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Статті в журналах з теми "Complexe GATOR1"
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Kurrle, Nina, Frank Schnütgen, Juliana Heidler, Ina Poser, Frank Wempe, Diego Yepes, Ilka Wittig, et al. "Exploring the Function of Sestrin/Gator As Novel Regulators of Hematopoiesis." Blood 128, no. 22 (December 2, 2016): 1484. http://dx.doi.org/10.1182/blood.v128.22.1484.1484.
Повний текст джерелаАнотація:
Abstract The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that responds to multiple environmental cues such as reactive oxygen species (ROS) and thereby regulates many fundamental biological processes including cell growth and autophagy. mTOR is found in two distinct multiprotein complexes, mTORC1 and mTORC2, of which mTORC1 has been established to play an important role in the regulation of hematopoiesis. For example, mTORC1 inhibition, combined with activation of canonical Wnt-signaling, was shown to increase long term repopulating (LT)-HSC self-renewal, whereas its activation depletes LT-HSCs. The activity of mTORC1 is tightly controlled by multiple layers of upstream regulators, including the recently discovered GTPase activating protein (GAP) activity towards Rags (GATOR) complex, which is an AMP-Kinase/Tuberous sclerosis complex (TSC)-independent mTORC1 inhibitor induced by amino acid deprivation. GATOR consists of two subcomplexes, GATOR1 and GATOR2, whereby GATOR2 inhibits GATOR1. Inactivation of GATOR2 prevents mTORC1 activation by amino acids, whereas inactivation of GATOR1 constitutively activates mTORC1. Sestrins (Sesn1, Sesn2 and Sesn3) are a family stress-inducible, redox-sensitive proteins that are involved in cellular- or organism-level adaptation to diverse metabolic challenges. They have been identified as direct interactors of GATOR2 and shown to inhibit mTORC1 by preventing GATOR2 from inhibiting GATOR1 in presence of amino acids. In quantitative affinity purification-mass spectrometry (AP-MS) and coimmunoprecipitation experiments with HeLa- and mouse embryonic stem cells harboring in situ GFP-tagged Sesn2, WDR59 and NPRL3 alleles, we could confirm the Sesn2/GATOR interaction under nearly physiological conditions. To analyze the function of Sestrin/GATOR during hematopoiesis in more detail, we isolated Lin- Sca+ hematopoietic cells from the bone marrow of Sesn2-/- mice and performed serial replating experiments and competitive hematopoietic repopulation experiments in lethally irradiated mice and observed that Sesn2-/- progenitor cells proliferate significantly faster than their wild type counterparts albeit only during the initial engraftment phase. At later stages, the wild type cells took over, exceeding the Sesn2-/- cells by 3-4 fold in peripheral blood, bone marrow and spleen three months after transplantation. This suggests that the increased proliferative potential of Sesn2-/- progenitor cells leads to a depletion of the LT-HSC pool, strikingly resembling the phenotype of activated mTORC1. Disclosures No relevant conflicts of interest to declare.
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Solanki, Sumeet, Jun-Hee Lee, and Yatrik Shah. "AMINO ACID SENSING PATHWAYS IN INFLAMMATORY BOWEL DISEASE." Inflammatory Bowel Diseases 28, Supplement_1 (January 22, 2022): S23—S24. http://dx.doi.org/10.1093/ibd/izac015.036.
Повний текст джерелаАнотація:
Abstract IBD is a chronic inflammatory disease of the gastrointestinal tract affecting millions of people worldwide. The last few decades have seen rapid increase of IBD cases in the US contributing to exorbitant health-care costs and morbidity rates. IBD comprises of two major subtypes: ulcerative colitis and Crohn’s disease. Although the etiology of IBD is not completely understood, a complex interaction of environmental, genetic, immune, and gut microbial factors contributes to its pathogenesis. These factors ultimately converge to disrupt intestinal epithelial cell homeostasis, compromising mucosal barrier function, leading to unresolved relapsing inflammatory injury. Poor dietary habits such as Western diet are thought to play a pivotal role in the development of colitis. A healthy and balanced diet is important in management of the disease. Epidemiological and experimental studies demonstrate that high-protein diet triggers inflammatory flares and colitis patients are often advised to reduce animal dietary protein. However, colitis patients are also at high risk of a protein malnutrition. Thus, the precise mechanisms by which low dietary protein increases incidence of colitis and/or aggravate already established disease remains unknown. Our preliminary findings suggest that low dietary protein intake aggravated dextran sulfate sodium (DSS)-induced colitis with reduced body weight, colon length and increased histological injury. Dietary habits impact intestinal epithelial cell homeostasis and regeneration process in the event of an injury. The mechanistic target of rapamycin complex 1 (mTORC1), a ‘master’ regulator of cell growth participates in intestinal tissue regeneration. Remarkably, studies inhibiting mTORC1 activity have shown to disrupt the regenerative capacity of intestinal epithelium and increased susceptibility to colitis while activating mTORC1 had a positive effect. As amino acids potently activate mTORC1, we assessed and found that low dietary protein significantly reduce colonic mTORC1 activation. The newly discovered GAP activity towards Rags (GATOR1 & GATOR2) complexes act as amino acid sensing pathways by which mTORC1 activity is modulated. GATOR1 is a negative regulator, whereas GATOR2 is a positive regulator of mTORC1. CRISPR/CAS9 knockout of Wdr24 (GATOR2) led to inactivation of mTORC1 under amino acid culture conditions. Next, we investigated the role of amino acid sensing pathway in colitis models and found that disruption of intestinal epithelial specific GATOR2 complex (Wdr24ΔIE) attenuated mTORC1 activity and increased susceptibility to colitis. These findings suggest that low protein diet impacts colitis by modulating the intestinal epithelial amino acid sensing pathway.
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Padi, Sathish K. R., Neha Singh, Jeremiah J. Bearss, Virginie Olive, Jin H. Song, Marina Cardó-Vila, Andrew S. Kraft, and Koichi Okumura. "Phosphorylation of DEPDC5, a component of the GATOR1 complex, releases inhibition of mTORC1 and promotes tumor growth." Proceedings of the National Academy of Sciences 116, no. 41 (September 23, 2019): 20505–10. http://dx.doi.org/10.1073/pnas.1904774116.
Повний текст джерелаАнотація:
The Pim and AKT serine/threonine protein kinases are implicated as drivers of cancer. Their regulation of tumor growth is closely tied to the ability of these enzymes to mainly stimulate protein synthesis by activating mTORC1 (mammalian target of rapamycin complex 1) signaling, although the exact mechanism is not completely understood. mTORC1 activity is normally suppressed by amino acid starvation through a cascade of multiple regulatory protein complexes, e.g., GATOR1, GATOR2, and KICSTOR, that reduce the activity of Rag GTPases. Bioinformatic analysis revealed that DEPDC5 (DEP domain containing protein 5), a component of GATOR1 complex, contains Pim and AKT protein kinase phosphorylation consensus sequences. DEPDC5 phosphorylation by Pim and AKT kinases was confirmed in cancer cells through the use of phospho-specific antibodies and transfection of phospho-inactive DEPDC5 mutants. Consistent with these findings, during amino acid starvation the elevated expression of Pim1 overcame the amino acid inhibitory protein cascade and activated mTORC1. In contrast, the knockout of DEPDC5 partially blocked the ability of small molecule inhibitors against Pim and AKT kinases both singly and in combination to suppress tumor growth and mTORC1 activity in vitro and in vivo. In animal experiments knocking in a glutamic acid (S1530E) in DEPDC5, a phospho mimic, in tumor cells induced a significant level of resistance to Pim and the combination of Pim and AKT inhibitors. Our results indicate a phosphorylation-dependent regulatory mechanism targeting DEPDC5 through which Pim1 and AKT act as upstream effectors of mTORC1 to facilitate proliferation and survival of cancer cells.
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Wei, Youheng, Brad Reveal, Weili Cai, and Mary A. Lilly. "The GATOR1 Complex Regulates Metabolic Homeostasis and the Response to Nutrient Stress in Drosophila melanogaster." G3 Genes|Genomes|Genetics 6, no. 12 (December 1, 2016): 3859–67. http://dx.doi.org/10.1534/g3.116.035337.
Повний текст джерелаАнотація:
Abstract TORC1 regulates metabolism and growth in response to a large array of upstream inputs. The evolutionarily conserved trimeric GATOR1 complex inhibits TORC1 activity in response to amino acid limitation. In humans, the GATOR1 complex has been implicated in a wide array of pathologies including cancer and hereditary forms of epilepsy. However, the precise role of GATOR1 in animal physiology remains largely undefined. Here, we characterize null mutants of the GATOR1 components nprl2, nprl3, and iml1 in Drosophila melanogaster. We demonstrate that all three mutants have inappropriately high baseline levels of TORC1 activity and decreased adult viability. Consistent with increased TORC1 activity, GATOR1 mutants exhibit a cell autonomous increase in cell growth. Notably, escaper nprl2 and nprl3 mutant adults have a profound locomotion defect. In line with a nonautonomous role in the regulation of systemic metabolism, expressing the Nprl3 protein in the fat body, a nutrient storage organ, and hemocytes but not muscles and neurons rescues the motility of nprl3 mutants. Finally, we show that nprl2 and nprl3 mutants fail to activate autophagy in response to amino acid limitation and are extremely sensitive to both amino acid and complete starvation. Thus, in Drosophila, in addition to maintaining baseline levels of TORC1 activity, the GATOR1 complex has retained a critical role in the response to nutrient stress. In summary, the TORC1 inhibitor GATOR1 contributes to multiple aspects of the development and physiology of Drosophila.
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Shen, Kuang, Rick K. Huang, Edward J. Brignole, Kendall J. Condon, Max L. Valenstein, Lynne Chantranupong, Aimaiti Bomaliyamu, et al. "Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes." Nature 556, no. 7699 (March 28, 2018): 64–69. http://dx.doi.org/10.1038/nature26158.
Повний текст джерела
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Muller, Maéline, Jasmine Bélanger, Imane Hadj-Aissa, Conghao Zhang, Chantelle F. Sephton, and Paul A. Dutchak. "GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1." International Journal of Molecular Sciences 25, no. 4 (February 8, 2024): 2068. http://dx.doi.org/10.3390/ijms25042068.
Повний текст джерелаАнотація:
GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells. Genetic mutations in the GATOR1 subunits, NPRL2 (nitrogen permease regulator-like 2), NPRL3 (nitrogen permease regulator-like 3), and DEPDC5 (DEP domain containing 5), have been associated with epilepsy in humans; however, the specific effects of these mutations on GATOR1 function and mTORC1 regulation are not well understood. Herein, we report that epilepsy-linked mutations in the NPRL2 subunit of GATOR1, NPRL2-L105P, -T110S, and -D214H, increase basal mTORC1 signal transduction in cells. Notably, we show that NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity even under conditions of amino acid deprivation. Furthermore, our studies reveal that the GATOR1 complex is necessary for the rapid and robust inhibition of mTORC1 in response to growth factor withdrawal or pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids.
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Gu, Xin, Jose M. Orozco, Robert A. Saxton, Kendall J. Condon, Grace Y. Liu, Patrycja A. Krawczyk, Sonia M. Scaria, J. Wade Harper, Steven P. Gygi, and David M. Sabatini. "SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway." Science 358, no. 6364 (November 9, 2017): 813–18. http://dx.doi.org/10.1126/science.aao3265.
Повний текст джерелаАнотація:
mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor S-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.
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Jang, Ki Beom, Agus Suryawan, Marta L. Fiorotto, and Teresa A. Davis. "PSII-18 Prematurity alters nutrient signaling and protein synthesis in skeletal muscle of neonatal piglets." Journal of Animal Science 102, Supplement_3 (September 1, 2024): 694–95. http://dx.doi.org/10.1093/jas/skae234.783.
Повний текст джерелаАнотація:
Abstract Extrauterine growth restriction is common in infants born preterm, and negatively affects lean mass accretion and health. Prematurity has been shown to inhibit the feeding-induced stimulation of protein synthesis in skeletal muscle. We hypothesized that nutrient signaling, activation of the mechanistic target of rapamycin complex 1 (mTORC1), and protein synthesis in the muscle are limited in preterm infants which negatively impacts muscle growth. The objective of this study was to examine how prematurity influences the mechanisms involved in insulin- and amino acid-induced signaling and protein synthesis in skeletal muscle of piglets delivered either 9 d preterm (104 d, n = 25) or at term (112 d, n = 26) by cesarean section. After resuscitation, they were surgically implanted with jugular vein and carotid artery catheters and placed in individual incubators. They were randomly allotted to one of three treatments within each preterm and term birth groups: euaminoacidemic-euglycemic (FAST), hyperinsulinemic-euaminoacidemic-euglycemic (INS), or euinsulinemic-hyperaminoacidemic-euglycemic (AA) clamps on 4 d after birth. After the clamp procedure, the piglets were euthanized to collect longissimus dorsi muscle for estimating in vivo fractional protein synthesis rates and the abundance and activation of components related to insulin and amino acid signaling. Data were analyzed using the MIXED procedure of SAS. The leucine sensor, Sestrin1 bound to GATOR2 (P < 0.05) was reduced in response to AA whereas the abundance of the mTOR-RagA and mTOR-RagC complexes increased (P < 0.05). The phosphorylation of Akt was increased (P < 0.05) in response to INS and the phosphorylation of mTORC1 and protein synthesis increased (P < 0.05) in response to both AA and INS. Prematurity did not affect the protein abundances of the AA transporters for glutamine (SLC38A2), leucine (SLC7A5), and arginine (SLC38A9). However, prematurity reduced (P < 0.05) the abundances of the leucine sensors SAR1B, the Sestrin1-GATOR complex, the AA sensor, RAB1A, and the threonine sensor, TARS2 (P < 0.05). The abundances of the glutamine sensor, ARF1, the arginine sensor, CASTOR, and the methionine-SAMTOR GATOR complex were similar. Prematurity reduced (P < 0.05) the abundance of the mTOR-RagA and mTOR-RagC complexes, the phosphorylation of mTORC1 and muscle protein synthesis (P < 0.05). In conclusion, prematurity negatively affects protein synthesis in skeletal muscle of neonatal preterm piglets by blunting anabolic pathways responsible for nutrient-sensing and mTORC1 activation. The reduced anabolic response likely contributes to reduced lean growth and extrauterine growth restriction following preterm birth.
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Smieszek, S. P. "0018 Whole Genome Sequencing Study Identifies Novel Variants Associated with Intrinsic Circadian Period in Humans." Sleep 43, Supplement_1 (April 2020): A7—A8. http://dx.doi.org/10.1093/sleep/zsaa056.017.
Повний текст джерелаАнотація:
Abstract Introduction Non-24 is a circadian rhythm disorder in which the master body clock runs either slightly earlier or, more commonly in the disorder, longer than 24 hours. Methods We conducted the first whole genome sequencing study of a non-24 population of 174 individuals that we identified as being totally blind with Non-24 Disorder. We have directly tested the association between SNPs and circadian period length (tau) (n=69). Linear regression corrected for PCs and covariates identified a strong signal in HCN1, Brain Cyclic Nucleotide-Gated Channel 1, HCN1. Results HCN1 channel is responsible for the feedback on the rods regulating the dynamic range of light reactivity under dim or intermediate light conditions. Minor allele rs72762058 associated with longer tau, a difference of 12 minutes, and mean tau of 24.71. In Drosophila there is only one HCN channel encoding gene, DmIh. Interestingly, DmIh mutant flies display alterations in the rest:activity pattern, and altered circadian rhythms, specifically, arrhythmic behavior or a shorter period in constant darkness. We report a variant that associated with longer tau. In addition, we identify others variants that strongly associate with tau, such as a missense variant (rs16989535), (minor allele associated with longer tau), within DEPDC5, GATOR Complex Protein). Subjects carrying the rare allele have a period > 25.2. DEPDC5 is part of GATOR1 complex, together with NPRL2 and NPRL3acts to inhibit the mTORC1 pathway. The GATOR1 seizure phenotype consists mostly of focal seizures, often sleep-related and drug-resistant and is associated with focal cortical dysplasia (20%). mTOR signaling is part of the photic entrainment pathway in the SCN, it regulates autonomous clock properties in a variety of circadian oscillators. Light-induced mTORC1 activation appears to be important for photic entrainment of the SCN clock, as rapamycin modulates light-induced phase shifts of wheel-running and body temperature rhythms in mice. Conclusion We identify variants in HCN1 and DEPDC5 implicated in significantly longer tau. Knowledge of the circadian clock and period length is not only essential for understanding of the basic clockwork mechanisms but also could provide insights into mechanistic links between circadian dysfunctions and human diseases such as epilepsy. Support Vanda Pharmaceuticals
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Xu, Dandan, Kevin L. Shimkus, Holly A. Lacko, Lydia Kutzler, Leonard S. Jefferson, and Scot R. Kimball. "Evidence for a role for Sestrin1 in mediating leucine-induced activation of mTORC1 in skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 316, no. 5 (May 1, 2019): E817—E828. http://dx.doi.org/10.1152/ajpendo.00522.2018.
Повний текст джерелаАнотація:
Previous studies established that leucine stimulates protein synthesis in skeletal muscle to the same extent as a complete mixture of amino acids, and the effect occurs through activation of the mechanistic target of rapamycin in complex 1 (mTORC1). Recent studies using cells in culture showed that the Sestrins bind leucine and are required for leucine-dependent activation of mTORC1. However, the role they play in mediating leucine-dependent activation of the kinase in vivo has been questioned because the dissociation constant of Sestrin2 for leucine is well below circulating and intramuscular levels of the amino acid. The goal of the present study was to compare expression of the Sestrins in skeletal muscle to other tissues and to assess their relative role in mediating activation of mTORC1 by leucine. The results show that the relative expression of the Sestrin proteins varies widely among tissues and that in skeletal muscle Sestrin1 expression is higher than Sestrin3, whereas Sestrin2 expression is markedly lower. Analysis of the dissociation constants of the Sestrins for leucine as assessed by leucine-induced dissociation of the Sestrin·GAP activity toward Rags 2 (GATOR2) complex revealed that Sestrin1 has the highest affinity for leucine and that Sestrin3 has the lowest affinity. In agreement with the dissociation constants calculated using cells in culture, oral leucine administration promotes disassembly of the Sestrin1·GATOR2 complex but not the Sestrin2 or Sestrin3·GATOR2 complex. Overall, the results presented herein are consistent with a model in which leucine-induced activation of mTORC1 in skeletal muscle in vivo occurs primarily through release of Sestrin1 from GATOR2.
Дисертації з теми "Complexe GATOR1"
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Pan, Zhenrui. "Functional characterization of the GATOR1 complex in cisplatin resistance." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL053.
Повний текст джерелаАнотація:
L'administration de cisplatine constitue la principale approche de chimiothérapie pour de nombreux cancers épithéliaux. Cependant, la résistance à ce médicament pose un défi considérable à un traitement efficace. Malgré l'identification de nombreux facteurs associés à la résistance aux médicaments, des biomarqueurs fiables permettant de prédire la réponse au traitement restent insaisissables. Auparavant, une faible expression du suppresseur de tumeur NPRL2 était liée à la résistance au cisplatine. NPRL2, ainsi que NPRL3 et DEPDC5, forment le complexe GATOR1, un régulateur en amont du complexe mTOR 1, dont la fonction est perturbée dans de nombreux cancers, en particulier ceux résistants au cisplatine.Ici, nous comparons les cellules épithéliales bronchiques non cancéreuses BEAS-2B avec des délétions de GATOR1, servant de modèle de résistance intrinsèque au cisplatine, avec les lignées de cancer du poumon non à petites cellules A549, H460, H1975 présentant une résistance acquise au médicament. Nous avons découvert que la déplétion de n'importe quel membre de GATOR1, et non uniquement NPRL2, favorise la résistance au cisplatine alors que leur surexpression rend les cellules sensibles au médicament. Dans les cellules avec des délétions de GATOR1, l'expression du transporteur ATP7A, nécessaire à l'efflux de cisplatine, est augmentée tandis que l'expression des transporteurs d'influx de cisplatine CTR2 et LRCC8A est diminuée. Cela empêche l'accumulation du médicament dans les cellules, entraînant la formation de moins d'adduits cisplatine-ADN. Simultanément, ces cellules présentent une réponse accrue aux dommages de l'ADN et une activité mTORC1 renforcée. La surexpression des composants de GATOR1 et/ou le traitement concomitant avec des inhibiteurs de mTORC1 restaurent la sensibilité au cisplatine. L'analyse transcriptomique des cellules BEAS-2B déplétées en GATOR1, traitées ou non avec le médicament, identifie de nouvelles signatures importantes pour comprendre la fonction de GATOR1 et son rôle dans la résistance au cisplatine. Ainsi, GATOR1 ne participe pas seulement à la réponse cellulaire à la disponibilité des acides aminés, mais joue également un rôle dans la résistance aux médicaments anticancéreux endommageant l'ADN. Cette nouvelle fonction de GATOR1 doit être prise en compte lors du développement de nouvelles stratégies pour lutter contre la chimiorésistanceCisplatin administration is the primary chemotherapy approach for many epithelial cancers. However, resistance to this drug poses a significant challenge to effective treatment. Despite the identification of numerous factors associated with drug resistance, reliable biomarkers predicting drug response remain elusive. Previously, low expression of the tumor suppressor NPRL2 was linked to cisplatin resistance. NPRL2, along with NPRL3 and DEPDC5, forms the GATOR1 complex, an upstream regulator of the mTOR complex 1, the function of which is perturbed in many cancers, particularly those resistant to cisplatin.Here, we compare non-cancerous bronchial epithelium BEAS-2B cells with GATOR1 deletions, serving as a model of intrinsic cisplatin resistance, with non-small cell lung cancer lines A549, H460, H1975 with acquired resistance to the drug. We found that depletion of any GATOR1 member, not solely NPRL2, promotes cisplatin resistance whereas their overexpression renders cells sensitive to the drug. In the cells with GATOR1 depletions, expression of the transporter ATP7A required for cisplatin efflux is increased while expression of cisplatin influx transporters CTR2 and LRCC8A is downregulated, especially after treatment with the drug. This hinders drug accumulation in cells, resulting in the formation of fewer cisplatin-DNA adducts. Simultaneously, these cells exhibit enhanced DNA damage response and mTORC1 activity. Overexpression of GATOR1 components and/or concomitant treatment with mTORC1 inhibitors restores sensitivity to cisplatin. Transcriptomic analysis of GATOR1-depleted BEAS-2B cells, treated or not with the drug, identifies new signatures important for understanding GATOR1 function and its role in cisplatin resistance. Thus, GATOR1 not only participates in the cellular response to the amino acid availability, but also plays a role in resistance to DNA-damaging anticancer drugs. This novel function of GATOR1 should be taken into account when developing new strategies to combat chemoresistance
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Ma, Yinxing. "Functional characterization of tumor suppressors from the SEA / GATOR complex." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS275.
Повний текст джерелаАнотація:
La plupart des voies de signalisation qui régule la croissance cellulaire et le métabolisme sont sous le contrôle du mécanisme du complexe I de la rapamycine (mTORC1). L'un des régulateurs en amont de mTORC1, impliqués dans la détection des acides aminés et l'autophagie, est complexe SEA, chez la levure, et le complexe GATOR, chez les mammifères. Plusieurs composants de GATOR sont dérégulés dans de nombreux cancers et maladies neurodégénératives. Malgré l'intérêt scientifique vis à vis du complexe SEA / GATOR, de nombreux détails concernant sa fonction et son implication dans différents troubles humains sont encore inconnus et restent à investiguer.L'objectif principal de ma thèse était d’élargir notre connaissance sur le complexe SEA / GATOR, et plus particulièrement en ce qui concerne son rôle dans la modulation des voies de signalisation cellulaire. Étant donné que le SEA / GATOR est très conservé, j'ai effectué les expériences en utilisant deux modèles cellulaires : levure S. cerevisiae et lignées cellulaires humaines. Les résultats obtenus ont permis de démontrer un nouveau rôle pour le NPRL2, composant de GATOR, distinct de sa fonction dans la régulation de la voie mTORC1. Nous avons constaté que l'expression ectopique de la NPRL2 induit un stress oxydant et conduit aux dommages de l'ADN et à l'apoptose. Les études sur la levure ont révélé que le complexe SEA relie la voie mTORC1 et la régulation du contrôle de la qualité des mitochondries. Par conséquent, le complexe SEA / GATOR émerge en tant que régulateur multifonctionnel de plusieurs processus cellulairesThe major signaling pathway that regulates cell growth and metabolism is under the control of the mechanistic target of rapamycin complex 1 (mTORC1). One of the mTORC1 upstream regulators involved in amino acid sensing and autophagy is called the SEA complex in yeast and GATOR in mammalian cells. Several GATOR components are deregulated in many cancers and neurodegenerative diseases. Despite of the growing interest to the SEA/GATOR, many details concerning its function and implication in different human disorders are still unknown.The main objective of my thesis was to extend our knowledge about the SEA/GATOR, especially what concerns its role in the modulating cellular signaling network. Because the SEA/GATOR is highly conserved I performed the experiments using two model systems - budding yeast S. cerevisiae and human cells lines. The results I obtained allowed to demonstrate a new role for the GATOR component NPRL2, distinct from its function in mTORC1 regulation. We found that ectopic expression of NPRL2 induces oxidative stress and leads to the DNA damage and apoptosis. The studies in yeast revealed that the SEA complex connects the TORC1 pathway and the regulation of mitochondria quality control. Therefore, the SEA/GATOR complex is emerging as a multifunctional regulator of several cellular processes
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Gonzalez, Alba. "On the edge between cell division and differentiation : role of Seh1 in mouse embryonic stem cells." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7039.
Повний текст джерелаАнотація:
Les complexes des pores nucléaires (NPCs) sont des larges structures macromoléculaires ancrées dans l'enveloppe nucléaire, et composées d'environ 30 protéines différentes appelées nucléoporines ou Nups. Au-delà de leur rôle critique dans le transport des molécules, les NPCs participent à une grande variété de processus biologiques, tels que la division cellulaire, l'organisation de la chromatine et la régulation de l'expression des gènes. Le principal sous-complexe structural des NPCs est le complexe Y-complexe, qui est composé de 9 nucléoporines distinctes. Le Y-complexe est aussi localisé aux kinétochores pendant la mitose où il régule la congression et la ségrégation des chromosomes. Une nucléoporine de ce complexe, Nup133, a été impliquée dans le développement embryonnaire de la souris. Nup133 n’est pas requise pour la survie des cellules souches embryonnaires murines (mESCs) à l'état pluripotent mais devient essentielle lors de leur différenciation. Le Y-complexe joue donc un rôle majeur dans de multiples processus biologiques mais le rôle spécifique de chacune de ses sous-unités n’a pas été étudié en profondeur. En particulier, une nucléoporine, Seh1, est critique pour la localisation du Y-complexe et de plusieurs régulateurs mitotiques clés, notamment Aurora B aux kinétochores. Dans ce contexte, Seh1 apparaît comme un candidat intéressant, non seulement en raison de son implication en mitose, mais aussi parce qu'elle appartient à un second sous-complexe, nommé GATOR2, qui régule indirectement la voie mTORC1. On ne sait toutefois pas si les fonctions mitotiques de Seh1 reposent sur sa localisation au niveau du pore, des kinétochores ou du complexe GATOR2. Les travaux réalisés au cours de cette thèse ont révélé que les mESCs Seh1-/- sont viables à l'état indifférencié, mais que leur viabilité est gravement compromise lors de la différenciation. Nous avons constaté que l'inactivation de Seh1 est associée à un retard dans la progression mitotique et à un allongement général du cycle cellulaire. Contrairement aux études précédentes, le retard mitotique des mESC Seh1-/- n'est pas lié à une délocalisation du Y-complexe ni de la kinase Aurora B au niveau des kinétochores.Pour comprendre si ce retard est dû à un rôle dans les NPC ou au sein du complexe GATOR2, j'ai ensuite conçu une stratégie visant spécifiquement à altérer l'interaction entre Seh1 et Nup85 (∆N-Nup85), son partenaire direct dans le Y-complexe. Dans les mutants ∆N-Nup85 Seh1 n'est plus détectable au niveau des kinétochores et est largement délocalisé du NPC. Cependant, les mESCs ∆N-Nup85 ne présentent aucun défaut de division cellulaire ni pendant la différenciation. D’autre part, j'ai constitutivement inactivé Mios, un autre membre du complexe GATOR2. Les cellules Mios-/- résultantes survivent pendant la différenciation et aucun retard de croissance cellulaire n'a été observé. En plus des défauts mentionnés précédemment, nous avons observé une diminution inattendue de la densité des NPC dans les cellules Seh1-/- et ∆N-Nup85, qui n'a cependant pas été observée dans le mutant Mios. Ceci indique une fonction de Seh1 dans la régulation de l'assemblage des NPC. Remarquablement, nous avons également observé une réduction de la taille dues noyaux des mutants Seh1 qui n'est pas observée dans les mutants ∆N Nup85, ce qui pourrait refléter un rôle de Seh1 dans le complexe GATOR2. Mes recherches ont élargi nos connaissances sur les différents rôles de Seh1 et ont commencé à aborder la localisation critique de cette protéineThe nuclear pore complexes (NPCs) are large macromolecular structures embedded in the nuclear envelope, composed of around 30 different proteins called nucleoporins or Nups. Besides their function in regulating nucleo-cytoplasmic transport, several Nups have been reported to play essential roles in other unrelated processes such as chromatin organization, gene regulation, cell cycle control and cell differentiation. The Nup107 complex (also termed Y-complex) is the major structural component of the NPC and is composed of 9 distinct Nups. The Y-complex has been shown to also localize at kinetochores, where it contributes to cell cycle progression. Moreover, one of the components of the Y-complex, Nup133, is required for embryonic stem cell differentiation and proper mouse development. More recent data further indicated a function of Nup133 in the assembly of the nuclear pore basket that may underlie some of its functions. The Y-complex has thus appeared as a key player in multiple biological processes. However, the specific roles of each of its subunits have just started to be investigated. Among the subunits of the Y-complex, Seh1 has been previously reported to play a role in chromosome alignment and segregation in cancer cell lines, by recruiting the Y-complex and several key mitotic regulators (including notably Aurora B) to kinetochores. Interestingly, Seh1 also belongs to the unrelated GATOR2 complex, an essential activator of the mTORC1 kinase, a master regulator of cell growth and proliferation. It is however unknown whether the mitotic functions of Seh1 rely on its localization at the pore, at kinetochores, or the GATOR2-complex. Due to the increasing number of studies implicating nuclear pore components in regulatory processes, Seh1 appears as a good candidate for the coordination of cell cycle and possibly differentiation. My data has revealed that Seh1-/- mESCs are viable in pluripotent state, but that cell survival is severely impaired upon differentiation. Pluripotent Seh1-/- mESCs also feature a cell growth rate delay when in the pluripotent state, correlated with a small (10 min) mitotic delay and and lenghthening of the interphase lenght as compared to WT mESCs. In contrast to previous studies performed in HeLa cells, we observed that both the Y-complex and Aurora B are still properly targeted to kinetochores in these cells. To understand if this delay is due to a role at NPCs or within the GATOR2 complex, I designed a strategy to specifically impair the interaction between Seh1 and Nup85 (∆N-Nup85), its direct partner within the Y-complex. In the resulting ∆N-Nup85 mutants, Seh1 is no longer detectable at kinetochores and is largely mislocalized from the NPC. In parallel, I constitutively inactivated Mios, another member of the GATOR2 complex. Surprisingly, the resulting ∆N-Nup85 and Mios-/- cells did progress through differentiation and no cell growth delay was observed. Interestingly, we observed an unexpected decrease in NPC density in the Seh1-/- and ∆N-Nup85 mESCs that was in contrast not observed in the Mios-/-cells. This pointed to a function of Seh1 in the context of the Y-complex in the regulation of NPC assembly.We also observed a reduction in nuclear size in the Seh1 mutants that is not shared by the ∆-Nup85mutants but that could be consistent with a role of Seh1 within the GATOR2 complex. My research has expanded our knowledge regarding the different roles of Seh1 and has started to tease apart the relative contributions of this protein in its different subcellular contexts
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Bazzi, Talissa. "CARACTERÍSTICAS CLÍNICO-EPIDEMIOLÓGICAS, HISTOMORFOLÓGICAS E HISTOQUÍMICAS DA ESPOROTRICOSE FELINA." Universidade Federal de Santa Maria, 2015. http://repositorio.ufsm.br/handle/1/10218.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorSporotricosis is an acute or subacute mycotic infection caused by the Sporothrix complex species. The disease was already described in humans and in several animal species, mostly in cats, horses and dogs. Based on several outbreak reports in the literature, the species more predominant in cats of the Southeast and South regions of Brazil is S. brasiliensis. The transmission to humans include the occupational and the zoonotic forms. The presentation form more often seen in cats is multiple skin and mucosal lesions. The diagnostic methods include the isolation and identification of the agente in culture, the histopathology, the cytology, the intradermal sporotrichin test, the immunohistochemistry technique, and the polymerase chain reaction (PCR). The histopathological diagnosis is based on the morphological characteristics of the fungus and the respective inflammatory reaction. The main objectives of this retrospective study were to characterize the histomorphological and histochemical aspects of sporotrichosis in 10 cats, and also to evaluate epidemiological and clinical aspects, and gross findings obtained from the biopsy and necropsy protocols of the archives of the Laboratório de Patologia Veterinária of the Universidade Federal de Santa Maria. The disease affected mostly male mongrel cats, and was mostly observed in the cutaneous disseminated form. Gross lesions were characterized by cutaneous nodules (ulcerated or not) and by ulcerated masses or plaques. By histopathology, there were a relationship between the fungal load and two patterns of inflammatory response. The first pattern was characterized by high fungal load, and most yeasts were inside of numerous macrophages with abundant, many times vacuolated cytoplasm. The amount of neutrophils ranged from mild to moderate in this pattern. The second pattern was characterized by numerous epiteliod cells and many neutrophils. The fungal load was low and most yeasts were observed in the extracellular space. The yeasts were round, oval or cigar-shaped. Several histochemical techniques, such as Grocott s silver stain, periodic Schiff acid, and Alcian blue were utilized and they made it easier to visualize, to characterize the morphology, and to quantify the organisms. The Giemsa stain allowed visualizing the agent, but it not allowed to sharply highlight them from other intralesional components. Organisms were negative for melanin granules through the Fontana-Masson stain in all cases. The histomorphological and histochemical study allowed demonstrating determinant fungal characteristics to the establishment of the diagnosis by means of this diagnostic tool.
Esporotricose é uma infecção fúngica subaguda ou crônica, causada por espécies do complexo Sporothrix. A doença já foi descrita em humanos e em diversas espécies animais, mas ocorre com maior frequência em gatos, cavalos e cães. Baseado em vários relatos de surtos na literatura, a espécie mais predominante em gatos das regiões Sul e Sudeste do Brasil é S. brasiliensis. As formas de transmissão para humanos incluem a ocupacional e a zoonótica. A forma de apresentação mais frequente em gatos é de múltiplas lesões de pele e mucosas. Os métodos de diagnóstico compreendem o isolamento e identificação do agente em cultura, a histopatologia, a citologia, o teste intradérmico da esporotriquina, a técnica de imuno-histoquímica (IHQ) e a reação em cadeia de polimerase (PCR). O diagnóstico histopatológico é realizado observando-se as características morfológicas do fungo e a respectiva reação inflamatória. Os principais objetivos deste estudo retrospectivo foram caracterizar os aspectos histomorfológicos e histoquímicos da esporotricose em 10 gatos, além de avaliar os aspectos epidemiológicos, clínicos e os achados macroscópicos obtidos dos protocolos de biópsias e necropsias dos arquivos do Laboratório de Patologia Veterinária da Universidade Federal de Santa Maria. A doença afetou predominantemente gatos machos, sem raça definida e na forma cutânea disseminada. As lesões macroscópicas caracterizaram-se como nódulos cutâneos (ulcerados ou não) e como massas e placas ulceradas. Na histopatologia observou-se uma relação entre a quantidade de leveduras observada e dois padrões de resposta inflamatória. O primeiro padrão caracterizou-se por numerosas leveduras encontradas, na sua maioria, no interior de numerosos macrófagos com citoplasma abundante e muitas vezes vacuolizado. A quantidade de neutrófilos variava de leve a moderada e havia infiltrado geralmente leve de linfócitos e plasmócitos. O segundo padrão caracterizava-se por leve quantidade de leveduras observadas geralmente livres no espaço extracelular, numerosas células epitelioides e infiltrado predominantemente acentuado de neutrófilos. As leveduras eram redondas, ovais ou alongadas (em forma de charuto). Foram utilizadas várias técnicas histoquímicas como a impregnação pela prata de Grocott, ácido periódico de Schiff e azul Alciano que facilitaram a visualização, caracterização da morfologia e quantificação dos organismos. A coloração de Giemsa permitiu a visualização do agente, porém não permitiu destacá-los dos debris celulares. Os organismos foram negativos para grânulos de melanina pela coloração de Fontana-Masson em todos os casos. O estudo histomorfológico e histoquímico permitiu demonstrar características fúngicas determinantes para o estabelecimento do diagnóstico de esporotricose através dessa ferramenta diagnóstica.
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Oikonomopoulos, Spyridon. "Inferring structural properties of protein-DNA binding using high-throughput sequencing : the paradigm of GATA1, KLF1 and their complexes GATA1/FOG1 and GATA1/KLF1 : insights into the transcriptional regulation of the erythroid cell lineage." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:72b92906-4ef6-4c1d-9155-484521027e2e.
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GATA1 and KLF1 are transcription factors that regulate genes which are important for the development of erythroid cells. The GATA1 transcriptional co-factor FOG1 has been shown to be essential in a wide range of GATA1 dependent cellular functions. Here we tried to understand the diverse mechanisms by which GATA1 and KLF1 recognize their binding sites, how the GATA1 recognition mechanisms are affected by complexation with either FOG1 or KLF1 and how the GATA1 recognition mechanisms affect the transcriptional regulation of the erythroid differentiation. We profiled the DNA binding specificities/affinities of a GATA1 fragment (mGATA1NC), that contains only the two DNA binding domains (N-terminal and C-terminal Zn finger), and the DNA binding specificities/affinities of a KLF1 fragment (mKLF1257-358), that contains the three DNA binding domains, using a novel methodology that combines EMSA with high throughput sequencing (EMSA-seq (Wong et al., 2011a)). We also profiled the DNA binding specificities of the C-terminal Zn finger of GATA1 alone (mGATA1C), the wt-mGATA1, the wt-mGATA1/wt-mFOG1 complex and the mGATA1NC/mKLF1257-358 complex. At first, we confirmed that the N-terminal Zn finger of GATA1 has a strong preference for the “GATC” motif, whereas the C-terminal Zn finger of GATA1 has a strong preference for the “GATA” motif. Next, we found that in the mGATA1NC, both DNA binding domains can bind simultaneously a wide range of different positional combinations of the co-occurring “GATA” and “GATC” motifs, on the same DNA sequence. The wt-mGATA1 did not show the ability to bind in the same co-occurring motifs implying an effect of the non-DNA binding domains of the protein in the regulation of its DNA binding specificities. On the contrary, complexation of wt-mGATA1 with the wt-mFOG1 partially restored its ability to bind in a now limited range of different positional combinations of the co-occurring “GATA” and “GATC” motifs, on the same DNA sequence. Similar observations were made for other pairs of GATA1 N-terminal and C-terminal Zn finger specific motifs. We then projected the GATA1 DNA binding specificities/affinities in vivo and we classified the GATA1 ChIP-seq peaks in low, medium or high affinity based on the number of the GATA1 motifs. We noticed that high affinity GATA1 ChIP-seq peaks tend to appear in regions with low nucleosome occupancy. We also noticed that GATA1 ChIP-seq peaks in the enhancer regions are usually high affinity whereas GATA1 ChIP-seq peaks in the proximal promoter regions are usually low affinity. Additionally, we observed that high affinity GATA1 ChIP-seq peaks are usually found in regions with increased levels of H3K4me2 and are associated with a higher decrease in the H3K4me3 levels on the TSS of the nearby genes. None of these GATA1 related in vivo observations were found for the KLF1 ChIP-seq positions. These findings significantly advance our understanding of the DNA binding properties of GATA1, KLF1 and their complexes and give an insight on the importance of the GATA1 DNA binding affinities in the regulation of the erythroid transcriptional program. Overall the work establishes an experimental and analytical framework to investigate how transcriptional co-factors can change the DNA binding specificities of specific transcription factors and how integration of the transcription factor DNA binding affinities with in vivo data can give novel insights into the transcriptional regulation.
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Seki, Meire Christina [UNESP]. "Chlamydophila felis em gatos (Felis catus): detecção de antígeno e pesquisa de anticorpos." Universidade Estadual Paulista (UNESP), 2008. http://hdl.handle.net/11449/95975.
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seki_mc_me_jabo.pdf: 576519 bytes, checksum: d22961f6b04eb42b3628b080392fb7c3 (MD5)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
O presente trabalho, primeiro estudo sobre clamidiose felina no Brasil, teve o objetivo de pesquisar a presença direta e indireta de Chlamydophila (elis em gatos domésticos provenientes de cinco municípios da região nordeste do estado de São Paulo. Adicionalmente, correlacionar os dados de ficha clínica com os resultados positivos obtidos nos três testes laboratoriais utilizados, ou seja, reação em cadeia pela polimerase (PCR), reação de imunotluorescência indireta (RI FI) e reação de fixação do complemento (RFC). O grupo experimental final foi constituído de 151 animais, dos quais 73 eram provenientes de gatis, 18 de clínica/hospitais veterinários e 60 de abrigos públicos para animais. Das 151 amostras de suabes de conjuntiva submetidas à PCR, em 6,0% (9/151) foi encontrado DNA de C. (elis. Anticorpos anti-Chlamydiaceae foram detectados em 72,1% (106/147) das amostras de soros submetidas à RIFI. Em somente 9,4% (10/106) dos soros positivos à RIFI, foram detectados anticorpos fixadores do complemento, revelando que a RFC, embora específica, apresenta baixa sensibilidade quando utilizada na pesquisa de anticorpos anti-Chlamydiaceae em gatos domésticos. Foi também observado que gatos provenientes de gatis, animais com idade maior que um ano e inferior a seis anos, bem como as fêmeas, estão mais predispostos a soroprevalência para C.felis pela RIFI. Entretanto, tais resultados não foram observados nos animais PCR positivo. Ademais, pode-se verificar uma estreita relação entre as presenças de DNA clamidial e de anticorpos anti-Chlamydiaceae em gatos domésticos brasileiros aos dados das fichas clínica relacionados à doença do trato respiratório superior, a secreção ocular e a conjuntivite.
This work, first study about feline chlamydiosis in Brazil, had the objective to evaluate the direct and indirect presence to Chlamydophila felis in domestic cats coming trom tive cities of northeast of São Paulo state. Additionally, relate informations of clinical records with positives results get in the three laboratories tests used, whatever, complement fixation test (CFT), immunofluorescende assay (IFI) and Polymerase Chain Reaction (PCR). Experimental group had 151 animais, witch 73 coming from catteries, 18 coming trom veterinary clinicallhospital and 60 coming from public animal shelters. From 151 samples of conjunctival swabs submitled to PCR, in 6% (9/151) were detect DNA of C.felis. Anti-Chlamydophila antibodies were detect in 72,1%(106/147) of samples of serum submitted to IFI. In just 9,4% (10/106) of the positive serums in IFI, had complement fixation antibodies, detected by CFT. The CFT, although specific, presented low sensibility when to use to research of anti-Chlamydiaceae antibodies in domestic cats. In cats from catteries, animais between one and six year, and female were more predispose to a presence of antibodies anti-Chlamydophila by IFI. However, these results were not observed in animais PCR positive. Thus, was observed a relationship between the presence of chlamydial DNA and antibodies anti-Chlamydiaceae in Brazilian domestic cats, added with informations of clinical records, like with upper respiratory tract disease, ocular discharge and conjunctivitis.
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Vargas, Zúñiga Juan Alberto. "Reporte de un caso de epidermitis supurativa necrótica por Acinetobacter calcoaceticus - Acinetobacter baumannii (Acb-) complex en gato (Felis catus) en el Perú." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2017. https://hdl.handle.net/20.500.12672/11379.
Повний текст джерелаАнотація:
Manifiesta que el Acinetobacter baumannii es una bacteria responsable de infecciones nosocomiales con alta mortalidad en humanos, elevada tasa de resistencia a los antibióticos y con presentaciones reportadas en animales cada vez más frecuentes. Un gato doméstico pelo corto de 7 meses de edad y 4,4 kgs es llevado a la veterinaria por vómitos y decaimiento, al día siguiente regresa con temperatura de 40.1 °C, Posteriormente presenta linfadenomegalia únicamente de lado izquierdo (pre escapular, axilar, inguinal), además se hace evidente lesión cutánea alopécica en miembro anterior izquierdo, la lesión se extendió abarcando antebrazo y hombro y posteriormente el otro hombro. A la evaluación histopatológica de una muestra lesional de la piel, se evidenció epidermitis supurativa necrótica y leve dermatitis linfocítica perivascular, el tratamiento con cefalosporinas (ceftriaxona y cefovecin sódico) y fluoroquinolonas fue infructuoso, se realizó un cultivo aislándose Acinetobacter baumannii complex. Los propietarios deciden la eutanasia del paciente. No se conocen reportes previos en Perú acerca de esta bacteria como causante de procesos infecciosos en animales.Trabajo académico
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Abreu, Daniel Paiva Barros de. "Caracteriza??o fenot?pica, genot?pica e perfil de sensibilidade a antif?ngicos de isolados cl?nicos de c?es e gatos pertencentes ao Complexo Sporothrix schenckii oriundos do estado do Rio de Janeiro." Universidade Federal Rural do Rio de Janeiro, 2017. https://tede.ufrrj.br/jspui/handle/jspui/2031.
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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq
Dimorphic fungi belonging to Sporothrix schenckii complex are responsible for sporotrichosis, important fungal infection with worldwide distribution. The anthropozoonotic characteristic is of high relevance in the state of Rio de Janeiro, where an increasing in the number of cases in human patients was observed in the last decades, highlighting the role of domestic cat as a transmitter agent. The description of new species compounding de Sporothrix genus, based on phenotypic and genotypic evaluations, showed the involvement of other members of this group in the epidemic status installed in Rio de Janeiro. The verification of strains resistant to itraconazole, a widely used antifungal in human and animal medicine for the treatment of this mycosis, is an important factor that possibly results in relapse and therapeutic failure of this disease. The present study aimed to identify, by phenotypic and molecular approaches, 168 isolates obtained from the routine of Veterinary Clinical Microbiology Laboratory ? UFRRJ, and the determination of minimal inhibitory concentration (MIC) for amphotericin B (AMB), ketoconazole (KTC), itraconazole (ITC), terbinafine (TRB) and voriconazole (VRC). Based on morphophysiological characteristics it was possible to identify 159 (94.64%) isolates as S. brasiliensis and 9 (5.36%) as S. luriei. However, applying PCR-RFLP of calmodulin 168 (100%) samples were identified as S. brasilensis. The susceptibility test, based on M38-A2 document (CLSI), showed that TRB was the most effective antifungal tested, followed by ITC, KTC, AMB, and VRC, respectively. No ITC resistant isolates were detected in the present study. These results demonstrate that the identification reached only by phenotypic evaluation is not recommended for the characterization of Sporothrix schenckii complex components. It also proves the predominance of S. brasiliensis in other regions of RJ state. The better efficacy of TRB added to the absence of isolates resistant to ITC support the necessity of pharmacodynamics and pharmacokinetics studies for the optimization of the therapeutic protocols. More information about isolates from dogs and cats correlated with the species from the S. schenckii complex, as well as in vitro antifungal efficacy evaluation provide knowledge about therapeutic alternatives. In this way, the present study also provides relevant information about the endemic status in Rio de Janeiro and important data for the treatment of human and animal sporotrichosis.
Fungos dim?rficos pertencentes ao complexo Sporothrix schenckii s?o respons?veis pela esporotricose, importante infec??o f?ngica que apresenta distribui??o mundial. Sua conhecida caracter?stica antropozoon?tica apresenta grande relev?ncia no estado do Rio de Janeiro, onde se verifica aumento significativo no n?mero de pacientes humanos e animais acometidos pela doen?a nas ?ltimas d?cadas, destacando-se em tais casos o papel do felino como agente transmissor. A descri??o de novas esp?cies pertencentes ao g?nero Sporothrix, baseada em caracter?sticas fenot?picas e genot?picas, demonstrou o envolvimento de outros componentes deste g?nero na epidemia instalada no estado. A verifica??o de isolados resistentes a itraconazol, antif?ngico amplamente utilizado na medicina humana e veterin?ria para o tratamento da doen?a, ? fato preocupante e tem poss?vel associa??o a recidivas e falhas terap?uticas. O presente estudo objetiva a identifica??o fenot?pica e genot?pica de 168 exemplares oriundos de pacientes felinos e caninos, obtidos na rotina do Diagn?stico Microbiol?gico Veterin?rio - UFRRJ, com determina??o da Concentra??o Inibit?ria M?nima (CIM) frente ? anfotericina B (AMB), cetoconazol (KTC), itraconazol (ITC), terbinafina (TRB) e voriconazol (VRC). A partir de caracter?sticas morfofisiol?gicas foi poss?vel identificar 159 (94,64%) isolados como S. brasiliensis e 9 (5,36%) como S. luriei. Contudo, metodologias moleculares identificaram 168 (100%) S. brasiliensis, a partir de PCR-RFLP em gene respons?vel pela s?ntese de calmodulina. O teste de sensibilidade, realizado a partir do documento M38-A2 (CLSI) determinou maior efic?cia in vitro para TRB, seguido por ITC, KTC, AMB e VRC, respectivamente. Cepas resistentes a ITC n?o foram detectadas no presente estudo. Tais resultados demonstram que a identifica??o alcan?ada exclusivamente por m?todos fenot?picos n?o ? recomendada para caracteriza??o de componentes do complexo Sporothrix schenckii. Comprova-se ainda a predomin?ncia de S. brasiliensis em outras regi?es do estado do RJ. A maior efic?cia de TRB, somada a aus?ncia de exemplares resistentes a ITC, refor?a a necessidade de estudos farmacodin?micos e farmacocin?ticos para otimiza??o dos protocolos terap?uticos atualmente utilizados. Obten??o de maiores informa??es acerca dos isolados provenientes de amostras provenientes de c?es e gatos correlacionados a esp?cies dentro do complexo S. schenckii, bem como a avalia??o da efic?cia in vitro de antif?ngicos proporcionam conhecimento sobre alternativas terap?uticas. Tais informa??es auxiliam no entendimento do quadro instalado no estado do Rio de Janeiro e fornece dados de grande utilidade para o tratamento humano e veterin?rio
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Dawson, Ruby Emily. "Investigation of the GATOR1 complex genes in focal cortical dysplasia and focal epilepsy." Thesis, 2019. http://hdl.handle.net/2440/121340.
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Epilepsy is a complex disease characterised by seizures due to abnormal neuronal activity. Both hereditable and non-hereditable epilepsy forms of epilepsy exist, and understanding their underlying mechanisms leads to more effective and targeted treatments. Following advances in DNA sequencing technologies, more cases of epilepsy caused by genetic mutations have been identified. Therefore, the investigation into how these mutations result in seizures is a worthwhile avenue of research, and will improve diagnosis and treatment of affected individuals. DEPDC5, NPRL2 and NPRL3 encode the GATOR1 complex and mutations in each of these genes have been found in patients with familial focal epilepsy and focal cortical dysplasia (FCD) type II. Heterozygous patients are affected with variable severity, variable foci and incomplete penetrance. The function of these genes and the mechanisms of how their mutation cause the disease are not well understood. In vitro studies have recently found that GATOR1 functions to downregulate the mTORC1 signalling pathway in response to depleted amino acid levels. The mTORC1 pathway is involved in regulating many cellular processes including protein synthesis, cell growth and autophagy. Many diseases, including some epilepsies, arise from mTORC1 dysregulation and are termed ‘mTORopothies’. mTOR dysregulation is therefore hypothesised to be the major factor in the pathology of GATOR1-related epilepsy. To better understand the roles these genes play in causing epilepsy and FCD, this thesis uses mutant mouse models and cell lines engineered with CRISPR/CAS9 genome editing technology. Firstly, a knockout mouse model for Depdc5 highlights the gene’s in vivo role in regulating the mTORC1 signalling pathway and in embryonic development. Depdc5 homozygous null mice do not survive past the mid-late stages of gestation, showing a range of gross malformations in the head and brain. Brain lysates show hyperactivity of the mTORC1 pathway, establishing a role for the deregulation of this pathway in disease. Heterozygous mice, however, develop normally and do not show any susceptibility to seizures despite patients of this genotype being affected. Interestingly, heterozygous GATOR1 patients present with focal neurological pathologies. It is hypothesised that this may result from a second somatic mutation occurring during the brain development of germline heterozygotes, causing a region of tissue lacking GATOR1 function. We investigate this mechanism and accurately model the features of the disease with a Depdc5 conditional mouse. Using CRISPR/CAS9, we generated a floxed allele which, following the unilateral electroporation of Cre into developing embryo brains, recombines to result in discrete regions of null neuron ‘clones’. This successfully modelled FCD and epilepsy phenotypes including increased soma growth, increased dendritic complexity, abnormal morphology, migration defects and lower seizure thresholds. mTORC1 hyperactivity is evident in regions of brain pathology, where the gene function has been abolished, which further supports deregulation of mTORC1 as the major pathogenic mechanism. To investigate the functional outcomes of specific patient variants of all three GATOR1 genes, we develop a functional assay using GATOR1 null cell lines, measured by the ability to rescue of null phenotypes in vitro and in vivo contexts. We confirm that some variants for each of the GATOR1 genes have lost the ability to inhibit mTORC1 activity in amino acid starvation conditions. Additionally, using the Depdc5 conditional mouse model, we confirm the functional outcome of two DEPDC5 variants in vivo, and the downstream effects their loss-of-function has on disease phenotypes. Importantly, we also find the majority of missense variants were not functionally compromised. This highlights the importance of functional screening of GATOR1 gene variants in regard to pathogenic classification and accurate diagnosis, which in turn leads to improved therapies and genetic counselling . Collectively, these investigations using mutant cell lines and mutant mice support the involvement of mTORC1 dysregulation in GATOR1-related epilepsy and FCD through a second-hit disease mechanism.Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2019
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Santos, Bárbara Costa Matias Machado dos. "Complexo gengivite-estomatite-faringite dos felinos." Master's thesis, 2016. http://hdl.handle.net/10348/5977.
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Dissertação de Mestrado Integrado em Medicina VeterináriaO Complexo Gengivite-Estomatite-Faringite dos Felinos é uma doença frequente nestes animais e caracteriza-se por uma intensa inflamação da cavidade oral e da gengiva. Afeta, principalmente, gatos adultos com cerca de 8 anos de idade, não havendo predisposição sexual. A etiologia não é claramente conhecida, mas suspeita-se que determinadas bactérias, alguns vírus, a alimentação, o ambiente e o maneio (stresse), ou uma conjugação destes fatores com fatores genéticos, originem esta doença. Crê-se que a causa mais provável seja o calicivírus felino. Os sinais clínicos mais frequentemente visualizados são inapetência, disfagia, anorexia, ptialismo, halitose e perda de peso. Para a obtenção do diagnóstico definitivo realiza-se a técnica de Reação em Cadeia da Polimerase, testando a presença de calicivírus, e a Eletroforese de Proteínas para evidenciação de uma gamopatia policlonal. Não existe nenhum protocolo terapêutico totalmente eficaz para esta doença, podendo ser usada uma abordagem médica, cirúrgica, ou uma combinação das duas. No entanto, a extração dentária múltipla ou radical constitui o tratamento de eleição. Esta dissertação tem como objetivo ressaltar aspetos atuais do Complexo Gengivite Estomatite Faringite dos Felinos, desde os principais sinais clínicos, os vários agentes etiológicos envolvidos, os meios de diagnóstico mais relevantes e as diversas formas de tratamento. Nomeadamente, é pretendido mostrar a viabilidade da abordagem com homeopatia no tratamento desta condição. Para além disso, pretendemos alertar os Médicos Veterinários e os proprietários para esta doença, tão frequente na medicina felina. Foram abordados três casos clínicos recolhidos no Hospital Veterinário da Universidade de Trás-os-Montes e Alto Douro em Vila Real. Apenas se obteve o diagnóstico definitivo num dos casos, tendo-se obtido um diagnóstico presuntivo nos restantes, devido à impossibilidade financeira dos proprietários para realizar mais exames. Em relação ao tratamento, é corroborada a ideia de que a extração dentária parcial ou total é a tratamento de eleição para esta doença, tendo sido usada nos três casos. No caso da Clarinha, apenas a homeopatia se revelou eficaz, técnica que ainda não é muito usada, mas que constitui mais uma ferramenta no tratamento desta doença. Estes casos retratam bem a característica recidivante desta doença e o desafio clínico que a mesma representa. O Complexo-Gengivite-Estomatite-Faringite dos Felinos é uma condição frustrante para os Médicos Veterinários e para os proprietários, uma vez que tanto o diagnóstico como o tratamento constituem um enorme desafio clínico e continuará a ser um dos maiores problemas em medicina felina enquanto a patogenia não estiver totalmente esclarecida. Em particular, o papel do calicivírus, do VIF e da disfunção do sistema imunitário e as suas implicações no tratamento precisam de ser melhor esclarecidos.
Feline Chronic Gingivitis Stomatitis (FCGS) is a common disease within the cats and it is characterized by intense oral cavity and gingival inflammation. The FCGS affects, mainly, adult cats around 8 years old and there is no sexual predisposition. The etiology is not clearly known, but it is suspected that certain bacteria, some viruses, food, the environment and management (stress), or a combination of these factors with genetic factors may cause this disease. It is believed that the most likely cause is the feline calicivirus. The most frequently displayed clinical signs are loss of appetite, dysphagia, anorexia, drooling, halitosis and weight loss. In order to obtain a definitive diagnosis it is performed the technique of Polymerase Chain Reaction that tests the presence of calicivirus and Protein Electrophoresis for disclosure of a polyclonal gammopathy. There is no completely effective therapy for this disease, and it can be used surgical, medical approach or a combination of both. However, the multiple or radical tooth extraction is the most used treatment. This dissertation is aimed to highlight aspects of the current Feline Chronic Gingivitis Stomatitis, from the main clinical signs, the various etiological agents involved, the most relevant diagnostic procedures until the various forms of treatment. Namely, it is intended to show the feasibility of the homeopathic approach in the treatment of this condition. Furthermore, we intend to alert veterinarians and owners to this disease, so frequent in feline medicine. It was approached three clinical cases in the Veterinary Hospital of the University of Trás-os-Montes and Alto Douro (VH-UTAD), in Vila Real. The definitive diagnosis was obtained in just one of the clinical cases and it was obtained a presumptive diagnosis in the remaining cases, due to the financial impossibility of the owners to conduct more tests. Concerning the treatment, it is supported that the partial or total dental extraction is the treatment of choice for this disease and it was used in the three clinical cases. In the case of Clarinha, only homeopathy has proved effective though it is a technique that is not yet widely used, but it is another useful tool in the treatment of this disease. These clinical cases demonstrate well the recurrent feature of this disease and the clinical challenge it represents. Feline Chronic Gingivitis Stomatitis is a frustrating condition for veterinarians and owners, since both diagnosis and treatment are a huge clinical challenge and as long as the pathogenesis is not fully understood, it will continue to be a major problem in feline medicine. In particular, the calicivirus and FIV role and the dysfunction of the immune system and its implications in the treatment need to be better understood.
Книги з теми "Complexe GATOR1"
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Guia Completa De Razas De Gatos/ Complete Guide of Cat Breeds. Edilupa Ediciones Sl, 2007.
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Guia Completa De Razas De Gatos/ Complete Guide of Cat Breeds. Edilupa Ediciones Sl, 2007.
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Pinto, Analía Verónica. Orozquianas. Editorial de la Universidad Nacional de La Plata (EDULP), 2017. http://dx.doi.org/10.35537/10915/59418.
Повний текст джерелаАнотація:
<i>Orozquianas</i> apela a las nociones de reescritura y homenaje en forma explícita, algo que en la poesía suele hacerse de modo menos contundente. Aquí se ponen de relieve dichos recursos, como una forma de homenajear y agradecer tanta felicidad deparada por la lectura de la <i>Poesía completa</i> de Olga Orozco, de donde fueron extraídos todos los versos utilizados como disparadores. El mundo de Orozco, así, es revelado a través de la admiración y la apropiación poética de algunos de sus íconos (como el otoño o los gatos), conformando un nuevo caleidoscopio, que también funge de respetuosa ofrenda.
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Crumb, R. Crumb obras completas: El gato Fritz/ Crumb Complete Comics: Fritz the Cat (Crumb Obras Completas / Crumb Complete Comics:). Public Square Books, 2006.
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Ivanova, Ilina, and Kuang Shen. "Structures and Functions of the Human GATOR1 Complex." In Subcellular Biochemistry, 269–94. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-031-58843-3_12.
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Leal, Janaina de Fatima Rodrigues, and Fabiane Schneider. "Parceria da gestão pública e do terceiro setor nas políticas públicas de proteção animal." In Administração Contemporânea Vol 4, 19–31. 4th ed. Editora ZH4, 2021. http://dx.doi.org/10.51360/zh4.20218-8-p19-31.
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Esta pesquisa tem como objetivo a análise das vantagens de se aliar a gestão pública ao trabalho do terceiro setor, e mais especificamente sobre a contribuição da AMAHTEB (Associação dos Amigos do Melhor Amigo do Homem para o Bem-Estar Animal de Telêmaco Borba) em políticas públicas de proteção animal e controle ético da população de cães e gatos, conforme dispõe a Lei 17422 de 18 de dezembro de 2012 no município de Telêmaco Borba/PR. Desta forma, se direcionando a ampliar a visão a respeito do aumento da população de animais de rua no município, e em decorrência disso a proliferação de zoonoses, a pesquisa propõe-se a examinar as políticas públicas neste aspecto, analisar as possíveis falhas do poder público, assim como avaliar o método de trabalho da AMAHTEB. Portanto, a presente pesquisa, se propõe a usar a metodologia aplicada, qualitativa e exploratória, procurando responder tais questões específicas e buscando resultados e soluções concretas, gerando assim, conhecimentos para aplicação prática, dirigidos à solução de problemas específicos, envolvendo verdades e interesses locais. Pautada em dados secundários, e a partir da interpretação destes dados, a pesquisa mostra a situação investigada de uma forma mais completa. Observa-se então, a possibilidade de se reverter tal quadro que se caracteriza como um problema de saúde pública para o município, visto que mesmo sem apoio governamental a ong em questão já vem realizando cadastros e registros relacionando animais de rua, animais adotados e animais comunitários, sua localização e necessidade de castrações.
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Queiroz, Bruna Barros de, Laís Macêdo Maciel, Gabriel Lúcio Guimarães dos Santos, Caio Victor Barros Gonçalves da Silva, Maria Júlia Brito Couto, and Beatriz Santana Rocha. "Os avanços no tratamento da doença falciforme através da terapia gênica com CRISPR/CAS9." In Avanços em Genética Humana um panorama do 1° simpósio da LAGH, 26–28. Instituto Internacional Despertando Vocações, 2024. http://dx.doi.org/10.31692/978-65-88970-44-7.26-28.
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A doença falciforme (DF) é uma hemoglobinopatia causada por uma mutação estrutural hereditária na formação das cadeias globínicas1 . Essa alteração ocorre por uma mutação pontual A/T na posição 6 do gene da β globina, causando a troca do aminoácido ácido glutâmico pela valina, resultando na síntese da cadeia variante bS globina, que compõe a Hemoglobina S (HbS)2 . A baixa tensão de oxigênio leva à polimerização da HbS, mudando a estrutura da hemácia, inicialmente bicôncava, para falciforme, facilitando a agregação, resultando em oclusão vascular, hipóxia, risco de AVC, esplenomegalia, úlceras e infarto tecidual, o que promove crises de dor frequente em pacientes com DF3 . A hemoglobina fetal (HbF) é composta por 2 cadeias alfa e 2 cadeias gama, sendo intensamente expressa no período fetal até o sexto mês de vida. Posteriormente, há uma diminuição da cadeia gama e um aumento da cadeia beta, a fim de elevar a síntese da hemoglobina A4. O tratamento é realizado com Hidroxiuréia, que eleva os níveis de HbF, aliviando a clínica do paciente, mas há um risco de lesões cutâneas e alopecia. A transfusão sanguínea também é uma possibilidade, porém, é limitado à disponibilidade de doadores compatíveis e ainda há um 27 risco de aloimunização, agravando o quadro clínico dos pacientes3 . Com isso, a técnica de CRISPR/CAS9 tem se destacado como ferramenta alternativa de edição precisa de genes, sendo capaz de corrigir o dano original advindo da doença5 . Essa técnica pode ser aplicada como terapia gênica para diminuir os sintomas da doença e melhorar o quadro clínico e qualidade de vida dos pacientes. O objetivo deste estudo é avaliar a abordagem terapêutica da edição gênica por CRISPR/CAS9 para a DF. Nesse sentido, foram realizadas buscas de artigos no Google Acadêmico e SciElo, utilizando como descritores: “Doença Falciforme”, “Terapia Gênica” e “CRISPR/CAS9”. Os critérios de escolha foram artigos e trabalhos experimentais escritos em inglês e português, publicados entre 2020 e 2023. O gene BCL11A, localizado no cromossomo 2, codifica uma proteína repressora da expressão da gama globina, logo, diminui a síntese de HbF. A terapia gênica CRISPR/CAS9 insere células CD34+, previamente coletadas da medula do paciente e modificadas com vetor, que atuam na clivagem do sítio de ligação GATA1 , uma região intensificadora da linhagem eritróide do gene BCL11A4 . Dessa forma, há um impedimento da sua ligação, o que minimiza a expressão do gene. Os artigos selecionados demonstraram que a tecnologia CRISPR/CAS9 corrigiu a mutação e elevou os níveis de HbF2 . Alves e colaboradores (2023) submeteram pacientes a essa terapia, apresentando um aumento significativo da HbF após 3 meses, além de redução de crises vaso-oclusivas5 . No entanto, é uma técnica com alto custo e complexa, além de ser necessário encontrar um vetor adequado para transportar o CRISPR/CAS9. Portanto, a terapia gênica com CRISPR/CAS9 é bastante promissora para DF, ainda sendo necessários mais estudos para concretizar a eficácia e segurança dessa estratégia, e assim ampliar o seu uso à nível global1 .
Тези доповідей конференцій з теми "Complexe GATOR1"
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Young, Sarah, Michael McClure, and Ursula Emery McClure. "GATOR House: A Typology of Resilience." In 108th Annual Meeting Proceedings. ACSA Press, 2020. http://dx.doi.org/10.35483/acsa.am.108.43.
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In the modern era, most buildings in southern Louisiana’s wet, hot, humid, and often volatile climate seek to resist the extreme conditions by creating a presumed impenetrable barrier. Since the advent of HVAC, levees, dams, and surge barriers, a construction culture of resistance has permeated the built environment. This has proven less than resilient and has resulted in billions of dollars in remediation and billions more tons of construction debris. Historically, buildings in this subtropical area were forced to employ every manner of passive systems to mediate their physical environment to the greatest extent possible. The GATOR house resists the false choices of historical vs. modern, man vs. nature, active vs. passive, and celebrates the complex interaction of the built, natural, and cultural systems of southern Louisiana. Geography is the description of how the signs of history have become forms, therefore the architectural project is charged with the task of revealing the essence of the geo-environmental context through the transformation of form. The environment is therefore not a system in which to dissolve architecture. On the contrary, it is the most important material from which to develop the project. - Vittorio Gregotti 1
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Sabnis, Amit J., David V. Allegakoen, and Trever G. Bivona. "Abstract 3656: The mTOR-activating GATOR2 complex is essential inPAX3-FOXO1-positive rhabdomyosarcoma." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-3656.
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Sabnis, Amit J., David V. Allegakoen, and Trever G. Bivona. "Abstract 3656: The mTOR-activating GATOR2 complex is essential inPAX3-FOXO1-positive rhabdomyosarcoma." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-3656.
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Karla Alves da Silva, Jéssica, Rebeca Santana Malheiros, and Mary'Anne Rodrigues de Souza. "ESPOROTRICOSE CONJUNTIVAL EM UM FELINO DOMÉSTICO." In Congresso Online Acadêmico de Medicina Veterinária. Congresse.me, 2022. http://dx.doi.org/10.54265/folq8411.
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Introdução Esporotricose é uma micose causada por fungos pertencentes ao complexo Sporothrix schenckii. A infecção pode acontecer pela Inoculação do fungo na pele ou inalação de conídios (menos frequente). Os sinais clínicos variam desde lesão única ou lesões múltiplas até a forma sistêmica. A forma mais frequente é apresentada por múltiplas lesões cutâneas com envolvimento da mucosa nasal, as mucosas conjuntival, oral e genital também podem ser afetadas. Achados oftalmológicos como uveíte granulomatosa, retinite granulomatosa, coroidite e endoftalmite foram relatados em pacientes humanos. Objetivos O objetivo do estudo é relatar um caso de lesão única conjuntival provocada por fungos do complexo Sporothrix schenckii em um gato no recife. Métodos Um gato SRD, macho de aproximadamente 2 anos, não orquiectomizado, semi-domiciliado foi atendido na zona sul de Recife-PE por apresentar uma lesão ulcerativa na conjuntiva palpebral do olho direito. O animal apresentava hiperemia conjuntival, quemose e descarga sanguinolenta na conjuntiva do olho direito. Foi realizado o exame citopatológico pela esfoliação com escova microaplicadora da conjuntiva palpebral, onde foram observadas estruturas leveduriformes compatíveis com fungos do complexo Sporothrix schenckii. O tratamento foi realizado com Itraconazol (100 mg/gato) por via oral/ SID por 50 dias e Tobramicina pomada oftálmica QID por 14 dias. Resultados e discussão A Manifestação clínica clássica da esporotricose é a forma cutânea, com ou sem sinais extracutâneos. Poucos relatos foram encontrados de gatos com esporotricose conjuntival e a maioria tem acometimento cutâneo associado. A esporotricose ocular em humanos pode provocar conjuntivite, dacriocistite, uveíte, coroidite e lesões retrobulbares, nas quais as lesões conjuntivais são relacionadas a inoculação direta (por trauma ou autoinoculação) e as lesões posteriores ocorrem por disseminação hematogênica. Em gatos essa diferenciação é pouco clara, no entanto há a sugestão de inoculação do fungo nos olhos devido os seus hábitos de higiene e a sua disseminação provavelmente é hematogênica. O uso do Itraconazol como monoterapia apresentou eficácia como descrito na literatura. O animal do presente estudo mostrou boa evolução clínica com remissão total após 20 dias de tratamento. O tratamento com Itraconazol foi mantido por mais 4 semanas após a remissão clínica, como se indica nos estudos mais recentes O método de diagnóstico utilizado foi o citopatológico, que é um exame rápido, econômico e neste caso foi o suficiente para chegar ao diagnóstico final. Para esse método, o resultado negativo não exclui a presença de fungos na lesão, sendo necessário o uso de outros métodos de diagnóstico como cultura fúngica (padrão-ouro), histopatológico, PCR, imunohistoquímica, sorológi co. Neoplasias, dermatose eosinofílica, micobacteriose, criptococose, histoplasmose, leishmaniose e outras coinfeccões não são incomuns, por isso o diagnóstico diferencial deve ser realizado. Conclusão A esporotricose é uma doença relevante na medicina veterinária que requer testes específicos para o seu diagnóstico e tratamento precoces. Os poucos registros encontrados para a esporotricose conjuntival como lesão única pode ser consequência de subdiagnóstico, visto que as alterações observadas podem ser facilmente confundidas com outras afecções conjuntivais. Resumo - sem apresentação PALAVRAS-CHAVE: Esporotricose felina, Sporothrix schenckii, Lesão única
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Medrano, L., J. R. Spinelli, and A. R. Bertuccelli. "Sustainability and the megacities: the Gato Park Housing Complex in São Paulo, Brazil." In SUSTAINABLE DEVELOPMENT 2009. Southampton, UK: WIT Press, 2009. http://dx.doi.org/10.2495/sdp090071.
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Watanabe, Paola Tieko Chiozzi, Gabriel de Amorim Marques, Izabella Machado Casado, Gabrieli Junqueira Gonçalves, Danielli Aparecida Lavelli, and Leonardo Martins Leal. "Fratura completa de tíbia em canino filhote tratado com tala: relato de caso." In II Congresso Internacional Interdisciplinar da Uningá. Editora Uningá, 2023. http://dx.doi.org/10.46311/ed.un.20221018198.
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As fraturas são comuns na rotina de cães e de gatos. Seu diagnóstico se baseia na anamnese e exame físico ortopédico. Sua confirmação é feita pelo exame radiográfico. A osteossíntese é o tratamento de eleição na maioria dos casos, porém, em situações específicas, pode-se realizar o manejo das fraturas de tíbia com o uso de tala. Objetivou-se relatar o caso de um cão jovem com fratura completa de tíbia direita, que obteve rápida consolidação óssea somente com o uso de tala. Tal fato foi possível pois a fíbula direita não fraturou, o que possibilitou a manutenção do alinhamento interno do membro.
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Lino de Araújo, Cláudia, and Adriana Torrecilhas Jorge. "NEUROFIBROSSARCOMA EM ESCLERA E REGIÃO PERILIMBICA EM UM GATO." In Congresso Online Acadêmico de Medicina Veterinária. Congresse.me, 2022. http://dx.doi.org/10.54265/rvgd2224.
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Objetivou-se com presente trabalho relatar a ocorrência de neurofibrossarcoma em região escleral e perilimbica de um gato. Foi atendido uma fêmea da espécie felina, SRD, 10 anos idade, com queixa principal aumento de volume em região ocular esquerda há 2 meses e lacrimejamento excessivo. Após exame ocular completo observou se um nódulo aderido e ulcerado em região da esclera e perilimbica na posição de 11 horas de um relógio, em olho esquerdo. O teste de fluoresceína foi negativo em ambos os olhos, teste da lágrima de Schimer (DrogaVet) olho esquerdo 12mm/min e direito 14mm/min e Tonometria (Tonovet)o valor foi de 16mmHg e direito 18mmHg. Com auxílio da lente de fundoscopia (Pan Retinal 2.2 Volk) e Finoff, não se observou alterações em fundo ocular. Realizou-se exames complementares tais como, hemograma completo, perfil bioquímico completo (Alt, Fosfatase Alcalina, Uréia e Creatinina) e ultrassom ocular. Não obtivemos alterações em exames sanguíneos, os achados ultrassonográficos evidenciaram uma formação entre conjuntiva e região perilimbica medindo aproximadamente 1,0 cm, contornos irregulares, sugestivo de hiperplasia nodular e ou infiltração neoplásica, sem alterações intraoculares no momento do exame. Após, realizou-se a remoção da neoplasia e posterior histopatológico. No exame histopatológico observou neoplasia maligna fuso celular, suspeitando sarcoma. Ato continuo, realizou exame de imunoistoquimica que evidenciou neurofibrossarcoma em região da esclera e perilimbica. Decorridos 3 meses da remoção cirúrgica, houve recidiva, com rápido crescimento e agressividade tumoral, sendo assim, indicada enucleação do bulbo ocular esquerdo. Com base neste caso clínico, podemos concluir que a realização dos exames histopatológicos associados a imunoistoquímica foi fundamental para o diagnóstico definitivo. Ainda, que os tumores da bainha do nervo periférico apresentam rápida recidivas no local de origem, porém, não houve até o presente momento metástase em outras áreas. PALAVRAS-CHAVE: neurofibrossarcoma, neoplasia felino, cirurgia veterinária
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Marinho, Bruna Sthephany dos Santos. "COMPARAÇÃO CLÍNICA DE AMOSTRAS MICÓTICAS DE GATOS DOMÉSTICOS (FELIS CATUS): ESPOROTRICOSE E CRIPITOCOCOSE." In I Congresso Brasileiro On-line Multiprofissional de Análises Clínicas e Laboratoriais. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/conalab/7839.
Повний текст джерелаАнотація:
Introdução: A esporotricose (complexo Sporothrix sp.) e a criptococose (Cryptococcus sp.) são doenças fúngicas induzidas por leveduras. Elas causam lesões de forma aguda ou crônica nos tecidos dos mamíferos como principal meio de manifestação clínica. Ambas de carater zoonótico, sendo o gato a espécie mais suceptível a elas. São dermatologicamente idênticas e, portanto, de diagnóstico macroscópico impreciso. Elas clinicamente possuem morfologias microscópicas semelhantes, e por isso são a maior causa de confusão no diagnóstico durate a fase analítica. Embora isto, elas apresentam particularidades morfológicas diferentes. Objetivo: Destrinchar a morfologia microscópica das amostras de esporotricose e cripitococose a fim de auxiliar na identificação sugestiva das amostras. Metodologia: Foram coletadas amostras de gatos com suspeita das doenças pela técnica de imprint e biópsia para obtenção de amostras citológicas e para cofecção das preparações histopatológicas, respectivamente. As amotras foram fixadas em formol tamponado a 10%, coradas com Ácido Periódico de Schiff (PAS) e posteriormente analisadas por microscopia óptica. Resultado: A histopatologia de ambas as doenças caracterizaram-se por inflamações granulomatosa ou piogranulomatosa, com quantidade e tipo de leucócitos variados, incluindo: neutrófilos, macrófagos, eosinófilos, linfócitos, células gigantes multinucleadas, mastócitos e plasmócitos. A carga fúngica variou de acordo com o quadro clínico do animal, influenciando na quantidade de leucócitos encontradas. Em ambos os casos é possível observar as leveduras fagocitadas por macrófagos e neutrófilos, bem como no meio extracelular. Como diferencial, no entanto, a esporotricose apresenta levedura com morfologia oval, redonda ou alongada em “forma de charuto” com halo claro, medindo de 4μm a 8μm e geralmente exibe brotamento de base estreita. Já a criptococose apresenta leveduras esféricas, medindo de 2μm a 10μm com presença de uma cápsula gelatinosa em seu entorno que não se cora. Conclusão: Portanto, a citologia e/ou histopatologia é um método de triagem confiável, que garante resultados preciso para clínicos e veterinários evitarem erros durante a fase analítica.
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Foques Falleiro, Manuela, Carolina Schell Franceschina, Marina Ritter Schüler, Anna Eduarda Oliveira Pires Gonçalves, André Mello da Costa Ellwanger, and Roxana Pinto Nishimura. "Esporotricose felina e humana na região metropolitana de Porto Alegre, Rio Grande do Sul." In Congresso Online Acadêmico de Medicina Veterinária. Congresse.me, 2022. http://dx.doi.org/10.54265/uqqz4582.
Повний текст джерелаАнотація:
A esporotricose é uma micose cutânea ou subcutânea e granulomatosa causada por um complexo de espécies conhecido como Sporothrix schenckii, ocorrendo principalmente em felinos e humanos. É uma doença emergente no Brasil, apesar de negligenciada, e o gato doméstico é o principal disseminador da doença para outros animais e para o homem, através de arranhaduras ou mordeduras e pelo contato direto com as lesões. A esporotricose felina e humana não é de notificação obrigatória no estado do Rio Grande do Sul, e, até o ano de 2020, a doença nunca havia sido registrada no município de Sapucaia do Sul. O objetivo deste trabalho foi monitorar os casos de esporotricose felina e humana em Sapucaia do Sul, na região metropolitana de Porto Alegre, identificando as suas características epidemiológicas e ambientais. Para tanto, foi realizada uma pesquisa de campo descritiva, observacional e de abrangência quantitativa. Os dados foram obtidos a partir de registros documentais do setor de Vigilância Ambiental do município. Entre 18 de agosto de 2020 e 30 de junho de 2021, foram contabilizados 56 casos de esporotricose em felinos e 14 casos da doença em humanos, com 64,28% das ocorrências sendo em pacientes mulheres e 35,71% em homens. Dos casos humanos, 13 desses pacientes eram tutores de felinos com esporotricose, tendo sido contaminados através de contato com o próprio animal. Dois bairros do município concentraram a maior parte desses casos, totalizando 82% dos casos de esporotricose felina e 51% dos casos de esporotricose humana, configurando-se como pontos de alta densidade. Pôde-se observar um padrão clássico de distribuição da doença na cidade, uma vez que a aglomeração de casos em regiões específicas é característica, ocorrendo na forma de surtos, em locais com alto número de hospedeiros. A maior parte dos felinos infectados possuía livre acesso à rua, perfazendo 80% dos casos, e 73% do total de felinos doentes não eram castrados. A alimentação e a manutenção de felinos de rua nos locais com alta densidade de casos de esporotricose, sem qualquer tipo de controle populacional e sanitário, associado à circulação de gatos domésticos pelo bairro, foram as possíveis causas que levaram ao descontrole desta zoonose na região. A ausência de tratamento dos gatos de rua doentes e o abandono de animais infectados também foram fatores importantes na dispersão da esporotricose para animais sadios semidomiciliados, que se tornaram fonte de infecção para o homem, demonstrando a importância da saúde pública e integrada. Durante a realização do trabalho, foram promovidas capacitações aos trabalhadores da rede pública de saúde do município para o diagnóstico da doença em usuários do Sistema Único de Saúde e foram feitos alertas à população, além de campanhas sobre a importância da guarda responsável dos animais. A educação em saúde da população do município torna-se, agora, prioridade de ação dos gestores públicos. PALAVRAS-CHAVE: Felino doméstico, Saúde Pública, Sporothrix schenckii
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Vaughan, D. E., and J. Loscalzo. "STREPTOKINASE-INDUCED, ANTIBODY-MEDIATED PLATELET AGGREGATION: A POTENTIAL CAUSE OF CLOT PROPAGATION IN VIVO." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642989.
Повний текст джерелаАнотація:
We identified a patient who exhibited paradoxical propagation of thrombus coincident with the administration of intracoronary streptokinase (SK) that was mediated by anti-SK antibodies. The patient had not been treated with SK in the past and had a plasma SK-neutralizing capacity of 160 U/ml. Using platelet-rich plasma (PRP) obtained from the patient, we found that SK initiated spontaneous platelet aggregation and secretion in vitro. Aggregation was specific for SK and not induced by urokinase or tissue plasminogen activator. In 14 of 15 controls, no platelet aggregation was observed in PRP with addition of SK. The addition of plasma or purified IgG from our index case to the PRP of all 14 controls supported SK-induced aggregation. This aggre-gatory response was not inhibited by aprotinin. Using purified proteins in a washed platelet system, we found that platelet aggregation was dependent on the presence of SK, specific anti-SK IgG, plasminogen, and platelets. These data demonstrate that anti-SK antibodies can promote platelet aggregation, presumably by binding to platelet-bound plasminogen-SK complexes. These data also imply that some individuals may possess anti-SK antibodies that are capable of inducing platelet aggregation in vivo and, thereby, promoting clot propagation or thromboembolic complications. In the absence of adequate, specific screening, this observation argues for the use of nonimmunogenic thrombolytic agents in the emergent setting.