Dimethyl Fumarate Modulates the Immune Environment and Improves Prognosis in the Acute Phase after Ischemic Stroke.

INTRODUCTION: Dimethyl fumarate (DMF) has shown potential for protection in various animal models of neurological diseases. However, the impact of DMF on changes in peripheral immune organs and the central nervous system (CNS) immune cell composition after ischemic stroke remains unclear. METHODS: Eight-week-old C57BL/6J mice with photothrombosis ischemia and patients with acute ischemic stroke (AIS) were treated with DMF. TTC staining, flow cytometry, and immunofluorescence staining were used to evaluate the infarct volume and changes in immune cells in the periphery and the CNS. RESULTS: DMF reduced the infarct volume on day 1 after PT. DMF reduced the percentages of peripheral immune cells, such as neutrophils, dendritic cells, macrophages, and monocytes, on day 1, followed by NK cells on day 3 and B cells on day 7 after PT. In the CNS, DMF significantly reduced the percentage of monocytes in the brain on day 3 after PT. In addition, DMF increased the number of microglia in the peri-infarct area and reduced the number of neurons in the peri-infarct area in the acute and subacute phases after PT. In AIS patients, B cells decreased in patients receiving alteplase in combination with DMF. CONCLUSION: DMF can change the immune environment of the periphery and the CNS, reduce infarct volume in the acute phase, promote the recruitment of microglia and preserve neurons in the peri-infarct area after ischemic stroke.

Multidelay Arterial Spin Labeling Versus Computed Tomography Perfusion in Penumbra Volume of Acute Ischemic Stroke.

BACKGROUND: Multidelay arterial spin labeling (ASL) is a novel perfusion method of ASL, with arterial transit time (ATT) calculated by multiple postlabeling delays to correct cerebral blood flow (CBF). We verify the accuracy of multidelay ASL in evaluating the ischemic penumbra and perfusion levels in patients with acute ischemic stroke, compared with computed tomography perfusion (CTP). METHODS: Patients with acute ischemic stroke with anterior circulation large vessel occlusion received baseline CTP, multidelay ASL, and diffusion-weighted imaging (DWI) in succession. Multidelay ASL image was processed to reconstruct ATT, CBF without ATT correction, and CBF corrected by ATT. The consistency of hypoperfusion and ischemic penumbra volume calculated by CTP and multidelay ASL were quantified by intraclass correlation coefficient (ICC) in 2-way mixed effects, absolute agreement, and single measure. Wilcoxon signed-rank test was used to compare the difference in penumbra volume between CTP, corrected ASL, and uncorrected ASL. RESULTS: Thirty patients were included. Hypoperfusion volume based on multidelay ASL with different thresholds were 117.95 (87.77-151.49) mL for corrected relative CBF<40%, 130.29 (85.99-249.37) mL for CBF corrected by ATT<20 mL·100g-1·min-1, no statistical difference (P>0.05) compared with the volume of CTP, and consistency was almost excellent (ICC, 0.91) and substantial consistent (ICC, 0.727). The volumes of ischemic penumbra were 91.00 (42.68-125.27) mL for corrected relative CBF<40%-DWI, 108.94 (62.03-150.86) mL for CBF corrected by ATT<20 mL·100 g-1·min-1-DWI, which showed no statistical difference compared with the penumbra volume of CTP (P>0.05). The consistency was excellent (ICC, 0.822) and moderate (ICC, 0.501), respectively. The volume of uncorrected relative CBF <40%-DWI was 209.57 (123.21-292.45) mL, statistically larger than corrected relative CBF <40%-DWI (P<0.001) and CTP (P<0.001). The volume of uncorrected CBF<20 mL·100g-1·min-1-DWI was 186.23 (86.56-298.22) mL, statistically larger than CBF corrected by ATT<20 mL·100g-1·min-1-DWI (P<0.001) and CTP(P<0.001). CONCLUSIONS: The volume of ischemic penumbra determined by CBF/DWI mismatch based on multidelay ASL is consistent with CTP. The penumbra volume calculated by CBF adjusted by ATT is more accurate.

m6A writer WTAP targets NRF2 to accelerate bladder cancer malignancy via m6A-dependent ferroptosis regulation.

Recent evidence have indicated that ferroptosis, a novel iron-dependent form of non-apoptotic cell death, plays a critical role in human cancers. Besides, emerging literatures have revealed the ovel function of N6-methyladenosine (m6A) in bladder cancer physiological. However, the underlying mechanism of m6A on bladder cancer is still unclear. Here, present work revealed that m6A methyltransferase ('writer') WTAP up-regulated in bladder cancer tissue and cells, indicating the poor prognosis of bladder cancer patients. Functionally, gain/loss-of-functional experiments illustrated that WTAP promoted the viability of bladder cancer cells and inhibited the erastin-induced ferroptosis. Mechanistically, there was a remarkable m6A modification site on 3'-UTR of endogenous antioxidant factor NRF2 RNA and WTAP could install its methylation. Moreover, m6A reader YTHDF1 recognized the m6A site on NRF2 mRNA and enhanced its mRNA stability. Therefore, these findings demonstrated potential therapeutic strategyies for bladder cancer via m6A-dependent manner.

Mutations adjacent to the end of transmembrane helices 6 and 7 independently affect drug efflux capacity of yeast ABC transporter Pdr5p.

As a mammalian p-glycoprotein homolog, Pdr5p is a major ATP-binding cassette transporter for cellular detoxification in the yeast Saccharomyces cerevisiae. In this study, two novel loss-of-function mutations located adjacent to the ends of the predicted transmembrane helices of Pdr5p were identified. C793F and S1230L mutations considerably impaired the transport activity of Pdr5p without affecting the ATPase activity and the expression level of the protein. Our results demonstrate that the size of residue 793 and the hydrophobicity of residue 1230 are important for Pdr5p efflux function. It reveals that amino acid residues located near the end of transmembrane helix play an important role in drug efflux of Pdr5p. Molecular docking results further suggest that these two single mutations might have disturbed interactions between the drugs and Pdr5p, preventing the drugs from approaching the intracellular or extracellular portal and subsequently from being exported by Pdr5p.

Effect of Dietary Flavonoids on Circadian Syndrome: A Population-Based Cross-Sectional Study.

Background: Altering the dietary patterns can potentially decrease the likelihood of metabolic syndrome and circadian syndrome (CircS), but it remains unclear which types of flavonoid compounds are responsible for these effects, particularly among nationally representative populations. Thus, we conducted a cross-sectional study to investigate the impact of flavonoid intake on CircS. Methods: The study included 9212 noninstitutionalized adults from two survey cycles (2007-2008 and 2009-2010) of the National Health and Nutrition Examination Survey (NHANES). Data on six dietary flavonoids were collected through a 24-hr dietary recall, including isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols. All statistical analyses were weighted to account for the complex survey sampling design to generate nationally representative estimates. Multivariable logistic regression and propensity score matching (PSM) were performed to control for potential confounders and assess the association between the six flavonoids and risk of short sleep. Results: After adjusting for all covariates, only individuals with high intake of total flavanones exhibited a 28% [odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.64-0.83, P < 0.001] decrease in the risk of CircS. The results obtained through PSM were consistent with this finding (OR = 0.70, 95% CI = 0.61-0.80, P < 0.001). Total flavanone intake displayed a linear dose-response relationship with the likelihood of CircS (P for interaction = 0.448). Conclusions: Our findings suggest that high dietary intakes of flavanones have beneficial effects on reducing the risk of CircS.

Oxygen extraction fraction mapping based combining quantitative susceptibility mapping and quantitative blood oxygenation level-dependent imaging model using multi-delay PCASL.

BACKGROUND AND PURPOSE: The oxygen extraction fraction is an essential biomarker for the assessment of brain metabolism. A recently proposed method combined with quantitative susceptibility mapping and quantitative blood oxygen level-dependent magnitude enables noninvasive mapping of the oxygen extraction fraction. Our study investigated the oxygen extraction fraction mapping variations of single-delay and multi-delay arterial spin-labeling. MATERIALS AND METHODS: A total of twenty healthy participants were enrolled. The multi-echo spoiled gradient-echo, multi-delay arterial spin-labeling, and magnetization-prepared rapid gradient echo sequences were acquired at 3.0 T. The mean oxygen extraction fraction was generated under a single delay time of 1780 ms, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume. The results were compared via paired t tests and the Wilcoxon test. Linear regression analyses were used to investigate the relationships among the oxygen extraction fraction, cerebral blood flow, and venous cerebral blood volume. RESULTS: The oxygen extraction fraction estimate with multi-delay arterial spin-labeling yielded a significantly lower value than that with single-delay arterial spin-labeling. The average values for the whole brain under single-delay arterial spin-labeling, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume were 41.5 ±â€¯1.7 % (P < 0.05), 41.3 ±â€¯1.9 % (P < 0.001), and 40.9 ±â€¯1.9 % (N = 20), respectively. The oxygen extraction fraction also showed a significant inverse correlation with the venous cerebral blood volume under steady-state conditions when multi-delay arterial spin-labeling was used (r = 0.5834, p = 0.0069). CONCLUSION: These findings suggest that the oxygen extraction fraction is significantly impacted by the arterial spin-labeling methods used in the quantitative susceptibility mapping plus the quantitative blood oxygen level-dependent model, indicating that the differences should be accounted for when employing oxygen extraction fraction mapping based on this model in diseases.

Height identification of water-permeable fractured zone based on synchronous movement in overlying strata.

Height identification of water-permeable fractured zone (WPFZ) is one of the decisive influence factors for mining safety, especially in some specific conditions, such as mining under aquifer. In order to demonstrate the formation process of the WPFZ, the scaling model experiment is carried out. Through the analysis of movement and breaking in overlying strata, the WPFZ height is significantly affected by mining range, movement characteristics of key strata and its follow-up strata. Based on the research findings, a new theoretical method, " overlying strata synchronous movement method " (OSSM) is established to predict the WPFZ height. Taking 3301 mining face of Zhujiamao Coal Mine in China as the engineering background, the WPFZ height is estimated by OSSM. Additionally, the field detection is carried out by the downhole segmented water injection method combined with borehole camera method. By comparing the results of different methods, the accuracy of OSSM is verified and the WPFZ height is determined finally. What´s more, various methods for determining WPFZ height are evaluated.

Comparison of Image Quality and Radiation Dose Between Single-Energy and Dual-Energy Images for the Brain With Stereotactic Frames on Dual-Energy Cerebral CT.

Background: Preoperative stereotactic planning of deep brain stimulation (DBS) using computed tomography (CT) imaging in patients with Parkinson's disease (PD) is of clinical interest. However, frame-induced metal artifacts are common in clinical practice, which can be challenging for neurosurgeons to visualize brain structures. Objectives: To evaluate the image quality and radiation exposure of patients with stereotactic frame brain CT acquired using a dual-source CT (DSCT) system in single- and dual-energy modes. Materials and Methods: We included 60 consecutive patients with Parkinson's disease (PD) and randomized them into two groups. CT images of the brain were performed using DSCT (Group A, an 80/Sn150 kVp dual-energy mode; Group B, a 120 kVp single-energy mode). One set of single-energy images (120 kVp) and 10 sets of virtual monochromatic images (50-140 keV) were obtained. Subjective image analysis of overall image quality was performed using a five-point Likert scale. For objective image quality evaluation, CT values, image noise, signal-to-noise ratio (SNR), and contrast-to-noise (CNR) were calculated. The radiation dose was recorded for each patient. Results: The mean effective radiation dose was reduced in the dual-energy mode (1.73 mSv ± 0.45 mSv) compared to the single-energy mode (3.16 mSv ± 0.64 mSv) (p < 0.001). Image noise was reduced by 46-52% for 120-140 keV VMI compared to 120 kVp images (both p < 0.01). CT values were higher at 100-140 keV than at 120 kVp images. At 120-140 keV, CT values of brain tissue showed significant differences at the level of the most severe metal artifacts (all p < 0.05). SNR was also higher in the dual-energy mode 90-140 keV compared to 120 kVp images, showing a significant difference between the two groups at 120-140 keV (all p < 0.01). The CNR was significantly better in Group A for 60-140 keV VMI compared to Group B (both p < 0.001). The highest subjective image scores were found in the 120 keV images, while 110-140 keV images had significantly higher scores than 120 kVp images (all p < 0.05). Conclusion: DSCT images using dual-energy modes provide better objective and subjective image quality for patients with PD at lower radiation doses compared to single-energy modes and facilitate brain tissue visualization with stereotactic frame DBS procedures.

A mutation in intracellular loop 4 affects the drug-efflux activity of the yeast multidrug resistance ABC transporter Pdr5p.

Multidrug resistance protein Pdr5p is a yeast ATP-binding cassette (ABC) transporter in the plasma membrane. It confers multidrug resistance by active efflux of intracellular drugs. However, the highly polymorphic Pdr5p from clinical strain YJM789 loses its ability to expel azole and cyclohexmide. To investigate the role of amino acid changes in this functional change, PDR5 chimeras were constructed by segmental replacement of homologous BY4741 PDR5 fragments. Functions of PDR5 chimeras were evaluated by fluconazole and cycloheximide resistance assays. Their expression, ATPase activity, and efflux efficiency for other substrates were also analyzed. Using multiple lines of evidence, we show that an alanine-to-methionine mutation at position 1352 located in the predicted short intracellular loop 4 significantly contributes to the observed transport deficiency. The degree of impairment is likely correlated to the size of the mutant residue.