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AbstractIndividuals vary in their immune response and, as a result, some are more susceptible to infectious disease than others. Little is known about the nature of this individual variation in natural populations, or which components of immune pathways are most responsible, but defining this underlying landscape of variation is an essential first step to understanding the drivers of this variation and, ultimately, predicting the outcome of infection. We describe transcriptome-wide variation in response to a standardised immune challenge in wild field voles. We find that genes (hereafter 'markers') can be categorised into a limited number of types. For the majority of markers, the response of an individual is dependent on its baseline expression level, with significant enrichment in this category for conventional immune pathways. Another, moderately sized, category contains markers for which the responses of different individuals are also variable but independent of their baseline expression levels. This category lacks any enrichment for conventional immune pathways. We further identify markers which display particularly high individual variability in response, and could be used as markers of immune response in larger studies. Our work shows how a standardised challenge performed on a natural population can reveal the patterns of natural variation in immune response.

Funding: Canadian Institute for Advanced Research. In this paper, we analyse the conditions under which the COVID‐19 pandemic will lead either to social order (adherence to measures put in place by authorities to control the pandemic) or to social disorder (resistance to such measures and the emergence of open conflict). Using examples from different countries (principally the United Kingdom, the United States, and France), we first isolate three factors which determine whether people accept or reject control measures. These are the historical context of state‐public relations, the nature of leadership during the pandemic and procedural justice in the development and operation of these measures. Second, we analyse the way the crisis is policed and how forms of policing determine whether dissent will escalate into open conflict. We conclude by considering the prospects for order/disorder as the pandemic unfolds. Publisher PDF Peer reviewed

BackgroundCognitive impairment precedes the diagnosis of Alzheimer's disease. It is unclear which psychometric measures predict dementia, and what cut-off points should be used. Replicable cognitive measures to provide information about differential diagnosis and prognosis would be clinically useful.AimsIn a prospective cohort study we investigated which measures distinguish between individuals with amnestic mild cognitive impairment (aMCI) that converts to dementia and those whose impairment does not, and which combination of measures best predicts the fate of people with aMCI.MethodForty-four participants with aMCI underwent extensive neuropsychological assessment at baseline and annually thereafter for an average of 4 years. Differences in baseline cognitive performance of participants who were converters and non-converters to clinically diagnosed dementia were analysed. Classification accuracy was estimated by sensitivity, specificity, positive and negative predictive values and using logistic regression.ResultsForty-one percent of participants had progressed to dementia by the end of study, with a mean annual conversion rate of 11%. Most (63%) showed persisting or progressive cognitive impairment, irrespective of diagnosis. The Addenbrooke's Cognitive Examination together with the discrimination index of the Hopkins Verbal Learning Test – Revised (but none of the demographic indices) differentiated the participants who were converters from the non-converters at baseline with 74% accuracy.ConclusionsTargeted neuropsychological assessment, beyond simple cognitive screening, could be used in clinical practice to provide individuals with aMCI with prognostic information and aid selective early initiation of monitoring and treatment among those who progress towards a clinically diagnosable dementia.

Polarity underlies all directional growth responses in plants including growth towards the light (phototropism). The plasma-membrane associated protein, NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) is a key determinant of phototropic growth which is regulated by phototropin (phot) AGC kinases. Here we demonstrate that NPH3 is directly phosphorylated by phot1 within a conserved C-terminal consensus sequence (RxS) that is necessary to promote phototropism and petiole positioning in Arabidopsis. RxS phosphorylation also triggers 14-3-3 binding combined with changes in NPH3 phosphorylation and localisation status. Mutants of NPH3 that are unable to bind or constitutively bind 14-3-3 s show compromised functionality consistent with a model where phototropic curvature is established by signalling outputs arising from a gradient of NPH3 RxS phosphorylation across the stem. Our findings therefore establish that NPH3/RPT2-Like (NRL) proteins are phosphorylation targets for plant AGC kinases. Moreover, RxS phosphorylation is conserved in other members of the NRL family, suggesting a common mechanism of regulating plant growth to the prevailing light environment. The plasma membrane-localized NPH3 protein is required for phototropic growth in Arabidopsis. Here the authors show that phototropin 1 phosphorylates NPH3 at a conserved C-terminal sequence motif triggering binding of 14-3-3 proteins to NPH3 that is necessary for the phototropic response.

BACKGROUND: The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. We aimed to investigate the relation between QuantiFERON-TB Gold In-Tube (QFT) conversion interferon-γ values and risk of subsequent active tuberculosis disease and of QFT reversion. METHODS: We analysed data from a reported vaccine efficacy trial of the tuberculosis vaccine MVA85A in South Africa. QFT negative, HIV uninfected young children aged 18-24 weeks were enrolled. We stratified participants by quantitative QFT result (interferon-γ <0·35 IU/mL, 0·35-4·00 IU/mL, and >4·00 IU/mL) at the intermediate study visit (day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6-24 months. No QFT differences were observed between placebo and MVA85A groups at day 336 or end of study; therefore, both groups were included in analyses. Study clinicians were not masked to QFT values, but strict case definitions were used that excluded QFT results. We used generalised additive models to evaluate the quantitative relation between day 336 QFT value and subsequent disease risk, and we compared disease rates between QFT strata using a two-sample Poisson test. FINDINGS: Among 2512 young children with QFT tests done at day 336, 172 (7%) were positive; 87 (7%) of 1267 in placebo group and 85 (7%) of 1245 in the MVA85A group (p=1·00). Compared with QFT non-converters (tuberculosis disease incidence 0·7 per 100 person-years [95% CI 0·4-1·1]), children with QFT conversion at interferon-γ values between 0·35-4·00 IU/mL did not have significantly increased risk of disease (2·5 per 100 person-years [95% CI 0·4-9·4]; incidence rate ratio (IRR) 3·7 (95% CI 0·4-15·8; p=0·23). However, QFT conversion at interferon-γ values higher than 4·00 IU/mL was associated with substantially increased disease incidence (28·0 per 100 person-years [95% CI 14·9-45·7]) compared with non-converters (IRR 42·5 [95% CI 17·2-99·7]; p<0·0001), and compared with children with interferon-γ values between 0·35-4·00 IU/mL (IRR 11·4 [95% CI 2·4-107·2]; p=0·00047). Among 91 QFT converters who were given a repeat test, 53 (58%) reverted from positive to negative. QFT reversion risk was inversely associated with interferon-γ value at QFT conversion and was highest with interferon-γ values less than 4·00 IU/mL (47 [77%] of 61). INTERPRETATION: In young children, tuberculosis disease risk was not significantly increased, and QFT reversion was common, following QFT conversion at interferon-γ values up to 10 times the recommended test threshold (0·35 IU/mL). By contrast, QFT conversion at very high interferon-γ values (>4·00 IU/mL) warrants intensified diagnostic and preventive intervention because of the extremely high risk of tuberculosis disease in these young children. FUNDING: Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC) were the funders of the MVA85A 020 Trial. National Institute of Allergy and Infectious Diseases supported this analysis.

Information studies have identified numerous needs and barriers to the integration of asylum seekers and refugees; however, little emphasis has been placed thus far on their need to keep their own culture, values, and traditions alive. In this work we use ethnographic constructivist grounded theory to explore the place of heritage in the information experience of people who have sought asylum in the United Kingdom. Based on our findings, we propose to conceptualise heritage as an affective and meaningful information literacy practice. Such conceptualisation fosters integration by allowing people to simultaneously maintain their own ways of knowing and adapt to local ones. Our research approach provides scholars with a conceptual tool to holistically explore affective, meaningful, and cultural information practices. This study also reveals implications for policymakers, third sector organisations, and cultural institutions working towards the more sustainable integration of asylum seekers and refugees.

We present a high-frequency, tunable, piezoelectric MEMS resonant scanner producing an optical scan angle of more than 2° at frequencies above 100 kHz, with non-contact frequency tuning capabilities. The device is fabricated using a cost-efficient multiuser silicon-on-insulator (SOI) process. The scanner uses thin-film piezoelectric aluminium nitride actuators to drive out-of-plane rotation of a 200 µm diameter mirror plate through mechanical coupling stages. Up to 3.6 kHz frequency tuning is achieved through on-chip thermally actuated non-contact beam tips placed adjacent to the scanner. The scanner is intended for use in small-scale, fast optomechanical applications requiring careful synchronization through frequency tuning.