Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events

Conexiones entre las características sensoriales y la información que proporcionan los tests de estabilidad del aceite de soja

The relationship between sensorial deterioration (shelf-life) and induction period of refined soybean oil was studied, according to data obtained with the Rancimat method and peroxide value during 190 days of storage of the sample at room temperature. The Rancimat curve was obtained at 110 ºC, 10 l/h of air flow and 5,0 g of sample and showed an induction period of 6.75 h. From the variation of the peroxide value the induction period was 107 days, equivalent to 6,4 meg/kg. The sensorial analysis was carried out by a well trained panel which established that the sensorial deterioration of the sample was 102 days.Se estudió la relación existente entre el deterioro sensorial (vida útil) del aceite de soja y el tiempo de inducción de la oxidación, según datos obtenidos con el Rancimat y la variación del índice de peróxidos durante el almacenamiento del aceite a lo largo de 190 días a temperatura ambiente. La curva del Rancimat se calculó a 110°C con flujo de aire de 101/ h, 5,0 g de muestra, resultando un período de inducción de 6,75 h. Según la variación del índice de peróxidos, el período de inducción resultó de 107 días, equivalente a 6,4 meq/kg. El análisis sensorial estuvo a cargo de catadores quienes establecieron que el deterioro sensorial se producía a los 102 días

Sensitivity of outcome instruments in a priori selected patient groups after traumatic brain injury:Results from the CENTER-TBI study

Traumatic brain injury (TBI) can negatively impact patients' lives on many dimensions. Multiple instruments are available for evaluating TBI outcomes, but it is still unclear which instruments are the most sensitive for that purpose. This study examines the sensitivity of nine outcome instruments in terms of their ability to discriminate within and between specific patient groups, selected a priori as identified from the literature, at three different time points within a year after TBI (i.e., 3, 6, and 12 months post injury). The sensitivity of the instruments to sociodemographic (sex, age, education), premorbid (psychological health status), and injury-related (clinical care pathways, TBI and extracranial injury severity) factors was assessed by means of cross-sectional multivariate Wei-Lachin analyses. The Glasgow Outcome Scale Extended (GOSE)-the standard in the field of TBI for measuring functional recovery-demonstrated the highest sensitivity in most group comparisons. However, as single functional scale, it may not be able to reflect the multidimensional nature of the outcome. Therefore, the GOSE was used as a reference for further sensitivity analyses on more specific outcome scales, addressing further potential deficits following TBI. The physical component summary score (PCS) of the generic health-related quality of life (HRQOL) instruments (SF-36v2/-12v2) and the TBI-specific HRQOL instruments (QOLIBRI/-OS) were most sensitive in distinguishing recovery after TBI across all time points and patient groups, followed by the RPQ assessing post-concussion symptoms and the PHQ-9 measuring depression. The SF-36v2/-12v2 mental component summary score and the GAD-7 measuring anxiety were less sensitive in several group comparisons. The assessment of the functional recovery status combined with generic HRQOL (the PCS of the SF-12v2), disease-specific HRQOL (QOLIBRI-OS), and post-concussion symptoms (RPQ) can provide a sensitive, comprehensive, yet time-efficient evaluation of the health status of individuals after TBI in different patient groups.</p

Psychometric Characteristics of the Patient-Reported Outcome Measures Applied in the CENTER-TBI Study.

Traumatic brain injury (TBI) may lead to impairments in various outcome domains. Since most instruments assessing these are only available in a limited number of languages, psychometrically validated translations are important for research and clinical practice. Thus, our aim was to investigate the psychometric properties of the patient-reported outcome measures (PROM) applied in the CENTER-TBI study. The study sample comprised individuals who filled in the six-months assessments (GAD-7, PHQ-9, PCL-5, RPQ, QOLIBRI/-OS, SF-36v2/-12v2). Classical psychometric characteristics were investigated and compared with those of the original English versions. The reliability was satisfactory to excellent; the instruments were comparable to each other and to the original versions. Validity analyses demonstrated medium to high correlations with well-established measures. The original factor structure was replicated by all the translations, except for the RPQ, SF-36v2/-12v2 and some language samples for the PCL-5, most probably due to the factor structure of the original instruments. The translation of one to two items of the PHQ-9, RPQ, PCL-5, and QOLIBRI in three languages could be improved in the future to enhance scoring and application at the individual level. Researchers and clinicians now have access to reliable and valid instruments to improve outcome assessment after TBI in national and international health care

Atualização do levantamento de reconhecimento de solos dos municípios da Bacia do Paraná 3 e Palotina.

Os municípios formadores da Bacia do Paraná 3 (BP3) e o município de Palotina, todos localizados no Terceiro Planalto Paranaense, foram o objeto do presente estudo. Em boa parte dessas paisagens predominam solos com boas características para a agricultura industrial conexa à produção intensiva de grãos e de proteína animal. O setor primário e a agroindústria dos municípios geram riquezas que sustentam o desenvolvimento regional em níveis muito superiores à média nacional, justificando a iniciativa da atualização do levantamento de solos aqui apresentado, considerando que a espacialização dos solos é ferramenta essencial à definição de políticas de planejamento de uso da terra. Assim, o presente trabalho objetivou atualizar, no perímetro de abrangência dos municípios da BP3 e Palotina, o mapa de solos gerado por Bhering e Santos (2008), considerando: resoluções da 5a edição do Sistema Brasileiro de Classificação de Solos (Santos et al., 2018), ampla checagem de nomeação das unidades de mapeamento (realizada polígono a polígono), reagrupamento das unidades de mapeamento de solos e qualificação das unidades de mapeamento em atributos de retenção de água (incluindo viagens de campo, coleta de amostras e análises de retenção de água). São partes interativas desse estudo o presente relatório, o mapa de solos na escala 1:250.000 e os arquivos shapes que formam a base de dados cartográfica em ambiente de Sistema Geográfico de Informações. Características gerais da região são apresentadas por Gomes et al. (2020)

The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach

The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion

Hirnorganoide – Modellsysteme des menschlichen Gehirns

This is the final version. Available from Deutsche Akademie der Naturforscher Leopoldina via the DOI in this record. Hirnorganoide sind Gewebestrukturen aus dem Labor, die Teile der Hirnfunktion imitieren. Sie eröffnen als vereinfachtes Modellsystem einen experimentellen Zugang zu Fragen rund um die Entwicklung und die Funktion des menschlichen Gehirns. Während die Forschung an menschlichen lebenden Gehirnen aus ethischen Gründen enge Grenzen hat und Tiermodelle viele Fragen nur bedingt beantworten können, bieten Hirnorganoide neue Forschungsmöglichkeiten. In der Stellungnahme „Hirnorganoide ‒ Modellsysteme des menschlichen Gehirns“ der Nationalen Akademie der Wissenschaften Leopoldina beschreiben Wissenschaftlerinnen und Wissenschaftler die Möglichkeiten dieses Forschungsgebietes und erörtern, ob es aus ethischen oder juristischen Gründen stärker reguliert werden sollte

Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression

Loss of the coxsackie and adenovirus receptor (CAR) has previously been observed in gastric cancer. The role of CAR in gastric cancer pathobiology, however, is unclear. We therefore analysed CAR in 196 R0-resected gastric adenocarcinomas and non-cancerous gastric mucosa samples using immunohistochemistry and immunofluorescence. Coxsackie and adenovirus receptor was found at the surface and foveolar epithelium of all non-neoplastic gastric mucosa samples (n=175), whereas only 56% of gastric cancer specimens showed CAR positivity (P<0.0001). Loss of CAR correlated significantly with decreased differentiation, increased infiltrative depths, presence of distant metastases, and was also associated with reduced carcinoma-specific survival. To clarify whether CAR impacts the tumorbiologic properties of gastric cancer, we subsequently determined the role of CAR in proliferation, migration, and invasion of gastric cancer cell lines by application of specific CAR siRNA or ectopic expression of a human full-length CAR cDNA. These experiments showed that RNAi-mediated CAR knock down resulted in increased proliferation, migration, and invasion of gastric cancer cell lines, whereas enforced ectopic CAR expression led to opposite effects. We conclude that the association of reduced presence of CAR in more severe disease states, together with our findings in gastric cancer cell lines, suggests that CAR functionally contributes to gastric cancer pathogenesis, showing features of a tumour suppressor

Synchronized turbo apoptosis induced by cold-shock

In our research on the role of apoptosis in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE), we aim to evaluate the effects of early and late apoptotic cells and blebs on antigen presenting cells. This requires the in vitro generation of sufficiently large and homogeneous populations of early and late apoptotic cells. Here, we present a quick method encountered by serendipity that results in highly reproducible synchronized homogeneous apoptotic cell populations. In brief, granulocytic 32Dcl3 cells are incubated on ice for 2 h and subsequently rewarmed at 37°C. After 30–90 min at 37°C more than 80–90% of the cells become early apoptotic (Annexin V positive/propidium iodide negative). After 24 h of rewarming at 37°C 98% of the cells were late apoptotic (secondary necrotic; Annexin V positive/propidium iodide positive). Cells already formed apoptotic blebs at their cell surface after approximately 20 min at 37°C. Inter-nucleosomal chromatin cleavage and caspase activation were other characteristics of this cold-shock-induced process of apoptosis. Consequently, apoptosis could be inhibited by a caspase inhibitor. Finally, SLE-derived anti-chromatin autoantibodies showed a high affinity for apoptotic blebs generated by cold-shock. Overall, cold-shock induced apoptosis is achieved without the addition of toxic compounds or antibodies, and quickly leads to synchronized homogeneous apoptotic cell populations, which can be applied for various research questions addressing apoptosis