Saffron Walden Museum

Abstract As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations (1–10. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq)11, a duplex sequencing method with error rates <5 errors per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 49 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

ABSTRACTA series of SARS-CoV-2 variants of concern (VOCs) have evolved in humans during the COVID-19 pandemic—Alpha, Beta, Gamma, Delta, and Omicron. Here, we used global proteomic and genomic analyses during infection to understand the molecular responses driving VOC evolution. We discovered VOC-specific differences in viral RNA and protein expression levels, including for N, Orf6, and Orf9b, and pinpointed several viral mutations responsible. An analysis of the host response to VOC infection and comprehensive interrogation of altered virus-host protein-protein interactions revealed conserved and divergent regulation of biological pathways. For example, regulation of host translation was highly conserved, consistent with suppression of VOC replication in mice using the translation inhibitor plitidepsin. Conversely, modulation of the host inflammatory response was most divergent, where we found Alpha and Beta, but not Omicron BA.1, antagonized interferon stimulated genes (ISGs), a phenotype that correlated with differing levels of Orf6. Additionally, Delta more strongly upregulated proinflammatory genes compared to other VOCs. Systematic comparison of Omicron subvariants revealed BA.5 to have evolved enhanced ISG and proinflammatory gene suppression that similarly correlated with Orf6 expression, effects not seen in BA.4 due to a mutation that disrupts the Orf6-nuclear pore interaction. Our findings describe how VOCs have evolved to fine-tune viral protein expression and protein-protein interactions to evade both innate and adaptive immune responses, offering a likely explanation for increased transmission in humans.One sentence summarySystematic proteomic and genomic analyses of SARS-CoV-2 variants of concern reveal how variant-specific mutations alter viral gene expression, virus-host protein complexes, and the host response to infection with applications to therapy and future pandemic preparedness.

1. Following oral administration of prochloraz (1-[N-propyl-N-2-(2,4,6-trichlorophenoxy)ethylcarbamoyl]imidazole) at 100 mg/kg body weight to rats, the compound underwent extensive metabolism, the primary route appearing to be opening of the imidazole ring followed by hydrolysis of the alkyl chain. The major metabolites were 2,4,6-trichlorophenoxyacetic acid and 2-(2,4,6-trichlorophenoxy)ethanol, which is present mainly as a glucuronide conjugate. Ring hydroxylation occurred to produce several minor metabolites. No unchanged prochloraz was excreted in the urine. 2. Tissue residues 96 h after dosing were generally less than 1 mg prochloraz equivalents/kg tissue. The highest residues were found in the liver (2.8-5.1 mg prochloraz equivalents/kg tissue) and kidney (1.5-2.1 mg prochloraz equivalents/kg tissue), the principal organs of metabolism and excretion. Residues in female rats were generally slightly higher than those found in males. 3. The metabolites were quantitatively excreted within 96 h, with greater than 50% of the dosed radioactivity being found in the 0-24 h excreta. Urinary excretion accounted for 65% dose in male and 41% in female rats, respectively.

This study was designed to measure potential dermal and respiratory exposure of agricultural workers during the application of a typical herbicide, 2,4-dichlorophenoxy acetic acid, with five types of application equipment commonly used in the United Kingdom. The workers were monitored during filling and loading operations and during spray application. Potential dermal exposure was higher during mixing and loading all tractor-powered sprayers than during spraying. Potential dermal exposure from tractor-powered sprayers fitted with conventional hydraulic nozzles was lower than from knapsack sprayers, with exposure from a tractor-powered sprayer fitted with controlled-droplet application equipment intermediate in this regard. There was no difference in potential dermal exposure between tractor-mounted and tractor-drawn sprayers fitted with conventional hydraulic nozzles. The hands were the most highly exposed part of the body during mixing and loading operations for all sprayers, and during spraying with tractor-powered sprayers. The lower legs of the workers were exposed principally when knapsack sprayers were used. For all five sprayers, potential respiratory exposure, where detectable at all, was negligible compared with potential dermal exposure.

Abstract The rate of the ionic polymerization of isobutene, induced at low temperatures by high energy radiation, is considerably increased when the reaction is carried out in the presence of certain inorganic compounds, notably metal oxides, of high surface area. The acceleration is not accompanied by a corresponding increase in the molecular weight of the polymer. The rate of polymerization of methyl methacrylate when exposed at room temperature to electrons at high intensity is increased by the presence of polyethylene powder. A consideration of the mechanisms of acceleration under heterogeneous conditions leads us to believe that the increase in rate in the first case is due to an increase in the rate of initiation and in the second case to a decrease in the bimolecular termination rate constant.

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