Do all roads lead to rome? The potential of different approaches to diagnose Aelurostrongylus abstrusus infection in cats

An infection with the cat lungworm, Aelurostrongylus abstrusus, can be subclinical, but it can also cause severe respiratory clinical signs. Larvae excretion, antibody levels, clinical assessment findings of the respiratory system and diagnostic imaging findings were recorded and compared for six cats with experimental aelurostrongylosis. In five cats, patency started 33–47 days post infection (pi), but two cats excreted larvae only in long intervals and low numbers. Positive ELISA results were observed in four cats with patent aelurostrongylosis, starting between five days before and 85 days after onset of patency. One seropositive cat remained copromicroscopically negative. Mild respiratory signs were observed in all cats examined. A computed tomographic (CT) examination of the lungs displayed distinct alterations, even in absence of evident clinical signs or when larvae excretion was low or negative. The thoracic radiograph evaluation correlated with the CT results, but CT was more distinctive. After anthelmintic treatment in the 25th week post infection, pulmonary imaging findings improved back to normal within 6–24 weeks. This study shows that a multifaceted approach, including diagnostic imaging, can provide a clearer diagnosis and monitoring of disease progression. Furthermore, a CT examination provides an alternative to post mortem examination and worm counts in anthelmintic efficacy studies

The Fringe Detection Laser Metrology for the GRAVITY Interferometer at the VLTI

Interferometric measurements of optical path length differences of stars over large baselines can deliver extremely accurate astrometric data. The interferometer GRAVITY will simultaneously measure two objects in the field of view of the Very Large Telescope Interferometer (VLTI) of the European Southern Observatory (ESO) and determine their angular separation to a precision of 10 micro arcseconds in only 5 minutes. To perform the astrometric measurement with such a high accuracy, the differential path length through the VLTI and the instrument has to be measured (and tracked since Earth's rotation will permanently change it) by a laser metrology to an even higher level of accuracy (corresponding to 1 nm in 3 minutes). Usually, heterodyne differential path techniques are used for nanometer precision measurements, but with these methods it is difficult to track the full beam size and to follow the light path up to the primary mirror of the telescope. Here, we present the preliminary design of a differential path metrology system, developed within the GRAVITY project. It measures the instrumental differential path over the full pupil size and up to the entrance pupil location. The differential phase is measured by detecting the laser fringe pattern both on the telescopes' secondary mirrors as well as after reflection at the primary mirror. Based on our proposed design we evaluate the phase measurement accuracy based on a full budget of possible statistical and systematic errors. We show that this metrology design fulfills the high precision requirement of GRAVITY.Comment: Proc. SPIE in pres

The Infrared Behavior of Gluon and Ghost Propagators in Landau Gauge QCD

A solvable systematic truncation scheme for the Dyson-Schwinger equations of Euclidean QCD in Landau gauge is presented. It implements the Slavnov-Taylor identities for the three-gluon and ghost-gluon vertices, whereas irreducible four-gluon couplings as well as the gluon-ghost and ghost-ghost scattering kernels are neglected. The infrared behavior of gluon and ghost propagators is obtained analytically: The gluon propagator vanishes for small spacelike momenta whereas the ghost propagator diverges stronger than a massless particle pole. The numerical solutions are compared with recent lattice data for these propagators. The running coupling of the renormalization scheme approaches a fixed point, $\alpha_c \simeq 9.5$, in the infrared.Comment: 4 pages, 2 figures, Revtex; revised version accepted for publication in Physical Review Letter

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

Background: While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing. Methods: Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom. Results: Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p \u3c 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p \u3c 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time. Conclusions: This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint. Trial Registration: SAMURAI (NCT02439320); SPARTAN (NCT02605174)

Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21(Waf1/Cip1) as a novel mechanism of neuroprotection by glucocorticoids

The role of glucocorticoids in the regulation of apoptosis remains incongruous. Here, we demonstrate that corticosterone protects neurons from apoptosis by a mechanism involving the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21(Waf1/Cip1) at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21(Waf1/Cip1) preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21(Waf1/Cip1) and neuroprotection are completely abolished by glucocorticoid and mineralocorticoid receptor antagonists as well as inhibitors of PI3- and Akt-kinase. Both germline and somatically induced p21(Waf1/Cip1) deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21(Waf1/Cip1) suffices to protect neurons from apoptosis. We identify p21(Waf1/Cip1) as a novel antiapoptotic factor for postmitotic neurons and implicate p21(Waf1/Cip1) as the molecular target of neuroprotection by high-dose glucocorticoids

Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection

Abstract: Bcl-2 family proteins including the pro-apoptotic BH3-only proteins are central regulators of apoptotic cell death. Here we show by a focused siRNA miniscreen that the synergistic action of the BH3-only proteins Bim and Bmf is required for apoptosis induced by infection with Neisseria gonorrhoeae (Ngo). While Bim and Bmf were associated with the cytoskeleton of healthy cells, they both were released upon Ngo infection. Loss of Bim and Bmf from the cytoskeleton fraction required the activation of Jun-N-terminal kinase-1 (JNK-1), which in turn depended on Rac-1. Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases. Apoptosis could be reconstituted in Bim-depleted and Bmf-depleted cells by additional silencing of antiapoptotic Mcl-1 and Bcl-XL, respectively. Our data indicate a synergistic role for both cytoskeletal-associated BH3-only proteins, Bim, and Bmf, in an apoptotic pathway leading to the clearance of Ngo-infected cells. Author Summary: A variety of physiological death signals, as well as pathological insults, trigger apoptosis, a genetically programmed form of cell death. Pathogens often induce host cell apoptosis to establish a successful infection. Neisseria gonorrhoeae (Ngo), the etiological agent of the sexually transmitted disease gonorrhoea, is a highly adapted obligate human-specific pathogen and has been shown to induce apoptosis in infected cells. Here we unveil the molecular mechanisms leading to apoptosis of infected cells. We show that Ngo-mediated apoptosis requires a special subset of proapoptotic proteins from the group of BH3-only proteins. BH3-only proteins act as stress sensors to translate toxic environmental signals to the initiation of apoptosis. In a siRNA-based miniscreen, we found Bim and Bmf, BH3-only proteins associated with the cytoskeleton, necessary to induce host cell apoptosis upon infection. Bim and Bmf inactivated different inhibitors of apoptosis and thereby induced cell death in response to infection. Our data unveil a novel pathway of infection-induced apoptosis that enhances our understanding of the mechanism by which BH3-only proteins control apoptotic cell death

On the Infrared Exponent for Gluon and Ghost Propagation in Landau Gauge QCD

In the covariant description of confinement, one expects the ghost correlations to be infrared enhanced. Assuming ghost dominance, the long-range behavior of gluon and ghost correlations in Landau gauge QCD is determined by one exponent kappa. The gluon propagator is infrared finite (vanishing) for kappa =1/2 (kappa > 1/2) which is still under debate. Here, we study critical exponent and coupling for the infrared conformal behavior from the asymptotic form of the solutions to the Dyson-Schwinger equations in an ultraviolet finite expansion scheme. The value for kappa is directly related to the ghost-gluon vertex. Assuming that it is regular in the infrared, one obtains kappa = 0.595. This value maximizes the critical coupling alpha_c(kappa), yielding alpha_c^max = (4 Pi/Nc) 0.709 approx. 2.97 for Nc=3. For larger kappa the vertex acquires an infrared singularity in the gluon momentum, smaller ones imply infrared singular ghost legs. Variations in alpha_c remain within 5% from kappa = 0.5 to 0.7. Above this range, alpha_c decreases more rapidly with alpha_c -> 0 as kappa -> 1 which sets the upper bound on kappa.Comment: 22 Pages, 10 Figures, LaTeX2e, revtex4, some notes and references added in response to communication

Determining the Physical Properties of the B Stars I. Methodology and First Results

We describe a new approach to fitting the UV-to-optical spectra of B stars to model atmospheres and present initial results. Using a sample of lightly reddened stars, we demonstrate that the Kurucz model atmospheres can produce excellent fits to either combined low dispersion IUE and optical photometry or HST FOS spectrophotometry, as long as the following conditions are fulfilled: 1) an extended grid of Kurucz models is employed, 2) the IUE NEWSIPS data are placed on the FOS absolute flux system using the Massa & Fitzpatrick (1999) transformation, and 3) all of the model parameters and the effects of interstellar extinction are solved for simultaneously. When these steps are taken, the temperatures, gravities, abundances and microturbulence velocities of lightly reddened B0-A0 V stars are determined to high precision. We also demonstrate that the same procedure can be used to fit the energy distributions of stars which are reddened by any UV extinction curve which can be expressed by the Fitzpatrick & Massa (1990) parameterization scheme. We present an initial set of results and verify our approach through comparisons with angular diameter measurements and the parameters derived for an eclipsing B star binary. We demonstrate that the metallicity derived from the ATLAS 9 fits to main sequence B stars is essentially the Fe abundance. We find that a near zero microturbulence velocity provides the best-fit to all but the hottest or most luminous stars (where it may become a surrogate for atmospheric expansion), and that the use of white dwarfs to calibrate UV spectrophotometry is valid.Comment: 17 pages, including 2 pages of Tables and 6 pages of Figures. Astrophysical Jounral, in pres

Experimental Observation of ABCB Stacked Tetralayer Graphene

In tetralayer graphene, three inequivalent layer stackings should exist; however, only rhombohedral (ABCA) and Bernal (ABAB) stacking have so far been observed. The three stacking sequences differ in their electronic structure, with the elusive third stacking (ABCB) being unique as it is predicted to exhibit an intrinsic bandgap as well as locally flat bands around the K points. Here, we use scattering-type scanning near-field optical microscopy and confocal Raman microscopy to identify and characterize domains of ABCB stacked tetralayer graphene. We differentiate between the three stacking sequences by addressing characteristic interband contributions in the optical conductivity between 0.28 and 0.56 eV with amplitude and phase-resolved near-field nanospectroscopy. By normalizing adjacent flakes to each other, we achieve good agreement between theory and experiment, allowing for the unambiguous assignment of ABCB domains in tetralayer graphene. These results establish near-field spectroscopy at the interband transitions as a semiquantitative tool, enabling the recognition of ABCB domains in tetralayer graphene flakes and, therefore, providing a basis to study correlation physics of this exciting phase

Full genome ultra-deep pyrosequencing associates G-to-A hypermutation of the hepatitis B virus genome with the natural progression of hepatitis

SUMMARY. Human APOBEC3 (A3) cytosine deaminases are antiviral restriction factors capable of editing the genome the hepatitis B virus (HBV). Despite the importance of the human A3 protein family for the innate immune response little is known about the clinical relevance for hepatitis B. The aim of this study was to utilize ultra-deep pyrosequencing (UDPS) data to analyse the phenomenon of G-to-A hypermutation of the complete HBV genome and to relate it to fundamental characteristics of patients with chronic hepatitis B. By analysing the viral population of 80 treatment na€ ıve patients (47 HBeAg-positive and 33 HBeAg-negative), we identified an unequal distribution of G-to-A hypermutations across the genome. Our data indicate that G-to-A hypermutation occurs predominantly in a region between nucleotide positions 600 and 1800 a region which is usually single stranded in matured HBV particles. This implies that A3 likely edits HBV in the virion. Hypermutation rates for HBeAg-negative patients were more than 10-fold higher than those of HBeAg-positive patients. For HBeAg-negative patients higher hypermutation rates were significantly associated with the degree of fibrosis. Additionally, we found that for HBeAg-positive chronic hepatitis G-to-A hypermutation rates were significantly associated with the relative prevalence of the G1764A mutation, which is related to HBeAg seroconversion. In total, our data imply an important association of hypermutation mediated by A3 deaminases with the natural progression of chronic hepatitis B infections both in terms of HBeAg seroconversion and disease progression towards cirrhosis