Serotonin (5-hydroxytryptamine; 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. Dogma states that beyond fetal 5-HT neurons, there are significant maternal contributions to fetal 5-HT during pregnancy1,2, but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used the Pet-1−/− mice in which most dorsal raphe (DR) neurons lack 5-HT3. Measures of 5-HT revealed previously unknown differences in accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. We show that this source is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and implicates novel maternal-placental-fetal interactions that could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.
Summary Dynamic changes in 5-methylcytosine (5mC) have been implicated in the regulation of gene expression critical for consolidation of memory. However, little is known about how these changes in 5mC are regulated in the adult brain. The enzyme Tet methylcytosine dioxygenase 1 (TET1) has been shown to promote active DNA demethylation in the nervous system. Therefore, we took a viral-mediated approach to overexpress the enzyme in the hippocampus and test its potential involvement in memory formation. We found that Tet1 is a neuronal-activity regulated gene and that its overexpression leads to changes in global modified cytosine levels. Furthermore, expression of TET1 or a catalytically inactive mutant (TET1m) resulted in the up-regulation of several neuronal memory-associated genes and impaired contextual fear memory. In summary, we show that neuronal Tet1 regulates DNA methylation levels and that its expression, independent of its catalytic activity, regulates the expression of CNS activity- dependent genes and memory formation.
IntroductionThrombopoietin (Tpo) is critical for the maintenance of hematopoietic stem and progenitor cells and is also the primary regulator of megakaryocyte development. 1,2 The binding of Tpo to its receptor, c-Mpl, causes associated Janus kinase 2 (Jak2) activation, which in turn phosphorylates (activates) several downstream effectors including signal transducers and activators of transcription (STAT) 3 and 5, mitogen-activated protein kinase (MAPK), phosphotidylinositol-3-kinase (PI3-K), and protein kinase C (PKC). [3][4][5][6][7] Activation of these pathways promotes proliferation and survival in c-Mplexpressing cell lines and hematopoietic progenitor cells, in addition to megakaryocyte lineage differentiation and maturation. [8][9][10][11] It is critical that Tpo signal transduction is stringently controlled to prevent uncontrolled proliferation. Suppressors of cytokine signaling (SOCS) proteins, phosphatases, and negative regulators such FAK, Lnk, and Lyn have all been shown to down-modulate Tpo-induced signaling. [12][13][14][15] However, the most effective method of regulating Tpo signaling is by controlling expression of c-Mpl on the plasma membrane. Tpo-mediated c-Mpl endocytosis, recycling, and degradation are rapid mechanisms to control signaling longevity and represent a mechanism that regulates Tpo signaling without new protein expression.The principal mechanism of receptor-mediated endocytosis in eukaryotic cells is the clathrin-coated vesicle. 16 Soluble clathrin molecules self-assemble and are recruited to the plasma membrane, where they form lattice structures and interact with transmembrane receptors via adaptor proteins (APs), such as AP2, to form clathrin-coated pits. 17,18 These pits then further invaginate before finally budding from the membrane to form clathrin-coated vesicles. AP2 is a heterotetramer composed of ␣2, 2, 2, and 2 subunits. The ␣2 and 2 subunits localize AP2 to the membrane, recruit endocytic accessory proteins, and bind clathrin heavy chain. [19][20][21] Transmembrane proteins are associated with the AP2-clathrin complex via the 2 domain, which binds directly to cytoplasmic YXX⌽ (where X ϭ any amino acid and ⌽ ϭ bulky hydrophobic residue) and [DE]XXX-L[IL] motifs. 22,23 To ensure that AP2 specifically associates with membrane-bound proteins, phosphorylation of 156 Thr in the 2 subunit results in a conformational change in AP2, dramatically increasing the affinity of 2 for YXX⌽ motifs. 24,25 156 Thr is phosphorylated by adaptor-associated kinase 1 (AAK1), 26 the activity of which is maximized by its association with clathrin, 27,28 ensuring that AP2-cargo protein interactions are initiated only at the plasma membrane. In addition to being an endocytic signal, YXX⌽ motifs located between 6 to 9 amino acids from the transmembrane domain mediate targeting of cargo protein to the lysosome and lysosome-like organelles via interactions with AP3. [29][30][31][32] c Methods Chemicals and reagentsPharmacologic inhibitors JakI, LY294002, SU6656, and U0126 where all purchased f...
Abstract. Wake steering is a form of wind farm control in which turbines use yaw offsets to affect wakes in order to yield an increase in total energy production. In this first phase of a study of wake steering at a commercial wind farm, two turbines implement a schedule of offsets. Results exploring the observed performance of wake steering are presented, as well as some first lessons learned. For two closely spaced turbines, an approximate 13 % increase in energy was measured on the downstream turbine over a 10° sector. Additionally, the increase of energy for the combined upstream/downstream pair was found to be in line with prior predictions. Finally, the influence of atmospheric stability over the results is explored.
Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.
Combination antiretroviral therapy with two or more protease inhibitors has become the standard of care in the treatment of HIV infection. Dual protein inhibitor (PI) regimens, such as lopinavir/ritonavir, are commonly used as initial PI therapy. As viral resistance increases and the development of mechanistically novel protease inhibitors decreases, clinicians turn to ritonavir-enhanced dual PI therapy to treat salvage patients. Potency of these combination regimens is increased while pill burden, food restrictions and often, side effects are decreased. These clinical advantages result from the enhancement of their pharmacological properties, including alterations in the absorption and metabolism process. Alterations in the absorption and metabolism of protease inhibitors when co-administered with a cytochrome P450 (CYP) enzyme inhibitor, such as low dose ritonavir, are reflected by impressive changes in pharmacokinetic parameters. For example, the addition of ritonavir 100 or 200 mg to saquinavir 1200-1800 mg has been shown to increase saquinavir area under the concentration-time curve (AUC) by approximately 300-800% compared with saquinavir alone. The ability of ritonavir to increase plasma trough concentrations (C(min)) of concomitantly administered PIs is perhaps the greatest clinical benefit of dual or ritonavir-enhanced dual PI therapy since inadequate concentrations of antiretrovirals may support long term antiretroviral resistance. For example, lopinavir 400mg alone in healthy volunteers produced plasma concentrations that briefly exceeded the concentration required to inhibit 50% of viral replication (IC(50)). Yet, when low doses of ritonavir were added, C(min) values were 50- to 100-fold greater than the concentration required to produce 50% of the maximum effect for wild-type HIV (EC(50)). The following manuscript will discuss the rationale for combining protease inhibitors and will review pertinent pharmacokinetic and clinical data on these combination regimens.
Suspected fetal macrosomia appeared associated with increased risk for a composite measure of childbirth morbidity.
Purpose: Dihydropyrimidine dehydrogenase (DPD) deficiency is critical in the predisposition to 5-fluorouracil dose-related toxicity. We recently characterized the phenotypic [2-13 C]uracil breath test (UraBT) with 96% specificity and 100% sensitivity for identification of DPD deficiency. In the present study, we characterize the relationships among UraBT-associated breath C]uracil concentrations were determined over 180 minutes using IR spectroscopy and liquid chromatography-tandem mass spectrometry, respectively. Pharmacokinetic variables were determined using noncompartmental methods. Peripheral blood mononuclear cell (PBMC) DPD activity was measured using the DPD radioassay. Results: The UraBT identified 19 subjects with normal activity, 11 subjects with partial DPD deficiency, and 1 subject with profound DPD deficiency with PBMC DPD activity within the corresponding previously established ranges. UraBT breath Dihydropyrimidine dehydrogenase (EC 1.3.1.2, DPD) is the rate-limiting enzyme in uracil and 5-fluorouracil (5-FU) catabolism, converting >80% of an administered dose of 5-FU to inactive metabolites (1, 2). The initial step of catabolism is mediated by DPD converting 5-FU to 5-dihydrofluorouracil, with subsequent catabolism by dihydropyrimidinase and h-ureidopropionase enzymes to ultimately produce fluoroh-alanine, ammonia, and CO 2 . The latter final metabolic endproducts are excreted in the urine and breath (3).The pharmacogenetic syndrome of complete and partial DPD deficiency is prevalent in f0.1% and 3% to 5% of the general population, respectively (4). DPD deficiency is a significant pharmacogenetic factor in the predisposition of cancer patients to increased risk of altered 5-FU pharmacokinetics and associated toxicity. Specifically, 60% of patients presenting with severe 5-FU-related hematologic toxicity showed reduced DPD activity (5).Recent studies have investigated the predictive value of the ratio of plasma dihydrouracil area under the curve (AUC) to uracil AUC (DUUR) for the assessment of DPD activity and potential individualization of 5-FU therapy. Specifically, 5-FU dose optimization may be based on the plasma DUUR observed before 5-FU administration (6). Jiang et al. have also showed that the pre-5-FU treatment DUUR may be a good index of DPD activity (7,8).Our laboratory recently reported the rapid noninvasive phenotypic [2-13 C]uracil breath test (UraBT) for assessment of DPD activity with 96% specificity and 100% sensitivity (9). Application of the UraBT to a large population of cancer-free subjects (n = 255) showed an observed 86% sensitivity (with 12 of 14 DPD-deficient subjects identified as DPD deficient) and
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