60419 research outputs found
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Alkyladenine DNA glycosylase deficiency uncouples alkylation-induced strand break generation from PARP-1 activation and glycolysis inhibition
No full textDNA alkylation damage is repaired by base excision repair (BER) initiated by alkyladenine DNA
glycosylase (AAG). Despite its role in DNA repair, AAG-initiated BER promotes cytotoxicity in a process
dependent on poly (ADP-ribose) polymerase-1 (PARP-1); a NAD+-consuming enzyme activated by
strand break intermediates of the AAG-initiated repair process. Importantly, PARP-1 activation has
been previously linked to impaired glycolysis and mitochondrial dysfunction. However, whether
alkylation affects cellular metabolism in the absence of AAG-mediated BER initiation is unclear.
To address this question, we temporally profiled repair and metabolism in wild-type and Aag−I−
cells treated with the alkylating agent methyl methanesulfonate (MMS). We show that, although
Aag−I− cells display similar levels of alkylation-induced DNA breaks as wild type, PARP-1 activation
is undetectable in AAG-deficient cells. Accordingly, Aag−I− cells are protected from MMS-induced
NAD+ depletion and glycolysis inhibition. MMS-induced mitochondrial dysfunction, however, is AAG-independent. Furthermore, treatment with FK866, a selective inhibitor of the NAD+ salvage pathway
enzyme nicotinamide phosphoribosyltransferase (NAMPT), synergizes with MMS to induce cytotoxicity
and Aag−I− cells are resistant to this combination FK866 and MMS treatment. Thus, AAG plays an
important role in the metabolic response to alkylation that could be exploited in the treatment of
conditions associated with NAD+ dysregulation
Selenium and selenoproteins in viral infection with potential relevance to COVID-19
No full textSelenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection
The Materiality Balanced Scorecard: A framework for stakeholder-led integration of sustainable hospitality management and reporting
No full textThe Materiality Balanced Scorecard is an integrated framework that links sustainable hospitality performance management and reporting, as an instrument to define, communicate and operationalise strategic sustainability objectives. We integrate the Balanced Scorecard as a well-established performance management system with the inclusiveness, materiality and responsiveness principles of the AA1000 Stakeholder Engagement Standard, to aid an organisation to respond to its stakeholder expectations. The framework provides a systemic, structured and integrated approach, and an opportunity for sustainable value creation. We test the framework with data reported by 20 of the world’s largest hotel groups, to find that current sustainability reports lack hierarchical cause-and-effect chains and hard evidence of impact at the system level. We argue that hospitality organisations can improve their management controls by addressing the quality, transparency and consistency of their sustainability response, thereby responding to sustainable development challenges without undermining their organisational viability
Identification of an oblate K-isomer of 94Se60 and implications for a ground-state shape transition between N = 58 - 60
No full textIn this letter we report on new information on the shape evolution of the very neutron-rich 92;94Se
nuclei from an isomer-decay spectroscopy experiment at the Radioactive Isotope Beam Factory at
RIKEN. High-resolution germanium detectors were used to identify delayed -rays emitted following
the decay of these nuclei. New transitions are reported extending the previously known level
schemes. The isomeric levels are interpreted as originating from high-K quasi-neutron states with an
oblate deformation of B ~ - 0:25, with the high-K state in 94Se being metastable and K hindered.
Following this, 94Se is the lowest-mass nucleus known to date with K-forbidden decay and a substantial
K hindrance. Furthermore, it is the first observation of an oblate K isomer in a deformed
nucleus. From the decay patterns, an oblate deformation is suggested for the 94Se60 ground-state
band, in line with the predictions of recent beyond-mean-field calculations
Limit on the LMC mass from a census of its satellites
No full textWe study the orbits of dwarf galaxies in the combined presence of the Milky Way and Large Magellanic Cloud (LMC) and find six dwarfs that were likely accreted with the LMC (Car 2, Car 3, Hor 1, Hyi 1, Phe 2, and Ret 2), in addition to the Small Magellanic Cloud (SMC), representing strong evidence of dwarf galaxy group infall. This procedure depends on the gravitational pull of the LMC, allowing us to place a lower bound on the Cloud’s mass of MLMC˃1.24×1011M⊙ if we assume that these are LMC satellites. This mass estimate is validated by applying the technique to a cosmological zoom-in simulation of a Milky Way-like galaxy with an LMC analogue where we find that while this lower bound may be overestimated, it will improve in the future with smaller observational errors. We apply this technique to dwarf galaxies lacking radial velocities and find that Eri 3 has a broad range of radial velocities for which it has a significant chance (˃0.4) of having been bound to the Cloud. We study the non-Magellanic classical satellites and find that Fornax has an appreciable probability of being an LMC satellite if the LMC is sufficiently massive (∼2.5×1011M⊙). In addition, we explore how the orbits of Milky Way satellites change in the presence of the LMC and find a significant change for several objects. Finally, we find that the dwarf galaxies likely to be LMC satellites are slightly smaller than Milky Way satellites at a fixed luminosity, possibly due to the different tidal environments they have experienced
Households as hotspots of Lassa fever? Assessing the spatial distribution of Lassa virus-infected rodents in rural villages of Guinea
No full textThe Natal multimammate mouse (Mastomys natalensis) is the reservoir host of Lassa virus (LASV), an arenavirus that causes Lassa haemorrhagic fever in humans in West Africa. While previous studies suggest that spillover risk is focal within rural villages due to the spatial behaviour of the rodents, the level of clustering was never specifically assessed. Nevertheless, detailed information on the spatial distribution of infected rodents would be highly valuable to optimize LASV-control campaigns, which are limited to rodent control or interrupting human–rodent contact considering that a human vaccine is not available. Here, we analysed data from a four-year field experiment to investigate whether LASV-infected rodents cluster in households in six rural villages in Guinea. Our analyses were based on the infection status (antibody or PCR) and geolocation of rodents (n = 864), and complemented with a phylogenetic analysis of LASV sequences (n = 119). We observed that the majority of infected rodents were trapped in a few houses (20%) and most houses were rodent-free at a specific point in time (60%). We also found that LASV strains circulating in a specific village were polyphyletic with respect to neighbouring villages, although most strains grouped together at the sub-village level and persisted over time. In conclusion, our results suggest that: (i) LASV spillover risk is heterogeneously distributed within villages in Guinea; (ii) viral elimination in one particular village is unlikely if rodents are not controlled in neighbouring villages. Such spatial information should be incorporated into eco-epidemiological models that assess the cost-efficiency of LASV control strategies
Large‐Scale Surfactant Exfoliation of Graphene and Conductivity‐Optimized Graphite Enabling Wireless Connectivity
No full textGraphene and other graphitic materials are suggested as a route to cheap, high‐performance, environmentally‐sustainable electronic devices owing to their almost unique combination of properties. Liquid‐phase exfoliation is a family of shear‐based techniques that produce dispersions of nanosheets from bulk layered material crystallites. High‐quality nanosheets of graphene can be produced in solvents or surfactant dispersions; however the lateral size of these sheets limits the network transport properties observed in printed films. A high‐throughput, industrially‐scalable aqueous process for the production of graphene and related layered nanomaterials is presented. By considering not only the exfoliation process, but also the size selection and deposition processes, printable graphitic nanoparticulate materials with conductivities up to 50 000 S m−1 are demonstrated. This value is ten times larger than is typically obtained for few‐layer graphene produced by liquid‐phase exfoliation. The size selection process is critical to obtaining the maximum conductivity of deposited films, with an optimized nanographite having greater performance than few‐layer graphene or graphite that is processed and used without size selection. Building on these results a radio‐frequency antenna application is demonstrated, which is competitive with the state‐of‐the‐art, and a route to recycling of such printed short‐lifetime electronic devices to lower the environmental impact is discussed
Paramedic independent prescribing in primary care – seven steps to success
No full textParamedic practice is evolving and the number of advanced paramedics in primary care
roles in the UK has risen dramatically. A significant milestone for the paramedic profession,
recent legislation granting paramedics independent prescribing rights means UK paramedics
are the first worldwide to receive this extension in scope of practice. Paramedic prescribing
capability is expected to increase autonomy for independent case management and
enhance capacity for service development. Local and national success is however likely to
depend on skilful implementation and the avoidance of historical barriers. This article aims to
raise awareness of potential barriers to early adoption of paramedic independent prescribing
in primary care. It identifies common pitfalls prior to training and provides seven practical
steps for paramedics considering pursuing non-medical prescribing training
Development and evaluation of a composite supercapacitor-based 12 V transient start-stop (TSS) power system for vehicles: modelling, design and fabrication scaling up
No full textThe study involves a bottom-up approach, from bottom cells to large supercapacitor pouch cells, encompassing the design, modelling and fabrication stages of the cells leading to a 12 V transient start-stop (TSS) power system for automotive applications. More specifically, the design of a large composite supercapacitor is presented, consisting of a high power density component and a high energy density component, hybridised at material level. The composition of the composite supercapacitor is optimised to be application-specific so that it satisfies a specified energy-to-maximum power ratio for the 12 V TSS system. The testing of the large composite supercapacitor pouch cells and the 12 V TSS system proves the validity of the bottom-up approach, validates the design and the proposed electric circuit model and its parameters, fitted according to experimental data of small laboratory cells and applied successfully to the large cells, and proves the high quality of the scaled up fabrication processes. The 12 V TSS power system of seven large composite supercapacitor cells satisfies the set criteria of energy and maximum power for the specified duration, 15 Wh and 4.2 kW respectively, at a total mass of 3.94 kg, below the original set limit of 5 kg
Ensemble-based method for the Inverse Frobenius-Perron Operator Problem: Data Driven Global Analysis from Spatiotemporal "Movie" data
No full textGiven a sequence of empirical distribution data (e.g. a movie of a spatiotemporal process
such as a fluid
flow), this work develops an ensemble data assimilation method to estimate the
transition probability that represents a finite approximation of the Frobenius-Perron operator.
This allows a dynamical systems knowledge to be incorporated into a prior ensemble, which provides
sensible estimates in instances of limited observation. We demonstrate improved estimates over a constrained optimization approach (based on a quadratic programming problem) which does not impose a prior on the solution except for Markov properties. The estimated transition
probability then enables several probabilistic analysis of dynamical systems. We focus only on the identification of coherent patterns from the estimated Markov transition to demonstrate its application as a proof-of-concept. To the best of our knowledge, there have not been many
works on data-driven methods to identify coherent patterns from this type of data. While here the results are presented only in the context of dynamical systems applications, this work we present here has the potential to make a contribution in wider application areas that require the
estimation of transition probabilities from a time-ordered spatio-temporal distribution data
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