Gilead Sciences.

Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.

Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SPHK), acts both by intracellular and extracellular modes. We evaluated the role of SPHK1 and S1P in osteoclastogenesis using bone marrow-derived macrophage (BMM) single and BMM/osteoblast coculture systems. In BMM single cultures, the osteoclastogenic factor receptor activator of NF-kappaB ligand (RANKL) upregulated SPHK1 and increased S1P production and secretion. SPHK1 siRNA enhanced and SPHK1 overexpression attenuated osteoclastogenesis via modulation of p38 and ERK activities, and NFATc1 and c-Fos levels. Extracellular S1P had no effect in these cultures. These data suggest that intracellular S1P produced in response to RANKL forms a negative feedback loop in BMM single cultures. In contrast, S1P addition to BMM/osteoblast cocultures greatly increased osteoclastogenesis by increasing RANKL in osteoblasts via cyclooxygenase-2 and PGE(2) regulation. S1P also stimulated osteoblast migration and survival. The RANKL elevation and chemotactic effects were also observed with T cells. These results indicate that secreted S1P attracts and acts on osteoblasts and T cells to augment osteoclastogenesis. Taken together, S1P plays an important role in osteoclastogenesis regulation and in communication between osteoclasts and osteoblasts or T cells.

We discovered that La-doped BaSnO3 with the perovskite structure has an unprecedentedly high mobility at room temperature while retaining its optical transparency. In single crystals, the mobility reached 320 cm^2(Vs)^-1 at a doping level of 8x10^19 cm^-3, constituting the highest value among wide-band-gap semiconductors. In epitaxial films, the maximum mobility was 70 cm^2(Vs)^-1 at a doping level of 4.4x10^20 cm^-3. We also show that resistance of (Ba,La)SnO3 changes little even after a thermal cycle to 530 Deg. C in air, pointing to an unusual stability of oxygen atoms and great potential for realizing transparent high-frequency, high-power functional devices.Comment: 15 pages, 3 figure

Molecular gradients play an important role in diverse physiological and pathological phenomena such as immune response, wound healing, development and cancer metastasis. In the past 10 years, engineering tools have been increasingly used to develop experimental platforms that capture important aspects of cellular microenvironments to allow quantitative and reproducible characterization of cellular response to gradients. This review discusses the emergence of microfluidics-based gradient generators and their applications in enhancing our understanding of fundamental biological processes such as chemotaxis and morphogenesis. The principles and applications of microfluidic gradient generation in both 2D and 3D cellular microenvironments are discussed with emphasis on approaches to manipulate spatial and temporal distribution of signaling molecules.