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Objectives: Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs., Methods: Forty patients with rheumatoid arthritis who had been in remission for more than 12 months were included in the study. The patients discontinued their biological DMARD treatment and were monitored monthly for the next 24 months. Out of the 40 patients, 14 (35%) remained in remission at the end of the 24-month period, while 26 (65%) experienced relapses at different time points. Among the relapse cases, 13 patients experienced early relapse within 6 months, and another 13 patients had late relapse between 6 months and 24 months. Seventy-three cytokines in the sera collected longitudinally from the 13 patients with late relapse were measured by multiplex immunoassay. Using cytokines at two time points, immediately after withdrawal and just before relapse, volcano plot and area under the receiver operating characteristic curves (AUC) were drawn to select cytokines that distinguished imminent relapse. Univariate and multivariate logistic regression analyses were used for the imminent relapse prediction model., Results: IL-6, IL-29, MMP-3, and thymic stromal lymphopoietin (TSLP) were selected as potential biomarkers for imminent relapse prediction. All four cytokines were upregulated at imminent relapse time point. Univariate and multivariate logistic regression showed that a combination model with IL-6, MMP-3, and TSLP yielded an AUC of 0.828 as top predictors of imminent relapse., Conclusions: This methodology allows for the prediction of imminent relapse while patients are in remission, potentially enabling the implementation of on- and off-treatments while maintaining remission. It also helps alleviate patient anxiety regarding the high cost and infection risks associated with biological DMARDs, which are the main obstacles to benefiting from their superb efficacy., Competing Interests: None, (Copyright: © 2024 Sakashita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases., Competing Interests: The authors have declared that no competing interests exist.