Supermassive Black Hole Binaries: The Search Continues

Gravitationally bound supermassive black hole binaries (SBHBs) are thought to be a natural product of galactic mergers and growth of the large scale structure in the universe. They however remain observationally elusive, thus raising a question about characteristic observational signatures associated with these systems. In this conference proceeding I discuss current theoretical understanding and latest advances and prospects in observational searches for SBHBs.Comment: 17 pages, 4 figures. To appear in the Proceedings of 2014 Sant Cugat Forum on Astrophysics. Astrophysics and Space Science Proceedings, ed. C.Sopuerta (Berlin: Springer-Verlag

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories

Development and application of novel multicomponent reactions using (a)alfa-acidic isocyanides

The research described in this thesis deals with: i) the exploitation of the a-acidity of isocyanides in the development of new multicomponent reactions; ii) the application of such MCRs for the synthesis of NHC complexes; and iii) the C–2 functionalisation of 2 imidazolines as a route towards libraries of potential p53-MDM2 interaction inhibitors. In Chapter 2, the translation of Schöllkopf’s aldol type chemistry with a-isocyanoacetates to a novel multicomponent synthesis of 2H-2-imidazolines is described. The scope of this MCR is further explored in Chapter 3 by the use of 9-isocyanofluorene and p-nitrobenzyl isocyanide as well as functionalised amines and aldehydes. Also the application of ketones instead of aldehydes and the influence of chiral inputs are addressed. Differences in reactivity of the employed isocyanides are explained using high level Density Functional Theory (DFT) calculations. Chapter 4 contains a review on the history, structure, reactivity and synthesis of NHCs and their metal complexes. Furthermore, the use of 2H-2-imidazolines prepared with our MCR in the synthesis of unprecedented types of NHC complexes is displayed. This procedure allows the variation of all substituents of the NHC ligands. The NHC-transition metal complexes are characterised using NMR, IR and X-ray crystal structures. Chapter 5 starts with a comprehensive overview of the role of the p53 tumour suppressor and its interaction with MDM2, its natural inhibitor and regulator. Then, a recently discovered class of p53-MDM2 interaction inhibitors called Nutlins is introduced and our synthetic efforts towards Nutlin analogues via the C–2 functionalisation of 2H-2-imidazolines are described. The first part of Chapter 6 is an introduction to conformationally constrained peptides as ß-turn mimics. The next part deals with the discovery of a new MCR involving the reaction of in situ generated azadienes with a-isocyanoacetates, in which the versatile isocyano group is preserved. The products, 3-isocyano-3,4-dihydropyridones can be regarded as Freidinger type lactams suited for additional multicomponent chemistry, possibly leading to new ß-turn mimics. In the final Chapter of this thesis, a retrospection on the different topics described in this thesis is presented. Finally, some proposals for the future elaboration of the different projects are displayed. Some parts of this thesis have been published or will be published in the near future.Groen, M.B. [Promotor]Orru, R.V.A. [Copromotor

Multicomponent Synthesis of N-Heterocyclic Carbene Complexes

N-Heterocyclic carbenes (NHCs) are valuable ligands in transition metal catalysis, due to their unique electronic properties. However, only a few routes toward unsymmetrically substituted, saturated NHCs are known. We have successfully applied the multicomponent synthesis of 2H-2-imidazolines for the preparation of a range of diversely substituted imidazolidin-2-ylidene complexes under mild conditions. In the desired NHC precursors the substituents at N-1, N-3, C-4, and C-5 were varied easily and independently by choosing the appropriate amine, aldehyde, isocyanide, or halide as starting material. Subsequent formation of the imidazolium salts followed by deprotonation with KOtBu and direct complexation of the in situ-generated NHCs at room temperature affords Rh- and Ir-NHC complexes. Properties of the resulting complexes were studied with 13C NMR spectroscopy and X-ray crystallography

Efficient C2 functionalisation of 2H-2-imidazolines

Alkylation and oxidation of 2H-2-imidazolines, followed by regioselective deprotection, thionation and microwave-assisted Liebeskind-Srogl reaction, efficiently led to 2-aryl-2-imidazolines as new analogues of p53-hdm2 interaction inhibitors (Nutlins). © The Royal Society of Chemistry 2008