Linearly Supporting Feature Extraction For Automated Estimation Of Stellar Atmospheric Parameters

We describe a scheme to extract linearly supporting (LSU) features from stellar spectra to automatically estimate the atmospheric parameters $T_{eff}$, log$~g$, and [Fe/H]. "Linearly supporting" means that the atmospheric parameters can be accurately estimated from the extracted features through a linear model. The successive steps of the process are as follow: first, decompose the spectrum using a wavelet packet (WP) and represent it by the derived decomposition coefficients; second, detect representative spectral features from the decomposition coefficients using the proposed method Least Absolute Shrinkage and Selection Operator (LARS)$_{bs}$; third, estimate the atmospheric parameters $T_{eff}$, log$~g$, and [Fe/H] from the detected features using a linear regression method. One prominent characteristic of this scheme is its ability to evaluate quantitatively the contribution of each detected feature to the atmospheric parameter estimate and also to trace back the physical significance of that feature. This work also shows that the usefulness of a component depends on both wavelength and frequency. The proposed scheme has been evaluated on both real spectra from the Sloan Digital Sky Survey (SDSS)/SEGUE and synthetic spectra calculated from Kurucz's NEWODF models. On real spectra, we extracted 23 features to estimate $T_{eff}$, 62 features for log$~g$, and 68 features for [Fe/H]. Test consistencies between our estimates and those provided by the Spectroscopic Sarameter Pipeline of SDSS show that the mean absolute errors (MAEs) are 0.0062 dex for log$~T_{eff}$ (83 K for $T_{eff}$), 0.2345 dex for log$~g$, and 0.1564 dex for [Fe/H]. For the synthetic spectra, the MAE test accuracies are 0.0022 dex for log$~T_{eff}$ (32 K for $T_{eff}$), 0.0337 dex for log$~g$, and 0.0268 dex for [Fe/H].Comment: 21 pages, 7 figures, 8 tables, The Astrophysical Journal Supplement Series (accepted for publication

Nitric oxide synthase-3 promotes embryonic development of atrioventricular valves.

Nitric oxide synthase-3 (NOS3) has recently been shown to promote endothelial-to-mesenchymal transition (EndMT) in the developing atrioventricular (AV) canal. The present study was aimed to investigate the role of NOS3 in embryonic development of AV valves. We hypothesized that NOS3 promotes embryonic development of AV valves via EndMT. To test this hypothesis, morphological and functional analysis of AV valves were performed in wild-type (WT) and NOS3(-/-) mice at postnatal day 0. Our data show that the overall size and length of mitral and tricuspid valves were decreased in NOS3(-/-) compared with WT mice. Echocardiographic assessment showed significant regurgitation of mitral and tricuspid valves during systole in NOS3(-/-) mice. These phenotypes were all rescued by cardiac specific NOS3 overexpression. To assess EndMT, immunostaining of Snail1 was performed in the embryonic heart. Both total mesenchymal and Snail1(+) cells in the AV cushion were decreased in NOS3(-/-) compared with WT mice at E10.5 and E12.5, which was completely restored by cardiac specific NOS3 overexpression. In cultured embryonic hearts, NOS3 promoted transforming growth factor (TGFβ), bone morphogenetic protein (BMP2) and Snail1expression through cGMP. Furthermore, mesenchymal cell formation and migration from cultured AV cushion explants were decreased in the NOS3(-/-) compared with WT mice. We conclude that NOS3 promotes AV valve formation during embryonic heart development and deficiency in NOS3 results in AV valve insufficiency

Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development

Background-Defects in cardiac septation are the most common form of congenital heart disease, but the mechanisms underlying these defects are still poorly understood. The small GTPase Rac1 is implicated in planar cell polarity of epithelial cells in Drosophila; however, its role in mammalian cardiomyocyte polarity is not clear. We tested the hypothesis that Rac1 signaling in the second heart field regulates cardiomyocyte polarity, chamber septation, and right ventricle development during embryonic heart development. Methods and Results-Mice with second heart field-specific deficiency of Rac1 (Rac1SHF) exhibited ventricular and atrial septal defects, a thinner right ventricle myocardium, and a bifid cardiac apex. Fate-mapping analysis showed that second heart field contribution to the interventricular septum and right ventricle was deficient in Rac1SHF hearts. Notably, cardiomyocytes had a spherical shape with disrupted F-actin filaments in Rac1SHF compared with elongated and well-aligned cardiomyocytes in littermate controls. Expression of Scrib, a core protein in planar cell polarity, was lost in Rac1SHF hearts with decreased expression of WAVE and Arp2/3, leading to decreased migratory ability. In addition, Rac1-deficient neonatal cardiomyocytes displayed defects in cell projections, lamellipodia formation, and cell elongation. Furthermore, apoptosis was increased and the expression of Gata4, Tbx5, Nkx2.5, and Hand2 transcription factors was decreased in the Rac1SHF right ventricle myocardium. Conclusions-Deficiency of Rac1 in the second heart field impairs elongation and cytoskeleton organization of cardiomyocytes and results in congenital septal defects, thin right ventricle myocardium, and a bifid cardiac apex. Our study suggests that Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development

Rac1 activation induces tumour necrosis factor-α expression and cardiac dysfunction in endotoxemia

Induction of tumour necrosis factor-α (TNF-α) expression leads to myocardial depression during sepsis. However, the underlying molecular mechanisms are not fully understood. The aim of this study was to investigate the role of Rac1 in TNF-α expression and cardiac dysfunction during endotoxemia and to determine the involvement of phosphoinositide-3 kinase (PI3K) in lipopolysaccharide (LPS)-induced Rac1 activation. Our results showed that LPS-induced Rac1 activation and TNF-α expression in cultured neonatal mouse cardiomyocytes. The response was inhibited in Rac1 deficient cardiomyocytes or by a dominant-negative Rac1 (Rac1N17). To determine whether PI3K regulates Rac1 activation, cardiomyocytes were treated with LY294002, a PI3K selective inhibitor. Treatment with LY294002 decreased Rac1 activity as well as TNF-α expression stimulated by LPS. Furthermore, inhibition of PI3K and Rac1 activity decreased LPS-induced superoxide generation which was associated with a significant reduction in ERK1/2 phosphorylation. To investigate the role of Rac1 in myocardial depression during endotoxemiain vivo, wild-type and cardiomyocyte-specific Rac1 deficient mice were treated with LPS (2 mg/kg, i.p.). Deficiency in Rac1 significantly decreased myocardial TNF-α expression and improved cardiac function during endotoxemia. We conclude that PI3K-mediated Rac1 activation is required for induction of TNF-α expression in cardiomyocytes and cardiac dysfunction during endotoxemia. The effect of Rac1 on TNF-α expression seems to be mediated by increased NADPH oxidase activity and ERK1/2 phosphorylation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

Myocardial infarction in neonatal mice, a model of cardiac regeneration

Myocardial infarction induced by coronary artery ligation has been used in many animal models as a tool to study the mechanisms of cardiac repair and regeneration, and to define new targets for therapeutics. For decades, models of complete heart regeneration existed in amphibians and fish, but a mammalian counterpart was not available. The recent discovery of a postnatal window during which mice possess regenerative capabilities has led to the establishment of a mammalian model of cardiac regeneration. A surgical model of mammalian cardiac regeneration in the neonatal mouse is presented herein. Briefly, postnatal day 1 (P1) mice are anesthetized by isoflurane and placed on an ice pad to induce hypothermia. After the chest is opened, and the left anterior descending coronary artery (LAD) is visualized, a suture is placed around the LAD to inflict myocardial ischemia in the left ventricle. The surgical procedure takes 10-15 min. Visualizing the coronary artery is crucial for accurate suture placement and reproducibility. Myocardial infarction and cardiac dysfunction are confirmed by triphenyl-tetrazolium chloride (TTC) staining and echocardiography, respectively. Complete regeneration 21 days post myocardial infarction is verified by histology. This protocol can be used to as a tool to elucidate mechanisms of mammalian cardiac regeneration after myocardial infarction

A charge-sensing region in the stromal interaction molecule 1 luminal domain confers stabilization-mediated inhibition of soce in response to s-nitrosylation

Store-operated Ca2 entry (SOCE) is a major Ca2 signaling pathway facilitating extracellular Ca2 influx in response to the initial release of intracellular endo/sarcoplasmic reticulum (ER/ SR) Ca2 stores. Stromal interaction molecule 1 (STIM1) is the Ca2 sensor that activates SOCE following ER/SR Ca2 depletion. The EF-hand and the adjacent sterile -motif (EFSAM) domains of STIM1 are essential for detecting changes in luminal Ca2 concentrations. Low ER Ca2 levels trigger STIM1 destabilization and oligomerization, culminating in the opening of Orai1-composed Ca2 channels on the plasma membrane. NO-mediated S-nitrosylation of cysteine thiols regulates myriad protein functions, but its effects on the structural mechanisms that regulate SOCE are unclear. Here, we demonstrate that S-ni-trosylation of Cys49 and Cys56 in STIM1 enhances the thermodynamic stability of its luminal domain, resulting in suppressed hydrophobic exposure and diminished Ca2 depletion– dependent oligomerization. Using solution NMR spectroscopy, we pinpointed a structural mechanism for STIM1 stabilization driven by complementary charge interactions between an electropositive patch on the core EFSAM domain and the S-nitrosy-lated nonconserved region of STIM1. Finally, using live cells, we found that the enhanced luminal domain stability conferred by either Cys49 and Cys56 S-nitrosylation or incorporation of negatively charged residues into the EFSAM electropositive patch in the full-length STIM1 context significantly suppresses SOCE. Collectively, our results suggest that S-nitrosylation of STIM1 inhibits SOCE by interacting with an electropositive patch on the EFSAM core, which modulates the thermodynamic stability of the STIM1 luminal domain

Myocardium-specific deletion of rac1 causes ventricular noncompaction and outflow tract defects

Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase Rac1 acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of Rac1 in embryonic heart development. Methods and Results: The Nkx2.5-Cre transgenic mice were crossed with Rac1f/f mice to generate mice with a cardiomyocyte specific deletion of Rac1 (Rac1Nkx2.5 ) during heart development. Embryonic Rac1Nkx2.5 hearts at E12.5–E18.5 were collected for histological analysis. Overall, Rac1Nkx2.5 hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. Rac1Nkx2.5 hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in Rac1Nkx2.5 hearts. In addition, cell proliferation rate was significantly decreased in the Rac1Nkx2.5 ventricular myocardium at E9.5. Conclusions: Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in Rac1Nkx2.5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development

Cardiomyocyte specific overexpression of a 37 amino acid domain of regulator of G protein signalling 2 inhibits cardiac hypertrophy and improves function in response to pressure overload in mice

Regulator of G protein signalling 2 (RGS2) is known to play a protective role in maladaptive cardiac hypertrophy and heart failure via its ability to inhibit Gq- and Gs- mediated GPCR signalling. We previously demonstrated that RGS2 can also inhibit protein translation and can thereby attenuate cell growth. This G protein-independent inhibitory effect has been mapped to a 37 amino acid domain (RGS2eb) within RGS2 that binds to eukaryotic initiation factor 2B (eIF2B). When expressed in neonatal rat cardiomyocytes, RGS2eb attenuates both protein synthesis and hypertrophy induced by Gq- and Gs- activating agents. In the current study, we investigated the potential cardioprotective role of RGS2eb by determining whether RGS2eb transgenic (RGS2eb TG) mice with cardiomyocyte specific overexpression of RGS2eb show resistance to the development of hypertrophy in comparison to wild-type (WT) controls. Using transverse aortic constriction (TAC) in a pressure-overload hypertrophy model, we demonstrated that cardiac hypertrophy was inhibited in RGS2eb TG mice compared to WT controls following four weeks of TAC. Expression of the hypertrophic markers atrial natriuretic peptide (ANP) and β-myosin heavy chain (MHC-β) was also reduced in RGS2eb TG compared to WT TAC animals. Furthermore, cardiac function in RGS2eb TG TAC mice was significantly improved compared to WT TAC mice. Notably, cardiomyocyte cell size was significantly decreased in TG compared to WT TAC mice. These results suggest that RGS2 may limit pathological cardiac hypertrophy at least in part via the function of its eIF2B-binding domain