EP4 receptor stimulation down-regulates human eosinophil function

Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE₂ receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca²⁺ mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE₂ and the EP4 agonist. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of PI 3-kinase and PKC, but not cAMP. Finally, we found that EP4 receptors are expressed by human eosinophils, and are also present on infiltrating leukocytes in inflamed human nasal mucosa. These data indicate that EP4 agonists might be a novel therapeutic option in eosinophilic diseases.     

P2X7, NMDA and BDNF receptors converge on GSK3 phosphorylation and cooperate to promote survival in cerebellar granule neurons

Glycogen synthase kinase-3 (GSK3) is a key player in the regulation of neuronal survival. Herein, we report evidence of an interaction between P2X7 receptors with NMDA and BDNF receptors at the level of GSK3 signalling and neuroprotection. The activation of these receptors in granule neurons led to a sustained pattern of GSK3 phosphorylation that was mainly PKC-dependent. BDNF was the most potent at inducing GSK3 phosphorylation, which was also dependent on PI3K. The P2X7 agonist, BzATP, exhibited additive effects with both NMDA and BDNF to rescue granule neurons from cell death induced by PI3K inhibition. This survival effect was mediated by the PKC-dependent GSK3 pathway. In addition, ERK1/2 proteins were also involved in BDNF protective effect. These results show the function of ATP in amplifying neuroprotective actions of glutamate and neurotrophins, and support the role of GSK3 as an important convergence point for these survival promoting factors in granule neurons.     

Eulers “Harmony” Between the Principles of “Rest” and “Least Action”

In 1751, LEONHARD EULER established “harmony” between two principles that had been stated by PIERRE-LOUIS-MOREAU DE MAUPERTUIS a few years earlier. These principles are intended to be the foundations of Mechanics; they are the principle of rest and the principle of least action. My claim is that the way in which “harmony” is achieved sets the foundations of so called Analytical Mechanics: it discloses the physical bases of the general ideas, concepts, and motivations of the formalism. My paper intends to show what those physical bases are, and how a picture of the formalism issues from them. This picture is shown to be recast in JOSEPH-LOUIS LAGRANGES justification of the formalism, which strengthens my claim.     

Copper binds the carboxy-terminus of trefoil protein 1 (TFF1), favoring its homodimerization and motogenic activity

Trefoil protein 1 (TFF1) is a small secreted protein belonging to the trefoil factor family of proteins, that are present mainly in the gastrointestinal (GI) tract and play pivotal roles as motogenic factors in epithelial restitution, cell motility, and other incompletely characterized biological processes. We previously reported the up-regulation of TFF1 gene in copper deficient rats and the unexpected property of the peptide to selectively bind copper. Following the previous evidence, here we report the characterization of the copper binding site by fluorescence quenching spectroscopy and mass spectrometric analyses. We demonstrate that Cys58 and at least three Glu surrounding residues surrounding it, are essential to efficiently bind copper. Moreover, copper binding promotes the TFF1 homodimerization, thus increasing its motogenic activity in in vitro wound healing assays. Copper levels could then modulate the TFF1 functions in the GI tract, as well as its postulated role in cancer progression and invasion.     

Alternative complement pathway: Activity levels in allogeneic pregnancy

Summary Classical and alternative complement pathway activities have been evaluated in sera of women in progressive stages of gestation and in pregnant mice belonging to outbred or inbred matings, as compared to suitable controls. While classical C pathway was found to be unmodified, the alternative one attained in pregnancy significantly higher activity levels. Results are discussed in the light of mother-conceptus relationships.     

Mosaicism for sulfoiduronate sulfatase deficiency in carriers of Hunter's syndrome

Summary Using an assay for sulfoiduronate sulfatase based on the degradation of³⁵S mucopolysaccharides in a cellfree system, two clonal populations have been demonstrated in fibroblasts of heterozygotes for Hunter's syndrome. The locus responsible for sulfoiduronate sulfatase deficiency in thisX-linked mucopolysaccharidosis is therefore subjected to dosage compensation in females.Acknowledgments. The technical assistance of Mr.Antonio De Falco and Mrs.Carmela Salzano is gratefully acknowledged. The authors are indebted to Dr.H. Kresse (Münster, BRD) for helpful suggestions.     

Origin of the synaptonemal complex

Résumé La microscopie életronique des noyaux méiotiques de l'amphibien tétraploïdeO. americanus et de la souris a permis d'émettre l'hypothese suivant laquelle le complexe synaptonémique résulte de l'invagination de la membrane nucléaire, le synapsis étant la conséquence de ce mécanisme.     

Inhibitory action of dehydroepiandrosterone (DHEA) on fibroblast growth

Summary Dehydroepiandrosterone inhibits thymidine incorporation into human fibroblasts and may thus interfere with cellular growth.This investigation was supported in part by USPHS NIH training award AM 00329 and The New York State Health Research Council under contract #272.Acknowledgment. The authors wish to thank A. B. Rifkind, from the Department of Pharmacology at Cornell University Medical College for provision of skin biopsies.     

Preliminary report on the influence of the plasma upon the effect of ADP on arterial and venous platelets

Riassunto È stato dimostrato mediante prove crociate e la osservazione del comportamento di piastrine lavate risospese in PPP venoso o arterioso che la causa dell maggior risposta delle piastrine venose rispetto a quella delle piastrine arteriose all'ADP è nel plasma. La responsività all'ADP aumenta col tempo di incubazione nel plasma delle piastrine lavate.