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801.
小W (2022-09-30 23:53):
#paper https://doi.org/10.1038/s41573-022-00538-9 The expanding role for small molecules in immuno-oncology. 发表在 Nat Rev Drug Discov (2022). 的一篇小分子在免疫肿瘤中应用的综述文章。从靶向致瘤途径的药物 、 靶向代谢途径 、 小分子ICIs 三个方向,分别描述 了用于直接刺激抗肿瘤免疫反应的不同靶点小分子的发现 、 优缺点、成药 、 临床试验 进展等。本文对 不同机理小分子药物的展望 以及 各靶点的临床试验进展 , 还是挺有意思的。
Abstract:
The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed … >>>
The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, there is an increasing interest in small-molecule immuno-oncology drugs that address intracellular pathways, some of which have recently entered clinical trials. In parallel, small molecules that target pro-tumorigenic pathways in cancer cells and the tumour microenvironment have been found to have immunostimulatory effects that synergize with the action of ICI antibodies, leading to the approval of an increasing number of regimens that combine such drugs. Combinations with small molecules targeting cancer metabolism, cytokine/chemokine and innate immune pathways, and T cell checkpoints are now under investigation. This Review discusses the recent milestones and hurdles encountered in this area of drug development, as well as our views on the best path forward. <<<
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802.
cellsarts (2022-09-30 23:43):
#paper DOI 10.1074/jbc.M111.293795 Crystal Structure of Human  -Galactosidase STRUCTURAL BASIS OF GM1 GANGLIOSIDOSIS AND MORQUIO B DISEASES* author: Umeharu Ohto , THE JOURNAL OF BIOLOGICAL CHEMISTRY January 13, 2012 人β -半乳糖苷酶的晶体结构 GM1神经节肥瘦症和Morquio B是常染色体隐性遗传与神经退行性疾病相关的溶酶体积储病, 这些疾病是因溶酶体缺乏β -半乳糖苷酶引起的,β -半乳糖苷酶缺乏导致β -半乳糖苷酶底物---GM1神经节苷和角蛋白硫酸盐---的积累分别导致了侏儒症和骨骼异常。缺乏 β -半乳糖苷酶会导致溶酶体储存性疾病。文章首次报道了人类β -半乳糖苷酶的晶体结构。人类β -半乳糖苷酶是由TIM 催化结构域和两个β -折叠结构域所组成人类β -半乳糖苷酶突变可分为直接影响配体识别的突变、蛋白质内部核心突变、或位于蛋白质表面的突变。文章探讨了这一些结构突变与:对溶酶体储存疾病的关系。
Abstract:
G(M1) gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the … >>>
G(M1) gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme β-d-galactosidase (β-Gal), which lead to accumulations of the β-Gal substrates, G(M1) ganglioside, and keratan sulfate. β-Gal is an exoglycosidase that catalyzes the hydrolysis of terminal β-linked galactose residues. This study shows the crystal structures of human β-Gal in complex with its catalytic product galactose or with its inhibitor 1-deoxygalactonojirimycin. Human β-Gal is composed of a catalytic TIM barrel domain followed by β-domain 1 and β-domain 2. To gain structural insight into the molecular defects of β-Gal in the above diseases, the disease-causing mutations were mapped onto the three-dimensional structure. Finally, the possible causes of the diseases are discussed. <<<
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803.
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。
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 … >>>
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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804.
Arwen (2022-09-30 23:41):
#paper doi:https://doi.org/10.48550/arXiv.2202.02000,Cross-Modality Multi-Atlas Segmentation via Deep Registration and Label Fusion 基于多图谱的分割技术是医学影像分割问题中一个比较有效的方法。一般来说,多图谱技术通过将多个图谱非线性配准到个体图像,并将对应的图谱分割图变换到个体图像空间,并利用融合算法融合多图谱分割图得到个体图像的分割图。但是,传统的多图谱分割技术受限两点:一是配准过程计算量太大,二是标签融合算法会影响到最终分割图的精度。这篇文章构建了两个神经网络,一个网络用于生成形变场,将图谱映射到个体空间,另一个网络用于计算各个图谱分割标签的融合权重,用于后续的分割图融合。不过这篇文章做的一般,我个人觉得不咋地。配准网络部分明明使用scaling and squaring算法就可以生成合理的形变场,非要做没啥必要的创新,应该就是强行扩充文章内容吧。
Abstract:
Multi-atlas segmentation (MAS) is a promising framework for medical image segmentation. Generally, MAS methods register multiple atlases, i.e., medical images with corresponding labels, to a target image; and the transformed … >>>
Multi-atlas segmentation (MAS) is a promising framework for medical image segmentation. Generally, MAS methods register multiple atlases, i.e., medical images with corresponding labels, to a target image; and the transformed atlas labels can be combined to generate target segmentation via label fusion schemes. Many conventional MAS methods employed the atlases from the same modality as the target image. However, the number of atlases with the same modality may be limited or even missing in many clinical applications. Besides, conventional MAS methods suffer from the computational burden of registration or label fusion procedures. In this work, we design a novel cross-modality MAS framework, which uses available atlases from a certain modality to segment a target image from another modality. To boost the computational efficiency of the framework, both the image registration and label fusion are achieved by well-designed deep neural networks. For the atlas-to-target image registration, we propose a bi-directional registration network (BiRegNet), which can efficiently align images from different modalities. For the label fusion, we design a similarity estimation network (SimNet), which estimates the fusion weight of each atlas by measuring its similarity to the target image. SimNet can learn multi-scale information for similarity estimation to improve the performance of label fusion. The proposed framework was evaluated by the left ventricle and liver segmentation tasks on the MM-WHS and CHAOS datasets, respectively. Results have shown that the framework is effective for cross-modality MAS in both registration and label fusion. <<<
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805.
Ricardo (2022-09-30 23:32):
#paper doi:https://doi.org/10.48550/arXiv.2202.03563,Aladdin: Joint Atlas Building and Diffeomorphic Registration Learning with Pairwise Alignment 图谱构建和图像配准是医学影像分析中的重要任务,但是图谱估计和无参形变的计算需要极高的计算代价。此外,以前的图谱构建方法通常计算模糊图谱和每个单独的图像之间的相似度驱动模型优化,这可能会增加预估的图谱和个体图像之间配准的难度,因为预估的模糊图谱相比个体图像不具有更清楚的解剖结构。这篇文章基于forward model从多个角度约束了图谱的生成空间,并做了充足的理论分析。但是由于模型较为复杂,并且涉及所有图像的同时优化,所以不太适合3d图像数据,目前还只是在2d图像数据上做实验。
Abstract:
Atlas building and image registration are important tasks for medical image analysis. Once one or multiple atlases from an image population have been constructed, commonly (1) images are warped into … >>>
Atlas building and image registration are important tasks for medical image analysis. Once one or multiple atlases from an image population have been constructed, commonly (1) images are warped into an atlas space to study intra-subject or inter-subject variations or (2) a possibly probabilistic atlas is warped into image space to assign anatomical labels. Atlas estimation and nonparametric transformations are computationally expensive as they usually require numerical optimization. Additionally, previous approaches for atlas building often define similarity measures between a fuzzy atlas and each individual image, which may cause alignment difficulties because a fuzzy atlas does not exhibit clear anatomical structures in contrast to the individual images. This work explores using a convolutional neural network (CNN) to jointly predict the atlas and a stationary velocity field (SVF) parameterization for diffeomorphic image registration with respect to the atlas. Our approach does not require affine pre-registrations and utilizes pairwise image alignment losses to increase registration accuracy. We evaluate our model on 3D knee magnetic resonance images (MRI) from the OAI-ZIB dataset. Our results show that the proposed framework achieves better performance than other state-of-the-art image registration algorithms, allows for end-to-end training, and for fast inference at test time. <<<
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806.
钟鸣 (2022-09-30 22:51):
#paper doi:10.1128/IAI.71.11.6192-6198.2003 , infection and immunity, 2003, Genetic basis for the structural difference between Streptococcus pneumoniae serotype 15B and 15C capsular polysaccharides 肺炎链球菌血清型众多,血清型的不同取决于荚膜结构,且荚膜在激发免疫反应时占主导作用,因此血清型间缺少交叉保护作用。对肺炎球菌荚膜形成机制的深入了解有助于指导疫苗的开发。 此前有报道称血清型15B与15C会相互转化,这里,作者通过比较这两种血清型的荚膜编码基因,发现编码O-乙酰转移酶的基因中TA序列重复数量不同决定该酶是否有完全活性,进而导致荚膜结构不同。而TA数量的可变性,正是两种血清型可以相互转化的原因。 作者将荚膜结构不同的原因定位到了具体的基因,感觉是大道至简的规律。也为其他细菌的荚膜研究提供了参考和借鉴。
Abstract:
In a search for the genetic basis for the structural difference between the related Streptococcus pneumoniae capsular serotypes 15B and 15C and for the reported reversible switching between these serotypes, … >>>
In a search for the genetic basis for the structural difference between the related Streptococcus pneumoniae capsular serotypes 15B and 15C and for the reported reversible switching between these serotypes, the corresponding capsular polysaccharide synthesis (cps) loci were investigated by keeping in mind that at the structural level, the capsules differ only in O acetylation. The cps locus of a serotype 15B strain was identified, partially PCR amplified with primers based on the related serotype 14 sequence, and sequenced. Sequence analysis revealed, among other open reading frames, an intact open reading frame (designated cps15bM) whose product, at the protein level, exhibited characteristics of previously identified acetyltransferases. Genetic analysis of the corresponding region in a serotype15C strain indicated that the same gene was present but had a premature stop in translation. Closer analysis indicated that the serotype 15B gene contained a short tandem TA repeat consisting of eight TA units. In serotype 15C, this gene contained nine TA units that resulted in a frameshift and a truncated product. Genetic analysis of 17 serotype 15B and 15C clinical isolates revealed a perfect correlation between the serotype and the length of the short tandem repeat in the putative O-acetyltransferase gene. The number of TA repeating units varied between seven and nine in the various isolates. Together, the data strongly suggest that the structural difference between serotypes 15B and 15C is based on variation in the short tandem TA repeat in the O-acetyltransferase gene and that the transition between serotypes is due to slipped-strand mispairing with deletion or insertion of TA units in the cps15bM gene. <<<
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807.
林海onrush (2022-09-30 22:25):
#paper arXiv, 2209.00796 (2022) , Diffusion Models: A Comprehensive Survey of Methods and Applications, Diffusion model在诸多领域都有着优异的表现,并且考虑到不同领域的应用中diffusion model产生了不同的变形,论文系统地介绍了diffusion model的应用研究,其中包含如下领域:计算机视觉,NLP、波形信号处理、多模态建模、分子图建模、时间序列建模、对抗性净化。工作的主要贡献总结如下:新的分类方法:我们对扩散模型和其应用提出了一种新的、系统的分类法。具体将模型分为三类:采样速度增强、最大似然估计增强、数据泛化增强。进一步地,将扩散模型的应用分为七类:计算机视觉,NLP、波形信号处理、多模态建模、分子图建模、时间序列建模、对抗性净化。全面地概述了现代扩散模型及其应用,展示了每种扩散模型的主要改进,和原始模型进行了必要的比较,并总结了相应的论文。扩散模型的基本思想是正向扩散过程来系统地扰动数据中的分布,然后通过学习反向扩散过程恢复数据的分布,这样就了产生一个高度灵活且易于计算的生成模型。
Abstract:
Diffusion models are a class of deep generative models that have shown impressive results on various tasks with a solid theoretical foundation. Despite demonstrated success than state-of-the-art approaches, diffusion models … >>>
Diffusion models are a class of deep generative models that have shown impressive results on various tasks with a solid theoretical foundation. Despite demonstrated success than state-of-the-art approaches, diffusion models often entail costly sampling procedures and sub-optimal likelihood estimation. Significant efforts have been made to improve the performance of diffusion models in various aspects. In this article, we present a comprehensive review of existing variants of diffusion models. Specifically, we provide the taxonomy of diffusion models and categorize them into three types: sampling-acceleration enhancement, likelihood-maximization enhancement, and data-generalization enhancement. We also introduce the other generative models (i.e., variational autoencoders, generative adversarial networks, normalizing flow, autoregressive models, and energy-based models) and discuss the connections between diffusion models and these generative models. Then we review the applications of diffusion models, including computer vision, natural language processing, waveform signal processing, multi-modal modeling, molecular graph generation, time series modeling, and adversarial purification. Furthermore, we propose new perspectives pertaining to the development of generative models. Github: this https URL. <<<
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808.
洪媛媛 (2022-09-30 22:09):
#paper https://doi.org/10.2144/04372ST03 BioTechniques 37:226-231 (August 2004). AutoDimer: a screening tool for primer-dimer and hairpin structures.这篇文章关于AutoDimer软件,可以分析多重引物之间的dimer和引物自身的hairpin,介绍了软件的序列输入格式、需要输入的参数、比对算法原理和输出的参数和score意义。
IF:2.200Q4 BioTechniques, 2018. DOI: 10.2144/04372ST03
Abstract:
The ability to select short DNA oligonucleotide sequences capable of binding solely to their intended target is of great importance in developing nucleic acid based detection technologies. Applications such as … >>>
The ability to select short DNA oligonucleotide sequences capable of binding solely to their intended target is of great importance in developing nucleic acid based detection technologies. Applications such as multiplex PCR rely on primers binding to unique regions in a genome. Competing side reactions with other primer pairs or template DNA decrease PCR efficiency. Freely available primer design software such as Primer3 screens for potential hairpin and primer-dimer interactions while selecting a single primer pair. The development of multiplex PCR assays (in the range of 5 to 20 loci) requires the screening of all primer pairs for potential cross-reactivity. However, a logistical problem results due to the number of total number of comparisons required. Comparing the primer set for a 10-plex assay (20 total primer sequences) results in 210 primer-primer combinations that must be screened. The ability to screen sets of candidate oligomers rapidly for potential cross-reactivity reduces overall assay development time. Here we report the application of a familiar sliding algorithm for comparing two strands of DNA in an overlapping fashion. The algorithm has been employed in a software package wherein the user can compare multiple sequences in a single computational run. After the screening is completed, a score is assigned to potential duplex interactions exceeding a user-defined threshold. Additional criteria of predicted melting temperature (Tm) and free energy of melting (ΔG) are included for further ranking. Sodium counterion and total stand concentrations can be adjusted for the Tm and ΔG calculations. The predicted interactions are saved in a text file for further evaluation. <<<
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809.
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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810.
小年 (2022-09-30 20:36):
#paper doi: 10.3389/fimmu.2021.687975. eCollection 2021. IOBR: Multi-Omics Immuno-Oncology Biological Research to Decode Tumor Microenvironment and Signatures. Front Immunol. 2021. 随着当前免疫疗法和大数据时代的发展,在复杂的多组学数据集中识别新的生物标志物和筛选特征以指导调整治疗策略已成为免疫肿瘤学的焦点。 这篇文章中开发的IOBR包,旨在一站式完成肿瘤多组学数据的免疫学研究,揭示肿瘤微环境和临床特征的关系。包括四个主要的分析模块:特征和TME反卷积模块(the signature and TME deconvolution module)、表型模块(the phenotype module)、突变模块(the mutation module)和模型构建模块(the model construction module),可以有效和系统地分析肿瘤免疫学、临床、基因组学和scRNA-seq数据。集成了8种已发表的用于定量肿瘤微环境(TME)的算法: CIBERSORT, TIMER, xCell, MCPcounter, ESITMATE, EPIC, IPS, quanTIseq,值得注意的是,IOBR收集并使用多种方法进行变量转换、生存分析、特征选择和统计分析,并且支持批量分析和相应结果的可视化。总体而言,基因组和转录组学数据的整合可能会更新和加深我们对肿瘤进展的理解,并通过联合考虑基因组、代谢和TME谱之间的串扰来提供治疗见解。
Abstract:
Recent advances in next-generation sequencing (NGS) technologies have triggered the rapid accumulation of publicly available multi-omics datasets. The application of integrated omics to explore robust signatures for clinical translation is … >>>
Recent advances in next-generation sequencing (NGS) technologies have triggered the rapid accumulation of publicly available multi-omics datasets. The application of integrated omics to explore robust signatures for clinical translation is increasingly emphasized, and this is attributed to the clinical success of immune checkpoint blockades in diverse malignancies. However, effective tools for comprehensively interpreting multi-omics data are still warranted to provide increased granularity into the intrinsic mechanism of oncogenesis and immunotherapeutic sensitivity. Therefore, we developed a computational tool for effective Immuno-Oncology Biological Research (IOBR), providing a comprehensive investigation of the estimation of reported or user-built signatures, TME deconvolution, and signature construction based on multi-omics data. Notably, IOBR offers batch analyses of these signatures and their correlations with clinical phenotypes, long non-coding RNA (lncRNA) profiling, genomic characteristics, and signatures generated from single-cell RNA sequencing (scRNA-seq) data in different cancer settings. Additionally, IOBR integrates multiple existing microenvironmental deconvolution methodologies and signature construction tools for convenient comparison and selection. Collectively, IOBR is a user-friendly tool for leveraging multi-omics data to facilitate immuno-oncology exploration and to unveil tumor-immune interactions and accelerating precision immunotherapy. <<<
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811.
半面阳光 (2022-09-30 20:30):
#paper DOI: https://doi.org/10.1016/j.gim.2022.05.011 Detection and characterization of male sex chromosome abnormalities in the UK Biobank study. 这篇文章发表在2022年9月的Genetics in Medicine,可以概括为一篇综合分析类的文章。 作者以UK Biobank数据库中的20万欧洲血统的男性的基因检测(SNV芯片)数据和健康记录作为数据来源,系统性地分析研究了两种常见的男性性染色体异常(47,XXY和47,XYY)以及这两种性染色体异常所关联的疾病风险。 这篇研究的一个主要切入点是以往研究中存在的样本采集偏差(sampling bias)。47,XXY(即Klinefelter综合征简称(KS))的特征和相关风险疾病报道较多,而相比较之下,47,XYY的特征和相关联的疾病则没有较为系统的归纳,主要原因是很多XYY的人没有到临床机构就诊,进而无从得知自己的基因型。这些性染色体异常表型特征报道受到样本采集偏差(sampling bias)的影响,就导致我们无法全面地了解此类染色体异常相关的临床特征。 一个尽量减小样本采集偏差研究方法是基于大规模人群进行系统性评估分析。本研究就采样了这一方法来研究这两种性染色体异常的发病率和疾病表型特征。作者首先根据UK Biobank数据库中的基因检测数据筛选出213例XXY和143例XYY,得到了成年男性性染色体异常的发病率数据,同时发现这些病例大部分未能在常规临床中检出。对这些性染色体异常人群的医疗健康记录进一步研究还发现XXY和XYY在生殖相关的表型上有明显差异,但是两者在其他相关疾病风险上却表现出惊人一致,比如2型糖尿病、肺栓塞和动脉硬化等,但是对这种现象目前还没有比较明确的解释。最后作者提到,在未来的研究中,如果针对某种疾病风险(如血栓风险)进行基因检测时,可以考虑同时将性染色体异常的评估纳入进来。
Abstract:
PURPOSE: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes.METHODS: We analyzed genotyping array or … >>>
PURPOSE: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes.METHODS: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data.RESULTS: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 × 10-8), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P < 7 × 10-6).CONCLUSION: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking. <<<
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812.
白义民 (2022-09-30 19:28):
#paper 秋瑾遗迹在绍兴的有三处,在这种多少名过其实,大肆宣传的背后有何深意,本文探究了其原因。现代知识分子往往喜欢挪用固有文化的某些符号、概念与习俗来“重构传统”,为现代化的某种目的服务。不过,这其中隐含的困境也在于,当现代文化自觉发扬传统道德,传统道德不仅会借现代名义重新复活,而且会对现代思想形成不自觉、无意识的深层制约。在由古代列女进入现代烈士的书写过程中,被解放的秋瑾在名誉上获得了和男性烈士同等的地位,然而传统女德模式中的道德枷锁并未因此真正获得解除。为了捍卫秋瑾的圣洁形象,除了去性化,“死烈”背后的女德模式和烈女想象仍是重塑女烈士形象的关键因素。这也是近现代文学史上女性形象塑造的一个普遍的怪现状:英雄人物在思想上越是激进主义,在道德上也越是保守主义。
Abstract:
颂扬牺牲是危机时代女性解放议程中必然的一部分。尽管如此,作为传统中国"列女传"的一脉,女性牺牲者进入男性荣誉的烈士谱系并非名正言顺。看似悖谬的是,现代第一女烈士秋瑾在革命告成之前因为是"女性"被排除在外,革命胜利之后又因为是"女性"而备受优待。女性进入烈士谱系是一个神圣化的过程,也是一个去性别化的过程。在文学史的意义上,丁玲的"准烈士"小说不仅颠覆了传统文学节妇烈女的叙事模式,而且打破了烈士文章过度颂扬的刻板程式。 >>>
颂扬牺牲是危机时代女性解放议程中必然的一部分。尽管如此,作为传统中国"列女传"的一脉,女性牺牲者进入男性荣誉的烈士谱系并非名正言顺。看似悖谬的是,现代第一女烈士秋瑾在革命告成之前因为是"女性"被排除在外,革命胜利之后又因为是"女性"而备受优待。女性进入烈士谱系是一个神圣化的过程,也是一个去性别化的过程。在文学史的意义上,丁玲的"准烈士"小说不仅颠覆了传统文学节妇烈女的叙事模式,而且打破了烈士文章过度颂扬的刻板程式。 <<<
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813.
沈么是快乐星球 (2022-09-30 19:16):
#paper doi: https://doi.org/10.1038/s41477-021-00963-5. Nat. Plants. 2021. 红豆杉基因组为紫杉醇生物合成提供了新的见解. 红豆杉基因组测序、组装和注释;鉴于全基因组复制(WGD)是促进植物基因组规模扩大的重要进化力量,作者研究了红豆杉是否经历过WGD事件。结果分析指明红豆杉在柏科植物中经历了一个全基因组复制事件;红豆杉基因组扩增与反转录转座子连锁。红豆杉的Gypsy和Copia超家族经历了相对独特的进化模式,特别是特定的Gypsy家族I和Copia家族V;比较了红豆杉与选定的裸子植物、被子植物和隐花植物之间的直系同源基因,红豆杉含有 9,747 个独特的基因,其中许多富含特殊代谢物的生物合成,包括萜烯、苯丙烷和黄酮。57 个基因家族被注释为细胞色素 P450(CYP450)基因家族。红豆杉基因家族的进化和次生代谢升高;分析了紫杉 CYP450 家族,系统基因组分析表明,与其他 68 个代表性物种相比,CYP750 和 CYP725 家族在红豆杉中明显扩展,而紫杉醇途径中 CYP450 基因都属于 CYP725A 亚家族,这表明 CYP725A 亚家族的扩增在红豆杉紫杉醇生物合成的进化中起着至关重要的作用。大部分紫杉醇途径基因是在红豆杉进化过程中出现的;参与紫杉醇生物合成途径的两个初始步骤的基因排列在一个名为“紫杉二烯基因簇”的基因簇中。紫杉二烯基因簇可能是由红豆杉中的基因复制和新功能化形成的,可能与先前对植物中操纵子样基因簇的研究有些相似。除 CYP450 酶外,乙酰转移酶在紫杉醇的生物合成中发挥重要作用,尤其是 BAHD 酰基转移酶。
IF:15.800Q1 Nature plants, 2021-08. DOI: 10.1038/s41477-021-00963-5 PMID: 34267359
Abstract:
The ancient gymnosperm genus Taxus is the exclusive source of the anticancer drug paclitaxel, yet no reference genome sequences are available for comprehensively elucidating the paclitaxel biosynthesis pathway. We have … >>>
The ancient gymnosperm genus Taxus is the exclusive source of the anticancer drug paclitaxel, yet no reference genome sequences are available for comprehensively elucidating the paclitaxel biosynthesis pathway. We have completed a chromosome-level genome of Taxus chinensis var. mairei with a total length of 10.23 gigabases. Taxus shared an ancestral whole-genome duplication with the coniferophyte lineage and underwent distinct transposon evolution. We discovered a unique physical and functional grouping of CYP725As (cytochrome P450) in the Taxus genome for paclitaxel biosynthesis. We also identified a gene cluster for taxadiene biosynthesis, which was formed mainly by gene duplications. This study will facilitate the elucidation of paclitaxel biosynthesis and unleash the biotechnological potential of Taxus. <<<
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814.
LXJ (2022-09-30 19:06):
#paper DOI:10.1016/j.molcel.2022.01.002. E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression. mTOR复合物1(mTORC1)是一个重要的代谢中枢,可以将细胞代谢与营养物质(包括氨基酸)的可用性相协调。Sestrin2已被鉴定为一种细胞溶质亮氨酸传感器,可将亮氨酸状态信号传输至mTORC1。在本研究中,作者鉴定了一种E3泛素连接酶环指蛋白167(RNF167)和一种双歧化酶STAMBPL1,二者协同作用,控制Sestrin1的多泛素化水平,以响应亮氨酸的可用性。Sestrin2的泛素化促进其与GATOR2的相互作用并抑制mTORC1信号。生物信息学分析显示胃和结肠肿瘤中RNF167表达降低,STAMBPL1表达增加。在人类结肠癌细胞系中敲除STAMBPL1或纠正杂合STAMBPL 1突变可抑制异种移植瘤的生长。通过上述研究,作者旨在阐述一种阻断STAMBPL1-Sestrin2相互作用的细胞渗透性肽抑制mTORC1,为癌症治疗提供了潜在的选择。
IF:14.500Q1 Molecular cell, 2022-02-17. DOI: 10.1016/j.molcel.2022.01.002 PMID: 35114100
Abstract:
The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine … >>>
The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. In this study, we identify an E3 ubiquitin ligase RING finger protein 167 (RNF167) and a deubiquitinase STAMBPL1 that function in concert to control the polyubiquitination level of Sestrin2 in response to leucine availability. Ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling. Bioinformatic analysis reveals decreased RNF167 expression and increased STAMBPL1 expression in gastric and colorectal tumors. Knockout of STAMBPL1 or correction of the heterozygous STAMBPL1 mutation in a human colon cancer cell line suppresses xenograft tumor growth. Lastly, a cell-permeable peptide that blocks the STAMBPL1-Sestrin2 interaction inhibits mTORC1 and provides a potential option for cancer therapy. <<<
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815.
张贝 (2022-09-30 18:50):
#paper doi: 10.1038/s41587-020-0548-6. PICRUSt2 for prediction of metagenome functions. Nat Biotechnol. 2020. PICRUSt2是一款基于标记基因序列(通常为16S rRNA)来预测宏基因组功能丰度的软件,本文自2020年发表以来,已被引用近1200次(Google Scholar)。PICRUSt2在原有PICRUSt1版本的基础上进行升级,更新了基因家族和参考基因组数据库(扩大10倍以上),可与任何OTU选择或去噪算法的互操作,并能够进行表型预测。Benchmarking结果表明,PICRUSt2总体上比PICRUSt和其他竞争方法更准确。同时,PICRUSt2还允许添加自定义参考数据库。
816.
Vincent (2022-09-30 14:56):
#paper doi: https://doi.org/10.1038/s43586-021-00056-9 Genome-wide association studies. Nature Reviews Methods Primers. 2021. GWAS旨在寻找基因型和表型之间的关联。截止目前,总共有超过5700项,涵盖3300性状的GWAS研究。这篇review文章丛统计原理、实验设计、实际操作、结果解释,下游应用等方面很好地介绍了全基因组关联研究(GWAS)。在统计原理方面,文章介绍了假设检验常用的线性混合模型,假发现率的控制(FDR control)和下游fine mapping方法。实验设计方面,文章详细介绍了人群的选择(population-based, family-based 和 isolation populations),以及测序技术(microarray, WES, WGS)方面的优缺点。应用上,文章介绍了GWAS的两大重要应用:疾病风险预测(PRS score) 和 揭示生物性状的遗传基础。文章最后还提及了GWAS研究目前的局限和对未来发展的期待。总结起来是篇很不错的GWAS入门文章。
Abstract:
Genome-wide association studies (GWAS) test hundreds of thousands of genetic variants across many genomes to find those statistically associated with a specific trait or disease. This methodology has generated a … >>>
Genome-wide association studies (GWAS) test hundreds of thousands of genetic variants across many genomes to find those statistically associated with a specific trait or disease. This methodology has generated a myriad of robust associations for a range of traits and diseases, and the number of associated variants is expected to grow steadily as GWAS sample sizes increase. GWAS results have a range of applications, such as gaining insight into a phenotype’s underlying biology, estimating its heritability, calculating genetic correlations, making clinical risk predictions, informing drug development programmes and inferring potential causal relationships between risk factors and health outcomes. In this Primer, we provide the reader with an introduction to GWAS, explaining their statistical basis and how they are conducted, describe state-of-the art approaches and discuss limitations and challenges, concluding with an overview of the current and future applications for GWAS results. <<<
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817.
大象城南 (2022-09-30 14:31):
#paper doi.org/10.1016/j.neuroimage.2012.12.054 Track-weighted functional connectivity (TW-FC): A tool for characterizing the structural–functional connections in the brain. NeuroImage. 2013. MRI 为无创研究大脑中的功能和结构连接提供了强大的工具。功能连接 (FC) 技术利用缓慢自发信号波动的内在时间相关性来表征大脑功能网络。此外,弥散 MRI 纤维追踪可用于研究白质结构连接。近年来,人们对结合这两种技术以提供大脑的整体结构-功能描述产生了相当大的兴趣。在这项工作中,我们应用了最近提出的超分辨率轨迹加权成像 (TWI) 方法来演示如何将全脑纤维跟踪数据与 FC 数据相结合以生成轨迹加权 (TW) FC 图FC 网络。该方法应用于来自 8 名健康志愿者的数据,并用 ( i ) 使用基于种子连接的分析获得的 FC 网络(在楔前叶/后扣带回皮层,PCC 中播种,已知是默认模式网络的一部分)进行说明,和(二) 使用独立成分分析生成的 FC 网络(特别是默认模式、注意力、视觉和感觉运动网络)。TW-FC 图在连接 FC 网络节点的白质结构中显示出高强度。例如,扣带束在基于 PCC 种子的分析中显示出最强的 TW-FC 值,因为它们在内侧额叶皮层和楔前叶/后扣带皮层之间的连接中起主要作用;类似地,上纵束在注意力网络、视觉网络中的视辐射以及感觉-运动网络中的皮质脊髓束和胼胝体中都有很好的表现。TW-FC 地图突出显示与给定 FC 网络相关的白质连接,并且它们在给定体素中的强度反映了由穿过该体素的结构连接连接的网络节点部分的功能连接性。因此,它们包含与用于生成它们的图像不同的(和新颖的)图像对比度。本研究中显示的结果说明了 TW-FC 方法在将结构和功能数据融合为单一的定量图像。因此,这种技术可以在神经科学和神经学中具有重要的应用,例如基于体素的比较研究。
IF:4.700Q1 NeuroImage, 2013-Apr-15. DOI: 10.1016/j.neuroimage.2012.12.054 PMID: 23298749
Abstract:
MRI provides a powerful tool for studying the functional and structural connections in the brain non-invasively. The technique of functional connectivity (FC) exploits the intrinsic temporal correlations of slow spontaneous … >>>
MRI provides a powerful tool for studying the functional and structural connections in the brain non-invasively. The technique of functional connectivity (FC) exploits the intrinsic temporal correlations of slow spontaneous signal fluctuations to characterise brain functional networks. In addition, diffusion MRI fibre-tracking can be used to study the white matter structural connections. In recent years, there has been considerable interest in combining these two techniques to provide an overall structural-functional description of the brain. In this work we applied the recently proposed super-resolution track-weighted imaging (TWI) methodology to demonstrate how whole-brain fibre-tracking data can be combined with FC data to generate a track-weighted (TW) FC map of FC networks. The method was applied to data from 8 healthy volunteers, and illustrated with (i) FC networks obtained using a seeded connectivity-based analysis (seeding in the precuneus/posterior cingulate cortex, PCC, known to be part of the default mode network), and (ii) with FC networks generated using independent component analysis (in particular, the default mode, attention, visual, and sensory-motor networks). TW-FC maps showed high intensity in white matter structures connecting the nodes of the FC networks. For example, the cingulum bundles show the strongest TW-FC values in the PCC seeded-based analysis, due to their major role in the connection between medial frontal cortex and precuneus/posterior cingulate cortex; similarly the superior longitudinal fasciculus was well represented in the attention network, the optic radiations in the visual network, and the corticospinal tract and corpus callosum in the sensory-motor network. The TW-FC maps highlight the white matter connections associated with a given FC network, and their intensity in a given voxel reflects the functional connectivity of the part of the nodes of the network linked by the structural connections traversing that voxel. They therefore contain a different (and novel) image contrast from that of the images used to generate them. The results shown in this study illustrate the potential of the TW-FC approach for the fusion of structural and functional data into a single quantitative image. This technique could therefore have important applications in neuroscience and neurology, such as for voxel-based comparison studies. <<<
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818.
尹志 (2022-09-30 11:06):
#paper doi:10.48550/arXiv.1907.10830 U-GAT-IT: Unsupervised Generative Attentional Networks with Adaptive Layer-Instance Normalization for Image-to-Image Translation, ICLR 2020. 这又是一篇图像翻译的文章,还是在网络结构上做了有效的改进。作者通过提出一个新的注意力模块和一种新的归一化函数实现无监督的图像翻译工作。作者提出的注意力模块对于图像的几何形变能够做出很好的处理,这也让文章的架构对于很多艺术风格的变化处理具有优越的效果。
Abstract:
We propose a novel method for unsupervised image-to-image translation, which incorporates a new attention module and a new learnable normalization function in an end-to-end manner. The attention module guides our … >>>
We propose a novel method for unsupervised image-to-image translation, which incorporates a new attention module and a new learnable normalization function in an end-to-end manner. The attention module guides our model to focus on more important regions distinguishing between source and target domains based on the attention map obtained by the auxiliary classifier. Unlike previous attention-based method which cannot handle the geometric changes between domains, our model can translate both images requiring holistic changes and images requiring large shape changes. Moreover, our new AdaLIN (Adaptive Layer-Instance Normalization) function helps our attention-guided model to flexibly control the amount of change in shape and texture by learned parameters depending on datasets. Experimental results show the superiority of the proposed method compared to the existing state-of-the-art models with a fixed network architecture and hyper-parameters. Our code and datasets are available at this https URL or this https URL. <<<
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819.
lsj (2022-09-30 08:58):
#paper DOI:The Journal of Neuroscience, January 1995, 15(l): 70-66 背景:之前的研究已知在postsubiculum中记录到在平面上与动物头朝向功能的神经元,这类神经元的放电独立于动物在环境中的行为和位置。解剖学研究发现postsubiculum和ATN具有双向连接。 目的:为了能够探究大脑中头朝向细胞信号处理,在自由运动的小鼠脑中采用单细胞记录的技术刻画神经元行为和空间的关联。 实验环境:在包含单一朝向线索的圆柱形环境中训练小鼠获取食物。 结论:在ATN中单记录的细胞中大约60%的细胞放电都与平面上头朝向有关。实验中包含朝向线索的旋转表明偏好方向发放朝向可以被显著的视觉线索控制。与postsubicular的HD细胞相比,受抑制动物的被动旋转显示,当动物的头部朝向偏好方向时,大多数ATN的HD细胞停止放电。这些发现证明了ATN中头朝向细胞的存在并且表明这个区域在空间导航方面的潜在重要性。 相关结论:在动物的观察和定量分析中发现头朝向细胞的发放不依赖于动物的行为,位置,线性速度,角头速度或者环境中的位置,这样的细胞大多数在丘脑前背核(anterior dorsal thalamic nucleus)。每个头朝向细胞都有一个偏好方向,在该偏好方向上放电最大,当远离偏好方向时细胞的发放率线性下降。所有的偏好方向覆盖360度。定量分析发现这些细胞与在postsubicular中的HD细胞具有相同的参数值,比如发放率峰值,朝向发放范围。 讨论:头朝向信号的起源是被讨论的,因为postsubiculum和ATN之间具有双向连接的存在,所以下一步的研究进一步探究头朝向信息流。最后ATN中HD细胞和postsubicular中HD细胞有不同之处,在于ATN需要意志的运动输入。
Abstract:
Previous studies have identified neurons in the postsubiculum which discharge as a function of the animal's head direction in the horizontal plane, independent of its behavior and location in the … >>>
Previous studies have identified neurons in the postsubiculum which discharge as a function of the animal's head direction in the horizontal plane, independent of its behavior and location in the environment. Anatomical studies have shown that the postsubiculum contains reciprocal connections with the anterior thalamic nuclei (ATN). In order to determine how the head direction (HD) cell signal is processed in the brain, single- unit recordings were monitored in the ATN of freely moving rats in order to characterize their behavioral and spatial correlates. Animals were trained to retrieve food pellets thrown randomly into a cylindrical apparatus containing a single orientation cue. Single unit recordings in the ATN showed that approximately 60% of the recorded cells discharged in relation to the animal's head direction in the horizontal plane. Observation of the animal and quantitative analyses showed that HD cell firing was not dependent on the animal's behavior, trunk position, linear speed, angular head velocity, or location in the environment. Most of these cells were localized to the anterior dorsal thalamic nucleus. Each HD cell contained only one head direction at which the cell discharged maximally and the firing rate decreased linearly away from this preferred direction. The preferred firing directions from all cells recorded were distributed over a 360° range. Quantitative analysis showed that these cells contained similar discharge parameters (peak firing rate, directional firing range) to values reported previously for post-subicular HD cells (Taube et el., 1990a). Experiments involving rotation of the orientation cue showed that the preferred firing direction could be controlled by a salient visual cue. In contrast to postsubicular HD cells, passive rotation of a restrained animal showed that most ATN HD cells ceased discharging when the animal's head was oriented in the preferred direction. These findings demonstrate the presence of HD cells in the ATN and indicate the potential importance of this area for spatial navigation. The origin of the head direction signal is discussed and it is concluded that because of the presence of reciprocal connections between the postsubiculum and the ATN, further studies are required in order to determine the direction in which this head-directional information is flowing. Finally, ATN HD cells differ from postsubicular HD cells by appearing to require volitional motoric input. <<<
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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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