279 research outputs found

    Crystal structure of Thermoplasma acidophilum citrate synthase

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    Conservation of a crystallographic interface suggests a role for β-sheet augmentation in influenza virus NS1 multifunctionality

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    The structure of a monomeric effector domain from influenza A virus NS1 is presented from diffraction data extending to 1.8 Å resolution. Comparison of this and other NS1 effector-domain structures shows conformational changes at a strand–strand packing interface, hinting at a role for β-strand augmentation in NS1 function

    Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase

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    This work was supported by the Medical Research Council and the Scottish Funding Council.Influenza virus sialidase has an essential role in the virus’ life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the ‘150-loop’, providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme.Publisher PDFPeer reviewe

    Surface temperature of tools during the high-pressure die casting of aluminium

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    The objective of this work was to determine the temperature experienced within a pressure die-casting tool during aluminium part production. It was important to determine the temperature profile of the production process so that an accurate thermal cycle could later be simulated. The research overcame several challenges of this aggressive environment to show that the surface temperature of a die could be obtained from an H13 steel tool running on an aluminium pressure die-casting machine. The results show that the surface of a typical aluminium pressure die-casting tool heats to 400-450°C within approximately 1 s and cools to 150-200°C within approximately 20 s

    A new fatigue test procedure for die-casting tool materials

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    The objective of this research was to investigate a new test procedure for simulating the temperatures in die casting so that materials can be evaluated as tool materials for the high-pressure die casting of aluminium. Other procedures have been used for evaluating the thermal fatigue performance of tool materials, but these tests do not reproduce all the conditions found in production environments. A new test method has been established that enables the thermal fatigue resistance of materials to be identified. The test is robust, reliable, and versatile and has a large operating temperature range (25-1200°C), and the cycle times and dwell times are adjustable. The results have shown a similar number of cycles to induce the same level of fatigue cracking as in actual die-casting tools. The performance of different materials can be compared, and an approximate fatigue life for high-pressure die-casting tools can be determined

    Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding

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    The crystal structures of six complexes between aminoglycoside antibiotics (neamine, gentamicin C1A, kanamycin A, ribostamycin, lividomycin A and neomycin B) and oligonucleotides containing the decoding A site of bacterial ribosomes are reported at resolutions between 2.2 and 3.0 Å. Although the number of contacts between the RNA and the aminoglycosides varies between 20 and 31, up to eight direct hydrogen bonds between rings I and II of the neamine moiety are conserved in the observed complexes. The puckered sugar ring I is inserted into the A site helix by stacking against G1491 and forms a pseudo base pair with two H-bonds to the Watson–Crick sites of the universally conserved A1408. This central interaction helps to maintain A1492 and A1493 in a bulged-out conformation. All these structures of the minimal A site RNA complexed to various aminoglycosides display crystal packings with intermolecular contacts between the bulging A1492 and A1493 and the shallow/minor groove of Watson–Crick pairs in a neighbouring helix. In one crystal, one empty A site is observed. In two crystals, two aminoglycosides are bound to the same A site with one bound specifically and the other bound in various ways in the deep/major groove at the edge of the A sites

    Estimating the effectiveness of routine asymptomatic PCR testing at different frequencies for the detection of SARS-CoV-2 infections

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    AbstractBackgroundRoutine asymptomatic testing using RT-PCR of people who interact with vulnerable populations, such as medical staff in hospitals or care workers in care homes, has been employed to help prevent outbreaks among vulnerable populations. Although the peak sensitivity of RT-PCR can be high, the probability of detecting an infection will vary throughout the course of an infection. The effectiveness of routine asymptomatic testing will therefore depend on testing frequency and how PCR detection varies over time.MethodsWe fitted a Bayesian statistical model to a dataset of twice weekly PCR tests of UK healthcare workers performed by self-administered nasopharyngeal swab, regardless of symptoms. We jointly estimated times of infection and the probability of a positive PCR test over time following infection, we then compared asymptomatic testing strategies by calculating the probability that a symptomatic infection is detected before symptom onset and the probability that an asymptomatic infection is detected within 7 days of infection.FindingsWe estimated that the probability that the PCR test detected infection peaked at 77% (54 - 88%) 4 days after infection, decreasing to 50% (38 - 65%) by 10 days after infection. Our results suggest a substantially higher probability of detecting infections 1–3 days after infection than previously published estimates. We estimated that testing every other day would detect 57% (33-76%) of symptomatic cases prior to onset and 94% (75-99%) of asymptomatic cases within 7 days if test results were returned within a day.InterpretationOur results suggest that routine asymptomatic testing can enable detection of a high proportion of infected individuals early in their infection, provided that the testing is frequent and the time from testing to notification of results is sufficiently fast.FundingWellcome Trust, National Institute for Health Research (NIHR) Health Protection Research Unit, Medical Research Council (UKRI)</jats:sec
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