Patterns of mutation in the human genome

The processes that underlie point mutations in the human genome are largely unknown. However, the cumulative effect of these processes have a large impact on how mutation rates vary across a number of different scales and contexts, and consequently guide our understanding of human disease and evolution. Although variation in the mutation rate has been characterized on many different levels, it is not fully understood the extent to which the rate of mutation can vary outside of the general patterns already observed. Beginning with the human genome project, many studies have produced large unbiased sequence datasets within a number of human populations. To that end, we analysed a number of sequence datasets in an attempt to better understand the patterns and causes of variation in the rate of mutation that exists across the genome. Firstly, we find that the mutation rates of single sites vary by more than is currently understood, and that this variation is not associated with any specific process or feature on either a local or genomic scale. Although we have been unable to uncover the source of such variation, understanding the range of mutability at sites in the human genome is important since it may point to functional regions, disease phenotypes and prompt further ideas on the underlying mechanisms associated with such a result. Furthermore, we find evidence that a mutational process that can generate the simultaneous production of two new alleles within the same individual during a single, or tightly linked series of mutation events increases the number of tri-allelic sites in the human genome. There are a number of potential mechanisms that may drive this process, and the consequences of such an event may be far reaching, as the generation of two new alleles at a single site in functional regions may allow a more rapid exploration of evolutionary space. Furthermore, this process appears to make a reasonable contribution to variation in the human genome, thus providing a substrate for evolutionary change. Finally, we observe significant variation in the mutation rate over all scales in cancer genomes. Part of this result can be explained by the actions of specific carcinogens, however it is striking that patterns of mutation can be both consistent across different cancer types, but also very different between individuals with the same type of cancer over different scales. This result points to the idea that the patterns of mutation may vary widely between different genomes under different conditions, and the identification of general patterns in a small number of samples may not fully describe the extent to which mutation rates can vary. Taken together, these conclusions suggest that the patterns and processes underlying mutation are highly complex, and require further analysis if they are to be fully understood

Accuracy of monitors used for blood pressure checks in English retail pharmacies::a cross-sectional observational study

BACKGROUND: Free blood pressure (BP) checks offered by community pharmacies provide a potentially useful opportunity to diagnose and/or manage hypertension, but the accuracy of the sphygmomanometers in use is currently unknown. AIM: To assess the accuracy of validated automatic BP monitors used for BP checks in a UK retail pharmacy chain. DESIGN AND SETTING: Cross-sectional, observational study in 52 pharmacies from one chain in a range of locations (inner city, suburban, and rural) in central England. METHOD: Monitor accuracy was compared with a calibrated reference device (Omron PA-350), at 50 mmHg intervals across the range 0–300 mmHg (static pressure test), with a difference from the reference monitor of +/− 3 mmHg at any interval considered a failure. The results were analysed by usage rates and length of time in service. RESULTS: Of 61 BP monitors tested, eight (13%) monitors failed (that is, were >3 mmHg from reference), all of which underestimated BP. Monitor failure rate from the reference monitor of +/− 3 mmHg at any testing interval varied by length of time in use (2/38, 5% <18 months; 4/14, 29% >18 months, P = 0.038) and to some extent, but non-significantly, by usage rates (4/22, 18% in monitors used more than once daily; 2/33, 6% in those used less frequently, P = 0.204). CONCLUSION: BP monitors within a pharmacy setting fail at similar rates to those in general practice. Annual calibration checks for blood pressure monitors are needed, even for new monitors, as these data indicate declining performance from 18 months onwards

Synthesis and biological evaluation of 1,2-disubsubstituted 4-quinolone analogues of Pseudonocardia sp. natural products.

A series of analogues of Pseudonocardia sp. natural products were synthesized, which have been reported to possess potent antibacterial activity against Helicobacter pylori and induce growth defects in Escherichia coli and Staphylococcus aureus. Taking inspiration from a methodology used in our total synthesis of natural products, we applied this methodology to access analogues possessing bulky N-substituents, traditionally considered to be challenging scaffolds. Screening of the library provided valuable insights into the structure-activity relationship of the bacterial growth defects, and suggested that selectivity between bacterial species should be attainable. Furthermore, a structurally related series of analogues was observed to inhibit production of the virulence factor pyocyanin in the human pathogen Pseudomonas aeruginosa, which may be a result of their similarity to the Pseudomonas quinolone signal (PQS) quorum sensing autoinducer. This provided new insights regarding the effect of N-substitution in PQS analogues, which has been hitherto underexplored.SF was supported by a BBSRC studentship. DRS acknowledges support from the Engineering and Physical Sciences Research Council (EP/P020291/1) and Royal Society (Wolfson Research Merit Award)

Dispelling the myths of online education: learning via the information superhighway

There continues to be a perception that online education is inferior to traditional education. In the U.S. online learning is more developed than in the U.K. This paper provides insights into a U.S. provision and takes a close look at what are perceived as weaknesses of on line learning and argues that these are not necessarily inherent weaknesses of this form of educational delivery. Then, results of two major studies, undertaken in the U.S. are provided comparing the effectiveness of online education to traditional education as perceived by current MBA students and past graduates. Results of these studies suggest that students of MBA modules and MBA graduates perceive the quality and effectiveness of online education to be similar to, if not higher than, the quality and effectiveness of traditional modules and programmes

A Critical Assessment of the Black Lives Matter Movement in Britain

The death of George Floyd in May 2020 in the United States of America (USA) generated protests across the world, fronted by the Black Lives Matter (BLM) movement. The BLM movement cast the killing of Floyd by police officer Derek Chauvin as emblematic of the criminal justice system’s (CJS) long history of racism. Whilst the core message - that black lives matter - is indisputable, noble and a worthy rallying call, little scholarly attention has been given to the movement’s underlying philosophy and aims, particularly in relation to the CJS in Britain. This article explicates Britain’s BLM movement by considering four core themes – (a) critical race theory and British social science, (b) the policing of black people in Britain, (c) the omission of social class from the analyses of BLM scholars and activists in Britain and, (d) the aims of Britain’s BLM movement. It suggests that the BLM movement potentially offers a flawed understanding of racism within the CJS. The paper also critiques and problematizes BLM’s use of the terms ‘white privilege and ‘whiteness’. It closes with a critical discussion of the movement’s aims, including defunding and abolishing the police, suggesting that critical engagement with both CRT and BLM should form a core part of criminological debate

Proteomic profiling and protein identification by MALDI-TOF mass spectrometry in unsequenced parasitic nematodes.

Lack of genomic sequence data and the relatively high cost of tandem mass spectrometry have hampered proteomic investigations into helminths, such as resolving the mechanism underpinning globally reported anthelmintic resistance. Whilst detailed mechanisms of resistance remain unknown for the majority of drug-parasite interactions, gene mutations and changes in gene and protein expression are proposed key aspects of resistance. Comparative proteomic analysis of drug-resistant and -susceptible nematodes may reveal protein profiles reflecting drug-related phenotypes. Using the gastro-intestinal nematode, Haemonchus contortus as case study, we report the application of freely available expressed sequence tag (EST) datasets to support proteomic studies in unsequenced nematodes. EST datasets were translated to theoretical protein sequences to generate a searchable database. In conjunction with matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF-MS), Peptide Mass Fingerprint (PMF) searching of databases enabled a cost-effective protein identification strategy. The effectiveness of this approach was verified in comparison with MS/MS de novo sequencing with searching of the same EST protein database and subsequent searches of the NCBInr protein database using the Basic Local Alignment Search Tool (BLAST) to provide protein annotation. Of 100 proteins from 2-DE gel spots, 62 were identified by MALDI-TOF-MS and PMF searching of the EST database. Twenty randomly selected spots were analysed by electrospray MS/MS and MASCOT Ion Searches of the same database. The resulting sequences were subjected to BLAST searches of the NCBI protein database to provide annotation of the proteins and confirm concordance in protein identity from both approaches. Further confirmation of protein identifications from the MS/MS data were obtained by de novo sequencing of peptides, followed by FASTS algorithm searches of the EST putative protein database. This study demonstrates the cost-effective use of available EST databases and inexpensive, accessible MALDI-TOF MS in conjunction with PMF for reliable protein identification in unsequenced organisms