基于文本挖掘和生物医学数据库的新型冠状病毒肺炎药物发现

目的 基于文本挖掘技术和生物医学数据库对新型冠状病毒肺炎（COVID-19）相关文献进行数据挖掘分析，探究COVID-19及其主要症状发热、咳嗽、呼吸障碍相关基因靶点，筛选潜在有效的化学药和中药。方法 使用GenCLiP 3网站获取COVID-19和其主要症状咳嗽、发热、呼吸障碍共4个关键词的共有靶点，在METASCAPE数据库中对其进行基因本体（GO）和通路富集分析，再利用String数据库和Cytoscape软件构建共有靶点的蛋白质相互作用网络，筛选获得核心基因，运用DGIdb数据库、SymMap数据库针对核心基因进行中西医治疗药物预测。结果 获得COVID-19及其主要症状共有基因靶点28个，其中有IL2、IL1B、CCL2等核心基因16个，使用DGIdb数据库筛选获得与16个关键靶点相互作用的化学药包括沙利度胺、来氟米特、环孢素等28种，中药包括虎杖、黄芪、芦荟等70味。结论 COVID-19及其主要症状的病理机制可能和CD4、KNG1、VEGFA等28个共有基因相关，可能通过介导TNF、IL-17等信号通路参与COVID-19病理过程。潜在有效药物可能通过作用相关靶点通路起到治疗COVID-19的作用。     

Robust antibody response after a third BNT162b2 vaccine compared to the second among immunocompromised and healthy individuals,a prospective longitudinal cohort study

PurposeAs protection from COVID-19 following two doses of the BNT162b2 vaccine showed a time dependent waning, a third (booster) dose was administrated. This study aims to compare the antibody response following the third dose versus the second and to evaluate post-booster seroconversion.MethodsA prospective observational study conducted in Maccabi Healthcare Services. Serial SARS-CoV-2 Spike IgG tests, 1,2,3 and 6 months following the second vaccine dose and one month following the third were obtained. Neutralizing antibody levels were measured in a subset of participants. Per individual SARS-CoV-2 Spike IgG titer ratios were calculated one month after the booster administration compared to titers one month following the second dose and prior to booster.ResultsAmong 110 participants, 56 (51%) were women. Mean age was 61.7 ± 1.9 years and 66 (60%) were immunocompromised. One month after third dose, IgG titers were induced 7.83 (95 %CI 5.25–11.67) folds and 2.40 (95 %CI 1.90–3.03) folds compared to one month after the second, in the immunocompromised and immunocompetent groups, respectively. Of the 17 immunocompromised participants who were seronegative after the second dose, 4 (24%) became seropositive following the third. Comparing the titers prior to the third dose, an increase of 50.7 (95 %CI 32.5–79.1) fold in the immunocompromised group and 25.7 (95 %CI 19.1–34.7) fold in and immunocompetent group, was observed.ConclusionA third BNT162b2 vaccine elicited robust humoral response, superior to the response observed following the second, among immunocompetent and immunocompromised individuals.     

WHO working group meeting to amend WHO Recommendations to assure the quality,safety and efficacy of live attenuated yellow fever vaccines

The current WHO Recommendations to assure the quality, safety and efficacy of live attenuated yellow fever vaccines were adopted in 2010. This document recommends that vaccine virus master and working seed lots should be tested for viscerotropism, immunogenicity and neurovirulence in monkeys. A vaccine manufacturer has reported, recently, discrepancies on the clinical scoring of monkeys during assessment of working seed lots and suggested aligning neurotropism assessment of yellow fever vaccines virus seed lots with that of neurovirulence testing of polio vaccines virus seed lots. In this approach, clinical signs are recorded but do not form part of the assessment or pass/fail criteria. At its 71^st meeting in August 2020, the ECBS agreed to establish a drafting group and to consult with manufacturers and other stakeholders on the proposed amendment. Then a survey had been conducted to seek opinions of stakeholders on the neurotropism testing and revision of current WHO Recommendations for yellow fever vaccines. It was recognized from the answers of the survey that the test for neurovirulence in monkeys presents several technical challenges which could be addressed in the amended version of the Recommendations.On 18–19 March 2021, a virtual WHO working group meeting was held to discuss a proposed draft of the amended text with participants of yellow fever vaccine manufacturers and relevant regulators. Overall, there was a consensus among manufacturers and regulators that clinical evaluation provides important information and should be retained as part of the neurotropism test. However, there was also agreement that the test is somewhat subjective, and that analysis can be difficult. It was recognized that there was potential for improvement in both test execution and analysis to increase harmonization between manufacturers. Alternative tests to the non-human primates neurovirulence test would be useful but it was agreed that none seem to be sufficiently developed at present. Based on these working group discussions, it was proposed that the appendix on neurotropism test to be further revised by the WHO drafting group and submitted to ECBS for review and adoption.Issues other than neurotropism test were discussed in the meeting as well. There were a number of points identified during the meeting, such as new platform of production, animal models, deep sequencing, international standards, that are outside the current recommendations that are worthy of further discussion. Therefore, it is recommended that there would be a future meeting with various stakeholders to discuss the potential revision of the whole Recommendations for yellow fever vaccines in order to meet the current needs.     

地鳖纤溶蛋白口服时间/pH依赖结肠靶向微囊的开发及评价＊

地鳖中的纤溶活性蛋白是从地鳖中提取的具有抗栓及抗肿瘤作用的有效成分，其口服易被上消化道酶分解从而限制了应用。采用恒流泵滴制法开发地鳖纤溶活性蛋白时间/pH依赖口服结肠靶向微囊（EnpolypHaga fibrinolytic protein oral colon targeting microcapsules， CTM-EFP）。采用单因素实验和正交实验相结合的方法寻找到包封率为60.17 % ± 2.72 %、载药量为15.50 % ± 0.44 % 的最佳配方。扫描电子显微镜（SEM）显示微囊呈球形、表面光滑，在人工肠液中24 h的累积释放度为99.53 % ± 0.69 %，在人工胃液中24 h累积释放度为7.43 ± 1.04 %，通过时间/pH依赖达到结肠靶向作用。CTM-EFP在人工肠液中的体外释放曲线符合Korsmeyer方程，提示地鳖纤溶活性蛋白（EnpolypHaga fibrinolytic protein， EFP）是通过扩散和侵蚀机制结合释放的。CTM-EFP为EFP的口服给药提供了一种新的剂型，为EFP应用于临床提供参考。     

A Priori Subcell Limiting Approach for the FR/CPR Method on Unstructured Meshes

A priori subcell limiting approach is developed for high-order flux reconstruction/correction procedure via reconstruction (FR/CPR) methods on two-dimensional unstructured quadrilateral meshes. Firstly, a modified indicator based on modal energy coefficients is proposed to detect troubled cells, where discontinuities exist. Then, troubled cells are decomposed into nonuniform subcells and each subcell has one solution point. A second-order finite difference shock-capturing scheme based on nonuniform nonlinear weighted (NNW) interpolation is constructed to perform the calculation on troubled cells while smooth cells are calculated by the CPR method. Numerical investigations show that the proposed subcell limiting strategy on unstructured quadrilateral meshes is robust in shock-capturing.     

Knockdown of DEAD-box 51 inhibits tumor growth of esophageal squamous cell carcinoma via the PI3K/AKT pathway

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is one of the most prevalent malignancies that seriously threaten people’s health worldwide.DEAD-box helicase 51(DDX51)is a member of the DEAD-box(DDX)RNA helicase family,and drives or inhibits tumor progression in multiple cancer types.AIM To determine whether DDX51 affects the biological behavior of ESCC.METHODS The expression of DDX51 in ESCC tumor tissues and adjacent normal tissues was detected by Immunohistochemistry(IHC)analyses and quantitative PCR(qPCR).We knocked down DDX51 in ESCC cell lines by using a small interfering RNA(siRNA)transfection.The proliferation,apoptosis,and mobility of DDX51 siRNAtransfected cells were detected.The effect of DDX51 on the phosphoinositide 3-kinase(PI3K)/AKT pathway was investigated by western blot analysis.A mouse xenograft model was established to investigate the effects of DDX51 knockdown on ESCC tumor growth.RESULTS DDX51 exhibited high expression in ESCC tissues compared with normal tissues and represented a poor prognosis in patients with ESCC.Knockdown of DDX51 induced inhibition of ESCC cell proliferation and promoted apoptosis.Moreover,DDX51 siRNA-expressing cells also exhibited lower migration and invasion rates.Investigations into the underlying mechanisms suggested that DDX51 knock down induced inactivation of the PI3K/AKT pathway,including decreased phosphorylation levels of phosphate and tensin homolog,PI3K,AKT,and mammalian target of rapamycin.Rescue experiments demonstrated that the AKT activator insulin-like growth factor 1 could reverse the inhibitory effects of DDX51 on ESCC malignant development.Finally,we injected DDX51 siRNA-transfected TE-1 cells into an animal model,which resulted in slower tumor growth.CONCLUSION Our study suggests for the first time that DDX51 promotes cancer cell proliferation by regulating the PI3K/AKT pathway;thus,DDX51 might be a therapeutic target for ESCC.     

注意缺陷多动障碍儿童执行功能的评估与干预

ADHD儿童认知障碍的主要特征之一是执行功能损害,涉及包括前额叶皮层在内的特定脑区域及多层级脑网络异常。执行功能按照功能性分为冷-热两方面:冷执行功能损害主要表现于反应抑制、工作记忆以及认知灵活性等;热执行功能损害通常涉及延迟满足、赏罚相关决策、自我调节及情绪调节等。ADHD儿童的执行功能评估应基于可信范式进行文化适应性调整。临床干预不能单一聚焦于冷执行功能,需关注儿童的身体发育以及热执行功能(情绪社会方面)的发展进程,结合其他共病与心理状况,进行全面的动态随访与干预,以达到最佳的长期疗效。     

The role of dark adaptation in understanding early AMD

The main aim of the paper is to discuss current knowledge on how Age Related Macular Degeneration (AMD) affects Dark Adaptation (DA). The paper is divided into three parts. Firstly, we outline some of the molecular mechanisms that control DA. Secondly, we review the psychophysical issues and the corresponding analytical techniques. Finally, we characterise the link between slowed DA and the morphological abnormalities in early AMD.Historically, DA has been regarded as too cumbersome for widespread clinical application. Yet the technique is extremely useful; it is widely accepted that the psychophysically obtained slope of the second rod-mediated phase of the dark adaptation function is an accurate assay of photoreceptor pigment regeneration kinetics. Technological developments have prompted new ways of generating the DA curve, but analytical problems remain. A simple potential solution to these, based on the application of a novel fast mathematical algorithm, is presented. This allows the calculation of the parameters of the DA curve in real time.Improving current management of AMD will depend on identifying a satisfactory endpoint for evaluating future therapeutic strategies. This must be implemented before the onset of severe disease. Morphological changes progress too slowly to act as a satisfactory endpoint for new therapies whereas functional changes, such as those seen in DA, may have more potential in this regard. It is important to recognise, however, that the functional changes are not confined to rods and that building a mathematical model of the DA curve enables the separation of rod and cone dysfunction and allows more versatility in terms of the range of disease severity that can be monitored. Examples are presented that show how analysing the DA curve into its constituent components can improve our understanding of the morphological changes in early AMD.