Inhibition of an IUD-induced precocious luteolysis by prostaglandin E1 (PGE1) in sheep

Fifteen ewes were assigned as they came into estrus to one of three randomized treatment groups: 1. Sham IUD + Vehicle, 2. IUD + Vehicle or 3. IUD + PGE₁ in vehicle. An IUD was inserted adjacent to the luteal-bearing ovary on day 3 postestrus. Prostaglandin E₁ (500 μg) in vehicle (Na₂CO₃) or vehicle was given intrauterine through an indwelling uterine cannula every four hours from day 3 postestrus until ewes returned to estrus. Precocious estrus was induced in both the sham IUD groups receiving vehicle. Prostaglandin E₁ prevented an IUD-induced premature luteolysis based on daily concentrations of progesterone in peripheral blood and the interestrous interval. It is concluded that an IUD-induced premature luteolysis is not necessarily via physical distention by the IUD. It is also concluded that chronic intrauterine infusions of PGE₁ can prevent an IUD-induced premature luteolysis.     

Confirmation of Childhood Acute Lymphoblastic Leukemia Variants,ARID5B and IKZF1, and Interaction with Parental Environmental Exposures

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child’s sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38–1.93, P = 2.13×10⁻⁹), and IKZF1 rs1110701 (OR 1.69, CI 1.42–2.02, p = 7.26×10⁻⁹). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.     

Resolution of epoxide enantiomers of polycyclic aromatic hydrocarbons by chiral stationary-phase high-performance liquid chromatography

Enantiomers of nine K-region and one non-K-region epoxides of polycyclic aromatic hydrocarbons have been resolved by high-performance liquid chromatography with chiral stationary phases either ionically or covalently bonded to gamma-aminopropylsilanized silica. Resolution of enantiomers was confirmed by ultraviolet-visible absorption, circular dichroism, and mass spectral analyses. This method has been applied to the determination of optical purity and absolute configuration of the K-region epoxides formed in the metabolism of 1-methylbenz[a]anthracene, 7-methylbenz[a]anthracene, and 12-methylbenz[a]anthracene by rat liver microsomes.     

Resolution and absolute configuration of 7,12-dimethylbenz[a]anthracene 5,6-epoxide enantiomers

The enantiomers of 7,12-dimethylbenz[a]anthracene (DMBA) 5,6-epoxide were directly resolved by normal-phase high-performance liquid chromatography with an ionically bonded chiral stationary phase. The absolute configurations of the resolved enantiomers were determined by comparison of circular dichroism spectra of the methanolysis products formed from the epoxide enantiomers with that of a DMBA trans-5,6-dihydrodiol enantiomer of known absolute stereochemistry. DMBA 5R,6S-epoxide is hydrated by rat liver microsomal epoxide hydrolase predominantly (95%) to a 5S,6S-dihydrodiol. The results indicate that the 5S,6S-dihydrodiol formed from the metabolism of DMBA by microsomes prepared from the livers of 3-methylcholanthrene-treated rats is predominantly derived from a 5R,6S-epoxide intermediate.     

Confirmation of the Reported Association of Clonal Chromosomal Mosaicism with an Increased Risk of Incident Hematologic Cancer

Chromosomal abnormalities provide clinical utility in the diagnosis and treatment of hematologic malignancies, and may be predictive of malignant transformation in individuals without apparent clinical presentation of a hematologic cancer. In an effort to confirm previous reports of an association between clonal mosaicism and incident hematologic cancer, we applied the anomDetectBAF algorithm to call chromosomal anomalies in genotype data from previously conducted Genome Wide Association Studies (GWAS). The genotypes were initially collected from DNA derived from peripheral blood of 12,176 participants in the Group Health electronic Medical Records and Genomics study (eMERGE) and the Women’s Health Initiative (WHI). We detected clonal mosaicism in 169 individuals (1.4%) and large clonal mosaic events (>2 mb) in 117 (1.0%) individuals. Though only 9.5% of clonal mosaic carriers had an incident diagnosis of hematologic cancer (multiple myeloma, myelodysplastic syndrome, lymphoma, or leukemia), the carriers had a 5.5-fold increased risk (95% CI: 3.3–9.3; p-value = 7.5×10⁻¹¹) of developing these cancers subsequently. Carriers of large mosaic anomalies showed particularly pronounced risk of subsequent leukemia (HR = 19.2, 95% CI: 8.9–41.6; p-value = 7.3×10⁻¹⁴). Thus we independently confirm the association between detectable clonal mosaicism and hematologic cancer found previously in two recent publications.     

In vivo intra-luteal implants of prostaglandin (PG) E(1) or E(2) (PGE(1), PGE(2)) prevent luteolysis in cows. I. Luteal weight, circulating progesterone, mRNA for luteal luteinizing hormone (LH) receptor, and occupied and unoccupied luteal receptors for LH

Previously, it was reported that chronic intra-uterine infusion of PGE(1) or PGE(2) every four hours inhibited luteolysis in ewes. However, estradiol-17β or PGE(2) given intra-uterine every 8h did not inhibit luteolysis in heifers, but infusion of estradiol+PGE(2) inhibited luteolysis in heifers. The objective of this experiment was to determine whether and how intra-luteal implants containing PGE(1) or PGE(2) prevent luteolysis in Angus or Brahman cows. On day-13 post-estrus, Angus cows received no intra-luteal implant and corpora lutea were retrieved or Angus and Brahman cows received intra-luteal silastic implants containing Vehicle, PGE(1), or PGE(2) and corpora lutea were retrieved on day-19. Coccygeal blood was collected daily for analysis for progesterone. Breed did not influence the effect of PGE(1) or PGE(2) on luteal mRNA for LH receptors or unoccupied or occupied luteal LH receptors did not differ (P>0.05) so the data were pooled. Luteal weights of Vehicle-treated Angus or Brahman cows from days-13-19 were lower (P<0.05) than those treated with intra-luteal implants containing PGE(1) or PGE(2). Day-13 Angus luteal weights were heavier (P<0.05) than Vehicle-treated Angus cows on day-19 and luteal weights of day-13 corpora lutea were similar (P>0.05) to Angus cows on day-19 treated with intra-luteal implants containing PGE(1) or PGE(2). Profiles of circulating progesterone in Angus or Brahman cows treated with intra-luteal implants containing PGE(1) or PGE(2) differed (P<0.05) from controls, but profiles of progesterone did not differ (P>0.05) between breeds or between cows treated with intra-luteal implants containing PGE(1) or PGE(2). Intra-luteal implants containing PGE(1) or PGE(2) prevented (P<0.05) loss of luteal mRNA for LH receptors and unoccupied or occupied receptors for LH compared to controls. It is concluded that PGE(1) or PGE(2) alone delays luteolysis regardless of breed. We also conclude that either PGE(1) or PGE(2) prevented luteolysis in cows by up-regulating expression of mRNA for LH receptors and by preventing loss of unoccupied and occupied LH receptors in luteal tissue.     

Prostaglandin E1 or E2 (PGE1, PGE2) prevents premature luteolysis induced by progesterone given early in the estrous cycle in ewes

The objective of this study was to determine whether prostaglandin E₁ (PGE₁) or prostaglandin E₂ (PGE₂) prevents premature luteolysis in ewes when progesterone is given during the first 6 days of the estrous cycle. Progesterone (3 mg in oil, im) given twice daily from Days 1 to 6 (estrus = Day 0) in ewes decreased (P < 0.05) luteal weights on Day 10 postestrus. Plasma progesterone concentrations differed (P < 0.05) among the treatment groups; toward the end of the experimental period, concentrations in jugular venous blood decreased (P < 0.05) compared with the other treatment groups. Plasma progesterone concentrations in ewes receiving PGE₁ or PGE₁ + progesterone were greater (P < 0.05) than in vehicle controls or in ewes receiving PGE₂ or PGE₂ or PGE₂ + progesterone. Chronic intrauterine treatment with PGE₁ or PGE₂ prevented (P < 0.05) decreases in plasma progesterone concentrations, luteal weights, and the proportion of luteal unoccupied and occupied LH receptors on Day 10 postestrus in ewes given exogenous progesterone, but did not affect (P > 0.05) concentrations of PGF_2α in inferior vena cava blood. Progesterone given on Days 1 to 6 in ewes advanced (P < 0.05) increases in PGF_2α in inferior vena cava blood. We concluded that PGE₁ or PGE₂ prevented progesterone-induced premature luteolysis by suppressing loss of luteal LH receptors (both unoccupied and occupied).     

Three-year longitudinal study of perceptions of competence and well-being among youth exposed to disasters

This article examines perceptions of competence/well-being over time and linkages to exposure to natural disaster experiences and stress associated with the Deepwater Horizon Oil Spill in youth. A multi-wave naturalistic design was used to follow N?=?3,399 students, ages 8–18 years who were evaluated for perceptions of competence/well-being, posttraumatic stress disorder (PTSD) symptoms, hurricane exposure experiences, and stress related to the oil spill at three time points across three years. Examination of longitudinal trajectories of competence/well-being revealed growth within youth over time. Age predicted trajectories of competence/well-being, such that older youth had higher ratings of competence/well-being; however, with higher oil spill stress, older youth experienced declines in competence/well-being post-oil spill. There was a negative association between PTSD symptoms and competence/well-being. Findings suggest that perceptions of competence/well-being may be compromised by exposure to disasters, but if maintained may serve as a protective factor.     

Background Predation Risk and Learned Predator Recognition in Convict Cichlids: Does Risk Allocation Constrain Learning?

Exposure to elevated levels of background predation risk is known to shape the behavioural response of prey organisms to known and unknown predation threats. However, less is known regarding the effects of background predation risk on predator recognition learning. Here, we test the potential effects of elevated background predation risk on the strength and retention of learned predator recognition in juvenile convict cichlids (Amatitlania nigrofasciata). In a series of laboratory trials, we exposed shoals of juvenile cichlids to conditions of elevated (vs. low) levels of background risk and then conditioned them to recognize a novel predator odour (rainbow trout, Oncorhynchus mykiss). The results of our first experiment demonstrate that despite showing reduced response intensities during initial conditioning (due to risk allocation), conditioned cichlids from high vs. low background risk show similar intensities of learned recognition when tested 24 h post‐conditioning. Moreover, elevated levels of background risk induced a predator avoidance response among unconditioned cichlids (due to induced neophobia). Our second experiment demonstrates that while we find no difference in the strength of learning when tested 24 h post‐conditioning, retention of acquired recognition is enhanced among cichlids from the high background predation risk treatment. Together, our results highlight the complex interacting effects past experience plays in shaping the response to acute predation threats.     

Structural genomics for drug design against the pathogen Coxiella burnetii

Coxiella burnetii is a highly infectious bacterium and potential agent of bioterrorism. However, it has not been studied as extensively as other biological agents, and very few of its proteins have been structurally characterized. To address this situation, we undertook a study of critical metabolic enzymes in C. burnetii that have great potential as drug targets. We used high‐throughput techniques to produce novel crystal structures of 48 of these proteins. We selected one protein, C. burnetii dihydrofolate reductase (CbDHFR), for additional work to demonstrate the value of these structures for structure‐based drug design. This enzyme's structure reveals a feature in the substrate binding groove that is different between CbDHFR and human dihydrofolate reductase (hDHFR). We then identified a compound by in silico screening that exploits this binding groove difference, and demonstrated that this compound inhibits CbDHFR with at least 25‐fold greater potency than hDHFR. Since this binding groove feature is shared by many other prokaryotes, the compound identified could form the basis of a novel antibacterial agent effective against a broad spectrum of pathogenic bacteria. Proteins 2015; 83:2124–2136. © 2015 Wiley Periodicals, Inc.