Asymmetric synthesis of heterocyclic chloroamines and aziridines by enantioselective protonation of catalytically generated enamines

L.A.M. and J.W.B.F. thank EPSRC for postdoctoral funding (EP/S027165/1; EP/R025754/1). J.W.B.F. thanks the Leverhulme Trust for postdoctoral funding (RPG-2018-362). M.W.A. thanks the University of St Andrews for a PhD studentship.We report a method for the synthesis of chiral vicinal chloroamines via asymmetric protonation of catalytically generatedprochiral chloroenamines using chiral Brønsted acids. The processis highly enantioselective, with the origin of asymmetry and catalystsubstituent effects elucidated by DFT calculations. We show theutility of the method as an approach to the synthesis of a broadrange of heterocycle-substituted aziridines by treatment of thechloroamines with base in a one-pot process, as well as the utility ofthe process to allow access to vicinal diamines.Publisher PDFPeer reviewe

Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020.

BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019.ResultsAll samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5-6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic.ConclusionAlthough blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak

How Much Rugby is Too Much? A Seven-Season Prospective Cohort Study of Match Exposure and Injury Risk in Professional Rugby Union Players.

INTRODUCTION: Numerous studies have documented the incidence and nature of injuries in professional rugby union, but few have identified specific risk factors for injury in this population using appropriate statistical methods. In particular, little is known about the role of previous short-term or longer-term match exposures in current injury risk in this setting. OBJECTIVES: Our objective was to investigate the influence that match exposure has upon injury risk in rugby union. METHOD: We conducted a seven-season (2006/7-2012/13) prospective cohort study of time-loss injuries in 1253 English premiership professional players. Players' 12-month match exposure (number of matches a player was involved in for ≥20 min in the preceding 12 months) and 1-month match exposure (number of full-game equivalent [FGE] matches in preceding 30 days) were assessed as risk factors for injury using a nested frailty model and magnitude-based inferences. RESULTS: The 12-month match exposure was associated with injury risk in a non-linear fashion; players who had been involved in fewer than ≈15 or more than ≈35 matches over the preceding 12-month period were more susceptible to injury. Monthly match exposure was linearly associated with injury risk (hazard ratio [HR]: 1.14 per 2 standard deviation [3.2 FGE] increase, 90% confidence interval [CI] 1.08-1.20; likely harmful), although this effect was substantially attenuated for players in the upper quartile for 12-month match exposures (>28 matches). CONCLUSION: A player's accumulated (12-month) and recent (1-month) match exposure substantially influences their current injury risk. Careful attention should be paid to planning the workloads and monitoring the responses of players involved in: (1) a high (>≈35) number of matches in the previous year, (2) a low (<≈15) number of matches in the previous year, and (3) a low-moderate number of matches in previous year but who have played intensively in the recent past. These findings make a major contribution to evidence-based policy decisions regarding match workload limits in professional rugby union

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal coronavirus disease (COVID-19) outcomes is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses, and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response

Bronze Age upland settlement decline in southwest England: testing the climate change hypothesis

The division of land on Dartmoor during the Bronze Age by the construction of moor-wide boundaries known as reaves represents a significant development in agricultural practice and land tenure. Previous research relating to the Dartmoor reaves suggests this way of life may have continued for no longer than 200-400 years. It has been suggested that their abandonment occurred as the result of a deteriorating climate, although there are no published palaeoclimatic reconstructions from the area. We therefore test the hypothesis that on Dartmoor, a marked climatic deterioration occurred in the late Bronze Age that can be linked to the abandonment of the reaves. A palaeoclimatic reconstruction derived from testate amoebae and peat humification analyses is presented from Tor Royal Bog, central Dartmoor, the first such record from southwest England. A major shift to a cooler and/or wetter climate is inferred from ca. 1395-1155 cal BC that is coincident with the period hypothesised as encompassing the abandonment. This climatic deterioration is replicated in sites in northern Britain, suggesting it was a widespread event. It is concluded that while the evidence supports a climatically forced retreat, there are a range of other socioeconomic factors that must also be taken into consideration

CCDC 2111088 - 2111089: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures