Although workplace incivility has received increasing attention in organizational research over the past two decades, there have been recurring questions about its construct validity, especially ...vis-à-vis other forms of workplace mistreatment. Also, the antecedents of experienced incivility remain understudied, leaving an incomplete understanding of its nomological network. In this meta-analysis using Schmidt and Hunter's Methods of meta-analysis: Correcting error and bias in research findings (3rd ed.), Sage random-effect meta-analytic methods, we validate the construct of incivility by testing its reliability, convergent and discriminant validity, as well as its incremental predictive validity over other forms of mistreatment. We also extend its nomological network by drawing on the perpetrator predation framework to systematically study the antecedents of experienced incivility. Based on 105 independent samples and 51,008 participants, we find extensive support for incivility's construct validity. Besides, we demonstrate that demographic characteristics (gender, race, rank, and tenure), personality traits (agreeableness, conscientiousness, neuroticism, negative affectivity, and self-esteem), and contextual factors (perceived uncivil climate and socially supportive climate) are important antecedents of experienced incivility, with contextual factors displaying a stronger association with incivility. In a supplementary primary study with 457 participants, we find further support for the construct validity of incivility. We discuss the theoretical and practical implications of this study.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ
State tax and nontax incentives have been widespread in the United States, though their efficacy in job creation and economic development has been repeatedly questioned in the literature by scholars ...and policy makers. Why, then, do states persistently pursue these incentive policies? Using the newly developed Panel Database on Incentives and Taxes, we adopt a dynamic spatial Durbin panel model to account for both temporal and spatial dependence and to shed light on this question. Empirical evidence suggests a statistically significant and positive relationship between tax credits and tax burdens (i.e., elevated tax breaks are used to offset higher tax differentials). States therefore may seek to create a level playing field in business attraction and retention by overcoming tax disadvantages. Besides, high-serial dependence is present in the use of various tax credits, suggesting a high self-perpetuating tendency that tax breaks, once introduced, are likely to be persistent over time. States are also found to be engaged both in spatial competition or imitation among geographically proximate states, and in strategic benchmarking among states that are geographically distant but economically alike.
In this paper, we examine the interactive effects of positive affect and perspective-taking on workplace incivility and family incivility, through moral disengagement. We draw from broaden-and-build ...and moral disengagement theories to suggest a potential negative consequence of positive affect. Specifically, we argue that positive affect increases incivility toward coworkers and spouses through moral disengagement among employees with low, but not high perspective-taking. Data from two time-lagged field studies and one online experiment provide support for our hypotheses. These findings suggest that the beneficial effects of positive feelings are not universal, and the fostering of positive feelings at work might have unintended negative consequences, namely moral disengagement, and increased incivility at work and at home. Implications for theory and research are discussed.
Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes. The pancreatic hormone glucagon increases and insulin suppresses HGP, ...controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser
in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A-dependent phosphorylation of Foxo1 at Ser
Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser
phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser
is a new target site identified in the control of Foxo1 bioactivity and associated metabolic diseases.
Background
Addition of oxaliplatin to adjuvant 5-FU has significantly improved the disease-free survival and served as the first line adjuvant chemotherapy in advanced colorectal cancer (CRC) ...patients. However, a fraction of patients remains refractory to oxaliplatin-based treatment. It is urgent to establish a preclinical platform to predict the responsiveness toward oxaliplatin in CRC patients as well as to improve the efficacy in the resistant patients.
Methods
A living biobank of organoid lines were established from advanced CRC patients. Oxaliplatin sensitivity was assessed in patient-derived tumor organoids (PDOs)
in vitro
and in PDO-xenografted tumors in mice. Based on
in vitro
oxaliplatin IC
50
values, PDOs were classified into either oxaliplatin-resistant (OR) or oxaliplatin-sensitive (OS) PDOs. The outcomes of patients undergone oxaliplatin-based treatment was followed. RNA-sequencing and bioinformatics tools were performed for molecular profiling of OR and OS PDOs. Oxaliplatin response signatures were submitted to Connectivity Map algorithm to identify perturbagens that may antagonize oxaliplatin resistance.
Results
Oxaliplatin sensitivity in PDOs was shown to correlate to oxaliplatin-mediated inhibition on PDO xenograft tumors in mice, and parallelled clinical outcomes of CRC patients who received FOLFOX treatment. Molecular profiling of transcriptomes revealed oxaliplatin-resistant and -sensitive PDOs as two separate entities, each being characterized with distinct hallmarks and gene sets. Using Leave-One-Out Cross Validation algorithm and Logistic Regression model, 18 gene signatures were identified as predictive biomarkers for oxaliplatin response. Candidate drugs identified by oxaliplatin response signature-based strategies, including inhibitors targeting c-ABL and Notch pathway, DNA/RNA synthesis inhibitors, and HDAC inhibitors, were demonstrated to potently and effectively increase oxaliplatin sensitivity in the resistant PDOs.
Conclusions
PDOs are useful in informing decision-making on oxaliplatin-based chemotherapy and in designing personalized chemotherapy in CRC patients.
Real-world data on effectiveness and safety of a single non-vitamin K antagonist oral anticoagulant in the Chinese population with atrial fibrillation (AF) are limited. This study reports ...characteristics of patients treated with edoxaban and factors associated with dosing patterns from routine care in China. ETNA-AF-China (NCT04747496) is a multicentre, prospective, observational study enrolling edoxaban-treated patients from four economic regions with a targeted 2-year follow-up. Of the 4930 patients with AF (mean age: 70.2 ± 9.5 years; male, 57.1%), the mean creatinine clearance (CrCl), CHA
DS
-VASc, and HAS-BLED scores were 71.2 mL/min, 2.9, and 1.6. Overall, 6.4% of patients were perceived as frail by investigators. Available label dose reduction criteria (N = 4232) revealed that 3278 (77.5%) patients received recommended doses and 954 (22.5%) non-recommended doses. Northeast (53.0%) and West (43.1%) regions had the highest prescriptions of 60 mg and 30 mg recommended doses, respectively. Non-recommended 30 mg doses were more frequently prescribed in patients with antiplatelet use and history of heart failure than recommended 60 mg. Multivariate analysis identified advanced age as the strongest associated factor with non-recommended doses. Frailty had the strongest association with 30 mg except for age, and history of TIA was the most relevant factor associated with 60 mg. In conclusion, patients in the ETNA-AF-China study were predominantly aged 65 years and older, had mild-to-moderate renal impairment and good label adherence. Advanced age was associated with non-recommended doses, with frailty most common for non-recommended 30 mg and a history of TIA for the non-recommended 60 mg dose.
Tumor-derived extracellular vesicles (TEVs) suppress the proliferation and cytotoxicity of CD8+ T cells, thereby contributing to tumor immune evasion. Here, we report that the adhesion molecule ...intercellular adhesion molecule 1 (ICAM-1) co-localizes with programmed death ligand 1 (PD-L1) on the exosomes; both ICAM-1 and PD-L1 are upregulated by interferon-γ. Exosomal ICAM-1 interacts with LFA-1, which is upregulated in activated T cells. Blocking ICAM-1 on TEVs reduces the interaction of TEVs with CD8+ T cells and attenuates PD-L1-mediated suppressive effects of TEVs. During this study, we have established an extracellular vesicle-target cell interaction detection through SorTagging (ETIDS) system to assess the interaction between a TEV ligand and its target cell receptor. Using this system, we demonstrate that the interaction of TEV PD-L1 with programmed cell death 1 (PD-1) on T cells is significantly reduced in the absence of ICAM-1. Our study demonstrates that ICAM-1-LFA-1-mediated adhesion between TEVs and T cells is a prerequisite for exosomal PD-L1-mediated immune suppression.
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•ICAM-1 and PD-L1 co-localize on exosomes and are both upregulated by interferon-γ•ICAM-1 is a prerequisite for exosomal PD-L1-mediated inhibition of CD8+ T cells•Reciprocal upregulation of ICAM-1 and LFA-1 promotes exosome-T cell interaction•Established an assay system for the interaction of exosomal PD-L1 with PD-1 on T cells
Tumor-derived exosomes can suppress the proliferation and cytotoxicity of CD8+ T cells. Zhang and colleagues report that the exosomes adhere to activated CD8 T cells through an ICAM-1-LFA-1 interaction, which is a prerequisite for exosomal PD-L1-PD-1 binding and T cell suppression.
Malignant hyperthermia (MH) is a potentially fatal inherited pharmacogenetic disorder related to pathogenic variants in the RYR1, CACNA1S, or STAC3 genes. Early recognition of the occurrence of MH ...and prompt medical treatment are indispensable to ensure a positive outcome. The purpose of this study was to provide valuable information for the early identification of MH by summarizing epidemiological and clinical features of MH. This scoping review followed the methodological framework recommended by Arksey and O'Malley. PubMed, Embase, and Web of science databases were searched for studies that evaluated the epidemical and clinical characteristics of MH. A total of 37 studies were included in this review, of which 26 were related to epidemiology and 24 were associated with clinical characteristics. The morbidity of MH varied from 0.18 per 100 000 to 3.9 per 100 000. The mortality was within the range of 0%–18.2%. Identified risk factors included sex, age, disorders associated with MH, and others. The most frequent initial clinical signs included hyperthermia, sinus tachycardia, and hypercarbia. The occurrence of certain signs, such as hypercapnia, delayed first temperature measurement, and peak temperature were associated with poor outcomes. The epidemiological and clinical features of MH varied considerably and some risk factors and typical clinical signs were identified. The main limitation of this review is that the treatment and management strategies were not assessed sufficiently due to limited information.
A scoping review was conducted to summarize and analyze the clinical and epidemiological features of malignant hyperthermia according to the latest literature from 2010 to 2021.
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