Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses.

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease

Theoretical Study of the Mechanism of CO and Acetylene Migratory Insertions into Pt–Cp* Bonds

Density functional theory computation for the reaction of Cp*Pt­(CO)­I with PMe₃ indicates that insertion of CO into the Pt–Cp* bond of Cp*Pt­(CO)­(PMe₃)I proceeds via interaction of a π orbital of Cp* with a π* orbital of CO. A similar pathway is predicted for an insertion reaction of the acetylene complex Cp*Pt­(C₂H₂)­(PMe₃)­I. The conventional mechanism for CO and acetylene insertions, involving direct insertion into the Pt–C bond, is shown to be inoperative in this system

A Mechanistic Investigation of the Gold(III)-Catalyzed Hydrofurylation of C–C Multiple Bonds

The gold-catalyzed direct functionalization of aromatic C–H bonds has attracted interest for constructing organic compounds which have application in pharmaceuticals, agrochemicals, and other important fields. In the literature, two major mechanisms have been proposed for these catalytic reactions: inner-sphere <i>syn</i>-addition and outer-sphere <i>anti</i>-addition (Friedel–Crafts-type mechanism). In this article, the AuCl₃-catalyzed hydrofurylation of allenyl ketone, vinyl ketone, ketone, and alcohol substrates is investigated with the aid of density functional theory calculations, and it is found that the corresponding functionalizations are best rationalized in terms of a novel mechanism called “concerted electrophilic ipso-substitution” (CEIS) in which the gold­(III)-furyl σ-bond produced by furan auration acts as a nucleophile and attacks the protonated substrate via an outer-sphere mechanism. This unprecedented mechanism needs to be considered as an alternative plausible pathway for gold­(III)-catalyzed arene functionalization reactions in future studies

Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response

Peptidyl arginine deiminase (PAD) 4 is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and identity of reader domains specifically recognising citrulline modifications remain unclear. E2F transcription factors play an important role in regulating gene expression in diverse biological processes. Here, we show that E2F-1 is citrullinated by PAD4 on functionally important arginine residues. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells, and augments binding of the bromodomain reader BRD4 to an acetylated domain in E2F-1. Accordingly, the combined inhibition of PAD4 and BRD4 suppresses cytokine gene expression, and when administered as a combination therapy in the murine collagen-induced arthritis model, provides an effective approach for preventing collagen-induced arthritis. Our results shed light on a new E2F-dependent pathway that mediates the inflammatory effect of PAD4 and, for the first time, establish the interplay between citrullination and acetylation as a regulatory interface for driving inflammatory gene expression

Mobile crowdsourced sensors selection for journey services

We propose a mobile crowdsourced sensors selection approach to improve the journey planning service especially in areas where no wireless or vehicular sensors are available. We develop a location estimation model of journey services based on an unsupervised learning model to select and cluster the right mobile crowdsourced sensors that are accurately mapped to the right journey service. In our model, the mobile crowdsourced sensors trajectories are clustered based on common features such as speed and direction. Experimental results demonstrate that the proposed framework is efficient in selecting the right crowdsourced sensors

Semirings of Evidence

In traditional justification logic, evidence terms have the syn-tactic form of polynomials, but they are not equipped with the corre-sponding algebraic structure. We present a novel semantic approach tojustification logic that models evidence by a semiring. Hence justificationterms can be interpreted as polynomial functions on that semiring. Thisprovides an adequate semantics for evidence terms and clarifies the roleof variables in justification logic. Moreover, the algebraic structure makesit possible to compute with evidence. Depending on the chosen semiringthis can be used to model trust, probabilities, cost, etc. Last but notleast the semiring approach seems promising for obtaining a realizationprocedure for modal fixed point logic