PARP1 Characterization as a Potential Biomarker for BCR::ABL1 p190+ Acute Lymphoblastic Leukemia.

Detection of t(9;22), and consequent BCR::ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR::ABL1 p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment of BCR::ABL1 p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice.

Correction: MicroRNAs expressed during normal wound healing and their associated pathways: A systematic review and bioinformatics analysis.

[This corrects the article DOI: 10.1371/journal.pone.0281913.].

Genome Editing for Engineering the Next Generation of Advanced Immune Cell Therapies.

Our current genetic engineering capacity through synthetic biology and genome editing is the foundation of a revolution in biomedical science: the use of genetically programmed cells as therapeutics. The prime example of this paradigm is the adoptive transfer of genetically engineered T cells to express tumor-specific receptors, such as chimeric antigen receptors (CARs) or engineered T-cell receptors (TCR). This approach has led to unprecedented complete remission rates in patients with otherwise incurable hematological malignancies. However, this approach is still largely ineffective against solid tumors, which comprise the vast majority of neoplasms. Also, limitations associated with the autologous nature of this therapy and shared markers between cancer cells and T cells further restrict the access to these therapies. Here, we described how cutting-edge genome editing approaches have been applied to unlock the full potential of these revolutionary therapies, thereby increasing therapeutic efficacy and patient accessibility.

MicroRNAs expressed during normal wound healing and their associated pathways: A systematic review and bioinformatics analysis.

MicroRNAs (miRNAs) are responsible for regulating gene expression post-transcriptionally. Are involved in several biological processes, such as wound healing. Understanding the miRNAs involved in this process is fundamental for the development of new therapies. So, due to the need to understand the role of these molecules, we aimed systematically review the literature in order to identify which miRNAs are involved in the wound healing and determine, through bioinformatics analysis, which signaling pathways are associated with these miRNAs. An electronic search was performed in the following databases: National Library of Medicine National Institutes of Health (PubMed), Science Direct, Scifinder, Scopus and Web of Science, using the descriptors: "(microRNA [MeSH])" and "(skin [MeSH])" and "(wound healing [MeSH])". After the search, two independent and previously calibrated reviewers selected the articles that analyzed the expression pattern of miRNAs in wound healing in in vivo studies, using the software Zotero bibliography manager. Following, bioinformatic analysis was performed using the software DIANA Tools, mirPath v.3 and the data was interpreted. The bioinformatics analysis revealed that on the day 1 there were 13 union pathways, eight of which were statistically significant. Still on the day 1, among the miRNAs that had a decrease in their expression, 12 of 17 union pathways found were statistically significant. On the day 5, among the miRNAs with an increase in expression, 16 union pathways were found, 12 of which were statistically significant. Finally, among the miRNAs with decreased expression, 11 of 15 union pathways found were statistically significant. Although it has been found substantial heterogeneity in the studies, with this systematic review, it was possible to study the panorama of miRNAs that may be altered in the wound healing. The present review summarizes existing evidence of miRNAs associated to wound healing, and these findings can contribute to new therapeutic approaches.

Maternal expression of miR-let-7d-3p and miR-451a during gestation influences the neuropsychomotor development of 90 days old babies: "Pregnancy care, healthy baby" study.

INTRODUCTION: Studies on maternal microRNA expression have emerged to better understand regulatory mechanisms during the gestational period, since microRNA expression has been associated with pregnancy disorders. OBJECTIVES: This study aims to investigate the association between the expression of the maternal microRNAs miR-let-7d-3p and miR-451a during the second gestational trimester and neuropsychomotor development at 90 days of life of infants. METHODS: This is a case-control study nested within a cohort, with the groups being divided into dyads in which pregnant women presented Major Depressive Episode (MDE) (n = 64), these being the cases, and their respective controls (no MDE; n = 64). The Bayley Scale III was used to assess the outcome of child development, and MDE was assessed through the Mini International Neuropsychiatric Interview Plus. The analysis of miR-let-7d-3p and miR-451a was done via serum from the pregnant women, utilizing the qRT-PCR (n = 128). RESULTS: The results indicated a negative association between expression levels of miR-451a (ß -3.3 CI95% -6.4;-0.3) and a positive associated of the miR-let-7d-3p with the cognitive development domain (ß 1.7 CI95% 0.1; 3.0), and a positive association between expression of miR-let-7d-3p with motor development of the infants (ß 1.6 CI95% 0.3; 2.9). CONCLUSION: This is a pioneering study on the topic that indicates a biological interrelationship between the miRNAs miR-let-7d-3p and miR-451a evaluated during the pregnancy and the motor and cognitive domains of infant development at 90 days postpartum.

Adesão ao tratamento da Tuberculose: estratégias biopolíticas de promoção da saúde na vertente neoliberal / Adherence to tuberculosis treatment: biopolitical health promotion strategies in the neoliberal perspective / Cumplimiento del tratamiento de la tuberculosis: tácticas biopolíticas para fomentar la salud en el contexto neoliberal

Objetivo: analisar como as recomendações sobre adesão terapêutica presentes em manuais de controle da tuberculose constituem estratégias biopolíticas de Promoção da Saúde na vertente neoliberal. Método: pesquisa documental e qualitativa que analisou cinco manuais publicados entre 2002 e 2019, a partir da metodologia pós-crítica de inspiração foucaultiana. Resultados: foram identificadas quatro estratégias biopolíticas, que correspondem às categorias analítica deste estudo: i) Exaltação do saber da estatística como fortalecimento da lógica gerencialista; ii) Priorização do tratamento dos casos bacilíferos e instituição de medidas de controle do risco da contaminação como forma de manter a segurança da população saudável; iii) Ênfase discursiva na população vulnerável como forma de omitir corpos precarizados; e iv) Discurso do empreendimento de si para superação da pobreza, como compensação da falta de políticas de proteção social. Conclusões: algumas recomendações de controle da tuberculose consistem em estratégias biopolíticas de Promoção da Saúde na vertente neoliberal, promovendo discursos sanitários que enfatizam os aspectos individuais, como o autocuidado, a autorresponsabilização, a autonomia e o empoderamento do sujeito. Mesmo nos casos em que percebemos associação do adoecimento com determinantes sociais da saúde e com situações de vulnerabilidade, as ações de controle da tuberculose insistem em ações inscritas numa perspectiva gerencialista da saúde. Na prática, parece haver um vazio de políticas de proteção social e de ações capazes de combater as iniquidades, o que é imprescindível para a efetiva adesão terapêutica e para a cura.(AU)

Objective: to analyze how the recommendations on therapeutic adherence present in tuberculosis control manuals constitute biopolitical Health Promotion strategies in the neoliberal perspective. Method: documentary and qualitative research that analyzed five manuals published between 2002 and 2019, based on the post-critical methodology inspired by Foucault. Results: four biopolitical strategies were identified, which correspond to the analytical categories of this study: i) Exaltation of statistical knowledge as a strengthening of managerial logic; ii) Prioritizing the treatment of bacilliferous cases and establishing measures to control the risk of contamination as a way of maintaining the safety of the healthy population; iii) Discursive emphasis on the vulnerable population as a way of omitting precarious bodies; and iv) Discourse about self-employment to overcome poverty, as compensation for the lack of social protection policies. Conclusions: some recommendations for tuberculosis control consist of biopolitical Health Promotion strategies in a neoliberal perspective, promoting health discourses that emphasize individual aspects, such as self-care, self-responsibility, autonomy, and empowerment of the subject. Even in cases where we perceive an association between illness and social determinants of health and situations of vulnerability, tuberculosis control actions insist on actions based on a health managerial perspective. In practice, there appears to be a lack of social protection policies and actions capable of combating inequities, which is essential for effective therapeutic adherence and cure.(AU)

Objetivo: el propósito es examinar de qué manera las directrices sobre el cumplimiento terapéutico en los manuales de control de la tuberculosis representan estrategias biopolíticas de Promoción de la Salud en el contexto neoliberal. Método:Se llevó a cabo una investigación documental cualitativa que analizó cinco Manuales publicados entre 2002 y 2019, utilizando un enfoque postcrítico inspirado en las ideas de Foucault.Resultados: se identificaron cuatro tácticas biopolíticas (categorías de análisis): 1) Enfatizar el valor del conocimiento estadístico como refuerzo de la lógica administrativa; 2) Priorizar el tratamiento de los casos con bacilos y establecer medidas de control del riesgo de contagio para salvaguardar a la población sana; 3) Poner un énfasis discursivo en la población vulnerable para dejar de lado a los cuerpos en situación precaria; y 4) Promover el autoempleo como solución para superar la pobreza, en sustitución de políticas de protección social insuficientes.Conclusiones: algunas recomendaciones dirigidas al control de la tuberculosis adoptan tácticas biopolíticas de fomento de la salud en el marco neoliberal, empleando discursos relacionados con la salud que ponen un énfasis en aspectos individuales como el autocuidado, la asunción de responsabilidad personal, la autonomía y el empoderamiento del individuo. Aun en situaciones en las que se percibe una correlación entre la enfermedad y los factores sociales que afectan la salud, así como con contextos de vulnerabilidad, las medidas de control de la tuberculosis siguen promoviendo enfoques alineados con una perspectiva de gestión...(AU)

Dental schools in Brazil and their social, macro-regional and oral health policy repercussions / Cursos de Odontologia no Brasil e suas repercussões sociais, macrorregionais e sobre as políticas de saúde bucal

Dentistry is a profession that has shown considerable growth in the last few years, as far as qualitative aspects and scientific production are concerned, and also in the number of undergraduate courses. Objective: to describe the profile of dentistry courses through official data and unofficial data, such as the existence of student support programs, gender disparities and availability of study places. Material and Methods: to this end, a survey of the 565 Dentistry courses registered by the Ministry of Education was carried out by three trained researchers and then of their respective websites and public domain information, followed by data analysis (R 4.1.2 R Core Team software, Vienna) and georeferencing (Qgis and ArcGis software). Results: as for the profile of the institutions that offer the course, 89.4% are private and as for the unofficial data, 63% of the sites do not have information regarding the teaching staff, 44.2% of the courses present a woman as coordinator and more than half report having at least one type of student support activity. It was possible to observe that the greatest availability of Dentistry vacancies is offered by private institutions and in courses coordinated by men. Conclusion: considering the information available on the college websites, it is important to keep them up to date and complete, so that students have access to the support activities that are relevant to their education.(AU)

A odontologia é uma profissão que tem apresentado crescimento considerável nos últimos anos, tanto no que diz respeito aos aspectos qualitativos e produção científica, como também no número de cursos de graduação. Objetivo: descrever o perfil dos cursos de odontologia por meio de dados oficiais e não oficiais, como a existência de programas de apoio estudantil, disparidades de gênero e disponibilidade de vagas de estudo. Material e Métodos: para tanto, foi realizado um levantamento dos 565 cursos de Odontologia cadastrados no Ministério da Educação por três pesquisadores treinados e, posteriormente, de seus respectivos sites e informações de domínio público, seguido da análise dos dados (R 4.1.2 R Núcleo Team software, Viena) e georreferenciamento (software Qgis e ArcGis). Resultados: quanto ao perfil das instituições que oferecem o curso, 89,4% são privadas e quanto aos dados não oficiais, 63% dos sites não possuem informações sobre o corpo docente, 44,2% dos cursos apresentam uma mulher como coordenadora e mais de metade refere ter pelo menos um tipo de atividade de apoio ao aluno. Foi possível observar que a maior oferta de vagas de Odontologia é oferecida por instituições privadas e em cursos coordenados por homens. Conclusão: considerando as informações disponibilizadas nos sites das faculdades, é importante mantê-las atualizadas e completas, para que os alunos tenham acesso às atividades de apoio pertinentes à sua formação (AU)

Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer.

Immune checkpoint (IC) blockade using monoclonal antibodies is currently one of the most successful immunotherapeutic interventions to treat cancer. By reinvigorating antitumor exhausted T cells, this approach can lead to durable clinical responses. However, the majority of patients either do not respond or present a short-lived response to IC blockade, in part due to a scarcity of tumor-specific T cells within the tumor microenvironment. Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) provide the necessary tumor-specific immune cell population to target cancer cells. However, this therapy has been considerably ineffective against solid tumors in part due to IC-mediated immunosuppressive effects within the tumor microenvironment. These limitations could be overcome by associating adoptive cell transfer of genetically engineered T cells and IC blockade. In this comprehensive review, we highlight the strategies and outcomes of preclinical and clinical attempts to disrupt IC signaling in adoptive T-cell transfer against cancer. These strategies include combined administration of genetically engineered T cells and IC inhibitors, engineered T cells with intrinsic modifications to disrupt IC signaling, and the design of CARs against IC molecules. The current landscape indicates that the synergy of the fast-paced refinements of gene-editing technologies and synthetic biology and the increased comprehension of IC signaling will certainly translate into a novel and more effective immunotherapeutic approaches to treat patients with cancer.

Práticas de promoção da saúde como resistência e contraconduta à governamentalidade neoliberal / Health promotion practices as resistance and counter-conduct to neoliberal governmentality

Resumo Esse artigo tem como objetivo analisar as práticas de Promoção da Saúde (PS), realizadas na Atenção Primária em Saúde (APS), capazes de se constituírem como ações de resistência e contraconduta à governamentalidade neoliberal. Realizamos uma pesquisa de campo, descritiva e exploratória, de abordagem qualitativa, no contexto da APS de um município do sul do Brasil. Foram entrevistados 23 trabalhadores. Os resultados apontam possibilidades a serem exploradas para potencializar a PS na APS: o fortalecimento das atividades formativas no âmbito das unidades de saúde; a problematização dos Determinantes Sociais da Saúde; os métodos de fomento à participação; a coletivização das demandas em saúde; a valorização e reforço das conquistas e das ações coletivas; o resgate da cultura e de hábitos comunitários locais; e, o advocacy pela PS na APS.

Abstract This article analyzes the discourses within Health Promotion (HP) practices in Primary Health Care (PHC) that constitute actions of resistance and counter-conduct to the neoliberal governmentality inscribed in these tools. Drawing upon descriptive and exploratory field research, together with a qualitative approach, we interviewed 23 PHC workers in a municipality in southern Brazil. The results point out possibilities to enhance HP in PHC: strengthening training activities within health units; problematizing Social Determinants of Health (SDH); methods to encourage participation; collectivization of health demands; appreciation and reinforcement of achievements and collective actions; recovery of the local community's culture and habits; and HP advocacy in PHC.

Health promotion practices as resistance and counter-conduct to neoliberal governmentality. / Práticas de promoção da saúde como resistência e contraconduta à governamentalidade neoliberal.

This article analyzes the discourses within Health Promotion (HP) practices in Primary Health Care (PHC) that constitute actions of resistance and counter-conduct to the neoliberal governmentality inscribed in these tools. Drawing upon descriptive and exploratory field research, together with a qualitative approach, we interviewed 23 PHC workers in a municipality in southern Brazil. The results point out possibilities to enhance HP in PHC: strengthening training activities within health units; problematizing Social Determinants of Health (SDH); methods to encourage participation; collectivization of health demands; appreciation and reinforcement of achievements and collective actions; recovery of the local community's culture and habits; and HP advocacy in PHC.

Esse artigo tem como objetivo analisar as práticas de Promoção da Saúde (PS), realizadas na Atenção Primária em Saúde (APS), capazes de se constituírem como ações de resistência e contraconduta à governamentalidade neoliberal. Realizamos uma pesquisa de campo, descritiva e exploratória, de abordagem qualitativa, no contexto da APS de um município do sul do Brasil. Foram entrevistados 23 trabalhadores. Os resultados apontam possibilidades a serem exploradas para potencializar a PS na APS: o fortalecimento das atividades formativas no âmbito das unidades de saúde; a problematização dos Determinantes Sociais da Saúde; os métodos de fomento à participação; a coletivização das demandas em saúde; a valorização e reforço das conquistas e das ações coletivas; o resgate da cultura e de hábitos comunitários locais; e, o advocacy pela PS na APS.

Effect of photobiomodulation treatment on pain control in patients with temporomandibular dysfunction disorder: systematic review.

OBJECTIVE: To critically evaluate the literature and answer the question, "How effective is photobiomodulation treatment on pain control in patients with TMJ disorder?". METHODS: PRISMA, PubMed, Web of Science, Scopus, and Embase databases were used for the personalized search strategy. For risk of bias, Rob 2.0 for randomized clinical trials and ROBINS-I for non-randomized clinical trials were used. RESULTS: Eighty-four articles were found and, after removing duplicates, seventy one studies were included for titles and abstracts. For a full reading, 30 articles were selected and, according to the eligibility criteria, 24 remained for qualitative analysis. The studies showed a low risk of bias. Due to the heterogeneity of the studies, it was not possible to perform a meta-analysis. CONCLUSION: Photobiomodulation is an effective adjunct for the treatment of temporomandibular disorders, being a less invasive approach, safe, low-cost, and without side effects.

Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer

Immune checkpoint (IC) blockade using monoclonal antibodies is currently one of the most successful immunotherapeutic interventions to treat cancer. By reinvigorating antitumor exhausted T cells, this approach can lead to durable clinical responses. However, the majority of patients either do not respond or present a short-lived response to IC blockade, in part due to a scarcity of tumor-specific T cells within the tumor microenvironment. Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) provide the necessary tumor-specific immune cell population to target cancer cells. However, this therapy has been considerably ineffective against solid tumors in part due to IC-mediated immunosuppressive effects within the tumor microenvironment. These limitations could be overcome by associating adoptive cell transfer of genetically engineered T cells and IC blockade. In this comprehensive review, we highlight the strategies and outcomes of preclinical and clinical attempts to disrupt IC signaling in adoptive T-cell transfer against cancer. These strategies include combined administration of genetically engineered T cells and IC inhibitors, engineered T cells with intrinsic modifications to disrupt IC signaling, and the design of CARs against IC molecules. The current landscape indicates that the synergy of the fast-paced refinements of gene-editing technologies and synthetic biology and the increased comprehension of IC signaling will certainly translate into a novel and more effective immunotherapeutic approaches to treat patients with cancer.

Uso de club drugs entre estudantes de graduação: prevalência, características associadas e a influência dos pares / Club drugs use among undergraduate students: prevalence, associated characteristics and peer influence

OBJETIVO: Medir a prevalência do uso na vida, no último ano e no último mês de duas club drugs ­ o ecstasy e o LSD ­, bem como as características associadas ao uso dessas substâncias, no último mês, entre estudantes de graduação de uma universidade no Sul do Brasil. MÉTODOS: Trata-se de um estudo transversal conduzido no ano de 2015 com amostragem aleatória sistemática por conglomerados. Participaram 1.423 estudantes de graduação. Foi utilizado um modelo de análise multivariável em três níveis hierárquicos por meio da regressão de Poisson com ajuste robusto da variância. RESULTADOS: As prevalências de uso na vida, no último ano e no último mês de club drugs foram de 12,7%, 7,8% e 3,8%, respectivamente. Indivíduos do sexo masculino, com orientação sexual homossexual ou bissexual, mais jovens, que moravam com seus pares, solteiros, e que relataram uso no último mês de tabaco e maconha apresentaram maior probabilidade de ter feito uso no último mês de alguma club drug. Entretanto, a variável mais fortemente associada a esse desfecho foi ter algum amigo que já fez uso de alguma droga ilícita na vida (RP = 19,54). CONCLUSÕES: O ambiente universitário parece ser um terreno fértil para a difusão do uso de club drugs. O fortalecimento de uma rede de apoio institucional da universidade, capaz de propor atividades de prevenção, bem como de identificar, acolher e encaminhar casos em que haja abuso e dependência dessas substâncias, pode ser uma estratégia importante para lidar com essa problemática.

OBJECTIVE: To measure the prevalence of lifetime, last-year, and last-month use of two club drugs ­ ecstasy and LSD ­, as well as the characteristics associated with the last-month use of these substances among undergraduate students at a university in southern Brazil. METHODS: This was a cross-sectional study conducted in 2015 with a clustered systematic sampling strategy. Overall, 1,423 undergraduate students participated. A three-level hierarchical multivariate analysis model was used through Poisson regression with robust adjustment of variance. RESULTS: Prevalence of lifetime, last-year, and lastmonth use of club drugs were 12.7%, 7.8% and 3.8%, respectively. Male participants, with homosexual or bisexual sexual orientation, younger, who lived with their peers, who were single, and who reported last-month use of tobacco and marijuana had higher probability of last-month use club drugs. However, the variable most strongly associated with this outcome was having a friend with lifetime use of illicit drugs (PR = 19.54). CONCLUSIONS: University environment seems to be a fertile ground for the spread of the use of club drugs. The strengthening of the university's institutional assistance network, capable of proposing prevention activities, as well as identifying, supporting and referring cases where there is abuse and dependence on these substances can be an important strategy to deal with this problem.

Strategies to Enhance the Therapeutic Efficacy, Applicability, and Safety of Genetically Engineered Immune Cells.

The field of cell therapy is leading a paradigm shift in drug development. The recent convergence of several fields, including immunology, genetics, and synthetic biology, now allows for the introduction of artificial receptors and the design of entire genetic circuitries to finely program the behavior of injected cells. A prime example of these next-generation living drugs comes in the form of T cells expressing chimeric antigen receptors (CARs), which have already demonstrated definitive evidence of therapeutic efficacy against some hematological malignancies. However, several obstacles still restrict the antitumor efficacy of and impair the widespread use of CAR-T cells. Critical challenges include limited persistence and antitumor activity in vivo, antigen escape, scarcity of suitable single markers for targeting, and therapy-related toxicity. Nevertheless, intense research activity in this field has resulted in a plethora of creative solutions to address each of these limitations. In this review, we provide a comprehensive snapshot of the current strategies used to enhance the therapeutic efficacy, applicability, and safety of genetically engineered immune cells to treat cancer.

Viral metagenomics in blood donations with post-donation illness reports from Brazil.

BACKGROUND: Post-donation illness can be described as appearance of clinical symptoms in blood donors after donation. The consequent call back of the donor to report these symptoms to the blood collection institution is considered a post-donation illness report (PDIR). The most suitable way to examine whether PDIR is related to infection is to apply next-generation sequencing (NGS) and viral metagenomics. Investigation into a PDIR can reveal its importance for transfusion safety and help elaborate strategies for donor education in order to prevent the transfusion transmission of infections which are not routinely tested by the blood collection services. MATERIALS AND METHODS: We applied NGS and viral metagenomics on blood donations which were deferred due to a PDIR. Thirty-three PDIR donations obtained in the Blood Center of Ribeirão Preto, Southeast Brazil, were evaluated. Sequencing was performed using Illumina NextSeq 550 (Illumina Inc, San Diego, CA, USA) equipment and the reads obtained for each sample were analysed by specific bioinformatic pipeline for the classification and discovery of emerging viruses. The identified viral agents by metagenomics were directly confirmed by molecular methods. RESULTS: In all PDIR donations, we found abundant reads of commensal viruses belonging to the Anelloviridae family as well as human pegivirus-1. However, we were also able to identify blood donations positive for clinically important viruses like dengue serotype-2 (DENV-2) of the Asian-American genotype and parvovirus B19 (B19V). Both viruses were also confirmed by real-time polymerase chain reaction, detecting DENV-2 RNA in a significant number of cases (7 samples, 21.2%), compared to B19V which was confirmed in 1 case (3.0%). DISCUSSION: Our study applies for the first time viral metagenomics to evaluate the significance of PDIRs. We confirm the crucial importance of the donor providing a timely PDIR for the prevention of transfusion transmission of viral infections which are not routinely tested in the blood banks worldwide.

Mapeamento da Rede de Atenção à Saúde Bucal da Região Metropolitana de Porto Alegre / Mapping the Oral Health Care Network in the Metropolitan Region of Porto Alegre

Objetivo: identificar a organização da rede de atenção à saúde bucal da região metropolitana de Porto Alegre através do questionário do Programa de Melhoria do Acesso e da Qualidade da Atenção Básica. Método: foram inseridas neste estudo 125 equipes de saúde bucal da região metropolitana que participaram do segundo ciclo do Programa de Melhoria do Acesso e da Qualidade da Atenção Básica. As variáveis de interesse foram analisadas através do programa IBM SPSS Statistics 18 e apresentadas por meio de suas frequências absolutas e relativas. Resultados: a partir dos dados coletados foi possível mapear a rede de atenção à saúde bucal da região metropolitana de Porto Alegre, os resultados apresentam-se favoráveis em relação à educação permanente em saúde, sendo que 93,6% (n= 117) realizam pelo menos uma das ações propostas. Em relação à coordenação do cuidado, 84% (n=105) das equipes têm disponível oferta de consultas especializadas, entretanto, a oferta de prótese dentária é escassa na região. Conclusão: foi observado desempenho regular no programa por parte das Equipes de Saúde Bucal da Região Metropolitana de Porto Alegre, no entanto, o município de Gravataí apresentou as melhores estimativas de desempenho entre os avaliados no nosso estudo. Salienta-se a importância de avaliação contínua para orientar o planejamento da assistência à saúde com o propósito de melhorar a assistência odontológica da população

Two Functional Variants of AP-1 Complexes Composed of either γ2 or γ1 Subunits Are Independently Required for Major Histocompatibility Complex Class I Downregulation by HIV-1 Nef.

The HIV-1 accessory protein Nef downregulates the cell surface expression of major histocompatibility complex class I (MHC-I) molecules to facilitate virus spreading. The Nef-induced downregulation of MHC-I molecules such as HLA-A requires the clathrin adaptor protein 1 (AP-1) complex. The cooperative interaction of Nef, AP-1, and the cytosolic tail (CT) of HLA-A leads to a redirection of HLA-A targeting from the trans-Golgi network (TGN) to lysosomes for degradation. Although the γ-adaptin subunit of AP-1 has two distinct isoforms (γ1 and γ2), which may form two AP-1 complex variants, so far, only the importance of AP-1γ1 in MHC-I downregulation by Nef has been investigated. Here, we report that the AP-1γ2 isoform also participates in this process. We found that AP-1γ2 forms a complex with Nef and HLA-A2_CT and that this interaction depends on the Y320 residue in HLA-A2_CT and Nef expression. Moreover, Nef targets AP-1γ1 and AP-1γ2 to different compartments in T cells, and the depletion of either AP-1 variant impairs the Nef-mediated reduction of total endogenous HLA-A levels and rescues HLA-A levels on the cell surface. Finally, immunofluorescence and immunoelectron microscopy analyses reveal that the depletion of γ2 in T cells compromises both the Nef-mediated retention of HLA-A molecules in the TGN and targeting to multivesicular bodies/late endosomes. Altogether, these results show that in addition to AP-1γ1, Nef also requires the AP-1γ2 variant for efficient MHC-I downregulation.IMPORTANCE HIV-1 Nef mediates evasion of the host immune system by inhibiting MHC-I surface presentation of viral antigens. To achieve this goal, Nef modifies the intracellular trafficking of MHC-I molecules in several ways. Despite being the subject of intense study, the molecular details underlying these modifications are not yet fully understood. Adaptor protein 1 (AP-1) plays an essential role in the Nef-mediated downregulation of MHC-I molecules such as HLA-A in different cell types. However, AP-1 has two functionally distinct variants composed of either γ1 or γ2 subunit isoforms. Because previous studies on the role of AP-1 in MHC-I downregulation by Nef focused on AP-1γ1, an important open question is the participation of AP-1γ2 in this process. Here, we show that AP-1γ2 is also essential for Nef-mediated depletion of surface HLA-A molecules in T cells. Our results indicate that Nef hijacks AP-1γ2 to modify HLA-A intracellular transport, redirecting these proteins to lysosomes for degradation.

MicroRNAs expressed in neuronal differentiation and their associated pathways: Systematic review and bioinformatics analysis.

MicroRNAs (miRNAs) plays an important role in the human brain from the embryonic period to adulthood. In this sense, they influence the development of neural stem cells (NSCs), regulating cellular differentiation and survival. Therefore, due to the importance of better comprehending the regulation of miRNAs in NSCs differentiation and the lack of studies that show the panorama of miRNAs and their signaling pathways studied until now we aimed to systematically review the literature to identify which miRNAs are currently being associated with neuronal differentiation and using bioinformatics analysis to identify their related pathways. A search was carried out in the following databases: Scientific Electronic Library Online (Scielo), National Library of Medicine National Institutes of Health (PubMed), Scopus, Web of Science and Science Direct, using the descriptors "(microRNA [MeSH])" and "(neurogenesis [MeSH])". From the articles found, two independent and previously calibrated reviewers, using the EndNote X7 (Thomson Reuters, New York, NY, US), selected those that concern miRNA in the development of NSCs, based on in vitro studies. After, bioinformatic analysis was performed using the software DIANA Tools, mirPath v.3. Subsequently, data was tabulated, analyzed and interpreted. Among the 106 miRNAs cited by included studies, 55 were up-regulated and 47 were down-regulated. The bioinformatics analysis revealed that among the up-regulated miRNAs there were 24 total and 6 union pathways, and 3 presented a statistically significant difference (p ≤ 0.05). Among the down-regulated miRNAs, 46 total and 13 union pathways were found, with 7 presenting a significant difference (p ≤ 0.05). The miR-125a-5p, miR-423-5p, miR-320 were the most frequently found miRNAs in the pathways determined by bioinformatics. In this study a panel of altered miRNAs in neuronal differentiation was created with their related pathways, which could be a step towards understanding the complex network of miRNAs in neuronal differentiation.