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Tgf-β1 Inhibits Cftr Biogenesis and Prevents Functional Rescue of ΔF508-Cftr in Primary Differentiated Human Bronchial Epithelial Cells
Steven M. Snodgrass, Kristine M. Cihil, Pamela K. Cornuet, Michael M. Myerburg, Agnieszka Swiatecka-Urban
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063167
Abstract: CFTR is an integral transmembrane glycoprotein and a cAMP-activated Cl？ channel. Mutations in the CFTR gene lead to Cystic Fibrosis (CF)–an autosomal recessive disease with majority of the morbidity and mortality resulting from airway infection, inflammation, and fibrosis. The most common disease-associated mutation in the CFTR gene–deletion of Phe508 (ΔF508) leads to a biosynthetic processing defect of CFTR. Correction of the defect and delivery of ΔF508-CFTR to the cell surface has been highly anticipated as a disease modifying therapy. Compared to promising results in cultured cell this approach was much less effective in CF patients in an early clinical trial. Although the cause of failure to rescue ΔF508-CFTR in the clinical trial has not been determined, presence of factor(s) that interfere with the rescue in vivo could be considered. The cytokine TGF-β1 is frequently elevated in CF patients. TGF-β1 has pleiotropic effects in different disease models and genetic backgrounds and little is known about TGF-β1 effects on CFTR in human airway epithelial cells. Moreover, there are no published studies examining TGF-β1 effects on the functional rescue of ΔF508-CFTR. Here we found that TGF-β1 inhibits CFTR biogenesis by reducing mRNA levels and protein abundance in primary differentiated human bronchial epithelial (HBE) cells from non-CF individuals. TGF-β1 inhibits CFTR biogenesis without compromising the epithelial phenotype or integrity of HBE cells. TGF-β1 also inhibits biogenesis and impairs the functional rescue of ΔF508-CFTR in HBE cells from patients homozygous for the ΔF508 mutation. Our data indicate that activation of TGF-β1 signaling may inhibit CFTR function in non-CF individuals and may interfere with therapies directed at correcting the processing defect of ΔF508-CFTR in CF patients.
Liquid hyper-absorption as a cause of increased DTPA clearance in the cystic fibrosis airway
Timothy E Corcoran, Kristina M Thomas, Stefanie Brown, Michael M Myerburg, Landon W Locke and Joseph M Pilewski
EJNMMI Research , 2013, DOI: 10.1186/2191-219X-3-14
Abstract: These results imply that DTPA absorption is directly related to liquid absorption, consistent with increased rates of airway surface liquid absorption in the CF airway, and that modification of liquid absorption from osmotic therapies might be detectable through DTPA absorption measurements in vivo.
Cartilage Oligomeric Matrix Protein in Idiopathic Pulmonary Fibrosis
Louis J. Vuga, Jadranka Milosevic, Kusum Pandit, Ahmi Ben-Yehudah, Yanxia Chu, Thomas Richards, Joshua Sciurba, Michael Myerburg, Yingze Zhang, Anil V. Parwani, Kevin F. Gibson, Naftali Kaminski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083120
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and life threatening disease with median survival of 2.5–3 years. The IPF lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein (COMP), a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes (Fold change 13, p-value <0.05) in IPF lungs. This finding was confirmed at the mRNA level by nCounter？ expression analysis in additional 115 IPF lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of IPF lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-β1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-β1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of IPF patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity (FVC). Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-β1 activity in patients with IPF. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in IPF and interfere with the amplification of TGF-β1 signaling should be persuaded.
The Principles of Causal Conspiracy  [PDF]
Michael M. Anthony
Journal of Quantum Information Science (JQIS) , 2014, DOI: 10.4236/jqis.2014.43016
Abstract: The human mind understands logical processes and causality and formulates theories based on logical descriptions of empirical evidence. The Principles of Causal Conspiracy is based on defining information as logical charges similar to electric charges. Such information charges can be modeled in the vacuum of a quantum probability firmament as symmetry of quantum charges with a zero net charge. Observation of a state lifts one of these charges in a Möbius transformation from a multipolar field of possibilities that maximizes a local monopole field that is observable. In the first of several papers, I introduce new and profound principles, the Principles of Causal Conspiracy, to provide a consistent epistemology for quantum theory, relativity theory and all the known sciences.
The Towering Zeta Function  [PDF]
Michael M. Anthony
Advances in Pure Mathematics (APM) , 2016, DOI: 10.4236/apm.2016.65026
Abstract: Over a century and half has passed when Bernhard Riemann hypothesized that the non-trivial roots of the Riemann zeta function ζ(s) all lie on the half-line \"\". In this paper the Zeta function is iterated as a power tower and its properties are applied as an approach to an indication that the Riemann hypothesis might be true. It is known that complex valued Power towers converge under certain conditions to exponential power towers of entire functions. These properties can be used to resolve the Riemann Hypothesis.
Analysis of Post-Burial Soil Developments of Pre-AD 79 Roman Paleosols near Pompeii (Italy)  [PDF]
Sebastian Vogel, Michael M？rker
Open Journal of Soil Science (OJSS) , 2014, DOI: 10.4236/ojss.2014.410035
Abstract: The AD 79 eruption of Somma-Vesuvius completely buried the ancient landscape around Pompeii (Italy) to some extent conserving the pre-AD 79 Roman paleosols of the Sarno River plain. To estimate potential post-burial soil developments of these paleosols detailed soil liquid and solid phase analysis were carried out. Firstly, an in-situ soil hydrological monitoring was conducted within a pre-AD 79 paleosol in natural undisturbed stratification. The results show that soil water flow and nutrient transport from the overlying volcanic deposits into the pre-AD 79 paleosol take place. Secondly, to estimate their influence on the paleosol’s mineral soil properties, the solid phase of four pre-AD 79 paleosols and associated modern unburied soils were analysed and compared. By combining the data from the soil liquid and solid phase analysis, potential post-burial changes in the paleosols were estimated. Finally, a rise of the mean groundwater table was determined since AD 79. This distinguishes the Sarno River plain into two different zones of post-burial soil developments: 1) lower altitudes where formerly terrestrial paleosols are now influenced by groundwater dynamics and 2) higher altitudes where the paleosols are still part of the vadose zone and rather influenced by infiltration water or interflow. Thus, the mechanism of potential post-burial soil development being active in the pre-AD 79 paleosols is not uniform for the entire Sarno River plain but strongly depends on the paleotopographic situation.
Siltstone Geochemical Compositions: Applications for Event Size and Correlation  [PDF]
Kannipa Motanated, Michael M. Tice
International Journal of Geosciences (IJG) , 2016, DOI: 10.4236/ijg.2016.72015
Abstract: Thinly laminated siltstone and sandy siltstone are major components of the Upper Permian Brushy Canyon Formation, west Texas and south New Mexico. These rocks have been variously interpreted as the deposits of low-density turbidity currents or as windblown sediment deposited over water. Nevertheless, all models agreed that this lithology was deposited without subsequent reworking by bottom currents or burrowing organisms. These siltstones, thus, are ideal test units for quantitatively estimating hydraulic properties of the flows that formed them. In particular, the Zr/Ti ratio was tested as a geochemical proxy for flow size and transport distance. In situ geochemical abundance and grain size of particles with contrasting susceptibility to erosion—Zr- and Ti-rich particles—were mapped and measured by X-ray fluorescence analytical microscopy, μXRF. Lamination thickness was measured from Fe fluorescence intensity, which increased sharply at the top of each layer. Within the same sample, zircon grains were systematically finer than rutilated quartz grains. Zr/Ti fluorescence ratio positively correlated with lamination thickness, not particle sizes. In other words, Zr/Ti fluorescence ratio fluctuations resulted from variations in mineral abundance. Therefore, variations of Zr/Ti fluorescence ratio in these siltstones are likely caused by fluctuations in the intensity of erosional events rather than transport distance. High Zr/Ti ratios and thick laminations reflect periods of enhanced erosion. The average wind velocity during typical events was estimated to be at least 150 km?hr?1, or the equivalent of a Category 1 hurricane. The method used here could be applied to both outcrop and subsurface strata correlation.
Riemann and Euler Sum Investigation in an Introductory Calculus Class  [PDF]
Michael M. Henry, Dennis M. Cates
Open Journal of Discrete Mathematics (OJDM) , 2011, DOI: 10.4236/ojdm.2011.12007
Abstract: This paper provides a detailed outline of a mathematical research exploration for use in an introductory high school or college Calculus class and is directed toward teachers of such courses. The discovery is accomplished by introducing a novel method to generate a polynomial expression for each of the Euler sums, ΣNk=0kn,n∈Z+ . The described method flows simply from initial discussions of the Riemann sum definition of a definite integral and is readily accessible to all new calculus students. Students investigate the Bernoulli numbers and the interesting connections with Pascal's Triangle. Advice is offered throughout as to how the project can be assigned to students and offers multiple suggestions for additional exploration for any motivated student.
Quantum Tomography of Semi-Algebraic Sets with Constrained Measurements
Michael Kech,Michael M. Wolf
Mathematics , 2015,
Abstract: We analyse quantum state tomography in scenarios where measurements and states are both constrained. States are assumed to live in a semi-algebraic subset of state space and measurements are supposed to be rank-one POVMs, possibly with additional constraints. Specifically, we consider sets of von Neumann measurements and sets of local observables. We provide upper bounds on the minimal number of measurement settings or outcomes that are required for discriminating all states within the given set. The bounds exploit tools from real algebraic geometry and lead to generic results that do not only show the existence of good measurements but guarantee that almost all measurements with the same dimension characteristic perform equally well. In particular, we show that on an $n$-dimensional Hilbert space any two states of a semi-algebraic subset can be discriminated by $k$ generic von Neumann measurements if $k(n-1)$ is larger than twice the dimension of the subset. In case the subset is given by states of rank at most $r$, we show that $k$ generic von Neumann measurements suffice to discriminate any two states provided that $k(n-1)>4r(n-r)-2$. Furthermore, we obtain corresponding results for low-rank matrix recovery of hermitian matrices and the phase retrieval problem.
Obstructive Sleep Apnea and Post-Operative Complications: Single Center Data, Review of Literature and Guidelines for Practicing Internists and Surgeons  [PDF]
Kenneth M. Nugent, Michael Phy, Rishi Raj
Surgical Science (SS) , 2012, DOI: 10.4236/ss.2012.32012
Abstract: Obstructive sleep apnea has been linked to higher rates of post-operative complications in some studies. We examined the prevalence of obstructive sleep apnea and its impact on post-operative complications in 125 patients (21 prospective, 104 retrospective) undergoing various elective outpatient surgeries at our institution. Ten percent of these patients had OSA, and half of them were on continuous positive airway pressure therapy (CPAP). Patients who were on CPAP as outpatients received CPAP post-operatively as well. No patients died, and the prevalence of post-operative complications was low. There was no difference in complication rates between patients with and without OSA. We also review the existing literature on this subject and make practical recommendations regarding pre-operative evaluation and post-operative management of these patients for practicing internists and surgeons based on the current literature.
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