面向世界科技前沿,面向国家重大需求,面向国民经济主战场,率先实现科学技术跨越发展,率先建成国家创新人才高地,率先建成国家高水平科技智库,率先建设国际一流科研机构。

——中国科学院办院方针

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Leipzig clinch 2******

BERLIN, Dec. 7 (Xinhua) -- Leipzig sealed the third place in Group A and booked its berth for the Europa League after goals from Dominik Szoboszlai and Andre Silva helped the "Red Bulls" to edge Manchester City 2-1 in the final round of the Champions League's group stage on Tuesday.。

Both sides staged well-positioned defences from the kick-off hence goal scoring opportunities were at premium in the opening period.。

Leipzig's Konrad Laimer and City's Kevin De Bruyne produced the first half-chances before Jack Grealish pulled wide from promising position to waste a good chance for the visitors in the 22nd minute.。

The hosts showed a clinical chance conversion at the other end of the green, as Laimer's perfectly timed through ball was sent to Szoboszlai, who rounded goalkeeper Zackary Steffen before finishing the job into the empty goal with 24 minutes played.。

Leipzig almost doubled its advantage two minutes later, but Steffen was on guard and defused Emil Forsberg's dangerous effort from 12 meters.。

The hosts continued on the front foot and should have extended the lead, but Steffen was equal to Silva's header in the 39th minute.。

Manchester City sparked to life before the half time as Peter Gulacsi had to tip Phil Foden's hammer to the post before the Leipzig goalkeeper neutralized De Bruyne's free kick in the closing stages of the first half.。

After the restart, City assumed control and dominated possession but for all that the visitors couldn't do damage to Leipzig's bulwark.。

To make things worse for the visitors, passive Leipzig doubled its advantage against the flow of the game as Silva benefitted on a counterattack via Forsberg to beat Steffen with a well-placed low shot in the 71st minute.。

It was a short-lived joy for the hosts though as the "Sky Blues" halved the deficit after Oleksandr Zinchenko's cross fed Riyad Mahrez, whose diving header caught Gulacsi on the wrong foot in the 77th minute.。

City's comeback hopes suffered a heavy setback in the 83rd minute when Kyle Walker was sent off with a straight red card following a rude foul play on Silva.。

The visitors pushed forward despite their numerical disadvantage, but Leipzig's defence stood firm and secured all three points on home soil.。

With the result, Manchester City top Group A with 12 points whereas Leipzig finish on the 3rd spot to continue in the Europa League.。

"I am very thankful that the team eventually showed a reaction after the last poor performances in the league. We expected a reaction, but we are happy about the win. I hope we can take the momentum into Saturday's clash with Monchengladbach," Leipzig chairman Oliver Mintzlaff said. Enditem。

宝鸡建设“博物馆之城”规划出台:新建一批、提升一批、规划一批******

  据来自陕西省文物局的消息,宝鸡市政府近日印发《关于加快博物馆之城建设推进博物馆事业高质量发展的实施意见》,对宝鸡“博物馆之城”建设进行了规划部署,将新建一批、提升一批、规划一批。

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  根据该实施意见,宝鸡市将结合“一带一路”倡议、黄河流域高质量发展等国家重大战略,以及长征、黄河国家文化公园建设等国家重大文化工程,将博物馆建设纳入城市发展规划,通过新建、提升、规划一批博物馆,扩大数量,补全门类,合理布局。

  将结合宝鸡实际,建设秦都雍城博物馆、麟游九成宫博物馆、宝鸡秦腔博物馆、凤县航天精神纪念馆、扶风县博物馆等,筹建宝鸡历史博物馆、国家军事博物馆宝鸡分馆、宝鸡铁路博物馆、宝鸡钛博物馆、宝鸡航天科技馆、宝鸡秦岭自然博物馆、宝鸡种子博物馆等。

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  将对标国内一流博物馆,从提升基础设施、展陈手段、创新能力等方面,实施法门寺博物馆、宝鸡先秦陵园博物馆、宝鸡北首岭博物馆、岐山县博物馆、陇县博物馆等综合改造,提升宝鸡青铜器博物院、宝鸡周原博物院、宝天铁路英烈纪念馆、张载纪念馆、扶眉战役纪念馆、凤县革命纪念馆、太白山杨文洲纪念馆、冯家山水库展览馆以及陈仓区西秦大队、陇县纸沟村、凤翔区大塬村、岐山县小强村等社区博物馆等展陈和服务水平。

  此外,还将依托宝鸡人文历史、非遗民俗、红色遗存、自然生态等优质资源和工业、农业、水利、交通等发展优势,规划一批行业博物馆和专题性博物馆。

  针对文物资源分散,难以形成合力、做大品牌,宝鸡市还将突破行政区划界限,有效整合市县文物资源。另外还将成立全市推进博物馆事业高质量发展领导小组,并根据需要成立重点项目建设专班。

  华商报记者 马虎振


来源:华商网-华商报

编辑:方正

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双语热点:2022年七大前沿科技:量子模拟和靶向基因医疗******

日前《自然》杂志最新列举2022年七项重要的科学技术,它们可能会在未来一年对科学领域产生重大影响。

Seven technologies to watch in 2022

From gene editing to protein-structure determination to quantum computing, here are seven technologies that are likely to have an impact on science in the year ahead.

从基因编辑到蛋白质结构确定再到量子计算,有七项重要的科学技术可能在未来一年产生重大影响。

Fully finished genomes

完整版基因组

Roughly one-tenth of the human genome remained uncharted when genomics researchers Karen Miga at the University of California, Santa Cruz, and Adam Phillippy at the National Human Genome Research Institute in Bethesda, Maryland, launched the Telomere-to-Telomere (T2T) consortium in 2019. Now, that number has dropped to zero. In a preprint published in May last year, the consortium reported the first end-to-end sequence of the human genome, adding nearly 200 million new base pairs to the widely used human consensus genome sequence known as GRCh38, and writing the final chapter of the Human Genome Project.

2019年,美国加州圣克鲁兹分校基因组学研究员凯伦·米加(Karen Miga)和马里兰州贝塞斯达国家人类基因组研究所研究员亚当·菲利普(Adam Phillippy)启动了“端粒至端粒(T2T)”的联合研究项目,当时大约全球十分之一的人类基因组仍未完成测序,然而,现在该数据已降至零。2021年5月,该联合研究项目声称发现第一个端粒至端粒的人类基因组序列,使用人类共识基因组序列图谱GRCh38增加了近2亿新碱基对,并为人类基因组计划写上了最后一章。

First released in 2013, GRCh38 has been a valuable tool — a scaffold on which to map sequencing reads. But it’s riddled with holes. This is largely because the widely used sequencing technology developed by Illumina, in San Diego, California, produces reads that are accurate, but short. They are not long enough to unambiguously map highly repetitive genomic sequences, including the telomeres that cap chromosome ends and the centromeres that coordinate the partitioning of newly replicated DNA during cell division.

最早发布于2013年的GRCh38基因组序列图谱是一个具有价值的研究工具,它是绘制基因序列读数的“脚手架”,但它也存在许多漏洞,其主要问题在于基因序列读数虽然精确,但过于简短,无法明确绘制高度重复的基因组序列,包括:覆盖染色体末端的端粒,细胞分裂期间协调新复制DNA分裂的着丝粒(centromeres)。

Long-read sequencing technologies proved to be the game-changer. Developed by Pacific Biosciences in Menlo Park, California, and Oxford Nanopore Technologies (ONT) in Oxford, UK, these technologies can sequence tens or even hundreds of thousands of bases in a single read, but — at least at the outset — not without errors. By the time the T2T team reconstructed their first individual chromosomes — X and 8 — in 2020, however, Pacific Biosciences’ sequencing had advanced to the extent that T2T scientists could detect tiny variations in long stretches of repeated sequences. These subtle ‘fingerprints’ made long repetitive chromosome segments tractable, and the rest of the genome quickly fell into line. The ONT platform also captures many modifications to DNA that modulate gene expression, and T2T was able to map these ‘epigenetic tags’ genome-wide as well.

长读测序技术被证明是改变游戏规则的技术,该技术是美国太平洋生物科学公司和英国牛津纳米孔技术公司共同开发的,它能在一次性基因序列读取中,对数万至数十亿个碱基对进行排序,但至少在测序初期,并不是没有错误。时值2020年,T2T项目研究人员重建了他们的第2、3条单独染色体——X和8,然而,太平洋生物科学公司的测序工作已取得重大进展,T2T科学家能检测到长时间重复序列的微小变化,这些微妙的“指纹”使长而重复的染色体片段变得更易处理,基因组剩余部分则很快排列起来,牛津纳米孔技术公司还捕获了许多调节基因表达的DNA修饰,同时,T2T基因测序能在基因组范围内绘制“表观遗传标记”。

The genome T2T solved was from a cell line that contains two identical sets of chromosomes. Normal diploid human genomes contain two versions of each chromosome, and researchers are now working on ‘phasing’ strategies that can confidently assign each sequence to the appropriate chromosome copy. “We’re already getting some pretty phenomenal phased assemblies,” says Miga.

已测序的T2T基因组源自包含两组相同染色体的细胞株,正常的二倍体人类基因组的每个染色体有两个版本,目前研究人员正在研究“阶段策略”,能够自信地将每个序列分配给合适的染色体副本。

This diploid assembly work is being conducted in collaboration with T2T’s partner organization, the Human Pangenome Reference Consortium, which aspires to produce a more representative genome map, based on hundreds of donors from around the world. “We’re aiming to capture an average of 97% of human allelic diversity,” says Erich Jarvis, one of the consortium’s lead investigators and a geneticist at the Rockefeller University in New York City. As chair of the Vertebrate Genomes Project, Jarvis also hopes to leverage these complete genome assembly capabilities to generate full sequences for every vertebrate species on Earth. “I think within the next 10 years, we’re going to be doing telomere-to-telomere genomes routinely,” he says.

T2T项目首席研究员之一、纽约洛克菲勒大学遗传学家埃里希·贾维斯(Erich Jarvis)说:“我们的目标是掌握平均97%的人类等位基因多样性,我认为未来10年之内,我们能将端粒至端粒基因组测序作为常规操作,同时,我们希望利用完整的基因组装配能力提供地球每种脊椎动物的完整基因组序列。”

Protein structure solutions

解析蛋白质结构

Structure dictates function. But it can be hard to measure. Major experimental and computational advances in the past two years have given researchers complementary tools for determining protein structures with unprecedented speed and resolution.

结构决定功能。但研究人员很难衡量。在过去两年时间里,科学实验和计算领域取得的进步,为研究人员以前所未有的速度和分辨率解析蛋白质结构。

The AlphaFold2 structure-prediction algorithm, developed by Alphabet subsidiary DeepMind in London, relies on ‘deep learning’ strategies to extrapolate the shape of a folded protein from its amino acid sequence. Since its public release last July, AlphaFold2 has been applied to proteomes, to determine the structures of all the proteins expressed in humans and in 20 model organisms, as well as nearly 440,000 proteins in the Swiss-Prot database, greatly increasing the number of proteins for which high-confidence modelling data are available.

由DeepMind子公司Alphabet开发的AlphaFold2结构预测算法基于“深度学习”策略,能推算出氨基酸序列折叠蛋白质的结构。该算法自2021年7月发布以来,已被应用于蛋白质组学,用于确定人类和20个模型生物中表达的所有蛋白质结构,以及Swiss-Prot数据库中近44万个蛋白质结构,大幅增加了高可信度建模数据的蛋白质数量。

In parallel, improvements in cryogenic-electron microscopy (cryo-EM) are enabling researchers to experimentally solve even the most challenging proteins and complexes. Cryo-EM scans flash-frozen molecules with an electron beam, generating images of the proteins in multiple orientations that can then be computationally reassembled into a 3D structure. In 2020, improvements in cryo-EM hardware and software enabled two teams to generate structures with a resolution of less than 1.5 ångströms, capturing the position of individual atoms. “Prior to this, we bandied about the term ‘atomic resolution’ with wild abandon, but it’s only been near-atomic,” says Bridget Carragher, co-director of the New York Structural Biology Center’s Simons Electron Microscopy Center in New York City. “This truly is atomic.” And, although both teams used an especially well-studied model protein called apoferritin, Carragher says, these studies suggest that near-atomic resolution is feasible for other, more difficult targets as well.

与此同时,低温电子显微镜的技术改进使研究人员能以实验方法解决最具挑战性的蛋白质和复合物,低温电子显微镜采用电子束扫描快速冻结的分子,生成多个方向的蛋白质图像,然后可以通过计算重新组装成一个蛋白质3D结构。2020年,低温电子显微镜硬件和软件的改进使研究团队能够生成分辨率小于1.5埃的水平解析蛋白质结构,捕捉到单个原子的位置。纽约结构生物学中心西蒙斯电子显微镜中心副主任布里奇特·卡拉格(Bridget Carragher)说:“此前我们曾深入讨论‘原子分辨率’这个术语,但它仅是接近原子,目前我们实验证实获得原子等级清晰度解析蛋白质结构是可行的。”

There is also considerable excitement around a related method, cryo-electron tomography (cryo-ET), which captures naturalistic protein behaviour in thin sections of frozen cells. But interpretation of these crowded, complicated images is challenging, and Carragher thinks computational advances from the machine-learning world will be essential. “How else are we going to solve these almost intractable problems?” she asks.

还有一种相关方法,即低温电子断层扫描(cryo-ET),它可以捕捉冷冻细胞薄片中自然蛋白质特征,但利用该技术解析复杂而拥挤的图像仍存在困难。卡拉格说:“采用机器学习世界的先进算法是必不可少的,相信未来我们能解决棘手的科学难题。”

Quantum simulation

量子模拟

Atoms are, well, atomic in size. But under the right conditions, they can be coaxed into a highly-excited, super-sized state with diameters on the order of one micrometre or more. By performing this excitation on carefully positioned arrays of hundreds of atoms in a controlled fashion, physicists have demonstrated that they can solve challenging physics problems that push conventional computers to their limits.

原子在特定条件下,能被诱导至一个高度激发状态,直径达到1微米或者更大。目前物理学家现已证实,通过对数百个原子阵列进行这种可控激发,可以解决一些具有挑战性的物理问题,实现传统计算机“极限升级”。

Quantum computers manage data in the form of qubits. Coupled together using the quantum physics phenomenon called entanglement, qubits can influence each other at a distance. These qubits can drastically increase the computing power that can be achieved with a given allotment of qubits relative to an equivalent number of bits in a classical computer.

量子计算机以量子位的形式管理数据,利用“量子纠缠”物理现象进行数据耦合,量子位可以在一定距离内相互影响。相对于经典计算机,这些量子位可大幅提高计算能力,而这可以通过给定的量子位分配来实现。

Several groups have successfully used individual ions as qubits, but their electrical charges make them challenging to assemble at high density. Physicists including Antoine Browaeys at the French national research agency CNRS in Paris and Mikhail Lukin at Harvard University in Cambridge, Massachusetts, are exploring an alternative approach. The teams use optical tweezers to precisely position uncharged atoms in tightly packed 2D and 3D arrays, then apply lasers to excite these particles into large-diameter ‘Rydberg atoms’ that become entangled with their neighbours. “Rydberg atom systems are individually controllable, and their interactions can be turned on and off,” explains physicist Jaewook Ahn at the Korea Advanced Institute of Science and Technology in Daejeon, South Korea. This in turn confers programmability.

目前,已有几个研究团队成功利用单个离子作为离子位,但这些离子的电荷很难在高密度下组装,物理学家正在探索另一种方法,其中包括法国国家科学研究中心的安东尼·布罗维(Antoine browwaeys)和美国哈佛大学的米哈伊尔·卢金(Mikhail Lukin),他们使用光学镊子精确地将不带电原子定位在紧密排列的2D和3D阵列中,然后应用激光将这些粒子成为大直径的“里德堡原子(Rydberg atoms)”,使其与它们邻近粒子纠缠在一起。韩国高级科学技术研究所物理学家Jaewook Ahn解释说:“里德堡原子系统是独立可控的,它们的相互作用可以打开和关闭,反之赋予了可编程性。”

This approach has gained considerable momentum in the span of just a few years, with technological advances that have improved the stability and performance of Rydberg atom arrays, as well as rapid scaling from a few dozen qubits to several hundred.

量子模拟技术在短短几年时间里就获得了重大突破进展,技术进步提高了里德堡原子阵列的稳定性和性能,以及从几十个量子位快速扩展至几百个。

Pioneers in the field have founded companies that are developing Rydberg atom array-based systems for laboratory use, and Browaeys estimates that such quantum simulators could be commercially available in a year or two. But this work could also pave the way towards quantum computers that can be applied more generally, including in economics, logistics and encryption.

量子模拟领域的先驱者已成立了公司,正在开发实验室使用的里德堡原子阵列系统,布罗维估计这种先进量子模拟器可以在一两年内投入商业应用,但这项工作也可能为量子计算机的更广泛应用铺平道路,包括:经济学、物流和数字加密领域等。

Precise genome manipulation

精准基因操控

For all its genome-editing prowess, CRISPR–Cas9 technology is better suited to gene inactivation than repair. That’s because although targeting the Cas9 enzyme to a genomic sequence is relatively precise, the cell’s repair of the resulting double-stranded cut is not. Mediated by a process called non-homologous end-joining, CRISPR–Cas9 repairs are often muddied by small insertions or deletions.

尽管CRISPR–Cas9技术拥有强大的基因组编辑能力,但该技术更容易基因失活,而不是达到基因修复,因为尽管针对Cas9酶的基因组序列相对精确,但细胞对该技术产生的双链切割修复却并不精确,CRISPR–Cas9修复通过一种称为“非同源端连接”的过程进行,通常会被微小的基因插入或者删除所混淆。

Most genetic diseases require gene correction rather than disruption, notes David Liu, a chemical biologist at Harvard University in Cambridge. Liu and his team have developed two promising approaches to do just that. The first, called base editing, couples a catalytically impaired form of Cas9 to an enzyme that aids chemical conversion of one nucleotide to another — for example, cytosine to thymine or adenine to guanine. But only certain base-to-base changes are currently accessible using this method. Prime editing, the team’s newer development, links Cas9 to a type of enzyme known as reverse transcriptase and uses a guide RNA that is modified to include the desired edit to the genomic sequence. Through a multistage biochemical process, these components copy the guide RNA into DNA that ultimately replaces the targeted genome sequence. Importantly, both base and prime editing cut only a single DNA strand, a safer and less disruptive process for cells.

美国哈佛大学化学生物学家大卫·刘指出,大多数遗传疾病需要的是基因修正,而不是基因破坏。目前他和研究同事现已开发两种颇有希望的基因操控方法,第一种叫做碱基编辑(base editing),将一种催化受损Cas9与一种酶结合,该酶可以帮助一种核苷酸转化为另一种核苷酸,例如:胞嘧啶转化为胸腺嘧啶,腺嘌呤转化为鸟嘌呤,但目前该方法仅对特定碱基对有效;第二种叫做精准编辑(Prime editing),是该团队最新的研发成果,将Cas9与逆转录酶连接起来,并引导DNA将所需编辑内容精准插入基因组序列。通过一个多阶段的生化过程,这些成分将引导RNA复制成DNA,最终取代目标基因组序列。重要的是,碱基编辑和精准编辑都仅剪切一条DNA链,这对细胞而言是一个更安全、破坏性更小的过程。

First described in 2016, base editing is already en route to the clinic: Beam Therapeutics, founded by Liu and also based in Cambridge, got the nod in November from the US Food and Drug Administration to trial this approach in humans for the first time, with the goal of repairing the gene that causes sickle-cell disease.

碱基编辑技术首次公布于2016年,现已投入临床应用,由大卫·刘创建的Beam Therapeutics公司已于11月获美国食品药物管理局批准,首次应用于人类镰状细胞病基因修复。

Prime editing is not as far along, but improved iterations continue to emerge, and the method’s promise is clear. Hyongbum Henry Kim, a genome-editing specialist at Yonsei University College of Medicine in Seoul, and his team have shown that they can achieve up to 16% efficiency using prime editing to correct retinal gene mutations in mice.

相比之下,精准编辑仍是一项新技术,但改进的迭代技术不断出现,该技术的应用前景也非常明确。韩国首尔延世大学医学院基因组编辑专家Hyongbum Henry Kim现已证实,使用精准编辑技术来纠正老鼠视网膜基因突变,可达到16%的治愈率。

“If we used recently reported, more advanced versions, the efficiencies would be improved even more,” he says,“In some cases, it’s known that if you can replace a gene at a 10% or even a 1% level, you can rescue the disease.”

他说:“如果我们使用最近报道的更先进技术,治疗效率将获得大幅提高,在某些情况下,如果能以10%,甚至以1%的基因进行替换,就可以治愈该疾病。”

Targeted genetic therapies

靶向基因治疗

Nucleic acid-based medicines might be making an impact in the clinic, but they are still largely limited in terms of the tissues in which they can be applied. Most therapies require either local administration or ex vivo manipulation of cells that are harvested from and then transplanted back into a patient. One prominent exception is the liver, which filters the bloodstream and is proving to be a robust target for selective drug delivery. In this instance, intravenous — or even subcutaneous — administration can get the job done.

基于核酸的药物可能会对临床治疗产生某些影响,但它们在可应用的组织方面仍受到限制,大多数治疗方法要么需要局部给药,要么需要体外操作,从患者体内提取细胞,然后将其移植到患者体内。一个显著的例子是肝脏,可以过滤血液,被证明是选择性药物输送的有效靶点,在这种情况下,静脉注射,甚至是皮下注射,均可达到该效果。

“Just getting delivery at all to any tissue is difficult, when you really think about the challenge,” says Daniel Anderson, a chemical engineer at the Massachusetts Institute of Technology (MIT) in Cambridge. “Our bodies are designed to use the genetic information we have, not to accept newcomers.” But researchers are making steady progress in developing strategies that can help to shepherd these drugs to specific organ systems while sparing other, non-target tissues.

美国麻省理工学院化学工程师丹尼尔·安德森(Daniel Anderson)说:“靶向基因治疗存在很大的挑战性,仅是将药物输送至人体任何组织进了困难的,我们的身体是基因信息集合体,而不是接受新的基因信息。”目前研究人员在开发基因治疗方面正取得稳步进展,这些方案可以帮助引导药物进入特定器官系统,而不影响其他非靶向组织。

Adeno-associated viruses are the vehicle of choice for many gene-therapy efforts, and animal studies have shown that careful selection of the right virus combined with tissue-specific gene promoters can achieve efficient, organ-restricted delivery. Viruses are sometimes challenging to manufacture at scale, however, and can elicit immune responses that undermine efficacy or produce adverse events.

腺相关病毒是许多基因治疗工作的首选载体,相关动物研究表明,理性选择合适的病毒,结合组织特异性基因启动子,可以实现高效、器官靶向治疗。然而,相关病毒有时难以大规模生产,并潜在引起人体免疫反应,破坏疗效或者产生身体不良反应。

Lipid nanoparticles provide a non-viral alternative, and several studies published over the past few years highlight the potential to tune their specificity. For example, the selective organ targeting (SORT) approach developed by biochemist Daniel Siegwart and his colleagues at the University of Texas Southwestern Medical Center in Dallas, enables the rapid generation and screening of lipid nanoparticles to identify those that can effectively target cells in tissues such as the lung or spleen.

脂质纳米颗粒提供了一种非病毒的替代方法,之前研究人员发表的研究报告强调了脂质纳米颗粒具有组织特异性送递的潜力,例如:德克萨斯大学西南医学中心的生物化学家 Daniel Siegwart 及其同事开发的选择性器官靶向 (SORT) 方法能快速生成和筛选识别脂质纳米颗粒,使其有效在肺或脾等器官实现靶向治疗。

“That was one of the first papers that showed that if you do systematic screening of these lipid nanoparticles and start changing their compositions, you can skew the biodistribution,” says Roy van der Meel, a biomedical engineer at the Eindhoven University of Technology in the Netherlands.

荷兰埃因霍温理工大学生物医学工程师罗伊·范德米尔(Roy van der Meel)称:“目前首次研究表明,如果对这些脂质纳米颗粒进行系统筛选,并且改变它们的成分,就可以改变它们在生物体中的分布。”

Spatial multi-omics

空间多组学分析

The explosion in single-cell ’omics development means researchers can now routinely derive genetic, transcriptomic, epigenetic and proteomic insights from individual cells — sometimes simultaneously. But single-cell techniques also sacrifice crucial information by ripping these cells out of their native environments.

单细胞组学的迅速发展意味着研究人员可以常规地从单个细胞中获得遗传、转录、表观和蛋白质组学的见解,有时是同时获取,但是单细胞技术在将细胞从原生环境中剥离过程中,也失去了关键信息。

In 2016, researchers led by Joakim Lundeberg at the KTH Royal Institute of Technology in Stockholm devised a strategy to overcome this problem. The team prepared slides with barcoded oligonucleotides — short strands of RNA or DNA — that can capture messenger RNA from an intact tissue slice, such that each transcript could be assigned to a particular position in the sample according to its barcode. “No one really believed that we could pull out a transcriptome-wide analysis from a tissue section,” says Lundeberg. “But it turned out to be surprisingly easy.”

2016年,瑞士皇家理工学院乔基姆·伦德伯格(Joakim Lundeberg)设计了一种策略克服了该问题,他和同事使用条形码寡核苷酸(RNA或者DNA短链)制作载玻片,该载玻片能从完整的组织切片中捕获信使RNA,这样每个转录RNA可以依据条形码被分配至样本中的特定位置,他说:“无人相信我们能从组织切片中提取全转录RNA分析,但事实证明,该策略非常简单。”

The field of spatial transcriptomics has since exploded. Multiple commercial systems are now available, including the Visium Spatial Gene Expression platform from 10x Genomics, which builds on Lundeberg’s technology. Academic groups continue to develop innovative methods that can map gene expression with ever-increasing depth and spatial resolution.

此后空间转录组学技术倍受科学家青睐,目前已有多个商业系统进行应用,包括:10x Genomics公司推出的Visium空间基因表达平台,该平台系统基于伦德伯格的最新技术。随着学术团队不断开发创新的方法,将不断增加深度和空间分辨率来绘制基因表达。

Now researchers are layering further ’omic insights on top of their spatial maps. For example, biomedical engineer Rong Fan at Yale University in New Haven, Connecticut, developed a platform known as DBiT-seq, which employs a microfluidic system that can simultaneously generate barcodes for thousands of mRNA transcripts and hundreds of proteins labelled with oligonucleotide-tagged antibodies.

现在,研究人员正在他们的空间地图之上进一步分层“组学见解”。例如,康涅狄格州纽黑文耶鲁大学的生物医学工程师 Rong Fan 开发了一个名为 DBiT-seq 的平台,该平台采用了一种微流体系统,可以同时为数千个 mRNA 转录本和数百个用寡核苷酸标记的抗体标记的蛋白质生成条形码。

CRISPR-based diagnostics

基于CRISPR技术的诊断

The CRISPR–Cas system’s capacity for precise cleavage of specific nucleic acid sequences stems from its role as a bacterial ‘immune system’ against viral infection. This link inspired early adopters of the technology to contemplate the system’s applicability to viral diagnostics. “It just makes a lot of sense to use what they’re designed for in nature,” says Pardis Sabeti, a geneticist at the Broad Institute of MIT and Harvard in Cambridge. “You have billions of years of evolution on your side.”

CRISPR–Cas系统技术精确切割特定核酸序列的能力源于它作为细菌“免疫系统”对抗病毒感染的作用,这种关联性激发了早期采用该技术的科学家考虑它对病毒诊断的适用性。美国麻省理工学院布罗德研究所、哈佛大学剑桥分校遗传学家帕尔迪斯·萨贝提(Pardis Sabeti)说:“利用它们在自然界中设计的功能非常有意义,毕竟它们已演化了数十亿年。”

But not all Cas enzymes are created equal. Cas9 is the go-to enzyme for CRISPR-based genome manipulation, but much of the work in CRISPR-based diagnostics has employed the family of RNA-targeting molecules known as Cas13, first identified in 2016 by molecular biologist Feng Zhang and his team at the Broad. “Cas13 uses its RNA guide to recognize an RNA target by base-pairing, and activates a ribonuclease activity that can be harnessed as a diagnostic tool by using a reporter RNA,” explains Jennifer Doudna at the University of California, Berkeley, who shared the 2020 Nobel Prize in Chemistry with Emmanuelle Charpentier, now at the Max Planck Unit for the Science of Pathogens in Berlin, for developing the genome-editing capabilities of CRISPR–Cas9. This is because Cas13 doesn’t just cut the RNA targeted by the guide RNA, it also performs ‘collateral cleavage’ on any other nearby RNA molecules. Many Cas13-based diagnostics use a reporter RNA that tethers a fluorescent tag to a quencher molecule that inhibits that fluorescence. When Cas13 is activated after recognizing viral RNA, it cuts the reporter and releases the fluorescent tag from the quencher, generating a detectable signal. Some viruses leave a strong enough signature that detection can be achieved without amplification, simplifying point-of-care diagnostics. For example, last January, Doudna and Melanie Ott at the Gladstone Institute of Virology in San Francisco, California, demonstrated a rapid, nasal-swab-based CRISPR–Cas13 test for amplification-free detection of SARS-CoV-2 using a mobile phone camera.

但并不是所有Cas酶都是一样的,Cas9是基于CRISPR的基因组操作的首选酶,但基于CRISPR的诊断的大部分工作都使用了被称为Cas13的RNA靶向分子家族,该分子家族是2016年由分子生物学家张峰(音译)首次发现的。美国加州大学伯克利分校詹妮弗·杜德纳(Jennifer Doudna)解释称:“Cas13利用其RNA向导通过碱基对识别RNA靶标,并激活核糖核酸酶活性,该活性通过使用报告RNA作为诊断工作进行临床应用。”据悉,她与马克斯·普朗克病原体科学研究所艾曼纽·卡彭特(Emmanuelle Charpentier)因这项研究发现共同获得2020年诺贝尔化学奖。这是因为Cas13不仅会切割向导RNA靶向的RNA,还会对附近任何其他RNA分子进行“旁系切割”。许多基于Cas13的诊断使用报告RNA,使用荧光标记抑制荧光的淬灭分子,当Cas13识别病毒RNA后被激活时,它会切断报告RNA,并从淬灭分子中释放荧光标记,产生可检测信号。有些病毒留下足够强的信号,可以在不进行扩增的情况下进行检测,从而简化了即时诊断。例如:2021年1月,美国加州旧金山格莱斯顿病毒学研究所演示了一种基于鼻拭子的CRISPR-Cas13快速检测方法,可以使用手机摄像头对新冠病毒进行无扩增检测。

RNA-amplification procedures can boost sensitivity for trace viral sequences, and Sabeti and her colleagues have developed a microfluidic system that screens for multiple pathogens in parallel using amplified genetic material from just a few microlitres of sample. “Right now, we have an assay to do 21 viruses simultaneously for less than US$10 a sample,” she says. Sabeti and her colleagues have developed tools for CRISPR-based detection of more than 169 human viruses at once, she adds.

RNA扩增可以提高对微量病毒序列的灵敏度,萨贝提和她的同事现已开发一种微流体系统,仅利用几微升样本中扩增出的基因物质,就能同时筛选多种病原体。“现在,我们已掌握一种同时检测21种病毒的方法,而每个样本的成本不足10美元。”她说。萨贝提还补充说,她和同事还开发出基于CRISPR技术的工具,可以同时检测169种以上的人类病毒。

Other Cas enzymes could flesh out the diagnostic toolbox, Doudna notes, including the Cas12 proteins, which exhibit similar properties to Cas13 but target DNA rather than RNA. Collectively, these could detect a broader range of pathogens, or even enable efficient diagnosis of other non-infectious diseases.

杜德纳称,其他Cas酶可以充实诊断工具箱,包括Cas12蛋白,它表现出与Cas13相似的特性,但其目标是DNA而不是RNA。总体而言,这些技术可以检测范围更广的病原体,甚至可以有效诊断其他非传染性疾病。

平板只能娱乐?未必!华为平板M6让孩子拥有不一样的学习体验******

作为手机与电脑之间的补充产品,平板自诞生以来几乎都在力推娱乐功能。但当手机屏幕越来越大、绝大多数娱乐需求被解决之后,包括笔者在内很多人家中的平板都沦为了吃灰产品。平板的未来可能会在哪里?华为平板M6给出一个答案:教育。

笔者作为两个小孩子的父亲,也算是一枚过来人。那么我就来谈谈如何为孩子选购一台适合孩子学习的平板。虽然现在平板的价格、尺寸、售后在大品牌间都相差不大,但有一点经常被大家忽略却直接影响孩子学习体验——音质。

如果不是亲自体验,很难理解音质竟然会成为选购一款教育用途平板的重要因素。与成年人使用手机时用耳机听声音的方式截然不同,小孩子用平板看视频或学习课程时几乎不会佩戴耳机,即使是发育期的大孩子也不适合长期佩戴耳机,所以扬声器的音质能直接决定一款平板的体验感受。

低端平板普遍只有一个扬声器,大部分平板也都只是底部有双扬声器。以巧虎、学而思等教育软件为例,小孩子在学习过程中会经常拿起平板进行互动。暂且不讨论音质好坏,仅扬声器的数量和设计就会导致手部频繁堵塞声音传输。

洞察到上述痛点,华为平板M6专门采用上下分布的扬声器设计,其中,10.8英寸版更是采用四声道四扬声器设计,与同品类产品直接拉开距离。物理结构与扬声器数量上的优势可以让华为平板M6在任何使用姿态下,都能有非常出色的声音输出,不必担心遮挡问题。不仅扬声器数量多,华为平板M6在音质调教上也非常重视。据了解,华为平板M6的声音是由哈曼卡顿“金耳朵“音频工程师团队调教的,足见对音质的重视。

四声道四扬声器的设计,让华为平板M6在教学体验中拥有更好的优势。其实,孩子跟随网校老师学习语言类课程的时候并不需要很大的音量,而是需要通过有品质的声音传输更加清晰的听到老师的发音。比如,很多家长非常重视孩子的外语学习,而接收到老师准确的发音对孩子的听力和口语学习都至关重要。此外,乐器类的课程学习对音质会提出更高的要求,这些乐器的声音在华为平板M6上都能得到很好的还原。

和我们小时候的生长环境截然不同,这个时代很难不让孩子接触数码产品,所以家长只能通过更恰当的方式去引导。严格来说,连手机都不适合小孩子用,手机信息过于繁杂,也不利于家长与孩子的互动,而平板在尺寸上非常适合,家长和孩子互动起来也非常方便。而且,平板作为非必要的工作工具,可以只给孩子安装如学而思、猿辅导、巧虎等教育类APP。

为了突出华为平板M6对儿童教育的重视,系统中还内置了方便低龄儿童学习的儿童乐园功能。在这里,家长可以设置屏幕蓝光护眼、使用姿态矫正、电纸书模式、使用时长限制等等。

通过使用不难发现,教育功能是华为平板M6重点研发的功能,而不是补充功能。作为家长的我们在选购产品时一定要对产品有足够的了解,才能放心给孩子使用。

时尚男士发型24款 越看越有型!

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