FGF ligands in Drosophila have distinct activities required to support cell migration and differentiation

Fibroblast growth factor (FGF) signaling controls a vast array of biological processes including cell differentiation and migration, wound healing and malignancy. In vertebrates, FGF signaling is complex, with over 100 predicted FGF ligand-receptor combinations. Drosophila melanogaster presents a simpler model system in which to study FGF signaling, with only three ligands and two FGF receptors (FGFRs) identified. Here we analyze the specificity of FGFR [Heartless (Htl) and Breathless (Btl)] activation by each of the FGF ligands [Pyramus (Pyr), Thisbe (Ths) and Branchless (Bnl)] in Drosophila. We confirm that both Pyr and Ths can activate Htl, and that only Bnl can activate Btl. To examine the role of each ligand in supporting activation of the Htl FGFR, we utilize genetic approaches that focus on the earliest stages of embryonic development. When pyr and ths are equivalently expressed using the Gal4 system, these ligands support qualitatively different FGFR signaling responses. Both Pyr and Ths function in a non-autonomous fashion to support mesoderm spreading during gastrulation, but Pyr exhibits a longer functional range. pyr and ths single mutants exhibit defects in mesoderm spreading during gastrulation, yet only pyr mutants exhibit severe defects in dorsal mesoderm specification. We demonstrate that the Drosophila FGFs have different activities and that cell migration and differentiation have different ligand requirements. Furthermore, these FGF ligands are not regulated solely by differential expression, but the sequences of these linked genes have evolved to serve different functions. We contend that inherent properties of FGF ligands make them suitable to support specific FGF-dependent processes, and that FGF ligands are not always interchangeable

Analysis of Thisbe and Pyramus functional domains reveals evidence for cleavage of Drosophila FGFs

Background: As important regulators of developmental and adult processes in metazoans, Fibroblast Growth Factor (FGF) proteins are potent signaling molecules whose activities must be tightly regulated. FGFs are known to play diverse roles in many processes, including mesoderm induction, branching morphogenesis, organ formation, wound healing and malignant transformation; yet much more remains to be learned about the mechanisms of regulation used to control FGF activity. Results: In this work, we conducted an analysis of the functional domains of two Drosophila proteins, Thisbe (Ths) and Pyramus (Pyr), which share homology with the FGF8 subfamily of ligands in vertebrates. Ths and Pyr proteins are secreted from Drosophila Schneider cells (S2) as smaller N-terminal fragments presumably as a result of intracellular proteolytic cleavage. Cleaved forms of Ths and Pyr can be detected in embryonic extracts as well. The FGF-domain is contained within the secreted ligand portion, and this domain alone is capable of functioning in the embryo when ectopically expressed. Through targeted ectopic expression experiments in which we assay the ability of full-length, truncated, and chimeric proteins to support cell differentiation, we find evidence that (1) the C-terminal domain of Pyr is retained inside the cell and does not seem to be required for receptor activation and (2) the C-terminal domain of Ths is secreted and, while also not required for receptor activation, this domain does plays a role in limiting the activity of Ths when present. Conclusions: We propose that differential protein processing may account for the previously observed inequalities in signaling capabilities between Ths and Pyr. While the regulatory mechanisms are likely complex, studies such as ours conducted in a tractable model system may be able to provide insights into how ligand processing regulates growth factor activity

PyR@TE: Renormalization Group Equations for General Gauge Theories

Although the two-loop renormalization group equations for a general gauge field theory have been known for quite some time, deriving them for specific models has often been difficult in practice. This is mainly due to the fact that, albeit straightforward, the involved calculations are quite long, tedious and prone to error. The present work is an attempt to facilitate the practical use of the renormalization group equations in model building. To that end, we have developed two completely independent sets of programs written in Python and Mathematica, respectively. The Mathematica scripts will be part of an upcoming release of SARAH 4. The present article describes the collection of Python routines that we dubbed PyR@TE which is an acronym for "Python Renormalization group equations At Two-loop for Everyone". In PyR@TE, once the user specifies the gauge group and the particle content of the model, the routines automatically generate the full two-loop renormalization group equations for all (dimensionless and dimensionful) parameters. The results can optionally be exported to Latex and Mathematica, or stored in a Python data structure for further processing by other programs. For ease of use, we have implemented an interactive mode for PyR@TE in form of an IPython Notebook. As a first application, we have generated with PyR@TE the renormalization group equations for several non-supersymmetric extensions of the Standard Model and found some discrepancies with the existing literature.Comment: 33 page

Evolutionary analysis of the TPP-dependent enzyme family

The evolutionary relationships of the thiamine pyrophosphate (TPP)-dependent family of enzymes was investigated by generation of a neighbor joining phylogenetic tree using sequences from the conserved pyrophosphate (PP) and pyrimidine (Pyr) binding domains of 17 TPP-dependent enzymes. This represents the most comprehensive analysis of TPP-dependent enzyme evolution to date. The phylogeny was shown to be robust by comparison with maximum likelihood trees generated for each individual enzyme and also broadly confirms the evolutionary history proposed recently from structural comparisons alone (Duggleby 2006). The phylogeny is most parsimonious with the TPP enzymes having arisen from a homotetramer which subsequently diverged into an α2β2 heterotetramer. The relationship between the PP- and Pyr-domains and the recruitment of additional protein domains was examined using the transketolase C-terminal (TKC)-domain as an example. This domain has been recruited by several members of the family and yet forms no part of the active site and has unknown function. Removal of the TKC-domain was found to increase activity toward β-hydroxypyruvate and glycolaldehyde. Further truncations of the Pyr-domain yielded several variants with retained activity. This suggests that the influence of TKC-domain recruitment on the evolution of the mechanism and specificity of transketolase (TK) has been minor, and that the smallest functioning unit of TK comprises the PP- and Pyr-domains, whose evolutionary histories extend to all TPP-dependent enzymes

Impact of Controlling the Site Distribution of Al Atoms on Catalytic Properties in Ferrierite-Type Zeolites

Zeolites with the ferrierite (FER) topology are synthesized using a combination of tetramethylammonium (TMA) cations with differently sized cyclic amines (pyrrolidine (Pyr), hexamethyleneimine (HMI), and 1,4- diazabicyclo[2.2.2]octane (DAB)). Using these organic structure-directing agents (SDAs), low Si/Al ratios and concentrated synthesis mixtures favor the crystallization of FER materials. Increasing the size of the cyclic amine or decreasing the aluminum content leads to the crystallization of other phases or the creation of excessive amounts of connectivity defects. TMA cations play a decisive role in the synthesis of the FER materials, and their presence allows the use of HMI to synthesize FER. Proton MAS NMR is used to quantify the accessibility of pyridine to acid sites in these FER samples, where it is found that the FER + HMI + TMA sample contains only 27% acid sites in the 8-MR channels, whereas FER + Pyr and FER + Pyr + TMA contain 89% and 84%, respectively. The constraint index (CI) test and the carbonylation of dimethyl ether (DME) with carbon monoxide are used as probe reactions to evaluate how changes in the aluminum distribution in these FER samples affect their catalytic behavior. Results show that the use of Pyr as an SDA results in the selective population of acid sites in the 8-MR channels, whereas the use of HMI generates FER zeolites with an increased concentration of acid sites in the 10-MR channels

Short-term hemodynamic effects of apelin in patients with pulmonary arterial hypertension

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr 1 )apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr 1 )apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170