Pluripotency of spermatogonial stem cells from adult mouse testis

Embryonic germ cells as well as germline stem cells from neonatal mouse testis are pluripotent and have differentiation potential similar to embryonic stem cells, suggesting that the germline lineage may retain the ability to generate pluripotent cells. However, until now there has been no evidence for the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male. Here we show the isolation of SSCs from adult mouse testis using genetic selection, with a success rate of 27%. These isolated SSCs respond to culture conditions and acquire embryonic stem cell properties. We name these cells multipotent adult germline stem cells (maGSCs). They are able to spontaneously differentiate into derivatives of the three embryonic germ layers in vitro and generate teratomas in immunodeficient mice. When injected into an early blastocyst, SSCs contribute to the development of various organs and show germline transmission. Thus, the capacity to form multipotent cells persists in adult mouse testis. Establishment of human maGSCs from testicular biopsies may allow individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells. Furthermore, these cells may provide new opportunities to study genetic diseases in various cell lineages.     

Long-term forecasting with innovation diffusion models: The impact of replacement purchases

The model presented in this paper integrates two distinct components of the demand for durable goods: adoptions and replacements. The adoption of a new product is modeled as an innovation diffusion process, using price and population as exogenous variables. Adopters are expected to eventually replace their old units of the product, with a probability which depends on the age of the owned unit, and other random factors such as overload, style-changes etc. It is shovn that the integration of adoption and replacement demand components in our model yields quality sales forecasts, not only under conditions where detailed data on replacement sales is available, but also when the forecaster's access is limited to total sales data and educated guesses on certain elements of the replacement process.     

Antagonism of 2-Br-α-ergokryptine-methanesulfonate (CB 154) to certain endocrine actions of centrally active drugs

Zusammenfassung Bei Ratten mit drei verschiedenen Modellen pharmakologisch induzierter Pseudogravidität wird gezeigt, dass 2-Br--ergokryptin-methansulfonat (CB 154) auch die durch Pharmaka stimulierte Prolactinsekretion zu hemmen vermag.     

Influence of temperature on the sensitivity of adrenergic β-receptors

Zusammenfassung Versuche am Ileum des Kaninchens und der Trachea des Meerschweinchens mit dem Resorcinderivat Orciprenalin⁷ bei 25 bis 42°C führten zu folgenden Ergebnissen: Temperaturerhöhung verminderte am Ileum die Affinität des Orciprenalins, an der Trachea dagegen war sie ohne Einfluss⁸.     

Two novel prolactin release-inhibiting 8α-amino-ergolines

Summary Prolactin secretion inhibition and changes in striatal dopamine metabolism in rats were compared after the administration of 8a-amino-ergoline CH 29-717 and 2 derivates. CQ 32-084 was similar to but less potent than CH 29-717. while 32-085, the 1-methyl derivative, showed delayed dopaminomimetic effects.     

Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition

Tenascin-X is a large extracellular matrix protein of unknown function. Tenascin-X deficiency in humans is associated with Ehlers-Danlos syndrome, a generalized connective tissue disorder resulting from altered metabolism of the fibrillar collagens. Because TNXB is the first Ehlers-Danlos syndrome gene that does not encode a fibrillar collagen or collagen-modifying enzyme, we suggested that tenascin-X might regulate collagen synthesis or deposition. To test this hypothesis, we inactivated Tnxb in mice. Tnxb-/- mice showed progressive skin hyperextensibility, similar to individuals with Ehlers-Danlos syndrome. Biomechanical testing confirmed increased deformability and reduced tensile strength of their skin. The skin of Tnxb-/- mice was histologically normal, but its collagen content was significantly reduced. At the ultrastructural level, collagen fibrils of Tnxb-/- mice were of normal size and shape, but the density of fibrils in their skin was reduced, commensurate with the reduction in collagen content. Studies of cultured dermal fibroblasts showed that although synthesis of collagen I by Tnxb-/- and wildtype cells was similar, Tnxb-/- fibroblasts failed to deposit collagen I into cell-associated matrix. This study confirms a causative role for TNXB in human Ehlers-Danlos syndrome and suggests that tenascin-X is an essential regulator of collagen deposition by dermal fibroblasts.     

Activation of chloride channels in normal and cystic fibrosis airway epithelial cells by multifunctional calcium/calmodulin-dependent protein kinase.

Cystic fibrosis is associated with defective regulation of apical membrane chloride channels in airway epithelial cells. These channels in normal cells are activated by cyclic AMP-dependent protein kinase and protein kinase C. In cystic fibrosis these kinases fail to activate otherwise normal Cl- channels. But Cl- flux in cystic fibrosis cells, as in normal cells, can be activated by raising intracellular Ca2+ (refs 5-10). We report here whole-cell patch clamp studies of normal and cystic fibrosis-derived airway epithelial cells showing that Cl- channel activation by Ca2+ is mediated by multifunctional Ca2+/calmodulin-dependent protein kinase. We find that intracellular application of activated kinase and ATP activates a Cl- current similar to that activated by a Ca2+ ionophore, that peptide inhibitors of either the kinase or calmodulin block Ca2(+)-dependent activation of Cl- channels, and that a peptide inhibitor of protein kinase C does not block Ca2(+)-dependent activation. Ca2+/calmodulin activation of Cl- channels presents a pathway with therapeutic potential for circumventing defective regulation of Cl- channels in cystic fibrosis.     

Insights from von Willebrand disease animal models

von Willebrand disease is a genetic bleeding disorder that arises from abnormalities in von Willebrand factor, an adhesive glycoprotein involved in both primary hemostasis and coagulation. It is the most common inherited bleeding disorder in humans, and over the years several animal species have also been described as suffering from this disease whether through a spontaneous mutation (pigs, dogs) or a genetically engineered one (mouse). These different animal models are extremely useful in exploring the characteristics of von Willebrand disease and in testing new treatments. This review provides an update of the various von Willebrand disease models and the contribution that these models can make to a better understanding of human von Willebrand disease.