来自杂志 Nature 的文献。
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61.
白鸟 (2023-07-31 22:58):
#paper https://doi.org/10.1038/s41586-023-06252-9 A spatially resolved single-cell genomic atlas of the adult human breast 该项目是陈-扎克伯格倡议(Chan Zuckerberg Initiative)支持的全球人类细胞图谱(Human Cell Atlas)联盟的一部分,该联盟利用最新技术为人体的每个器官系统构建细胞参考图谱。 研究目的: 人类乳腺的解剖学和组织病理学已经研究了几十年,为发育、哺乳和疾病提供了深入见解。最近,用分子和基因组技术对正常乳腺组织进行了表征,这些方法主要集中在上皮细胞上。迄今为止,仍然缺乏对所有细胞类型及其生物亚型(细胞状态)的无偏的全面解析。 研究意义: 1.HBCA图谱数据为研究乳腺生物学和乳腺癌等疾病状态提供了前所未有的成人正常乳腺组织的参考; 2.HBCA项目的所有单细胞和空间数据都可以通过官方的门户网站公开访问; 3. 人类细胞图谱(HCA,Human Cell Atlas)的一部分;
IF:50.500Q1 Nature, 2023-Aug. DOI: 10.1038/s41586-023-06252-9 PMID: 37380767
Abstract:
The adult human breast is comprised of an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue. Although most previous studies have focused on … >>>
The adult human breast is comprised of an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue. Although most previous studies have focused on the breast epithelial system, many of the non-epithelial cell types remain understudied. Here we constructed the comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics study profiled 714,331 cells from 126 women, and 117,346 nuclei from 20 women, identifying 12 major cell types and 58 biological cell states. These data reveal abundant perivascular, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Spatial mapping using four different technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide a reference of the adult normal breast tissue for studying mammary biology and diseases such as breast cancer. <<<
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62.
惊鸿 (2023-07-29 17:48):
#paper CAR T therapy beyond cancer: the evolution of a living drug DOI : 10.1038/s41586-023-06243-w 2023-07-26 通过改造患者自身的 T 细胞来选择性地靶向并消除肿瘤细胞,已经治愈了患有无法治疗的血液癌症的患者。这些结果推动了嵌合抗原受体 (CAR) T 疗法在整个肿瘤学领域的应用。然而,临床和临床前研究的证据强调了 CAR T 疗法在肿瘤学之外治疗自身免疫、慢性感染、心脏纤维化、衰老相关疾病和其他疾病方面的潜力。同时,新技术和平台的部署为 CAR T 疗法应用于非癌症病理提供了进一步的机会。在这里,我们回顾了 CAR T 疗法背后的基本原理、当前肿瘤学面临的挑战、非癌症疾病初步报告的概要,以及对相关新兴技术的讨论。我们研究了这种疗法在各种情况下的潜在应用。最后,我们强调了对特异性和安全性的担忧,并概述了 CAR T 疗法超越癌症的前进道路。
Abstract:
Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen … >>>
Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer. <<<
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63.
张贝 (2023-06-30 23:14):
#paper DNA methylation-based classification of central nervous system tumours Nature. 2018 Mar 22;555(7697):469-474.doi:10.1038/nature26000 肿瘤的正确诊断对于后期治疗至关重要,然而在已知的近100多种中枢神经系统肿瘤 (central nervous system tumor,CNS tumor)中,相关标准化的诊断面临很大的挑战。为了高效、迅速的对CNS肿瘤进行分类,作者开发了一个机器学习模型,它可以对甲基化数据进行分类。开发出来的程序经过训练后,可以使用甲基化特征鉴定91种CNS肿瘤。训练集采用的参照数据来自约2800名癌症患者。作者在1104例已经经过人工检查的中枢神经系统肿瘤上进行了测试,发现有12%例存在误诊。该模型不仅可以提高诊断准确率,而且还可以鉴定出新型罕见肿瘤。为了让这种新方法得到广泛应用,作者生成了一款免费在线工具 (Molecular Neuropathology 2.0; http://www.kitz-heidelberg.de/molecular-diagnostics),可以在几分钟内分析上传的数据。自2016年12月上线以来,该工具已被使用逾4500次,用户可以选择分享他们的数据,以便进一步优化算法。作者总结表示,将甲基化特征与脑肿瘤自动分类器整合起来还可以为创造类似的肿瘤分类算法用于诊断其它癌症类型提供一个蓝图。
IF:50.500Q1 Nature, 2018-03-22. DOI: 10.1038/nature26000 PMID: 29539639
David Capper, David T W Jones, Martin Sill, Volker Hovestadt, Daniel Schrimpf, Dominik Sturm, Christian Koelsche, Felix Sahm, Lukas Chavez, David E Reuss, Annekathrin Kratz, Annika K Wefers, Kristin Huang, Kristian W Pajtler, Leonille Schweizer, Damian Stichel, Adriana Olar, Nils W Engel, Kerstin Lindenberg, Patrick N Harter, Anne K Braczynski, Karl H Plate, Hildegard Dohmen, Boyan K Garvalov, Roland Coras, Annett Hölsken, Ekkehard Hewer, Melanie Bewerunge-Hudler, Matthias Schick, Roger Fischer, Rudi Beschorner, Jens Schittenhelm, Ori Staszewski, Khalida Wani, Pascale Varlet, Melanie Pages, Petra Temming, Dietmar Lohmann, Florian Selt, Hendrik Witt, Till Milde, Olaf Witt, Eleonora Aronica, Felice Giangaspero, Elisabeth Rushing, Wolfram Scheurlen, Christoph Geisenberger, Fausto J Rodriguez, Albert Becker, Matthias Preusser, Christine Haberler, Rolf Bjerkvig, Jane Cryan, Michael Farrell, Martina Deckert, Jürgen Hench, Stephan Frank, Jonathan Serrano, Kasthuri Kannan, Aristotelis Tsirigos, Wolfgang Brück, Silvia Hofer, Stefanie Brehmer, Marcel Seiz-Rosenhagen, Daniel Hänggi, Volkmar Hans, Stephanie Rozsnoki, Jordan R Hansford, Patricia Kohlhof, Bjarne W Kristensen, Matt Lechner, Beatriz Lopes, Christian Mawrin, Ralf Ketter, Andreas Kulozik, Ziad Khatib, Frank Heppner, Arend Koch, Anne Jouvet, Catherine Keohane, Helmut Mühleisen, Wolf Mueller, Ute Pohl, Marco Prinz, Axel Benner, Marc Zapatka, Nicholas G Gottardo, Pablo Hernáiz Driever, Christof M Kramm, Hermann L Müller, Stefan Rutkowski, Katja von Hoff, Michael C Frühwald, Astrid Gnekow, Gudrun Fleischhack, Stephan Tippelt, Gabriele Calaminus, Camelia-Maria Monoranu, Arie Perry, Chris Jones, Thomas S Jacques, Bernhard Radlwimmer, Marco Gessi, Torsten Pietsch, Johannes Schramm, Gabriele Schackert, Manfred Westphal, Guido Reifenberger, Pieter Wesseling, Michael Weller, Vincent Peter Collins, Ingmar Blümcke, Martin Bendszus, Jürgen Debus, Annie Huang, Nada Jabado, Paul A Northcott, Werner Paulus, Amar Gajjar, Giles W Robinson, Michael D Taylor, Zane Jaunmuktane, Marina Ryzhova, Michael Platten, Andreas Unterberg, Wolfgang Wick, Matthias A Karajannis, Michel Mittelbronn, Till Acker, Christian Hartmann, Kenneth Aldape, Ulrich Schüller, Rolf Buslei, Peter Lichter, Marcel Kool, Christel Herold-Mende, David W Ellison, Martin Hasselblatt, Matija Snuderl, Sebastian Brandner, Andrey Korshunov, Andreas von Deimling, Stefan M Pfister <<<
Abstract:
Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has … >>>
Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology. <<<
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64.
muton (2023-06-30 21:57):
# Paper: Doeller, C. F., Barry, C., & Burgess, N. (2010). Evidence for grid cells in a human memory network. Nature, 463(7281), 657–661. https://doi.org/10.1038/nature08704 自由运动大鼠内嗅皮层中的网格细胞提供了自我定位的显著周期性表征,这表明了非常特殊的计算机制。然而,网格细胞在人类中的存在及其在整个大脑中的分布是未知的。本研究表明,大鼠内嗅皮层定向调节的网格细胞的优先放电方向与网格对齐,并且快跑与慢跑相比,网格细胞放电的空间组织更为明显。由于网格细胞的一致性特征,作者预测了在更宏观的信号,也就是人类的功能性磁共振成像(fMRI)记录中也会发现网格细胞的相关证据。因此,作者模拟老鼠的觅食任务,让参与者探索虚拟现实环境,结果显示fMRI激活和适应在跑步方向上显示出由速度调节的六倍旋转对称的特性。这种信号在鼻内/丘下、顶叶后部和内侧、颞外侧和前额叶内侧的网络中都有发现。并且该效应在右内嗅皮层表现最为明显,方向信号在内嗅皮层间的相干性与空间记忆表现相关。本研究提示了将单细胞电生理学与功能磁共振成像在系统神经科学中结合的潜在可能。本研究结果为人类的网格细胞样表征提供了证据,并暗示在支持空间认知和自传体记忆的区域网络中存在一种特定类型神经表征。
IF:50.500Q1 Nature, 2010-Feb-04. DOI: 10.1038/nature08704 PMID: 20090680
Abstract:
Grid cells in the entorhinal cortex of freely moving rats provide a strikingly periodic representation of self-location which is indicative of very specific computational mechanisms. However, the existence of grid … >>>
Grid cells in the entorhinal cortex of freely moving rats provide a strikingly periodic representation of self-location which is indicative of very specific computational mechanisms. However, the existence of grid cells in humans and their distribution throughout the brain are unknown. Here we show that the preferred firing directions of directionally modulated grid cells in rat entorhinal cortex are aligned with the grids, and that the spatial organization of grid-cell firing is more strongly apparent at faster than slower running speeds. Because the grids are also aligned with each other, we predicted a macroscopic signal visible to functional magnetic resonance imaging (fMRI) in humans. We then looked for this signal as participants explored a virtual reality environment, mimicking the rats' foraging task: fMRI activation and adaptation showing a speed-modulated six-fold rotational symmetry in running direction. The signal was found in a network of entorhinal/subicular, posterior and medial parietal, lateral temporal and medial prefrontal areas. The effect was strongest in right entorhinal cortex, and the coherence of the directional signal across entorhinal cortex correlated with spatial memory performance. Our study illustrates the potential power of combining single-unit electrophysiology with fMRI in systems neuroscience. Our results provide evidence for grid-cell-like representations in humans, and implicate a specific type of neural representation in a network of regions which supports spatial cognition and also autobiographical memory. <<<
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65.
大勇 (2023-06-30 21:35):
#paper Dmitrieva-Posocco, O., Wong, A.C., Lundgren, P. et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 605, 160–165 (2022). https://doi.org/10.1038/s41586-022-04649-6 主要是讲述生酮饮食对小鼠结肠癌的抑制作用及可能的机制探讨,整篇文献降解较为精简,细节可以在文章中继续探索,生酮饮食对脂质、糖类和蛋白的代谢都会造成影响,从而导致结肠癌生长的抑制,酮类中的β羟丁酸可以通过Hcar2基因诱导Hopx的表达升高,从而抑制结肠癌进展。在生酮饮食研究中,其实还有其他研究表明生酮饮食会造成肿瘤的进展而非抑制,并且生酮饮食可能还会加速衰老和增加心血管疾病的风险,因此若非药用,日常不适宜进行尝试,目前在临床中没有太多的验证,而对于遗传代谢病中糖代谢异常的患者,生酮饮食则可能是他们目前最为稳妥的饮食方式,因为糖类可能对他们来说反而是毒药。
IF:50.500Q1 Nature, 2022-05. DOI: 10.1038/s41586-022-04649-6 PMID: 35477756
Abstract:
Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed. Here we identify a metabolite signalling pathway that … >>>
Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC. <<<
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66.
笑对人生 (2023-06-30 21:33):
#paper doi: 10.1038/s41586-021-03894-5. Epub 2021 Sep 8. Bentham R, et al. Using DNA sequencing data to quantify T cell fraction and therapy response. Nature. 2021 Sep;597(7877):555-560. doi: 10.1038/s41586-021-03894-5. Epub 2021 Sep 8. 在V(D)J重排过程中,T细胞受体alpha链编码基因(TCRA或TRA,T cell receptor-alpha gene)通常会发生丢失(TREC,T cell receptor excision circle)。基于此,本研究针对肿瘤配对的全外显子组测序数据开发了一个名为T cell ExTRECT的T细胞比例估计工具。该工具的原理主要是通过检测TRA基因发生肿瘤体细胞拷贝数变化(RDR,read-depth ratio),进而直接定量T细胞的比例。局限性:不能区分发生新抗原反应的T细胞和检测克隆型(clonotype);只能应用于全外显子组测序,要求测序深度大于30x。
IF:50.500Q1 Nature, 2021-09. DOI: 10.1038/s41586-021-03894-5 PMID: 34497419
Abstract:
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate … >>>
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes. <<<
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67.
符毓 (2023-06-26 23:22):
#paper doi:10.1038/171737a0 Nature, 2014, Passive radiative cooling below ambient air temperature under direct sunlight。辐射制冷材料通过反射包括紫外线、可视光、近红外和中红外等让物体温度低于环境温度。本文通过7层材料构成的冷却材料,首次在日间成功实现辐射制冷。在850W/平方米的日照下实现4.9度的降温
68.
大勇 (2023-05-31 22:11):
#paper doi: https://doi.org/10.1038/s41586-022-05443-0 Kim, R., Hashimoto, A., Markosyan, N. et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature 612, 338–346 (2022). 该文章主要是对肿瘤相关中性粒,也叫做髓源性抑制细胞(PMN-MDSC)在抗肿瘤免疫中的作用进行了研究,PMN-MDSC中所产生的铁死亡相关脂质代谢产物,可以通过抑制T细胞等的增殖从而抑制肿瘤进展和免疫检查点抑制剂治疗疗效。
IF:50.500Q1 Nature, 2022-12. DOI: 10.1038/s41586-022-05443-0 PMID: 36385526
Abstract:
Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown … >>>
Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression. <<<
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69.
哪有情可长 (2023-04-30 21:56):
#paper reducing brassinosteroid signalling enhances grain yield in semi-dwarf wheat doi: doi.org/10.1038/s41586-023-06023-6. 通过多年的大规模田间表型调查和遗传学研究,鉴定到一个能够提升小麦群体产量的关键位点,其中该位点跟已知的Rht基因处于相同的区段,通过构建小麦该区段内三个基因的突变体,发现该基因跟绿色革命基因相比,能够保持半矮杆株型,且茎秆强度、植株耐密性、收获指数、千粒重和产量均有显著的提升。该基因可以是近现代小麦品种后期育种增产的目标基因,对于小麦产量提升具有重要的作用。同时该研究历时10年,通过正向遗传鉴定基因后,对于小麦中的明星基因如何处理也是一个很好的典范,同时也给我分析小麦数据提供了思路,GWAS结果中一些定位到明星基因的位点还可以看下SVN等情况。
IF:50.500Q1 Nature, 2023-05. DOI: 10.1038/s41586-023-06023-6 PMID: 37100915
Abstract:
Modern green revolution varieties of wheat (Triticum aestivum L.) confer semi-dwarf and lodging-resistant plant architecture owing to the Reduced height-B1b (Rht-B1b) and Rht-D1b alleles. However, both Rht-B1b and Rht-D1b are … >>>
Modern green revolution varieties of wheat (Triticum aestivum L.) confer semi-dwarf and lodging-resistant plant architecture owing to the Reduced height-B1b (Rht-B1b) and Rht-D1b alleles. However, both Rht-B1b and Rht-D1b are gain-of-function mutant alleles encoding gibberellin signalling repressors that stably repress plant growth and negatively affect nitrogen-use efficiency and grain filling. Therefore, the green revolution varieties of wheat harbouring Rht-B1b or Rht-D1b usually produce smaller grain and require higher nitrogen fertilizer inputs to maintain their grain yields. Here we describe a strategy to design semi-dwarf wheat varieties without the need for Rht-B1b or Rht-D1b alleles. We discovered that absence of Rht-B1 and ZnF-B (encoding a RING-type E3 ligase) through a natural deletion of a haploblock of about 500 kilobases shaped semi-dwarf plants with more compact plant architecture and substantially improved grain yield (up to 15.2%) in field trials. Further genetic analysis confirmed that the deletion of ZnF-B induced the semi-dwarf trait in the absence of the Rht-B1b and Rht-D1b alleles through attenuating brassinosteroid (BR) perception. ZnF acts as a BR signalling activator to facilitate proteasomal destruction of the BR signalling repressor BRI1 kinase inhibitor 1 (TaBKI1), and loss of ZnF stabilizes TaBKI1 to block BR signalling transduction. Our findings not only identified a pivotal BR signalling modulator but also provided a creative strategy to design high-yield semi-dwarf wheat varieties by manipulating the BR signal pathway to sustain wheat production. <<<
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70.
李翛然 (2023-04-28 17:37):
#paper De novo design of protein interactions with lerned surface pingerprints doi: 10.1038/s41586-023-05993-x. 文章的主要思路是分为三个阶段:(1)使用MaSIF-site预测目标蛋白质表面上具有高结合倾向的埋藏界面位点;(2)使用MaSIF-seed基于表面指纹寻找互补的结构基元(结合种子),这些基元具有与目标位点相匹配的特征;(3)将结合种子移植到蛋白质骨架上,使用Rosetta优化设计界面,增加稳定性和额外的接触。 文章的主要结论是,作者利用这种表面为中心的方法成功地设计并实验验证了针对四种蛋白质靶标的从头结合剂:SARS-CoV-2刺突蛋白、PD-1、PD-L1和CTLA-4。其中一些设计经过实验优化,而另一些则完全在计算机上生成,达到了纳摩尔级别的亲和力。结构和突变分析显示预测非常准确。总体而言,作者的方法能够捕捉分子识别的物理和化学决定因素,为从头设计蛋白质相互作用以及更广泛地设计具有功能的人工蛋白质提供了一种方法. 以上是通过chat GPT总结的。 不过我读完的感受就是,我并不认为这篇文章的水平是 nature 正刊的水平, masif 的算法在蛋白质结构对比上确实有用,但是背后有个深层次的问题这篇文章没有谈到,即目前来说,对于已知蛋白设计一个有效的配体蛋白,算法已经比较丰富了。并且最近2年发的文章已经有很好的实验结果来验证。 但是对于结构全新,或者说没有任何可用配体的蛋白来说,这个挑战非常巨大,文章并没有提到这种问题出现后的解决思路,而且甚至算法的创新比不上前段时间的 baker 的 rf diffusion. 总之吧 现在真的是蓝海市场。 这个领域机会太多了
IF:50.500Q1 Nature, 2023-05. DOI: 10.1038/s41586-023-05993-x PMID: 37100904
Abstract:
Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural … >>>
Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural data increase. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications. Here we use a geometric deep-learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features that are critical to drive protein-protein interactions. We hypothesized that these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof of principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1 and CTLA-4. Several designs were experimentally optimized, whereas others were generated purely in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling an approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function. <<<
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71.
尹志 (2023-03-31 00:12):
#paper https://doi.org/10.1038/s41586-023-05870-7. Nature, 2023, Programmable protein delivery with a bacterial contractile injection system。这是今年张锋组的一篇新文章。文章介绍了一种叫做外胞质收缩注射系统(eCISs)的纳米机器,它们可以被重新编程以针对人类细胞并传递各种蛋白质负载,包括Cas9、碱基编辑器和毒素。这些系统可以用于基因治疗、癌症治疗和生物控制等领域。还讨论了利用收缩注射系统(CIS)作为蛋白质传递和基因编辑的潜在工具以及它们在生物技术和医学中的应用。基本都是实验,方法部分简直大开眼界,琳琅满目,基本看不懂;但看结论还是觉得挺有前瞻性的工作,而且使用了AF技术作为structure-guided engineering,这个很引起我的兴趣。总之,先浅浅仰慕读一下
IF:50.500Q1 Nature, 2023-04. DOI: 10.1038/s41586-023-05870-7 PMID: 36991127
Abstract:
Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One example, the extracellular contractile injection systems (eCISs), are syringe-like macromolecular complexes that inject … >>>
Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One example, the extracellular contractile injection systems (eCISs), are syringe-like macromolecular complexes that inject protein payloads into eukaryotic cells by driving a spike through the cellular membrane. Recently, eCISs have been found to target mouse cells, raising the possibility that these systems could be harnessed for therapeutic protein delivery. However, whether eCISs can function in human cells remains unknown, and the mechanism by which these systems recognize target cells is poorly understood. Here we show that target selection by the Photorhabdus virulence cassette (PVC)-an eCIS from the entomopathogenic bacterium Photorhabdus asymbiotica-is mediated by specific recognition of a target receptor by a distal binding element of the PVC tail fibre. Furthermore, using in silico structure-guided engineering of the tail fibre, we show that PVCs can be reprogrammed to target organisms not natively targeted by these systems-including human cells and mice-with efficiencies approaching 100%. Finally, we show that PVCs can load diverse protein payloads, including Cas9, base editors and toxins, and can functionally deliver them into human cells. Our results demonstrate that PVCs are programmable protein delivery devices with possible applications in gene therapy, cancer therapy and biocontrol. <<<
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72.
林海onrush (2023-02-28 21:45):
#paper,doi: https://doi.org/10.1038/s41586-023-05859-2,Continuous Symmetry Breaking in a Two-dimensional Rydberg Array,,自发对称性破坏是对物质相位及其相关跃迁进行分类的基础。被打破的潜在对称性的性质决定了相的许多定性特性;离散与连续对称性破坏的情况说明了这一点。与离散情况相反,连续对称性的破坏导致无间隙Goldstone模式的出现,例如控制有序相的热力学稳定性.作者利用可编程的里德伯量子模拟器实现了二维偶极XY模型,展示了XY铁磁体和XY反铁磁体相关低温态的绝热制备。在铁磁情况下,表征了长程XY阶的存在。这项工作对XY相互作用的多体物理学做出了贡献,补充了最近利用里德伯-封锁机制实现表现出离散自旋旋转对称性的Ising型相互作用的工作。该文近期被收录于nature,也证实了工作的严谨和创新。
IF:50.500Q1 Nature, 2023-04. DOI: 10.1038/s41586-023-05859-2 PMID: 36848931
Abstract:
Spontaneous symmetry breaking underlies much of our classification of phases of matter and their associated transitions. The nature of the underlying symmetry being broken determines many of the qualitative properties … >>>
Spontaneous symmetry breaking underlies much of our classification of phases of matter and their associated transitions. The nature of the underlying symmetry being broken determines many of the qualitative properties of the phase; this is illustrated by the case of discrete versus continuous symmetry breaking. Indeed, in contrast to the discrete case, the breaking of a continuous symmetry leads to the emergence of gapless Goldstone modes controlling, for instance, the thermodynamic stability of the ordered phase. Here, we realize a two-dimensional dipolar XY model that shows a continuous spin-rotational symmetry using a programmable Rydberg quantum simulator. We demonstrate the adiabatic preparation of correlated low-temperature states of both the XY ferromagnet and the XY antiferromagnet. In the ferromagnetic case, we characterize the presence of a long-range XY order, a feature prohibited in the absence of long-range dipolar interaction. Our exploration of the many-body physics of XY interactions complements recent works using the Rydberg-blockade mechanism to realize Ising-type interactions showing discrete spin rotation symmetry. <<<
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73.
笑对人生 (2022-11-30 23:55):
#paper doi: 10.1038/s41586-022-05426-1. Schmitt M, Ceteci F, Gupta J, Pesic M, Böttger TW, Nicolas AM, Kennel KB, Engel E, Schewe M, Callak Kirisözü A, Petrocelli V, Dabiri Y, Varga J, Ramakrishnan M, Karimova M, Ablasser A, Sato T, Arkan MC, de Sauvage FJ, Greten FR. Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation. Nature. 2022 Nov 16. 研究背景:实体瘤的不断形成和生长依赖于细胞死亡和增殖之间的动态平衡。越来越多的研究表明,肿瘤细胞凋亡的增加会通过旁分泌引起微环境内其他细胞激活,启动组织修复相关机制,最终反而为肿瘤生长提供支持。 科学问题:濒死的肿瘤细胞对邻近细胞究竟产生哪些直接影响,以及这种旁分泌机制是否与化疗耐药有关。 研究结果或结论:(1)在结直肠癌患者来源的肿瘤类器官中,化疗诱导肿瘤细胞死亡的同时,会释放ATP,从而触发邻近细胞中由离子通道受体P2X4介导的mTOR信号通路依赖的促存活机制,这使得存活的肿瘤上皮细胞对mTOR抑制敏感。(2)持续存在的上皮细胞中诱发的mTOR抑制敏感是由于活性氧的产生升高,以及随后对邻近细胞死亡的DNA损伤增加。因此,对化疗处理的细胞,使用针对P2X4受体的抑制剂或mTOR直接阻断剂,可防止诱导S6磷酸化,导致活性氧诱导的大量细胞死亡和明显的肿瘤消退。然而,如果单独使用抑制剂或阻断剂,并不能观察到该现象。相反,清除活性氧可防止肿瘤细胞对mTOR激活的依赖。总的来说,本研究详细阐明了肿瘤细胞死亡对邻近细胞存活一种可能机制,未来可就P2X4这一靶点进行结直肠癌治疗药物的开发。
IF:50.500Q1 Nature, 2022-12. DOI: 10.1038/s41586-022-05426-1 PMID: 36385525
Abstract:
Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in … >>>
Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition. The induced mTOR addiction in persisting epithelial cells is due to elevated production of reactive oxygen species and subsequent increased DNA damage in response to the death of neighbouring cells. Accordingly, inhibition of the P2X4 receptor or direct mTOR blockade prevents induction of S6 phosphorylation and synergizes with chemotherapy to cause massive cell death induced by reactive oxygen species and marked tumour regression that is not seen when individually applied. Conversely, scavenging of reactive oxygen species prevents cancer cells from becoming reliant on mTOR activation. Collectively, our findings show that dying cancer cells establish a new dependency on anti-apoptotic programs in their surviving neighbours, thereby creating an opportunity for combination therapy in P2X4-expressing epithelial tumours. <<<
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74.
张贝 (2022-11-30 22:20):
#paper  DOI: 10.1038/s41586-020-1969-6 Nature . 2020 Feb;578(7793):82-93 Pan-cancer analysis of whole genomes 本文是泛癌全基因组分析(PCAWG)联盟在nature上发表的一篇文章,对ICGC和TCGA的38种常见癌症的2658例肿瘤及其配对正常组织样本的全基因组测序数据进行系统整合分析。癌症基因组平均有4-5个驱动突变(结合编码和非编码基因元件);约有5%的病例未发现驱动突变,表明癌症驱动基因的发现仍未完全;常见和罕见的遗传变异会影响体细胞突变的模式,包括点突变、结构变异和体细胞反转录转座。同时文章描述了非编码突变、识别了导致碱基替换、小片段插入和缺失以及结构变异的突变过程的新特征;分析了肿瘤演化的时机和模式;描述了体细胞突变对剪接、表达水平、融合基因和启动子活性的多种转录结果;并评估了癌症基因组的一系列特征。
IF:50.500Q1 Nature, 2020-02. DOI: 10.1038/s41586-020-1969-6 PMID: 32025007
Abstract:
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis … >>>
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes. <<<
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75.
哪有情可长 (2022-11-30 19:24):
#paper THP9 enhances seed protein content and nitrogen-use efficiency in maize, Nature 2022 October, https://doi.org/10.1038/s41586-022-05441-2. 鉴定未驯化的野生型玉米大刍草的蛋白发现其要比现代玉米籽粒蛋白含量高,由于玉米大刍草的基因型复杂,其参考基因组一直没有被组装,作者通过构建已知参考基因组B73和大刍草杂交后代,测定后代基因型去掉已知的参考基因组B73进行组装大刍草的参考基因组,将两套参考基因组进行共线性分析发现存在大量的结构变异,推测蛋白含量的高低可能是由于结构变异引起。作者们继续构建群体,通过BSA鉴定到了控制籽粒蛋白含量的基因THP9,该基因在现代品种中存在48bp的缺失,导致剪切位点发生变化后导致基因翻译提前终止,最终导致现代玉米籽粒蛋白含量降低。作者又利用525份自然群体进行GWAS分析,也鉴定到该基因所处的区间。对525份材料按照基因型可以分成三种单倍型,Hap1跟野生型基因型一致,作者又通过转基因验证该基因的确能够提高蛋白含量,又通过构建NIL群体,继续验证该基因的功能,发现当籽粒蛋白含量高时,根部的氮吸收效率高,该基因也是首次在玉米中鉴定的第一个高蛋白基因。
IF:50.500Q1 Nature, 2022-12. DOI: 10.1038/s41586-022-05441-2 PMID: 36385527
Abstract:
Teosinte, the wild ancestor of maize (Zea mays subsp. mays), has three times the seed protein content of most modern inbreds and hybrids, but the mechanisms that are responsible for … >>>
Teosinte, the wild ancestor of maize (Zea mays subsp. mays), has three times the seed protein content of most modern inbreds and hybrids, but the mechanisms that are responsible for this trait are unknown. Here we use trio binning to create a contiguous haplotype DNA sequence of a teosinte (Zea mays subsp. parviglumis) and, through map-based cloning, identify a major high-protein quantitative trait locus, TEOSINTE HIGH PROTEIN 9 (THP9), on chromosome 9. THP9 encodes an asparagine synthetase 4 enzyme that is highly expressed in teosinte, but not in the B73 inbred, in which a deletion in the tenth intron of THP9-B73 causes incorrect splicing of THP9-B73 transcripts. Transgenic expression of THP9-teosinte in B73 significantly increased the seed protein content. Introgression of THP9-teosinte into modern maize inbreds and hybrids greatly enhanced the accumulation of free amino acids, especially asparagine, throughout the plant, and increased seed protein content without affecting yield. THP9-teosinte seems to increase nitrogen-use efficiency, which is important for promoting a high yield under low-nitrogen conditions. <<<
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76.
笑对人生 (2022-10-01 23:59):
#paper doi: 10.1038/s41586-018-0414-6. RNA velocity of single cells. Nature. 2018 Aug;560(7719):494-498. 本研究首次将RNA速率(RNA velocity)这一概念引入单细胞转录组测序数据科学中,即利用新生(未剪切)和成熟(剪切)mRNA相对丰度变化来评估基因剪切和降解的速率。此外,研究者运用该概念揭示了小鼠胚胎海马组织和人类胚胎大脑中细胞转录动力学特征,表明了RNA速率在单细胞数据科学中的应用价值。RNA速率的发现:在真核生物中,细胞核的DNA首先经过转录形成初级mRNA(或未成熟mRNA),接着需要经过加工(可变剪接)才产生成熟的mRNA。在这个过程中,细胞内就可能存在不同状态的mRNAs。传统转录组测序的mRNA富集方法是利用带有oligo(dT)的磁珠对mRNA进行分离纯化。本研究通过对不同技术平台的单细胞转录组测序数据进行read检查发现,存在15-25%的reads包含内含子序列(内含子序列在mRNA加工成熟过程会被切掉,在成熟mRNA一般不会存在)。基于这些reads的内含子序列和对应外显子序列可认为它们代表的是未剪接的mRNAs前体。 RNA速率中未剪接(unspliced)和剪接(spliced)事件的预测公式(微积分方程):du/dt=α(t)-β(t)u(t),ds/dt=β(t)u(t)-γ(t)s(t),α表示转录速率,β表示剪接速率,s表示剪切mRNAs分子数,t表示时间,u表示未剪切的mRNA分子数,γ表示降解的速率。RNA速率是由unspliced mRNA形成spliced mRNA和mRNA降解两个事件的动态平衡来决定的。对于给定某个基因的,利用unspliced和spliced分子数可以建立一个线性回归模型,本文将其定义为steady-state model。在这个方程拟合直线上的细胞认为具有正速度(unspliced更占优),细胞处于下方则具有负速度(降解更占优),若在直线上,就处于稳态。
IF:50.500Q1 Nature, 2018-08. DOI: 10.1038/s41586-018-0414-6 PMID: 30089906
Abstract:
RNA abundance is a powerful indicator of the state of individual cells. Single-cell RNA sequencing can reveal RNA abundance with high quantitative accuracy, sensitivity and throughput. However, this approach captures … >>>
RNA abundance is a powerful indicator of the state of individual cells. Single-cell RNA sequencing can reveal RNA abundance with high quantitative accuracy, sensitivity and throughput. However, this approach captures only a static snapshot at a point in time, posing a challenge for the analysis of time-resolved phenomena such as embryogenesis or tissue regeneration. Here we show that RNA velocity-the time derivative of the gene expression state-can be directly estimated by distinguishing between unspliced and spliced mRNAs in common single-cell RNA sequencing protocols. RNA velocity is a high-dimensional vector that predicts the future state of individual cells on a timescale of hours. We validate its accuracy in the neural crest lineage, demonstrate its use on multiple published datasets and technical platforms, reveal the branching lineage tree of the developing mouse hippocampus, and examine the kinetics of transcription in human embryonic brain. We expect RNA velocity to greatly aid the analysis of developmental lineages and cellular dynamics, particularly in humans. <<<
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77.
muton (2022-09-30 21:34):
#paper doi:10.1038/nature02223 Sleep inspires insight. 睡眠激发洞察力(Insight):洞察力表示一种心理重组的过程,指突然获得显性知识,从而使行为发生质的变化的过程。科学报告表明,可以通过睡眠获得这种洞察力(有点像顿悟的意思)。睡眠可以巩固最近的记忆,同时,可以通过改变其表征结构来获得洞察力。本文中,作者让被试执行了一种需要学习刺激-反应序列的认知任务,在学习这项任务过程中,被试通过提高任务组块间的反应速度体现出了表现的提升。然而,被试也可以通过洞察到所有序列背后隐藏的抽象规则来提高行为表现。实验条件分为三种:初始训练后的 8 小时夜间睡眠、夜间清醒或白天清醒。在随后的重新测试中,睡眠后对隐藏规则的洞察力是清醒后的两倍多。然而在没有初始训练的情况下,睡眠并不能增强洞察力,所以,本文认为睡眠通过重构新的记忆表征,有助于提取显性知识和有洞察力的行为。行为实验例子:让被试在给定的两个规则中将8位数字序列减少到7位,这两个规则是相同规则:如两个相同的数字仍得到此数字;还有不同规则:即两个数字不同得到另外一个数字:如11449494,通过前两位得到1,然后1和4比较得到9,最终得到1914419的7位数字序列,然而没有告诉被试的是在最终得到的7位数字序列中,2-4位和5-7位总是镜像对称的,如果被试能够发现这一隐藏规则,其反应时会大大减少,而作者发现在之前睡眠或清醒的三个条件中,在经过睡眠之后,能够发现这一隐藏规则的被试大大增加,也表明了睡眠对于获得洞察力的贡献。
IF:50.500Q1 Nature, 2004-Jan-22. PMID: 14737168
Abstract:
Insight denotes a mental restructuring that leads to a sudden gain of explicit knowledge allowing qualitatively changed behaviour. Anecdotal reports on scientific discovery suggest that pivotal insights can be gained … >>>
Insight denotes a mental restructuring that leads to a sudden gain of explicit knowledge allowing qualitatively changed behaviour. Anecdotal reports on scientific discovery suggest that pivotal insights can be gained through sleep. Sleep consolidates recent memories and, concomitantly, could allow insight by changing their representational structure. Here we show a facilitating role of sleep in a process of insight. Subjects performed a cognitive task requiring the learning of stimulus-response sequences, in which they improved gradually by increasing response speed across task blocks. However, they could also improve abruptly after gaining insight into a hidden abstract rule underlying all sequences. Initial training establishing a task representation was followed by 8 h of nocturnal sleep, nocturnal wakefulness, or daytime wakefulness. At subsequent retesting, more than twice as many subjects gained insight into the hidden rule after sleep as after wakefulness, regardless of time of day. Sleep did not enhance insight in the absence of initial training. A characteristic antecedent of sleep-related insight was revealed in a slowing of reaction times across sleep. We conclude that sleep, by restructuring new memory representations, facilitates extraction of explicit knowledge and insightful behaviour. <<<
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78.
xh (2022-09-30 06:12):
#paper DOI: 10.1038/nature08494 Nature 10/2009 Finding the missing heritability of complex diseases. 本文研究人类疾病中缺失遗传性的潜在来源,并提出了研究策略,包括并超越了目前的全基因组关联方法,以阐明复杂疾病的遗传学,并提高其潜力以实现有效的疾病预防或治疗。 但是对于神经精神疾病方面检测到的变异体的相对缺乏,如自闭症谱系障碍。
IF:50.500Q1 Nature, 2009-Oct-08. DOI: 10.1038/nature08494 PMID: 19812666
Abstract:
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far … >>>
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment. <<<
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79.
哪有情可长 (2022-09-18 20:36):
#paper 'Green revolution' genes encode mutant gibberellin response modulators, Nature 1999 Jul 15;400(6741):256-61. doi: 10.1038/22307. 绿色革命是将在拟南芥中发现的矮杆的基因引用到作物中,降低了水稻、小麦等作物的株高,然后加上水肥等配套设施开始完善,从而使得作物产量增加,也降低了作物成熟后期大风和降雨导致的倒伏减产。进而使得矮杆基因在’绿色革命‘中得以应用。作物中的矮杆突变主要是由于该类基因突变后,导致对GA(赤霉素)不敏感,反应异常导致的。该文主要从拟南芥、水稻、玉米、小麦中的矮杆基因的基因结构,蛋白功能以及突变位点的差异导致的表型的差异变化。分析物种之间矮杆基因的共线性、矮杆基因中发现的SH2 domain结构。且赤霉素信号转导在单子叶和双子叶植物中非常相似,可能涉及SH2 domian与磷酸化酪氨酸残基的相互作用。 该作者首先在1993年在拟南芥中发现了一个GAI的基因,该基因是负调控赤霉素(GA)信号通路的一个基因。获取拟南芥中该基因突变体,后再1997年又发了一篇关于拟南芥GAI基因的文章,后续他又在小麦中进行研究,发现无论是双子叶植物还是单子叶植物,该类基因的功能是同源性较好的基因。
IF:50.500Q1 Nature, 2002. DOI: 10.1038/22307
Abstract:
World wheat grain yields increased substantially in the 1960s and 1970s because farmers rapidly adopted the new varieties and cultivation methods of the so-called ‘green revolution’1,2,3,4. The new varieties are … >>>
World wheat grain yields increased substantially in the 1960s and 1970s because farmers rapidly adopted the new varieties and cultivation methods of the so-called ‘green revolution’1,2,3,4. The new varieties are shorter, increase grain yield at the expense of straw biomass, and are more resistant to damage by wind and rain3,4. These wheats are short because they respond abnormally to the plant growth hormone gibberellin. This reduced response to gibberellin is conferred by mutant dwarfing alleles at one of two Reduced height-1 (Rht-B1 and Rht-D1) loci4,5. Here we show that Rht-B1/Rht-D1 and maize dwarf-8 (d8)6,7 are orthologues of the Arabidopsis Gibberellin Insensitive (GAI) gene8,9. These genes encode proteins that resemble nuclear transcription factors and contain an SH2-like10 domain, indicating that phosphotyrosine may participate in gibberellin signalling. Six different orthologous dwarfing mutant alleles encode proteins that are altered in a conserved amino-terminal gibberellin signalling domain. Transgenic rice plants containing a mutant GAI allele give reduced responses to gibberellin and are dwarfed, indicating that mutant GAI orthologues could be used to increase yield in a wide range of crop species. <<<
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80.
小W (2022-08-31 22:43):
#paper doi:Shilts, J., Severin, Y., Galaway, F. et al. A physical wiring diagram for the human immune system. Nature 608, 397–404 (2022). https://doi.org/10.1038/s41586-022-05028-x 这篇论文的亮点是开发了一种能够高效和高通量筛选重组细胞外结构域之间的蛋白质结合相互作用的方法(SAVEXIS),结合其他多组学数据系统注释了免疫细胞的物理相互作用的关系图谱。其内容包括:1.组装( 630 种)了一个包含在先前对外周免疫细胞研究中检测到的细胞表面蛋白质的完整胞外域,以及兼容的所有 CD 编号蛋白质文库,使用 SAVEXIS 方法 得到 187 种蛋白质的相互作用矩阵(低于万分之一的误报率独立捕获了所有先前报告的交互作用,确定了 28 个新的相互作用)。2.表面等离子体共振(SPR) 数据和ELISA四聚化测量结合亲和力,单细胞表达数据集检测到体和配体对的表达位置,结合蛋白质组学数据,建模每种血液免疫细胞的细胞结合动力学的数学模型,并基于质量作用定律的微分方程系统进行扰动预测。3.提供了网页端的数据接口,具体数据集未开放。
IF:50.500Q1 Nature, 2022. DOI: 10.1038/s41586-022-05028-x
Abstract:
The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes1. … >>>
The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes1. Despite their therapeutic potential2, our map of these surface interactions remains incomplete3,4. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention. <<<
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