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Aussie state warned to prepare for severe weather after 5 deaths from floods******
Although the East Coast Low weather affecting Australia's New South Wales (NSW) state since last week has weakened, local residents are still told to keep preparing for severe weather for the weekend.
Till Friday, NSW police confirmed at least five deaths in the state's ongoing flood rescues, with many people reported to be missing or trapped. The NSW State Emergency Service (SES) Deputy Commissioner Daniel Austin warned the flooding is "far from over" around Sydney and suggested there may be a new weather system from Sunday.
Currently, the state has 68 evacuation orders and 14 evacuation warnings in place, with more evacuation centers opened to people affected by the severe weather.
NSW Northern Rivers town of Mullumbimby, one of the worst-hit areas, is out of phone or Internet access and is cut off from essential supplies, while rescuers cannot access anyone west of the town.
"We currently have no phones, Internet and communications in a number of areas across Mullumbimby and our smaller communities. It is very challenging to get help to communities," the SES Mullumbimby said in a statement on Friday.
The severe weather ravaged NSW hard on Thursday, and SES said it responded to 3,133 requests for assistance in 24 hours, including 219 flood rescues, 56 of which were in the Greater Sydney area.
NSW Bureau of Meteorology (BOM) said that while most floodwaters are receding, enormous flood warnings remain, including major flood warnings for Clarence, Hawkesbury, Nepean, Richmond, Gloucester and Weir rivers.
For the rest of NSW, residents are told to prepare for some likely heavier rainfalls during the weekend, which may lead to renewed river rises and flooding. Communities are encouraged to keep up to date with the latest forecasts and warnings and to follow the advice of emergency services.
左图：吴春艳和王思俊展示金牌 记者 李东峰 摄
本报讯 (记者 李东峰)10月14日，全国第十一届残运会暨第八届特奥会(简称“残特奥会”)射箭项目肢残组团体比赛全部结束，总计决出了9枚金牌，陕西队共获5枚金牌，西安姑娘吴春艳一日“射落”两枚金牌。
Palmeiras beat Gremio to climb to second in Brazil's Serie A******
PORTO ALEGRE, Oct. 31 (Xinhua) -- Raphael Veiga scored twice as Palmeiras recovered from an early deficit to beat Gremio 2-1 in Brazil's Serie A championship on Sunday.。
Diego Souza gave the hosts an early lead with a close-range strike after Douglas Costa's run and cross from the left side of the penalty area.。
Raphael Veiga equalized by converting a penalty after Thiago Santos clattered into Marcos Rocha.。
Veiga put the visitors ahead in first half stoppage time when he angled a drive into the far corner after Gustavo Scarpa's pass.。
Breno Lopes guaranteed Palmeiras' 16th win of the campaign in the 94th minute, running onto Danilo's layoff and taking one touch before lashing a shot into the far corner.。
The result at Arena do Gremio leaves Palmeiras second in the 20-team standings, seven points behind leaders Atletico Mineiro. Gremio are 19th with just 26 points from 27 matches.。
In other Brazilian Serie A fixtures on Sunday, Ceara won 1-0 at home to Fluminense and Sao Paulo secured a 1-0 home win over Internacional. Enditem。
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.
Fully finished genomes
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.
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.
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.
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.
Protein structure solutions
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.
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.
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.
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.
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.
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.
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.
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.
Precise genome manipulation
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.
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.
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.”
Targeted genetic therapies
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.
“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.
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.
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。”
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.
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.”
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.
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。
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.”
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.
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.