[(1,2,5,6-η)-Cyclo-octa-1,5-diene](4-isopropyl-1-methyl-1,2,4-triazol-5-yl-idene)(tri-phenyl-phos-phane)iridium(I) tetra-fluorido-borate di-chloro-methane 0.8-solvate.

A new triazole-based N-heterocyclic carbene iridium(I) cationic complex with a tetra-fluorido-borate counter-anion, [Ir(C8H12)(C18H15P)(C6H11N3)]BF4·0.8CH2Cl2, has been synthesized and structurally characterized. The central IrI atom of the cationic complex has a distorted square-planar coordination environment, formed by a bidentate cyclo-octa-1,5-diene (COD) ligand, an N-heterocyclic carbene, and a tri-phenyl-phosphane ligand. The crystal structure comprises C-H⋯π(ring) inter-actions that orient the phenyl rings; non-classical hydrogen-bonding inter-actions between the cationic complex and the tetra-fluorido-borate anion are also present. The complex crystallizes in a triclinic unit cell with two structural units and an incorporation of di-chloro-methane solvate mol-ecules with an occupancy of 0.8.

An exploratory analysis of the relationship of problematic Facebook use with loneliness and self-esteem: the mediating roles of extraversion and self-presentation.

Studies indicate that loneliness and self-esteem are predictive factors of problematic social media use. Further, it is proposed that self-presentation and extraversion may explain individual differences in online activity and problematic social media use. The present study confirms the relationship of loneliness and self-esteem with problematic Facebook use and investigates the hypothesis that these psychological factors may be linked to problematic Facebook use through their association with self-presentation and extraversion. The sample of university students consisted of 477 Facebook users, 64% females, aged 18-64. Social media usage intensity was assessed by collecting passive data on the total time spent and the number of sessions on Facebook per day for the last 6 months. The psychological factors, personality, motives and problematic Facebook use were assessed via self-report measures. Results showed that the relationship of loneliness and self-esteem with problematic Facebook use was significantly positive and negative respectively. The relationship between self-esteem and problematic Facebook use was found to be inconsistently mediated by both self-presentation and extraversion, while loneliness was partially mediated by self-presentation only. The total effect of loneliness and self-esteem remained positive and negative respectively, although extraversion and self-presentation had a suppressing effect on the relationship between self-esteem and problematic Facebook use. Further, the prevalence of 'at-risk' Facebook users was found to be 6.0%. It was also determined that the usage intensity of 'at-risk' users was significantly different from other Facebook users. These results highlight the existence of different patterns of associations linking psychological factors, usage intensity and problematic Facebook use. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-03505-0.

Needs affordance as a key factor in likelihood of problematic social media use: Validation, latent Profile analysis and comparison of TikTok and Facebook problematic use measures.

Despite increasing concerns of maladaptive cognitive responses associated with social media, estimates of its prevalence are lacking in the literature. Further, existing studies have disproportionately focused on Facebook, while ignoring the penetration of TikTok and concerns of associated maladaptive behaviors. This study aims to 1) validate scale measures for problematic Facebook and TikTok use (PFU and PTTU) 2) comparatively assess the underlying cognitive pathways of the PFU and PTTU among a sample of university students, 3) determine the cut-off score of the PTTU assessment scale using Latent Profile Analysis (LPA) and 4) evaluate the contribution of specific criteria in the diagnosis of PTTU. The scales used to assess PFU and PTTU were found to have appropriate psychometric properties. The scores between the PFU and PTTU scales were found to be strongly associated, however, the relationship was stronger in the group of Facebook users than in the group of TikTok users. Further, the manifestation of problematic use was not consistent between TikTok and Facebook. Loneliness was positively associated with both PFU and PTTU, while self-esteem was negatively associated with PFU only. The optimal cut-off score of the PTTU scale was determined to be 21, giving 8.7% as the estimated prevalence of PTTU. The criteria with the highest predictive power in the diagnosis of addiction among university students were "withdrawal" and "relapse". The study concludes that while the underlying addiction pathways are similar between platforms the manifestation of maladaptive behavior and the drivers for usage intensity and problematic use are unique.

Work-leisure blending: An integrative conceptual review and framework to guide future research.

Since the industrial revolution, work and leisure have largely been considered opposing domains. A growing number of organizations, however, enable and/or promote blending leisure activities into the workplace. Similarly, several conceptualizations across different disciplines examine how work and leisure can coexist. These different conceptualizations have yielded a rich but fragmented theoretical account of work-leisure blending. To address this problem, we provide a comprehensive theoretical integration of multiple literature streams where research has explored work-leisure blending. Further, we develop a tripartite dimensional framework designed to elucidate the central dimensions of work-leisure blending (i.e., segmentation-integration, unstructured-structured, and independent-interactive) undergirding this phenomenon. Using this framework as a theoretical foundation, we then discuss important contextual considerations and future research directions related to work-leisure blending. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma.

Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context-specific roles for the mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) in various cancer lineages. Here, we find evidence that the SWI/SNF complex is essential through analysis of functional genomics screens and further validation in a panel of uveal melanoma cell lines using both genetic tools and small-molecule inhibitors of SWI/SNF. In addition, we describe a functional relationship between the SWI/SNF complex and the melanocyte lineage-specific transcription factor Microphthalmia-associated Transcription Factor, suggesting that these two factors cooperate to drive a transcriptional program essential for uveal melanoma cell survival. These studies highlight a critical role for SWI/SNF in uveal melanoma, and demonstrate a novel path toward the treatment of this cancer.

When challenges hinder: An investigation of when and how challenge stressors impact employee outcomes.

Over the past two decades, accumulating evidence has indicated that individuals experience challenge and hindrance stressors in qualitatively different ways, with the former being linked to more positive outcomes than the latter. Indeed, challenge stressors are believed to have net positive effects even though they can also lead to a range of strains, eliciting beliefs that managers can enhance performance outcomes by increasing the frequency of challenge stressors experienced in the workplace. The current article questions this conventional wisdom by developing theory that explains how different patterns of challenge stressor exposure influence employee outcomes. Across 2 field studies, our results supported our theory, indicating that when challenge stressors vary across time periods, they have negative indirect effects on employee performance and well-being outcomes. In contrast, when employees experience a stable pattern of challenge stressors across time periods, they have positive indirect effects on employee performance and well-being outcomes. These results, which suggest that the benefits of challenge stressors may not outweigh their costs when challenge stressors fluctuate, have important implications for theory and practice. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A context-change account of temporal distinctiveness.

The distinctiveness effect refers to the finding that items that stand out from other items in a learning set are more likely to be remembered later. Traditionally, distinctiveness has been defined based on item features; specifically, an item is deemed to be distinctive if its features are different from the features of other to-be-learned items. We propose that distinctiveness can be redefined based on context change-distinctive items are those with features that deviate from the others in the current temporal context, a recency-weighted running average of experience-and that this context change modulates learning. We test this account with two novel experiments and introduce a formal mathematical model that instantiates our proposed theory. In the experiments, participants studied lists of words, with each word appearing on one of two background colors. Within each list, each color was used for 50% of the words, but the sequence of the colors was controlled so that runs of the same color for that list were common in Experiment 1 and common, rare, or random in Experiment 2. In both experiments, participants' source memory for background color was enhanced for items where the color changed, especially if the change occurred after a stable run without color changes. Conversely, source memory was not significantly better for nonchanges after runs of alternating colors with each item. This pattern is inconsistent with theories of learning based on prediction error, but is consistent with our context-change account.

Cardiovascular Risk Reduction: A Pharmacotherapeutic Update for Antiplatelet Medications.

This update presents evidence for new antiplatelet therapies including modified P2Y12 inhibitors and a new class of thromboxane antagonists. Discussed are emerging data on established antihyperlipidemic medications that support an additional antiplatelet effect. Current information about the effectiveness of several bleeding reversal agents is discussed, and the concept of personalized antiplatelet therapy, wherein selection of an antiplatelet therapy is based on genetic factors or laboratory testing that predict response to therapy and risk of adverse effects. Finally, future drug targets are introduced and drug interactions that can be leveraged to design more effective and safe antiplatelet therapies are described.

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript.

Multiple team membership and empowerment spillover effects: Can empowerment processes cross team boundaries?

In today's organizations, employees are often assigned as members of multiple teams simultaneously (i.e., multiple team membership), and yet we know little about important leadership and employee phenomena in such settings. Using a scenario-based experiment and 2 field studies of leaders and their employees in the People's Republic of China and the United States, we examined how empowering leadership exhibited by 2 different team leaders toward a single employee working on 2 different teams can spillover to affect that employee's psychological empowerment and subsequent proactivity across teams. Consistent across all 3 studies, we found that each of the team leaders' empowering leadership uniquely and positively influenced an employee's psychological empowerment and subsequent proactive behaviors. In the field studies, we further found that empowering leadership exhibited by one team leader influenced the psychological empowerment and proactive behaviors of their team member not only in that leader's team but also in the other team outside of that leader's stewardship. Finally, across studies, we found that empowering leadership exhibited on one team can substitute for lower levels of empowering leadership experienced in a different team led by a distinct leader. We discuss our contributions to the motivation, teams, and leadership literatures and provide practical guidance for leaders charged with managing employees that have multiple team memberships. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

How much force is required to perforate a colon during colonoscopy? An experimental study.

INTRODUCTION: Colonoscopy is a commonly-performed procedure to diagnose pathology of the large intestine. Perforation of the colon is a rare but feared complication. It is currently unclear how much force is actually required to cause such injury nor how this is altered in certain diseases. Our aim was to analyze the forces required to perforate the colon in experiments using porcine tissues. METHODS: Using 3D printing technology, models of two commercially available colonoscope heads were printed under three configurations: straight (I), 90°- bent (L) and fully bent (U). Samples of porcine colon were assessed with the models and configurations under perpendicular and angular load application and these data compared to the maximum force typically exerted by experienced colonoscopists. RESULTS: The force required for perforation was significantly lower for the I compared to the L of the larger colonoscope head configuration under angular loading (14.1 vs. 46.5 N). Similar differences were found for linear stiffness when loaded (I vs. L small when loaded perpendicular: 0.8 vs. 2.4 N/mm, I vs. L large when loaded angled 0.7 vs. 2.1 N/mm). The mode and site of failure varied significantly between the scopes, with delamination of the mucosa/submucosa below the sample (96%) for the I, blunt mucosa/submucosa/muscularis failure adjacent to the loading site (77%) for the L, and failure of all colon layers lateral to the loading site (59%) for the U configuration, respectively. Perpendicular and angulated loading resulted in similar load-deformation values. Maximum forces typically exerted by colonoscopists averaged 13.9-27.9 N, depending on the colonoscope model and head configuration. DISCUSSION: The force required for colon perforation varies depending on the type mode of loading and is likely lower than the force an experienced colonoscopist would exert in daily practice. There is a real risk of perforation, especially when the end of the scope is advancing directly into the colonic wall. The given experimental setup allowed to obtain reliable data of the colon in a standardized scenario, forming the basis for further experiments.

Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers.

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases.

The experience of vivid autobiographical reminiscence is supported by subjective content representations in the precuneus.

The human posteromedial cortex, which includes core regions of the default mode network (DMN), is thought to play an important role in episodic memory. However, the nature and functional role of representations in these brain regions remain unspecified. Nine participants (all female) wore smartphone devices to record episodes from their daily lives for multiple weeks, each night indicating the personally-salient attributes of each episode. Participants then relived their experiences in an fMRI scanner cued by images from their own lives. Representational Similarity Analysis revealed a broad network, including parts of the DMN, that represented personal semantics during autobiographical reminiscence. Within this network, activity in the right precuneus reflected more detailed representations of subjective contents during vivid relative to non-vivid, recollection. Our results suggest a more specific mechanism underlying the phenomenology of vivid autobiographical reminiscence, supported by rich subjective content representations in the precuneus, a hub of the DMN previously implicated in metacognitive evaluations during memory retrieval.

Understanding the Economic Benefit Associated with Research and Services at the National Institute for Occupational Safety and Health: An Approach and Three Case Studies.

The National Institute for Occupational Safety and Health (NIOSH) asked the RAND Corporation to develop an approach, reported here, for estimating the economic benefit of NIOSH research, using three case studies. The cases provide concrete illustrations of the ways in which NIOSH research could affect worker health and safety practices and outcomes, as well as some initial estimates of the economic benefit associated with those impacts. The authors selected the case studies to illustrate variation in types of NIOSH research and in intended users. The first case study examines research to develop, test, and support implementation of engineering control measures to limit exposure to silica among road construction workers. This case study offers an example of NIOSH's intervention and surveillance research and provision of technical assistance. The second case study involves two NIOSH studies that strengthened the evidence base about the linkage between firefighting activities and increased risk of certain cancers among firefighters. This case study provides an example of etiological and exposure surveillance research, coupled with an intervention study. The third case study involves a NIOSH evaluation of the effectiveness of Ohio's Safety Intervention Grant Program in reducing the prevalence and costs of workplace injuries. This case study illustrates intervention research targeting government organizations. The first and second case studies led to the development of control technologies, and all three case studies involved dissemination and stakeholder engagement efforts that promoted the adoption of risk-reducing technologies and practices.

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.

A single trial analysis of EEG in recognition memory: Tracking the neural correlates of memory strength.

Recent work in perceptual decision-making has shown that although two distinct neural components differentiate experimental conditions (e.g., did you see a face or a car), only one tracked the evidence guiding the decision process. In the memory literature, there is a distinction between a fronto-central evoked potential measured with EEG beginning at 350ms that seems to track familiarity and a late parietal evoked potential that peaks at 600ms that tracks recollection. Here, we applied single-trial regressor analysis (similar to multivariate pattern analysis, MVPA) and diffusion decision modeling to EEG and behavioral data from two recognition memory experiments to test whether these two components contribute to the recognition decision process. The regressor analysis only involved whether an item was studied or not and did not involve any use of the behavioral data. Only late EEG activity distinguishes studied from not studied items that peaks at about 600ms following each test item onset predicted the diffusion model drift rate derived from the behavioral choice and reaction times (but only for studied items). When drift rate was made a linear function of the trial-level regressor values, the estimate for studied items was different than zero. This showed that the later EEG activity indexed the trial-to-trial variability in drift rate for studied items. Our results provide strong evidence that only a single EEG component reflects evidence being used in the recegnition decision process.

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight.

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

Human hippocampus represents space and time during retrieval of real-world memories.

Memory stretches over a lifetime. In controlled laboratory settings, the hippocampus and other medial temporal lobe brain structures have been shown to represent space and time on the scale of meters and seconds. It remains unclear whether the hippocampus also represents space and time over the longer scales necessary for human episodic memory. We recorded neural activity while participants relived their own experiences, cued by photographs taken with a custom lifelogging device. We found that the left anterior hippocampus represents space and time for a month of remembered events occurring over distances of up to 30 km. Although previous studies have identified similar drifts in representational similarity across space or time over the relatively brief time scales (seconds to minutes) that characterize individual episodic memories, our results provide compelling evidence that a similar pattern of spatiotemporal organization also exists for organizing distinct memories that are distant in space and time. These results further support the emerging view that the anterior, as opposed to posterior, hippocampus integrates distinct experiences, thereby providing a scaffold for encoding and retrieval of autobiographical memories on the scale of our lives.

It's all in the attitude: The role of job attitude strength in job attitude-outcome relationships.

Integrating attitude theory with the job attitudes literature, we position job attitude strength (JAS) as a missing yet important theoretical concept in the study of job attitudes. We examine JAS as a moderator of the relationship between job satisfaction and several criteria of interest to organizational scholars (job performance, organizational citizenship behavior, withdrawal). We also examine multiple relevant indicators of JAS (i.e., attitude certainty, attitude extremity, latitude of rejection, and structural consistency), both to shed light on its conceptual nature and to provide meaningful practical direction to researchers interested in incorporating JAS into job attitude research. Data were collected in five field samples (total N = 816). Results support our hypotheses: JAS moderates the relationships between job satisfaction and performance, organizational citizenship behavior, and turnover intentions; in each case, these relationships are significantly stronger for employees with stronger job satisfaction attitudes. However, as expected, not all JAS indicators are equally effective as moderators. We discuss our findings in terms of their theoretical, empirical, and practical implications for the future study of job attitudes.