来自杂志 Science (New York, N.Y.) 的文献。
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1.
哪有情可长 (2024-07-31 15:18):
#paper Biofortification of iron content by regulating a NAC transcription factor in maize, Science, 7 Dec 2023, DOI: 10.1126/science.adf3256. 玉米籽粒铁的含量对人类健康具有重要的作用,该项研究发现一个NAC的转录因子能够提高籽粒中的Fe的含量,并且该基因能够在果仁基部胚乳转移层中富集表达,该蛋白可以直接调节铁转运体mRNA的丰度,并且该课题组也培育了富含铁元素的玉米品种。该项工作从GWAS找候选基因的流程,逻辑性强,一步步的验证该基因的确是籽粒富含铁的候选基因,这个方法可以借鉴。
Abstract:
Iron (Fe) deficiency remains widespread among people in developing countries. To help solve this problem, breeders have been attempting to develop maize cultivars with high yields and high Fe concentrations … >>>
Iron (Fe) deficiency remains widespread among people in developing countries. To help solve this problem, breeders have been attempting to develop maize cultivars with high yields and high Fe concentrations in the kernels. We conducted a genome-wide association study and identified a gene, (), that regulates Fe concentrations in maize kernels. We cultivated maize varieties with both high yield and high Fe concentrations in their kernels by using a molecular marker developed from a 42-base pair insertion or deletion (indel) in the promoter of . expression is enriched in the basal endosperm transfer layer of kernels, and the ZmNAC78 protein directly regulates messenger RNA abundance of Fe transporters. Our results thus provide an approach to develop maize varieties with Fe-enriched kernels. <<<
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白鸟 (2024-06-30 23:11):
#paper http://doi.org/10.1126/science.abg4696,Developmental and evolutionary dynamics ofcis-regulatory elements in mouse cerebellar cells, science, 2021. 文章系统的揭示了小鼠小脑中细胞从早期神经发生到成年发育的顺式调控元件调控机制。该文章提供了scATAC数据和代码,很清晰地分析思路,很值得初学者学习和借鉴。
Abstract:
Organ development is orchestrated by cell- and time-specific gene regulatory networks. In this study, we investigated the regulatory basis of mouse cerebellum development from early neurogenesis to adulthood. By acquiring … >>>
Organ development is orchestrated by cell- and time-specific gene regulatory networks. In this study, we investigated the regulatory basis of mouse cerebellum development from early neurogenesis to adulthood. By acquiring snATAC-seq (single-nucleus assay for transposase accessible chromatin using sequencing) profiles for ~90,000 cells spanning 11 stages, we mapped cerebellar cell types and identified candidate cisregulatory elements (CREs). We detected extensive spatiotemporal heterogeneity among progenitor cells and a gradual divergence in the regulatory programs of cerebellar neurons during differentiation. Comparisons to vertebrate genomes and snATAC-seq profiles for ∼20,000 cerebellar cells from the marsupial opossum revealed a shared decrease in CRE conservation during development and differentiation as well as differences in constraint between cell types. Our work delineates the developmental and evolutionary dynamics of gene regulation in cerebellar cells and provides insights into mammalian organ development. <<<
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哪有情可长 (2024-05-31 16:03):
#paper Defective pollen tube tip growth inducesneo-polyploid infertility, Science,1 March 2024, DOI: 10.1126/science.adh0755. 多倍体过程与植物的进化和适应有关。自然环境中的多倍体植物形成能够进行有性生殖,而利用技术新形成的多倍体个体通常完全或几乎完全不育,不容易繁殖。研究人员利用二倍体和自然形成四倍体和秋水仙素处理的新四倍体以及新形成的四倍体与自然形成的四倍体的杂交子一代,通过鉴定其花粉管的生长速率、花粉大小、花粉管等状态鉴定出新四倍体有差异,后续发现是因为新四倍体的花粉管缺乏正常的钙离子浓度梯度,导致花粉管中微管蛋白分布异常,导致花粉管中细胞壁的酸性果胶酯化分布异常。对上述材料的花粉管进行转录组分析,鉴定到一些钙信号相关的基因。结合全基因组测序分析,发现两个基因AGC1.5和ACA8在多倍体和二倍体植物件存在显著差异,表明在多倍体中受到强烈的正向选择,且基因的表达模式存在不同程度的差异。
Abstract:
Genome duplication (generating polyploids) is an engine of novelty in eukaryotic evolution and a promising crop improvement tool. Yet newly formed polyploids often have low fertility. Here we report that … >>>
Genome duplication (generating polyploids) is an engine of novelty in eukaryotic evolution and a promising crop improvement tool. Yet newly formed polyploids often have low fertility. Here we report that a severe fertility-compromising defect in pollen tube tip growth arises in new polyploids of . Pollen tubes of newly polyploid grow slowly, have aberrant anatomy and disrupted physiology, often burst prematurely, and have altered gene expression. These phenotypes recover in evolved polyploids. We also show that gametophytic (pollen tube) genotypes of two tip-growth genes under selection in natural tetraploid are strongly associated with pollen tube performance in the tetraploid. Our work establishes pollen tube tip growth as an important fertility challenge for neo-polyploid plants and provides insights into a naturally evolved multigenic solution. <<<
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4.
颜林林 (2024-05-25 18:44):
#paper doi:10.1126/science.adh2602, Science, 2024, Molecular cascades and cell type-specific signatures in ASD revealed by single-cell genomics. 这周的Science集中发表了一大波脑科学的单细胞或空间转录组文章,本文是其中一篇。本文是联合使用了单核RNA-seq、单核ATAC-seq和空间转录组,研究遗传变异如何在健康和疾病状态下影响人脑,特别是在孤独症谱系障碍(ASD)中的作用。这是对ASD队列进行了迄今为止规模最大的单细胞分析,包括33例ASD和31例对照(共计64例),取样了这些受试者死后的大脑皮层组织,进行的实验。分析结果揭示了在ASD中从稳态到反应性的细胞状态转变过程,识别了涉及数千个基因的表达差异和转录因子网络,为理解ASD在人脑中的分子变化提供了有力的因果锚点和分子表型。
Abstract:
Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition are … >>>
Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) to examine cell composition and transcriptomics, identifying dysregulation of cell type-specific gene regulatory networks (GRNs) in autism spectrum disorder (ASD), which we corroborated using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) and spatial transcriptomics. Transcriptomic changes were primarily cell type specific, involving multiple cell types, most prominently interhemispheric and callosal-projecting neurons, interneurons within superficial laminae, and distinct glial reactive states involving oligodendrocytes, microglia, and astrocytes. Autism-associated GRN drivers and their targets were enriched in rare and common genetic risk variants, connecting autism genetic susceptibility and cellular and circuit alterations in the human brain. <<<
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5.
muton (2024-04-30 22:07):
#paper doi: 10.1126/science.adk8261. Epub 2024 Mar 28. Selection of experience for memory by hippocampal sharp wave ripples 记忆对人类来说是非常重要的,但是并不是所有经历过的事件都能够被记住,那么大脑是如何筛选出值得记住的瞬间的呢? 纽约大学的György Buzsáki教授发现一种神经振荡的信号叫做SWR,也就是尖波涟漪波,他们认为清醒时期尖波涟漪波的发放会帮助记忆“打标”,帮助我们从事件中选择出有用的部分,并且在本文中的设想是清醒时起有尖波涟漪波发放附近的事件在睡眠时期会同样发放SWR并以replay的形式进行记忆巩固,帮助增强了记忆。本文运用了序列非负矩阵分解(seqNMF) 与统一流形的估计投影技术(UMAP)帮助解码了小鼠在迷宫路径探索下的行为和时间信息,使这一假设得到了数据的支持。
Abstract:
Experiences need to be tagged during learning for further consolidation. However, neurophysiological mechanisms that select experiences for lasting memory are not known. By combining large-scale neural recordings in mice with … >>>
Experiences need to be tagged during learning for further consolidation. However, neurophysiological mechanisms that select experiences for lasting memory are not known. By combining large-scale neural recordings in mice with dimensionality reduction techniques, we observed that successive maze traversals were tracked by continuously drifting populations of neurons, providing neuronal signatures of both places visited and events encountered. When the brain state changed during reward consumption, sharp wave ripples (SPW-Rs) occurred on some trials, and their specific spike content decoded the trial blocks that surrounded them. During postexperience sleep, SPW-Rs continued to replay those trial blocks that were reactivated most frequently during waking SPW-Rs. Replay content of awake SPW-Rs may thus provide a neurophysiological tagging mechanism to select aspects of experience that are preserved and consolidated for future use. <<<
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6.
Vincent (2023-12-31 21:15):
#paper doi: 10.1126/science.adi6000 Prediction-powered inference, science 2023 目前很多领域里已标注的数据(金标准)较稀缺而未标注的数据较丰富,如何使用这些数据得到严谨的统计结论还面临着颇多挑战。传统方法的思路是只使用这些少数的金标准的数据进行统计推断,这种方案得到的统计结果有效,但样本量少会导致可能的发现较少。另一种思路是使用预测模型对未标注的数据进行标注,用补全标签后的数据和金标准数据进行统计推断,这种方案样本量大,但其假设了预测模型是完美的, 很多时候这种假设并不成立,预测误差与偏差累计可能会导致无效的统计结论。这篇文章提出了一个通用的框架,在使用预测模型的同时也保证了统计结论的有效性。该框架分为三步,1.选择需要估计的参数,2.从未标注数据估计拟合度,从标注数据估计矫正量,3.结合拟合度与校正量获取参数的置信区间。文章在数学上证明了对于任意的预测算法与数据分布,这种基于预测的统计推断能够确保置信区间涵盖真实值的概率达到给定的置信度。由于该方法能够使用的样本量更大,后续数据分析也验证了其较传统方法得到的置信区间更窄,p-value更有效。
Abstract:
Prediction-powered inference is a framework for performing valid statistical inference when an experimental dataset is supplemented with predictions from a machine-learning system. The framework yields simple algorithms for computing provably … >>>
Prediction-powered inference is a framework for performing valid statistical inference when an experimental dataset is supplemented with predictions from a machine-learning system. The framework yields simple algorithms for computing provably valid confidence intervals for quantities such as means, quantiles, and linear and logistic regression coefficients without making any assumptions about the machine-learning algorithm that supplies the predictions. Furthermore, more accurate predictions translate to smaller confidence intervals. Prediction-powered inference could enable researchers to draw valid and more data-efficient conclusions using machine learning. The benefits of prediction-powered inference were demonstrated with datasets from proteomics, astronomy, genomics, remote sensing, census analysis, and ecology. <<<
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7.
小年 (2023-10-30 22:31):
#paper Andrews G, Fan K, Pratt HE, Phalke N; Zoonomia Consortium§; Karlsson EK, Lindblad-Toh K, Gazal S, Moore JE, Weng Z. Mammalian evolution of human cis-regulatory elements and transcription factor binding sites. Science. 2023 Apr 28;380(6643):eabn7930. doi: 10.1126/science.abn7930. Epub 2023 Apr 28. PMID: 37104580. 哺乳动物之所以具有高度的生物体复杂性,很大程度上是由于它们的蛋白质调节的多样性。描述人类基因组的调控景观是现代生物学的一个长期目标。现代方法测量全基因组的生化信号,包括染色质可及性、组蛋白修饰、DNA甲基化和人类基因组中约1600个转录因子(tf)的结合。本篇文章作者利用Zoonomia项目(Zoonomia project)开发的工具---胎盘哺乳动物的进化限制(evolutionary constraint)和无参考基因组的241种哺乳动物的基因组比对---对胎盘哺乳动物的进化动态进行了研究。作者探索了从表观基因组学数据中获得的ENCODE cCRE和从染色质免疫沉淀数据中获得的367种转录因子的结合位点。他们发现了哺乳动物调控元件的保护性图谱:一端是高度保守的cCRE和进化受限的TFBS,另一端是灵长类动物特有的与转座因子(transposable element)重叠的cCRE和TFBSs。保守性的调控元件主要位于在基本细胞过程(代谢、发育)中起作用的基因附近,并且在其他哺乳动物的基因组中往往具有功能性,而不存在进化限制的调控元件位于涉及与环境相互作用的基因附近。
Abstract:
Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted … >>>
Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome. <<<
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8.
小擎子 (2023-06-30 23:20):
#paper doi:10.1126/science.aba6527 Science, 2020, Designed protein logic to target cells with precise combinations of surface antigens 设计蛋白质逻辑,以靶向具有表面抗原精确组合的细胞。文献从头设计了协同定位依赖性蛋白质开关(Co-LOCKR),可执行“AND”、“OR”和“NOT”布尔逻辑运算。只有当满足所有条件时,这些开关才会通过构象变化激活,实现在复杂细胞群中以单细胞分辨率产生快速的、转录依赖的反应。使用“AND”门来重定向T细胞对表达两种表面抗原的肿瘤细胞的特异性,同时避免对单抗原细胞的脱靶识别,以及添加“NOT”或“OR”以避免或包括表达第三抗原的细胞。文章涉及蛋白质设计知识太多了,有点看不懂,但是这个设计是很有想象力很有意思的,可以实现只在特定细胞的细胞膜附近反应的效果。蛋白质设计的门槛现在降得很低,但就像David Baker说的,关键是你想设计什么样的蛋白。
Abstract:
Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells using specific … >>>
Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells using specific combinations of proteins present on their surfaces. In this study, we design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations. We implement AND gates to redirect T cell specificity against tumor cells expressing two surface antigens while avoiding off-target recognition of single-antigen cells, and three-input switches that add NOT or OR logic to avoid or include cells expressing a third antigen. Thus, de novo designed proteins can perform computations on the surface of cells, integrating multiple distinct binding interactions into a single output. <<<
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小擎子 (2023-05-31 23:05):
#paper 10.1126/science.1257481 Science, 2014 , High thermodynamic stability of parametrically designed helical bundles 参数化设计的螺旋束的高热力学稳定性。通过参数化骨架生成与Rosetta蛋白质设计相结合的方法,生成非常稳定的蛋白质结构。不依赖已知序列基序的情况下轻松生成具有精细几何形状的超稳定蛋白质,有助于基于蛋白质的纳米结构、疗法和催化剂的设计。核心是参数化设计,依靠的是对Crick Coiled-coil方程做参数扰动。0.1埃的扰动可以生成成千上万个α螺旋设计骨架。文章找了几种低能量的设计做测试,实验验证,晶体结构与设计一致,且稳定性超好,堪称“砖头”。ps 因文章较早,用的是Rosetta设计序列,如果改用ProteinMPNN,可以生成有更多活性表达的蛋白质序列。
Abstract:
We describe a procedure for designing proteins with backbones produced by varying the parameters in the Crick coiled coil-generating equations. Combinatorial design calculations identify low-energy sequences for alternative helix supercoil … >>>
We describe a procedure for designing proteins with backbones produced by varying the parameters in the Crick coiled coil-generating equations. Combinatorial design calculations identify low-energy sequences for alternative helix supercoil arrangements, and the helices in the lowest-energy arrangements are connected by loop building. We design an antiparallel monomeric untwisted three-helix bundle with 80-residue helices, an antiparallel monomeric right-handed four-helix bundle, and a pentameric parallel left-handed five-helix bundle. The designed proteins are extremely stable (extrapolated ΔGfold > 60 kilocalories per mole), and their crystal structures are close to those of the design models with nearly identical core packing between the helices. The approach enables the custom design of hyperstable proteins with fine-tuned geometries for a wide range of applications. <<<
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10.
林海onrush (2023-05-31 22:41):
#paper,Mastering the Game of Stratego with Model-Free Multiagent Reinforcement Learning,DOI: 10.1126/science.add4679,强化学习在军事战略模拟领域的尝试如何?作者团队给出了一个可行的思路:如何使用无模型的多智能体强化学习来掌握战略游戏Stratego。本文提出了DeepNash,一个能够学习玩不完美信息游戏Stratego1从零开始,直至达到人类专家的水平。战略游戏是人工智能尚未掌握的少数标志性棋盘游戏之一。(AI)还没有掌握的少数标志性棋盘游戏之一。这个流行的游戏有一个巨大的游戏树10535个节点,也就是说,比围棋大0175倍。它有它还有一个额外的复杂性,就是需要在不完美的信息下进行决策。在tratego中,决策是在大量没有明显的离散行动的情况下做出的。行动和结果之间没有明显的联系。情节很长,在玩家获胜之前往往有几百步棋,而且战略游戏中的情况不容易被分解为可管理的大小的子问题。由于这些原因,几十年来《策略》一直是人工智能领域的一个巨大挑战,而现有的人工智能方法几乎没有达到业余水平。业余水平的游戏。DeepNash使用了一种游戏理论的、无模型的深度强化学习方法,不需要搜索,它通过自我游戏来学习掌握Stratego。正则化纳什动力学(R-aD)算法是DeepNash的一个关键组成部分,它收敛到一个近似的纳什均衡,通过直接修改基础的多Agent学习动态性。DeepNash击败了Stratego中现有的最先进的人工智能方法。并在Gravon游戏平台上取得了年度(2022年)和历史上前三名的成绩。平台上取得了年度(2022年)和历史上的前三名,与人类专家玩家竞争。本文的工作很有意思,有进一步探索的空间。个人认为此思路在MOBA类游戏中有很强的可拓展性。
Abstract:
We introduce DeepNash, an autonomous agent that plays the imperfect information game Stratego at a human expert level. Stratego is one of the few iconic board games that artificial intelligence … >>>
We introduce DeepNash, an autonomous agent that plays the imperfect information game Stratego at a human expert level. Stratego is one of the few iconic board games that artificial intelligence (AI) has not yet mastered. It is a game characterized by a twin challenge: It requires long-term strategic thinking as in chess, but it also requires dealing with imperfect information as in poker. The technique underpinning DeepNash uses a game-theoretic, model-free deep reinforcement learning method, without search, that learns to master Stratego through self-play from scratch. DeepNash beat existing state-of-the-art AI methods in Stratego and achieved a year-to-date (2022) and all-time top-three ranking on the Gravon games platform, competing with human expert players. <<<
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11.
张贝 (2023-03-31 22:30):
#paper RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science. 2019 Jun 7;364(6444):eaaw0726.doi: 10.1126/science.aaw0726. 体细胞突变是如何在正常细胞中积累的,目前尚不清楚。本文通过对来自29个正常组织的6700个样本的RNA测序数据的综合分析揭示了多个体细胞变异,表明在许多正常组织中可以发现宏观克隆。本文证实阳光照射的皮肤、食道和肺比其他测试组织有更高的突变负担,这表明环境因素可以促进体细胞嵌合。突变负担与年龄和组织特异性细胞增殖率相关,强调突变随着时间和细胞分裂数量的增加而积累。最后,作者发现正常组织中存在已知癌症基因和热点突变。本研究提供了人体组织中宏观克隆扩增的广阔视野,从而作为将克隆扩增与环境因素、衰老和疾病风险联系起来的基础
Abstract:
How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, demonstrating that … >>>
How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We found that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests that environmental factors can promote somatic mosaicism. Mutation burden was associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over both time and number of cell divisions. Finally, normal tissues were found to harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as a foundation for associating clonal expansion with environmental factors, aging, and risk of disease. <<<
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12.
AI 5.0.3 (2023-03-31 20:44):
#paper 主要内容:快速伽马震荡精准协调上下神经系统,分别从海马外内侧收集神经元信息传入海马实现在物体识别和方位判断的作用。主要结论:空间导航中快伽马震荡协调齿状回和MEC,慢伽马震荡协调齿状回和LEC,MEC和LEC的信息以伽马周期对任务进行特异性选择。A. Fernández-Ruiz et al., Science 372, eabf3119 (2021). DOI: 10.1126/science.abf3119
Abstract:
Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat … >>>
Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication. <<<
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13.
哪有情可长 (2023-03-24 21:51):
#paper A Gg protein regulates alkaline sensitivity in crops,science,24 march,2023,doi.org/10.1126/science.ade8416. 为了增加粮食产量,利用盐碱地,培养抗盐碱的作物,实现废田利用是现在作物育种的一大趋势。谢旗团队利用高粱这个抗碱性材料来挖掘基因。首先是通过GWAS鉴定到一个跟水稻中同源的基因(GS3)并命名为AT1(Alkaline tolerance 1),对部分高粱品种测序发现该基因能够分成两个单倍型,发现这个基因能够编码非典型G蛋白γ亚基,通过实验证明该基因能够调节环境胁迫下产生的过氧化氢外流,降低碱性敏感性。并且对该基因在小麦,玉米,水稻等作物中都进行大田试验验证,的确能够抗盐碱。
Abstract:
The use of alkaline salt lands for crop production is hindered by a scarcity of knowledge and breeding efforts for plant alkaline tolerance. Through genome association analysis of sorghum, a … >>>
The use of alkaline salt lands for crop production is hindered by a scarcity of knowledge and breeding efforts for plant alkaline tolerance. Through genome association analysis of sorghum, a naturally high-alkaline-tolerant crop, we detected a major locus, (), specifically related to alkaline-salinity sensitivity. An allele with a carboxyl-terminal truncation increased sensitivity, whereas knockout of increased tolerance to alkalinity in sorghum, millet, rice, and maize. encodes an atypical G protein γ subunit that affects the phosphorylation of aquaporins to modulate the distribution of hydrogen peroxide (HO) These processes appear to protect plants against oxidative stress by alkali. Designing knockouts of homologs or selecting its natural nonfunctional alleles could improve crop productivity in sodic lands. <<<
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14.
惊鸿 (2022-12-29 15:54):
#paper DOI : 10.1126/science.abl6620 Glassfrogs conceal blood in their liver to maintain transparency 20221222 动物的透明体是一种复杂的伪装形式,涉及减少整个生物体的光散射和吸收的机制。在脊椎动物中,获得透明度很困难,因为它们的循环系统充满了强烈减弱光线的红细胞 (RBC)。在此,这个实验团队记录了玻璃蛙如何通过隐藏这些细胞。该实验团队使用光声成像在体内追踪红细胞,表明静息玻璃蛙通过从循环中去除约 89% 的红细胞并将其包装在肝脏中,从而将透明度提高两到三倍。因此,脊椎动物的透明性需要透明组织和从这些组织中“清除”呼吸色素的活跃机制。此外,玻璃蛙能够调节位置、密度。
Abstract:
Transparency in animals is a complex form of camouflage involving mechanisms that reduce light scattering and absorption throughout the organism. In vertebrates, attaining transparency is difficult because their circulatory system … >>>
Transparency in animals is a complex form of camouflage involving mechanisms that reduce light scattering and absorption throughout the organism. In vertebrates, attaining transparency is difficult because their circulatory system is full of red blood cells (RBCs) that strongly attenuate light. Here, we document how glassfrogs overcome this challenge by concealing these cells from view. Using photoacoustic imaging to track RBCs in vivo, we show that resting glassfrogs increase transparency two- to threefold by removing ~89% of their RBCs from circulation and packing them within their liver. Vertebrate transparency thus requires both see-through tissues and active mechanisms that "clear" respiratory pigments from these tissues. Furthermore, glassfrogs' ability to regulate the location, density, and packing of RBCs without clotting offers insight in metabolic, hemodynamic, and blood-clot research. <<<
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15.
小擎子 (2022-10-31 23:59):
#paper doi:10.1126/science.aao3290 Science, 2019, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. 共生微生物组与转移性黑色素瘤患者的抗PD-1疗效相关,对免疫治疗有反应为R组,无反应为NR组。 文章开始用了16S测序、宏基因组测序和定量PCR,后比较发现,宏基因组的数据在R与NR的差异代表物种较少且与16S重叠(比较奇怪),后选用16S测序来做分析。在R组中,细菌物种, Bifidobacterium longum(长双歧杆菌), Collinsella aerofaciens(科林塞拉菌)和 Enterococcus faecium(屎肠球菌)含量较高,通过无菌小鼠实验,确认来自R组的粪便可以改善肿瘤控制,增强T细胞反应,提供抗PD-L1治疗的疗效。文献结尾的话,“除了微生物组之外,其他肿瘤和宿主因素会影响抗肿瘤免疫和癌症免疫治疗的疗效。Wnt/β-连环蛋白通路的肿瘤内在激活和Pte的缺失或突变已被证明会导致 T细胞浸润不足进入肿瘤微环境和对检查点阻断免疫疗法的耐药性。免疫调节基因中的种系多态性也有可能影响自发抗肿瘤T细胞反应的程度。我们在这里描述的结果开辟了将共生微生物组成以及肿瘤基因组学和种系遗传学整合到多参数模型中的途径,该模型可以最大限度地提高预测哪些患者可能对抗PD-1等免疫疗法产生反应的能力。”
Abstract:
Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition … >>>
Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16 ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included , , and Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients. <<<
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16.
小擎子 (2022-08-31 23:41):
#paper doi: 10.1126/science.aaw7479 Nature, 2022, Akkermansia muciniphila phospholipid induces homeostatic immune responses. 找到了明星益生菌Akk调节免疫的物质a15:0-i15:0 PE,解释了其作用机制。a15:0-i15:0 PE是Akk菌膜脂质的主要成分之一。Akk菌隶属于疣微菌门(Verrucomicrobia),是肠道微生物中唯一一个来自疣微菌门的细菌。大海捞针式的研究,对什么样的生长环境能使Akk菌产生a15:0-i15:0 PE比较好奇。
Abstract:
Intestinal adaptive immune responses influence host health, yet only a few intestinal bacteria species that induce cognate adaptive immune responses during homeostasis have been identified. Here, we show that , … >>>
Intestinal adaptive immune responses influence host health, yet only a few intestinal bacteria species that induce cognate adaptive immune responses during homeostasis have been identified. Here, we show that , an intestinal bacterium associated with systemic effects on host metabolism and PD-1 checkpoint immunotherapy, induces immunoglobulin G1 (IgG1) antibodies and antigen-specific T cell responses in mice. Unlike previously characterized mucosal responses, T cell responses to are limited to T follicular helper cells in a gnotobiotic setting, without appreciable induction of other T helper fates or migration to the lamina propria. However, -specific responses are context dependent and adopt other fates in conventional mice. These findings suggest that, during homeostasis, contextual signals influence T cell responses to the microbiota and modulate host immune function. <<<
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17.
哪有情可长 (2022-07-30 21:34):
#paper doi: 10.1126/science.abl7392 Gametophyte genome activation occurs at pollen mitosis I in maize. 孢子体经过减数分裂成单倍体的孢子,然后经细胞增殖和分化,形成配子体。配子体世代的主要功能是形成单倍体配子,而精、卵细胞的融合又产生了新的孢子体,从而完成了一个生活周期。母体基因控制着植物受精后大多数早期事件,随后是母体到合子的转变,这个过程中母体产物的降解与合子基因组的激活相协调。本研究对玉米减数分裂开始到花粉脱落的26天内单个玉米花粉前体细胞和籽粒RNA含量进行测序,发现,花粉发育到一半的过程中,花粉粒的单倍体基因组从亲本的二倍体基因组中夺取控制权,随着孢子体到配子体的转变,为下一代的生长发育奠定了基础。
Abstract:
Flowering plants alternate between multicellular haploid (gametophyte) and diploid (sporophyte) generations. Pollen actively transcribes its haploid genome, providing phenotypic diversity even among pollen grains from a single plant. In this … >>>
Flowering plants alternate between multicellular haploid (gametophyte) and diploid (sporophyte) generations. Pollen actively transcribes its haploid genome, providing phenotypic diversity even among pollen grains from a single plant. In this study, we used allele-specific RNA sequencing of single pollen precursors to follow the shift to haploid expression in maize pollen. We observed widespread biallelic expression for 11 days after meiosis, indicating that transcripts synthesized by the diploid sporophyte persist long into the haploid phase. Subsequently, there was a rapid and global conversion to monoallelic expression at pollen mitosis I, driven by active new transcription from the haploid genome. Genes showed evidence of increased purifying selection if they were expressed after (but not before) pollen mitosis I. This work establishes the timing during which haploid selection may act in pollen. <<<
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18.
李翛然 (2022-07-28 13:15):
#paper DOI: 10.1126/science.aba2374 Preventing Engrailed-1 activation in Mbrob- lasts yields wound regeneration without scarring 2021年4月份发表在Science的皮肤损伤修复靶点很有意思,号称不留伤疤,目前发现一个老药作用在这个靶点,没有其它药物进入临床,但是有其它抑制剂。那个老药Verteporfin是通过激光照射眼睛治疗眼部血管破裂的,不知道用于皮肤损伤新靶点的疗效会受制于老药靶点(假定靶点不同)。这个靶点已经成功地引起了我司注意
Abstract:
Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. lineage-positive fibroblasts (EPFs) are known to function in scarring, but lineage-negative fibroblasts (ENFs) remain … >>>
Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. lineage-positive fibroblasts (EPFs) are known to function in scarring, but lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated). <<<
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19.
颜林林 (2022-07-14 21:57):
#paper doi:10.1126/science.abl9283 Science, 2022, Substitution mutational signatures in whole-genome–sequenced cancers in the UK population. 这篇今年四月发表在《Science》上的文章,被最新一期《Cancer Cell》所推荐(doi:10.1016/j.ccell.2022.05.011)。这些年做大规模人群做全基因组测序(WGS)的文章并不少见,时至今日仍能发表于顶刊,其创新点及意义,大概还是值得关注和了解下的。本文的入组病例样本来自Genomics England (GEL) 100,000 Genomes Project (100kGP),共计12,222个肿瘤样本(来自11,585位个体)的WGS,在分析得到与肿瘤发生的突变特征后,又在另外两个大型独立队列(来自国际癌症基因组联盟 (ICGC) 的 3001 例原发性癌症和来自 Hartwig 医学基金会的 3417 例转移性癌症)中进行了验证。本文重点关注由WGS分析得到的单碱基替换 (SBS) 和双碱基替换 (DBS) 特征,并建立了一个名为 Signature Fit Multi-Step (FitMS) 的计算框架。该方法用来区分哪些特征是各不同癌种中常见的,而哪些是罕见的、仅出现在特定癌种或器官。而通过对组织特异性特征进行聚类分析,并将其组合起来形成一组参考特征,帮助进行机制和病因的解释。从所解决的问题及方法看,似乎并无特别重大的创新,因此初步推断,之所以能跻身顶刊,与其超大人群及数据量,以及相应的工作量(参见长达94页的补充材料),还是密不可分的。
Abstract:
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses … >>>
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses. <<<
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20.
June (2022-06-30 23:59):
#paper doi: 10.1126/science.aaw9021. Epub 2022 Jan 7.Tissue geometry drives deterministic organoid patterning该研究提出了一种指导基于干细胞的器官发生的方法,该过程完全由“随机”自组织驱动。该研究还验证了长期存在但未充分探索的形态发生范例,其中组织的当前形状可以帮助图案化和指定组织的发育过程,从而确定组织的未来形状。在肠隐窝形成的情况下,出芽不仅可以跟随Paneth细胞的出现,而且还可以先于它。该研究的类器官培养物可用于回答现有类器官和动物模型无法解决的问题,它们可以将类器官技术转化为现实世界的应用。
Abstract:
Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they self-organize, but … >>>
Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they self-organize, but the structures formed are often heterogeneous and irreproducible, which limits their use in the lab and clinic. We describe methodologies for spatially and temporally controlling organoid formation, thereby rendering a stochastic process more deterministic. Bioengineered stem cell microenvironments are used to specify the initial geometry of intestinal organoids, which in turn controls their patterning and crypt formation. We leveraged the reproducibility and predictability of the culture to identify the underlying mechanisms of epithelial patterning, which may contribute to reinforcing intestinal regionalization in vivo. By controlling organoid culture, we demonstrate how these structures can be used to answer questions not readily addressable with the standard, more variable, organoid models. <<<
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