Variation In Steady-state Levels Research Articles

Transcriptome variance in single oocytes within, and between, genotypes

Transcriptome variance in single oocytes within, and between, genotypes

The Human Mitochondrial Transcriptome

The human mitochondrial genome comprises a distinct genetic system transcribed as precursor polycistronic transcripts that are subsequently cleaved to generate individual mRNAs, tRNAs, and rRNAs. Here, we provide a comprehensive analysis of the human mitochondrial transcriptome across multiple cell lines and tissues. Using directional deep sequencing and parallel analysis of RNA ends, we demonstrate wide variation in mitochondrial transcript abundance and precisely resolve transcript processing and maturation events. We identify previously undescribed transcripts, including small RNAs, and observe the enrichment of several nuclear RNAs in mitochondria. Using high-throughput in vivo DNaseI footprinting, we establish the global profile of DNA-binding protein occupancy across the mitochondrial genome at single-nucleotide resolution, revealing regulatory features at mitochondrial transcription initiation sites and functional insights into disease-associated variants. This integrated analysis of the mitochondrial transcriptome reveals unexpected complexity in the regulation, expression, and processing of mitochondrial RNA and provides a resource for future studies of mitochondrial function (accessed at http://mitochondria.matticklab.com).

Trends and Transitions in the Long Run Growth of Nations

Empirical work on cross-country growth has focussed almost exclusively on the speed of convergence to steady state and the variations in steady state levels. This paper examines the estimated long-run growth rate, i.e. the rate of steady state growth, in a Solow growth model. All estimates of common world steady state growth are shown to be zero or significantly negative under the null model. The null of a common world steady state growth rate is rejected in favor of a modifications of the basic Solow model to allow for heterogeneous long run growth rates across countries. This alternative yields plausible estimates of the capital share and speed of convergence but shows that steady states for different countries are quite diverse in both levels and growth rates. An alternative framework is presented to relate long run growth rates to fundamentals.

Dose-effect relationships for tricyclic antidepressants: the basis for rational clinical testing of new antidepressants.

The dose-effect relationship is a basic element in all research in experimental pharmacology. In clinical pharmacology, the central role of the dose-effect concept has usually been acknowledged, but the actual demonstration of dose-effect relationships in clinical drug research is often extremely difficult. In the early years after the introduction of imipramine and subsequently other tricyclic antidepressants (TCA), the dose-effect problems were not infrequently discussed in the clinical reports, usually on the basis of uncontrolled clinical assessments (Delay and Deniker 1959; Ayd 1959). However, towards the end of the 1960s, the question of appropriate dosing appeared to receive little attention, clinically or in research trials. In a larger review attempting to identify variables important for the therapeutic efficacy of TCA, the dose was not even considered (Smith et al. 1969). At that time, the demonstration of pronounced variations in steady state levels in patients on standard TCA (Sjoqvist et al. 1968) gave rise to a series of studies on concentration-effect relationships during the following two decades. For the introduction of new antidepressants, there is an increasing demand for data on the dose-effect relationship. In this situation, it seems awkward that our knowledge about the dose-effect relationship for the usual control therapy, TCA, is rather limited. Also for the clinical use of TCA, the dose-effect issue has been reintroduced by some authors in the 1980s (Quitkin 1985; Roose et al. 1986; Goethe et al. 1988). However, in clinical trials, this problem is seldom even discussed as a source of bias or variability.

Pharmacokinetics of 3-keto-desogestrel and ethinylestradiol released from different types of contraceptive vaginal rings

Pharmacokinetics of 3-keto-desogestrel and ethinylestradiol released from contraceptive vaginal rings (CVRs) with different release rates ( 75 15 , 100 15 and 150 15 μg 3-ketodesogestrel/ethinylestradiol daily) were investigated in two studies in young healthy female volunteers. As reference, an oral preparation containing 150 μg desogestrel and 30 μg ethinylestradiol (Marvelon R tablets) was also administered to the volunteers. To assess the disposition parameters of 3-ketodesogestrel and ethinylestradiol, some of the volunteers were additionally given an i.v. preparation containing 150 μg 3-ketodesogestrel and 30 μg ethinylestradiol. Serum levels obtained with CVRs showed an initial increase during the first three days, followed by a plateau decreasing only slightly during the remainder of the treatment period. Mean plateau levels (± s.d.) of 3-keto-desogestrel were 2.3 ± 0.9, 2.8 ± 1.1 and 3.8 ± 1.1 pmol/ ml for CVR 75 15 , 100 15 and 150 15 , respectively. Mean plateau levels of ethinylestradiol were 184 ± 75, 262 ± 102 and 233 ± 102 pmol/ l, respectively. The in vivo release rates of 3-keto-desogestrel and ethinylestradiol from the CVRs were in good agreement with the in vitro release rates. For both steroids the bioavailability from the CVRs was approximately 1.2 times higher than that from the tablets. The 3-keto-desogestrel serum levels were found directly proportional to the release rates within the range studied (75–150 μg/day). For ethinylestradiol the intra-individual variation in steady-state levels was too large to draw pertinent conclusions.

Insulin-Like Growth Factor-I Expression during Early Conceptus Development in the Pig1

Porcine conceptuses (embryo and associated membranes) in utero undergo developmental morphological transformations coincident with structural and biochemical changes in the uterine endometrium during early gestation. To elucidate a possible role for insulin-like growth factor-I (IGF-I) in these events, porcine endometrial (Days 8, 10, 11, 12, 14, and 30) and conceptus (Days 12, 14, and 16) tissues were characterized for the presence of IGF-I peptide and mRNAs. The corresponding uterine luminal fluids (ULF) at these stages of pregnancy were also analyzed for immunoreactive IGF-I concentration. ULF IGF-I was lowest on Day 8, highest on Day 12, and declined by Day 14. In contrast, endometrial tissue IGF-I content remained constant during this period. Conceptus tissues contained less IGF-I than endometrial tissues; however, conceptus IGF-I values were maximum on Day 12 coincident with peak values for ULF IGF-I. Dot-blot hybridization analyses revealed temporal variation in steady-state levels of IGF-I mRNAs in endometrium. Highest levels of endometrial IGF-I mRNA were detected on Day 12 and were about 4-fold greater than on Day 30 of pregnancy. IGF-I mRNA expression in conceptus tissues on Days 12, 14, and 16 was the same and was significantly less than that in endometrium on Day 12. These results demonstrate the temporal variation of IGF-I mRNA abundance in uterine endometrium and of immunoreactive IGF-I in ULF and in conceptus tissues, with the developmental processes occurring in the conceptuses at early pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic variation affecting the expression of catalase in Drosophila melanogaster: correlations with rates of enzyme synthesis and degradation.

Both second and third chromosome substitution lines isolated from natural populations of Drosophila melanogaster affect the expression of catalase (EC 1.11.1.6) at both the larval and adult stages of development. In each case, the level of catalase activity is strongly related to the level of catalase-specific cross-reacting material. Turnover studies employing the catalase inhibitor 3-amino-1,2,4-triazole were conducted on a selected number of lines. Although the variation in steady state levels of catalase protein was highly significant among lines, variation in intracellular degradation rate was not. These results suggest that the different steady state levels observed among lines largely reflect different rates of catalase synthesis.

Penfluridol: A Neuroleptic Drug Designed for Long Duration of Action

1. Penfluridol is a unique, long-acting, oral neuroleptic belonging to the diphenylbutylpiperidines. The synthesis of penfluridol represented the result of a well-planned scientific search for a highly lipophilic compound structurally related to haloperidol and pimozide. 2. Because of its unusual lipophilicity, penfluridol distributes extensively in fatty tissues following oral administration. This depot effect produces a very slow release of drug from the tissues, and results in a very long duration of activity. 3. Penfluridol is extensively metabolized by oxidative N-dealkylation to afford, as isolated metabolites, the beta-glucuronide conjugate of the diphenylbutyric acid derivative A1 and the unconjugated basic piperidine moiety B1. It is assumed, at this time, that the pharmacological activity is attributable to the parent compound. 4. When administered clinically at oral doses of 20 to 100 mg/week, penfluridol has been found to be an effective antipsychotic agent. This frequency of dosing is consistent with the pharmacokinetic behavior of the drug in man, and does not appear to result in any inappropriate accumulation of the drug in patients. Wide variations in steady-state levels and plasma elimination half-life have been observed in patient populations.