Activin Limits Progenitor Capability by Promoting Epithelial Cell Differentiation in the Mammary Gland

Transforming growth factor beta (TGF-beta) and activin utilize common signaling pathways, via smad2/3 and smad4, to mediate tumor suppression by effecting cell cycle arrest and apoptosis. Differences in temporal expression patterns suggest that each cytokine has specific roles in mammary gland development. Activin is expressed during pregnancy and lactation and is required for branching and lactogenesis, implying a role in mammary gland maturation. In contrast, TGF-beta is expressed during involution during mammary gland regression and functions to re-organize the mammary epithelial content to the non-lactating state. Previously, we found that TGF-beta and activin do share common signaling pathways allowing both cytokines to restrict the growth of mammary epithelial cells. However, extended exposure to TGF-beta (5ng/ml; 14 days) causes epithelial to mesencymal transition (EMT). The TGF-beta-treated cells were de-differentiated with loss of both luminal and basal markers. Activin treatment (50ng/ml; 14 days) did not activate EMT. Rather, activin promotes luminal epithelial differentiation with increased expression of prolactin receptor and luminal keratins. Therefore, to test the hypothesis that activin-treatment promotes luminal differentiation and decreases the proportion of progenitor cells in the epithelial population, we compared mammosphere forming capability in vitro and performed limiting dilution experiments in vivo by transplanting 50,000 or 500,000 pre-treated cells into cleared mouse mammary fat pads. The mammosphere assay showed that secondary mammospheres were significantly decreased in the activin-treated cells compared to both the control and TGF-beta treated cells. Tumor incidence between activin-treated and control cells were similar for transplants of 50,000 cells, but tumor incidence was significantly greater in TGF-beta-treated transplants. However, the activin-treated cells had poor outgrowth potential at both 50,000 and 500,000 cells relative to control. We conclude that activin may have the potential to reduce the stem cell population by promoting epithelial cell differentiation

Validation of the Wiedemann-Franz Law in solid and molten tungsten above 2000 K through thermal conductivity measurements via steady state temperature differential radiometry

We measure the thermal conductivity of solid and molten tungsten using Steady State Temperature Differential Radiometry. We demonstrate that the thermal conductivity can be well described by application of Wiedemann-Franz Law to electrical resistivity data, thus suggesting the validity of Wiedemann-Franz Law to capture the electronic thermal conductivity of metals in their molten phase. We further support this conclusion using ab initio molecular dynamics simulations with a machine-learned potential. Our results show that at these high temperatures, the vibrational contribution to thermal conductivity is negligible compared to the electronic component

Persistent mullerian duct syndrome in a patient with bilateral cryptorchid testes with seminoma

Persistent mullerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism in which mullerian duct derivatives are present in an otherwise normally differentiated 46 XY male. We report a case of a 33-year-old male with PMDS operated for postchemotherapy seminoma. A diagnosis of PMDS was made on subsequent histopathological evaluation

Robust reprogramming of Ataxia-Telangiectasia patient and carrier erythroid cells to induced pluripotent stem cells

Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases. Previous studies revealed low reprogramming efficiency from A-T and carrier fibroblasts, a barrier to iPS cell-based modeling and regeneration. Here, we tested the feasibility of employing circulating erythroid cells, a compartment no or minimally affected in A-T, for the generation of A-T and carrier iPS cells. Our results indicate that episomal expression of Yamanaka factors plus BCL-xL in erythroid cells results in highly efficient iPS cell production in feeder-free, xeno-free conditions. Moreover, A-T iPS cells generated with this protocol maintain long-term replicative potential, stable karyotypes, re-elongated telomeres and capability to differentiate along the neural lineage in vitro and to form teratomas in vivo. Finally, we find that haploinsufficiency for ATM does not limit reprogramming from human erythroid cells or in vivo teratoma formation in the mouse

Integration-free erythroblast-derived human induced pluripotent stem cells (iPSCs) from an individual with Ataxia-Telangiectasia (A-T)

Peripheral blood was obtained from a 12-year old male carrying bialleleic inactivating mutations at the ATM locus, causing Ataxia-Telangiectasia (A-T). Blood erythroid cells were briefly expanded in vitro and induced pluripotent stem cells (iPSCs) were generated via transfection with episomal vectors carrying hOCT4, hSOX2, hKLF4, hMYC and hBCL2L1. SF-003 iPSCs were free of genomically integrated reprogramming genes, had the specific compound heterozygous mutations, stable karyotype, expressed pluripotency markers and formed teratomas in immunodeficient (NOD scid gamma; NGS) mice. The SF-003 iPSC line may be a useful resource for in vitro modeling of A-T