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Atmosphere‐ocean dynamics in the tropics play a key role in global climate change. An abrupt cooling event that occurred between 4500 and 3900a BP, known as the 4.2 ka event, has long been believed to be linked to changes in sea surface temperatures (SSTs) associated with intensified El Niño and Southern Oscillation (ENSO) variability. However, the precise timing and amplitude of ENSO variability during the 4.2 ka event remain uncertain, largely due to the lack of resolution in records from the ENSO‐sensitive regions. Here we present a 104‐year‐long monthly resolved coral record from the South China Sea that spans from 4400 to 4300 years BP, corresponding to the onset of the 4.2 ka event. Using the Sr/Ca paleo‐thermometry, we show a significant decrease in ENSO variability during this time interval compared to the modern period. The ENSO events decrease in the frequency from one every 3.5 years during the modern era to one every 5.6 years during the onset of the 4.2 ka event, with weaker magnitude in the latter period. This reduction in ENSO variability is largely associated with an intensification of the Pacific Walker circulation. We therefore suggest that ENSO variability was a response to, not a driver of, the development of the 4.2 ka event. Plain Language Summary: Abrupt climate change occurred between 4,500 and 3,900 years ago, known as the 4.2 ka event, stands out as one of the most prominent climatic events in the Holocene and witnesses a northern hemisphere cooling and agricultural‐based civilization collapsed. A growing number of terrestrial records have shown that anomalous sea surface temperatures in the tropical oceans associated with intensified El Niño and Southern Oscillation (ENSO) variability triggered this abrupt climatic event. However, precise ENSO variability based on tropical oceanic records is still scarce, hindering our understanding of this event. Here, we evidence a significant reduction in ENSO variability during the onset of the 4.2 ka event using multiple monthly resolved coral records from the tropical oceans. This contrasts with previous studies that suggest increased ENSO variability triggers the 4.2 ka event, implying that anomalous ENSO variability may be a response to the 4.2 ka event. Key Points: Monthly resolved coral Sr/Ca record provides a century‐long evolution of El Niño and Southern Oscillation (ENSO) variability during the onset of the 4.2 ka eventThere is a significant reduction in ENSO variability during the onset of the 4.2 ka eventReduced ENSO variability during this time interval is associated with intensified Pacific Walker circulation [ABSTRACT FROM AUTHOR]

Aim: To elucidate whether mitochondrial biogenesis disorder and damage from oxidative stress promote refractory apical periodontitis (RAP) in rat and human. Methodology: Twenty Enterococcus faecalis‐induced RAPs were established in the maxillary first molars of male Wistar rats. Concurrently, 12 periapical lesion specimens from patients presenting with RAP were obtained by apicoectomy. Radiographic examination and histologic analysis were conducted to evaluate periapical bone tissue destruction and morphological changes. The expression of key regulators of mitochondrial biogenesis, PGC‐1α and Nrf2, were detected by immunohistochemistry and double immunofluorescence staining, Western blot and real‐time PCR were also assayed. Mitochondrial ROS (mtROS) was identified by MitoSOX staining. Mitochondrial function was detected by the quantification of ATP production, mitochondrial DNA (mtDNA) copy number and activities of mitochondrial respiratory chain complexes. Furthermore, mitochondrial oxidative stress was evaluated by the determination of 3‐nitrotyrosine (3‐NT), 4‐hydroxy‐2‐nonenal (4‐HNE) and 8‐hydroxy‐deoxyguanosine (8‐OHdG) expression levels, as well as malondialdehyde (MDA) expression and antioxidant capacity. Student's t‐test was performed to determine significance between the groups; p <.05 was considered significant. Results: In the maxilla, significantly more bone resorption, greater number of periapical apoptotic cells and Tartrate‐resistant acid phosphatase (TRAP)‐positive multinucleated cells were observed in the RAP group compared with the control group (p <.01). PGC‐1α and Nrf2 were significantly reduced in rat and human RAP lesions compared to the control group (p <.01) at both the mRNA and protein levels. Double immunofluorescence analysis of PGC‐1α or Nrf2 with TOMM20 also indicated that mitochondrial biogenesis was impaired in RAP group (p <.01). Additionally, mitochondrial dysfunction was observed in RAP group, as reflected by increased mtROS, decreased ATP production, reduced mtDNA copy number and complexes of the mitochondrial respiratory chain. Finally, the expression levels of mitochondrial oxidative stress markers, 3‐NT, 4‐HNE and 8‐OHdG, were significantly increased in the RAP group (p <.01). Consistent with this, systemic oxidative damage was also present in the progression of RAP, including increased MDA expression and decreased antioxidant activity (p <.01). Conclusions: Mitochondrial biogenesis disorder and damage from oxidative stress contribute to the development of RAP. [ABSTRACT FROM AUTHOR]