Effects of deoxycholylglycine, a conjugated secondary bile acid, on myogenic tone and agonist-induced contraction in rat resistance arteries

Background

Bile acids (BAs) regulate cardiovascular function via diverse mechanisms. Although in both health and disease serum glycine-conjugated BAs are more abundant than taurine-conjugated BAs, their effects on myogenic tone (MT), a key determinant of systemic vascular resistance (SVR), have not been examined.

Methodology/Principal Findings

Fourth-order mesenteric arteries (170–250 µm) isolated from Sprague-Dawley rats were pressurized at 70 mmHg and allowed to develop spontaneous constriction, i.e., MT. Deoxycholylglycine (DCG; 0.1–100 µM), a glycine-conjugated major secondary BA, induced reversible, concentration-dependent reduction of MT that was similar in endothelium-intact and -denuded arteries. DCG reduced the myogenic response to stepwise increase in pressure (20 to 100 mmHg). Neither atropine nor the combination of L-NAME (a NOS inhibitor) plus indomethacin altered DCG-mediated reduction of MT. K⁺ channel blockade with glibenclamide (K_ATP), 4-aminopyradine (K_V), BaCl₂ (K_IR) or tetraethylammonium (TEA, K_Ca) were also ineffective. In Fluo-2-loaded arteries, DCG markedly reduced vascular smooth muscle cell (VSM) Ca²⁺ fluorescence (∼50%). In arteries incubated with DCG, physiological salt solution (PSS) with high Ca²⁺ (4 mM) restored myogenic response. DCG reduced vascular tone and VSM cytoplasmic Ca²⁺ responses (∼50%) of phenylephrine (PE)- and Ang II-treated arteries, but did not affect KCl-induced vasoconstriction.

Conclusion

In rat mesenteric resistance arteries DCG reduces pressure- and agonist-induced vasoconstriction and VSM cytoplasmic Ca²⁺ responses, independent of muscarinic receptor, NO or K⁺ channel activation. We conclude that BAs alter vasomotor responses, an effect favoring reduced SVR. These findings are likely pertinent to vascular dysfunction in cirrhosis and other conditions associated with elevated serum BAs.     

The effects of floor incline on lower extremity biomechanics during unilateral landing from a jump in dancers

Retrospective studies have suggested that dancers performing on inclined ("raked") stages have increased injury risk. One study suggests that biomechanical differences exist between flat and inclined surfaces during bilateral landings; however, no studies have examined whether such differences exist during unilateral landings. In addition, little is known regarding potential gender differences in landing mechanics of dancers. Professional dancers (N = 41; 14 male, 27 female) performed unilateral drop jumps from a 30 cm platform onto flat and inclined surfaces while extremity joint angles and moments were identified and analyzed. There were significant joint angle and moment effects due to the inclined flooring. Women had significantly decreased peak ankle dorsiflexion and hip adduction moment compared with men. Findings of the current study suggest that unilateral landings on inclined stages create measurable changes in lower extremity biomechanical variables. These findings provide a preliminary biomechanical rationale for differences in injury rates found in observational studies of raked stages.     

Alcohol Affects the Brain's Resting-State Network in Social Drinkers

Acute alcohol intake is known to enhance inhibition through facilitation of GABA_A receptors, which are present in 40% of the synapses all over the brain. Evidence suggests that enhanced GABAergic transmission leads to increased large-scale brain connectivity. Our hypothesis is that acute alcohol intake would increase the functional connectivity of the human brain resting-state network (RSN). To test our hypothesis, electroencephalographic (EEG) measurements were recorded from healthy social drinkers at rest, during eyes-open and eyes-closed sessions, after administering to them an alcoholic beverage or placebo respectively. Salivary alcohol and cortisol served to measure the inebriation and stress levels. By calculating Magnitude Square Coherence (MSC) on standardized Low Resolution Electromagnetic Tomography (sLORETA) solutions, we formed cortical networks over several frequency bands, which were then analyzed in the context of functional connectivity and graph theory. MSC was increased (p<0.05, corrected with False Discovery Rate, FDR corrected) in alpha, beta (eyes-open) and theta bands (eyes-closed) following acute alcohol intake. Graph parameters were accordingly altered in these bands quantifying the effect of alcohol on the structure of brain networks; global efficiency and density were higher and path length was lower during alcohol (vs. placebo, p<0.05). Salivary alcohol concentration was positively correlated with the density of the network in beta band. The degree of specific nodes was elevated following alcohol (vs. placebo). Our findings support the hypothesis that short-term inebriation considerably increases large-scale connectivity in the RSN. The increased baseline functional connectivity can -at least partially- be attributed to the alcohol-induced disruption of the delicate balance between inhibitory and excitatory neurotransmission in favor of inhibitory influences. Thus, it is suggested that short-term inebriation is associated, as expected, to increased GABA transmission and functional connectivity, while long-term alcohol consumption may be linked to exactly the opposite effect.     

Endogenous ghrelin and 5-HT regulate interdigestive gastrointestinal contractions in conscious rats

Endogenous ghrelin causes interdigestive contractions of the stomach in rats. In contrast, previous studies showed that 5-HT(3) and 5-HT(4) receptors were involved in regulating intestinal interdigestive contractions. We studied the possible role of endogenous ghrelin and 5-HT regulating interdigestive gastrointestinal (GI) contractions in rats. Four strain gauge transducers were implanted on the antrum, duodenum, and proximal and distal jejunum. After an overnight fast, GI contractions were recorded in freely moving conscious rats and ghrelin receptor antagonists [(d-lys3)GHRP6; 1 micromol/kg], 5-HT(3) antagonists (Ondansetron; 0.5 mg/kg) and 5-HT(4) antagonists (GR 125,487; 1 mg/kg) were administered (bolus iv). To evaluate the relationship between the luminal concentrations of 5-HT and phase III-like contractions of the duodenum, duodenal juice was collected via the intraduodenal catheter. 5-HT content of the duodenal juice was measured by HPLC. (d-lys3)GHRP6 significantly attenuated the occurrence and amplitude of phase III-like contractions of the antrum, but not the duodenum and jejunum. 5-HT(4) antagonists significantly reduced spontaneous phase III-like contractions of the jejunum, without affecting those of the antrum and duodenum. In contrast, 5-HT(3) antagonists did not affect phase III-like contractions in GI tract. Luminal concentration of 5-HT at the phase III-like contraction (36.0 +/- 13.3 ng/ml, n = 9) was significantly higher than that at the phase I-like contractions of the duodenum (4.9 +/- 1.6 ng/ml, n = 9, P < 0.05). It is suggested that released ghrelin from the gastric mucosa mediates gastric phase III-like contractions, whereas 5-HT released from enterochromaffin cells of the duodenal mucosa mediates intestinal phase III-like contractions via 5-HT(4) receptors.     

Cell-cell signaling and the Agrobacterium tumefaciens Ti plasmid copy number fluctuations

The Agrobacterium tumefaciens oncogenic Ti plasmids replicate and segregate to daughter cells via repABC cassettes, in which repA and repB are plasmid partitioning genes and repC encodes the replication initiator protein. repABC cassettes are encountered in a growing number of plasmids and chromosomes of the alpha-proteobacteria, and findings from particular representatives of agrobacteria, rhizobia and Paracoccus have began to shed light on their structure and functions. Amongst repABC replicons, Ti plasmids and particularly the octopine-type Ti have recently stood as model in regulation of repABC basal expression, which acts in plasmid copy number control, but also appear to undergo pronounced up-regulation of repABC, upon interbacterial and host-bacterial signaling. The last results in considerable Ti copy number increase and collective elevation of Ti gene expression. Inhibition of the Ti repABC is in turn conferred by a plant defense compound, which primarily affects Agrobacterium virulence and interferes with cell-density perception. Altogether, the above suggest that the entire Ti gene pool is subjected to the bacterium-eukaryote signaling network, a phenomenon quite unprecedented for replicons thought of as stringently controlled. It remains to be seen whether similar copy number variations characterize related replicons or if they are of even broader significance in plasmid biology.     

Place prioritization for biodiversity conservation using probabilistic surrogate distribution data

We analyse optimal and heuristic place prioritization algorithms for biodiversity conservation area network design which can use probabilistic data on the distribution of surrogates for biodiversity. We show how an Expected Surrogate Set Covering Problem (ESSCP) and a Maximal Expected Surrogate Covering Problem (MESCP) can be linearized for computationally efficient solution. For the ESSCP, we study the performance of two optimization software packages (XPRESS and CPLEX) and five heuristic algorithms based on traditional measures of complementarity and rarity as well as the Shannon and Simpson indices of α‐diversity which are being used in this context for the first time. On small artificial data sets the optimal place prioritization algorithms often produced more economical solutions than the heuristic algorithms, though not always ones guaranteed to be optimal. However, with large data sets, the optimal algorithms often required long computation times and produced no better results than heuristic ones. Thus there is generally little reason to prefer optimal to heuristic algorithms with probabilistic data sets.     

Nonuniform shortening in the biceps brachii during elbow flexion.

This study tested the common assumption that skeletal muscle shortens uniformly in the direction of its fascicles during low-load contraction. Cine phase contrast magnetic resonance imaging was used to characterize shortening of the biceps brachii muscle in 12 subjects during repeated elbow flexion against 5 and 15% maximum voluntary contraction (MVC) loads. Mean shortening was relatively constant along the anterior boundary of the muscle and averaged 21% for both loading conditions. In contrast, mean shortening was nonuniform along the centerline of the muscle during active elbow flexion. Centerline shortening in the distal region of the biceps brachii (7.3% for 5% MVC and 3.7% for 15% MVC) was significantly less (P < 0.001) than shortening in the muscle midportion (26.3% for 5% MVC and 28.2% for 15% MVC). Nonuniform shortening along the centerline was likely due to the presence of an internal aponeurosis that spanned the distal third of the longitudinal axis of the biceps brachii. However, muscle shortening was also nonuniform proximal to the centerline aponeurosis. Because muscle fascicles follow the anterior contour and centerline of the biceps brachii, our results suggest that shortening is uniform along anterior muscle fascicles and nonuniform along centerline fascicles.     

RARbeta involvement in enhancement of lung tumor cell immunogenicity revealed by array analysis.

The retinoid receptors (RARs and RXRs) are mediators of the multiple effects of retinoic acid. Of these, the retinoic acid receptor beta2 (RARbeta2) has frequently been shown to be the principal mediator of the growth and tumor suppressive effects of retinoic acid; this gene is inactivated in many epithelial tumors and their derived cell lines. We have searched for genes that are regulated by this isoform and are potentially involved in tumor suppression. Using the Atlas human cDNA array I, we identified 27 genes (not counting RARbeta itself) that are regulated, directly or indirectly, by RARbeta2 when it is transfected into Calu-1, a lung tumor-derived line that does not normally express RARbeta. Several of the affected genes code for proteins whose functions would augment the process of apoptosis and/or the host's immune response. The latter group included ICAM-1 and MHC class I heavy chain, whose protein products play particularly important roles in the mounting of an effective anti-tumor response. We then confirmed by flow cytometry that the observed increases in message levels were reflected in increased cell surface protein levels for ICAM-1 and MHC class I in RARbeta2 transfectants of two RARbeta-deficient lines, Calu-1 and the epidermoid lung cancer-derived line SK-MES. Finally, we showed that RARbeta2 transfection of Calu-1 cells enhanced the heterologous CTL response in both the induction and the effector phases by up to threefold. These results support the hypothesis that down-regulation of these genes (and possibly others) in RARbeta-deficient tumor cells contributes to immune system evasion, and suggest a novel therapeutic approach for this disease.