Wnt4 and LAP2alpha as pacemakers of Thymic Epithelial Senescence

Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes

Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS)

Rationale: Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated. Objectives: To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity. Methods: Human, murine and in vitro primary alveolar epithelial cell work were included in this study. Findings: Vitamin D deficiency (plasma 25(OH)D levels 600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients. Conclusions: Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed

Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis

BACKGROUND: CD248 or Endosialin is a transmembrane molecule expressed in stromal cells binding to extracellular matrix (ECM) components. It has been previously implicated in kidney fibrosis, rheumatoid arthritis as well as in tumour-stromal interactions. This study investigates the role of CD248 in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis (IPF). METHODS: CD248 quantitative immunohistochemistry (IHC) was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of CD248 silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong CD248 expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of CD248 staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO (r2 > 0 · 35, p < 0 · 01). CD248 protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts (p < 0 · 01) and CD248 silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that CD248 overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that CD248 ligands are collagen type I, IV and fibronectin, we hypothesise that CD248 signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12890-016-0211-7) contains supplementary material, which is available to authorized users

The HIBEAM program: search for neutron oscillations at the ESS

With the construction of the European Spallation Source, a remarkable opportunity has emerged to conduct high sensitivity searches for neutron oscillations, including a first search for thirty years for free neutrons converting to antineutrons. Furthermore, searches can be made for transitions of neutrons and antineutrons to sterile neutron states. The HIBEAM program provides an increase in sensitivity of an order of magnitude compared to previous work. The HIBEAM program corresponds to baryon number violation by one and two units. The observation of a process satisfying a Sakharov condition addresses the open question of the origin of the matter-antimatter asymmetry in the Universe. Sterile neutron states would belong to a `dark' sector of particles which may explain dark matter. As electrically neutral, meta-stable objects that can be copiously produced and studied, neutrons represent an attractive portal to a `dark' sector. This paper describes the capability, design, infrastructure, and potential of the HIBEAM program. This includes a dedicated beamline, neutron optical system, magnetic shielding and control, and detectors for neutrons and antineutrons.Comment: 41 pages, 12 figure

The Rivet Parameter Influence in Fatigue Strength

The paper deals with the experimental analysis of the influence of the rivet parameters upon the fatigue strength of aircraft structures. Different riveted samples were tested on fatigue machine taking into account the diameter of the rivet and the forming pressure influence. By superposing the resulting Wöhler curves on the same graphic, some interesting conclusions were pointed

Numerical Models for Fatigue Crack Evolution Study

The paper presents some considerations regarding to the numerical simulation of the behaviour of the riveted structures in fatigue loading conditions. In order to estimate the stress intensity factor, “k”, different constitutive laws for the materials were considered. Choosing different contours for “J” integral calculation, some simplified models were studied. The final numerical results were analysed with respect to the physical tests

Epithelial-mesenchymal transition in lung development and disease: Does it exist and is it important?

Epithelial-mesenchymal transition (EMT) is a process when epithelial cells gradually transform into mesenchymal-like cells losing their epithelial functionality and characteristics. EMT is thought to be involved in the pathogenesis of numerous lung diseases ranging from developmental disorders, fibrotic tissue remodelling to lung cancer. The most important question-namely what is the importance and contribution of EMT in the pathogenesis of several chronic lung conditions (asthma, COPD, bronchiolitis obliterans syndrome and lung fibrosis)-is currently intensely debated. This review gives a brief insight into the mechanism and assessment methods of EMT in various pulmonary diseases and summarises the recent literature highlighting the controversial experimental data and conclusions

Integrated coal preparation and CWF processing plant: Conceptual design and costing. Final technical report

At the request of the US Department of Energy (DOE), Pittsburgh Energy Technology Center, a study was conducted to provide DOE with a reliable, documented estimate of the cost of producing coal-water fuel (CWF). The approach to the project was to specify a plant capacity and location, identify and analyze a suitable coal, and develop a conceptual design for an integrated coal preparation and CWF processing plant. Using this information, a definitive costing study was then conducted, on the basis of which an economic and sensitivity analysis was performed utilizing a financial evaluation model to determine a price for CWF in 1992. The design output of the integrated plant is 200 tons of coal (dry basis) per hour. Operating at a capacity factor of 83 percent, the baseline design yields approximately 1.5 million tons per year of coal on a dry basis. This is approximately equivalent to the fuel required to continuously generate 500 MW of electric power. The CWF produced by the plant is intended as a replacement for heavy oil or gas in electric utility and large industrial boilers. The particle size distribution, particularly the top size, and the ash content of the coal in the CWF are specified at significantly lower levels than is commonly found in typical pulverized coal grinds. The particle top size is 125 microns (vs typically 300m{mu} for pulverized coal) and the coal ash content is 3.8 percent. The lower top size is intended to promote complete carbon burnout at less derating in boilers that are not designed for coal firing. The reduced mineral matter content will produce ash of very fine particle size during combustion, which leads to less impaction and reduced fouling of tubes in convective passages

Integrated coal preparation and CWF processing plant: Conceptual design and costing

At the request of the US Department of Energy (DOE), Pittsburgh Energy Technology Center, a study was conducted to provide DOE with a reliable, documented estimate of the cost of producing coal-water fuel (CWF). The approach to the project was to specify a plant capacity and location, identify and analyze a suitable coal, and develop a conceptual design for an integrated coal preparation and CWF processing plant. Using this information, a definitive costing study was then conducted, on the basis of which an economic and sensitivity analysis was performed utilizing a financial evaluation model to determine a price for CWF in 1992. The design output of the integrated plant is 200 tons of coal (dry basis) per hour. Operating at a capacity factor of 83 percent, the baseline design yields approximately 1.5 million tons per year of coal on a dry basis. This is approximately equivalent to the fuel required to continuously generate 500 MW of electric power. The CWF produced by the plant is intended as a replacement for heavy oil or gas in electric utility and large industrial boilers. The particle size distribution, particularly the top size, and the ash content of the coal in the CWF are specified at significantly lower levels than is commonly found in typical pulverized coal grinds. The particle top size is 125 microns (vs typically 300m[mu] for pulverized coal) and the coal ash content is 3.8 percent. The lower top size is intended to promote complete carbon burnout at less derating in boilers that are not designed for coal firing. The reduced mineral matter content will produce ash of very fine particle size during combustion, which leads to less impaction and reduced fouling of tubes in convective passages