Contemporary population structure and post-glacial genetic demography in a migratory marine species, the blacknose shark, Carcharhinus acronotus.

Patterns of population structure and historical genetic demography of blacknose sharks in the western North Atlantic Ocean were assessed using variation in nuclear-encoded microsatellites and sequences of mitochondrial (mt)DNA. Significant heterogeneity and/or inferred barriers to gene flow, based on microsatellites and/or mtDNA, revealed the occurrence of five genetic populations localized to five geographic regions: the southeastern U.S Atlantic coast, the eastern Gulf of Mexico, the western Gulf of Mexico, Bay of Campeche in the southern Gulf of Mexico and the Bahamas. Pairwise estimates of genetic divergence between sharks in the Bahamas and those in all other localities were more than an order of magnitude higher than between pairwise comparisons involving the other localities. Demographic modelling indicated that sharks in all five regions diverged after the last glacial maximum and, except for the Bahamas, experienced post-glacial, population expansion. The patterns of genetic variation also suggest that the southern Gulf of Mexico may have served as a glacial refuge and source for the expansion. Results of the study demonstrate that barriers to gene flow and historical genetic demography contributed to contemporary patterns of population structure in a coastal migratory species living in an otherwise continuous marine habitat. The results also indicate that for many marine species, failure to properly characterize barriers in terms of levels of contemporary gene flow could in part be due to inferences based solely on equilibrium assumptions. This could lead to erroneous conclusions regarding levels of connectivity in species of conservation concern.

Intraoperator, intraobserver and interoperator variability of echocardiographic measurements in healthy foals.

REASON FOR PERFORMING STUDY: The repeatability of various echocardiographic measurements is unknown. OBJECTIVES: To determine the intraoperator, intraobserver and interoperator variability of echocardiographic measures in healthy foals. METHODS: Echocardiographic examinations were carried out on 6 healthy foals by 3 experienced echocardiographers. Intraoperator variability was determined by having a single echocardiographer obtain and measure images from 6 foals scanned on 3 consecutive days. Interoperator and intraobserver variability were determined by having 3 echocardiographers each obtain images from an additional 6 sedated foals. Within-day interoperator variability was determined by having each echocardiographer measure their own images. Intraobserver variability was determined by having a single echocardiographer measure images obtained by all 3 echocardiographers. The coefficient of variation (CV) and standard error were calculated for each measure. RESULTS: The variability for most measurements was either very low (CV < 5%) or low (CV = 5-15%). Measurements of right ventricular internal diameter (RVID) in systole and E-point to septal separation (EPSS) showed moderate (CV 15-25%) to high variability (CV > 25%) in all 3 categories. Measurements of the left ventricular ejection time (LVET) and velocity time integral from the right parasternal long axis view of right outflow tract in the fourth intercostal space showed moderate intraoperator variability. Measurements of the LVET, RVID in diastole and left atrial appendage (LAA) showed moderate interoperator variability and measurements of the RVID in diastole and acceleration time from the short axis view of the right outflow tract in the right third intercostal space showed moderate interobserver variability. CONCLUSION: The intraoperator, intraobserver and interoperatorvariabilities for most echocardiographic measurements in foals are low. POTENTIAL RELEVANCE: Most standard transthoracic echocardiographic measurements in foals have a low enough variability to warrant their use in serial clinical evaluations or experimental studies. Repeated measurements of RVID, EPSS, LVET and LAA should be interpreted with caution.

Protein processing and inflammatory signaling in Cystic Fibrosis: challenges and therapeutic strategies.

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that regulates epithelial surface fluid secretion in respiratory and gastrointestinal tracts. The deletion of phenylalanine at position 508 (DeltaF508) in CFTR is the most common mutation that results in a temperature sensitive folding defect, retention of the protein in the endoplasmic reticulum (ER), and subsequent degradation by the proteasome. ER associated degradation (ERAD) is a major quality control pathway of the cell. The majority (99%) of the protein folding, DeltaF508-, mutant of CFTR is known to be degraded by this pathway to cause CF. Recent studies have revealed that inhibition of DeltaF508-CFTR ubiquitination and proteasomal degradation can increase its cell surface expression and may provide an approach to treat CF. The finely tuned balance of ER membrane interactions determine the cytosolic fate of newly synthesized CFTR. These ER membrane interactions induce ubiquitination and proteasomal targeting of DeltaF508- over wild type- CFTR. We discuss here challenges and therapeutic strategies targeting protein processing of DeltaF508-CFTR with the goal of rescuing functional DeltaF508-CFTR to the cell surface. It is evident from recent studies that CFTR plays a critical role in inflammatory response in addition to its well-described ion transport function. Previous studies in CF have focused only on improving chloride efflux as a marker for promising treatment. We propose that methods quantifying the therapeutic efficacy and recovery from CF should not include only changes in chloride efflux, but also recovery of the chronic inflammatory signaling, as evidenced by positive changes in inflammatory markers (in vitro and ex vivo), lung function (pulmonary function tests, PFT), and chronic lung disease (state of the art molecular imaging, in vivo). This will provide novel therapeutics with greater opportunities of potentially attenuating the progression of the chronic CF lung disease.