Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli

Adiponectin exerts anti-inflammatory effects via macrophages, suppressing the production of pro-inflammatory cytokines in response to bacterial lipopolysaccharide (LPS). Here, we provide experimental evidence that the "anti-inflammatory" effect of adiponectin may be due to an induction of macrophage tolerance: globular adiponectin (gAd) is a powerful inducer of TNF-alpha and IL-6 secretion in primary human peripheral macrophages, in the THP-1 human macrophage cell line, and in primary mouse peritoneal macrophages. Pre-exposure of macrophages to 10 microg/ml gAd rendered them tolerant to further gAd exposure or to other pro-inflammatory stimuli such as TLR3 ligand polyI:C and TLR4 ligand LPS, while pre-exposure to 1 microg/ml of and re-exposure to 10 microg/ml gAd unmasked its pro-inflammatory properties. GAd induced NF-kappaB activation and tolerance to further gAd or LPS exposure. Our data suggest that adiponectin constant presence in the circulation in high levels (in lean subjects) renders macrophages resistant to pro-inflammatory stimuli, including its own.     

<Emphasis Type=Italic>MEFV</Emphasis> heterogeneity in Turkish Familial Mediterranean Fever patients

Turkey is one of the few countries in the world where Familial Mediterranean Fever (FMF), an autoinflammatory disease caused by mutations in MEFV, the gene encoding pyrin, is not rare. Many interesting studies regarding the genetics of Familial Mediterranean Fever in Turkey have been already published. Despite that different MEFV genetic profiles have been revealed for Turkish FMF patients, deriving from different regions of Turkey, a systematic population genetics analysis has not been carried out yet. The present study aims to investigate the population genetics of MEFV in Turkish FMF patients so as to additionally facilitate the clinical interpretation of individualized genetic data. All relevant studies have been recruited by searching PubMed with the terms “MEFV”, “FMF”, and “Turkey”. Seven of them, including 3,061 FMF patients, contained all necessary data concerning allelic and genotypic frequencies of the 4 commonest MEFV mutations in Turkey (M694V, V726A, M680I, E148Q). From all 6,122 MEFV alleles analyzed, the M694V mutation was recognized in 15.6–52.2% (mean 29.3%), the V726A in 1.5–9.7% (mean 4.8%), the M680I in 1.5–15.5% (mean 7.6%), and the E148Q in 3.2–13.9% (mean 5.5%). Unidentified mutations ranged from 0–42.9% (mean 16.8%). No mutations were found in 0–54.5% (mean 36.0%) of the patients. The allelic and genotypic frequencies of the most frequent mutation (M694V) showed aberration of the Hardy–Weinberg law for all 7 populations studied. By application of the Arlequin 2.0 population genetics software, the Fixation index (F _ST) was found to be 0.09994, thus demonstrating that the observed variability is mainly within (90.006%) and not among (9.994%) populations (P < 0.00001). Moreover, the global test of differentiation demonstrated that every population differs from each other (P < 0.00325). Finally, the Ewens–Watterson test of selective neutrality yielded to statistical significance in only 3 populations. In conclusion, Turkish FMF patients are characterized by an increased genetic heterogeneity, explained by the intrapopulation differentiation. Thus, the regional origin should be regarded as a determining factor in the diagnosis of FMF in Turkish patients.     

One Step forward: Benthic Pelagic Coupling and Indicators for Environmental Status

A large data set from the Eastern Mediterranean was analyzed to explore the relationship between seawater column variables and benthic community status. Our results showed a strong quantitative link between the seawater column variables (Chlorophyll a and Eutrophication Index) and various indicators describing benthic diversity and community composition. The percentage of benthic opportunistic species increased significantly in the stations with high trophic status of the seawater column and so did the strength of the coupling between values of seawater column and benthic indicators. The Eutrophication Index threshold level of 0.85, separating the “Bad and Poor” from “Moderate to High” conditions could serve as an acceptable critical value above which there is a readily observable change in benthic community composition.     

The Streptococcal Binding Site in the Gelatin-binding Domain of Fibronectin Is Consistent with a Non-linear Arrangement of Modules

Fibronectin-binding proteins (FnBPs) of Staphylococcus aureus and Streptococcus pyogenes mediate invasion of human endothelial and epithelial cells in a process likely to aid the persistence and/or dissemination of infection. In addition to binding sites for the N-terminal domain (NTD) of fibronectin (Fn), a number of streptococcal FnBPs also contain an upstream region (UR) that is closely associated with an NTD-binding region; UR binds to the adjacent gelatin-binding domain (GBD) of Fn. Previously, UR was shown to be required for efficient streptococcal invasion of epithelial cells. Here we show, using a Streptococcus zooepidemicus FnBP, that the UR-binding site in GBD resides largely in the ⁸F1⁹F1 module pair. We also show that UR inhibits binding of a peptide from the α1 chain of type I collagen to ⁸F1⁹F1 and that UR binding to ⁸F1 is likely to occur through anti-parallel β-zipper formation. Thus, we propose that streptococcal proteins that contain adjacent NTD- and GBD-binding sites form a highly unusual extended tandem β-zipper that spans the two domains and mediates high affinity binding to Fn through a large intermolecular interface. The proximity of the UR- and NTD-binding sequences in streptococcal FnBPs is consistent with a non-linear arrangement of modules in the tertiary structure of the GBD of Fn.     

Recognition pliability is coupled to structural heterogeneity: a calmodulin intrinsically disordered binding region complex

Protein interactions within regulatory networks should adapt in a spatiotemporal-dependent dynamic environment, in order to process and respond to diverse and versatile cellular signals. However, the principles governing recognition pliability in protein complexes are not well understood. We have investigated a region of the intrinsically disordered protein myelin basic protein (MBP(145-165)) that interacts with calmodulin, but that also promiscuously binds other biomolecules (membranes, modifying enzymes). To characterize this interaction, we implemented an NMR spectroscopic approach that calculates, for each conformation of the complex, the maximum occurrence based on recorded pseudocontact shifts and residual dipolar couplings. We found that the MBP(145-165)-calmodulin interaction is characterized by structural heterogeneity. Quantitative comparative analysis indicated that distinct conformational landscapes of structural heterogeneity are sampled for different calmodulin-target complexes. Such structural heterogeneity in protein complexes could potentially explain the way that transient and promiscuous protein interactions are optimized and tuned in complex regulatory networks.     

Reproduction of Mothocya epimerica (Crustacea: Isopoda: Cymothoidae), parasitic on the sand smelt Atherina boyeri (Osteichthyes: Atherinidae) in Greek lagoons

The reproduction and growth pattern of Mothocya epimerica (Crustacea: Isopoda: Cymothoidae), a protandrous hermaphroditic gill parasite of Atherina boyeri (Osteichthyes: Atherinidae), were investigated in the Mesolongi and Etolikon lagoons. The parasite shows an extensive reproductive period. Gravid females were found between April and November, and juveniles between May and December. M. epimerica grew allometrically (slopes of the total weight-total length regressions were >3). Females were significantly heavier than males. The relationship between number of eggs or mancas larvae (F) and total length (TL) was investigated in gravid female parasites in which the marsupium was still closed; the relationship was clearly curvilinear: F = 0.128TL3.18. The number of eggs or mancas larvae held in the marsupia of females increased proportionally with female length, varying from 39 in an isopod of 6.3 mm length to 158 in one of 8.5 mm length. The average number of eggs or mancas larvae was 76.70 +/- 27.8.