In the conventional pathway of protein secretion, leader sequence-containing proteins leave the cell following processing through the endoplasmic reticulum (ER) and Golgi body. However, leaderless ...proteins also enter the extracellular space through mechanisms collectively known as unconventional secretion. Unconventionally secreted proteins often have vital roles in cell and organism function such as inflammation. Amongst the best-studied inflammatory unconventionally secreted proteins are interleukin (IL)-1β, IL-1α, IL-33 and high-mobility group box 1 (HMGB1). In this review we discuss the current understanding of the unconventional secretion of these proteins and highlight future areas of research such as the role of nuclear localisation.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the ...proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics.
The interleukin-1 (IL-1) receptor and ligand families are components of the immune system. Knowledge of their evolutionary history is essential to understand their function. Using chromosomal anatomy ...and sequence similarity, we show that IL-1 receptor family members are related and nine members are likely formed from duplication and modification of a proto-IL-1R1 receptor. The IL-1 ligands have a different evolutionary history. The first proto-IL-1β gene coincided with proto-IL-1R1 and duplication events resulted in the majority of IL-1 ligand family members. However, large evolutionary distances are observed for IL-1α, IL-18 and IL-33 proteins. Further analysis show that IL-33 and IL-18 have poor sequence similarity and no chromosomal evidence of common ancestry with the IL-1β cluster and therefore should not be included in the IL-1 ligand ancestral family. IL-1α formed from the duplication of IL-1β, and moonlighting functions of pro-IL-1α acted as divergent selection pressures for the observed sequence dissimilarity.
Power distance is a value that differentiates individuals, groups, organizations, and nations based on the degree to which inequalities are accepted either as unavoidable or as functional. ...Understanding power distance is especially important in organizational research because power is fundamental to all relationships, is inherent in hierarchical organizations, and affects many organizational processes and outcomes. We begin by reviewing existing value taxonomies and definitional elements of power distance. Next, we review theories and research linking power distance to micro and macro work-related outcomes. We conclude by identifying areas where additional organizational research on power distance is needed and, in doing so, provide an agenda for future research in this area. Our review highlights power distance as an important explanatory variable and boundary condition for many relations that organizational (not just cross-cultural) scientists examine.
In longitudinal studies, it is not uncommon to make multiple attempts to collect a measurement after baseline. Recording whether these attempts are successful provides useful information for the ...purposes of assessing missing data assumptions. This is because measurements from subjects who provide the data after numerous failed attempts may differ from those who provide the measurement after fewer attempts. Previous models for these designs were parametric and/or did not allow sensitivity analysis. For the former, there are always concerns about model misspecification and for the latter, sensitivity analysis is essential when conducting inference in the presence of missing data. Here, we propose a new approach which minimizes issues with model misspecification by using Bayesian nonparametrics for the observed data distribution. We also introduce a novel approach for identification and sensitivity analysis. We re‐analyze the repeated attempts data from a clinical trial involving patients with severe mental illness and conduct simulations to better understand the properties of our approach.
Shame is a powerful and relevant discrete emotion in the workplace, as organizations are rife with potential to induce shame, and reactions to shame relate to important organizationally relevant ...outcomes. In this article, we review shame-related research from a variety of disciplines, integrating and identifying common patterns to better understand the shame process as it relates to organizational life. In doing so, we develop a framework that outlines the more internal psychological processes at the heart of the emotion of shame and situates these processes within the context of organizations. This framework highlights the organizational factors that help instigate shame in employees (i.e., unintentional shame triggers and purposeful shaming behaviors) as well as the behavioral outcomes important to organizations (i.e., prosocial, withdrawal, and aggressive behaviors) and provides insights regarding moderators that likely impact this process. In addition, we discuss future research implications as they pertain to each of the components in our framework, hoping that our article not only improves our understanding of organizational shame but encourages much-needed future research on it.
Microglial endolysosomal (dys)function is strongly implicated in neurodegenerative disease. Transcriptomic studies show that a microglial state characterised by a set of genes involved in ...endolysosomal function is induced in both mouse Alzheimer's disease (AD) models and human AD brain, and that the emergence of this state is emphasised in females.
(encoding cystatin F) is among the most highly upregulated genes in these microglia. However, despite such striking and robust upregulation, the function of
in neurodegenerative disease is not understood. Here, we crossed
mice with the
mouse to test the role of
in a model of amyloid-driven AD. Surprisingly, we found that
plays a sexually dimorphic role regulating microglia in this model. In females,
microglia had greater endolysosomal gene expression, lysosomal burden, and amyloid beta (Aβ) burden
and were more phagocytic
. However, in males,
microglia were less inflammatory and had a reduction in lysosomal burden but had no change in Aβ burden. Overall, our study reveals functional roles for one of the most commonly upregulated genes in microglia across disease models, and the sex-specific profiles of
-altered microglial disease phenotypes. More broadly, the findings raise important implications for AD including crucial questions on sexual dimorphism in neurodegenerative disease and the interplay between endolysosomal and inflammatory pathways in AD pathology.
Research on emotional labor focuses on how employees utilize 2 main regulation strategies-surface acting (i.e., faking one's felt emotions) and deep acting (i.e., attempting to feel required ...emotions)-to adhere to emotional expectations of their jobs. To date, researchers largely have considered how each strategy functions to predict outcomes in isolation. However, this variable-centered perspective ignores the possibility that there are subpopulations of employees who may differ in their combined use of surface and deep acting. To address this issue, we conducted 2 studies that examined surface acting and deep acting from a person-centered perspective. Using latent profile analysis, we identified 5 emotional labor profiles-non-actors, low actors, surface actors, deep actors, and regulators-and found that these actor profiles were distinguished by several emotional labor antecedents (positive affectivity, negative affectivity, display rules, customer orientation, and emotion demands-abilities fit) and differentially predicted employee outcomes (emotional exhaustion, job satisfaction, and felt inauthenticity). Our results reveal new insights into the nature of emotion regulation in emotional labor contexts and how different employees may characteristically use distinct combinations of emotion regulation strategies to manage their emotional expressions at work.
Mediation analysis with contemporaneously observed multiple mediators is a significant area of causal inference. Recent approaches for multiple mediators are often based on parametric models and thus ...may suffer from model misspecification. Also, much of the existing literature either only allow estimation of the joint mediation effect or estimate the joint mediation effect just as the sum of individual mediator effects, ignoring the interaction among the mediators. In this article, we propose a novel Bayesian nonparametric method that overcomes the two aforementioned drawbacks. We model the joint distribution of the observed data (outcome, mediators, treatment, and confounders) flexibly using an enriched Dirichlet process mixture with three levels. We use standardization (g-computation) to compute all possible mediation effects, including pairwise and all other possible interaction among the mediators. We thoroughly explore our method via simulations and apply our method to a mental health data from Wisconsin Longitudinal Study, where we estimate how the effect of births from unintended pregnancies on later life mental depression (CES-D) among the mothers is mediated through lack of self-acceptance and autonomy, employment instability, lack of social participation, and increased family stress. Our method identified significant individual mediators, along with some significant pairwise effects.
As the population of the older individuals continues to grow, it is important to study the relationship among the variables measuring financial health and physical health of the older individuals to ...better understand the demand for healthcare, and health insurance. We propose a semiparametric approach to jointly model these variables. We use data from the Health and Retirement Study which includes a set of correlated longitudinal variables measuring financial and physical health. In particular, we propose a dynamic hierarchical matrix stick-breaking process prior for some of the model parameters to account for the time dependent aspects of our data. This prior introduces dependence among the parameters across different groups which varies over time. A Lasso type shrinkage prior is specified for the covariates with time-invariant effects for selecting the set of covariates with significant effects on the outcomes. Through joint modeling, we are able to study the physical health of the older individuals conditional on their financial health, and vice-versa. Based on our analysis, we find that the health insurance (medicare) provided by the government (of the United States) to the older individuals is very effective, and it covers most of the medical expenditures. However, none of the health insurances conveniently cover the additional medical expenses due to chronic diseases like cancer and heart problem. Simulation studies are performed to assess the operating characteristics of our proposed modeling approach.
Supplementary materials
for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.
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