Identification of a Novel Calotropis procera Protein That Can Suppress Tumor Growth in Breast Cancer through the Suppression of NF-κB Pathway

10.1371/journal.pone.0048514PLoS ONE712

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Structural analysis of the role of TPX2 in branching microtubule nucleation

The mitotic spindle consists of microtubules (MTs), which are nucleated by the γ-tubulin ring complex (γ-TuRC). How the γ-TuRC gets activated at the right time and location remains elusive. Recently, it was uncovered that MTs nucleate from preexisting MTs within the mitotic spindle, which requires the protein TPX2, but the mechanism basis for TPX2 action is unknown. Here, we investigate the role of TPX2 in branching MT nucleation. We establish the domain organization of Xenopus laevis TPX2 and define the minimal TPX2 version that stimulates branching MT nucleation, which we find is unrelated to TPX2’s ability to nucleate MTs in vitro. Several domains of TPX2 contribute to its MT-binding and bundling activities. However, the property necessary for TPX2 to induce branching MT nucleation is contained within newly identified γ-TuRC nucleation activator motifs. Separation-of-function mutations leave the binding of TPX2 to γ-TuRC intact, whereas branching MT nucleation is abolished, suggesting that TPX2 may activate γ-TuRC to promote branching MT nucleation

Peptides as models for the structure and function of viral capsid proteins : insights on dengue virus capsid

© 2013 Wiley Periodicals Inc.The structural organization of viral particles is among the most astonishing examples of molecular self-assembly in nature, involving proteins, nucleic acids, and, sometimes, lipids. Proper assembly is essential to produce well structured infectious virions. A great variety of structural arrangements can be found in viral particles. Nucleocapsids, for instance, may display highly ordered geometric shapes or consist in macroscopically amorphous packs of the viral genome. Alphavirus and flavivirus are viral genera that exemplify these extreme cases, the former comprising viral particles structured with a T=4 icosahedral symmetry, whereas flavivirus capsids have no regular geometry. Dengue virus is a member of flavivirus genus and is used in this article to illustrate how viral protein-derived peptides can be used advantageously over full-length proteins to unravel the foundations of viral supramolecular assemblies. Membrane- and viral RNA-binding data of capsid protein-derived dengue virus peptides are used to explain the amorphous organization of the viral capsid. Our results combine bioinformatic and spectroscopic approaches using two- or three-component peptide and/or nucleic acid and/or lipid systems.Contract grant sponsor: Fundação para a Ciência e Tecnologia—Ministério da Educação e Ciência (FCT-MEC, Portugal) Contract grant numbers: PTDC/QUI-BIQ/112929/2009; SFRH/BD/70423/2010 Contract grant sponsor: Fundação Calouste Gulbenkian Contract grant sponsor: International Research Staff Exchange Scheme project MEMPEPACROSS (EU) Contract grant numbers: FP7-PEOPLE IRSES; FP7-HEALTH-F3–2008-223414 Contract grant sponsor: Spanish Ministry of Economy and Competitivity Contract grant number: SAF2011–24899 Contract grant sponsor: Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico (CNPq) Contract grant number: 550114/2010-6 Contract grant sponsor: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) Contract grant number: E-26/102.919/2011 Contract grant sponsor: National Institute of Science and Technology in Dengue (INCT-Dengue) Contract grant sponsor: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil) Contract grant number: PVE 171/201

Targeted diversity generation by intraterrestrial archaea and archaeal viruses

Paul BG, Bagby SC, Czornyj E, et al. Targeted diversity generation by intraterrestrial archaea and archaeal viruses. Nature Communications. 2015;6(1): 6585.In the evolutionary arms race between microbes, their parasites, and their neighbours, the capacity for rapid protein diversification is a potent weapon. Diversity-generating retroelements (DGRs) use mutagenic reverse transcription and retrohoming to generate myriad variants of a target gene. Originally discovered in pathogens, these retroelements have been identified in bacteria and their viruses, but never in archaea. Here we report the discovery of intact DGRs in two distinct intraterrestrial archaeal systems: a novel virus that appears to infect archaea in the marine subsurface, and, separately, two uncultivated nanoarchaea from the terrestrial subsurface. The viral DGR system targets putative tail fibre ligand-binding domains, potentially generating >10(18) protein variants. The two single-cell nanoarchaeal genomes each possess ≥4 distinct DGRs. Against an expected background of low genome-wide mutation rates, these results demonstrate a previously unsuspected potential for rapid, targeted sequence diversification in intraterrestrial archaea and their viruses