Interleukin-1, an inflammatory cytokine, is considered to have diverse physiological functions and pathological significances and play an important role in health and disease. In this decade, ...interleukin-1 family members have been expanding and evidence is accumulating that highlights the importance of interleukin-1 in linking innate immunity with a broad spectrum of diseases beyond inflammatory diseases. In this review, we look back on the definition of "inflammation" in traditional general pathology and discuss new insights into interleukin-1 in view of its history and the molecular bases of diseases, as well as current progress in therapeutics.
When participants control periodic isometric force cycling between two target forces, they more accurately control force in a joint action than in an individual action. In some other studies, ...however, individuals tend to outperform dyads in joint action. The present study thus examined experimental conditions in which dyads outperformed individuals in a task of force produced by two people. This study consisted of two tasks with two target conditions and three force production conditions. The individual task was performed by one participant, and the joint task was performed by two participants. In absolute and relative target conditions, the participants made continuous, discrete, and periodic isometric pressing movements with the index finger. Although no difference was seen in force error between tasks in the continuous condition, the joint task had a smaller error than the individual task in the two other conditions. The joint task had a smaller variable force than the individual task in the periodic conditions, but no difference was seen in force variability between tasks in the two other conditions. Participants mainly controlled force in both tasks in the continuous condition. In the periodic or discrete condition at a prescribed interval, however, participants had to control both force and timing in the individual task, and muscle force must be mainly controlled to compensate for force errors by synchronizing interpersonal force outputs in the joint task. Thus, dyads can reduce the dimensionality of the control problem because they can synchronize their action which provides timing information.
The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/caspase-1/interleukin(IL)-1β axis, also known as the inflammasome pathway, is indispensable for IL-1β ...activation in response to various pathogens or own damages. Previously, we developed an NLRP3-inflammasome using a cell-free system and identified ASC targeting drugs; thus, examination of ASC-related histopathology in various diseases could help to provide indications for these drugs. Here, we generated mice deficient only in ASC-protein (ASC-deficient (AD) mice) using CRISPR/Cas9 technology, studied which tissues were most affected, and obtained histopathological images of lipopolysaccharide (LPS)-induced endotoxemia. C57BL/6 wild-type (WT) and (AD) mice were injected intraperitoneally with a lethal dose (50 μg/g) of LPS. Statistical analysis of the survival of C57BL/6 mice and AD mice was performed using the Kaplan-Meier method and the log-rank test. The histopathological findings of multiple tissues from these mice were compared. Acute inflammation (e.g., catarrhal inflammation), along with congestion was observed in the colon of WT mice but not in that of AD mice. Adhesion of neutrophils to capillaries, along with interstitial infiltration, were observed in multiple tissues from WT mice. In AD mice, neutrophil infiltration was less severe but remained evident in the stomach, small intestine, heart, liver, kidney, spleen, and brain. Notably, there was no difference between WT and AD mice with respect to alveolar neutrophil infiltration and interstitial edema. These findings suggest that even though ASC contributes to systemic inflammation, it is dependent on the tissue involved. Intestinal congestion and edema might be good candidates for anti-ASC-targeted therapy.
Human death domain superfamily proteins (DDSPs) play important roles in many signaling pathways involved in cell death and inflammation. Disruption or constitutive activation of these DDSP ...interactions due to inherited gene mutations is closely related to immunodeficiency and/or autoinflammatory diseases; however, responsible gene mutations have not been found in phenotypical diagnosis of these diseases. In this study, we comprehensively investigated the interactions of death-fold domains to explore the signaling network mediated by human DDSPs. We obtained 116 domains of DDSPs and conducted a domain-domain interaction assay of 13,924 reactions in duplicate using amplified luminescent proximity homogeneous assay. The data were mostly consistent with previously reported interactions. We also found new possible interactions, including an interaction between the caspase recruitment domain (CARD) of CARD10 and the tandem CARD-CARD domain of NOD2, which was confirmed by reciprocal co-immunoprecipitation. This study enables prediction of the interaction network of human DDSPs, sheds light on pathogenic mechanisms, and will facilitate identification of drug targets for treatment of immunodeficiency and autoinflammatory diseases.
The present study aimed to determine the effects of force asymmetry on interpersonal force production. This study consisted of an individual task executed by one participant at a time in a pair, and ...three joint tasks executed by two participants simultaneously under conditions of 1:1, 1:0.75, and 1:0.5. Two individuals produced discrete forces at the same time so that the sum of forces they produced was the target force in the joint task. Under the 1:1 condition, the target force was the sum of the maximum voluntary contraction (MVC) produced by the index finger of each participant × 0.1 (10% MVC). Under the 1:0.75 condition, the investigators manipulated the force produced by only one of the pair, for example,
B
, but not
A
. The feedback was also scaled as a result. The target force was the MVC of participant
A
+ the MVC of participant
B
× 0.75 × 0.1. Similarly, the target force under the 1:0.5 condition was the MVC of participant
A
+ the MVC of participant
B
× 0.5 × 0.1. The present study found that forces produced by pairs were negatively correlated and the correlation value was higher under the 1:1 condition than the 1:0.75 and 1:0.5 conditions. The absolute error was smaller under the 1:1 condition than the 1:0.5 condition. Complementary force production was attenuated and the error increased as differences between forces produced by two participants increased. Thus, asymmetry of forces produced by pairs deteriorated complementary force production and interpersonal performance.
Background- Inflammation plays a key role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury; however, the mechanism by which myocardial I/R induces inflammation remains unclear. ...Recent evidence indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple-protein complex called the inflammasome. Therefore, we hypothesized that the inflammasome is an initial sensor for danger signal(s) in myocardial I/R injury. Methods and Results- We demonstrate that inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, is crucially involved in the initial inflammatory response after myocardial I/R injury. We found that inflammasomes are formed by I/R and that its subsequent activation of inflammasomes leads to interleukin-1β production, resulting in inflammatory responses such as inflammatory cell infiltration and cytokine expression in the heart. In mice deficient for apoptosis-associated speck-like adaptor protein and caspase-1, these inflammatory responses and subsequent injuries, including infarct development and myocardial fibrosis and dysfunction, were markedly diminished. Bone marrow transplantation experiments with apoptosis-associated speck-like adaptor protein-deficient mice revealed that inflammasome activation in bone marrow cells and myocardial resident cells such as cardiomyocytes or cardiac fibroblasts plays an important role in myocardial I/R injury. In vitro experiments revealed that hypoxia/reoxygenation stimulated inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, and that hypoxia/reoxygenation-induced activation was mediated through reactive oxygen species production and potassium efflux. Conclusions- Our results demonstrate the molecular basis for the initial inflammatory response after I/R and suggest that the inflammasome is a potential novel therapeutic target for preventing myocardial I/R injury.
If two people lift and carry an object, they not only produce complementary forces on the object but also walk in synchrony. Previous studies have not examined how two types of coordination strategy ...are adopted simultaneously. The present study thus tested the hypothesis that complementary and synchronous strategies simultaneously facilitate the action coordination performed by two people. Ten pairs of participants produced periodic isometric forces such that the sum of forces they produced was the target force cycling between 5% and 10% of maximum voluntary contraction with an interval of 1,000 ms (joint action), while individuals alone produced the same target forces with the right hand (individual action). The correlation between forces produced by two participants was highly negative when the total force was visible, indicating that the two participants produced complementary forces. When the image of the total or partner force was presented, the coherence between force-time series produced by two participants was highest at 1 Hz. The relative phase angles were also distributed at the 0-20° phase region. These innovative findings indicate that two participants simultaneously adopted both complementary and temporal synchronous strategies exclusively when the total force was visible. With the vision of total force, surprisingly, while the joint action exhibited a less variable force than the individual action, the joint action exhibited a smaller absolute error of forces than the individual action. These new findings indicated that the joint action controlled force more accurately than the individual action.
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction ...in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan-Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.
The present study examined bidirectional learning transfer between joint and individual actions involving discrete isometric force production with the right index finger. To examine the effects of ...practice of joint action on performance of the individual action, participants performed a pre-test (individual condition), practice blocks (joint condition), and a post-test (individual condition) (IJI task). To examine the effects of practice of the individual action on performance during the joint action, the participants performed a pre-test (joint condition), practice blocks (individual condition), and a post-test (joint condition) (JIJ task). Whereas one participant made pressing movements with a target peak force of 10% maximum voluntary contraction (MVC) in the individual condition, two participants produced the target force of the sum of 10% MVC produced by each of them in the joint condition. In both the IJI and JIJ tasks, absolute errors and standard deviations of peak force were smaller post-test than pre-test, indicating bidirectional transfer between individual and joint conditions for force accuracy and variability. Although the negative correlation between forces produced by two participants (complementary force production) became stronger with practice blocks in the IJI task, there was no difference between the pre- and post-tests for the negative correlation in the JIJ task. In the JIJ task, the decrease in force accuracy and variability during the individual action did not facilitate complementary force production during the joint action. This indicates that practice performed by two people is essential for complementary force production in joint action.
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