Abstract. Accurate delineation and characterization of valley-bottom settings is crucial to the assessment of the biological and geomorphological components ofriverine systems; yet, to date, most valley-bottom mapping endeavors have been done manually. To improve this situation, we developed automated techniques in a Geographic Information System (GIS) for delineating and characterizing valley-bottom settings in river basins ranging in size from approximately 1,000-10,000 km 2 • All procedures were developed with ARC/INFO GIS software and fully automated in Arc Macro Language (AML). The GRID module is required for valley-bottom delineation and slope calculations; whereas characterization (i.e., measuring the width of the valley-bottom zone) requires Coordinate Geometry (COGO) in the ARCEDIT module. The process requires three inputs: a polygon coverage ofthe analysis area; an arc coverage of its hydrography, and a grid representing its digital elevation. The AML is designed to operate within a wide range of computer memory/disk space options, and it allows users to customize several procedures to match the scale and complexity of a given analysis area with available computer hardware.
P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely because of the difficulty in engineering specificity and selectivity. Here, we describe for the first time the generation of a panel of diverse monoclonal antibodies (mAbs) to human and mouse P2X4, capable of both positive and negative modulation of channel function. The affinity-optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity for human P2X4 and induced potent and complete block of P2X4 currents. Site-directed mutagenesis of P2X4 revealed the head domain as a key interaction site for inhibitory mAbs. Inhibition of spinal P2X4 either by intrathecal delivery of an anti-P2X4 mAb or by systemic delivery of an anti-P2X4 bispecific mAb with enhanced blood–spinal cord barrier permeability produced long-lasting (>7 days) analgesia in a mouse model of neuropathic pain. We therefore propose that inhibitory mAbs binding the head domain of P2X4 have therapeutic potential for the treatment of neuropathic pain.
The present study investigated conditions under which the conditioned reinforcement principles of delay-reduction theory and views based on simple maximization of reinforcement rate make ordinally opposing predictions with respect to foraging-related choice behavior. The use of variable-ratio schedules in the choice phase also represents an extension of delay-reduction theory to schedules that may better mimic the effort involved in searching. Pigeons responded on modified concurrent-chains schedules in which equal variable-ratio schedules led to unequal variable-interval outcomes and unequal reinforcer amounts. All 4 subjects completed a minimum of two replications of conditions for which the predictions of delay-reduction theory and a simple rate-maximizing theory were opposed. Results were consistent with delay reduction's ordinal predictions in 11 of 11 replications of the divergent predictions favoring the smaller, more immediate alternative. The predictions of rate maximization were upheld only when they were consistent with those of delay reduction. Results are discussed in terms of conditioned reinforcement, sensitivity to reductions in delay to food, and possible rules of thumb that may be useful in characterizing foraging.
Ion channels play critical roles in physiology and disease by modulation of cellular functions such as electrical excitability, secretion, cell migration, and gene transcription. Ion channels represent an important target class for drug discovery that has been largely addressed, to date, using small-molecule approaches. A significant opportunity exists to target these channels with antibodies and alternative formats of biologics. Antibodies display high specificity and affinity for their target antigen, and they have the potential to target ion channels very selectively. Nevertheless, isolating antibodies to this target class is challenging due to the difficulties in expression and purification of ion channels in a format suitable for antibody drug discovery in addition to the complexity of screening for function. In this article, we will review the current state of ion channel biologics discovery and the progress that has been made. We will also highlight the challenges in isolating functional antibodies to these targets and how these challenges may be addressed. Finally, we also illustrate successful approaches to isolating functional monoclonal antibodies targeting ion channels by way of a number of case studies drawn from recent publications.
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