A multi-omics dataset for the analysis of frontotemporal dementia genetic subtypes.

Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Systematic studies on human post-mortem brain tissue of patients with genetic subtypes of FTD are currently lacking. The Risk and Modyfing Factors of Frontotemporal Dementia (RiMod-FTD) consortium therefore has generated a multi-omics dataset for genetic subtypes of FTD to identify common and distinct molecular mechanisms disturbed in disease. Here, we present multi-omics datasets generated from the frontal lobe of post-mortem human brain tissue from patients with mutations in MAPT, GRN and C9orf72 and healthy controls. This data resource consists of four datasets generated with different technologies to capture the transcriptome by RNA-seq, small RNA-seq, CAGE-seq, and methylation profiling. We show concrete examples on how to use the resulting data and confirm current knowledge about FTD and identify new processes for further investigation. This extensive multi-omics dataset holds great value to reveal new research avenues for this devastating disease.

The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism.

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Desafios para prevenção e tratamento do câncer cervicouterino no interior do Nordeste / Challenges for prevention and treatment of cervico-uterine cancer in Northeast Brazil / Desafíos para la prevención y el tratamiento del cáncer cervicouterino en el noreste brasileño

Analisa-se a articulação entre Atenção Primária à Saúde (APS) e os diferentes pontos de atenção para controle do câncer do colo do útero (CCU). Trata-se de estudo qualitativo, com dados produzidos em dez grupos focais (70 participantes - enfermeiros e agentes comunitários em saúde) e 12 entrevistas semiestruturadas (seis gestores e seis ginecologistas). Os resultados foram agrupados em três eixos: detecção precoce e controle do CCU na APS; acesso à confirmação diagnóstica; e acesso ao tratamento do CCU e ao transporte sanitário. Os resultados indicam problemas desde o rastreamento (falhas na coleta do Papanicolaou e/ou na leitura das lâminas no laboratório, baixo envolvimento de médicos da APS, ausência de coordenação do cuidado entre níveis) até o tratamento do CCU (barreiras de acesso aos serviços especializados, fragmentação entre os serviços, atraso no tratamento). Entre os achados animadores, destacam-se a prática clínica e o vínculo do enfermeiro com as mulheres durante exame de Papanicolaou e a alta cobertura do exame na APS. Como recomendações apontam-se realização permanente de educação em serviço para ampliar a prática clínica do/a enfermeiro/a e maior envolvimento de médicos, bem como estreitar as relações entre especialistas e profissionais da APS para viabilizar a coordenação do cuidado.

The article analyzes the articulation between Primary Health Care (PHC) and the different points of care for cervical cancer (CC) control. It is a qualitative study, with data originated in 10 focus groups (70 participants - nurses and community health agents) and 12 semi-structured interviews (6 managers and 6 gynecologists). The results were grouped into three axes: Early detection and control of CC in PHC; Access to diagnostic confirmation; and Access to CC treatment and health transportation. Results showed problems ranging from screening (failures in Pap smear collection and/or in reading slides in the laboratory, low involvement of PHC physicians, lack of coordination of care between levels) to the treatment of CC (barriers to access to specialized services, fragmentation between services, delay in treatment). Encouraging findings include the clinical practice and the nurses' bond with women during the Pap exam as well as high coverage of the exam in PHC. Main recommendations include permanent in-service education to expand nurses' clinical practice and greater involvement of physicians, as well as closer relations between specialists and PHC professionals to enable care coordination.

Se analiza la articulación entre la Atención Primaria de Salud (APS) y los diferentes puntos de atención para controlar el cáncer de cuello uterino (CCU). Se trata de un estudio cualitativo con datos de diez grupos focales (setenta participantes —enfermeras y agentes comunitarios— y doce entrevistas semiestructuradas a seis gestores y seis ginecólogos). Los resultados se agruparon en tres ejes: 1) detección precoz y control de CCU en la APS; 2) acceso a la confirmación diagnóstica, y 3) acceso al tratamiento del CCU y transporte sanitario e indicaron problemas que van desde el rastreo (fallos en la recolección del Papanicolaou o en la lectura de láminas en el laboratorio, poco involucramiento de los médicos de la APS, falta de coordinación entre niveles) hasta el tratamiento del CCU (barreras para el acceso a los servicios especializados, fragmentación entre servicios, retrasos en el tratamiento). Como resultados alentadores se destacaron la práctica clínica y el vínculo del personal de enfermería con las mujeres durante el Papanicolaou y la alta cobertura del examen en la APS. Como recomendaciones, se debe garantizar la formación permanente en servicio para ampliar la práctica clínica del personal de enfermería y aumentar la participación de médicos, así como una relación más estrecha entre especialistas y profesionales de la APS que permita la coordinación de los cuidados.

Automated Production of Human Induced Pluripotent Stem Cell-Derived Cortical and Dopaminergic Neurons with Integrated Live-Cell Monitoring.

Manual culture and differentiation protocols for human induced pluripotent stem cells (hiPSC) are difficult to standardize, show high variability and are prone to spontaneous differentiation into unwanted cell types. The methods are labor-intensive and are not easily amenable to large-scale experiments. To overcome these limitations, we developed an automated cell culture system coupled to a high-throughput imaging system and implemented protocols for maintaining multiple hiPSC lines in parallel and neuronal differentiation. We describe the automation of a short-term differentiation protocol using Neurogenin-2 (NGN2) over-expression to produce hiPSC-derived cortical neurons within 6‒8 days, and the implementation of a long-term differentiation protocol to generate hiPSC-derived midbrain dopaminergic (mDA) neurons within 65 days. Also, we applied the NGN2 approach to a small molecule-derived neural precursor cells (smNPC) transduced with GFP lentivirus and established a live-cell automated neurite outgrowth assay. We present an automated system with protocols suitable for routine hiPSC culture and differentiation into cortical and dopaminergic neurons. Our platform is suitable for long term hands-free culture and high-content/high-throughput hiPSC-based compound, RNAi and CRISPR/Cas9 screenings to identify novel disease mechanisms and drug targets.

[Access to uterine cervical cytology in a health region: invisible women and vulnerable bodies]. / Acesso ao exame citológico do colo do útero em região de saúde: mulheres invisíveis e corpos vulneráveis.

This article evaluates access to the Papanicolaou test in the Family Health Strategy (FHS) in municipalities in a health region. Cervical cancer control depends on a well-organized Family Health Strategy, so assessment of access to the Papanicolaou test reflects the quality of care at this level. This is a qualitative study with data produced in 10 focus groups, totaling 70 participants in four municipalities. We analyzed the organizational, symbolic, and technical dimensions of access to the Pap test, with cervical cancer control as the marker. The results indicate that living in rural areas was a barrier to access to the Papanicolaou test and exacerbated the inequalities. Nurses were the principal reference for access to the Pap test. The absence of necessary items for collecting cervical cytopathology specimens was a barrier to access in all the municipalities. There were obstacles to access for women with disabilities and lesbian women, with care that was fragmented and out of sync with individual characteristics. The numerous obstacles to access to the Papanicolaou test exposed the selectiveness of the Family Health Strategy in the health region, since it reproduced the invisibility of women with greater social vulnerability and exacerbated the existing inequalities.

Este artigo avalia o acesso ao exame Papanicolaou na Estratégia Saúde da Família (ESF), em municípios de uma região de saúde. O controle do câncer do colo do útero depende de uma ESF organizada, portanto, avaliar o acesso ao teste de Papanicolaou revela a qualidade da assistência neste nível de atenção. Trata-se de estudo qualitativo, com dados produzidos em 10 grupos focais, perfazendo 70 participantes, em quatro municípios. Analisaram-se as dimensões organizacional, simbólica e técnica do acesso ao exame preventivo, tendo como condição marcadora o câncer do colo do útero. Os resultados indicaram que residir em zona rural era barreira para o acesso ao exame Papanicolaou e reforçavam as iniquidades. Enfermeiros eram a principal referência para a realização do exame preventivo. A ausência de itens necessários à coleta de material citopatológico foi uma barreira de acesso em todos os municípios. Havia entraves de acesso às mulheres com alguma deficiência e às mulheres lésbicas, com atendimento fragmentado e descontextualizado das singularidades pessoais. Os inúmeros entraves de acesso ao Papanicolaou expuseram a seletividade da ESF na região de saúde, visto que reproduzia a invisibilidade das mulheres com maior vulnerabilidade social e acentuava as desigualdades.

Este artículo evalúa el acceso al examen Papanicolaou dentro del programa Estrategia Salud de la Familia (ESF), en municipios de una región de salud. El control del cáncer de cuello uterino depende de una ESF organizada, por lo tanto, evaluar el acceso al test de Papanicolaou revela la calidad de la asistencia en este nivel de atención. Se trata de un estudio cualitativo, con datos producidos dentro de 10 grupos focales, donde estaban incluidos 70 participantes en cuatro municipios. Se analizaron las dimensiones organizativas, simbólicas y técnicas del acceso al examen preventivo, considerándose condición marcadora el cáncer de cuello uterino. Los resultados indicaron que residir en una zona rural era una barrera para el acceso al examen Papanicolaou y reforzaba las inequidades. Los enfermeros eran la principal referencia para la realización del examen preventivo. La ausencia de ítems necesarios para la recogida de material citopatológico fue una barrera de acceso en todos los municipios. Había trabas de acceso a mujeres con alguna deficiencia y a mujeres lesbianas, con atención fragmentada y descontextualizada de las singularidades personales. Las innumerables trabas de acceso al Papanicolaou expusieron la selectividad de la ESF en la región de salud, debido a que reproducía la invisibilidad de las mujeres con mayor vulnerabilidad social y acentuaba desigualdades.

Trajetórias assistenciais de usuárias pela APS em uma região de saúde: trânsito livre, pontos de lentidão e parada / Care trajectories of users with precursor lesions of cervical cancer by primary health care in a health region: free transit, length and stop points

Resumo O artigo objetiva avaliar o acesso e a organização das ações da Atenção Primária à Saúde (APS) utilizando o câncer do colo do útero (CCU) como evento traçador. Foram construídas trajetórias assistenciais de mulheres com diagnóstico de lesão de alto grau do colo uterino, adscritas a Unidades Básicas de Saúde Tradicionais e Unidades de Saúde da Família, de zonas urbana e rural, em municípios do interior e na sede de uma região de saúde da Bahia. As mulheres indicam dificuldade de acesso às consultas médicas na APS, sobretudo na zona rural. Além dos obstáculos para agendamento do citopatológico, a maioria relata não receber convocação para sua realização e não participar de atividades educativas sobre o tema. As ações de controle do CCU na APS são restritas à realização do citopatológico, avaliação do resultado e encaminhamento para rede especializada, sem seguimento do cuidado e com falhas na comunicação profissional-usuária. Foram identificadas barreiras no acesso à APS, em geral, e para controle do CCU relacionadas ao escopo de ações, principalmente nas unidades localizadas no município com menor disponibilidade de serviços, na zona rural e nas UBS tradicionais.

Abstract The article aims to evaluate the access and organization of Primary Health Care (PHC) actions using cervical cancer (CCU) as a tracer event. Assistance trajectories of women with diagnosis of high grade cervical lesion were constructed, from Basic Health Units and Family Health Units, urban and rural areas, in the interior municipalities and at the headquarters of a health region of the Bahia. Women indicate difficulty accessing medical consultations in PHC, especially in rural areas. In addition to the obstacles to cytopathological scheduling, most patients report not being called to accomplish it and do not participate in educational activities on the issue. The control actions of the CCU in PHC are restricted to cytopathology, evaluation of the outcome and referral to specialized care, without follow-up care and with failures in professional-user communication. Barriers to access to PHC in general and to CCU control related to the scope of actions were identified, mainly in the units located in the municipality with less availability of services, in the rural area and in the traditional Basic Health Units.

Acesso ao exame citológico do colo do útero em região de saúde: mulheres invisíveis e corpos vulneráveis / Access to uterine cervical cytology in a health region: invisible women and vulnerable bodies / Acceso a la citología de cuello de útero en una región de salud: mujeres invisibles y cuerpos vulnerables

Este artigo avalia o acesso ao exame Papanicolaou na Estratégia Saúde da Família (ESF), em municípios de uma região de saúde. O controle do câncer do colo do útero depende de uma ESF organizada, portanto, avaliar o acesso ao teste de Papanicolaou revela a qualidade da assistência neste nível de atenção. Trata-se de estudo qualitativo, com dados produzidos em 10 grupos focais, perfazendo 70 participantes, em quatro municípios. Analisaram-se as dimensões organizacional, simbólica e técnica do acesso ao exame preventivo, tendo como condição marcadora o câncer do colo do útero. Os resultados indicaram que residir em zona rural era barreira para o acesso ao exame Papanicolaou e reforçavam as iniquidades. Enfermeiros eram a principal referência para a realização do exame preventivo. A ausência de itens necessários à coleta de material citopatológico foi uma barreira de acesso em todos os municípios. Havia entraves de acesso às mulheres com alguma deficiência e às mulheres lésbicas, com atendimento fragmentado e descontextualizado das singularidades pessoais. Os inúmeros entraves de acesso ao Papanicolaou expuseram a seletividade da ESF na região de saúde, visto que reproduzia a invisibilidade das mulheres com maior vulnerabilidade social e acentuava as desigualdades.

This article evaluates access to the Papanicolaou test in the Family Health Strategy (FHS) in municipalities in a health region. Cervical cancer control depends on a well-organized Family Health Strategy, so assessment of access to the Papanicolaou test reflects the quality of care at this level. This is a qualitative study with data produced in 10 focus groups, totaling 70 participants in four municipalities. We analyzed the organizational, symbolic, and technical dimensions of access to the Pap test, with cervical cancer control as the marker. The results indicate that living in rural areas was a barrier to access to the Papanicolaou test and exacerbated the inequalities. Nurses were the principal reference for access to the Pap test. The absence of necessary items for collecting cervical cytopathology specimens was a barrier to access in all the municipalities. There were obstacles to access for women with disabilities and lesbian women, with care that was fragmented and out of sync with individual characteristics. The numerous obstacles to access to the Papanicolaou test exposed the selectiveness of the Family Health Strategy in the health region, since it reproduced the invisibility of women with greater social vulnerability and exacerbated the existing inequalities.

Este artículo evalúa el acceso al examen Papanicolaou dentro del programa Estrategia Salud de la Familia (ESF), en municipios de una región de salud. El control del cáncer de cuello uterino depende de una ESF organizada, por lo tanto, evaluar el acceso al test de Papanicolaou revela la calidad de la asistencia en este nivel de atención. Se trata de un estudio cualitativo, con datos producidos dentro de 10 grupos focales, donde estaban incluidos 70 participantes en cuatro municipios. Se analizaron las dimensiones organizativas, simbólicas y técnicas del acceso al examen preventivo, considerándose condición marcadora el cáncer de cuello uterino. Los resultados indicaron que residir en una zona rural era una barrera para el acceso al examen Papanicolaou y reforzaba las inequidades. Los enfermeros eran la principal referencia para la realización del examen preventivo. La ausencia de ítems necesarios para la recogida de material citopatológico fue una barrera de acceso en todos los municipios. Había trabas de acceso a mujeres con alguna deficiencia y a mujeres lesbianas, con atención fragmentada y descontextualizada de las singularidades personales. Las innumerables trabas de acceso al Papanicolaou expusieron la selectividad de la ESF en la región de salud, debido a que reproducía la invisibilidad de las mujeres con mayor vulnerabilidad social y acentuaba desigualdades.

SUMOylation represses SnRK1 signaling in Arabidopsis.

The SnRK1 protein kinase balances cellular energy levels in accordance with extracellular conditions and is thereby key for plant stress tolerance. In addition, SnRK1 has been implicated in numerous growth and developmental processes from seed filling and maturation to flowering and senescence. Despite its importance, the mechanisms that regulate SnRK1 activity are poorly understood. Here, we demonstrate that the SnRK1 complex is SUMOylated on multiple subunits and identify SIZ1 as the E3 Small Ubiquitin-like Modifier (SUMO) ligase responsible for this modification. We further show that SnRK1 is ubiquitinated in a SIZ1-dependent manner, causing its degradation through the proteasome. In consequence, SnRK1 degradation is deficient in siz1-2 mutants, leading to its accumulation and hyperactivation of SnRK1 signaling. Finally, SnRK1 degradation is strictly dependent on its activity, as inactive SnRK1 variants are aberrantly stable but recover normal degradation when expressed as SUMO mimetics. Altogether, our data suggest that active SnRK1 triggers its own SUMOylation and degradation, establishing a negative feedback loop that attenuates SnRK1 signaling and prevents detrimental hyperactivation of stress responses.

Conserved and highly expressed tRNA derived fragments in zebrafish.

BACKGROUND: Small non-coding RNAs (sncRNAs) are a class of transcripts implicated in several eukaryotic regulatory mechanisms, namely gene silencing and chromatin regulation. Despite significant progress in their identification by next generation sequencing (NGS) we are still far from understanding their full diversity and functional repertoire. RESULTS: Here we report the identification of tRNA derived fragments (tRFs) by NGS of the sncRNA fraction of zebrafish. The tRFs identified are 18-30 nt long, are derived from specific 5' and 3' processing of mature tRNAs and are differentially expressed during development and in differentiated tissues, suggesting that they are likely produced by specific processing rather than random degradation of tRNAs. We further show that a highly expressed tRF (5'tRF-Pro(CGG)) is cleaved in vitro by Dicer and has silencing ability, indicating that it can enter the RNAi pathway. A computational analysis of zebrafish tRFs shows that they are conserved among vertebrates and mining of publicly available datasets reveals that some 5'tRFs are differentially expressed in disease conditions, namely during infection and colorectal cancer. CONCLUSIONS: tRFs constitute a class of conserved regulatory RNAs in vertebrates and may be involved in mechanisms of genome regulation and in some diseases.