Discovery of AZD3147: a potent, selective dual inhibitor of mTORC1 and mTORC2.

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

Why do women opt out? Sense of belonging and women's representation in mathematics.

Sense of belonging to math-one's feelings of membership and acceptance in the math domain-was established as a new and an important factor in the representation gap between males and females in math. First, a new scale of sense of belonging to math was created and validated, and was found to predict unique variance in college students' intent to pursue math in the future (Studies 1-2). Second, in a longitudinal study of calculus students (Study 3), students' perceptions of 2 factors in their math environment-the message that math ability is a fixed trait and the stereotype that women have less of this ability than men-worked together to erode women's, but not men's, sense of belonging in math. Their lowered sense of belonging, in turn, mediated women's desire to pursue math in the future and their math grades. Interestingly, the message that math ability could be acquired protected women from negative stereotypes, allowing them to maintain a high sense of belonging in math and the intention to pursue math in the future.

Comparison of midwifery, family medicine, and obstetric patients' understanding of weight gain during pregnancy: a minority of women report correct counselling.

OBJECTIVE: We hypothesized that differences in models of care between health care providers would result in variations in patients' reports of counselling. Our objective was to compare what women reported being advised about weight gain during pregnancy and the risks of inappropriate weight gain according to their type of health care provider. METHODS: A cross-sectional survey was conducted using a self-administered questionnaire at obstetric, midwifery, and family medicine clinics in Hamilton, Ontario. Women were eligible to participate if they had had at least one prenatal visit, could read English, and had a live, singleton pregnancy. RESULTS: Three hundred and eight women completed the survey, a 93% response rate. Care for 90% of the group was divided approximately evenly between midwives, family physicians, and obstetricians. A minority of women looked after by any of the types of care providers reported being counselled correctly about how much weight to gain during pregnancy (16.3%, 10.3%, 9.2%, and 5.7% of patients of midwives, family physicians, obstetricians, or other types of care providers, respectively, P = 0.349). A minority of women with any category of care provider was planning to gain an amount of weight that fell within the guidelines or reported being told that there were risks to themselves or their babies with inappropriate gain. CONCLUSION: In this study comparing reported counselling between patients of obstetricians, midwives, family physicians, and other health care providers, low rates of counselling about gestational weight gain were universally reported. There is a common need for more effective counselling.

Emotion blocks the path to learning under stereotype threat.

Gender-based stereotypes undermine females' performance on challenging math tests, but how do they influence their ability to learn from the errors they make? Females under stereotype threat or non-threat were presented with accuracy feedback after each problem on a GRE-like math test, followed by an optional interactive tutorial that provided step-wise problem-solving instruction. Event-related potentials tracked the initial detection of the negative feedback following errors [feedback related negativity (FRN), P3a], as well as any subsequent sustained attention/arousal to that information [late positive potential (LPP)]. Learning was defined as success in applying tutorial information to correction of initial test errors on a surprise retest 24-h later. Under non-threat conditions, emotional responses to negative feedback did not curtail exploration of the tutor, and the amount of tutor exploration predicted learning success. In the stereotype threat condition, however, greater initial salience of the failure (FRN) predicted less exploration of the tutor, and sustained attention to the negative feedback (LPP) predicted poor learning from what was explored. Thus, under stereotype threat, emotional responses to negative feedback predicted both disengagement from learning and interference with learning attempts. We discuss the importance of emotion regulation in successful rebound from failure for stigmatized groups in stereotype-salient environments.

Despite 2009 guidelines, few women report being counseled correctly about weight gain during pregnancy.

OBJECTIVE: The purpose of this study was to determine the information that pregnant women report receiving when being counseled about weight gain and the risks of inappropriate gain. STUDY DESIGN: With the use of a self-administered questionnaire at prenatal clinics in Hamilton, Ontario, Canada, a cross-sectional survey was conducted of women who had had at least 1 prenatal visit, who could read English, and who had a live singleton gestation. RESULTS: Three hundred ten women completed the survey, which was a 93.6% response rate. Although 28.5% (95% confidence interval, 23.5-33.6%) reported that their health care provider had made a recommendation about how much weight they should gain, only 12.0% (95% confidence interval, 8-16.1%) of the women reported having achieved the recommended weight gain in accordance with the 2009 guidelines. One quarter of the women reported being told that there were risks with inappropriate gain. CONCLUSION: Despite the recent 2009 publication of the gestational weight gain guidelines, only 12% of women reported being counseled correctly, which suggests an urgent need for improved patient education.

Why do beliefs about intelligence influence learning success? A social cognitive neuroscience model.

Students' beliefs and goals can powerfully influence their learning success. Those who believe intelligence is a fixed entity (entity theorists) tend to emphasize 'performance goals,' leaving them vulnerable to negative feedback and likely to disengage from challenging learning opportunities. In contrast, students who believe intelligence is malleable (incremental theorists) tend to emphasize 'learning goals' and rebound better from occasional failures. Guided by cognitive neuroscience models of top-down, goal-directed behavior, we use event-related potentials (ERPs) to understand how these beliefs influence attention to information associated with successful error correction. Focusing on waveforms associated with conflict detection and error correction in a test of general knowledge, we found evidence indicating that entity theorists oriented differently toward negative performance feedback, as indicated by an enhanced anterior frontal P3 that was also positively correlated with concerns about proving ability relative to others. Yet, following negative feedback, entity theorists demonstrated less sustained memory-related activity (left temporal negativity) to corrective information, suggesting reduced effortful conceptual encoding of this material-a strategic approach that may have contributed to their reduced error correction on a subsequent surprise retest. These results suggest that beliefs can influence learning success through top-down biasing of attention and conceptual processing toward goal-congruent information.