当前共找到 14 篇文献分享。
1.
惊鸿
(2023-12-30 08:42):
#paper The quantum house of cards 10.1073/pnas.2313269120 Pub Date : 2023-12-26
量子计算机已被提议解决许多重要问题,例如发现新药、肥料生产的新催化剂、破解加密协议、优化金融投资组合或实施新的人工智能应用。然而,迄今为止,诸如 3 乘以 5 之类的简单任务超出了现有的量子硬件的能力。本文探讨了量子计算机兑现其承诺需要解决的困难。我讨论了构建量子计算机的整个技术堆栈,从顶层(实际算法和相关应用程序)到最底层(量子硬件、其控制电子设备、低温等),而不是忘记了量子纠错的关键中间层。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2024-Jan-02.
DOI: 10.1073/pnas.2313269120
PMID: 38147549
Abstract:
Quantum computers have been proposed to solve a number of important problems such as discovering new drugs, new catalysts for fertilizer production, breaking encryption protocols, optimizing financial portfolios, or implementing …
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Quantum computers have been proposed to solve a number of important problems such as discovering new drugs, new catalysts for fertilizer production, breaking encryption protocols, optimizing financial portfolios, or implementing new artificial intelligence applications. Yet, to date, a simple task such as multiplying 3 by 5 is beyond existing quantum hardware. This article examines the difficulties that would need to be solved for quantum computers to live up to their promises. I discuss the whole stack of technologies that has been envisioned to build a quantum computer from the top layers (the actual algorithms and associated applications) down to the very bottom ones (the quantum hardware, its control electronics, cryogeny, etc.) while not forgetting the crucial intermediate layer of quantum error correction.
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2.
muton
(2023-10-31 22:43):
#paper: https://doi.org/10.1073/pnas.2304085120 Modeling naturalistic face processing in humans with deep convolutional neural networks 大脑在加工信息的过程中,都是一个动态变化的过程,以往使用深度卷积神经网络可以模拟出大脑在记忆过程中的动态变化过程,但是对人脸材料而言,都是基于静态的材料进行解码,少有研究使用深度卷积神经网络的方法来解释大脑加工人脸的过程。由于人脸对于人类而言是具有特殊属性的一类材料,并且具有多维属性,如性别,表情,年龄等等,使用此方法解码是非常必要的。本文中作者使用700多个陌生面孔的自然刺激,每个视频长达4s,结合行为以及FMRI成像数据,对人脸加工过程进行了解码,结果发现,深度卷积神经网络模型在中间层/阶段可以很好的解码出分类情况,此阶段与行为结果也一致(行为结果更多体现出了分类信息),但是在全连接层可能更多体现了其他认知过程,如个性化信息等,神经信号的结果包含了更多动态和其他信息加工的信息。因此此模型可以很好的预测面部分类情况,但是对于随后的认知情况和动态变化情况并不能有一个很好的分类效果,因此,解码人脸动态加工过程的深度卷积神经网络模型仍有待进一步发展。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2023-10-24.
DOI: 10.1073/pnas.2304085120
PMID: 37847731
Abstract:
Deep convolutional neural networks (DCNNs) trained for face identification can rival and even exceed human-level performance. The ways in which the internal face representations in DCNNs relate to human cognitive …
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Deep convolutional neural networks (DCNNs) trained for face identification can rival and even exceed human-level performance. The ways in which the internal face representations in DCNNs relate to human cognitive representations and brain activity are not well understood. Nearly all previous studies focused on static face image processing with rapid display times and ignored the processing of naturalistic, dynamic information. To address this gap, we developed the largest naturalistic dynamic face stimulus set in human neuroimaging research (700+ naturalistic video clips of unfamiliar faces). We used this naturalistic dataset to compare representational geometries estimated from DCNNs, behavioral responses, and brain responses. We found that DCNN representational geometries were consistent across architectures, cognitive representational geometries were consistent across raters in a behavioral arrangement task, and neural representational geometries in face areas were consistent across brains. Representational geometries in late, fully connected DCNN layers, which are optimized for individuation, were much more weakly correlated with cognitive and neural geometries than were geometries in late-intermediate layers. The late-intermediate face-DCNN layers successfully matched cognitive representational geometries, as measured with a behavioral arrangement task that primarily reflected categorical attributes, and correlated with neural representational geometries in known face-selective topographies. Our study suggests that current DCNNs successfully capture neural cognitive processes for categorical attributes of faces but less accurately capture individuation and dynamic features.
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3.
尹志
(2023-09-30 22:52):
#paper https://doi.org/10.1073/pnas.2112677119 Thoughts on how to think (and talk) about RNA structure。mRNA疫苗的出现,再一次唤起了生物学家们对RNA结构与功能研究的热情。本文强调了重新审视rna,开展未来更多研究的重要性,反思了当前对rna结构与功能理解上可能存在的误区,并结合自己的经验,提出了6条rna研究上值得注意的点,这些观点对未来rna研究提供了一个很有价值的方向。rna的复杂性及目前的开放性是一个特别吸引计算研究者入坑的原因。传统上将rna看做一条松垮的面条的方式目前看来恐怕不能很好的描述rna的结构,rna折叠的预测目前存在非常大的挑战或者说研究空间,据我所知,目前rna折叠连二级结构都做不好,那三级结构呢?即使结构测定相对容易的情况下,作为计算工作者,能不能很好的跟进?作者在文中多次强调了rna的“unstructed”的表述问题,所谓的非结构给rna的结构预测反而提出了更大挑战:所谓“Inherently Structured”Does Not Mean “Static”, 从计算角度而言,rna的骨架约束变少,自由能landscape梯度较低,那么给计算优化带来了很多有趣的问题,面对大量的局部最优,有不有更合适的优化算法?特别是rna的动态敏感性,怎么在实际预测中考虑
这些因素,如何建模这些环境影响?Non-Watson–Crick Pairing在在RNA的功能和调控中的作用如何被考虑,等等问题。正如作者在文末呼吁的:RNA has gone mainstream, solet’s make sure RNA structure properties return to thefront seat。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2022-04-26.
DOI: 10.1073/pnas.2112677119
PMID: 35439059
Abstract:
Recent events have pushed RNA research into the spotlight. Continued discoveries of RNA with unexpected diverse functions in healthy and diseased cells, such as the role of RNA as both …
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Recent events have pushed RNA research into the spotlight. Continued discoveries of RNA with unexpected diverse functions in healthy and diseased cells, such as the role of RNA as both the source and countermeasure to a severe acute respiratory syndrome coronavirus 2 infection, are igniting a new passion for understanding this functionally and structurally versatile molecule. Although RNA structure is key to function, many foundational characteristics of RNA structure are misunderstood, and the default state of RNA is often thought of and depicted as a single floppy strand. The purpose of this perspective is to help adjust mental models, equipping the community to better use the fundamental aspects of RNA structural information in new mechanistic models, enhance experimental design to test these models, and refine data interpretation. We discuss six core observations focused on the inherent nature of RNA structure and how to incorporate these characteristics to better understand RNA structure. We also offer some ideas for future efforts to make validated RNA structural information available and readily used by all researchers.
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4.
徐炳祥
(2023-05-29 09:11):
#paper doi: 10.1073/pnas.2023347118 PNAS, 2021, DNA methylation-linked chromatin accessibility affects genomic architecture in Arabidopsis。DNA甲基化是重要的表观遗传调控维度,CpG岛甲基化水平的改变对基因表达起了重要的调控作用。然而DNA甲基化和表观遗传的其他维度之间的关系研究尚十分缺乏。本文通过对具有不同DNA甲基转移酶活性的拟南芥品系进行染色质开放性图谱和染色质空间构象图谱的测定和比较,对此问题进行了研究。结果显示,低DNA甲基化确实与染色质开放和染色质区室从B向A的转换有关。该研究是目前仅有的几项DNA甲基化与染色质空间构象直接关联的研究,但不同品系的相互比较仍不能说明二者之间是否以及具有何种因果关系。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2021-02-02.
DOI: 10.1073/pnas.2023347118
PMID: 33495321
Abstract:
DNA methylation is a major epigenetic modification found across species and has a profound impact on many biological processes. However, its influence on chromatin accessibility and higher-order genome organization remains …
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DNA methylation is a major epigenetic modification found across species and has a profound impact on many biological processes. However, its influence on chromatin accessibility and higher-order genome organization remains unclear, particularly in plants. Here, we present genome-wide chromatin accessibility profiles of 18 mutants that are deficient in CG, CHG, or CHH DNA methylation. We find that DNA methylation in all three sequence contexts impacts chromatin accessibility in heterochromatin. Many chromatin regions maintain inaccessibility when DNA methylation is lost in only one or two sequence contexts, and signatures of accessibility are particularly affected when DNA methylation is reduced in all contexts, suggesting an interplay between different types of DNA methylation. In addition, we found that increased chromatin accessibility was not always accompanied by increased transcription, suggesting that DNA methylation can directly impact chromatin structure by other mechanisms. We also observed that an increase in chromatin accessibility was accompanied by enhanced long-range chromatin interactions. Together, these results provide a valuable resource for chromatin architecture and DNA methylation analyses and uncover a pivotal role for methylation in the maintenance of heterochromatin inaccessibility.
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5.
钟鸣
(2022-12-31 19:23):
#paper Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues https://doi.org/10.1073/pnas.2105968118
许多新冠感染者康复后依然能通过PCR检测到病毒,但是却分离不到活病毒,考虑到新冠病毒是一种RNA病毒,因此合理怀疑其逆转录整合到了宿主基因组上。为了证实,作者使用了三种测序方法来对人类细胞来源的基因组测序,结果均发现了新冠基因组。此外作者还回顾了感染者组织来源的RNA测序数据,发现了包括新冠在内的许多病毒的转录本。比较简单的一篇论文,比较可看的地方是讨论。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2021-05-25.
DOI: 10.1073/pnas.2105968118
PMID: 33958444
Abstract:
Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some of these …
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Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some of these patients do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the DNA of human cells in culture and that transcription of the integrated sequences might account for some of the positive PCR tests seen in patients. In support of this hypothesis, we found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected human cells. We found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites, consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition mechanism. We also found, in some patient-derived tissues, evidence suggesting that a large fraction of the viral sequences is transcribed from integrated DNA copies of viral sequences, generating viral-host chimeric transcripts. The integration and transcription of viral sequences may thus contribute to the detection of viral RNA by PCR in patients after infection and clinical recovery. Because we have detected only subgenomic sequences derived mainly from the 3' end of the viral genome integrated into the DNA of the host cell, infectious virus cannot be produced from the integrated subgenomic SARS-CoV-2 sequences.
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6.
他者
(2022-12-31 17:34):
#paper doi: doi.org/10.1073/pnas.2202394119,Sleep facilitates spatial memory but not navigation using the Minecraft Memory and Navigation tas,PNAS这篇文章是今年10月刚发表的,基于《我的世界》这个游戏分别研究了睡眠对于导航能力、导航记忆的作用。之前的研究已经证实睡眠可以促进海马相关的记忆,而我们知道海马可以支持空间环境的获取和内部表征,也就是海马可以支持认知地图的形成,认知地图是通过环境探索构建的,是导航的重要表征。那么,推出睡眠可以促进导航相关的记忆就是相当自然的。但是,之前的研究者对于睡眠对导航相关空间记忆的作用的研究结果却不乐观,有一些证实了该推测,而有一些没有。本文研究者认为,睡眠对导航相关空间记忆的作用,要拆成睡眠对空间记忆的作用,以及睡眠对导航能力的作用两部分来看。研究结果支持睡眠促进空间记忆,但不能促进导航能力。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2022-10-25.
DOI: 10.1073/pnas.2202394119
PMID: 36252023
Abstract:
Sleep facilitates hippocampal-dependent memories, supporting the acquisition and maintenance of internal representation of spatial relations within an environment. In humans, however, findings have been mixed regarding sleep's contribution to spatial …
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Sleep facilitates hippocampal-dependent memories, supporting the acquisition and maintenance of internal representation of spatial relations within an environment. In humans, however, findings have been mixed regarding sleep's contribution to spatial memory and navigation, which may be due to task designs or outcome measurements. We developed the Minecraft Memory and Navigation (MMN) task for the purpose of disentangling how spatial memory accuracy and navigation change over time, and to study sleep's independent contributions to each. In the MMN task, participants learned the locations of objects through free exploration of an open field computerized environment. At test, they were teleported to random positions around the environment and required to navigate to the remembered location of each object. In study 1, we developed and validated four unique MMN environments with the goal of equating baseline learning and immediate test performance. A total of 86 participants were administered the training phases and immediate test. Participants' baseline performance was equivalent across all four environments, supporting the use of the MMN task. In study 2, 29 participants were trained, tested immediately, and again 12 h later after a period of sleep or wake. We found that the metric accuracy of object locations, i.e., spatial memory, was maintained over a night of sleep, while after wake, metric accuracy declined. In contrast, spatial navigation improved over both sleep and wake delays. Our findings support the role of sleep in retaining the precise spatial relationships within a cognitive map; however, they do not support a specific role of sleep in navigation.
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7.
庞庞
(2022-11-17 18:14):
#paper https://doi.org/10.1073/pnas.2110416119 Sex differences in the functional topography of association networks in youth 之前的工作已经证实,大脑皮层功能网络的空间分布存在个体间差异。然而,至今仍不知道年轻人大脑功能网络形态是否存在性别差异。该研究基于693个年轻人被试,使用NMF定义个体的功能网络,并使用多变量(LSVM)模型,用个体功能形态指标对性别进行分类,准确率达到82.9%,对预测做出显著贡献的脑区分布在联合网络:包括额顶网络,默认模式网络,背外侧注意网络。同时,作者也使用单变量(GAM)模型探究形态指标和性别的关系,发现了一致的结果。最后,作者使用艾伦脑图谱的基因表达数据,揭示了功能形态存在差异的脑区与X染色体的基因表达相关。综上,该研究表明性别是塑性功能形态的重要生物因素。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2022-08-16.
DOI: 10.1073/pnas.2110416119
PMID: 35939696
Abstract:
Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there …
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Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here, we leveraged an advanced machine learning method (sparsity-regularized non-negative matrix factorization) to define individualized functional networks in 693 youth (ages 8 to 23 y) who underwent functional MRI as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 82.9% accuracy ( < 0.0001). Brain regions most effective in classifying participant sex belonged to association networks, including the ventral attention, default mode, and frontoparietal networks. Mass univariate analyses using generalized additive models with penalized splines provided convergent results. Furthermore, transcriptomic data from the Allen Human Brain Atlas revealed that sex differences in multivariate patterns of functional topography were spatially correlated with the expression of genes on the X chromosome. These results highlight the role of sex as a biological variable in shaping functional topography.
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8.
负负
(2022-10-29 19:25):
#paper Understanding the role of individual units in a deep neural network (https://doi.org/10.1073/pnas.1907375117) PNAS, 2020.
作者通过对Place365数据集上训练得到的VGG16网络的神经元激活图进行上采样观察到了深度学习神经网络中的单个神经元所学习到的概念特征,讨论了这些神经元在“场景分类器”以及生成对抗网络中的“生成器”中的作用,最后讨论了这一发现的应用前景。本项工作的主要研究发现:
1、场景分类器中较“浅”层的神经元倾向于学习到“颜色”、“材质”等抽象概念,较“深”层的神经元倾向于学习到“物体”、“零件”等具体概念。
2、部分神经元对场景识别有重要的作用,关闭这些神经元会导致场景识别能力降低,在多个场景识别任务中都发挥重要作用的神经元具有更好的可解释性。
3、GANs中生成器的神经元学习到的特征与辨别器相反,即,“浅”层的神经元倾向于学习具体概念,而较“深”层的神经元倾向于学习到抽象概念。
4、关闭或启动生成器中的部分神经元,会使生成的图片中去除或增添部分场景元素,同时生成器会根据场景的特性在合适的位置生成物体,因此可以通过操纵GANs中的神经元的激活情况来进行场景绘画。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2020-12-01.
DOI: 10.1073/pnas.1907375117
PMID: 32873639
Abstract:
Deep neural networks excel at finding hierarchical representations that solve complex tasks over large datasets. How can we humans understand these learned representations? In this work, we present network dissection, …
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Deep neural networks excel at finding hierarchical representations that solve complex tasks over large datasets. How can we humans understand these learned representations? In this work, we present network dissection, an analytic framework to systematically identify the semantics of individual hidden units within image classification and image generation networks. First, we analyze a convolutional neural network (CNN) trained on scene classification and discover units that match a diverse set of object concepts. We find evidence that the network has learned many object classes that play crucial roles in classifying scene classes. Second, we use a similar analytic method to analyze a generative adversarial network (GAN) model trained to generate scenes. By analyzing changes made when small sets of units are activated or deactivated, we find that objects can be added and removed from the output scenes while adapting to the context. Finally, we apply our analytic framework to understanding adversarial attacks and to semantic image editing.
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9.
林李泽强
(2022-09-30 23:42):
#paper doi:10.1073/pnas.1910666116,PNAS, 2019, Population-based neuroimaging reveals traces of childbirth in the maternal brain.
这项利用神经成像和机器学习(大脑年龄分析范式),分析了来自the UK Biobank的12021名中年女性的大脑结构特征,结果表明,与未分娩的同龄人相比,产妇大脑老化证据较少(即产妇展现出更'年轻'的大脑)。分娩(生育)和“看起来更年轻”的大脑之间的关系不受常见的基因变异或相关的混杂因素影响。结果表明,胎次可能涉及神经变化,可能会影响女性晚年的大脑老化,当然这需要更进一步的纵向研究确认。这项研究的结果还是相当有意思,与我们平时的认知(生多孩子的人‘老得快’)是截然相反。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2019-10-29.
DOI: 10.1073/pnas.1910666116
PMID: 31615888
Abstract:
Maternal brain adaptations have been found across pregnancy and postpartum, but little is known about the long-term effects of parity on the maternal brain. Using neuroimaging and machine learning, we …
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Maternal brain adaptations have been found across pregnancy and postpartum, but little is known about the long-term effects of parity on the maternal brain. Using neuroimaging and machine learning, we investigated structural brain characteristics in 12,021 middle-aged women from the UK Biobank, demonstrating that parous women showed less evidence of brain aging compared to their nulliparous peers. The relationship between childbirths and a "younger-looking" brain could not be explained by common genetic variation or relevant confounders. Although prospective longitudinal studies are needed, the results suggest that parity may involve neural changes that could influence women's brain aging later in life.
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10.
象棋
(2022-08-31 22:56):
#paper doi:10.1073/pnas.1719616115, PNAS, (2018), Mid-level visual features underlie the high-level categorical organization of the ventral stream. 这篇文章说明大脑的腹侧枕颞叶区域(VOTC)加工的是Mid-level(物体的大小属性、有无生命等特征)信息。研究者使用了一种纹理合成算法,这种算法生成的texforms保留了物体图片Mid-level的信息,但又不被识别出来是什么东西。然后分析texforms和原图在VOTC的激活,结果发现二者的激活非常相似,这说明VOTC区实际上加工的是物体Mid-level的信息。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2018-09-18.
DOI: 10.1073/pnas.1719616115
PMID: 30171168
Abstract:
Human object-selective cortex shows a large-scale organization characterized by the high-level properties of both animacy and object size. To what extent are these neural responses explained by primitive perceptual features …
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Human object-selective cortex shows a large-scale organization characterized by the high-level properties of both animacy and object size. To what extent are these neural responses explained by primitive perceptual features that distinguish animals from objects and big objects from small objects? To address this question, we used a texture synthesis algorithm to create a class of stimuli-texforms-which preserve some mid-level texture and form information from objects while rendering them unrecognizable. We found that unrecognizable texforms were sufficient to elicit the large-scale organizations of object-selective cortex along the entire ventral pathway. Further, the structure in the neural patterns elicited by texforms was well predicted by curvature features and by intermediate layers of a deep convolutional neural network, supporting the mid-level nature of the representations. These results provide clear evidence that a substantial portion of ventral stream organization can be accounted for by coarse texture and form information without requiring explicit recognition of intact objects.
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11.
cellsarts
(2022-08-31 17:40):
Paper# www.pnas.org/cgi/doi/10.1073/pnas.1714249114 Distinct roles of N- and O-glycans in cellulase activity and stability
N-和O-聚糖在纤维素酶活性和稳定性中的独特的作用
在自然界中,许多微生物分泌糖苷水解酶,氧化还原酶,辅助的生物酶的混合物,以降解多糖衍生物和植物的木质素等。这些酶通常被糖基化修饰,通常分为N-和o -糖基化,其作用已被广泛认为是为应对细胞外的恶略的环境,防止这些生物酶被水解。糖基化修饰酶蛋白已被证明对活性成倍的影响,但这些影响尚未完全被了解。在这里,我们研究了糖苷水解酶家族7的纤维生物水解酶(Cel7A), 模拟了其的含有o -糖基化位修饰点的纤维素结合结构域,模拟了其的含有N-和o -糖基化位点的催化结构域,以及含了o -糖基化位点修饰有抑制水解功能的链接linker结构域。我们报道了纤维素酶Cel7A 糖基化修饰的共识图谱,包括糖链位点和基序。此外,我们检查糖基化修饰在降解多糖得活性、底物结合和热和蛋白水解稳定性等方面的作用。纤维生物水解酶(Cel7A)催化结构域(CD)上的N-糖基化位点被敲除后的实验结果显示,N-糖基化位点的敲除对纤维生物水解酶(Cel7A)催化活性及与纤维素底物的结合程度的影响很小, 但确实影响纤维生物水解酶(Cel7A)的稳定性。纤维素结合结构域(CBM)的O-糖基化位点的敲除,含对酶结合纤维素底物的影响并不大,对整个酶蛋白的抗外界的酶解作用,对整个酶蛋白的活性的影响都不大。然而,连接纤维素结合结构域和催化结构域的linker的o -糖基化,极大的增加了整个酶蛋白抗水解的能力。通过分子模拟预测了连接子(linker)区域的o -糖基化的附加作用,即当纤维素结合于Cel7A为在上,模型预测了α-螺旋的形成和增加了非糖基化连接子与纤维素的相互作用。总的来说,这项研究揭示了N-和o -糖基化可能的关键作用广泛适用于其他植物细胞壁降解酶。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2017-12-26.
DOI: 10.1073/pnas.1714249114
PMID: 29229855
Abstract:
In nature, many microbes secrete mixtures of glycoside hydrolases, oxidoreductases, and accessory enzymes to deconstruct polysaccharides and lignin in plants. These enzymes are often decorated with N- and O-glycosylation, the …
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In nature, many microbes secrete mixtures of glycoside hydrolases, oxidoreductases, and accessory enzymes to deconstruct polysaccharides and lignin in plants. These enzymes are often decorated with N- and O-glycosylation, the roles of which have been broadly attributed to protection from proteolysis, as the extracellular milieu is an aggressive environment. Glycosylation has been shown to sometimes affect activity, but these effects are not fully understood. Here, we examine N- and O-glycosylation on a model, multimodular glycoside hydrolase family 7 cellobiohydrolase (Cel7A), which exhibits an O-glycosylated carbohydrate-binding module (CBM) and an O-glycosylated linker connected to an N- and O-glycosylated catalytic domain (CD)-a domain architecture common to many biomass-degrading enzymes. We report consensus maps for Cel7A glycosylation that include glycan sites and motifs. Additionally, we examine the roles of glycans on activity, substrate binding, and thermal and proteolytic stability. N-glycan knockouts on the CD demonstrate that N-glycosylation has little impact on cellulose conversion or binding, but does have major stability impacts. O-glycans on the CBM have little impact on binding, proteolysis, or activity in the whole-enzyme context. However, linker O-glycans greatly impact cellulose conversion via their contribution to proteolysis resistance. Molecular simulations predict an additional role for linker O-glycans, namely that they are responsible for maintaining separation between ordered domains when Cel7A is engaged on cellulose, as models predict α-helix formation and decreased cellulose interaction for the nonglycosylated linker. Overall, this study reveals key roles for N- and O-glycosylation that are likely broadly applicable to other plant cell-wall-degrading enzymes.
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12.
LXJ
(2022-07-31 22:39):
#paper Kato Y, Ohsugi K, Fukuno Y, Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment.Proc Natl Acad Sci U S A 2022 Jul 26;119(30)二十碳五烯酸(EPA)是一种ω-3多不饱和脂肪酸,具有抗炎、神经保护和心血管保护活性等作用。虽然EPA被用作基于营养的药物制剂或膳食补充剂,但其分子靶点仍有争议。作者发现EPA及其代谢产物可逆地抑制囊泡核苷酸转运体(VNUT),VNUT是嘌呤能化学传递中囊泡储存和释放ATP的关键分子。EPA损害神经元的囊泡ATP释放,而不影响其他神经递质的囊泡释放。在体内,小鼠表现出神经病理性疼痛的延迟发作以及对神经病理性和炎性疼痛的抵抗。EPA可有效减轻野生型小鼠的神经病理性疼痛和炎性疼痛,但在不影响基础伤害感受的情况下,对小鼠无效。鞘内注射嘌呤受体激动剂可抵消EPA的镇痛作用,其镇痛作用强于用于神经病理性疼痛治疗的现有药物,且副作用很少。这篇研究结果表明,VNUT是EPA的一个分子靶点,可以减轻神经病理性和炎症性疼痛以及胰岛素抵抗。EPA可能是针对嘌呤能化学传递的神经、免疫和代谢疾病的一种独特的基于营养的治疗和预防策略。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2022-07-26.
DOI: 10.1073/pnas.2122158119
PMID: 35858418
Abstract:
Eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid, is an essential nutrient that exhibits antiinflammatory, neuroprotective, and cardiovascular-protective activities. Although EPA is used as a nutrient-based pharmaceutical agent or …
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Eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid, is an essential nutrient that exhibits antiinflammatory, neuroprotective, and cardiovascular-protective activities. Although EPA is used as a nutrient-based pharmaceutical agent or dietary supplement, its molecular target(s) is debatable. Here, we showed that EPA and its metabolites strongly and reversibly inhibit vesicular nucleotide transporter (VNUT), a key molecule for vesicular storage and release of adenosine triphosphate (ATP) in purinergic chemical transmission. In vitro analysis showed that EPA inhibits human VNUT-mediated ATP uptake at a half-maximal inhibitory concentration (IC) of 67 nM, acting as an allosteric modulator through competition with Cl. EPA impaired vesicular ATP release from neurons without affecting the vesicular release of other neurotransmitters. In vivo, mice showed a delay in the onset of neuropathic pain and resistance to both neuropathic and inflammatory pain. EPA potently attenuated neuropathic and inflammatory pain in wild-type mice but not in mice without affecting the basal nociception. The analgesic effect of EPA was canceled by the intrathecal injection of purinoceptor agonists and was stronger than that of existing drugs used for neuropathic pain treatment, with few side effects. Neuropathic pain impaired insulin sensitivity in previous studies, which was improved by EPA in the wild-type mice but not in the mice. Our results showed that VNUT is a molecular target of EPA that attenuates neuropathic and inflammatory pain and insulin resistance. EPA may represent a unique nutrient-based treatment and prevention strategy for neurological, immunological, and metabolic diseases by targeting purinergic chemical transmission.
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13.
半面阳光
(2022-07-26 14:25):
#paper DOI: 10.1073/pnas.2019768118, 2021 Feb 2;118(5):e2019768118. Genome-wide detection of cytosine methylation by single molecule real-time sequencing. 这篇文章并非一篇最新发表的文献,是香港中文大学卢煜明团队于2021年发表在PANS上一篇研究文献。因为近期在一个学术会议上听到卢煜明教授介绍了这篇文献有关的研究结果,因此拿来研读。这篇文章的核心内容是利用PacBio的SMRT三代测序技术和卷积神经网络来检测DNA的甲基化。胞嘧啶的甲基化修饰,5-Methylcytosine (5mC) 是表观修饰中最重要的一种类型。应用比较广泛的检测CpG测序方法是亚硫酸盐测序(BS-seq)。但是BS-seq有一些不足之处,比如亚硫酸盐会导致DNA降解、还会将DNA序列中非甲基化的胞嘧啶(C)转化为胸腺嘧啶(T),影响后续的比对;而原始序列中C->T的点突变则又无法被亚硫酸盐所修饰。因此,在这篇文献中,作者采用单分子实时测序(Single molecular rea-time sequencing, SMRT sequencing)技术,开发了一个直接检测5mC的方法。这个方法将SMRT测序中的两个关键信息作为输入数据,结合卷积神经网络(CNN)构建了一个称为Holistic Kinetic (HK)Model 的检测方法。关键输入数据包括两个:一是SMRT测序中DNA聚合酶的动态信号(包括单个碱基发出荧光信号的时间和两个连续碱基之间的间隔时间),二是“序列背景”信息,即待检测的一段固定长度的DNA序列信息,这段固定长度的序列被称为一个“检测窗口”。作者首先用全基因组扩增的方法构建了一个非甲基化的数据集(阴性数据集,所有序列几乎都没有甲基化),同时用M.SssI 转甲基酶处理DNA样本构建了一个甲基化(阳性数据集, M.SssI 能够对双链DNA上的所有CpG位点进行甲基化);接着从这两个数据集中各取出一半数据来训练卷积神经网络,剩下的数据用于验证HK model的检测效果。结果显示,用HK model来区分甲基化状态的AUC最高达到了0.97。全基因组范围内在单碱基分辨率水平上检测5mC的敏感性和特异性分别达到90%和94%。研究结果还发现通过调节检测窗口大小和测序深度能够改变HK模型的检测效果。为了平衡下游数据分析与准确性之间的关系,最后选定21nt作为检测窗口的默认值,将10×作为测序深度的默认值。后续,作者采用一段人和小鼠杂交序列验证了HK模型在检测“杂合甲基化”序列(即同一段序列中同时包括甲基化和非甲基化的CpG )的可行性。此外,作者还对BS-seq的检测效果和HK model的检测效果进行了简单的比较研究。看这篇文献的感受一方面是工作量大,二是体现了作者对分子生物学的理论知识和测序技术特点的充分理解和应用。另外,这篇文献的整体研究框架和卢煜明团队以往的研究在思维上有着一脉相承的感觉,都体现了透彻地理解基本理论、灵活地运用测序技术来解决临床检测的难题。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2021-02-02.
DOI: 10.1073/pnas.2019768118
PMID: 33495335
Abstract:
5-Methylcytosine (5mC) is an important type of epigenetic modification. Bisulfite sequencing (BS-seq) has limitations, such as severe DNA degradation. Using single molecule real-time sequencing, we developed a methodology to directly …
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5-Methylcytosine (5mC) is an important type of epigenetic modification. Bisulfite sequencing (BS-seq) has limitations, such as severe DNA degradation. Using single molecule real-time sequencing, we developed a methodology to directly examine 5mC. This approach holistically examined kinetic signals of a DNA polymerase (including interpulse duration and pulse width) and sequence context for every nucleotide within a measurement window, termed the holistic kinetic (HK) model. The measurement window of each analyzed double-stranded DNA molecule comprised 21 nucleotides with a cytosine in a CpG site in the center. We used amplified DNA (unmethylated) and M.SssI-treated DNA (methylated) (M.SssI being a CpG methyltransferase) to train a convolutional neural network. The area under the curve for differentiating methylation states using such samples was up to 0.97. The sensitivity and specificity for genome-wide 5mC detection at single-base resolution reached 90% and 94%, respectively. The HK model was then tested on human-mouse hybrid fragments in which each member of the hybrid had a different methylation status. The model was also tested on human genomic DNA molecules extracted from various biological samples, such as buffy coat, placental, and tumoral tissues. The overall methylation levels deduced by the HK model were well correlated with those by BS-seq ( = 0.99; < 0.0001) and allowed the measurement of allele-specific methylation patterns in imprinted genes. Taken together, this methodology has provided a system for simultaneous genome-wide genetic and epigenetic analyses.
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14.
Ricardo
(2022-01-20 18:02):
#paper doi:https://doi.org/10.1073/pnas.1821523116 Developmental topography of cortical thickness during infancy. 这篇文章于2019年发表在pnas上。在出生后的两年时间里,人类大脑经历了快速的动态发育,这表现在行为和认知能力上的快速发展。而绘制健康婴幼儿大脑皮层厚度的发育模式对于理解一些神经发育疾病来说有着重要价值。虽然利用磁共振成像技术研究人类大脑的发育老化规律已经有几十年的时间了,但是对于两岁以前这样非常早期的研究其实还非常少。这主要是因为婴幼儿大脑的核磁成像数据非常难以获取(需要婴幼儿保持几十分钟的相对静止)以及婴幼儿大脑磁共振图像相对于成年人来说非常难处理(所以需要开发特定的影像处理算法)。这篇文章利用了一个被称为Baby Connectome Project的脑影像数据库,并利用作者所在研究组开发的一系列图像处理算法对婴幼儿脑影像数据进行预处理。他们还利用非负矩阵分解这一经典的分析技术建模婴幼儿大脑皮层厚度的时空发育轨迹。
这篇文章主要有两个发现:1.在出生后的两年,婴幼儿大脑的平均皮层厚度先快速增加,然后大约在14个月的时候达到峰值点,之后在以缓慢的速度减少;2.作者根据皮层厚度的发育模式将婴幼儿大脑分成若干个区域,他们发现不同脑区都有不同的皮层厚度的发育特点,有的脑区在不同时间点达到皮层厚度的峰值点,有的区域则在这两年时间里保持持续的增长。
IF:9.400Q1
Proceedings of the National Academy of Sciences of the United States of America,
2019-08-06.
DOI: 10.1073/pnas.1821523116
PMID: 31332010
Abstract:
During the first 2 postnatal years, cortical thickness of the human brain develops dynamically and spatially heterogeneously and likely peaks between 1 and 2 y of age. The striking development …
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During the first 2 postnatal years, cortical thickness of the human brain develops dynamically and spatially heterogeneously and likely peaks between 1 and 2 y of age. The striking development renders this period critical for later cognitive outcomes and vulnerable to early neurodevelopmental disorders. However, due to the difficulties in longitudinal infant brain MRI acquisition and processing, our knowledge still remains limited on the dynamic changes, peak age, and spatial heterogeneities of cortical thickness during infancy. To fill this knowledge gap, in this study, we discover the developmental regionalization of cortical thickness, i.e., developmentally distinct regions, each of which is composed of a set of codeveloping cortical vertices, for better understanding of the spatiotemporal heterogeneities of cortical thickness development. We leverage an infant-dedicated computational pipeline, an advanced multivariate analysis method (i.e., nonnegative matrix factorization), and a densely sampled longitudinal dataset with 210 serial MRI scans from 43 healthy infants, with each infant being scheduled to have 7 longitudinal scans at around 1, 3, 6, 9, 12, 18, and 24 mo of age. Our results suggest that, during the first 2 y, the whole-brain average cortical thickness increases rapidly and reaches a plateau at about 14 mo of age and then decreases at a slow pace thereafter. More importantly, each discovered region is structurally and functionally meaningful and exhibits a distinctive developmental pattern, with several regions peaking at varied ages while others keep increasing in the first 2 postnatal years. Our findings provide valuable references and insights for early brain development.
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