Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1:a novel anticancer small-molecule

Restoration of the p53 pathway, namely by reactivation of mutant (mut) p53, represents a valuable anticancer strategy. Herein, we report the identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type (wt) and mut p53, using a yeast-based screening strategy. SLMP53-1 has a p53-dependent anti-proliferative activity in human wt and mut p53R280K-expressing tumor cells. Additionally, SLMP53-1 enhances p53 transcriptional activity and restores wt-like DNA binding ability to mut p53R280K. In wt/mut p53-expressing tumor cells, SLMP53-1 triggers p53 transcription-dependent and mitochondrial apoptotic pathways involving BAX, and wt/mut p53 mitochondrial translocation. SLMP53-1 inhibits the migration of wt/mut p53-expressing tumor cells, and it shows promising p53-dependent synergistic effects with conventional chemotherapeutics. In xenograft mice models, SLMP53-1 inhibits the growth of wt/mut p53-expressing tumors, but not of p53-null tumors, without apparent toxicity. Collectively, besides the potential use of SLMP53-1 as anticancer drug, the tryptophanol-derived oxazoloisoindolinone scaffold represents a promissing starting point for the development of effective p53-reactivating drugs

Análise exploratória do modelo de simulação de rodovias de pista simples do VISSIM

A modelagem de rodovias de pista simples tem sido incorporada em simuladores de tráfego. Como a lógica de simulação em rodovias de pista simples teve que se adequar a outros submodelos comportamentais dos simuladores, como o de car-following e o de mudança de faixas, surge a necessidade de avaliar se a modelagem desse tipo de rodovia tem sido realizada adequadamente. Este artigo, portanto, teve como meta realizar essa análise para o VISSIM, devidamente calibrado por meio de dados de campo e com um Algoritmo Genético. Foram analisadas as variações de duas medidas de desempenho, velocidade média de viagem (ATSd) e número de ultrapassagens (NUd), de acordo com a variação das zonas de ultrapassagens proibidas, da porcentagem de veículos pesados e do fluxo de tráfego unidirecional. Não foram observadas grandes diferenças quando foram avaliados os valores de ATSd, ao contrário do que ocorreu com NUd.A modelagem de rodovias de pista simples tem sido incorporada em simuladores de tráfego. Como a lógica de simulação em rodovias de pista simples teve que se adequar a outros submodelos comportamentais dos simuladores, como o de car-following e o de mudança de faixas, surge a necessidade de avaliar se a modelagem desse tipo de rodovia tem sido realizada adequadamente. Este artigo, portanto, teve como meta realizar essa análise para o VISSIM, devidamente calibrado por meio de dados de campo e com um Algoritmo Genético. Foram analisadas as variações de duas medidas de desempenho, velocidade média de viagem (ATSd) e número de ultrapassagens (NUd), de acordo com a variação das zonas de ultrapassagens proibidas, da porcentagem de veículos pesados e do fluxo de tráfego unidirecional. Não foram observadas grandes diferenças quando foram avaliados os valores de ATSd, ao contrário do que ocorreu com NUd

Aligned silk-based 3-D architectures for contact guidance in tissue engineering

An important challenge in the biomaterials field is to mimic the structure of functional tissues via cell and extracellular matrix (ECM) alignment and anisotropy. Toward this goal, silk-based scaffolds resembling bone lamellar structure were developed using a freeze-drying technique. The structure could be controlled directly by solute concentration and freezing parameters, resulting in lamellar scaffolds with regular morphology. Different post-treatments, such as methanol, water annealing and steam sterilization, were investigated to induce water stability. The resulting structures exhibited significant differences in terms of morphological integrity, structure and mechanical properties. The lamellar thicknesses were ∼2.6 μm for the methanol-treated scaffolds and ∼5.8 μm for water-annealed. These values are in the range of those reported for human lamellar bone. Human bone marrow-derived mesenchymal stem cells (hMSC) were seeded on these silk fibroin lamellar scaffolds and grown under osteogenic conditions to assess the effect of the microstructure on cell behavior. Collagen in the newly deposited ECM was found aligned along the lamellar architectures. In the case of methanol-treated lamellar structures, the hMSC were able to migrate into the interior of the scaffolds, producing a multilamellar hybrid construct. The present morphology constitutes a useful pattern onto which hMSC cells attach and proliferate for guided formation of a highly oriented extracellular matrix.A.L.O. wishes to thank financial support from the Portuguese Foundation for Science and Technology (SFRH/BPD/39102/2007) under POCTI Program. This work was partially supported by FCT through POCTI and/or FEDER programs and by the NIH [DE017207, EB003210 and EB002520]

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe