Dynamical damping terms for symmetry-seeking shift conditions

Suitable gauge conditions are fundamental for stable and accurate numerical-relativity simulations of inspiralling compact binaries. A number of well-studied conditions have been developed over the last decade for both the lapse and the shift and these have been successfully used both in vacuum and non-vacuum spacetimes when simulating binaries with comparable masses. At the same time, recent evidence has emerged that the standard "Gamma-driver" shift condition requires a careful and non-trivial tuning of its parameters to ensure long-term stable evolutions of unequal-mass binaries. We present a novel gauge condition in which the damping constant is promoted to be a dynamical variable and the solution of an evolution equation. We show that this choice removes the need for special tuning and provides a shift damping term which is free of instabilities in our simulations and dynamically adapts to the individual positions and masses of the binary black-hole system. Our gauge condition also reduces the variations in the coordinate size of the apparent horizon of the larger black hole and could therefore be useful when simulating binaries with very small mass ratios.Comment: 11 pages, 8 figure

Matched Filtering of Numerical Relativity Templates of Spinning Binary Black Holes

Tremendous progress has been made towards the solution of the binary-black-hole problem in numerical relativity. The waveforms produced by numerical relativity will play a role in gravitational wave detection as either test-beds for analytic template banks or as template banks themselves. As the parameter space explored by numerical relativity expands, the importance of quantifying the effect that each parameter has on first the detection of gravitational waves and then the parameter estimation of their sources increases. In light of this, we present a study of equal-mass, spinning binary-black-hole evolutions through matched filtering techniques commonly used in data analysis. We study how the match between two numerical waveforms varies with numerical resolution, initial angular momentum of the black holes and the inclination angle between the source and the detector. This study is limited by the fact that the spinning black-hole-binaries are oriented axially and the waveforms only contain approximately two and a half orbits before merger. We find that for detection purposes, spinning black holes require the inclusion of the higher harmonics in addition to the dominant mode, a condition that becomes more important as the black-hole-spins increase. In addition, we conduct a preliminary investigation of how well a template of fixed spin and inclination angle can detect target templates of arbitrary spin and inclination for the axial case considered here

Targeting ferroptosis for neuroprotection: Novel diphenylamine compounds targeting mitochondrial pathways of oxidative cell death

Neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease as well as stroke are of growing concern in our aging societies. In the last decades, biochemical hallmarks of these pathologies, containing excessive lipid peroxide formation, iron overload and mitochondrial impairments were linked to recently described forms of regulated, oxidative cell death mechanisms such as oxytosis and ferroptosis. Neurons are vulnerable to mitochondrial damage due to their high energy demand associated with the high electrical activity. Thus, protecting mitochondria is a reasonable approach for preventing neuronal dysfunction and cell death. In particular, the pro-apoptotic protein BID is of central interest in the pathology of neurodegeneration. Studies using Bid KO mice showed a significant decrease in infarct volumes upon stroke induction. Moreover, Bid knock-out trials in HT22 neurons demonstrated that BID was crucially involved in the mechanisms of oxidative cell death model of oxytosis and ferroptosis, possibly participating in the transfer of the ROS-dependent upstream events to mitochondria. Hence, BID is an attractive target molecule for ferroptosis inhibition and, therefore, for the development of novel compounds targeting neurodegenerative diseases. However, in silico compound search was always hampered by a missing high-resolution X-ray structure of the BID protein. To improve the current understanding of the protein, the previously started approaches to elucidate the 3D crystal structure of the BID protein were continued. These experiments were conducted using the established Bid3CCSS construct. Previous high-throughput screens showed that in the Morpheus A5 condition, Bid3CCSS crystals could be consistently obtained in the form of ingrown needle clusters. Due to intensive screening of the components from the Morpheus A5 condition during the presented work, crystal quality was considerably enhanced. The best crystals from this optimization process were then subjected to a streak seeding protocol and cryoprotection. X-ray measurements of the obtained non-ingrown crystals resulted in data sets for the apo Bid3CCSS crystal with a resolution of 2.0 – 2.3 Å. After successful phase determination using gadolinium-acetate-soaked crystals, a crystal structure of the BID3CCSS could be modeled for the first time. The Bid3CCSS protein crystallized as a trimer. Although the protein is constructed mainly of alpha helices, large parts of two monomers were disordered, which resulted in below-average refinement statistics. However, one monomer is well-resolved and therefore could serve as a basis for targeted in silico compound development against the BID protein in the future. Further crystallographic experiments should be conducted to lower the protein’s flexibility in the crystal assembly, change the crystal packing by improving the crystal contacts, and identify (novel) binding pockets by the introduction of ligands. In the second part of the thesis, novel diphenylamine (DPA) compounds were characterized in ferroptosis. These compounds were previously developed upon a medicinal chemistry approach using the first BID inhibitor BI-6c9 as a scaffold molecule to identify novel inhibitors of oxidative cell death. The selected DPA compounds 1-3 were the most potent inhibitors against glutamate induced oxytosis in preliminary experiments. Similarly, these novel DPA compounds were very potent and selective ferroptosis inhibitors. With EC50 values between 0.23-0.32 µM, the compounds were 10-20-fold more potent in preventing oxidative cell death than the previously described BID inhibitors. The DPA compounds abrogated lipid ROS formation, as the most conclusive hallmark of ferroptosis, as well as cytosolic and mitochondrial ROS formation without affecting the upstream cascade of ferroptosis including glutathione levels and GPX4 expression. Interestingly, a pronounced ROS scavenging effect by the DPA compounds could be excluded indicating that a direct antioxidant effect, possibly provided by the diphenylamine structure, was of minor relevance for the observed protective effects. Moreover, mitochondrial respiration and constitution were maintained in a concentration-dependent manner. Post-treatment experiments substantiated the suggestion that mitochondrial protection and an interference in the ROS development processes by the compounds may contribute to the protective mechanism. Testing BID as a potential target structure in t-BID overexpression assays, failed to demonstrate a significant effect of the DPA compounds on t-BID. Moreover, preliminary binding assays of the compounds to the Bid3CCSS protein construct using MST and NMR techniques as well as co-crystallization and soaking experiments showed no clear binding activities so far, although these assays need further optimization. In conclusion, these results highlight the role for mitochondrial protection as a strategy for the development of anti-ferroptotic compounds as possible new treatment options of neurodegenerative disorders in the future. The in vitro results encourage for further in vivo testing of the DPA compounds to evaluate the toxicity and effectiveness in models where ferroptosis might play a significant role, as for example in cerebral hemorrhage

Exploring the impact of user involvement on health and social care services for cancer in the UK.

This report presents the findings from a study of cancer network partnership groups in the UK. Cancer network partnership groups are regional organisations set up to enable joint working between people affected by cancer and health professionals, with the aim of improving cancer care

Enriching the Symphony of Gravitational Waves from Binary Black Holes by Tuning Higher Harmonics

For the first time, we construct an inspiral-merger-ringdown waveform model within the effective-one-body formalism for spinning, nonprecessing binary black holes that includes gravitational modes beyond the dominant $(\ell,|m|) = (2,2)$ mode, specifically $(\ell,|m|)=(2,1),(3,3),(4,4),(5,5)$. Our multipolar waveform model incorporates recent (resummed) post-Newtonian results for the inspiral and information from 157 numerical-relativity simulations, and 13 waveforms from black-hole perturbation theory for the (plunge-)merger and ringdown. We quantify the improved accuracy including higher-order modes by computing the faithfulness of the waveform model against the numerical-relativity waveforms used to construct the model. We define the faithfulness as the match maximized over time, phase of arrival, gravitational-wave polarization and sky position of the waveform model, and averaged over binary orientation, gravitational-wave polarization and sky position of the numerical-relativity waveform. When the waveform model contains only the $(2,2)$ mode, we find that the averaged faithfulness to numerical-relativity waveforms containing all modes with $\ell \leq$ 5 ranges from $90\%$ to $99.9\%$ for binaries with total mass $20-200 M_\odot$ (using the Advanced LIGO's design noise curve). By contrast, when the $(2,1),(3,3),(4,4),(5,5)$ modes are also included in the model, the faithfulness improves to $99\%$ for all but four configurations in the numerical-relativity catalog, for which the faithfulness is greater than $98.5\%$. Using our results, we also develop also a (stand-alone) waveform model for the merger-ringdown signal, calibrated to numerical-relativity waveforms, which can be used to measure multiple quasi-normal modes. The multipolar waveform model can be extended to include spin-precession, and will be employed in upcoming observing runs of Advanced LIGO and Virgo.Comment: 28 page