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Serotonin modulates infraslow oscillation in the dentate gyrus during Non-REM sleep. 羟色胺调节非快速眼动睡眠期间齿状回的次低振荡
Pub Date : 2024-10-21 DOI: 10.1101/2023.05.12.540575
Gergely F Turi, Sasa Teng, Xinyue Chen, Emily Cy Lim, Carla Dias, Ruining Hu, Ruizhi Wang, Fenghua Zhen, Yueqing Peng

Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01 - 0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by 5-HT1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.

在不同的脑区和大脑状态下,神经元的同步活动被组织成具有不同频率和时域的神经元振荡。例如,海马的θ波、γ波和尖波振荡对于记忆的形成以及海马亚区与大脑皮层之间的交流至关重要。在这项研究中,我们利用电生理和光学成像工具研究了齿状回(DG)在睡眠-觉醒周期中的神经元活动。我们发现,在 NREM 睡眠期间,DG 中主要谷氨酸能细胞群的活动被组织成次低振荡(0.01 - 0.03 Hz)。尽管在清醒状态下,DG 被认为是一个稀疏活跃的网络,但我们发现,在 NREM 睡眠期间,50% 的颗粒细胞和约 25% 的苔藓细胞表现出更高的活性。进一步的实验发现,DG 的次低频振荡受到睡眠时节律性血清素释放的调节,血清素的振荡频率相同,但相位相反。对5-羟色胺受体的遗传操作显示,这种神经调节是由5-羟色胺1a受体介导的,而敲除这些受体会导致记忆受损。我们的研究结果为了解 5-HT 系统如何影响睡眠过程中的海马活动模式提供了新的机理。
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引用次数: 0
YAP-Driven Oral Epithelial Stem Cell Malignant Reprogramming at Single Cell Resolution. 在体内以单细胞分辨率将口腔上皮祖细胞直接重编程为癌症干细胞。
Pub Date : 2024-10-21 DOI: 10.1101/2023.07.24.550427
Farhoud Faraji, Sydney I Ramirez, Lauren Clubb, Kuniaki Sato, Valeria Burghi, Thomas S Hoang, Adam Officer, Paola Y Anguiano Quiroz, William Mg Galloway, Zbigniew Mikulski, Kate Medetgul-Ernar, Pauline Marangoni, Kyle B Jones, Alfredo A Molinolo, Kenneth Kim, Kanako Sakaguchi, Joseph A Califano, Quinton Smith, Alon Goren, Ophir D Klein, Pablo Tamayo, J Silvio Gutkind

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

肿瘤起始是肿瘤发生的第一步,在这一过程中,正常祖细胞经历了细胞命运转变为癌细胞的过程。大多数调查实体瘤致癌机制的研究都依赖于对已形成的恶性病变的分析,因此无法直接捕捉正常祖细胞重编程为癌细胞的过程。在这里,我们在基因工程系统中使用时空控制的癌基因表达,证明同时激活YAP和HPV E6-E7介导的抑制肿瘤途径足以将口腔上皮祖细胞(OEPCs)快速重编程为癌症干细胞(CSCs)。对这些新生 CSC 的单细胞分析揭示了驱动肿瘤发生的标志性转录程序。重要的是,这些富含癌干细胞的表达特征将正常组织与恶性头颈部肿瘤区分开来,并与患者存活率低有关。阐明OEPC到CSC重编程的内在机制可能会为阻止恶性前细胞转化为浸润性癌提供新的见解:YAP和HPV E6-E7将口腔上皮祖细胞重编程为癌症干细胞。摘要:YAP和HPV E6-E7将口腔上皮祖细胞重编程为癌症干细胞。单细胞分析揭示了肿瘤启动的转录结构。CSC转录程序将正常组织与癌细胞区分开来:
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引用次数: 0
Localized synthesis of molecular chaperones sustains neuronal proteostasis. 分子伴侣的局部合成维持神经元的蛋白稳定。
Pub Date : 2024-10-19 DOI: 10.1101/2023.10.03.560761
Celia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez-Comaduran, Morgane Verbrugghe, Jia Stella M Xu, Sandra Minotti, James Lynch, Jeetayu Biswas, Tad Wu, Heather Durham, Gene W Yeo, Maria Vera

Neurons are challenged to maintain proteostasis in neuronal projections, particularly with the physiological stress at synapses to support intercellular communication underlying important functions such as memory and movement control. Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. Using high-resolution fluorescent microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites, particularly more proximal regions, and increase this asymmetric localization following proteotoxic stress through microtubule-based transport from the soma. The most abundant chaperone mRNA in dendrites encodes the constitutive heat shock protein 70, HSPA8. Proteotoxic stress in cultured neurons, induced by inhibiting proteasome activity or inducing oxidative stress, enhanced transport of Hspa8 mRNAs to dendrites and the percentage of mRNAs engaged in translation on mono and polyribosomes. Knocking down the ALS-related protein Fused in Sarcoma (FUS) and a dominant mutation in the heterogenous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) impaired stress-mediated localization of Hspa8 mRNA to dendrites in cultured murine motor neurons and human iPSC-derived neurons, respectively, revealing the importance of these RNA-binding proteins in maintaining proteostasis. These results reveal the increased dendritic localization and translation of the constitutive HSP70 Hspa8 mRNA as a crucial neuronal stress response to uphold proteostasis and prevent neurodegeneration.

神经元在神经元投射中维持蛋白稳定受到挑战,特别是在突触处的生理压力下,以支持细胞间通信,这是记忆和运动控制等重要功能的基础。蛋白质稳定是通过调节蛋白质合成和降解以及伴侣辅助蛋白质折叠来维持的。使用高分辨率荧光显微镜,我们发现神经元将伴侣信使核糖核酸的一个子集定位到其树突,特别是更近端的区域,并在蛋白毒性应激后通过基于微管的胞体转运增加这种不对称定位。树突中最丰富的伴侣mRNA编码组成型热休克蛋白70,HSPA8。在培养的神经元中,通过抑制蛋白酶体活性或诱导氧化应激诱导的蛋白质毒性应激,增强了Hspa8信使核糖核酸向树突的转运,以及参与单核糖体和多核糖体翻译的信使核糖核酸的百分比。敲除肌萎缩侧索硬化症相关蛋白融合肉瘤(FUS)和异质核核糖核蛋白A2/B1(HNRNPA2B1)的显性突变分别损害了培养的小鼠运动神经元和人iPSC衍生神经元中Hspa8mRNA在树突上的应激介导定位,揭示了这些RNA结合蛋白在维持蛋白稳定中的重要性。这些结果揭示了组成型HSP70Hspa8mRNA的树突定位和翻译增加,这是维持蛋白稳定和防止神经退行性变的关键神经元应激反应。摘要:在神经元树突中定位伴侣信使核糖核酸是一种新的按需系统,可以在压力下维持蛋白稳定。
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引用次数: 0
Functional Localization of the Human Auditory and Visual Thalamus Using a Thalamic Localizer Functional Magnetic Resonance Imaging Task. 利用丘脑定位器功能磁共振成像任务对人类听觉和视觉丘脑进行功能定位
Pub Date : 2024-10-18 DOI: 10.1101/2024.04.28.591516
John C Williams, Philip N Tubiolo, Zu Jie Zheng, Eilon B Silver-Frankel, Dathy T Pham, Natalka K Haubold, Sameera K Abeykoon, Anissa Abi-Dargham, Guillermo Horga, Jared X Van Snellenberg

Functional magnetic resonance imaging (fMRI) of the auditory and visual sensory systems of the human brain is an active area of investigation in the study of human health and disease. The medial geniculate nucleus (MGN) and lateral geniculate nucleus (LGN) are key thalamic nuclei involved in the processing and relay of auditory and visual information, respectively, and are the subject of blood-oxygen-level-dependent (BOLD) fMRI studies of neural activation and functional connectivity in human participants. However, localization of BOLD fMRI signal originating from neural activity in MGN and LGN remains a technical challenge, due in part to the poor definition of boundaries of these thalamic nuclei in standard T1-weighted and T2-weighted magnetic resonance imaging sequences. Here, we report the development and evaluation of an auditory and visual sensory thalamic localizer (TL) fMRI task that produces participant-specific functionally-defined regions of interest (fROIs) of both MGN and LGN, using 3 Tesla multiband fMRI and a clustered-sparse temporal acquisition sequence, in less than 16 minutes of scan time. We demonstrate the use of MGN and LGN fROIs obtained from the TL fMRI task in standard resting-state functional connectivity (RSFC) fMRI analyses in the same participants. In RSFC analyses, we validated the specificity of MGN and LGN fROIs for signals obtained from primary auditory and visual cortex, respectively, and benchmark their performance against alternative atlas- and segmentation-based localization methods. The TL fMRI task and analysis code (written in Presentation and MATLAB, respectively) have been made freely available to the wider research community.

人脑听觉和视觉感觉系统的功能磁共振成像(fMRI)是人类健康和疾病研究中一个活跃的研究领域。内侧膝状核(MGN)和外侧膝状核(LGN)是丘脑的关键核团,分别参与听觉和视觉信息的处理和传递,是血氧水平依赖性(BOLD)fMRI 研究的对象,用于研究人类参与者的神经激活和功能连接。然而,源于 MGN 和 LGN 神经活动的 BOLD fMRI 信号的定位仍然是一项技术挑战,部分原因是这些丘脑核在标准 T1 加权和 T2 加权磁共振成像序列中的边界界定不清。在此,我们报告了听觉和视觉丘脑定位器 (TL) fMRI 任务的开发和评估情况,该任务使用 3 特斯拉多波段 fMRI 和聚类稀疏时间采集序列,在不到 16 分钟的扫描时间内产生了 MGN 和 LGN 参与者特定功能定义的感兴趣区 (fROIs)。我们演示了如何将从 TL fMRI 任务中获得的 MGN 和 LGN fROIs 用于同一参与者的标准静息态功能连接 (RSFC) fMRI 分析。在 RSFC 分析中,我们验证了 MGN 和 LGN fROIs 对分别从初级听觉皮层和视觉皮层获得的信号的特异性,并将其性能与其他基于图谱和分割的定位方法进行了比较。TL fMRI 任务和分析代码(分别用 Presentation 和 MATLAB 编写)已免费提供给更广泛的研究团体。
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引用次数: 0
Hierarchical motion perception as causal inference. 层次运动知觉作为因果推理。
Pub Date : 2024-10-18 DOI: 10.1101/2023.11.18.567582
Sabyasachi Shivkumar, Gregory C DeAngelis, Ralf M Haefner

Since motion can only be defined relative to a reference frame, which reference frame guides perception? A century of psychophysical studies has produced conflicting evidence: retinotopic, egocentric, world-centric, or even object-centric. We introduce a hierarchical Bayesian model mapping retinal velocities to perceived velocities. Our model mirrors the structure in the world, in which visual elements move within causally connected reference frames. Friction renders velocities in these reference frames mostly stationary, formalized by an additional delta component (at zero) in the prior. Inverting this model automatically segments visual inputs into groups, groups into supergroups, etc. and "perceives" motion in the appropriate reference frame. Critical model predictions are supported by two new experiments, and fitting our model to the data allows us to infer the subjective set of reference frames used by individual observers. Our model provides a quantitative normative justification for key Gestalt principles providing inspiration for building better models of visual processing in general.

既然运动只能相对于一个参考系来定义,那么哪个参考系指导感知呢?一个世纪的心理物理学研究产生了相互矛盾的证据:视网膜中心、自我中心、世界中心,甚至是客体中心。我们引入了一个层次贝叶斯模型,将视网膜速度映射到感知速度。我们的模型反映了世界的结构,其中视觉元素在因果关联的参考框架内移动。摩擦使得这些参考系中的速度大多是静止的,在先前的参考系中有一个额外的δ分量(在零处)。反过来,这个模型会自动将视觉输入分成组,组分成超组等,并在适当的参考框架中“感知”运动。两个新的实验支持了关键的模型预测,将我们的模型拟合到数据中使我们能够推断出个体观察者使用的主观参考框架集。我们的模型为格式塔的关键原则提供了定量的规范性论证,为建立更好的视觉处理模型提供了灵感。
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引用次数: 0
BIBSNet: A Deep Learning Baby Image Brain Segmentation Network for MRI Scans. BIBSNet:一个用于MRI扫描的深度学习婴儿图像大脑分割网络。
Pub Date : 2024-10-17 DOI: 10.1101/2023.03.22.533696
Timothy J Hendrickson, Paul Reiners, Lucille A Moore, Jacob T Lundquist, Begim Fayzullobekova, Anders J Perrone, Erik G Lee, Julia Moser, Trevor K M Day, Dimitrios Alexopoulos, Martin Styner, Omid Kardan, Taylor A Chamberlain, Anurima Mummaneni, Henrique A Caldas, Brad Bower, Sally Stoyell, Tabitha Martin, Sooyeon Sung, Ermias Fair, Kenevan Carter, Jonathan Uriarte-Lopez, Amanda R Rueter, Essa Yacoub, Monica D Rosenberg, Christopher D Smyser, Jed T Elison, Alice Graham, Damien A Fair, Eric Feczko

Objectives: Brain segmentation of infant magnetic resonance (MR) images is vitally important in studying developmental mental health and disease. The infant brain undergoes many changes throughout the first years of postnatal life, making tissue segmentation difficult for most existing algorithms. Here, we introduce a deep neural network BIBSNet (Baby and Infant Brain Segmentation Neural Network), an open-source, community-driven model that relies on data augmentation and a large sample size of manually annotated images to facilitate the production of robust and generalizable brain segmentations.

Experimental design: Included in model training and testing were MR brain images on 84 participants with an age range of 0-8 months (median postmenstrual ages of 13.57 months). Using manually annotated real and synthetic segmentation images, the model was trained using a 10-fold cross-validation procedure. Testing occurred on MRI data processed with the DCAN labs infant-ABCD-BIDS processing pipeline using segmentations produced from gold standard manual annotation, joint-label fusion (JLF), and BIBSNet to assess model performance.

Principal observations: Using group analyses, results suggest that cortical metrics produced using BIBSNet segmentations outperforms JLF segmentations. Additionally, when analyzing individual differences, BIBSNet segmentations perform even better.

Conclusions: BIBSNet segmentation shows marked improvement over JLF segmentations across all age groups analyzed. The BIBSNet model is 600x faster compared to JLF and can be easily included in other processing pipelines.

目的:婴儿磁共振(MR)图像的大脑分割在研究发育性心理健康和疾病方面至关重要。婴儿大脑在出生后的头几年经历了许多变化,这使得大多数现有算法难以进行组织分割。在这里,我们介绍了一个深度神经网络BIBSNet(婴儿和婴儿大脑分割神经网络),这是一个开源的社区驱动模型,依赖于数据增强和大量手动注释图像的样本量,以促进生成稳健和可推广的大脑分割。实验设计:模型训练和测试包括84名年龄在0-8个月(月经后中位年龄为13.57个月)的参与者的MR大脑图像。使用手动注释的真实和合成分割图像,使用10倍交叉验证程序对模型进行训练。使用金标准手动注释、联合标签融合(JLF)和BIBSNet生成的分割,对DCAN实验室婴儿ABCD BIDS处理管道处理的MRI数据进行测试,以评估模型性能。主要观察结果:使用组分析,结果表明使用BIBSNet分割产生的皮层指标优于JLF分割。此外,在分析个体差异时,BIBSNet分割的表现甚至更好。结论:在所分析的所有年龄组中,BIBSNet分割比JLF分割显示出显著的改进。与JLF相比,BIBSNet模型的速度快了600倍,并且可以很容易地包含在其他处理管道中。
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引用次数: 0
Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation. Desmosome突变影响肿瘤微环境以促进黑色素瘤增殖。
Pub Date : 2024-10-17 DOI: 10.1101/2023.09.19.558457
Maayan Baron, Mohita Tagore, Patrick Wall, Fan Zheng, Dalia Barkley, Itai Yanai, Jing Yang, Maija Kiuru, Richard M White, Trey Ideker

Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in >70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma cells. In further support of a microenvironmental origin, we find that desmosome gene knockdown in keratinocytes yields markedly increased proliferation of adjacent melanoma cells in keratinocyte/melanoma co-cultures. Similar increases in melanoma proliferation are observed in media preconditioned by desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.

Desmosome是一种跨膜蛋白复合物,有助于上皮和其他组织中的细胞-细胞粘附。在这里,我们报道了在人类癌症中桥粒频繁发生基因改变的发现,其中在皮肤黑色素瘤中发现的信号最强,超过70%的病例中桥粒发生突变。在原发性但非转移性黑色素瘤活检中,桥粒基因编码突变的负担与桥粒基因表达的强烈减少有关。空间转录组学分析表明,这些表达减少发生在微环境中的角质形成细胞中,而不是原发性黑色素瘤肿瘤细胞中。为了进一步支持微环境起源,我们发现角质形成细胞中桥粒的功能缺失敲除导致角质形成细胞/黑素细胞共培养物中相邻黑素细胞的增殖显著增加。因此,桥粒突变在邻近细胞中的逐渐积累可能为黑色素细胞的肿瘤转化提供条件。
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引用次数: 0
Predicting the effect of CRISPR-Cas9-based epigenome editing. 预测基于CRISPR-Cas9的表观基因组编辑的效果。
Pub Date : 2024-10-16 DOI: 10.1101/2023.10.03.560674
Sanjit Singh Batra, Alan Cabrera, Jeffrey P Spence, Jacob Goell, Selvalakshmi S Anand, Isaac B Hilton, Yun S Song

Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ~ 0.70 - 0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.

表观遗传学调控协调哺乳动物的转录,但它们之间的功能联系仍然难以捉摸。为了解决这个问题,我们在这里使用来自13种ENCODE细胞类型的表观基因组和转录组数据来训练机器学习模型,以预测组蛋白翻译后修饰(PTMs)的基因表达,对大多数样本实现了约0.70-0.79的转录组相关性。除了概括组蛋白PTM和表达模式之间的已知关联外,我们的模型预测,转录起始位点(TSS)附近的组蛋白亚基H3赖氨酸残基27(H3K27ac)的乙酰化显著增加了表达水平。为了通过实验验证这一预测,并研究H3K27ac的工程沉积与自然沉积如何不同地影响表达,我们将合成的dCas9-p300组蛋白乙酰转移酶系统应用于HEK293T细胞系中的8个基因。此外,为了促进模型构建,我们进行MNase-seq来绘制HEK293T中的全基因组核小体占有水平。我们观察到,我们的模型在准确排序基因对dCas9-p300系统的相对倍数变化方面表现良好;然而,与从其天然表观遗传学特征预测跨细胞类型的表达相比,它们对单个基因内倍数变化进行排序的能力明显减弱。我们的发现突出表明,需要更全面的基因组规模表观基因组编辑数据集,更好地了解表观基因组剪辑工具所做的实际修改,以及改进的因果模型,以便更好地从内源性细胞测量转移到扰动实验。这些改进加在一起将有助于理解和可预测地控制对人类健康产生影响的动态人类表观基因组。
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引用次数: 0
saseR: Juggling offsets unlocks RNA-seq tools for fast and Scalable differential usage, Aberrant Splicing and Expression Retrieval. saseR: Juggling offsets解锁RNA-seq工具,实现快速、可扩展的差异使用、异常剪接和表达检索。
Pub Date : 2024-10-16 DOI: 10.1101/2023.06.29.547014
Alexandre Segers, Jeroen Gilis, Mattias Van Heetvelde, Davide Risso, Elfride De Baere, Lieven Clement

RNA-seq data analysis relies on many different tools, each tailored to specific applications and coming with unique assumptions and restrictions. Indeed, tools for differential transcript usage, or diagnosing patients with rare diseases through splicing and expression outliers, either lack in performance, discard information, or do not scale to massive data compendia. Here, we show that replacing the normalisation offsets unlocks bulk RNA-seq workflows for scalable differential usage, aberrant splicing and expression analyses. Our method, saseR, is much faster than state-of-the-art methods, dramatically outperforms these to detect aberrant splicing, and provides a single workflow for various short- and long-read RNA-seq applications.

RNA-seq 数据分析依赖于许多不同的工具,每种工具都是为特定应用量身定制的,并带有独特的假设和限制。事实上,用于差异转录本使用或通过剪接和表达异常值诊断罕见疾病患者的工具要么性能不足,要么丢弃信息,要么无法扩展到海量数据集。在这里,我们展示了替换归一化偏移量可以解锁批量 RNA-seq 工作流,从而进行可扩展的差异使用、异常剪接和表达分析。我们的方法(saseR)比最先进的方法快得多,在检测异常剪接方面大大优于这些方法,并为各种短线程和长线程 RNA-seq 应用提供了单一的工作流程。
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引用次数: 0
Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A. 免疫球蛋白A对上皮细胞增殖和肿瘤发生的抑制作用。
Pub Date : 2024-10-16 DOI: 10.1101/2023.10.06.561290
Gregory P Donaldson, Gabriella L Reis, Marwa Saad, Christopher Wichmann, Izabela Mamede, Guo Chen, Nicole L DelGaudio, Dayu Zhang, Begüm Aydin, Caroline E Harrer, Tiago B R Castro, Sergei Grivennikov, Bernardo S Reis, Beth M Stadtmueller, Gabriel D Victora, Daniel Mucida

Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis 1 . Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function 2,3 with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities 4-8 . Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.

免疫球蛋白A(IgA)是哺乳动物中产生的最丰富的抗体同种型,在粘膜稳态中发挥特殊作用1。IgA不断分泌到肠腔中,与共生微生物群结合以调节其定植和功能2,3,对健康的影响尚不清楚。IgA缺乏症在人类中很常见,但由于其复杂的病因和合并症4-8,很难进行研究。使用基因和环境控制的小鼠,我们发现IgA缺乏的动物结肠上皮的基线改变增加了对多种癌症模型的易感性。基于转录组、成像和流式细胞术的分析表明,在缺乏IgA的情况下,结肠上皮细胞诱导抗菌因子,并加速细胞循环以响应微生物群。IgA的口服治疗足以抑制不依赖于细菌结合的异常上皮增殖,这表明IgA向上皮细胞提供反馈信号与其在微生物组形成中的已知作用平行。在原代结肠类器官培养系统中,IgA直接抑制上皮生长。相反,IgA缺乏小鼠对结直肠癌癌症的易感性通过抑制Notch以抑制可吸收的结肠细胞发育程序,或通过抑制细胞因子MIF逆转,细胞因子MIF的受体在IgA缺乏动物的干细胞中上调。这些研究证明了IgA在调节上皮对微生物群的生理反应以维持粘膜健康方面的稳态功能。
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引用次数: 0
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