Annexin A1 N-Terminal Derived Peptide Ac2-26 Exerts Chemokinetic Effects on Human Neutrophils

It is postulated that peptides derived from the N-terminal region of Annexin A1, a glucocorticoid-regulated 37-kDa protein, could act as biomimetics of the parent protein. However, recent evidence, amongst which the ability to interact with distinct receptors other then that described for Annexin A1, suggest that these peptides might fulfill other functions at variance to those reported for the parent protein. Here we tested the ability of peptide Ac2-26 to induce chemotaxis of human neutrophils, showing that this peptide can elicit responses comparable to those produced by the canonical activator formyl-Met-Leu-Phe (or FMLP). However, whilst disruption of the chemical gradient abolished the FMLP response, addition of peptide Ac2-26 in the top well of the chemotaxis chamber did not affect (10 μM) or augmented (at 30 μM) the neutrophil locomotion to the bottom well, as elicited by 10 μM peptide Ac2-26. Intriguingly, the sole addition of peptide Ac2-26 in the top wells produced a marked migration of neutrophils. A similar behavior was observed when human primary monocytes were used. Thus, peptide Ac2-26 is a genuine chemokinetic agent toward human blood leukocytes. Neutralization strategies indicated that engagement of either the GPCR termed FPR1 or its cognate receptor FPR2/ALX was sufficient to sustain peptide Ac2-26 induced neutrophil migration. Similarly, application of pharmacological inhibitors showed that cell locomotion to peptide Ac2-26 was mediated primarily by the ERK, but not the JNK and p38 pathways. In conclusion, we report here novel in vitro properties for peptide Ac2-26, promoting neutrophil and monocyte chemokinesis; a process that may contribute to accelerate the resolution phase of inflammation. We postulate that the generation of Annexin A1 N-terminal peptides at the site of inflammation may expedite the egress of migrated leukocytes thus promoting the return to homeostasis

Human Research Ethics Committee Experiences and Views About Children's Participation in Research: Results From the MESSI Study.

As part of a larger study, Australian Human Research Ethics Committee (HREC) members and managers were surveyed about their decision-making and views about social research studies with child participants. Responses of 229 HREC members and 42 HREC managers are reported. While most HREC members had received ethical training, HREC training and guidelines specific to research involving children were rare. Most applications involving children had to go through a full ethical review, but few adverse events were reported to HRECs regarding the conduct of the studies. Revisions to study proposals requested by HRECs were mostly related to consent processes and age-appropriate language. One-third of HREC members said that they would approve research on any topic. Most were also concerned that the methodology was appropriate, and the risks and benefits were clearly articulated. Specific training and guidance are needed to increase HREC members' confidence to judge ethical research with children

Localization of Quaternary slip rates in an active rift in 10(5) years: an example from central Greece constrained by U-234-Th-230 coral dates from uplifted paleoshorelines

Mapping, dating, and modeling of paleoshorelines uplifted in the footwall of the 1981 Gulf of Corinth earthquake fault, Greece (Ms 6.9–6.7), are used to assess its slip rate history relative to other normal faults in the area and study strain localization. The 234U-230Th coral ages from Cladocora caespitosa date uplifted shoreface sediments, and paleoshorelines from glacioeustatic sea level highstands at 76, (possibly) 100, 125, 175, 200, 216, 240, and 340 ka. Uplifted Quaternary and Holocene paleoshorelines decrease in elevation toward the western tip of the fault, exhibiting larger tilt angles with age, showing that uplift is due to progressive fault slip. Since 125 ka, uplift rates varied from 0.25 to 0.52 mm/yr over a distance of 5 km away from the fault tip. Tilting was also occurring prior to 125 ka, but uplift rates were lower because the 125 ka paleoshoreline is at 77% of the elevation of the 240 ka paleoshoreline despite being nearly half its age. Comparison of paleoshoreline elevations and sedimentology with the Quaternary sea level curve shows that slip rates increased by a factor of 3.2 ± 0.2 at 175 ± 75 ka, synchronous with cessation of activity on a neighboring normal fault at 382–112 ka. We suggest that the rapid localization of up to 10–15 mm/yr of extension into the narrow gulf (∼30 km wide) resulted from synchronous fault activity on neighboring faults followed by localization rather than sequential faulting, with consequences for the mechanism controlling localization of extension

Ectoplasm & Superspace Integration Measure for 2D Supergravity with Four Spinorial Supercurrents

Building on a previous derivation of the local chiral projector for a two dimensional superspace with eight real supercharges, we provide the complete density projection formula required for locally supersymmetrical theories in this context. The derivation of this result is shown to be very efficient using techniques based on the Ectoplasmic construction of local measures in superspace.Comment: 18 pages, LaTeX; V2: minor changes, typos corrected, references added; V3: version to appear in J. Phys. A: Math. Theor., some comments and references added to address a referee reques

A New Calibration Of Galactic Cepheid Period-Luminosity Relations From B To K Bands, And A Comparison To LMC Relations

Context. The universality of the Cepheid period-luminosity (PL) relations has been under discussion since metallicity effects were assumed to play a role in the value of the intercept and, more recently, of the slope of these relations. Aims. The goal of the present study is to calibrate the Galactic PL relations in various photometric bands (from B to K) and to compare the results to the well-established PL relations in the LMC. Methods. We use a set of 59 calibrating stars, the distances of which are measured using five different distance indicators: Hubble Space Telescope and revised Hipparcos parallaxes, infrared surface brightness and interferometric Baade-Wesselink parallaxes, and classical Zero-Age-Main-Sequence-fitting parallaxes for Cepheids belonging to open clusters or OB stars associations. A detailed discussion of absorption corrections and projection factor to be used is given. Results. We find no significant difference in the slopes of the PL relations between LMC and our Galaxy. Conclusions. We conclude that the Cepheid PL relations have universal slopes in all photometric bands, not depending on the galaxy under study (at least for LMC and Milky Way). The possible zero-point variation with metal content is not discussed in the present work, but an upper limit of 18.50 for the LMC distance modulus can be deduced from our data.McDonald Observator

Spin dependent D-brane interactions and scattering amplitudes in matrix theory

Spin interactions beteween two moving Dp-branes are analyzed using the Green-Schwarz formalism of boundary states. This approach turns out to be extremely efficient to compute all the spin effects related by supersymmetry to the leading v^4/r^7-p term. All these terms are shown to be scale invariant, supporting a matrix model description of supergravity interactions. By employing the LSZ reduction formula for matrix theory and the mentioned supersymmetric effective potential for D0-branes, we compute the t-pole of graviton-graviton and three form-three form scattering in matrix theory. The results are found to be in complete agreement with tree level supergravity in the corresponding kinematical regime and provide, moreover, an explicit map between these degrees of freedom in both theories.Comment: 8 pages, no figures, talk presented at the conference "Quantum aspects of gauge theories, supergravity and unification", Corfu, Greece, to appear in the proceeding

Stimulation of the Pro-Resolving Receptor Fpr2 Reverses Inflammatory Microglial Activity by Suppressing NFκB Activity

Neuroinflammation driven primarily by microglia directly contributes to neuronal death in many neurodegenerative diseases. Classical anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution may also be of benefit. A key driver of peripheral inflammatory resolution, formyl peptide receptor 2 (Fpr2), is expressed by microglia, but its therapeutic potential in neurodegeneration remains unclear. Here, we studied whether targeting of Fpr2 could reverse inflammatory microglial activation induced by the potent bacterial inflammogen lipopolysaccharide (LPS). Exposure of murine primary or immortalised BV2 microglia to LPS triggered pro-inflammatory phenotypic change and activation of ROS production, effects significantly attenuated by subsequent treatment with the Fpr2 agonist C43. Mechanistic studies showed C43 to act through p38 MAPK phosphorylation and reduction of LPS-induced NFκB nuclear translocation via prevention of IκBα degradation. Here, we provide proof-of-concept data highlighting Fpr2 as a potential target for control of microglial pro-inflammatory activity, suggesting that it may be a promising therapeutic target for the treatment of neuroinflammatory disease

Effective Average Action in N=1 Super-Yang-Mills Theory

For N=1 Super-Yang-Mills theory we generalize the effective average action Gamma_k in a manifest supersymmetric way using the superspace formalism. The exact evolution equation for Gamma_k is derived and, introducing as an application a simple truncation, the standard one-loop beta-function of N=1 SYM theory is obtained.Comment: 17 pages, LaTeX, some remarks added, misprints corrected, to appear in Phys. Rev.

The SU(N) Matrix Model at Two Loops

Multi-loop calculations of the effective action for the matrix model are important for carrying out tests of the conjectured relationship of the matrix model to the low energy description of M-theory. In particular, comparison with N-graviton scattering amplitudes in eleven-dimensional supergravity requires the calculation of the effective action for the matrix model with gauge group SU(N). A framework for carrying out such calculations at two loops is established in this paper. The two-loop effective action is explicitly computed for a background corresponding to the scattering of a single D0-brane from a stack of N-1 D0-branes, and the results are shown to agree with known results in the case N=2.Comment: 30 pages, 1 figure; v2 - typos corrected, references update

Characterisation of the mammalian family of DCN-type NEDD8 E3 ligases

Cullin-RING ligases (CRL) are ubiquitin E3s that bind substrates through variable substrate-receptor proteins. CRLs are activated by attachment of the ubiquitin-like protein NEDD8 to the Cullin subunit and DCNs are NEDD8 E3 ligases that promote neddylation. Mammalian cells express five DCN-like proteins and little is known about their specific functions or interaction partners. We found that DCNLs form stable stoichiometric complexes with CAND1 and Cullins that can only be neddylated in the presence of substrate adaptor. These DCNL-CUL-CAND1 complexes may represent “reserve” CRLs that can be rapidly activated when needed. We further found that all DCNLs interact with most Cullin subtypes, but that they are likely responsible for the neddylation of different subpopulations of any given Cullin. This is consistent with the fact that the subcellular localization of DCNLs in tissue culture cells differs and that they show unique tissue specific expression patterns in mice. Thus, the specificity between DCNL-type NEDD8 E3 enzymes and their Cullin substrates is only apparent in well-defined physiological contexts and related to their subcellular distribution and restricted expression