The role of hypothalamic progestin receptors in the activation and maintenance of sexual receptivity in female rats and guinea pigs

The role of hypothalamic (HTH) intracellular progestin receptors (PRs) in the activation and termination of sexual receptivity (heat) in female rats and guinea pigs was examined. In the first study, the progestin antagonist, RU 486, was found to inhibit progesterone-facilitated sexual behavior in ovariectomized (OVX) estrogen-treated guinea pigs. RU 486 bound in vitro to neural PRs, and decreased the availability of HTH PRs when administered to estradiol-treated animals. These findings support the hypothesis that intracellular PRs mediate the facilitation of sexual behavior by progesterone. In a second study, OVX rats were treated with daily injections of the pesticide, o,p\u27-DDT (which has estrogenic properties), for 3 days, followed by progesterone on day 4. A dose of 400 mg/kg o,p\u27-DDT resulted in the activation of sexual behavior in 50% of the animals, and increased HTH cytosol PR concentration by 43%. Following progesterone treatment, the concentration of nuclear-bound PRs increased 137%. These findings support the hypothesis that estrogen-induced PRs are required for the facilitation of sexual receptivity by progesterone, and contradict a recent study using DDT that suggested that estrogen induction of PRs is not necessary. The last three studies tested the hypothesis that loss of PRs from the HTH cell nuclei results in heat termination. A supplemental injection of progesterone given 8 h after an initial injection delayed heat termination by more than 2 h, and also delayed the loss of HTH nuclear PRs. In an attempt to further delay heat termination, OVX guinea pigs were treated with capsules containing estradiol and one of several doses of progesterone. Heat termination occurred at about the same time regardless of the dose of progesterone, and despite the continued presence of both hormones. Nuclear PRs were also found to decrease in the presence of continued administration of estradiol and progesterone. As nuclear PR levels decreased, sexual receptivity terminated. In the final study, RU 486 administered to estradiol-progesterone treated guinea pigs accelerated both the loss of nuclear PRs and the termination of sexual receptivity. These studies support the hypothesis that heat termination results from the loss of PRs from HTH cell nuclei, and provide further evidence that intracellular PRs are involved in mediating progesterone\u27s effects on sexual behavior

Developmental Exposure of Rats to Chlorpyrifos Elicits Sex-Selective Hyperlipidemia and Hyperinsulinemia in Adulthood

Developmental exposure to chlorpyrifos alters cell signaling both in the brain and in peripheral tissues, affecting the responses to a variety of neurotransmitters and hormones. We administered 1 mg/kg/day chlorpyrifos to rats on postnatal days 1–4, a regimen below the threshold for systemic toxicity. When tested in adulthood, chlorpyrifos-exposed animals displayed elevations in plasma cholesterol and triglycerides, without underlying alterations in nonesterified free fatty acids and glycerol. This effect was restricted to males. Similarly, in the postprandial state, male rats showed hyperinsulinemia in the face of normal circulating glucose levels but demonstrated appropriate reduction of circulating insulin concentrations after fasting. These outcomes and sex selectivity resemble earlier findings at the cellular level, which identified hepatic hyperresponsiveness to gluconeogenic inputs from β-adrenoceptors or glucagon receptors. Our results thus indicate that apparently subtoxic neonatal chlorpyrifos exposure, devoid of effects on viability or growth but within the parameters of human fetal or neonatal exposures, produce a metabolic pattern for plasma lipids and insulin that resembles the major adult risk factors for atherosclerosis and type 2 diabetes mellitus

Decreased progesterone receptor isoform expression in luteal phase fallopian tube epithelium and high-grade serous carcinoma

We previously reported that BRCA1/2-mutated fallopian tube epithelium (FTE) collected during the luteal phase exhibits gene expression profiles more closely resembling that of high-grade serous carcinoma (HGSC) specimens than FTE collected during the follicular phase or from control patients. Since the luteal phase is characterised by high levels of progesterone, we determined whether the expression of progesterone receptor (PR) and PR-responsive genes was altered in FTE obtained from BRCA mutation carriers during the luteal phase of the menstrual cycle. RT-qPCR confirmed a decreased expression of PR mRNA in FTE during the luteal phase relative to follicular phase, in both BRCA1/2 mutation carriers and control patients. Immunohistochemistry using isoform-specific antibodies confirmed a low level of both PR-A and PR-B in HGSC and a lower level of staining in FTE samples obtained during the luteal phase compared with the follicular phase. No significant difference in PR-A or PR-B staining was found based on patient BRCA mutation status. Analysis of our previously reported gene expression profiles based upon known PR-A- and PR-B-specific target genes did not partition samples by BRCA mutation status, indicating that overall FTE PR response is not altered in BRCA mutation carriers. HGSC samples grouped separately from other samples, consistent with the observed loss of PR expression. These findings indicate no overall difference in PR signalling in FTE as a function of BRCA mutation status. Thus, the molecular similarity of BRCA1/2-mutated luteal phase FTE and HGSC likely results from an altered response to luteal phase factors other than progesterone

The peripheral blood transcriptome in septic cardiomyopathy: an observational, pilot study.

BACKGROUND:Septic cardiomyopathy (SCM) is common in sepsis and associated with increased morbidity and mortality. Left ventricular global longitudinal strain (LV GLS), measured by speckle tracking echocardiography, allows improved identification of impaired cardiac contractility. The peripheral blood transcriptome may be an important window into SCM pathophysiology. We therefore studied the peripheral blood transcriptome and LV GLS in a prospective cohort of patients with sepsis. RESULTS:In this single-center observational pilot study, we enrolled adult patients (age > 18) with sepsis within 48 h of admission to the ICU. SCM was defined as LV GLS > - 17% based on echocardiograms performed within 72 h of admission. We enrolled 27 patients, 24 of whom had high-quality RNA results; 18 (75%) of 24 had SCM. The group was 50% female and had a median (IQR) age of 59.5 (48.5-67.0) years and admission APACHE II score of 21.0 (16.0-32.3). Forty-six percent had septic shock. After filtering for low-expression and non-coding genes, 15,418 protein coding genes were expressed and 73 had significantly different expression between patients with vs. without SCM. In patients with SCM, 43 genes were upregulated and 30 were downregulated. Pathway analysis identified enrichment in type 1 interferon signaling (adjusted p < 10-5). CONCLUSIONS:In this hypothesis-generating study, SCM was associated with upregulation of genes in the type 1 interferon signaling pathway. Interferons are cytokines that stimulate the innate and adaptive immune response and are implicated in the early proinflammatory and delayed immunosuppression phases of sepsis. While type 1 interferons have not been implicated previously in SCM, interferon therapy (for viral hepatitis and Kaposi sarcoma) has been associated with reversible cardiomyopathy, perhaps suggesting a role for interferon signaling in SCM

In vitro antimicrobial activities of novel anilinouracils which selectively inhibit DNA polymerase III of gram-positive bacteria

The 6-anilinouracils are novel dGTP analogs that selectively inhibit the replication-specific DNA polymerase III of gram-positive eubacteria. Two specific derivatives, IMAU (6-[3\u27-iodo-4\u27-methylanilino]uracil) and EMAU (6-[3\u27-ethyl-4\u27-methylanilino]uracil), were substituted with either a hydroxybutyl (HB) or a methoxybutyl (MB) group at their N3 positions to produce four agents: HB-EMAU, MB-EMAU, HB-IMAU, and MB-IMAU. These four new agents inhibited Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Time-kill assays and broth dilution testing confirmed bactericidal activity. These anilinouracil derivatives represent a novel class of antimicrobials with promising activities against gram-positive bacteria that are resistant to currently available agents, validating replication-specific DNA polymerase III as a new target for antimicrobial development

Atomic effects in astrophysical nuclear reactions

Two models are presented for the description of the electron screening effects that appear in laboratory nuclear reactions at astrophysical energies. The two-electron screening energy of the first model agrees very well with the recent LUNA experimental result for the break-up reaction $He3(He3,2p)He^{4}$, which so far defies all available theoretical models. Moreover, multi-electron effects that enhance laboratory reactions of the CNO cycle and other advanced nuclear burning stages, are also studied by means of the Thomas-Fermi model, deriving analytical formulae that establish a lower and upper limit for the associated screening energy. The results of the second model, which show a very satisfactory compatibility with the adiabatic approximation ones, are expected to be particularly useful in future experiments for a more accurate determination of the CNO astrophysical factors.Comment: 14 RevTex pages + 2 ps (revised) figures. Phys.Rev.C (in production

Within-host evolution of Enterococcus faecium during longitudinal carriage and transition to bloodstream infection in immunocompromised patients.

BACKGROUND: Enterococcus faecium is a leading cause of hospital-acquired infection, particularly in the immunocompromised. Here, we use whole genome sequencing of E. faecium to study within-host evolution and the transition from gut carriage to invasive disease. METHODS: We isolated and sequenced 180 E. faecium from four immunocompromised patients who developed bloodstream infection during longitudinal surveillance of E. faecium in stool and their immediate environment. RESULTS: A phylogenetic tree based on single nucleotide polymorphisms (SNPs) in the core genome of the 180 isolates demonstrated several distinct clones. This was highly concordant with the population structure inferred by Bayesian methods, which contained four main BAPS (Bayesian Analysis of Population Structure) groups. The majority of isolates from each patient resided in a single group, but all four patients also carried minority populations in stool from multiple phylogenetic groups. Bloodstream isolates from each case belonged to a single BAPS group, which differed in all four patients. Analysis of 87 isolates (56 from blood) belonging to a single BAPS group that were cultured from the same patient over 54 days identified 30 SNPs in the core genome (nine intergenic, 13 non-synonymous, eight synonymous), and 250 accessory genes that were variably present. Comparison of these genetic variants in blood isolates versus those from stool or environment did not identify any variants associated with bloodstream infection. The substitution rate for these isolates was estimated to be 128 (95% confidence interval 79.82 181.77) mutations per genome per year, more than ten times higher than previous estimates for E. faecium. Within-patient variation in vancomycin resistance associated with vanA was common and could be explained by plasmid loss, or less often by transposon loss. CONCLUSIONS: These findings demonstrate the diversity of E. faecium carriage by individual patients and significant within-host diversity of E. faecium, but do not provide evidence for adaptive genetic variation associated with invasion

Astrophysical factors:Zero energy vs. Most effective energy

Effective astrophysical factors for non-resonant astrophysical nuclear reaction are invariably calculated with respect to a zero energy limit. In the present work that limit is shown to be very disadvantageous compared to the more natural effective energy limit. The latter is used in order to modify the thermonuclear reaction rate formula so that it takes into account both plasma and laboratory screening effects.Comment: 7 RevTex pages. Accepted for publication in Phys.Rev.

Baker Center Journal of Applied Public Policy - Vol. IV, No.II

This special edition includes articles from speakers at a 2010 conference - Howard H. Baker, Jr: A Life in Public Service and a special addendum including photographs and cartoons from Sen. Baker\u27s career