SIGNIFICANCE STATEMENT Using a mathematical modeling approach, the quantitative relationships of an orally available anticancer small molecule EZH2 inhibitor, PF06821497, were characterized among pharmacokinetics, pharmacodynamic biomarker inhibition and disease responses in nonclinical xenograft models with diffuse large B-cell lymphoma. The modeling results suggest that >70% H3K27me3 inhibition would be required for tumor stasis (i.e., 100% tumor growth inhibition). Accordingly, we would propose that an EC70 estimate for H3K27me3 inhibition could be considered a minimum target efficacious concentration of PF06821497 in cancer patients. The American Society for Pharmacology and Experimental Therapeutics.Preeclampsia (PE)-induced fetal programming predisposes offspring to health hazards in adult life. Here, we tested the hypothesis that preeclamptic fetal programming elicits sexually dimorphic inflammatory and cardiovascular complications to endotoxemia in adult rat offspring. PE was induced by oral administration of L-NAME (50 mg/kg/day for 7 consecutive days) starting from day 14 of conception. Cardiovascular studies were performed in conscious adult male and female offspring pre-instrumented with femoral indwelling catheters. Compared with non-PE male counterparts, intravenous (i.v.) administration of lipopolysaccharide (LPS, 5 mg/kg) to PE male offspring caused significantly greater (i) falls in blood pressure (BP), (ii) rises in heart rate (HR) and left ventricular contractility (dP/dtmax), and (iii) decreases in time- and frequency-domain indices of heart rate variability. By contrast, the hypotensive and tachycardic actions of LPS in female offspring were independent of the preeclamptic state and no clendotoxemia in adult life. Preeclampsia accentuates endotoxic manifestations of hypotension, tachycardia, and cardiac autonomic dysfunction in male offspring via exacerbating myocardial and central inflammatory pathways. The absence of such detrimental effects in female littermates suggests sexual dimorphism in the interaction of preeclamptic fetal programming with endotoxemia. The American Society for Pharmacology and Experimental Therapeutics.Treatments for cognitive deficits associated with CNS disorders such as Alzheimer's disease (AD) and schizophrenia remain significant unmet medical needs that incur substantial pressure on the healthcare system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine (ACh)-evoked α7 currents with only marginal effect onIn vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in CNS diseases with cognitive impairments. The American Society for Pharmacology and Experimental Therapeutics.Serial section electron microscopy (ssEM), a technique where volumes of tissue can be anatomically reconstructed by imaging consecutive tissue slices, has proven to be a powerful tool for the investigation of brain anatomy. Between the process of cutting the slices-or "sections"-and imaging them, however, handling 10°-106 delicate sections remains a bottleneck in ssEM, especially for batches in the "mesoscale" regime, i.e.,102-103 sections. We present a tissue section handling device that transports and positions sections-accurately and repeatability-for automated, robotic section pick-up and placement onto an imaging substrate. The device interfaces with a conventional ultramicrotomy diamond knife, accomplishing in-line, exact-constraint trapping of sections with 100 µm repeatability. An associated mathematical model includes capillary- and Stokes-based forces, accurately describing observed behavior and fundamentally extends the modeling of water-air interface forces. Using the device, we demonstrate and destrate. As a part of this device, we characterize a trapping technique that utilizes curvature-induced capillary-based forces and hydrodynamic Stokes drag-based forces. In total, this work represents an automated mesoscale serial sectioning system for scalable 3D-EM connectomics. Copyright © 2020 Lee et al.To make full use of optogenetic and molecular techniques in the study of motor control, rich behavioral paradigms for rodentsmust rise to the same level of sophistication and applicability. We describe the layout, construction, use and analysis of data from joystick-based reaching in ahead-fixed mouse. The step-by-step guide is designed for both experienced rodent motor labs and new groups looking to enter into this research space. Using this platform,mice learn to consistently perform large, easily-quantified reaches, including during a two-armed bandit probabilistic learning task.The metrics of performance (reach trajectory, amplitude, speed, duration, and inter-reach interval) can be used to quantify behavior or administer stimulation in closed loop with behavior. We provide a highly customizable, low costand reproducible open-source behavior training platform for studying motor control, decision making, and reaching reaction time. The development of this software and hardware platform enables behavioral work to complement recent advances in rodents, while remaining accessible to smaller institutions and labs, thus providing a high-throughput method to study unexploredfeatures of action selection, motivation, and value-based decisions.Significance Statement We are realizing that the behavioral repertoire of mice is much richer than previously thought, including motor control and decision-making using reaches. Modern neuroscience is now capturing this richness, paired with new genetic tools, to understand fundamental neuroscience principles. Here, we provide an illustrated build guide, code, multiple use scenarios, and analytic tools to a low-cost, highly customizable mouse joystick.  https://www.selleckchem.com/products/AZD2281(Olaparib).html  This tool will enable improved throughput, accessibility, and experimental design (e.g. spatiotemporal reach trajectories over lever presses) for labs wishing to study a range of reach-based experiments. Copyright © 2020 Belsey et al.