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Evolution of enhanced innate immune evasion by SARS-CoV-2

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四川生理科学杂志 2021年第10期43卷 1695-1695页

作者： Lucy G Thorne Division of Infection and Immunity University College London London WC1E 6BT United Kingdom Quantitative Biosciences Institute (QBI) Coronavirus research Group (QCRG) San Francisco CA 94158 USA Global health and Emerging Pathogens Institute Icahn School of Medicine at Mount Sinai New York NY 10029 USA Quantitative Biosciences Institute (QBI) University of California San Francisco San Francisco CA 94158 USA J. David Gladstone Institutes San Francisco CA 94158 USA Department of Cellular and Molecular Pharmacology University of California San Francisco San Francisco CA 94158 USA Howard Hughes medical Institute San Francisco CA 94158 USA Division of Advanced Therapies National Institute for Biological Standards and Control South Mimms UK Cardiovascular research Institute University of California - San Francisco San Francisco CA 94158 USA Division of Virology Department of Pathology University of Cambridge Addenbrooke’s Hospital Hills Road Cambridge CB2 2QQ UK Epithelial Stem Cell Biology & Regenerative Medicine laboratory The Francis Crick Institute 1 Midland Road London NW1 1AT UK Institute of Immunity & Transplantation Division of Infection & Immunity UCL Pears Building London NW3 2PF UK MIT Computer Science and Artificial Intelligence Laboratory Cambridge MA 02139 USA Broad Institute of MIT and Harvard Cambridge MA 02142 USA European Molecular Biology Laboratory (EMBL) European Bioinformatics Institute Wellcome Genome Campus Hinxton Cambridge UK Department of Microbiology Icahn School of Medicine at Mount Sinai New York NY 10029 USA The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY 10029 USA Department of Medicine Division of Infectious Diseases Icahn School of Medicine at Mount Sinai New York NY 10029 USA Department of Pathology Molecular and Cell-Based Medicine Icahn School of Medicine at Mount Sinai New York NY 10029 USA

Emergence of SARS-CoV-2 variants of concern(VOCs)suggests viral adaptation to enhance human-to-human transmission1,*** much effort has focused on characterisation of spike changes in VOCs,mutations outside spike likely contribute to *** we used unbiased abundance proteomics,phosphoproteomics,RNAseq and viral replication assays to show that isolates of the Alpha(B.1.1.7)variant3 more effectively suppress innate immune responses in airway epithelial cells,compared to first wave *** found that Alpha has dramatically increased subgenomic RNA and protein levels of N,Orf9b and Orf6,all known innate immune *** of Orf9b alone suppressed the innate immune response through interaction with TOM70,a mitochondrial protein required for RNA sensing adaptor MAVS ***,the activity of Orf9b and its association with TOM70 was regulated by *** propose that more effective innate immune suppression,through enhanced expression of specific viral antagonist proteins,increases the likelihood of successful Alpha transmission,and may increase in vivo replication and duration of *** importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions.

关键词： outside likely alone

Critically dysregulated signaling pathways and clinical utility of the pathway biomarkers in lymphoid malignancies

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Chronic Diseases and Translational Medicine 2018年第1期4卷 29-44页

作者： Rui-Fang Sun Qian-Qian Yu Ken H. Young Tumor Biobank Department of PathologyShanxi Cancer HospitalTaiyuanShanxi 030013China Department of Hematopathology The University of Texas MD Anderson Cancer CenterHoustonTX 77025USA

Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the 'driver' oncogenic biomarkers, as well as to develop reliable and reproducible risk-stratification based on biomarkers will be challenging. Never-theless, pathway-based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine.

关键词： Lymphoma Signaling pathway Biomarker Therapeutic target

Science:蛋白折叠远比想象中的更加复杂

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现代生物医学进展 2017年第18期17卷 I0001-I0001页

作者： Hao Yu Aric W. Sanders Thomas T. Perkins,† Department of Molecular Cellular and Developmental Biology University of Colorado Boulder CO 80309 USA.

在一项新的研究中，来自美国国家标准技术研究所和科罗拉多大学博尔德分校的研究人员比以前更加详细地测量蛋白折叠，从而揭示出这种折叠过程比之前所知的更加复杂。这些结果提示着在此之前。对科学界而言，蛋白折叠在很大程度上仍然是... 详细信息

在一项新的研究中，来自美国国家标准技术研究所和科罗拉多大学博尔德分校的研究人员比以前更加详细地测量蛋白折叠，从而揭示出这种折叠过程比之前所知的更加复杂。这些结果提示着在此之前。对科学界而言，蛋白折叠在很大程度上仍然是未知的，这是因为这种折叠过程在如此短的时间内发生而且蛋白结构发生如此小的变化以至于常规的方法不能够检测出来。相关研究结果发表在Science期刊上。

关键词：蛋白折叠科罗拉多大学折叠过程研究人员标准技术蛋白结构研究所

四联与三联抗逆转录病毒疗法作为HIV感染者一线治疗效果比较:一项随机对照试验的系统综述和meta分析

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英国医学杂志中文版 2020年第1期23卷 19-28页

作者：冯倚(译) 周傲霜邹华春 Suzanne M Ingle Margaret T May 蔡卫平 Chien-Yu Cheng 杨祖耀唐金陵冯琦(译) 唐金陵(译) Division of Epidemiology Jockey Club School of Public Health and Primary CareChinese University of Hong KongHong KongChina School of Public health(Shenzhen) Sun Yat-Sen UniversityShenzhenChina Kirby Institute University of New South WalesSydneyAustralia Population health Sciences Bristol Medical SchoolUniversity of BristolBristolUK Department of Infectious Disease Guangzhou Eighth People′s HospitalGuangzhouChina Division of Infectious Diseases Department of Internal MedicineTaoyuan General HospitalMinistry of Health and WelfareTaoyuanTaiwanChina School of Public health National Yang-Ming UniversityTaipeiTaiwanChina Shenzhen Key Laboratory for health Risk Analysis Shenzhen Research Institute of the Chinese University of Hong KongShenzhenChina 香港中文大学公共卫生及基层医疗学院

目的比较四药联用(四联)和三药联用(三联)的抗逆转录病毒疗法作为HIV感染者一线治疗的疗效和安全性,并探讨现有的临床试验对临床实践及未来研究的启示。研究设计随机对照试验的系统综述和meta分析。数据来源系统检索了PubMed、EMBASE、C... 详细信息

目的比较四药联用(四联)和三药联用(三联)的抗逆转录病毒疗法作为HIV感染者一线治疗的疗效和安全性,并探讨现有的临床试验对临床实践及未来研究的启示。研究设计随机对照试验的系统综述和meta分析。数据来源系统检索了PubMed、EMBASE、CENTRAL、Web of Science及Allied health Literature数据库2001年3月至2016年12月期间发表的研究(其中PubMed和EMBASE的检索更新至2018年6月),以及合格研究和相关综述的参考文献。入选标准比较四联与三联抗逆转录病毒疗法作为HIV感染者一线治疗的作用,并评价了至少一种疗效或安全性结局的随机对照试验。分析方法对检测不到的HIV-1 RNA、CD4 T细胞计数、病毒学失败、新发艾滋病事件、死亡和严重不良反应等结局的资料采用随机效应模型进行meta分析。结果共找到12项合格研究,包括4251例HIV感染者。四联和三联抗逆转录病毒疗法对各个疗效和安全性结局的影响均类似,且没有一个总体效应估计值的点值落在支持四联疗法的一侧。与三联疗法相比,四联疗法组出现不同结局的相对危险度及其95%可信区间如下:检测不到的HIV-1 RNA,0.99(0.93~1.05);病毒学失败,1.00(0.90~1.11);新发艾滋病事件,1.17(0.84~1.63);死亡,1.23(0.74~2.05);严重不良反应,1.09(0.89~1.33)。两组CD4 T细胞计数增加的平均差值为-19.55个细胞/μl(-43.02~3.92)。无论联合抗逆转录病毒疗法的具体方案如何,上述2组比较的结果大体不变,且在所有亚组和敏感性分析中均变化不大。结论在HIV感染者的一线治疗中,四联抗逆转录病毒疗法的效果并不优于三联疗法。这一发现为当前推荐三联疗法作为一线治疗的指南提供了支持。除非对现有证据的系统综述显示确有必要,否则不应该再开展新的临床试验去比较四联与三联疗法。当然,本系统综述并不排除当有新的抗逆转录病毒药物种类出现时包含该类药物的四联疗法比三联疗法更好的可能性。

关键词： meta分析相对危险度四联疗法三联疗法系统综述 HIV感染者临床试验随机效应模型

Amyotrophic lateral sclerosis

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四川生理科学杂志 2022年第9期44卷 1527-1527页

作者： Eva L Feldman Department of Neurology Michigan Medicine University of Michigan Ann Arbor MI USA Department of Neurology Hannover Medical School Hannover Germany ALS Centre Azienda Ospedaliero-Universitaria Maggiore della Carità Novara Italy Department of Neurology University of Piemonte Orientale Novara Italy Sheffield Institute for Translational Neuroscience (SITraN) University of Sheffield Sheffield UK Department of Neurology Aichi Medical University Nagakute Aichi Japan

Amyotrophic lateral sclerosis is a fatal CNS neurodegenerative disease. Despite intensive research, current management of amyotrophic lateral sclerosis remains suboptimal from diagnosis to prognosis. Recognition of the phenotypic heterogeneity of amyotrophic lateral sclerosis, global CNS dysfunction, genetic architecture, and development of novel diagnostic criteria is clarifying the spectrum of clinical presentation and facilitating diagnosis. Insights into the pathophysiology of amyotrophic lateral sclerosis, identification of disease biomarkers and modifiable risks, along with new predictive models, scales, and scoring systems, and a clinical trial pipeline of mechanism-based therapies, are changing the prognostic landscape. Although most recent advances have yet to translate into patient benefit, the idea of amyotrophic lateral sclerosis as a complex syndrome is already having tangible effects in the clinic. This Seminar will outline these insights and discuss the status of the management of amyotrophic lateral sclerosis for the general neurologist, along with future prospects that could improve care and outcomes for patients with amyotrophic lateral sclerosis.

关键词： sclerosis diagnosis translate

澳大利亚初级保健诊所新发腰背痛患者的预后：起始队列研究

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英国医学杂志中文版 2008年第6期11卷 339-342页

作者： Nicholas Henschke Christopher G Maher Kathryn M Refshauge Robert D Herbert Robert G Cumming Jane Bleasel John York Anurina Das James H McAuley 蓝恭涛(译) Musculoskeletal Division The George Institute for International Health Sydney Australia Back Pain research Group Faculty of Health Sciences University of Sydney School of Public health University of Sydney Department of Rheumatology Royal Prince Alfred Hospital Sydney 不详

目的估计初级保健诊所内新发腰背痛患者的1年预后，并确定其预后因素。设计1年随访队列研究。地点澳大利亚悉尼的初级保健诊所。参试者初级保健诊所接诊的973例非特异性腰背痛连续患者（平均年龄43.3岁，男性54.8％）。该起始队列患者... 详细信息

目的估计初级保健诊所内新发腰背痛患者的1年预后，并确定其预后因素。设计1年随访队列研究。地点澳大利亚悉尼的初级保健诊所。参试者初级保健诊所接诊的973例非特异性腰背痛连续患者（平均年龄43.3岁，男性54.8％）。该起始队列患者腰背痛时间不足两周，征集自170名全科医生、理疗师或按摩师诊所。主要评估指标参试者完成基线调查问卷后，分别于初次就诊后6周、3个月和21个月时复查评估。评估内容包括：工作恢复情况、功能恢复情况和疼痛消失情况。潜在预后因素与恢复所需时间的关联性用Cox回归建模分析。结果12个月随访率〉97％。基线时工作能力下降的患者半数在14天内恢复了以前的工作状态（95％可信区间11-17天），83％在3个月内恢复。残疾（中位恢复时间31天，25-37天）和疼痛（中位58天，52-63天）则需要较长的时间才能恢复。只有72％的受试者于基线访问后12个月获得完全康复。高龄、赔偿诉讼、疼痛较重、就诊前腰背痛时间较长、就诊前因疼痛活动减少天数较多、抑郁情绪以及预期危险持续与所需恢复时问较长相关。结论在这个急性腰背痛初级保健患者队列，患者的预后并不像临床指南声称的那样乐观。多数患者的恢复缓慢。近三分之一的患者在腰背痛发作后1年尚未恢复。

关键词：腰背痛患者初级保健预后因素队列研究澳大利亚诊所新发评估指标

Unconsciously Implanted Visuoauditory Memory in the Presence of Cholecystokinin Retrieved in a Behaviorally Relevant Context

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Unconsciously Implanted Visuoauditory Memory in the Presence...

Biomarkers in schizophrenia:A focus on blood based diagnostics and theranostics

中国神经科学学会第十二届全国学术会议

作者： Zicong Zhang Christine Xuejiao Zheng Yujie Peng Xi Chen Yiping Guo Danyi Lu Xiao Li Wenjian Sun Peng Tang Sherry Ling He Min Li Qing Liu Fuqiang Xu Gabriel Ng Jufang He Departments of Biomedical Sciences and Biology and Chemistry City University of Hong Kong Department of Rehabilitation Sciences The Hong Kong Polytechnic University City University of Hong Kong Shenzhen research Institute Guangzhou Institute of Biomedicine and health Chinese Academy of Sciences Wuhan Institute of Physics and Mathematics Chinese Academy of Sciences

We investigated whether an associative memory can be artificially implanted under anesthesia and then retrieved in a behaviorally relevant context. Rats with bilateral electrodes in the auditory cortex were trained to approach the left or the right hole of a behavioral apparatus to retrieve a reward depending on whether the right or left auditory cortex was electrically stimulated. Next, under anesthesia, a previously irrelevant visual stimulus（VS） was repeatedly paired with electrical stimulation of the auditory cortex（EAC） in the presence of cholecystokinin（CCK）, after which auditory cortex neurons started to respond to the light stimulus in both anesthetized and awake states. In subsequent behavioral testing, in response to the VS, rats approached the hole that was "engineered" to be associated with reward availability. High-frequency（HF） activation of the terminals of the entorhinal CCK neurons in the auditory cortex, which was followed by the pairing of the VS and EAC, enhanced neuronal responses to the VS in the auditory cortex of anesthetized mice. When the mice were pre-conditioned EAC with footshock, mice showed significantly increased freezing responses to the VS after the pairings. Application of CCK antagonist blocked the establishment of visuoauditory association in the behavioral experiment. CCK-/-mice have deficit in forming the visuoauditory association, but systemic administration of tetropeptide CCK rescued the formation of associative memory in CCK-/-mice. Our finding that an artificial memory formed under anesthesia could be translated into behavioral action provides a scientific foundation for "memory implantation" and CCK is the switching chemical for the formation of visuoauditory associative memory.

关键词： auditory cortex neural plasticity operant conditioning entorhinal cortex memory encoding cholecystokinin

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World Journal of Psychiatry 2016年第1期6卷 102-117页

作者： Chi-Yu Lai Elizabeth Scarr Madhara Udawela Ian Everall Wei J Chen Brian Dean the Florey Institute of Neuroscience and Mental health Institute of Epidemiology and Preventive Medicine College of Public HealthNational Taiwan University Center of Genomic Medicine National Taiwan University Department of Psychiatry the University of Melbourne

Identifying biomarkers that can be used as diagnostics or predictors of treatment response(theranostics) in people with schizophrenia(Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophreniaassociated phenotype. We sorted the studies into six categories which include:(1) brain-derived neurotrophic factor;(2) inflammation and immune function;(3) neurochemistry;(4) oxidative stress response and metabolism;(5) epigenetics and micro RNA; and(6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, bloodoriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.

关键词： Schizophrenia Peripheral blood Biomarker Diagnostics Schizophrenia-associated phenotype Treatment response Clinical courses

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临床实践指南应当包含治疗负担

中国医院院长 2019年第3期15卷 22-22,24,26页

作者： Claudia C Dobler Nathan Harb Catherine A Maguire Carol L Armour Courtney Coleman M Hassan Murad 邓璇(翻译) 莫云凌(校) Evidence Based Practice Center Robert D and Patricia E Kern Center for the Science of Health Care Delivery Mayo Clinic Rochester MN USA Woolcock Institute of medical research University of Sydney Sydney NSW Australia South Western Sydney Clinical School University of New South Wales NSW Sydney Australia

Claudia Dobler和同事们认为,指南中明确增加有关治疗负担的内容能够改善治疗决策。医疗方案的实施需要花费大量时间和精力,给慢性病患者带来巨大负担。然而,临床实践指南高度重视的是得到某些临床结果(如呼吸急促减少或存活率增加),传... 详细信息

Claudia Dobler和同事们认为,指南中明确增加有关治疗负担的内容能够改善治疗决策。医疗方案的实施需要花费大量时间和精力,给慢性病患者带来巨大负担。然而,临床实践指南高度重视的是得到某些临床结果(如呼吸急促减少或存活率增加),传统指南的建议也是从同样角度提出的。最近的指南会考虑患者的价值观以及指南建议行为的可接受性和可行性,但对治疗负担没有明确规定。这使患者很难根据自己的价值观和能力对治疗作出明智的决定。

关键词：临床实践指南慢性阻塞性肺疾病肺康复急性加重治疗建议慢性病患者工作量