Synthetic lethality driven by N-Myristoyltransferase inhibition in MYC deregulated cancers.

N-myristoylation is the irreversible attachment of myristate (a C14 fatty acid) to the N-terminal glycine of a given substrate. The enzyme responsible for this reaction is N-myristoyl transferase (NMT), a protein shown to be essential for many organisms, ranging from eukaryotes, plants, fungi, to infectious parasites. Initially, the NMTs of the fungi and infectious parasites sparked the interest of researchers in drug discovery to target these pathogens. However, the question remained whether one could target NMT in cancer. While early studies suggested potential upregulation of NMT1 in some early stage cancers, it remained unclear which cancer types to target and for which mechanistical reason. In this study, data from pharmacogenomics screens across hundreds of cancer cell lines, treated with three different NMT inhibitors, were analysed. Haematological malignancies were amongst the most responsive cell lines; however, also cancers originating from other tissues were sensitive, indicating a more complicated picture. Detailed phenotypical and omics-based analysis of the effects of NMT inhibition in an example cancer cell line from the haematological malignancies, and an unbiased bioinformatics approach across the pharmacogenomics data hinted at the same protooncogene: MYC. Two different isogenic system with inducible MYC confirmed that MYC deregulated cells are highly dependent on myristoylation. This newly uncovered synthetic lethality has potentially wide implications as MYC, a key transcription factor, is commonly deregulated in cancer and involved in most of the hallmarks of cancer. Targeting MYC or its downstream program attracted wide attention of the field; however, to date no drug has been approved to specifically target either. Novel approaches to target MYC, in the context of cancer, are urgently needed, and this study identified a potential new one.Open Acces

Observation of dressed excitonic states in a single quantum dot

We report the observation of dressed states of a quantum dot. The optically excited exciton and biexciton states of the quantum dot are coupled by a strong laser field and the resulting spectral signatures are measured using differential transmission of a probe field. We demonstrate that the anisotropic electron-hole exchange interaction induced splitting between the x- and y-polarized excitonic states can be completely erased by using the AC-Stark effect induced by the coupling field, without causing any appreciable broadening of the spectral lines. We also show that by varying the polarization and strength of a resonant coupling field, we can effectively change the polarization-axis of the quantum dot

Genomic diversity associated with polymorphic inversions in humans and their close relatives

Individuals of one species share the bulk of their genetic material, yet no two genomes are the same. Aside from displaying classical variation such as deletions, insertions, or substitutions of base pairs, two DNA segments can also differ in their orientation relative to the rest of their chromosomes. Such inversions are known for a range of biological implications and contribute critically to genome evolution and disease. However, inversions are notoriously challenging to detect, a fact which still impedes comprehensive analysis of their specific properties. This thesis describes several highly inter-connected projects aimed at identifying and functionally characterizing inversions present in the human population and related great ape species. First, inversions between human and four great ape species were assessed for their potential to disrupt topologically associating domains (TADs), potentially prompting gene misregulation. TAD boundaries co-located with breakpoints of long inversions, and while disrupted TADs displayed elevated rates of differen- tially expressed genes, this effect could be attributed the vicinity to inversion breakpoints, suggesting overall robustness of gene expression in response to TAD disruption. The second part of this thesis describes contributions to a collaborative project aimed at characterizing the full spectrum of inversions in 43 humans. In this study, I co-developed a novel inversion genotyping algorithm based on Strand- specific DNA sequencing and contributed to the description of 398 inversion polymorphisms. Inversions exhibited various underlying formation mechanisms, promotion of gene dysregulation, widespread recurrence, and association with genomic disease. These results suggest that long inversions are much more prominent in humans than previously thought, with at least 0.6% of the genome subject to inversion recurrence and, sometimes, the associated risk of subsequent deleterious mutation. With a focus on the link between inversions and disease-causing copy num- ber variations, the last project describes a novel algorithm to identify loci hit sequentially by several overlapping mutation events. This algorithm enabled the description of detailed mutation sequences in 20 highly dynamic regions in the human genome, and additional complex variants on chromosome Y. Six complex loci associate directly with a genomic disease, thereby highlighting in detail the intrinsic link between inversions and CNVs. In summary, these projects provide novel insights into the landscape of in- versions in humans and primates, which are much more frequent, and often more complex than previously thought. These findings provide a basis for future inversion studies and highlight the crucial contribution of this class of mutation to genome variation

Smart Order Routing and Best Execution

In the past decade traditional market structures have been drastically revolutionized, creating new potential for electronic trading. The driving forces are changes in trading behavior, advances in technology and new regulation. Traditional exchanges are challenged by new electronic trading platforms competing on the basis of price, cost, speed and efficiency. As trading has become more fragmented occurring in multiple venues the complexity for intelligent order routing decisions (smart order routing) will increase and extend the demand for sophisticated trading tools and efficient technology. Market fragmentation and dispersion of liquidity impose new challenges for investment firms to achieve best execution for their client orders. Against this background we examine two order execution strategies where one approach applies a pre-defined rule framework (static best execution); the alternative considers smart order routing decisions using real-time market data (dynamic best execution). We elaborate the benefits of smart order routing and outline our research approach for the validation of these findings