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781.
庞庞 (2022-12-31 18:17):
#paper Causes and Consequences of Diagnostic Heterogeneity in Depression: Paths to Discovering Novel Biological Depression Subtypes https://doi.org/10.1016/j.biopsych.2020.01.012 抑郁症是一种高度异质性的综合症。 该综述文章回顾了抑郁症诊断异质性的主要原因。 并讨论使用数据驱动策略根据功能性神经影像学测量发现新的抑郁症亚型的前景,包括维度、分类和混合方法来解析诊断异质性和理解其生物学基础。 最后,文章考虑了使用静息态功能磁共振成像功能连接技术进行子类型化的优点以及一系列技术挑战和潜在解决方案。
Abstract:
Depression is a highly heterogeneous syndrome that bears only modest correlations with its biological substrates, motivating a renewed interest in rethinking our approach to diagnosing depression for research purposes and … >>>
Depression is a highly heterogeneous syndrome that bears only modest correlations with its biological substrates, motivating a renewed interest in rethinking our approach to diagnosing depression for research purposes and new efforts to discover subtypes of depression anchored in biology. Here, we review the major causes of diagnostic heterogeneity in depression, with consideration of both clinical symptoms and behaviors (symptomatology and trajectory of depressive episodes) and biology (genetics and sexually dimorphic factors). Next, we discuss the promise of using data-driven strategies to discover novel subtypes of depression based on functional neuroimaging measures, including dimensional, categorical, and hybrid approaches to parsing diagnostic heterogeneity and understanding its biological basis. The merits of using resting-state functional magnetic resonance imaging functional connectivity techniques for subtyping are considered along with a set of technical challenges and potential solutions. We conclude by identifying promising future directions for defining neurobiologically informed depression subtypes and leveraging them in the future for predicting treatment outcomes and informing clinical decision making. <<<
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782.
Vincent (2022-12-31 17:51):
#paper DNA methylation aging clocks: challenges and recommendations, Genome Biology, 2019, https://doi.org/10.1186/s13059-019-1824-y 衰老通常伴随着疾病的发生,理解人类为何以及如何衰老是生物学中的重要课题。衰老伴随着分子层面的变化,过去十年内,不少研究发现可以使用基因组上的一部分CpG位点甲基化水平来准确预测年龄,这样的一组CpG位点又被称为 表观遗传时钟。事实上表观遗传时钟的预测误差与疾病发生率和死亡率也被发现有联系,从而广泛引起了研究者们的兴趣。这篇综述文章总结了表观遗传时钟领域的如下七大挑战,并分别介绍了研究现状,不确定性和未来研究方向的推荐:1. 拆分表观时钟的时序成分和生物成分;2. 组织特异或者疾病特异时钟的功能性研究;3.大规模时序种群研究的表观遗传学整合; 4. 衰老的全基因组分析以及其他表观遗传标记物的探索;5. 衰老与疾病的单细胞组学分析; 6. 稳健产生其他物种的衰老数据; 7. 将表观遗传学与遗传学的伦理和法律框架融合起来。个人感觉文章质量一般
IF:10.100Q1 Genome biology, 2019-11-25. DOI: 10.1186/s13059-019-1824-y PMID: 31767039
Abstract:
Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans … >>>
Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual. <<<
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783.
姗姗来迟 (2022-12-31 17:48):
#paper https://link.springer.com/article/10.1007/s11263-022-01654-0?utm_source=xmol&utm_content=meta PageNet: Towards End-to-End Weakly Supervised Page-Level Handwritten Chinese Text Recognition 该工作针对篇幅级手写中文文本识别问题,提出了端到端弱监督的方法PageNet。该方法的主要优势在于:(1)从一个新的角度解决篇幅级中文文本识别问题——检测识别单字并预测单字间的阅读顺序。(2)模型可以弱监督地训练。对于真实数据仅需要标注文本,不需要任何边界框标注,极大地降低了数据的标注成本。(3)尽管只需要文本标注信息,模型却可以预测出单字级和文本行级的检测和识别结果。(4)该方法深入研究篇幅级文本识别中的阅读顺序问题,所提出的阅读顺序模块可以处理多方向文本、弯曲文本等复杂的阅读顺序。
Abstract:
Handwritten Chinese text recognition (HCTR) has been an active research topic for decades. However, most previous studies solely focus on the recognition of cropped text line images, ignoring the error … >>>
Handwritten Chinese text recognition (HCTR) has been an active research topic for decades. However, most previous studies solely focus on the recognition of cropped text line images, ignoring the error caused by text line detection in real-world applications. Although some approaches aimed at page-level text recognition have been proposed in recent years, they either are limited to simple layouts or require very detailed annotations including expensive line-level and even character-level bounding boxes. To this end, we propose PageNet for end-to-end weakly supervised page-level HCTR. PageNet detects and recognizes characters and predicts the reading order between them, which is more robust and flexible when dealing with complex layouts including multi-directional and curved text lines. Utilizing the proposed weakly supervised learning framework, PageNet requires only transcripts to be annotated for real data; however, it can still output detection and recognition results at both the character and line levels, avoiding the labor and cost of labeling bounding boxes of characters and text lines. Extensive experiments conducted on five datasets demonstrate the superiority of PageNet over existing weakly supervised and fully supervised page-level methods. These experimental results may spark further research beyond the realms of existing methods based on connectionist temporal classification or attention. The source code is available at https://github.com/shannanyinxiang/PageNet. <<<
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784.
DeDe宝 (2022-12-31 17:34):
#paper doi: doi.org/10.1073/pnas.2202394119,Sleep facilitates spatial memory but not navigation using the Minecraft Memory and Navigation tas,PNAS这篇文章是今年10月刚发表的,基于《我的世界》这个游戏分别研究了睡眠对于导航能力、导航记忆的作用。之前的研究已经证实睡眠可以促进海马相关的记忆,而我们知道海马可以支持空间环境的获取和内部表征,也就是海马可以支持认知地图的形成,认知地图是通过环境探索构建的,是导航的重要表征。那么,推出睡眠可以促进导航相关的记忆就是相当自然的。但是,之前的研究者对于睡眠对导航相关空间记忆的作用的研究结果却不乐观,有一些证实了该推测,而有一些没有。本文研究者认为,睡眠对导航相关空间记忆的作用,要拆成睡眠对空间记忆的作用,以及睡眠对导航能力的作用两部分来看。研究结果支持睡眠促进空间记忆,但不能促进导航能力。
Abstract:
Sleep facilitates hippocampal-dependent memories, supporting the acquisition and maintenance of internal representation of spatial relations within an environment. In humans, however, findings have been mixed regarding sleep's contribution to spatial … >>>
Sleep facilitates hippocampal-dependent memories, supporting the acquisition and maintenance of internal representation of spatial relations within an environment. In humans, however, findings have been mixed regarding sleep's contribution to spatial memory and navigation, which may be due to task designs or outcome measurements. We developed the Minecraft Memory and Navigation (MMN) task for the purpose of disentangling how spatial memory accuracy and navigation change over time, and to study sleep's independent contributions to each. In the MMN task, participants learned the locations of objects through free exploration of an open field computerized environment. At test, they were teleported to random positions around the environment and required to navigate to the remembered location of each object. In study 1, we developed and validated four unique MMN environments with the goal of equating baseline learning and immediate test performance. A total of 86 participants were administered the training phases and immediate test. Participants' baseline performance was equivalent across all four environments, supporting the use of the MMN task. In study 2, 29 participants were trained, tested immediately, and again 12 h later after a period of sleep or wake. We found that the metric accuracy of object locations, i.e., spatial memory, was maintained over a night of sleep, while after wake, metric accuracy declined. In contrast, spatial navigation improved over both sleep and wake delays. Our findings support the role of sleep in retaining the precise spatial relationships within a cognitive map; however, they do not support a specific role of sleep in navigation. <<<
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785.
哪有情可长 (2022-12-31 16:21):
#paper MicroTom Metabolic Network: Rewiring Tomato Metabolic Regulatory Network throughout the Growth Cycle,Molecular Plant , August 2020 ,https://doi.org/10.1016/j.molp.2020.06.005. 作者对整个番茄生命周期的根、茎、叶、花、果实进行取样进行转录组和代谢中测序,构建了番茄生长时期的代谢图谱和番茄发育过程的时间天空网络。除了验证前人已经发表过的重要代谢物的调控网络,也鉴定到一个一个转录因子可以调节重要的次级代谢物的合成,黄酮类的代谢物。该文章的模式跟该课题组发水稻的代谢调控网络类似,包括处理方法都是类似(Rice metabolic regulatory network spanning the entire life cycle)。作为植物中进行代谢组和转录组数据联合分析的入门可以精读下。但是内在的代谢物的作用,还是需要一篇篇文献积累。
IF:17.100Q1 Molecular plant, 2020-08-03. DOI: 10.1016/j.molp.2020.06.005 PMID: 32561360
Abstract:
Tomato (Solanum lycopersicum) is a major horticultural crop worldwide and has emerged as a preeminent model for metabolic research. Although many research efforts have focused on the analysis of metabolite … >>>
Tomato (Solanum lycopersicum) is a major horticultural crop worldwide and has emerged as a preeminent model for metabolic research. Although many research efforts have focused on the analysis of metabolite differences between varieties and species, the dynamics of metabolic changes during the tomato growth cycle and the regulatory networks that underlie these changes are poorly understood. In this study, we integrated high-resolution spatio-temporal metabolome and transcriptome data to systematically explore the metabolic landscape across 20 major tomato tissues and growth stages. In the resulting MicroTom Metabolic Network, the 540 detected metabolites and their co-expressed genes could be divided into 10 distinct clusters based on their biological functions. Using this dataset, we constructed a global map of the major metabolic changes that occur throughout the tomato growth cycle and dissected the underlying regulatory network. In addition to verifying previously well-established regulatory networks for important metabolites, we identified novel transcription factors that regulate the biosynthesis of important secondary metabolites such as steroidal glycoalkaloids and flavonoids. Our findings provide insights into spatio-temporal changes in tomato metabolism and generate a valuable resource for the study of metabolic regulatory processes in model plants. <<<
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786.
尹志 (2022-12-31 14:48):
#paper doi: https://doi.org/10.48550/arXiv.2210.11250,Structure-based drug design with geometric deep learning. 这是一篇比较新的关于药物设计和深度学习的短小的综述。主要探讨了在结构化药物设计领域的若干重要子任务上,几何深度学习技术是如何发挥其作用的。考虑到结构化药物设计主要使用大分子(比如蛋白质、核酸)的三维几何信息来识别合适的配体,几何深度学习作为一种将几何对称性引入深度学习的技术是非常有潜力的工具。文章主要探讨了1)分子性质预测(结合亲和度、蛋白质功能、位置分数);2)结合位点和结合面预测(小分子结合位点和蛋白-蛋白结合面);3)结合位置生成和分子对接(配体-蛋白和蛋白-蛋白对接);4)基于结构的小分子配体de novo 设计几个子任务。从分子的常见表征谈起,再讨论结构化药物设计中存在的对称性问题,然后通过四个小节,分别讨论了几何深度学习对四个子任务的研究现状。是基于AI的结构化药物设计领域的一篇很不错的guideline。
Abstract:
Structure-based drug design uses three-dimensional geometric information of macromolecules, such as proteins or nucleic acids, to identify suitable ligands. Geometric deep learning, an emerging concept of neural-network-based machine learning, has … >>>
Structure-based drug design uses three-dimensional geometric information of macromolecules, such as proteins or nucleic acids, to identify suitable ligands. Geometric deep learning, an emerging concept of neural-network-based machine learning, has been applied to macromolecular structures. This review provides an overview of the recent applications of geometric deep learning in bioorganic and medicinal chemistry, highlighting its potential for structure-based drug discovery and design. Emphasis is placed on molecular property prediction, ligand binding site and pose prediction, and structure-based de novo molecular design. The current challenges and opportunities are highlighted, and a forecast of the future of geometric deep learning for drug discovery is presented. <<<
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787.
徐炳祥 (2022-12-31 14:45):
#paper doi: 10.1186/s13059-022-02835-3 Genome Biology, 2022, NetAct: a computational platform to construct core transcription factor regulatory networks using gene activity。如何构建基因表达调控网络始终是系统生物学面临的重要课题。当前的基因调控网络构造方法普遍基于基因表达数据,而转录因子的功能往往体现在表达之外;此外,当前常用的基因表达调控网络构建的数学/统计方法擅长关注相关性而非因果性;这些缺陷使得当前对基因调控网络的构造效果不佳。本文从文献整理的转录因子和靶基因数据库出发,借助基因表达数据和GSEA提出了一种新的评估某过程中TF活性的策略。在评估的基础上使用互信息完成了基因表达调控网络的构造。本文中结合数据库中转录因子——靶基因关系和基因表达数据进行的转录因子活性定量方法是值得借鉴的。
IF:10.100Q1 Genome biology, 2022-12-27. DOI: 10.1186/s13059-022-02835-3 PMID: 36575445 PMCID:PMC9793520
Abstract:
A major question in systems biology is how to identify the core gene regulatory circuit that governs the decision-making of a biological process. Here, we develop a computational platform, named … >>>
A major question in systems biology is how to identify the core gene regulatory circuit that governs the decision-making of a biological process. Here, we develop a computational platform, named NetAct, for constructing core transcription factor regulatory networks using both transcriptomics data and literature-based transcription factor-target databases. NetAct robustly infers regulators' activity using target expression, constructs networks based on transcriptional activity, and integrates mathematical modeling for validation. Our in silico benchmark test shows that NetAct outperforms existing algorithms in inferring transcriptional activity and gene networks. We illustrate the application of NetAct to model networks driving TGF-β-induced epithelial-mesenchymal transition and macrophage polarization. <<<
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788.
笑对人生 (2022-12-31 13:24):
#paper doi: 10.1016/j.cell.2021.03.009. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell. 2021 Apr 15;184(8):2239-2254.e39. 瘤内异质性(Intra-tumor heterogeneity,ITH)是癌症治疗耐药发生的重要因素之一。ITH的计算其实是首先通过计算突变在所有肿瘤细胞的占比(即CCF),然后将具有相似肿瘤占比的突变进行聚类,最终区分肿瘤组织中哪些细胞是clone,哪些是subclone。因此,ITH的形成与肿瘤组织内clone和subclone的比例密切相关。一般来说,患者ITH低,具有免疫原性的肿瘤新生抗原主要来自clone,那么在经过治疗后,大部分的肿瘤细胞会杀死,患者预后较好。本研究通过对38种癌症类型,共2658份肿瘤组织样本的全基因组测序数据(Whole-genome sequencing,WGS)进行了ITH分析。该分析的数据集来自PCAWG,分析的内容包括单核苷酸变异、插入或缺失、结构变异、拷贝数变异、亚克隆结构推断和进化关系、以及突变特征分析,每种分析使用了4-11种算法。研究发现,大概95.1%的样本在复杂的亚克隆支型进化关系种存在明显的亚克隆扩张。在大多数癌症类型中存在亚克隆驱动突变的正向选择(positive selection)。正向选择通常会引起突变位点的多态性降低,累积有利变异,最终引起selective sweep。Selective sweep就是指当某种有利突变受到强的自然选择后,引起该位点所在染色体区域的基因多态性降低的现象。此外,该研究进一步揭示了亚克隆扩张之间存在具有癌种特异性的驱动基因突变、基因融合、结构变异和拷贝数变异的亚克隆模式,以及一些动态的突变过程。类似的研究在2019年曾有报道 (doi: 10.1038/s41586-019-1689-y),但主要关注肿瘤的转移灶,认为相比于原发肿瘤,转移灶的肿瘤内异质性相对较低。文章中涉及的一些专有名词如下:CCF,cancer cell fraction是指包含某种变异的细胞在所有肿瘤细胞的占比。如果肿瘤组织中所有肿瘤细胞携带某个特定的体细胞突变,那么这个突变的CCF即为1。乘客突变(passenger mutation)指肿瘤的发生和发展无关的突变、与之相对的促进肿瘤发展的驱动突变(driver mutation)。WGD,whole-genome duplication/doubling,全基因组倍增涉及整套染色体复制,可引起所有基因的拷贝增加,是人类肿瘤非整倍体变异进化的主要影响因素。2021年,有研究使用了约10000个原发肿瘤样本,涵盖32种不同肿瘤类型,全面分析了具有WGD的肿瘤基因组特征(doi: 10.1038/s41586-020-03133-3)。
IF:45.500Q1 Cell, 2021. DOI: 10.1016/j.cell.2021.03.009
Stefan C. Dentro , Ignaty Leshchiner , Kerstin Haase , Maxime Tarabichi , Jeff Wintersinger , Amit G. Deshwar , Kaixian Yu , Yulia Rubanova , Geoff Macintyre , Jonas Demeulemeester , Ignacio Vázquez-García , Kortine Kleinheinz , Dimitri G. Livitz , Salem Malikic , Nilgun Donmez , Subhajit Sengupta , Pavana Anur , Clemency Jolly , Marek Cmero , Daniel Rosebrock , Steven E. Schumacher , Yu Fan , Matthew Fittall , Ruben M. Drews , Xiaotong Yao , Thomas B.K. Watkins , Juhee Lee , Matthias Schlesner , Hongtu Zhu , David J. Adams , Nicholas McGranahan , Charles Swanton , Gad Getz , Paul C. Boutros , Marcin Imielinski , Rameen Beroukhim , S. Cenk Sahinalp , Yuan Ji , Martin Peifer , Inigo Martincorena , Florian Markowetz , Ville Mustonen , Ke Yuan , Moritz Gerstung , Paul T. Spellman , Wenyi Wang , Quaid D. Morris , David C. Wedge , Peter Van Loo , Stefan C. Dentro , Ignaty Leshchiner , Moritz Gerstung , Clemency Jolly , Kerstin Haase , Maxime Tarabichi , Jeff Wintersinger , Amit G. Deshwar , Kaixian Yu , Santiago Gonzalez , Yulia Rubanova , Geoff Macintyre , Jonas Demeulemeester , David J. Adams , Pavana Anur , Rameen Beroukhim , Paul C. Boutros , David D. Bowtell , Peter J. Campbell , Shaolong Cao , Elizabeth L. Christie , Marek Cmero , Yupeng Cun , Kevin J. Dawson , Nilgun Donmez , Ruben M. Drews , Roland Eils , Yu Fan , Matthew Fittall , Dale W. Garsed , Gad Getz , Gavin Ha , Marcin Imielinski , Lara Jerman , Yuan Ji , Kortine Kleinheinz , Juhee Lee , Henry Lee-Six , Dimitri G. Livitz , Salem Malikic , Florian Markowetz , Inigo Martincorena , Thomas J. Mitchell , Ville Mustonen , Layla Oesper , Martin Peifer , Myron Peto , Benjamin J. Raphael , Daniel Rosebrock , S. Cenk Sahinalp , Adriana Salcedo , Matthias Schlesner , Steven E. Schumacher , Subhajit Sengupta , Ruian Shi , Seung Jun Shin , Lincoln D. Stein , Oliver Spiro , Ignacio Vázquez-García , Shankar Vembu , David A. Wheeler , Tsun-Po Yang , Xiaotong Yao , Ke Yuan , Hongtu Zhu , Wenyi Wang , Quaid D. Morris , Paul T. Spellman , David C. Wedge , Peter Van Loo <<<
Abstract:
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To … >>>
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data. <<<
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789.
小年 (2022-12-31 13:02):
#paper doi: 10.1038/s41417-021-00418-1. Use of CAR T-cell for acute lymphoblastic leukemia (ALL) treatment: a review study. Cancer Gene Ther. 2022. 急性淋巴细胞白血病(ALL)是一种癌症特异性淋巴细胞。近年来,新的治疗方法得到了广泛的应用。造血干细胞移植(HSCT)存在显着的局限性。虽然可以实现疾病的完全或部分缓解,但复发/难治性(R/R)AML患者的预后较差,移植后复发率高,需要新药物和新方案改善这类患者的长期生存。因此,使用替代方法来解决这些治疗挑战似乎至关重要。在过去十年中,用嵌合抗原受体(CAR)治疗ALL的基因工程T细胞得到了广泛的研究。根据I/II期临床试验,这项技术结果似乎非常有希望,可以在未来用作ALL治疗的有效和安全的治疗方法。 在本综述中,讨论了与嵌合抗原受体(CAR)T细胞用于ALL治疗相关的不同世代,挑战和临床研究,具体通过CAR-T细胞制造和治疗、靶向抗原、临床试验、CAR-T毒性、CAR-T治疗的优势、CAR-T细胞疗法的挑战、克服挑战的策略等方面。文中指出,当前研究和未来调查的核心部分集中在鉴定新的靶标抗原和当前可用靶标的新组合上,一个主要的挑战是选择更好的临床前研究来识别潜在的组合。此外,探索抗原损失机制和确定克服策略对于研究目的至关重要,克服肿瘤微环境中的T细胞功能抑制剂可以加速CAR-T细胞产品的开发和进步。
IF:4.800Q1 Cancer gene therapy, 2022-08. DOI: 10.1038/s41417-021-00418-1 PMID: 34987176
Abstract:
Acute lymphoblastic leukemia (ALL) is a cancer-specific lymphoid cell. Induction and consolidation chemotherapy alone or in combination with different therapeutic approaches remain the main treatment. Although complete or partial remission … >>>
Acute lymphoblastic leukemia (ALL) is a cancer-specific lymphoid cell. Induction and consolidation chemotherapy alone or in combination with different therapeutic approaches remain the main treatment. Although complete or partial remission of the disease can be achieved, the risk of relapse or refractory leukemia is still high. More effective and safe therapy options are yet unmet needs. In recent years' new therapeutic approaches have been widely used. Hematopoietic Stem Cell Transplantation (HSCT) presents significant limitations and the outcome of the consolidation treatment is patient dependent. Side effects such as Graft versus Host Disease (GvHD) in allogeneic hematopoietic stem cell transplantation are extremely common, therefore, using alternative methods to address these challenges for treatment seems crucial. In the last decade, T cells genetically engineered with Chimeric Antigen Receptor (CAR) treatment for the ALL are largely studied and represent the new era of strategy. According to the Phase I/II clinical trials, this technology results seem very promising and can be used in the next future as an effective and safe treatment for ALL treatment. In this review different generations, challenges, and clinical studies related to chimeric antigen receptor (CAR) T-cells for ALL treatment are discussed. <<<
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790.
LXJ (2022-12-31 11:55):
#paper doi: 10.1016/j.it.2022.10.005. Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment. Trends Immunol. 2022 Dec;43(12):969-977. 这是一篇综述研究,乳酸的产生被认为是恶性细胞逃避免疫监视的一种机制。最近的质谱技术进步和使用具有生理营养成分的细胞培养基,为乳酸及其共轭乳酸在肿瘤微环境中的作用提供了新的视角。本文作者回顾了鉴定乳酸作为哺乳动物肿瘤和免疫细胞的生理碳源的新工作,强调了其作为底物的用途不同于乳酸质子对细胞外环境的免疫抑制酸化的证据。总之,数据表明,应在维持细胞毒性CD8+T细胞生理乳酸代谢的同时,中和肿瘤内酸性的影响,以提高抗肿瘤免疫力。
IF:13.100Q1 Trends in immunology, 2022-12. DOI: 10.1016/j.it.2022.10.005 PMID: 36319537
Abstract:
Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a … >>>
Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8 T cells should be pursued to boost anti-tumor immunity. <<<
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791.
前进 (2022-12-31 11:39):
#paper Liu Y, Chen J, Wei S, et al. On Finite Difference Jacobian Computation in Deformable Image Registration[J]. arXiv preprint arXiv:2212.06060, 2022. 产生微分同胚的空间变换一直是变形图像配准的中心问题。作为一个微分同胚变换,应在任何位置都具有正的雅可比行列式|J|。|J|<0的体素数已被用于测试微分同胚性,也用于测量变换的不规则性。 对于数字变换,|J|通常使用中心差来近似,但是对于即使在体素分辨率级别上也明显不具有差分同胚性的变换,这种策略可以产生正的|J|。为了证明这一点,论文首先研究了|J|的不同有限差分近似的几何意义。为了确定数字图像的微分同胚性,使用任何单独的有限差分逼近|J|是不够的。论文证明对于2D变换,|J|的四个唯一的有限差分近似必须是正的,以确保整个域是可逆的,并且在像素级没有折叠。在3D中,|J|的十个唯一的有限差分近似值需要是正的。论文提出的数字微分同胚准则解决了|J|的中心差分近似中固有的几个误差,并准确地检测非微分同胚数字变换。
Abstract:
Producing spatial transformations that are diffeomorphic has been a central problem in deformable image registration. As a diffeomorphic transformation should have positive Jacobian determinant |J| everywhere, the number of voxels … >>>
Producing spatial transformations that are diffeomorphic has been a central problem in deformable image registration. As a diffeomorphic transformation should have positive Jacobian determinant |J| everywhere, the number of voxels with |J|<0 has been used to test for diffeomorphism and also to measure the irregularity of the transformation. For digital transformations, |J| is commonly approximated using central difference, but this strategy can yield positive |J|'s for transformations that are clearly not diffeomorphic -- even at the voxel resolution level. To show this, we first investigate the geometric meaning of different finite difference approximations of |J|. We show that to determine diffeomorphism for digital images, use of any individual finite difference approximations of |J| is insufficient. We show that for a 2D transformation, four unique finite difference approximations of |J|'s must be positive to ensure the entire domain is invertible and free of folding at the pixel level. We also show that in 3D, ten unique finite differences approximations of |J|'s are required to be positive. Our proposed digital diffeomorphism criteria solves several errors inherent in the central difference approximation of |J| and accurately detects non-diffeomorphic digital transformations. <<<
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792.
颜林林 (2022-12-30 20:49):
#paper doi:10.1038/s41551-022-00952-9 Nat. Biomed. Eng, 2022, A deep-learning model for transforming the style of tissue images from cryosectioned to formalin-fixed and paraffin-embedded. 在肿瘤诊治过程中,经常需要通过对肿瘤组织进行组织学检查,得到病理诊断结果,才能做出合适的治疗方案。病理组织学检查,需要对组织进行福尔马林固定、石蜡包埋和切片制片,然后将切片放置在显微镜下进行观察,整个过程非常耗时耗力,因而难以应用于手术期间快速决策。冰冻组织切片虽然可以快速进行,但该技术面临细胞结构不容易保留、经常出现各类人为实验因素造成的伪影(artefacts)等挑战,干扰组织学检查过程。本文构建了一个基于GAN的深度学习模型AI-FFPE,用来将冰冻组织切片图像转换成为石蜡包埋组织切片风格,并以此修正各类伪影,提升通过冰冻组织切片来进行组织学检查的效率。经该模型应用于脑肿瘤和肺癌的病理图像公共数据集,进行验证和评估,确实有效修正了相关伪影问题,且效果相对其他专门进行病理图像修正的工具算法更好。此外,本文还将AI-FFPE的输出图像,交给27位病理医生进行人工评估,以及交给之前已发表的AI阅片程序进行分类,其结果也都支持AI-FFPE策略的有效性。
Abstract:
Histological artefacts in cryosectioned tissue can hinder rapid diagnostic assessments during surgery. Formalin-fixed and paraffin-embedded (FFPE) tissue provides higher quality slides, but the process for obtaining them is laborious (typically … >>>
Histological artefacts in cryosectioned tissue can hinder rapid diagnostic assessments during surgery. Formalin-fixed and paraffin-embedded (FFPE) tissue provides higher quality slides, but the process for obtaining them is laborious (typically lasting 12-48 h) and hence unsuitable for intra-operative use. Here we report the development and performance of a deep-learning model that improves the quality of cryosectioned whole-slide images by transforming them into the style of whole-slide FFPE tissue within minutes. The model consists of a generative adversarial network incorporating an attention mechanism that rectifies cryosection artefacts and a self-regularization constraint between the cryosectioned and FFPE images for the preservation of clinically relevant features. Transformed FFPE-style images of gliomas and of non-small-cell lung cancers from a dataset independent from that used to train the model improved the rates of accurate tumour subtyping by pathologists. <<<
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793.
惊鸿 (2022-12-29 15:54):
#paper DOI : 10.1126/science.abl6620 Glassfrogs conceal blood in their liver to maintain transparency 20221222 动物的透明体是一种复杂的伪装形式,涉及减少整个生物体的光散射和吸收的机制。在脊椎动物中,获得透明度很困难,因为它们的循环系统充满了强烈减弱光线的红细胞 (RBC)。在此,这个实验团队记录了玻璃蛙如何通过隐藏这些细胞。该实验团队使用光声成像在体内追踪红细胞,表明静息玻璃蛙通过从循环中去除约 89% 的红细胞并将其包装在肝脏中,从而将透明度提高两到三倍。因此,脊椎动物的透明性需要透明组织和从这些组织中“清除”呼吸色素的活跃机制。此外,玻璃蛙能够调节位置、密度。
Abstract:
Transparency in animals is a complex form of camouflage involving mechanisms that reduce light scattering and absorption throughout the organism. In vertebrates, attaining transparency is difficult because their circulatory system … >>>
Transparency in animals is a complex form of camouflage involving mechanisms that reduce light scattering and absorption throughout the organism. In vertebrates, attaining transparency is difficult because their circulatory system is full of red blood cells (RBCs) that strongly attenuate light. Here, we document how glassfrogs overcome this challenge by concealing these cells from view. Using photoacoustic imaging to track RBCs in vivo, we show that resting glassfrogs increase transparency two- to threefold by removing ~89% of their RBCs from circulation and packing them within their liver. Vertebrate transparency thus requires both see-through tissues and active mechanisms that "clear" respiratory pigments from these tissues. Furthermore, glassfrogs' ability to regulate the location, density, and packing of RBCs without clotting offers insight in metabolic, hemodynamic, and blood-clot research. <<<
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794.
李翛然 (2022-12-28 21:08):
#paper doi:10.1016/S1473-3099(22)00291-2 Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape. Lancet Infect Dis. 2022 Aug 8:S1473-3099(22)00291-2. . 这篇文章非常好的梳理了正在北美和欧洲大杀四方的rsv 病毒疫苗研发情况。 现在国门打开,未来必然是新冠+rsv+流感的轮流爆发,我司准备开一个这个管线。这篇综述写的非常好。 很有参考价值的梳理了技术路线,临床阶段,为我们的布局很有指导性意义。
Abstract:
Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a … >>>
Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results. <<<
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795.
魏魏魏 (2022-12-22 21:45):
#paper doi:10.1038/s44184-022-00011-w Mental Health Research (2022), The mental health and well-being profile of young adults using social media. 青(少)年社交媒体的使用历来吸引人的关注,研究者和政策制定者都对社交媒体使用与心理健康的关系都予以重视,然而,社交媒体对青年心理的影响并不为人所知,对他们关系的影响因素也知之甚少,甚至存在误解。当前研究被试广泛选取了Facebook, Twitter, Instagram, Snapchat和YouTube用户,共计有4083人,均为同辈群体。在当前研究中,研究者采用了追踪研究设计。研究者全面测量了抑郁症状、自杀想法、饮食失调、幸福感、生活满意度、感恩和人生意义等表征心理健康的变量,同时测量了自我决定理论中的三个基本心理需要,也测量了社交媒体的使用情况,包括是否使用软件以及使用频率等情况。当前研究最有价值的发现是,不同类型的社交媒体使用并不必然会导致青少年心理健康变好或变坏,结果因使用软件类型和性别等的差异而有所不同。当前研究有助于我们了解此前研究出现不同结果的原因,也有助于我们了解青少年社交媒体使用的情况。
Abstract:
The relationship between mental health and social media has received significant research and policy attention. However, there is little population representative data about who social media users are which limits … >>>
The relationship between mental health and social media has received significant research and policy attention. However, there is little population representative data about who social media users are which limits understanding of confounding factors between mental health and social media. Here we profile users of Facebook, Twitter, Instagram, Snapchat and YouTube from the Avon Longitudinal Study of Parents and Children population cohort (N=4,083). We provide estimates of demographics and mental health and well-being outcomes by platform. We find that users of different platforms and frequencies are not homogeneous. User groups differ primarily by sex and YouTube users are the most likely to have poorer mental health outcomes. Instagram and Snapchat users tend to have higher well-being than the other social media sites considered. Relationships between use-frequency and well-being differ depending on the specific well-being construct measured. The reproducibility of future research may be improved by stratifying by sex and being specific about the well-being constructs used. <<<
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796.
张德祥 (2022-12-14 19:10):
#paper https://doi.org/10.1371/journal.pone.0277199 Structure learning enhances concept formation in synthetic Active Inference agents 结构学习 抽象学习 概念学习是人类认知的高级功能,物体和场景关系在推理中互相影响,现在AI还做不到这样的智能认知,这篇论文超结构学习迈出了第一步,而且是在结构学习下链接行动和感知。世界模型的学习和推理 自由能在学习的时间尺度上,从最快的推理,到慢一点的网络参数学习,再到最慢的睡眠离线模型的结构学习,次论文这三个层次都有介绍,核心是最高级的结构学习。在自由能框架下 结构学习如何自然出现。结构学习可以联系都洞察力,让人恍然大悟的时刻。涉及贝叶斯模型选择推理。
IF:2.900Q1 PloS one, 2022. DOI: 10.1371/journal.pone.0277199 PMID: 36374909
Abstract:
Humans display astonishing skill in learning about the environment in which they operate. They assimilate a rich set of affordances and interrelations among different elements in particular contexts, and form … >>>
Humans display astonishing skill in learning about the environment in which they operate. They assimilate a rich set of affordances and interrelations among different elements in particular contexts, and form flexible abstractions (i.e., concepts) that can be generalised and leveraged with ease. To capture these abilities, we present a deep hierarchical Active Inference model of goal-directed behaviour, and the accompanying belief update schemes implied by maximising model evidence. Using simulations, we elucidate the potential mechanisms that underlie and influence concept learning in a spatial foraging task. We show that the representations formed-as a result of foraging-reflect environmental structure in a way that is enhanced and nuanced by Bayesian model reduction, a special case of structure learning that typifies learning in the absence of new evidence. Synthetic agents learn associations and form concepts about environmental context and configuration as a result of inferential, parametric learning, and structure learning processes-three processes that can produce a diversity of beliefs and belief structures. Furthermore, the ensuing representations reflect symmetries for environments with identical configurations. <<<
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797.
龙海晨 (2022-12-01 17:34):
#paper Wang L, Jiang D, Zhang L. A thermophilic 8-oxoguanine DNA glycosylase from Thermococcus barophilus Ch5 is a new member of AGOG DNA glycosylase family[J]. Acta biochimica et biophysica Sinica.PMID: 35713316 DOI: 10.3724/abbs.2022072 DNA中的8-氧代胍(8oxoguanine,8oxoG)是一种主要的氧化碱基,对基因组稳定性构成严重威胁。细胞已经进化出8oxoG-DNA糖苷酶(OGG)来抵消8oxoG在DNA中产生的诱变。目前,OGG酶分为三个家族:OGG1、OGG2和AGOG。文章研究发现,来自超嗜热性欧氏菌T嗜酸乳杆菌Ch5的Tb-AGOG能在75-95摄氏度pH9.0的时候去除8oxoG有最大效率。Tb-AGOG是一种双功能DNA糖苷酶,具有糖苷酶活性和AP裂解酶活性。文章阐述了AGOG的作用机制。Tb-AGOG中的残基D41和D229对催化至关重要。
Abstract:
8-Oxoguanine (8oxoG) in DNA is a major oxidized base that poses a severe threat to genome stability. To counteract the mutagenic effect generated by 8oxoG in DNA, cells have evolved … >>>
8-Oxoguanine (8oxoG) in DNA is a major oxidized base that poses a severe threat to genome stability. To counteract the mutagenic effect generated by 8oxoG in DNA, cells have evolved 8oxoG DNA glycosylase (OGG) that can excise this oxidized base from DNA. Currently, OGG enzymes have been divided into three families: OGG1, OGG2 and AGOG (archaeal 8oxoG DNA glycosylase). Due to the limited reports, our understanding on AGOG enzymes remains incomplete. Herein, we present evidence that an AGOG from the hyperthermophilic euryarchaeon Ch5 (Tb-AGOG) excises 8oxoG from DNA at high temperature. The enzyme displays maximum efficiency at 75°C-95°C and at pH 9.0. As expected, Tb-AGOG is a bifunctional glycosylase that harbors glycosylase activity and AP (apurinic/apyrimidinic) lyase activity. Importantly, we reveal for the first time that residue D41 in Tb-AGOG is essential for 8oxoG excision and intermediate formation, but not essential for DNA binding or AP cleavage. Furthermore, residue E79 in Tb-AGOG is essential for 8oxoG excision and intermediate formation, and is partially involved in DNA binding and AP cleavage, which has not been described among the reported AGOG members to date. Overall, our work provides new insights into catalytic mechanism of AGOG enzymes. <<<
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798.
小W (2022-11-30 23:58):
#paper doi:https://doi.org/10.1038/s41577-022-00796-z TGFβ control of immune responses in cancer: a holistic immuno-oncology perspective TGFβ对癌症免疫反应的控制。作为一种进化上古老的调节细胞因子,TGFβ在免疫系统内外具有多效性功能,其促肿瘤或抗肿瘤免疫活性取决于其来源、剂量、环境和白细胞及其靶点,以及癌症类型和疾病阶段。本文使用小鼠肿瘤模型数据,在 TGFβ对不同免疫细胞调节效应 和 TGFβ在癌症先天免疫中的作用 进行了详细的论述,最后介绍了 TGFβ途径的全身阻断 和 靶向阻断TGFβ途径 两类将 TGFβ 用于癌症免疫治疗的尝试。有意思的一点,在本文介绍的 作用于 TGFβ 的 制剂多 与 其他治疗方式连用 ,而去年的 PD-L1/TGFβ双抗 临床试验全都铩羽而归。
Abstract:
The immune system responds to cancer in two main ways. First, there are prewired responses involving myeloid cells, innate lymphocytes and innate-like adaptive lymphocytes that either reside in premalignant tissues … >>>
The immune system responds to cancer in two main ways. First, there are prewired responses involving myeloid cells, innate lymphocytes and innate-like adaptive lymphocytes that either reside in premalignant tissues or migrate directly to tumours, and second, there are antigen priming-dependent responses, in which adaptive lymphocytes are primed in secondary lymphoid organs before homing to tumours. Transforming growth factor-β (TGFβ) - one of the most potent and pleiotropic regulatory cytokines - controls almost every stage of the tumour-elicited immune response, from leukocyte development in primary lymphoid organs to their priming in secondary lymphoid organs and their effector functions in the tumour itself. The complexity of TGFβ-regulated immune cell circuitries, as well as the contextual roles of TGFβ signalling in cancer cells and tumour stromal cells, necessitates the use of rigorous experimental systems that closely recapitulate human cancer, such as autochthonous tumour models, to uncover the underlying immunobiology. The diverse functions of TGFβ in healthy tissues further complicate the search for effective and safe cancer therapeutics targeting the TGFβ pathway. Here we discuss the contextual complexity of TGFβ signalling in tumour-elicited immune responses and explain how understanding this may guide the development of mechanism-based cancer immunotherapy. <<<
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799.
小擎子 (2022-11-30 23:57):
# paper doi:10.1186/s13059-016-0997-x;Genome Biol.2016 Mash: fast genome and metagenome distance estimation using MinHash, Mash工具,用MinHash快速衡量基因组和宏基因组距离。Mash主要实现sketch和dist两个功能,sketch将序列或者序列合集转换为MinHash sketch,可以大幅缩小内存占用,dist计算Jaccard index可以在可控误差范围内近似ANI,且计算效率大大提供。重点是k-mer和s(sketch的size大小)的选择,会影响误差。Mash的特点是计算消耗主要是生成sketch上,sketch一旦生成,上万基因组的相似性比较和聚类几乎是瞬时完成的。
IF:10.100Q1 Genome biology, 2016-06-20. DOI: 10.1186/s13059-016-0997-x PMID: 27323842
Abstract:
Mash extends the MinHash dimensionality-reduction technique to include a pairwise mutation distance and P value significance test, enabling the efficient clustering and search of massive sequence collections. Mash reduces large … >>>
Mash extends the MinHash dimensionality-reduction technique to include a pairwise mutation distance and P value significance test, enabling the efficient clustering and search of massive sequence collections. Mash reduces large sequences and sequence sets to small, representative sketches, from which global mutation distances can be rapidly estimated. We demonstrate several use cases, including the clustering of all 54,118 NCBI RefSeq genomes in 33 CPU h; real-time database search using assembled or unassembled Illumina, Pacific Biosciences, and Oxford Nanopore data; and the scalable clustering of hundreds of metagenomic samples by composition. Mash is freely released under a BSD license ( https://github.com/marbl/mash ). <<<
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800.
Arwen (2022-11-30 23:56):
#paper doi:10.1001/jamanetworkopen.2022.44049 Poverty, Cortical Structure, and Psychopathologic Characteristics in Adolescence 儿童时期的贫困与青春期内化和外化问题的增加有关,青春期是精神问题的高峰发作期。潜在的神经机制尚不清楚,因为缺乏对贫困、大脑结构和精神症状变化的纵向研究。 目的:探讨家庭贫困与青少年早期精神症状变化之间是否存在脑皮层结构差异的中介作用。本纵向队列研究使用了青少年大脑认知发展研究的基线数据和1年随访数据。美国9到10岁的儿童在2016年9月1日至2018年10月15日期间注册。数据分析时间为2021年8月13日至2022年9月30日。以收入需求比衡量的家庭贫困程度,该比率包含了家庭收入,并根据家庭规模占联邦贫困水平的百分比进行了调整。 主要结果和测量指标是:儿童的皮质表面积,厚度和体积,通过磁共振成像获得。1年随访时,产妇使用儿童行为检查表报告内化和外化问题的结果。分析根据基线精神问题和社会人口学变量进行了调整,包括性别、种族和民族、父母教育水平和研究地点。本研究的结果表明:随着青春期早期的时间推移,儿童贫困与外化问题的增加有关,但与内化问题无关。这种联系是由许多大脑区域的皮质表面积减少所介导的。这些发现强调了潜在的神经生物学机制之间的联系,贫穷和外化问题的出现在青春期早期。
IF:10.500Q1 JAMA network open, 2022-11-01. DOI: 10.1001/jamanetworkopen.2022.44049 PMID: 36445708
Abstract:
Importance: Childhood poverty has been associated with increased internalizing and externalizing problems in adolescence, a period of peak onset for psychiatric problems. The underlying neural mechanisms remain unclear because longitudinal … >>>
Importance: Childhood poverty has been associated with increased internalizing and externalizing problems in adolescence, a period of peak onset for psychiatric problems. The underlying neural mechanisms remain unclear because longitudinal studies of poverty, brain structure, and changes in psychiatric symptoms are lacking.Objective: To examine whether structural differences in cortical regions mediate the association between household poverty and change in psychiatric symptoms in early adolescence.Design, Setting, and Participants: This longitudinal cohort study used baseline and 1-year follow-up data from the Adolescent Brain Cognitive Development Study. Children aged 9 to 10 years in the US were enrolled between September 1, 2016, and October 15, 2018. Data analysis was performed from August 13, 2021, to September 30, 2022.Exposures: Household poverty as measured by income-to-needs ratio, which incorporates family income and adjusts for family size as a percentage of the federal poverty level.Main Outcomes and Measures: Mediators were children's cortical surface area, thickness, and volume, obtained using magnetic resonance imaging. Internalizing and externalizing problems at 1-year follow-up were outcomes measured by maternal report using the Child Behavior Checklist. Analyses were adjusted for baseline psychiatric problems and sociodemographic variables, including sex, race and ethnicity, parental educational level, and study site.Results: Of the 7569 children (mean [SD] age, 9.91 [0.62] years; 3970 boys [52.5%]) included in the analysis, 1042 children (13.8%) lived below the poverty threshold between 2016 and 2018. Poverty was associated with increased externalizing symptoms score at 1-year follow-up (b = 1.57; 95% CI, 1.14-1.99), even after adjustment for baseline externalizing symptoms (b = 0.35; 95% CI, 0.06-0.64). The longitudinal associations of poverty with increases in externalizing problems over time were mediated by reductions in surface area in multiple cortical regions that support executive functioning (middle frontal gyrus), decision-making (lateral orbitofrontal cortex), visual processing (fusiform gyrus), auditory processing (transverse temporal gyrus), and emotion and language processing (superior temporal gyrus).Conclusions and Relevance: The findings of this study suggest that childhood poverty is associated with increases in externalizing problems, but not internalizing problems, over time in early adolescence. This association is mediated by reductions in cortical surface area across numerous brain regions. These findings highlight potential neurobiological mechanisms underlying the link between poverty and the emergence of externalizing problems during early adolescence. <<<
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