Stuart A. Macgregor

Description:Reaction of [Ru(IPr)2(CO)H][BArF4] (1; IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; BArF4 = B{3,5(CF3)2C6H3}4) with an excess of ZnH2 in THF gives the structurally characterized neutral Ru(ZnH) complex [Ru(IPr)2(CO)(ZnH)H3] (6) and Ru(ZnH)2 salt [Ru(IPr)2(CO)(ZnH)2H3][BArF4] (5). Crystallographic and computational analyses show the presence of both bridging Ru-H-Zn hydrides and terminal Ru-hydrides in the two products. Calculations also identify a low-energy H/ZnH exchange pathway that rationalizes the experimentally observed (EXSY) fluxionality of the hydrides in 5. At room temperature, this compound undergoes stoichiometric exchange with ZnMe2 to give [Ru(IPr)2(CO)(ZnMe)2H3][BArF4] (7), and also proves to be catalytically active for the hydrogenation of 1-hexene and 5-hexene-2-one.

Description:Thyroid diseases are common and highly heritable. Under the Global Biobank Meta-analysis Initiative, we performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer, benign nodular goiter, Graves' disease, lymphocytic thyroiditis, and primary hypothyroidism. We analyzed genetic association data from ~2.9 million genomes and identified 235 known and 501 novel independent variants significantly linked to thyroid diseases. We discovered genetic correlations between thyroid cancer, benign nodular goiter, and autoimmune thyroid diseases (r 2 =0.21-0.97). Telomere maintenance genes contribute to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair, and DNA damage response genes are predominantly associated with thyroid cancer. We proposed a paradigm explaining genetic predisposition to benign and malignant thyroid nodules. We evaluated thyroid cancer polygenic risk scores (PRS) for clinical applications in thyroid cancer diagnosis. We found PRS associations with thyroid cancer risk features: multifocality, lymph node metastases, and extranodal extension.

Description:Incorporating genetic data from diverse populations is crucial for understanding genetic contributions to diseases and ensuring health equity in healthcare practices. However, existing reference panels either capture a limited number of populations or have small sample sizes. We examine the UK Biobank's performance as a reference for clustering genetically similar individuals. Leveraging data from participants of diverse origins, we aim to improve population representation and mitigate bias caused by the limited number of populations in other reference panels. We combined countries of birth and ethnic backgrounds data fields from the UK Biobank and genetic information to infer genetically similar population labels. A random forest model was then trained on genetic principal components to identify each individual's most genetically similar population. The model's performance was validated using the 1000 Genomes and the CARTaGENE biobank data. We identified more diverse reference populations than present in datasets such as 1000 Genomes, covering 19 populations worldwide. Our model achieved medium to high precision and recall for most labeled populations, although lower rates were observed in closely related groups. For instance, we identified 519 people in CARTaGENE most genetically similar to the Middle Eastern reference sample derived in the UK Biobank (there are no Middle Eastern samples in 1000 Genomes), yielding an 81.1% precision and a 97.0% recall rate compared to demographic-based information. This practical approach of clustering genetically similar individuals utilizing existing biobank data may facilitate downstream analyses, such as genomewide association studies or polygenic risk scores in underrepresented populations in genetic studies.

Description:The mechanism of Ru-catalysed N-directed C-H ortho-arylation with haloarenes has been under intense scrutiny over the last decade, with conflicting proposals concerning the relevance of various catalytic intermediates and the nature of the key steps. This work presents experimental and computational studies that address these long-standing questions. Stoichiometric, catalytic and mechanistic kinetic studies, supported by DFT calculations, reveal that bis-cyclometallated ruthenium species are key intermediates in these reactions. These studies also show that oxidative addition with bromoarenes proceeds via a concerted oxidative addition pathway, as demonstrated by DFT and experimental kinetic orders. Bromoarene activation does not proceed at mono-cyclometalated species. In the catalytic process, zero order kinetics are observed on both reaction substrates, an observation that is rationalised by DFT calculations which predict a rate-limiting step within the product-release stage. These results showcase how detailed experimental and DFT studies can combine to probe mechanistic questions, as well as resolving opposing views around the mechanism of these Ru-catalysed arylations that form the basis of promising mild C-H functionalisations.

Description:The metal-catalyzed intermolecular C-H borylation of arenes is an extremely powerful C-H functionalization methodology. However, to date it is effectively restricted to forming organo-boronate esters (Aryl-B(OR)2) with its application to form other organoboranes rarely explored. Herein, we report a catalytic intermolecular heteroarene C-H borylation method using the commercial hydroborane 9-borabicyclo-[3.3.1]-nonane, (H-BBN)2. This process is effective for mono- and di-borylation to form a range of heteroaryl-BBN compounds using either NacNacAl or NacNacZn (NacNac = {(2,6-iPr2C6H3)N(CH3)C}2CH) based catalysts. Notably, mechanistic studies indicated a highly unusual σ-bond metathesis process between NacNacZn-Aryl and the dimeric hydroborane, with first order kinetics in the hydroborane dimer ((H-BBN)2). Our calculated metathesis pathway involves ligand non-innocence and addition of both H-BBN units in (H-BBN)2 to the NacNacZn-heteroaryl complex. This is in contrast to the conventional σ-bond metathesis mechanism using other hydroboranes which invariably proceeds by reaction of one equivalent of a monomeric hydroborane (e.g., H-B(OR)2) with a M-C unit. Overall, this work demonstrates the potential of extending catalytic arene C-H borylation beyond boronate esters, while highlighting that the σ-bond metathesis reaction can be mechanistically more complex when utilizing dimeric hydroboranes such as (H-BBN)2.