Framing obesity a disease: Indirect effects of affect and controllability beliefs on weight bias.

BACKGROUND/OBJECTIVES: Obesity has been declared a disease by the American and Canadian Medical Associations. Although these declarations sparked much debate as to the impact of framing obesity as a disease on weight bias, strong empirical research is needed to examine this impact. The current study examined the impact of framing obesity a disease on weight bias, focusing on moderating and mediating processes. SUBJECTS/METHODS: A sample of 309 participants living in the United States or Canada was recruited from Crowdflower. Participants completed measures of demographics, ideology, general attitudes, and previous contact quality and quantity with people living with obesity. Participants then read one of three articles as part of an experimental manipulation framing obesity as a disease, obesity not as a disease, and a control article unrelated to obesity. Post-manipulation included measures of affect, disgust, empathy, blame, and weight bias. RESULTS: Orthogonal contrasts were used to compare the obesity-disease condition to the obesity-not-disease condition and control condition. The manipulation had a direct effect on affect (emotions), such that affect toward individuals with obesity was more positive in the obesity-disease condition than the obesity-not-disease and control condition combined. Exploration of moderating effects revealed that both the belief in a just world and weight satisfaction moderated the relationship between the obesity-disease manipulation and blame for obesity. Two models of indirect effects on weight bias were also examined, which demonstrated that the obesity-disease manipulation predicted less weight bias through more positive affect (model 1) as well as less weight bias through decreased blame among individuals high in belief in a just world (model 2). CONCLUSIONS: This study further highlights the complex effects of declaring obesity a disease, uncovering a new direction for future research into the role of affect as well as indirect effects of characterising obesity a disease on weight bias.

Identification and optimisation of a series of tetrahydrobenzotriazoles as metabotropic glutamate receptor 5-selective positive allosteric modulators that improve performance in a preclinical model of cognition.

Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.

Weighty words: exploring terminology about weight among samples of physicians, obesity specialists, and the general public.

BACKGROUND: The words used to refer to weight and individuals with large bodies can be used to reinforce weight stigma. Given that most previous research has examined preferred terminology within homogenous groups, this research sought to examine terminology preferences across populations. METHODS: This paper reports on data gathered with the general public, family physicians, and obesity researchers/practitioners. Participants were asked about the words they commonly: (1) used to refer to people with large bodies (general public); (2) heard in their professional contexts (physicians and obesity specialists); and (3) perceived to be the most socially or professionally acceptable (all samples). RESULTS: Similarities and differences were evident between samples, especially related to weight-related clinical terms, the word fat, and behavioral stereotypes. CONCLUSION: The results provide some clarity into the differences between populations and highlight the need to incorporate use of strategies that may move beyond person-first language to humanize research and clinical practice with people with large bodies.

Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform.

d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.

Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases.

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold.

Examining Weight Bias among Practicing Canadian Family Physicians.

OBJECTIVES: The aim of this study was to examine the attitudes of practicing Canadian family physicians about individuals with obesity, their healthcare treatment, and perceptions of obesity treatment in the public healthcare system. METHOD: A national sample of Canadian practicing family physicians (n = 400) completed the survey. Participants completed measures of explicit weight bias, attitudes towards treating patients with obesity, and perceptions that people with obesity increase demand on the public healthcare system. RESULTS: Responses consistent with weight bias were not observed overall but were demonstrated in a sizeable minority of respondents. Many physicians also reported feeling frustrated with patients with obesity and agreed that people with obesity increase demand on the public healthcare system. Male physicians had more negative attitudes than females. More negative attitudes towards treating patients with obesity were associated with greater perceptions of them as a public health demand. CONCLUSION: Results suggest that negative attitudes towards patients with obesity exist among some family physicians in Canada. It remains to be determined if physicians develop weight bias partly because they blame individuals for their obesity and its increased demand on the Canadian public healthcare system. More research is needed to better understand causes and consequences of weight bias among health professionals and make efforts towards its reduction in healthcare.

Gambling as a search for justice: examining the role of personal relative deprivation in gambling urges and gambling behavior.

The present article explores the hypothesis that gambling might serve a justice-seeking function for some people, as gambling might offer a means to pursuing desirable outcomes that people feel they deserve but might be unable or unwilling to attain through conventional means. In Study 1, across two separate samples, self-reports of personal relative deprivation predict problem gambling and gambling urges over and above relevant control variables. In Study 2, the authors manipulate personal relative deprivation by informing participants that they have either less or more discretionary income than "similar others." They then give participants $20 and the opportunity to gamble. The results show that a greater percentage of participants who are "relatively deprived" (vs. "not relatively deprived") opt to gamble. Two manipulation validation studies demonstrate that the "relatively deprived" participants are preoccupied with justice during a modified Stroop task and feel resentful. Implications for understanding why people gamble are discussed.

The paper trail to mental health.

OBJECTIVE: The aim of this article was to examine the concept of mental health and the policies that have been advanced to improve the wellbeing of the population. CONCLUSIONS: In the last century there have been many changes in the phenomena of psychiatric disorder, the management of those disorders and the outcomes. All of the changes have largely been due to the efforts of those working pragmatically at the coalface. There is little to suggest that the plans and programs advanced in the last half century have achieved more than enhancing the status of those who advance them. CONCLUSION: It is difficult to define mental health and equally difficult to develop a comprehensive program that will benefit the whole field.

The belief in a just world and immanent justice reasoning in adults.

Deciding that negative experiences are punishment for prior misdeeds, even when plausible causal links are missing, is immanent justice (IJ) reasoning (Piaget, 1932/1965). Three studies examined a just world theory analysis of IJ reasoning in adults (Lerner, 1980). Studies 1 and 2 varied the valence of a target person's behavior prior to them experiencing an unrelated negative (car accident, Study 1) or positive (lottery win, Study 2) outcome. Participants viewed the outcomes as the result of prior behavior most when they fit deservingness expectations (good person won the lottery, bad person injured in automobile accident), suggesting that just world concerns influenced IJ reasoning. The lottery-winning finding (Study 2) also extends IJ reasoning to positive experiences. A third study found that a manipulation of just world threat in one context (prolonged or ended suffering of an HIV victim) influenced IJ responses in a subsequent unrelated context (automobile accident scenario).

L-arginyl-3,4-spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission.

1. Stroke is the third most common cause of death in the world, and there is a clear need to develop new therapeutics for the stroke victim. To address this need, we generated a combinatorial library of polyamine compounds based on sFTX-3.3 toxin from which L-Arginyl-3,4-Spermidine (L-Arg-3,4) emerged as a lead neuroprotective compound. In the present study, we have extended earlier results to examine the compound's neuroprotective actions in greater detail. 2. In an in vitro ischaemia model, L-Arg-3,4 significantly reduced CA1 cell death when administered prior to induction of 60 min of ischaemia as well as when administered immediately after ischaemia. Surprisingly, L-Arg-3,4 continued to prevent cell death significantly when administration was delayed for as long as 60 min after ischaemia. 3. L-Arg-3,4 significantly reduced cell death in excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike glutamate receptor antagonists, 300 microM L-Arg-3,4 did not suppress synaptic transmission as measured by evoked responses in acute hippocampal slices. 4. L-Arg-3,4 provided significant protection, in vitro, in a superoxide mediated injury model and prevented an increase of superoxide production after AMPA or NMDA stimulation. It also decreased nitric oxide production after in vitro ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide synthase directly. 5. Furthermore, L-Arg-3,4 was significantly neuroprotective in an in vivo model of global forebrain ischaemia, without any apparent neurological side-effects. 6. Taken together, these results demonstrate that L-Arg-3,4 is protective in several models of neurodegeneration and may have potential as a new therapeutic compound for the treatment of stroke, trauma, and other neurodegenerative diseases.

Cell penetrable peptoid carrier vehicles: synthesis and evaluation.

Using a highly efficient solid-phase route a series of fluorescein conjugated peptoid oligomers were synthesised and observed to display remarkable cell penetrating properties, offering the possibility of highly efficient cellular targeting.

Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.

Euthanasia: the final paradox.

OBJECTIVE: The aim of this paper is to consider the history of human beings killing one another and reflect upon their reasons. Has it ever been altruistic? METHOD: Important examples of large episodes of killing, such as wars, the Crusades, the Inquisition and genocides were examined. RESULTS: Reasons are always advanced for killing large numbers of people who did not want to die. They were not based on logic nor on altruism but on moralities constructed from religious and political beliefs. Those who wanted to die because of unrelievable pain involved in the process of dying from an incurable illness are always preserved against their wishes. Once more, the reasons were usually religious and/or politically supported. CONCLUSION: The belief that it is acceptable to kill those who do not want to die but unacceptable to kill those who want to die provides a curious paradox.