MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)

There is confusion about the role that IFN-α plays in the pathogenesis of pulmonary arterial hypertension (PAH) with different investigators reporting a causative or a protective role. There is now clear evidence in PAH pathogenesis for the involvement of BMP4 and BMP9 signaling, and its disruption by mutations in BMPR2. In the present study, we investigated MxA, an IFN-α-inducible cytoplasmic dynamin-family GTPase for effects on BMP4/9 signaling, including in the presence of PAH-disease-associated mutants of BMPR2. In human pulmonary arterial endothelial cells (HPAECs), IFN-α-induced endogenous as well as exogenously expressed MxA was associated with endosomes that aligned alongside microtubules and tubules of the endoplasmic reticulum (ER). Moreover, IFN-α and MxA stimulated basal and BMP4/9 signaling to a Smad1/5/8-responsive pBRE-Luc reporter. In HEK293T cells, immunoelectron microscopy confirmed the association of MxA with endosomes, and immunofluorescence methods showed these to be positive for early endosome markers (early endosomal antigen 1, clathrin light chain and Rab5) and RSmad1/5/8. Functionally, using different genetic and inhibitor approaches, we observed that clathrin-mediated endocytosis enhanced and caveolin-mediated endocytosis inhibited the transcriptional response to BMP4 and BMP9. MxA produced a further 3-4-fold enhancement of the BMP-induced response in a clathrin-endocytosis dependent manner. The microtubule inhibitor nocodazole and stabilizer paclitaxel respectively attenuated and enhanced the effect of MxA, implicating microtubule integrity in this process. MxA enhanced BMP-induced signaling in the presence of wild-type BMPR2, and partially rescued signaling from some PAH-disease-associated BMPR2 mutants. Taken together, the data identify MxA as a novel stimulator of BMP4 and BMP9 transcriptional signaling, and suggest it to be a candidate IFN-α-inducible mechanism that might have a protective role against development of PAH and other vascular diseases

Seismic Behaviour of Multistorey RC Frames with vertical Mass Irregularities

The buildings with mass irregularity behave differently as compared to regular buildings. In the present study, a parameter called mass irregularity index has been proposed to quantify the mass irregularity. The proposed factor depends mainly upon magnitude and location of mass irregularity. Further the present study aims to modify the expression of time period proposed by IS 1893:2002 and relation between mass irregularity coefficient and time period has been evaluated. For present study a family of 108 frames with mass irregularity have been modelled and analyzed by time history analysis. The proposed expression for time period has been validated for buildings with mass irregularity

Smooth Muscle-Specific BCL6+/- Knockout Abrogates Sex Bias in Chronic Hypoxia-Induced Pulmonary Arterial Hypertension in Mice

The estrogen paradox in pulmonary arterial hypertension (PAH) refers to observations that while there is a higher incidence of idiopathic PAH in women, rodent models of PAH show male dominance and estrogens are protective. To explain these differences, we previously proposed the neuroendocrine-STAT5-BCL6 hypothesis anchored in the sex-biased and species-specific patterns of growth hormone (GH) secretion by the pituitary, the targeting of the hypothalamus by estrogens to feminize GH secretion patterns, and the role of the transcription factors STAT5a/b and BCL6 as downstream mediators of this patterned GH-driven sex bias. As a test of this hypothesis, we previously reported that vascular smooth muscle cell- (SMC-) specific deletion of the STAT5a/b locus abrogated the male-dominant sex bias in the chronic hypoxia model of PAH in mice. In the present study, we confirmed reduced BCL6 expression in pulmonary arterial (PA) segments in both male and female SMC:STAT5a/b-/- mice. In order to test the proposed contribution of BCL6 to sex bias in PAH, we developed mice with SMC-specific deletion of BCL6+/- by crossing SM22alpha-Cre mice with BCL6-floxed mice and investigated sex bias in these mutant mice in the chronic hypoxia model of PAH. We observed that the male-bias observed in wild-type- (wt-) SM22alpha-Cre-positive mice was abrogated in the SMC:BCL6+/- knockouts-both males and females showed equivalent enhancement of indices of PAH. The new data confirm BCL6 as a contributor to the sex-bias phenotype observed in hypoxic PAH in mice and support the neuroendocrine-STAT5-BCL6 hypothesis of sex bias in this experimental model of vascular disease

Positronium Decay : Gauge Invariance and Analyticity

The construction of positronium decay amplitudes is handled through the use of dispersion relations. In this way, emphasis is put on basic QED principles: gauge invariance and soft-photon limits (analyticity). A firm grounding is given to the factorization approaches, and some ambiguities in the spin and energy structures of the positronium wavefunction are removed. Non-factorizable amplitudes are naturally introduced. Their dynamics is described, especially regarding the enforcement of gauge invariance and analyticity through delicate interferences. The important question of the completeness of the present theoretical predictions for the decay rates is then addressed. Indeed, some of those non-factorizable contributions are unaccounted for by NRQED analyses. However, it is shown that such new contributions are highly suppressed, being of order alpha^3. Finally, a particular effective form factor formalism is constructed for parapositronium, allowing a thorough analysis of binding energy effects and analyticity implementation.Comment: 34 pages, 13 figure

Magnetic and axial vector form factors as probes of orbital angular momentum in the proton

We have recently examined the static properties of the baryon octet (magnetic moments and axial vector coupling constants) in a generalized quark model in which the angular momentum of a polarized nucleon is partly spin $\langle S_z \rangle$ and partly orbital $\langle L_z \rangle$. The orbital momentum was represented by the rotation of a flux-tube connecting the three constituent quarks. The best fit is obtained with $\langle S_z \rangle = 0.08\pm 0.15$, $\langle L_z \rangle = 0.42\pm 0.14$. We now consider the consequences of this idea for the $q^2$-dependence of the magnetic and axial vector form factors. It is found that the isovector magnetic form factor $G_M^{\mathrm{isovec}}(q^2)$ differs in shape from the axial form factor $F_A(q^2)$ by an amount that depends on the spatial distribution of orbital angular momentum. The model of a rigidly rotating flux-tube leads to a relation between the magnetic, axial vector and matter radii, $\langle r^2 \rangle_{\mathrm{mag}} = f_{\mathrm{spin}} \langle r^2 \rangle_{\mathrm{axial}} + \frac{5}{2} f_{\mathrm{orb}} \langle r^2 \rangle_{\mathrm{matt}}$, where $f_{\mathrm{orb}}/ f_{\mathrm{spin}} = \frac{1}{3}\langle L_z \rangle / G_A$, $f_{\mathrm{spin}} + f_{\mathrm{orb}} = 1$. The shape of $F_A(q^2)$ is found to be close to a dipole with $M_A = 0.92\pm 0.06$ GeV.Comment: 18 pages, 5 ps-figures, uses RevTe

A collateral missing value estimation algorithm for DNA microarrays

Genetic microarray expression data often contains multiple missing values that can significantly affect the performance of statistical and machine learning algorithms. This paper presents an innovative missing value estimation technique, called collateral missing value estimation (CMVE) which has demonstrated superior estimation performance compared with the K-nearest neighbour (KNN) imputation algorithm, the least square impute (LSImpute) and Bayesian principal component analysis (BPCA) techniques. Experimental results confirm that CMVE provides an improvement of 89%, 12% and 10% for the BRCA1, BRCA2 and sporadic ovarian cancer mutations, respectively, compared to the average error rate of KNN, LSImpute and BPCA imputation methods, over a range of randomly selected missing values. The underlying theory behind CMVE also means that it is not restricted to bioinformatics data, but can be successfully applied to any correlated data set

Pit Growth Study in Al Alloys by the Foil Penetration Technique

The foil penetration technique was used to study pit growth in AA1100-O and AA2024-T3. Preliminary work on AA1100-O foils of different thicknesses indicated that the pit growth rate increased with increasing applied potential, suggesting that pit growth was not under transport control. Foil penetration experiments were also carried out on AA2024-T3 foils of a given thickness, at open circuit as well as anodic potentials. Dichromate ions and other oxidizing agents were added to some test solutions. Dichromate ions were shown to have little influence on the pit growth rate at controlled anodic potentials, even when added in large concentrations. However, dichromate ions effectively inhibited pitting at open circuit when present in very small amounts. Polarization curves of AA2024-T3 in 1 M NaCl with various additives show a large effect of dichromate ions in the cathodic region and no effect in the anodic region. These observations suggest that chromate (or its reduction product) acts as a cathodic inhibitor. Examination of penetrated samples was performed by optical and scanning electron microscopies, as well as by microradiography.This work was supported by Major H. DeLong at the Air Force Office of Scientific Research, under contract F49620-96-0042

Automatic, context-specific generation of Gene Ontology slims

Background: The use of ontologies to control vocabulary and structure annotation has added value to genome-scale data, and contributed to the capture and re-use of knowledge across research domains. Gene Ontology (GO) is widely used to capture detailed expert knowledge in genomic-scale datasets and as a consequence has grown to contain many terms, making it unwieldy for many applications. To increase its ease of manipulation and efficiency of use, subsets called GO slims are often created by collapsing terms upward into more general, high-level terms relevant to a particular context. Creation of a GO slim currently requires manipulation and editing of GO by an expert (or community) familiar with both the ontology and the biological context. Decisions about which terms to include are necessarily subjective, and the creation process itself and subsequent curation are time-consuming and largely manual