Alpha-1 antitrypsin limits neutrophil extracellular trap disruption of airway epithelial barrier function.

Neutrophil extracellular traps contribute to lung injury in cystic fibrosis and asthma, but the mechanisms are poorly understood. We sought to understand the impact of human NETs on barrier function in primary human bronchial epithelial and a human airway epithelial cell line. We demonstrate that NETs disrupt airway epithelial barrier function by decreasing transepithelial electrical resistance and increasing paracellular flux, partially by NET-induced airway cell apoptosis. NETs selectively impact the expression of tight junction genes claudins 4, 8 and 11. Bronchial epithelia exposed to NETs demonstrate visible gaps in E-cadherin staining, a decrease in full-length E-cadherin protein and the appearance of cleaved E-cadherin peptides. Pretreatment of NETs with alpha-1 antitrypsin (A1AT) inhibits NET serine protease activity, limits E-cadherin cleavage, decreases bronchial cell apoptosis and preserves epithelial integrity. In conclusion, NETs disrupt human airway epithelial barrier function through bronchial cell death and degradation of E-cadherin, which are limited by exogenous A1AT.

Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression.

BACKGROUND: The majority of prostate cancers (CaP) are detected in early stages with uncertain prognosis. Therefore, an intensive effort is underway to define early predictive markers of CaP with aggressive progression characteristics. METHODS: In order to define such prognostic markers, we performed comparative analyses of transcriptomes of well- and poorly differentiated (PD) tumor cells from primary tumors of patients (N=40) with 78 months of mean follow-up after radical prostatectomy. Validation experiments were carried out at transcript level by quantitative real-time reverse transcriptase-PCR (RT-PCR) (N=110) and at protein level by immunohistochemistry (N=53) in primary tumors from an independent patient cohort. RESULTS: Association of a biochemical network of 12 genes with SPARC gene as a central node was highlighted with PD phenotype. Of note, there was remarkable enrichment of NKXH_NKXH_HOX composite regulatory elements in the promoter of the genes in this network suggesting a biological significance of this gene-expression regulatory mechanism in CaP progression. Further, quantitative expression analyses of SPARC mRNA in primary prostate tumor cells of 110 patients validated the association of SPARC expression with poor differentiation and higher Gleason score. Most significantly, higher SPARC protein expression at the time of prostatectomy was associated with the subsequent development of metastasis (P=0.0006, AUC=0.803). CONCLUSIONS: In summary, we propose that evaluation of SPARC in primary CaP has potential as a prognostic marker of metastatic progression.

Practical criterion for delay estimation using random perturbations.

Many systems contain an internal time delay, which significantly influences their dynamical properties. Methods to estimate this delay from times series in the presence of dynamical noise are not systematically studied. Addressing this problem, we demonstrate that it is sufficient to analyze the system's response to short-correlated external disturbances or internal noise. Following this idea, it is shown for linear and nonlinear systems, as well as for periodic dynamics, that the delay can be estimated by analyzing the correlation function. This method covers the case of strong noise and multiple delays.

Different cascade speeds for longitudinal and transverse velocity increments of small-scale turbulence.

We address the problem of differences between longitudinal and transverse velocity increments in isotropic small scale turbulence. The relationship of these two quantities is analyzed experimentally by means of stochastic Markovian processes leading to a phenomenological Fokker-Planck equation from which a generalization of the Kármán equation is derived. From these results, a simple relationship between longitudinal and transverse structure functions is found which explains the differences in the scaling properties of these two structure functions.