The H9N2 avian influenza virus (AIV) has emerged, spread and established itself in poultry globally, in just under 30 years. During this time, multiple reassortants of H9N2 with increased zoonotic potential have been isolated in poultry and humans, causing a major threat to the economy and global health. Curiously, H9N2 appears to be compatible with multiple Hemagglutinin (HA) and Neuraminidase subtypes, in nature. Here, the aim was to investigate the HA reassortment dynamics of the poultry adapted H9N2 AIV, in a laboratory setting. Firstly, HA subtypes from wild bird isolates were cloned, before being co-transfected with the backbone of a chicken H9N2 AIV. The rescued H9N2 reassortants were titred on cells before the replication kinetics of a subset of the HA reassortants was assessed. The cDNA sequence of seven HA subtypes induced extensive recombination in E. coli, but ultimately ten out of eleven available HA subtypes were successfully cloned. Further, the chicken H9N2 AIV was compatible with all ten HA subtypes, producing infectious viral particles after co-transfection. However, all HA reassortants displayed decreased replicative fitness in MDCK-2 cells, compared to the wild-type virus. Interestingly, HA subtypes with similar genotypes cluster into distinct HA clades and groups, but these HA clades did not correlate with the replicative fitness of the reassortants. This study suggests that poultry adapted H9N2 AIV is compatible with many HA subtypes, highlighting the importance of reducing its spread in poultry, to reduce reassortment opportunities.

Simple Summary Soft tissue sarcomas (STS) are a group of rare malignant tumors with high tissue heterogeneity and poor prognosis, and which are still without effective individualized immunotherapy approaches. In this study, four potential tumor antigens, six STS immune subtypes, and six functional gene modules were identified. The different immune subtypes have different molecular, cellular, and clinical characteristics. The superiority of mRNA vaccine therapies has been demonstrated during the current pandemic as well as in tumor vaccine studies, and the present study provides guidance for future mRNA vaccine development. Furthermore, in future individualized immunotherapies for STS, it is possible to select different immunotherapies based on the different immune subtypes identified in this study. In fact, the immune subtypes identified in this study explain, to some extent, the failure of immunotherapy for certain STS subtypes in previous clinical trials, and facilitate further understanding of strategy selection for the immunotherapy of STS. To our knowledge, this is the first study to address STS mRNA vaccine development and immunophenotyping. This study provides a theoretical framework for STS mRNA vaccine development and the selection of patients for vaccination and provides a reference for promoting individualized immunotherapy. Abstract Soft tissue sarcomas (STS) are a rare disease with high recurrence rates and poor prognosis. Missing therapy options together with the high heterogeneity of this tumor type gives impetus to the development of individualized treatment approaches. This study identifies potential tumor antigens for the development of mRNA tumor vaccines for STS and explores potential immune subtypes, stratifying patients for immunotherapy. RNA-sequencing data and clinical information were extracted from 189 STS samples from The Cancer Genome Atlas (TCGA) and microarray data were extracted from 103 STS samples from the Gene Expression Omnibus (GEO). Potential tumor antigens were identified using cBioportal, the Oncomine database, and prognostic analyses. Consensus clustering was used to define immune subtypes and immune gene modules, and graph learning-based dimensionality reduction analysis was used to depict the immune landscape. Finally, four potential tumor antigens were identified, each related to prognosis and antigen-presenting cell infiltration in STS: HLTF, ITGA10, PLCG1, and TTC3. Six immune subtypes and six gene modules were defined and validated in an independent cohort. The different immune subtypes have different molecular, cellular, and clinical characteristics. The immune landscape of STS reveals the immunity-related distribution of patients and intra-cluster heterogeneity of immune subtypes. This study provides a theoretical framework for STS mRNA vaccine development and the selection of patients for vaccination, and provides a reference for promoting individualized immunotherapy.

This paper investigates the impact the LASSO, mRMR, SHAP, and Reinforcement Feature Selection techniques on random forest models for the breast cancer subtypes markers ER, HER2, PR, and TN as well as identifying a small subset of biomarkers that could potentially cause the disease and explain them using explainable AI techniques. This is important because in areas such as healthcare understanding why the model makes a specific decision is important it is a diagnostic of an individual which requires reliable AI. Another contribution is using feature selection methods to identify a small subset of biomarkers capable of predicting if a specific RNA sequence will have one of the cancer labels positive. The study begins by obtaining baseline accuracy metric using a random forest model on The Cancer Genome Atlas's breast cancer database to then explore the effects of feature selection, selecting different numbers of features, significantly influencing model accuracy, and selecting a small number of potential biomarkers that may produce a specific type of breast cancer. Once the biomarkers were selected, the explainable AI techniques SHAP and LIME were applied to the models and provided insight into influential biomarkers and their impact on predictions. The main results are that there are some shared biomarkers between some of the subsets that had high influence over the model prediction, LASSO and Reinforcement Feature selection sets scoring the highest accuracy of all sets and obtaining some insight into how the models used the features by using existing explainable AI methods SHAP and LIME to understand how these selected features are affecting the model's prediction.

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Glutamate excitotoxicity is the predominant mechanism implicated in neuronal cell death associated with neurological disorders such as stroke, epilepsy, traumatic brain injury and ALS. Excessive stimulation of NMDA subtypes of glutamate receptors leads to protracted intracellular calcium elevations triggering calcium mediated neurotoxic mechanisms culminating in delayed neuronal cell death. In addition, glutamate excitotoxicity induces a NMDA dependent extended neuronal depolarization mediated by continuous calcium influx that correlates with delayed neuronal death. Attempts to prevent neuronal death by blocking calcium entry into the neurons using calcium channel blockers or NMDA receptor antagonists have failed to provide any beneficial effects in clinical trials. Thus, calcium continues to enter the neurons despite the presence of calcium entry blockers. This phenomenon is known as the "calcium paradox of stroke" and represents a major problem in developing effective therapies for treatment of stroke. Here employing a combination of patch clamp recordings, fluorescent calcium imaging and neuronal cell death assays in well-characterized in vivo and in vitro models of glutamate excitotoxicity, we report the discovery of a novel calcium permeable ion channel that is activated by excitotoxic glutamate injury and mediates a calcium current that is an early initiating step in causing neuronal death. Blocking this calcium permeable channel with high concentrations of Zn2+ or Gd3+ by removing extracellular calcium for a significant time period after the initial injury is effective in preventing calcium entry, apoptosis and neuronal death, thus accounting for the calcium paradox. This injury induced-calcium permeable channel provides a unique mechanism for calcium entry following stroke and offers a new target for extending the therapeutic window for preventing neuronal death after the initial excitotoxic (stroke) injury.

Das Ubiquitin-Proteasom-System sorgt in eukaryontischen Zellen für einen kontrollierten Abbau von Proteinen. Das 20S Proteasom ist als Multikatalytischer Protease Komplex der zentrale Bestandteil dieses Systems. In der vorliegenden Arbeit konnte gezeigt werden, dass sich gereinigtes 20S Proteasom aus HeLa-Zellen chromatographisch in Subtypen auftrennen lässt, die sich strukturell und in ihrer proteolytischen Aktivität unterscheiden. Nach Induktion der Zellen mit gamma-Interferon (gamma-IFN) werden Immuno-Proteasomen gebildet und es kommt zu einer Veränderung des Subtypen-Musters und der Aktivitäten. Unter dem Einfluss von gamma-IFN bilden sich hauptsächlich Mischkomplexe mit sowohl konstitutiven als auch Immuno-Untereinheiten. Weiterhin konnte gezeigt werden, dass in den Zellkompartimenten Cytoplasma, Zellkern und Microsomen von HeLaS3-Zellen unterschiedliche 20S Proteasom-Subtypen vorkommen. Dies war unter anderem auf eine unterschiedliche Glykosylierung einzelner proteasomaler Untereinheiten zurückzuführen. Die genaue Kenntnis von Struktur und Funktion der 20S Proteasom-Subtypen ist im Hinblick auf neue diagnostische und therapeutische Ansätze in der Humanmedizin von großem Interesse. / The Ubiquitin-proteasome system is responsible for the regulated protein degradation in eucaryotic cells. The 20S proteasome is as a multicatalytic protease the central complex of these system. This study has shown that it is possible to separate 20S proteasome subtypes from HeLa cells by chromatography. 20s proteasome subtypes differ in structure and proteolytic activity. The subtype-pattern and the activity are significantly changed after an induction of the cells with gamma-Interferon (gamma-IFN) under formation of immuno proteasomes. After gamma-IFN induction mainly mixed complexes have been formed with both constitutive and immuno subunits. Further it has been shown that in cell compartements cytoplasm, microsomes and nucleus of HeLaS3 cells different 20S proteasome subtypes are located. Among other things glycosylation of some subunits is responsible for that phenomenon. With regard to new strategies in diagnostic and therapy of human diseases the exactly knowledge of structure and function of the proteasome subtypes is a case of interest.

Introdução. A depressão é uma síndrome clínica heterogênea caracterizada por perfis sintomatológicos distintos. Contudo, raros são os estudos que investigaram subtipos depressivos na comunidade e seus correlatos sociodemográficos e clínicos, diferenciando-os quanto à apresentação de acordo com o gênero. Métodos. Utilizou-se o banco de dados do Estudo São Paulo Megacity. Entraram na análise 1.212 sujeitos (869 mulheres e 343 homens) que responderam sobre a presença ou ausência dos sintomas constantes no módulo de depressão do questionário WMH-CIDI. Foi usado o método de análise de classes latentes (ACL). Critérios estatísticos (como o Critério de Informação Bayesiano [BIC] e a entropia) foram empregados para a determinação do número de classes que melhor classificava os sujeitos. Após a obtenção dos modelos mais adequados, as classes foram validadas por correlatos sociodemográficos e clínicos, utilizando-se regressão logística multinomial. Posteriormente, examinou-se a associação entre os subtipos depressivos e a utilização dos serviços de saúde ao longo da vida. Todas as análises foram realizadas no programa Mplus 6.12. Resultados. O melhor modelo de ACL para a amostra geral foi o de 3 classes denominadas Melancólica (37,8%), Atípica (17,83%) e Leve (44,37%). Os sujeitos da classe Atípica apresentaram elevada probabilidade de irritabilidade (81,8%) e ansiedade (90,7%). No modelo final ajustado, pertencer à classe Melancólica associou-se significativamente com: transtorno do espectro bipolar; transtorno de ansiedade; dependência de álcool e drogas; maior incapacitação; e maior escolaridade. Mulheres na classe Atípica foram mais propensas a ter maior escolaridade e comorbidade com transtorno do espectro bipolar e transtorno de ansiedade. Na análise da subamostra de mulheres, o melhor modelo de ACL foi o de 3 classes, semelhantes ao modelo da amostra total: Melancólica (39,34%), Atípica (19,53%) e Leve (41,13%). No modelo final ajustado para o sexo feminino, a classe Melancólica associou-se significativamente com: transtorno do espectro bipolar; transtorno de ansiedade; dependência de álcool e drogas; transtorno disfórico pré-menstrual; e maior incapacitação. Mulheres desta classe, comparadas com às das outras classes, foram mais propensas a ter maior escolaridade e estarem separadas, divorciadas ou viúvas. A classe Atípica associou-se significativamente com: transtorno do espectro bipolar; transtorno de ansiedade; dependência de álcool e drogas; e maior escolaridade. Para o sexo masculino, o melhor modelo de ACL foi também o de 3 classes: Melancólica (40,37%), Agitada (19,56%) e Leve (40,07%). Praticamente todos os homens pertencentes à classe Agitada apresentaram agitação e ansiedade, e uma grande proporção (ao redor de 84%), irritabilidade. Ainda, os sujeitos desta classe apresentaram as maiores proporções de pensamento acelerado (43,9%), aumento de energia (10,6%) e tentativa de suicídio (10,5%), em um perfil de sintomas semelhante aos estados mistos. A classe Agitada associou-se significativamente com os transtornos do espectro bipolar, embora esta associação não tenha permanecido no modelo ajustado. A classe Melancólica entre os homens associou-se com transtorno de ansiedade e dependência de nicotina. Mesmo os sujeitos das classes mais sintomáticas relataram baixo uso de serviços ao longo da vida. Conclusões. Nosso estudo confirma que subtipos depressivos, como melancólico, atípico e agitado podem ser identificados em amostras da população geral, corroborando a heterogeneidade sintomatológica do construto de depressão das classificações atuais. Tanto os perfis sintomatológicos, como as comorbidades com outros transtornos psiquiátricos, como espectro bipolar, ansiedade e dependência de substâncias, têm implicações na escolha do tratamento. Estes resultados podem também contribuir para a determinação de melhores critérios e especificadores dos subtipos depressivos nas próximas edições do DSM e da CID / Introduction. Depression is a heterogeneous clinical syndrome characterized by distinct symptom profiles. However, few studies have investigated depressive subtypes in the community and their sociodemographic and clinical correlates, differentiating them on the presentation according to gender. Methods. Data comes from the São Paulo Megacity Mental Health Survey. One thousand two hundred and twelve subjects (869 women and 343 men) entered in the analysis and responded to the presence or absence of symptoms of the depression module of the WMH-CIDI questionnaire. Latent class analysis (LCA) was used. Statistical criteria (such as the Bayesian Information Criteria [BIC] and entropy) were applied to the determination of the number of classes that best classified the subjects. After obtaining the most suitable models, the classes were validated by clinical and sociodemographic correlates, using multinomial logistic regression. We also later examined the association between depressive subtypes and lifetime health service utilization. All analyses were performed in the program Mplus 6.12. Results. The best LCA model for the overall sample was a 3-class model, which were named Melancholic (37.8%), Atypical (17.83%) and Mild (44.37%). Those in the Atypical class had a high probability of irritability (81.8%) and anxiety (90.7%). In the final adjusted model, being in the Melancholic class was significantly associated with: having a bipolar spectrum disorder; an anxiety disorder; alcohol and drug dependence; greater disability; and higher education. Women in the Atypical class were more likely to have higher education and comorbidity with bipolar spectrum disorder and anxiety disorder. In the analysis of the subsample of women, the best LCA model was a 3-class model, with classes similar to the model of the overall sample: Melancholic (39.34%), Atypical (19.53%) and Mild (41.13%). In the final adjusted model for females, the Melancholic class was significantly associated with: bipolar spectrum disorder; anxiety disorder; alcohol and drug dependence; premenstrual dysphoric disorder; and greater disability. Women in this class, as compared to those in other classes, were more likely to have higher education and be separated, divorced or widowed. The Atypical class was significantly associated with: bipolar spectrum disorder; anxiety disorder; alcohol and drug dependence; and higher education. For males, the best LCA model was also a 3-class model: Melancholic (40.37%), Agitated (19.56%) and Mild (40.07%). Virtually all men belonging to Agitated class endorsed agitation and anxiety, and a large proportion (around 84%), irritability. In addition, respondents belonging to this class presented the highest proportions of racing thought (43.9%), increased energy (10.6%), and suicide attempt (10.5%), in a symptom profile similar to mixed states. The Agitated class was significantly associated with bipolar spectrum disorders, although this association did not remain in the adjusted model. The Melancholic class among men was associated with anxiety disorder and nicotine dependence. Even subjects of more symptomatic classes reported low lifetime use of services. Conclusions. Our study confirms that depressive subtypes such as melancholic, atypical and agitated can be identified in samples from the general population, corroborating the symptomatologic heterogeneity of the construct of depression of current classifications. Both symptom profiles and comorbidity with other psychiatric disorders, such as bipolar spectrum, anxiety and substance dependence, have implications for the choice of treatment. These results may also contribute to establishing better criteria and specifiers of depressive subtypes in future editions of DSM and ICD

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No. of bitstreams: 2 Dissertação- Luciana Oliveira Bento - 2016.pdf: 3533613 bytes, checksum: f67fe73c6af12700e4cba39192ea7c95 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-03-24 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The prevalence of isolates of HIV-1 with resistance mutations to antiretroviral drugs should be monitored continuously and in different population groups from geographical regions Brazilian, since Brazil offers universal access to treatment for all people living with HIV and AIDS. Because of the scarcity of related studies in cities of the interior of Brazil, this study aimed to identify the HIV-1 genetic diversity and to evaluate the profile and the prevalence of HIV-1 isolates with mutations in non-antiretroviral (ARV) exposed patients attended at the Specialized Service in STD/AIDS of the Jataí city, southwestern of Goiás state. From January 2015 to January 2016, 57 patients not exposed to ARVs were recruited and whole blood samples were collected. The protease (PR) and about 2/3 of the reverse transcriptase (RT) regions were amplified in 46 samples by "nested"-PCR and sequenced. Resistance mutations to ARVs were determined by Calibrated Population Resistance Tool from Stanford University and HIV-1 subtypes were identified by REGA and phylogenetic inference. In this study, the prevalence of HIV-1 resistant was more frequent among young male population, heterosexual, especially in the reproductive age group and brown race. Among 46 HIV-1 isolates sequenced, 5 had primary resistance mutations to ARVs, giving a prevalence of 10.9%. The mutations were detected both non-nucleoside RT inhibitors-NNRTIs (K103N, E138K/A and V179E) and for PR inhibitors-IP (M46L and T74S). As the K103N mutation confers resistance to high profile ARV composing the first line of treatment (EFV), it was introduced into the second line with IP for this patient. The E138K mutation confers resistance to an ARV not used in Brazil (RPV), allowing the introduction of the first line of treatment with the fixed-dose combination (formulation 3 in 1). Two isolates of HIV-1 were IP resistance mutations (M46L and T74S) but not yet started therapy. In this case, the introduction of the treatment with the formulation 3 to 1 is possible, since the first line has no IP in its formulation. HIV-1 subtype B was the prevalent isolates and three recombinants involving subtypes B and F1 were observed. The subtype C and recombinant forms were first reported in Goiás southwestern region. The moderate prevalence of primary resistance of HIV-1 isolates among patients from southwestern Goiás state and co-circulation of “pure” HIV-1 subtypes and recombinant forms, it is evident the importance of monitoring of newly diagnosed patients to optimize initial therapy, improving clinical management and control of transmission of HIV-1. / A prevalência de isolados do HIV-1 com mutações de resistência aos antirretrovirais deve ser monitorada continuamente nas diferentes regiões geográficas e grupos populacionais brasileiros, visto que o Brasil disponibiliza acesso universal ao tratamento para todas as pessoas vivendo com HIV e aids. Devido à escassez de estudos relacionados em cidades do interior do Brasil, este trabalho teve como objetivo identificar a diversidade genética do HIV-1 e avaliar o perfil e a prevalência de isolados do HIV-1 com mutações, em pacientes não expostos aos antirretrovirais (ARVs) atendidos no Serviço de Atendimento Especializado em DST/aids do município de Jataí, no sudoeste goiano. De janeiro de 2015 a janeiro de 2016, foram recrutados 57 pacientes não expostos aos ARVs e amostras de sangue total foram coletadas. Os genes da protease (PR) e cerca de 2/3 da transcriptase reversa (TR) foram amplificados em 46 amostras pela “nested”-PCR e sequenciados. As mutações de resistência aos ARVs foram determinadas mediante a ferramenta Calibrated Population Resistance Tool da Universidade de Stanford e os subtipos do HIV-1 foram identificados pela análise por REGA e inferência filogenética. Neste estudo, a prevalência da resistência aos antirretrovirais foi mais frequente na população jovem não exposta do sexo masculino, heterossexual, na cor parda, e especialmente nas faixas etárias de 30 a 34 anos, e de 40 a 49 anos de idade. Entre os 46 isolados de HIV-1 sequenciados, 5 apresentaram mutações de resistência primária aos ARVs, conferindo uma prevalência de 10,9%. Foram detectadas mutações tanto para inibidores da TR não nucleosídicos-NNRTI (K103N, E138K/A e V179E) quanto para inibidores da PR-IP (M46L e T74S). Como a mutação K103N confere alto perfil de resistência ao ARV que compõe o esquema de primeira linha de tratamento (EFV), foi introduzida a segunda linha com IP (LPV/r) para este paciente. A mutação E138K confere resistência a um ARV ainda não utilizado no Brasil (RPV), o que permitiu a introdução da primeira linha de tratamento constituída pela dose fixa combinada com TDF+3TC+EFV (formulação 3 em 1). Dois isolados do HIV-1 apresentaram mutações de resistência (M46L e T74S) que conferem resistência ao IP (NFV), mas ainda não iniciaram a terapia. Nesse caso, a introdução do tratamento com a formulação 3 em 1 será possível, já que a primeira linha não tem o IP (NFV) em sua formulação. O subtipo B do HIV-1 foi o prevalente e três isolados recombinantes foram observados, envolvendo os subtipos B e F1. O subtipo C e as formas recombinantes foram relatados pela primeira vez na região do sudoeste goiano. Com a identificação de uma prevalência moderada de isolados de HIV-1 com resistência primária entre pacientes do sudoeste goiano e a co-circulação de subtipos “puros” e mosaicos do HIV-1, fica evidente a importância do monitoramento dos pacientes recém-diagnosticados para a otimização da terapia inicial, melhorando a conduta clínica e o controle da transmissão do HIV-1.

Die Behandlung menopausaler und postmenopausaler Beschwerden ist mit einem erhöhten Risiko verbunden, an Mamma- und Endometriumskarzinomen zu erkranken. Darüber hinaus zeigen epidemiologische Studien, dass in ostasiatischen Ländern postmenopausale Beschwerden, osteoporotische Frakturen und Herz-Kreislauferkrankungen seltener auftreten als in westlichen Ländern. Vor diesem Hintergrund war es Ziel der Untersuchungen dieser Arbeit, in dem Tiermodell der ovarektomierten Ratte die mögliche Bedeutung von estrogenrezeptorsubtypspezifischen Einflüssen für hormonell bedingte Erkrankungen und Beschwerden zu untersuchen. Hierbei sollten gewebespezifische Wirkungen estrogenrezeptorsubtypspezifischer Liganden untersucht und explizit die Bedeutung der Estrogenrezeptorsubtypen ERα und ERβ bei der Gewebehomöostase in Knochen und Darm analysiert werden. Darüber hinaus sollten vor dem Hintergrund estrogenrezeptorsubtypspezifischer Wirkungsweisen gewebespezifische Einflüsse des Phytoestrogens Genistein (Gen) näher charakterisiert werden. Es konnte gezeigt werden, dass nach einer subkutanen Applikation der knochenprotektive Einfluss von Gen mit dem von Estradiol (E2) vergleichbar ist, durch die Kombination mit Bewegung verstärkt wird und über den ERα vermittelt zu sein scheint. Es zeigte sich außerdem, dass der stimulierende Einfluss von E2 auf den motorischen Antrieb ERα-vermittelt ist und ERβ-spezifische Liganden ebenso wie Gen diesen Effekt antagonisieren. Des Weiteren wurde deutlich, dass E2, nicht aber Gen über den ERα Einfluss auf die Körperfettverteilung nimmt. Mit einer phytoestrogenreichen Diät konnten in adulten Ratten physiologisch relevante Gen/Dai-Plasmaspiegel erreicht werden, allerdings blieben hierbei die nach einer subkutanen Applikation beobachteten knochenprotektiven Effekte dieser Phytoestrogene aus. Bei der näheren Betrachtung der Gewebehomöostase im Dünndarm zeigte sich, dass über den im Darm verstärkt exprimierten ERβ antiproliferative und proapoptotische Effekte vermittelt werden und Gen in diesem Gewebe wie ein ERβ-spezifischer Agonist wirkt. Bezogen auf eine hormonell bedingte Osteoporose, wie sie bei einem Großteil postmenopausaler Frauen auftritt, scheint das Phytoestrogen Genistein eine mögliche Alternative zur Hormonersatztherapie darzustellen. Außerdem zeigt sich, dass Genistein gewebe- und estrogenrezeptorsubtypspezifische antagonistische und agonistische Einflüsse hat und somit die Charakterisierung als „Phyto-SERMs“ (pflanzlicher selektiver Estrogenrezeptormodulator) zutreffend ist. Sollten sich in weiterführenden Studien die beobachteten Effekte im Dünndarm auch für die Gewebehomöostase im Kolon beschreiben lassen, können vor diesem Hintergrund Genistein und ERβ-spezifische Liganden für die Darmkrebsprävention diskutiert werden…