New advances in the treatment of infertility in women with ovarian failure

Ovarian failure is heterogeneous in etiology and may occur at various points in a woman's life. As such, it may interfere with fertility. Clinical presentation ranges from complete cessation of menses to oligomenorrhea to the continuation of menses with elevated gonadotropins. Various therapies have been used in an attempt to induce fertility, including sex steroids and gonadotropin-releasing hormone agonists to suppress circulating gonadotropin alone or in combination with estrogen or gonadotropin-releasing hormone agonists to induce ovulation. Corticosteroids are also used to overcome autoimmunity. Randomized therapeutic trials are rare and fail to demonstrate any significant improvement in ovulation and pregnancy rates. Donor oocytes have demonstrated high success rates and have proven to be useful in patients with both premature ovarian failure and natural menopause. Pregnancies have been initiated and maintained in women through 60 years of age. Thus, for those accepting of the technique, oocyte donation appears to be the treatment of choice for hypergonadotropic hypogonadism.     

TGF-beta mediated G1 arrest in a human melanoma cell line lacking p15INK4B: evidence for cooperation between p21Cip1/WAF1 and p27Kip1

We have studied TGF-beta mediated G1 arrest in WM35, an early stage human melanoma cell line. These cells have lost p15INK4B expression through loss of one chromosome 9 and rearrangement of the other. In asynchronously growing WM35, TGF-beta caused reductions in cyclin D1, cyclin A and cdk4 proteins and their associated kinase activities and an increase in both p21Cip1/WAF1 and p27Kip1. These findings were confirmed in cells released from quiescence in the presence of TGF-beta, in which TGF-beta inhibited or delayed the reduction in the cdk inhibitors that normally occurs in late G1. In contrast to observations in other cell types, there was an increased association of both p21Cip1/WAF1 and p27Kip1 with cyclin D1/cdk4 and with cyclin E/cdk2 during TGF-beta mediated arrest of asynchronously growing cells. Upregulation of p21Cip1/WAF1 preceded that of p27Kip1. Furthermore, p21Cip1/WAF1 and p27Kip1 were not present in the same cdk complexes but bound distinct populations of target cdk molecules. Both p21Cip1/WAF1 and p27Kip1 immunoprecipitates from asynchronously growing cells contained active kinase complexes. These KIP-associated kinase activities were reduced in TGF-beta arrested cells. It has been proposed that in TGF-beta arrested epithelial cells, up-regulation of p15INK4B and of p15INK4B binding to cdk4 serves to destabilize the association of p27Kip1 with cyclin D1/cdk4, promoting p27Kip1 binding and inhibition of cyclin E/cdk2. Our findings demonstrate that this is not a universal mechanism of G1 arrest by TGF-beta. In TGF-beta arrested WM35, which lack p15INK4B, the increased p21Cip1/WAF1 may serve a similar function to that of p15INK4B: initiating kinase inhibition and providing an additional mechanism to supplement the effect of p27Kip1 on G1 cyclin/cdks.     

Structure effects of double D-amino acid replacements: a nuclear magnetic resonance and circular dichroism study using amphipathic model helices

D-Amino acid replacements and the determination of resulting structural changes are a useful tool to recognize amphipathic helices in biologically active peptides such as neuropeptide Y and corticotropin-releasing factor. In this paper the secondary structures of one amphipathic alpha-helical peptide and its double D-amino acid analog have been determined by means of 1H NMR and CD spectroscopies under equivalent conditions. The chemical shifts (NH and C alpha H) and the analysis of nuclear Overhauser effects show a split of the continuous helix for the all-L peptide into two helices at the position of double D-amino acid replacement. Hydrogen exchange rates correlate with water accessibilities in the hydrophobic/hydrophilic face and confirm the amphipathic helical structure in the all-L peptide as well as in its double D-amino acid analog. A significantly accelerated hydrogen isotope exchange rate is observed for the D-Ala9 backbone proton, implying an increased flexibility at that position. These results show that the incorporation of an adjacent pair of D-amino acids only causes a local change in structure and flexibility, which makes the double D replacement interesting as a tool for specific helix-disturbing modifications to search for helical conformations in biologically active peptides.     

Rethinking infant knowledge: toward an adaptive process account of successes and failures in object permanence tasks

Infants seem sensitive to hidden objects in habituation tasks at 3.5 months but fail to retrieve hidden objects until 8 months. The authors first consider principle-based accounts of these successes and failures, in which early successes imply knowledge of principles and failures are attributed to ancillary deficits. One account is that infants younger than 8 months have the object permanence principle but lack means-ends abilities. To test this, 7-month-olds were trained on means-ends behaviors and were tested on retrieval of visible and occluded toys. Means-ends demands were the same, yet infants made more toy-guided retrievals in the visible case. The authors offer an adaptive process account in which knowledge is graded and embedded in specific behavioral processes. Simulation models that learn gradually to represent occluded objects show how this approach can account for success and failure in object permanence tasks without assuming principles and ancillary deficits.