Peaks in the Hartle-Hawking Wave Function from Sums over Topologies

Recent developments in ``Einstein Dehn filling'' allow the construction of infinitely many Einstein manifolds that have different topologies but are geometrically close to each other. Using these results, we show that for many spatial topologies, the Hartle-Hawking wave function for a spacetime with a negative cosmological constant develops sharp peaks at certain calculable geometries. The peaks we find are all centered on spatial metrics of constant negative curvature, suggesting a new mechanism for obtaining local homogeneity in quantum cosmology.Comment: 16 pages,LaTeX, no figures; v2: some changes coming from revision of a math reference: wave function peaks sharp but not infinite; v3: added paragraph in intro on interpretation of wave functio

Privacy by Design: From Technologies to Architectures (Position Paper)

Existing work on privacy by design mostly focus on technologies rather than methodologies and on components rather than architectures. In this paper, we advocate the idea that privacy by design should also be addressed at the architectural level and be associated with suitable methodologies. Among other benefits, architectural descriptions enable a more systematic exploration of the design space. In addition, because privacy is intrinsically a complex notion that can be in tension with other requirements, we believe that formal methods should play a key role in this area. After presenting our position, we provide some hints on how our approach can turn into practice based on ongoing work on a privacy by design environment

Identification of a Novel Class of Farnesylation Targets by Structure-Based Modeling of Binding Specificity

Farnesylation is an important post-translational modification catalyzed by farnesyltransferase (FTase). Until recently it was believed that a C-terminal CaaX motif is required for farnesylation, but recent experiments have revealed larger substrate diversity. In this study, we propose a general structural modeling scheme to account for peptide binding specificity and recapitulate the experimentally derived selectivity profile of FTase in vitro. In addition to highly accurate recovery of known FTase targets, we also identify a range of novel potential targets in the human genome, including a new substrate class with an acidic C-terminal residue (CxxD/E). In vitro experiments verified farnesylation of 26/29 tested peptides, including both novel human targets, as well as peptides predicted to tightly bind FTase. This study extends the putative range of biological farnesylation substrates. Moreover, it suggests that the ability of a peptide to bind FTase is a main determinant for the farnesylation reaction. Finally, simple adaptation of our approach can contribute to more accurate and complete elucidation of peptide-mediated interactions and modifications in the cell

TRIAMF: A New Method for Delivery of Cas9 Ribonucleoprotein Complex to Human Hematopoietic Stem Cells

Abstract CRISPR/Cas9 mediated gene editing of patient-derived hematopoietic stem and progenitor cells (HSPCs) ex vivo followed by autologous transplantation of the edited HSPCs back to the patient can provide a potential cure for monogenic blood disorders such as β-hemoglobinopathies. One challenge for this strategy is efficient delivery of the ribonucleoprotein (RNP) complex, consisting of purified Cas9 protein and guide RNA, into HSPCs. Because β-hemoglobinopathies are most prevalent in developing countries, it is desirable to have a reliable, efficient, easy-to-use and cost effective delivery method. With this goal in mind, we developed TRansmembrane Internalization Assisted by Membrane Filtration (TRIAMF), a new method to quickly and effectively deliver RNPs into HSPCs by passing a RNP and cell mixture through a filter membrane. We achieved robust gene editing in HSPCs using TRIAMF and demonstrated that the multilineage colony forming capacities and the competence for engraftment in immunocompromised mice of HSPCs were preserved post TRIAMF treatment. TRIAMF is a custom designed system using inexpensive components and has the capacity to process HSPCs at clinical scale