Backgroundβ1- and β2–adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF).ResultsWe crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular “brake” that PDE4D poses on β2AR signaling to contractility stimulation is thus “released”. Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed.ConclusionsGRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, although this effect is short-lived.
Fecal indicator microbes such as enterococci are often used to assess potential health risks caused by pathogens at recreational beaches. Microbe levels often vary based on collection time and sampling location. The primary goal of this study was to assess how spatial and temporal variations in sample collection which are driven by environmental parameters impact enterococci measurements and beach management decisions. A secondary goal was to assess whether enterococci levels can be predictive of the presence of Staphylococcus aureus a skin pathogen. Over a ten day period hydrometeorologic data hydrodynamic data bather densities enterococci levels and S. aureus levels including methicillin-resistant S. aureus (MRSA) were measured in both water and sand. Samples were collected hourly for both water and sediment at knee-depth and every 6 hours for water at waist-depth supratidal sand intertidal sand and waterline sand. Results showed that solar radiation tides and rainfall events were major environmental factors that impacted enterococci levels. S. aureus levels were associated with bathing load but did not correlate with enterococci levels or any other measured parameters. The results imply that frequencies of advisories depend heavily upon sample collection policies due to spatial and temporal variation of enterococci levels in response to environmental parameters. Thus sampling at different times of the day and at different depths can significantly impact beach management decisions. Additionally the lack of correlation between S. aureus and enterococci suggests that use of fecal indicators may not accurately assess risk for some pathogens.
A combination of 454 pyrosequencing and Sanger sequencing was used to sample and characterize the transcriptome of the entomopathogenic oomycete Lagenidium giganteum. More than 50,000 high-throughput reads were annotated through homology searches. Several selected reads served as seeds for the amplification and sequencing of full-length transcripts. Phylogenetic analyses inferred from full-length cellulose synthase alignments revealed that L giganteum is nested within the peronosporalean galaxy and as such appears to have evolved from a phytopathogenic ancestor. In agreement with the phylogeny reconstructions, full-length L. giganteum oomycete effector orthologs, corresponding to the cellulose-binding elicitor lectin (CBEL), crinkler (CRN), and elicitin proteins, were characterized by domain organizations similar to those of pathogenicity factors of plantpathogenic oomycetes. Importantly, the L. giganteum effectors provide a basis for detailing the roles of canonical CRN, CBEL, and elicitin proteins in the infectious process of an oomycete known principally as an animal pathogen. Finally, phylogenetic analyses and genome mining identified members of glycoside hydrolase family 5 subfamily 27 (GH5_27) as putative virulence factors active on the host insect cuticle, based in part on the fact that GH5_27 genes are shared by entomopathogenic oomycetes and fungi but are underrepresented in nonentomopathogenic genomes. The genomic resources gathered from the L. giganteum transcriptome analysis strongly suggest that filamentous entomopathogens (oomycetes and fungi) exhibit convergent evolution: they have evolved independently from plant-associated microbes, have retained genes indicative of plant associations, and may share similar cores of virulence factors, such as GH5_27 enzymes, that are absent from the genomes of their plant-pathogenic relatives.
In May of 2011, a live mass stranding of 26 short-finned pilot whales (Globicephala macrorhynchus) occurred in the lower Florida Keys. Five surviving whales were transferred from the original stranding site to a nearby marine mammal rehabilitation facility where they were constantly attended to by a team of volunteers. Bacteria cultured during the routine clinical care of the whales and necropsy of a deceased whale included methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA). In order to investigate potential sources or reservoirs of MSSA and MRSA, samples were obtained from human volunteers, whales, seawater, and sand from multiple sites at the facility, nearby recreational beaches, and a canal. Samples were collected on 3 days. The second collection day was 2 weeks after the first, and the third collection day was 2 months after the last animal was removed from the facility. MRSA and MSSA were isolated on each day from the facility when animals and volunteers were present. MSSA was found at an adjacent beach on all three collection days. Isolates were characterized by utilizing a combination of quantitative real-time PCR to determine the presence of mecA and genes associated with virulence, staphylococcal protein A typing, staphylococcal cassette chromosome mec typing, multilocus sequence typing, and pulsed field gel electrophoresis (PFGE). Using these methods, clonally related MRSA were isolated from multiple environmental locations as well as from humans and animals. Non-identical but genetically similar MSSA and MRSA were also identified from distinct sources within this sample pool. PFGE indicated that the majority of MRSA isolates were clonally related to the prototype human strain USA300. These studies support the notion that S. aureus may be shed into an environment by humans or pilot whales and subsequently colonize or infect exposed new hosts.
Introduction: It is widely accepted nowadays that elevation of serum levels of aldosterone, a mineralocorticoid hormone with toxic effects in several cardiovascular tissues, including the heart and cerebral blood vessels, can significantly raise stroke risk. The success of mineralocorticoid receptor blockers, such as eplerenone, at preventing stroke attacks attests to this. Aldosterone is normally produced and secreted by the adrenal cortex in response to angiotensin II. We recently reported that adrenal βarrestin1 (βarr1) plays a crucial role in the physiological angiotensin II-stimulated aldosterone production in the adrenal cortex, leading to marked elevation of circulating serum aldosterone levels in vivo (Lymperopoulos A. et al., Proc. Natl. Acad. Sci. USA. 2009;106:5825-5830). Hypothesis: Herein, we examined the potential impact of this adrenal βarr1-dependent aldosterone elevation on stroke risk in experimental animals in vivo. Methods: We used the βarr1 knockout (βarr1KO) mouse model, studying it alongside wild type (WT) control mice, and also adult male Sprague-Dawley rats, in which adrenal βarr1 was overexpressed in vivo via adrenal-targeted adenoviral-mediated βarr1 gene transfer. Serum aldosterone was measured by ELISA and blood pressure via telemetry. Results: Serum aldosterone at 7 days post-in vivo gene delivery was markedly elevated in adrenal βarr1-overexpressing rats (536+50 pg/ml), compared to control rats receiving the green fluorescent protein (GFP) adenoviral transgene (235+40 pg/ml, p<0.05, n=5). This translated to a significant increase in mean arterial pressure of the βarr1-overexpressing rats (155+5 mmHg) compared to control GFP-expressing rats (137+8 mmHg, p<0.05, n=5), again at 7 days post-in vivo gene delivery, which was prevented by concurrent eplerenone treatment. In contrast, βarr1KO mice had significantly lower serum aldosterone levels (270+20 pg/ml) compared to WT controls (498+35 pg/ml, p<0.05, n=5), at 4 weeks post-experimental myocardial infarction. Conclusions: Adrenal βarr1 up-regulation can dramatically increase circulating aldosterone levels and systemic blood pressure, thus conferring increased risk for stroke in experimental rodents.
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