Neuregulin-ErbB4 signaling in the developing lung alveolus: a brief review

Lung immaturity is the major cause of morbidity and mortality in premature infants, especially those born <28 weeks gestation. Proper lung development from 23–28 weeks requires coordinated cell proliferation and differentiation. Infants born at this age are at high risk for respiratory distress syndrome (RDS), a lung disease characterized by insufficient surfactant production due to immaturity of the alveoli and its constituent cells in the lung. The ErbB4 receptor and its stimulation by neuregulin (NRG) plays a critical role in surfactant synthesis by alveolar type II epithelial cells. In this review, we first provide an introduction to normal human alveolar development, followed by a discussion of the neuregulin and ErbB4-mediated mechanisms regulating alveolar development and surfactant production.     

Geographic Patterns of Genetic Variation in a Broadly Distributed Marine Vertebrate: New Insights into Loggerhead Turtle Stock Structure from Expanded Mitochondrial DNA Sequences

Previous genetic studies have demonstrated that natal homing shapes the stock structure of marine turtle nesting populations. However, widespread sharing of common haplotypes based on short segments of the mitochondrial control region often limits resolution of the demographic connectivity of populations. Recent studies employing longer control region sequences to resolve haplotype sharing have focused on regional assessments of genetic structure and phylogeography. Here we synthesize available control region sequences for loggerhead turtles from the Mediterranean Sea, Atlantic, and western Indian Ocean basins. These data represent six of the nine globally significant regional management units (RMUs) for the species and include novel sequence data from Brazil, Cape Verde, South Africa and Oman. Genetic tests of differentiation among 42 rookeries represented by short sequences (380 bp haplotypes from 3,486 samples) and 40 rookeries represented by long sequences (∼800 bp haplotypes from 3,434 samples) supported the distinction of the six RMUs analyzed as well as recognition of at least 18 demographically independent management units (MUs) with respect to female natal homing. A total of 59 haplotypes were resolved. These haplotypes belonged to two highly divergent global lineages, with haplogroup I represented primarily by CC-A1, CC-A4, and CC-A11 variants and haplogroup II represented by CC-A2 and derived variants. Geographic distribution patterns of haplogroup II haplotypes and the nested position of CC-A11.6 from Oman among the Atlantic haplotypes invoke recent colonization of the Indian Ocean from the Atlantic for both global lineages. The haplotypes we confirmed for western Indian Ocean RMUs allow reinterpretation of previous mixed stock analysis and further suggest that contemporary migratory connectivity between the Indian and Atlantic Oceans occurs on a broader scale than previously hypothesized. This study represents a valuable model for conducting comprehensive international cooperative data management and research in marine ecology.     

A Statistical Model for Estimation of Fish Density Including Correlation in Size,Space, Time and between Species from Research Survey Data

Trawl survey data with high spatial and seasonal coverage were analysed using a variant of the Log Gaussian Cox Process (LGCP) statistical model to estimate unbiased relative fish densities. The model estimates correlations between observations according to time, space, and fish size and includes zero observations and over-dispersion. The model utilises the fact the correlation between numbers of fish caught increases when the distance in space and time between the fish decreases, and the correlation between size groups in a haul increases when the difference in size decreases. Here the model is extended in two ways. Instead of assuming a natural scale size correlation, the model is further developed to allow for a transformed length scale. Furthermore, in the present application, the spatial- and size-dependent correlation between species was included. For cod (Gadus morhua) and whiting (Merlangius merlangus), a common structured size correlation was fitted, and a separable structure between the time and space-size correlation was found for each species, whereas more complex structures were required to describe the correlation between species (and space-size). The within-species time correlation is strong, whereas the correlations between the species are weaker over time but strong within the year.     

Genetic Diversity and Population Structure Analysis of European Hexaploid Bread Wheat (Triticum aestivum L.) Varieties

Progress in plant breeding is facilitated by accurate information about genetic structure and diversity. Here, Diversity Array Technology (DArT) was used to characterize a population of 94 bread wheat (Triticum aestivum L.) varieties of mainly European origin. In total, 1,849 of 7,000 tested markers were polymorphic and could be used for population structure analysis. Two major subgroups of wheat varieties, GrI and GrII, were identified using the program STRUCTURE, and confirmed by principal component analysis (PCA). These subgroups were largely separated according to origin; GrI comprised varieties from Southern and Eastern Europe, whereas GrII contained mostly modern varieties from Western and Northern Europe. A large proportion of the markers contributing most to the genetic separation of the subgroups were located on chromosome 2D near the Reduced height 8 (Rht8) locus, and PCR-based genotyping suggested that breeding for the Rht8 allele had a major impact on subgroup separation. Consistently, analysis of linkage disequilibrium (LD) suggested that different selective pressures had acted on chromosome 2D in the two subgroups. Our data provides an overview of the allele composition of bread wheat varieties anchored to DArT markers, which will facilitate targeted combination of alleles following DArT-based QTL studies. In addition, the genetic diversity and distance data combined with specific Rht8 genotypes can now be used by breeders to guide selection of crossing parents.     

A Possible Link between Food and Mood: Dietary Impact on Gut Microbiota and Behavior in BALB/c Mice

Major depressive disorder is a debilitating disease in the Western World. A western diet high in saturated fat and refined sugar seems to play an important part in disease development. Therefore, this study is aimed at investigating whether saturated fat or sucrose predisposes mice to develop behavioral symptoms which can be interpreted as depression-like, and the possible influence of the gut microbiota (GM) in this. Fourty-two mice were randomly assigned to one of three experimental diets, a high-fat, a high-sucrose or a control diet for thirteen weeks. Mice on high-fat diet gained more weight (p = 0.00009), displayed significantly less burrowing behavior than the control mice (p = 0.034), and showed decreased memory in the Morris water maze test compared to mice on high-sucrose diet (p = 0.031). Mice on high-sucrose diet burrowed less goal-oriented, showed greater latency to first bout of immobility in the forced swim test when compared to control mice (p = 0.039) and high-fat fed mice (p = 0.013), and displayed less anxiety than mice on high-fat diet in the triple test (p = 0.009). Behavioral changes were accompanied by a significant change in GM composition of mice fed a high-fat diet, while no difference between diet groups was observed for sucrose preferences, LPS, cholesterol, HbA1c, BDNF and the cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12(p70), IL-17 and TNF-α. A series of correlations was found between GM, behavior, BDNF and inflammatory mediators. In conclusion, the study shows that dietary fat and sucrose affect behavior, sometimes in opposite directions, and suggests a possible association between GM and behavior.     

Insights into Alpha-Hemolysin (Hla) Evolution and Expression among Staphylococcus aureus Clones with Hospital and Community Origin

Background

Alpha-hemolysin (Hla) is a major virulence factor in the pathogenesis of Staphylococcus aureus infection, being active against a wide range of host cells. Although hla is ubiquitous in S. aureus, its genetic diversity and variation in expression in different genetic backgrounds is not known. We evaluated nucleotide sequence variation and gene expression profiles of hla among representatives of hospital (HA) and community-associated (CA) S. aureus clones.

Methods

51 methicillin-resistant S. aureus and 22 methicillin-susceptible S. aureus were characterized by PFGE, spa typing, MLST and SCCmec typing. The internal regions of hla and the hla promoter were sequenced and gene expression was assessed by RT-PCR.

Results

Alpha-hemolysin encoding- and promoter sequences were diverse, with 12 and 23 different alleles, respectively. Based on phylogenetic analysis, we suggest that hla may have evolved together with the S. aureus genetic background, except for ST22, ST121, ST59 and ST93. Conversely, the promoter region showed lack of co-evolution with the genetic backgrounds. Four non-synonymous amino acid changes were identified close to important regions of hla activity. Amino acid changes in the RNAIII binding site were not associated to hla expression. Although expression rates of hla were in general strain-specific, we observed CA clones showed significantly higher hla expression (p = 0.003) when compared with HA clones.

Conclusion

We propose that the hla gene has evolved together with the genetic background. Overall, CA genetic backgrounds showed higher levels of hla expression than HA, and a high strain-to-strain variation of gene expression was detected in closely related strains.     

Distal Renal Tubules Are Deficient in Aggresome Formation and Autophagy upon Aldosterone Administration

Prolonged elevations of plasma aldosterone levels are associated with renal pathogenesis. We hypothesized that renal distress could be imposed by an augmented aldosterone-induced protein turnover challenging cellular protein degradation systems of the renal tubular cells. Cellular accumulation of specific protein aggregates in rat kidneys was assessed after 7 days of aldosterone administration. Aldosterone induced intracellular accumulation of 60 s ribosomal protein L22 in protein aggregates, specifically in the distal convoluted tubules. The mineralocorticoid receptor inhibitor spironolactone abolished aldosterone-induced accumulation of these aggregates. The aldosterone-induced protein aggregates also contained proteasome 20 s subunits. The partial de-ubiquitinase ataxin-3 was not localized to the distal renal tubule protein aggregates, and the aggregates only modestly colocalized with aggresome transfer proteins dynactin p62 and histone deacetylase 6. Intracellular protein aggregation in distal renal tubules did not lead to development of classical juxta-nuclear aggresomes or to autophagosome formation. Finally, aldosterone treatment induced foci in renal cortex of epithelial vimentin expression and a loss of E-cadherin expression, as signs of cellular stress. The cellular changes occurred within high, but physiological aldosterone concentrations. We conclude that aldosterone induces protein accumulation in distal renal tubules; these aggregates are not cleared by autophagy that may lead to early renal tubular damage.     

Tissue MicroRNAs as Predictors of Outcome in Patients with Metastatic Colorectal Cancer Treated with First Line Capecitabine and Oxaliplatin with or without Bevacizumab

Purpose

We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC).

Experimental Design

Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs.

Results

In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts.

Conclusions

We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.     

Decrease in Vitamin D Status in the Greenlandic Adult Population from 1987–2010

Background

Low vitamin D status may be pronounced in Arctic populations due to limited sun exposure and decreasing intake of traditional food.

Objective

To investigate serum 25(OH)D3 as a measure of vitamin D status among adult Inuit in Greenland, predictors of low serum 25(OH)D3 concentrations and the trend from 1987 to 2005–2010.

Design

A total of 2877 randomly selected Inuit (≥18 years) from the Inuit Health in Transition study were included. A sub-sample (n = 330) donated a blood sample in 1987 which allowed assessment of time trends in vitamin D status.

Results

The geometric mean serum 25(OH)D3 (25[OH]D2 concentrations were negligible and not reported) in 2005–2010 was lowest among the 18–29 year old individuals (30.7 nmol/L; 95% CI: 29.7; 31.7) and increased with age. In all age-groups it decreased from 1987 to 2005–2010 (32%–58%). Low 25(OH)D3 concentrations (<50 nmol/L) were present in 77% of the 18–29 year old and decreased with age. A characteristic seasonal variation in 25(OH)D3 concentrations was observed (range 33.2–57.1 nmol/L, p<0.001), with the highest concentrations in August to October. Age (2.0% per year increase; CI: 1.7, 2.2), female gender (7.1%; CI: 2.0; 12.5), alcohol intake (0.2% per increase in drinks/week; 0.0; 0.4), and traditional diet (10.0% per 100 g/d increase; CI: 7.9; 12.1) were associated with increased serum 25(OH)D3, whereas smoking (−11.6%; CI: −16.2; −6.9), BMI (−0.6%; CI: −1.1; −0.2) and latitude (−0.7% per degree increase; CI: −1.3; −0.2) were associated with decreased concentrations.

Conclusion

We identified a remarkable decrease in vitamin D status from 1987 to 2005–2010 and a presently low vitamin D status among Inuit in Greenland. A change away from a traditional diet may well explain the observed decline. The study argues for the need of increased dietary intake of vitamin D and supplementation might be considered.