Netrin-1 protects blood-brain barrier (BBB) integrity after cerebral ischemia-reperfusion by activating the Kruppel-like factor 2 (KLF2)/occludin pathway.

Ischemia/reperfusion (I/R)-induced neural damage and neuroinflammation have been associated with pathological progression during stroke. Netrin-1 is an important member of the family of laminin-related secreted proteins, which plays an important role in governing axon elongation. However, it is unknown whether Netrin-1 possesses a beneficial role in stroke. Here, we employed the middle cerebral artery occlusion (MCAO) model to study the function of Netrin-1 in alleviating brain injuries. Our results demonstrate that Netrin-1 rescued poststroke neurological deficits and inhibited production of the inflammatory cytokines such as interleukin 6 (IL-6) and endothelial chemokine (C-X-C motif) ligand 1 (Cxcl1). Importantly, Netrin-1 protected against MCAO-induced dysfunction of the blood-brain barrier (BBB) in mice and a reduction in the expression of the tight junction (TJ) protein occludin. Additionally, we report that Netrin-1 could ameliorate oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury and prevent aggravation in endothelial monolayer permeability in bEnd.3 human brain microvascular endothelial cells (HBMVECs). Mechanistically, Netrin-1 ameliorated OGD/R-induced decrease in occludin and Kruppel-like factor 2 (KLF2) in HBMVECs. Notably, silencing of KLF2 abolished the beneficial effects of Netrin-1 in protecting endothelial permeability and occludin expression, suggesting that these effects are mediated by KLF2. In conclusion, our findings suggest that Netrin-1 could constitute a novel therapeutic strategy for ischemic stroke.

Attapulgite-enhanced ε-poly-l-lysine for heightened antibacterial efficiency against Pseudomonas syringae pv. Tomato.

ε-Poly-l-lysine (ε-PL) is an effective antimicrobial peptide for controlling fungal plant diseases, exhibiting significant antifungal activity and safety. Despite its known efficacy, the potential of ε-PL in combating plant bacterial diseases remains underexplored. This study evaluated the effectiveness of ε-PL and its nanomaterial derivative in managing tomato bacterial spot disease caused by Pseudomonas syringae pv. tomato. Results indicated that ε-PL substantially inhibited the growth of Pseudomonas syringae pv. tomato. Additionally, when ε-PL was loaded onto attapulgite (encoded as ATT@PL), its antibacterial effect was significantly enhanced. Notably, the antibacterial efficiency of ATT@PL containing 18.80 µg/mL ε-PL was even close to that of 100 µg/mL pure ε-PL. Further molecular study results showed that, ATT@PL stimulated the antioxidant system and the salicylic acid signaling pathway in tomatoes, bolstering the plants disease resistance. Importantly, the nanocomposite demonstrated no negative effects on both seed germination and plant growth, indicating its safety and aligning with sustainable agricultural practices. This study not only confirmed the effectiveness of ε-PL in controlling tomato bacterial spot disease, but also introduced an innovative high antibacterial efficiency ε-PL composite with good bio-safety. This strategy we believe can also be used in improving other bio-pesticides, and has high applicability in agriculture practice.

Streptomyces virginiae XDS1-5, an antagonistic actinomycete, as a biocontrol to peach brown rot caused by Monilinia fructicola.

BACKGROUND: Peach brown rot, caused by the pathogen Monilinia fructicola, represents a significant postharvest infectious disease affecting peach fruit. This disease is responsible for a substantial increase in fruit decay rates, leading to significant economic losses, often exceeding 50%. Currently, there is a growing interest in identifying biocontrol agents to mitigate peach brown rot, with a predominant interest in Bacillus species. RESULTS: In this investigation, we isolated 410 isolates of actinomycetes from non-farmland ecosystem soil samples. Subsequently, 27 isolates exhibiting superior inhibitory capabilities were selected. Among these, strain XDS1-5 demonstrated the most robust fungistatic effect against brown rot disease, achieving an 80% inhibition rate in vitro and a 66% inhibition rate in vivo. XDS1-5 was identified as belonging to the Streptomyces virginiae species. Furthermore, a fermentation filtrate of XDS1-5 exhibited the ability to metabolize 34.21% of the tested carbon sources and 7.37% of the tested nitrogen sources. Particularly noteworthy was its capacity to disrupt the cell membrane structure directly, leading to increased cell membrane permeability and cytoplasmic leakage. Additionally, our investigation indicated that indoline, a metabolite produced by XDS1-5, played a pivotal role in inhibiting the growth of M. fructicola. CONCLUSION: In summary, our study has identified a biocontrol actinomycete, XDS1-5, with the potential to effectively inhibit postharvest brown rot disease in peaches. This finding holds great significance for the biological control of peach brown rot, offering promising prospects for mitigating the economic losses associated with this devastating disease. © 2024 Society of Chemical Industry.

Tobacco mosaic virus hijacks its coat protein-interacting protein IP-L to inhibit NbCML30, a calmodulin-like protein, to enhance its infection.

Calcium is an important plant immune signal that is essential for activating host resistance, but how RNA viruses manipulate calcium signals to promote their infections remains largely unknown. Here, we demonstrated that tobacco mosaic virus (TMV) coat protein (CP)-interacting protein L (IP-L) associates with calmodulin-like protein 30 (NbCML30) in the cytoplasm and nucleus, and can suppress its expression at the nucleic acid and protein levels. NbCML30, which lacks the EF-hand conserved domain and cannot bind to Ca2+ , was located in the cytoplasm and nucleus and was downregulated by TMV infection. NbCML30 silencing promoted TMV infection, while its overexpression inhibited TMV infection by activating Ca2+ -dependent oxidative stress in plants. NbCML30-mediated resistance to TMV mainly depends on IP-L regulation as the facilitation of TMV infection by silencing NbCML30 was canceled by co-silencing NbCML30 and IP-L. Overall, these findings indicate that in the absence of any reported silencing suppressor activity, TMV CP manipulates IP-L to inhibit NbCML30, influencing its Ca2+ -dependent role in the oxidative stress response. These results lay a theoretical foundation that will enable us to engineer tobacco (Nicotiana spp.) with improved TMV resistance in the future.

Fabrication of an alginate-based ZhiNengCong gel showed an enhanced antiviral and plant growth promoting functions.

Tobacco mosaic disease is a worldwide viral disease that can cause huge economic losses. Plant immune inducers have become the main force in the prevention and treatment of viral disease own to their high efficiency and rapid effect. However, since tobacco mosaic disease can occur at any point in the plant growth cycle, a single application period cannot guarantee the completely management. In this study, an extract from Paecilomyces variotii named ZhiNengCong (ZNC), which can fight against tobacco mosaic disease with 65% control effect, and improve the promotion of tobacco stem girth, was selected from five commercial antiviral medicines, and a sustained release sodium alginate (Alg)-based ZNC (ZNC@Alg) was prepared by physical absorption. ZNC@Alg, who contains only 5 mg/mL ZNC, can release ZNC for 7 consecutive days, and displayed an enhanced effect in inducing the PAL-mediated salicylic acid signaling pathway activation to participate in the inhibition of green fluorescent protein (GFP)-tagged tobacco mosaic virus (TMV-GFP) infection, even after 7 days of the application. Notably, field experiments showed that the control effect of ZNC@Alg was up to 88%, which was significantly better than that of ZNC with the same concentration (10 µg per plant). In addition, ZNC@Alg exhibited a stronger growth-promoting effect than ZNC, which significantly increased the wet weight of tobacco. Taken together, we screened out a plant immune inducer ZNC that can effectively inhibit tobacco virus disease, and created ZNC@Alg with higher control effect and growth promotion effect, laying a foundation for effective field management of tobacco mosaic disease.

Transcriptome analysis reveals the mechanism of zinc ion-mediated plant resistance to TMV in Nicotiana benthamiana.

Zinc ions (Zn2+) are used to promote plant growth and treat multiple diseases. However, it is still unclear which pathways in plants respond to Zn2+. In this study, we found that supplying (CH3COO)2Zn can effectively delay tobacco mosaic virus (TMV) replication and movement in Nicotiana benthamiana. To further understand the regulatory mechanism of antiviral activity mediated by Zn2+, we examined the transcriptomic changes of leaves treated with Zn2+. Three days after treatment, 7575 differential expression genes (DEGs) were enriched in the Zn2+ treatment group compared with the control group. Through GO and KEGG analysis, the pathway of phosphatidylinositol signaling system and inositol phosphate metabolism were significantly enriched after treated with Zn2+, and a large number of ethylene-responsive transcription factors (ERFs) involved in inositol phosphate metabolism were found to be enriched. We identified ERF5 performed a positive effect on plant immunity. Our findings demonstrated that Zn2+-mediated resistance in N. benthamiana activated signal transduction and regulated the expression of resistance-related genes. The results of the study uncover a global view of mRNA changes in Zn2+-mediated cellular processes involved in the competition between plants and viruses.

Gradient-based elephant herding optimization for cluster analysis.

Clustering analysis is essential for obtaining valuable information from a predetermined dataset. However, traditional clustering methods suffer from falling into local optima and an overdependence on the quality of the initial solution. Given these defects, a novel clustering method called gradient-based elephant herding optimization for cluster analysis (GBEHO) is proposed. A well-defined set of heuristics is introduced to select the initial centroids instead of selecting random initial points. Specifically, the elephant optimization algorithm (EHO) is combined with the gradient-based algorithm GBO for assigning initial cluster centers across the search space. Second, to overcome the imbalance between the original EHO exploration and exploitation, the initialized population is improved by introducing Gaussian chaos mapping. In addition, two operators, i.e., random wandering and variation operators, are set to adjust the location update strategy of the agents. Nine datasets from synthetic and real-world datasets are adopted to evaluate the effectiveness of the proposed algorithm and the other metaheuristic algorithms. The results show that the proposed algorithm ranks first among the 10 algorithms. It is also extensively compared with state-of-the-art techniques, and four evaluation criteria of accuracy rate, specificity, detection rate, and F-measure are used. The obtained results clearly indicate the excellent performance of GBEHO, while the stability is also more prominent.

Coronavirus disease 2019 is threatening stroke care systems: a real-world study.

BACKGROUND: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the stroke care systems have been seriously affected because of social restrictions and other reasons. As the pandemic continues to spread globally, it is of great significance to understand how COVID-19 affects the stroke care systems in mainland China. METHODS: We retrospectively studied the real-world data of one comprehensive stroke center in mainland China from January to February 2020 and compared it with the data collected during the same period in 2019. We analyzed DTN time, onset-to-door time, severity, effects after treatment, the hospital length of stays, costs of hospitalization, etc., and the correlation between medical burden and prognosis of acute ischemic stroke (AIS) patients. RESULTS: The COVID-19 pandemic was most severe in mainland China in January and February 2020. During the pandemic, there were no differences in pre-hospital or in-hospital workflow metrics (all p>0.05), while the degree of neurological deficit on admission and at discharge, the effects after treatment, and the long-term prognosis were all worse (all p<0.05). The severity and prognosis of AIS patients were positively correlated with the hospital length of stays and total costs of hospitalization (all p<0.05). CONCLUSIONS: COVID-19 pandemic is threatening the stroke care systems. Measures must be taken to minimize the collateral damage caused by COVID-19.

Spectrum of SLC20A2, PDGFRB, PDGFB, and XPR1 mutations in a large cohort of patients with primary familial brain calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0.9% (2/226) of all patients, respectively. Clinically, 44.8% of genetically confirmed patients (probands and relatives) were considered symptomatic. The most frequent symptoms were chronic headache, followed by movement disorders and vertigo. Moreover, the total calcification score was significantly higher in the symptomatic group compared to the asymptomatic group. Functionally, we observed impaired phosphate transport induced by seven novel missense mutations in SLC20A2 and two novel mutations in XPR1. The mutation p.D164Y in XPR1 might result in low protein expression through an enhanced proteasome pathway. In conclusion, our study further confirms that mutations in SLC20A2 are the major cause of PFBC and provides additional evidence for the crucial roles of phosphate transport impairment in the pathogenies of PFBC.

Cellulose Nanocrystal Surface Cationization: A New Fungicide with High Activity against Phycomycetes capsici.

At present, the management of Phytophthora capsici (P. capsici) mainly relies on chemical pesticides. However, along with the resistance generated by P. capsici to these chemical pesticides, the toxicity and non-degradability of this chemical molecule may also cause serious environmental problems. Herein, a new bio-based nano-antifungal material (CNC@CTAB) was made with coating hexadecyl trimethyl ammonium bromide (CTAB) on the surface of a cellulose nanocrystal (CNC). This material was then applied to the prevention of P. capcisi. This particle was facilely fabricated by mixing CTAB and sulfuric group modified CNC in an aqueous solvent. Compared to pure CTAB, the enrichment of CTAB on the CNC surface showed a better anti-oomycete activity both in vitro and in vivo. When CNC@CTAB was applied on P. capsici in vitro, the inhibition rate reached as high as 100%, while on the pepper leaf, the particle could also efficiently prevent the infection of P. capsici, and achieve a disease index as low as zero Thus, considering the high safety of CNC@CTAB in agricultural applications, and its high anti-oomycete activity against P. capsici, we believe that this CNC@CTAB has great application potential as a new green nano-fungicide in P. capsici management during the production of peppers or other vegetables.

Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

BACKGROUND: Genetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. METHODS: We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis. RESULTS: 111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations. CONCLUSIONS: These findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS.

Characteristics of white coat hypertension in Chinese Han patients with type 2 diabetes mellitus.

OBJECTIVES: This study documented the prevalence and clinical features of white coat hypertension (WCH) among Chinese Han patients with type 2 diabetes mellitus (T2DM). METHODS: Clinic and ambulatory blood pressure (BP) measurements were compared in 856 patients with T2DM to determine the frequency of WCH (WCH was defined as clinical blood pressure ≥140/90 mmHg and daytime blood pressure <135/85 mmHg and/or 24-h ambulatory BP (ABP) mean value of <130/80 mmHg on ambulatory BP monitoring (ABPM). Weight, waist circumference (WC), body mass index (BMI), waist to height ratio (WHtR), fasting blood glucose, glycosylated hemoglobin level and circadian BP patterns were also measured to find clinical features predictive of WCH in T2DM. RESULTS: The prevalence of WCH was 7.36% (63/856) in the overall population, 6.13% (29/473) in male and 8.88% (34/383) in female (p < 0.05). WCH accounted for 14.03% (63/449) of diagnosed hypertension. Age, course of T2DM, male WC were independent protective factors, whereas female sex, smoking and alcohol consumption were independent risk factors for WCH in T2DM. Non-dippers and reverse dippers made up larger proportion of the WCH group (p < 0.01). CONCLUSION: WCH is relatively common among T2DM patients, it is a unique condition distinct from essential hypertension (EH), and WCH patients also exhibit significant differences in clinical parameters.

[Predictors of internal borderzone infarcts in atherosclerotic middle cerebral artery stenosis].

OBJECTIVE: To explore the independent predictors of internal borderzone (IBZ) infarcts in patients with atherosclerotic middle cerebral artery stenosis/occlusion (MCAS). METHODS: A total of 167 hospitalized patients with atherosclerotic MCAS during January 2008 and March 2014 were retrospectively analyzed. They were divided into "with IBZ group" (n = 55) and "without IBZ group" (n = 112) according to the findings of magnetic resonance images (MRI). Their clinical data were collected including demographics, traditional vascular risk factors, stenotic degree of MCA and other cerebral supply arteries, TICI grading for antegrade blood flow, ASITN/SIR grading for collateral circulation and other variables. The intra-group data were compared by univariate analysis. Variables with P < 0.1 were included into multivariate Logistic regression model for obtaining the independent predictors of IBZ. Two models were established including either TICI-grading or stenotic degree of MCAS due to close correlations between two variables. RESULTS: There were 45 females and 122 males with a mean age of 54 ± 12 years. Variables with a P value <0.1 in univariate analysis included relatively low blood pressure (P = 0.006), stenotic degree of MCAS (P = 0.012), TICI-grading (P = 0.003), history of hypertension (P = 0.055) and ASITN-grading (P = 0.067). In multivariate model I, independent predictors of IBZ included TICI-grading (OR 4.310, 95%CI 1.698-10.869, P = 0.002), history of hypertension (OR 0.458, 95%CI 0.224-0.936, P = 0.032), relatively low blood pressure (OR 3.848; 95%CI 1.345-7.983, P = 0.039). In multivariate model II, independent predictors of IBZ included stenotic degree of MCAS (P = 0.006; severe vs moderate: OR 4.796, 95%CI 1.676-13.729, P = 0.003; occlusion vs moderate: OR 5.537, 95%CI 1.846-16.603, P = 0.002). The two models had a similar area under the curve (AUC) of receiver operating curve (ROC) of 0.702 (95%CI 0.618~0.787, P < 0.001) and 0.709 (95%CI 0.626-0.792, P < 0.001). CONCLUSION: Severe stenosis or total occlusion of MCA, impairment of antegrade blood flow and relatively low blood pressure are the independent risk factors of IBZ. And history of hypertension is a protective fact or of IBZ in patients with MCAS.

Pharmacological inhibition of S6K1 rescues synaptic deficits and attenuates seizures and depression in chronic epileptic rats.

BACKGROUND: Recent studies have shown that mTOR signaling plays an important role in synaptic plasticity. However, the function of S6K1, the mechanistic target of rapamycin kinase complex 1 (mTORC1) substrate, in epilepsy remains unknown. AIMS: Our present study aimed to explore the mechanism by which S6K1 is involved in chronic epilepsy. METHODS: First, immunostaining was used to measure neurite length and complexity in kainic acid (KA)-treated primary cultured neurons treated with PF-4708671, a highly selective S6K1 inhibitor. We obtained evidence for the role of S6K1 in protecting and promoting neuronal growth and development in vitro. Next, to explore the function and mechanism of the S6K1 inhibitor in epilepsy, a pilocarpine-induced chronic epileptic rat model was established. In vivo electrophysiology (including local field potentiation in CA1 and long-term potentiation), depression/anxiety-like behavior tests, and Golgi staining were performed to assess seizure behavior, power spectral density, depression/anxiety-like behavior, and synaptic plasticity. Furthermore, western blotting was applied to explore the potential molecular mechanisms. RESULTS: We found that inhibition of S6K1 expression significantly decreased seizures and depression-like behavior and restored power at low frequencies (1-80 Hz), especially in the delta, theta, and alpha bands, in chronic epileptic rats. In addition, PF-4708671 reversed the LTP defect in hippocampal CA3-CA1 and corrected spine loss and dendritic pathology. CONCLUSION: In conclusion, our data suggest that inhibition of S6K1 attenuates seizures and depression in chronic epileptic rats via the rescue of synaptic structural and functional deficits. Given the wide range of physiological functions of mTOR, inhibition of its effective but relatively simple functional downstream molecules is a promising target for the development of drugs for epilepsy.

A high rain-erosion resistant bio-based nanogel with continuous immunity induction for plant virus inhibition.

Tobacco mosaic virus (TMV) is the most widely spread and harmful virus in the world, causing serious economic losses annually. However, the low anti-erosion ability of the pesticides for TMV management make it easy to be washed by the rain, which makes the effective duration of the pesticides shorter. In this paper, a new bio-based nanogel with superior antiviral activity was reported, and its slow-release behavior, rain erosion resistance and the antiviral mechanism was systematically studied. The results determined that the nanogels (Zn2+@ALGNP and Zn2+@ALGNP@PL) exhibited sustained releasing of Zn2+ with a 7 days duration, and the ε-PL coating could enhance the releasing rate of Zn2+. Moreover, Zn2+@ALGNP@PL displayed a lower contact angle, indicating greater adhesion to the leaf surface, and in consequence imposed better resistance to simulate rain erosion than pure Zn2+. Strikingly, Zn2+@ALGNP@PL could inhibit plant virus infection by aggregating the virions and reducing its coat protein stability, as well as inducing the efficient expression of reactive oxygen species, antioxidant enzymes and resistance genes to enhance plant resistance and promote plant growth. Overall, this study had successfully developed a high rain-erosion resistant bio-based nanogel capable of continue to induce resistant plants and promote plant growth.

Inhibition of Monilinia fructicola sporulation and pathogenicity through eucalyptol-mediated targeting of MfCat2 by Streptomyces lincolnensis strain JCP1-7.

Peach brown rot, attributed to Monilinia fructicola, presents a significant threat to postharvest peach cultivation, causing losses of up to 80%. With an increasing number of countries, spearheaded by the European Union, imposing bans on chemical agents in fruit production, there is a growing interest in mining highly active antibacterial compounds from biological control strains for postharvest disease management. In this study, we highlight the unique ability of Streptomyces lincolnensis strain JCP1-7 to inhibit M. fructicola sporulation, despite its limited antimicrobial efficacy. Through GC-MS analysis, eucalyptol was identified as the key compound. Fumigation of diseased fruits with eucalyptol at a concentration of 0.0335 µg cm-3 demonstrated an in vivo inhibition rate against M. fructicola of 93.13%, completely suppressing spore formation. Transcriptome analysis revealed the impact of eucalyptol on multiple pathogenesis-related pathways, particularly through the inhibition of catalase 2 (Cat2) expression. Experiments with a MfCat2 knockout strain (ΔMfCat2) showed reduced pathogenicity and sensitivity to JCP1-7 and eucalyptol, suggesting MfCat2 as a potential target of JCP1-7 and eucalyptol against M. fructicola. Our findings elucidate that eucalyptol produced by S. lincolnensis JCP1-7 inhibits M. fructicola sporulation by regulating MfCat2, thereby effectively reducing postharvest peach brown rot occurrence. The use of fumigation of eucalyptol offers insights into peach brown rot management on a large scale, thus making a significant contribution to agricultural research.

Eomesodermin expression in CD4+T-cells associated with disease progression in amyotrophic lateral sclerosis.

AIM: To clarify the role of Eomesodermin (EOMES) to serve as a disease-relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4+T subsets in amyotrophic lateral sclerosis (ALS). METHODS: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T-cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1-year longitudinal follow-ups, the ALSFRS-R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort. RESULTS: In the derivation cohort, the CD4+EOMES+T-cell subsets were significantly increased (p < 0.001). EOMES+ subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4+EOMES+T-cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p = .010) and worse prognosis (p = .003). CONCLUSIONS: We demonstrated that increased CD4+EOMES+T-cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS.

Association between high-resolution magnetic resonance vessel wall imaging characteristics and recurrent stroke in patients with intracranial atherosclerotic steno-occlusive disease: A prospective multicenter study.

BACKGROUND: High-resolution magnetic resonance vessel wall imaging (HRMR-VWI) is a promising technique for identifying intracranial vulnerable plaques beyond lumen narrowing. However, the association between HRMR-VWI characteristics and recurrent stroke remains uncertain. AIMS: This study aimed to investigate the association between HRMR-VWI characteristics and recurrent ipsilateral stroke in patients with symptomatic intracranial atherosclerotic steno-occlusive disease (ICAS). METHODS: This multicenter, observational study recruited first-ever acute ischemic stroke patients attributed to ICAS (>50% stenosis or occlusion) within 7 days after onset. Participants were assessed by multiparametric magnetic resonance imaging (MRI) including diffusion-weighted imaging, three-dimension time-of-flight magnetic resonance angiography, and three-dimensional T1-weighted HRMR-VWI. The patients were recommended to receive best medical therapy and were systematically followed up for 12 months. The association between HRMR-VWI characteristics and the time to recurrent ipsilateral stroke was investigated by univariable and multivariable analysis. RESULTS: Two hundred and fifty-five consecutive patients were enrolled from 15 centers. The cumulative 12 month ipsilateral recurrence incidence was 4.1% (95% confidence interval (CI): 1.6-6.6%). Patients with recurrent ipsilateral stroke exhibited higher rates of intraplaque hemorrhage (IPH) (30.0% vs 6.5%) and eccentric plaque (90.0% vs 48.2%), and lower occurrence of occlusive thrombus (10.0% vs 23.7%). Plaque length (5.69 ± 2.21 mm vs 6.67 ± 4.16 mm), plaque burden (78.40 ± 7.37% vs 78.22 ± 8.32%), degree of stenosis (60.25 ± 18.95% vs 67.50% ± 22.09%) and remodeling index (1.07 ± 0.27 vs 1.03 ± 0.35) on HRMR-VWI did not differ between patients with and without recurrent ipsilateral stroke. In the multivariable Cox regression analysis, IPH (hazard ratio: 6.64, 95% CI: 1.23-35.8, p = 0.028) was significantly associated with recurrent ipsilateral stroke after adjustment.Conclusions:Our results suggest intraplaque hemorrhage (IPH) is significantly associated with recurrent ipsilateral stroke and has potential value in the selection of patients for aggressive treatment strategies. DATA ACCESS STATEMENT: Data from this study are available and can be accessed upon request.

Double whammy: the genetic variants in CECR2 and high Hcy on the development of neural tube defects.

Introduction: Neural tube defects (NTDs) are serious congenital malformations. The etiology of NTDs involves both genetic and environmental factors. Loss of CECR2 in mice has been shown to result in NTDs. Our previous study indicated that high homocysteine (HHcy) levels could further reduced the expression level of CECR2. This investigation aims to explore the genetic influence of the chromatin remodeling gene, CECR2, in humans and determine if HHcy can have a synergistic effect on protein expression. Methods: We conducted Next-Generation Sequencing (NGS) of the CECR2 gene in 373 NTD cases and 222 healthy controls, followed by functional assay application to select and evaluate CECR2 missense variants and subsequent Western blotting to identify protein expression levels. Results: From the analysis, we identified nine rare, NTD-specific mutations within the CECR2 gene. Significantly, four missense variants (p.E327V, p.T521S, p.G701R, and p.G868R) were selected via functional screening. The E9.5 mouse ectodermal stem cell line NE-4C, transfected with plasmids expressing p.E327V, p.T521S, p.G868R variants or a recombinant harboring all four (named as 4Mut), exhibited notable reductions in CECR2 protein expression. Furthermore, exposure to homocysteine thiolactone (HTL), an extremely reactive homocysteine metabolite, amplified the reduction in CECR2 expression, accompanied by a significant increase in the apoptotic molecule Caspase3 activity, a potential NTD inducer. Importantly, folic acid (FA) supplementation effectively counteracted the CECR2 expression decline induced by CECR2 mutation and HTL treatment, leading to reduced apoptosis. Discussion: Our observations underscore a synergistic relationship between HHcy and genetic variations in CECR2 concerning NTDs, thereby reinforcing the concept of gene-environment interaction phenomena in NTD etiology.