The oxytocin receptor (OXTR) and its ligand, oxytocin (OXT), regulate reproductive physiology (i.e., parturition and lactation) and sociosexual behaviors. To define the essential functions of OXTR, we generated mice with a null mutation in the Oxtr gene (Oxtr ؊/؊ ) and compared them with OXT-deficient (Oxt ؊/؊ ) mice. Oxtr ؊/؊ mice were viable and had no obvious deficits in fertility or reproductive behavior. Oxtr ؊/؊ dams exhibited normal parturition but demonstrated defects in lactation and maternal nurturing. Infant Oxtr ؊/؊ males emitted fewer ultrasonic vocalizations than wild-type littermates in response to social isolation. Adult Oxtr ؊/؊ males also showed deficits in social discrimination and elevated aggressive behavior. Ligand Oxt ؊/؊ males from Oxt ؊/؊ dams, but not from Oxt ؉/؊ dams, showed similar high levels of aggression. These data suggest a developmental role for the OXT͞OXTR system in shaping adult aggressive behavior. Our studies demonstrate that OXTR plays a critical role in regulating several aspects of social behavior and may have important implications for developmental psychiatric disorders characterized by deficits in social behavior.lactation ͉ maternal behavior ͉ ultrasonic vocalization ͉ social discrimination ͉ aggressive behavior

Recent reports have linked the expression of specific microRNAs (miRNAs) with tumorigenesis and metastasis. Here, we show that microRNA (miR)-16, which is expressed at lower levels in prostate cancer cells, affects the proliferation of human prostate cancer cell lines both in vitro and in vivo. Transient transfection with synthetic miR-16 significantly reduced cell proliferation of 22Rv1, Du145, PPC-1, and PC-3M-luc cells. A prostate cancer xenograft model revealed that atelocollagen could efficiently deliver synthetic miR-16 to tumor cells on bone tissues in mice when injected into tail veins. In the therapeutic bone metastasis model, injection of miR-16 with atelocollagen via tail vein significantly inhibited the growth of prostate tumors in bone. Cell model studies indicate that miR-16 likely suppresses prostate tumor growth by regulating the expression of genes such as CDK1 and CDK2 associated with cell-cycle control and cellular proliferation. There is a trend toward lower miR-16 expression in human prostate tumors versus normal prostate tissues. Thus, this study indicates the therapeutic potential of miRNA in an animal model of cancer metastasis with systemic miRNA injection and suggest that systemic delivery of miR-16 could be used to treat patients with advanced prostate cancer.

␣ (IL-1R␣), IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein 1, nerve growth factor, and hepatocyte growth factor in a volume higher than both BMMSCs and NHDFs. Thus, our findings suggest that ATMSCs may account for their broad therapeutic efficacy in animal models of liver diseases and in the clinical settings for liver disease treatment. STEM CELLS 2008;26: 2705-2712 Disclosure of potential conflicts of interest is found at the end of this article.

A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and whether such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules, Y-27632, A-83-01, and CHIR99021, can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Thus, our study advances the goals of liver regenerative medicine.

At present, genetically modified rats have not been generated from ES cells because stable ES cells and a suitable injection method are not available. To monitor the pluripotency of rat ES cells, we generated Oct4-Venus transgenic (Tg) rats via a conventional method, in which Venus is expressed by the Oct4 promoter/enhancer. This monitoring system enabled us to define a significant condition of culture to establish authentic rat ES cells based on a combination of 20% FBS and cell signaling inhibitors for Rhoassociated kinase, mitogen-activated protein kinase, TGF-β, and glycogen synthase kinase-3. The rat ES cells expressed ES cell markers such as Oct4, Nanog, Sox2, and Rex1 and retained a normal karyotype. Embryoid bodies and teratomas were also produced from the rat ES cells. All six ES cell lines derived from three different rat strains successfully achieved germline transmission, which strongly depended on the presence of the inhibitors during the injection process. Most importantly, high-quality Tg rats possessing a correct transgene expression pattern were successfully generated via the selection of gene-manipulated ES cell clones through germline transmission. Our rat ES cells should be sufficiently able to receive gene targeting as well as Tg manipulation, thus providing valuable animal models for the study of human diseases.genetic engineering | rat | embryonic stem cells T he laboratory rat was the earliest mammalian species domesticated for scientific research and has been used as an animal model in physiology, toxicology, nutrition, behavior, immunology, and neoplasia for over 150 y (1). Despite this history, rats lag far behind mice in functional genetic studies and the generation of knockout animal models reflecting human diseases because of the absence of germline-competent rat ES cells, which are vital in a reverse genetics approach (2, 3). Recently, gene-targeting rats were created by the zinc finger nuclease strategy (4). However, the system is not available for most researchers because a special technique is required to make algorithm-based sequence-specific DNA nucleases. Thus, establishment of rat ES cells has been desired to produce gene-targeting rats, such as mutant mice, routinely.Although we established rat ES cell lines with chimeric contribution, none could complete germline transmission (5). Soon after our report, other groups succeeded in establishing rat ES cells with germline transmission by using 2i, mitogen-activated protein kinase (MEK) inhibitor PD0325901, and glycogen synthase kinase-3 (GSK3) inhibitor CHIR99021 (6, 7). The 2i is widely used in the establishment of ES cells or induced pluripotent stem (iPS) cells in mice (8, 9), rats (6, 7, 10), and humans (10). Thus, the inhibition of MEK and GSK3 has been thought to maintain a ground state of pluripotency in various species. Rat iPS cells with chimeric contribution were established by using an inhibitor of type 1 TGF-β receptor Alk5 (A-83-01) with the 2i, although germline transmission was not accomplished (10). Furthermore...

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Abstract-This paper proposes a new method for online secondary path modeling in active noise control systems. The existing methods for active noise control systems with online secondary path modeling consist of three adaptive filters. The main feature of the proposed method is that it uses only two adaptive filters. In the proposed method, the modified-FxLMS (MFxLMS) algorithm is used in adapting the noise control filter and a new variable step size (VSS) least mean square (LMS) algorithm is proposed for adaptation of the secondary path modeling filter. This VSS LMS algorithm is different from the normalized-LMS (NLMS) algorithm, where the step size is varied in accordance with the power of the reference signal. Here, on the other hand, the step size is varied in accordance with the power of the disturbance signal in the desired response of the modeling filter. The basic idea of the proposed VSS algorithm stems from the fact that the disturbance signal in the desired response of the modeling filter is decreasing in nature, (ideally) converging to zero. Hence, a small step size is used initially and later its value is increased accordingly. The disturbance signal, however, is not available directly, and we propose an indirect method to track its variations. Computer simulations show that the proposed method gives better performance than the existing methods. This improved performance is achieved at the cost of a slightly increased computational complexity.Index Terms-Active noise control, FxLMS algorithm, modified FxLMS algorithm, online secondary path modeling, variable step size least mean square (VSS LMS) algorithm.

The cells of Candida albicans NIH A-207 strain (A-strain) cultivated in YSLM at high temperatures (37 and 4O'C) did not undergo agglutination with the factor sera 4, 5, and 6 in a commercially available factor serum kit, 'Candida Check', and formed a grape-like shape. The mannans isolated from the cells had lost their reactivity against the factor sera in ELISA. It was also revealed by 'H NMR analysis that the maxmans contained neither a phosphate group nor ap-1,2-linked mannopyranose unit, although these mannans increased the non-reducing terminal a-1,3-linked mannopyranose unit. The cells and the mannans prepared by cultivation at such high temperatures followed by 27°C in the same medium entirely recovered the reactivity with the factor sera.