The rockefeller university

Previously, we demonstrated that progesterone (P(4)) promoted adult rat neural progenitor cell (rNPC) proliferation with concomitant regulation of cell-cycle gene expression via the P(4) receptor membrane component/ERK pathway. Here, we report the efficacy of seven clinically relevant progestins alone or in combination with 17 beta-estradiol (E(2)) on adult rNPC proliferation and hippocampal cell viability in vitro and in vivo. In vitro analyses indicated that P(4), norgestimate, Nestorone, norethynodrel, norethindrone, and levonorgestrel (LNG) significantly increased in rNPC proliferation, whereas norethindrone acetate was without effect, and medroxyprogesterone acetate (MPA) inhibited rNPC proliferation. Proliferative progestins in vitro were also neuroprotective. Acute in vivo exposure to P(4) and Nestorone significantly increased proliferating cell nuclear antigen and cell division cycle 2 expression and total number of hippocampal 5-bromo-2-deoxyuridine (BrdU)-positive cells, whereas LNG and MPA were without effect. Mechanistically, neurogenic progestins required activation of MAPK to promote proliferation. P(4), Nestorone, and LNG significantly increased ATP synthase subunit alpha (complex V, subunit alpha) expression, whereas MPA was without effect. In combination with E(2), P(4), Nestorone, LNG, and MPA significantly increased BrdU incorporation. However, BrdU incorporation induced by E(2) plus LNG or MPA was paralleled by a significant increase in apoptosis. A rise in Bax/Bcl-2 ratio paralleled apoptosis induced by LNG and MPA. With the exception of P(4), clinical progestins antagonized E(2)-induced rise in complex V, subunit alpha. These preclinical translational findings indicate that the neurogenic response to clinical progestins varies dramatically. Progestin impact on the regenerative capacity of the brain has clinical implications for contraceptive and hormone therapy formulations prescribed for pre- and postmenopausal women. (Endocrinology 151: 5782-5794, 2010)

Stress of social defeat in rodents is known to have a strong and long-lasting effect on brain physiology and behavior which bears similarities with certain human stress related psychopathologies Previous experiments in this lab showed that social defeat stress suppresses testosterone secretion and causes a lasting desensitization of the serotonergic 5-HT(1A) receptors Testosterone supplementation in socially stressed tree shrews prevented a decrease in hippocampal 5-HT(1A) receptor binding These receptors are hypothesized to play an important role in neurogenesis in this brain structure We designed the present experiment to test if social defeat reduces hippocampal cell proliferation and neurogenesis in rats and if testosterone supplementation can prevent this reduction The results indicate that repeated social defeat stress on 5 successive days Induces a significant drop in plasma testosterone levels in male rats and suppresses hippocampal cell proliferation 24 h and 3 weeks after the end of the stress period Testosterone supplementation prevented the social stress induced drop in plasma testosterone levels The hormone supplementation also reduced the negative effect of stress on hippocampal BrdU labeling at 3 weeks post-defeat This effect was however rather weak and was caused by the tendency of the hormone in itself to suppress proliferation and the failure to fully recover the proliferation rate Survival of dentate gyrus cells that either proliferated prior to the stress period or 24 h after the last defeat was not affected by the social defeats Thus the stress-induced lowering of hippocampal cell proliferation is not likely to be caused by transient inhibition of testosterone secretion during social stress (C) 2010 Elsevier Inc All rights reserved

The incidence of hepatitis C virus (HCV) genotype 4 infection in Egypt provides a unique opportunity to study the innate immune response to symptomatic acute HCV infection. We investigated whether plasmacytoid dendritic cells (pDCs) are activated as a result of HCV infection. We demonstrate that, even during symptomatic acute infection, circulating pDCs maintained a similar precursor frequency and resting phenotype, compared with pDCs in healthy individuals. Moreover, stimulation with a Toll-like receptor 9 agonist resulted in an intact inflammatory response. These data support the growing consensus that pDCs are not directly activated by HCV and therefore are viable targets for immunotherapy throughout HCV infection.

The first LHC pp collisions at centre-of-mass energies of 0.9 and 2.36 TeV were recorded by the CMS detector in December 2009. The trajectories of charged particles produced in the collisions were reconstructed using the all-silicon Tracker and their momenta were measured in the 3.8 T axial magnetic field. Results from the Tracker commissioning are presented including studies of timing, efficiency, signal-to-noise, resolution, and ionization energy. Reconstructed tracks are used to benchmark the performance in terms of track and vertex resolutions, reconstruction of decays, estimation of ionization energy loss, as well as identification of photon conversions, nuclear interactions, and heavy-flavour decays.

MicroRNAs (miRs) are known to repress target genes at posttranscriptional level and play important roles in the maturation of cells. However, the expression profiles of miRs during follicular maturation have not been fully elucidated. This study was designed to investigate the expression profiles of miRs in murine follicles according to human chorionic gonadotropin (hCG) treatment and vitamin C status during in vitro culture. Ovaries were removed from the 12-day-old wild-type and vitamin C-deficient (L-gulono-gammalactone oxidase knockout, Gulo-/-) C57BL6 mice. Preantral follicles were isolated and cultured in 20 mu L droplets of culture media supplemented with follicle-stimulating hormone and luteinizing hormone (FSH + LH). After their full maturation, follicles were divided into 2 groups: with and without hCG treatment. Real-time polymerase chain reaction (PCR) was performed using oocytes and granulosa cells (G-cells) to evaluate the miRs known to be expressed mainly in the mouse ovary. After the addition of hCG, miR profiles showed divergent changes between oocytes and G-cells. These profiles significantly differed from those of hCG(-) group. Compared to wild type, Gulo-/- mice showed altered miR profiles in matured oocytes and G-cells. Conclusively, hCG supplementation and vitamin C status alter the miR expression profiles in oocytes and G-cells during in vitro growth of murine follicles.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease composed of at least two distinct subtypes: germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. These phenotypic subtypes segregate with largely unique genetic lesions, suggesting the involvement of different pathogenetic mechanisms. In this report we show that the BLIMP1/PRDM1 gene is inactivated by multiple mechanisms, including homozygous deletions, truncating or missense mutations, and transcriptional repression by constitutively active BCL6, in similar to 53% of ABC-DLBCL. In vivo, conditional deletion of Blimp1 in mouse B cells promotes the development of lymphoproliferative disorders recapitulating critical features of the human ABC-DLBCL. These results demonstrate that BLIMP1 is a bona fide tumor-suppressor gene whose loss contributes to lymphomagenesis by blocking plasma cell differentiation.

FANCJ/BRIP1 encodes a helicase that has been implicated in the maintenance of genomic stability. Here, to better understand FANCJ function in DNA damage responses, we have examined the regulation of its cellular localization. FANCJ nuclear foci assemble spontaneously during S phase and are induced by various stresses. FANCJ foci colocalize with the replication fork following treatment with hydroxyurea, but not spontaneously. Using FANCJ mutants, we find that FANCJ helicase activity and the capacity to bind BRCA1 are both involved in FANCJ recruitment. Given similarities to the recruitment of another Fanconi anemia protein, FANCD2, we tested for colocalization of FANCJ and FANCD2. Importantly, these proteins show substantial colocalization, and FANCJ promotes the assembly of FANCD2 nuclear foci. This process is linked to the proper localization of FANCJ itself since both FANCJ and FANCD2 nuclear foci are compromised by FANCJ mutants that abrogate its helicase activity or interaction with BRCA1. Our results suggest that FANCJ is recruited in response to replication stress and that FANCJ/BRIP1 may serve to link FANCD2 to BRCA1.

Compounds acting on delta opioid receptors (DOR) modulate anxiety-like behaviors, yet the site of action underlying this effect is unknown. DOR mRNA and protein are expressed in the central nucleus of the amygdala, a region that plays an important role in processing fear, stress, and anxiety. We hypothesized that this brain region may contribute to the modulation of anxiety by DOR drugs. The present study investigated the role of DOR in the central amygdala in anxiety-like behaviors. The selective DOR agonist [D-Pen 2,5]-enkephalin (DPDPE) or antagonist naltrindole was bilaterally microinjected into the central nucleus of the amygdala of adult male Sprague Dawley rats and anxiety-like behaviors were assessed using the elevated plus maze. The effects of DOR agonists on heightened anxiety produced by stress were also investigated. Rats injected with DPDPE into the central nucleus of the amygdala demonstrated less anxiety-like behavior, as evidenced by significantly greater number of open-arm entries and time spent in the open arms than controls. Naltrindole administered alone did not affect the duration or number of entries onto the open arms; however, naltrindole pre-treatment blocked the anxiolytic effects produced by DPDPE. Systemic administration of the selective DOR agonist, SNC80, or microinjection of DPDPE into the central amygdala prior to a swim stress blocked the anxiogenic effect produced by the swim stress. These findings provide direct evidence that activation of DOR in the central amygdala reduces anxiety-like behavior and suggest that DOR in this area are important for regulating anxious states.

Two recent theoretical models, Bai et al (2004, 2007) and Tadigotla et al (2006), formulated thermodynamic explanations of sequence-dependent transcription pausing by RNA polymerase (RNAP). The two models differ in some basic assumptions and therefore make different yet overlapping predictions for pause locations, and different predictions on pause kinetics and mechanisms. Here we present a comprehensive comparison of the two models. We show that while they have comparable predictive power of pause locations at low NTP concentrations, the Bai et al model is more accurate than Tadigotla et al at higher NTP concentrations. The pausing kinetics predicted by Bai et al is also consistent with time-course transcription reactions, while Tadigotla et al is unsuited for this type of kinetic prediction. More importantly, the two models in general predict different pausing mechanisms even for the same pausing sites, and the Bai et al model provides an explanation more consistent with recent single molecule observations.