Identification of autoantigens and their potential post-translational modification in EGPA and severe eosinophilic asthma.

BACKGROUND: The chronic airway inflammation in severe eosinophilic asthma (SEA) suggests potential autoimmune aetiology with unidentified autoantibodies analogous to myeloperoxidase (MPO) in ANCA-positive EGPA (eosinophilic granulomatosis with polyangiitis). Previous research has shown that oxidative post-translational modification (oxPTM) of proteins is an important mechanism by which autoantibody responses may escape immune tolerance. Autoantibodies to oxPTM autoantigens in SEA have not previously been studied. METHODS: Patients with EGPA and SEA were recruited as well as healthy control participants. Autoantigen agnostic approach: Participant serum was incubated with slides of unstimulated and PMA-stimulated neutrophils and eosinophils, and autoantibodies to granulocytes were identified by immunofluorescence with anti-human IgG FITC antibody. Target autoantigen approach: Candidate proteins were identified from previous literature and FANTOM5 gene set analysis for eosinophil expressed proteins. Serum IgG autoantibodies to these proteins, in native and oxPTM form, were detected by indirect ELISA. RESULTS: Immunofluorescence studies showed that serum from patients with known ANCA stained for IgG against neutrophils as expected. In addition, serum from 9 of 17 tested SEA patients stained for IgG to PMA-stimulated neutrophils undergoing NETosis. Immunofluorescent staining of eosinophil slides was evident with serum from all participants (healthy and with eosinophilic disease) with diffuse cytoplasmic staining except for one SEA individual in whom subtle nuclear staining was evident. FANTOM5 gene set analysis identified TREM1 (triggering receptor expressed on myeloid cells 1) and IL-1 receptor 2 (IL1R2) as eosinophil-specific targets to test for autoantibody responses in addition to MPO, eosinophil peroxidase (EPX), and Collagen-V identified from previous literature. Indirect ELISAs found high concentrations of serum autoantibodies to Collagen-V, MPO, and TREM1 in a higher proportion of SEA patients than healthy controls. High concentrations of serum autoantibodies to EPX were evident in serum from both healthy and SEA participants. The proportion of patients with positive autoantibody ELISAs was not increased when examining oxPTM compared to native proteins. DISCUSSION: Although none of the target proteins studied showed high sensitivity for SEA, the high proportion of patients positive for at least one serum autoantibody shows the potential of more research on autoantibody serology to improve diagnostic testing for severe asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier, NCT04671446

Fundamental limitations for quantum and nano thermodynamics

The relationship between thermodynamics and statistical physics is valid in the thermodynamic limit - when the number of particles becomes very large. Here, we study thermodynamics in the opposite regime - at both the nano scale, and when quantum effects become important. Applying results from quantum information theory we construct a theory of thermodynamics in these limits. We derive general criteria for thermodynamical state transformations, and as special cases, find two free energies: one that quantifies the deterministically extractable work from a small system in contact with a heat bath, and the other that quantifies the reverse process. We find that there are fundamental limitations on work extraction from nonequilibrium states, owing to finite size effects and quantum coherences. This implies that thermodynamical transitions are generically irreversible at this scale. As one application of these methods, we analyse the efficiency of small heat engines and find that they are irreversible during the adiabatic stages of the cycle.Comment: Final, published versio

Locomotor adaptability in persons with unilateral transtibial amputation

Background Locomotor adaptation enables walkers to modify strategies when faced with challenging walking conditions. While a variety of neurological injuries can impair locomotor adaptability, the effect of a lower extremity amputation on adaptability is poorly understood. Objective Determine if locomotor adaptability is impaired in persons with unilateral transtibial amputation (TTA). Methods The locomotor adaptability of 10 persons with a TTA and 8 persons without an amputation was tested while walking on a split-belt treadmill with the parallel belts running at the same (tied) or different (split) speeds. In the split condition, participants walked for 15 minutes with the respective belts moving at 0.5 m/s and 1.5 m/s. Temporal spatial symmetry measures were used to evaluate reactive accommodations to the perturbation, and the adaptive/de-adaptive response. Results Persons with TTA and the reference group of persons without amputation both demonstrated highly symmetric walking at baseline. During the split adaptation and tied post-adaptation walking both groups responded with the expected reactive accommodations. Likewise, adaptive and de-adaptive responses were observed. The magnitude and rate of change in the adaptive and de-adaptive responses were similar for persons with TTA and those without an amputation. Furthermore, adaptability was no different based on belt assignment for the prosthetic limb during split adaptation walking. Conclusions Reactive changes and locomotor adaptation in response to a challenging and novel walking condition were similar in persons with TTA to those without an amputation. Results suggest persons with TTA have the capacity to modify locomotor strategies to meet the demands of most walking conditions despite challenges imposed by an amputation and use of a prosthetic limb

X-ray emission from isolated neutron stars

X-ray emission is a common feature of all varieties of isolated neutron stars (INS) and, thanks to the advent of sensitive instruments with good spectroscopic, timing, and imaging capabilities, X-ray observations have become an essential tool in the study of these objects. Non-thermal X-rays from young, energetic radio pulsars have been detected since the beginning of X-ray astronomy, and the long-sought thermal emission from cooling neutron star's surfaces can now be studied in detail in many pulsars spanning different ages, magnetic fields, and, possibly, surface compositions. In addition, other different manifestations of INS have been discovered with X-ray observations. These new classes of high-energy sources, comprising the nearby X-ray Dim Isolated Neutron Stars, the Central Compact Objects in supernova remnants, the Anomalous X-ray Pulsars, and the Soft Gamma-ray Repeaters, now add up to several tens of confirmed members, plus many candidates, and allow us to study a variety of phenomena unobservable in "standard'' radio pulsars.Comment: Chapter to be published in the book of proceedings of the 1st Sant Cugat Forum on Astrophysics, "ICREA Workshop on the high-energy emission from pulsars and their systems", held in April, 201

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis

Antibiotics prescribing practices in oral implantology among jordanian dentists. A cross sectional, observational study

<p>Abstract</p> <p>Background</p> <p>In oral implantology, there is no consensus on the most appropriate regimen for antibiotics prescribing, the decision to prescribe antibiotic is usually based on procedure, patient and clinician related factors. The aim of this study was to investigate the rationale of antibiotic prescribing among Jordanian clinicians who practice oral implantology.</p> <p>Findings</p> <p>The target sample for the study was the 250 Jordan Dental Implant Group members. A five page questionnaire contained 41 questions, both closed and open questions were used to collect data. Statistical analysis was performed using SPSS Windows 16.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics were generated.</p> <p>The response rate was (70.4%) 176/250. Mean age was 37.2 yrs, 49.4% always prescribe antibiotics mainly oral amoxicillin and amoxicillin with clavulinic acid. Antibiotics prescribing increased with flap raising, multiple implants and sinus or bone augmentation. Patient medical condition, periodontitis and oral hygiene were the most important clinical factors in antibiotic prescribing, non-clinical factors were; reading scientific materials, courses and lectures, knowledge gained during training, and the effectiveness and previous experience with the drug.</p> <p>Conclusions</p> <p>Wide variations in antibiotics types, routes, dose and duration of administration were found. Recommendations on antibiotic prescribing are needed to prevent antibiotic overprescribing and misuse.</p

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Molecular Analysis of Precursor Lesions in Familial Pancreatic Cancer

PMCID: PMC3553106This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Discovery of the Onset of Rapid Accretion by a Dormant Massive Black Hole

Massive black holes are believed to reside at the centres of most galaxies. They can be- come detectable by accretion of matter, either continuously from a large gas reservoir or impulsively from the tidal disruption of a passing star, and conversion of the gravitational energy of the infalling matter to light. Continuous accretion drives Active Galactic Nuclei (AGN), which are known to be variable but have never been observed to turn on or off. Tidal disruption of stars by dormant massive black holes has been inferred indirectly but the on- set of a tidal disruption event has never been observed. Here we report the first discovery of the onset of a relativistic accretion-powered jet in the new extragalactic transient, Swift J164449.3+573451. The behaviour of this new source differs from both theoretical models of tidal disruption events and observations of the jet-dominated AGN known as blazars. These differences may stem from transient effects associated with the onset of a powerful jet. Such an event in the massive black hole at the centre of our Milky Way galaxy could strongly ionize the upper atmosphere of the Earth, if beamed towards us.Comment: Submitted to Nature. 4 pages, 3 figures (main paper). 26 pages, 13 figures (supplementary information