Application of genomic evaluation to dairy cattle in New Zealand.

A hybrid method of estimating genomically enhanced breeding values (GEBV) that uses features of a single-step approach and traditional national estimated breeding value (EBV), based on pedigree, as the starting point was developed and assessed. The method uses deregressed EBV from the traditional EBV estimation procedures and a pedigree matrix that is augmented by a genomic relationship matrix based on a Euclidean distance (EDM) in a Gaussian kernel. Genotypes were obtained using the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA). The pedigree information is restricted to animals with genotypes, as well as all of their ancestors, resulting in a system of equations that is considerably smaller than that of the national evaluation. Genome-wide association studies were used to identify regions of the genome that had high association with the traits in the New Zealand national breeding objective. The EDM were created for each selected region. The amount of variance accounted for by each region was estimated, and the variances, relative to the EDM excluding these areas, were used to create trait-specific weighted EDM that were used for the evaluations. The evaluation is done on the restricted data set and is a reversal of the deregression procedure using the augmented pedigree-based relationship matrix. The method was tested using data on 7,204 progeny-tested sires, in which the daughter records for the 3 youngest cohorts (i.e., validation data; n=1,410) were excluded. Evaluations were done for the 7 traits (3 production, 4 nonproduction) in the New Zealand national breeding objective. Regression of the traditional EBV based on daughter information on the GEBV for validation sires had an average slope of 0.99 (range 0.93 to 1.06); the average correlation between the EBV was 0.79 (range 0.56 to 0.84). The average slope and correlation for the previously used blended GEBV were 0.64 and 0.61, respectively. The method was applied to all genotyped animals that included approximately 13,000 genotyped males and 47,000 genotyped females and their ancestors. The correlation between the traditional EBV and GEBV of the proven bulls was 0.99; the correlations obtained from the previously used blended GEBV were 0.88 (no inflation adjustment) and 0.94 (following inflation adjustment). The values for the unproven bulls were 0.95 (parent average EBV and GEBV), 0.56 (blended GEBV, no inflation adjustment), and 0.88 (blended GEBV, following inflation adjustment). The use of trait-specific weighted EDM provided a 1 to 2% improvement in the accuracy of the genomic evaluations of the production traits and no improvement in the nonproduction traits. The hybrid method of estimating GEBV was found to be considerably less biased and generally more accurate than the previously used blended genomic breeding value.

Experimental identification of diffusive coupling using 2D NMR.

Spin relaxation based nuclear magnetic resonance (NMR) methods have been used extensively to determine pore size distributions in a variety of materials. This approach is based on the assumption that each pore is in the fast diffusion limit but that diffusion between pores can be neglected. However, in complex materials these assumptions may be violated and the relaxation time distribution is not easily interpreted. We present a 2D NMR technique and an associated data analysis that allow us to work directly with the time dependent experimental data without Laplace inversion to identify the signature of diffusive coupling between different pores. Measurements on microporous glass beads and numerical simulations are used to illustrate the technique.

CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study.

AIMS: Macrophage recruitment through C-C motif chemokine receptor-2 (CCR2) into adipose tissue is believed to play a role in the development of insulin resistance and type 2 diabetes mellitus (T2DM). The objective of this Phase 2 proof-of-concept study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-41443532, an orally bioavailable CCR2 antagonist, in patients with T2DM. METHODS: This was a 4-week, double-blind, placebo-controlled, randomized, multicenter study. A total of 89 patients were randomized to receive either 250- or 1000-mg of JNJ-41443532 twice daily, 30-mg of pioglitazone once daily (reference arm), or placebo. The primary endpoint was change from baseline in 23-h weighted mean glucose (WMG); secondary endpoints included change from baseline in fasting plasma glucose (FPG), insulin resistance (Homeostatic Model Assessment [HOMA-IR]), insulin secretion (HOMA-%B) and body weight. RESULTS: Absorption of JNJ-41443532 into the systemic circulation occurred at a median tmax of 2 h, and the mean t½ was approximately 8 h for both doses; plasma systemic exposures increased slightly more than dose-proportionally. After 4 weeks, reductions in 23-h WMG and FPG were observed in all treatment groups compared with placebo and were significantly lower for 250-mg JNJ-41443532 and pioglitazone. HOMA-IR was lower for all treatment groups, but significantly lower only for pioglitazone. Conversely, HOMA-%B was increased for all groups, but significantly increased only for 250-mg JNJ-41443532. All groups, including placebo, had decreased body weight over time. There were no clinically significant findings during routine safety assessments and the incidence of treatment-emergent adverse events was similar across all groups. CONCLUSIONS: Administration of JNJ-41443532 resulted in modest improvement in glycaemic parameters compared with placebo, and was generally well tolerated in patients with T2DM.

Pregnancy outcome in women exposed to leflunomide before or during pregnancy.

OBJECTIVE: Findings from animal studies have suggested that leflunomide may be a human teratogen. In the only human cohort study published to date, an increase in adverse outcomes in pregnancies after exposure to leflunomide was not detected. The aim of the present analysis was to expand on the previously published data with a description of birth outcomes among women who did not meet the previous cohort study criteria but who were exposed to leflunomide either during pregnancy or prior to conception. METHODS: Data on pregnancy exposures and outcomes were collected from 45 pregnant women who had contacted counseling services of the Organization of Teratology Information Specialists in the US or Canada between 1999 and 2009. Sixteen women were exposed to leflunomide during the first trimester of pregnancy and 29 women were exposed preconception. RESULTS: All 16 of the pregnancies with leflunomide exposure during pregnancy and 27 (93%) of the pregnancies with exposure prior to conception resulted in liveborn infants. There were 2 infants with major malformations from mothers who were exposed during pregnancy, and no malformations reported in the preconception group. There was a potential known alternative etiology for at least some of the defects observed. CONCLUSION: These data provide additional reassurance to women who inadvertently become pregnant while taking leflunomide and who undergo the washout procedure, as well as women who discontinue the medication prior to conception but have no prepregnancy documentation of drug clearance. However, until more conclusive data become available, women receiving leflunomide should be advised to use contraceptive methods and avoid pregnancy.

Change in paternity and select perinatal outcomes: causal or confounded?

Select social, behavioural and maternal characteristics were evaluated to determine if they were confounding factors in the association between paternity change and pre-eclampsia, small for gestational age (SGA) and pre-term delivery, in a sample of 1,409 women. Multivariate logistic regression analysis was used to determine if any of these risk factors modified the association between changing paternity and the selected perinatal outcomes. Results of the analysis showed that women who changed partners were more likely to possess potentially confounding risk factors compared with those who had not. Paternity change was 2.75 times more likely to be associated with the development of pre-eclampsia (95% CI 1.33; 5.68) and 2.25 times more likely to be associated with an SGA infant on weight (95% CI 1.13; 4.47), after adjusting for selected risk factors. Paternity change remains a significant risk factor for pre-eclampsia and SGA in the presence of select risk factors.

Potentially modifiable risk factors for adverse pregnancy outcomes in women with psoriasis.

BACKGROUND: Data on pregnancy outcomes among women with psoriasis are lacking. However, there are several known comorbidities of psoriasis, including obesity, smoking and depression, each of which increases the risk for negative birth outcomes. OBJECTIVES: To determine if pregnant women with psoriasis have an excess of potentially modifiable risk factors for adverse pregnancy outcomes. METHODS: Prospectively collected data from the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project were analysed to compare the prevalence of selected risk factors between 170 pregnant women with psoriasis and 158 nondiseased controls. RESULTS: Women with psoriasis were more likely to be overweight/obese prior to pregnancy (P < 0.0001), to smoke (P < 0.0001), or to have a diagnosis of depression (P = 0.03), and were less likely to have been taking preconceptional vitamin supplements (P = 0.004). After controlling for race/ethnicity and socioeconomic status, women with psoriasis were 2.37 (95% confidence interval 1.45-3.87) times more likely to be overweight/obese as women without psoriasis. Duration of disease, age at onset, measures of disease impact during pregnancy, or use of biologics in pregnancy were not significant predictors of overweight/obesity in the subset of psoriatic women. CONCLUSIONS: Pregnant women with psoriasis may be at increased risk for adverse pregnancy outcomes due to comorbidities or other health behaviours associated with the disease. These should be taken into consideration during clinical treatment of women with psoriasis who are in their childbearing years.

Effects of prostaglandin E and F receptor agonists in vivo on luteal function in ewes.

Loss of progesterone secretion at the end of the estrous cycle is via uterine PGF(2alpha) secretion; however, uterine PGF(2alpha) is not decreased during early pregnancy in ewes to prevent luteolysis. Instead the embryo imparts resistance to PGF(2alpha)-induced luteolysis, which is via the 2-fold increase in prostaglandins E(1) and E(2) (PGE(1), PGE(2); PGE) in the endometrium during early pregnancy. Chronic intrauterine infusion of PGE(1) or PGE(2) prevents spontaneous or an estradiol-17beta, IUD, or PGF(2alpha)-induced luteolysis. Four PGE receptor subtypes (EP(1), EP(2), EP(3), and EP(4)) and an FP receptor specific for PGF(2alpha) have been identified. The objective of this experiment was to determine the effects of EP(1), EP(2), EP(3), or FP receptor agonists in vivo on luteal mRNA for LH receptors, occupied and unoccupied LH receptors, and circulating progesterone in ewes. Ewes received a single treatment of 17-phenyl-tri-Nor-PGE(2) (EP(1), EP(3)), butaprost (EP(2)), 19-(R)-OH-PGE(2) (EP(2)), sulprostone (EP(1), EP(3)), or PGF(2alpha) (FP) receptor agonists into the interstitial tissue of the ovarian vascular pedicle adjacent to the luteal-containing ovary. 17-Phenlyl-tri-Nor-PGE(2) had no effect (P> or =0.05) on any parameter analyzed. Butaprost and 19-(R)-OH-PGE(2) increased (P< or =0.05) mRNA for LH receptors, occupied and unoccupied LH receptors, and circulating progesterone. Both sulprostone and PGF(2alpha) decreased (P< or =0.05) mRNA for LH receptors, occupied and unoccupied LH receptors, and circulating progesterone. It is concluded that both EP(3) and FP receptors may be involved in luteolysis. In addition, EP(2) receptors may mediate prevention of luteolysis via regulation of luteal mRNA for LH receptors to prevent loss of occupied and unoccupied LH receptors and therefore to sustaining luteal function.

Prostaglandin E1 (PGE1), but not prostaglandin E2 (PGE2), alters luteal and endometrial luteinizing hormone (LH) occupied and unoccupied LH receptors and mRNA for LH receptors in ovine luteal tissue to prevent luteolysis.

Loss of luteal progesterone secretion at the end of the ovine estrous cycle is via uterine PGF(2)alpha secretion. However, uterine PGF(2)alpha secretion is not decreased during early pregnancy in ewes. Instead, the embryo imparts a resistance to PGF(2)alpha. Prostaglandins E (PGE; PGE(1)+PGE(2)) are increased in endometrium and uterine venous blood during early pregnancy in ewes to prevent luteolysis. Chronic intrauterine infusion of PGE(1) or PGE(2) prevents spontaneous or IUD, estradiol-17beta, or PGF(2)alpha-induced premature luteolysis in nonbred ewes. The objective was to determine whether chronic intrauterine infusion of PGE(1) or PGE(2) affected mRNA for LH receptors, occupied and unoccupied receptors for LH in luteal and caruncular endometrium, and luteal function. Ewes received Vehicle, PGE(1), or PGE(2) every 4h from days 10 to 16 of the estrous cycle via a cathether installed in the uterine lumen ipsilateral to the luteal-containing ovary. Jugular venous blood was collected daily for analysis of progesterone and uterine venous blood was collected on day-16 for analysis of PGF(2)alpha and PGE. Corpora lutea and caruncular endometrium were collected from day-10 preluteolytic control ewes and day-16 ewes treated with Vehicle, PGE(1) or PGE(2) for analysis of the mRNA for LH receptors and occupied and unoccupied receptors for LH. Luteal weights on day-16 in ewes treated with PGE(1) or PGE(2) and day-10 control ewes were similar (P>or=0.05), but were greater (PPGE(2)>Vehicle-treated ewes. Concentrations of PGF(2)alpha and PGE in uterine venous plasma on day-16 were similar (P>or=0.05) in the three treatment groups. Luteal mRNA for LH receptors and unoccupied and occupied LH receptors were similar (P>or=0.05) in day-10 control ewes and day-16 ewes treated with PGE(2) and were lower (P

Genomic predictions for New Zealand dairy bulls and integration with national genetic evaluation.

A method is described for the prediction of breeding values incorporating genomic information. The first stage involves the prediction of genomic breeding values for genotyped individuals. A novel component of this is the estimation of the genomic relationship matrix in the context of a multi-breed population. Because not all ancestors of genotyped animals are genotyped, a selection index procedure is used to blend genomic predictions with traditional ancestral information that is lost between the process of deregression of the national breeding values and subsequent re-estimation using the genomic relationship matrix. Finally, the genomically enhanced predictions are filtered through to nongenotyped descendants using a regression procedure.

Hot topic: a unified approach to utilize phenotypic, full pedigree, and genomic information for genetic evaluation of Holstein final score.

The first national single-step, full-information (phenotype, pedigree, and marker genotype) genetic evaluation was developed for final score of US Holsteins. Data included final scores recorded from 1955 to 2009 for 6,232,548 Holsteins cows. BovineSNP50 (Illumina, San Diego, CA) genotypes from the Cooperative Dairy DNA Repository (Beltsville, MD) were available for 6,508 bulls. Three analyses used a repeatability animal model as currently used for the national US evaluation. The first 2 analyses used final scores recorded up to 2004. The first analysis used only a pedigree-based relationship matrix. The second analysis used a relationship matrix based on both pedigree and genomic information (single-step approach). The third analysis used the complete data set and only the pedigree-based relationship matrix. The fourth analysis used predictions from the first analysis (final scores up to 2004 and only a pedigree-based relationship matrix) and prediction using a genomic based matrix to obtain genetic evaluation (multiple-step approach). Different allele frequencies were tested in construction of the genomic relationship matrix. Coefficients of determination between predictions of young bulls from parent average, single-step, and multiple-step approaches and their 2009 daughter deviations were 0.24, 0.37 to 0.41, and 0.40, respectively. The highest coefficient of determination for a single-step approach was observed when using a genomic relationship matrix with assumed allele frequencies of 0.5. Coefficients for regression of 2009 daughter deviations on parent-average, single-step, and multiple-step predictions were 0.76, 0.68 to 0.79, and 0.86, respectively, which indicated some inflation of predictions. The single-step regression coefficient could be increased up to 0.92 by scaling differences between the genomic and pedigree-based relationship matrices with little loss in accuracy of prediction. One complete evaluation took about 2h of computing time and 2.7 gigabytes of memory. Computing times for single-step analyses were slightly longer (2%) than for pedigree-based analysis. A national single-step genetic evaluation with the pedigree relationship matrix augmented with genomic information provided genomic predictions with accuracy and bias comparable to multiple-step procedures and could account for any population or data structure. Advantages of single-step evaluations should increase in the future when animals are pre-selected on genotypes.

Susceptibility of Rice to Oebalus pugnax (F.) (Hemiptera: Pentatomidae) Feeding at Different Levels of Grain Maturity and Impacts on Insecticide Termination.

The stages of rice, Oryza sativa L. (Poales: Poaceae), grain maturity that are most susceptible to rice stink bug, Oebalus pugnax (F.), damage have been identified; however, the stage at which they are no longer capable of causing appreciable damage during grain maturity is unclear. The objective of this study was to determine the susceptibility of rice to rice stink bug feeding at different levels of grain maturity and determine an insecticide termination timing. Rice stink bug damage was examined using five levels of grain maturity described as percent of kernels reaching mature straw coloration referred to as hard dough (20, 40, 60, 80, and 100%) across a range of infestation levels using single panicle sleeve cages and large cages. Hybrid and conventional cultivar rice panicles at 20, 40, and 60% hard dough were found to be susceptible to indirect yield loss, as two rice stink bugs per panicle resulted in over 7% peck. In large cage trials, 25 rice stink bugs caused 0.7-1% peck to hybrid and conventional rice plots at 20% hard dough. Much less damage was observed once rice reached 60% hard dough, where peck averages only reached 0.4%. Decreased damage at 60% hard dough was validated using uncaged trials where 0.4% additional peck was observed in unsprayed plots. These data indicate that rice in the early stages of hard dough is susceptible to large levels of indirect yield loss, but unless significant densities of rice stink bug are present at 60% hard dough, no more sampling or applications are necessary.

Evaluation of the femoral midshaft in children with cerebral palsy using magnetic resonance imaging.

SUMMARY: Magnetic resonance imaging was used to show that children with quadriplegic cerebral palsy and unable to ambulate independently compared to typically developing children have a remarkably underdeveloped femoral midshaft as indicated by a very thin diameter, a very thin cortical wall, and very low strength estimates. INTRODUCTION: The femoral shaft is very susceptible to fracture in children with quadriplegic cerebral palsy (QCP); however, its structure and strength have not been evaluated. METHODS: The volume and width of the middle third of the femur (midfemur) and its cortical wall and medullary cavity were assessed in children with QCP and unable to ambulate independently and typically developing children (n = 10/group) using magnetic resonance imaging (MRI). Estimates of cross-sectional moment of inertia (CSMI), section modulus (Z), and polar moment of inertia (J) were also determined. RESULTS: Total volume of the midfemur and volume of its cortical wall and medullary cavity were substantially lower in children with QCP than controls (51-55%; p < 0.001). In addition, the total midfemur, its medullary cavity and the anterior, posterior, and lateral sections of its cortical wall were thinner (27-43%) in children with QCP (p < 0.001). The midfemur in children with QCP also had remarkably lower CSMI, Z, and J (60-71%; p < 0.001). CONCLUSIONS: Children with QCP who lack the ability to ambulate independently have midfemurs that are very thin with very thin cortical walls and very low estimated strength. The disparity can be detected using MRI.

Honey bees: do they use the direction information contained in their dance maneuver?

Direction communication experiments, when controlled against unilateral visitation of trained foragers at the experimental site, exhibited no evidence supporting the precision of communication suggested in the dance "language" hypothesis. Results compare well with those which might be expected on the basis of the geometric arrangement of the feeding dishes.

Honey bee recruitment to food sources: olfaction or language?

Honey bee recruits locate food sources by olfaction and not by use of distance and direction information contained in the recruitment dance. Recruitment efficiency increases as odor of the food source accumulates in the hive, from hour to hour and from day to day. Flight patterns, landing patterns, bee odor, and Nassanoff secretion apparently do not aid in recruitment of bees.

Kimmswick: a clovis-mastodon association in eastern missouri.

Stone tools characteristic of the Clovis culture have been found in direct association with bones of the American mastodon at Kimmswick, Missouri. The vertebrate fauna from Clovis components suggests a deciduous woodland and meadow habitat. Such an environmental reconstruction provides a new perspective for Clovis adaptations and the ecological tolerances of Mammut americanum.

Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.

Erythropoietin receptor (EPOR) is thought to be activated by ligand-induced homodimerization. However, structures of agonist and antagonist peptide complexes of EPOR, as well as an EPO-EPOR complex, have shown that the actual dimer configuration is critical for the biological response and signal efficiency. The crystal structure of the extracellular domain of EPOR in its unliganded form at 2.4 angstrom resolution has revealed a dimer in which the individual membrane-spanning and intracellular domains would be too far apart to permit phosphorylation by JAK2. This unliganded EPOR dimer is formed from self-association of the same key binding site residues that interact with EPO-mimetic peptide and EPO ligands. This model for a preformed dimer on the cell surface provides insights into the organization, activation, and plasticity of recognition of hematopoietic cell surface receptors.

Small peptides as potent mimetics of the protein hormone erythropoietin.

Random phage display peptide libraries and affinity selective methods were used to isolate small peptides that bind to and activate the receptor for the cytokine erythropoietin (EPO). In a panel of in vitro biological assays, the peptides act as full agonists and they can also stimulate erythropoiesis in mice. These agonists are represented by a 14- amino acid disulfide-bonded, cyclic peptide with the minimum consensus sequence YXCXXGPXTWXCXP, where X represents positions allowing occupation by several amino acids. The amino acid sequences of these peptides are not found in the primary sequence of EPO. The signaling pathways activated by these peptides appear to be identical to those induced by the natural ligand. This discovery may form the basis for the design of small molecule mimetics of EPO.

Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8 A.

The functional mimicry of a protein by an unrelated small molecule has been a formidable challenge. Now, however, the biological activity of a 166-residue hematopoietic growth hormone, erythropoietin (EPO), with its class 1 cytokine receptor has been mimicked by a 20-residue cyclic peptide unrelated in sequence to the natural ligand. The crystal structure at 2.8 A resolution of a complex of this agonist peptide with the extracellular domain of EPO receptor reveals that a peptide dimer induces an almost perfect twofold dimerization of the receptor. The dimer assembly differs from that of the human growth hormone (hGH) receptor complex and suggests that more than one mode of dimerization may be able to induce signal transduction and cell proliferation. The EPO receptor binding site, defined by peptide interaction, corresponds to the smaller functional epitope identified for hGH receptor. Similarly, the EPO mimetic peptide ligand can be considered as a minimal hormone, and suggests the design of nonpeptidic small molecule mimetics for EPO and other cytokines may indeed be achievable.

Geographic patterns of non-carpeted floor dust loading in Syracuse, New York (USA) homes.

Residential floor dust loading was measured on the smooth floor surface of 488 houses in Syracuse, New York, during the summers of 2003 and 2004. Using U.S. Environmental Protection Agency (EPA) wipe methods, pre-weighed Ghost Wipes, Lead Wipes, or Whatman Filters were employed to collect duplicate samples from (predominantly) kitchens. The collection efficiency of the various media was determined from multiple wipe tests and side-by-side comparisons. The results were normalized and aggregated at the census tract level to determine whether spatial patterns of dust loading could be observed. Loading was found to be log-normally distributed, with a geometric mean value of 0.311 g m(-2) (29 mg of dust per square foot of floor); 95% of the observations fell in the range of 0.042-2.330 g m(-2) (4-216 mg foot(-2)). The sampling for floor dust loading shows some bias for day of the week in which visits to the residential properties were made. After a first-order correction for this effect, results were aggregated by census tract and mapped in a geographic information system (GIS); strong spatial patterns can be identified in an inverse distance weighted mapping. The geographic patterns exhibit a strong correlation with socio-economic/demographic covariates extracted from the 2000 census summaries. Dust mass on the floors is positively correlated with renter-occupied properties and family size; it is negatively correlated with measures of household income.

Three wave mixing test of hyperelasticity in highly nonlinear solids: sedimentary rocks.

Measurements of three-wave mixing amplitudes on solids whose third order elastic constants have also been measured by means of the elasto-acoustic effect are reported. Because attenuation and diffraction are important aspects of the measurement technique results are analyzed using a frequency domain version of the KZK equation, modified to accommodate an arbitrary frequency dependence to the attenuation. It is found that the value of beta so deduced for poly(methylmethacrylate) (PMMA) agrees quite well with that predicted from the stress-dependent sound speed measurements, establishing that PMMA may be considered a hyperelastic solid, in this context. The beta values of sedimentary rocks, though they are typically two orders of magnitude larger than, e.g., PMMA's, are still a factor of 3-10 less than those predicted from the elasto-acoustic effect. Moreover, these samples exhibit significant heterogeneity on a centimeter scale, which heterogeneity is not apparent from a measurement of the position dependent sound speed.