The acute antiviral response is mediated by a family of interferon-stimulated genes (ISGs), providing cell-intrinsic immunity. Mutations in genes encoding these proteins are often associated with ...increased susceptibility to viral infections. One family of ISGs with antiviral function is the interferon-inducible transmembrane proteins (IFITMs), of which IFITM3 has been studied extensively. In contrast, IFITM1 has not been studied in detail. Since IFITM1 can localize to the plasma membrane, we investigated its function with a range of enveloped viruses thought to infect cells by fusion with the plasma membrane. Overexpression of IFITM1 prevented infection by a number of
and
, including respiratory syncytial virus (RSV), mumps virus, and human metapneumovirus (HMPV). IFITM1 also restricted infection with an enveloped DNA virus that can enter via the plasma membrane, herpes simplex virus 1 (HSV-1). To test the importance of plasma membrane localization for IFITM1 function, we identified blocks of amino acids in the conserved intracellular loop (CIL) domain that altered the subcellular localization of the protein and reduced antiviral activity. By screening reported data sets, 12 rare nonsynonymous single nucleotide polymorphisms (SNPs) were identified in human
, some of which are in the CIL domain. Using an
mouse, we show that RSV infection was more severe, thereby extending the range of viruses restricted
by IFITM proteins and suggesting overall that IFITM1 is broadly antiviral and that this antiviral function is associated with cell surface localization.
Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon-stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect on their function. One ISG located at the plasma membrane is interferon-inducible transmembrane protein 1 (IFITM1). Here we demonstrate that IFITM1 can inhibit infection with a range of viruses that enter via the plasma membrane. Mutant IFITM1 proteins that were unable to localize to the plasma membrane did not restrict viral infection. We also observed for the first time that IFITM1 plays a role
, and
mice were more susceptible to viral lung infection. These data contribute to our understanding of how ISGs prevent viral infections.
Abstract
It is common practice to test the optical properties of
photomultiplier tubes (PMTs) by illuminating the entire photocathode
region from the front at once and measuring the average
...performance. However, for optimal utilisation of the PMT performance
in experiments, especially in the single-photon region, it is
essential to also know the systematic variations across the
photocathode, which requires measurements with focused light sources
that illuminate only small regions of the PMT. We present a detailed
uniformity characterisation of the gain, transit time, transit time
spread, and pulse shape of the 80 mm Hamamatsu R15458-02 PMT. We
find that the parameters exhibit asymmetry along one axis, likely
caused by the position and geometry of the dynode system. For all
parameters except the transit time, the observed variations are
small given the intrinsic variation of the parameters. For positions
with shifted transit time we observe on average underamplified
pulses which can potentially be exploited to improve the pulse
reconstruction.
There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert ...group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury.
An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors.
The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies.
These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.
•Models and elements used for integrated chronic illness care are presented.•Identified elements are structured according to the six WHO health system building blocks.•Most models and elements ...identified do not explicitly focus on multi-morbidity.•A comprehensive framework better accounting for the complexities resulting from multi-morbidity is needed.
In order to provide adequate care for the growing group of persons with multi-morbidity, innovative integrated care programmes are appearing. The aims of the current scoping review were to i) identify relevant models and elements of integrated care for multi-morbidity and ii) to subsequently identify which of these models and elements are applied in integrated care programmes for multi-morbidity.
A scoping review was conducted in the following scientific databases: Cochrane, Embase, PubMed, PsycInfo, Scopus, Sociological Abstracts, Social Services Abstracts, and Web of Science. A search strategy encompassing a) models, elements and programmes, b) integrated care, and c) multi-morbidity was used to identify both models and elements (aim 1) and implemented programmes of integrated care for multi-morbidity (aim 2). Data extraction was done by two independent reviewers. Besides general information on publications (e.g. publication year, geographical region, study design, and target group), data was extracted on models and elements that publications refer to, as well as which models and elements are applied in recently implemented programmes in the EU and US.
In the review 11,641 articles were identified. After title and abstract screening, 272 articles remained. Full text screening resulted in the inclusion of 92 articles on models and elements, and 50 articles on programmes, of which 16 were unique programmes in the EU (n=11) and US (n=5). Wagner’s Chronic Care Model (CCM) and the Guided Care Model (GCM) were most often referred to (CCM n=31; GCM n=6); the majority of the other models found were only referred to once (aim 1). Both the CCM and GCM focus on integrated care in general and do not explicitly focus on multi-morbidity. Identified elements of integrated care were clustered according to the WHO health system building blocks. Most elements pertained to ‘service delivery’. Across all components, the five elements referred to most often are person-centred care, holistic or needs assessment, integration and coordination of care services and/or professionals, collaboration, and self-management (aim 1). Most (n=10) of the 16 identified implemented programmes for multi-morbidity referred to the CCM (aim 2). Of all identified programmes, the elements most often included were self-management, comprehensive assessment, interdisciplinary care or collaboration, person-centred care and electronic information system (aim 2).
Most models and elements found in the literature focus on integrated care in general and do not explicitly focus on multi-morbidity. In line with this, most programmes identified in the literature build on the CCM. A comprehensive framework that better accounts for the complexities resulting from multi-morbidity is needed.
BackgroundAlthough rhinovirus (RV) respiratory infections trigger asthma exacerbations, the etiologic association between this virus and severe exacerbations, as well as the clinical characteristics ...of adults at risk for RV-associated asthma that necessitates hospitalization, have not been established MethodsDuring 1999–2003, we conducted a cohort study of 101 adults prospectively enrolled at hospital admission for an asthma exacerbation. Patient characteristics and frequencies of RV in nasal specimens were analyzed, by reverse-transcription polymerase chain reaction (RT-PCR), at asthma-related hospital admission and at a 3-month convalescent follow-up visit ResultsRV was detected by RT-PCR in 21% of hospitalized patients over a 4-year period and in 1.3% of patients who returned for a 3-month follow-up visit. RV detection was strongly associated with hospitalization for asthma (adjusted odds ratio OR, 15.1 95% confidence interval {CI}, 1.88–121.4). After adjustment for baseline asthma severity, RV-positive patients were more likely than RV-negative patients to be current smokers and nonusers of inhaled corticosteroids (ICSs) (adjusted OR, 11.18 95% CI, 2.37–52.81; P=.002) ConclusionsRV respiratory infection is an etiologic agent in severe asthma exacerbations necessitating hospitalization in adults. Compared with hospitalized patients with asthma who were RV negative, RV-positive patients were significantly more likely to be smokers and nonusers of ICSs
Summary
Background
Allergic rhinitis and asthma often co‐exist and appear to produce a continuum of airway disease, but whether the clinical characteristics of asthma in patients with seasonal ...rhinitis differ from those of persistent asthma has not been examined.
Objective
The aim of this retrospective study was to characterize the clinical features of patients with seasonal allergic rhinitis with concomitant asthma and to compare them with those in patients with persistent asthma.
Methods
The patient populations for this study were derived from nine prospective, placebo‐controlled planned clinical trials of similar design. Six studies (958 patients) enrolled patients with seasonal allergic rhinitis and concomitant asthma; three (607 patients) involved patients with persistent asthma. In all studies, patients were excluded from oral corticosteroid therapy in the preceding 3 months, and from inhaled corticosteroids in the preceding month.
Results
Patients with seasonal rhinitis and asthma had a significantly (P<0.001) higher total asthma symptom score than those with persistent asthma. In particular, cough was three times more severe. The need for β2‐agonist as a rescue medication and the ratio of forced expiratory volume in 1 s/forced vital capacity (FVC) were similar in the two groups whereas forced expiratory fraction 25–75%/FVC was significantly (P<0.02) reduced in the persistent asthmatics. Asthma and nasal symptom severity scores were correlated in patients with seasonal rhinitis and asthma (P<0.0001).
Conclusions
Patients with seasonal allergic rhinitis and concomitant asthma appear to differ from those with persistent asthma. A prospective study should be designed to discover whether patients with seasonal rhinitis and asthma may represent a distinct nosological entity, ‘allergic airway disease’.
A search for point-like and extended sources of cosmic neutrinos using data collected by the ANTARES and IceCube neutrino telescopes is presented. The data set consists of all the track-like and ...shower-like events pointing in the direction of the Southern Sky included in the nine-year ANTARES point-source analysis, combined with the throughgoing track-like events used in the seven-year IceCube point-source search. The advantageous field of view of ANTARES and the large size of IceCube are exploited to improve the sensitivity in the Southern Sky by a factor of ∼2 compared to both individual analyses. In this work, the Southern Sky is scanned for possible excesses of spatial clustering, and the positions of preselected candidate sources are investigated. In addition, special focus is given to the region around the Galactic Center, whereby a dedicated search at the location of SgrA* is performed, and to the location of the supernova remnant RXJ 1713.7-3946. No significant evidence for cosmic neutrino sources is found, and upper limits on the flux from the various searches are presented.
Along their long propagation from production to detection, neutrinos undergo flavour conversions that convert their types or flavours1,2. High-energy astrophysical neutrinos propagate unperturbed ...over a billion light years in vacuum3 and are sensitive to small effects caused by new physics. Effects of quantum gravity4 are expected to appear at the Planck energy scale. Such a high-energy universe would have existed only immediately after the Big Bang and is inaccessible by human technologies. On the other hand, quantum gravity effects may exist in our low-energy vacuum5–8, but are suppressed by inverse powers of the Planck energy. Measuring the coupling of particles to such small effects is difficult via kinematic observables, but could be observable through flavour conversions. Here we report a search with the IceCube Neutrino Observatory, using astrophysical neutrino flavours9,10 to search for new space–time structure. We did not find any evidence of anomalous flavour conversion in the IceCube astrophysical neutrino flavour data. We apply the most stringent limits of any known technologies, down to 10−42 GeV−2 with Bayes factor greater than 10 on the dimension-six operators that parameterize the space–time defects. We thus unambiguously reach the parameter space of quantum-gravity-motivated physics.The IceCube Collaboration reports a search for quantum gravity effects imprinted in flavour conversions of astrophysical neutrinos. No evidence for anomalous conversions between neutrino flavours is observed.
We have used quinazoline inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase to study the link between EGFR signaling and G(1) to S traverse. Treatment of A431 and MDA-468 human ...tumor cells with 0.1-10 microM AG-1478 inhibited basal and ligand-stimulated EGFR phosphorylation without a decrease in receptor content, EGF-binding sites, or binding affinity. Incubation of A431 cells with 0.1-1 microM AG-1517 abrogated (125)I-EGF internalization. Both AG-1478 and AG-1517 markedly inhibited A431 and MDA-468 colony formation in soft agarose at concentrations between 0.01 and 1 microM. Daily injections of AG-1478 at 50 mg/kg delayed A431 tumor formation in athymic nude mice. A transient exposure of A431 cells to AG-1478 resulted in a dose-dependent up-regulation of the cyclin-dependent kinase inhibitor p27, down-regulation of cyclin D1 and of active MAPK, and hypophosphorylation of the retinoblastoma protein (Rb). These changes were temporally associated with recruitment of tumor cells in G(1) phase and a marked reduction of the proportion of cells in S phase. Upon removal of the kinase inhibitor, EGFR and Rb phosphorylation and the levels of cyclin D1 protein were quickly restored, but the cells did not reenter S phase until p27 protein levels were decreased. Phosphorothioate p27 oligonucleotides decreased p27 protein in A431 cells and abrogated the quinazoline-mediated G(1) arrest. Treatment of A431 cells with PD 098509, a synthetic inhibitor of MEK1, inhibited MAPK activity without inducing G(1) arrest or increasing the levels of p27. However, treatment with LY 294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), inhibited basal Akt activity, up-regulated p27, and recruited cells in G(1). These data suggest that p27 is required for the growth arrest that follows interruption of the EGFR kinase in receptor-overexpressing cells. In addition, the G(1) arrest and up-regulation of p27 resulting from EGFR blockade are not due to the interruption of MAPK, but to the interruption of constitutively active PI3K function.
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