To elucidate the hidden dynamics of extracellular-signal-regulated kinase (ERK) signalling networks, we developed a simulation model of ERK signalling networks by constraining in silico dynamics based on in vivo dynamics in PC12 cells. We predicted and validated that transient ERK activation depends on rapid increases of epidermal growth factor and nerve growth factor (NGF) but not on their final concentrations, whereas sustained ERK activation depends on the final concentration of NGF but not on the temporal rate of increase. These ERK dynamics depend on Ras and Rap1 dynamics, the inactivation processes of which are growth-factor-dependent and -independent, respectively. Therefore, the Ras and Rap1 systems capture the temporal rate and concentration of growth factors, and encode these distinct physical properties into transient and sustained ERK activation, respectively.

SCAD is not a rare cause for ACS, especially in females without classical coronary risk factors.

Atorvastatin therapy at 20 mg/day provided a greater increase in fibrous cap thickness in coronary plaques compared with 5 mg/day of atorvastatin. The increase of fibrous cap was associated with the decrease in serum atherogenic lipoproteins and inflammatory biomarkers during atorvastatin therapy. (Effect of Atorvastatin Therapy on Fibrous Cap Thickness in Coronary Atherosclerotic Plaque as Assessed by Optical Coherence Tomography: The EASY-FIT Study; NCT00700037).

Meiosis is an indispensable process of sexual reproduction. However, detailed information on the regulatory mechanisms that initiate meiosis is not available. Progestins are important steroids regulating final maturation in male and female vertebrates. In male teleosts, it is known that progestin induces spermiation and sperm maturation. However, a role for progestin in early spermatogenesis or meiosis has not yet been described. In this study, we examined the functions of progestin on the initiation of meiosis in male Japanese eel. A natural progestin in teleost fish 17␣,20␤-dihydroxy-4-pregnen-3-one (DHP) and its receptors were present in the testis at an early stage of spermatogenesis. By using an eel testicular culture system, DHP was shown to induce DNA replication in spermatogonia. Although 11-ketotestosterone, a known initiator of spermatogenesis, also stimulated DNA synthesis in spermatogonia, antibodies against DHP prevented DNA replication when added during the period in which meiosis was initiated. DHP treatment also induced the expression of meiosis-specific markers, such as DmcI and Spo11. Furthermore, Spo11 expression and synaptonemal complexes, specific features of the meiotic prophase, were detected in testicular fragments cultured with DHP in some germ cells that showed morphological characteristics of undifferentiated spermatogonia. We conclude that DHP, a progestin, is an essential factor for the initiation of meiosis.in vitro culture ͉ Japanese eel ͉ spermatogenesis ͉ androgen ͉ Spo11

In fish spermatogenesis, the main action of progestins is generally regarded as the induction of sperm maturation. Our previous in vitro study demonstrated that a progestin, 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP), induced the initiation of meiosis in spermatogenesis in the Japanese eel (Anguilla japonica). In the present study, to elucidate the molecular mechanisms underlying the action of DHP, we attempted to clone cDNAs encoding genes whose expression was induced by DHP in eel testis, using cDNA subtraction. One of the cDNAs we isolated encodes eel 11beta-hydroxysteroid dehydrogenase short form (e11beta-HSDsf), and Northern blot and RT-PCR analysis showed that transcripts of e11beta-HSDsf in testis were induced by DHP. The recombinant e11beta-HSDsf had 11beta-dehydrogenase activity, metabolizing cortisol to cortisone, and 11beta-hydroxytestosterone to 11-ketotestosterone (11-KT). In vitro experiments revealed that eel immature testis had 11beta-dehydrogenase activity, and DHP treatment enhanced the activity. To understand the role of 11beta-HSD in spermatogenesis, we examined the direct effects of cortisol on eel spermatogenesis using an organ culture system. Cortisol induced DNA replication in spermatogonia and enhanced the spermatogonial proliferation induced by 11-KT. However, excess cortisol inhibited proliferation. In addition, 11-KT production was induced in testicular fragments incubated with cortisol. These results suggest that optimal levels of cortisol induced spermatogonial mitosis by increasing 11-KT production. Furthermore, two possible roles of DHP on spermatogenesis, via the up-regulation of 11beta-HSD expression, are suggested: positive feedback control of 11-KT production and the modulation of cortisol levels to protect testes from excess circulating cortisol.