HJURP is recruited to double-strand break sites and facilitates DNA repair by promoting chromatin reorganization.

HJURP is overexpressed in several cancer types and strongly correlates with patient survival. However, the mechanistic basis underlying the association of HJURP with cancer aggressiveness is not well understood. HJURP promotes the loading of the histone H3 variant, CENP-A, at the centromeric chromatin, epigenetically defining the centromeres and supporting proper chromosome segregation. In addition, HJURP is associated with DNA repair but its function in this process is still scarcely explored. Here, we demonstrate that HJURP is recruited to DSBs through a mechanism requiring chromatin PARylation and promotes epigenetic alterations that favor the execution of DNA repair. Incorporation of HJURP at DSBs promotes turnover of H3K9me3 and HP1, facilitating DNA damage signaling and DSB repair. Moreover, HJURP overexpression in glioma cell lines also affected global structure of heterochromatin independently of DNA damage induction, promoting genome-wide reorganization and assisting DNA damage response. HJURP overexpression therefore extensively alters DNA damage signaling and DSB repair, and also increases radioresistance of glioma cells. Importantly, HJURP expression levels in tumors are also associated with poor response of patients to radiation. Thus, our results enlarge the understanding of HJURP involvement in DNA repair and highlight it as a promising target for the development of adjuvant therapies that sensitize tumor cells to irradiation.

Expression Profiling of Glioblastoma Cell Lines Reveals Novel Extracellular Matrix-Receptor Genes Correlated With the Responsiveness of Glioma Patients to Ionizing Radiation.

Glioblastoma (GBM) is the most lethal and frequent type of brain tumor, leading patients to death in approximately 14 months after diagnosis. GBM treatment consists in surgical removal followed by radio and chemotherapy. However, tumors commonly relapse and the treatment promotes only a slight increase in patient survival. Thus, uncovering the cellular mechanisms involved in GBM resistance is of utmost interest, and the use of cell lines has been shown to be an extremely important tool. In this work, the exploration of RNAseq data from different GBM cell lines revealed different expression signatures, distinctly correlated with the behavior of GBM cell lines regarding proliferation indexes and radio-resistance. U87MG and U138MG cells, which presented expressively reduced proliferation and increased radio-resistance, showed a particular expression signature encompassing enrichment in many extracellular matrix (ECM) and receptor genes. Contrasting, U251MG and T98G cells, that presented higher proliferation and sensibility to radiation, exhibited distinct signatures revealing consistent enrichments for DNA repair processes and although several genes from the ECM-receptor pathway showed up-regulation, enrichments for this pathway were not detected. The ECM-receptor is a master regulatory pathway that is known to impact several cellular processes including: survival, proliferation, migration, invasion, and DNA damage signaling and repair, corroborating the associations we found. Furthermore, searches to The Cancer Genome Atlas (TCGA) repository revealed prognostic correlations with glioma patients for the majority of genes highlighted in the signatures and led to the identification of 31 ECM-receptor genes individually correlated with radiation responsiveness. Interestingly, we observed an association between the number of upregulated genes and survivability greater than 5 years after diagnosis, where almost all the patients that presented 21 or more upregulated genes were deceased before 5 years. Altogether our findings suggest the clinical relevance of ECM-receptor genes signature found here for radiotherapy decision and as biomarkers of glioma prognosis.

RNA sequencing data of different grade astrocytoma cell lines.

Astrocytomas are the most common and aggressive type of primary brain tumors in adults. The World Health Organization (WHO) assorts them into grades, from I to IV, based on histopathological features that reflect their malignancy [1]. Alongside with tumor progression, comes an increased proliferation, genomic instability, infiltration in normal brain tissue and resistance to treatments. The high genomic instability forges tumor cells enhancing key proteins that avoid cells from collapsing and favor therapy resistance [2]. To explore genes and pathways associated with tumor progression phenotypes we analyzed gene expression in a panel of non-tumor and glioma cell lines, namely: ACBRI371, non-tumor human astrocytes; HDPC, fibroblasts derived from dental pulp; Res186, Res259, Res286 and UW467 that include grade I, II and III astrocytoma cell lines derived from pediatric tumors; and T98G, U343MG, U87MG, U138MG and U251MG, all derived from GBM (grade IV). We also profiled gene expression changes caused by exogenously induced replicative stress, performing RNA sequencing with camptothecin (CPT)-treated cells. Here we describe the RNA-sequencing data set acquired, including quality of reads and sequencing consistency, as well as the bioinformatics strategy used to analyze it. We also compared gene expression patterns and pathway enrichment between non-tumor versus lower-grade (LGG), non-tumor versus GBM, LGG versus GBM, and CPT-treated versus non-treated cells. In brief, a total of 6467 genes showed differential expression and 5 pathways were enriched in tumor progression, while 2279 genes and 7 pathways were altered under the replication stress condition. The raw data was deposited in the NCBI BioProject database under the accession number PRJNA631805. Our dataset is valuable for researchers interested in differential gene expression among different astrocytoma grades and in expression changes caused by replicative stress, facilitating studies that seek novel biomarkers of glioma progression and treatment resistance.

Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition.

Leishmania RNA virus (LRV) is an important virulence factor associated with the development of mucocutaneous Leishmaniasis, a severe form of the disease. LRV-mediated disease exacerbation relies on TLR3 activation, but downstream mechanisms remain largely unexplored. Here, we combine human and mouse data to demonstrate that LRV triggers TLR3 and TRIF to induce type I IFN production, which induces autophagy. This process results in ATG5-mediated degradation of NLRP3 and ASC, thereby limiting NLRP3 inflammasome activation in macrophages. Consistent with the known restricting role of NLRP3 for Leishmania replication, the signaling pathway triggered by LRV results in increased parasite survival and disease progression. In support of this data, we find that lesions in patients infected with LRV+ Leishmania are associated with reduced inflammasome activation and the development of mucocutaneous disease. Our findings reveal the mechanisms triggered by LRV that contribute to the development of the debilitating mucocutaneous form of Leishmaniasis.

DISTÚRBIO OSTEOMUSCULAR RELACIONADO AO TRABALHO: IDENTIFICAÇÃO DOS FATORES SOCIOECONÔMICOS E CLÍNICOS AUTORREFERIDOS POR TRABALHADORES DE SAÚDE DE UMA INSTITUIÇÃO HOSPITALAR DO MUNICÍPIO DE ESPINOSA, MINAS GERAIS, BRASIL / WORK-RELATED MUSCULOSKELETAL DISORDER: IDENTIFICATION OF SOCIOECONOMIC AND CLINICAL FACTORS SELF-REFERRED BY HEALTH WORKERS OF A HOSPITAL INSTITUTION OF THE CITY OF ESPINOSA, MINAS GERAIS, BRAZIL

Introdução: Os distúrbios osteomusculares relacionados ao trabalho podem repercutir em questões sociais e econômicas para o trabalhador, principalmente quando combinadas às incapacidades funcionais, afetando a sua capacidade produtiva e propiciando o seu afastamento laboral. Objetivo: Identificar os fatores socioeconômicos e clínicos autorreferidos por trabalhadores de saúde de uma instituição hospitalar quanto aos distúrbios osteomusculares relacionados ao trabalho. Método: Trata-se de um estudo quantitativo, descritivo e prospectivo, na qual a amostra compreendeu 22 profissionais de saúde de um hospital. Foi utilizado um questionário semiestruturado como instrumento de coleta de dados. Resultado: Prevalência de profissionais jovens do sexo feminino, idade média de 32,27 anos, tempo de serviço médio de 6,89 anos. Apenas 31,8% relataram ter sintomas. Destes, 85,7% relatou dor de coluna. Não houve desenvolvimento de limitações e/ou incapacidades. O risco ergonômico foi unanimemente citado com prevalência da postura inadequada e da dor lombar baixa como principal diagnóstico. Não houve afastamento do trabalho por parte dos profissionais. Conclusão: Houve uma parcela significativa que manifestou sintoma osteomuscular com risco para a alteração em sua qualidade de vida. Palavras-chave: transtornos traumáticos cumulativos; saúde do trabalhador; qualidade de vida.

Introduction: Work-related musculoskeletal disorders can have repercussions on social and economic issues for the worker, especially when combined with functional disabilities, affecting their productive capacity and causing them to leave work. Objective: To identify the socioeconomic and clinical factors self-referred by health workers of a hospital institution regarding work-related musculoskeletal disorders. Method: This is a quantitative study, descriptive and prospective, in which the sample comprised 22 health professionals from a hospital. Was used a semi-structured questionnaire as a tool for collecting data. Results: Prevalence of young female professionals, mean age of 32.27 years, average working time of 6.89 years. Only 31.8% reported clinical symptomatology. Of these, 85,7% reported spinal pain. There was no development of limitations and/or incapacities. Ergonomic risk was cited by all workers. Of the repetitive activities at work, inadequate posture was the most prevalent. As for the diagnosis, low back pain prevailed. There was no withdrawal from work by professionals. Conclusion: There was a significant portion that presented musculoskeletal symptoms with a risk for the alteration in their quality of life.

Novel Role of VisP and the Wzz System during O-Antigen Assembly in Salmonella enterica Serovar Typhimurium Pathogenesis.

Salmonella enterica serovars are associated with diarrhea and gastroenteritis and are a helpful model for understanding host-pathogen mechanisms. Salmonella enterica serovar Typhimurium regulates the distribution of O antigen (OAg) and presents a trimodal distribution based on Wzy polymerase and the WzzST (long-chain-length OAg [L-OAg]) and WzzfepE (very-long-chain-length OAg [VL-OAg]) copolymerases; however, several mechanisms regulating this process remain unclear. Here, we report that LPS modifications modulate the infectious process and that OAg chain length determination plays an essential role during infection. An increase in VL-OAg is dependent on Wzy polymerase, which is promoted by a growth condition resembling the environment of Salmonella-containing vacuoles (SCVs). The virulence- and stress-related periplasmic protein (VisP) participates in OAg synthesis, as a ΔvisP mutant presents a semirough OAg phenotype. The ΔvisP mutant has greatly decreased motility and J774 macrophage survival in a colitis model of infection. Interestingly, the phenotype is restored after mutation of the wzzST or wzzfepE gene in a ΔvisP background. Loss of both the visP and wzzST genes promotes an imbalance in flagellin secretion. L-OAg may function as a shield against host immune systems in the beginning of an infectious process, and VL-OAg protects bacteria during SCV maturation and facilitates intramacrophage replication. Taken together, these data highlight the roles of OAg length in generating phenotypes during S Typhimurium pathogenesis and show the periplasmic protein VisP as a novel protein in the OAg biosynthesis pathway.

Epidemiologia da leishmaniose visceral em crianças no município de Montes Claros / Epidemiología de la leishmaniasis visceral en niños en el condado de Montes Claros / Epidemiology of the visceral leishmaniasis in children in the city of Montes Claros

RESUMO Introdução: a Leishmaniose Visceral é uma doença infecciosa cujo agente etiológico é um protozoário do gênero Leishmania. Trata-se de um grave problema de saúde pública com prevalência na região nordeste do Brasil. Objetivo: identificar o perfil epidemiológico dos casos de Leishmaniose Visceral em crianças no município de Montes Claros, Minas Gerais. Métodos: foi realizada uma investigação retrospectiva dos casos confirmados de Leishmaniose Visceral, na faixa etária de 0 a 12 anos, notificados ao Sistema Nacional de Agravos de Notificação (SINAN), no período de 2009 a 2011. Resultados: foram confirmados 37 casos de Leishmaniose Visceral em crianças, sendo a maioria (94,59 porcento) procedente da zona urbana. Verificou-se que 51,36 porcento eram do sexo feminino e a faixa etária entre 1 a 4 anos (54,05 porcento) foi a mais acometida pela doença. Os principais sinais e sintomas apresentados pelos casos foram febre (100 porcento), esplenomegalia (100 porcento), hepatomegalia (92 porcento) e palidez (92 porcento). No que se refere à evolução dos casos, 35 crianças (94,59 porcento) tiveram cura e dois (5,41 porcento) evoluíram para óbito. Conclusão: os resultados contribuem para o conhecimento das características da Leishmaniose Visceral na população infantil de Montes Claros, caracterizado como área endêmica da doença(AU)

RESUMEN Introducción: la leishmaniasis visceral es una enfermedad infecciosa cuyo agente etiológico es un protozoario del género Leishmania. Este es un problema grave de salud pública con una prevalencia del noreste de Brasil. Objetivo: identificar el perfil epidemiológico de los casos de Leishmaniasis Visceral en niños en lo condado de Montes Claros, Minas Gerais. Métodos: fue realizada una investigación retrospectiva de los casos confirmados de leishmaniasis visceral, en el grupo de edad de 0 a 12 años, notificados al Sistema Nacional de Agravios y Notificación (SINAN), en el período de 2009-2011. Resultados: fueran confirmados 37 casos de leishmaniasis visceral en niños, siendo la mayoría (94,59 por ciento) procedente del campo. Se verificó que 51,36 por ciento eran del sexo femenino y el grupo de edad entre 1 a 4 años (54,05 por ciento) fue la más acometida por esa enfermedad. Los principales signos y síntomas presentados pelos casos fueran fiebre (100 por ciento), esplenomegalia (100 por ciento), hepatomegalia (92 por ciento) y palidez (92 por ciento). En el que se refiere a la evolución de los casos, 35 niños (94,59 por ciento) tuvieron cura y dos (5,41 por ciento) evaluaran para muerte. Conclusión: los resultados contribuyen al conocimiento de las características de la leishmaniasis visceral en la populación infantil de Montes Claros, caracterizado como área endémica de la enfermedad(AU)

ABSTRACT Introduction: The visceral leishmaniasis is an infectious disease whose etiologic agent is a protozoan of the genus Leishmania. This is a serious public health problem with a prevalence of northeastern Brazil. Objective: To identify the epidemiological profile of Visceral leishmaniasis cases in children in Montes Claros, Minas Gerais. Methods: We realized a retrospective study of confirmed cases of visceral leishmaniasis in children aged 0 to 12 years, reported to Information System Diseases and Notifications in the period from 2009 to 2011. Results: Were confirmed 37 cases of visceral leishmaniasis in children, which 51.36 percent were female and children aged 1 to 4 years (54.05 percent) were the most affected by the disease. It was found that the majority (94.59 percent) of these children lived in urban areas. The main signs and symptoms shown in the cases were fever (100 percent), splenomegaly (100 percent), hepatomegaly (92 percent) and pallor (92 percent). Regarding cases' evolution, 35 children (94.59 percent) had cure and two (5.41 percent) died. Conclusion: The results contribute to the knowledge of the visceral leishmaniasi's characteristics in the child population of Montes Claros, characterized as endemic area of this disease(AU)