Mouse anti-Human PTN monoclonal antibody, clone 3F4

Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea-and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities. (C) 2017 Elsevier Ltd. All rights reserved.

To establish the optimal route layout estimation technology based on reliability optimization, a more accurate and realistic reliability model of a weighted public transit network (PTN) is the indispensable basis. This paper establishes a cascading failures (CFs) perspective based mesoscopic reliability model for measuring PTN survivability. First, a modeling method for abstracting weighted PTN and determining its initial passenger flow and bearing capacity is proposed, making the network passenger flow pattern follow the aggregated flow pattern. Second, three basic concepts (time step, congestion effect of a road section, and CFs judging method) for establishing the CFs model are defined to clarify the overall evolution process of CFs. Furthermore, the aggregated passenger flow evacuation that exists in an emergency occurring at a station (i.e., failure load dynamic redistribution (FLDR)) is considered as a conscious dynamic game process through following the user equilibrium rule. As a result, a novel CFs model that considers congestion effect and user equilibrium evacuation is obtained. Finally, based on the collected data of Jinan's PTN, a case simulation analysis is conducted to verify the adaptability of this model through showing a significantly different dynamics characteristic with the existing FLDR patterns and to provide optimization direction for effectively controlling PTN survivability, that is, guide the transformation among varying FLDR patterns through some technical measures or traffic policies.