Superconducting cavity transducer for resonant gravitational radiation antennas

Parametric transducers, such as superconducting rf cavities, can boost the bandwidth and sensitivity of the next generation resonant antennas, thanks to a readily available technology. We have developed a fully coupled dynamic model of the system "antenna--transducer" and worked out some estimates of signal--to--noise ratio and the stability conditions in various experimental configurations. We also show the design and the prototype of a rf cavity which, together with a suitable read--out electronic, will be used as a test bench for the parametric transducer.Comment: 7 pages, 3 eps figures. Presented at the 6th Amaldi Conference on Gravitational Waves (2005). Accepted for publication in Journal of Physics: Conference Serie

Experimental simulation of quantum graphs by microwave networks

We present the results of experimental and theoretical study of irregular, tetrahedral microwave networks consisting of coaxial cables (annular waveguides) connected by T-joints. The spectra of the networks were measured in the frequency range 0.0001-16 GHz in order to obtain their statistical properties such as the integrated nearest neighbor spacing distribution and the spectral rigidity. The comparison of our experimental and theoretical results shows that microwave networks can simulate quantum graphs with time reversal symmetry. In particular, we use the spectra of the microwave networks to study the periodic orbits of the simulated quantum graphs. We also present experimental study of directional microwave networks consisting of coaxial cables and Faraday isolators for which the time reversal symmetry is broken. In this case our experimental results indicate that spectral statistics of directional microwave networks deviate from predictions of Gaussian orthogonal ensembles (GOE) in random matrix theory approaching, especially for small eigenfrequency spacing s, results for Gaussian unitary ensembles (GUE). Experimental results are supported by the theoretical analysis of directional graphs.Comment: 16 pages, 7 figures, to be published in Phys. Rev.

Experimental and numerical investigation of the reflection coefficient and the distributions of Wigner's reaction matrix for irregular graphs with absorption

We present the results of experimental and numerical study of the distribution of the reflection coefficient P(R) and the distributions of the imaginary P(v) and the real P(u) parts of the Wigner's reaction K matrix for irregular fully connected hexagon networks (graphs) in the presence of strong absorption. In the experiment we used microwave networks, which were built of coaxial cables and attenuators connected by joints. In the numerical calculations experimental networks were described by quantum fully connected hexagon graphs. The presence of absorption introduced by attenuators was modelled by optical potentials. The distribution of the reflection coefficient P(R) and the distributions of the reaction K matrix were obtained from the measurements and numerical calculations of the scattering matrix S of the networks and graphs, respectively. We show that the experimental and numerical results are in good agreement with the exact analytic ones obtained within the framework of random matrix theory (RMT).Comment: 15 pages, 8 figure

Intestinal intraepithelial lymphocyte activation promotes innate antiviral resistance.

Unrelenting environmental challenges to the gut epithelium place particular demands on the local immune system. In this context, intestinal intraepithelial lymphocytes (IEL) compose a large, highly conserved T cell compartment, hypothesized to provide a first line of defence via cytolysis of dysregulated intestinal epithelial cells (IEC) and cytokine-mediated re-growth of healthy IEC. Here we show that one of the most conspicuous impacts of activated IEL on IEC is the functional upregulation of antiviral interferon (IFN)-responsive genes, mediated by the collective actions of IFNs with other cytokines. Indeed, IEL activation in vivo rapidly provoked type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium. Consistent with this, activated IEL mediators protected cells against virus infection in vitro, and pre-activation of IEL in vivo profoundly limited norovirus infection. Hence, intraepithelial T cell activation offers an overt means to promote the innate antiviral potential of the intestinal epithelium.Support was provided by the Wellcome Trust (A.C.H., J.L.H., G.R) and Cancer Research UK (A.C.H.), Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust (L.A.-D.; A.C.H.); Marie Curie and EMBO fellowships (M.S.).This is the final published version. It first appeared at http://www.nature.com/ncomms/2015/150519/ncomms8090/full/ncomms8090.html

Evading innate immunity in nonviral mRNA delivery : don't shoot the messenger

In de field of non-viral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known the introduction of IVT mRNA into mammalian cells elicits an innate immune response which has favored mRNA use towards immunotherapeutic vaccination strategies. However, for non-immunotherapy related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, as it can seriously compromise the expression of the desired protein. This review presents an overview of the immune-related obstacles that limit mRNA advance for non-immunotherapy related applications

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood\u2014a study of 155 patients

Background: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. Methods: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. Results: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. Conclusions: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trial

Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: Analysis of the HIV-2 Belgium and Luxembourg database

BACKGROUND: Guidelines established for the treatment of HIV-1 infection and genotype interpretation do not apply for HIV-2. Data about antiretroviral (ARV) drug efficacy and resistance mutations is scarce. METHODS: Clinical data about HIV-2 infected patients in Belgium and Luxembourg were collected and the effect of ARV therapy on plasma viral load and CD4 counts were analysed. Viral RNA encoding for protease (PR) and reverse transcriptase (RT) from ARV-naive and treated patients were sequenced. RESULTS: Sixty-five HIV-2 infected patients were included in this cohort. Twenty patients were treated with 25 different ARV combinations in a total of 34 regimens and six months after the start of ARV therapy, only one third achieved viral load suppression. All of these successful regimens bar one contained protease inhibitors (PIs). Mean CD4 gains in the group of viral load suppressors and the group of patients treated with PI-containing regimens were respectively significantly higher than in the group of non-suppressors and the group of PI-sparing regimens. The most frequent mutations selected under therapy (compared to HIV-2 ROD) were V71I, L90M and I89V within PR. Within RT, they were M184V, Q151M, V111I and K65R. All of these mutations, except K65R and M184V, were also found in variable proportions in ARV-naive patients. CONCLUSION: Despite a high rate of ARV treatment failure, better virological and immunological results were achieved with PI-containing regimens. The analysis of polymorphic positions and HIV-2 specific mutations selected during therapy showed for the first time that transmission of drug resistant viruses has occurred in Belgium and Luxembourg. The high heterogeneity in ARV combinations reflects a lack of guidelines for the treatment of HIV-2 infection

Innate Killing of Leishmania donovani by Macrophages of the Splenic Marginal Zone Requires IRF-7

Highly phagocytic macrophages line the marginal zone (MZ) of the spleen and the lymph node subcapsular sinus. Although these macrophages have been attributed with a variety of functions, including the uptake and clearance of blood and lymph-borne pathogens, little is known about the effector mechanisms they employ after pathogen uptake. Here, we have combined gene expression profiling and RNAi using a stromal macrophage cell line with in situ analysis of the leishmanicidal activity of marginal zone macrophages (MZM) and marginal metallophilic macrophages (MMM) in wild type and gene targeted mice. Our data demonstrate a critical role for interferon regulatory factor-7 (IRF-7) in regulating the killing of intracellular Leishmania donovani by these specialised splenic macrophage sub-populations. This study, therefore, identifies a new role for IRF-7 as a regulator of innate microbicidal activity against this, and perhaps other, non-viral intracellular pathogens. This study also highlights the importance of selecting appropriate macrophage populations when studying pathogen interactions with this functionally diverse lineage of cells

European Cystic Fibrosis Society standards of care: best practice guidelines

Specialised CF care has led to a dramatic improvement in survival in CF: in the last four decades, well above what was seen in the general population over the same period. With the implementation of newborn screening in many European countries, centres are increasingly caring for a cohort of patients who have minimal lung disease at diagnosis and therefore have the potential to enjoy an excellent quality of life and an even greater life expectancy than was seen previously. To allow high quality care to be delivered throughout Europe, a landmark document was published in 2005 that sets standards of care. Our current document builds on this work, setting standards for best practice in key aspects of CF care. The objective of our document is to give a broad overview of the standards expected for screening, diagnosis, pre-emptive treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support. For comprehensive details of clinical care of CF, references to the most up to date European Consensus Statements, Guidelines or Position Papers are provided in Table 1. We hope that this best practice document will be useful to clinical teams both in countries where CF care is developing and those with established CF centres

Beyond water homeostasis:diverse functional roles of mammalian aquaporins

Background - Aquaporin (AQP) water channels are best known as passive transporters of water that are vital for water homeostasis. Scope of review - AQP knockout studies in whole animals and cultured cells, along with naturally occurring human mutations suggest that the transport of neutral solutes through AQPs has important physiological roles. Emerging biophysical evidence suggests that AQPs may also facilitate gas (CO2) and cation transport. AQPs may be involved in cell signalling for volume regulation and controlling the subcellular localization of other proteins by forming macromolecular complexes. This review examines the evidence for these diverse functions of AQPs as well their physiological relevance. Major conclusions - As well as being crucial for water homeostasis, AQPs are involved in physiologically important transport of molecules other than water, regulation of surface expression of other membrane proteins, cell adhesion, and signalling in cell volume regulation. General significance - Elucidating the full range of functional roles of AQPs beyond the passive conduction of water will improve our understanding of mammalian physiology in health and disease. The functional variety of AQPs makes them an exciting drug target and could provide routes to a range of novel therapies