Ubiquitin-specific protease 12 interacting partners Uaf-1 and WDR20 are potential therapeutic targets in prostate cancer

The androgen receptor (AR) is a key transcription factor in the initiation and progression of prostate cancer (PC) and is a major therapeutic target for the treatment of advanced disease. Unfortunately, current therapies are not curative for castration resistant PC and a better understanding of AR regulation could identify novel therapeutic targets and biomarkers to aid treatment of this disease. The AR is known to be regulated by a number of post-translational modifications and we have recently identified the deubiquitinating enzyme Usp12 as a positive regulator of AR. We determined that Usp12 deubiquitinates the AR resulting in elevated receptor stability and activity. Furthermore, Usp12 silencing was shown to reduce proliferation of PC cells. Usp12 is known to require the co-factors Uaf-1 and WDR20 for catalytic activity. In this report we focus further on the role of Uaf-1 and WDR20 in Usp12 regulation and investigate if these co-factors are also required for controlling AR activity. Firstly, we confirm the presence of the Usp12/Uaf-1/WDR20 complex in PC cells and demonstrate the importance of Uaf-1 and WDR20 for Usp12 stabilisation. Consequently, we show that individual silencing of either Uaf-1 or WDR20 is sufficient to abrogate the activity of the Usp12 complex and down-regulate AR-mediated transcription via receptor destabilisation resulting in increased apoptosis and decreased colony forming ability of PC cells. Moreover, expression of both Uaf-1 and WDR20 is higher in PC tissue compared to benign controls. Overall these results highlight the potential importance of the Usp12/Uaf-1/WDR20 complex in AR regulation and PC progression. Androgen receptor is a key transcriptional regulator in prostate cancer. Usp12/Uaf-1/WDR20 complex plays a crucial role in androgen receptor stability and activity. Destabilising an individual Usp12/Uaf-1/WDR20 complex member reduces the protein levels of the whole complex and diminishes androgen receptor activity. Protein levels of all members of the Usp12/Uaf-1/WDR20 complex are significantly increased in PC

Inclusão escolar de alunos portadores de Transtorno do Espectro Autista na educação infantil: uma revisão sistemática: School inclusion of students with Autistic Spectrum Disorder in early childhood education: a systematic review

Este artigo debate o problema da inclusão escolar de crianças com transtorno do espectro autista (TEA). Para estabelecer o debate, foi feito um levantamento bibliográfico e referencial para uma revisão sistemática do tema. O objetivo é clarificar os conceitos de inclusão escolar e TEA para debater como é feito o processo educacional de crianças com TEA. Sendo assim, a partir da pesquisa científica de descritores como “inclusão escolar”, “transtorno do espectro autista”, foi observado, pelos diversos autores trabalhados, que ainda há muito o que se debater e trabalhar para que ocorra a inclusão escolar de crianças com TEA. Apesar das muitas tentativas, erros e acertos, o tema ainda é pouco trabalhado e divulgado, visto que há poucos profissionais capacitados na área

Aminoquinolones and Their Benzoquinone Dimer Hybrids as Modulators of Prion Protein Conversion

Prion Diseases or Transmissible Spongiform Encephalopathies are neurodegenerative conditions associated with a long incubation period and progressive clinical evolution, leading to death. Their pathogenesis is characterized by conformational changes of the cellular prion protein—PrPC—in its infectious isoform—PrPSc—which can form polymeric aggregates that precipitate in brain tissues. Currently, there are no effective treatments for these diseases. The 2,5-diamino-1,4-benzoquinone structure is associated with an anti-prion profile and, considering the biodynamic properties associated with 4-quinolones, in this work, 6-amino-4-quinolones derivatives and their respective benzoquinone dimeric hybrids were synthesized and had their bioactive profile evaluated through their ability to prevent prion conversion. Two hybrids, namely, 2,5-dichloro-3,6-bis((3-carboxy-1-pentyl-4-quinolone-6-yl)amino)-1,4-benzoquinone (8e) and 2,5-dichloro-3,6-bis((1-benzyl-3-carboxy-4-quinolone-6-yl)amino)-1,4-benzoquinone (8f), stood out for their prion conversion inhibition ability, affecting the fibrillation process in both the kinetics—with a shortening of the lag phase—and thermodynamics and their ability to inhibit the formation of protein aggregates without significant cytotoxicity at ten micromolar