Telemediations

Postprin

Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor α and Role of the Hypothalamic-Pituitary-Adrenal Axis*

A previous study identified the peroxisome proliferator-activated receptor α (PPARα) activation biomarkers 21-steroid carboxylic acids 11β-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11β,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA). In the present study, the molecular mechanism and the metabolic pathway of their production were determined. The PPARα-specific time-dependent increases in HDOPA and 20α-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPARα induced hepatic FGF21, which caused increased neuropeptide Y and agouti-related protein mRNAs in the hypothalamus, stimulation of the agouti-related protein/neuropeptide Y neurons, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased adrenal cortex hyperplasia and corticosterone production, revealing a link between PPARα and the HPA axis in controlling energy homeostasis and immune regulation. Corticosterone was demonstrated as the precursor of 21-carboxylic acids both in vivo and in vitro. Under PPARα activation, the classic reductive metabolic pathway of corticosterone was suppressed, whereas an alternative oxidative pathway was uncovered that leads to the sequential oxidation on carbon 21 resulting in HDOPA. The latter was then reduced to the end product 20α-DHOPA. Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPARα resulted in the induction of Aldh3a2 and Akr1c18, both of which were confirmed as target genes through introduction of promoter luciferase reporter constructs into mouse livers in vivo. This study underscores the power of mass spectrometry-based metabolomics combined with genomic and physiologic analyses in identifying downstream metabolic biomarkers and the corresponding upstream molecular mechanisms

Workshop on Field Inspection and Rehabilitation of Traffic Control Devices - Proceedings

DTFH61-69-C-00058The Federal Highway Administration (FHWA) has begun a number of initiatives to improve signing on the Nation's roadways. These include workshops to obtain input from experts across the country, a review of each State's highway sign replacement and refurbishing program, and a training course. This report documents the proceedings of the workshops, one held in the Western United States and one in the Eastern United States. The workshops opened with a plenary session on Issues, Needs, and the FHWA Research Program, followed by a plenary session on Development of Minimum Requirements. The program continued with a panel discussion on Performance Standard Criteria, followed by a plenary session on Materials Selection. Breakout sessions on freeway signing, non-freeway signing, and motorist services and tourist-oriented signing completed the first day of the workshops. The second day opened with reports of the breakout sessions and continued with a plenary session on Field Assessment Techniques. A plenary session on Maintenance Procedures and Programs followed. The second day ended with breakout sessions on sign replacement methods, using contracting versus in-house and prison industries, and traffic control during sign replacement. The third day opened with reports on the previous day's breakout sessions, followed by a plenary session on Improved Inventory Techniques. The workshops closed with a look to the future plenary session. This report details the remarks made by the panelists and the comments and concerns of the participants on each of these issues