Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks ...associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.
Abstract Aim To use published literature and experts’ opinion to investigate the clinical meaning and magnitude of changes in the Quality of Life (QOL) of groups of patients measured with the ...European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Methods An innovative method combining systematic review of published studies, expert opinions and meta-analysis was used to estimate large, medium, and small mean changes over time for QLQ-C30 scores. Results Nine hundred and eleven papers were identified, leading to 118 relevant papers. One thousand two hundred and thirty two mean changes in QOL over time were combined in the meta-analysis, with timescales ranging from four days to five years. Guidelines were produced for trivial, small, and medium size classes, for each subscale and for improving and declining scores separately. Estimates for improvements were smaller than respective estimates for declines. Conclusions These guidelines can be used to aid sample size calculations and interpretation of mean changes over time from groups of patients. Observed mean changes in the QLQ-C30 scores are generally small in most clinical situations, possibly due to response shift. Careful consideration is needed when planning studies where QOL changes over time are of primary interest; the timing of follow up, sample attrition, direction of QOL changes, and subscales of primary interest are key considerations.
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater ...understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.
We present high-precision multiband photometry for the globular cluster (GC) M2. We combine the analysis of the photometric data obtained from the Hubble Space Telescope UV Legacy Survey of Galactic ...GCs GO-13297, with chemical abundances by Yong et al., and compare the photometry with models in order to analyse the multiple stellar sequences we identified in the colour–magnitude diagram. We find three main stellar components, composed of metal-poor, metal-intermediate, and metal-rich stars (hereafter referred to as population A, B, and C, respectively). The components A and B include stars with different s-process element abundances. They host six sub-populations with different light-element abundances, and exhibit an internal variation in helium up to ΔY ∼ 0.07 dex. In contrast with M22, another cluster characterized by the presence of populations with different metallicities, M2 contains a third stellar component, C, which shows neither evidence for sub-populations nor an internal spread in light-elements. Population C does not exhibit the typical photometric signatures that are associated with abundance variations of light elements produced by hydrogen burning at hot temperatures. We compare M2 with other GCs with intrinsic heavy-element variations and conclude that M2 resembles M22, but it includes an additional stellar component that makes it more similar to the central region of the Sagittarius galaxy, which hosts a GC (M54) and the nucleus of the Sagittarius galaxy itself.
Summary
The potential aerosolised transmission of severe acute respiratory syndrome coronavirus‐2 is of global concern. Airborne precaution personal protective equipment and preventative measures are ...universally mandated for medical procedures deemed to be aerosol generating. The implementation of these measures is having a huge impact on healthcare provision. There is currently a lack of quantitative evidence on the number and size of airborne particles produced during aerosol‐generating procedures to inform risk assessments. To address this evidence gap, we conducted real‐time, high‐resolution environmental monitoring in ultraclean ventilation operating theatres during tracheal intubation and extubation sequences. Continuous sampling with an optical particle sizer allowed characterisation of aerosol generation within the zone between the patient and anaesthetist. Aerosol monitoring showed a very low background particle count (0.4 particles.l−1) allowing resolution of transient increases in airborne particles associated with airway management. As a positive reference control, we quantitated the aerosol produced in the same setting by a volitional cough (average concentration, 732 (418) particles.l−1, n = 38). Tracheal intubation including facemask ventilation produced very low quantities of aerosolised particles (average concentration, 1.4 (1.4) particles.l−1, n = 14, p < 0.0001 vs. cough). Tracheal extubation, particularly when the patient coughed, produced a detectable aerosol (21 (18) l−1, n = 10) which was 15‐fold greater than intubation (p = 0.0004) but 35‐fold less than a volitional cough (p < 0.0001). The study does not support the designation of elective tracheal intubation as an aerosol‐generating procedure. Extubation generates more detectable aerosol than intubation but falls below the current criterion for designation as a high‐risk aerosol‐generating procedure. These novel findings from real‐time aerosol detection in a routine healthcare setting provide a quantitative methodology for risk assessment that can be extended to other airway management techniques and clinical settings. They also indicate the need for reappraisal of what constitutes an aerosol‐generating procedure and the associated precautions for routine anaesthetic airway management.
THE PERDIGÃO Fernando, H. J. S.; Mann, J.; Palma, J. M. L. M. ...
Bulletin of the American Meteorological Society,
05/2019, Letnik:
100, Številka:
5
Journal Article
Recenzirano
Odprti dostop
A grand challenge from the wind energy industry is to provide reliable forecasts on mountain winds several hours in advance at microscale (∼100 m) resolution. This requires better microscale ...wind-energy physics included in forecasting tools, for which field observations are imperative. While mesoscale (∼1 km) measurements abound, microscale processes are not monitored in practice nor do plentiful measurements exist at this scale. After a decade of preparation, a group of European and U.S. collaborators conducted a field campaign during 1 May–15 June 2017 in Vale Cobrão in central Portugal to delve into microscale processes in complex terrain. This valley is nestled within a parallel double ridge near the town of Perdigão with dominant wind climatology normal to the ridges, offering a nominally simple yet natural setting for fundamental studies. The dense instrument ensemble deployed covered a ∼4 km × 4 km swath horizontally and ∼10 km vertically, with measurement resolutions of tens of meters and seconds. Meteorological data were collected continuously, capturing multiscale flow interactions from synoptic to microscales, diurnal variability, thermal circulation, turbine wake and acoustics, waves, and turbulence. Particularly noteworthy are the extensiveness of the instrument array, space–time scales covered, use of leading-edge multiple-lidar technology alongside conventional tower and remote sensors, fruitful cross-Atlantic partnership, and adaptive management of the campaign. Preliminary data analysis uncovered interesting new phenomena. All data are being archived for public use.
Correcting errors in real time is essential for reliable large-scale quantum computations. Realizing this high-level function requires a system capable of several low-level primitives, including ...single-qubit and two-qubit operations, midcircuit measurements of subsets of qubits, real-time processing of measurement outcomes, and the ability to condition subsequent gate operations on those measurements. In this work, we use a 10-qubit quantum charge-coupled device trapped-ion quantum computer to encode a single logical qubit using the 7,1,3 color code, first proposed by Steane Phys. Rev. Lett. 77, 793 (1996)PRLTAO0031-900710.1103/PhysRevLett.77.793. The logical qubit is initialized into the eigenstates of three mutually unbiased bases using an encoding circuit, and we measure an average logical state preparation and measurement (SPAM) error of 1.7(2)×10^{-3}, compared to the average physical SPAM error 2.4(4)×10^{-3} of our qubits. We then perform multiple syndrome measurements on the encoded qubit, using a real-time decoder to determine any necessary corrections that are done either as software updates to the Pauli frame or as physically applied gates. Moreover, these procedures are done repeatedly while maintaining coherence, demonstrating a dynamically protected logical qubit memory. Additionally, we demonstrate non-Clifford qubit operations by encoding a Tover ¯|+⟩_{L} magic state with an error rate below the threshold required for magic state distillation. Finally, we present system-level simulations that allow us to identify key hardware upgrades that may enable the system to reach the pseudothreshold.
Summary
Mast cells have long been recognized for their role in the genesis of allergic inflammation; and more recently for their participation in innate and acquired immune responses. Mast cells ...reside within tissues including the skin and mucosal membranes, which interface with the external environment; as well as being found within vascularized tissues next to nerves, blood vessels and glandular structures. Mast cells have the capability of reacting both within minutes and over hours to specific stimuli, with local and systemic effects. Mast cells express the high affinity IgE receptor (FcɛRI) and upon aggregation of FcɛRI by allergen‐specific IgE, mast cells release and generate biologically active preformed and newly synthesized mediators which are involved in many aspects of allergic inflammation. While mast cells have been well documented to be essential for acute allergic reactions, more recently the importance of mast cells in reacting through pattern recognition receptors in innate immune responses has become recognized. Moreover, as our molecular understanding of the mast cell has evolved, novel targets for modulation have been identified with promising therapeutic potential.
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