No abstract

The results obtained suggest that the changes of amount of RANKL and OPG may be involved in bone resorption as a response to compression force.

The existence of localized knowledge spillovers found by Jaffe, Trajtenberg and Henderson (1993) has recently been challenged by Thompson and Fox-Kean (2005). To settle this debate, we develop a new approach by incorporating their concepts of control patents into the distance-based test of localization (Duranton and Overman, 2005).Using microgeographic data, we identify localization distance for each technology class while allowing for cross-boundary spillovers, unlike the existing literature where localization is detected at the state or metropolitan statistical area level. We find solid evidence supporting localized knowledge spillovers even when finer controls are used. We further relax the commonly made assumption of perfect controls, and show that the majority of technology classes exhibit localization unless hidden biases induced by imperfect controls are extremely large.Keywords: localized knowledge spillovers; distance-based tests; microgeographic data; K-density; patent citations; control patents JEL classifications: O31; R12 * We are very grateful to Gilles Duranton and Peter Thompson for detailed comments and suggestions on earlier drafts of this paper. We have also benefited from comments and suggestions by William Kerr, Jungmin Lee, as well as other participants at various conferences and workshops.

IL-8 (CINC-1) and MCP-1 may therefore facilitate the process of root resorption because of excessive orthodontic force.

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexindeficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists. neuropeptides produced by neurons exclusively localized to the lateral hypothalamus that act on two G protein-coupled receptors termed OX1R and OX2R (1). Orexin-producing neurons send axons diffusely through the central nervous system, with especially dense innervations to several nuclei involved in sleep/wakefulness regulation (2, 3). Because orexins have been implicated in the maintenance of wakefulness, many groups are trying to develop nonpeptidic orexin receptor antagonists aiming at new medication for insomnia. Recently, suvorexant, a dual orexin receptor antagonist, was clinically approved in Japan and the United States (4, 5).A crucial role of the orexin system in the regulation of sleep/ wakefulness was initially uncovered by the discovery that OX2R-deficient dogs (6) and prepro-orexin knockout (Hcrt −/− , abbreviated as OXKO) mice (2) exhibited symptoms resembling human narcolepsy-cataplexy. According to the clinical definition by the International Classification of Sleep Disorders-Third Edition, two types of narcoleptic disorders are categorized (7). Narcolepsy type 1 is characterized by the existence of cataplexy and low levels of orexin-A in cerebrospinal fluid (CSF) (8-10). However, patients with narcolepsy type 2 show no cataplexy and normal orexin-A levels in CSF. Narcolepsy-cataplexy, or narcolepsy type 1 (11), is characterized by a marked instability of sleep/ wake state transitions, resulting in nonrapid eye movement (NREM) sleep-related symptoms (e.g., excessive daytime sleepiness, "sleep attacks," and fragmented nighttime sleep), and rapid eye movement (REM) sleep-related symptoms (e.g., cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations). In polysomnography, narcolepsy-cataplexy patients show markedly reduced daytime sleep latency, and sleep-onset REM periods (SOREMs). Currently available treatments for narcolepsyca...