The vision of people with arare inherited condition that causes them to lose much of their sight early in childhood was 100 times better after they received gene therapy to address the genetic mutation causing it.Some patients even experienced a10,000-fold improvement in their vision after receiving the highest dose of the therapy,according to researchers from the Perelman School of Medicine who co-led the clinical trial published in The Lancet.“That 10,000-fold improvement is the same as apatient being able to see their surroundings on amoonlit night outdoors as opposed to requiring bright indoor lighting before treatment,”says the study’s lead author,Artur Cideciyan,a research professor of ophthalmology and co-director of the Center for Hereditary Retinal Degenerations.“One patient reported for the first time being able to navigate at midnight outdoors only with the light of abonfire.”A total of 15 people participated in the Phase 1/2 trial,including three pediatric patients.Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene,which is essential to producing proteins critical for vision.This specific condition,which affects less than 100,000 people worldwide and is abbreviated as LCA1,causes asignificant amount of vision loss as early as infancy.Improvements were noticed quickly,often within the first month,after the therapy was applied and lasted for at least 12 months.Observations of participating patients are also ongoing.Three of six high-dosage patients who were tested to navigate amobility course in varying levels of light achieved the maximum-possible score.Other tests used eye charts or measured the dimmest flashes of light patients perceived in adark environment.Of the nine patients who received the maximum dosage,two had the 10,000-fold improvement in vision.“Even though we previously predicted alarge vision improvement potential in LCA1,we did not know how receptive patients’photoreceptors would be to treatment after decades of blindness,”says Cideciyan.“It is very satisfying to see asuccessful multi-center trial that shows gene therapy can be dramatically efficacious.” 查看详细>>

南京大学物理学院李绍春教授课题组在二维拓扑绝缘体研究中取得重大进展。该课题组使用精控分子束外延技术首次生长出大带隙的二维拓扑绝缘体ZrTe5单层，通过扫描隧道显微学测量发现单层ZrTe5具有不同于体结构的两种全新结构相，并存在高达~250 mV的拓扑非平庸带隙和边界金属态，为未来实现室温量子自旋霍尔效应提供了可能的材料平台。二维拓扑绝缘体存在绝缘体态和拓扑保护的导电边界态，是实现量子自旋霍尔效应的材料平台。为了在高温甚至室温下观测到量子自旋霍尔效应，需要大带隙的二维拓扑绝缘体来有效抑制体电导和热涨落。然而，目前大多数的候选材料都表现出窄带隙甚至负带隙，仅在很低的温度下才能观测到量子自旋霍尔效应。曾有理论预测表明ZrTe5单层可能是具有大带隙的拓扑绝缘体材料。然而，由于ZrTe5是相图中最不稳定的结构，且对空气非常敏感，在实验上很难获得单层ZrTe5，而通过外延方法直接生长单层ZrTe5更是面临极大的挑战。需要强调的是，单晶ZrTe5在近十年来被学术界广泛关注，很多新奇的拓扑量子现象陆续被发现。然而，由于在实验上一直未获得成功，对单层ZrTe5的拓扑性质仍然不清楚。李绍春教授课题组长期致力于二维拓扑绝缘体的实验探索。早在2016年，该课题组首次利用扫描隧道显微谱学技术证实了单晶ZrTe5为三维弱拓扑绝缘体[X.-B.Li et al.,Phys.Rev.Lett.116,176803(2016)]。随后，又利用分子束外延技术成功获得二维拓扑绝缘体单层1T’-WTe2并发现了电子相互作用的库仑能隙[Z.-Y.Jia et al.,Phys.Rev.B 96,(2017);Y.-H.Song et al.,Nat.Commun.9,4071(2018)]。然而，扫描隧道显微谱学测量显示单层1T’-WTe2具有半金属型能带（负能隙），不利于量子自旋霍尔效应的观测。最近，该课题组通过发展范德华外延方法，进一步提高了外延过程中的温度和束流精度，首次成功生长出了二维拓扑绝缘体单层ZrTe5。高分辨形貌图显示，单层ZrTe5具有两种不同于体相的新结构相（如图1），而这两种结构分别对应于面内ZrTe3三棱柱的不同排列方式（如图2）。扫描隧道显微谱显示，两种单层ZrTe5结构均具有体能隙，且高达250 meV左右。如此大的带隙满足了在室温下观测量子自选霍尔效应的要求。隧道谱学测量还显示在两种结构的边界上都具有鲁棒的一维导电边界态（如图3），通过第一性原理计算，进一步证实了如此大的能隙来源于强自旋-轨道耦合，并且这两种结构相的边界态都是拓扑非平庸的（如图4）。该发现为探索室温量子自旋霍尔效应提供了一个非常理想的材料平台。 查看详细>>

A team of physicists from The University of Hong Kong(HKU),Texas Tech University(TTH),and the University of Michigan(UMich),has made an important discovery in the study of van der Waals(vdW)magnetic materials,a special class of materials with unique electronic and magnetic properties that make them attractive for use in various applications.Their research is the first to experimentally observe atransition in Nickel Phosphorus Trisulfide(NiPS3),a type of van der Waals material that has been studied for its potential applications in electronic devices and energy storage,from a3-dimensional(3D)long-range order state to a2-dimensional(2D)flat pattern vestigial order state.They have shown how the material changes its magnetic properties as it becomes thinner,revealing new insights into how this material can be used.This research is significant because it helps us understand how to control the magnetic properties of materials at very small scales,which could lead to advancements in technology,such as more efficient electronics,high-density data storage,and innovative computing devices that consume less energy.Their findings have just been published in Nature Physics and featured in‘News and Views’,highlighting its significance and implications for the field.What could we do with layered structures with just the right layers?’Richard Feynman,the Nobel Prize winner in Physics in 1965,posted this intriguing question in his famous 1959 lecture,‘Plenty of Room at the Bottom’.This statement did not receive much attention at the time,but it was revisited in the 1990s,as it was fundamentally related to the foundations of nanotechnology.In recent years,the emergence of van der Waals materials,such as NiPS3,has provided exciting opportunities for exploration of Feynman’s question.These materials consist of layers that can be easily stacked or separated,enabling researchers to investigate their properties at varying thicknesses.To address Feynman’s question,the research team turned their attention to NiPS3,which exhibits fascinating magnetic behaviour when reduced to just afew layers or even asingle layer.This unique property makes NiPS3 an ideal candidate for studying how its magnetic characteristics evolve as its thickness changes.In condensed matter physics,one of the key ways to study materials is to understand how they transition between different phases or states as their properties,like temperature or thickness change.These transitions often involve changes in the material’s symmetry,a concept known as symmetry breaking.In the case of NiPS3,the researchers observed an intermediate symmetry breaking which leads to avestigial order.Just as the term‘vestigial’refers to the retention of certain traits during the process of evolution,the vestigial order here can also be viewed as the retention during the process of symmetry breaking.This happens when the primary magnetic long-range order state melts or breaks down into asimpler form,in the NiPS3 case,a 2D vestigial order state(known as Z3 Potts-nematicity),as the material is thinned.Unlike conventional symmetry breaking,which involves the breaking of all symmetries,vestigial order only involves the breaking of some symmetries.While there are numerous examples from atheoretical standpoint,experimental realisations of vestigial order have remained challenging.However,the investigation of this 2D magnetic material has shed the first light on this issue,demonstrating that such aphenomenon can be observed through dimension crossover. 查看详细>>

近日，由复旦大学工程与应用技术研究院（下文简称“工研院”）生物医学工程技术研究所常务副所长、附属华山医院放射科学术带头人耿道颖教授团队牵头研发并成功转化的科研成果“颅内动脉瘤磁共振造影图像辅助检测软件（AIneurysm）”正式获批中国国家药品监督管理局(NMPA)三类医疗器械注册证。这项重要成果的落地与转化，标志着复旦大学“医工结合”全链条创新探索取得原创性重大突破。AI加持之下，该产品将辅助医生快速、精准救治患者，提高颅内动脉瘤的诊疗效率。值得一提的是，此次获批的注册证为国内首张由高校主导、临床医生牵头研发的颅内动脉瘤磁共振AI三类医疗器械注册证，将有望为高校牵头进行同类产品的产学研研发和转化提供经验。守护人民生命健康，高水平的影像学诊断扮演着至关重要的角色，它不仅能提高疾病诊断的准确性和效率，助力早期发现和治疗，还能指导治疗方案的制定和评估疾病预后。在AI方兴未艾的时代，是否能研发一系列智能系统，学习和推广高水平医生的经验和技术，辅助提升各类疾病的诊断效率，更好地为人群服务？耿道颖团队的答案是“能”。近年来，耿道颖牵头组建了由工研院生物工程技术研究所、中科院苏州医工所及附属华山医院为骨干的智能影像医工结合团队，让临床医生、算法团队和工程师紧密结合，进行多种重大疾病智能诊断辅助系统的研发和成果转化。“颅内动脉瘤磁共振造影图像辅助检测软件”便是这支智能影像医工结合团队进行平行研发并率先落地的智能诊断辅助系统。据团队介绍，所谓颅内动脉瘤，是一种动脉壁异常膨出所形成的突起，普遍存在于全球成年人群中，动脉瘤一旦破裂即会发生急性蛛网膜下腔出血甚至破入脑实质和脑室系统，具有发病率高、致残率高、死亡率高的“三高”特点，因此又有“颅内炸弹”之称，在临床诊疗上面临着早检查、早诊断、早治疗的“三早”需求。与此同时，我国成年人群颅内动脉瘤的患病率高达7%，是欧美成年人群发病率的2-4倍，高血压糖尿病等高危人群患病率达15%左右，对颅内动脉瘤的及时诊断和治疗干预，对于急性蛛网膜下出血等脑重大疾病的预防有重要意义。据耿道颖介绍，因受限于影像设备及影像医生的水平，临床中存在着大量重大疾病误诊、漏诊等情况，针对颅内动脉瘤研发一款智能诊断辅助系统已刻不容缓。标注图像、建立AI模型、将AI模型工程化、临床测试……研发流程每个环节必须严丝合缝，在这个痛并快乐着的过程中，团队成员经历了一次次磨合，产品也经历了一次次发补材料及模型优化，而技术研发仅仅是个开始，产品在实验室出炉后，还要经过成果转化、上海检测所检测、注册前全国多中心临床试验、提交国家医疗器械审评中心审评、上海医疗器械审批中心现场体系核查等重重考验。从2019年开始立项，到2023年7月完成临床实验，再到2024年取得三类注册证，经过6年努力，团队终于走通从0到1的产学研用创新全链条，并掌握了自主研发的人工智能核心算法。作为一款人工智能产品，颅内动脉瘤磁共振造影图像辅助检测软件能辅助医生进行精准影像决策，对颅脑磁共振造影图像的显示、处理、测量和分析，对3mm及以上颅内动脉瘤辅助检测可提示疑似颅内动脉瘤患者，助力医生进行有效检测，同时量化分析动脉瘤区域，给出相关建议。“我们的产品不仅让医生的诊断效率大大提高，而且敏感性和特异性都高于医生组。”耿道颖说。据介绍，注册前全国多中心、回顾性临床试验结果表明，该软件提升动脉瘤检出率10%诊断效能由82%提高到94%，每例阅片时间缩短60%，且上手简单，3分钟即可完成培训。“希望随着产品的推广和临床应用，能提高不同地区影像医生的动脉瘤的识别水平，减轻国家、社会和家庭医疗负担，缩小不同区域和不同医院医师的阅片水平差异，让更多患者获益。”面对未来，耿道颖如是期待。 查看详细>>

A new tool for monitoring immune health patterns over time has revealed how apair of checkpoint inhibitor therapies works together to recruit new cancer-fighting Tcells with every infusion.Findings from the use of the new tool,developed by researchers at the Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center(ACC),are published in Cancer Cell.The study challenges fundamental assumptions about how acommon immunotherapy drug combination activates different types of Tcells to defeat cancer and could help researchers more precisely measure immune response in future clinical trials.Immune checkpoint inhibitors work by unleashing Tcells to find and kill cancer cells.It was thought that this type of combination immunotherapy works by equipping an army of Tcells to recognize and fight cancer throughout the course of treatment.In asense,the idea was that if this group of Tcells stayed strong for long enough,they would conquer cancer,but if they became too depleted,they would lose the battle.The study,which analyzed data from 36 patients treated with immunotherapy for advanced melanoma,found that the combination therapy produces waves of new Tcells—known as aclonal response—with each dose,rather than continually strengthening the same pool of Tcells.“We found that after every infusion,you have anew immune response,with anew group of Tcells coming in to fight the cancer,”says senior author Alexander Huang,an assistant professor of hematology-oncology and aresearch investigator with the Tara Miller Melanoma Center at the ACC.“Think about these Tcells like an army:For many cancer patients,even when they have tumors growing,experienced Tcell fighters are trying to slow down the advance of the enemy cancer cells.We call them‘exhausted Tcells’because they’ve been fighting so long,but they’re elite because they’re able to survive in ahostile environment and know how to recognize and fight the cancer cells.”To make these discoveries,the team developed anew algorithm called Cyclone to track immune response and patterns over time by following the unique receptors from individual Tcells.Looking at blood samples from the same patients,taken during different points throughout their treatment,the researchers were able to see which Tcells moved,remained,or disappeared over each patients’nine-week course of treatment.This approach also allows researchers to evaluate the magnitude of response,including how many and what type of immune cells are being activated over time as patients go through treatment.Comparatively,other current single-cell methods of studying immune response provide more of anarrow“snapshot”in time.The research team is planning to apply Cyclone in upcoming clinical trials for new cancer immunotherapy approaches,including neoadjuvant studies where Tcells can be tracked in both blood and tumor samples,and new immunotherapy combinations,such as drugs targeting PD-1 and LAG-3,a new type of checkpoint inhibitor therapy. 查看详细>>

Cognitive decline and dementia can stem from illnesses like Alzheimer’s disease and conditions like hypertension that damage blood vessels in the brain.People with both may have an even greater risk of developing cognitive impairment,a new Yale study finds.This additive effect,say researchers,will likely have an outsized impact on medically underserved populations,which makes it imperative that racially diverse trials be conducted to evaluate how to treat both contributions to dementia effectively.For the study—published Sept.4 in Alzheimer’s and Dementia:The Journal of the Alzheimer’s Association—the researchers used data from the Systolic Blood Pressure Intervention Trial,which took place between 2010 and 2015 and included adults aged 50 or older with hypertension.All told,the new study included data from 467 racially diverse trial participants aged 60 or older.wo biomarkers served as proxies for the vascular-and Alzheimer’s-related contributions to cognitive impairment.The first—white matter hyperintensity—which is abiomarker for brain scarring caused by damage to small blood vessels in the brain often due to high blood pressure,was measured via MRI when participants joined the trial.“White matter hyperintensity means that when we look at the brain via MRI,the white matter,or the nerve connections between different regions of the brain,shows up as extra white,”said Dr.Adam de Havenon,an associate professor of neurology at Yale School of Medicine and lead author of the study.“We see it as scarring of the neurons when we look at the brain during autopsies of individuals who had vascular dementia.”Alzheimer’s disease is marked by the formation of amyloid plaques,aggregates of aprotein called amyloid-beta that collect in the brain.The plaques can be seen during post-mortem analyses but can’t be directly measured non-invasively.An alternative is to measure the ratio of two peptides—Abeta42 and Abeta40—that circulate in the blood and correlate with amyloid-beta levels in the brain.The researchers evaluated which participants had scores representing the highest and lowest risks of brain scarring and amyloid plaque buildup during the first evaluation as well as who developed cognitive impairment over the following four years.“We found that the risk of developing cognitive impairment was considerably higher for the participants who had more white matter hyperintensity and more amyloid-beta than for those who just had one or the other,”said de Havenon.Specifically,the researchers found that those with the lowest risk scores for white matter hyperintensity and amyloid-beta also had the lowest rates of cognitive impairment(5.3%).Those with high scores for one risk factor but low scores for the other had higher rates of cognitive impairment(7.8%for white matter hyperintensity and 11.8%for amyloid-beta).And participants with high scores for both risk factors had the highest rates of cognitive impairment at 22.6%. 查看详细>>

A cancer drug that unlocks the anti-inflammatory power of the immune system could help to reduce the risk of future heart attacks,according to research part-funded by the British Heart Foundation.By repurposing an existing drug,researchers hope it could soon become part of routine treatment for patients after aheart attack.The findings will be presented at the European Society of Cardiology Congress in London by Dr Rouchelle Sriranjan,NIHR Clinical Lecturer in Cardiology at the University of Cambridge.High levels of inflammation in blood vessels are linked to an increased risk of heart disease and heart attacks.After aheart attack,the body’s immune response can aggravate existing inflammation,causing more harm and increasing risk even further.However,NICE guidelines don’t currently recommend the use of any anti-inflammatory drugs to reduce future risk.Now,a team of researchers,led by Dr Joseph Cheriyan from Cambridge University Hospitals NHS Foundation Trust,have found that low doses of an anti-inflammatory drug called aldesleukin,injected under the skin of patients after aheart attack,significantly reduces inflammation in arteries.The researchers are currently following up patients to investigate the longer-term impact of this fall in inflammation.To date,in the two and ahalf years after their treatment,there have been no major adverse cardiac events in the group that received aldesleukin,compared to seven in the group that received the placebo.Professor Ziad Mallat,BHF Professor of Cardiovascular Medicine at the University of Cambridge who developed the trial,said:“We associate inflammation with healing–an inbuilt response that protects us from infection and injury.But it’s now clear that inflammation is aculprit in many cardiovascular conditions.“Early signs from our ongoing trial suggest that people treated with aldesleukin may have better long-term outcomes,including fewer heart attacks.If these findings are repeated in alarger trial,we’re hopeful that aldesleukin could become part of routine care after aheart attack within five to 10 years.”Aldesleukin is already used to treat kidney cancer,as high doses stimulate the immune system to attack cancer cells.The Cambridge team previously found that doses one thousand times lower than those used in cancer treatment increased the number of regulatory Tcells–a type of anti-inflammatory white blood cell–in patients’blood compared to aplacebo.In the current trial at Addenbrooke‘s and Royal Papworth hospitals in Cambridge,60 patients admitted to hospital with aheart attack or unstable angina received either low dose aldesleukin or placebo.Patients received an injection once aday for the first five days,then once per week over the next seven weeks.Neither the participants nor their doctors knew whether they had received the drug or placebo.At the end of treatment,Positron Emission Tomography(PET)scans showed that inflammation in the artery involved in patients’heart attack or angina was significantly lower in the group treated with aldesleukin,compared to those who received the placebo.The anti-inflammatory effect of aldesleukin appeared even more striking in the most inflamed arteries,leading to alarger reduction in inflammation levels in these vessels and abigger difference between the two groups by the end of the study.Dr Sonya Babu-Narayan,Associate Medical Director at the British Heart Foundation and consultant cardiologist said:“Thanks to research,we have an array of effective treatments to help people avoid heart attacks and strokes and save lives.But,even after successful heart attack treatment,unwanted inflammation in the coronary arteries can remain,which can lead to life-threatening complications.“A treatment to reduce inflammation after aheart attack could be agame-changer.It would help doctors to interrupt the dangerous feedback loop that exacerbates inflammation and drives up risk.This research is an important step towards that treatment becoming areality.”The study was predominantly funded by the Medical Research Council,with significant support from the BHF and National Institute for Health and Care Research Cambridge Biomedical Research Centre(NIHR-BRC).Originally published by the British Heart Foundation. 查看详细>>

Bacterial cells can“remember”brief,temporary changes to their bodies and immediate surroundings,a new Northwestern University and University of Texas-Southwestern study has found.And,although these changes are not encoded in the cell’s genetics,the cell still passes memories of them to its offspring—for multiple generations.Not only does this discovery challenge long-held assumptions of how the simplest organisms transmit and inherit physical traits,it also could be leveraged for new medical applications.For example,researchers could circumvent antibiotic resistance by subtly tweaking apathogenic bacterium to render its offspring more sensitive to treatment for generations.The study was published today(Aug.28)in the journal Science Advances.“A central assumption in bacterial biology is that heritable physical characteristics are determined primarily by DNA,”said Northwestern’s Adilson Motter,the study’s senior author.“But,from the perspective of complex systems,we know that information also can be stored at the level of the network of regulatory relationships among genes.We wanted to explore whether there are characteristics transmitted from parents to offspring that are not encoded in DNA,but rather in the regulatory network itself.We found that temporary changes to gene regulation imprint lasting changes within the network that are passed on to the offspring.In other words,the echoes of changes affecting their parents persist in the regulatory network while the DNA remains unchanged.”Motter is the Charles E.and Emma H.Morrison Professor of Physics at Northwestern’s Weinberg College of Arts and Sciences and director of the Center for Network Dynamics.The study’s co-first authors are postdoctoral fellow Thomas Wytock and graduate student Yi Zhao,who are both members of Motter’s laboratory.The study also involves acollaboration with Kimberly Reynolds,a systems biologist at the University of Texas Southwestern Medical Center. 查看详细>>

轴手性羰基化合物不仅广泛存在于天然产物、生物活性分子、药物和材料中，也是一类具有优势结构的手性配体或有机催化剂，在不对称催化中具有广阔的应用前景。但是这类结构的合成往往需要繁琐的步骤，一定程度上限制了它们的进一步发展。尽管近年来不对称催化合成轴手性化合物的方法得到了空前发展，但通过不对称羰基化反应直接合成轴手性羰基化合物仍有待发展。催化羰基化反应是合成羰基化合物最高效的方法，自19世纪30年代首次实现以来，羰基化已经成为均相催化领域工业应用规模最大的反应，通过该技术每年生产超过千万吨大宗和精细化学品。相比之下，不对称羰基化反应的发展则相对滞后，主要存在以下挑战：（1）高压CO与手性配体竞争配位，削弱了配体的手性控制能力；（2）酰基金属物种的转化能垒高，且往往是反应的决速步，需要较高的温度；（3）产生的手性羰基化合物在反应体系中易消旋化。尽管如此，在过去的几十年里仍有许多不对称羰基化反应被开发出来，但底物范围大多局限于降冰片烯、苯乙烯、环丙烯等活化的烯烃，且反应主要构筑具有中心手性的羰基化合物，利用不对称羰基化反应合成轴手性羰基化合物的方法仍有待开发。近日，上海交通大学变革性分子前沿科学中心刘家旺课题组，利用手性钯催化剂，通过底物动态动力学不对称转化的策略，发展了外消旋联杂芳基三氟甲磺酸酯与CO以及胺类亲核试剂的不对称胺羰化反应，实现了轴手性酰胺的高效、高对映选择性合成。详细的机理研究表明：酰胺产物的杂环氮原子与NH结构之间的分子内氢键作用会加速产物的轴旋转，从而导致产物的对映选择性显著下降，而碳酸铯的使用破坏了这种分子内氢键，是反应取得高对映选择性的关键。此外，合成的部分酰胺产物可以直接作为手性三齿配体应用到铜催化的不对称自由基反应中，展示了其作为手性配体的应用潜力。 查看详细>>

024年8月7日，生研院汪方炜实验室在《美国国家科学院院刊》（PNAS）发表了题为Molecular mechanism and functional significance of Wapl interaction with the Cohesin complex的研究论文，揭示了黏连蛋白功能的重要调控机制。黏连蛋白（Cohesin）是一个在进化上高度保守的环状结构复合体，参与调控一系列基于DNA和染色质的重要生物学过程（图1）。黏连蛋白可以拓扑联结两个DNA分子，通过介导姐妹染色单体粘连（sister chromatid cohesion）调控染色体分离、DNA复制和同源重组DNA修复，进而维护基因组的稳定性。黏连蛋白还可以拓扑结合单个DNA分子，通过形成染色质环（chromatin loop）调控基因组三维构象和基因转录。黏连蛋白的突变常见于癌细胞中，与癌症等疾病的发生发展密切相关。024年8月7日，生研院汪方炜实验室在《美国国家科学院院刊》（PNAS）发表了题为Molecular mechanism and functional significance of Wapl interaction with the Cohesin complex的研究论文，揭示了黏连蛋白功能的重要调控机制。黏连蛋白（Cohesin）是一个在进化上高度保守的环状结构复合体，参与调控一系列基于DNA和染色质的重要生物学过程（图1）。黏连蛋白可以拓扑联结两个DNA分子，通过介导姐妹染色单体粘连（sister chromatid cohesion）调控染色体分离、DNA复制和同源重组DNA修复，进而维护基因组的稳定性。黏连蛋白还可以拓扑结合单个DNA分子，通过形成染色质环（chromatin loop）调控基因组三维构象和基因转录。黏连蛋白的突变常见于癌细胞中，与癌症等疾病的发生发展密切相关。本项研究利用一系列体内外蛋白互作实验，以及基于AlphaFold2的人工智能蛋白质结构分析，发现Wapl分别通过FGF基序和YNARHWN基序结合黏连蛋白核心亚基Scc1与SA2互作界面的不同区域（图3）。破坏FGF基序或YNARHWN基序与Scc1-SA2界面的结合，仅部分减弱Wapl与Scc1-SA2界面的结合，并部分削弱Wapl从染色体上移除黏连蛋白的能力。当FGF基序和YNARHWN基序被同时突变后，Wapl几乎不能结合黏连蛋白核心亚基，导致黏连蛋白异常紧密地结合DNA，进而阻碍有丝分裂期姐妹染色单体粘连的及时解除，造成染色体分离错误。此外，FGF基序和YNARHWN基序的叠加突变还会导致细胞分裂间期染色质异常凝缩，提示了基因组三维构象的改变。以上结果说明，Wapl通过两个独立的结构模块同时结合黏连蛋白核心亚基Scc1与SA2的互作界面，赋予Wapl从染色质上移除黏连蛋白的最大活性，从而确保了有丝分裂期染色体精确分离，以及分裂间期细胞中基因组的正常三维结构。有丝分裂期染色体着丝粒区的黏连蛋白不能被Wapl移除。那么，Wapl的活性在着丝粒区又是如何被拮抗的呢？先前的研究表明，Sgo1在保护着丝粒区黏连蛋白中发挥重要作用。本研究发现，类似于Wapl的FGF基序与Scc1-SA2的相互作用，Sgo1利用其YNF基序结合Scc1-SA2界面。当YNF基序被突变为不能结合Scc1-SA2界面的ANA后，Sgo1保护黏连蛋白的活性大幅下降。有意思的是，Sgo1的YNF基序只能与Wapl的FGF基序竞争结合Scc1-SA2界面，而不能与Wapl的YNARHWN基序竞争。以上结果提示，着丝粒区可能存在一个含有YNARHWN基序的蛋白，该蛋白与Sgo1以及内层动粒蛋白CENP-U（包含一个可以结合Scc1-SA2界面的FDF基序）协同作用，充分抑制了Wapl与着丝粒区黏连蛋白核心亚基的结合。综上所述，这项研究揭示了Wapl结合黏连蛋白复合体核心亚基的分子基础和功能，为受黏连蛋白调控的染色体行为和生物学功能研究提供了新的见解，并为黏连蛋白突变促进癌变的转化研究奠定了重要基础。 查看详细>>