Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs

A diet high in fat induces cardiac hypertrophy, inflammation, and oxidative stress. Although such actions have largely been ascribed to fat deposition, the accumulation of advanced glycation end products (AGEs) and subsequent activation of the receptor for AGEs (RAGE) may also represent important mediators of cardiac injury following exposure to a Western diet. In this study, male C57BL6J and RAGE knockout mice were placed on either a standard diet (7% fat) or a Western "fast-food" diet (21% fat). Animals receiving a high-fat diet were further randomized to receive the AGE inhibitor alagebrium chloride (1 mg.kg(-1).day(-1)) and followed for 16 wk. A Western diet was associated with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide production, and cardiac AGE accumulation in wild-type mice. Although RAGE-KO mice fed a Western diet also became obese and accumulated intramyocardial lipid, cardiomyocyte hypertrophy, inflammation, and oxidative stress were attenuated compared with wild-type mice. Similarly, mice of both strains receiving alagebrium chloride had reduced levels of inflammation and oxidative stress, in association with a reduction in cardiac AGEs and RAGE. This study suggests that AGEs represent important mediators of cardiac injury associated with a Western fast-food diet. These data point to the potential utility of AGE-reducing strategies in the prevention and management of cardiac disease.     

Linking Ras to myosin function: RasGEF Q, a Dictyostelium exchange factor for RasB, affects myosin II functions

Ras guanine nucleotide exchange factor (GEF) Q, a nucleotide exchange factor from Dictyostelium discoideum, is a 143-kD protein containing RasGEF domains and a DEP domain. We show that RasGEF Q can bind to F-actin, has the potential to form complexes with myosin heavy chain kinase (MHCK) A that contain active RasB, and is the predominant exchange factor for RasB. Overexpression of the RasGEF Q GEF domain activates RasB, causes enhanced recruitment of MHCK A to the cortex, and leads to cytokinesis defects in suspension, phenocopying cells expressing constitutively active RasB, and myosin-null mutants. RasGEF Q(-) mutants have defects in cell sorting and slug migration during later stages of development, in addition to cell polarity defects. Furthermore, RasGEF Q(-) mutants have increased levels of unphosphorylated myosin II, resulting in myosin II overassembly. Collectively, our results suggest that starvation signals through RasGEF Q to activate RasB, which then regulates processes requiring myosin II.     

A hydrophobic patch on proteinase 3, the target of autoantibodies in Wegener granulomatosis, mediates membrane binding via NB1 receptors

Proteinase 3 (PR3), the target antigen of antineutrophil cytoplasm autoantibodies, which are found in patients with Wegener granulomatosis, is a neutrophil serine protease localized within cytoplasmic granules. Recently, the human neutrophil antigen NB1 was identified as a specific neutrophil cell surface receptor of PR3. We hypothesized that the unique hydrophobic cluster of PR3 that is not present on human neutrophil elastase and cathepsin G and presumably is also missing in other human PR3 homologs accounts for its binding to the NB1 receptor expressed on the cellular surface of NB1 cells. Instead of generating and testing various artificial human PR3 mutants, we cloned and expressed the very closely related gibbon (Hylobates pileatus) PR3 homolog, which did not bind to the human NB1 receptor. Moreover, a human-gibbon hybrid constructed from the N- and C-terminal half of the human and gibbon PR3, respectively, also did not interact with human NB1. The C-terminal half of gibbon PR3 differs only by 9 residues from human PR3, among which four closely spaced hydrophobic residues are substituted in a nonconservative manner (F166L, W218R, G219A, and L223H). The NB1-bound PR3 was active and was cleared from the surface by alpha-1-protease inhibitor. Conformational distortion of the hydrophobic 217-225 loop by alpha-1-protease inhibitor most likely triggers rapid solubilization.     

Do plant-community-based grazing regimes lead to epizoochorous dispersal of high proportions of target species?

The contribution of large-herbivore epizoochory to the transfer of seeds within and between areas is thought to be significant. But often seeds of ubiquitous species are dispersed, which may enhance ruderalization processes. In order to study the dispersal of target species by sheep, we employed a community-based grazing approach followed by intra- and inter-area sheep transfers (maximum transfer distance 3 km). In case of inter-area transfers, well-developed target communities of an open inland sand ecosystem are used as “source”, linked to less-developed sand habitats (“sink”) via sheep. Also other factors determining which species become dispersed under field conditions were tested: seed surface structure, seed mass, plant seed-releasing height and animal behaviour. Finally the influence of animal movement on seed detachment and the actual arrival of seeds within a “sink” were studied.

Sheep transfers resulted in the dispersal of 56 seed species, dominated by Red List (seven species) and other target species. Quantitatively, most transported seeds belonged to target species, whereas graminoid competitors were highly under-represented. Morphological traits enhance the attachment probability regardless of seed mass. But for seeds without these epizoochory-facilitating traits, mass seems to affect attachment negatively. Plant height affected the number of species present in sheep coats but not the seed quantities. Probably certain species in the vegetation produced large numbers of seeds, e.g. low-growing Medicago minima with seed surface structures and high-growing species Verbascum phlomoides without seed surface structures. Also, although transfer half-times were three times lower than grazing half-times, naturally attached Stipa capillata and Agrimonia procera seeds showed no significant detachment rates during transfer, whereas considerable losses were found during grazing. Other 3-km sheep transfers did not result in significant losses of either epizoochorously transported seed or species quantities. Our study shows that community-based grazing can lead to the dispersal of especially target species. Besides that, different habitat fragments can be connected to each other via sheep without significant seed losses along the way.     

Organization of medical care of patients with pneumonia caused by Legionella during outbreak in Sverdlovsk region

Data on organization of medical care during outbreak of Legionnaires' disease in July-August, 2007 in town Verkhnyaya Pyshma in Sverdlovsk region are presented. Special feature of this outbreak was spreading of infection in boundaries of the town with total population of 70,600 people. Results of organizational work of health authorities in order to provide timely and adequate medical care for patients with Legionnaires' disease on both outpatient and inpatient levels of care, conduction of preventive measures in foci of infection, coordination of interaction between different medical organizations and services are summarized in the article.     

Actions of 3-methyl-N-oleoyldopamine, 4-methyl-N-oleoyldopamine and N-oleoylethanolamide on the rat TRPV1 receptor in vitro and in vivo

N-oleoyldopamine (OLDA) has been identified as an agonist of the transient receptor potential vanilloid type 1 (TRPV1) receptor. A related fatty acid amide, N-oleoylethanolamide (OEA), was found to excite sensory neurons and produce visceral hyperalgesia via activation of the TRPV1 receptor, however, a recent study described this agent as an antinociceptive one. The aim of the present paper was to characterize two newly synthesized derivatives of N-oleoyldopamine, 3-methyl-N-oleoyldopamine (3-MOLDA) and 4-methyl-N-oleoyldopamine (4-MOLDA) as well as OEA with regard to their effects on the TRPV1 receptor. Radioactive 45Ca2+ uptake was measured in HT5-1 cells transfected with the rat TRPV1 receptor and intracellular Ca2+ concentration was monitored by fura-2 microfluorimetry in cultured trigeminal sensory neurons. Thermonociception was assessed by determining the behavioral noxious heat threshold in rats. 3-MOLDA induced 45Ca2+ uptake in a concentration-dependent manner, whereas 4-MOLDA and OEA were without effect. 4-MOLDA and OEA, however, concentration-dependently reduced the 45Ca2+ uptake-inducing effect of capsaicin. In trigeminal sensory neurons, 3-MOLDA caused an increase in intracellular Ca2+ concentration and this effect exhibited tachyphylaxis upon repeated application. Again, 4-MOLDA and OEA failed to alter intracellular Ca2+ levels. Upon intraplantar injection, 3-MOLDA caused an 8-10 degrees C drop of the noxious heat threshold in rats which was inhibited by the TRPV1 receptor antagonist iodo-resiniferatoxin. 4-MOLDA and OEA failed to alter the heat threshold but inhibited the threshold drop induced by the TRPV1 receptor agonist resiniferatoxin. These data show that 3-MOLDA behaves as an agonist, whereas 4-MOLDA and OEA appear to be antagonists, at the rat TRPV1 receptor.     

Coronavirus and paramyxovirus in bats from Northwest Italy

Background

Bat-borne virus surveillance is necessary for determining inter-species transmission risks and is important due to the wide-range of bat species which may harbour potential pathogens. This study aimed to monitor coronaviruses (CoVs) and paramyxoviruses (PMVs) in bats roosting in northwest Italian regions. Our investigation was focused on CoVs and PMVs due to their proven ability to switch host and their zoonotic potential. Here we provide the phylogenetic characterization of the highly conserved polymerase gene fragments.

Results

Family-wide PCR screenings were used to test 302 bats belonging to 19 different bat species. Thirty-eight animals from 12 locations were confirmed as PCR positive, with an overall detection rate of 12.6% [95% CI: 9.3–16.8]. CoV RNA was found in 36 bats belonging to eight species, while PMV RNA in three Pipistrellus spp. Phylogenetic characterization have been obtained for 15 alpha- CoVs, 5 beta-CoVs and three PMVs; moreover one P. pipistrellus resulted co-infected with both CoV and PMV. A divergent alpha-CoV clade from Myotis nattereri SpA is also described. The compact cluster of beta-CoVs from R. ferrumequinum roosts expands the current viral sequence database, specifically for this species in Europe. To our knowledge this is the first report of CoVs in Plecotus auritus and M. oxygnathus, and of PMVs in P. kuhlii.

Conclusions

This study identified alpha and beta-CoVs in new bat species and in previously unsurveyed Italian regions. To our knowledge this represents the first and unique report of PMVs in Italy. The 23 new bat genetic sequences presented will expand the current molecular bat-borne virus databases. Considering the amount of novel bat-borne PMVs associated with the emergence of zoonotic infections in animals and humans in the last years, the definition of viral diversity within European bat species is needed. Performing surveillance studies within a specific geographic area can provide awareness of viral burden where bats roost in close proximity to spillover hosts, and form the basis for the appropriate control measures against potential threats for public health and optimal management of bats and their habitats.