Positive allosteric modulators of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor

L-glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a fundamental role in the control of motor function, cognition and mood. The physiological effects of glutamate are mediated through two functionally distinct receptor families. While activation of metabotropic (G-protein coupled) glutamate receptors results in modulation of neuronal excitability and transmission, the ionotropic glutamate receptors (ligand-gated ion channels) are responsible for mediating the fast synaptic response to extracellular glutamate

Rapid Maize Leaf and Immature Ear Responses to UV-B Radiation

Because of their sessile lifestyle, plants have evolved adaptations to environmental factors, including UV-B present in solar radiation. To gain a better understanding of the initial events in UV-B acclimation, we have analyzed a 10 min to 1 h time course of transcriptome responses in irradiated and shielded leaves, and immature maize ears to unravel the systemic physiological and developmental responses in exposed and shielded organs. After 10 min of UV-B exposure, 262 transcripts are changed by at least two-fold in irradiated leaves, and this number doubles after 1 h. Indicative of the rapid modulation of transcription, 130 transcripts are only changed after 10 min. This is true not only in irradiated leaves, but also in shielded tissues. After 10 min of exposure, the overlap in transcriptome changes in irradiated and shielded organs is significant; however, after 30 min of UV-B, there are only two transcripts showing similar UV-B regulation between the three organs; 35 are similarly regulated in both IL and SL. Therefore, at longer irradiation times, there is more specificity of responses, and these are organ-specific. We suggest that early signaling in different tissues may be elicited by common signaling pathways, while at longer exposure times responses become more specific. To identify metabolites as possible signaling molecules, we looked for compounds that increased within 5–90 min in both irradiated and shielded leaves, to explain the kinetics of profound transcript changes within 1 h. We found that myoinositol is one such candidate metabolite; and we also demonstrate that if 0.1 mM myoinositol is applied to leaves of greenhouse maize, some metabolites that are changed by UV-B are also changed similarly by the chemical treatment. Therefore, this metabolite can partially mimic UV irradiation

A Novel Method for the Quantitative Assessment of Fingered Robot Hand Designs for In-Hand Manipulation using Human Studies and Object-Centric Benchmarks

Fingered robot hands are complicated systems made of three essential system components: its morphology, its actuation, and its software control. These system components are tightly coupled to each other. Due to this, it is hard to benchmark robot hand performance in a way to understand the contributions of the individual system components. This defense introduces a new approach to characterizing a robot hand's system components using human subjects and novel object-centric benchmarks to study the contributions of the morphology and actuation system components at in-hand manipulation tasks. What is demonstrated are two studies using this method to study a hand's actuation and morphological system components. In the first, a hand's actuation component is studied at how well it can utilize tools (pen, spray bottle). In the second, a hand's morphological component is studied at how well it can perform fundamental in-hand manipulation tasks. Hand performance is compared between designs in order to build a quantitative understanding of how a robot hand's design affects its performance. Other roboticists can use this method on their own hands and on their own tasks to improve the systemic understanding of their own hands

AICPA audit committee toolkit : public companies

https://egrove.olemiss.edu/aicpa_guides/1582/thumbnail.jp

Advances in Above- and In-Water Radiometry, Volume 3: Hybridspectral Next-Generation Optical Instruments

This publication documents the scientific advances associated with new instrument systems and accessories built to improve above- and in-water observations of the apparent optical properties (AOPs) for a diversity of water masses, including optically complex waters. The principal objective is to be prepared for the launch of next-generation ocean color satellites with the most capable commercial off-the-shelf (COTS) instrumentation in the shortest time possible. The technologies described herein are entirely new hybrid sampling capabilities, so as to satisfy the requirements established for next-generation missions. Both above- and in-water instruments are documented with software options for autonomous control of data collection activities as applicable. The instruments were developed for the Hybridspectral Alternative for Remote Profiling of Optical Observations for NASA Satellites (HARPOONS) vicarious calibration project. The state-of-the-art accuracy required for vicarious calibration also led to the development of laboratory instruments to ensure the field observations were within uncertainty requirements. Separate detailed presentations of the individual instruments provide the hardware designs, accompanying software for data acquisition and processing, and examples of the results achieved

Insulin-stimulated phosphorylation of endothelial nitric oxide synthase at serine-615 contributes to nitric oxide synthesis

Insulin stimulates endothelial NO (nitric oxide) synthesis via PKB (protein kinase B)/Akt-mediated phosphorylation and activation of eNOS (endothelial NO synthase) at Ser-1177. In previous studies, we have demonstrated that stimulation of eNOS phosphorylation at Ser-1177 may be required, yet is not sufficient for insulin-stimulated NO synthesis. We therefore investigated the role of phosphorylation of eNOS at alternative sites to Ser-1177 as candidate parallel mechanisms contributing to insulin-stimulated NO synthesis. Stimulation of human aortic endothelial cells with insulin rapidly stimulated phosphorylation of both Ser-615 and Ser-1177 on eNOS, whereas phosphorylation of Ser-114, Thr-495 and Ser-633 was unaffected. Insulin-stimulated Ser-615 phosphorylation was abrogated by incubation with the PI3K (phosphoinositide 3-kinase) inhibitor wortmannin, infection with adenoviruses expressing a dominant-negative mutant PKB/Akt or pre-incubation with TNFα (tumour necrosis factor α), but was unaffected by high culture glucose concentrations. Mutation of Ser-615 to alanine reduced insulin-stimulated NO synthesis, whereas mutation of Ser-615 to aspartic acid increased NO production by NOS in which Ser-1177 had been mutated to an aspartic acid residue. We propose that the rapid PKB-mediated stimulation of phosphorylation of Ser-615 contributes to insulin-stimulated NO synthesis

Advances in Above- and In-Water Radiometry, Volume 2: Autonomous Atmospheric and Oceanic Observing Systems

This publication documents the scientific advances associated with new instrument systems and accessories built to improve above- and in-water observations of the apparent optical properties (AOPs) of optically complex waters. The principal objective is to be prepared for the launch of next-generation ocean color satellites with the most capable commercial off-the-shelf (COTS) instrumentation in the shortest time possible. The Hybridspectral Alternative for Remote Profiling of Optical Observations for NASA Satellites (HARPOONS) is presented as a case example of technologies conceived, developed, and deployed operationally in support of next-generation mission requirements. The field trials, field commissioning, and operational demonstration resulted in a technology readiness level (TRL) value of 9 for a diversity of laboratory and field instrument systems. Separate detailed presentations of the individual instruments provide the hardware designs, accompanying software for data acquisition and processing, and examples of the results achieved. For the laboratory components, calibration and characterization procedures are described along with an estimation of the sources of uncertainty, which culminates in a full uncertainty budget for the radiometers deployed to the field

Advances in Above- and In-Water Radiometry, Volume 1: Enhanced Legacy and State-of-the-Art Instrument Suites

This publication documents the scientific advances associated with new instrument systems and accessories built to improve above- and in-water observations of the apparent optical properties (AOPs) of aquatic ecosystems. The perspective is to obtain high quality data in offshore, nearshore, and inland waters with equal efficacy. The principal objective is to be prepared for the launch of the next-generation ocean color satellites with the most capable commercial off-the-shelf (COTS) instrumentation in the shortest time possible. The technologies described herein are designed to either improve legacy radiometric systems or to provide entirely new hybrid sampling capabilities, so as to satisfy the requirements established for diverse remote sensing requirements. Both above- and in-water instrument suites are documented with software options for autonomous control of data collection activities. The latter includes an airborne instrument system plus unmanned surface vessel (USV) and buoy concepts

Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: Exploratory phase 1 results in healthy volunteers

A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine\u27s unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder

Chordin Is a Modifier of Tbx1 for the Craniofacial Malformations of 22q11 Deletion Syndrome Phenotypes in Mouse

Point mutations in TBX1 can recapitulate many of the structural defects of 22q11 deletion syndromes (22q11DS), usually associated with a chromosomal deletion at 22q1.2. 22q11DS often includes specific cardiac and pharyngeal organ anomalies, but the presence of characteristic craniofacial defects is highly variable. Even among family members with a single TBX1 point mutation but no cytological deletion, cleft palate and low-set ears may or may not be present. In theory, such differences could depend on an unidentified, second-site lesion that modifies the craniofacial consequences of TBX1 deficiency. We present evidence for such a locus in a mouse model. Null mutations of chordin have been reported to cause severe defects recapitulating 22q11DS, which we show are highly dependent on genetic background. In an inbred strain in which chordin−/− is fully penetrant, we found a closely linked, strong modifier—a mutation in a Tbx1 intron causing severe splicing defects. Without it, lack of chordin results in a low penetrance of mandibular hypoplasia but no cardiac or thoracic organ malformations. This hypomorphic Tbx1 allele per se results in defects resembling 22q11DS but with a low penetrance of hallmark craniofacial malformations, unless chordin is mutant. Thus, chordin is a modifier for the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11DS