Elevated dietary salt suppresses renin secretion but not thirst evoked by arterial hypotension in rats

Increased dietary salt intake was used as a nonpharmacological tool to blunt hypotension-induced increases in plasma renin activity (PRA) in order to evaluate the contribution of the renin-angiotensin system (RAS) to hypotension-induced thirst. Rats were maintained on 8% NaCl (high) or 1% NaCl (standard) diet for at least 2 wk, and then arterial hypotension was produced by administration of the arteriolar vasodilator diazoxide. Despite marked reductions in PRA, rats maintained on the high-salt diet drank similar amounts of water, displayed similar latencies to drink, and had similar degrees of hypotension compared with rats maintained on the standard diet. Furthermore, blockade of ANG II production by an intravenous infusion of the angiotensin-converting enzyme inhibitor captopril attenuated the hypotension-induced water intake similarly in rats fed standard and high-salt diet. Additional experiments showed that increases in dietary salt did not alter thirst stimulated by the acetylcholine agonist carbachol administered into the lateral ventricle; however, increases in dietary salt did enhance thirst evoked by central ANG II. Collectively, the present findings suggest that hypotension-evoked thirst in rats fed a high-salt diet is dependent on the peripheral RAS despite marked reductions in PRA.     

Impact of pericardial restraint on right atrial mechanics during acute right ventricular pressure load

Optimization of right atrial (RA) mechanics is important for maintaining right ventricular (RV) filling and global cardiac output. However, the impact of pericardial restraint on RA function and the compensatory role of the right atrium to changes in RV afterload remain poorly characterized. In eight open-chest sheep, RA elastance (contractility) and chamber stiffness were measured (RA pressure-volume relations) at baseline and during partial pulmonary artery (PA) occlusion. Data were collected before and after pericardiotomy. With the pericardium intact and partial PA occlusion, RA elastance increased by 28% (P < 0.04), whereas RA stiffness tended to rise (P = 0.08). However, after pericardiotomy, there was a significant fall in both RA elastance (54%, P < 0.04) and stiffness (39%, P < 0.04), and subsequent PA occlusion failed to induce a change in elastance (P > 0.19) or stiffness (P > 0.84). After pericardiotomy, RA elastance and stiffness fell dramatically, and the compensatory response of the right atrium to elevated RV afterload was lost. The ability of the right atrium to respond to changes in RV hemodynamics is highly dependent on pericardial integrity.     

A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets

Hypoxia triggers a reversible inhibition of protein synthesis thought to be important for energy conservation in O2-deficient environments. The mammalian target of rapamycin (mTOR) pathway integrates multiple environmental cues to regulate translation in response to nutrient availability and stress, suggesting it as a candidate for O2 regulation. We show here that hypoxia rapidly and reversibly triggers hypophosphorylation of mTOR and its effectors 4E-BP1, p70S6K, rpS6, and eukaryotic initiation factor 4G. Hypoxic regulation of these translational control proteins is dominant to activation via multiple distinct signaling pathways such as insulin, amino acids, phorbol esters, and serum and is independent of Akt/protein kinase B and AMP-activated protein kinase phosphorylation, ATP levels, ATP:ADP ratios, and hypoxia-inducible factor-1 (HIF-1). Finally, hypoxia appears to repress phosphorylation of translational control proteins in a manner analogous to rapamycin and independent of phosphatase 2A (PP2A) activity. These data demonstrate a new mode of regulation of the mTOR pathway and position this pathway as a powerful point of control by O2 of cellular metabolism and energetics.     

Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals

The US National Cancer Institute has recently sponsored the formation of a Cohort Consortium (http://2002.cancer.gov/scpgenes.htm) to facilitate the pooling of data on very large numbers of people, concerning the effects of genes and environment on cancer incidence. One likely goal of these efforts will be generate a large population-based case-control series for which a number of candidate genes will be investigated using SNP haplotype as well as genotype analysis. The goal of this paper is to outline the issues involved in choosing a method of estimating haplotype-specific risk estimates for such data that is technically appropriate and yet attractive to epidemiologists who are already comfortable with odds ratios and logistic regression. Our interest is to develop and evaluate extensions of methods, based on haplotype imputation, that have been recently described (Schaid et al., Am J Hum Genet, 2002, and Zaykin et al., Hum Hered, 2002) as providing score tests of the null hypothesis of no effect of SNP haplotypes upon risk, which may be used for more complex tasks, such as providing confidence intervals, and tests of equivalence of haplotype-specific risks in two or more separate populations. In order to do so we (1) develop a cohort approach towards odds ratio analysis by expanding the E-M algorithm to provide maximum likelihood estimates of haplotype-specific odds ratios as well as genotype frequencies; (2) show how to correct the cohort approach, to give essentially unbiased estimates for population-based or nested case-control studies by incorporating the probability of selection as a case or control into the likelihood, based on a simplified model of case and control selection, and (3) finally, in an example data set (CYP17 and breast cancer, from the Multiethnic Cohort Study) we compare likelihood-based confidence interval estimates from the two methods with each other, and with the use of the single-imputation approach of Zaykin et al. applied under both null and alternative hypotheses. We conclude that so long as haplotypes are well predicted by SNP genotypes (we use the Rh2 criteria of Stram et al. [1]) the differences between the three methods are very small and in particular that the single imputation method may be expected to work extremely well.     

A comparative cytogenetic study of five piranha species (Serrasalmus,Serrasalminae) from the Amazon basin

Cytogenetic studies were conducted on five piranha species belonging to the genus Serrasalmus, subfamily Serrasalminae (Serrasalmus altispinis, S. compressus, S. elongatus, S. manuelli, and S. spilopleura). All the species were collected in the Amazon basin: confluence of Negro and Solimõoes Rivers (CatalãoLake), Solimões River (Marchantaria Island – Camaleão Lake), Uatumã River (Hydroelectric Power Station of Balbina), and Pitinga River (Hydroelectric Power Station of Pitinga). All the five species possess 2n = 60 chromosomes with 5–12 subtelo- and acrocentric chromosomes bearing nucleolar organizer regions. A proximal C-band positive heterochromatin block was evident on the long arms of a medium-sized metacentric chromosome pair in all the analized species, thus making it a cytogenetic marker for the genus. It is hypothesized that 2n = 60 chromosomes represents a derived feature in terms of the chromosomal evolution of piranhas because the basal lineages possess 2n = 62. Both Robertsonian centric fusion and non-Robertsonian rearragements such as pericentric inversions seem implicated in the chromosomal evolution of this group.     

bullwinkle and shark regulate dorsal-appendage morphogenesis in Drosophila oogenesis

bullwinkle (bwk) regulates embryonic anteroposterior patterning and, through a novel germline-to-soma signal, morphogenesis of the eggshell dorsal appendages. We screened for dominant modifiers of the bullwinkle mooseantler eggshell phenotype and identified shark, which encodes an SH2-domain, ankyrin-repeat tyrosine kinase. At the onset of dorsal-appendage formation, shark is expressed in a punctate pattern in the squamous stretch cells overlying the nurse cells. Confocal microscopy with cell-type-specific markers demonstrates that the stretch cells act as a substrate for the migrating dorsal-appendage-forming cells and extend cellular projections towards them. Mosaic analyses reveal that shark is required in follicle cells for cell migration and chorion deposition. Proper shark RNA expression in the stretch cells requires bwk activity, while restoration of shark expression in the stretch cells suppresses the bwk dorsal-appendage phenotype. These results suggest that shark plays an important downstream role in the bwk-signaling pathway. Candidate testing implicates Src42A in a similar role, suggesting conservation with a vertebrate signaling pathway involving non-receptor tyrosine kinases.