMIN.REACTIVE SITE VARIANTS PRODUCED BY SITE-DIRECTED MUTAGENESIS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644766.
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α2-Antiplasmin (α2AP) is the primary physiological plasmin inhibitor in human plasma. The inhibition is rapid (second order rate constants (k1) are expressed as M−1 s−1 ) (k1 = 2 × 107) and occurs as the consequence of an irreversible 1:1 stoichiometric complex formation; the exact nature of and the forces involved in complex formation are not fully understood. In fact, what makes α2AP an inhibitor, rather than simply a substrate remains unresolved. Recently, we deduced the primary structure of α2 AP from the sequence of its cDNA. 95%of this sequence was confirmed by amino acid (aa) sequence analysis of naturalα2 AP (α2 AP)? The 452 aa molecule contains 2 disulfide bonds and 4 glycosylated Asn residues, aa sequence alignment confirmed α2AP's membership in the Serpin family. The reactive site sequence as determined by NH2 - and COOH-terminal aa sequence analysis of the plasmin-modified inhibitor and the released M−r ∼ 8000 peptide is Met362-Ser363-Arg364-Met365-Ser366, P3-P2-P1-P'1-P'2, respectively.Natural and engineered P1 residue substitutions in the Serpin α2 -antitrypsin ( α2 AT) have shown altered specificities and efficiencies. To further examine the role of P and P' residues in determining Serpin specificity, in the present study we have by site-directed mutagenesis, deleted (△) the P'l-Met365 residue of a AP thereby producing a recombinant (r) inhibitor (r α2 AP△Met365) whose putative new reactive site mimics that of antithrombin III (ATIII) and a AT-Pittsburgh (Pl-Arg-P'1-Ser). A second variant was constructed (ra2AP△Arg364) in which the Pl-Arg364 residue was deleted, producing the new sequence Met362-Ser363-Met364-Ser365, containing 2 potential sites analogous to the Pl-P'l, Met-Ser reactive site of α2 AT. The variants and r α2 AP were expressed in CH0 cells, purified and compared with n α2 AP, α2AT and ATIII for the ability to inhibit plasmin, thrombin, trypsin and elastase. n α2 AP and r α2 AP had nearly identical inhibition constants and like ATIII did not inhibit neutrophil elastase. Without heparin both α2 APs and ATIII inhibited thrombin moderately (k1 = 2 to 4× 103 ). Bovine trypsin was neutralized by the α2 APs with k1 = 3 × 106 and by ATIII with k1 = 1 × 105. The α2APs inhibited plasmin (k1 = 2 ×107 ) much more efficiently than ATIII (K1 =2 × 103 ). In contrast, was a highly effective antielastase (k1 = 1 × 107 ), a poor plasmin and thrombin inhibitor ancl inhibited bovine trypsin with = 2 × 10. As reported by others, α2 AT-Pittsburg has greatly reduced antielastase activity and greatly enhanced antithrombin activity. Analysis of ra APAMet365 revealed little change in activity toward plasmin, trypsin and elastase. Thus, α2 AP has no absolute requirement for Met .in the P'l position in order to effectively inhibit plasmin and trypsin. The other P^ subsites appear to be spatially flexible as deletion of the natural P'l residue must displace them. Contrary to prediction a 20-fold decrease in antithrombin activity was observed rather than an enhanced activity. Analysis of rα2 AP△Arg364 showed that it is unreactive with plasmin, trypsin and thrombin, but that it has acquired a significant antielastase activity (k1 = 1.5 × 105). The exact PI residue(s) has not been determined but removal of the bulky basic Arg364 may have resulted in accessibility of the predicted reactive site(s) peptide bond(s) Met362-Ser363 or Met364-Ser365 to the active site cleft of elastase. α2AP'Enschede', a natural mutant with deficient antiplasmin activity, was shown to contain an Ala insertion between aa 353 and 357, 7 to 10 positions NH2-terminal to its reactive site (Holmes et al., this meeting). This mutation results in conversion of α2 AP'Enschede' from an inhibitor to a substrate that retains a high affinity for the active site of plasmin.
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Mysliwiec, M., D. Alderson, L. Poller, and P. Ackrill. "PROTEIN C AND OTHER CLOTTING STUDIES IN MEMBRANOUS AND NON-MEMBRANOUS GLOMERULONEPHRITIS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644310.
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The occurrence of thrombosis in the nephrotic syn drome has long been known. Thrombotic complications are predominantly associated with membranous glomerulonephritis (MG). The aim of the present work was to study whether the tendency of nephrotic patients with MG to thrombotic episodes could be attributed to a hypercoagulable state. Thirty consecutive patients with the nephrotic syndrome were studied. Of these 17 suffered from MG and 13 had other forms of glomerulonephritis. The control group consisted of 10 healthy volunteers. In addition to standard coagulation assays, we studied: soluble fibrin monomer complexes (FM test, Boehringer), fibrin monomer polymerization, factor VIII:C, factor VIII:vWF, anti thrombin III (AT III) and alpha2 antiplasmin (alpha2AP) using chromogenie substrates; the levels of AT III and alpha2 AP were measured immunologically; beta thromboglobulin (BTG), platelet factor 4 and fibrinopeptide A (FPA) using radioimmunoassay kits; protein C was studied functionally and immunologically. There was a significant shortening of the prothrombin time and activated partial thromboplastin time, increase in alpha9 AP, factor V111:vWF, FPA and BTG in nephrotic patients associated with in or eases in both functional and imminclogical protein C levels and impairment of fibrin polymerization. FM test was negative in all but one of the patients. None of the coagulation tests showed a significant difference in the two nephrotic groups. High protein C and impaired polymerization may be considered as mechanisms counteracting disclosed hypercoagulability in the nephrotic syndrome.
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Riccardi, Fabio, Federico DelGrande, Giuliano Prando, Valentina Giuliani, Matteo Pecoraro, and Andrea Ragazzi. "NGCTR-TD Tiltrotor Autorotation Numerical Investigation." In Vertical Flight Society 78th Annual Forum & Technology Display. The Vertical Flight Society, 2022. http://dx.doi.org/10.4050/f-0078-2022-17551.
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Within the Clean Sky 2 Fast Rotorcraft platform, a Next Generation Civil Tilt-Rotor Technology Demonstrator (NGCTR-TD) is under development. The design phase has been successfully completed and first flight phase is planned within 2023. As part of design verification, the capability to perform a safe landing procedure after losing all engines power is investigated, with dedicated analysis planned in order to improve the transport category performance requirements, as verified for Legacy tilt-rotor platform. Such procedure consists in 4 different steps when starting from AP mode, and the analysis are focused on VTOL steady autorotation phase, being the one where tilt-rotor configuration shows higher peculiarity with respect to helicopter configuration, due to the presence of lifting surfaces. As first, preliminary considerations from helicopter theory are cited, and tilt-rotor peculiarities listed. Then, adopting the developed FlightLab numerical model, different solutions are investigated, starting from characterization in airspeed for a baseline configuration. Different sensitivity analyses are conducted to map the major effect for the specific topic, and best trade-off autorotation configuration/control strategy is obtained for NGCTR-TD. Such solution is investigated in the complete Weight/CG envelope to ensure control strategy robustness.
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Pereira, Berta Vaz Andrade de Faria, Júlia Raquel Silva do Ó, Deon Vinicius Moreira Pimentel, Daniela Textor, Fabiana Chaveiro Gomes, and Marina Araújo e. Rocha. "Acretismo placentário com invasão extensa de estruturas adjacentes: um relato de caso." In 45º Congresso da SGORJ XXIV Trocando Ideias. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/jbg-0368-1416-20211311107.
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Introdução: O acretismo placentário (AP) é definido pela inserção anormal da placenta, à qual o vilo placentário adere profundamente, atingindo o miométrio e até órgãos adjacentes. Uma complicação importante é a hemorragia maciça pós-parto, mas ele pode cursar com ruptura uterina anteparto, falência de múltiplos órgãos e histerectomia total (HT) de emergência, evoluindo com até 10% de mortalidade materna. Relato de caso: I.M.B.S., 34 anos, G4P2CA1, foi encaminhada ao Hospital Materno Infantil em Goiânia (HMI) com hipótese diagnóstica de placenta prévia (PP) e AP, em uso de sintomáticos e hidratação venosa (HV) de manutenção. Gestação de feto único, idade gestacional de 36 semanas e 6 dias, com queixa de hematúria há dois dias confirmada no exame de sedimentos anormais da urina. Na ultrassonmografia (USG) de vias urinárias com doppler, foi identificada placenta anterior, com aumento de fluxo próximo à bexiga. Ao exame físico, estava em bom estado geral, hipocorada 1+/4, hidratada, com batimentos fetais cardíacos de 146 bpm, dinâmica uterina ausente, tônus uterino normal e movimento fetal presente. No hemograma, apresentou hemoglobina (Hb) de 9,5 g/dL e, na USG transvaginal com doppler, perda do plano de clivagem entre placenta e parede uterina, hipervascularização em colo uterino e doppler de artéria umbilical em parede vesical. Agendaram-se cesariana e realização de hemoconcentrado (CH) para o dia seguinte. No parto, extraiu-se de recém-nascido vivo com Apgar 9/10 e identificou-se placenta com sinais de invasão extensa de parede posterior da bexiga, parede abdominal, colo, porção superior de vagina e peritônio. Com auxílio do cirurgião geral, realizou-se dissecção cautelosa, livramento das paredes, HT com placenta in situ e fechamento da bexiga em dois planos. A paciente evoluiu com sangramento importante e instabilidade hemodinâmica corrigida com drogas vasoativas e politransfusão de hemoderivados. Foi encaminhada para a unidade de terapia intensiva (UTI) com Hb 4,3, hematócrito 12,4% e plaquetas 71.000, apresentando melhora após nova transfusão de hemoderivados, cristaloides e vitamina K. No 3º dia pós-operatório (PO), evoluiu com leve edema de subcutâneo nas adjacências da ferida operatória associado a coleções flegmosas em superfícies percicatriciais e iniciou ceftriaxone por 10 dias. Recebeu alta da UTI no 5º dia PO, com prescrição de ácido fólico, complexo B e enoxaparina em dose profilática. No 10º dia PO, a paciente, assintomática, recebeu alta médica com sonda vesical de demora (SVD), profilaxia com amoxicilina-clavulanato por sete dias e enoxaparina 40 mg subcutânea por 10 dias. Retornou ao ambulatório no 17º dia PO, com retirada de pontos de sutura e SVD e micção espontânea após uma hora. Conclusão: Curetagens uterinas, miomectomias, PP e cesarianas anteriores são fatores de risco para AP, e I.M.B.S. apresentava PP e duas cesárias anteriores. É de extrema importância que o diagnóstico seja feito no pré-natal para a programação cirúrgica adequada e a diminuição da mortalidade por complicações, sendo a USG com doppler o principal método diagnóstico e a HT abdominal o principal tratamento.
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"THC COMO PRECIPITANTE DE PSICOSIS. A PROPÓSITO DE UN CASO." In 23° Congreso de la Sociedad Española de Patología Dual (SEPD) 2021. SEPD, 2021. http://dx.doi.org/10.17579/sepd2021p027v.
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1.Objetivos 1.Dificultades en diagnóstico precoz de PEP. 2.Describir importancia consumo THC en aparición síntomas psicóticos. 3.Describir importancia de conciencia de enfermedad en patología dual. 4.Describir utilidad de ILP. 2. Material y métodos Se presenta el caso clínico de una mujer de 19 años sin AP somáticos ni de salud mental, tampoco familiares, cuyo primer contacto con salud mental es un ingreso hospitalario de 3 semanas con clínica consistente en: angustia psicótica, perplejidad, ecopraxias y ecolalias, pensamiento disgregado con bloqueos y discurso desorganizado que se intercala de forma intermitente con otros más coherentes. Afecto inapropiado y labilidad afectiva. Previamente solo síntomas de ansiedad nunca presentes antes en la paciente e insomnio. La paciente presentaba consumo habitual de THC desde los 17 años y ocasionalmente cocaína y setas. Desde el primer momento, conciencia parcial de trastorno, lo cual ha sido crucial en la buena evolución del caso. La clínica psicótica remitió por completo, reapareciendo ocasionalmente cuando consume o duerme poco. El consumo ha sido el aspecto más difícil a la hora de trabajar, este se ve fomentado por un entorno social poco favorable, desocupación y bajo nivel socio económico. Actualmente, en tratamiento con ILP (Maintena 400 mg IM) sin haber presentado secundarismos y que vive de forma favorable. 3. Resultados y conclusiones 1.El diagnóstico precoz en PEP resulta complicado debido a la presentación vaga de los síntomas iniciales. 2.El consumo de THC se presenta como precipitante claro en la aparición de síntomas psicóticos. 3.La conciencia de enfermedad resulta un factor clave de buen pronóstico.