Objective
Increased protein phosphatase magnesium‐dependent 1A (PPM1A) levels in patients with ankylosing spondylitis regulate osteoblast differentiation in bony ankylosis; however, the potential ...mechanisms that regulate osteoclast differentiation in relation to abnormal bone formation remain unclear. This study was undertaken to investigate the relationship of PPM1A to osteoclast differentiation by generating conditional gene‐knockout (PPM1Afl/fl;LysM‐Cre) mice and evaluating their bone phenotype.
Methods
The bone phenotypes of LysM‐Cre mice (n = 6) and PPM1Afl/fl;LysM‐Cre mice (n = 6) were assessed by micro–computed tomography. Osteoclast differentiation was induced by culturing bone marrow–derived macrophages in the presence of RANKL and macrophage colony‐stimulating factor (M‐CSF), and was evaluated by counting tartrate‐resistant acid phosphatase–positive multinucleated cells. Levels of messenger RNA for PPM1A, RANK, and osteoclast‐specific genes were examined by real‐time quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Surface RANK expression was analyzed by fluorescence flow cytometry.
Results
The PPM1Afl/fl;LysM‐Cre mice displayed reduced bone mass (P < 0.001) and increased osteoclast differentiation (P < 0.001) and osteoclast‐specific gene expression (P < 0.05) compared with their LysM‐Cre littermates. Mechanistically, reduced PPM1A function in osteoclast precursors in PPM1Afl/fl;LysM‐Cre mice induced osteoclast lineage commitment by up‐regulating RANK expression (P < 0.01) via p38 MAPK activation in response to M‐CSF. PPM1A expression in macrophages was decreased by Toll‐like receptor 4 activation (P < 0.05). The Ankylosing Spondylitis Disease Activity Score was negatively correlated with the expression of PPM1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = −0.7072, P < 0.0001).
Conclusion
The loss of PPM1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM1A in dynamic bone metabolism in axial SpA.
Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer ...patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology.
Innovations in communication technology have changed the way news is produced and consumed. Various digital platforms, ranging from news websites to social media sites to personal blogs, have enabled ...news users to indicate how much they like the news they have read, to share it with others, and to leave comments. News users' mouse clicks are automatically recorded and aggregated by computational systems and made publicly visible (e.g., “Most Read Articles”). This essay reviews the ever‐growing research on how audience feedback online, a hybrid form of interpersonal and mass communication, alters various stages of news production and influences the way people select, process, and make sense of the news. Future research agendas are proposed.
In this study, we investigated the effect of nZVI on plant root elongation in Arabidopsis thaliana and showed, for the first time, that nZVI enhanced root elongation by inducing OH radical-induced ...cell wall loosening. Exposure of plants to 0.5 g/L nZVI enhanced root elongation by 150–200% over that in the control, and further mechanistic studies showed that this occurred via nZVI-mediated OH radical-induced cell wall loosening. The oxidation capacity of nZVI, leading to release of H2O2, allowed it to cause OH radical-induced cell wall loosening in roots. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometers (MALDI-TOFMS)-based analysis clearly revealed that pectin-polysaccharides in roots were degraded; they are one of the main matrix-polysaccharide-connecting and load-bearing polymers in cell walls. Rapid root elongation led to structural changes in root cell walls: reduction of cell wall thickness and a bias on the orientation of cellulose microfibrils. Additionally, the asymmetrical distribution of tensional strength resulted from the OH radical-induced cell wall loosening enhanced endocytosis. These findings emphasize that OH radical-induced cell wall loosening is important for mechanical regulation of the cell wall and provide new insights into the cellular responses of plants exposed to reactive metal nanoparticles.
This study investigated if user‐generated comments on Internet news sites affect readers' inferences about public opinion, and subsequently, their perceptions of media bias, and how ego‐involvement ...moderates such effects. Supporting the notion that hostile media perception (HMP) stems from defensive processing, those who read others' comments discordant (vs. concordant) with their own opinion believed that the public was against their position and perceived the news report to be more hostile and partial in its coverage, but such effects were limited to those with higher ego‐involvement. Readers' comments also had a direct effect on HMP among more involved individuals, without altering their perceptions of public opinion, suggesting that people might misattribute the opinions expressed in others' comments to the news article.
Abstract
While several major theories and models have emerged and guided research on computer-mediated communication (CMC) in the interpersonal context, equivalent theoretical development seems to be ...lacking in the study of mass-oriented CMC, despite a large volume of amassed research. This article aims to propose an integrative conceptual framework for the study of mass-oriented, including mass-personal CMC, with (perceived) authenticity as its core unifying construct. A range of theoretical constructs independently developed in various subdisciplines and pertinent research findings are reviewed in light of the authenticity of source, message, and interaction. Several testable propositions are derived concerning antecedents to and consequences of authenticity judgments, with a view to stimulating programmatic empirical investigations on the role of authenticity in CMC.
Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via ...tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.
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•Thalamic astrocytes synthesize GABA via DAO and Aldh1a1 to mediate tonic inhibition•Tonic GABA improves linearity and temporal fidelity of synaptically evoked TC firing•Astrocytic tonic GABA improves tactile discrimination performance
Kwak et al. report that astrocytes synthesize GABA using DAO and Aldh1a1 and release GABA through the Best1 channel to mediate tonic GABA in the thalamus. Astrocytic tonic GABA fine-tunes the dynamic range and precision of stimulation to response of TC firing, thus enhancing the performance of sensory discrimination of mice.
Will consumers accept artificial intelligence (AI) as a medical care provider? On the basis of evolution theory, we investigate the implicit psychological mechanisms that underlie consumers’ ...interactions with medical AI and a human doctor. In a behavioral investigation (Study 1), consumers expressed a positive intention to use medical AI's healthcare services when it used personalized rather than mechanical conversation. However, neural investigation (Study 2) using functional magnetic resonance imaging revealed that some consumers’ implicit attitudes toward medical AI differed from their expressed behavioral intentions. The brain areas linked with implicitly apathetic emotions were activated even when medical AI used a personalized conversation, whereas consumers’ brains were activated in areas associated with prosociality when they interacted with a human doctor who used a personalized conversation. On the basis of our neural evidence, consumers perceive an identical personalized conversation differently when it is offered by a medical AI versus a human doctor. These findings have implications for the area of human–AI interactions and medical decision‐making and suggest that replacing human doctors with medical AI is still an unrealistic proposition.
With the rampant increase of misinformation produced and distributed online at an alarming rate, it has become more imperative than ever to understand what makes people fall for misinformation. ...Drawing on the literature on persuasion, credibility of online information, and digital deception, we first review a list of factors associated with the source, message, channel, and receiver that may alter the extent to which people judge information as truthful and believable. Based on critical assessments of the gaps in the literature, suggestions are offered to shape future research agendas and develop an integrative conceptual framework.
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