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981.
大象城南
(2022-07-10 09:35):
#paper doi:10.1016/j.ymeth.2022.06.001 Methods, 2022. Structural and functional connectivity abnormalities of the default mode network in patients with Alzheimer's disease and mild cognitive impairment within two independent阿尔茨海默病 (AD) 是一种以进行性痴呆为特征的慢性神经退行性疾病,遗忘性轻度认知障碍 (aMCI) 已被定义为正常衰老和 AD 之间的过渡阶段。越来越多的证据表明,默认模式网络 (DMN) 中改变的功能连接 (FC) 和结构连接 (SC) 是 AD 的突出标志。然而,DMN 的 SC 和 FC 变化之间的关系尚不清楚。在本研究中,我们利用功能性磁共振成像 (fMRI) 和弥散加权成像 (DWI) 数据导出了 DMN 的 FC 和 SC 矩阵,并在 120 名参与者(39 名正常对照)的发现数据集中进一步评估了 FC 和 SC 异常, 34 名 aMCI 患者和 47 名 AD 患者), 以及 122 名参与者(43 名正常对照、37 名 aMCI 患者和 42 名 AD 患者)的复制数据集。在发现数据集中的 aMCI 和 AD 组患者的 DMN 成分(例如,后扣带皮层 (PCC)、内侧前额叶皮层 (mPFC) 和海马)中发现了中断的 SC 和 FC;在复制数据集中也发现了大部分中断的连接。更重要的是,一些 SC 和 FC 元素与 aMCI 和 AD 患者的认知能力显着相关。此外,我们发现 aMCI 和 AD 组患者的 PCC 和右侧海马体之间存在结构-功能脱钩。这些关于神经退行性队列中 DMN 连接性改变的发现加深了我们对 AD 病理生理机制的理解。37 名 aMCI 患者和 42 名 AD 患者)。在发现数据集中的 aMCI 和 AD 组患者的 DMN 成分(例如,后扣带皮层 (PCC)、内侧前额叶皮层 (mPFC) 和海马)中发现了中断的 SC 和 FC;在复制数据集中也发现了大部分中断的连接。更重要的是,一些 SC 和 FC 元素与 aMCI 和 AD 患者的认知能力显着相关。此外,我们发现 aMCI 和 AD 组患者的 PCC 和右侧海马体之间存在结构-功能脱钩。这些关于神经退行性队列中 DMN 连接性改变的发现加深了我们对 AD 病理生理机制的理解。37 名 aMCI 患者和 42 名 AD 患者)。在发现数据集中的 aMCI 和 AD 组患者的 DMN 成分(例如,后扣带皮层 (PCC)、内侧前额叶皮层 (mPFC) 和海马)中发现了中断的 SC 和 FC;在复制数据集中也发现了大部分中断的连接。更重要的是,一些 SC 和 FC 元素与 aMCI 和 AD 患者的认知能力显着相关。此外,我们发现 aMCI 和 AD 组患者的 PCC 和右侧海马体之间存在结构-功能脱钩。这些关于神经退行性队列中 DMN 连接性改变的发现加深了我们对 AD 病理生理机制的理解。发现数据集中 aMCI 和 AD 组患者的后扣带皮层 (PCC)、内侧前额叶皮层 (mPFC) 和海马体;在复制数据集中也发现了大部分中断的连接。更重要的是,一些 SC 和 FC 元素与 aMCI 和 AD 患者的认知能力显着相关。此外,我们发现 aMCI 和 AD 组患者的 PCC 和右侧海马体之间存在结构-功能脱钩。这些关于神经退行性队列中 DMN 连接性改变的发现加深了我们对 AD 病理生理机制的理解。发现数据集中 aMCI 和 AD 组患者的后扣带皮层 (PCC)、内侧前额叶皮层 (mPFC) 和海马体;在复制数据集中也发现了大部分中断的连接。更重要的是,一些 SC 和 FC 元素与 aMCI 和 AD 患者的认知能力显着相关。此外,我们发现 aMCI 和 AD 组患者的 PCC 和右侧海马体之间存在结构-功能脱钩。这些关于神经退行性队列中 DMN 连接性改变的发现加深了我们对 AD 病理生理机制的理解。在复制数据集中也发现了大部分中断的连接。更重要的是,一些 SC 和 FC 元素与 aMCI 和 AD 患者的认知能力显着相关。此外,我们发现 aMCI 和 AD 组患者的 PCC 和右侧海马体之间存在结构-功能脱钩。这些关于神经退行性队列中 DMN 连接性改变的发现加深了我们对 AD 病理生理机制的理解。在复制数据集中也发现了大部分中断的连接。更重要的是,一些 SC 和 FC 元素与 aMCI 和 AD 患者的认知能力显着相关。此外,我们发现 aMCI 和 AD 组患者的 PCC 和右侧海马体之间存在结构-功能脱钩。这些关于神经退行性队列中 DMN 连接性改变的发现加深了我们对 AD 病理生理机制的理解。
Abstract:
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive dementia, and amnestic mild cognitive impairment (aMCI) has been defined as a transitional stage between normal aging and AD. …
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Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive dementia, and amnestic mild cognitive impairment (aMCI) has been defined as a transitional stage between normal aging and AD. Accumulating evidence has shown that altered functional connectivity (FC) and structural connectivity (SC) in the default mode network (DMN) is the prominent hallmarks of AD. However, the relationship between the changes in SC and FC of the DMN is not yet clear. In the present study, we derived the FC and SC matrices of the DMN with functional magnetic resonance imaging (fMRI) and diffusion-weighted imaging (DWI) data and further assessed FC and SC abnormalities within a discovery dataset of 120 participants (39 normal controls, 34 patients with aMCI and 47 patients with AD), as well as a replication dataset of 122 participants (43 normal controls, 37 patients with aMCI and 42 patients with AD). Disrupted SC and FC were found among DMN components (e.g., the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), and hippocampus) in patients in the aMCI and AD groups in the discovery dataset; most of the disrupted connections were also identified in the replication dataset. More importantly, some SC and FC elements were significantly correlated with the cognitive ability of patients with aMCI and AD. In addition, we found structural-functional decoupling between the PCC and the right hippocampus in patients in the aMCI and AD groups. These findings of the alteration of DMN connectivity in neurodegenerative cohorts deepen our understanding of the pathophysiological mechanisms of AD.
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982.
大象城南
(2022-07-10 09:29):
#paper doi:10.1111/epi.17320 Epilepsia, 2022. Development and validation of machine learning models for prediction of seizure outcome after pediatric epilepsy surgery. 小儿癫痫手术后报告的癫痫发作结果存在很大差异,并且缺乏可以评估术后癫痫发作自由概率的个体化预测工具。本研究的目的是开发和验证用于预测小儿癫痫手术后无癫痫发作的监督机器学习 (ML) 模型。这是一项针对在北美五个儿科癫痫中心接受癫痫手术的儿童的多中心回顾性研究。收集临床信息、诊断调查和手术特征,并将其用作预测术后 1 年无癫痫发作结果的特征。数据集被随机分成 80% 的训练数据和 20% 的测试数据。使用 10 倍交叉验证模型开发,在训练队列上评估了 5 个特征集和 7 个 ML 分类器的 35 个组合。在测试队列中评估 ML 分类器和特征集的最佳组合的性能,并与经典统计方法逻辑回归进行比较。在纳入的 801 名患者中,61.3% 的患者术后 1 年无癫痫发作。在模型开发过程中,最佳组合是 XGBoost ML 算法,它具有来自单变量特征集的五个特征,包括抗癫痫药物数量、磁共振成像病变、癫痫发作年龄、视频脑电图一致性和手术类型,平均面积低于0.73 的曲线 (AUC)(95% 置信区间 [CI] = .69–.77)。然后在测试队列上评估 XGBoost 和单变量特征集的组合并达到 0.74 的 AUC(95% CI = .66–.82;敏感性 = .87,95% CI = .81–.94;特异性 = .58, 95% CI = .47–.71)。XGBoost 模型优于逻辑回归模型(AUC = .72, 95% CI = .63–.80;敏感性 = .72, 95% CI = .63–.82;特异性 = .66, 95% CI = .53 –.77) 在测试队列 (p = .005)。本研究确定了重要特征并验证了用于预测小儿癫痫手术后无癫痫发作概率的 ML 算法 XGBoost。改善癫痫手术的预后对于术前咨询至关重要,并将为治疗决策提供信息。
Abstract:
OBJECTIVE: There is substantial variability in reported seizure outcome following pediatric epilepsy surgery, and lack of individualized predictive tools that could evaluate the probability of seizure freedom postsurgery. The aim …
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OBJECTIVE: There is substantial variability in reported seizure outcome following pediatric epilepsy surgery, and lack of individualized predictive tools that could evaluate the probability of seizure freedom postsurgery. The aim of this study was to develop and validate a supervised machine learning (ML) model for predicting seizure freedom after pediatric epilepsy surgery.METHODS: This is a multicenter retrospective study of children who underwent epilepsy surgery at five pediatric epilepsy centers in North America. Clinical information, diagnostic investigations, and surgical characteristics were collected, and used as features to predict seizure-free outcome 1 year after surgery. The dataset was split randomly into 80% training and 20% testing data. Thirty-five combinations of five feature sets with seven ML classifiers were assessed on the training cohort using 10-fold cross-validation for model development. The performance of the optimal combination of ML classifier and feature set was evaluated in the testing cohort, and compared with logistic regression, a classical statistical approach.RESULTS: Of the 801 patients included, 61.3% were seizure-free 1 year postsurgery. During model development, the best combination was XGBoost ML algorithm with five features from the univariate feature set, including number of antiseizure medications, magnetic resonance imaging lesion, age at seizure onset, video-electroencephalography concordance, and surgery type, with a mean area under the curve (AUC) of .73 (95% confidence interval [CI] = .69-.77). The combination of XGBoost and univariate feature set was then evaluated on the testing cohort and achieved an AUC of .74 (95% CI = .66-.82; sensitivity = .87, 95% CI = .81-.94; specificity = .58, 95% CI = .47-.71). The XGBoost model outperformed the logistic regression model (AUC = .72, 95% CI = .63-.80; sensitivity = .72, 95% CI = .63-.82; specificity = .66, 95% CI = .53-.77) in the testing cohort (p = .005).SIGNIFICANCE: This study identified important features and validated an ML algorithm, XGBoost, for predicting the probability of seizure freedom after pediatric epilepsy surgery. Improved prognostication of epilepsy surgery is critical for presurgical counseling and will inform treatment decisions.
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983.
颜林林
(2022-07-10 09:00):
#paper doi:10.1109/TR.2022.3171220 IEEE Transactions on Reliability, 2022, Detecting C++ Compiler Front-End Bugs via Grammar Mutation and Differential Testing. 这篇来自大连理工大学的文章,设计了一套名为CCoft的软件框架,用以自动识别C++编译器前端部分的bug。编译器的内部结构,通常按流程分为两部分,前端和后端,前端是从C++源代码识别语义、并将其转化为中间语言的阶段,后端则是根据中间语言生成机器代码的步骤。本文仅针对前端部分。本文的框架,首先将C++语法转换为一种结构化格式,然后使用“突变”的方式,来生成大批量的各种C++代码,其中包括符合语法的,也包括不符合语法的,目的是覆盖尽可能多的代码场景,用以挑战C++编译器,看编译器是否能够符合预期地进行处理。之后,将代码丢给编译器,根据编译器的输出信息,评判是否得到了正确处理,从而识别出一系列软件bug,包括:错误拒绝了合法代码、错误接受了不合法代码、代码语义处理错误、代码编译执行崩溃、代码编译时间过长而超时等。通过使用主流编译器GCC和Clang进行测试,在三个月内找到了136个编译器bug,对比市面上主流的工具,有大幅提升。
Abstract:
C++ is a widely used programming language and the C++ front-end is a critical part of a C++ compiler. Although many techniques have been proposed to test compilers, few studies …
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C++ is a widely used programming language and the C++ front-end is a critical part of a C++ compiler. Although many techniques have been proposed to test compilers, few studies are devoted to detecting bugs in C++ compiler. In this study, we take the first step to detect bugs in C++ compiler front-ends. To do so, two main challenges need to be addressed, namely, the acquisition of test programs that are more likely to trigger bugs in compiler front-ends and the bug identification from complicated compiler outputs. In this article, we propose a novel framework named Ccoft to detect bugs in C++ compiler front-ends. To address the first challenge, Ccoft implements a practical program generator. The generator first transforms C++ grammars into a flexible structured format and then utilizes an equal-chance selection (ECS) strategy to conduct structure-aware grammar mutation to generate diverse C++ programs. Next, Ccoft employs a set of differential testing strategies to identify various kinds of bugs in C++ compiler front-ends by comparing complex outputs emitted by C++ compilers, thus tackling the second challenge. Empirical evaluation results over two mainstream compilers (i.e., GCC and Clang) show that Ccoft greatly improves two state-of-the-art approaches (i.e., Dharma and Grammarinator) by 135% and 111% in terms of the numbers of detected bugs, respectively. By running Ccoft for three months, we have successfully reported 136 bugs for two C++ compilers, of which 78 (57 confirmed, assigned, or fixed) for GCC and 58 (10 confirmed or fixed) for Clang.
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984.
颜林林
(2022-07-09 07:36):
#paper doi:10.1186/s13073-022-01079-x Genome Medicine, 2022, Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for immunotherapy resistance. 这是一篇纯数据挖掘的文章,试图回答肺鳞癌中免疫检查点抑制剂耐药的机制问题。文章通过收集了来自TCGA和GEO的624例肺鳞癌转录组数据,使用无监督聚类,从中识别出与 T 细胞衰竭特征、免疫抑制细胞、临床特征和免疫治疗反应相关的表达模式,并定义了一组衰竭免疫等级 (EIC) 的免疫抑制患者。这些患者占到28%至36%,尽管他们表现出高密度的肿瘤浸润淋巴细胞,却因显著富集、高比例的免疫抑制细胞、多个免疫检查点基因同时上调等特性,表现出对ICB的耐药性。相应的表达特征,在具有 ICB 治疗抗性的黑色素瘤患者中也得到印证。文章还检查了基因组和表观组的数据,发现这些患者呈现出较低的染色体突变负担和独特的甲基化模式。由此,作者还建立了一个在线网站,整合了用到的数据及分析方法,供研究人员使用多组学数据分析来研究 ICB 耐药性的潜在关联。从分析方法看,这篇文章的套路应该是比较常见的,算不上有什么创新性,不过在单病种上整合数据,并以在线网站的形式来使分析过程能够泛化并提供他人使用,也算是一类可行的生信“原创”工作吧。
Abstract:
BACKGROUND: Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of lung squamous cell carcinoma (LUSC). However, a significant proportion of patients with high tumour PD-L1 expression remain resistant to …
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BACKGROUND: Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of lung squamous cell carcinoma (LUSC). However, a significant proportion of patients with high tumour PD-L1 expression remain resistant to immune checkpoint inhibitors. To understand the underlying resistance mechanisms, characterization of the immunosuppressive tumour microenvironment and identification of biomarkers to predict resistance in patients are urgently needed.METHODS: Our study retrospectively analysed RNA sequencing data of 624 LUSC samples. We analysed gene expression patterns from tumour microenvironment by unsupervised clustering. We correlated the expression patterns with a set of T cell exhaustion signatures, immunosuppressive cells, clinical characteristics, and immunotherapeutic responses. Internal and external testing datasets were used to validate the presence of exhausted immune status.RESULTS: Approximately 28 to 36% of LUSC patients were found to exhibit significant enrichments of T cell exhaustion signatures, high fraction of immunosuppressive cells (M2 macrophage and CD4 Treg), co-upregulation of 9 inhibitory checkpoints (CTLA4, PDCD1, LAG3, BTLA, TIGIT, HAVCR2, IDO1, SIGLEC7, and VISTA), and enhanced expression of anti-inflammatory cytokines (e.g. TGFβ and CCL18). We defined this immunosuppressive group of patients as exhausted immune class (EIC). Although EIC showed a high density of tumour-infiltrating lymphocytes, these were associated with poor prognosis. EIC had relatively elevated PD-L1 expression, but showed potential resistance to ICB therapy. The signature of 167 genes for EIC prediction was significantly enriched in melanoma patients with ICB therapy resistance. EIC was characterized by a lower chromosomal alteration burden and a unique methylation pattern. We developed a web application ( http://lilab2.sysu.edu.cn/tex & http://liwzlab.cn/tex ) for researchers to further investigate potential association of ICB resistance based on our multi-omics analysis data.CONCLUSIONS: We introduced a novel LUSC immunosuppressive class which expressed high PD-L1 but showed potential resistance to ICB therapy. This comprehensive characterization of immunosuppressive tumour microenvironment in LUSC provided new insights for further exploration of resistance mechanisms and optimization of immunotherapy strategies.
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985.
颜林林
(2022-07-08 07:19):
#paper doi:10.1038/s41540-022-00233-w npj Systems Biology and Applications, Adaptive coding for DNA storage with high storage density and low coverage. 基于生物大分子(如DNA)实现大规模数据存储功能,是我个人比较感兴趣的方向之一。这几年在这个领域突然涌现了许多优秀文章,这可能与高通量测序技术发展,以及相关的合成生物学的进步有关。这篇来自大连理工的文章,也正是这样一个案例。本文提出了一种自适应编码DNA存储系统,针对不同的编码区域位置采用不同的编码方案,将 698 KB 大小的图像、视频和 PDF 文件存储在 DNA 中,之后又将其无损地解码还原为原始数据。相比过去同类工作,本文在编码数据过程中,更细致地设计了各种DNA分子特性及约束,使在保持碱基平衡和避免非特异性杂交的同时,能在尽量低测序深度下,对测序错误的噪声进行容错。将原始内容打散并接上索引片段,从而使所存储的内容可以通过特异性扩增并测序的方式进行随机读取。比较可惜的是,本文只做了理论上的模拟和探讨,尚未开展实际的DNA合成和测序,这大大削弱了文章的说服力。
IF:3.500Q1
NPJ systems biology and applications,
2022-07-04.
DOI: 10.1038/s41540-022-00233-w
PMID: 35788589
Abstract:
The rapid development of information technology has generated substantial data, which urgently requires new storage media and storage methods. DNA, as a storage medium with high density, high durability, and …
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The rapid development of information technology has generated substantial data, which urgently requires new storage media and storage methods. DNA, as a storage medium with high density, high durability, and ultra-long storage time characteristics, is promising as a potential solution. However, DNA storage is still in its infancy and suffers from low space utilization of DNA strands, high read coverage, and poor coding coupling. Therefore, in this work, an adaptive coding DNA storage system is proposed to use different coding schemes for different coding region locations, and the method of adaptively generating coding constraint thresholds is used to optimize at the system level to ensure the efficient operation of each link. Images, videos, and PDF files of size 698 KB were stored in DNA using adaptive coding algorithms. The data were sequenced and losslessly decoded into raw data. Compared with previous work, the DNA storage system implemented by adaptive coding proposed in this paper has high storage density and low read coverage, which promotes the development of carbon-based storage systems.
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986.
颜林林
(2022-07-07 07:41):
#paper doi:10.1186/s13059-022-02699-7 Genome Biology, 2022, Storing and analyzing a genome on a blockchain. 好几年前,我就听很多人说起,想把区块链技术用于基因组相关的应用,然而,后来各种结局惨淡,似乎都没了下文。在币圈跌跌不休一片哀嚎的最近,竟然《Genome Biology》上会发表出这么一篇文章,也真是神奇和亮眼。这篇来自耶鲁的文章,其全文和源码都是开放访问的,值得对区块链技术感兴趣的朋友仔细一读。文章设想了一个由测序仪、所有者、临床医生和研究人员组成的网络,每个人都参与同步 VCFchain 或 SAMchain,以此来形成分布式的数据共享,且数据分析过程也穿插在链的延伸过程中。在区块链有限的额外字节存储中,保存巨大的基因组数据,也确实需要一些技巧(如数据拆分和查询时的重新组合)加以实现,这篇文章也确实因此做了一些工作。但整体上还是有一种“为了区块链而区块链”的感觉。权限的管理和不容篡改可能是其特点和优势,但并未在文章中充分呈现,这与此前分享过的提及区块链技术的另外两篇文章有所不同(那两篇文章的DOI分别是:10.1038/s41591-022-01768-5 和 10.1038/s41586-021-03583-3,分别发表在 Nature Medicine 和 Nature,它们更多是AI算法及数据分享价值),而本文的重点还是在于区块链相关的程序实现细节。有这篇做铺垫,说不定类似文章后续真能冲击NBT呢。
IF:10.100Q1
Genome biology,
2022-06-29.
DOI: 10.1186/s13059-022-02699-7
PMID: 35765079
PMCID:PMC9241283
Abstract:
There are major efforts underway to make genome sequencing a routine part of clinical practice. A critical barrier to these is achieving practical solutions for data ownership and integrity. Blockchain …
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There are major efforts underway to make genome sequencing a routine part of clinical practice. A critical barrier to these is achieving practical solutions for data ownership and integrity. Blockchain provides solutions to these challenges in other realms, such as finance. However, its use in genomics is stymied due to the difficulty in storing large-scale data on-chain, slow transaction speeds, and limitations on querying. To overcome these roadblocks, we developed a private blockchain network to store genomic variants and reference-aligned reads on-chain. It uses nested database indexing with an accompanying tool suite to rapidly access and analyze the data.
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987.
颜林林
(2022-07-06 00:02):
#paper doi:10.1186/s12864-022-08717-z BMC Genomics, 2022, The effects of sequencing depth on the assembly of coding and noncoding transcripts in the human genome. 众所周知,测序深度会影响其数据的分析结果。然而,到底影响多大,怎么影响的,往往视研究目的和研究对象而定,得具体分析,也值得研究。这篇文章,就是在系统研究测序深度对转录组数据的转录本组装的影响。文章纳入了来自150个人类干细胞样本的不同细胞组织的RNA-seq数据,除了短读长平台外,还包括四个PacBio平台的长读长数据。其中有两个样本还测了高达200M reads的NGS数据量,于是可以用它们来抽取不同比例数据,以模拟不同的测序数据量。分析结果表明,编码转录本与非编码转录本之间存在差异,前者随着测序深度增加而迅速进入饱和,后者在所分析的数据中则几乎始终未达到饱和。这可能与两者的组装难度有关。此外,长读长信息有助于含有转座元件的转录本组装。比较有意思的是单细胞RNA-seq(scRNA-seq),其非编码转录本的表达水平低,是由于表达细胞较少,而在表达的细胞中,非编码转录本的表达水平其实与编码转录本相似,这个现象的发现得益于长读长测序平台,因此文章得出结论是长读长测序更适合scRNA-seq。但我个人多少还是怀疑这些结论很可能与分析评估方法有关,也许值得重复下这篇文章的分析过程。
Abstract:
Investigating the functions and activities of genes requires proper annotation of the transcribed units. However, transcript assembly efforts have produced a surprisingly large variation in the number of transcripts, and …
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Investigating the functions and activities of genes requires proper annotation of the transcribed units. However, transcript assembly efforts have produced a surprisingly large variation in the number of transcripts, and especially so for noncoding transcripts. This heterogeneity in assembled transcript sets might be partially explained by sequencing depth. Here, we used real and simulated short-read sequencing data as well as long-read data to systematically investigate the impact of sequencing depths on the accuracy of assembled transcripts. We assembled and analyzed transcripts from 671 human short-read data sets and four long-read data sets. At the first level, there is a positive correlation between the number of reads and the number of recovered transcripts. However, the effect of the sequencing depth varied based on cell or tissue type, the type of read and the nature and expression levels of the transcripts. The detection of coding transcripts saturated rapidly with both short and long-reads, however, there was no sign of early saturation for noncoding transcripts at any sequencing depth. Increasing long-read sequencing depth specifically benefited transcripts containing transposable elements. Finally, we show how single-cell RNA-seq can be guided by transcripts assembled from bulk long-read samples, and demonstrate that noncoding transcripts are expressed at similar levels to coding transcripts but are expressed in fewer cells. This study highlights the impact of sequencing depth on transcript assembly.
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988.
DeDe宝
(2022-07-05 22:49):
#paper doi:10.1016/j.tics.2015.03.002 TRENDS IN COGNITIVE SCIENCES, 2015, A Bayesian perspective on magnitude estimation. 这篇综述可以结合作者11年发表的Iterative Bayesian Estimation as an Explanation for Range and Regression Effects: A Study on Human Path Integration(DOI:10.1523/JNEUROSCI.2028-11.2011)一起看。综述简要介绍了人类被试估计物理量(如距离估计、角度估计、时长估计)时的行为特征,如回归效应、范围效应、序列效应等,并使用贝叶斯模型模拟并解释行为特征。综述还列举了贝叶斯模型在心理物理学、神经成像研究和临床研究中的应用,适合贝叶斯模型入门。11年的文章里有对经典贝叶斯模型(固定先验)和二阶贝叶斯模型(可迭代先验)的详细推导。
Abstract:
Our representation of the physical world requires judgments of magnitudes, such as loudness, distance, or time. Interestingly, magnitude estimates are often not veridical but subject to characteristic biases. These biases …
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Our representation of the physical world requires judgments of magnitudes, such as loudness, distance, or time. Interestingly, magnitude estimates are often not veridical but subject to characteristic biases. These biases are strikingly similar across different sensory modalities, suggesting common processing mechanisms that are shared by different sensory systems. However, the search for universal neurobiological principles of magnitude judgments requires guidance by formal theories. Here, we discuss a unifying Bayesian framework for understanding biases in magnitude estimation. This Bayesian perspective enables a re-interpretation of a range of established psychophysical findings, reconciles seemingly incompatible classical views on magnitude estimation, and can guide future investigations of magnitude estimation and its neurobiological mechanisms in health and in psychiatric diseases, such as schizophrenia.
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989.
颜林林
(2022-07-05 00:03):
#paper doi:10.1093/database/baac049 Database, 2022, dbBIP: a comprehensive bipolar disorder database for genetic research. 这篇文章,正如其期刊名,是一个数据库。它的研究主题和对象是bipolar disorder(BIP,双相情感障碍,又称躁狂抑郁症)。通过整合既往关于该疾病的大规模组学数据,包括两个基于芯片的GWAS队列(PGC2和PGC3,分别贡献了20352例BIP病例和31358名对照、41917例BIP和371549对照),也包括后续多项研究的WGS/WES测序数据,还包括大规模脑组织的转录组测序数据(表达谱数据),并通过各类组学分析方法,提供了对这些数据的功能注释、连锁关联、蛋白质相互作用、时空表达模式等信息。所有这些信息都以网站形式提供查询和在线分析功能。这是典型的生物信息学类型研究工作,也是深入开启某一研究方向的有效开局方式。
Database : the journal of biological databases and curation,
2022-07-02.
DOI: 10.1093/database/baac049
PMID: 35779245
Abstract:
Bipolar disorder (BIP) is one of the most common hereditary psychiatric disorders worldwide. Elucidating the genetic basis of BIP will play a pivotal role in mechanistic delineation. Genome-wide association studies …
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Bipolar disorder (BIP) is one of the most common hereditary psychiatric disorders worldwide. Elucidating the genetic basis of BIP will play a pivotal role in mechanistic delineation. Genome-wide association studies (GWAS) have successfully reported multiple susceptibility loci conferring BIP risk, thus providing insight into the effects of its underlying pathobiology. However, difficulties remain in the extrication of important and biologically relevant data from genetic discoveries related to psychiatric disorders such as BIP. There is an urgent need for an integrated and comprehensive online database with unified access to genetic and multi-omics data for in-depth data mining. Here, we developed the dbBIP, a database for BIP genetic research based on published data. The dbBIP consists of several modules, i.e.: (i) single nucleotide polymorphism (SNP) module, containing large-scale GWAS genetic summary statistics and functional annotation information relevant to risk variants; (ii) gene module, containing BIP-related candidate risk genes from various sources and (iii) analysis module, providing a simple and user-friendly interface to analyze one's own data. We also conducted extensive analyses, including functional SNP annotation, integration (including summary-data-based Mendelian randomization and transcriptome-wide association studies), co-expression, gene expression, tissue expression, protein-protein interaction and brain expression quantitative trait loci analyses, thus shedding light on the genetic causes of BIP. Finally, we developed a graphical browser with powerful search tools to facilitate data navigation and access. The dbBIP provides a comprehensive resource for BIP genetic research as well as an integrated analysis platform for researchers and can be accessed online at http://dbbip.xialab.info. Database URL: http://dbbip.xialab.info.
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990.
颜林林
(2022-07-04 20:59):
#paper doi:10.1038/s41467-022-31236-0, Nature Communications, 2022, A convolutional neural network highlights mutations relevant to antimicrobial resistance in Mycobacterium tuberculosis. 本文建立了一套CNN(卷积神经网络)模型,从2万多个结核分枝杆菌的测序数据中,使用18个根据先验知识挑选的与其耐药性相关的基因座,将基因座的整个序列作为输入,以此来预测耐药性。结果显示,该CNN模型性能超过了目前其他基于传统机器学习方法和非卷积的常规神经网络方法。而且,由于深度学习方法提取了序列中的隐含特征信息,可以有效帮助预测未知突变对耐药性的影响。
IF:14.700Q1
Nature communications,
2022-07-02.
DOI: 10.1038/s41467-022-31236-0
PMID: 35780211
PMCID:PMC9250494
Abstract:
Long diagnostic wait times hinder international efforts to address antibiotic resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution. However, …
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Long diagnostic wait times hinder international efforts to address antibiotic resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution. However, generalizability and clinical adoption have been limited by a lack of interpretability, especially in deep learning methods. Here, we present two deep convolutional neural networks that predict antibiotic resistance phenotypes of M. tuberculosis isolates: a multi-drug CNN (MD-CNN), that predicts resistance to 13 antibiotics based on 18 genomic loci, with AUCs 82.6-99.5% and higher sensitivity than state-of-the-art methods; and a set of 13 single-drug CNNs (SD-CNN) with AUCs 80.1-97.1% and higher specificity than the previous state-of-the-art. Using saliency methods to evaluate the contribution of input sequence features to the SD-CNN predictions, we identify 18 sites in the genome not previously associated with resistance. The CNN models permit functional variant discovery, biologically meaningful interpretation, and clinical applicability.
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991.
颜林林
(2022-07-03 00:04):
#paper doi:10.1002/ajmg.c.31987 American Journal of Medical Genetics, 2022, Genetic testing and glomerular hematuria - A nephrologist's perspective. 这篇综述介绍了Alport综合征(一种遗传性肾炎)的诊断和早期治疗方法的演变。该疾病表现为血尿,但并非急性外伤引起,而是与慢性炎症相关,且具有遗传性。该疾病发现于1920年,但直至2003年才被报道有药物可以进行治疗(之前只能选择透析和肾移植)。长期的临床病例积累和观察研究,确定了该疾病的遗传性,以及定位出COL4A3、COL4A4和COL4A5这三个基因与该疾病相关。由于血尿的原因很多,Alport综合征也存在各种不同程度症状的谱系分布,因此其诊断也需要开展对上述三个基因的突变检测。基因检测方法早期使用Sanger(一代测序),后来改为使用NGS(新一代测序,或者称为二代测序),无论哪种方法,都存在费用高昂等问题。在临床肾病专家的角度,会通过显微镜观察尿液中血细胞的形态等特征,帮助确定血尿的来源是否为肾小球,并综合考虑患者个体因素,确定是采取基因检测方法,或是肾活检方法。各种检测方法都并不完美,需要通过彼此互补来帮助进行疾病确诊。诸如对三个基因的检测,在NGS时代可以开展全外显子测序,不仅可能发现这三个基因上从未被报道过的难以判断致病性的突变,也可能发现与此疾病相关的其他基因突变,这些突变的解读,则需要依赖于遗传咨询师的辅助配合。这篇综述中展示的临床诊治路径(及其演化),反映了对这些信息的综合利用,以及从使患者受益的角度,该以何种顺序来组合不同的检测方法。
Abstract:
Alport syndrome is an inherited disorder of the kidneys that results from variants in three collagen IV genes-COL4A3, COL4A4, and COL4A5. Early diagnosis and pharmacologic intervention can delay the progression …
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Alport syndrome is an inherited disorder of the kidneys that results from variants in three collagen IV genes-COL4A3, COL4A4, and COL4A5. Early diagnosis and pharmacologic intervention can delay the progression of chronic kidney disease and the onset of kidney failure in patients with Alport syndrome. This article describes the evolution of approaches to the diagnosis and early treatment of Alport syndrome.
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992.
龙海晨
(2022-07-02 20:10):
#paper Zheng Y, Jönsson J, Hao C, et al. hnRNP A1 and hnRNP A2 inhibit splicing to HPV16 splice site SA409 through a UAG-containing sequence in the E7 coding region[J]. Journal of Virology, 2020. DOI: 10.1128/jvi.01509-20 PMID: 32759322 PMCID: PMC7527060 该文章研究发现hnRNP A1和hnRNP A2通过E7编码区中含有UAG的序列抑制HPV16剪接位点SA409的剪接。人乳头瘤病毒16型(HPV16)属于HPV的高危型,并导致多种肛门,生殖器癌和头颈癌,一般大家最熟悉的就是宫颈癌,实际上高危型HPV可以引发多种癌症。HPV16的两种蛋白E6和E7可防止细胞凋亡并促进有丝分裂,对HPV16生命周期的完成、感染细胞的转化和恶性肿瘤的维持至关重要。E6和E7由两个通过选择性剪接以互斥方式生成的mRNA产生。虽然E6蛋白是由未拼接的mRNA制成的,但E7是由相同前体mRNA的拼接版本制成的。由于恶性转化需要足够数量的E6和E7,这种复杂的基因表达排列使得E6和E7的表达容易受到外部干扰。由于没有针对HPV16的抗病毒药物,详细了解HPV16 E6和E7 mRNA剪接的调节可能会发现新的治疗靶点。文章可总结为:1. E6,E7是HPV的重要蛋白他们对HPV的繁殖至关重要同时可以改变宿主的基因导致癌症。 2. E6,E7由HPV的同一段基因上的位点来调控。 3. 受到hnRNA1或者hnRNA2的调节,位点会做出不同反应从而影响E6或者E7的产生。hnRNP A1和A2对E6编码区这个非常脆弱的HPV16剪接事件有相反的影响。 4. hnrnpa1和A2对hpv16mrna剪接的影响差异主要是由于这两种蛋白的C端保守程度较低。结果还表明,hnRNP A2与其他下游RNA序列相互作用,以促进剪接到下游的3′-剪接SA742,而不是导致内含子保留在E6编码区。
Abstract:
Human papillomavirus type 16 (HPV16) belongs to the high-risk-group of HPVs and is causing a variety of anogenital cancers and head and neck cancer. The two HPV16 oncoproteins E6 and …
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Human papillomavirus type 16 (HPV16) belongs to the high-risk-group of HPVs and is causing a variety of anogenital cancers and head and neck cancer. The two HPV16 oncoproteins E6 and E7 prevent apoptosis and promote mitosis and are essential for completion of the HPV16 life cycle and for transformation of the infected cell and maintenance of malignancy. E6 and E7 are produced from two mRNAs that are generated in a mutually exclusive manner by alternative splicing. While E6 protein is made from the unspliced mRNA, E7 is made from the spliced version of the same pre-mRNA. Since sufficient quantities of both E6 and E7 are required for malignant transformation, this intricate arrangement of gene expression renders E6 and E7 expression vulnerable to external interference. Since antiviral drugs to HPV16 are not available, a detailed knowledge of the regulation of HPV16 E6 and E7 mRNA splicing may uncover novel targets for therapy.
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993.
颜林林
(2022-07-02 00:24):
#paper doi:10.1186/s12859-022-04798-5 BMC Bioinformatics, 2022, DeepPN: a deep parallel neural network based on convolutional neural network and graph convolutional network for predicting RNA-protein binding sites. 识别RNA与蛋白的结合位点(RBP),是研究基因调控的重要内容。传统采用免疫沉淀等方法进行高通量的筛选和测定,但实验方法存在诸多局限,故人们尝试开发了许多计算工具来预测RBP,这其中大多为根据序列和结构信息进行数学计算的方法。深度学习技术,由于能够自动根据数据学习到重要且复杂的隐藏特征,因此也逐步被应用到这个问题上来。本文的研究,在考虑深度学习技术时,采用了图卷积网络(GCN)中的ChebNet。该方法过去多被用于光谱数据,且近年的研究在fMRI、图像语义分割等领域也都取得不错效果。于是本文基于CNN和ChebNet搭建了一个名为DeepPN的并行深度神经网络,并在24个真实数据集上进行测试,效果优于其他同类方法。推测可能是由于本文方法利用了统计频率来补充特征,因此取得了更好的性能。
Abstract:
BACKGROUND: Addressing the laborious nature of traditional biological experiments by using an efficient computational approach to analyze RNA-binding proteins (RBPs) binding sites has always been a challenging task. RBPs play …
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BACKGROUND: Addressing the laborious nature of traditional biological experiments by using an efficient computational approach to analyze RNA-binding proteins (RBPs) binding sites has always been a challenging task. RBPs play a vital role in post-transcriptional control. Identification of RBPs binding sites is a key step for the anatomy of the essential mechanism of gene regulation by controlling splicing, stability, localization and translation. Traditional methods for detecting RBPs binding sites are time-consuming and computationally-intensive. Recently, the computational method has been incorporated in researches of RBPs. Nevertheless, lots of them not only rely on the sequence data of RNA but also need additional data, for example the secondary structural data of RNA, to improve the performance of prediction, which needs the pre-work to prepare the learnable representation of structural data.RESULTS: To reduce the dependency of those pre-work, in this paper, we introduce DeepPN, a deep parallel neural network that is constructed with a convolutional neural network (CNN) and graph convolutional network (GCN) for detecting RBPs binding sites. It includes a two-layer CNN and GCN in parallel to extract the hidden features, followed by a fully connected layer to make the prediction. DeepPN discriminates the RBP binding sites on learnable representation of RNA sequences, which only uses the sequence data without using other data, for example the secondary or tertiary structure data of RNA. DeepPN is evaluated on 24 datasets of RBPs binding sites with other state-of-the-art methods. The results show that the performance of DeepPN is comparable to the published methods.CONCLUSION: The experimental results show that DeepPN can effectively capture potential hidden features in RBPs and use these features for effective prediction of binding sites.
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994.
颜林林
(2022-07-01 07:57):
#paper doi:10.1101/2022.06.27.497710 bioRxiv, 2022, PaliDIS: A tool for fast discovery of novel insertion sequences. 这是一篇有关的生信工具的文章,通讯作者来自Wellcome Sanger Institute。该工具从宏基因组数据中,寻找彼此之间含有相同重复片段的序列,将其比对到各组装好的微生物基因组上,将连锁位于同一组装序列且彼此反向互补的重复片段筛选出来,并经过一系列质控过滤,从而鉴别出在微生物基因组上发生的倒位形式的移动元件,以此帮助对耐药基因及其在不同菌种之间传播进行研究。类似流程在人类基因组分析中并不少见,且基本都是根据基因组事件及其序列特征直接进行实现,方法本身算不上有什么特别的创新之处。只不过应用于特定场景的特定数据集(在这篇文章里,数据是来自HMP,Human Microbiome Project,人类微生物计划),对分析结果进行(关于该移动元件的)统计描述和分析,倒是可行且常见的研究套路。
bioRxiv,
2022.
DOI: 10.1101/2022.06.27.497710
Abstract:
The diversity of microbial insertion sequences, crucial mobile genetic elements in generating diversity in microbial genomes, needs to be better represented in current microbial databases. Identification of these sequences in …
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The diversity of microbial insertion sequences, crucial mobile genetic elements in generating diversity in microbial genomes, needs to be better represented in current microbial databases. Identification of these sequences in microbiome communities presents some significant problems that have led to their underrepresentation. Here, we present a software tool called PaliDIS that recognises insertion sequences in metagenomic sequence data rapidly by identifying inverted terminal repeat regions from mixed microbial community genomes. Applying this software to 266 human metagenomes identifies 11,681 unique insertion sequences. Querying this catalogue against a large database of isolate genomes reveals evidence of horizontal gene transfer events of clinically relevant antimicrobial resistance genes between classes of bacteria. We will continue to apply this tool more widely, building the Insertion Sequence Catalogue, a valuable resource for researchers wishing to query their microbial genomes for insertion sequences.
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995.
June
(2022-06-30 23:59):
#paper doi: 10.1126/science.aaw9021. Epub 2022 Jan 7.Tissue geometry drives deterministic organoid patterning该研究提出了一种指导基于干细胞的器官发生的方法,该过程完全由“随机”自组织驱动。该研究还验证了长期存在但未充分探索的形态发生范例,其中组织的当前形状可以帮助图案化和指定组织的发育过程,从而确定组织的未来形状。在肠隐窝形成的情况下,出芽不仅可以跟随Paneth细胞的出现,而且还可以先于它。该研究的类器官培养物可用于回答现有类器官和动物模型无法解决的问题,它们可以将类器官技术转化为现实世界的应用。
Abstract:
Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they self-organize, but …
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Epithelial organoids are stem cell–derived tissues that approximate aspects of real organs, and thus they have potential as powerful tools in basic and translational research. By definition, they self-organize, but the structures formed are often heterogeneous and irreproducible, which limits their use in the lab and clinic. We describe methodologies for spatially and temporally controlling organoid formation, thereby rendering a stochastic process more deterministic. Bioengineered stem cell microenvironments are used to specify the initial geometry of intestinal organoids, which in turn controls their patterning and crypt formation. We leveraged the reproducibility and predictability of the culture to identify the underlying mechanisms of epithelial patterning, which may contribute to reinforcing intestinal regionalization in vivo. By controlling organoid culture, we demonstrate how these structures can be used to answer questions not readily addressable with the standard, more variable, organoid models.
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996.
笑对人生
(2022-06-30 23:48):
#paper BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer.Cell Rep. 2022 Feb 15;38(7):110374. doi:10.1016/j.celrep.2022.110374
世界卫生组织国际癌症研究机构(IARC)公布的2020年全球最新癌症负担数据显示,我国结直肠癌的总体发病率已升至第二位。早期的结直肠癌患者,在采取有效治疗的情况下,5年生存率能达到90%。然而,如果对于晚期,尤其是发生转移的结直肠癌患者,尽管采取化疗和靶向治疗,生存率也仅为5%-15%。耐药性是治疗失败产生的重要原因之一。前期的研究表明,瘤内肿瘤干细胞(CSC)是导致结直肠癌患者发生耐药的潜在帮凶,未被杀死的CSC往往会利用本身干细胞特性,促进肿瘤的发生和发展。BCL-XL是Bcl-2家族成员之一,具有抗凋亡的功能。BCL-XL主要是通过两种机制来防止凋亡,一是通过与凋亡蛋白结合来抑制其凋亡作用,二是直接在线粒体外膜上形成寡聚体通道以在细胞应激时维持线粒体膜正常形态。BH3 mimetics是BCL-2、MCL1、BCL-XL 的特异性抑制剂。临床上,使用高剂量的BH3 mimetics虽然能够很好诱导肿瘤细胞的凋亡,但也对大大损伤正常细胞。本研究通过一种高效的药物靶点筛选系统,发现了FGFR4是在使用低剂量BCL-XL抑制剂下,负反馈调节通路中的一个重要协同物。同时,通过实验证实了FGFR4介导的信号通路下游分子ERK和MCL-1。ERK和MCL-1蛋白分别是促进细胞增殖和存活重要分子。体外细胞实验和患者来源体外类器官证实,FGFR4抑制剂能通过抑制MCL-1的表达,提高低剂量BCL-XL抑制剂对CSC的促凋亡作用,并且对正常结肠细胞和血小板的损伤较少。
Abstract:
The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in …
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The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3 mimetics can induce apoptosis. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.
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997.
张贝
(2022-06-30 23:44):
#paper DOI: 10.1038/s41556-020-0477-0 Nat Cell Biol. 2020 Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. 本文建立了患者来源的乳腺癌异种移植(PDX)小鼠模型,利用单细胞测序技术来检测乳腺癌转移过程中少量转移细胞的转录组变化。通路分析显示线粒体氧化磷酸化是微转移肿瘤上调的top通路,而乳腺癌原发灶主要是糖酵解酶上调。利用流式细胞分析,qPCR以及代谢组学证明微转移灶中氧化磷酸化途径的上调。当使用寡霉素抑制氧化磷酸化途径时,可显著减弱乳腺癌肿瘤转移至肺,表明线粒体氧化磷酸化途径可作为防止乳腺癌患者转移的治疗靶点。本研究表明,转移的乳腺癌细胞不是通过糖酵解来获得能量,而是优先通过线粒体氧化磷酸化途径供能,这为预防癌症的扩散提供了新思路。
Abstract:
Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic …
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Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer.
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998.
小W
(2022-06-30 23:25):
#paper doi: DOI: 10.1038/s41590-022-01244-9 Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle
stem-cell niche 本篇文章主要讲述利用小鼠模型研究糖皮质激素信号传导和调节性 T 细胞协同维持毛囊干细胞的生态位。在本研究中,通过特异性性敲除小鼠(GR cKO) Treg 细胞中的糖皮质激素受体 ( GR),证明GR 和 Foxp3 在 Treg 细胞中协同作用以诱导转化生长因子 β3 (TGF-β3),从而激活 HFSCs 中的 Smad2/3 并促进 HFSC 增殖,促进毛发的再生。实验过程:在 HF 处于静止期(休止期)时去除毛干,pSmad1/5 信号通路呈阳性,48 小时内,局部皮肤中的糖皮质激素水平逐渐增加,对 PD4 天对从 GR cKO 和 WT 对照小鼠分离的 CD34+进行RNA-seq 差异基因表达和多细胞相互作用网络分析,发现Tgfβ3--Tgfbr 信号通路具有较高得分。免疫荧光和流式细胞术分析评估,Treg 细胞中 GR 的消融不会破坏脱毛后的整体皮肤免疫稳态。染色质免疫沉淀和CRISPRi系统,证实Tgfb3 和 Ttll5 的内含子区域中的 GR 和 Foxp3 结合峰是 GR 和 Foxp3 用于直接调节 Treg 细胞中 Tgfb3 表达的增强子,WT 小鼠pSmad2/3 呈阳性,确定了由 GR--TGF-β3 轴介导的 Treg 细胞和 HFSC 之间的通路。其他:1.不同组织驻留 Treg 细胞是否共享的共同调节模块2.不同浓度的糖皮质激素通过不同途径来促进和抑制斑秃
Abstract:
Maintenance of tissue homeostasis is dependent on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (T cells) are emerging as a critical component …
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Maintenance of tissue homeostasis is dependent on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (T cells) are emerging as a critical component of the stem-cell niche for supporting their differentiation. How T cells sense dynamic signals in this microenvironment and communicate with stem cells is mostly unknown. In the present study, by using hair follicles (HFs) to study T cell-stem cell crosstalk, we show an unrecognized function of the steroid hormone glucocorticoid in instructing skin-resident T cells to facilitate HF stem-cell (HFSC) activation and HF regeneration. Ablation of the glucocorticoid receptor (GR) in T cells blocks hair regeneration without affecting immune homeostasis. Mechanistically, GR and Foxp3 cooperate in T cells to induce transforming growth factor β3 (TGF-β3), which activates Smad2/3 in HFSCs and facilitates HFSC proliferation. The present study identifies crosstalk between T cells and HFSCs mediated by the GR-TGF-β3 axis, highlighting a possible means of manipulating T cells to support tissue regeneration.
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999.
小擎子
(2022-06-30 23:08):
#paper 10.1158/2159-8290.CD-17-1134 Cancer Discov. The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression 文章要点 1.与正常的胰腺相比,癌性胰腺有明显更丰富的微生物组 2.肿瘤胰腺特定细菌数量有所增加 3.微生物群消融可以防止侵袭前和侵袭性PDA 4.细菌消融与肿瘤微环境免疫原性重编程有关 5. 上述变化包括髓源性抑制细胞的减少和 M1 巨噬细胞分化的增加,促进 CD4 + T 细胞和 CD8 + 的Th1 分化T 细胞活化 6.细菌消融通过上调 PD-1 表达来提高检查点靶向免疫疗法的疗效 7.PDA 微生物组通过差异激活单核细胞中的选择 toll 样受体来产生耐受性免疫程序 8.内源性微生物群促进了 PDA 的免疫抑制特性,微生物组具有作为调节疾病进展的治疗靶点的潜力 9.文章发现独特而丰富的微生物组通过选择性 toll 样受体连接导致 T 细胞无反应性驱动抑制性单核细胞分化。靶向微生物组可防止肿瘤发生、逆转肿瘤内免疫耐受性,并使基于检查点的免疫疗法有效。这些数据对于理解胰腺癌中的免疫抑制及其在临床中的逆转具有重要意义。
Abstract:
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous …
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We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4 T cells and CD8 T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. .
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1000.
哪有情可长
(2022-06-30 22:52):
#paper 10.1038/s41586-020-03091-w. Nature. Genomic basis of geographical adaptation to soil nitrogen in rice. 推荐理由:这篇文章是水稻里面发现了一个关于适应当地土壤环境相关氮利用效率的基因。本研究课题的试验方式是先通过GWAS在不同区域环境下氮素利用的密切相关的性状进行定位,鉴定发现OsTCP19。后续发现该基因缺失了29bp的插入导致不同水稻品种之间不同的基因表达量和对氮素反应分蘖能力的变化。在野生稻和栽培稻中鉴定该基因29bp位点的变化,且发现现代栽培品种中该位点丢失,丢失的位点导致氮的利用率低。后续又进行全国各个区域试验,证明这个基因能够提高氮利用率,可以减少氮肥的施用,也能改善土壤中过量的氮素对环境的污染。很漂亮的正向遗传研究,从基因定位,得到转基因,转基因验证,大田产量验证,每一步逻辑都很严谨且证明的过程流畅。
Abstract:
The intensive application of inorganic nitrogen underlies marked increases in crop production, but imposes detrimental effects on ecosystems: it is therefore crucial for future sustainable agriculture to improve the nitrogen-use …
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The intensive application of inorganic nitrogen underlies marked increases in crop production, but imposes detrimental effects on ecosystems: it is therefore crucial for future sustainable agriculture to improve the nitrogen-use efficiency of crop plants. Here we report the genetic basis of nitrogen-use efficiency associated with adaptation to local soils in rice (Oryza sativa L.). Using a panel of diverse rice germplasm collected from different ecogeographical regions, we performed a genome-wide association study on the tillering response to nitrogen-the trait that is most closely correlated with nitrogen-use efficiency in rice-and identified OsTCP19 as a modulator of this tillering response through its transcriptional response to nitrogen and its targeting to the tiller-promoting gene DWARF AND LOW-TILLERING (DLT). A 29-bp insertion and/or deletion in the OsTCP19 promoter confers a differential transcriptional response and variation in the tillering response to nitrogen among rice varieties. The allele of OsTCP19 associated with a high tillering response to nitrogen is prevalent in wild rice populations, but has largely been lost in modern cultivars: this loss correlates with increased local soil nitrogen content, which suggests that it might have contributed to geographical adaptation in rice. Introgression of the allele associated with a high tillering response into modern rice cultivars boosts grain yield and nitrogen-use efficiency under low or moderate levels of nitrogen, which demonstrates substantial potential for rice breeding and the amelioration of negative environment effects by reducing the application of nitrogen to crops.
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