Inhibition of pancreatic cholesterol esterase reduces cholesterol absorption in the hamster

BACKGROUND: Pancreatic cholesterol esterase has three proposed functions in the intestine: 1) to control the bioavailability of cholesterol from dietary cholesterol esters; 2) to contribute to incorporation of cholesterol into mixed micelles; and 3) to aid in transport of free cholesterol to the enterocyte. Inhibitors of cholesterol esterase are anticipated to limit the absorption of dietary cholesterol. RESULTS: The selective and potent cholesterol esterase inhibitor 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyrone (figure 1, structure 1) was administered to hamsters fed a high cholesterol diet supplemented with radiolabeled cholesterol ester. Hamsters were gavage fed (3)H-labeled cholesteryl oleate along with inhibitor 1, 0–200 micromoles. Twenty-four hours later, hepatic and serum radioactive cholesterol levels were determined. The ED(50 )of inhibitor 1 for prevention of the uptake of labeled cholesterol derived from hydrolysis of labeled cholesteryl oleate was 100 micromoles. The toxicity of inhibitor 1 was investigated in a 30 day feeding trial. Inhibitor 1, 100 micromoles or 200 micromoles per day, was added to chow supplemented with 1% cholesterol and 0.5% cholic acid. Clinical chemistry urinalysis and tissue histopathology were obtained. No toxicity differences were noted between control and inhibitor supplemented groups. CONCLUSIONS: Inhibitors of cholesterol esterase may be useful therapeutics for limiting cholesterol absorption

Differentiation for the Gifted in American Islamic Schools

A brief narrative description of the journal article, document, or resource. This research focuses on teacher instructional and curricular practices in gifted students\u27 experiences in Islamic schools in the United States. Surveys were administered at private, full-time Islamic elementary schools to determine the extent to which differentiation practices for meeting the needs of gifted students and the integration of Islamic values were employed. Findings suggest that Islamic schools in the United States have limited programs for gifted students. A majority of teachers in Islamic schools differentiate little between gifted and average students in instructional strategies. When differentiation occurs, it is very basic. Further, teachers at Islamic schools generally do not integrate Islamic values into other academic areas and present them to all students without differentiation. (Contains 5 tables and 2 endnotes.

Stick-Fixed Maneuver Points in Roll, Pitch, and Yaw and Associated Handling Qualities

The stick-fixed pitch maneuver point is an important measure of aircraft longitudinal dynamic response and handling quality characteristics, and includes effects of both aerodynamic and inertia properties of the aircraft about the pitch axis. In the present work, the existence of stick-fixed roll and yaw maneuver points is demonstrated, which are determined from the lateral forces, moments, and inertial properties of the aircraft. These stick-fixed roll and yaw maneuver points are directly related to the predicted lateral handling qualities. Example results are included for several aircraft that demonstrate the importance of this parameter when predicting the dynamic response of the aircraft. A better understanding of stick-fixed roll, pitch, and yaw maneuver points can inform aircraft design during early stages to ensure adequate handling qualities for both longitudinal and lateral modes

The hippocampi of children with chromosome 22q11.2 deletion syndrome have localized anterior alterations that predict severity of anxiety

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an elevated risk for schizophrenia, which increases with history of childhood anxiety. Altered hippocampal morphology is a common neuroanatomical feature of 22q11.2DS and idiopathic schizophrenia. Relating hippocampal structure in children with 22q11.2DS to anxiety and impaired cognitive ability could lead to hippocampus-based characterization of psychosis-proneness in this at-risk population. METHODS: We measured hippocampal volume using a semiautomated approach on MRIs collected from typically developing children and children with 22q11.2DS. We then analyzed hippocampal morphology with Localized Components Analysis. We tested the modulating roles of diagnostic group, hippocampal volume, sex and age on local hippocampal shape components. Lastly, volume and shape components were tested as covariates of IQ and anxiety. RESULTS: We included 48 typically developing children and 69 children with 22q11.2DS in our study. Hippocampal volume was reduced bilaterally in children with 22q11.2DS, and these children showed greater variation in the shape of the anterior hippocampus than typically developing children. Children with 22q11.2DS had greater inward deformation of the anterior hippocampus than typically developing children. Greater inward deformation of the anterior hippocampus was associated with greater severity of anxiety, specifically fear of physical injury, within the 22q11.2DS group. LIMITATIONS: Shape alterations are not specific to hippocampal subfields. CONCLUSION: Alterations in the structure of the anterior hippocampus likely affect function and may impact limbic circuitry. We suggest these alterations potentially contribute to anxiety symptoms in individuals with 22q11.2DS through modulatory pathways. Altered hippocampal morphology may be uniquely linked to anxiety risk factors for schizophrenia, which could be a powerful neuroanatomical marker of schizophrenia risk and hence protection

Is overconfidence a social liability? The effect of verbal versus nonverbal expressions of confidence.

[Correction Notice: An Erratum for this article was reported in Vol 116(3) of Journal of Personality and Social Psychology (see record 2019-08943-002). In the article "Is Overconfidence a Social Liability? The Effect of Verbal Versus Nonverbal Expressions of Confidence" by Elizabeth R. Tenney, Nathan L. Meikle, David Hunsaker, Don A. Moore, and Cameron Anderson (Journal of Personality and Social Psychology. Advance online publication. October 11, 2018. http://dx.doi.org/10.1037/pspi0000150), the Editor' Note acknowledging David Dunning as the action editor for this article was omitted. All versions of this article have been corrected.] What are the reputational consequences of being overconfident? We propose that the channel of confidence expression is one key moderator-that is, whether confidence is expressed verbally or nonverbally. In a series of experiments, participants assessed target individuals (potential collaborators or advisors) who were either overconfident or cautious. Targets expressed confidence, or a lack thereof, verbally or nonverbally. Participants then learned targets' actual performance. Across studies, overconfidence was advantageous initially-regardless of whether targets expressed confidence verbally or nonverbally. After performance was revealed, overconfident targets who had expressed confidence verbally were viewed more negatively than cautious targets; however, overconfident targets who had expressed confidence nonverbally were still viewed more positively than cautious ones. The one condition wherein nonverbal overconfidence was detrimental was when confidence was clearly tied to a falsifiable claim. Results suggest that, compared with verbal statements, nonverbal overconfidence reaps reputational benefits because of its plausible deniability. (PsycINFO Database Record (c) 2019 APA, all rights reserved)

Uncharged isocoumarin-based inhibitors of urokinase-type plasminogen activator

BACKGROUND: Urokinase-type plasminogen activator (uPA) plays a major role in extracellular proteolytic events associated with tumor cell growth, migration and angiogenesis. Consequently, uPA is an attractive target for the development of small molecule active site inhibitors. Most of the recent drug development programs aimed at nonpeptidic inhibitors targeted at uPA have focused on arginino mimetics containing amidine or guanidine functional groups attached to aromatic or heterocyclic scaffolds. There is a general problem of limited bioavailability of these charged inhibitors. In the present study, uPA inhibitors were designed on an isocoumarin scaffold containing uncharged substituents. RESULTS: 4-Chloro-3-alkoxyisocoumarins were synthesized in which the 3-alkoxy group contained a terminal bromine; these were compared with similar inhibitors that contained a charged terminal functional group. Additional variations included functional groups attached to the seven position of the isocoumarin scaffold. N- [3-(3-Bromopropoxy)-4-chloro-1-oxo-1H-isochromen-7-yl]benzamide was identified as an uncharged lead inhibitor of uPA, K(i )= 0.034 μM. Molecular modeling of human uPA with these uncharged inhibitors suggests that the bromine occupies the same position as positively charged arginino mimetic groups. CONCLUSION: This study demonstrates that potent uncharged inhibitors of uPA can be developed based upon the isocoumarin scaffold. A tethered bromine in the three position and an aromatic group in the seven position are important contributors to binding. Although the aim was to develop compounds that act as mechanism-based inactivators, these inhibitors are competitive reversible inhibitors