The anti-epileptic drug Valproic Acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro

Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC

A functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production

Bone morphogenetic proteins (BMP) are firmly implicated as intra-ovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>2-fold; P<0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3) was the most heavily down-regulated gene (-43-fold) with CYP17A1 and other key transcripts involved in TC steroidogenesis including LHCGR, INHA, STAR, CYP11A1 and HSD3B1 also down-regulated. BMP6 also reduced expression of NR5A1 encoding steroidogenic factor-1 known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA and secreted protein level (75 and 94%, respectively) and elicited a 77% reduction in CYP17A1 mRNA level and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 mRNA level (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ~2-fold. The CYP17 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling

A precise extraction of the induced polarization in the 4He(e,e'p)3H reaction

We measured with unprecedented precision the induced polarization Py in 4He(e,e'p)3H at Q^2 = 0.8 (GeV/c)^2 and 1.3 (GeV/c)^2. The induced polarization is indicative of reaction-mechanism effects beyond the impulse approximation. Our results are in agreement with a relativistic distorted-wave impulse approximation calculation but are over-estimated by a calculation with strong charge-exchange effects. Our data are used to constrain the strength of the spin independent charge-exchange term in the latter calculation.Comment: submitted to Physical Review Letter

Polarization Transfer in the 4He(e,e'p)3H Reaction at Q^2 = 0.8 and 1.3 (GeV/c)^2

Proton recoil polarization was measured in the quasielastic 4He(e,e'p)3H reaction at Q^2 = 0.8 (GeV/c)^2 and 1.3 (GeV/c)^2 with unprecedented precision. The polarization-transfer coefficients are found to differ from those of the 1H(e,e' p) reaction, contradicting a relativistic distorted-wave approximation, and favoring either the inclusion of medium-modified proton form factors predicted by the quark-meson coupling model or a spin-dependent charge-exchange final-state interaction. For the first time, the polarization-transfer ratio is studied as a function of the virtuality of the proton

Low Q^2 measurements of the proton form factor ratio mupGE/GMmu_p G_E / G_M

We present an updated extraction of the proton electromagnetic form factor ratio, mu_p G_E/G_M, at low Q^2. The form factors are sensitive to the spatial distribution of the proton, and precise measurements can be used to constrain models of the proton. An improved selection of the elastic events and reduced background contributions yielded a small systematic reduction in the ratio mu_p G_E/G_M compared to the original analysis.Comment: 12 pages, 5 figures, archival paper for proton form factor extraction from Jefferson Lab "LEDEX" experimen

Hard Photodisintegration of a Proton Pair

We present a study of high energy photodisintegration of proton-pairs through the gamma + 3He -> p+p+n channel. Photon energies from 0.8 to 4.7 GeV were used in kinematics corresponding to a proton pair with high relative momentum and a neutron nearly at rest. The s-11 scaling of the cross section, as predicted by the constituent counting rule for two nucleon photodisintegration, was observed for the first time. The onset of the scaling is at a higher energy and the cross section is significantly lower than for deuteron (pn pair) photodisintegration. For photon energies below the scaling region, the scaled cross section was found to present a strong energy-dependent structure not observed in deuteron photodisintegration.Comment: 7 pages, 3 figures, for submission to Phys. Lett.

The Proton Elastic Form Factor Ratio at Low Momentum Transfer

High precision measurements of the proton elastic form factor ratio have been made at four-momentum transfers, Q^2, between 0.2 and 0.5 GeV^2. The new data, while consistent with previous results, clearly show a ratio less than unity and significant differences from the central values of several recent phenomenological fits. By combining the new form-factor ratio data with an existing cross-section measurement, one finds that in this Q^2 range the deviation from unity is primarily due to GEp being smaller than the dipole parameterization.Comment: 5 pages, 2 figure

High-Precision Branching Ratio Measurement for the Superallowed + Emitter 74Rb

A high-precision branching-ratio measurement for the superallowed β + decay of 74Rb was performed at the TRIUMF Isotope Separator and Accelerator (ISAC) radioactive ion-beam facility. The scintillating electronpositron tagging array (SCEPTAR), composed of 10 thin plastic scintillators, was used to detect the emitted β particles; the 8π spectrometer, an array of 20 Compton-suppressed HPGe detectors, was used for detecting γ rays that were emitted following Gamow-Teller and nonanalog Fermi β + decays of 74Rb; and the Pentagonal Array of Conversion Electron Spectrometers (PACES), an array of 5 Si(Li) detectors, was employed for measuring β-delayed conversion electrons. Twenty-three excited states were identified in 74Kr following 8.241(4) × 108 detected 74Rb β decays. A total of 58 γ -ray and electron transitions were placed in the decay scheme, allowing the superallowed branching ratio to be determined as B0 = 99.545(31)%. Combined with previous half-life and Q-value measurements, the superallowed branching ratio measured in this work leads to a superallowed f t value of 3082.8(65) s. Comparisons between this superallowed f t value and the world-average-corrected Ft value, as well as the nonanalog Fermi branching ratios determined in this work, provide guidance for theoretical models of the isospin-symmetry-breaking corrections in this mass region.IS