Melanocortin Receptors as Novel Effectors of Macrophage Responses in Inflammation

Macrophages have crucial functions in initiating the inflammatory reaction in a strict temporal and spatial manner to provide a “clear-up” response required for resolution. Hormonal peptides such as melanocortins modulate macrophage reactivity and attenuate inflammation ranging from skin inflammation to joint disease and reperfusion injury. The melanocortins (e.g., adrenocorticotrophin, ACTH and αMSH) elicit regulatory properties through activation of a family of GPCRs, the melanocortin (MC) receptors; MC1–MC5. Several studies have focused on MC1 and MC3 as anti-inflammatory receptors expressed on cells of the macrophage lineage. We review here elements of the melanocortin pathway with particular attention to macrophage function in anti-inflammatory and pro-resolving inflammatory settings. Evidence shows that ACTH, αMSH, and other MC agonists can activate MC1 and MC3 on macrophage through cAMP and/or NFκB-dependent mechanisms to abrogate pro-inflammatory cytokines, chemokines, and NO and enhance anti-inflammatory mediators such as IL-10 and HO-1. Melanocortins and their receptors regulate inflammation by inhibiting leukocyte recruitment to and interaction with inflamed tissue. An intensely exciting addition to this field of research has been the ability of an αMSH analog; AP214 to activate MC3 expressed on macrophage to enhance their clearance of both zymosan particles and apoptotic neutrophils thus putting melanocortins in line with other pro-resolving mediators. The use of mouse colonies mutated or nullified for MC1 or MC3, respectively as well as availability of selective MC receptor agonist/antagonists have been key to deciphering mechanisms by which elements of the melanocortin system play a role in these phenomena. We review here melanocortin pathway components with attention to the macrophage, reiterating receptor targets required for pro-resolving properties. The overall outcome will be identification of selective MC agonists as a strategy for innovative anti-inflammatory therapeutics

Derivation of an Analytical Model to Calculate Junction Depth in HgCdTe Photodiodes

Presents an enhanced analytical model to calculate junction depth and Hg interstitial profile during n-on-p junction formation in HgCdTe photodiodes. Detailed information on the enhanced model; Function of the model; Information on HgCdTe; Detailed information on how the model was obtained

Chemical abundances for 11 bulge stars from high-resolution, near-IR spectra

It is debated whether the Milky Way bulge has the characteristics of a classical bulge sooner than those of a pseudobulge. Detailed abundance studies of bulge stars is a key to investigate the origin, history, and classification of the bulge. The aim is to add to the discussion on the origin of the bulge and to study detailed abundances determined from near-IR spectra for bulge giants already investigated with optical spectra, the latter also providing the stellar parameters which are very significant for the results of the present study. Especially, the important CNO elements are better determined in the near-IR. High-resolution, near-infrared spectra in the H band are recorded using the CRIRES spectrometer on the Very Large Telescope. The CNO abundances can all be determined from the numerous molecular lines in the wavelength range observed. Abundances of the alpha elements are also determined from the near-IR spectra. [O/Fe], [Si/Fe] and [S/Fe] are enhanced up to metallicities of at least [Fe/H]=-0.3, after which they decline. This suggests that the Milky Way bulge experienced a rapid and early star-formation history like that of a classical bulge. However, a similarity between the bulge trend and the trend of the local thick disk seems present. Such a similarity could suggest that the bulge has a pseudobulge origin. Our [C/Fe] trend does not show any increase with [Fe/H] which could have been expected if W-R stars have contributed substantially to the C abundances. No "cosmic scatter" can be traced around our observed abundance trends; the scatter found is expected, given the observational uncertainties.Comment: Accepted for publication in A&

Interpretive analysis of 85 systematic reviews suggests narrative syntheses and meta-analyses are incommensurate in argumentation

Introduction. Using Toulmin’s argumentation theory, we analysed the texts of systematic reviews in the area of workplace health promotion to explore differences in the modes of reasoning embedded in reports of narrative synthesis as compared to reports of meta-analysis. Methods. We used framework synthesis, grounded theory and cross-case analysis methods to analyse 85 systematic reviews addressing intervention effectiveness in workplace health promotion. Results. Two core categories, or ‘modes of reasoning’, emerged to frame the contrast between narrative synthesis and meta-analysis: practical-configurational reasoning in narrative synthesis (‘what is going on here? what picture emerges?’) and inferential-predictive reasoning in meta-analysis (‘does it work, and how well? will it work again?’). Modes of reasoning examined quality and consistency of the included evidence differently. Meta-analyses clearly distinguished between warrant and claim, whereas narrative syntheses often presented joint warrant-claims. Conclusion. Narrative syntheses and meta-analyses represent different modes of reasoning. Systematic reviewers are likely to be addressing research questions in different ways with each method. It is important to consider narrative synthesis in its own right as a method and to develop specific quality criteria and understandings of how it is done, not merely as a complement to, or second-best option for, meta-analysis

Myosin II has distinct functions in PNS and CNS myelin sheath formation

The myelin sheath forms by the spiral wrapping of a glial membrane around the axon. The mechanisms responsible for this process are unknown but are likely to involve coordinated changes in the glial cell cytoskeleton. We have found that inhibition of myosin II, a key regulator of actin cytoskeleton dynamics, has remarkably opposite effects on myelin formation by Schwann cells (SC) and oligodendrocytes (OL). Myosin II is necessary for initial interactions between SC and axons, and its inhibition or down-regulation impairs their ability to segregate axons and elongate along them, preventing the formation of a 1:1 relationship, which is critical for peripheral nervous system myelination. In contrast, OL branching, differentiation, and myelin formation are potentiated by inhibition of myosin II. Thus, by controlling the spatial and localized activation of actin polymerization, myosin II regulates SC polarization and OL branching, and by extension their ability to form myelin. Our data indicate that the mechanisms regulating myelination in the peripheral and central nervous systems are distinct

Chemical abundances in giants stars of the tidally disrupted globular cluster NGC 6712 from high-resolution infrared spectroscopy

We present abundances of C, N, O, F, Na, and Fe in six giant stars of the tidally disrupted globular cluster NGC 6712. The abundances were derived by comparing synthetic spectra with high resolution infrared spectra obtained with the Phoenix spectrograph on the Gemini South telescope. We find large star-to-star abundance variations of the elements C, N, O, F, and Na. NGC 6712 and M4 are the only globular clusters in which F has been measured in more than two stars, and both clusters reveal F abundance variations whose amplitude is comparable to, or exceeds, that of O, a pattern which may be produced in M > 5M_sun AGB stars. Within the limited samples, the F abundance in globular clusters is lower than in field and bulge stars at the same metallicity. NGC 6712 and Pal 5 are tidally disrupted globular clusters whose red giant members exhibit O and Na abundance variations not seen in comparable metallicity field stars. Therefore, globular clusters like NGC 6712 and Pal 5 cannot contribute many field stars and/or field stars do not form in environments with chemical enrichment histories like that of NGC 6712 and Pal 5. Although our sample size is small, from the amplitude of the O and Na abundance variations, we infer a large initial cluster mass and tentatively confirm that NGC 6712 was once one of the most massive globular clusters in our Galaxy.Comment: Accepted for publication in Ap

Accelerated repair of demyelinated CNS lesions in the absence of non-muscle myosin IIB

The oligodendrocyte (OL), the myelinating cell of the central nervous system, undergoes dramatic changes in the organization of its cytoskeleton as it differentiates from a precursor (oligodendrocyte precursor cells) to a myelin-forming cell. These changes include an increase in its branching cell processes, a phenomenon necessary for OL to myelinate multiple axon segments. We have previously shown that levels and activity of non-muscle myosin II (NMII), a regulator of cytoskeletal contractility, decrease as a function of differentiation and that inhibition of NMII increases branching and myelination of OL in coculture with neurons. We have also found that mixed glial cell cultures derived from NMIIB knockout mice display an increase in mature myelin basic protein-expressing OL compared with wild-type cultures. We have now extended our studies to investigate the role of NMIIB ablation on myelin repair following focal demyelination by lysolecithin. To this end, we generated an oligodendrocyte-specific inducible knockout model using a Plp-driven promoter in combination with a temporally activated CRE-ER fusion protein. Our data indicate that conditional ablation of NMII in adult mouse brain, expedites lesion resolution and remyelination by Plp+ oligodendrocyte-lineage cells when compared with that observed in control brains. Taken together, these data validate the function of NMII as that of a negative regulator of OL myelination in vivo and provide a novel target for promoting myelin repair in conditions such as multiple sclerosis

Interneuronal Nitric Oxide Signaling Mediates Post-synaptic Long-Term Depression of Striatal Glutamatergic Synapses

SummaryExperience-driven plasticity of glutamatergic synapses on striatal spiny projection neurons (SPNs) is thought to be essential to goal-directed behavior and habit formation. One major form of striatal plasticity, long-term depression (LTD), has long appeared to be expressed only pre-synaptically. Contrary to this view, nitric oxide (NO) generated by striatal interneurons was found to induce a post-synaptically expressed form of LTD at SPN glutamatergic synapses. This form of LTD was dependent on signaling through guanylyl cyclase and protein kinase G, both of which are abundantly expressed by SPNs. NO-LTD was unaffected by local synaptic activity or antagonism of endocannabinoid (eCb) and dopamine receptors, all of which modulate canonical, pre-synaptic LTD. Moreover, NO signaling disrupted induction of this canonical LTD by inhibiting dendritic Ca2+ channels regulating eCb synthesis. These results establish an interneuron-dependent, heterosynaptic form of post-synaptic LTD that could act to promote stability of the striatal network during learning

Scale-free Networks from Optimal Design

A large number of complex networks, both natural and artificial, share the presence of highly heterogeneous, scale-free degree distributions. A few mechanisms for the emergence of such patterns have been suggested, optimization not being one of them. In this letter we present the first evidence for the emergence of scaling (and smallworldness) in software architecture graphs from a well-defined local optimization process. Although the rules that define the strategies involved in software engineering should lead to a tree-like structure, the final net is scale-free, perhaps reflecting the presence of conflicting constraints unavoidable in a multidimensional optimization process. The consequences for other complex networks are outlined.Comment: 6 pages, 2 figures. Submitted to Europhysics Letters. Additional material is available at http://complex.upc.es/~sergi/software.ht