A study of velocity fields in the transition region of ε Eri (K2 V)

Analyses of the widths and shifts of optically thin emission lines in the ultraviolet spectrum of the active dwarf e Eri (K2 V) are presented. The spectra were obtained using the Space Telescope Imaging Spectrograph on the Hubble Space Telescope and the Far Ultraviolet Spectroscopic Explorer. The linewidths are used to find the non-thermal energy density and its variation with temperature from the chromosphere to the upper transition region. The energy fluxes that could be carried by Alfvén and acoustic waves are investigated, to test their possible roles in coronal heating. Acoustic waves do not appear to be a viable means of coronal heating. There is, in principle, ample flux in Alfvén waves, but detailed calculations of wave propagation are required before definite conclusions can be drawn concerning their viability. The high sensitivity and spectral resolution of the above instruments have allowed two-component Gaussian fits to be made to the profiles of the stronger transition region lines. The broad and narrow components that result share some similarities with those observed in the Sun, but in e Eri the broad component is redshifted relative to the narrow component and contributes more to the total line flux. The possible origins of the two components and the energy fluxes implied are discussed. On balance our results support the conclusion of Wood, Linsky & Ayres, that the narrow component is related to Alfvén waves reaching to the corona, but the origin of the broad component is not clear.

Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7

Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis-associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during DN has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. Here we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readout, Grem1 consistently demonstrated a higher affinity for BMP-2>4>7. Cell-associated Grem1 did not inhibit BMP-2 or BMP-4 mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.

Characterizing K2 Planet Discoveries: A super-Earth transiting the bright K-dwarf HIP 116454

We report the first planet discovery from the two-wheeled Kepler (K2) mission: HIP 116454 b. The host star HIP 116454 is a bright (V = 10.1, K = 8.0) K1 dwarf with high proper motion and a parallax-based distance of 55.2 +/- 5.4 pc. Based on high-resolution optical spectroscopy, we find that the host star is metal-poor with [Fe/H]= -0.16 +/- 0.08 and has a radius R-star = 0.716 +/- 0.024 R-circle dot and mass M-star = 0.775 +/- 0.027M(circle dot). The star was observed by the Kepler spacecraft during its Two-Wheeled Concept Engineering Test in 2014 February. During the 9 days of observations, K2 observed a single transit event. Using a new K2 photometric analysis technique, we are able to correct small telescope drifts and recover the observed transit at high confidence, corresponding to a planetary radius of R-p = 2.53 +/- 0.18 R-circle plus. Radial velocity observations with the HARPS-N spectrograph reveal a 11.82 +/- 1.33 M-circle plus planet in a 9.1 day orbit, consistent with the transit depth, duration, and ephemeris. Follow-up photometric measurements from the MOST satellite confirm the transit observed in the K2 photometry and provide a refined ephemeris, making HIP 116454 b amenable for future follow-up observations of this latest addition to the growing population of transiting super-Earths around nearby, bright stars.

BMP signalling: agony and antagony in the family

Bone morphogenetic proteins (BMPs) are secreted extracellular matrix (ECM)-associated proteins that regulate a wide range of developmental processes, including limb and kidney formation. A critical element of BMP regulation is the presence of secreted antagonists that bind and inhibit BMP binding to their cognate Ser/Thr kinase receptors at the plasma membrane. Antagonists such as Noggin, Chordin, Gremlin (Grem1), and twisted gastrulation-1 (Twsg1) have been shown to inhibit BMP action in a range of different cell types and developmental stage-specific contexts. Here we review new developments in the field of BMP and BMP antagonist biology during mammalian development and suggest strategies for targeting these proteins in human disease.

Llenado óseo con BMP-6 en defectos óseos de tres paredes mediante el estimulo directo o indirecto de formación de hueso en perros Beagle

[Tesis] ( Maestría en Ciencias Odontológicas con Especialidad en Periodoncia ) U.A.N.L.

Analyse fonctionnelle du gène BMP-2 lors de la régénération du membre chez l’axolotl

Les amphibiens urodèles (e.g. les axolotls) possèdent la remarquable capacité de régénérer plusieurs parties de leur corps. Ils peuvent, entre autres, régénérer parfaitement un membre amputé par épimorphose, un processus biphasique comprenant une phase de préparation, spécifique à la régénération, et une phase de redéveloppement, commune à l’épimorphose et au développement embryonnaire. Durant la phase de préparation, les cellules du moignon se dédifférencient en cellules pseudo-embryonnaires, prolifèrent et migrent distalement au plan d’amputation pour former un blastème de régénération. Parmi les vertébrés, la dédifférenciation est unique aux urodèles. Afin de mieux comprendre le contrôle moléculaire de la régénération chez les urodèles, nous avons choisi d’étudier BMP-2, un facteur de croissance, en raison de son implication dans la régénération des phalanges distales chez les mammifères. Le facteur de transcription MSX-1 a également été sélectionné en raison de sa capacité à induire la dédifférenciation cellulaire in vitro et de son interaction potentielle avec la signalisation des BMPs. Les résultats présentés dans cette thèse démontrent que BMP-2 et MSX-1 sont exprimés lors des phases de préparation et de redéveloppement de l’épimorphose, et que leur profil d'expression spatio-temporel est très semblable, ce qui suggère une interaction de leurs signaux. En outre, chez les tétrapodes amniotes, l’expression de Shh est restreinte au mésenchyme postérieur des membres en développement et chevauche l’expression de BMP-2. Toutefois, l’expression de BMP-2 n’est pas restreinte à la région postérieure mais forme un gradient postéro-antérieur. Shh est le principal régulateur de la formation du patron de développement antéro-postérieur du ii membre. Étant donné les domaines d’expression chevauchants de BMP-2 et Shh et la restriction postérieure d’expression de Shh, on croit que Shh régule la formation du patron de développement de postérieur à antérieur par l’activation de l’expression de BMP-2. Fait intéressant, l’axolotl exprime également Shh dans la région postérieure, mais le développement des pattes se fait de la région antérieure à la région postérieure au lieu de postérieur à antérieur comme chez les autres tétrapodes, et ceci durant le développement et la régénération. Nous avons utilisé cette caractéristique de l’axolotl pour démontrer que la signalisation Shh ne structure pas l’autopode via BMP-2. En effet, l’expression de BMP-2 n'est pas régulée par l'inhibition de la signalisation Shh, et son expression est du côté opposé à celle de Shh durant le développement et la régénération des pattes de l’axolotl. Il a été observé durant le développement du membre chez la souris que MSX-1 est régulé par la signalisation Shh. Nos résultats ont démontrés que chez l’axolotl, MSX-1 ne semble pas régulé par l'inhibition de la signalisation Shh au cours de la régénération du membre. De plus, nous avons démontré que contrairement à l’expression de Shh, l’expression de BMP-2 est corrélée avec l’ordre de formation des phalanges, est impliquée dans la condensation cellulaire et dans l'apoptose précédant la chondrogenèse. L’ensemble de ces résultats suggère un rôle de BMP-2 dans l’initiation de l’ossification endochondrale. Enfin, nous avons démontré que la signalisation BMP est indispensable pour l’épimorphose du membre durant la phase de redéveloppement.

Apatite-Polymer Composites for the Controlled Dual Delivery of BMP-2 and BMP-6 for Bone Tissue Engineering

The release of growth factors from tissue engineering scaffolds provides signals that influence the migration, differentiation, and proliferation of cells. The incorporation of a drug delivery platform that is capable of tunable release will give tissue engineers greater versatility in the direction of tissue regeneration. We have prepared a novel composite of two biomaterials with proven track records - apatite and poly(lactic-co-glycolic acid) (PLGA) – as a drug delivery platform with promising controlled release properties. These composites have been tested in the delivery of a model protein, bovine serum albumin (BSA), as well as therapeutic proteins, recombinant human bone morphogenetic protein-2 (rhBMP-2) and rhBMP-6. The controlled release strategy is based on the use of a polymer with acidic degradation products to control the dissolution of the basic apatitic component, resulting in protein release. Therefore, any parameter that affects either polymer degradation or apatite dissolution can be used to control protein release. We have modified the protein release profile systematically by varying the polymer molecular weight, polymer hydrophobicity, apatite loading, apatite particle size, and other material and processing parameters. Biologically active rhBMP-2 was released from these composite microparticles over 100 days, in contrast to conventional collagen sponge carriers, which were depleted in approximately 2 weeks. The released rhBMP-2 was able to induce elevated alkaline phosphatase and osteocalcin expression in pluripotent murine embryonic fibroblasts. To augment tissue engineering scaffolds with tunable and sustained protein release capabilities, these composite microparticles can be dispersed in the scaffolds in different combinations to obtain a superposition of the release profiles. We have loaded rhBMP-2 into composite microparticles with a fast release profile, and rhBMP-6 into slow-releasing composite microparticles. An equi-mixture of these two sets of composite particles was then injected into a collagen sponge, allowing for dual release of the proteins from the collagenous scaffold. The ability of these BMP-loaded scaffolds to induce osteoblastic differentiation in vitro and ectopic bone formation in a rat model is being investigated. We anticipate that these apatite-polymer composite microparticles can be extended to the delivery of other signalling molecules, and can be incorporated into other types of tissue engineering scaffolds.

Apatite-Polymer Composite Particles for Controlled Delivery of BMP-2: In Vitro Release and Cellular Response

Bone morphogenetic protein-2 (BMP-2) has the ability to induce osteoblast differentiation of undifferentiated cells, resulting in the healing of skeletal defects when delivered with a suitable carrier. We have applied a versatile delivery platform comprising a novel composite of two biomaterials with proven track records – apatite and poly(lactic-co-glycolic acid) (PLGA) – to the delivery of BMP-2. Sustained release of this growth factor was tuned with variables that affect polymer degradation and/or apatite dissolution, such as polymer molecular weight, polymer composition, apatite loading, and apatite particle size. The effect of released BMP-2 on C3H10T1/2 murine pluripotent mesenchymal cells was assessed by tracking the expression of osteoblastic makers, alkaline phosphatase (ALP) and osteocalcin. Release media collected over 100 days induced elevated ALP activity in C3H10T1/2 cells. The expression of osteocalcin was also upregulated significantly. These results demonstrated the potential of apatite-PLGA composite particles for releasing protein in bioactive form over extended periods of time.

Bone morphogenetic proteins (BMP)-4,-6, and-7 potently suppress basal and luteinizing hormone-induced androgen production by bovine theca interna cells in primary culture: Could ovarian hyperandrogenic dysfunction be caused by a defect in thecal BMP signaling?

We reported recently that bovine theca interna cells in primary culture express several type-I and type-II receptors for bone morphogenetic proteins (BMPs). The same cells express at least two potential ligands for these receptors (BMP-4 and - 7), whereas bovine granulosa cells and oocytes express BMP-6. Therefore, BMPs of intrafollicular origin may exert autocrine/paracrine actions to modulate theca cell function. Here we report that BMP-4, - 6, and - 7 potently suppress both basal ( P < 0.0001; respective IC50 values, 0.78, 0.30, and 1.50 ng/ml) and LH-induced ( P < 0.0001; respective IC50 values, 5.00, 0.55, and 4.55 ng/ml) androgen production by bovine theca cells while having only a moderate effect on progesterone production and cell number. Semiquantitative RT-PCR showed that all three BMPs markedly reduced steady-state levels of mRNA for P450c17. Levels of mRNA encoding steroidogenic acute regulatory protein, P450scc, and 3 beta-hydroxysteroid dehydrogenase were also reduced but to a much lesser extent. Immunocytochemistry confirmed a marked reduction in cellular content of P450c17 protein after BMP treatment ( P < 0.001). Exposure to BMPs led to cellular accumulation of phosphorylated Smad1, but not Smad2, confirming that the receptors signal via a Smad1 pathway. The specificity of the BMP response was further explored by coincubating cells with BMPs and several potential BMP antagonists, chordin, gremlin, and follistatin. Gremlin and chordin were found to be effective antagonists of BMP-4 and - 7, respectively, and the observation that both antagonists enhanced ( P < 0.01) androgen production in the absence of exogenous BMP suggests an autocrine/paracrine role for theca-derived BMP- 4 and - 7 in modulating androgen production. Collectively, these data indicate that an intrafollicular BMP signaling pathway contributes to the negative regulation of thecal androgen production and that ovarian hyperandrogenic dysfunction could be a result of a defective autoregulatory pathway involving thecal BMP signaling.

Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4,-6 and-7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin

Given the paucity of information on the potential roles of bone morphogenetic proteins (BMPs) in the ruminant ovary we conducted immunolocalization and functional studies on cells isolated from bovine antral follicles. Immunocytochemistry revealed expression of BMP-4 and -7 in isolated theca cells whereas granulosa cells and oocytes selectively expressed RMP-6. All three cell types expressed a range of BMP-responsive type-I (BMPRIB, ActRI) and type-II (BMPRII, ActRII, ActRIIB) receptors supporting autocrine/paracrine roles within the follicle. This was reinforced by functional experiments on granulosa cells which showed that BMP-4, -6 and -7 promoted cellular accumulation of phosphorylated Smad-1 but not Smad-2 and enhanced 'basal' and IGF-stimulated secretion of oestradiol (E2), inhibin-A, activin-A and follistatin (FS). Concomitantly, each BMP suppressed 'basal' and IGF-stimulated progesterone secretion, consistent with an action to prevent or delay atresia and/or luteinization. BMPs also increased viable cell number under 'basal' (BMP-4 and -7) and IGF-stimulated (BMP-4, -6 and -7) conditions. Since FS, a product of bovine granulosa cells, has been shown to bind several BMPs, we used the Biacore technique to compare its binding affinities for activin-A (prototype FS ligand) and BMP-4, -6 and -7. Compared with activin-A (K-d 0.28 +/- 0.02 nM; 100%), the relative affinities of FS for BMP-4, -6 and -7 were 10, 5 and 1% respectively. Moreover, studies on granulosa cells showed that preincubation of ligand with excess FS abolished activin-A-induced phosphorylation of Smad-2 and BMP-4-induced phosphorylation of Smad-1. However, FS only partially reversed BMP-6-induced Smad-1 phosphorylation and had no inhibitory effect on BMP-7-induced Smad-1 phosphorylation. These findings support functional roles for BMP-4, -6 and -7 as paracrine/autocrine modulators of granulosa cell steroidogenesis, peptide secretion and proliferation in bovine antral follicles. The finding that FS can differentially modulate BMP-induced receptor activation and that this correlates with the relative binding affinity of FS for each BMP type implicates FS as a potential modulator of BMP action in the ovary.

Coupling aerosol surface and bulk chemistry with a kinetic double layer model (K2-SUB): oxidation of oleic acid by ozone

We present a kinetic double layer model coupling aerosol surface and bulk chemistry (K2-SUB) based on the PRA framework of gas-particle interactions (Poschl-Rudich-Ammann, 2007). K2-SUB is applied to a popular model system of atmospheric heterogeneous chemistry: the interaction of ozone with oleic acid. We show that our modelling approach allows de-convoluting surface and bulk processes, which has been a controversial topic and remains an important challenge for the understanding and description of atmospheric aerosol transformation. In particular, we demonstrate how a detailed treatment of adsorption and reaction at the surface can be coupled to a description of bulk reaction and transport that is consistent with traditional resistor model formulations. From literature data we have derived a consistent set of kinetic parameters that characterise mass transport and chemical reaction of ozone at the surface and in the bulk of oleic acid droplets. Due to the wide range of rate coefficients reported from different experimental studies, the exact proportions between surface and bulk reaction rates remain uncertain. Nevertheless, the model results suggest an important role of chemical reaction in the bulk and an approximate upper limit of similar to 10(-11) cm(2) s(-1) for the surface reaction rate coefficient. Sensitivity studies show that the surface accommodation coefficient of the gas-phase reactant has a strong non-linear influence on both surface and bulk chemical reactions. We suggest that K2-SUB may be used to design, interpret and analyse future experiments for better discrimination between surface and bulk processes in the oleic acid-ozone system as well as in other heterogeneous reaction systems of atmospheric relevance.

Functional Analysis of saxophone, the Drosophila Gene Encoding the BMP Type I Receptor Ortholog of Human ALK1/ACVRL1 and ACVR1/ALK2

In metazoans, bone morphogenetic proteins (BMPS) direct a myriad of developmental and adult homeostatic evens through their heterotetrameric type I and type II receptor complexes. We examined 3 existing and 12 newly generated mutations in the Drosophila type I receptor gene, saxophone (sax), the ortholog of the human Activin Receptor-Like. Kinasel and -2 (ALK1/ACVR1 and ALK2/ACVR1) genes. Our genetic analyses identified two distinct classes of sax alleles. The first class consists of homozygous viable gain-of-function (GOF) alleles that exhibit (1) synthetic lethality in combination with mutations in BMP pathway components, and (2) significant maternal effect lethality that can be rescued by an increased dosage of the BMP encoding gene, dpp(+). In contrast, the second class consists of alleles that are recessive lethal and do not exhibit lethality in combination with mutations in other BMP pathway components. The alleles in this second class are clearly loss-of-function (LOF) with both complete and partial loss-of-function mutations represented. We find that one allele in the second class of recessive lethals exhibits dominant-negative behavior, albeit distinct from the GOF activity of the first class of viable alleles. On the basis of the fact that the first class of viable alleles can be reverted to lethality and on our ability to independently generate recessive lethal sat mutations, our analysis demonstrates that sax is an essential gene. Consistent with this conclusion, we find that a normal sax transcript is produced by sax(P), a viable allele previously reported to be mill, and that this allele can be reverted to lethality. Interestingly, we determine that two mutations in the first: class of sax alleles show the same amino acid substitutions as mutations in the human receptors ALK1/ACVR1-1 and ACVR1/ALK2, responsible for cases of hereditary hemorrhagic telangiectasia type 2 (HHT2) and fibrodysplasia ossificans progressiva (FOP), respectively. Finally, the data presented here identify different functional requirements for the Sax receptor, support the proposal that Sax participates in a heteromeric receptor complex, and provide a mechanistic framework for future investigations into disease states that arise from defects in BMP/TGF-beta signaling.

Relação da imunoexpressão da bmp-2, bmpr-ia e bmpr-ii com o perfil clínico-patológico em carcinoma epidermóide de lábio inferior

Currently, bone morphogenetic proteins (BMPs) have effective participation in the growth of malignancies. Knowing that there are few studies involving BMPs and oral squamous cell carcinoma, this work constitutes an immunohistochemical study of BMP-2, BMPR IA and BMPR II in squamous cell carcinomas (SCC) of the lower lip relating to the clinical and pathological aspects of this lesion. The sample consisted of 40 cases of SCC of the lower lip, being 20 cases of SCC of the lower lip with regional metastasis and 20 cases without metastasis. We evaluated the intensity of expression (score 1 to mark absent / weak, score 2 for high ) and was found the percentage of labeled cells, where the score was 1 cases with 0 to 50% of positive cells, score 2 with 51 to 75% of positive cells, and score 3 more than 75% of positive cells. The sample comprised 72.5% of men with a mean age of 65.8 years, there was a predominance of stage II and 52.5% of the carcinomas were classified as low grade, being carcinoma with metastasis presenting most cases (70%) as carcinomas of high malignancy grade (p = 0.004). The largest number of cases of SCC of the lower lip that were in stages I / II (61, 9%) were classified as carcinomas of low grade malignancy and carcinomas in stages III / IV were classified as high-grade tumors (p = 0, 024). The BMP-2 showed strong intensity of immunostaining in 82.5%, BMPR-IA showed 55% of cases with an intensity of immunostaining absent / weak and BMPR-II showed 85% of cases with an intensity of immunostaining absent / weak. Only the protein BMPR-IA were significantly associated with all clinic-pathological parameters studied, metastasis (p <0.001), TNM (p <0.001) and histological grade of malignancy with (p = 0.028). The percentage of positive cells, all markers showed the highest number of cases with more than 75% of positive cells (score 3) and only BMPR-II showed statistical difference when related to the presence and absence of metastasis (p = 0.049 ). We conclude that there is disturbance in the BMP signaling pathway in EC-mediated lower lip and that high expression of BMP-2 associated with the expression of BMPR-IA and BMPR-II are associated with metastasis in carcinoma