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.
A transmission electron microscope and an atom probe tomography were used to quantitatively characterize the microstructural evolution of Al-XCu alloys (X = 1.0, 1.5, and 2.5 wt%) with 0.3 wt% Sc ...addition. A dual solute alloying/microalloying effect on the microstructural evolution was demonstrated. On the one hand, the nucleation and coarsening of Al3Sc dispersoids displayed a Cu alloying effect. By increasing the Cu content, both the Al3Sc disperoid size and the volume fraction decreased after solution treatment. On the other hand, the precipitation of θ′-Al2Cu strengthening particles during aging treatment was promoted by Sc segregation at the θ′/matrix interfaces, showing a notable Sc microalloying effect. The strongest interfacial Sc segregation was generated in the Al-2.5 wt%Cu-Sc alloy, resulting in the most promoted θ′ precipitation. The Sc partitioning between Al3Sc dispersoids and Sc segregation at the θ′/matrix interfaces, tailored by the Cu content, impacted the mechanical properties and deformation behavior at both room temperature and high temperature. The Al-2.5 wt%Cu-Sc alloy had a room temperature yield strength of approximately 2.2 times that in its Sc-free counterpart and approximately 1.8 times that in the Al-1.5 wt%Cu-Sc alloy, which is rationalized by strengthening models. In addition, the improvement in the high-temperature mechanical properties after Sc addition was discussed in terms of the Sc segregation-induced high coarsening resistance of θ′ precipitates.
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Brain metastasis (BM) is a major cause of mortality in small-cell lung cancer (SCLC) patients; however, the molecular pathway of SCLC BM remains largely unknown because of a lack of investigation. ...Here we screen the levels of some candidate-soluble factors in the serum of SCLC patients and find that SCLC patients with high levels of placental growth factor (PLGF) are prone to BM. Using in vitro blood-brain barrier model, we show that PLGF derived from SCLC cells triggers vascular endothelial growth factor receptor-1-Rho-extracellular regulated protein kinase 1/2 signaling axis activation, results in disassembly of tight junction in brain endothelial cells and promotes SCLC cell transendothelial migration. Furthermore, the downregulation of PLGF suppresses SCLC cell metastasis to the brain in an experimental BM model. These data suggest that PLGF is a potential signature of SCLC BM and a prospective therapeutic target for SCLC BM.
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.
An expanded model for the thermodynamics of co-clusters and their strengthening is presented and applied to predict co-cluster formation and strengthening in Al–Mg–Si alloys. The models were tested ...against data on a wide range of Al–Mg–Si alloys aged at room temperature. The strengthening due to co-clusters is well predicted. The formation of co-clusters was studied in an Al–0.5at.% Mg–1at.% Si alloy using three-dimensional atom probe analysis. The results correspond well with the model. It is shown that in general (short-range) order strengthening due to co-clusters will be the main strengthening mechanism in these alloys. Apart from the co-clusters, Si clusters also form, but due to their low enthalpy of formation they contribute little to the strength.
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