Detection of Haplotypes Associated with Prenatal Death in Dairy Cattle and Identification of Deleterious Mutations in GART,SHBG and SLC37A2

The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbéliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10⁻⁴) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle.     

Does bone mineralization reflect economic conditions? An examination using a national US sample

BACKGROUND: Bone density is the most important determinant of osteoporotic fractures, which lead to significant morbidity, disability and mortality for older persons, particularly women. Sensitive periods for bone mineralization in infancy, childhood and adolescence overlap with those for height attainment. After peak density is reached in early adulthood, there is age-related decline. We ask whether bone density, as height, reflects economic conditions. SUBJECTS AND METHODS: Using the third National Health and Nutrition Examination Survey, a probability sample of the US population which over-sampled Blacks and Mexican Americans, we examine the associations between adult bone mineral content (BMC) adjusted for bone and body size and three economic indicators: education, height and the poverty income ratio (PIR). We compare four groups: US-born Whites, Blacks and Mexican Americans and Mexican-born Mexican Americans. RESULTS: Education is positively associated with BMC only for White women, although there are similar, non-significant associations for Black women and White and Black men. For women, BMC is more strongly associated with height for Mexican Americans, especially the Mexican-born, than for Whites. For men, the only significant association is a negative one with education for men born in Mexico. PIR is not significantly associated with BMC, although there is pattern of lower income being associated with lower BMC for Whites and Blacks and higher BMC for Mexican Americans. CONCLUSION: Bone density does not reflect economic conditions as strongly or consistently as does physical stature. However, for women there is evidence that lower economic status in childhood or adolescence is associated with lower bone density.     

The role of the rock cod Notothenia coriiceps Richardson, 1844 in the life-cycle of Antarctic parasites

Fifty specimens of Notothenia coriiceps caught in Potter Cove, King George Island, were examined for ecto- and endoparasites. Of the 22 parasite species found, 18 were helminths, 2 were hirudineans and 2 were crustaceans. The isopod Aega antarctica and an unidentified hirudinean are reported for the first time from this fish host. Dominant parasites were the adults of Aspersentis megarhynchus, the invasive stage of Corynosoma spp. (cystacanth) and the adults of Macvicaria pennelli, with respective prevalences of infestation of 94, 76 and 74%. The preferred sites of infestation were the pylorus and intestine, where five different larval (nematodes and cestodes) and eight adult (digeneans and acanthocephalans) parasite species were found. No adult nematodes and cestodes were found and no parasites could be isolated from the musculature. The results of the present study are related to previous findings on the parasite fauna of N. coriiceps. The comparison implies a high parasite diversity in this benthic Antarctic fish species. Most parasites found appear to have a wide range of distribution within Antarctic waters together with a low host specificity. Besides its role as final host for several species of trematodes and acanthocephalans, N. coriiceps serves as transmitter of parasite larvae to piscivorous birds and seals. It is concluded that the parasite fauna in Antarctic fish species provides important insights into the different habitat use and trophic relationship of their fish hosts. Received: 11 September 1997 / Accepted: 12 January 1998     

Inactivation of Pseudomonas aeruginosa biofilms formed under high shear stress on various hydrophilic and hydrophobic surfaces by a continuous flow of ozonated water

Abstract

The inactivation of Pseudomonas aeruginosa biofilms grown on glass under high shear stress and exposed to a range of dissolved ozone concentrations (2, 5 and 7?ppm) at 10 and 20?min was investigated. The regression equation, log reduction (biofilm)?=?0.64?+?0.59×(C – 2)?+?0.33×(T – 10), described the dependence of biofilm inactivation on the dissolved ozone concentration (C, ppm) and contact time (T, min). The predicted D-values were 11.1, 5.7 and 2.2?min at 2, 5 and 7?ppm, respectively. Inactivation of biofilms grown on various surfaces was tested at a single dissolved ozone concentration of 5?ppm and a single exposure time of 20?min. Biofilms grown on plastic materials showed inactivation results similar to that of biofilms on glass, while biofilms grown on ceramics were statistically significantly more difficult to inactivate, suggesting the importance of utilizing non-porous materials in industrial and clinical settings.     

A new microinvertebrate with features of mites and tardigrades in Dominican amber

From time to time, small, fragile, previously unknown fossil invertebrates are found in specialized habitats. Occasionally, as in the present case, a fragment of the original habitat that existed millions of years ago is also preserved. The present article describes a previously unknown microinvertebrate in Dominican amber that cannot be placed in any group of extant invertebrates. Placed in a new family, genus, and species, the fossil shares characters with both tardigrades and mites, but clearly belongs to neither group. The several hundred fossil individuals preserved in the amber shared their moist, warm habitat with pseudoscorpions, nematodes, fungi, and protozoa. The large number of fossils provided additional evidence of their biology, including their reproductive behavior, developmental stages, and food. While there is no extant group that can accommodate these fossils, and we have no knowledge of any extant descendants, this discovery shows that unique lineages of minute invertebrates were surviving in the mid‐Tertiary.     

Rust fungal effectors mimic host transit peptides to translocate into chloroplasts

Parasite effector proteins target various host cell compartments to alter host processes and promote infection. How effectors cross membrane‐rich interfaces to reach these compartments is a major question in effector biology. Growing evidence suggests that effectors use molecular mimicry to subvert host cell machinery for protein sorting. We recently identified chloroplast‐targeted protein 1 (CTP1), a candidate effector from the poplar leaf rust fungus Melampsora larici‐populina that carries a predicted transit peptide and accumulates in chloroplasts and mitochondria. Here, we show that the CTP1 transit peptide is necessary and sufficient for accumulation in the stroma of chloroplasts. CTP1 is part of a Melampsora‐specific family of polymorphic secreted proteins. Two members of that family, CTP2 and CTP3, also translocate in chloroplasts in an N‐terminal signal‐dependent manner. CTP1, CTP2 and CTP3 are cleaved when they accumulate in chloroplasts, while they remain intact when they do not translocate into chloroplasts. Our findings reveal that fungi have evolved effector proteins that mimic plant‐specific sorting signals to traffic within plant cells.     

Using Drugs to Probe the Variability of Trans-Epithelial Airway Resistance

Background

Precision medicine aims to combat the variability of the therapeutic response to a given medicine by delivering the right medicine to the right patient. However, the application of precision medicine is predicated on a prior quantitation of the variance of the reference range of normality. Airway pathophysiology provides a good example due to a very variable first line of defence against airborne assault. Humans differ in their susceptibility to inhaled pollutants and pathogens in part due to the magnitude of trans-epithelial resistance that determines the degree of epithelial penetration to the submucosal space. This initial ‘set-point’ may drive a sentinel event in airway disease pathogenesis. Epithelia differentiated in vitro from airway biopsies are commonly used to model trans-epithelial resistance but the ‘reference range of normality’ remains problematic. We investigated the range of electrophysiological characteristics of human airway epithelia grown at air-liquid interface in vitro from healthy volunteers focusing on the inter- and intra-subject variability both at baseline and after sequential exposure to drugs modulating ion transport.

Methodology/Principal Findings

Brushed nasal airway epithelial cells were differentiated at air-liquid interface generating 137 pseudostratified ciliated epithelia from 18 donors. A positively-skewed baseline range exists for trans-epithelial resistance (Min/Max: 309/2963 Ω·cm²), trans-epithelial voltage (-62.3/-1.8 mV) and calculated equivalent current (-125.0/-3.2 μA/cm²; all non-normal, P<0.001). A minority of healthy humans manifest a dramatic amiloride sensitivity to voltage and trans-epithelial resistance that is further discriminated by prior modulation of cAMP-stimulated chloride transport.

Conclusions/Significance

Healthy epithelia show log-order differences in their ion transport characteristics, likely reflective of their initial set-points of basal trans-epithelial resistance and sodium transport. Our data may guide the choice of the background set point in subjects with airway diseases and frame the reference range for the future delivery of precision airway medicine.     

Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel.

The epithelial Na+ channel (ENaC) forms the pathway for Na+ absorption across epithelia, including the kidney collecting duct, where it plays a critical role in Na+ homeostasis and blood pressure control. Na+ absorption is regulated in part by mechanisms that control the expression of ENaC at the apical cell surface. Nedd4 family members (e.g. Nedd4, Nedd4-2) bind to the channel and decrease its surface expression by catalyzing its ubiquitination and degradation. Conversely, serum and glucocorticoid-regulated kinase (SGK), a downstream mediator of aldosterone, increases the expression of ENaC at the cell surface. Here we show that SGK and human Nedd4-2 (hNedd4-2) converge in a common pathway to regulate epithelial Na+ absorption. Consistent with this model, we found that SGK bound to hNedd4-2 and hNedd4. A PY motif in SGK mediated the interaction and was required for SGK to stimulate ENaC. SGK phosphorylated hNedd4-2 (but not hNedd4), altering hNedd4-2 function; phosphorylation reduced the binding of hNedd4-2 to alphaENaC, and hence, the hNedd4-2-mediated inhibition of Na+ absorption. These data suggest that SGK regulates epithelial Na+ absorption in part by modulating the function of hNedd4-2.     

High-selenium yeast supplementation in free-living North American men: no effect on thyroid hormone metabolism or body composition.

In a prior study, we observed decreased serum 3,3',5-triiodothyronine (T(3)), increased serum thyrotropin and increased body weight in five men fed 297 microg/d of selenium (Se) in foods naturally high in Se while confined in a metabolic research unit. In an attempt to replicate and confirm those observations, we conducted a randomized study of high-Se yeast supplements (300 microg/d) or placebo yeast administered to 42 healthy free-living men for 48 weeks. Serum thyroxine, T(3) and thyrotropin did not change in supplemented or control subjects. Body weight increased in both groups during the 48-week treatment period and remained elevated for the 48-week follow-up period. Body fat increased by 1.2 kg in both groups. Energy intake and voluntary activity levels were not different between the groups and remained unchanged during the treatment period. Dietary intakes of Se, macronutrients and micronutrients were not different between groups and remained unchanged during the treatment period. These results suggest that our previous observation of a hypothyroidal response to high-Se foods was confounded by some aspect of the particular foods used, or were merely chance observations. Because of the high dose and long administration period, the present study suggests that the effects of Se supplements on thyroid hormone metabolism and energy metabolism in healthy North American men with adequate Se status do not represent a significant risk for unhealthy weight gain.     

The hepcidin-binding site on ferroportin is evolutionarily conserved

Mammalian iron homeostasis is regulated by the interaction of the liver-produced peptide hepcidin and its receptor, the iron transporter ferroportin. Hepcidin binds to ferroportin resulting in degradation of ferroportin and decreased cellular iron export. We identify the hepcidin-binding domain (HBD) on ferroportin and show that a synthetic 19 amino acid peptide corresponding to the HBD recapitulates the characteristics and specificity of hepcidin binding to cell-surface ferroportin. The binding of mammalian hepcidin to ferroportin or the HBD shows an unusual temperature dependency with an increased rate of dissociation at temperatures below 15°C. The increased rate of dissociation is due to temperature- dependent changes in hepcidin structure. In contrast, hepcidin from poikilothermic vertebrates, such as fish or frogs, binds the HBD in a temperature-independent fashion. The affinity of hepcidin for the HBD permits a rapid, sensitive assay of hepcidin from all species and yields insights into the evolution of hepcidin.