The ataxia-telangiectasia mutated (ATM) protein is a key signaling molecule that modulates the DNA damage response. However, the exact mechanism by which ATM regulates DNA damage repair has not yet ...been elucidated. Here, we report that ATM regulates the DNA damage response by phosphorylating lysine-specific demethylase 2A (KDM2A), a histone demethylase that acts at sites of H3K36 dimethylation. ATM interacts with KDM2A, and their interaction significantly increases in response to DNA double-stranded, but not single-stranded, breaks. ATM specifically phosphorylates KDM2A at threonine 632 (T632) following DNA damage, as demonstrated by a mutagenesis assay and mass spectrometric analysis. Although KDM2A phosphorylation does not alter its own demethylase activity, T632 phosphorylation of KDM2A largely abrogates its chromatin-binding capacity, and H3K36 dimethylation near DNA damage sites is significantly increased. Consequently, enriched H3K36 dimethylation serves as a platform to recruit the MRE11 complex to DNA damage sites by directly interacting with the BRCT2 domain of NBS1, which results in efficient DNA damage repair and enhanced cell survival. Collectively, our study reveals a novel mechanism for ATM in connecting histone modifications with the DNA damage response.
Objectives
The impact of electrolyte imbalance on clinical outcomes after acute ischemic stroke (AIS) is still not understood. We investigated the association between hypochloremia and hyponatremia ...upon hospital admission and in‐hospital mortality in AIS patients.
Materials and methods
A total of 3314 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included in this study. Hypochloremia was defined as having a serum chloride concentration <98 mmol/L and hyponatremia as having a serum sodium concentration <135 mmol/L. The Cox proportional hazard model was used to examine the effect of hypochloremia and hyponatremia on all‐cause in‐hospital mortality in AIS patients.
Results
During hospitalization, 118 patients (3.6%) died from all causes. Multivariable model adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, serum sodium, and other potential covariates showed that hypochloremia was associated with a 2.43‐fold increase in the risk of in‐hospital mortality (hazard ratio HR 2.43; 95% confidence interval CI, 1.41‐4.19; P=.001). However, no significant association between hyponatremia (P=.905) and in‐hospital mortality was observed. Moreover, the multivariable analysis found that serum chloride (HR=0.92, 95% CI 0.88‐0.98; P=.004) but not serum sodium (P=.102) was significantly associated with in‐hospital mortality.
Conclusions
Hypochloremia at admission was independently associated with in‐hospital mortality in AIS patients.
Highlights • Intrathecal injection of DHA prevents and reverses inflammatory pain. • DHA decreases carrageenan-induced microglial activation in the spinal cord. • DHA decreases p38 phosphorylation ...and inflammatory mediators’ production in microglia.
•A comprehensive study was conducted upon Al–Mg–Si alloys with differing Mg/Si ratio and Cu content.•Corrosion investigations included naturally aged, under-, peak- and over-aged conditions.•Ageing ...conditions and solute content all had an influence on the corrosion (and morphology).•Cu content was dominant over the Mg/Si ratio in terms of corrosion response.
Specially prepared 6xxx series aluminium alloys (Al–Mg–Si) with different Mg/Si ratios and Cu contents were investigated in the naturally aged, under-aged, peak-aged and over-aged conditions. Potentiodynamic polarisation and immersion testing in 0.1M NaCl were used to investigate the corrosion behaviour of such alloys in a general sense. Results reveal a significant dependence of the corrosion rate and morphology on the ageing conditions and solute content. Whilst contributing to broader understanding of 6xxx alloy corrosion, we note that corrosion rate is lowest in the naturally aged condition and is principally influenced by Cu and subsequently by the Mg/Si ratio.
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