Eleutheroside B or E enhances learning and memory in experimentally aged rats

Eleutheroside B or E, the main component of Acanthopanax, can relieve fatigue, enhance memory, and improve human cognition. Numerous studies have confirmed that high doses of acetylcholine significantly attenuate clinical symptoms and delay the progression of Alzheimer＇s disease. The present study replicated a rat model of aging induced by injecting quinolinic acid into the hippocampal CA1 region. These rats were intraperitoneally injected with low, medium and high doses of eleutheroside B or E （50, 100, 200 mg/kg）, and rats injected with Huperzine A or PBS were used as controls. At 4 weeks after administration, behavioral tests showed that the escape latencies and errors in searching for the platform in a Morris water maze were dose-dependently reduced in rats treated with medium and high-dose eleutheroside B or E. Hematoxylin-eosin staining showed that the number of surviving hippocampal neurons was greater and pathological injury was milder in three eleutheroside B or E groups compared with model group. Hippocampal homogenates showed enhanced cholinesterase activity, and dose-dependent increases in acetylcholine content and decreases in choline content following eleutheroside B or E treatment, similar to those seen in the Huperzine A group. These findings indicate that eleutheroside B or E improves learning and memory in aged rats. These effects of eleutheroside B or E may be mediated by activation of cholinesterase or enhanced reuse of choline to accelerate the synthesis of acetylcholine in hippocampal neurons.

Inhibition of α5 GABAA receptors has preventive but not therapeutic effects on isoflurane-induced memory impairment in aged rats

The α5 subunit-containing gamma-amino butyric acid type A receptors(α5 GABAARs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 GABAARs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose(1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young(3-month-old) and aged(24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia.The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reaction showed that low-dose isoflurane decreased the mRNA expression of α5 GABAARs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China(approval No. NBCDSER-IACUC-2015128) in December 2015.

解析疫苗接种后抗体记忆的维持:进展与挑战

“首次感染可以为二次感染提供免疫保护”的生物学基本原理推动近代疫苗的诞生与使用。这种免疫保护的基础是抗体记忆,然而各种疫苗引起的有效抗体应答的持续时间各不相同。临床研究发现,接种减毒活疫苗后引起的中和抗体滴度通常水平较高且持续时间久。但减毒活疫苗存在难以回避的安全性风险,因此有必要进一步研究高水平、高质量抗体记忆的产生机制与调控因素,以开发兼具保护性与安全性的新型疫苗。抗体记忆的维持主要依赖于长寿浆细胞介导的抗体分泌,以及记忆B细胞在二次感染时介导的快速记忆性抗体应答。抗原结构与抗原效价、疫苗的抗原载量与免疫策略、病原体相关物质与疫苗佐剂等因素均可通过影响生发中心反应调控抗体记忆的持续时长。本文将梳理疫苗中各成分及因素对抗体记忆生成和维持的相关机制,并尝试讨论目前疫苗学和基础免疫学领域对此方面仍存有的问题与挑战。

Immunogenicity and reactogenicity of a recombinant hepatitis B vaccine in subjects over age of forty years and response of a booster dose among nonresponders

AIM:The study was initiated to evaluate the reactogenicity and immunogenicity of a recombinant hepatitis B vaccine in age group >40 years and to study the response of a single booster dose in primary non-responders to the hepatitis B vaccination. METHODS:A total of 102 volunteers without markers of hepatitis B infection (negative for HBsAg,anti-HBc antibody, HBeAg and anti-HBs antibody) received 20μg of recombinant HB vaccine intramuscularly at 0,1,and 6 months.Anti HBs titers were evaluated by a quantitative Elisa kit at 90 and 210 days.A booster dose of 20μg HB vaccine was given after 6 months of the 3^(rd) vaccine dose to the 15 non- responders and anti-HBs titers were measured after i month. RESULTS:Seroprotection (anti-HBs GMT^3 10 IU/L) was achieved in 85.3 % (87/102) volunteers.The mean GMT titers of the vaccine responders was 136.1 IU/L.Of the seroprotected individuals,there were 32.4% (33/102) hyporesponders (anti- HBs titers <10-99 mIU/ml) and 52.9% (54/102) were responders (anti-HBs titers >100 IU/L).All the non-responders (15/15) responded to a single dose of the booster dose of recombinant HB vaccine and their mean anti-HBs antibody titers were more than 100.5 mIU/ml after the booster dose. CONCLUSION:Recombinant hepatitis B vaccine offers good seroprotection in the age group >40 years and has a good safety profile.A single booster dose after 6 months in primary non-responders leads to good seroprotective anti-HBs antibody titers.However,larger population based studies are needed to evaluate the role of a booster dose in selected group of non-responders and whether such an approach will be cost effective.

Detection of anti-Helicobacter pyloriantibodies in serum and duodenal fluid in peptic gastroduodenal disease

AIM:To study the diagnosis of Helicobacter pylori(H pylori) infection through the determination of serum levels of anti- H pylori IgG and IgA antibodies,and the levels of anti-H pylori IgA antibodies in duodenal fluid. METHODS:Data were collected from 93 patients submitted to upper digestive endoscopy due to dyspeptic symptoms. The patients were either negative(group A)or positive (group B)to H pylori by means of both histological detection and urease tests.Before endoscopy,peripheral blood was collected for the investigation of anti-H pylori IgG and IgA antibodies.To perform the urease test,biopsies were obtained from the gastric antrum.For the histological evaluation,biopsies were collected from the gastric antrum (greater and lesser curvatures)and the gastric body. Following this,duodenal fluid was collected from the first and second portions of the duodenum.For the serological assaying of anti-Hpylori IgG and IgA,and anti-Hpylori IgA in duodenal fluids,the ELISA method was utilized. RESULTS:The concentration of serum IgG showed sensitivity of 64.0%,specificity of 83.7%,positive predictive value of 82.0%,negative predictive value of 66.6% and accuracy of 73.1% for the diagnosis of H pylori infection.For the same purpose,serum IgA showed sensitivity of 72.0%, specificity of 65.9%,positive predictive value of 72.0%, negative predictive value of 67.4% and accuracy of 69.8%. If the serological tests were considered together,i.e.when both were positive or negative,the accuracy was 80.0%, sensitivity was 86.6%,specificity was 74.2%,positive predictive value was 74.2% and negative predictive value was 86.6%.When values obtained in the test for detecting IgA in the duodenal fluid were analyzed,no significant difference(P=0.43)was observed between the values obtained from patients with or without H pylori infection. CONCLUSION:The results of serum IgG and IgA tests for H pylori detection when used simultaneously,are more efficient in accuracy,sensitivity and negative predictive value, than those when used alone.The concentration of IgA antibodies in duodenal fluid is not useful in identifying patients with or without H pylori.

Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer’s disease

During normal aging,there is a decline in all physiological functions in the organism.One of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive impairment.Aging is one of the main risk factors for the development of neurodegenerative diseases,such as Alzheimer’s disease.One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates.The most studied brain aggregates are the senile plaques,formed by Aβpeptide;however,the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity.It is reported that neurons undergo severe mitochondrial dysfunction with age,with a decrease in adenosine 5′-triphosphate production,loss of the mitochondrial membrane potential,redox imbalance,impaired mitophagy,and loss of calcium buffer capacity.Interestingly,abnormal tau protein interacts with several mitochondrial proteins,suggesting that it could induce mitochondrial dysfunction.Nevertheless,whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown.A recent study of our laboratory shows that phosphorylated tau at Ser396/404(known as PHF-1),an epitope commonly related to pathology,accumulates inside mitochondria during normal aging.This accumulation occurs preferentially in synaptic mitochondria,which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals.Here,we review the main tau modifications promoting mitochondrial dysfunction,and the possible mechanism involved.Also,we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging.Finally,we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer’s disease,which could be considered as an early event in the neurodegenerative process.Thus,phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.

Predicting COVID-19 fatality rate based on age group using LSTM

Objective: To predict the daily incidence and fatality rates based on long short-term memory(LSTM) in 4 age groups of COVID-19 patients in Mazandaran Province, Iran.Methods: To predict the daily incidence and fatality rates by age groups, this epidemiological study was conducted based on the LSTM model. All data of COVID-19 disease were collected daily for training the LSTM model from February 22, 2020 to April 10, 2021 in the Mazandaran University of Medical Sciences. We defined 4 age groups, i.e., patients under 29, between 30 and 49, between 50 and 59, and over 60 years old. Then, LSTM models were applied to predict the trend of daily incidence and fatality rates from 14 to 40 days in different age groups. The results of different methods were compared with each other.Results: This study evaluated 5 0826 patients and 5 109 deaths with COVID-19 daily in 20 cities of Mazandaran Province. Among the patients, 25 240 were females(49.7%), and 25 586 were males(50.3%). The predicted daily incidence rates on April 11, 2021 were 91.76, 155.84, 150.03, and 325.99 per 100 000 people, respectively;for the fourteenth day April 24, 2021, the predicted daily incidence rates were 35.91, 92.90, 83.74, and 225.68 in each group per 100 000 people. Furthermore, the predicted average daily incidence rates in 40 days for the 4 age groups were 34.25, 95.68, 76.43, and 210.80 per 100 000 people, and the daily fatality rates were 8.38, 4.18, 3.40, 22.53 per 100 000 people according to the established LSTM model. The findings demonstrated the daily incidence and fatality rates of 417.16 and 38.49 per 100 000 people for all age groups over the next 40 days. Conclusions: The results highlighted the proper performance of the LSTM model for predicting the daily incidence and fatality rates. It can clarify the path of spread or decline of the COVID-19 outbreak and the priority of vaccination in age groups.

B-cell and antibody responses to SARS-CoV-2:infection,vaccination,and hybrid immunity

The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)in 2019 prompted scientific,medical,and biotech communities to investigate infection-and vaccine-induced immune responses in the context of this pathogen.B-cell and antibody responses are at the center of these investigations,as neutralizing antibodies(nAbs)are an important correlate of protection(COP)from infection and the primary target of SARS-CoV-2 vaccine modalities.In addition to absolute levels,nAb longevity,neutralization breadth,immunoglobulin isotype and subtype composition,and presence at mucosal sites have become important topics for scientists and health policy makers.The recent pandemic was and still is a unique setting in which to study de novo and memory B-cell(MBC)and antibody responses in the dynamic interplay of infection-and vaccine-induced immunity.It also provided an opportunity to explore new vaccine platforms,such as mRNA or adenoviral vector vaccines,in unprecedented cohort sizes.Combined with the technological advances of recent years,this situation has provided detailed mechanistic insights into the development of B-cell and antibody responses but also revealed some unexpected findings.In this review,we summarize the key findings of the last 2.5 years regarding infection-and vaccine-induced B-cell immunity,which we believe are of significant value not only in the context of SARS-CoV-2 but also for future vaccination approaches in endemic and pandemic settings.

Temporal pattern of humoral immune response in mild cases of COVID-19

BACKGROUND Understanding the humoral response pattern of coronavirus disease 2019(COVID-19)is one of the essential factors to better characterize the immune memory of patients,which allows understanding the temporality of reinfection,provides answers about the efficacy and durability of protection against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),and consequently helps in global public health and vaccination strategy.Among the patients who became infected with SARS-CoV-2,the majority who did not progress to death were those who developed the mild COVID-19,so understanding the pattern and temporality of the antibody response of these patients is certainly relevant.AIM To investigate the temporal pattern of humoral response of specific immunoglobulin G(IgG)in mild cases of COVID-19.METHODS Blood samples from 191 COVID-19 real-time reverse transcriptase-polymerase chain reaction(RT-qPCR)-positive volunteers from the municipality of Toledo/Paraná/Brazil,underwent two distinct serological tests,enzyme-linked immunosorbent assay,and detection of anti-nucleocapsid IgG.Blood samples and clinicoepidemiological data of the volunteers were collected between November 2020 and February 2021.All assays were performed in duplicate and the manufacturers'recommendations were strictly followed.The data were statistically analyzed using multiple logistic regression;the variables were selected by applying the P<0.05 criterion.RESULTS Serological tests to detect specific IgG were performed on serum samples from volunteers who were diagnosed as being positive by RT-qPCR for COVID-19 or had disease onset in the time interval from less than 1 mo to 7 mo.The time periods when the highest number of participants with detectable IgG was observed were 1,2 and 3 mo.It was observed that 9.42%of participants no longer had detectable IgG antibodies 1 mo only after being infected with SARS-CoV-2 and 1.57%were also IgG negative at less than 1 mo.At 5 mo,3.14%of volunteers were IgG negative,and at 6 or 7 mo,1 volunteer(0.52%)had no detectable IgG.During the period between diagnosis by RT-qPCR/symptoms onset and the date of collection for the study,no statistical significance was observed for any association analyzed.Moreover,considering the age category between 31 and 59 years as the exposed group,the P value was 0.11 for the category 31 to 59 years and 0.32 for the category 60 years or older,showing that in both age categories there was no association between the pair of variables analyzed.Regarding chronic disease,the exposure group consisted of the participants without any comorbidity,so the P value of 0.07 for the category of those with at least one chronic disease showed no association between the two variables.CONCLUSION A temporal pattern of IgG response was not observed,but it is suggested that immunological memory is weak and there is no association between IgG production and age or chronic disease in mild COVID-19.

一种基于动态抗体记忆库的免疫优化算法在自动需求响应中的应用

自动需求响应是智能电网与用户实现信息和能量互动的重要实现手段。为解决基于实时电价的自动需求响应技术应用中包含多类负荷用户的电能综合规划问题,建立优化问题的数学模型。针对该模型提出一种基于动态抗体记忆库的免疫优化算法。设计依据二重亲和度阈值检测的抗体记忆库更新机制,在优化结束后能够为用户提供多个备选可行解。采用先验知识疫苗接种的方法,提高算法的求解精度。通过抗体种群的优值马尔可夫链的转移概率分析,证明了算法的收敛性;利用实际算例验证了所提算法的有效性。对比分析的结果表明,所提算法比其他算法具有更好的全局优化能力和搜索效率。

M胆碱受体亚型特异性抗体用于测定氯化铝中毒小鼠脑M受体量

人工合成Ｍ１和Ｍ２胆碱受体蛋白的细胞外肽段，联接血蓝蛋白后免疫家兔，制备出Ｍ１和Ｍ２受体的亚型特异性抗体．用此抗体观察脑室内注射Ａｌ－Ｃｌ３４０μｇ引起的学习记忆障碍小鼠部分脑区Ｍ受体的含量变化，发现实验组小鼠海马Ｍ１和Ｍ２受体数降低而顶叶皮层。

不同表型双价痢疾菌苗滴鼻免疫小鼠后黏膜和系统记忆反应观测

目的 观测 5株 2类不同表型的双价痢疾菌苗滴鼻免疫后所引起的黏膜和系统的记忆反应 ,为痢疾菌苗的构建提供理论依据。方法 以小鼠滴鼻免疫为模型 ,3次免疫 (间隔 2周 )后 ,2 0周再次免疫 ,分别于 3次免疫及 2 0周加强免疫后第 7天 ,收取鼻咽、肺、小肠及阴道冲洗液和血清 ,应用ELISA方法检测福氏、宋内氏特异性抗体。结果 2类双价菌苗株滴鼻免疫 3次后 ,多个黏膜部位及血清均产生了抗原特异性sIgA、IgG ,较PBS对照组有明显升高 ;2 0周后再次加强免疫 ,仍可诱导黏膜及系统的免疫反应 ,但较 3次免疫后水平明显降低。结论 2株双价痢疾菌苗滴鼻免疫小鼠后可诱导多个黏膜及系统的特异性抗体产生 ,并可产生一定时间的记忆反应 。

双价痢疾菌苗免疫小鼠后抗体记忆反应的观测

目的 :FSM 2 117和FS 5 416是我室构建的具有不同生物表型的福氏、宋内氏双价痢疾菌苗株 ,前者不表达侵袭蛋白 ,无侵袭力 ,而后者表达侵袭蛋白 (Ipa) ,具有侵袭力。拟观测两株菌苗FSM 2 117(Ipa- )、FS 5 416 (Ipa+ )免疫后所引起的肠粘膜局部和系统中的免疫记忆反应 ,为研制痢疾菌苗提供理论依据。方法 :以小鼠灌胃免疫为模型 ,3次免疫后 ,间隔 3个月再次免疫 ,第 7天取血清和小肠冲洗夜 ,应用ELISA方法检测福氏、宋内氏特异性抗体。结果 :两菌苗株免疫组 ,血清中及局部抗原特异性sIgA、IgG抗体明显升高。两株菌苗与对照组相比 ,都具有显著差异。结论 :两株双价痢疾菌苗免疫小鼠后 。

基于人工免疫思想的蚁群算法(AIACS)在配电网重构中的应用

针对多目标非线性整数规划的配电网重构问题,提出基于人工免疫思想的蚁群算法求解配电网重构问题。算法通过在原有蚁群模型上增加一个免疫记忆库,解对应于抗体,问题对应于抗原,并借鉴克隆选择和免疫记忆的思想进行解的构造和信息素更新。配电网编码采用基于环路的编码方式,算例结果表明,所提出算法在可以接受的计算迭代范围内可显著提高标准蚁群算法的性能。

多峰值函数优化的改进克隆选择算法

通过分析Castro提出的CLONALG算法在优化多峰值函数时存在峰值搜索能力弱、最优解易退化、收敛效率低等问题的根源,提出了一种基于记忆库小生境自适应克隆选择算法(MNACSA)。该算法首先采用小生境机制将种群分成若干类、分别从每个类中选出最优个体组成新种群;其次建立记忆库和自适应的高频变异率、且在库中引入最佳抗体抑制操作。对算法进行了分析和仿真实验,证明了该算法可以防止优秀个体退化、自动调节种群个体数目、提高优化效率、增强多峰搜索能力。

免疫粒子群优化在波阻抗反演中的应用

针对标准粒子群优化(PSO)算法易出现早熟而陷入局部最优以及进化后期收敛速度慢等缺陷,引入免疫系统的免疫记忆和抗体浓度选择机制,构造了基于免疫机制的粒子群优化(IPSO)算法,并将其应用到波阻抗反演问题中。免疫记忆能够保留高适应度个体,抗体浓度选择机制进一步保证了粒子的多样性,从而能较好地避免早熟收敛,提高算法的全局搜索能力。对理论模型试算表明,IPSO算法在进行波阻抗反演时不仅收敛速度快,而且具有较高的精确度和抗噪性能。

抗富亮氨酸胶质瘤失活1蛋白抗体相关性边缘叶脑炎4例临床分析和文献复习

目的通过对抗富亮氨酸胶质瘤失活1蛋白(LGI1)抗体相关性边缘叶脑炎患者的临床资料进行分析和总结,并复习相关文献,加强临床对该疾病的认识。方法回顾性选取2013年4月至2017年1月在首都医科大学附属北京友谊医院住院的确诊为LGI1抗体相关性边缘叶脑炎患者4例,总结其临床资料,包括临床表现、影像学结果、血液和脑脊液检测结果、治疗和转归、随访结果等。结果 4例患者中,男性3例,女性1例,均为中老年患者,均表现为明显认知减退,以近记忆减退和定向障碍为主;3例出现不自主运动或震颤等锥体外系症状;1例以癫痫发作起病,精神行为异常1例、虚构和异食症1例等。4例患者均无明显意识障碍和低通气表现;头部MRI检查以及PET-CT结果均提示海马或颞叶内侧异常信号;4例患者脑脊液抗LGI1抗体阳性;3例患者同时存在顽固性低钠血症和低钾血症,均为轻-中度,1例患者低钾血症甚至持续1年以上;1例同时合并血抗髓鞘少突胶质细胞糖蛋白抗体(MOG)抗体阳性;3例患者给予丙种球蛋白治疗,1例给予甲基强的松龙冲击治疗;4例患者均遗留有不同程度的认知减退,生活基本自理。1例出院后失访,3例随访1~3年,均无复发,1例出院3年后猝死。结论抗LGI1抗体相关性边缘叶脑炎多见于中老年人,以近记忆减退和定向障碍等认知减退为主要表现,部分合并有低钠血症和低钾血症,影像学显示海马和颞叶内侧受累,丙种球蛋白或激素等免疫治疗有效,但可遗留认知损害。

基于小波抗体记忆克隆算法的电机故障诊断

针对电机定子、转子、轴承偏心、气隙偏心等故障,提出了一种将小波分析和抗体克隆算法相结合的故障诊断新方法。使用小波技术对电机定子电流监控数据进行预处理,对采样信号进行小波分解,提取各频段的能量,归一化后将能量作为故障诊断的特征向量。将得到的故障特征向量作为抗原,由算法建立的聚类中心作为免疫系统的抗体,然后利用抗体记忆克隆算法对故障样本进行故障识别分类。试验和应用结果表明,用小波记忆克隆算法能很好地分类出电机的各种工作状态,使电机故障诊断具有较高的正确率和浓缩率。

基于记忆抗体克隆聚类算法的心音分类研究

为快速、准确地判断心音的正常与否,提出了一种记忆抗体克隆聚类算法。该方法将克隆选择算法和监督Gath-Geva算法相结合对心音信号进行识别与分类,并运用Sammon映射算法将高维心音特征数据映射成二维实现分类效果的可视化。试验中,首先对临床采集的主动脉听诊区的心音数据110组(60组正常,50组异常)和二尖瓣听诊区的心音数据100组(60组正常,40组异常)进行预处理和特征提取,然后采用提出的记忆抗体克隆聚类算法对提取的心音特征数据进行识别与分类,平均分类准确率分别达到98.1%和96.2%。