Assessment of Cerebral White Matter Involvement in Amyotrophic Lateral Sclerosis Patients With Disease Progression and Cognitive Impairment by Fixel-Based Analysis and Neurite Orientation Dispersion and Density Imaging.

BACKGROUND: Previous studies using emerging diffusion MRI techniques have revealed damage to the white matter (WM) microstructure in amyotrophic lateral sclerosis (ALS), particularly the influence of crossed fibers, but there is a lack of subgroup analyses. PURPOSE: To detect WM microstructural changes in ALS patients using fixel-based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI) MRI. STUDY TYPE: Prospective. POPULATION: Thirty-six ALS patients (aged 60.50 ± 9.5 years) and 25 healthy controls (HCs) (aged 58.90 ± 8.1 years). FIELD STRENGTH/SEQUENCE: 3 T; NODDI and FBA (b-values = 0, 1000, and 2500 seconds/mm2 ). ASSESSMENT: Subgroups were performed according to progression rate and cognition, including fast and slow progression (FP/SP), ALS with and without cognitive impairment (ALS-ci/ALS-nci). Fiber density (FD), fiber-bundle cross-section (FC), combined fiber density and cross-section (FDC), neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (ISO), and fractional anisotropy (FA) were calculated and their correlation with clinical variables examined. STATISTICAL TESTING: Chi-square test, Mann-Whitney U test, two-sample t test, partial correlation analysis, and false discovery rate (FDR) corrected. A P-value <0.05 was considered significant. RESULTS: ALS patients had lower FD and FDC values predominantly in the corticospinal tract (CST) and corpus callosum (CC) regions, as well as lower NDI value in the CC, radial crown, and internal capsule compared to HCs. Subgroup analysis based on progression rate and cognitive function showed significant differences in FBA results. The FC in the right CST region was significantly lower in the FP than SP, and the FD in the CC region was significantly lower in the ALS-ci than ALS-nci. Furthermore, a negative correlation was found between the mean FC value and the rate of progression in ALS patients (r = -0.408). DATA CONCLUSION: FBA is a powerful tool for detecting complex cerebral WM microstructural damage for evaluating ALS cognition and disease progression.

Disrupted phase behavior of FUS underlies poly-PR-induced DNA damage in amyotrophic lateral sclerosis.

GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. However, the molecular mechanism responsible for poly-PR-induced cell toxicity remains incompletely understood. Here, we found that poly-PR overexpression triggers severe DNA damage in cultured cells, primary cortical neurons, and the motor cortex of a poly-PR transgenic mouse model. Interestingly, we identified a linkage between poly-PR and RNA-binding protein fused in sarcoma (FUS), another ALS-related gene product associated with DNA repair. Poly-PR interacts with FUS both in vitro and in vivo, phase separates with FUS in a poly-PR concentration-dependent manner, and impairs the fluidity of FUS droplets in vitro and in cells. Moreover, poly-PR impedes the recruitment of FUS and its downstream protein XRCC1 to DNA damage foci after microirradiation. Importantly, overexpression of FUS significantly decreased the level of DNA damage and dramatically reduced poly-PR-induced cell death. Our data suggest the severe DNA damage caused by poly-PR and highlight the interconnection between poly-PR and FUS, enlightening the potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.

Effect of sacubitril/valsartan on brain natriuretic peptide level and prognosis of acute cerebral infarction.

BACKGROUND AND PURPOSE: Previous studies demonstrated that elevated brain natriuretic peptide (BNP) level is associated with adverse clinical outcomes of acute cerebral infarction (ACI). Researchers hypothesized that BNP might be a potential neuroprotective factor against cerebral ischemia because of the antagonistic effect of the natriuretic peptide system on the renin-angiotensin system and regulation of cardiovascular homeostasis. However, whether decreasing the BNP level can improve the prognosis of ACI has not been studied yet. The main effect of sacubitril/valsartan is to enhance the natriuretic peptide system. We investigated whether the intervention of plasma BNP levels with sacubitril/valsartan could improve the prognosis of patients with ACI. METHODS: In a randomized, controlled, parallel-group trial of patients with ACI within 48 hours of symptom onset and need for antihypertensive therapy, patients have randomized within 24 hours to sacubitril/valsartan 200mg once daily (the intervention group) or to conventional medical medication (the control group). The primary outcome was a change in plasma BNP levels before and after sacubitril/valsartan administration. The secondary outcomes included plasma levels of brain-derived neurotrophic factor (BDNF), Corin and neprilysin (NEP) before and after medication, the modified Rankin scale, and the National Institutes of Health Stroke Scale (at onset, at discharge, 30 days, and 90 days after discharge). RESULTS: We evaluated 80 eligible patients admitted to the Stroke Center of Lianyungang Second People's Hospital between 1st May, 2021 and 31st June, 2022. Except for 28 patients excluded before randomization and 14 patients who did not meet the criteria or dropped out or lost to follow-up during the trial, the remaining 38 patients (intervention group: 17, control group: 21) had well-balanced baseline features. In this trial, we found that plasma BNP levels (P = 0.003) decreased and NEP levels (P = 0.006) increased in enrolled patients after treatment with sacubitril/valsartan. There were no differences in plasma BDNF and Corin levels between the two groups. Furthermore, no difference in functional prognosis was observed between the two groups (all P values>0.05). CONCLUSIONS: Sacubitril/valsartan reduced endogenous plasma BNP levels in patients with ACI and did not affect their short-term prognosis.

Novel Phenylethanoid Glycosides Improve Hippocampal Synaptic Plasticity via the Cyclic Adenosine Monophosphate-CREB-Brain-Derived Neurotrophic Growth Factor Pathway in APP/PS1 Transgenic Mice.

INTRODUCTION: Alzheimer's disease (AD) is a major public health concern worldwide, but there are still no drugs available that treat it effectively. Previous studies have shown that phenylethanoid glycosides have pharmacological effects, which include anti-AD properties, but the underlying mechanisms by which they ameliorate AD symptoms remain unknown. METHODS: In this study, we used an APP/PS1 AD mouse model to explore the function and mechanisms underlying savatiside A (SA) and torenoside B (TB) in the treatment of AD. SA or TB (100 mg·kg-1·d-1) was orally administered to 7-month-old APP/PS1 mice for 4 weeks. Cognitive and memory functions were measured using behavioral experiments (including the Morris water maze test and the Y-maze spontaneous alternation test). Molecular biology experiments (including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays) were used to detect any corresponding changes in signaling pathways. RESULTS: The results showed that SA or TB treatment could significantly reduce cognitive impairment in APP/PS1 mice. We also showed that chronic treatment with SA/TB could prevent spine loss, synaptophysin immunoreactivity, and neuronal loss in mice, thereby improving synaptic plasticity and moderating learning and memory deficits. SA/TB administration also promoted the expression of synaptic proteins in APP/PS1 mouse brains and upregulated phosphorylation of proteins in the cyclic adenosine monophosphate (cAMP)/CREB/brain-derived neurotrophic growth factor (BDNF) pathway that are responsible for synaptic plasticity. Additionally, chronic SA/TB treatment increased the levels of BDNF and nerve growth factor (NGF) in the brains of APP/PS1 mice. Both astrocyte and microglia volumes, as well as the generation of amyloid ß, were also decreased in SA/TB-treated APP/PS1 mice compared to control APP/PS1 mice. CONCLUSION: In summary, SA/TB treatment was associated with activation of the cAMP/CREB/BDNF pathway and increased BDNF and NGF expression, indicating that SA/TB improves cognitive functioning via nerve regeneration. SA/TB is a promising candidate drug for the treatment of AD.

Au Nanozyme Driven Cascading Catalysis in Tollens' Reaction: An Insight of Glucose Oxidase-Like Mechanism.

Au nanoparticles (NPs) have been proven to be excellent glucose oxidase (GOx) mimics, which can catalyze the electrons transform pathway from glucose to oxygen. This study confirmed AuNPs can accelerate the reaction between [Ag(NH3 )2 ]+ and glucose under alkaline conditions, which is also known as the Tollens' reaction, and the possible mechanism was proposed. Here, [Ag(NH3 )2 ]+ instead of O2 acted directedly as an electron acceptor during glucose oxidation catalyzed by AuNPs, accompanied by hydrogen transfer. The as-synthesized Ag nanoparticles can also catalyze this process, similar to AuNPs, via a unique cascading catalysis mechanism in the Tollens' reaction. A simple and heatless glucose colorimetric assay can be established based on the plasmonic band of AgNPs with a liner range of 0.6-22.2 µM, and the limit of detection is 0.32 µM.

NT-proBNP Levels and Collateral Circulation Status in Patients with Acute Ischemic Stroke.

Methods: In this study, 326 hospitalized patients with acute anterior circulation ischemic stroke (AACIS) were included. A comparison of the clinical characteristics of those with and without AF was conducted. The Spearman rank correlation was used for the correlation analysis of plasma NT-proBNP level, regional leptomeningeal collateral (rLMC) score, and computed tomography perfusion (CTP) status in the AF and non-AF groups. An analysis of multivariate linear regression was used to determine how plasma NT-proBNP level, rLMC score, and CTP status influenced the score on the NIHSS. Results: There was a greater plasma NT-proBNP level in the AF group compared with the non-AF group, an increased CTP volume (including CTP ischemic volume, CTP infarct core volume, and CTP ischemic penumbra volume (P = 0.002)), higher NIHSS score on admission, and lower rLMC score (P < 0.001 for the remaining parameters). A negative correlation exists between plasma NT-proBNP level and rLMC score (r = -0.156, P = 0.022), but a positive correlation exists between plasma NT-proBNP level and both CTP ischemic volume and CTP infarct core volume (r = 0.148, P = 0.003) in the AF group, but not in the non-AF group. Multivariate linear regression analysis demonstrated that NT-proBNP, CTP ischemic penumbra volume, and rLMC score were associated with NIHSS score, and NT-proBNP was positively associated with NIHSS scores (95% confidence interval (CI), 0.000-0.002; P = 0.004) in the AF group, whatever in the unadjusted model or adjusted models, but not in the nonlarge artery atherosclerosis (LAA) group. Conclusion: In AACIS patients with AF, NT-proBNP level negatively correlated with collateral status, positively with CTP ischemic volume, and positively with NIHSS score.

Case report: Novel ETFDH compound heterozygous mutations identified in a patient with late-onset glutaric aciduria type II.

Glutaric aciduria type II (GA II) is an autosomal recessive metabolic disorder of fatty acid, amino acid, and choline metabolism. The late-onset form of this disorder is caused by a defect in the mitochondrial electron transfer flavoprotein dehydrogenase or the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Thus far, the high clinical heterogeneity of late-onset GA II has brought a great challenge for its diagnosis. In this study, we reported a 21-year-old Chinese man with muscle weakness, vomiting, and severe pain. Muscle biopsy revealed myopathological patterns of lipid storage myopathy, and urine organic acid analyses showed a slight increase in glycolic acid. All the aforementioned results were consistent with GA II. Whole-exome sequencing (WES), followed by bioinformatics and structural analyses, revealed two compound heterozygous missense mutations: c.1034A > G (p.H345R) on exon 9 and c.1448C>A (p.P483Q) on exon 11, which were classified as "likely pathogenic" according to American College of Medical Genetics and Genomics (ACMG). In conclusion, this study described the phenotype and genotype of a patient with late-onset GA II. The two novel mutations in ETFDH were found in this case, which further expands the list of mutations found in patients with GA II. Because of the treatability of this disease, GA II should be considered in all patients with muscular symptoms and acute metabolism decompensation such as hypoglycemia and acidosis.

Elevated Serum Ninjurin-1 Is Associated with a High Risk of Large Artery Atherosclerotic Acute Ischemic Stroke.

Ninjurin-1 is a novel adhesion molecule which is involved in many inflammatory diseases. Functional blockage of Ninjurin-1 has exerted an atheroprotective effect. The aim of the study is to explore the association between serum Ninjurin-1 and the risk of large artery atherosclerotic acute ischemic stroke. From August 2020 through December 2021, patients with large artery atherosclerotic acute ischemic stroke (LAA-AIS) admitted to the First Hospital Affiliated to Soochow University, and age- and sex-matched controls free of ischemic stroke were recruited. Serum Ninj1 was measured with an enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to calculate the odds ratios and 95% confidence intervals of LAA-AIS associated with serum Ninj1 levels, and receiver operating characteristic (ROC) curves were performed to assess the improvement value of Ninj1 for the prediction of LAA-AIS after adding Ninj1 to established risk factors. Of the 110 patients and 110 age- and sex-matched controls free of ischemic stroke enrolled, serum Ninj1 levels in LAA-AIS patients were significantly higher than that in control group (142.70 ng/ml [IQR: 110.41-163.44] vs 101.62 ng/ml [IQR: 86.63-120.86], p < 0.001). In multivariable analysis, Ninj1 levels were expressed as continuous variable and ordinal variable (tertiles), and it turned out that Ninj1 levels were positively associated with increased risk of LAA-AIS, especially in tertile3 compared with tertile1 (adjusted OR = 12.567, 95%CI: 5.148-30.678, p < 0.001), and the adjusted odds OR per 10 ng/ml increment was 1.541, 95%CI: 1.348-1.763, p < 0.001. Furthermore, adding Ninj1 to a multivariate logistic model including conventional risk factors associated LAA-AIS improved the area under ROC curves from 0.787 to 0.874. Elevated circulating levels of Ninj1 were associated with increased risk of LAA-AIS, indicating that serum Ninj1 may act as a predictor independent of established conventional risk factors.

Astaxanthin Ameliorates Worsened Muscle Dysfunction of MDX Mice Fed with a High-Fat Diet through Reducing Lipotoxicity and Regulating Gut Microbiota.

Duchenne muscular dystrophy (DMD), a severe X-linked inherited neuromuscular disease, has a high prevalence of obesity. Obesity exacerbates muscle damage and results in adverse clinical outcomes. Preventing obesity helps DMD patients delay disease progression and improve quality of life. Astaxanthin (AX) is a kind of carotenoid which has antioxidant and anti-adipogenesis effects. In this study, male C57BL/10ScSnDmdmdx/J mice were fed with a normal diet, a high-fat diet (HFD), and an HFD containing AX for 16 weeks, respectively. The results showed that AX significantly increased gastrocnemius fiber cross-section area and grip strength, improved treadmill endurance test and mitochondrial morphology, and reduced muscle triglyceride and malonaldehyde levels compared to the HFD. Lipidomic analysis revealed that AX decreased high levels of triglyceride, diglyceride, ceramides, and wax ester induced by HFD. Gut microbiota analysis indicated that AX supplementation failed to alleviate abnormal microbiota diversity, but increased the relative abundances of Akkermansia, Bifidobacterium, Butyricicoccus, and Staphylococcus. In conclusion, AX was expected to alleviate disease progression associated with obesity in DMD patients by reducing lipotoxicity and increasing the abundance of beneficial bacteria.

Identification of immune-related features involved in Duchenne muscular dystrophy: A bidirectional transcriptome and proteome-driven analysis.

Background: We aimed to investigate the biological mechanism and feature genes of Duchenne muscular dystrophy (DMD) by multi-omics and experimental verification strategy. Methods: We integrated the transcriptomic and proteomic methods to find the differentially expressed mRNAs (DEMs) and proteins (DEPs) between DMD and Control groups. Weighted gene co-expression network analysis (WGCNA) was then used to identify modules of highly correlated genes and hub genes. In the following steps, the immune and stromal cells infiltrations were accomplished by xCELL algorithm. Furthermore, TF and miRNA prediction were performed with Networkanalyst. ELISA, western blot and external datasets were performed to verify the key proteins/mRNAs in DMD patient and mouse. Finally, a nomogram model was established based on the potential biomarkers. Results: 4515 DEMs and 56 DEPs were obtained from the transcriptomic and proteomic study respectively. 14 common genes were identified, which is enriched in muscle contraction and inflammation-related pathways. Meanwhile, we observed 33 significant differences in the infiltration of cells in DMD. Afterwards, a total of 22 miRNAs and 23 TF genes interacted with the common genes, including TFAP2C, MAX, MYC, NFKB1, RELA, hsa-miR-1255a, hsa-miR-130a, hsa-miR-130b, hsa-miR-152, and hsa-miR-17. In addition, three genes (ATP6AP2, CTSS, and VIM) showed excellent diagnostic performance on discriminating DMD in GSE1004, GSE3307, GSE6011 and GSE38417 datasets (all AUC > 0.8), which is validated in patients (10 DMD vs. 10 controls), DMD with exon 55 mutations, mdx mouse, and nomogram model. Conclusion: Taken together, ATP6AP2, CTSS, and VIM play important roles in the inflammatory response in DMD, which may serve as diagnostic biomarkers and therapeutic targets.

Fecal Microbiota Transplantation Alleviated Cerebral Ischemia Reperfusion Injury in Obese Rats.

This study aimed to investigate whether fecal microbiota transplantation (FMT) provides protection for stroke injury in obese patients. Rats were fed high-fat diet (HFD) for 4 weeks and subjected to middle cerebral artery occlusion (MCAO). After FMT for 30 days, body weight, serum total cholesterol and triglyceride levels, neurological score, brain water content, and cerebral infarction volume were measured. Brain reactive oxygen species, superoxide dismutase and malondialdehyde were detected and the levels of Bcl-2, Bax and cleaved caspase-3 were examined. Rats fed with HFD had higher body weight and higher serum total cholesterol and triglyceride levels. Neurological score was lower, brain water content and cerebral infarction volume were higher in obese rats following MCAO, but FMT improved neurological deficit. Moreover, oxidative stress was enhanced in obese rats following MCAO, but FMT attenuated oxidative stress. Brain Bcl-2 level was lower while Bax and cleaved caspase-3 levels were higher in obese rats following MCAO, but FMT increased brain Bcl-2 level and decreased Bax and cleaved caspase-3 levels. In conclusion, FMT attenuated cerebral ischemic injury in obese rats and the beneficial effects of FMT may be mediated by the attenuation of oxidative stress and apoptosis in the brain.

High-risk screening of late-onset Pompe disease: A different early portrait in China.

Introduction: The lack of knowledge regarding the differences between Chinese and other ethnicities in the early manifestation of late-onset Pompe disease (LOPD) prohibits the development of an effective screening strategy. We conducted a multicenter screening study to determine LOPD prevalence in high-risk populations and define the early manifestation of LOPD in China. Methods: Between August 2020 and April 2021, the participants were prospectively identified through medical examination at 20 centers from inpatient departments and outpatient neuromuscular clinics in China. The inclusion criteria were as follows: (1) age ≥ 1 year and (2) either one of the following conditions: (a) persistent hyperCKemia, (b) muscle weakness of the axial and/or limb-girdle muscles, or (c) unexplained restrictive respiratory insufficiency (RI). Enzymatic activity of acid α-glucosidase (GAA) was measured in a dried blood spot (DBS) using a tandem mass spectrometry (MS/MS) assay. Next-generation sequencing (NGS) was used to evaluate all samples with decreased GAA activity, searching for GAA mutations and pseudodeficiency alleles. Results: Among the 492 cases, 26 positive samples (5.3%) were detected in the DBS test. Molecular studies confirmed a diagnosis of LOPD in eight cases (1.6%). Using MS/MS assay, GAA activities in individuals with pseudodeficiency could be distinguished from those in patients with LOPD. The median interval from the onset of symptoms to diagnosis was 5 years. All patients also showed RI, with a mean forced vital capacity (FVC) of 48%, in addition to axial/proximal muscle weakness. The creatine kinase (CK) level ranged from normal to no more than 5-fold the upper normal limit (UNL). LOPD with isolated hyperCKemia was not identified. Conclusion: Less frequent hyperCKemia and predominant RI depict a different early portrait of adult Chinese patients with LOPD. A modified high-risk screening strategy should be proposed for the early diagnosis of Chinese patients with LOPD.

Colorimetric assay of phosphate using a multicopper laccase-like nanozyme.

A new nanozyme (Cu-NADH) is reported composed of Cu-coordinated nicotinamide adenine dinucleotide (NADH) exhibiting laccase-like activity. The Cu-NADH nanozyme had higher heat tolerance and catalytic efficiency than natural laccase, and its catalytic activity can be enhanced by high concentration of Cl ions and it is intensely inhibited by phosphate. Therefore, a colorimetric method based on Cu-NADH and indigo carmine was successfully developed to detect phosphate in water. This method showed an excellent selectivity for phosphate, and it had a linear relationship in the phosphate concentration range 2-50 µM with a detection limit of 0.37 µM. We believe that this example of coordination between metal ions and biomolecules to mimic natural enzymes can inspire more effective and alternative strategies in nanozyme design and expand their use in sensing and determination.

Elevated NT-proBNP levels are associated with CTP ischemic volume and 90-day functional outcomes in acute ischemic stroke: a retrospective cohort study.

OBJECTIVE: To investigate the impact of N-terminal pro-B-type natriuretic peptide (NT-proBNP) on CTP infarct core volume and poor 90-day functional outcomes in acute ischemic stroke (AIS). METHODS: A total of 403 hospitalized patients with AIS in the Stroke Center of the First Hospital Affiliated to Soochow University were enrolled from March 2018 to January 2021. The association between NT-proBNP and clinical outcomes in acute ischemic patients was assessed by logistic regression and adjusted for confounding factors. Also, subgroup analyses were conducted based on treatment decisions. RESULTS: NT-proBNP was positively correlated with CTP ischemic volume (p < 0.001), infarct core volume (p < 0.001), and ischemic penumbra volume (p < 0.001). Univariate analysis showed that the influence of NT-proBNP and functional outcomes were statistically significant in model 1 (p = 0.002). This phenomenon was persistent after adjusted for age, sex, and body mass index in model 2 (p = 0.011), adjusted for SBP, current smoking, family history of stroke, hypertension, and diabetes mellitus in model 3 (p < 0.001), and adjusted for TnI, D-dimer, PLT, Cr, TC, TG, HDL-C, treatment decisions, and NIHSS score in model 4 (p = 0.027). A high NT-proBNP was associated with a high 90-days mRS score among the total population, IV rt-PA, and standardized treatment groups, but not in IV rt-PA + EVT, EVT, and EVT/IV rt-PA + EVT groups. CONCLUSION: Elevated NT-proBNP levels reveal large CTP infarct core volume and poor 90-day functional outcome in AIS. NT-pro BNP is an independent risk factor for functional outcomes.

Association of the Recessive Allele vrn-D1 With Winter Frost Tolerance in Bread Wheat.

Winter frost has been considered the primary limiting factor in wheat production. Shimai 12 is an elite wheat cultivar grown in central and southern Hebei province of China, but sensitive to winter frost. In this study, the winter frost tolerant cultivar Lunxuan 103 was bred by introducing the recessive allele vrn-D1 from winter wheat Shijiazhuang 8 (frost tolerance) into Shimai 12 using marker-assisted selection (MAS). Different from Shimai 12, Lunxuan 103 exhibited a winter growth habit with strong winter frost tolerance. In the Shimai 12 × Shijiazhuang 8 population, the winter progenies (vrn-D1vrn-D1) had significantly lower winter-killed seedling/tiller rates than spring progenies (Vrn-D1aVrn-D1a), and the consistent result was observed in an association population. Winter frost damage caused a significant decrease in grain yield and spike number/m2 in Shimai 12, but not in Lunxuan 103 and Shijiazhuang 8. The time-course expression analysis showed that the transcript accumulation levels of the cold-responsive genes were higher in Lunxuan 103 and Shijiazhuang 8 than in Shimai 12. Lunxuan 103 possessed the same alleles as its parents in the loci for plant height, vernalization, and photoperiod, except for the vernalization gene Vrn-D1. An analysis of genomic composition showed that the two parents contributed similar proportions of genetic compositions to Lunxuan 103. This study provides an example of the improvement of winter frost tolerance by introducing the recessive vernalization gene in bread wheat.

The effect of coupled inhibitory-facilitatory repetitive transcranial magnetic stimulation on shaping early reorganization of the motor network after stroke.

Neural plasticity is a major factor driving cortical reorganization after stroke. This study aimed to evaluate functional connectivity (FC) changes in the cortical motor network after coupled inhibitory-facilitatory repetitive transcranial magnetic stimulation (rTMS) treatment and to assess the correlation between FC changes and functional recovery, further characterizing the neural mechanisms underlying the beneficial effects of rTMS. We randomly divided 63 patients with acute stroke into four groups: (1) Group A received coupled inhibitory-facilitatory rTMS [1 Hz over the contralesional primary motor cortex (M1) and 10 Hz over ipsilesional M1]; (2) Group B received a contralesional sham stimulation and ipsilesional 10 Hz stimulation; (3) Group C received a contralesional 1 Hz rTMS and ipsilesional sham stimulation; and (4) Group D received bilateral sham stimulation only. Standardized rehabilitation therapy was performed immediately after rTMS, and each group was treated with their respective treatment modalities for 4 weeks. Twenty-four hours before and after the intervention, participants underwent resting-state functional magnetic resonance imaging. Additional functional assessments were conducted at baseline, after treatment, and at the 3 month follow-up. The rTMS treatment significantly changed the FCs of intra- and inter-hemispheric cortical motor networks in the rTMS groups (A and B) compared with the sham group (Group D). This effect was more pronounced in Group A, which displayed a changed FC between the contralesional postcentral gyrus and contralesional superior parietal gyrus, between the contralesional precentral gyrus and contralesional postcentral gyrus, and between the ipsilesional postcentral gyrus and contralesional superior parietal gyrus, when compared with Groups B and C. Importantly, FC changes were significantly correlated with improvement of motor function. In the early stages of ischemic stroke, coupled rTMS was more conducive to motor recovery by modulating the FCs of intra-hemispheric and inter-hemispheric motor networks. Our results suggested that FC changes were related to motor function recovery for early-stage cerebral stroke patients treated with coupled rTMS. These findings could help to understand the mechanism of coupled rTMS and further the use of this therapy as an adjunct rehabilitation technique in motor recovery.

Analyzing Corin-BNP-NEP Protein Pathway Revealing Differential Mechanisms in AF-Related Ischemic Stroke and No AF-Related Ischemic Stroke.

Background: The incidence of atrial fibrillation (AF)-related stroke increases with aging. Natriuretic peptides (NPs) family, including Corin-B type natriuretic peptide (BNP)-neprilysin (NEP) protein levels increased with age and are risk markers of cardiovascular and cerebrovascular diseases, such as AF and cardioembolic stroke. Aging is also linked to epigenetics, specifically DNA methylation. However, only a few studies have investigated the effect of DNA methylation on the NP system. Thus, the present study aimed to investigate whether the Corin-BNP-NEP protein pathway is involved in the pathogenesis of AF-stroke and CpG methylation in the promoter region of the Corin protein gene has an effect on AF-related ischemic stroke. Methods: A total of 82 patients hospitalized with acute ischemic strokes were enrolled in this study. The differences in clinical information were compared between the AF-stroke (n = 37) and no AF-stroke groups (n = 45). Plasma-soluble Corin and NEP were detected using an ELISA kit. CpG methylation in the promoter region of the gene was assessed by a next-generation sequencing-based bisulfite sequencing polymerase chain reaction (BSP). Results: (1) Patients in AF-stroke were older, had higher initial NIHSS score, 90-day mRs, higher D2-dimer, INR, and APTT, and low TG, TC, and HbA1c (all p < 0.05). (2) Serum levels of Corin and BNP in the AF-stroke group were significantly higher than that in the no AF-stroke group (p < 0.05). No significant difference was detected in the serum levels of NEP between the two groups. (3) The levels of CpG methylation in the promoter region of the Corin protein gene in the AF-stroke group was significantly lower than that in the no AF-stroke group (p < 0.05). The CpG sites with maximal methylation differences between the two groups were CORIN:678, CORIN:682, CORIN:694, and CORIN:700. Conclusion: The current findings raise the possibility that the Corin-BNP-NEP protein pathway may be involved in the pathogenesis of AF-related ischemic stroke. Deficient CpG methylation in the promoter region of the Corin protein gene is associated with AF-related ischemic stroke.

Effects of Virtual Reality Rehabilitation Training on Cognitive Function and Activities of Daily Living of Patients With Poststroke Cognitive Impairment: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the effects of virtual reality (VR) rehabilitation training on the cognitive function and activities of daily living (ADL) of patients with poststroke cognitive impairment (PSCI). DATA SOURCES: Four Chinese databases and 6 English databases were systematically searched for studies published until August 31, 2021, by using Medical Subject Headings of the National Library of Medicine terms such as virtual reality, cognition disorders, cognitive dysfunction, and stroke and free terms such as virtual environment, VR, cognition impairment, cerebrovascular accident, and PSCI. STUDY SELECTION: Randomized controlled trials treating PSCI with VR training were included. The control groups received conventional treatments such as conventional rehabilitation training and drug therapy; the experimental groups received VR rehabilitation training. The outcome measures were cognitive function and ADL. DATA EXTRACTION: Two researchers independently extracted key information from eligible studies. The methodological quality of the studies was evaluated using the Cochrane Handbook for Systematic Reviews of Interventions v5.1.0. Meta-analysis was performed using RevMan v5.4. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. DATA SYNTHESIS: Twenty-one studies (1149 participants) were included. Meta-analyses found that compared with the control group, VR rehabilitation training increased Mini-Mental State Examination, Montreal Cognitive Assessment, Loewenstein Occupational Therapy Cognitive Assessment, Rivermead Behavioral Memory Test Second Edition, Barthel Index, Modified Barthel Index, and FIM scores; event-related potential 300 (P300) amplitude; and the N-acetylaspartate/creatinine (Cr) ratio on proton magnetic resonance spectroscopy (1H-MRS) and reduced P300 latency; Trail Making Test scores; and the choline-containing compounds/Cr ratio on 1H-MRS (all P<.05). These results indicated that VR training improved cognitive function and ADL in PSCI. CONCLUSIONS: VR rehabilitation training promotes the rehabilitation of cognitive function and recovery of ADL in patients with PSCI and may be a good complementary approach to conventional cognitive interventions.

Improvement of sludge characteristics and mitigation of membrane fouling in the treatment of pesticide wastewater by electrochemical anaerobic membrane bioreactor.

Electrochemical anaerobic membrane bioreactor attracted attention due to stable treatment quality with low footprint, and draw solute has significant effect on the sludge characteristics and membrane fouling performance. In this pilot-scale study, an electrochemical anaerobic membrane bioreactor (E-AnMBR) was proposed for treating pesticide wastewater at different hydraulic retention times (HRTs), demonstrating that E-AnMBR was superior on improvement of sludge characteristics and mitigation of membrane fouling, compared with the conventional anaerobic membrane bioreactor (C-AnMBR). E-AnMBR reduced sludge yield by 41.2 ± 6.7% and the SVI was significantly decreased by 32.5±13.8%. The accumulation of VFA in E-AnMBR was slighter than that of C-AnMBR, and the minimum average VFA was 255±6 mg/L. The methane yield of E-AnMBR (0.22-0.29 L CH4/g CODremoved) was 1.2-1.4 times than that of C-AnMBR. The EPS contents in suspended and attached sludge of E-AnMBR were significantly reduced by 41.8 ± 3.3% and 77.4 ± 14.5% than that of C-AnMBR, respectively. These results suggested that E-AnMBR has lower sludge disposal pressure, higher stability and methane recovery potential. Not only that, E-AnMBR successfully reduced membrane resistance, delaying the fouling rate by 31.0-38.5%. Finally, the linear relationship between EPS characteristics and membrane pollution was determined.

Long non-coding RNA Plasmacytoma variant 1 in acute ischemic stroke: association with disease risk, severity, and recurrence-free survival and relation with inflammatory cytokines.

OBJECTIVE: Long non-coding RNA plasmacytoma variant 1 (Lnc-PVT1) is implied with neuron apoptosis, inflammatory cytokines recruitment, endothelial cell proliferation, and angiogenesis; the latter are closely implicated in acute ischemic stroke (AIS) pathology. However, clinical significance of Lnc-PVT1 in AIS management remains unexplored. Thus, this study aimed to investigate this topic. METHODS: In total, 110 patients AIS and 110 controls were enrolled. Peripheral blood mononuclear cells (PBMCs) and serum were extracted from AIS patients and controls. Then, RT-qPCR was performed to determine the PBMC Lnc-PVT1 expression in AIS patients and controls. Besides, we used ELISA to evaluate serum interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-17A in AIS patients. Additionally, in terms of recurrence-free survival (RFS) analysis, the Lnc-PVT1 expression was classified from quantile 1 to quantile 4 regarding the Lnc-PVT1 expression in AIS patients. RESULTS: AIS patients had higher Lnc-PVT1 expression compared with that in controls (P < 0.001) with a good supplementary diagnostic value for AIS (area under the curve (AUC) = 0.916 (95%CI 0.881-0.951). Furthermore, Lnc-PVT1 expression was positively linked with NIHSS score (r = 0.380, P < 0.001), IFN-γ (r = 0.217, P = 0.023), TNF-α (r = 0.311, P = 0.001), IL-6 (r = 0.235, P = 0.014), and IL-17A (r = 0.253, P = 0.008), separately. RFS of AIS patients with Lnc-PVT1 quantile 1-2 was higher than that of patients with Lnc-PVT1 quantile 3-4 somehow (P = 0.050). CONCLUSION: Lnc-PVT1 not only correlates with AIS risk, inflammation, and disease severity, but also reveals a dependable value for AIS prognostication, which still needs further studies for validation.