Mesenchymal stem cells (MSCs) are known to promote tissue regeneration and suppress excessive inflammation caused by infection or trauma. Reported evidence indicates that various factors influence the expression of MSCs' endogenous immunomodulatory properties. However, the detailed interactions of MSCs with macrophages, which are key cells involved in tissue repair, and their regulatory mechanisms are not completely understood. We herein investigated how age-related immunomodulatory impairment of MSCs alters the interaction of MSCs with macrophages during bone healing using young (5-week old) and aged (50-week old) mice. To clarify the relationship between inflammatory macrophages (M1) and MSCs, their spatiotemporal localization at the bone healing site was investigated by immunostaining, and possible regulatory mechanisms were analyzed in vitro co-cultures. Histomorphometric analysis revealed an accumulation of M1 and a decrease in MSC number at the healing site in aged mice, which showed a delayed bone healing. In in vitro co-cultures, MSCs induced M1 apoptosis through cell-to-cell contact but suppressed the gene expression of pro-inflammatory cytokines by soluble factors secreted in the culture supernatant. Interestingly, interleukin 38 (Il-38) expression was up-regulated in M1 after co-culture with MSCs. IL-38 suppressed the gene expression of inflammatory cytokines in M1 and promoted the expression of genes associated with M1 polarization to anti-inflammatory macrophages (M2). IL-38 also had an inhibitory effect on M1 apoptosis. These results suggest that MSCs may induce M1 apoptosis, suppress inflammatory cytokine production by M1, and induce their polarization toward M2. Nevertheless, in aged conditions, the decreased number and immunomodulatory function of MSCs could be associated with a delayed M1 clearance (i.e., apoptosis and/or polarization) and consequent delayed resolution of the inflammatory phase. Furthermore, M1-derived IL-38 may be associated with immunoregulation in the tissue regeneration site. [ABSTRACT FROM AUTHOR]
Zhang, Jiewen, Yang, Hongfeng, Zi, Jinping, Su, Jinrong, and Chen, Xiaowei
Abstract
Stress drop is a proxy of understanding earthquake source process, and it is controversial whether the stress drops of induced earthquakes associated with hydraulic fracturing and injection activities are similar to those of tectonic earthquakes. The measurement of stress drops is usually biased due to the limitations of observation means, or hidden issues in the estimation approaches. Utilizing a local short-period seismic network, we investigate the stress drops of induced earthquakes in Weiyuan Shale Gas Field in Sichuan Province, China from 2019 to 2020. Totally 11 844 earthquakes are involved in the analysis, and their stress drops are obtained using an improved approach on the basis of the traditional spectral decomposition method combined with a global optimization algorithm to avoid stacking of spectra that is found leading to source parameter underestimation. We divide the studied area into three subareas, and the results show strong stress drop heterogeneity across the entire region. We obtain an average stress drop of 2.29 MPa, piecewise stress drop dependence to earthquake magnitude, and complex depth dependence pattern. Our results indicate that stress drops of induced earthquakes are overall consistent with the induced earthquakes in other areas as well as tectonic earthquakes in different environments. Meanwhile, the complexity in the stress drop dependence to depth possibly reflects the variability of stress drops for different earthquake triggering mechanisms. [ABSTRACT FROM AUTHOR]
Background: Osteonecrosis of the femoral head (ONFH) is a prevalent orthopedic condition characterized by the disruption of blood supply to the femoral head, leading to ischemia of internal tissues, subchondral bone fractures, necrosis, and eventual collapse of the weight-bearing portion of the femoral head. This condition results in severe functional impairment, pain, and even disability of the hip joint. Existing animal models of ONFH have limitations in replicating the natural disease progression accurately. Thus, there is a critical need to develop a novel animal model capable of better simulating localized pressure on the human femoral head to facilitate ONFH-related research. Methods: In this study, we present a novel approach for modeling ONFH, which involves integrating stress factors into the modeling process through the utilization of 3D printing technology and principles of biomechanics. A total of 36 animals were randomly assigned to six groups, where they received either the novel modeling technique or the traditional hormone induction method. Subsequently, an 8-week treatment period was implemented, followed by conducting micro-CT scans and histological evaluations to assess tissue outcomes. Results: The study evaluated the cytotoxicity of the material used in the new model, and it was observed that the material did not exhibit any cytotoxic effects on cells. Additionally, the novel model successfully replicated the pathological features of ONFH, including femoral head collapse, along with a substantial presence of empty bone lacunae, cartilage defects, and subchondral bone fractures in the subchondral bone region. Conclusion: In conclusion, our study provides evidence that the new model shows the ability to simulate the progression of the disease, making it a valuable tool for research in this field and can contribute to the development of better treatment strategies for this debilitating condition. It holds great promise for advancing our understanding of the pathogenesis of ONFH and the potential therapeutic interventions for this challenging clinical problem. [ABSTRACT FROM AUTHOR]
Zhang, Jiewen, Chen, Xiaowei, and Abercrombie, Rachel E.
Subjects
*SEISMOMETRY, *EARTHQUAKES, *TIME pressure, *GROUND motion, *SHEARING force
Abstract
Earthquake stress drop is an important source parameter that directly links to strong ground motion and fundamental questions in earthquake physics. Stress drop estimations may contain significant uncertainties due to such factors as variations in material properties and data limitations, which limit the applications of stress drop interpretations. Using a high‐resolution borehole network, we estimate stress drop for 4551 (M0‐4) earthquakes on the San Andreas Fault at Parkfield, California, between 2001 and 2016 using spectral decomposition and an improved stacking method. To evaluate the influence of spatiotemporal variations of material properties on stress drop estimations, we apply different strategies to account for spatial variations of velocity and attenuation changes, and divide earthquakes into three separate time periods to correct temporal variations of attenuation. These results show that appropriate corrections can significantly reduce the scatter in stress drop estimates, and decrease apparent depth and magnitude dependence. We find that insufficient bandwidth can cause systematic underestimation of stress drop estimates and increased scatter. The stress drop measurements from the high‐frequency borehole recordings exhibit complex stable spatial patterns with no clear correlation with the nature of fault slip, or the slip distribution of the 2004 M6 earthquake. Temporal variations are significantly smaller, less well resolved and varying spatially. They do not affect the long‐term stress drop spatial variations, suggesting local material properties may control the spatial heterogeneity of stress drop. Plain Language Summary: Earthquake stress drop (the change in shear stress before and after the earthquake) reflects the properties of the fault where earthquakes occur. Determining the scaling relationships between earthquake stress drop and magnitude enables us to predict the behavior of infrequent large earthquakes from the measurements of the more abundant small earthquakes. Measurement of stress drop is challenging, especially for small earthquakes. Different studies can obtain different stress drop values for the same earthquakes, leading to different interpretations. We use recordings from a high‐resolution borehole network in Parkfield, California to measure source parameters for small earthquakes. We examine the influence of data limitation (e.g., frequency bandwidth) and corrections for material properties on stress drop resolution. We find that if the bandwidth is too narrow, the resulting source parameters can be systematically underestimated with large scatter. Insufficient corrections of material properties can lead to biased interpretation of stress drop patterns and scaling relationships. Our final results show that the stress drops of earthquakes in Parkfield do not depend on magnitude or depth, but exhibit strong spatial variations that are stable with time. The 2004 M6 earthquake caused temporal variations of stress drop, and the temporal changes are different at different fault patches. Key Points: Borehole data and an improved spectral decomposition approach provide better constraints on estimates of corner frequency and stress dropFrequency bandwidth, and corrections for variable attenuation and velocity with depth most influence stress drop estimates and interpretationsSpatial pattern of stress drop is heterogeneous on a ∼1 km scale, and stable with time; temporal changes are smaller and spatially variable [ABSTRACT FROM AUTHOR]
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a typical neurodegenerative disease associated with mitochondrial dysfunction. Methylation of the D-loop region and mitochondrial DNA copy number (mtDNAcn) play a critical role in the maintenance of mitochondrial function. However, the association between D-loop region methylation, mtDNAcn and CADASIL remains unclear. Methods: Overall, 162 individuals were recruited, including 66 CADASIL patients and 96 age- and sex-matched controls. After extracting genomic DNA from the peripheral white blood cells, levels of D-loop methylation and mtDNAcn were assessed using MethylTarget sequencing and real-time PCR, respectively. Results: We observed increased mtDNAcn and decreased D-loop methylation levels in CADASIL patients compared to the control group, regardless of gender stratification. Besides, we found a negative correlation between D-loop methylation levels and mtDNAcn. Mediation effect analysis shows that the proportion of the association between mtDNAcn and CADASIL that is mediated by D-loop methylation is 11.6% (95% CI 5.6, 22.6). After gender stratification, the proportions of such associations that are mediated by D-loop methylation in males and females were 7.2% (95% CI 2.4, 19.8) and 22.0% (95% CI 7.4, 50.1), respectively. Conclusion: Decreased methylation of the D-loop region mediates increased mtDNAcn in CADASIL, which may be caused by a compensatory mechanism of mitochondrial dysfunction in patients with CADASIL. [ABSTRACT FROM AUTHOR]
• The PSMUS showed good psychometrics in a sample of Chinese adults. • Confirmatory factor analyses supported the bifactor structure of the PSMUS. • ECV suggested that the scale may have a structure at least in part multidimensional. • Hierarchical omega and SEM supported the use of an overall score. The Problematic Social Media Use Scale (PSMUS) is a promising self-report measure assessing problematic use of social media among adolescents and adults. However, data concerning its psychometrics are still scant, and adaptation in Eastern cultures is missing. This study aimed to test the factorial structure, internal consistency, and external validity of the Chinese version of the PSMUS in a sample of 672 adults (31% males) aged between 18 and 58. A series of confirmatory factor analyses supported the bifactor structure of the PSMUS, including a general factor and five specific independent components, namely preference for online social interactions, mood regulation, cognitive preoccupation, compulsive use, and negative outcomes. Hierarchical Omega supported the presence of a general factor, and also ancillary indexes suggested that the questionnaire is not strictly unidimensional. Subsequent structural equation modeling testing the incremental contribution of each PSMUS facet in predicting negative emotional states showed that, above and beyond the general factor, only one of the five dimensions (i.e., negative outcomes) significantly links to our criterion measure further support the use of an overall PSMU score. Moreover, results support the external validity of the questionnaire, given its positive association with depression, anxiety, and stress scores. The Chinese version of the PSMUS is a psychometric sound instrument to assess the level of PSMU in adults. Future research may evaluate the cross-cultural validity of the bifactor model and its associations with other assessment methods. [ABSTRACT FROM AUTHOR]
Effect of donepezil on the homocysteine (Hcy) level in serum of Alzheimer's disease (AD) patients and correlation between Hcy and dyssomnia was investigated. A retrospective analysis of 124 AD patients in Zhengzhou University People's Hospital between January 2015 and October 2017 was performed, including 64 cases in the observation group and 60 cases in the control group. The control group was treated with folic acid, vitamin B12 and memantine hydrochloride tablet, and the observation group combined with donepezil on this basis, and both groups were treated for 4 months. The Hcy level before and after treatment was detected in the groups using ELISA method, dyssomnia score of patients was performed before and after treatment in the observation group according to Pittsburgh Sleep Quality Index (PSQI), and correlation analysis between the Hcy level before and after treatment and dyssomnia was performed in AD patients in the study group using Pearson's correlation analysis. The differences were statistically significant in the Hcy level before and after treatment in both groups (P<0.001). The Hcy level after treatment in the observation group was significantly lower than that in the control group (P<0.001). The dyssomnia score before treatment was higher that after treatment in the observation group (P<0.001). There was a positive correlation between the Hcy level before treatment and dyssomnia score (r=0.658, P<0.001). There was also a positive correlation between the Hcy level after treatment and dyssomnia score (r=0.670, P<0.001). Donepezil can effectively improve the sleep function of patients and reduce the Hcy level in serum in the treatment of AD patients. The application of donepezil was of great significance in the clinical treatment of AD patients. [ABSTRACT FROM AUTHOR]
Accumulation of amyloid-β peptide (Aβ) and massive neuronal death due to apoptosis were the essential steps in the pathogenesis of Alzheimer’s disease (AD). MiR-429 was reported to play an important role in the pathogenesis of AD. However, the detailed function and underlying molecular mechanism of miR-429 in the pathogenesis of AD remain elusive. Cortical neurons were stimulated with 20 µM of Aβ25−35 for 24 h to construct AD model in vitro. qRT-PCR assay was used to detect the expression of miR-429, and qRT-PCR or western blot analysis were performed to assess the levels of Sex-determining region Y-box 2 (SOX2) and B cell lymphoma-2 protein (BCL2) at mRNA or proteins levels in the AD mouse model and Aβ-induced treated cortical neurons. Luciferase reporter assay and western blot analysis were used to confirm the potential targets of miR-429. CCK-8 assay, flow cytometry analysis, and caspase3 activity assay were used to measure cell viability, cell apoptosis capacity and caspase3 activity, respectively. MiR-429 was upregulated and SOX2 and BCL2 were downregulated in the AD mouse model and Aβ-induced mouse cortical neurons. MiR-429 knockdown attenuated Aβ-induced cytotoxicity in mouse cortical neurons. SOX2 and BCL2 were direct targets of miR-429. Moreover, anti-miR-429-mediated neuroprotective effect was abated by the restoration of SOX2 or BCL2 expression. Knockdown of miR-429 might attenuate Aβ-induced cytotoxicity by targeting SOX2 and BCL2 in mouse cortical neurons, providing a novel prospect in AD therapy. [ABSTRACT FROM AUTHOR]
Background Accumulation of β-amyloid (Aβ) and neuroinflammation are implicated in the pathogenesis and development of Alzheimer's disease (AD). Neuron-enriched miR-137 was aberrantly downregulated and may be associated with the pathogenesis of AD. However, the detailed function of miR-137 in AD pathogenesis and the molecular mechanism have not been elucidated. Methods The expressions of miR-137 and tumor necrosis factor alpha (TNFα)-induced protein 1 (TNFAIP1) at mRNA and protein levels in primary mouse cortical neurons and Neuro2a (N2a) cells exposed to different concentrations of Aβ 25-35 were examined by qRT-PCR and western blot. Luciferase reporter assay was used to confirm the potential target of miR-137. MTT assay, flow cytometry analysis, caspase-3 activity assay, Enzyme-linked immunosorbent assay (ELISA), and western blot were used to detect cell viability, apoptosis, caspase-3 activity, Nuclear factor-kappa B (NF-κB) activity and level, respectively. Results Aβ 25-35 downregulated miR-137 and upregulated TNFAIP1 in primary mouse cortical neurons and N2a cells. In addition, miR-137 was found to directly target TNFAIP1 and suppress its mRNA and protein levels. Moreover, miR-137 restoration and TNFAIP1 knockdown facilitate Aβ 25-35 -induced cell toxicity, apoptosis, caspase-3 activity, and activated NF-κB in N2a cells, which was partially abolished by TNFAIP1 overexpression. Conclusion: miR-137 attenuated Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in N2a cells, shedding light on the molecular mechanism of miR-137 underlying Aβ-induced neurotoxicity. [ABSTRACT FROM AUTHOR]
Rebaudioside A is a natural noncaloric high-potency sweetener extracted from the leaves of Stevia rebaudiana. With rebaudioside A use increasing in foods, understanding the factors affecting its stability is necessary. This project evaluated the degradation rate constants of rebaudioside A in water, 0.1 M phosphate buffer, and 0.1 M citrate buffer at pH 3 and 7 as a function of ultraviolet (UV) light intensity (365 nm, 0 μW/cm2 for dark conditions, 27 μW/cm2 for low intensity, and 190 μW/cm2 for high intensity) at 32.5 °C. Rebaudioside A stability was adversely affected by light exposure. The pseudo-1st-order degradation rate constants increased significantly ( P < 0.05) with increasing light intensity in all solutions. Under dark conditions, rebaudioside A in phosphate buffers was more susceptible to breakdown than in water and citrate buffers at both pH levels. However, exposure to UV light resulted in rebaudioside A degradation occurring approximately 10 times faster in citrate than in phosphate buffers at both pH levels. The sensitivity of rebaudioside A to UV light was greater in citrate buffers than in water or phosphate buffers. The use of light-protective packaging for beverages containing rebaudioside A will improve its stability. [ABSTRACT FROM AUTHOR]
For microseismic monitoring, in order to obtain accurate microseismic locations, a good estimation of the velocity model for the region covering the monitoring stations and microseismic sources is crucial. Perforation shots are generally used to estimate a velocity model suitable for microseismic location. However, the origin times of the perforation shots are generally not accurate. To mitigate the effect of inaccurate origin times of perforation shots on calibrating the velocity model, we propose to search for a velocity model fitting for station-pair differential arrival times instead of absolute arrival times from perforation shots. Another advantage of using station-pair differential arrival times is that waveform cross-correlation can be used to estimate more accurate differential times because of waveform similarity among stations for perforation shots. Due to high nonlinearity of the objective function for estimating one-dimensional velocity model, the differential evolution (DE) method for solving high-dimensional global optimization problems is utilized in the optimization. Compared to the grid-search method, the DE method is much more efficient. Synthetic tests based on a downhole microseismic monitoring system show the effectiveness of the proposed method to recover the velocity model. We also test our DE-based method by using perforation shots for a real microseismic monitoring project. Compared to the well sonic velocity model, station-pair differential arrival times are better fitted and perforation shots are also more accurately relocated with the calibrated velocity model. [ABSTRACT FROM AUTHOR]
Hua, Xiaolin, Zhang, Jiewen, Guo, Yanfang, Shen, Minxue, Gaudet, Laura, Janoudi, Ghayath, Walker, Mark, and Wen, Shi Wu
Subjects
*PREECLAMPSIA, *HYPERTENSION in pregnancy, *FOLIC acid in human nutrition, *GESTATIONAL age, *META-analysis
Abstract
Objective: To evaluate the effect of folic acid supplementation during pregnancy on the risk of gestational hypertension/preeclampsia.Methods: A systematic review and meta-analysis were conducted. Medline, Embase, Scopus, and the Web of Science were searched from inception to December 2014.Results: Out of 1224 potentially relevant studies, 13 studies met our inclusion criteria (2 randomized controlled trials (RCTs), 10 cohort studies, and 1 case-control study). The pooled relative risk (RR) and 95% confidence interval (CI) of the two RCTs were 0.62 (0.45-0.87) in the trial arm as compared with the placebo arm. The pooled RR was 0.92 (95% CI: 0.79-1.08) for nine cohort studies with available data on folic acid supplementation in pregnancy and gestational hypertension/preeclampsia. Pooled RR was 0.88 (95% CI: 0.76-1.02) for eight cohort studies with available data on folic acid supplementation and preeclampsia.Conclusion: Whether folic acid supplementation in pregnancy can prevent the occurrence of gestational hypertension/preeclampsia remains uncertain. [ABSTRACT FROM AUTHOR]
*MOVEMENT disorders, *PARKINSON'S disease, *MULTIPLE system atrophy, *NEUROLOGISTS, *WOUNDS & injuries, *RESTLESS legs syndrome
Abstract
Keywords: dissociative conversion disorder; functional movement disorders; parkinsonism; psychological parkinsonism EN dissociative conversion disorder functional movement disorders parkinsonism psychological parkinsonism 1097 1098 2 08/07/21 20210901 NES 210901 CONFLICTS OF INTEREST The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Certainly, some patients did present with combined FMDs and organic movement disorders, which is about 10%.9 Functional movement disorders still remain an enormous therapeutic challenge. [Extracted from the article]
Objective: The purpose of the present study was to determine the learning curve for a novel seven-axis robot-assisted (RA) total knee arthroplasty (TKA) system and to explore whether it could provide superior short-term clinical and radiological outcomes compared with conventional surgery. Methods: In the present retrospective study, 90 patients who underwent RA-TKA were included in robot-assisted system (RAS) group and 90 patients who underwent conventional TKA were included in the conventional group. The duration of surgery and robot-related complications were recorded to evaluate the learning curve through cumulative sum and risk-adjusted cumulative sum methods. The demographic data, preoperative clinical data, preoperative imaging data, duration of surgery, alignment of the prosthesis, lower limb force line alignment, Knee Society score, 10-cm visual analog scale pain score and range of motion were compared between the RAS and conventional groups. In addition, the proficiency group was compared with the conventional group using propensity score matching. Results: RA-TKA was associated with a learning curve of 20 cases for the duration of surgery. There was no significant difference in indicators representing the accuracy of the prosthetic installation between the learning and proficiency phases in RA-TKA group patients. A total of 49 patients in the proficiency group were matched with 49 patients from the conventional group. The number of postoperative hip–knee–ankle (HKA) angle, component femoral coronal angle (CFCA), component tibial coronal angle (CTCA), and sagittal tibial component angle (STCA) outliers in the proficiency phase was lower than that in the conventional group, while deviations of the HKA angle, CFCA, CTCA, and STCA in the proficiency phase were significantly lower than those in the conventional group (P < 0.05). Conclusion: In summary, from the learning curve data, 20 cases are required for a surgeon using a novel seven-axis RA-TKA system to enter the proficiency phase. In the proficiency group, compared with the conventional group using propensity score matching, the RAS was found to be superior to the conventional group in prosthesis and lower limb alignment. [ABSTRACT FROM AUTHOR]
Aim Methods Results Conclusions To compare the efficacy and safety of a fixed‐ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs).In Soli‐D, a 24‐week, multicentre, open‐label, study, insulin‐naïve adults were randomized 1:1 to once‐daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium‐glucose co‐transporter‐2 inhibitors. The primary endpoint was non‐inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed.At week 24, iGlarLixi showed non‐inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: −0.20 [95% confidence interval {CI}: –0.33, −0.07]; P < .001 for non‐inferiority; [97.5% CI: –0.35, −0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of −1.49 kg in favour of iGlarLixi (97.5% CI: –2.32, −0.66; P < .001). Event rates (per person‐year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported.In Chinese people with T2D suboptimally controlled with OADs, once‐daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp. [ABSTRACT FROM AUTHOR]
Flowering Chinese cabbage (Brassica campestris L. ssp. Chinensis var. utilis Tsen et Lee) is an important and extensively cultivated vegetable in south China, whose major food product is the stalk. In the process of stalk formation, its initiation and development are regulated by a series of hormonal signals, such as cytokinin and gibberellin. In this study, we analyzed the effects of zeatin (ZT) and gibberellin A3 (GA3), and their interaction, on the bolting of flowering Chinese cabbage. The results indicated that the three-true-leaf spraying of ZT and GA synthesis inhibitor (PAC) inhibited plant height but increased stem diameter. Cytokinin (CTK) synthesis inhibitor (YZJ) and GA3 treatment increased plant height and decreased stem diameter. In addition, ZT and GA3 co-treated plants displayed antagonistic effect. Further, 19 type-B authentic response regulators (ARR-Bs), the positive regulators of cytokinin signal transduction were identified from flowering Chinese cabbage. Comprehensive analysis of phylogeny showed BcARR-Bs clustered into three subfamilies with 10 conserved motifs. Analysis of their expression patterns in different tissues and at various growth stage, and their response to hormone treatment suggest that ARR1-b localized in the nucleus displayed unique highest expression patterns in stem tips, are responsive both to ZT and GA, suggesting a significant role in mediating the crosstalk of ZT and GA in the bolting of flowering Chinese cabbage. [ABSTRACT FROM AUTHOR]
• Our investigation demonstrates a significant dynamic decline in lymphocyte infiltration within the subchondral bone during OA progression. • Compared to the late stage osteoarthritis, three upregulated genes (POU2AF1, TNFRSF13B, and CD247) identified in early osteoarthritis have been validated as biomarkers related to the growth or activation of T or B cells. • A Three-gene signature predictive staging model can effectively differentiate early- and late-stage OA, offering potential targets for precision intervention and progression stratification. Osteoarthritis (OA), a degenerative joint disorder, has an unclear immune infiltration mechanism in subchondral bone (SCB). Thus, this study aims to discern immune infiltration variations in SCB between early- and late-stages of OA and identify pertinent biomarkers. Utilizing the GSE515188 bulk-seq profile from the Gene Expression Omnibus database, we performed single-sample gene-set enrichment analysis alongside weighted gene co-expression network analysis to identify key cells and immune-related genes (IRGs) involved in SCB at both stages. At the meanwhile, differentially expressed genes (DEGs) were identified in the same dataset and intersected with IRGs to find IR-DEGs. Protein-protein interaction network and enrichment analyses and further gene filtering using LASSO regression led to the discovery of potential biomarkers, which were then validated by ROC curve analysis, single-cell RNA sequencing, qRT-PCR, western blot and immunofluorescence. ScRNA-seq analysis using GSE196678, qRT-PCR, western blot and immunofluorescence results confirmed the upregulation of their expression levels in early-stage OA SCB samples. Our comprehensive analysis revealed lymphocytes infiltration as a major feature in early OA SCB. A total of 13 IR-DEGs were identified, showing significant enrichment in T- or B-cell activation pathways. Three of them (CD247, POU2AF1, and TNFRSF13B) were selected via the LASSO regression analysis, and results from the ROC curve analyses indicated the diagnostic efficacy of these 3 genes as biomarkers. These findings may aid in investigating the mechanisms of SCB immune infiltration in OA, stratifying OA progression, and identifying relevant therapeutic targets. [ABSTRACT FROM AUTHOR]
T4 polynucleotide kinase (T4 PNK) plays an essential role in DNA phosphorylation during the DNA repair process. Therefore, the sensitive, selective and convenient detection of T4 PNK activity is of great significance. In this work, we proposed a sensitive non-amplification strategy for the sensing of T4 PNK activity via dark field microscope (DFM) based on magnetic bead (MB)-gold nanoparticle (AuNP) hybrids probe, MB-dsDNA-AuNP (MDA). In the presence of T4 PNK, the 5′-OH termini of DNA are phosphorylated and cleaved into oligonucleotides by lambda exonuclease (λexo), resulting in the destruction of the MDA probe and the separation of AuNP from the MB. Through automatic counting of AuNPs from DFM images, T4 PNK activity can be quantitatively measured. This strategy revealed a limit of detection (LOD) as low as 0.0058 U/mL and exhibited a dynamic range from 0.01 to 1 U/mL. The strategy presents an excellent ability to discriminate T4 PNK from the other proteins and enzymes. Notably, this strategy was applied to screen the T4 PNK inhibitors and test the activity in cell lysates, showing great potential for the discovery of new anticancer drugs and other related research field. • A simple, visible, sensitive and specific sensing for T4 PNK activity was proposed. • The probe can be applied to screen inhibitors and test activity in cell lysates. • The strategy can be easily generalized to other enzymes by replacing the sequences. [ABSTRACT FROM AUTHOR]
Wang, Bo, Xiong, Yongqiang, Li, Ren, Zhang, Jiewen, and Zhang, Shu
Subjects
*CYTOTOXIC T cells, *KILLER cells, *TELOMERES, *T cells, *LYMPHOCYTES
Abstract
Background: For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer. The newest research presented that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers. However, the relationship between genetically determined telomere length (TL) and immune cells remains unclear. Methods: The two‐sample Mendelian randomization analysis was conducted to elucidate the potential causal relationship. The genetic data of TL and immune cells were obtained from the Genome‐Wide Association Study. The inverse variance weighted (IVW) method was used to estimate the effects primarily and another four methods were as a supplement. Sensitivity analysis was used to test the results. Results: The IVW method showed a significant correlation between TL and the percentage of T cells in lymphocytes (odds ratio [OR]: 1.222, 95% confidence interval [CI]: 1.014–1.472, p =.035), indicating that shorter TL significantly increases the risk of low T cell percentage. Further analysis of T cell subsets indicated that shorter TL may primarily lead to a lower percentage of Natural Killer T cells (OR: 1.574, 95% CI: 1.281–1.935, p <.001). Analysis of B cell subsets revealed that shorter TL may be associated with a higher percentage of Naive‐mature B cells, and a lower percentage of Memory B cells. And the sensitivity analysis indicated the validity and robustness of our findings. Conclusion: In summary, our findings suggest that shorter TL may be associated with a decline in the percentage of T cell, as well as impediments in the differentiation of B cell, consequently leading to the onset of immunosenescence and immunodeficiency. The relevant mechanisms and potential therapeutic avenues still need further investigation. Shorter telomere length may be associated with a decline in the percentage of T cell, as well as impediments in the differentiation of B cell, consequently leading to the onset of immunosenescence and immunodeficiency. [ABSTRACT FROM AUTHOR]
Objective: Alzheimer's disease (AD) is the most common form of dementia characterized by memory loss at disease onset. The gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the frequent causes of AD. However, the clinical and genetic features of AD overlap with other neurodegenerative diseases. The present study aimed to identify the clinical and genetic characteristics in a Han Chinese AD cohort. Methods: Detailed clinical assessment was applied to all the patients. We screened amyloid precursor protein (APP), PSEN1, PSEN2, and microtubule‐associated protein tau (MAPT) genes were assessed in 83 sporadic AD patients by Sanger sequencing. A total of 25 probands from families with AD were subjected to next‐generation sequencing on 53 dementia‐associated genes to capture the target region, and Sanger sequencing was used to detect the variants in the DNA sequence. Results: PSEN1 p.L226R was found in an early‐onset AD (EOAD) family characterized by language impairment at disease onset, a novel probably pathogenetic variant (p.D534H) was identified in a frontal‐temporal dementia gene, TANK‐binding kinase 1 (TBK1) with a typical AD phenotype in a late‐onset AD (LOAD) family, and a PSEN2p.H169N mutation and two benign MAPT (p.Q230R and p.V48L) mutations were detected in three EOAD patients. Conclusions: Thus, five variants were identified in a Han Chinese cohort. In the present study, a novel, probably damaging FTLD gene TBK1variant with a typical AD phenotype was detected. Also, the phenotypic characteristics of PSEN1 p.L226R, a PSEN2pathogenic mutation, and two likely benign MAPT variants were described. Hence, screening for mutations in other dementia genes could be further explored in clinically diagnosed AD patients. Some gene mutations are associated with family Alzheimer's disease. In this work, we discovered five variants. We enrich the clinical phenotype and gene mutation database of AD. [ABSTRACT FROM AUTHOR]
We calculate rupture directivity and velocity for earthquakes in three well‐recorded repeating sequences (2001–2016) on the San Andreas Fault at Parkfield using P waves from borehole recordings and the empirical Green's function method. The individual events in each sequence all show the same directivity; the largest magnitude sequence (M ~ 2.7, 8 events) ruptures unilaterally NW (at ~0.8Vs), the second sequence (M ~ 2.3, 9 events) ruptures unilaterally SE, and the smallest magnitude sequence (M ~ 2, 11 events) is less well resolved. The highly repetitive rupture suggests that geometry or material properties might control nucleation of small locked patches. The source spectra of the M ~ 2.7 sequence exhibit no detectable temporal variation. The smaller M sequences both exhibit a decrease in high‐frequency energy following the M6 earthquake that recovers with time. This could indicate a decrease in stress drop, an increase in attenuation, or a combination of the two, followed by gradual healing. Plain Language Summary: Sequences of small earthquakes with very similar seismograms have been observed on the San Andreas Fault at Parkfield and many other faults that are also observed to be creeping. The similarity of the seismograms suggests that these earthquakes represent repeating slip on overlapping pieces of fault. Under this assumption they have been used to investigate changes in slip conditions and the slip rate on major faults with time. To date, most studies have treated these repeating earthquakes as just points because most are too small and too poorly recorded to observe details of the rupture area or direction. Here we identify three exceptionally well‐recorded repeating sequences and are able to resolve the direction of rupture. All the earthquakes in one sequence propagate toward the NW, and all those in another propagate to the SW. The rupture velocities are similar to those of much larger earthquakes. This improved resolution of the earthquake sources will help constrain modeling of the rupture and hence our understanding of the factors that control earthquake nucleation and dynamics. Key Points: All individual earthquakes in a repeating sequence at Parkfield exhibit identical directivity, unaffected by 2004 M6One sequence (M ~ 2.7) ruptures to the NW and one (M ~ 2.5) to the SE, at ~0.8 × shear wave velocitySmallest magnitude sequences show most response to M6 earthquake, but we cannot fully distinguish between path and source effects [ABSTRACT FROM AUTHOR]
A dicyanoisophorone-based near-infrared fluorescent probe (NIR-NP) was successfully designed for hydrogen sulfide (H2S) detection. 7-Nitro-1,2,3-benzoxadiazole (NBD) amine, an electron-withdrawing group, was applied to quench the fluorescence of dicyanoisophorone-based fluorescent dyes and could be removed by H2S-specific thiolysis of an NBD amine bond, leading to a significant fluorescence turn-on response. The probe could quantitatively detect H2S with a lower detection limit (0.03 μM) in vitro and in living cells. The probe with a large Stokes shift (186 nm) showed a high selectivity to H2S in the presence of other biothiols, including glutathione, homocysteine, and cysteine. Moreover, the probe was successfully applied to image endogenous H2S in different tumor cells and in liver tissues. The excellent properties of the probe and its applications in cell and tissue imaging indicated its potential for further exploration and application of H2S in the pathophysiology of cancers and even in the diagnosis of H2S-related diseases. [ABSTRACT FROM AUTHOR]
Aims: To present the results of an exploratory analysis of the BEYOND V study in which Chinese individuals with uncontrolled type 2 diabetes (T2D) received short‐term intensive insulin therapy (SIIT) during study run‐in (prior to randomization) using a basal‐first insulin titration method. Materials and methods: This was exclusively an exploratory analysis of the 7‐ to 10‐day run‐in period of BEYOND V. Participants were hospitalized and had oral therapies withdrawn (except metformin). They received SIIT with once‐daily insulin glargine and three‐times‐daily premeal insulin glulisine, titrated daily from a total starting dose of 0.4 to 0.5 units/kg/d, first adjusting insulin glargine to achieve fasting blood glucose (FBG) of 4.4 to 6.1 mmol/L (79 to 119 mg/dL), then insulin glulisine to achieve pre‐meal blood glucose of 4.4 to 6.1 mmol/L. Key outcomes were the proportions of participants achieving FBG and 2‐hour postprandial blood glucose (PBG) targets. Results: Overall, 397 entered the run‐in (mean 54.2 years, 235 males [59.2%]). At the end of SIIT, 374/396 participants (94.4%) had both FBG <7.0 mmol/L (<126 mg/dL) and 2‐hour PBG <10 mmol/L (<180 mg/dL) and 282/396 (71.2%) had both FBG <6.1 mmol/L (<100 mg/dL) and 2‐hour PBG <10 mmol/L. The mean first time taken to achieve FBG <7 mmol/L, 2‐hour PBG <10 mmol/L, and both, was 4.35, 3.88, and 5.04 days, respectively. Hypoglycaemia occurred in 99 participants (24.9%). There was no severe hypoglycaemia. Conclusions: Titrating basal insulin first is an effective and safe method of SIIT in individuals with T2D, rapidly achieving target glucose levels with a relatively low rate of hypoglycaemia. [ABSTRACT FROM AUTHOR]
Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune‐mediated disease that targets the myelin sheaths of the peripheral nerves. Fingolimod is a sphingosine 1 phosphate (S1P) receptor antagonist with a high affinity for S1P receptors through the Akt–mTOR pathway, and prior research has suggested that it might be helpful in autoimmune illnesses. Methods: Chronic experimental autoimmune neuritis (c‐EAN) was induced by immunizing Lewis rats with the S‐palm P0(180–199) peptide, and then the treatment group was intraperitoneally injected with fingolimod (1 mg/kg) daily. Hematoxylin and eosin staining was used to assess the severity of nerve injury. Immunohistochemistry staining showed that fingolimod's anti‐inflammatory effects on c‐EAN rats might be realized through the NF‐κB signaling pathway. Tumor necrosis factor‐α (TNF‐α), interferon‐γ (INF‐γ), interleukin‐1beta (IL‐1β), interleukin 6 (IL‐6), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule‐1 (ICAM‐1) were measured to evaluate the inflammation levels, and pAkt, p‐S6, and p‐p65 were used to measure the abundance of downstream activation markers to determine whether the Akt/mTOR/NF‐κB signaling pathway was activated in the c‐EAN model. Results: Fingolimod treatment reduced the inflammatory reaction and the expression of NF‐κB in sciatic nerves. It also decreased the mRNA levels of the proinflammatory cytokines TNF‐α, IFN‐γ, IL‐1β, IL‐6, iNOS, and ICAM‐1 and pAkt, p‐S6, and p‐p65, representing the Akt/mTOR/NF‐κB signaling pathway. Conclusion: Our data showed that fingolimod could improve the disease course, alleviate the decrease in inflammation, and reduce proinflammatory cytokines through the Akt/mTOR/NF‐κB axis in c‐EAN rats, which could be beneficial for the development of CIDP‐related research. [ABSTRACT FROM AUTHOR]
Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a subtype of CAA with an inflammatory response to the vascular β-amyloid deposits. Reliable and non-invasive clinical diagnostic methods may allow patients to avoid the side effects of brain biopsy. Objective: In this observational study, we retrospectively analyzed the clinical, laboratory, radiological features, treatment, and outcome of patients diagnosed with CAA-ri. The main purpose is to enhance knowledge of CAA-ri and to avoid misdiagnosis. Methods: We described 15 consecutive patients with probable or possible CAA-ri at Henan Provincial People's Hospital according to a validation study of proposed criteria for the diagnosis of CAA-ri. The clinical features, imaging, laboratory findings, and treatment which included the response to immunotherapy were revealed in the study. Results: The median age of 15 patients was 67.0 years (range 48.0–90.0 years), and the male-to-female ratio was 7: 8. In our study, the most common clinical manifestations were cognitive decline (7/15, 46.7%), focal neurologic deficit (6/15, 40.0%), and headache (5/15, 33.3%). In terms of imaging results, white matter hyperintensity (WMH) lesions were rarely seen in the cerebellum and brainstem, while no hemorrhagic lesion was observed in the brainstem of all 15 patients. In addition, 12 patients (80.0%) showed improvement or stability for the clinical and radiological outcomes after immunotherapy. Conclusion: CAA-ri should be considered as a differential diagnosis when brain MRI shows typical features in the elderly. Once the diagnosis is established, immunotherapy should be initiated as early as possible to promote neurological function recovery and reduce recurrence. [ABSTRACT FROM AUTHOR]
Objective: The purpose of this study was to identify the prevalence of severe headache or migraine and the association between dietary thiamine and riboflavin intake with headache history using a large, nationally representative population sample. Background: Severe headache and migraine are common and disabling neurological disorders worldwide. Previous studies revealed that the B vitamin group, as an important nutrient of diet, can reduce migraine disability. Methods: We performed a cross‐sectional study of American adults surveyed in the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Information on headache history was collected in the Miscellaneous Pain section of the Questionnaire Data. Dietary intake data of thiamine and riboflavin were obtained by 24‐h dietary recall interview. Results: The present study included 13,439 participants and indicated that 2745/13,439 (21.6%) adults (aged ≥20 years) experienced severe headache or migraine in the past 3 months. Dietary thiamine intake was significantly inversely associated with severe headache or migraine (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.88–1.00, p = 0.046). In the stratified analysis, the relationship was maintained in the female group (OR = 0.90, 95% CI = 0.82–0.98, p = 0.022), and the sex interaction term was significant (p = 0.020). However, no significant interaction was found between the age groups (p = 0.352). For dietary riboflavin, no significant negative association was observed between dietary riboflavin intake and headache history (OR = 0.98, 95% CI = 0.94–1.02, p = 0.367). After stratifying by sex or age, there remained no significant relationship between dietary riboflavin and migraine. Conclusions: We found that high intake of thiamine was significantly associated with lower odds of migraine, especially in females. In the future, more clinical studies are needed to confirm our conclusions, and additional experiments are needed to explore the possible mechanisms of prevention and treatment for migraine. [ABSTRACT FROM AUTHOR]
Except one little boy who received eculizumab treatment and had a good prognosis, the remaining three patients all presented with recurrent cerebral infarction and responded differently to antiplatelet therapy, which were detailed depicted in Table 1. Lost the ability to work for deteriorating weakness of the right limbs.
Our patient
42
Female
3 years
66, 85, 67
Dual antiplatelet therapy, prednisolone, washed red blood cell. In our case report, except the vasculitic moyamoya changes, the patient also presented with multiple cerebral infarction, pulmonary artery thrombosis, as well as intermuscular vein of the right lower extremity. [Extracted from the article]
*ANTICONVULSANTS, *PYROPTOSIS, *EPILEPSY, *MOLECULAR biology, *CELLULAR signal transduction, *EPILEPSY in animals
Abstract
Interleukin-1 receptor-associated kinase 4 (IRAK4) plays an important role in immune modulation in various central nervous system disorders. However, IRAK4 has not been reported in epilepsy models in animal and clinical studies, nor has its involvement in regulating pyroptosis in epilepsy. First, we performed transcriptome sequencing, quantitative real-time polymerase chain reaction, and western blot analysis on the hippocampal tissues of refractory epilepsy patients to measure the mRNA and protein levels of IRAK4 and pyroptosis-related proteins. Second, we successfully established a pentylenetetrazol (PTZ)-induced seizure mouse model. We conducted behavioral tests, electroencephalography, virus injection, and molecular biology experiments to investigate the role of IRAK4 in seizure activity regulation. IRAK4 is upregulated in the hippocampus of epilepsy patients and PTZ-induced seizure model mice. IRAK4 expression is observed in the hilar neurons of PTZ-induced mice. Knocking down IRAK4 in PTZ-induced mice downregulated pyroptosis-related protein expression and alleviated seizure activity. Overexpressing IRAK4 in naive mice upregulated pyroptosis-related protein expression and increased PTZ-induced abnormal neuronal discharges. IRAK4 and NF-κB were found to bind to each other in patient hippocampal tissue samples. Pyrrolidine dithiocarbamate reversed the pyroptosis-related protein expression increase caused by PTZ. PF-06650833 alleviated seizure activity and inhibited pyroptosis in PTZ-induced seizure mice. IRAK4 plays a key role in the pathological process of epilepsy, and its potential mechanism may be related to pyroptosis mediated by the NF-κB/NLRP3 signaling pathway. PF-06650833 has potential as a therapeutic agent for alleviating epilepsy. • IRAK4 and p-IRAK4 expression are upregulated in the hippocampus of refractory epilepsy patients and mice after epilepsy. • Inhibition of IRAK4 can reduce PTZ-induced seizures, and overexpression of IRAK4 can increase susceptibility to epilepsy. • IRAK4 exacerbates epilepsy by activating the NF-κB/NLRP3 signaling pathway. • PF-06650833 exerts antiepileptic effects by regulating IRAK4 to inhibit NLRP3-mediated pyroptosis. [ABSTRACT FROM AUTHOR]
• This study investigated the therapeutic effects of oridonin on epilepsy and its potential mechanisms. • Oridonin reduced seizure attacks, abnormal discharges, and neuronal excitability. • Oridonin inhibited neuronal pyroptosis mediated by the NLRP3 in epilepsy mice and HT22 cells. • Oridonin inhibited epilepsy through NLRP3 mediated pyroptosis in vivo and vitro. Epilepsy is a chronic disabling disease poorly controlled by available antiseizure medications. Oridonin, a bioactive alkaloid with anti-inflammatory properties and neuroprotective effects, can inhibit the increased excitability of neurons caused by glutamate accumulation at the cellular level. However, whether oridonin affects neuronal excitability and whether it has antiepileptic potential has not been reported in animal models or clinical studies. Pentylenetetrazol was injected into mice to create a model of chronic epilepsy. Seizure severity was assessed using the Racine scale, and the duration and latency of seizures were observed. Abnormal neuronal discharge was detected using electroencephalography, and neuronal excitability was assessed using calcium imaging. Damage to hippocampal neurons was evaluated using Hematoxylin-Eosin and Nissl staining. The expression of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and other pyroptosis-related proteins was determined using western blotting and immunofluorescence. A neuronal pyroptosis model was established using the supernatant of BV2 cells treated with lipopolysaccharide and adenosine triphosphate to stimulate hippocampal neurons. Oridonin (1 and 5 mg/kg) reduced neuronal damage, increased the latency of seizures, and shortened the duration of fully kindled seizures in chronic epilepsy model mice. Oridonin decreased abnormal discharge during epileptic episodes and suppressed increased neuronal excitability. In vitro experiments showed that oridonin alleviated pyroptosis in hippocampal HT22 neurons. Oridonin exerts neuroprotective effects by inhibiting pyroptosis through the NLRP3/caspase-1 pathway in chronic epilepsy model mice. It also reduces pyroptosis in hippocampal neurons in vitro, suggesting its potential as a therapy for epilepsy. [ABSTRACT FROM AUTHOR]
The objective of this research is to study the effect of obstructive sleep apnea-hypopnea syndrome on cognitive function of stroke. Based on linear regression equation and Montreal Cognitive Assessment Scale, the degree of cognitive impairment in OSAHS patients was evaluated and the influencing factors of OSAHS-induced cognitive impairment and the correlation between the degree of OSAHS and cognitive impairment were explored. The results are as follows: about 68% of OSAHS patients have cognitive dysfunction, and the incidence of cognitive dysfunction is positively correlated with OSAHS; cognitive impairment of OSAHS patients was associated with age, obesity, years of schooling, and intermittent nocturnal hypoxia or hypoventilation; the severity of cognitive dysfunction of OSAHS patients was positively correlated with age and obesity but negatively correlated with education level; Logistic regression analysis results showed that there were three factors that were finally entered into the regression equation, namely, LSaO2, BMI, and AHI, and the Logistic regression equation obtained was as follows: Logist P = − 0.109 X 1 + 0.785 X 2 + 1.228 X 3 . This study helps clinical workers to detect and intervene the impaired cognitive ability of patients with OSAHS early, so as to reduce the incidence and mortality of related complications and improve the quality of life of patients. [ABSTRACT FROM AUTHOR]
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear.Objective: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL.Methods: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro. The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis.Results: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G > A, p. A564T) in two pedigrees. In vitro, the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis.Conclusion: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations. [ABSTRACT FROM AUTHOR]
Background Pseudorabies virus (PRV) is a common pathogen in multiple animal species, particularly in pigs. However, PRV infection in humans is rare and, to the best of our knowledge, PRV has never been isolated from human cases before. Methods Four acute encephalitis cases in humans were confirmed as PRV infection based on clinical symptoms, laboratory diagnosis, and metagenomic next-generation sequencing (mNGS). Cerebrospinal fluid (CSF) samples were collected and applied for virus isolation. Etiological and genetic characteristics of this PRV human isolate were further determined. Results The patients manifested respiratory dysfunction and acute neurological symptoms. The mNGS revealed PRV-specific nucleotide sequences in patients' CSF samples (7–6198 reads and 0.2446%–80.58% coverage). The PRV envelope glycoprotein B antibody, glycoprotein E antibody, and neutralizing antibody were positively detected. For the first time, a PRV strain, designated hSD-1/2019, was isolated and identified from a CSF sample, and transmission electron microscopy revealed that hSD-1/2019 had typical morphology similar to that of swine PRV. Phylogenetic analysis illustrated that hSD-1/2019 was genetically closest to those PRV variant strains currently circulating in pigs in China, and this strain showed similar etiological characteristics to Chinese PRV variant strains, while different from Chinese classical strain. Moreover, hSD-1/2019 showed high pathogenicity and induced acute neurological symptoms in pigs. Conclusions A PRV strain was isolated from an acute human encephalitis case. This isolate showed close phylogenetic relationships and similar etiological characteristics to Chinese PRV variant strains, implying the great risk of PRV transmission from pigs to humans. [ABSTRACT FROM AUTHOR]
Abercrombie, Rachel E., Trugman, Daniel T., Shearer, Peter M., Chen, Xiaowei, Zhang, Jiewen, Pennington, Colin N., Hardebeck, Jeanne L., Goebel, Thomas H. W., and Ruhl, Christine J.
Subjects
*PLATE tectonics, *SEISMOLOGY, *EARTHQUAKES, *EARTH movements, *CRUST of the earth
Abstract
We combine earthquake spectra from multiple studies to investigate whether the increase in stress drop with depth often observed in the crust is real, or an artifact of decreasing attenuation (increasing Q) with depth. In many studies, empirical path and attenuation corrections are assumed to be independent of the earthquake source depth. We test this assumption by investigating whether a realistic increase in Q with depth (as is widely observed) could remove some of the observed apparent increase in stress drop with depth. We combine event spectra, previously obtained using spectral decomposition methods, for over 50,000 earthquakes (M0 to M5) from 12 studies in California, Nevada, Kansas and Oklahoma. We find that the relative high‐frequency content of the spectra systematically increases with increasing earthquake depth, at all magnitudes. By analyzing spectral ratios between large and small events as a function of source depth, we explore the relative importance of source and attenuation contributions to this observed depth dependence. Without any correction for depth‐dependent attenuation, we find a systematic increase in stress drop, rupture velocity, or both, with depth, as previously observed. When we add an empirical, depth‐dependent attenuation correction, the depth dependence of stress drop systematically decreases, often becoming negligible. The largest corrections are observed in regions with the largest seismic velocity increase with depth. We conclude that source parameter analyses, whether in the frequency or time domains, should not assume path terms are independent of source depth, and should more explicitly consider the effects of depth‐dependent attenuation. Plain Language Summary: The stress release (or stress drop) during an earthquake provides information about the energy budget, and the slip and area of rupture, which are needed to investigate earthquake triggering and rupture dynamics. Stress drop is also an important element of seismic hazard forecasting since high stress drop earthquakes radiate more high frequency energy, resulting in stronger ground shaking. As depth increases in the earth, the stress on faults increases because of the increased weight of the rocks above. Therefore, many models predict that deeper earthquakes should have higher stress drops. Deeper earthquakes radiate more high frequency energy than shallow ones, and some studies have interpreted this as an increase in stress drop with depth. However, attenuation of seismic energy as the waves travel through the earth is also depth‐dependent, and this is rarely explicitly included in analyses. We perform a combined analysis of frequency spectra from over 50,000 previously studied earthquakes. We compare ratios of large to small magnitude earthquakes, from different depth ranges, to separate the effects of depth‐dependent source radiation from depth‐dependent attenuation. We find that depth‐dependent attenuation can have a first‐order effect and account for much of the previously reported apparent increase in stress drop with depth. Key Points: A stacked spectral ratio approach can separate depth dependence of source and path effectsAnalyses of spectral decomposition inversions suggest that previous reports of increase in stress drop with depth may be overstatedSource parameter analyses should explicitly include depth‐dependent attenuation models or empirical corrections [ABSTRACT FROM AUTHOR]
Osimertinib has demonstrated promising efficacy against leptomeningeal metastasis (LM) associated with T790M-positive non-small-cell lung cancer (NSCLC). However, the effect of cerebrospinal fluid's (CSF's) epidermal growth factor receptor (EGFR) T790M mutation on osimertinib efficacy remains unclear.Seventy-eight patients were studied with EGFR-mutated NSCLC and LM. Case data were collected and EGFR mutation status of circulating cell-free DNA from paired CSF, and plasma of 23 patients with LM was detected using droplet digital PCR. The median overall survival (mOS) was 8.08 months (95% CI: 6.07–10.09) in the study. Forty-four osimertinib-treated patients had an improved mOS of 13.15 (95% CI: 5.74–20.57) and a median progression-free survival (PFS) of 9.50 months (95% CI: 6.77–12.23) when compared with patients treated with first- or second-generation EGFR-TKI (mOS = 3.00 months (95% CI: 1.32–4.68) and median PFS = 1.50 months (95% CI: 0.00–3.14)). In the osimertinib group, mOS values for CSF with and without T790M mutation were 22.15 months (95% CI: 9.44–34.87) and 13.39 months (95% CI: 7.01–19.76), respectively, with no statistical differences. Regardless of the CSF T790M mutation status, osimertinib demonstrated significant efficacy against LM associated with NSCLC. [ABSTRACT FROM AUTHOR]
Background: Chronic cerebral hypoperfusion (CCH) is the leading cause of cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WMLs) in CSVD. However, the effects of CCH on BBB integrity and components and the cellular and molecular mechanisms underlying the effects of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH-induced brain damage has also not been explored. Methods: In this study, we established a rat model of CSVD via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB were assessed using immunostaining, Western blotting, transmission electron microscopy (TEM) and RNA sequencing. We also observed the protective role of imatinib, a tyrosine kinase inhibitor, on BBB integrity and neuroprotective function following CCH. The data were analyzed using one-way or two-way ANOVA. Results: We noted transient yet severe breakdown of the BBB in the corpus callosum (CC) following CCH. The BBB was severely impaired as early as 1 day postoperation and most severely impaired 3 days postoperation. BBB breakdown preceded neuroinflammatory responses and the formation of WMLs. Moreover, pericyte loss was associated with BBB impairment, and the accumulation of serum protein was mediated by increased endothelial transcytosis in the CC. RNA sequencing also revealed increased transcytosis genes expression. BBB dysfunction led to brain damage through regulation of TGF-β/Smad2 signaling. Furthermore, imatinib treatment ameliorated serum protein leakage, oligodendrocyte progenitor cell (OPC) activation, endothelial transcytosis, microglial activation, and aberrant TGF-β/Smad2 signaling activation. Conclusions: Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis. Imatinib executes a protective role on the BBB integrity via inhibition of endothelial transcytosis. Maintenance of BBB integrity ameliorates brain damage through regulation of TGF-β/Smad2 signaling following CCH; therefore, reversal of BBB dysfunction may be a promising strategy for CSVD treatment. [ABSTRACT FROM AUTHOR]
Background: Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction. However, whether plasma exosomes change in CADASIL patients is still unclear.Objective: We are aimed to investigate the differences of plasma exosomes between CADASIL patients and healthy controls.Methods: The subjects included 30 CADASIL patients and 30 healthy controls without NOTCH3 mutation. The severity of white matter lesions (WMLs) of CADASIL patients was quantified by Fazekas score. Transmission electron microscopy and nanoparticle tracking analysis were performed to characterize plasma exosomes. In addition, NOTCH3, Neurofilament light and Aβ42 levels in plasma exosomes were quantified by enzyme-linked immunosorbent assays.Results: We found that exosomes from CADASIL patients were lower in quantity. In addition, CADASIL plasma exosomes had significantly lower levels of NOTCH3 and significantly increased levels of NFL than those of matched healthy subjects. Interestingly, plasma exosome NOTCH3 levels of CADASIL patients significantly correlated with severity of WMLs.Conclusion: The exosome NOTCH3 may be related to the pathological changes of CADASIL, which provides a basis for the pathogenesis research of CADASIL. In addition, plasma exosome NOTCH3 and NFL levels may act as biomarkers to monitor and predict disease progression and measure therapeutic effectiveness in the future clinical trials. [ABSTRACT FROM AUTHOR]
Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation. [ABSTRACT FROM AUTHOR]
Blood-brain barrier (BBB) dysfunction plays a pivotal role in the pathology of chronic cerebral hypoperfusion (CCH)-related neurodegenerative diseases. Continuous endothelial cells (EC) that line the blood vessels of the brain are important components of the BBB to strictly control the flow of substances and maintain the homeostatic environment of the brain. However, the molecular mechanisms from the perspective of EC-induced BBB dysfunction after CCH are largely unknown. In this study, the BBB function was assessed using immunostaining and transmission electron microscopy. The EC dysfunction profile was screened by using EC enrichment followed by RNA sequencing. After identified the key EC dysfunction factor, C-kit, we used the C-kit inhibition drug (imatinib) and C-kit down-regulation method (AAV-BR1-C-kit shRNA) to verify the role of C-kit on BBB integrity and EC transcytosis after CCH. Furthermore, we also activated C-kit with stem cell factor (SCF) to observe the effects of C-kit on BBB following CCH. We explored that macromolecular proteins entered the brain mainly through EC transcytosis after CCH and caused neuronal loss. Additionally, we identified receptor tyrosine kinase C-kit as a key EC dysfunction molecule. Furthermore, the pharmacological inhibition of C-kit with imatinib counteracted BBB leakage by reducing caveolae-mediated transcytosis. Moreover, treatment with AAV-BR1-C-kit shRNA, which targets brain EC to inhibit C-kit expression, also ameliorated BBB leakage by reducing caveolae-mediated transcytosis. Furthermore, the SCF increased the permeability of the BBB by actively increasing caveolae-mediated transcytosis. This study provides evidence that C-kit is a key BBB permeability regulator through caveolae-mediated transcytosis in EC after CCH. [Display omitted] [ABSTRACT FROM AUTHOR]
• PGC-1α KO in mice induced general activity and motor impairment in 10-month-olds. • PGC-1α KO in mice induced bradykinesia in 20-month-olds. • PGC-1α KO in mice induced degeneration of dopaminergic neurons in 20-month-olds. • PGC-1α KO in mice induced DA deficits in the striatum of 10-month-olds. • PGC-1α KO in mice induced mitochondrial dysfunction in 10-month-olds. Parkinson's disease is a disorder of adult onset involving the progressive degeneration of selective portions of the central nervous system. It is known that mitochondrial dysfunction is involved in the pathogenesis of PD. Given that PGC-1α induces proliferation of mitochondria via transcription regulation, it is possible that PGC-1α pathway dysregulation is involved in PD pathogenesis. To determine how derangement of the PGC-1α pathway in age contributes to PD, in this study, we have characterized the number of dopaminergic neuron in the substantia nigra pars compacta (SNpc), motor behaviors and related expression of mitochondrial markers (CoxIV, SDHA, and Tomm20) in the ventral midbrains of PGC-1α null mice. We found an overall decrease in spontaneous, voluntary movements and severely impaired motor coordination in all age groups (10 months and 20 months) of PGC-1α null mice, while pole testing detected impaired motor activity in older PGC-1α null mice only. TH-positive neurons were significantly less in older PGC-1α null mice. Concentration of DA as well as its two metabolites reduced in an age-dependent manner in PGC-1α null mice. Expression of CoxIV, SDHA and Tomm20 also significantly decreased in the ventral midbrains of 10-month-old PGC-1α null mice. Thus, PGC-1α KO in mice induced dopaminergic neuron degeneration in the SNpc and DA deficits in the striatum in an age-dependent manner. Progressive impairment of motor coordination in an age-dependent manner was correlated to the extent of nigrostriatal dopaminergic pathway degeneration and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]
Bcl2-associated athanogene 3 (BAG3) gene mutations cause dilated cardiomyopathy and myofibrillar myopathy. Recently, a novel c.625C>T (p.Pro209Ser) mutation in BAG3 was reported to cause axonal Charcot–Marie–Tooth (CMT) disease in three families. Here, we describe two patients with adult-onset and moderate CMT in a Chinese family. Nerve conduction velocity studies revealed an axonal sensorimotor neuropathy, which was supported by sural nerve biopsy. Lower limb magnetic resonance imaging (MRI) revealed fatty infiltration more severe in the soleus and deep posterior compartment muscles than in the medial gastrocnemius and anterior compartment muscles. Whole exome sequencing identified the same c.625C>T (p.Pro209Ser) mutation in BAG3, which co-segregated with the CMT disease in this family. This study further enforces the association between BAG3 gene and CMT disease, indicating that BAG3 should be considered in the genetic testing for CMT. The p.Pro209Ser mutation with different ethnic origins might be another hotspot mutation of BAG3. MRI is helpful to detect accurate extent of muscle involvement. [ABSTRACT FROM AUTHOR]
Immunologic changes in the hematoma of patients with intracerebral hemorrhage (ICH) and the contribution of these changes to prognosis are unknown. We collected the blood samples and hematoma fluid from 35 patients with acute ICH (<30 hours from symptom onset) and 55 age‐matched healthy controls. Using flow cytometry and ELISA, we found that the percentages of granulocytes, regulatory T cells, helper T (Th) 17 cells, and dendritic cells were higher in the peripheral blood of patients with ICH than in healthy controls, whereas the percentages of lymphocytes, M1‐like macrophages, and M2‐like macrophages were lower. Levels of IL‐6, IL‐17, IL‐23, TNF‐α, IL‐4, IL‐10, and TGF‐β were higher in the peripheral blood of patients with ICH. The absolute counts of white blood cells, lymphocytes, monocytes, and granulocytes in the hematoma tended to be greater at 12‐30 hours than they were within 12 hours after ICH, but the percentage of Th cells decreased in peripheral blood. Increased levels of IL‐10 in the serum and hematoma, and a reduction in M1‐like macrophages in hematoma were independently associated with favorable outcome on day 90. These results indicate that immunocytes present in the hematoma may participate in the acute‐phase inflammatory response after ICH. [ABSTRACT FROM AUTHOR]
Exosomes are nano-sized extracellular vesicles that are secreted by cells and usually found in body fluids. Since they freely cross the blood-brain barrier, neuronal exosomes respond directly to changes in the brain's environment. Recent studies have shown that exosomes contain both amyloid-β (Aβ) and tau proteins and have a controversial role in the Alzheimer's disease (AD) process. In this study, enzyme-linked immunosorbent assay was used to detect the levels of P-S396-tau and Aβ1-42 in plasma exosomes. We found that levels of P-S396-tau and Aβ1-42 in plasma exosomes of AD patients were significantly higher compared to those in matched healthy controls. The difference between plasma exosomes of AD patients and those of matched healthy controls was determined using transmission electron microscopy and nanoparticle tracking analysis. Exosomes from AD patients were smaller and lower in quantity. These data together may provide a basis for early diagnosis of AD. [ABSTRACT FROM AUTHOR]
*MEDICAL personnel, *DEMENTIA, *CHINESE medicine, *EPIDEMIOLOGY, *MEDICAL care, *SENILE dementia, *DIAGNOSIS of dementia, *TREATMENT of dementia
Abstract
China has the largest population of patients with dementia in the world, imposing a heavy burden on the public and health care systems. More than 100 epidemiological studies on dementia have been done in China, but the estimates of the prevalence and incidence remain inconsistent because of the use of different sampling methods. Despite improved access to health services, inadequate diagnosis and management for dementia is still common, particularly in rural areas. The Chinese Government issued a new policy to increase care facilities for citizens older than 65 years, but most patients with dementia still receive care at home. Western medicines for dementia symptoms are widely used in China, but many patients choose Chinese medicines even though they have little evidence supporting efficacy. The number of clinical trials of Chinese and western medicines has substantially increased as a result of progress in research on new antidementia drugs but international multicentre studies are few in number. Efforts are needed to establish a national system of dementia care enhance training in dementia for health professionals, and develop global collaborations to prevent and cure this disease. [ABSTRACT FROM AUTHOR]
Background: Exosomes are nano-sized extracellular vesicles secreted by most cell types and abundantly present in body fluids, including blood, saliva, urine, cerebrospinal fluid, and breast milk. Exosomes can spread toxic amyloid-beta (Aβ) and hyperphosphorylated tau between cells, contributing to neuronal loss in Alzheimer's disease (AD). Objective: To explore changes in the morphology, number, and pathological protein levels of urinary exosomes in AD patients compared with age-matched healthy subjects. Methods: In this study, enzyme-linked immunosorbent assay was used to detect the levels of Aβ1–42 and P-S396-tau (normalized by CD63) in urinary exosomes of AD patients and matched healthy subjects. We used transmission electron microscopy and nanoparticle tracking analysis to observe the exosomes. Results: We found that the levels of Aβ1–42 and P-S396-tau in the urinary exosomes of AD patients were higher than those of matched healthy controls. Exosomes taken from AD patients were more numerous. Conclusion: The differences in levels of Aβ1–42 and P-S396-tau and the quantity of urinary exosomes between AD patients and healthy controls may provide a basis for early diagnosis of AD. [ABSTRACT FROM AUTHOR]
Abstract Growing evidence indicates that circular RNA (circRNA) plays an important role in the regulation of tumor biological behaviors. In this study, we aimed to explore the role of a novel circRNA, circ_0034642, in glioma. qRT-PCR was conducted to evaluate the levels of circ_0034642 in glioma tissues and cells. In addition, the clinical severity and prognostic role of circ_0034642 were illustrated. Functionally, loss and gain-of function assays were performed by CCK-8, colony-forming, flow cytometric and transwell experiments in glioma cells. Moreover, luciferase reporter assay was used to detect the mechanism of circ_0034642. Circ_0034642 was upregulated in glioma tissues and cell lines. Overexpressed circ_0034642 was correlated with adverse phenotypes in the patients with glioma. In addition, circ_0034642 could be regarded as a prognostic predictor for glioma patients. Moreover, circ_0034642 could promote cell proliferation, migratory and invasive capacities and inhibit cell apoptosis. For the mechanism investigation, circ_0034642 was proved to be a sponge of miR-1205, and miR-1205 could regulate BATF3 expression via targeting 3′UTR of BATF3. Rescue assays also illustrated that the oncogenic function of circ_0034642 is partly attributed to its modulation on miR-1205/BATF3 axis. Collectively, circ_0034642/miR-1205/BATF3 pathway may play an important role in glioma. Highlights • Circ_0034642 is elevated in GM tissues and cells. • Circ_0034642 expression is associated with GM patients' clinical severity and prognosis. • Circ_0034642 promotes cell growth, migration and invasion and inhibit cell apoptosis in GM cells. • The oncogenic role of circ_0034642 is partly dependent on its regulation on miR-1205/BATF3 pathway. [ABSTRACT FROM AUTHOR]
*AMYOTROPHIC lateral sclerosis, *GENETIC mutation, *NUCLEOTIDE sequence, *EXONS (Genetics), HEALTH of Chinese people
Abstract
Abstract: Objects: This study aimed to report a novel point mutation associated with juvenile amyotrophic lateral sclerosis (JALS) in a Chinese Han family. Methods: Detailed clinical assessment was applied to two patients, including proband (II‐2) and his mother (I‐2). Next‐generation sequencing (NGS), also known as high‐throughput sequencing in whole exon sequence, was performed in the proband to reach the target region. Sanger sequencing was also used to detect DNA sequence variants of the proband and other three members of his family. Results: The proband (II‐2) and his mother (I‐2) were successfully diagnosed according to the clinical manifestations and physical examination. A novel point mutation c.1157T > C in the exon 10 of the SETX gene was identified in II‐2 and I‐2, resulting in a substitution of methionine (ATG) to threonine (ACG). However, we ultimately did not find the same variant in the other two normal members of his family in addition to 100 unrelated normal subjects. Conclusion: We presented a novel probably pathogenic missense mutation in exon 10 of SETX gene in a Chinese Han family with JALS. [ABSTRACT FROM AUTHOR]
Stroke is a severe and life-threatening disease, necessitating more research on new treatment strategies. Infiltrated T lymphocytes, an essential adaptive immune cell with extensive effector function, are crucially involved in post-stroke inflammation. Immediately after the initiation of the innate immune response triggered by microglia/macrophages, the adaptive immune response associated with T lymphocytes also participates in the complex pathophysiology of stroke and partially informs the outcome of stroke. Preclinical and clinical studies have revealed the conflicting roles of T cells in post-stroke inflammation and as potential therapeutic targets. Therefore, exploring the mechanisms that underlie the adaptive immune response associated with T lymphocytes in stroke is essential. The T-cell receptor (TCR) and its downstream signaling regulate T lymphocyte differentiation and activation. This review comprehensively summarizes the various molecules that regulate TCR signaling and the T-cell response. It covers both the co-stimulatory and co-inhibitory molecules and their roles in stroke. Because immunoregulatory therapies targeting TCR and its mediators have achieved great success in some proliferative diseases, this article also summarizes the advances in therapeutic strategies related to TCR signaling in lymphocytes after stroke, which can facilitate translation. [Display omitted] • The T-cell response is critical for brain injury and repair after stroke. • The T cell receptor (TCR)-mediated T-cell response exists in stroke. • The co-signaling pathways of TCR regulate T-cell response after stroke. • Immunomodulation targeting TCR and its co-receptors may benefit stroke patients. • Therapies targeting TCR and T-cell response deserve further exploration in stroke. [ABSTRACT FROM AUTHOR]
Abstract: Objects: To capture point mutations and short insertions/deletions in 49 previously reported genes associated with Parkinson's disease (PD) in a Chinese pedigree with early‐onset Parkinson's disease (EOPD)‐affected individuals. Methods: Clinical examinations and genomic analysis were performed on 21 subjects belonging to three generations of a Chinese family. Target region capture and high‐throughput sequencing were used for screening 49 genes, which were previously reported to be associated with PD. The direct Sanger sequencing method in all subjects further verified the abnormal DNA fragments in the PARK2 gene. Results: Four family members, including a mother (I‐1) and her three children (II‐2, II‐3, and II‐7), were diagnosed with PD by clinical manifestations and/or PET/CT imaging analyses. Novel compound heterozygous mutations, consisting of a fragment deletion in exon 1 to 2 (EX 1‐2 del) and a splicing point mutation c.619‐1 (G > C) in the 6th intron of the PARK2 gene, were identified in II‐2, II‐3, and II‐7. Individual EX 1‐2 del or c.619‐1 (G > C) mutations were detected in I‐1 and the third generation (III‐2, 3, 5, 10, and 11).Other mutations were not detected in the 49 known PD‐associated genes. Conclusion: Novel compound heterozygous mutations were identified in a Chinese pedigree and might represent a cause of familial EOPD with autosomal dominant inheritance. [ABSTRACT FROM AUTHOR]
*AWARENESS, *TREATMENT of epilepsy, *SPASMS, *HOSPITAL personnel attitudes, *HOSPITALS, *PREVENTION
Abstract
Aim The aim of this study was to evaluate awareness of, attitudes toward, and first aid knowledge of seizures of hospital staff in Henan, China. Method Two hundred nineteen hospital staff, including doctors, nurses, medical technicians, logisticians, and executives working at tertiary hospitals in Henan, China, completed the survey from March to September in 2016. The data comprised the demographic data section, awareness of epilepsy section, attitude toward epilepsy section, and first aid knowledge of seizure attack section. Results The participants obtained a mean score of 7.48 ± 1.705 on the awareness of epilepsy section, and a mean score of 5.32 ± 1.165 on the first aid knowledge of seizure attacks section. There were significant correlations between educational level ( r = 0.187, P = 0.006), occupation ( r = − 0.244, P = 0.000), and attitudes toward patients with epilepsy ( r = 0.351, P = 0.000) with the awareness of epilepsy. There were significant correlations between age ( r = 0.170, P = 0.014), educational status ( r = 0.139, P = 0.040), and professional titles ( r = 0.197, P = 0.004) with the first aid knowledge of seizures. Conclusion The study showed that hospital staff had a moderate level of knowledge regarding epilepsy, and they generally displayed a positive attitude. It was also determined that as the awareness of epilepsy increased, they displayed more positive attitudes toward patients with epilepsy. The study also suggests that specialists working on epilepsy should provide more lectures and educational sessions to improve the knowledge of and attitude toward epilepsy and first aid knowledge of seizures among hospital staff. [ABSTRACT FROM AUTHOR]