Airway smooth muscle cells from severe asthma patients with fixed airflow obstruction are responsive to steroid and bronchodilator treatment in vitro

Asthma is characterised by recurrent symptoms associated with variable airflow obstruction and airway hyperresponsiveness, all of which are improved with combination inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) treatment in mild-to-moderate asthma [1]. A proportion of patients however develop fixed airflow obstruction (FAO), despite optimised treatment. FAO is prevalent in up to 60% of patients with severe asthma and is associated with a more rapid decline in lung function and increased symptoms [2]. The underlying mechanisms of FAO in asthma are poorly understood; therefore, development of novel treatment strategies remains a challenge. Airway smooth muscle cells (ASMCs) are the major effector cells of bronchoconstriction in asthma and also contribute to the inflammatory process by secreting pro-inflammatory cytokines and chemokines. Therefore, ASMCs are a major target of both β2-agonist and ICS treatment [3]. Although several studies have suggested that steroid signalling [4] or β2-adrenoceptor (β2AR) signalling may be abnormally regulated in severe asthma [5], it remains unknown whether impaired airway smooth muscle corticosteroid and/or β2-agonist response may contribute to the development of FAO. The aim of this study was to investigate whether primary human ASMCs obtained from severe asthma patients with FAO differ in their response to β2-agonists and corticosteroids compared with asthma patients without FAO and healthy controls. We hypothesised that ASMCs from asthma patients with FAO are less responsive to corticosteroid and β2-agonist treatment than those from patients without FA

Right Ventricular Outflow Tract Stenting in a Low Birth Weight Infant Born With Tetralogy of Fallot and Prostaglandin E1 Dependency

Surgical skill and strategy for the correction of tetralogy of Fallot (TOF) have improved and resulted in satisfactory outcomes. However, prematurity and low birth weight continue to remain risk factors for poor outcomes. We present a case of a 2,150 g neonate born with TOF, in whom palliation was achieved with right ventricular outflow tract (RVOT) stenting. Seventy-seven days after the procedure, stenosis of RVOT below the stent was identified. At that time his body weight was 4.9 kg and total corrective surgery was deemed feasible. Eight months following surgical repair, the patient remained well without medical intervention. RVOT stenting may be a viable interim procedure while waiting for a low birth weight neonate born with TOF and prostaglandin E1 dependency to reach optimal weight to undergo corrective surgery

Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis

The Ten-eleven translocation (TET) enzymes regulate gene expression by promoting DNA demethylation and partnering with chromatin modifiers. TET2, a member of this family, is frequently mutated in hematological disorders. The contributions of TET2 in hematopoiesis have been attributed to its DNA demethylase activity, and the significance of its nonenzymatic functions has remained undefined. To dissect the catalytic and non-catalytic requirements of Tet2, we engineered catalytically inactive Tet2 mutant mice and conducted comparative analyses of Tet2 mutant and Tet2 knockout animals. Tet2 knockout mice exhibited expansion of hematopoietic stem and progenitor cells (HSPCs) and developed myeloid and lymphoid disorders, while Tet2 mutant mice predominantly developed myeloid malignancies reminiscent of human myelodysplastic syndromes. HSPCs from Tet2 knockout mice exhibited distinct gene expression profiles, including downregulation of Gata2. Overexpression of Gata2 in Tet2 knockout bone marrow cells ameliorated disease phenotypes. Our results reveal the non-catalytic roles of TET2 in HSPC homeostasis

Comprehensive Control of Optical Polarization Anisotropy in Semiconducting Nanowires

The demonstration of strong photoluminescence polarization anisotropy in semiconducting nanowires embodies both technological promise and scientific challenge. Here we present progress on both fronts through the study of the photoluminescence polarization anisotropy of randomly oriented nanowire ensembles in materials without/with crystalline anisotropy, small/wide bandgap, and both III-V/II-VI chemistry (InP/ZnO nanowires, respectively). Comprehensive control of the polarization anisotropy is realized by dielectric matching with conformally deposited Ta2O5 (dielectric ratios of 9.6:4.41 and 4.0:4.41 for InP and ZnO, respectively). After dielectric matching, the polarization anisotropy of the nanowire ensembles is reduced by 86% for InP:Ta2O5 and 84% for ZnO:Ta2O5

Optical Images and Source Catalog of AKARI North Ecliptic Pole Wide Survey Field

We present the source catalog and the properties of the $B-, R-$, and $I-$band images obtained to support the {\it AKARI} North Ecliptic Pole Wide (NEP-Wide) survey. The NEP-Wide is an {\it AKARI} infrared imaging survey of the north ecliptic pole covering a 5.8 deg$^2$ area over 2.5 -- 6 \micron wavelengths. The optical imaging data were obtained at the Maidanak Observatory in Uzbekistan using the Seoul National University 4k $\times$ 4k Camera on the 1.5m telescope. These images cover 4.9 deg$^2$ where no deep optical imaging data are available. Our $B-, R-$, and $I-$band data reach the depths of $\sim$23.4, $\sim$23.1, and $\sim$22.3 mag (AB) at 5$\sigma$, respectively. The source catalog contains 96,460 objects in the $R-$band, and the astrometric accuracy is about 0.15\arcsec at 1$\sigma$ in each RA and Dec direction. These photometric data will be useful for many studies including identification of optical counterparts of the infrared sources detected by {\it AKARI}, analysis of their spectral energy distributions from optical through infrared, and the selection of interesting objects to understand the obscured galaxy evolution.Comment: 39 pages, 12 figure

Development of novel adenoviral vectors to overcome challenges observed with HAdV-5 based constructs

Recombinant vectors based on human adenovirus serotype 5 (HAdV-5) have been extensively studied in pre-clinical models and clinical trials over the last two decades. However, the thorough understanding of the HAdV-5 interaction with human subjects has uncovered major concerns about its product applicability. High vector-associated toxicity and widespread pre-existing immunity have been shown to significantly impede the effectiveness of HAdV-5 mediated gene transfer. It is therefore that the in depth knowledge attained working on HAdV-5 is currently being used to develop alternative vectors. Here, we provide a comprehensive overview of data obtained in recent years disqualifying the HAdV-5 vector for systemic gene delivery as well as novel strategies being pursued to overcome the limitations observed with particular emphasis on the ongoing vectorization efforts to obtain vectors based on alternative serotypes

Rebirth of X-ray Emission from the Born-Again Planetary Nebula A 30

The planetary nebula (PN) A30 is believed to have undergone a very late thermal pulse resulting in the ejection of knots of hydrogen-poor material. Using HST images we have detected the angular expansion of these knots and derived an age of 850+280-150 yr. To investigate the spectral and spatial properties of the soft X-ray emission detected by ROSAT, we have obtained Chandra and XMM-Newton observations of A30. The X-ray emission from A30 can be separated into two components: a point-source at the central star and diffuse emission associated with the hydrogen-poor knots and the cloverleaf structure inside the nebular shell. To help us assess the role of the current stellar wind in powering this X-ray emission, we have determined the stellar parameters of the central star of A 30 using a non-LTE model fit to its optical and UV spectrum. The spatial distribution and spectral properties of the diffuse X-ray emission is suggestive that it is generated by the post-born-again and present fast stellar winds interacting with the hydrogen-poor ejecta of the born-again event. This emission can be attributed to shock-heated plasma, as the hydrogen-poor knots are ablated by the stellar winds, under which circumstances the efficient mass-loading of the present fast stellar wind raises its density and damps its velocity to produce the observed diffuse soft X-rays. Charge transfer reactions between the ions of the stellar winds and material of the born-again ejecta has also been considered as a possible mechanism for the production of diffuse X-ray emission, and upper limits on the expected X-ray production by this mechanism have been derived. The origin of the X-ray emission from the central star of A 30 is puzzling: shocks in the present fast stellar wind and photospheric emission can be ruled out, while the development of a new, compact hot bubble confining the fast stellar wind seems implausible.Comment: 29 pages, 11 figures, 4 tables; accepted for publication by Ap

SLC26A9 is a constitutively active, CFTR-regulated anion conductance in human bronchial epithelia

Human bronchial epithelial (HBE) cells exhibit constitutive anion secretion that is absent in cells from cystic fibrosis (CF) patients. The identity of this conductance is unknown, but SLC26A9, a member of the SLC26 family of CF transmembrane conductance regulator (CFTR)-interacting transporters, is found in the human airway and exhibits chloride channel behavior. We sought differences in the properties of SLC26A9 and CFTR expressed in HEK 293 (HEK) cells as a fingerprint to identify HBE apical anion conductances. HEK cells expressing SLC26A9 displayed a constitutive chloride current that was inhibited by the CFTR blocker GlyH-101 (71 ± 4%, 50 µM) and exhibited a near-linear current–voltage (I-V) relation during block, while GlyH-101–inhibited wild-type (wt)CFTR exhibited a strong inward-rectified (IR) I-V relation. We tested polarized HBE cells endogenously expressing either wt or ΔF508-CFTR for similar activity. After electrical isolation of the apical membrane using basolateral α-toxin permeabilization, wtCFTR monolayers displayed constitutive chloride currents that were inhibited by GlyH-101 (68 ± 6%) while maintaining a near-linear I-V relation. In the absence of blocker, the addition of forskolin stimulated a current increase having a linear I-V; GlyH-101 blocked 69 ± 7% of the current and shifted the I-V relation IR, consistent with CFTR activation. HEK cells coexpressing SLC26A9 and wtCFTR displayed similar properties, as well as forskolin-stimulated currents that exceeded the sum of those in cells separately expressing SLC26A9 or wtCFTR, and an I-V relation during GlyH-101 inhibition that was moderately IR, indicating that SLC26A9 contributed to the stimulated current. HBE cells from CF patients expressed SLC26A9 mRNA, but no constitutive chloride currents. HEK cells coexpressing SLC26A9 with ΔF508-CFTR also failed to exhibit SLC26A9 current. We conclude that SLC26A9 functions as an anion conductance in the apical membranes of HBE cells, it contributes to transepithelial chloride currents under basal and cAMP/protein kinase A–stimulated conditions, and its activity in HBE cells requires functional CFTR

Effects of Eimeria maxima infection doses on growth performance and gut health in dual-infection model of necrotic enteritis in broiler chickens

The objective of this study was to investigate the effects of the different doses of Eimeria maxima (EM) oocysts on growth performance and intestinal health in broiler chickens challenged with a dual infection model of necrotic enteritis (NE) using EM and NetB+Clostridium perfringens (CP). A total of 432 fourteen-d-old male Cobb 500 broiler chickens were divided into 6 groups with 6 replicates each. The six different groups were as follows: Control, non-challenged; T0+, challenged with CP at 1 × 109 colony forming unit; T5K+, T0+ + 5,000 EM oocysts; T10K+, T0+ + 10,000 EM oocysts; T20K+; T0+ + 20,000 EM oocysts; and T40K+; T0+ + 40,000 EM oocysts. The challenge groups were orally inoculated with EM strain 41A on d 14, followed by NetB+CP strain Del-1 on 4 days post inoculation (dpi). Increasing EM oocysts decreased d 21 body weight, body weight gain, feed intake (linear and quadratic, p < 0.001), and feed efficiency (linear, p < 0.001) from 0 to 7 dpi. Increasing EM oocysts increased jejunal NE lesion score and intestinal permeability on 5, 6, and 7 dpi (linear, p < 0.05). On 7 dpi, increasing the infection doses of EM oocysts increased jejunal CP colony counts (linear, p < 0.05) and increased fecal EM oocyst output (linear and quadratic, p < 0.001). Furthermore, increasing the infection doses of EM oocysts decreased the villus height to crypt depth ratios and the goblet cell counts (linear, p < 0.05) on 6 dpi. Increasing EM oocysts downregulated the expression of MUC2, B0AT, B0,+AT, PepT1, GLUT2, AvBD3 and 9, LEAP2, and TLR4, while upregulating CLDN1, CATHL3, IL-1β, IFN-γ, TNFSF15, TNF-α, IL-10, and Gam56 and 82 on 6 dpi (linear, p < 0.05). Additionally, increasing EM oocysts decreased Pielou’s evenness and Shannon’s entropy (linear, p < 0.01). In conclusion, increasing the infection doses of EM significantly aggravated the severity of NE and exerted negative impact on intestinal health from 5 to 7 dpi