The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this ...process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.
Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression ...may further predict cetuximab benefit.
Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction.
Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group.
In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this paper, we describe an adaptive softening length formalism for collisionless N-body and self-gravitating smoothed particle hydrodynamics (SPH) calculations which conserves momentum and energy ...exactly. This means that spatially variable softening lengths can be used in N-body calculations without secular increases in energy. The formalism requires the calculation of a small additional term to the gravitational force related to the gradient of the softening length. The extra term is similar in form to the usual SPH pressure force (although opposite in direction) and is therefore straightforward to implement in any SPH code at almost no extra cost. For N-body codes, some additional cost is involved as the formalism requires the computation of the density through a summation over neighbouring particles using the smoothing kernel. The results of numerical tests demonstrate that, for homogeneous mass distributions, the use of adaptive softening lengths gives a softening which is always close to the ‘optimal’ choice of fixed softening parameter, removing the need for fine-tuning. For a heterogeneous mass distribution (as may be found in any large-scale N-body simulation), we find that the errors on the least-dense component are lowered by an order of magnitude compared to the use of a fixed softening length tuned to the densest component. For SPH codes, our method presents a natural and an elegant choice of softening formalism which makes a small improvement to both the force resolution and the total energy conservation at almost zero additional cost.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Metal nanoshells are a class of nanoparticles with tunable optical resonances. In this article, an application of this technology to thermal ablative therapy for cancer is described. By tuning the ...nanoshells to strongly absorb light in the near infrared, where optical transmission through tissue is optimal, a distribution of nanoshells at depth in tissue can be used to deliver a therapeutic dose of heat by using moderately low exposures of extracorporeally applied near-infrared (NIR) light. Human breast carcinoma cells incubated with nanoshells in vitro were found to have undergone photothermally induced morbidity on exposure to NIR light (820 nm, 35 W/cm2), as determined by using a fluorescent viability stain. Cells without nanoshells displayed no loss in viability after the same periods and conditions of NIR illumination. Likewise, in vivo studies under magnetic resonance guidance revealed that exposure to low doses of NIR light (820 nm, 4 W/cm2) in solid tumors treated with metal nanoshells reached average maximum temperatures capable of inducing irreversible tissue damage (ΔT = 37.4 ± 6.6° C) within 4-6 min. Controls treated without nanoshells demonstrated significantly lower average temperatures on exposure to NIR light (ΔT < 10° C). These findings demonstrated good correlation with histological findings. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage, and loss of nuclear staining, which are indicators of irreversible thermal damage. Control tissues appeared undamaged.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Most studies of the role of biological entities as atmospheric ice-nucleating particles have focused on relatively rare supermicron particles such as bacterial cells, fungal spores and pollen grains. ...However, it is not clear that there are sufficient numbers of these particles in the atmosphere to strongly influence clouds. Here we show that the ice-nucleating activity of a fungus from the ubiquitous genus Fusarium is related to the presence of nanometre-scale particles which are far more numerous, and therefore potentially far more important for cloud glaciation than whole intact spores or hyphae. In addition, we quantify the ice-nucleating activity of nano-ice nucleating particles (nano-INPs) washed off pollen and also show that nano-INPs are present in a soil sample. Based on these results, we suggest that there is a reservoir of biological nano-INPs present in the environment which may, for example, become aerosolised in association with fertile soil dust particles.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We present observations of the young multiple system UX Tauri to look for circumstellar disks and for signs of dynamical interactions. We obtained SPHERE/IRDIS deep differential polarization images ...in the
J
and
H
bands. We also used ALMA archival CO data. Large extended spirals are well detected in scattered light coming out of the disk of UX Tau A. The southern spiral forms a bridge between UX Tau A and C. These spirals, including the bridge connecting the two stars, all have a CO (3–2) counterpart seen by ALMA. The disk of UX Tau C is detected in scattered light. It is much smaller than the disk of UX Tau A and has a major axis along a different position angle, suggesting a misalignment. We performed
PHANTOM
SPH hydrodynamical models to interpret the data. The scattered light spirals, CO emission spirals and velocity patterns of the rotating disks, and the compactness of the disk of UX Tau C all point to a scenario in which UX Tau A has been perturbed very recently (∼1000 years) by the close passage of UX Tau C.
Full text
Available for:
FMFMET, NUK, UL, UM, UPUK
Aims. We present a detailed study of the magnetic evolution of AR 12673 using a magnetofrictional modelling approach. Methods. The fully data-driven and time-dependent model was driven with maps of ...the photospheric electric field, inverted from vector magnetogram observations obtained from the Helioseismic and Magnetic Imager (HMI) on board the Solar Dynamics Observatory (SDO). Our analysis was aided by studying the evolution of metrics such as the free magnetic energy and the current-carrying helicity budget of the domain, maps of the squashing factor and twist, and plots of the current density. These allowed us to better understand the dynamic nature of the magnetic topology. Results. Our simulation captured the time-dependent nature of the active region and the erupting flux rope associated with the X-class flares on 6 September 2017, including the largest of solar cycle 24. Additionally, our results suggest a possible threshold for eruptions in the ratio of current-carrying helicity to relative helicity. Conclusion. The flux rope was found to be a combination of two structures that partially combine during the eruption process. Our time-dependent data-driven magnetofrictional model is shown to be capable of generating magnetic fields consistent with extreme ultraviolet (EUV) observations.
Full text
Available for:
FMFMET, NUK, UL, UM, UPUK
Agricultural dust emissions have been estimated to contribute around 20% to the global dust burden. In contrast to dusts from arid source regions, the ice-nucleating abilities of which have been ...relatively well studied, soil dusts from fertile sources often contain a substantial fraction of organic matter. Using an experimental methodology which is sensitive to a wide range of ice nucleation efficiencies, we have characterised the immersion mode ice-nucleating activities of dusts (d < 11 μm) extracted from fertile soils collected at four locations around England. By controlling droplet sizes, which ranged in volume from 10−12 to 10−6 L (concentration = 0.02 to 0.1 wt% dust), we have been able to determine the ice nucleation behaviour of soil dust particles at temperatures ranging from 267 K (−6 °C) down to the homogeneous limit of freezing at about 237 K (−36 °C). At temperatures above 258 K (−15 °C) we find that the ice-nucleating activity of soil dusts is diminished by heat treatment or digestion with hydrogen peroxide, suggesting that a major fraction of the ice nuclei stems from biogenic components in the soil. However, below 258 K, we find that the ice active site densities tend towards those expected from the mineral components in the soils, suggesting that the inorganic fraction of soil dusts, in particular the K-feldspar fraction, becomes increasingly important in the initiation of the ice phase at lower temperatures. We conclude that dusts from agricultural activities could contribute significantly to atmospheric IN concentrations, if such dusts exhibit similar activities to those observed in the current laboratory study.
These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical ...committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.
PDF
