A major gene for chilling tolerance variation in Indica rice codes for a kinase OsCTK1 that phosphorylates multiple substrates under cold.

Rice is susceptible to chilling stress. Identifying chilling tolerance genes and their mechanisms are key to improve rice performance. Here, we performed a genome-wide association study to identify regulatory genes for chilling tolerance in rice. One major gene for chilling tolerance variation in Indica rice was identified as a casein kinase gene OsCTK1. Its function and natural variation are investigated at the physiological and molecular level by its mutants and transgenic plants. Potential substrates of OsCTK1 were identified by phosphoproteomic analysis, protein-protein interaction assay, in vitro kinase assay, and mutant characterization. OsCTK1 positively regulates rice chilling tolerance. Three of its putative substrates, acidic ribosomal protein OsP3B, cyclic nucleotide-gated ion channel OsCNGC9, and dual-specific mitogen-activated protein kinase phosphatase OsMKP1, are each involved in chilling tolerance. In addition, a natural OsCTK1 chilling-tolerant (CT) variant exhibited a higher kinase activity and conferred greater chilling tolerance compared with a chilling-sensitive (CS) variant. The CT variant is more prevalent in CT accessions and is distributed more frequently in higher latitude compared with the CS variant. This study thus enables a better understanding of chilling tolerance mechanisms and provides gene variants for genetic improvement of chilling tolerance in rice.

The presence and clinical significance of autoantibodies in amyotrophic lateral sclerosis: a narrative review.

Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.

Identification of new bisabosqual-type meroterpenoids reveals non-enzymatic conversion of bisabosquals into seco-bisabosquals.

Bisabosqual-type meroterpenoids are fungi-derived polyketide-terpenoid hybrids bearing a 2,3,3a,3a1,9,9a-hexahydro-1H-benzofuro[4,3,2-cde]chromene skeleton (6/6/6/5 ring system) or its seco-C-ring structure, and exhibit diverse bioactivities. Their unique structural architecture and impressive biological activities have led to considerable interest in discovering new analogues. However, to date, only nine analogues have been identified. Herein, we reported the isolation and identification of six new bisabosqual-type meroterpenoids stachybisbins C-H (1-6), together with one known compound bisabosqual C (7), from Stachybotrys bisbyi PYH05-7. Intriguingly, we found that 7, which contains the intact tetracyclic skeleton, can be non-enzymatically converted into its seco derivative stachybisbin I (8), unveiling the biosynthetic relationship between bisabosquals and seco-bisabosquals. Moreover, based on CRISPR/Cas9-mediated gene disruption, we revealed that the three-gene cluster responsible for the formation of LL-Z1272ß is associated with the biosynthesis of bisabosqual-type meroterpenoids, and then proposed a plausible route to 1-8.

Transitional structure of {0001} twin in a deformed p-type (Bi,Sb)2Te3 alloy: a direct experimental basis for understanding the twinning mechanism.

Twin boundaries provide a strong phonon scattering center to hinder the lattice thermal conductivity in thermoelectric materials, but the underlying evolution process of deformation twinning remains to be figured out. By applying atomic resolution transmission electron microscope (TEM) observations, a novel type of transitional structure of {0001} twin was observed, for the first time, in the p-type (Bi,Sb)2Te3 alloy subjected to three-point bending deformation. The transformation from matrix to (0001) twin can be realized by the following path: matrix → transitional twin → (0001) twin, and this process was completed by the gliding of a total of four partial dislocations (b1 = 1/3[011̄0]) extended in the different (0001) planes. This new finding here will shed light on the nucleation and growth of deformation twins in the p-type (Bi, Sb)2Te3 alloy.

FLAIR vascular hyperintensity predicts early neurological deterioration in patients with acute ischemic stroke receiving endovascular thrombectomy.

Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is frequently observed in patients with acute ischemic stroke (AIS). FVH is associated with functional outcome at 3 months in AIS patients receiving endovascular thrombectomy. In the present study, we assessed whether FVH predicted early neurological deterioration (END) and hemorrhagic transformation (HT) within 72 h in AIS patients receiving endovascular thrombectomy. We retrospectively analyzed 104 patients with acute internal-carotid-artery or proximal middle-cerebral-artery occlusion within 16 h after symptom onset. Before thrombectomy, all patients underwent brain magnetic resonance imaging. END was defined as an increase of 4 points or more from baseline National Institutes of Health Stroke Scale (NIHSS) during 72 h following onset. HT was assessed by brain computed tomography. Statistical analyses were performed to predict END and HT. The proportion of high FVH score, high American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grade in non-END group was higher than that in END group (p < 0.001, p < 0.001, respectively). FVH score was positively correlated with ASITN/SIR grade (r = 0.461, p < 0.001). FVH score was a predictor factor for END (adjusted OR, 13.552; 95% CI, 2.408-76.260; p = 0.003), while FVH score was not a predictor factor for HT. Furthermore, NIHSS at admission (adjusted OR, 1.112; 95% CI, 1.006-1.228; p = 0.038) and high-density lipoprotein cholesterol (adjusted OR, 18.865; 95% CI, 2.998-118.683; p = 0.002) were predictor factors for HT. To assess FVH score before thrombectomy might be useful for predicting END in AIS patients receiving endovascular thrombectomy.

The association of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and lymphocyte to monocyte ratio with post-thrombolysis early neurological outcomes in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: To investigate the association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) with post-thrombolysis early neurological outcomes including early neurological improvement (ENI) and early neurological deterioration (END) in patients with acute ischemic stroke (AIS). METHODS: AIS patients undergoing intravenous thrombolysis were enrolled from April 2016 to September 2019. Blood cell counts were sampled before thrombolysis. Post-thrombolysis END was defined as the National Institutes of Health Stroke Scale (NIHSS) score increase of ≥ 4 within 24 h after thrombolysis. Post-thrombolysis ENI was defined as NIHSS score decrease of ≥ 4 or complete recovery within 24 h. Multinomial logistic regression analysis was performed to explore the relationship of NLR, PLR, and LMR to post-thrombolysis END and ENI. We also used receiver operating characteristic curve analysis to assess the discriminative ability of three ratios in predicting END and ENI. RESULTS: Among 1060 recruited patients, a total of 193 (18.2%) were diagnosed with END and 398 (37.5%) were diagnosed with ENI. Multinomial logistic model indicated that NLR (odds ratio [OR], 1.385; 95% confidence interval [CI] 1.238-1.551, P = 0.001), PLR (OR, 1.013; 95% CI 1.009-1.016, P = 0.001), and LMR (OR, 0.680; 95% CI 0.560-0.825, P = 0.001) were independent factors for post-thrombolysis END. Moreover, NLR (OR, 0.713; 95% CI 0.643-0.791, P = 0.001) served as an independent factor for post-thrombolysis ENI. Area under curve (AUC) of NLR, PLR, and LMR to discriminate END were 0.763, 0.703, and 0.551, respectively. AUC of NLR, PLR, and LMR to discriminate ENI were 0.695, 0.530, and 0.547, respectively. CONCLUSIONS: NLR, PLR, and LMR were associated with post-thrombolysis END. NLR and PLR may predict post-thrombolysis END. NLR was related to post-thrombolysis ENI.

Endovascular treatment of acute ischemic stroke due to anterior circulation large vessel occlusion beyond 6 hours: a real-world study in China.

BACKGROUND: We aimed to assess the safety and efficacy of endovascular treatment (EVT) in patients with anterior circulation emergent large vessel occlusion (ELVO) beyond 6 h from symptom onset in a real-world cohort of patients in China. METHODS: We retrospectively examined 305 patients with anterior circulation ELVO treated with EVT. Patients were divided into two groups: treated with known onset within 6 h (n = 238) and beyond 6 h (n = 67). Multivariable logistic regression and ordinal shift analyses were used to evaluate the associations between onset-to-groin puncture time and safety and efficacy outcomes. RESULTS: Treatment beyond 6 h was not associated with symptomatic intracranial hemorrhage within 48 h (sICH; odds ratio [OR] 2.03, 95% confidence interval [CI] 0.48-8.57, p = 0.334), in-hospital mortality (OR 1.95, 95% CI 0.48-7.91, p = 0.348), successful recanalization (modified Thrombolysis in Cerebral Infarction score 2b or 3; OR 0.73, 95% CI 0.31-1.73, p = 0.470), favorable functional outcome (modified Rankin Scale score 0-2; OR 0.55, 95% CI 0.25-1.23, p = 0.145), and functional improvement (modified Rankin Scale shift by 1-point decrease; common OR 0.80, 95%CI 0.45-1.42, p = 0.450) at 3 months compared with treatment within 6 h. Futher interaction analysis showed that stroke etiology did not modify the associations between onset-to-groin puncture time and outcomes (p > 0.05). CONCLUSIONS: In this real-world study, after careful assessment, EVT beyond 6 h from known stroke onset was safe, effective and had comparable short-term outcomes to EVT within 6 h.

Clinical significance of stroke nurse in patients with acute ischemic stroke receiving intravenous thrombolysis.

BACKGROUND: Reports have proven that shorter door-to-needle time (DTN time) indicates better outcomes in AIS patients received intravenous thrombolysis. Efforts have been made by hospitals and centers to minimize DTN time in many ways including introducing a stroke nurse. However, there are few studies to discuss the specific effect of stroke nurse on patients' prognosis. This study aimed to compare consecutive AIS patients before and after the intervention to analyze the effect of stroke nurse on clinical outcome of AIS patients. METHODS: In this retrospective study, we observed 1003 patients from November 2016 to December 2020 dividing in two groups, collected and analyzed AIS patients' medical history, clinical assessment information, important timelines, 90 mRS score, etc. Comparative analysis and mediation analysis were also used in this study. RESULTS: A total of 418 patients was included in this study, and 199 patients were enrolled in the stroke nurse group and 219 was in the preintervention group. Baseline characteristics of patients showed no significant difference except there seems more patients with previous ischemic stroke history in the group of stroke nurse. (p = 0.008). The median DTN time significantly decreased in the stroke nurse group (25 min versus 36 min, p < 0.001) and multivariate logistic regression analysis showed the 90-day mRS clinical outcome significantly improved in the stroke nurse group (p = 0.001). Mediation analysis indicated the reduction of DTN time plays a partial role on the 90 days mRS score and the stroke nurse has some direct effect on the improvement of clinical outcome (p = 0.006). CONCLUSIONS: The introduction of stroke nurse is beneficial to clinical outcome of AIS patients and can be use of reference in other hospitals or centers.

Hypersensitive C-reactive protein-albumin ratio predicts symptomatic intracranial hemorrhage after endovascular therapy in acute ischemic stroke patients.

BACKGROUND: Approximately 10% of patients would develop symptomatic intracranial hemorrhage (sICH) after endovascular therapy. The aim of our study was to explore the ability of hypersensitive C-reactive protein-albumin ratio (HAR) in predicting sICH after endovascular therapy. METHODS: From April 2016 to December 2018, 334 consecutive patients with anterior circulation infarction undergoing endovascular therapy were enrolled in our study. sICH was defined using Heidelberg bleeding classification after endovascular therapy. Multiple regression analysis was used to investigate the potential risk factors of sICH after endovascular therapy. We used receiver operating characteristic curve analysis and nomogram analysis to assess the overall discriminative ability of the HAR in predicting sICH after endovascular therapy. RESULTS: Among these 334 patients enrolled, 37 (11.1%) patients with anterior circulation infarction were identified with sICH after endovascular therapy. Univariate logistic regression analysis demonstrated that patients with higher levels of HAR may be inclined to develop sICH (odds ratio, 10.994; 95% confidence interval, 4.567-26.463; P = 0.001). This association remained significant even after adjustment for potential confounders. Also, a cutoff value of 0.526× 10- 3 for HAR was detected in predicting sICH (area under curve, 0.763). Furthermore, nomogram analysis also suggested that HAR was an indicator of sICH (c-index was 0.890, P< 0.001). CONCLUSIONS: This study showed that high levels of HAR could predict sICH after endovascular therapy.

Shielding effect of a lead apron on the peripheral radiation dose outside the applicator of electron beams from an Elekta linear accelerator.

PURPOSE: To evaluate the shielding effect of lead aprons (LAs) on peripheral radiation doses outside the applicator of electron beams from a linear accelerator. METHODS: Out-of-field radiation doses of 4-, 6-, 8-, 10-, 12-, and 15-MeV electron beams from an Elekta Synergy linear accelerator (linac) were measured by thermoluminescence dosimeters (TLD) at different depths (0, 0.5, 1.0, and 2.0 cm) and distances from the applicator edge (0-58 cm) in a water-equivalent slab phantom with a different number of layers of LA shielding (0-5 layers). Measurements were performed by 6 × 6, 10 × 10, 14 × 14, and 20 × 20-cm2 applicators at a gantry and collimator angle of 0°. The out-of-field radiation dose profiles were normalized to the maximum dose of every energy and measuring depth. RESULTS: The out-of-field radiation doses (beyond 3 cm away from the field edge) decreased with an increase in the number of LA layers and distance away from the central beam axis (CAX). After shielding with the LA, the out-of-field doses decreased by up to approximately 99% compared with the no shielding group. For 4-MeV electron beams, there was a peak at 24.5 cm from the CAX, which weakened with an increasing number of LA layers. CONCLUSION: The shielding effect of the LA varied for a different number of LA layers as well as different depths and distances away from the CAX. Four LA layers were sufficient for shielding out-of-field doses of 4-15-MeV electron beams.

One-step analysis of brain perfusion and function for acute stroke patients after reperfusion: A resting-state fMRI study.

BACKGROUND: Resting-state functional magnetic resonance imaging (rs-fMRI) can noninvasively estimate the perfusion and function of the brain. PURPOSE: To investigate the perfusion and functional status using rs-fMRI in acute ischemic stroke (AIS) patients after reperfusion therapy. STUDY TYPE: Prospective. SUBJECTS: Twenty-five AIS patients who underwent dynamic susceptibility contrast (DSC) upon hospital admission and both rs-fMRI and DSC scans at 24 hours after reperfusion therapy. FIELD STRENGTH/SEQUENCE: 3T; DSC, rs-fMRI. ASSESSMENT: The time delay of the blood oxygenation level-dependent (BOLD) signal was calculated using time-shift-analysis (TSA) and compared with the time to peak (TTP) derived from the DSC. For patients who exhibited partial or complete reperfusion in the supratentorial hemisphere, we quantified the function of different regions (healthy tissue, reperfused tissue, not reperfused tissue) by using three rs-fMRI measurements (functional connectivity, the amplitude of low-frequency fluctuation [ALFF] and regional homogeneity [ReHo]). Correlations between the functional measurements and modified Rankin Scale (mRS) scores were calculated. STATISTICAL TESTS: Dice coefficient (DC) analysis, two-sample t-tests, Pearson correlation coefficient. RESULTS: Twelve patients who exhibited complete reperfusion on their TTP maps showed no time-delayed areas on the TSA maps. For the remaining 13 patients with partial reperfusion (5/13) or no reperfusion (8/13) on the TTP maps, the TSA detected comparable time-delayed areas. Eleven out of 13 patients showed moderate to good overlap (mean DC, 0.58 ± 0.1) between the TTP and TSA results. Fourteen patients were chosen for functional analyses and most patients (12/14) showed abnormal functional connectivity in the reperfused regions. The reperfused and not reperfused tissues had lower mean ReHo values than those of the healthy tissue (both P < 0.001). The mRS scores showed negative correlation with mean ReHo values of reperfused region (R = -0.523, P = 0.027). DATA CONCLUSION: rs-fMRI might be a useful way to estimate both the perfusion and functional status for AIS patients after reperfusion therapy. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:221-229.

Berberine Facilitates Angiogenesis Against Ischemic Stroke Through Modulating Microglial Polarization via AMPK Signaling.

Evidence suggests that microglia/macrophages can change their phenotype to M1 or M2 and participate in tissue damage or repair. Berberine (BBR) has shown promise in experimental stroke models, but its effects on microglial polarization and long-term recovery after stroke are elusive. Here, we investigated the effects of BBR on angiogenesis and microglial polarization through AMPK signaling after stroke. In the present study, C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO), intragastrically administrated with BBR at 50 mg/kg/day. Neo-angiogenesis was observed by 68Ga-NODAGA-RGD micro-PET/CT and immunohistochemistry. Immunofluorescent staining further exhibited an increase of M2 microglia and a reduction of M1 microglia at 14 days after stroke. In vitro studies, the lipopolysaccharide (LPS)-induced BV2 microglial cells were used to confirm the AMPK activation effect of BBR. RT-PCR, Flow cytometry, and ELISA all demonstrated that BBR could inhibit M1 polarization and promote M2 polarization. Furthermore, treatment of human umbilical vein endothelial cells (HUVEC) with conditioned media collected from BBR-treated BV2 cells promoted angiogenesis. All effects stated above were reversed by AMPK inhibitor (Compound C) and AMPK siRNA. In conclusion, BBR treatment improves functional recovery and promotes angiogenesis following tMCAO via AMPK-dependent microglial M2 polarization.

The association between high-sensitivity C-reactive protein at admission and progressive motor deficits in patients with penetrating artery infarctions.

BACKGROUND: A fraction of patients with penetrating artery infarction (PAI) experience progressive motor deficit deterioration (PMD). We sought to investigate the role of high-sensitivity C-reactive protein (hs-CRP) at admission in predicting PMD. METHODS: From January 2015 to September 2018, consecutive patients with PAI from three centers were prospectively enrolled in this study. PMD was defined as worsening of motor function score by ≥1 point on the National Institutes of Health Stroke Scale during the first 5 days after admission. Multivariable logistic regression analyses were performed to explore the relationship between hs-CRP and PMD in patients with PAI. We also performed receiver operating characteristic curve analysis and constructed a nomogram to assess the overall discriminative ability of hs-CRP in predicting PMD. RESULTS: We ultimately included 544 patients (mean age, 65.4 ± 11.8 years). A total of 85 (15.6%) patients were identified to have PMD. Multivariate logistic regression analysis showed that hs-CRP was independently associated with PMD (P = 0.001). The optimal cutoff value for hs-CRP as a predictor for PMD was 3.48 mg/L, with a sensitivity of 73.64% and a specificity of 82.35% (area under curve, 0.792). Moreover, the nomogram we constructed indicated that higher level of hs-CRP was an indicator of PMD (c-index = 0.780, P < 0.001). CONCLUSIONS: Our study suggested that hs-CRP might be a useful biomarker for predicting the risk of PMD in patients with PAI.

Leukoaraiosis is associated with poor outcomes after successful recanalization for large vessel occlusion stroke.

BACKGROUND: Leukoaraiosis (LA) is related to the dysfunction of the microcirculation and results in the impairment of the perfusion state. We investigated the association of LA and poor outcomes after successful recanalization by thrombectomy. METHODS: We retrospectively analyzed 97 patients with anterior large-artery occlusion who underwent thrombectomy and had successful recanalization (modified Treatment in Cerebral Ischemia Scale score 2b or 3). All patients underwent magnetic resonance imaging (MRI). LA was evaluated using fluid-attenuated inversion recovery MRI and graded using the Fazekas scale. Poor functional outcome at day 90 and symptomatic intracerebral hemorrhage (sICH) were compared between patients with absent to mild LA and moderate to severe LA. Logistic regression analyses were performed to determine the association of LA severity and outcomes. RESULTS: Moderate and severe LA occurred in 28.9% and 26.8% patients respectively. A higher proportion of poor outcomes were observed in patients with moderate to severe LA compared to patients with absent to mild LA (77.8% vs. 39.5%, p < 0.001). Logistic regression analyses showed patients with moderate to severe LA had 3.77 times (95%CI 1.21-11.76, p = 0.022) higher risk of having poor outcomes compared to patients with absent to mild LA. CONCLUSIONS: LA severity may be associated with poor outcomes after successful recanalization for ischemic stroke with anterior large vessel occlusion.

Different Patterns of Functional Connectivity Alterations Within the Default-Mode Network and Sensorimotor Network in Basal Ganglia and Pontine Stroke.

BACKGROUND The aim of this study was to investigate whether patients with basal ganglia stroke and patients with pontine stroke have different types of functional connectivity (FC) alterations in the early chronic phase. MATERIAL AND METHODS We included 14 patients with pontine stroke, 17 patients with basal ganglia stroke, and 20 well-matched healthy controls (HCs). All of them underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. The independent component analysis (ICA) approach was applied to extract information regarding the default-mode network (DMN), including anterior DMN (aDMN) and posterior DMN (pDMN) components and the sensorimotor network (SMN). RESULTS Compared with HCs, patients with basal ganglia stroke exhibited significantly reduced FC in the left precuneus of the pDMN, right supplementary motor area (SMA), and right superior frontal gyrus (SFG) of the SMN. Additionally, FC in the left medial prefrontal gyrus (MFG) of the aDMN, right precuneus and right posterior cingulate cortex (PCC) of the pDMN, and left middle cingulate gyrus (mid-CC) of the SMN decreased in patients with pontine stroke. CONCLUSIONS The different patterns of FC damage in patients with basal ganglia stroke and patients with pontine stroke in the early chronic phase may provide a new method for investigating lesion-induced network plasticity.

Soluble TREM1 concentrations are increased and positively correlated with total tau levels in the plasma of patients with Alzheimer's disease.

BACKGROUND/AIMS: Recently, we showed that triggering receptor expressed on myeloid cells 1 (TREM1) was involved in the pathogenesis of Alzheimer's disease (AD) since it modulated microglial phagocytic functions and thus affected amyloid-ß clearance in the brain. Interestingly, a soluble form of TREM1 (sTREM1) can be detected in the plasma of human. To date, whether sTREM1 concentrations were altered in the plasma under AD context remained unclear. METHODS: In this study, we compared the plasma concentrations of sTREM1 between 110 AD patients and 128 age- and gender-matched controls. Meanwhile, the relationship of sTREM1 concentrations with total tau levels in the plasma of AD patients was also assessed. RESULTS: We revealed that the concentrations of sTREM1 were significantly increased in AD patients. Meanwhile, the sTREM1 concentrations were gradually increased during disease progression. More importantly, we showed that the sTREM1 concentrations were positively correlated with the levels of total tau in the plasma of AD patients (r = 0.61, P < 0.001). The subsequent subgroup analysis indicated that this correlation was more pronounced in patients with severe dementia (Mini-Mental State Exam score < 10, r = 0.81, P < 0.01). CONCLUSION: These findings indicate a potential association between sTREM1 and tau pathology, and further confirm an involvement of this immune receptor in AD pathogenesis.

PM2.5 exposure aggravates oligomeric amyloid beta-induced neuronal injury and promotes NLRP3 inflammasome activation in an in vitro model of Alzheimer's disease.

BACKGROUND: Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer's disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. METHODS: In the presence or absence of neurons, oligomeric amyloid beta (oAß)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAß-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. RESULTS: In the present study, we showed that PM2.5 exposure aggravated oAß-induced neuronal injury and inflammation in neurons-microglia co-cultures via increasing IL-1ß production. Further, PM2.5-induced IL-1ß production in oAß-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAß-stimulated microglia. ROS was required for PM2.5-induced IL-1ß production and NLRP3 inflammasome activation in oAß-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. CONCLUSIONS: For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis.

Berberine attenuates ischemia-reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation.

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and represents a new target for treatment of stroke. Berberine is a natural medicine with multiple beneficial biological activities. In this study, we explored the mechanisms underlying the neuroprotective action of berberine in mice subjected transient middle cerebral artery occlusion (tMCAO). Male mice were administered berberine (25, 50 mg/kg/d, intragastric; i.g.), glycyrrhizin (50 mg/kg/d, intraperitoneal), or berberine (50 mg/kg/d, i.g.) plus glycyrrhizin (50 mg/kg/d, intraperitoneal) for 14 consecutive days before tMCAO. The neurological deficit scores were evaluated at 24 h after tMCAO, and then the mice were killed to obtain the brain samples. We showed that pretreatment with berberine dose-dependently decreased the infarct size, neurological deficits, hispathological changes, brain edema, and inflammatory mediators in serum and ischemic cortical tissue. We revealed that pretreatment with berberine significantly enhanced uptake of 18F-fluorodeoxyglucose of ischemic hemisphere comparing with the vehicle group at 24 h after stroke. Furthermore, pretreatment with berberine dose-dependently suppressed the nuclear-to cytosolic translocation of high-mobility group box1 (HMGB1) protein, the cytosolic-to nuclear translocation of nuclear factor kappa B (NF-κB) and decreased the expression of TLR4 in ischemic cortical tissue. Moreover, co-administration of glycyrrhizin and berberine exerted more potent suppression on the HMGB1/TLR4/NF-κB pathway than berberine or glycyrrhizin administered alone. These results demonstrate that berberine protects the brain from ischemia-reperfusion injury and the mechanism may rely on its anti-inflammatory effects mediated by suppressing the activation of HMGB1/TLR4/NF-κB signaling.

Corticospinal tract changes in acute brainstem ischemic stroke patients: A diffusion kurtosis imaging study.

PURPOSE: The present study aimed to investigate the corticospinal tract (CST) changes in patients with brainstem ischemic stroke by using the diffusion kurtosis imaging (DKI) approach.. MATERIALS AND METHODS: Twenty-one patients with brainstem stroke and 21 group-matched healthy controls underwent brain DKI with 3.0 T magnetic resonance imaging (MRI). The DKI was obtained by using three b values of 0, 1,000, 2,000 s/mm2 with 15 diffusion directions. Regions of interest (ROIs) were placed at four levels: the pons, posterior limb of the internal capsule (PLIC), corona radiata, and precentral gyrus. The DKI parameters, including fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) values, in these regions were measured from the contralateral to the ipsilateral side of patients and both the left and right sides of healthy controls at all the four selected levels. RESULTS: The ipsilateral side of the ischemic lesion showed a decrease in FA and MD and an increase in MK when compared with the contralateral normal region at all the four selected levels with statistically differences (P < 0.05). At these four selected levels, there were no differences between the left and right sides in healthy controls with MD, FA, and MK (P > 0.05). The MD values of the contralateral side of the ischemic lesion in patients at the four selected levels were significantly higher than those in the corresponding side of the healthy controls (P < 0.05). Compared to the healthy controls, there was a decrease at the posterior limb of the internal capsule (PLIC) in FA of the contralateral side of the ischemic lesion in stroke patients (P < 0.05). However, no significant differences were observed for MK values between the groups (P > 0.05). CONCLUSION: The current results suggest that the DKI technique could identify the early microstructural changes along the motor pathway and that these changes were not limited to the ipsilateral side of the ischemic lesion; in fact, the contralateral changes also occurred, especially at the PLIC.

Age-related differences in interferon regulatory factor-4 and -5 signaling in ischemic brains of mice.

Stroke is a disease that mainly affects the elderly. Since the age-related differences in stroke have not been well studied, modeling stroke in aged animals is clinically more relevant. The inflammatory responses to stroke are a fundamental pathological procedure, in which microglial activation plays an important role. Interferon regulatory factor-5 (IRF5) and IRF4 regulate M1 and M2 activation of macrophages, respectively, in peripheral inflammation; but it is unknown whether IRF5/IRF4 are also involved in cerebral inflammatory responses to stroke and whether age-related differences of the IRF5/IRF4 signaling exist in ischemic brain. Here, we investigated the influences of aging on IRF5/IRF4 signaling and post-stroke inflammation in mice. Both young (9-12 weeks) and aged (18 months) male mice were subjected to middle cerebral artery occlusion (MCAO). Morphological and biochemical changes in the ischemic brains and behavior deficits were assessed on 1, 3, and 7 d post-stroke. After MCAO, the aged mice showed smaller infarct sizes but higher neurological deficits and corner test scores than young mice. Young mice had higher levels of IRF4 and CD206 microglia in the ischemic brains, whereas the aged mice expressed more IRF5 and MHCII microglia. After MCAO, serum pro-inflammatory cytokines (TNF-α, iNOS, IL-6) were more prominently up-regulated in aged mice, whereas serum anti-inflammatory cytokines (TGF-ß, IL-4, IL-10) were more prominently up-regulated in young mice. Our results demonstrate that aging has a significant influence on stroke outcomes in mice, which is probably mediated by age-specific inflammatory responses.