•We study the training effect of experience in multiple job holding (MJH).•MJH stimulates skills development for full-time workers who do not change jobs.•The same propensity is observed in volunteer ...workers and participation of job training, but the effect is small.•Japanese firms pay compensation to restrict job choice during leisure hours.
This study investigated the training effect of multiple job holding on the activity of main jobs. First, we developed a dual-labor supply model by adding the training effect of working second jobs. The theory showed that workers with unconstrained hours hold second jobs when they develop skills via the experience of second jobs. To verify the hypotheses from the theoretical model, the causal relationship between holding a second job and the wage rate of a main job was estimated using the Keio Household Panel Survey. Difference generalized method of moments was adopted to remove time-invariant individual effects and endogenous bias. Moreover, the estimations showed heterogeneity of main jobs in terms of length of working hours, tasks, and job turnover. Full-time workers engaged in intelligent tasks and those who did not change their jobs secured training effects from second jobs but only when the comparison group was the workers allowed to hold second jobs by their employers. It was presumed that employers paid to restrict employees’ activities. On the contrary, part-time workers engaged in physical tasks were exhausted by second jobs, which decreased the wage rate of their main jobs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
European League Against Rheumatism（EULAR）describes the situation before the onset of RA as follows: ①“Individual at risk on the basis of genetic and environmental risk factors with no identifiable ...laboratory abnormalities and no symptoms or signs of inflammatory arthritis”, ②“Individual at risk of RA on the basis of laboratory abnormalities（eg, ACPA, RF positivity with no symptoms or signs of inflammatory arthritis”, ③“Individual at risk on the basis of symptoms of inflammatory arthritis（eg, arthralgia/morning stiffness）but no clinical or imaging evidence of synovitis”, ④“Individuals with synovitis on imaging but no clinically apparent inflammatory arthritis”, ⑤“Individual with clinically apparent inflammatory arthritis not yet fulfilling classification criteria for RA”. Thus, EULAR proposes to express these with“Pre-RA”, “Pre-clinical RA”, “Inflammatory arthralgia”, “Autoantibody-positive arthralgia”, and“Undifferentiated arthritis”. Considering the “window of opportunity” and “treat-to-target” in RA treatment, it is necessary to grasp the pathological conditions before the onset of RA as accurately as possible and predict the “risk of developing RA” in each individual as accurately as possible. Accordingly, these are the extremely important research themes that is directly linked to the introduction of（ultra）early treatment toward inflammatory arthritis patients in the near future.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the bone erosion in RA has been ...demonstrated. Deregulated osteoclastogenesis which is affected by environmental factors including the inflammatory state, as well as genetic and epigenetic factors, is one of hallmarks of RA pathogenesis. An enhanced-monocyte-to-osteoclast transition plays an important role in osteoclast upregulation in RA because under specific stimuli, circulating monocytes might migrate to a specific location in the bones and fuse with each other to become mature multinucleated osteoclasts. To understand the mechanism of bone damage in RA and to develop novel treatments targeting osteoclast upregulation, it is important to clarify our understanding of the monocyte-to-osteoclast transition in RA. Several potential targets which inhibit both inflammation and osteoclastogenesis, as well as regulators that affect the monocyte-to-osteoclast transition have been revealed by recent studies. Here, we review the factors affecting osteoclastogenesis in RA, summarize the anti-osteoclastogenic effects of current RA treatments, and identify promising therapeutic targets relating to both inflammation and osteoclastogenesis.
Autoinflammatory diseases are characterized by abnormalities that prevent innate immune cells from producing autoantibodies. While interleukin (IL)-6 is not directly associated with inflammasomes, ...like IL-1β or IL-18, it plays an important role in the pathogenesis of autoinflammatory diseases. Studies of autoinflammatory diseases, such as familial Mediterranean fever, cryopyrin-associated periodic syndrome, and tumor necrosis factor receptor-associated periodic syndrome, have shown IL-6 to be a promising therapeutic target. It has also been suggested that inhibition of IL-6 may have a therapeutic effect on amyloidosis, which is frequently associated with these chronic inflammatory diseases. In this study, we discuss the most recent research on the role of IL-6 in autoinflammatory diseases and its potential as a therapeutic target in their treatment.
Cellular responses to injury are crucial for complete tissue regeneration, but their underlying processes remain incompletely elucidated. We have previously reported that myeloid-defective zebrafish ...mutants display apoptosis of regenerative cells during fin fold regeneration. Here, we found that the apoptosis phenotype is induced by prolonged expression of
(
). Myeloid cells are considered to be the principal source of Il1b, but we show that epithelial cells express
in response to tissue injury and initiate the inflammatory response, and that its resolution by macrophages is necessary for survival of regenerative cells. We further show that Il1b plays an essential role in normal fin fold regeneration by regulating expression of regeneration-induced genes. Our study reveals that proper levels of Il1b signaling and tissue inflammation, which are tuned by macrophages, play a crucial role in tissue regeneration.
The clinical manifestations of idiopathic multicentric Castleman disease (iMCD) are thought to be caused by an excess of inflammatory cytokines; however, the mechanism is yet to be known. In addition ...to IL-6, inflammatory cytokines, such as IL-1β and TNF-α, are noted to be elevated in iMCD, which are common in autoinflammatory diseases. The first-line treatment for iMCD is an IL-6 inhibitor. Furthermore, increases in inflammatory cytokines such as serum IL-10 and IL-23, chemokines such as CXCL13 and CXCL-10 (especially in iMCD-TAFRO), and VEGF-A have been observed, and their relationship to pathogenesis has attracted the attention of researchers. The PI3K/Akt/mTOR pathway, JAK/STAT3 pathway, and type I IFN as drivers have recently been identified as important signals and are expected to be therapeutic targets in cases where IL-6 inhibitors are ineffective.
Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- ...and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Genetic, environmental, and epigenetic factors simultaneously or serially contribute to immune cells and resident joint tissue cell abnormalities, invariably leading to joint destruction. ...Understanding the immune cell dysfunction in earlier years has brought forward life-changing therapeutics to patients with rheumatoid arthritis (RA). Further advances in the understanding of the immune and joint tissue-resident cell signaling and metabolic defects should produce additional tools to treat people with RA and foretell those who will respond to each biological or small drug. This review presents the latest evidence on RA pathogenesis and outlines the prospects for achieving precision medicine.
•This review presents the latest evidence on RA pathogenesis.•Synovial fibroblasts, B cells and T cells are important in the RA pathogenesis.•Mechanistic studies have highlighted cellular metabolism as a potential therapeutic target in RA.•It is desired that the pathogenesis of RA can be stratified to lead to personalized medicine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The regenerative epidermis (RE) is a specialized tissue that plays an essential role in tissue regeneration. However, the fate of the RE during and after regeneration is unknown. In this study, we ...performed Cre-
-mediated cell fate tracking and revealed the fates of a major population of the RE cells that express
(
) during zebrafish fin regeneration. Our study showed that these RE cells are mainly recruited from the inter-ray epidermis, and that they follow heterogeneous cell fates. Early recruited cells contribute to initial wound healing and soon disappear by apoptosis, while the later recruited cells contribute to the regenerated epidermis. Intriguingly, many of these cells are also expelled from the regenerated tissue by a dynamic caudal movement of the epidermis over time, and in turn the loss of epidermal cells is replenished by a global self-replication of basal and suprabasal cells in fin. De-differentiation of non-basal epidermal cells into the basal epidermal cells did not occur during regeneration. Overall, our study reveals the heterogeneous fates of RE cells and a dynamic rearrangement of the epidermis during and after regeneration.
The lasso peptide MS-271 is a ribosomally synthesized and post-translationally modified peptide (RiPP) consisting of 21 amino acids with D-tryptophan at the C-terminus, and is derived from the ...precursor peptide MslA. MslH, encoded in the MS-271 biosynthetic gene cluster (msl), catalyzes the epimerization at the Cα center of the MslA C-terminal Trp21, leading to epi-MslA. The detailed catalytic process, including the catalytic site and cofactors, has remained enigmatic. Herein, based on X-ray crystallographic studies in association with MslA core peptide analogues, we show that MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold. The crystal structure analysis, followed by site-directed mutagenesis, docking simulation, and ICP-MS studies demonstrate that MslH employs acid/base chemistry to facilitate the reversible epimerization of the C-terminal Trp21 of MslA, by utilizing two pairs of His/Asp catalytic residues that are electrostatically tethered to a six-coordination motif with a Ca(II) ion via water molecules.
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