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881.
颜林林
(2022-08-30 23:47):
#paper doi:10.1016/j.gpb.2022.08.003 Genomics, Proteomics & Bioinformatics, 2022, Dynamic Spatial-temporal Expression Ratio of X Chromosome to Autosomes but Stable Dosage Compensation in Mammals. 哺乳动物的性染色体,在雌性和雄性中分别为XX和XY,也即X染色体的数量在雌雄之间相差了一倍,然而X染色体上的基因并未因此在两性之间出现巨大的表达差异,这个现象称为剂量补偿效应。本文通过收集和分析多组学数据,包括转录组(RNA-seq)、翻译组(Ribo-seq)、蛋白组(质谱),涉及不同物种(人、鸭嘴兽、负鼠;使用鸡作为外类群),以及(小鼠模型的)不同发育阶段,对此现象进行了深入细致的研究。采用将X染色体连锁的各基因表达,与常染色体基因表达、直系同源基因的表达,分别计算比值,评估剂量补偿效应的量化情况,发现该表达量比值,在不同组织和不同发育阶段,存在时空动态性,且与演化相关。很有意思的一篇生信文章。
Genomics, proteomics & bioinformatics,
2023-06.
DOI: 10.1016/j.gpb.2022.08.003
PMID: 36031057
PMCID:PMC10787176
Abstract:
In the evolutionary model of dosage compensation, per-allele expression level of the X chromosome has been proposed to have twofold up-regulation to compensate its dose reduction in males (XY) compared …
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In the evolutionary model of dosage compensation, per-allele expression level of the X chromosome has been proposed to have twofold up-regulation to compensate its dose reduction in males (XY) compared to females (XX). However, the expression regulation of X-linked genes is still controversial, and comprehensive evaluations are still lacking. By integrating multi-omics datasets in mammals, we investigated the expression ratios including X to autosomes (X:AA ratio) and X to orthologs (X:XX ratio) at the transcriptome, translatome, and proteome levels. We revealed a dynamic spatial-temporal X:AA ratio during development in humans and mice. Meanwhile, by tracing the evolution of orthologous gene expression in chickens, platypuses, and opossums, we found a stable expression ratio of X-linked genes in humans to their autosomal orthologs in other species (X:XX ≈ 1) across tissues and developmental stages, demonstrating stable dosage compensation in mammals. We also found that different epigenetic regulations contributed to the high tissue specificity and stage specificity of X-linked gene expression, thus affecting X:AA ratios. It could be concluded that the dynamics of X:AA ratios were attributed to the different gene contents and expression preferences of the X chromosome, rather than the stable dosage compensation.
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882.
李翛然
(2022-08-30 14:08):
#paper doi:doi/full/10.1002/adfm.202010747 Thymus Extracellular Matrix-Derived Scaffolds Support Graft-Resident Thymopoiesis and Long-Term 胸腺细胞外基质衍生的支架支持移植后的胸腺造血和成年胸腺上皮细胞的长期体外培养 在这项研究中,开发了一种基于脱细胞胸腺组织细胞外基质的三维支架,命名为TS。当播种胎儿或成人胸腺组织时,TS可以以不同的效率支持淋巴前体的成熟,使其成为能够对有丝分裂刺激作出反应的常规和调节性T细胞。
一个功能性胸腺微环境的成功工程,关键取决于成年TEC的体外生长。然而,保存细胞的胸腺造血能力是在体外创建胸腺类器官的主要缺陷之一。因此,这种能力构成了一个关键的困难,需要有效地解决,以建立、研究和操纵T细胞的发展,无论是为实验研究开发一个体外平台,还是为体内替代工作开发一个器官。尽管在结构和细胞条件方面缺乏优化,可能反映在结果的稳健性相当有限,但我们的结果首次描述了允许成年TEC在体外和体内长期生存的工程条件,同时支持胸腺造血。
除了改善TS的工程之外,还需要努力确定具有长期再增殖潜力的TEC前体,能够产生所有的TEC谱系和亚群。来自小鼠TEC的单细胞转录组数据的使用揭示了TEC亚型的相当复杂性,并为确定这些细胞的发育轨迹的计算工作提供了依据。在适当的TS上长期重新填充TEC前体,将确保维持一个能够吸引血源性T细胞前体的环境,并在很长一段时间内指导他们分化和选择成熟的常规和调节性T细胞。在体外培养后,需要改进细胞检索的协议,以便对TEC进行深入的表型和定量调查。由于这些TEC前体很可能是脆弱的,因此需要部署一些条件,以保证有效、迅速和均匀地播种到ECM支架上,并允许用额外的基质细胞(包括间质细胞和内皮细胞)来补充这些基本环境,已知这有助于胸腺交叉对话。使用灌注式生物反应器和选择性条件将进一步帮助在体外创造一个自我组织的胸腺微环境,提供强大的持续T细胞输出。精确控制调节体外胸腺组织形成的化学物理条件对于可重复性和扩展性至关重要,无论是生成较小的器官用于药物筛选,还是生成较大的微环境用于器官替代策略,作为对无胸腺或胸腺发育不全者的治疗选择。
免疫治疗的核心问题:
让免疫系统恢复工作能力,目前的CarT CARNK等等 都是属于治标 如何恢复治本是全世界目前的前沿聚焦方向,也许中医真的可以发挥一些东西。
但是器官再造面临了太多挑战:
1. 类器官作为新型的药筛模型,成本虽然较PDX更低,但还是远高于细胞系。类器官成本占比较高的包括培养使用的基质胶,常用的基质胶为美国BD Biosciences公司的Matrigel,在行业内处于较为垄断的地位,价格较高。Matrigel可以产生类似于哺乳动物细胞基底膜的生物活性基质材料,帮助多种类型的细胞达到附着和分化。Matrigel的来源是小鼠肉瘤细胞系,除了成本较高的问题,同时批次间存在一定的变异性。且由于是动物来源,对于有机类的药物的检测有局限性。考虑到小鼠来源的细胞外基质对于药物筛选实验结果存在一定的干扰,因此基质的工程技术开发用于合成外源差异较小的、非动物来源的基质胶用于成本下降和性能优化将是类器官产业化需要解决的关键性问题之一。基质胶以外,培养也涉及多种细胞因子组合使用,细胞生长因子通常也价格不菲。选择效果更好的细胞因子以及尝试减少使用细胞因子的数量也可以带来成本下降的空间。
2. 目前大多类器官本身并不具备血管化的结构。因此,随着类器官体积的增长,类器官受限于氧气的缺失以及代谢废物的增加,可能导致的组织坏死。已有研究构建血管内皮细胞微环境的肿瘤类器官,将类器官肿瘤细胞和血管内皮细胞在Matrigel上共同培养,生成血管结构以期解决类器官血管化缺失的问题。
3. 血管化以外的难点还包括模拟肿瘤和免疫环境的相互作用关系。2019年Nature Protocol发表了肿瘤类器官和免疫细胞共同培养的相关protocol,可以体现和模拟出肿瘤微环境的部分特征。以上皮类器官和免疫细胞共培养模型为例,可通过在培养基中添加活化的免疫细胞、在组织消化成单细胞后和免疫细胞共同生长、添加ECM中的重组细胞因子等方法重塑类器官和免疫细胞的相互作用。
4. 相比于单个类器官,类器官系统的构建能够对药物疗效和潜在毒性做出更完整全面的评估。目前类器官仅能检测出药物对于肿瘤的抑制效果,对于其他器官组织是否存在其他副作用和安全性风险并不能做出预判。为了解决这一问题,2017年Skardal et al.构建了有心脏、肺部、肝脏组成的集成于闭合循环关注体中的类器官系统,以达到全面揭示药物对不同器官的毒性和药效的目的。
5. 重复性(reproducibility)和一致性 (consistency)也是类器官发展的重大瓶颈,这很大程度上由于过程控制的欠缺与行业标准的空白。类器官培养过程中人为因素的过多参与、自动化程度低导致因为系统偶然性造成的误差较大。同时,类器官检测手段十分匮乏,活体观察主要集中在形态学观察,断点观察集中在基于荧光的各类指标的检测,能够活体实时对类器官各项指标进行检测的光学、电化学等手段仍较为欠缺。当前,类器官很多研究者致力于制造更新的类器官,做出之前未能做出的类器官,我们可以制作海马体、垂体、腺体、脾、肾的类器官,却难以确定一个符合要求的类器官需要满足那些个体的诸如尺寸、形状、基因表达量等,群体的诸如类器官之间的方差等统计学指标。这将限制类器官的高效研究与向临床研究的转化。
6. 对于类器官培养过程中的工程控制也是亟待解决的问题。当前类器官培养大多使用Matrigel水凝胶作为培养基质,Matrigel是康宁生命科学公司生产的Engelbreth-Holm-Swarm (EHS)小鼠肉瘤细胞分泌的胶状蛋白混合物。Matrigel因其含有外源成分,难以应用在人的很多治疗场景。另一方面,虽然类器官与微流控技术已有一些结合研究的例子,但使用微流控芯片对类器官生存的流体环境进行模拟仍不成熟,如何使用微流控等技术对类器官培养时流体微环境进行控制是亟待解决的问题。同时,现有类器官的直径约在100-500μm之间,虽然具有一定程度的尺度效应,但还是难以模拟真实组织、器官的场景。倘若要制造尺度更大的类器官,类器官的血管化也是十分重要的问题。
Abstract:
The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen-specific response. A diverse population of …
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The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen-specific response. A diverse population of stroma cells provides surface-bound and soluble molecules that orchestrate the intrathymic maturation and selection of developing T cells. Forming an intricate 3D architecture, thymic epithelial cells (TEC) represent the most abundant and important constituent of the thymic stroma. Effective models for in and ex vivo use of adult TEC are still wanting, limiting the engineering of functional thymic organoids and the understanding of the development of a competent immune system. Here a 3D scaffold is developed based on decellularized thymic tissue capable of supporting in vitro and in vivo thymopoiesis by both fetal and adult TEC. For the first time, direct evidences of feasibility for sustained graft-resident T-cell development using adult TEC as input are provided. Moreover, the scaffold supports prolonged in vitro culture of adult TEC, with a retained expression of the master regulator Foxn1. The success of engineering a thymic scaffold that sustains adult TEC function provides unprecedented opportunities to investigate thymus development and physiology and to design and implement novel strategies for thymus replacement therapies.
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883.
颜林林
(2022-08-26 23:18):
#paper doi:10.1101/2022.08.24.505159 bioRxiv, 2022, A genome-wide atlas of recurrent repeat expansions in human cancer. 这篇来自斯坦福大学的Michael Snyder团队。通过重分析来自ICGC和TCGA的2622个癌症全基因组测序数据,涉及29个癌种,从中鉴定出160个重复序列扩张(recurrent repeat expansions, rRE)事件,且这些事件绝大多数都与特定癌症亚型相关。这些重复序列所处基因组区域,也富集在某些基因的调控元件附近,提示了它们在基因调控方面可能发挥作用。其中一个GAAA重复发生在UGT2B7基因的内含子中,在34%的肾细胞癌样本中都能观察到,于是通过斯坦福癌症中心入组了12例肾癌病例,对其样本开展了二代测序(Illumina NovaSeq)和三代测序(PacBio),验证了该rRE事件的发生。
bioRxiv,
2022.
DOI: 10.1101/2022.08.24.505159
Abstract:
Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases. However, repeat expansions are often not explored beyond neurological and …
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Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs (STRs), a phenomenon termed microsatellite instability (MSI); however larger repeat expansions have not been systematically analyzed in cancer. Here, we identified TR expansions in 2,622 cancer genomes, spanning 29 cancer types. In 7 cancer types, we found 160 recurrent repeat expansions (rREs); most of these (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with an enrichment near candidate cis-regulatory elements, suggesting a role in gene regulation. One rRE located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, targeting cells harboring this rRE with a rationally designed, sequence-specific DNA binder led to a dose-dependent decrease in cell proliferation. Overall, our results demonstrate that rREs are an important but unexplored source of genetic variation in human cancers, and we provide a comprehensive catalog for further study.
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884.
白义民
(2022-08-26 21:56):
#paper 《宋金时代两次汴京战役中的抛石之战》介绍了公元1200年左右,在宋金蒙元战争中,重型武器抛石机的使用,对关心历史的同学,提供了详实的参考史料。对很多玩游戏帝国时代的同学,有助于了解抛石机具体历史使用场景。在辽宋金代,战争中使用砲的记录远远超过前代”。依托众人合力、借助物理器械发射石弹的交战,成为当时战事中持续使用、效力凸显且制胜攸关的重要作战方式,石战水平发挥出历史上的极致。
清华大学学报(哲学社会科学版),
2022.
Abstract:
北宋末与金朝、金末与蒙古间相隔百年的两次汴京战役中,凭借人力发射的抛石之战最为激烈,抛石技法和强弱之势惊人相似。在当时的城池攻防战中,抛石战器的威力无比。靖康金人攻汴,抛石较量技高一筹,异常猛烈,且利用一批宋人遗弃战器。本具优势的宋人卫城也用抛石,兼取假山石材,但力所不及,应对之法效果不佳,痛失京城;角色转换的金、蒙汴京战役,犹如靖康石战重演。蒙军抛石强势无比,原具优势且取宋之长的金人卫城,也取假山之石,且手握利器,同样力所不逮而后告败。两战中两次汴京失守,抛石战均发挥关键性的作用。宋、金先后败于同一城池,其根本原因不是城址布局、抛石战术和技艺等问题,而在于昏庸政治环境下人事谋划的失策。两战中飞石如雨的场面令人称奇,其成败喜悲更令人思虑悠长。
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北宋末与金朝、金末与蒙古间相隔百年的两次汴京战役中,凭借人力发射的抛石之战最为激烈,抛石技法和强弱之势惊人相似。在当时的城池攻防战中,抛石战器的威力无比。靖康金人攻汴,抛石较量技高一筹,异常猛烈,且利用一批宋人遗弃战器。本具优势的宋人卫城也用抛石,兼取假山石材,但力所不及,应对之法效果不佳,痛失京城;角色转换的金、蒙汴京战役,犹如靖康石战重演。蒙军抛石强势无比,原具优势且取宋之长的金人卫城,也取假山之石,且手握利器,同样力所不逮而后告败。两战中两次汴京失守,抛石战均发挥关键性的作用。宋、金先后败于同一城池,其根本原因不是城址布局、抛石战术和技艺等问题,而在于昏庸政治环境下人事谋划的失策。两战中飞石如雨的场面令人称奇,其成败喜悲更令人思虑悠长。
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885.
刑无刀
(2022-08-26 19:19):
#paper Master Thesis,Business information technology Faculty of Electrical Engineering, Mathematics and Computer Science University Twente May 2016 , Applying Intelligence Amplification in Decision Making
Intelligence Amplification (IA,智力放大)最早是由Ashby在Introduction of Cybernetics中提出的一个概念,是研究如何用人工智能(AI)去提升人类智能的,类似概念也有Augmented Intelligence。本篇论文作者比较系统的研究了这一概念用于决策系统中。本文主要由三部分构成:首先较为系统的综述了这一领域的文献现状,也顺便说清楚了IA系统中人(Human)和智能体(Agent)的关系,第二部分详细描述了一个IA决策系统的框架及基本元素,最后介绍了如何评估这个系统,并评估了自己的方案。遗憾的是我才读一半,还没看到如何评估来。
Abstract:
This thesis proposes an intelligence amplification (IA) framework to apply IA in decision making. With this IA framework, IA is applied to solve planning problems of synchromodal transport in the …
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This thesis proposes an intelligence amplification (IA) framework to apply IA in decision making. With this IA framework, IA is applied to solve planning problems of synchromodal transport in the simulated environment. Through the case study, the proposed IA framework shows its effectiveness in solving the task assignment to achieve the human-intelligent agent collaboration. Besides, this thesis proves IA's benefits in improving decision and shows that humans' decision making performance is enhanced by IA.
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886.
前进
(2022-08-24 22:22):
#paper arXiv:2208.04939v1 ,2022,U-Net vs Transformer: Is U-Net Outdated in Medical Image Registration?
基于Transformer的网络由于其长距离建模能力,在可变形图像配准中越来越流行。然而本文认为,一个具有5层卷积Unet网络的感受野足以在不需要依赖长距离建模能力的情况下捕捉精确的图像形变。本文想要探究UNet网络在应用于医学图像配准时,与现代基于Transformer的方法相比是否已经过时?为此,作者提出了一个具有大的卷积核的UNet网络(LKU-Net),即通过在一个普通的UNet网络内嵌入平行的卷积块来争强网络的感受野。在公用3D IXI 大脑数据集上进行基于atlas的配准实验,作者证明了LKU-Net的变现依旧可以和如今最先进的基于Transformer的方法相当甚至超越,而且只用了TransMorph 1.12%的参数量和10.8%的计算量。作者进一步将算法应用在MICCAI 2021的配准比赛中,同样超越了Transmorph,目前排在第一。只对UNet进行了简单的改造,基于Unet的配准算法依旧可以达到最先进的效果,证明基于UNet的配准网络并未过时。
arXiv,
2022.
DOI: 10.48550/arXiv.2208.04939
Abstract:
Due to their extreme long-range modeling capability, vision transformer-based networks have become increasingly popular in deformable image registration. We believe, however, that the receptive field of a 5-layer convolutional U-Net …
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Due to their extreme long-range modeling capability, vision transformer-based networks have become increasingly popular in deformable image registration. We believe, however, that the receptive field of a 5-layer convolutional U-Net is sufficient to capture accurate deformations without needing long-range dependencies. The purpose of this study is therefore to investigate whether U-Net-based methods are outdated compared to modern transformer-based approaches when applied to medical image registration. For this, we propose a large kernel U-Net (LKU-Net) by embedding a parallel convolutional block to a vanilla U-Net in order to enhance the effective receptive field. On the public 3D IXI brain dataset for atlas-based registration, we show that the performance of the vanilla U-Net is already comparable with that of state-of-the-art transformer-based networks (such as TransMorph), and that the proposed LKU-Net outperforms TransMorph by using only 1.12% of its parameters and 10.8% of its mult-adds operations. We further evaluate LKU-Net on a MICCAI Learn2Reg 2021 challenge dataset for inter-subject registration, our LKU-Net also outperforms TransMorph on this dataset and ranks first on the public leaderboard as of the submission of this work. With only modest modifications to the vanilla U-Net, we show that U-Net can outperform transformer-based architectures on inter-subject and atlas-based 3D medical image registration. Code is available at this https URL.
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887.
陈亚伟
(2022-08-24 21:17):
#paper doi:10.1038/s41571-022-00660-y. Nature review clinical oncology, 2022, Circulating tumour DNA - looking beyond the blood.
液体活检,是近十年来发展最为迅速的肿瘤检测技术。区别于组织活检,它无创好获取,又能一定程度的克服组织异质性,因而成为组织检测的替代或补充。
到目前为止,绝大多数液体活检研究都聚焦在外周血里的ctDNA(循环肿瘤DNA),而实际上外周血之外的其他体液中也含有ctDNA,这些ctDNA在特定场景中可能有着比血浆ctDNA更多的优势。
近日,来自曼彻斯特大学的Natalie Cook教授和他的研究团队在Nature Reviews Clinical Oncology杂志上发表综述文章,系统阐述了非血液来源ctDNA在肿瘤诊疗中的研究进展。
这一研究详细探讨了这些替代来源的ctDNA相较于血液ctDNA的独特作用,并深入分析了非血液来源ctDNA适宜的应用场景及所面临的挑战,为我们理解和应用非血液来源的ctDNA提供了支持。
PS:群里学习了很多,感谢各位大佬,防止过期赶紧打个卡,因为同时在写一篇解读这个综述的文稿,所以格式有点自媒体的感觉,不是抄袭哈
Abstract:
Over the past decade, various liquid biopsy techniques have emerged as viable alternatives to the analysis of traditional tissue biopsy samples. Such surrogate 'biopsies' offer numerous advantages, including the relative …
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Over the past decade, various liquid biopsy techniques have emerged as viable alternatives to the analysis of traditional tissue biopsy samples. Such surrogate 'biopsies' offer numerous advantages, including the relative ease of obtaining serial samples and overcoming the issues of interpreting one or more small tissue samples that might not reflect the entire tumour burden. To date, the majority of research in the area of liquid biopsies has focused on blood-based biomarkers, predominantly using plasma-derived circulating tumour DNA (ctDNA). However, ctDNA can also be obtained from various non-blood sources and these might offer unique advantages over plasma ctDNA. In this Review, we discuss advances in the analysis of ctDNA from non-blood sources, focusing on urine, cerebrospinal fluid, and pleural or peritoneal fluid, but also consider other sources of ctDNA. We discuss how these alternative sources can have a distinct yet complementary role to that of blood ctDNA analysis and consider various technical aspects of non-blood ctDNA assay development. We also reflect on the settings in which non-blood ctDNA can offer distinct advantages over plasma ctDNA and explore some of the challenges associated with translating these alternative assays from academia into clinical use.
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888.
张浩彬
(2022-08-24 09:56):
#paper doi: 10.1007/s11222-022-10130-1 Merlo, L., Maruotti, A., Petrella, L., & Punzo, A. (2022). Quantile hidden semi-Markov models for multivariate time series. Statistics and Computing, 32(4). https://doi.org/10.1007/s11222-022-10130-1
模型关键词:
解决问题:多元时间序列,分位数回归;
解决技术:隐藏半马尔科夫(解决停留时间不满足几何分布有偏问题,模型可以选择更多的分布形式,从而更加灵活)、多元非对称拉普拉斯分布(解决一般非位数回归扩到高维的问题)
估计方法:极大似然估计,EM算法
实证:意大利大气空气质量预测,尤其是极端分位数的估计
Abstract:
This paper develops a quantile hidden semi-Markov regression to jointly estimate multiple quantiles for the analysis of multivariate time series. The approach is based upon the Multivariate Asymmetric Laplace (MAL) …
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This paper develops a quantile hidden semi-Markov regression to jointly estimate multiple quantiles for the analysis of multivariate time series. The approach is based upon the Multivariate Asymmetric Laplace (MAL) distribution, which allows to model the quantiles of all univariate conditional distributions of a multivariate response simultaneously, incorporating the correlation structure among the outcomes. Unobserved serial heterogeneity across observations is modeled by introducing regime-dependent parameters that evolve according to a latent finite-state semi-Markov chain. Exploiting the hierarchical representation of the MAL, inference is carried out using an efficient Expectation-Maximization algorithm based on closed form updates for all model parameters, without parametric assumptions about the states' sojourn distributions. The validity of the proposed methodology is analyzed both by a simulation study and through the empirical analysis of air pollutant concentrations in a small Italian city.
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889.
李欣
(2022-08-23 20:20):
#paper 10.1016/j.devcel.2021.01.014
Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring
精子表观基因组对环境压力源的敏感不仅限于宫内发育期,可能贯穿整个生命周期。不良饮食可致小鼠精子表观修饰改变,精子发生过程中KDM1A过表达介导精子启动子H3K4me2/3差异富集、子代出生后早期死亡及大量先天性异常,而精子H3K4me3水平的变化是否可从精子传递到植入前胚胎尚未得到证实。此外,微量营养素缺乏,包括叶酸缺乏症,如何影响哺乳动物精子染色质在全基因组水平上的建立和传递尚不清楚。
本研究旨在探究:(1)断奶后叶酸缺乏会改变精子H3K4me3的富集吗?(2)受损的精子表观基因组是否会受到另一种表观基因组调节剂(叶酸缺乏)的影响并导致后代发育缺陷增强?(3)精子H3K4me3富集变化是否在胚胎中持续存在,它们是否与胚胎基因表达和发育异常有关?作者得出结论:精子H3K4me3传递到胚胎并影响基因表达和发育,增加了暴露于多种环境压力可累积影响表观基因组的可能性。表观遗传错误可以在精子中积累并恶化子代的发育结局。
Abstract:
A father's lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes …
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A father's lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes to impact embryonic gene expression and development. Here, we demonstrate that a folate-deficient (FD) diet alters histone H3 lysine 4 trimethylation (H3K4me3) in sperm at developmental genes and putative enhancers. A subset of H3K4me3 alterations in sperm are retained in the pre-implantation embryo and associated with deregulated embryonic gene expression. Using a genetic mouse model in which sires have pre-existing altered H3K4me2/3 in sperm, we show that a FD diet exacerbates alterations in sperm H3K4me3 and embryonic gene expression, leading to an increase in developmental defect severity. These findings imply that paternal H3K4me3 is transmitted to the embryo and influences gene expression and development. It further suggests that epigenetic errors can accumulate in sperm to worsen offspring developmental outcomes.
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890.
张浩彬
(2022-08-23 15:36):
#paper doi: 10.1080/10618600.2021.1909601 Moon, S. J., Jeon, J.-J., Lee, J. S. H., & Kim, Y. (2021). Learning Multiple Quantiles With Neural Networks. Journal of Computational and Graphical Statistics, 30(4), 1238–1248.
提出了一个神经网络模型,用于估计满足非交叉属性的多个条件分位数。 传统的分位数回归会面临一个问题就是可能会出现分位数交叉,即85%分位数的值大于90%分位数的值。一般来说有两种处理策略:(1)调整转转模型参数;(2)将模型空间限制为非交叉分位数。本文采用了第二种思路,借鉴了线性非交叉分位数回归(非交叉SVR中的一个策略,这个策略问题在于计算量可能比较大),提出了一种具有不等式约束的非交叉分位数神经网络模型(把不等式约束用在了神经网络隐藏层)。
解决了交叉问题,第二个贡献是计算效率。为了使用一阶优化方法,文章开发了一种新算法来拟合所提出的模型。 该算法在没有需要多项式计算时间的投影梯度步骤的情况下给出了几乎最优的解决方案。
IF:1.400Q2
Journal of Computational and Graphical Statistics,
2021.
DOI: 10.1080/10618600.2021.1909601
Abstract:
We present a neural network model for estimation of multiple conditional quantiles that satisfies the noncrossing property. Motivated by linear noncrossing quantile regression, we propose a noncrossing quantile neural network …
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We present a neural network model for estimation of multiple conditional quantiles that satisfies the noncrossing property. Motivated by linear noncrossing quantile regression, we propose a noncrossing quantile neural network model with inequality constraints. In particular, to use the first-order optimization method, we develop a new algorithm for fitting the proposed model. This algorithm gives a nearly optimal solution without the projected gradient step that requires polynomial computation time. We compare the performance of our proposed model with that of existing neural network models on simulated and real precipitation data. Supplementary materials for this article are available online.
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891.
徐炳祥
(2022-08-18 17:16):
#paper doi: 10.1038/s41586-022-05030-3 Nature, 2022, Brown-fat-mediated tumour suppression by cold-altered global metabolism。有氧糖酵解是肿瘤细胞获取能量的主要方式,此过程需消耗大量葡萄糖,因此肿瘤组织对葡萄糖饥饿敏感。而暴露于寒冷环境中的动物通过棕色脂肪细胞(BAT)活化、白色脂肪细胞(WAT)棕色化进行非战栗产热的过程也需消耗大量葡萄糖。因此寒冷环境下的肿瘤患者势必存在BAT和肿瘤细胞之间的葡萄糖竞争,此竞争有可能使肿瘤组织处于葡萄糖饥饿状态从而抑制肿瘤生长。本文主要通过将异体肿瘤移植小鼠至于寒冷环境下对这一假设进行了验证。此为将代谢与肿瘤联系起来的又一新角度。
Abstract:
Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis. …
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Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
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892.
颜林林
(2022-08-18 00:34):
#paper doi:10.1186/s12859-022-04876-8 BMC Bioinformatics, 2022, IMSE: interaction information attention and molecular structure based drug drug interaction extraction. 让机器自动读取大量论文,并从中提炼有用信息,是很多人的梦想,BERT等模型让这件事逐步成为现实。本文便是基于PubMed摘要和PMC全文,进行BioBERT预训练,并由此改进DDIExtraction 2013的任务执行性能,该任务旨在从生物医学领域的自由文本中提取药物间相互作用(drug-drug interaction, DDI)。关于这项任务已有不少研究工作,本文引入了交互注意力向量(interaction attention vector),以及加入药物分子结构(以利用其特征空间信息)等,来改善模型性能及可解释性,取得不错的效果。
Abstract:
BACKGROUND: Extraction of drug drug interactions from biomedical literature and other textual data is an important component to monitor drug-safety and this has attracted attention of many researchers in healthcare. …
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BACKGROUND: Extraction of drug drug interactions from biomedical literature and other textual data is an important component to monitor drug-safety and this has attracted attention of many researchers in healthcare. Existing works are more pivoted around relation extraction using bidirectional long short-term memory networks (BiLSTM) and BERT model which does not attain the best feature representations.RESULTS: Our proposed DDI (drug drug interaction) prediction model provides multiple advantages: (1) The newly proposed attention vector is added to better deal with the problem of overlapping relations, (2) The molecular structure information of drugs is integrated into the model to better express the functional group structure of drugs, (3) We also added text features that combined the T-distribution and chi-square distribution to make the model more focused on drug entities and (4) it achieves similar or better prediction performance (F-scores up to 85.16%) compared to state-of-the-art DDI models when tested on benchmark datasets.CONCLUSIONS: Our model that leverages state of the art transformer architecture in conjunction with multiple features can bolster the performances of drug drug interation tasks in the biomedical domain. In particular, we believe our research would be helpful in identification of potential adverse drug reactions.
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893.
颜林林
(2022-08-17 23:55):
#paper doi:10.1016/j.xgen.2022.100168 Cell Genomics, 2022, Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes. 高通量测序技术的发展、降价和普及,拉动了一大批人类群体基因组学的研究。本文又是这样一篇大规模人群的全外显子组数据及其分析结果的发布,该人群来自UK biobank,入组人数超过39万。文章开发并使用了一个混合模型分析框架SAIGE-GENE,会同时考虑点突变的水平、基因水平的突变负荷、以及两者的组合,由此分析与4529种疾病或表型(包括II型糖尿病、心脏代谢等)存在关联关系的各类罕见突变。在此基础上,本文还提供了一个在线浏览器Genebass,以展示这些表型相关的罕见突变。作为一个实例,文章在结果部分还特意强调了所发现的一个基因SCRIB,以及它与MRI脑成像特征之间的关系。类似的大规模人群基因组分析文章层出不穷,分析方法各有侧重或不同,若有可能,倒是值得研究下它们之间的方法差异,是否可能对所报道的结果产生影响。
Abstract:
Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variations in human disease has not been explored at …
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Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variations in human disease has not been explored at scale. Exome-sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variations across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 4,529 phenotypes using single-variant and gene tests of 394,841 individuals in the UK Biobank with exome-sequence data. We find that the discovery of genetic associations is tightly linked to frequency and is correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside the Genebass browser for rapidly exploring rare-variant association results.
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894.
张德祥
(2022-08-16 10:19):
#paper DOI https://doi.org/10.1007/s10339-020-00981-9 Do Process-1 simulations generate the epistemic feelings that drive Process-2 decision making? 如何用范畴数学来描述人类过程1过程2的思考方式(快思考慢思考),并且可以用来分析心流的体验(p31),这种分析结合了全局神经工作空间及元认知。形成了一个人类认知的高级架构。慢思考过程2是快思考过程1的一个高阶功能或过程1的上层调度机制(其中包含了人类的高级情感:问题求解过程中的怀疑焦虑挫折兴奋等)。思维问题解决的慢过程由于与外界互动少,主要以内感受为主,所以内部情绪活动较多(即怀疑焦虑兴奋等)。机制底层仍然是贝叶斯的信念、confidence。
Abstract:
We apply previously developed Chu space and Channel Theory methods, focusing on the construction of Cone-Cocone Diagrams (CCCDs), to study the role of epistemic feelings, particularly feelings of confidence, in …
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We apply previously developed Chu space and Channel Theory methods, focusing on the construction of Cone-Cocone Diagrams (CCCDs), to study the role of epistemic feelings, particularly feelings of confidence, in dual process models of problem solving. We specifically consider "Bayesian brain" models of probabilistic inference within a global neuronal workspace architecture. We develop a formal representation of Process-1 problem solving in which a solution is reached if and only if a CCCD is completed. We show that in this representation, Process-2 problem solving can be represented as multiply iterated Process-1 problem solving and has the same formal solution conditions. We then model the generation of explicit, reportable subjective probabilities from implicit, experienced confidence as a simulation-based, reverse engineering process and show that this process can also be modeled as a CCCD construction.
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895.
惊鸿
(2022-08-14 18:12):
#paper doi:10.1101/2022.08.08.503198 Bilallelic germline mutations in MAD1L1 induce a novel syndrome of aneuploidy with high tumor susceptibility
MAD1L1是编码纺锤体组装检查点 (SAC) 蛋白MAD1的基因,发生在一名36岁的患有十几个肿瘤的女性身上,包括五个恶性肿瘤。外周血细胞的功能研究表明缺乏全长蛋白质和SAC反应不足,导致细胞遗传学和单细胞 (sc) 检测到约30-40% 的非整倍体细胞DNA分析。对患者血细胞的scRNA-seq分析确定了线粒体应激伴随全身炎症,干扰素和NFkB信号增强。MAD1L1突变还导致 γ δ T细胞的特异性克隆扩增,增加了18号染色体并增强了细胞毒性,以及具有慢性淋巴细胞白血病细胞特征的染色体12增益和转录组特征的中间b细胞。这些数据表明MAD1L1突变是一种新的具有全身炎症和前所未有的肿瘤易感性的非整倍体综合征的原因。
仅仅一个基因片段就可以给全身带来变化,这些变化有好有坏,所以基因编辑不是消消乐,是一个严谨的技术,这是一个基因工程师应有的心态
bioRxiv,
2022.
DOI: 10.1101/2022.08.08.503198
Abstract:
Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We …
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Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, the gene encoding the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias, including five malignant tumors. Functional studies in peripheral blood cells demonstrated lack of full-length protein and deficient SAC response, resulting in ∼30-40% of aneuploid cells as detected by cytogenetic and single-cell (sc) DNA analysis. scRNA-seq analysis of patient blood cells identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFkB signaling. The inference of chromosomal aberrations from scRNA-seq analysis detected inflammatory signals both in aneuploid and euploid cells, suggesting a non-cell autonomous response to aneuploidy. In addition to random aneuploidies, MAD1L1 mutations resulted in specific clonal expansions of γδ T-cells with chromosome 18 gains and enhanced cytotoxic profile, as well as intermediate B-cells with chromosome 12 gains and transcriptomic signatures characteristic of chronic lymphocytic leukemia cells. These data point to MAD1L1 mutations as the cause of a new aneuploidy syndrome with systemic inflammation and unprecedented tumor susceptibility.
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896.
DeDe宝
(2022-08-14 17:53):
#paper doi:10.1016/j.cub.2020.03.006 Current Biology,2020,Stress Disrupts Human Hippocampal-Prefrontal Function during Prospective Spatial Navigation and Hinders Flexible Behavior.前瞻对空间导航的规划非常重要,前瞻性规划部分依赖于情景记忆检索机制,而检索能力受到压力的负面影响。本研究采用虚拟空间导航任务,检查压力是否以及如何影响前瞻和决策行为。研究结果表明,压力可能对新目标的导航规划神经机制产生影响。从行为角度,压力限制了检索landmark的能力和有效导航的能力,降低了采取新捷径的可能性,并增加了达到目标的路径长度。从神经角度,压力会降低海马后部、FPC、广义CCN脑区和其他与记忆相关脑区(如角回)在新路程规划的神经活动。
Abstract:
The ability to anticipate and flexibly plan for the future is critical for achieving goal-directed outcomes. Extant data suggest that neural and cognitive stress mechanisms may disrupt memory retrieval and …
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The ability to anticipate and flexibly plan for the future is critical for achieving goal-directed outcomes. Extant data suggest that neural and cognitive stress mechanisms may disrupt memory retrieval and restrict prospective planning, with deleterious impacts on behavior. Here, we examined whether and how acute psychological stress influences goal-directed navigational planning and efficient, flexible behavior. Our methods combined fMRI, neuroendocrinology, and machine learning with a virtual navigation planning task. Human participants were trained to navigate familiar paths in virtual environments and then (concurrent with fMRI) performed a planning and navigation task that could be most efficiently solved by taking novel shortcut paths. Strikingly, relative to non-stressed control participants, participants who performed the planning task under experimentally induced acute psychological stress demonstrated (1) disrupted neural activity critical for mnemonic retrieval and mental simulation and (2) reduced traversal of shortcuts and greater reliance on familiar paths. These neural and behavioral changes under psychological stress were tied to evidence for disrupted neural replay of memory for future locations in the spatial environment, providing mechanistic insight into why and how stress can alter planning and foster inefficient behavior.
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897.
颜林林
(2022-08-13 23:36):
#paper doi:10.1038/s41586-022-04774-2 Nature, 2022, Stromal changes in the aged lung induce an emergence from melanoma dormancy. 众所周知,年龄是肿瘤发病的最重要因素。这篇文章将培养的黑色素瘤细胞(其中部分细胞系使用质粒体系过表达WNT通路相关基因),注入年轻与年老小鼠,观察其成瘤过程及表型变化,其中还穿插腹腔注射等干预实验,之后取样后对肺组织进行免疫组化、蛋白组(质谱)等检测,用以揭示衰老与肿瘤发生之间的关系。该研究发现,在老化的肺微环境中,黑色素瘤并未快速生长,反而是受到了抑制,处于一种休眠状态,但同时该微环境又会促进其转移扩散,使黑色素瘤细胞能够在转移性生态位中有效传播和播种。本文同时还详细研究了WNT通路在此过程中的作用,以及酪氨酸激酶受体 AXL 和 MER 对肿瘤休眠的促进再激活。这些结果为后续研究肿瘤休眠及肺组织微环境之间的关系提供了重要信息,同时也提示在肿瘤治疗过程中有必要关注年龄因素的影响。
Abstract:
Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance …
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Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells-in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.
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898.
魏魏魏
(2022-08-12 20:21):
#paper doi:10.1111/1467-8721.01259 Current Directions in Psychological Science, (2003), Understanding Families as Systems. 这是一篇比较古老的文献了,而且属于综述性质的文献,只是因为对于探讨父亲或母亲在子女心理发展中的作用有价值才阅读的。作者认为,应该把家庭看作是有婚姻关系和亲子关系等多个子系统构成的一个整体系统,这个系统是有层次的,像一个生命一样能够对外界刺激作出反应并适应外界的变化。这样的观点有助于我们深刻理解儿童心理发展,比如,基于上述家庭观,我们对亲子依恋、儿童气质类型的理解不再是静态的且二元的,应该看到夫妻关系或婚姻关系对儿童心理发展的影响,所以,现在我们的研究一般都把夫妻关系品质或父母任何一方的幸福感等作为控制变量。把家庭看作能够对外界刺激做出反应的系统也是有意义的,这意味着家庭系统内部不同层次之间是相互影响的,不同家庭发展阶段儿童受到的影响也是不同的,因此,采用追踪研究对儿童心理发展进行研究是有必要的。这篇文献对具体的实证研究有很大的启发。
Abstract:
In this article, we discuss recent research that has arisen from theoretical and conceptual models that use a systems metaphor for understanding families. We suggest that research stimulated by such …
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In this article, we discuss recent research that has arisen from theoretical and conceptual models that use a systems metaphor for understanding families. We suggest that research stimulated by such models leads social scientists in new and important directions in understanding the social and emotional development of children in their families. These models view development as resulting from the dynamic transactions across multiple levels of family systems, which regulate a child's behavior. Thus, these models are important in considering multiple influences on development and adaptation.
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899.
颜林林
(2022-08-12 07:42):
#paper doi:10.1016/j.ccell.2022.07.002 Cancer Cell, 2022, Integrative analysis of drug response and clinical outcome in acute myeloid leukemia. 这是一项关于AML(急性骨髓性白血病)的长达10年的真实世界临床研究,收集了来自多个中心的 805 名患者(942 个样本),对样本进行基因组和转录组的测序,同时使用离体细胞培养进行药物反应实验,此外还利用NLP技术整理和分析患者的病历数据。在数据分析方面,使用反卷积方法,通过转录组数据推断出样本的细胞类群组成,并结合临床信息和组学数据分析结果,识别出影响药物响应情况的因素(如年龄、基因表达、细胞分化状态等)。所建立的模型,揭示了单个基因 PEAR1 是患者生存的最强预测因子之一。所形成的数据集,也提供了一个在线交互式网站进行分析展示。分析方面基本都是很多生信数据挖掘类文章的常见套路,并没有特别新颖之处,但得益于长时间积累的队列及其完整的临床信息,作为一个重要的数据集资源,以及单病种的真实世界研究实例,也还是很有价值的。此外,关于药物响应的细胞实验部分相对独立,与患者预后进行关联解释并不容易,大概也是为了提升文章份量而加入的。
Abstract:
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large …
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Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.
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900.
张浩彬
(2022-08-11 16:10):
#paper 10.48550/arXiv.1901.10738
Unsupervised Scalable Representation Learning for Multivariate Time Series
论文关键是:正负样本构造, triplet loss以及因果空洞卷积
适用:该无监督学习模型可以用于不定长的序列;短序列及长序列均可使用;
1.正负样本构造:对于某序列,随机选择长度,构造一个子序列。在这个子序列中,随机抽样一个子序列作为正样本;从其他序列中随机抽样作为一个负样本
2.改造的triplet loss
3. exponentially dilated causal convolutions作为特征提取器代替传统的rnn、lstm
结果表明由于现有的无监督方法,并且不差于有监督方法。
arXiv,
2019.
DOI: 10.48550/arXiv.1901.10738
Abstract:
Time series constitute a challenging data type for machine learning algorithms, due to their highly variable lengths and sparse labeling in practice. In this paper, we tackle this challenge by …
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Time series constitute a challenging data type for machine learning algorithms, due to their highly variable lengths and sparse labeling in practice. In this paper, we tackle this challenge by proposing an unsupervised method to learn universal embeddings of time series. Unlike previous works, it is scalable with respect to their length and we demonstrate the quality, transferability and practicability of the learned representations with thorough experiments and comparisons. To this end, we combine an encoder based on causal dilated convolutions with a novel triplet loss employing time-based negative sampling, obtaining general-purpose representations for variable length and multivariate time series.
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