Classification of interstitial lung disease patterns with topological texture features

Topological texture features were compared in their ability to classify morphological patterns known as 'honeycombing' that are considered indicative for the presence of fibrotic interstitial lung diseases in high-resolution computed tomography (HRCT) images. For 14 patients with known occurrence of honey-combing, a stack of 70 axial, lung kernel reconstructed images were acquired from HRCT chest exams. A set of 241 regions of interest of both healthy and pathological (89) lung tissue were identified by an experienced radiologist. Texture features were extracted using six properties calculated from gray-level co-occurrence matrices (GLCM), Minkowski Dimensions (MDs), and three Minkowski Functionals (MFs, e.g. MF.euler). A k-nearest-neighbor (k-NN) classifier and a Multilayer Radial Basis Functions Network (RBFN) were optimized in a 10-fold cross-validation for each texture vector, and the classification accuracy was calculated on independent test sets as a quantitative measure of automated tissue characterization. A Wilcoxon signed-rank test was used to compare two accuracy distributions and the significance thresholds were adjusted for multiple comparisons by the Bonferroni correction. The best classification results were obtained by the MF features, which performed significantly better than all the standard GLCM and MD features (p < 0.005) for both classifiers. The highest accuracy was found for MF.euler (97.5%, 96.6%; for the k-NN and RBFN classifier, respectively). The best standard texture features were the GLCM features 'homogeneity' (91.8%, 87.2%) and 'absolute value' (90.2%, 88.5%). The results indicate that advanced topological texture features can provide superior classification performance in computer-assisted diagnosis of interstitial lung diseases when compared to standard texture analysis methods.Comment: 8 pages, 5 figures, Proceedings SPIE Medical Imaging 201

Cis-activation in the Notch signaling pathway

The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can also activate Notch receptors. This cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling ‘negative’ (repressive) signaling. These results establish cis-activation as an additional mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts

Phytotherapeutic control of food borne pathogens by Jasminum sambac L. flowers

Objective: This study is aimed to determine the antibacterial effect of Jasminum sambac against foodborne pathogens.Methods: Antibacterial activity of methanol and chloroform extract of J. sambac flowers against foodborne pathogens (Bacillus cereus, Listeria monocytogenes, Shigella flexeneri, Salmonella serovar enterica Typhi, Staphylococcus aureus and Escherichia coli) were performed using disc diffusion method and their minimal inhibitory concentration (MIC) was also determined. The preliminary phytochemical screening and gas chromatography-mass spectroscopic (GC-MS) analysis of methanol and chloroform extract of J. sambac was analyzed using GC Clarus 500 Perkin Elmer System and gas chromatograph interfaced with a mass spectrometer.Results: Phytochemical and GC-MS studies revealed the presence of bioactive compounds and found to possess antibacterial activity against foodborne pathogens.Conclusion: The present study supports the possible use of these phytotherapeutic agents in the clinical management of foodborne diseases.Keywords: GC-MS analysis, Foodborne pathogens, Jasminum sambac L., Antibacterial activit

Lung functions in children with Type 1 diabetes mellitus: A cross sectional study

Background: Diabetes mellitus (DM) is a metabolic disorder precipitating micro and macro vascular complicationsand peripheral vascular diseases. Normal lung mechanism and gas exchange are influenced by integrity of pulmonaryconnective tissues and microvasculature. Abnormality in either of these two structural components of lung leads tovariations in lung functions. Objective: This study was conducted to document lung function patterns by spirometryin patients with Type 1 DM. Materials and Methods: This cross-sectional study was conducted in Bangalore, India.Patients in the age group of 1-18 years diagnosed with Type 1 DM between December 2009, and January 2011 wereincluded. Data regarding respiratory symptoms, age, height and weight of each patient with Type 1 DM was collected.The children were trained to use spirometers. Multiple readings of forced expiratory volume in one second and forcedvital capacity were obtained until consistent, and the best reading was recorded and analyzed for any association.Results: A total of 51 children with Type 1 DM were studied, of whom 24 children were males, with a mean age of14.06 ± 3.25 years, the minimum age being 5 years and a maximum being 18 years. 25 children (49%) with Type 1DM were found to have pulmonary dysfunction, of which 19 children (76%) had restrictive lung pattern, and sixchildren (24%) had obstructive pattern. Conclusion: Spirometry evaluation showed that restrictive lung pattern wasvery common in children with Type 1 DM, and there is scope for further study

Fidelity of Phenylalanyl-tRNA Synthetase in Binding the Natural Amino Acids

Aminoacyl-tRNA synthetases guard the fidelity of cognate amino acid incorporation during protein biosynthesis; for example, phenylalanyl-tRNA synthetase (PheRS) activates and transfers only Phe to its tRNA. Since we are interested in using a computational protocol to identify nonnatural amino acids that are incorporated by wild-type PheRS, it is critical to understand the fidelity of PheRS in binding the 20 natural amino acids. To this end, HierDock, a computational protocol for predicting binding sites and relative binding affinities, was used for testing the natural amino acids in PheRS. Scanning the entire ligand-accessible protein surface for the best binding region, we find that HierDock correctly identifies the active site of Phe in PheRS and predicts Phe within 0.61 Å RMSD of the crystal structure. HierDock also successfully shows PheRS discriminates for Phe, as the noncognate amino acids bind less favorably in the binding site of Phe. However, we find that Met, Cys, and Tyr bind competitively but at positions distant from the Phe binding site. This result corroborates in vitro measurements of aminoacyl adenylate formation, which show Met competes with Phe at the amino acid binding stage. We predict that the binding site of Met would not activate PheRS, as the noncognate amino acid cannot establish suitable hydrogen bonds with the PheRS reaction center. These results validate the use of HierDock in predicting the binding sites of the cognate amino acids in PheRS. The HierDock procedure calculates the discrimination of aminoacyl-tRNA synthetases at the stage of binding the cognate amino acid and offers a molecular level understanding of the mistakes made in protein biosynthesis that are not readily uncovered through experiments. This technique is also useful for predicting the binding of a selected nonnatural amino acid analogue, thereby indicating whether the molecule would be incorporated into a wild-type aminoacyl-tRNA synthetase

Test of the Binding Threshold Hypothesis for olfactory receptors: Explanation of the differential binding of ketones to the mouse and human orthologs of olfactory receptor 912-93

We tested the Binding Threshold Hypothesis (BTH) for activation of olfactory receptors (ORs): To activate an OR, the odorant must bind to the OR with binding energy above some threshold value. The olfactory receptor (OR) 912‐93 is known experimentally to be activated by ketones in mouse, but is inactive to ketones in human, despite an amino acid sequence identity of ∼66%. To investigate the origins of this difference, we used the MembStruk first‐principles method to predict the tertiary structure of the mouse OR 912‐93 (mOR912‐93), and the HierDock first‐principles method to predict the binding site for ketones to this receptor. We found that the strong binding of ketones to mOR912‐93 is dominated by a hydrogen bond of the ketone carbonyl group to Ser105. All ketones predicted to have a binding energy stronger than E_(BindThresh) = 26 kcal/mol were observed experimentally to activate this OR, while the two ketones predicted to bind more weakly do not. In addition, we predict that 2‐undecanone and 2‐dodecanone both bind sufficiently strongly to activate mOR912‐93. A similar binding site for ketones was predicted in hOR912‐93, but the binding is much weaker because the human ortholog has a Gly at the position of Ser105. We predict that mutating this Gly to Ser in human should lead to activation of hOR912‐93 by these ketones. Experimental substantiations of the above predictions would provide further tests of the validity of the BTH, our predicted 3D structures, and our predicted binding sites for these ORs

Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor

The prevailing paradigm for G protein-coupled receptors is that each receptor is narrowly tuned to its ligand and closely related agonists. An outstanding problem is whether this paradigm applies to olfactory receptor (ORs), which is the largest gene family in the genome, in which each of 1,000 different G protein-coupled receptors is believed to interact with a range of different odor molecules from the many thousands that comprise “odor space.” Insights into how these interactions occur are essential for understanding the sense of smell. Key questions are: (i) Is there a binding pocket? (ii) Which amino acid residues in the binding pocket contribute to peak affinities? (iii) How do affinities change with changes in agonist structure? To approach these questions, we have combined single-cell PCR results [Malnic, B., Hirono, J., Sato, T. & Buck, L. B. (1999) Cell 96, 713–723] and well-established molecular dynamics methods to model the structure of a specific OR (OR S25) and its interactions with 24 odor compounds. This receptor structure not only points to a likely odor-binding site but also independently predicts the two compounds that experimentally best activate OR S25. The results provide a mechanistic model for olfactory transduction at the molecular level and show how the basic G protein-coupled receptor template is adapted for encoding the enormous odor space. This combined approach can significantly enhance the identification of ligands for the many members of the OR family and also may shed light on other protein families that exhibit broad specificities, such as chemokine receptors and P450 oxidases

Dynamic Ligand Discrimination in the Notch Signaling Pathway

The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency-modulated pulses that specifically upregulate the Notch target gene Hes1. By contrast, Dll4 activates Notch1 in a sustained, amplitude-modulated manner that predominantly upregulates Hey1 and HeyL. Ectopic expression of Dll1 or Dll4 in chick neural crest produced opposite effects on myogenic differentiation, showing that ligand discrimination can occur in vivo. Finally, analysis of chimeric ligands suggests that ligand-receptor clustering underlies dynamic encoding of ligand identity. The ability of the pathway to utilize ligands as distinct communication channels has implications for diverse Notch-dependent processes

Fusion barrier distributions in systems with finite excitation energy

Eigen-channel approach to heavy-ion fusion reactions is exact only when the excitation energy of the intrinsic motion is zero. In order to take into account effects of finite excitation energy, we introduce an energy dependence to weight factors in the eigen-channel approximation. Using two channel problem, we show that the weight factors are slowly changing functions of incident energy. This suggests that the concept of the fusion barrier distribution still holds to a good approximation even when the excitation energy of the intrinsic motion is finite. A transition to the adiabatic tunneling, where the coupling leads to a static potential renormalization, is also discussed.Comment: 9 pages, 4 figures, Submitted to Physical Review

Path integral approach to no-Coriolis approximation in heavy-ion collisions

We use the two time influence functional method of the path integral approach in order to reduce the dimension of the coupled-channels equations for heavy-ion reactions based on the no-Coriolis approximation. Our method is superior to other methods in that it easily enables us to study the cases where the initial spin of the colliding particle is not zero. It can also be easily applied to the cases where the internal degrees of freedom are not necessarily collective coordinates. We also clarify the underlying assumptions in our approach.Comment: 11 pages, Latex, Phys. Rev. C in pres