The molecular pharmacology and in vivo activity of 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase.

The microsomal prostaglandin E2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of α-(n-hexyl)- substituted pirinixic acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino) pyrimidin-2-ylthio)octanoic acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC 50 = 3.4 μM), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 (KD = 10-14 μM). In lipopolysaccharide-stimulated human whole blood, PGE2 formation was concentration dependently inhibited (IC50 =2 μM), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B2 and 6-keto PGF1α and the COX-1-derived 12(S)-hydroxy-5-cis-8,10- transheptadecatrienoic acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE2 and leukotriene B4 but also of 6-keto PGF 1α. Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo

Infrastructure Upgrades and Foreclosure with Coexistence of Service-Based and Facility-Based Firms

We investigate the incentives for facility-based firms to invest in infrastructure upgrades and to foreclose service-based firms. We focus on asymmetric regulation regarding servicebased firms' access to the infrastructure held by a facility-based firm. Spillovers from the infrastructure upgrades made by a regulated facility-based firm on service-based firms play a key role in the incentives for making these upgrades. The spillover effect can enhance the incentives for the regulated facility-based firm to make upgrades if access prices are not regulated. The existence of rival facility-based firms strengthens the incentives for a regulated facility-based firm to make infrastructure upgrades, especially when the spillover effect is significant. Furthermore, if access prices are not regulated, the existence of rival facility-based firms weakens the incentives for a regulated facility-based firm to foreclose service-based firms

Semi-automatic conversion of BioProp semantic annotation to PASBio annotation

<p>Abstract</p> <p>Background</p> <p>Semantic role labeling (SRL) is an important text analysis technique. In SRL, sentences are represented by one or more predicate-argument structures (PAS). Each PAS is composed of a predicate (verb) and several arguments (noun phrases, adverbial phrases, etc.) with different semantic roles, including main arguments (agent or patient) as well as adjunct arguments (time, manner, or location). PropBank is the most widely used PAS corpus and annotation format in the newswire domain. In the biomedical field, however, more detailed and restrictive PAS annotation formats such as PASBio are popular. Unfortunately, due to the lack of an annotated PASBio corpus, no publicly available machine-learning (ML) based SRL systems based on PASBio have been developed. In previous work, we constructed a biomedical corpus based on the PropBank standard called BioProp, on which we developed an ML-based SRL system, BIOSMILE. In this paper, we aim to build a system to convert BIOSMILE's BioProp annotation output to PASBio annotation. Our system consists of BIOSMILE in combination with a BioProp-PASBio rule-based converter, and an additional semi-automatic rule generator.</p> <p>Results</p> <p>Our first experiment evaluated our rule-based converter's performance independently from BIOSMILE performance. The converter achieved an F-score of 85.29%. The second experiment evaluated combined system (BIOSMILE + rule-based converter). The system achieved an F-score of 69.08% for PASBio's 29 verbs.</p> <p>Conclusion</p> <p>Our approach allows PAS conversion between BioProp and PASBio annotation using BIOSMILE alongside our newly developed semi-automatic rule generator and rule-based converter. Our system can match the performance of other state-of-the-art domain-specific ML-based SRL systems and can be easily customized for PASBio application development.</p

Network Competition with Income Effects

I generalize the workhorse model of network competition to include income effects in call demand. Empirical work has shown call demand to increase significantly with income. For any positive income effect, network operators prefer a termination rate above marginal cost if networks are sufficiently differentiated. This holds with or without call price discrimination. Under price discrimination, the networks charge a lower price for calls within the own network (on-net) than to other networks (off-net). Income effects thus deliver theoretical results consistent with stylized facts about call prices and in line with regulatory concern about excessive termination rates

Geographic Access Rules and Investment

We analyze competition between vertically integrated infrastructure operators that provide access in different geographical areas. A regulator may impose a uniform access price, set local access rates, or deregulate access locally. We analyze the impact of these alternative regulatory regimes on network investments. While cost-based access leads to both suboptimal rollout and duplication, uniform access prices bring too much duplication. Deregulation in competitive areas can spur investment and lead to social optimum, or call for continued regulatory intervention, depending on the resulting wholesale equilibriu

The editorial-Regulation and competition in communications markets

The special issue of Telecommunications Policy contains a series of papers presented at the first Scientific Seminar of the Communications and Media area of the Florence School of Regulation. All deal with hotly debated topics in evolving communications markets. Three main issues are considered: firstly, the regulation of mobile call termination and its effects on pricing strategies and competition; secondly, the development of broadband and ultra-broadband networks and the supply-side and demand-side policies intended to spur companies’ investment into an infrastructure that is expected to be fundamental for future communications markets and the growth of the whole economy; thirdly, in relation to media markets, this issue presents papers analysing how advertisement on different media such as commercial TV paid or free newspapers, blogs, radio, might be used to affect competition among firms in their respective product markets