The segment 708 TGDGVNDSPALKK 720 in the ␣-subunit P domain of Na,K-ATPase is highly conserved among cation pumps, but little is known about its role in binding of Mg 2؉ 710 3 Ala mutation also interferes with transmission of structural changes to the ouabain site and reduces the affinity for binding of Tl ؉ 2-to 3-fold, suggesting a role in transmission of K ؉ stimulation of phospho-enzyme hydrolysis from transmembrane segment 5 to the P domain.

These three case reports describe the long-term duration of function of ovarian cortical tissue grafts among patients in a university fertility preservation programme in Europe and in a private practice programme in the USA. One woman underwent sterilizing cancer treatment and had frozen ovarian tissue transplanted, and two women underwent fresh ovarian tissue transplants. The function of ovarian cortical strips has continued for more than 7 years in these three women, with the birth of eight healthy babies following a single graft per patient. In addition to these three cases, transplantation (repeatedly in some cases) of cryopreserved ovarian tissue has restored reproductive function to all other women in the study centres' programmes for some years. The sustained longevity of function of the transplanted tissue suggests that it may also be possible to postpone the normal time of menopause or to alleviate its symptoms.

Neurotrophic factors are secreted proteins responsible for migration, growth and survival of neurons during development, and for maintenance and plasticity of adult neurons. Here we present a novel secreted protein named Cometin which together with Meteorin defines a new evolutionary conserved protein family. During early mouse development, Cometin is found exclusively in the floor plate and from E13.5 also in dorsal root ganglions and inner ear but apparently not in the adult nervous system. In vitro, Cometin promotes neurite outgrowth from dorsal root ganglion cells which can be blocked by inhibition of the Janus or MEK kinases. In this assay, additive effects of Cometin and Meteorin are observed indicating separate receptors. Furthermore, Cometin supports migration of neuroblasts from subventricular zone explants to the same extend as stromal cell derived factor 1a. Given the neurotrophic properties in vitro, combined with the restricted inner ear expression during development, we further investigated Cometin in relation to deafness. In neomycin deafened guinea pigs, two weeks intracochlear infusion of recombinant Cometin supports spiral ganglion neuron survival and function. In contrast to the control group receiving artificial perilymph, Cometin treated animals retain normal electrically-evoked brainstem response which is maintained several weeks after treatment cessation. Neuroprotection is also evident from stereological analysis of the spiral ganglion. Altogether, these studies show that Cometin is a potent new neurotrophic factor with therapeutic potential.

Neural stem cells constitute a promising source of cells for transplantation in Parkinson’s disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti‐apoptotic protein Bcl‐xL and oxygen tension on dopaminergic differentiation and survival of a human ventral mesencephalic stem cell line (hVM1). hVM1 cells and a Bcl‐xL over‐expressing subline (hVMbcl‐xL) were differentiated by sequential treatment with fibroblast growth factor‐8, forskolin, sonic hedgehog, and glial cell line‐derived neurotrophic factor. After 10 days at 20% oxygen, hVMbcl‐xL cultures contained proportionally more tyrosine hydroxylase(TH)‐positive cells than hVM1 control cultures. This difference was significantly potentiated from 11 ± 0.8% to 17.2 ± 0.2% of total cells when the oxygen tension was lowered to 3%. Immunocytochemistry and Q‐PCR‐analysis revealed expression of several dopaminergic markers besides of TH just as dopamine was detected in the culture medium by HPLC analysis. Although Bcl‐xL‐over‐expression reduced cell death in the cultures, it did not alter the relative content of GABAergic, neurons, while the content of astroglial cells was reduced in hVMbcl‐xL cell cultures compared with control. We conclude that Bcl‐xL and lowered oxygen tension act in concert to enhance dopaminergic differentiation and survival of human neural stem cells.

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