Imprinting of bronchial epithelial cells upon in vivo rhinovirus infection in asthma patients

BackgroundDefective translocation of the translational repressor TIAR (T-cell internal antigen receptor) in bronchial epithelial cells (BECs) from asthma patients underlies epithelial hyperresponsiveness, reflected by an exaggerated production of a select panel of inflammatory cytokines like CXCL-8, IL-6, G-CSF, CXCL-10, upon exposure to TNF and IL-17A. With this study we aimed to clarify whether epithelial hyperresponsiveness is a consistent finding, is changed upon in vivo exposure to rhinovirus-A16 (RV-A16) and, also applies to the bronchoconstrictor endothelin-1.MethodsBECs were obtained from asthma patients (n=18) and healthy individuals (n=11), 1 day before and 6 days post RV-A16 exposure. BECs were cultured and stimulated with TNF and IL-17A and inflammatory mediators were analysed. The bronchoalveolar lavage fluid (BALF) was obtained in parallel with BECs to correlate differential cell counts and inflammatory mediators with epithelial hyperresponsiveness.ResultsEpithelial hyperresponsiveness was confirmed in sequential samples and even increased in BECs from asthma patients after RV-A16 exposure, but not in BECs from healthy individuals. Endothelin-1 tended to increase in BECs from asthma patients collected after RV-A16 exposure, but not in BECs from healthy individuals. In vitro CXCL-8 and endothelin-1 production correlated. In vivo relevance for in vitro CXCL-8 and endothelin-1 production was shown by correlations with FEV1% predicted and CXCL-8 BALF levels.ConclusionEpithelial hyperresponsiveness is an intrinsic defect in BECs from asthma patients, which increases upon viral exposure, but not in BECs from healthy individuals. This epithelial hyperresponsiveness also applies to the bronchoconstrictor endothelin-1, which could be involved in airway obstruction.

Investigation of defect levels in Bi12SiO20 single crystals by thermally stimulated current measurements

Bi12SiO20 (BSO) single crystal belongs to the sillenite semiconducting family known as defective compounds. The present paper investigates the defect centers in BSO grown by Czochralski method by means of thermally stimulated current (TSC) measurements performed in the 10-260 K range. The TSC glow curve obtained at heating rate of β = 0.1 K/s presented several peaks associated with intrinsic defect centers. The activation energies of defect centers were revealed as 0.09, 0.15, 0.18, 0.22, 0.34, 0.70 and 0.82 eV accomplishing the curve fit analyses method. The peak maximum temperatures and orders of kinetics of each deconvoluted peak were also determined as an outcome of fitting process. TSC experiments were expanded by making the measurements at various heating rates between 0.1 and 0.3 K/s to get information about the heating rate dependent peak parameters.

Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis

SummaryTissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis.We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from SSc patients deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This can be mimicked in healthy fibroblast stimulated by soluble factors that drive inflammation and fibrosis in SSc and is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling.In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.Abstract Figure

Intrinsic color centers in 4H-silicon carbide formed by heavy ion implantation and annealing

We study the generation and transformation of intrinsic luminescent centers in 4H-polytype of silicon carbide via heavy ion implantation and subsequent annealing. Defects induced by the implantation of germanium (Ge) or tin (Sn) have been characterized by photoluminescence (PL) spectra recorded at cryogenic temperatures. We find three predominant but as-yet-unidentified PL signatures (labeled as DI1–3) at the wavelength of 1002.8 nm (DI1), 1004.7 nm (DI2), and 1006.1 nm (DI3) after high dose implantation (> 4 × 1013 cm-2) and high temperature annealing (> 1700○C). The fact that the DI lines co-occur and are energetically close together suggest that they originate from the same defect. Regardless of the implanted ion (Ge or Sn), a sharp increase in their PL intensity is observed when the implantation damage becomes high (vacancy concentration > 1022 cm-3), indicating that the lines stem from an intrinsic defect caused by the damage. By tracking the PL signals after stepwise annealing, we examine how the overall intrinsic defects behave in the temperature range of 500 – 1800○C; the silicon vacancies formed by the implantation transform into either divacancies or antisite-vacancy pairs with annealing at about 1000○C. These spectra signatures are strongly reduced at 1200○C where the so-called TS defects are maximized in luminescence. As a final stage, the DI defects, which are most likely formed of antisites and vacancies, emerge at 1700○C. Our results provide a knowledge on how to incorporate and manipulate the intrinsic luminescent centers in SiC with ion implantation and annealing, paving the way for fully integrated quantum technology employing SiC.

Simulation-Based Defect Engineering in “α-Spodumene”

Naturally occurring lithium-rich α-spodumene (α-LiAlSi2O6) is a technologically important mineral that has attracted considerable attention in ceramics, polymer industries, and rechargeable lithium ion batteries (LIBs). The defect chemistry and dopant properties of this material are studied using a well-established atomistic simulation technique based on classical pair-potentials. The most favorable intrinsic defect process is the Al-Si anti-site defect cluster (1.08 eV/defect). The second most favorable defect process is the Li-Al anti-site defect cluster (1.17 eV/defect). The Li-Frenkel is higher in energy by 0.33 eV than the Al-Si anti-site defect cluster. This process would ensure the formation of Li vacancies required for the Li diffusion via the vacancy-assisted mechanism. The Li-ion diffusion in this material is slow, with an activation energy of 2.62 eV. The most promising isovalent dopants on the Li, Al, and Si sites are found to be Na, Ga, and Ge, respectively. The formation of both Li interstitials and oxygen vacancies can be facilitated by doping of Ga on the Si site. The incorporation of lithium is studied using density functional theory simulations and the electronic structures of resultant complexes are discussed.

Yippee like 4 (Ypel4) is essential for normal mouse red blood cell membrane integrity

The YPEL family genes are highly conserved across a diverse range of eukaryotic organisms and thus potentially involved in essential cellular processes. Ypel4, one of five YPEL family gene orthologs in mouse and human, is highly and specifically expressed in late terminal erythroid differentiation (TED). In this study, we investigated the role of Ypel4 in murine erythropoiesis, providing for the first time an in-depth description of a Ypel4-null phenotype in vivo. We demonstrated that the Ypel4-null mice displayed a secondary polycythemia with macro- and reticulocytosis. While lack of Ypel4 did not affect steady-state TED in the bone marrow or spleen, the anemia-recovering capacity of Ypel4-null cells was diminished. Furthermore, Ypel4-null red blood cells (RBC) were cleared from the circulation at an increased rate, demonstrating an intrinsic defect of RBCs. Scanning electron micrographs revealed an ovalocytic morphology of Ypel4-null RBCs and functional testing confirmed reduced deformability. Even though Band 3 protein levels were shown to be reduced in Ypel4-null RBC membranes, we could not find support for a physical interaction between YPEL4 and the Band 3 protein. In conclusion, our findings provide crucial insights into the role of Ypel4 in preserving normal red cell membrane integrity.

Dysregulated myogenesis and autophagy in genetically induced pulmonary emphysema

Patients with chronic obstructive pulmonary disease (COPD)-pulmonary emphysema often develop locomotor muscle dysfunction, which is independently associated with disability and higher mortality in that population. Muscle dysfunction entails reduced muscle mass and force-generation capacity, which are influenced by fibers integrity. Myogenesis, which is muscle turnover driven by progenitor cells such as satellite cells, contributes to the maintenance of muscle integrity in the context of organ development and injury-repair cycles. Injurious events crucially occur in COPD patients skeletal muscles in the setting of exacerbations and infections which lead to acute decompensations for limited periods of time after which, patients typically fail to recover the baseline status they had before the acute event. Autophagy, which is dysregulated in muscles from COPD patients, is a key regulator of satellite cells activation and myogenesis, yet very little research has so far investigated the mechanistic role of autophagy dysregulation in COPD muscles. Using a genetically inducible murine model of COPD-driven muscle dysfunction and confirmed with a second genetic animal model, we found a significant myogenic dysfunction associated with a reduced proliferative capacity of freshly isolated satellite cells. Transplantation experiments followed by lineage tracing suggest that an intrinsic defect in satellite cells, and not in the COPD environment, plays a dominant role in the observed myogenic dysfunction. RNA sequencing analysis of freshly isolated satellite cells suggests dysregulation of transcripts associated with control of cell cycle and autophagy, which is confirmed by a direct observation of COPD mice satellite cells fluorescent-tracked autophagosome formation. Moreover, spermidine-induced autophagy stimulation leads to improved satellite cells autophagosome turnover, replication rate and myogenesis. Our data suggests that pulmonary emphysema causes a disrupted myogenesis, which could be improved with stimulation of autophagy and satellite cells activation, leading to an attenuated muscle dysfunction in this context.