Now showing items 551-570 of 1299

• #### Galerkin finite element approximation of a stochastic semilinear fractional subdiffusion with fractionally integrated additive noise

Abstract A Galerkin finite element method is applied to approximate the solution of a semilinear stochastic space and time fractional subdiffusion problem with the Caputo fractional derivative of the order $\alpha \in (0, 1)$, driven by fractionally integrated additive noise. After discussing the existence, uniqueness and regularity results, we approximate the noise with the piecewise constant function in time, in order to obtain a regularized stochastic fractional subdiffusion problem. The regularized problem is then approximated by using the finite element method in spatial direction. The mean squared errors are proved based on the sharp estimates of the various Mittag–Leffler functions involved in the integrals. Numerical experiments are conducted to show that the numerical results are consistent with the theoretical findings.
• #### Gas decomposition and electrode degradation characteristics of a 20% C 3 F 7 CN and 80% CO 2 gas mixture for high voltage accelerators

Abstract: Sulphur hexafluoride (SF6) is a potent greenhouse gas used in high voltage accelerators. As a promising alternative to SF6, the C3F7CN/CO2 gas mixture and its by‐products are of great interest to ensure the safe operation of accelerators that will adopt any SF6‐free solution. This work experimentally examines the electrical ageing characteristics of a 20% C3F7CN/80% CO2 gas mixture tested using spark gaps under a pressure of 7.2 bar (abs.). Gas samples were collected after 1000 DC breakdowns and analysed using gas chromatography mass spectrometry (GC‐MS) with an estimated toxicity value of 54,459 ppmv, which indicates the aged mixture to be non‐toxic. Subsequent investigation was conducted on the gas‐solid interface after 500 breakdowns for both SF6 and the 20% C3F7CN/80% CO2 gas mixture. Aged electrodes were analysed using X‐ray photoelectron spectroscopy (XPS) and X‐ray diffraction (XRD) techniques. Electrode surface analysis revealed the formation of metal fluorides on the electrode surface tested using the 20% C3F7CN/80% CO2 mixture, whereas metal fluorides and sulphides were detected for electrodes tested with SF6. The findings provide a reference on the toxicity and gas‐solid interaction of the electrically aged 20% C3F7CN/80% CO2 gas mixture for potential retro‐fill application in high voltage accelerators.
• #### Gene Panel Testing for Breast Cancer Reveals Differential Effect of Prior BRCA1/2 Probability

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.
• #### Generation of Alkalinity by Stimulation of Microbial Iron Reduction in Acid Rock Drainage Systems: Impact of Natural Organic Matter Types

Abstract: To determine the role of organic matter in the attenuation of acid rock drainage (ARD), microcosm-based experiments were performed using ARD stimulated with plants and manures. Initial mineralogical, organic geochemical and microbial analyses indicated a predominance of goethite, a substantial amount of organic carbon originating from local sources, and a bacterial community comparable with those detected in a range of ARD sites worldwide. After 100 days of incubation, changes in the mineralogical, organic and microbiological composition of the ARD demonstrated that the plant additions stimulate microbes with the potential to degrade this organic matter but do not necessarily cause substantial Fe(III) reduction. Conversely, the greatest observed stimulation of Fe(III) reduction, associated with an increase in pH to near-neutral values, was observed using manure additions. These results demonstrate that the use of the optimal natural carbon source is important and can promote the metabolism of microorganisms potentially fuelling a range of geomicrobial processes, including iron and sulfate reduction.

• #### Genetic and process engineering strategies for enhanced recombinant N -glycoprotein production in bacteria

Abstract: Background: The production of N-linked glycoproteins in genetically amenable bacterial hosts offers great potential for reduced cost, faster/simpler bioprocesses, greater customisation, and utility for distributed manufacturing of glycoconjugate vaccines and glycoprotein therapeutics. Efforts to optimize production hosts have included heterologous expression of glycosylation enzymes, metabolic engineering, use of alternative secretion pathways, and attenuation of gene expression. However, a major bottleneck to enhance glycosylation efficiency, which limits the utility of the other improvements, is the impact of target protein sequon accessibility during glycosylation. Results: Here, we explore a series of genetic and process engineering strategies to increase recombinant N-linked glycosylation, mediated by the Campylobacter-derived PglB oligosaccharyltransferase in Escherichia coli. Strategies include increasing membrane residency time of the target protein by modifying the cleavage site of its secretion signal, and modulating protein folding in the periplasm by use of oxygen limitation or strains with compromised oxidoreductase or disulphide-bond isomerase activity. These approaches achieve up to twofold improvement in glycosylation efficiency. Furthermore, we also demonstrate that supplementation with the chemical oxidant cystine enhances the titre of glycoprotein in an oxidoreductase knockout strain by improving total protein production and cell fitness, while at the same time maintaining higher levels of glycosylation efficiency. Conclusions: In this study, we demonstrate that improved protein glycosylation in the heterologous host could be achieved by mimicking the coordination between protein translocation, folding and glycosylation observed in native host such as Campylobacter jejuni and mammalian cells. Furthermore, it provides insight into strain engineering and bioprocess strategies, to improve glycoprotein yield and titre, and to avoid physiological burden of unfolded protein stress upon cell growth. The process and genetic strategies identified herein will inform further optimisation and scale-up of heterologous recombinant N-glycoprotein production.
• #### Genetic and process engineering strategies for enhanced recombinant N-glycoprotein production in bacteria.

<h4>Background</h4>The production of N-linked glycoproteins in genetically amenable bacterial hosts offers great potential for reduced cost, faster/simpler bioprocesses, greater customisation, and utility for distributed manufacturing of glycoconjugate vaccines and glycoprotein therapeutics. Efforts to optimize production hosts have included heterologous expression of glycosylation enzymes, metabolic engineering, use of alternative secretion pathways, and attenuation of gene expression. However, a major bottleneck to enhance glycosylation efficiency, which limits the utility of the other improvements, is the impact of target protein sequon accessibility during glycosylation.<h4>Results</h4>Here, we explore a series of genetic and process engineering strategies to increase recombinant N-linked glycosylation, mediated by the Campylobacter-derived PglB oligosaccharyltransferase in Escherichia coli. Strategies include increasing membrane residency time of the target protein by modifying the cleavage site of its secretion signal, and modulating protein folding in the periplasm by use of oxygen limitation or strains with compromised oxidoreductase or disulphide-bond isomerase activity. These approaches achieve up to twofold improvement in glycosylation efficiency. Furthermore, we also demonstrate that supplementation with the chemical oxidant cystine enhances the titre of glycoprotein in an oxidoreductase knockout strain by improving total protein production and cell fitness, while at the same time maintaining higher levels of glycosylation efficiency.<h4>Conclusions</h4>In this study, we demonstrate that improved protein glycosylation in the heterologous host could be achieved by mimicking the coordination between protein translocation, folding and glycosylation observed in native host such as Campylobacter jejuni and mammalian cells. Furthermore, it provides insight into strain engineering and bioprocess strategies, to improve glycoprotein yield and titre, and to avoid physiological burden of unfolded protein stress upon cell growth. The process and genetic strategies identified herein will inform further optimisation and scale-up of heterologous recombinant N-glycoprotein production.

• #### Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile

Abstract: Aims: Change in weight, HbA1c, lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression. Methods: We involved people with type 2 diabetes from two UK‐based cohorts: 11,914 individuals with GP follow‐up data from the UK Biobank and 723 from Salford. We generated a ‘favourable adiposity’ genetic score and conducted cross‐sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow‐up time points with 1‐year intervals. Results: The ‘favourable adiposity’ genetic score was cross‐sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m2 [0.19,0.40]), but higher high‐density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (−0.04 mmol/L [−0.07, −0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow‐up. There was a trend for participants with higher ‘favourable adiposity’ genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid‐lowering (0.91 [0.86, 0.97]) and anti‐hypertensive medication (0.95 [0.91, 0.99]). Conclusions: In individuals with type 2 diabetes, having more ‘favourable adiposity’ alleles is associated with a marginally better lipid profile long‐term and having lower odds of requiring lipid‐lowering or anti‐hypertensive medication in spite of relatively higher adiposity.
• #### Geochemical compositional controls on DNA strand breaks induced in in vitro cell-free assays by crushed rock powders from the Panasqueira mine area, Portugal

Abstract: DNA strand breaks are a common form of DNA damage that can contribute to chromosomal instability or gene mutations. Such strand breaks may be caused by exposure to heavy metals. The aim of this study was to assess the level of DNA strand breaks caused by µm-scale solid particles of known chemical composition with elevated heavy metals/metalloids, notably arsenic, using an in vitro cell-free DNA plasmid scission assay. These samples were incubated with and without H2O2 to see whether damage occurs directly or indirectly through the Fenton reaction. Levels of DNA damage in the absence of H2O2 were < 10%, but in the presence of H2O2, all samples showed higher levels of damage ranging from 10 to 100% suggesting that damage was being incurred through the Fenton reaction. Using bivariate correlation analysis and multiple linear regression, manganese oxide (MnO), sulphur (S), copper (Cu), and zinc (Zn) concentrations in the particulates were found to be the most significant predictors of DNA damage. The mechanism of this DNA damage formation has yet to be thoroughly investigated but is hypothesised to be due to reactive oxygen species formation. Further work is required to assess the extent of contribution of reactive oxygen species to this DNA damage, but this study highlights the potential role of chemistry and/or mineralogy to the extent and/or nature of DNA damage caused by particulates.
• #### GeogEd: A new research group founded on the reciprocal relationship between geography education and the geographies of education

Abstract: In 2019, the Higher Education Research Group (HERG) formally became the Geography and Education Research Group (GeogEd). What may appear as a simple change in name masks a renewed understanding of the synergies between geography education (at all levels) and the geographies of education. In this paper we contextualise that change through the relationships between the two inter‐related fields. We suggest that these fields are integrally linked, iteratively and reciprocally, and that research across both is vital for a truly holistic understanding of each. We reflect on the discussions and process of forming the new Geography and Education Research Group, which we trust is sensitive to the historic remit of HERG while being inclusive to those working in geography and education beyond higher education. We conclude by looking ahead to a renewed, inclusive, and progressive Research Group, aspiring to be more diverse and enabling fruitful discussions across the geography and education nexus.
• #### Geostatistical model of the spatial distribution of arsenic in groundwaters in Gujarat State, India

Abstract: Geogenic arsenic contamination in groundwaters poses a severe health risk to hundreds of millions of people globally. Notwithstanding the particular risks to exposed populations in the Indian sub-continent, at the time of writing, there was a paucity of geostatistically based models of the spatial distribution of groundwater hazard in India. In this study, we used logistic regression models of secondary groundwater arsenic data with research-informed secondary soil, climate and topographic variables as principal predictors generate hazard and risk maps of groundwater arsenic at a resolution of 1 km across Gujarat State. By combining models based on different arsenic concentrations, we have generated a pseudo-contour map of groundwater arsenic concentrations, which indicates greater arsenic hazard (> 10 μg/L) in the northwest, northeast and south-east parts of Kachchh District as well as northwest and southwest Banas Kantha District. The total number of people living in areas in Gujarat with groundwater arsenic concentration exceeding 10 μg/L is estimated to be around 122,000, of which we estimate approximately 49,000 people consume groundwater exceeding 10 µg/L. Using simple previously published dose–response relationships, this is estimated to have given rise to 700 (prevalence) cases of skin cancer and around 10 cases of premature avoidable mortality/annum from internal (lung, liver, bladder) cancers—that latter value is on the order of just 0.001% of internal cancers in Gujarat, reflecting the relative low groundwater arsenic hazard in Gujarat State.
• #### Gertrude Elles: the pioneering graptolite geologist in a woolly hat. Her career, achievements and personal reflections from her family and colleagues

AbstractGertrude Elles gained worldwide renown for her seminal work with Ethel Wood on A Monograph of British Graptolites, which is still used today. She gained the MBE, pioneered female geological education, became the first female reader in Cambridge University and one of the first tranche of female Fellows of the Geological Society in 1919. An eccentric with a vast array of hats, PhD students and lodgers, she was a stalwart member of the Sedgwick Club and life member of the British Federation of University Women. She wrote obituaries for colleagues describing their achievements with humour and good nature. Her family describe her as ‘a fabulous woman’ with a huge range of interests including archaeology, botany and music. She related her geological and botanical knowledge in showing a nephew that plants growing along the Moine Thrust reflected change in the underlying rocks. Cambridge colleagues recall her as a ‘marvellous and well-respected figure’ who caused some amusement by her big old cluttered table from which she swept away material making room for new samples (and work for technicians). She died in 1960 in her beloved Scotland. However, her legacy survives in the classification of a group of fossils extinct for nearly 400 myr.
• #### Giant magneto-birefringence effect and tuneable colouration of 2D crystal suspensions

Abstract: One of the long-sought-after goals in light manipulation is tuning of transmitted interference colours. Previous approaches toward this goal include material chirality, strain and electric-field controls. Alternatively, colour control by magnetic field offers contactless, non-invasive and energy-free advantages but has remained elusive due to feeble magneto-birefringence in conventional transparent media. Here we demonstrate an anomalously large magneto-birefringence effect in transparent suspensions of magnetic two-dimensional crystals, which arises from a combination of a large Cotton-Mouton coefficient and relatively high magnetic saturation birefringence. The effect is orders of magnitude stronger than those previously demonstrated for transparent materials. The transmitted colours of the suspension can be continuously tuned over two-wavelength cycles by moderate magnetic fields below 0.8 T. The work opens a new avenue to tune transmitted colours, and can be further extended to other systems with artificially engineered magnetic birefringence.

• #### Global Constitutionalism and Democracy: the Case of Colombia

Abstract: Focusing on the case of Colombia, this article sets out a sociological examination of constitutions marked by strong, activist judiciaries, by entrenched systems of human rights protection, and by emphatic implementation of global human rights law. Contra standard critiques of this constitutional model, it argues that such constitutions need to be seen as creating a new pattern of democracy, which is often distinctively adapted to structures in societies in which the typical patterns of legitimation and subject formation required for democratic government were obstructed. In polities with such constitutions, legal institutions and norm setters have at times assumed the status of functional equivalents for more typical democratically mandated actors and institutions. In such polities, further, global law assumes essential importance as it creates new sources of normative authorization for legislation and stimulates new lines of articulation between government and society. The article concludes that analysis of such polities, exemplified by Colombia, shows that the common categories of democratic-constitutional analysis are no longer always adequate for understanding current tendencies in democratic formation, and they can easily undermine democracy itself.
• #### Global Prevalence of Adaptive and Prolonged Infections' Mutations in the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein.

Several vaccines with varying efficacies have been developed and are currently administered globally to minimize the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite having an RNA-dependent RNA polymerase with a proofreading activity, new variants of SARS-CoV-2 are on the rise periodically. Some of the mutations in these variants, especially mutations on the spike protein, aid the virus in transmission, infectivity and host immune evasion. Further, these mutations also reduce the effectiveness of some of the current vaccines and monoclonal antibodies (mAbs). In the present study, using the available 984,769 SARS-CoV-2 nucleotide sequences on the NCBI database from the end of 2019 till 28 July 2021, we have estimated the global prevalence of so-called 'adaptive mutations' and 'mutations identified in the prolonged infections', in the receptor-binding domain (RBD) of the spike (S) protein. Irrespective of the geographical region, in the case of the adaptive mutations, N501Y (48.38%) was found to be the dominant mutation followed by L452R (17.52%), T478K (14.31%), E484K (4.69%), S477N (3.29%), K417T (1.64%), N439K (0.7%) and S494P (0.7%). Other mutations were found to be less prevalent (less than 0.7%). Since the last two months, there has been a massive increase of L452R and T478K mutations (delta variant) in certain areas. In the case of prolonged infections' mutations (long-term SARS-CoV-2 infections), V483A (0.009%) was found to be dominant followed by Q493R (0.009%), while other mutations were found in less than 0.007% of the studied sequences. The data obtained in this study will aid in the development of better infection control policies, thereby curbing the spread of this virus.
• #### Global Prevalence of Adaptive and Prolonged Infections’ Mutations in the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein

Several vaccines with varying efficacies have been developed and are currently administered globally to minimize the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite having an RNA-dependent RNA polymerase with a proofreading activity, new variants of SARS-CoV-2 are on the rise periodically. Some of the mutations in these variants, especially mutations on the spike protein, aid the virus in transmission, infectivity and host immune evasion. Further, these mutations also reduce the effectiveness of some of the current vaccines and monoclonal antibodies (mAbs). In the present study, using the available 984,769 SARS-CoV-2 nucleotide sequences on the NCBI database from the end of 2019 till 28 July 2021, we have estimated the global prevalence of so-called ‘adaptive mutations’ and ‘mutations identified in the prolonged infections’, in the receptor-binding domain (RBD) of the spike (S) protein. Irrespective of the geographical region, in the case of the adaptive mutations, N501Y (48.38%) was found to be the dominant mutation followed by L452R (17.52%), T478K (14.31%), E484K (4.69%), S477N (3.29%), K417T (1.64%), N439K (0.7%) and S494P (0.7%). Other mutations were found to be less prevalent (less than 0.7%). Since the last two months, there has been a massive increase of L452R and T478K mutations (delta variant) in certain areas. In the case of prolonged infections’ mutations (long-term SARS-CoV-2 infections), V483A (0.009%) was found to be dominant followed by Q493R (0.009%), while other mutations were found in less than 0.007% of the studied sequences. The data obtained in this study will aid in the development of better infection control policies, thereby curbing the spread of this virus.
• #### Global technology companies and the politics of urban socio-technical imaginaries in the digital age: Processual proxies, Trojan horses and global beachheads

In this paper, we take the concept of ‘new urban spaces’ as our jumping off point to engage with the efforts of Alphabet/Google affiliate Sidewalk Labs to cultivate a new integrated digital and infrastructural urban space on the Toronto waterfront. We interrogate the process and politics of imagining this new, digital urban space as an urban socio-technical imaginary. The paper critically examines the central role of ‘big tech’ in producing the urban socio-technical imaginary not as a snapshot but, rather, as a ‘process of becoming’. This processual focus on the role of big tech allows us to develop three interrelated analytical contributions. First, we generate in-depth understanding of the proxy politics of urban socio-technical imaginaries in constituting new digital urban spaces. Second, we argue that an urban socio-technical imaginary was used as a Trojan horse to promote private experimentation with urban governance. Third, we demonstrate attempts to imagine a global beachhead via ‘the global model’ of a new digital urban space predicated on the digital control of integrated urban infrastructure systems.
• #### Glories, hidden rainbows and nearside-farside interference effects in the angular scattering of the state-to-state H + HD → H

Yuan et al. [Nat. Chem., 2018, 10, 653] have reported state-of-the-art measurements of differential cross sections (DCSs) for the H + HD → H2 + D reaction, measuring for the first time fast oscillations in the small-angle forward region of the DCSs. We theoretically analyse the angular scattering dynamics in order to quantitatively understand the physical content of structure in the DCSs. We study the H + HD(vi = 0, ji = 0, mi = 0) → H2(vf = 0, jf = 0,1,2,3, mf = 0) + D reaction for the whole range of scattering angles from θR = 0° to θR = 180°, where v, j, m are the vibrational, rotational and helicity quantum numbers respectively for the initial and final states. The restriction to mf = 0 arises because states with mf ≠ 0 have DCSs that are identically zero in the forward (θR = 0°) and backward (θR = 180°) directions. We use accurate quantum scattering matrix elements computed by Yuan et al. at a translational energy of 1.35 eV for the BKMP2 potential energy surface. The following theoretical techniques are employed to analyse the DCSs: (a) full and nearside-farside (NF) partial wave series (PWS) and local angular momentum theory, including resummations of the full PWS up to third order. We also use window representations of the scattering matrix, which give rise to truncated PWS, (b) six asymptotic (semiclassical) small-angle glory theories and four N rainbow theories, (c) we introduce "CoroGlo" tests, which let us distinguish between glory and corona scattering at small angles for Legendre PWS, (d) the semiclassical optical model (SOM) of Herschbach is employed to understand structure in the DCSs at intermediate and large angles. Our conclusions are: (a) the small-angle peaks in the DCSs arise mainly from glory scattering. For the 000 → 020 transition, there is also a contribution from a broad, or hidden, N rainbow, (b) at larger angles, the fast oscillations in the DCSs arise from NF interference, (c) the N scattering in the fast oscillation region contains a hidden rainbow for the 000, 020, 030 cases. For the 000 → 020 transition, the rainbow extends up to θR ≈ 60°; for the 000 and 030 cases, the angular ranges containing a N rainbow are smaller, (d) at intermediate and backward angles, the slowly varying DCSs, which merge into slow oscillations, are explained by the SOM. Physically it shows this structure in a DCS arises from direct scattering and is a distorted mirror image of the corresponding probability versus total angular momentum quantum number plot.