Down Syndrome

A genomic study of human and selected nonhuman primate centromeres has revealed their unimaginable diversity and speed of evolutionary change. Although centromeres are vital to proper cell replication by assuring faithful transmision of genetic materials when cells divide, the complexity of their genomic organization had been almost impossible to study. The lack of centromere sequences hindered exploration of how these regions help maintain genetic integrity. Now, advanced technologies have shown scientists how greatly centromeres differ in size and structure. A genomic study of human and selected nonhuman primate centromeres has revealed their unimaginable diversity and speed of evolutionary change. In cell genetics, a centromere is the spot where two sister chromatids attach. A chromatid is one-half of a duplicated chromosome. United pairs of chromosomes have identifiable shapes because centromeres are not in a uniform position. As a cell prepares to divide, the machinery to separate and segregate chromosomes goes into action at each centromere location. Unless the genetic material is distributed correctly between the two resulting cells, problems can arise. These include cancer, congenital disorders such as Down syndrome, and the inability of a fertilized cell to grow into a baby. Although centromeres are vital to proper cell replication, the complexity of their genomic organization had been almost impossible to study. The lack of centromere sequences hindered exploration of how these regions help maintain genetic integrity. Today, advances in long-read genome sequencing technologies, refined computerized genome assembly algorithms, and improved genome databases are enabling scientists to realize how greatly centromeres differ in size and structure. This opens new avenues toward figuring out what these differences might mean. A first look at the factors behind the vast variations in centromeres is reported today, April 3, in Nature. The findings suggest that centromeres are likely highly individualized among people. A set of centromeres might even be a personal signature, just as we each have characteristic voice patterns, iris colorations and fingerprints that distinguish us from one another. It's not yet known if certain centromere variations might make people susceptible to particular diseases. Only the human X chromosome appears to be mostly immutable, with very similar sequences and structure across a diversity of humans. The lead author of the Nature report is Glennis Logsdon, a recent postdoctoral scholar in Evan Eichler's genomic science lab at the University of Washington School of Medicine in Seattle. Logsdon is now a faculty member at the Perelman School of Medicine at the University of Pennsylvania. Eichler, who is also a Howard Hughes Medical Institute Investigator and a member of the Brotman Baty Institute for Precision Medicine, is the senior and corresponding author. "This recent research is a direct application of both the Human Pangenome Reference Consortium and the Telomere-to-Telomere (T2T) sequencing efforts to provide new biological insights into complex regions of the human genome critical for chromosome segregation," noted Eichler. He is known for his work on genome evolution and its potential to create new functions and also for studies of genetic instability associated with disease. To capture information on how human centromeres might have evolved, the team compared human genetic sequences of two completely sequenced human centromeres with those of some nonhuman primates. These were the chimpanzee and the orangutan, which are great apes and closely related species to humans, and the macaque, an Old World monkey and a more distant relative. The scientists discovered that centromeres have been evolving much faster than other unique portions of the human genome. They are among the most mutation-prone regions of the human genome. The researchers also found that the unique sequences and structure of centromeres were the culmination of different evolutionary forces moving at different rates. "The rapid mutation of the centromeric regions of the genome, along with their various mutation rates, has led to their diverse structure and organization," Logsdon noted. It was surprising to learn, the scientists said, that such vital areas of the genome were subject to swift changes, because, in general, critical functions tend to be genetically conserved. The scientists plan to expand these initial efforts by developing more genetic maps of centromeres in diverse human genomes and across various organs and tissues, and to perform multigeneration family studies of centromere sequences. The complete sequence of centromeres from other nonhuman primates will provide a better model of the evolutionary forces shaping these regions. Peering into the future, Logsdon and her team hope someday to apply their findings on centromeres to the design and engineering of customized human artificial chromosomes to transform medical science. Several years ago, Logsdon and her mentors worked on efforts to develop human artificial chromosomes that bypass centromeric DNA, which had then posed a constraint to mammalian synthetic genome research. Logsdon and others recently published another study last week in Science, which showed that enlarging the artificial chromosome DNA vector allowed for efficient formation of human artificial chromosomes in cells. The centromere studies reported today were supported by funding from the National Institutes of Health National Human Genome Research Institute (R01 HG010169); National Institute of General Medical Sciences (K99 GM147352 ); National Cancer Institute (R01 CA266339); Intramural Research Program of the National Human Genome Research Institute; Shanghai Jiao Tong University 2030 Program (WH510363001-7); Center for Integration in Science of the Ministry of Aliyah, Israel; and the Howard Hughes Medical Institute. This work utilized the computational resources of the National Institutes of Health High Performance Computing Biowulf Linux cluster.

深度聚焦类器官与3D培养论坛，OTC2024论坛合作详询：王晨 180 1628 8769作为干细胞领域的重大突破之一，类器官技术备受医学科研领域的关注，技术问世至今短短13年，技术迅速发展，相关论文呈爆炸式增长，甚至被预测为下一个诺奖。近日日本传出重磅消息，全球首例类器官移植成功实施，这会是一个崭新的再生医疗时代的开启吗？今天带大家走进干细胞与类器官的世界。众所周知，干细胞具有多向分化及自我更新潜能，在特定的环境下，可以被定向诱导为人体多种细胞，包括心肌细胞、成骨细胞、神经细胞等等，是培育类器官(Organoids)的理想来源。类器官是指利用干细胞进行体外三维培养而形成的细胞簇，包含其代表器官的一些关键特性。尽管类器官并不是真正意义上的人体器官，但能在结构和功能上模拟真实器官，能够最大程度地模拟体内组织结构及功能并能够长期稳定传代培养。发 展 历 程上世纪八十年代，“organoid（类器官）”一词就被提出。2009年，荷兰Hubrecht研究所Hans Clevers团队成功将Lgr5+肠道干细胞在体外培养成小肠类器官（small-intestinal organoids），具有小肠的隐窝和绒毛结构。2013年，来自日本、德国、美国的科研人员分别构建出肝芽、迷你肾和微型大脑，使该领域获得国际的广泛关注。同年，类器官被Science 评为年度十大技术。2018年初，类器官被Nature Method评为2017年度最佳技术，并给出评价：利用干细胞直接诱导生成三维组织模型，为人类生物学研究提供了强大的方法。2019年，全球三大顶级神刊CNS（CELL《细胞》、Nature《自然》、Science《科学》）不约而同地推出了关于类器官技术的特刊。目前，干细胞已成功构建多种具有部分关键生理结构和功能的脏器类器官，其中包括视网膜、小肠、胃、大脑、肝脏、胰腺、肾脏、心脏等，不仅有正常器官组织类器官，还有相应肿瘤组织类器官。不同种类类器官形貌图. (a）小肠类器官形貌图.（b） 结肠类器官形貌图.（c）食管类器官形貌图.（d）胃类器官形貌图.（e） 肝脏类器官形貌图.（f）胰腺类器官形貌图.（g）肺类器官形貌图.（h）乳腺类器官形貌图.（i）肾类器官形貌图.（j）脑类器官形貌图应 用 前 景干细胞衍生类器官技术在基础研究和临床诊疗研究中拥有广阔的应用前景，包括发育生物学、疾病病理学、细胞生物学、精准医学以及药物毒性和疗效测试。1.疾病模型研究干细胞衍生类器官，本质上是患者实际组织的分身，可以在体外模拟重现疾病模型，探索疾病机制。例如，Jiang团队通过培养唐氏综合征患者的脑类器官，发现21号染色体上OLIG的过表达会导致中间神经元的过度产生，表明唐氏综合征导致的神经发育异常有可能是过量的中间神经元导致的。2. 新药开发与筛选一般来说，新药的创制需要经过药物靶点选择、先导化合物鉴定、候选药物选择、动物安全性和有效性评价、人体临床试验等一系列过程。然而，动物模型与人体差距较大，而类器官更接近人体，可以起到重要的补充作用。目前为止，类器官已被用于治疗结肠癌和囊性纤维化等疾病的药物筛选。3. 个性化精准治疗将类器官应用于临床，指导临床用药和精准治疗是近期类器官技术的主要发展方向。以肿瘤为例，病人直接试药耗时长、风险大且过程痛苦，特别是缺乏有效药物只能通过化疗的肿瘤患者，难以及时找到有效解决方案。而类器官可代替病人试药，实现精准治疗。4. 再生医学干细胞衍生类器官，与胚胎干细胞相比能够避开伦理问题，同时因其取自患者自身，不易产生排异反应，是理想的移植器官来源。研究表明将体外扩增的类器官移植到动物中以替换受损或患病的组织具有可行性，为自体或异体细胞治疗提供了可能性。应 用 案 例2022年7月7日，日本东京医科齿科大学研究团队宣布实施了干细胞衍生类器官移植人体的临床研究，他们对一例难治性溃疡性大肠炎患者移植了使用患者自身健康的肠道黏膜干细胞培养的类器官。这种再生医疗的尝试属于世界首创，同时这项干细胞衍生类器官移植试验的安全性将在未来一年内得到验证。研究团队用内窥镜采集患者正常的大肠黏膜（包含干细胞等众多细胞），然后培养约1个月，构建了直径0.1～0.2毫米的“类器官”。图源：共同社/东京医科齿科大学团队用大肠黏膜培养制作的细胞块的显微镜照片随后研究者将“类器官”移植到患者大肠病患处，再覆盖上可在人体内降解的薄膜加以固定，力图用患者自身的组织来修复受损黏膜。整个过程无需进行开腹手术。据悉，“类器官”移植是在7月5日实施的，目前患者状况良好。团队成员、东京医科齿科大学副校长渡边守还表示：“预计投入1次就能修复患处。”研究团队计划在今后一年半中，将为7例现有药物难以起效的患者实施移植手术，并与以往药物一起实施治疗，以进一步确认此项新兴技术的有效性及安全性。如若进展顺利，那么不仅意味着溃疡性大肠炎可能被彻底治愈，还有望推动主要在消化道出现慢性炎症的难治性疾病——“克罗恩病”的治疗总结：作为一项正式诞生至今仅13年的前沿技术，干细胞衍生类器官技术的广泛应用仍处于起步阶段，但已经展出了治疗顽疾的潜力。相信随着干细胞及类器官研究的不断深入和技术的不断成熟，干细胞衍生的类器官将在转化医学和临床个体化治疗上扮演越来越重要的角色。名词解释什么是类器官定义类器官属于三维（3D）细胞培养物，包含其代表器官的一些关键特性。类器官的作用是什么作用类器官能够重现原始器官的结构和功能，模拟人体内的微环境和信号传导，提高实验的可靠性和准确性END深度聚焦类器官与3D培养论坛，OTC2024论坛合作详询：王晨 180 1628 8769

早产儿和幼儿因其发育尚未完全，对呼吸道病原体如呼吸道合胞病毒（RSV）特别敏感，容易发生严重的急性下呼吸道感染（ALRI）。鉴于全球范围内缺乏系统地评估早产儿RSV相关ALRI负担的研究，本研究旨在全面评估37周前出生婴儿和幼儿中RSV相关ALRI的疾病负担及相关风险因素，从而为未来的公共健康干预和政策制定提供科学依据。我们开展了一项系统回顾和荟萃分析，汇集了1995年1月1日-2021年12月31日期间，通过MEDLINE、Embase和Global Health数据库发表的研究数据，以及呼吸病毒全球流行病学网络分享的个体参与者数据。通过两阶段随机效应元回归分析，我们评估了社区、住院、住院死亡和总死亡中RSV相关ALRI的发病率，并考虑了年龄组、早产周数（极早期早产，<32周；晚期早产，32至<37周）及2000-2019年每五年间隔的变化。我们还利用个体参与者数据，通过两阶段荟萃分析（多变量逻辑回归和随机效应荟萃分析）评估围产期、社会人口学和家庭因素以及潜在医疗状况对RSV相关ALRI发病率、住院和三个严重结果（住院时间>4天、需要额外氧气和机械通气或需要进入重症监护室）的影响。结果：共纳入了来自文献的47项研究和17项由参与者提供的个体参与者水平数据的研究。在2019年，全球预计发生了165万例（95%不确定范围1.35-1.99百万）RSV相关ALRI事件，533,000例（38.5-73万）RSV相关住院，3050例（1080-8620）RSV相关住院死亡和26760例（11190-46240）RSV归因死亡。极早期早产儿在不同年龄组和结果中的RSV相关ALRI发病率和住院率显著高于所有早产儿。进入第二生命年，尽管发病率相似，极早期早产儿和幼儿的住院率仍然显著更高。虽然晚期早产儿的RSV相关ALRI发病率与一岁以下所有婴儿相似，但在前6个月的住院率更高。早产儿占所有早产儿RSV相关ALRI住院的25%。早产儿的RSV相关ALRI住院病死率与所有婴儿相似。影响RSV相关ALRI发病率的主要是围产期和社会人口学特征，而影响感染严重结果的主要是包括先天性心脏病、气管造口、支气管肺发育不良、慢性肺疾病或唐氏综合症在内的潜在医疗条件（比值比范围从1.40-4.23）。2019年，在不同国家发展水平下，早产儿及2岁以下幼儿中呼吸道合胞病毒相关急性下呼吸道感染的发病率和病例数量总之，本研究的结果明确显示，早产儿，尤其是极早期早产儿，面临着RSV相关疾病负担的显著高风险，占全球RSV住院负担的四分之一。这一群体在进入第二生命年时，仍承担着巨大的RSV住院风险。针对RSV的预防产品能够显著减少早产儿RSV相关ALRI的发生及其感染的严重结果，具有重大的公共卫生影响。此外，本研究识别的与RSV相关ALRI发病率和严重结果相关的风险因素，为针对这一特殊人群的预防和治疗措施提供了重要依据。未来的研究需要进一步探索早产儿RSV相关疾病的物理和临床结果，以便为这一脆弱人群提供更全面的保护策略。原始出处：Global disease burden of and risk factors for acute lower respiratory infections caused by respiratory syncytial virus in preterm infants and young children in 2019: a systematic review and meta-analysis of aggregated and individual participant data. Lancet. 2024 Feb 14:S0140-6736(24)00138-7. doi: 10.1016/S0140-6736(24)00138-7. Epub ahead of print. PMID: 38367641.来源｜梅斯官网撰文 | liangying编辑 | Swagpp● 热议！专科生应聘影像技师，主任无奈拒绝：你很优秀，但我们只招本科！医生：初中生都能胜任，赶快取消这个专业吧，本科生恨它恨得牙痒痒● Science重磅：长出头发和皮肤修复，都离不开这种常见的维生素！● “神药”减肥的机制明确了！连发两篇Nature，二甲双胍抑制食欲，竟与运动殊途同归？版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」 立刻下载梅斯医学APP！