Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'.

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required

High Energy Gamma-Ray Emission From Blazars: EGRET Observations

We will present a summary of the observations of blazars by the Energetic Gamma Ray Experiment Telescope (EGRET) on the Compton Gamma Ray Observatory (CGRO). EGRET has detected high energy gamma-ray emission at energies greater than 100 MeV from more that 50 blazars. These sources show inferred isotropic luminosities as large as $3\times 10^{49}$ ergs s$^{-1}$. One of the most remarkable characteristics of the EGRET observations is that the gamma-ray luminosity often dominates the bolometric power of the blazar. A few of the blazars are seen to exhibit variability on very short time-scales of one day or less. The combination of high luminosities and time variations seen in the gamma-ray data indicate that gamma-rays are an important component of the relativistic jet thought to characterize blazars. Currently most models for blazars involve a beaming scenario. In leptonic models, where electrons are the primary accelerated particles, gamma-ray emission is believed to be due to inverse Compton scattering of low energy photons, although opinions differ as to the source of the soft photons. Hardronic models involve secondary production or photomeson production followed by pair cascades, and predict associated neutrino production.Comment: 16 pages, 7 figures, style files included. Invited review paper in "Observational Evidence for Black Holes in the Universe," 1999, ed. S. K. Chakrabarti (Dordrecht: Kluwer), 215-23

Candida soluble cell wall β-glucan facilitates ovalbumin-induced allergic airway inflammation in mice: Possible role of antigen-presenting cells

<p>Abstract</p> <p>Background</p> <p>Although fungi have been implicated as initiating/deteriorating factors for allergic asthma, their contributing components have not been fully elucidated. We previously isolated soluble β-glucan from <it>Candida albicans </it>(CSBG) (Ohno et al., 2007). In the present study, the effects of CSBG exposure on airway immunopathology in the presence or absence of other immunogenic allergen was investigated <it>in vivo</it>, and their cellular mechanisms were analyzed both <it>in vivo </it>and <it>in vitro</it>.</p> <p>Methods</p> <p><it>In vivo</it>, ICR mice were divided into 4 experimental groups: vehicle, CSBG (25 μg/animal), ovalbumin (OVA: 2 μg/animal), and CSBG + OVA were repeatedly administered intratracheally. The bronchoalveolar lavage cellular profile, lung histology, levels of cytokines and chemokines in the lung homogenates, the expression pattern of antigen-presenting cell (APC)-related molecules in the lung digests, and serum immunoglobulin values were studied. <it>In vitro</it>, the impacts of CSBG (0–12.5 μg/ml) on the phenotype and function of immune cells such as splenocytes and bone marrow-derived dendritic cells (BMDCs) were evaluated in terms of cell proliferation, the surface expression of APC-related molecules, and OVA-mediated T-cell proliferating activity.</p> <p>Results</p> <p><it>In vivo</it>, repeated pulmonary exposure to CSBG induced neutrophilic airway inflammation in the absence of OVA, and markedly exacerbated OVA-related eosinophilic airway inflammation with mucus metaplasia in mice, which was concomitant with the amplified lung expression of Th2 cytokines and IL-17A and chemokines related to allergic response. Exposure to CSBG plus OVA increased the number of cells bearing MHC class II with or without CD80 in the lung compared to that of others. <it>In vitro</it>, CSBG significantly augmented splenocyte proliferation in the presence or absence of OVA. Further, CSBG increased the expression of APC-related molecules such as CD80, CD86, and DEC205 on BMDCs and amplified OVA-mediated T-cell proliferation through BMDCs.</p> <p>Conclusion</p> <p>CSBG potentiates allergic airway inflammation with maladaptive Th immunity, and this potentiation was associated with the enhanced activation of APCs including DC.</p

Cumulative signal transmission in nonlinear reaction-diffusion networks

Quantifying signal transmission in biochemical systems is key to uncover the mechanisms that cells use to control their responses to environmental stimuli. In this work we use the time-integral of chemical species as a measure of a network’s ability to cumulatively transmit signals encoded in spatiotemporal concentrations. We identify a class of nonlinear reaction-diffusion networks in which the time-integrals of some species can be computed analytically. The derived time-integrals do not require knowledge of the solution of the reaction-diffusion equation, and we provide a simple graphical test to check if a given network belongs to the proposed class. The formulae for the time-integrals reveal how the kinetic parameters shape signal transmission in a network under spatiotemporal stimuli. We use these to show that a canonical complex-formation mechanism behaves as a spatial low-pass filter, the bandwidth of which is inversely proportional to the diffusion length of the ligand

Targeting Cx43 and N-Cadherin, Which Are Abnormally Upregulated in Venous Leg Ulcers, Influences Migration, Adhesion and Activation of Rho GTPases

Venous leg ulcers can be very hard to heal and represent a significant medical need with no effective therapeutic treatment currently available

The presentation, clinical features, complications, and treatment of congenital dacryocystocele

Purpose To determine the incidence and presenting features of congenital dacryocystocele in the United Kingdom. To report on those cases complicated by dacryocystitis, respiratory compromise, and the treatment undertaken. Methods A prospective observational study of cases of congenital dacryocystocele presenting in the United Kingdom between September 2014 and October 2015. Infants <3 months of age presenting with a cystic swelling in the medial canthal area were included. Cases were identified via the British Ophthalmology Surveillance Unit (BOSU) reporting system. Results A total of 49 cases were reported during the study period. This gives an incidence of 1 in 18 597 live births. There was a 71% response rate to the questionnaire. The average age at presentation was 16.94 days. Dacryocystoceles were unilateral in 91% of cases. Dacryocystitis was a complicating factor in 49% of patients and 17% had respiratory distress. Uncomplicated dacryocystocele responded well to conservative measures in 86%. Surgical intervention was required in 23% of patients. Those cases complicated by dacryocystitis (29%) and nasal obstruction (17%) were more likely to require surgical intervention compared to those with dacryocystocele alone (14%). Digital massage appears to reduce the likelihood of requiring surgical intervention. The mean time to resolution was 19 days. Conclusions Congenital dacryocystocele is a rare presentation in the United Kingdom. Dacryocystitis and respiratory compromise commonly complicate a dacryocystocele. The use of digital massage as an early intervention is advocated and conservative measures may be sufficient in cases of uncomplicated dacryocystocele

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Evolutionary and pulsational properties of white dwarf stars

Abridged. White dwarf stars are the final evolutionary stage of the vast majority of stars, including our Sun. The study of white dwarfs has potential applications to different fields of astrophysics. In particular, they can be used as independent reliable cosmic clocks, and can also provide valuable information about the fundamental parameters of a wide variety of stellar populations, like our Galaxy and open and globular clusters. In addition, the high densities and temperatures characterizing white dwarfs allow to use these stars as cosmic laboratories for studying physical processes under extreme conditions that cannot be achieved in terrestrial laboratories. They can be used to constrain fundamental properties of elementary particles such as axions and neutrinos, and to study problems related to the variation of fundamental constants. In this work, we review the essentials of the physics of white dwarf stars. Special emphasis is placed on the physical processes that lead to the formation of white dwarfs as well as on the different energy sources and processes responsible for chemical abundance changes that occur along their evolution. Moreover, in the course of their lives, white dwarfs cross different pulsational instability strips. The existence of these instability strips provides astronomers with an unique opportunity to peer into their internal structure that would otherwise remain hidden from observers. We will show that this allows to measure with unprecedented precision the stellar masses and to infer their envelope thicknesses, to probe the core chemical stratification, and to detect rotation rates and magnetic fields. Consequently, in this work, we also review the pulsational properties of white dwarfs and the most recent applications of white dwarf asteroseismology.Comment: 85 pages, 28 figures. To be published in The Astronomy and Astrophysics Revie

Reduced Incidence of Slowly Progressive Heymann Nephritis in Rats Immunized With a Modified Vaccination Technique

A slowly progressive Heymann nephritis (SPHN) was induced in three groups of rats by weekly injections of a chemically modified renal tubular antigen in an aqueous medium. A control group of rats received the chemically unmodified version of the antigen in an aqueous solution. One group of SPHN rats were pre- and post-treated with weekly injections of IC made up of rKF3 and rarKF3 IgM antibody at antigen excess (MIC) (immune complexes [ICs] containing sonicated ultracentrifuged [u/c] rat kidney fraction 3 [rKF3] antigen and IgM antibodies specific against the antigen, at slight antigen excess). One group of SPHN rats were post-treated with MIC 3 weeks after the induction of the disease and one group of SPHN animals received no treatment. The control group of rats received pre- and post-treatment with sonicated u/c rKF3

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)