Early immune development, atopy and asthma: insights from ATS 2001, May 18-23, San Francisco

There is rising evidence that the initiation of atopy and asthma may occur in early life or even during fetal life. At the American Thoracic Society meeting 2001 in San Francisco, multiple reports addressed epidemiological and immunological factors and their influence on the early immune system, as well as the development of atopy and asthma. Epidemiologic studies presented at the meeting suggest a protective effect of farming and pet exposure. Early-life exposure to endotoxin, a cell wall component of Gram-negative bacteria which can be found in high levels in the presence of pets, may have a protective effect. Investigations of the mechanism of the early immune system indicate that mononuclear cord blood cells have the ability to mount a lymphoproliferative response to mitogens and allergens. Reports suggest, however, that the validity of Th1/Th2 paradigm may need to be scrutinized in early human immune responses, particularly regarding the assumption that the neonate immune system is Th2 skewed. The prospective longitudinal follow-up of these studies is promising to give further insight into risk and protective factors in the development in atopy and asthma

Complete genome sequence of BK polyomavirus subtype Ib-1 detected in a kidney transplant patient with BK viremia using shotgun sequencing

We report here the complete genome sequence of polyomavirus BK subtype Ib-1, isolate AR11, identified in urine from a human kidney transplant recipient with a clinical diagnosis of BK viremia. The AR11 isolate is closely related to reference strain human polyomavirus 1 isolate J2B-2 with 99% identity

Identification of an IL-4-Inducible Gene Expressed in Differentiating Lymphocytes and Male Germ Cells

Interleukin 4 (IL-4) is a cytokine that is involved in the differentiation of B and T lymphocytes. In this report, we describe the identification of a novel gene, N.52, which was cloned from the murine pre-B cell line R8205 grown in the presence of IL-4 for 48 hr. Although N.52 expression is detectable at low levels in unstimulated R8205 cells, the level of N.52 dramatically increases after only .4 hr exposure to IL-4 and remains at a high .level up to 48 hr. Although N.52 expression is low or absent in normal spleen B and T cells, its expression can be induced by the differentiation signals delivered by LPS in B cells and by Con A in T-cell hybrids. While N.52 mRNA is absent in all highly differentiated organs, it is detectable in stem cell harboring lymphoid tissues such as bone marrow, fetal liver, and thymus. Furthermore, N.52 mRNA is expressed at strikingly high levels in the testis, specifically in differentiating male germ cells. It is induced by differentiation signals triggered by the combination of cyclic AMP and retinoic acid in teratocarcinoma F9 cells. Taken together, these data suggest that N.52 is a developmentally regulated gene whose expression in cells of the immune and reproductive systems may be controlled by stimuli that induce differentiation

(R)-albuterol decreases immune responses: role of activated T cells

Racemic albuterol is an equimolar mixture of two isomers, (R) and (S). Whether (R) and (S) isomers and the combination of both exert different effects in immune activation is not well defined. We analyzed the effects of (R+S)-albuterol, (R)-albuterol and (S)-albuterol in a murine model of allergic pulmonary inflammation and in activated T cells. Mice (C57BL/6) sensitized and aerosol challenged with the allergen ovalbumin (OVA) or phosphate buffered saline (PBS) were treated with (R)-albuterol, (S)-albuterol or (R+S)-albuterol. Following administration of (R)-albuterol, allergen induced bronchoalveolar lavage eosinophils and IgE showed a decrease, albeit not significantly by ANOVA. As T cells are important in allergic inflammation, we asked whether (R+S), (R) or (S)-albuterol might differ in effects on T cells and on the activity of the inflammatory transcription factor NF-κB. In activated T cells, (R)-albuterol administration decreased levels of inflammatory cytokines and NF-κB activity. These studies suggest that (R)-albuterol decreases cytokine secretion and NF-κB activity in T cells

NuSTAR Spectroscopy of Multi-Component X-ray Reflection from NGC 1068

We report on observations of NGC1068 with NuSTAR, which provide the best constraints to date on its $>10$~keV spectral shape. We find no strong variability over the past two decades, consistent with its Compton-thick AGN classification. The combined NuSTAR, Chandra, XMM-Newton, and Swift-BAT spectral dataset offers new insights into the complex reflected emission. The critical combination of the high signal-to-noise NuSTAR data and a spatial decomposition with Chandra allow us to break several model degeneracies and greatly aid physical interpretation. When modeled as a monolithic (i.e., a single N_H) reflector, none of the common Compton-reflection models are able to match the neutral fluorescence lines and broad spectral shape of the Compton reflection. A multi-component reflector with three distinct column densities (e.g., N_H~1.5e23, 5e24, and 1e25 cm^{-2}) provides a more reasonable fit to the spectral lines and Compton hump, with near-solar Fe abundances. In this model, the higher N_H components provide the bulk of the Compton hump flux while the lower N_H component produces much of the line emission, effectively decoupling two key features of Compton reflection. We note that ~30% of the neutral Fe Kalpha line flux arises from >2" (~140 pc), implying that a significant fraction of the <10 keV reflected component arises from regions well outside of a parsec-scale torus. These results likely have ramifications for the interpretation of poorer signal-to-noise observations and/or more distant objects [Abridged].Comment: Submitted to ApJ; 23 pages (ApJ format); 11 figures and 3 tables; Comments welcomed

A diverse virome in kidney transplant patients contains multiple viral subtypes with distinct polymorphisms

Recent studies have established that the human urine contains a complex microbiome, including a virome about which little is known. Following immunosuppression in kidney transplant patients, BK polyomavirus (BKV) has been shown to induce nephropathy (BKVN), decreasing graft survival. In this study we investigated the urine virome profile of BKV+ and BKV− kidney transplant recipients. Virus-like particles were stained to confirm the presence of VLP in the urine samples. Metagenomic DNA was purified, and the virome profile was analyzed using metagenomic shotgun sequencing. While the BK virus was predominant in the BKV+ group, it was also found in the BKV− group patients. Additional viruses were also detected in all patients, notably including JC virus (JCV) and Torque teno virus (TTV) and interestingly, we detected multiple subtypes of the BKV, JCV and TTV. Analysis of the BKV subtypes showed that nucleotide polymorphisms were detected in the VP1, VP2 and Large T Antigen proteins, suggesting potential functional effects for enhanced pathogenicity. Our results demonstrate a complex urinary virome in kidney transplant patients with multiple viruses with several distinct subtypes warranting further analysis of virus subtypes in immunosuppressed hosts

International consensus guideline for reporting transmission electron microscopy results in the diagnosis of Primary Ciliary Dyskinesia (BEAT PCD TEM Criteria)

Primary Ciliary Dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy (TEM) as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by TEM. A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 14 countries. An initial meeting and discussion were followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres. The final guideline a) Provides agreed terminology and a definition of class 1 defects which are diagnostic for PCD; b) Identifies class 2 defects which can indicate a diagnosis of PCD in combination with other supporting evidence; c) Describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD d) Defines adequacy of a diagnostic sample. This tested and externally validated statement provides a clear guideline for the diagnosis of PCD by TEM which can be used to standardise diagnosis internationally.</p

Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis

Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.</p

The variable hard x-ray emission of NGC 4945 as observed by NUSTAR

We present a broadband (~0.5-79 keV) spectral and temporal analysis of multiple NuSTAR observations combined with archival Suzaku and Chandra data of NGC4945, the brightest extragalactic source at 100 keV. We observe hard X-ray (> 10 keV) flux and spectral variability, with flux variations of a factor 2 on timescales of 20 ksec. A variable primary continuum dominates the high energy spectrum (>10 keV) in all the states, while the reflected/scattered flux which dominates at E< 10 keV stays approximately constant. From modelling the complex reflection/transmission spectrum we derive a Compton depth along the line of sight of tau_Thomson ~ 2.9, and a global covering factor for the circumnuclear gas of ~ 0.15. This agrees with the constraints derived from the high energy variability, which implies that most of the high energy flux is transmitted, rather that Compton-scattered. This demonstrates the effectiveness of spectral analysis in constraining the geometric properties of the circumnuclear gas, and validates similar methods used for analyzing the spectra of other bright, Compton-thick AGN. The lower limits on the e-folding energy are between 200-300 keV, consistent with previous BeppoSAX, Suzaku and Swift BAT observations. The accretion rate, estimated from the X-ray luminosity and assuming a bolometric correction typical of type 2 AGN, is in the range ~0.1-0.3 lambda_Edd depending on the flux state. The substantial observed X-ray luminosity variability of NGC4945 implies that large errors can arise from using single-epoch X-ray data to derive L/L_Edd values for obscured AGNs.Comment: Accepted for publication in Ap