38 research outputs found

    The search for the ideal biocatalyst

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    While the use of enzymes as biocatalysts to assist in the industrial manufacture of fine chemicals and pharmaceuticals has enormous potential, application is frequently limited by evolution-led catalyst traits. The advent of designer biocatalysts, produced by informed selection and mutation through recombinant DNA technology, enables production of process-compatible enzymes. However, to fully realize the potential of designer enzymes in industrial applications, it will be necessary to tailor catalyst properties so that they are optimal not only for a given reaction but also in the context of the industrial process in which the enzyme is applied

    Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers

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    Introduction: Basal-like breast cancers behave more aggressively despite the presence of a dense lymphoid infiltrate. We hypothesised that immune suppression in this subtype may be due to T regulatory cells (Treg) recruitment driven by hypoxia-induced up-regulation of CXCR4 in Treg.Methods: Immunoperoxidase staining for FOXP3 and CXCL12 was performed on tissue microarrays from 491 breast cancers. The hypoxia-associated marker carbonic anhydrase IX (CA9) and double FOXP3/CXCR4 staining were performed on sections from a subset of these cancers including 10 basal-like and 11 luminal cancers matched for tumour grade.Results: High Treg infiltration correlated with tumour CXCL12 positivity (OR 1.89, 95% CI 1.22 to 2.94, P = 0.004) and basal phenotype (OR 3.14, 95% CI 1.08 to 9.17, P = 0.004) in univariate and multivariate analyses. CXCL12 positivity correlated with improved survival (P = 0.005), whereas high Treg correlated with shorter survival for all breast cancers (P = 0.001), luminal cancers (P < 0.001) and basal-like cancers (P = 0.040) that were confirmed in a multivariate analysis (OR 1.61, 95% CI 1.02 to 2.53, P = 0.042). In patients treated with hormone therapy, high Treg were associated with a shorter survival in a multivariate analysis (OR 1.78, 95% CI 1.01 to 3.15, P = 0.040). There was a tendency for luminal cancers to show CXCL12 expression (102/138, 74%) compared to basal-like cancers (16/27, 59%), which verged on statistical significance (P = 0.050). Up-regulation of CXCR4 in Treg correlated with the basal-like phenotype (P = 0.029) and tumour hypoxia, as indicated by CA9 expression (P = 0.049).Conclusions: Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response. © 2011 Yan et al.; licensee BioMed Central Ltd

    Deglacial and Holocene sea-ice and climate dynamics in the Bransfield Strait, northern Antarctic Peninsula

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    The reconstruction of past sea-ice distribution in the Southern Ocean is crucial for an improved understanding of ice–ocean–atmosphere feedbacks and the evaluation of Earth system and Antarctic ice sheet models. The Antarctic Peninsula (AP) has been experiencing a warming since the start of regular monitoring of the atmospheric temperature in the 1950s. The associated decrease in sea-ice cover contrasts the trend of growing sea-ice extent in East Antarctica. To reveal the long-term sea-ice history at the northern Antarctic Peninsula (NAP) under changing climate conditions, we examined a marine sediment core from the eastern basin of the Bransfield Strait covering the last Deglacial and the Holocene. For sea-ice reconstructions, we focused on the specific sea-ice biomarker lipid IPSO25, a highly branched isoprenoid (HBI), and sea-ice diatoms, whereas a phytoplankton-derived HBI triene (C25:3) and warmer open-ocean diatom assemblages reflect predominantly ice-free conditions. We further reconstruct ocean temperatures using glycerol dialkyl glycerol tetraethers (GDGTs) and diatom assemblages and compare our sea-ice and temperature records with published marine sediment and ice core data. A maximum ice cover is observed during the Antarctic Cold Reversal 13 800–13 000 years before present (13.8–13 ka), while seasonally ice-free conditions permitting (summer) phytoplankton productivity are reconstructed for the late Deglacial and the Early Holocene from 13 to 8.3 ka. An overall decreasing sea-ice trend throughout the Middle Holocene coincides with summer ocean warming and increasing phytoplankton productivity. The Late Holocene is characterized by highly variable winter sea-ice concentrations and a sustained decline in the duration and/or concentration of spring sea ice. Overall diverging trends in GDGT-based TEX86L and RI-OH' subsurface ocean temperatures (SOTs) are found to be linked to opposing spring and summer insolation trends, respectively.</p

    PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

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    Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

    Modelling approaches to compare sorption and degradation of metsulfuron-methyl in laboratory micro-lysimeter and batch experiments

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    Results of laboratory batch studies often differ from those of outdoor lysimeter or field plot experiments -with respect to degradation as well as sorption. Laboratory micro-lysimeters are a useful device for closing the gap between laboratory and field by both including relevant transport processes in undisturbed soil columns and allowing controlled boundary conditions. In this study, sorption and degradation of the herbicide metsulfuron-methyl in a loamy silt soil were investigated by applying inverse modelling techniques to data sets from different experimental approaches under laboratory conditions at a temperature of 10degreesC: first, batch-degradation studies and, second, column experiments with undisturbed soil cores (28 cm length x 21 cm diameter). The column experiments included leachate and soil profile analysis at two different run times. A sequential extraction method was applied in both study parts in order to determine different binding states of the test item within the soil. Data were modelled using ModelMaker and Hydrus-1D/2D. Metsulfuron-methyl half-life in the batch-experiments (t(1/2) = 66 days) was shown to be about four times higher than in the micro-lysimeter studies (t(1/2) about 17 days). Kinetic sorption was found to be a significant process both in batch and column experiments. Applying the one-rate-two-site kinetic sorption model to the sequential extraction data, it was possible to associate the stronger, bonded fraction of metsulfuron-methyl with its kinetically sorbed fraction in the model. Although the columns exhibited strong significance of multi-domain flow (soil heterogeneity), the comparison between bromide and metsulfuron-methyl leaching and profile data showed clear evidence for kinetic sorption effects. The use of soil profile data had significant impact on parameter estimates concerning sorption and degradation. The simulated leaching of metsulfuron-methyl as it resulted from parameter estimation was shown to decrease when soil profile data were considered in the parameter estimation procedure. Moreover, it was shown that the significance of kinetic sorption can only be demonstrated by the additional use of soil profile data in parameter estimation. Thus, the exclusive use of efflux data from leaching experiments at any scale can lead to fundamental misunderstandings of the underlying processes. (C) 2003 Society of Chemical Industry
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