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An adhesion signaling axis involving Dystroglycan, β1-Integrin, and Cas adaptor proteins regulates the establishment of the cortical glial scaffold. 涉及Dystroglycon、β1-整合素和Cas衔接蛋白的粘附信号轴调节皮层神经胶质支架的建立。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-04 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pbio.3002212
Wenny Wong, Jason A Estep, Alyssa M Treptow, Niloofar Rajabli, Jennifer N Jahncke, Teresa Ubina, Kevin M Wright, Martin M Riccomagno

The mature mammalian cortex is composed of 6 architecturally and functionally distinct layers. Two key steps in the assembly of this layered structure are the initial establishment of the glial scaffold and the subsequent migration of postmitotic neurons to their final position. These processes involve the precise and timely regulation of adhesion and detachment of neural cells from their substrates. Although much is known about the roles of adhesive substrates during neuronal migration and the formation of the glial scaffold, less is understood about how these signals are interpreted and integrated within these neural cells. Here, we provide in vivo evidence that Cas proteins, a family of cytoplasmic adaptors, serve a functional and redundant role during cortical lamination. Cas triple conditional knock-out (Cas TcKO) mice display severe cortical phenotypes that feature cobblestone malformations. Molecular epistasis and genetic experiments suggest that Cas proteins act downstream of transmembrane Dystroglycan and β1-Integrin in a radial glial cell-autonomous manner. Overall, these data establish a new and essential role for Cas adaptor proteins during the formation of cortical circuits and reveal a signaling axis controlling cortical scaffold formation.

成熟的哺乳动物皮层由6层结构和功能不同的层组成。组装这种层状结构的两个关键步骤是神经胶质支架的初始建立和随后有丝分裂后神经元迁移到其最终位置。这些过程涉及精确和及时地调节神经细胞与其基质的粘附和分离。尽管人们对粘附底物在神经元迁移和神经胶质支架形成过程中的作用知之甚少,但对这些信号如何在这些神经细胞中被解释和整合却知之甚少。在这里,我们提供了体内证据,证明Cas蛋白是一个细胞质适配器家族,在皮层层压过程中发挥着功能性和冗余性作用。Cas三重条件敲除(Cas-TcKO)小鼠表现出严重的皮质表型,其特征是鹅卵石畸形。分子上位性和遗传学实验表明,Cas蛋白以放射状神经胶质细胞自主的方式作用于跨膜Dystroglycon和β1-整合素的下游。总之,这些数据确立了Cas衔接蛋白在皮层回路形成过程中的新的重要作用,并揭示了控制皮层支架形成的信号轴。
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引用次数: 0
FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo. FBXO7/ntc和USP30拮抗地设定了基础有丝分裂的泛素化阈值,并为体内Pink1磷酸化提供了目标。
IF 7.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-03 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pbio.3002244
Alvaro Sanchez-Martinez, Aitor Martinez, Alexander J Whitworth

Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.

对与遗传性帕金森病(PD)相关基因的功能分析揭示了致病机制的基本生物学过程。PARK15/FBXO7 基因突变会导致常染色体隐性帕金森病,而 FBXO7 已被证明能调节线粒体的稳态。我们研究了 FBXO7 与果蝇直向同源物 ntc 的功能同源性,并探讨了它在体内有丝分裂中的作用。我们发现,ntc突变体部分表型与Pink1和parkin突变体相似,而ntc的过表达会抑制parkin的表型。此外,ntc 可以通过促进线粒体蛋白的泛素化,以一种不依赖于 Pink1 和 parkin 的方式调节基础有丝分裂,而这种机制是去泛素化酶 USP30 所反对的。这种基础泛素化是 Pink1 介导的磷酸化的底物,磷酸化可触发应激诱导的有丝分裂。我们认为,FBXO7/ntc 与 USP30 平衡作用,为体内基础条件下的线粒体质量控制提供了一个检查点,并为治疗方法提供了一条新途径。
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引用次数: 0
A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3. 一个以前未被识别的大锥虫毒素超家族包括感觉神经元钙通道Cav2.3抑制剂。
IF 7.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-03 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pbio.3002217
Celeste M Hackney, Paula Flórez Salcedo, Emilie Mueller, Thomas Lund Koch, Lau D Kjelgaard, Maren Watkins, Linda G Zachariassen, Pernille Sønderby Tuelung, Jeffrey R McArthur, David J Adams, Anders S Kristensen, Baldomero Olivera, Rocio K Finol-Urdaneta, Helena Safavi-Hemami, Jens Preben Morth, Lars Ellgaard

Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.

动物毒液肽是生物医学探索中有价值的化合物。海洋锥蜗牛的毒液构成了一种特别丰富的肽毒素来源,称为锥毒素。在这里,我们确定了一种异常大的芋螺毒素Mu8.1的序列,它定义了一类新的芋螺蛋白,在进化上与众所周知的芋螺素ikots和2个以前没有描述的另外的芋螺蛋白酶类有关。重组Mu8.1的晶体结构显示出saposin样折叠,并显示出与con-ikot-ikot的结构相似性。功能研究表明,Mu8.1抑制了特定类别的小鼠体感背根神经节(DRG)神经元中的钙流入。当在多种重组表达的电压门控离子通道上测试时,Mu8.1显示出对R型(Cav2.3)钙通道的最高效力。来自Mu8.1敏感DRG神经元的Ca2+信号也被SNX-482抑制,SNX-482是一种已知的Cav2.3和电压门控K+(Kv4)通道的蜘蛛肽调节剂。我们的发现强调了Mu8.1作为识别和研究表达Cav2.3的神经元亚类的分子工具的潜力。重要的是,这项多学科研究展示了在很大程度上未被探索的大锥虫毒素组中揭示新结构和生物活性的潜力。
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引用次数: 0
Characterization of a novel interaction of the Nup159 nucleoporin with asymmetrically localized spindle pole body proteins and its link with autophagy. Nup159核通道蛋白与不对称定位纺锤极体蛋白的新相互作用及其与自噬的联系的表征。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-03 eCollection Date: 2023-08-01 DOI: 10.1371/journal.pbio.3002224
Inés García de Oya, Javier Manzano-López, Alejandra Álvarez-Llamas, María de la Paz Vázquez-Aroca, Cristina Cepeda-García, Fernando Monje-Casas

Both the spindle microtubule-organizing centers and the nuclear pore complexes (NPCs) are convoluted structures where many signaling pathways converge to coordinate key events during cell division. Interestingly, despite their distinct molecular conformation and overall functions, these structures share common components and collaborate in the regulation of essential processes. We have established a new link between microtubule-organizing centers and nuclear pores in budding yeast by unveiling an interaction between the Bfa1/Bub2 complex, a mitotic exit inhibitor that localizes on the spindle pole bodies, and the Nup159 nucleoporin. Bfa1/Bub2 association with Nup159 is reduced in metaphase to not interfere with proper spindle positioning. However, their interaction is stimulated in anaphase and assists the Nup159-dependent autophagy pathway. The asymmetric localization of Bfa1/Bub2 during mitosis raises the possibility that its interaction with Nup159 could differentially promote Nup159-mediated autophagic processes, which might be relevant for the maintenance of the replicative lifespan.

纺锤体微管组织中心和核孔复合体(NPC)都是复杂的结构,在细胞分裂过程中,许多信号通路汇聚在一起协调关键事件。有趣的是,尽管这些结构具有独特的分子构象和整体功能,但它们共享共同的成分,并在调节基本过程中相互协作。我们通过揭示Bfa1/Bub2复合物和Nup159核孔蛋白之间的相互作用,在出芽酵母的微管组织中心和核孔之间建立了新的联系。Bfa1/Bub2与Nup159的结合在中期减少,不会干扰主轴的正确定位。然而,它们的相互作用在后期受到刺激,并有助于Nup159依赖的自噬途径。Bfa1/Bub2在有丝分裂过程中的不对称定位增加了其与Nup159的相互作用可能不同地促进Nup159介导的自噬过程的可能性,这可能与维持复制寿命有关。
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引用次数: 0
Gene amplifications cause high-level resistance against albicidin in gram-negative bacteria. 基因扩增导致革兰氏阴性菌对白杆菌素产生高水平耐药性。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-01 DOI: 10.1371/journal.pbio.3002186
Mareike Saathoff, Simone Kosol, Torsten Semmler, Karsten Tedin, Nicole Dimos, Johannes Kupke, Maria Seidel, Fereshteh Ghazisaeedi, Micela Condor Jonske, Silver A Wolf, Benno Kuropka, Wojciech Czyszczoń, Dmitry Ghilarov, Stefan Grätz, Jonathan G Heddle, Bernhard Loll, Roderich D Süssmuth, Marcus Fulde

Antibiotic resistance is a continuously increasing concern for public healthcare. Understanding resistance mechanisms and their emergence is crucial for the development of new antibiotics and their effective use. The peptide antibiotic albicidin is such a promising candidate that, as a gyrase poison, shows bactericidal activity against a wide range of gram-positive and gram-negative bacteria. Here, we report the discovery of a gene amplification-based mechanism that imparts an up to 1000-fold increase in resistance levels against albicidin. RNA sequencing and proteomics data show that this novel mechanism protects Salmonella Typhimurium and Escherichia coli by increasing the copy number of STM3175 (YgiV), a transcription regulator with a GyrI-like small molecule binding domain that traps albicidin with high affinity. X-ray crystallography and molecular docking reveal a new conserved motif in the binding groove of the GyrI-like domain that can interact with aromatic building blocks of albicidin. Phylogenetic studies suggest that this resistance mechanism is ubiquitous in gram-negative bacteria, and our experiments confirm that STM3175 homologs can confer resistance in pathogens such as Vibrio vulnificus and Pseudomonas aeruginosa.

抗生素耐药性是公共卫生领域日益关注的问题。了解耐药机制及其出现对开发新抗生素及其有效使用至关重要。作为一种gyrase毒药,肽抗生素albicidin对多种革兰氏阳性和革兰氏阴性细菌显示出杀灭活性,是一种很有前途的候选药物。在这里,我们报告了一种基于基因扩增的机制的发现,该机制使对白孢杆菌素的抗性水平增加了1000倍。RNA测序和蛋白质组学数据表明,这种新机制通过增加STM3175 (YgiV)的拷贝数来保护鼠伤寒沙门氏菌和大肠杆菌,STM3175是一种转录调节剂,具有类似gyri的小分子结合结构域,可以高亲和力地捕获白孢杆菌素。x射线晶体学和分子对接揭示了gyri -样结构域结合槽中的一个新的保守基序,该基序可以与白柔霉素的芳香构建块相互作用。系统发育研究表明,这种耐药机制在革兰氏阴性菌中普遍存在,我们的实验证实,STM3175同源物可以在创伤弧菌和铜绿假单胞菌等病原体中赋予耐药性。
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引用次数: 2
Towards a post-pandemic future for global pathogen genome sequencing. 迈向大流行后全球病原体基因组测序的未来。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-01 DOI: 10.1371/journal.pbio.3002225
Jason T Ladner, Jason W Sahl

Pathogen genome sequencing has become a routine part of our response to active outbreaks of infectious disease and should be an important part of our preparations for future epidemics. In this Essay, we discuss the innovations that have enabled routine pathogen genome sequencing, as well as how genome sequences can be used to understand and control the spread of infectious disease. We also explore the impact of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic on the field of pathogen genomics and outline the challenges we must address to further improve the utility of pathogen genome sequencing in the future.

病原体基因组测序已经成为我们应对传染病活跃暴发的常规部分,应该成为我们为未来流行病做准备的重要组成部分。在这篇文章中,我们讨论了使常规病原体基因组测序成为可能的创新,以及基因组序列如何用于理解和控制传染病的传播。我们还探讨了严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)大流行对病原体基因组学领域的影响,并概述了未来我们必须解决的挑战,以进一步提高病原体基因组测序的实用性。
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引用次数: 1
Pseudomonas aeruginosa type IV pili actively induce mucus contraction to form biofilms in tissue-engineered human airways. 铜绿假单胞菌IV型菌毛在组织工程人体气道中积极诱导粘液收缩形成生物膜。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-01 DOI: 10.1371/journal.pbio.3002209
Tamara Rossy, Tania Distler, Lucas A Meirelles, Joern Pezoldt, Jaemin Kim, Lorenzo Talà, Nikolaos Bouklas, Bart Deplancke, Alexandre Persat

The opportunistic pathogen Pseudomonas aeruginosa causes antibiotic-recalcitrant pneumonia by forming biofilms in the respiratory tract. Despite extensive in vitro experimentation, how P. aeruginosa forms biofilms at the airway mucosa is unresolved. To investigate the process of biofilm formation in realistic conditions, we developed AirGels: 3D, optically accessible tissue-engineered human lung models that emulate the airway mucosal environment. AirGels recapitulate important factors that mediate host-pathogen interactions including mucus secretion, flow and air-liquid interface (ALI), while accommodating high-resolution live microscopy. With AirGels, we investigated the contributions of mucus to P. aeruginosa biofilm biogenesis in in vivo-like conditions. We found that P. aeruginosa forms mucus-associated biofilms within hours by contracting luminal mucus early during colonization. Mucus contractions facilitate aggregation, thereby nucleating biofilms. We show that P. aeruginosa actively contracts mucus using retractile filaments called type IV pili. Our results therefore suggest that, while protecting epithelia, mucus constitutes a breeding ground for biofilms.

机会致病菌铜绿假单胞菌通过在呼吸道形成生物膜而引起抗生素顽固性肺炎。尽管进行了大量的体外实验,铜绿假单胞菌如何在气道粘膜形成生物膜仍未解决。为了研究生物膜在现实条件下的形成过程,我们开发了airgel: 3D,光学可及的组织工程人体肺模型,模拟气道粘膜环境。气凝胶概述了介导宿主-病原体相互作用的重要因素,包括粘液分泌、流动和气液界面(ALI),同时适应高分辨率的活体显微镜。利用气凝胶,我们研究了黏液在活体条件下对铜绿假单胞菌生物膜生物形成的贡献。我们发现铜绿假单胞菌在定植早期通过收缩腔内粘液在数小时内形成黏液相关的生物膜。粘液收缩促进聚集,从而形成生物膜。我们表明,铜绿假单胞菌积极收缩粘液使用可收缩的细丝称为IV型菌毛。因此,我们的结果表明,在保护上皮细胞的同时,粘液构成了生物膜的滋生地。
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引用次数: 1
Lmo4 synergizes with Fezf2 to promote direct in vivo reprogramming of upper layer cortical neurons and cortical glia towards deep-layer neuron identities. Lmo4与Fezf2协同作用,直接在体内促进上层皮质神经元和皮层胶质向深层神经元身份的重编程。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-01 DOI: 10.1371/journal.pbio.3002237
Torsten Felske, Chiara Tocco, Sophie Péron, Kawssar Harb, Christian Alfano, Chiara Galante, Benedikt Berninger, Michèle Studer
In vivo direct neuronal reprogramming relies on the implementation of an exogenous transcriptional program allowing to achieve conversion of a particular neuronal or glial cell type towards a new identity. The transcription factor (TF) Fezf2 is known for its role in neuronal subtype specification of deep-layer (DL) subcortical projection neurons. High ectopic Fezf2 expression in mice can convert both upper-layer (UL) and striatal projection neurons into a corticofugal fate, even if at low efficiency. In this study, we show that Fezf2 synergizes with the nuclear co-adaptor Lmo4 to further enhance reprogramming of UL cortical pyramidal neurons into DL corticofugal neurons, at both embryonic and early postnatal stages. Reprogrammed neurons express DL molecular markers and project toward subcerebral targets, including thalamus, cerebral peduncle (CP), and spinal cord (SC). We also show that co-expression of Fezf2 with the reprogramming factors Neurog2 and Bcl2 in early postnatal mouse glia promotes glia-to-neuron conversion with partial hallmarks of DL neurons and with Lmo4 promoting further morphological complexity. These data support a novel role for Lmo4 in synergizing with Fezf2 during direct lineage conversion in vivo.
在体内,直接神经元重编程依赖于外源性转录程序的实施,允许实现特定神经元或胶质细胞类型向新身份的转换。转录因子(TF) Fezf2因其在深层(DL)皮层下投射神经元的神经元亚型规范中的作用而闻名。Fezf2在小鼠中的高异位表达可以将上层(UL)和纹状体投射神经元转化为皮质命运,即使效率很低。在这项研究中,我们发现Fezf2与核共接头Lmo4协同作用,在胚胎和出生后早期阶段进一步增强UL皮质锥体神经元向DL皮质神经元的重编程。重编程神经元表达DL分子标记,并向丘脑、脑脚(CP)和脊髓(SC)等脑下靶点投射。我们还发现,Fezf2与重编程因子Neurog2和Bcl2在出生后早期小鼠胶质细胞中的共表达可促进胶质细胞向神经元的转化,具有DL神经元的部分特征,而与Lmo4的共表达可进一步促进形态复杂性。这些数据支持Lmo4在体内直接谱系转化过程中与Fezf2协同作用的新作用。
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引用次数: 2
Music can be reconstructed from human auditory cortex activity using nonlinear decoding models. 利用非线性解码模型可以从人类听觉皮层的活动中重构音乐。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-01 DOI: 10.1371/journal.pbio.3002176
Ludovic Bellier, Anaïs Llorens, Déborah Marciano, Aysegul Gunduz, Gerwin Schalk, Peter Brunner, Robert T Knight

Music is core to human experience, yet the precise neural dynamics underlying music perception remain unknown. We analyzed a unique intracranial electroencephalography (iEEG) dataset of 29 patients who listened to a Pink Floyd song and applied a stimulus reconstruction approach previously used in the speech domain. We successfully reconstructed a recognizable song from direct neural recordings and quantified the impact of different factors on decoding accuracy. Combining encoding and decoding analyses, we found a right-hemisphere dominance for music perception with a primary role of the superior temporal gyrus (STG), evidenced a new STG subregion tuned to musical rhythm, and defined an anterior-posterior STG organization exhibiting sustained and onset responses to musical elements. Our findings show the feasibility of applying predictive modeling on short datasets acquired in single patients, paving the way for adding musical elements to brain-computer interface (BCI) applications.

音乐是人类体验的核心,但音乐感知背后的精确神经动力学仍然未知。我们分析了29名患者的独特颅内脑电图(iEEG)数据集,这些患者听了Pink Floyd的歌曲,并应用了先前在语音领域使用的刺激重建方法。我们成功地从直接神经录音中重建了可识别的歌曲,并量化了不同因素对解码精度的影响。结合编码和解码分析,我们发现右半球主导音乐感知,颞上回(STG)起主要作用,证明了一个新的颞上回亚区适应音乐节奏,并定义了一个对音乐元素表现出持续和开始反应的前后侧STG组织。我们的研究结果表明,在单个患者获得的短数据集上应用预测建模是可行的,为在脑机接口(BCI)应用程序中添加音乐元素铺平了道路。
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引用次数: 5
Leveraging type 1 diabetes human genetic and genomic data in the T1D knowledge portal. 利用T1D知识门户中的1型糖尿病人类遗传和基因组数据。
IF 9.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-08-01 DOI: 10.1371/journal.pbio.3002233
Parul Kudtarkar, Maria C Costanzo, Ying Sun, Dongkeun Jang, Ryan Koesterer, Josyf C Mychaleckyj, Uma Nayak, Suna Onengut-Gumuscu, Stephen S Rich, Jason A Flannick, Kyle J Gaulton, Noël P Burtt

To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.

为了解决将1型糖尿病(T1D)的遗传发现转化为机制洞察的挑战,我们开发了T1D知识门户(T1DKP),这是一个开放获取的资源,用于T1D的假设发展和靶点发现。
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引用次数: 1
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