A shared role for RBF1 and dCAP-D3 in the regulation of transcription with consequences for innate immunity

Previously, we discovered a conserved interaction between RB proteins and the Condensin II protein CAP-D3 that is important for ensuring uniform chromatin condensation during mitotic prophase. The Drosophila melanogaster homologs RBF1 and dCAP-D3 co-localize on non-dividing polytene chromatin, suggesting the existence of a shared, non-mitotic role for these two proteins. Here, we show that the absence of RBF1 and dCAP-D3 alters the expression of many of the same genes in larvae and adult flies. Strikingly, most of the genes affected by the loss of RBF1 and dCAP-D3 are not classic cell cycle genes but are developmentally regulated genes with tissue-specific functions and these genes tend to be located in gene clusters. Our data reveal that RBF1 and dCAP-D3 are needed in fat body cells to activate transcription of clusters of antimicrobial peptide (AMP) genes. AMPs are important for innate immunity, and loss of either dCAP-D3 or RBF1 regulation results in a decrease in the ability to clear bacteria. Interestingly, in the adult fat body, RBF1 and dCAP-D3 bind to regions flanking an AMP gene cluster both prior to and following bacterial infection. These results describe a novel, non-mitotic role for the RBF1 and dCAP-D3 proteins in activation of the Drosophila immune system and suggest dCAP-D3 has an important role at specific subsets of RBF1-dependent genes

The Living Universe: NASA and the Development of Astrobiology

In the opening weeks of 1998 a news article in the British journal Nature reported that NASA was about to enter biology in a big way. A "virtual" Astrobiology Institute was gearing up for business, and NASA administrator Dan Goldin told his external advisory council that he would like to see spending on the new institute eventually reach $100 million per year. "You just wait for the screaming from the physical scientists (when that happens)," Goldin was quoted as saying. Nevertheless, by the time of the second Astrobiology Science Conference in 2002, attended by seven hundred scientists from many disciplines, NASA spending on astrobiology had reached nearly half that amount and was growing at a steady pace. Under NASA leadership numerous institutions around the world applied the latest scientific techniques in the service of astrobiology's ambitious goal: the study of what NASA's 1996 Strategic Plan termed the "living universe." This goal embraced nothing less than an understanding of the origin, history, and distribution of life in the universe, including Earth. Astrobiology, conceived as a broad interdisciplinary research program, held the prospect of being the science for the twenty-first century which would unlock the secrets to some of the great questions of humanity. It is no surprise that these age-old questions should continue into the twenty-first century. But that the effort should be spearheaded by NASA was not at all obvious to those - inside and outside the agency - who thought NASA's mission was human spaceflight, rather than science, especially biological science. NASA had, in fact, been involved for four decades in "exobiology," a field that embraced many of the same questions but which had stagnated after the 1976 Viking missions to Mars. In this volume we tell the colorful story of the rise of the discipline of exobiology, how and why it morphed into astrobiology at the end of the twentieth century, and why NASA was the engine for both the discipline's founding and for its transformation

Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells.

Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α(1)-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α(1)-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies