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Parietal cortex is recruited by frontal and cingulate areas to support action monitoring and updating during stopping.
Pub Date : 2025-03-02 DOI: 10.1101/2025.02.28.640787
Jung Uk Kang, Layth Mattar, José Vergara, Victoria E Gobo, Hernan G Rey, Sarah R Heilbronner, Andrew J Watrous, Benjamin Y Hayden, Sameer A Sheth, Eleonora Bartoli

Recent evidence indicates that the intraparietal sulcus (IPS) may play a causal role in action stopping, potentially representing a novel neuromodulation target for inhibitory control dysfunctions. Here, we leverage intracranial recordings in human subjects to establish the timing and directionality of information flow between IPS and prefrontal and cingulate regions during action stopping. Prior to successful inhibition, information flows primarily from the inferior frontal gyrus (IFG), a critical inhibitory control node, to IPS. In contrast, during stopping errors the communication between IPS and IFG is lacking, and IPS is engaged by posterior cingulate cortex, an area outside of the classical inhibition network and typically associated with default mode. Anterior cingulate and orbitofrontal cortex also display performance-dependent connectivity with IPS. Our functional connectivity results provide direct electrophysiological evidence that IPS is recruited by frontal and anterior cingulate areas to support action plan monitoring/updating, and by posterior cingulate during control failures.

In brief: Functional connectivity between the intraparietal sulcus (IPS) and a set of frontal and cingulate regions indicates that IPS is recruited to aid inhibitory control. Control failures are associated with increased communication with posterior cingulate. IPS could be a novel and tractable neuromodulation target for control-related neuropsychiatric disorders.

Highlights: Parietal cortex displays performance-dependent activity in action stoppingFunctional connectivity between IPS and IFG underlies successful stoppingEarly communication from ACC and OFC to IPS is also specific to successful stoppingCommunication from PCC to IPS is higher during lapses in control.

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引用次数: 0
The phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages.
Pub Date : 2025-03-02 DOI: 10.1101/2025.02.27.640612
Henry Yi Cheng, Jiachen Chu, Nathachit Limjunyawong, Jianan Chen, Yingzhi Ye, Kevin Hong Chen, Nicholas Koylass, Shuying Sun, Xinzhong Dong, Zhaozhu Qiu

Phagosome degradation is an evolutionally conserved and highly effective innate immune response against pathogen infections. The success of this process relies on the ability of phagocytes to regulate the maturation of phagosomes. However, the underlying molecular mechanisms and its roles in shaping downstream immune activation remain poorly understood. Here, we identify the proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion enhanced phagosomal acidification and protease activities, leading to augmented bacterial killing in large peritoneal macrophages (LPMs) upon peritoneal Escherichia coli infection in mice. Surprisingly, phagosome bacterial degradation also stimulated STING-IRF3-interferon responses and inflammasome activation in LPMs, both of which are enhanced upon PAC deletion. The increased inflammasome activation and pyroptosis induced an unexpected release of cleaved gasdermin D, which localized to the surface of bacteria in the peritoneum and further contributed to their killing. Finally, enhanced bacterial clearance by PAC-deficient LPMs reduced proinflammatory immune cell infiltration and overall peritoneal inflammation, resulting in improved survival in mice. Our study thus provides new insights into the molecular mechanism of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation in peritoneal macrophages. It also highlights the potential of targeting the PAC channel as a therapeutic strategy for treating bacterial infections.

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引用次数: 0
Shifted balance between ventral striatal prodynorphin and proenkephalin biases development of cocaine place avoidance.
Pub Date : 2025-03-02 DOI: 10.1101/2025.02.28.640871
Amélia Nicot, Pavankumar Yecham, Ilana Serin, David J Barker, Lauren K Dobbs

Evidence from human self-report and rodent models indicate cocaine can induce a negative affective state marked by panic and anxiety, which may reduce future cocaine use or promote co-use with opiates. Dynorphin-mediated signaling within the striatum is associated with negative affect following cocaine withdrawal and stress-induced cocaine seeking. Here, we used a trace conditioning procedure to first establish the optimum parameters to capture this transient cocaine negative affective state in wild type mice, then we investigated striatal opioid peptides as a substrate mediating cocaine conditioned place avoidance (CPA). Previous reports indicate that trace conditioning, where drug administration occurs after removal from the conditioning chamber, results in CPA to ethanol, nicotine, and amphetamine. We tested different cocaine doses, conditioning session lengths, and apparatus types, to determine which combination yields the best cocaine CPA. Cocaine CPA was moderately larger at the highest cocaine dose (25 mg/kg), but this did not generalize across apparatus types and the effect was transient, thus data were collapsed across all parameters. Cocaine conditioning scores were variable, but also became more polarized across conditioning, with approximately equal proportions developing preference and avoidance. We then correlated cocaine CPA with striatal gene expression levels of the opioid peptides enkephalin ( Penk ) and dynorphin ( Pdyn ) using qPCR. Cocaine CPA was correlated with low Pdyn levels and a low Pdyn : Penk ratio in the ventral, but not dorsal, striatum. Consistent with this, mice with higher striatal Pdyn relative to Penk were more resistant to developing cocaine CPA compared to littermate controls. This approach revealed a subset of subjects sensitive to the aversive state immediately following cocaine administration. Our findings suggest striatal dynorphin has opposing roles in mediating the aversion associated with acute cocaine intoxication versus cocaine withdrawal.

来自人类自我报告和啮齿动物模型的证据表明,可卡因会诱发以恐慌和焦虑为特征的负面情绪状态,这可能会减少可卡因的未来使用或促进与鸦片制剂的共同使用。纹状体内由吗啡素介导的信号传导与可卡因戒断后的负性情绪和应激诱导的可卡因寻求有关。在这里,我们使用痕量调节程序首先确定了捕捉野生型小鼠这种短暂的可卡因负性情绪状态的最佳参数,然后研究了纹状体阿片肽作为可卡因条件性场所回避(CPA)的介导底物。以前的报告表明,痕量条件反射(即在从条件反射室移出后施用药物)会导致对乙醇、尼古丁和苯丙胺的条件性回避(CPA)。我们测试了不同的可卡因剂量、条件反射时间长度和仪器类型,以确定哪种组合能产生最佳的可卡因CPA。可卡因最高剂量(25 毫克/千克)时,可卡因 CPA 会适度增大,但这并不会在不同仪器类型之间产生普遍影响,而且这种影响是短暂的,因此我们对所有参数的数据进行了合并。可卡因条件反射的得分是可变的,但在不同条件反射中也变得更加两极化,产生偏好和回避的比例大致相同。然后,我们利用 qPCR 将可卡因 CPA 与纹状体中阿片肽脑啡肽(Penk)和达因啡肽(Pdyn)的基因表达水平相关联。可卡因 CPA 与腹侧纹状体中低 Pdyn 水平和低 Pdyn : Penk 比率相关,而与背侧纹状体无关。与此相符的是,与同卵对照组相比,纹状体 Pdyn 相对于 Penk 较高的小鼠对可卡因 CPA 的发生更有抵抗力。这种方法揭示了对可卡因给药后立即出现的厌恶状态敏感的受试者子集。我们的研究结果表明,纹状体达诺啡在介导与急性可卡因中毒相关的厌恶和可卡因戒断中起着相反的作用。
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引用次数: 0
Rational design of next-generation filovirus vaccines with glycoprotein stabilization, nanoparticle display, and glycan modification.
Pub Date : 2025-03-02 DOI: 10.1101/2025.03.02.641072
Yi-Zong Lee, Yi-Nan Zhang, Maddy L Newby, Garrett Ward, Keegan Braz Gomes, Sarah Auclair, Connor DesRoberts, Joel D Allen, Andrew B Ward, Robyn L Stanfield, Linling He, Max Crispin, Ian A Wilson, Jiang Zhu

Filoviruses pose a significant threat to human health with frequent outbreaks and high mortality. Although two vector-based vaccines are available for Ebola virus, a broadly protective filovirus vaccine remains elusive. In this study, we evaluate a general strategy for stabilizing glycoprotein (GP) structures of Ebola, Sudan, and Bundibugyo ebolaviruses and Ravn marburgvirus. A 3.2 Å- resolution crystal structure provides atomic details for the redesigned Ebola virus GP, and cryo- electron microscopy reveals how a pan-ebolavirus neutralizing antibody targets a conserved site on the Sudan virus GP (3.13 Å-resolution), in addition to a low-resolution model of antibody- bound Ravn virus GP. A self-assembling protein nanoparticle (SApNP), I3-01v9, is redesigned at the N-terminus to allow the optimal surface display of filovirus GP trimers. Following detailed in vitro characterization, the lymph node dynamics of Sudan virus GP and GP-presenting SApNPs are investigated in a mouse model. Compared with soluble GP trimer, SApNPs show ∼112 times longer retention in lymph node follicles, up-to-28 times greater presentation on follicular dendritic cell dendrites, and up-to-3 times stronger germinal center reactions. Functional antibody responses induced by filovirus GP trimers and SApNPs bearing wildtype and modified glycans are assessed in mice. Our study provides a foundation for next-generation filovirus vaccine development.

One-sentence summary: Filovirus glycoproteins and nanoparticles were rationally designed and characterized in vitro and in vivo to aid filovirus vaccine development.

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引用次数: 0
Heart Scar-In-A-Dish: Tissue Culture Platform to Study Myocardial Infarct Healing In Vitro.
Pub Date : 2025-03-02 DOI: 10.1101/2025.02.28.640625
M J Potter, J D Heywood, S J Coeyman, W J Richardson

Myocardial Infarction (MI) is a major contributor to morbidity and mortality, wherein blood flow is blocked to a portion of the left ventricle and leads to myocardial necrosis and scar formation. Cardiac remodeling in response to MI is a major determinant of patient prognosis, so many therapies are under development to improve infarct healing. Part of this development involves in vitro therapy screening which can be accelerated by engineered heart tissues (EHTs). Unfortunately, EHTs often over-simplify the infarcted tissue microarchitecture by neglecting spatial variation found in infarcted ventricles. MI results in a spatially heterogeneous environment with an infarct zone composed mostly of extracellular matrix (ECM) and cardiac fibroblasts, contrasted with a remote (non-infarct) zone composed mostly of cardiomyocytes, and a border zone transitioning in between. The heterogeneous structure is accompanied by heterogeneous mechanics where the passive infarct zone is cyclically stretched under tension as the remote zone cyclically contracts with every heartbeat. We present an in vitro 3-dimensional tissue culture platform focused on mimicking the heterogeneous mechanical environment of post-infarct myocardium. Herein, EHTs were subjected to a cryowound injury to induce localized cell death in a central portion of beating tissues composed of neonatal rat cardiomyocytes and cardiac fibroblasts. After injury, the remote zone continued to contract (i.e., negative strains) while the wounded zone was cyclically stretched (i.e., positive tensile strains) with intermediate strains in the border zone. We also observed increased tissue stiffnesses in the wounded zone and border zone following injury, while the remote zone did not show the same stiffening. Collectively, this work establishes a novel in vitro platform for characterizing myocardial wound remodeling with both spatial and temporal resolution, contributing to a deeper understanding of MI and offering insights for potential therapeutic approaches.

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引用次数: 0
Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.
Pub Date : 2025-03-02 DOI: 10.1101/2025.02.27.640500
Lathan Lucas, Phoebe S Tsoi, My Diem Quan, Kyoung-Jae Choi, Josephine C Ferreon, Allan Chris M Ferreon

Proteins phase-separate to form condensates that partition and concentrate biomolecules into membraneless compartments. These condensates can exhibit dichotomous behaviors in biology by supporting cellular physiology or instigating pathological protein aggregation 1-3 . Tau and α- synuclein (αSyn) are neuronal proteins that form heterotypic (Tau:αSyn) condensates associated with both physiological and pathological processes. Tau and αSyn functionally regulate microtubules 8-12 , but are also known to misfold and co-deposit in aggregates linked to various neurodegenerative diseases 4,5,6,7 , which highlights the paradoxically ambivalent effect of Tau:αSyn condensation in health and disease. Here, we show that tubulin modulates Tau:αSyn condensates by promoting microtubule interactions, competitively inhibiting the formation of homotypic and heterotypic pathological oligomers. In the absence of tubulin, Tau-driven protein condensation accelerates the formation of toxic Tau:αSyn heterodimers and amyloid fibrils. However, tubulin partitioning into Tau:αSyn condensates modulates protein interactions, promotes microtubule polymerization, and prevents Tau and αSyn oligomerization and aggregation. We distinguished distinct Tau and αSyn structural states adopted in tubulin-absent (pathological) and tubulin-rich (physiological) condensates, correlating compact conformations with aggregation and extended conformations with function. Furthermore, using various neuronal cell models, we showed that loss of stable microtubules, which occurs in Alzheimer's disease and Parkinsons disease patients 13,14 , results in pathological oligomer formation and loss of neurites, and that functional condensation using an inducible optogenetic Tau construct resulted in microtubule stablization. Our results identify that tubulin is a critical modulator in switching Tau:αSyn pathological condensates to physiological, mechanistically relating the loss of stable microtubules with disease progression. Tubulin restoration strategies and Tau-mediated microtubule stabilization can be potential therapies targeting both Tau-specific and Tau/αSyn mixed pathologies.

蛋白质相分离形成凝聚物,将生物分子分隔并集中到无膜区块中。这些凝聚物在生物学中可表现出两种不同的行为,即支持细胞生理学或引发病理性蛋白质聚集1-3。Tau 和 α- 突触核蛋白(αSyn)是神经元蛋白质,它们形成的异型(Tau:αSyn)凝聚物与生理和病理过程都有关联。Tau 和 αSyn 具有调节微管的功能 8-12 ,但已知它们也会折叠错误并共同沉积在与各种神经退行性疾病相关的聚集体中 4,5,6,7,这突显了 Tau:αSyn 凝聚在健康和疾病中的矛盾作用。在这里,我们发现,微管蛋白通过促进微管相互作用来调节 Tau:αSyn 缩聚物,竞争性地抑制同型和异型病理低聚物的形成。在缺乏微管蛋白的情况下,Tau 驱动的蛋白质凝聚会加速有毒的 Tau:αSyn 异二聚体和淀粉样纤维的形成。然而,将微管蛋白分配到Tau:αSyn缩聚物中可调节蛋白质相互作用,促进微管聚合,并防止Tau和αSyn寡聚和聚集。我们区分了Tau和αSyn在缺乏微管蛋白(病理)和富含微管蛋白(生理)的凝聚体中的不同结构状态,并将紧密构象与聚集和扩展构象与功能联系起来。此外,我们还利用各种神经元细胞模型表明,阿尔茨海默病和帕金森病患者13,14 丧失稳定的微管会形成病理性寡聚体并丧失神经元,而利用诱导性光遗传 Tau 构建物进行功能性缩聚会导致微管稳定。我们的研究结果表明,微管蛋白是将 Tau:αSyn 病理缩聚物转变为生理缩聚物的关键调节因子,从机理上讲,稳定微管的丧失与疾病进展有关。微管蛋白恢复策略和Tau介导的微管稳定可成为针对Tau特异性和Tau/αSyn混合病理的潜在疗法。
{"title":"Tubulin transforms Tau and α-synuclein condensates from pathological to physiological.","authors":"Lathan Lucas, Phoebe S Tsoi, My Diem Quan, Kyoung-Jae Choi, Josephine C Ferreon, Allan Chris M Ferreon","doi":"10.1101/2025.02.27.640500","DOIUrl":"10.1101/2025.02.27.640500","url":null,"abstract":"<p><p>Proteins phase-separate to form condensates that partition and concentrate biomolecules into membraneless compartments. These condensates can exhibit dichotomous behaviors in biology by supporting cellular physiology or instigating pathological protein aggregation <sup>1-3</sup> . Tau and α- synuclein (αSyn) are neuronal proteins that form heterotypic (Tau:αSyn) condensates associated with both physiological and pathological processes. Tau and αSyn functionally regulate microtubules <sup>8-12</sup> , but are also known to misfold and co-deposit in aggregates linked to various neurodegenerative diseases <sup>4,5,6,7</sup> , which highlights the paradoxically ambivalent effect of Tau:αSyn condensation in health and disease. Here, we show that tubulin modulates Tau:αSyn condensates by promoting microtubule interactions, competitively inhibiting the formation of homotypic and heterotypic pathological oligomers. In the absence of tubulin, Tau-driven protein condensation accelerates the formation of toxic Tau:αSyn heterodimers and amyloid fibrils. However, tubulin partitioning into Tau:αSyn condensates modulates protein interactions, promotes microtubule polymerization, and prevents Tau and αSyn oligomerization and aggregation. We distinguished distinct Tau and αSyn structural states adopted in tubulin-absent (pathological) and tubulin-rich (physiological) condensates, correlating compact conformations with aggregation and extended conformations with function. Furthermore, using various neuronal cell models, we showed that loss of stable microtubules, which occurs in Alzheimer's disease and Parkinsons disease patients <sup>13,14</sup> , results in pathological oligomer formation and loss of neurites, and that functional condensation using an inducible optogenetic Tau construct resulted in microtubule stablization. Our results identify that tubulin is a critical modulator in switching Tau:αSyn pathological condensates to physiological, mechanistically relating the loss of stable microtubules with disease progression. Tubulin restoration strategies and Tau-mediated microtubule stabilization can be potential therapies targeting both Tau-specific and Tau/αSyn mixed pathologies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
2Danalysis: A toolbox for analysis of lipid membranes and biopolymers in two-dimensional space.
Pub Date : 2025-03-02 DOI: 10.1101/2025.02.27.640563
Ricardo X Ramirez, Antonio M Bosch, Ruben Perez, Horacio V Guzman, Viviana Monje

Molecular simulations expand our ability to learn about the interplay of biomolecules. Biological membranes, composed of diverse lipids with varying physicochemical properties, are highly dynamic environments involved in cellular functions. Proteins, nucleic acids, glycans and bio-compatible polymers are the machinery of cellular processes both in the cytosol and at the lipid membrane interface. Lipid species directly modulate membrane properties, and affect the interaction and function of other biomolecules. Natural molecular diffusion results in changes of local lipid distribution, affecting the membrane properties. Projecting biophysical and structural membrane and biopolymer properties to a two-dimensional plane can be beneficial to quantify molecular signatures in a reduced dimensional space to identify relevant interactions at the interface of interest, i.e. the membrane surface or biopolymer-surface interface. Here, we present a toolbox designed to project membrane and biopolymer properties to a two-dimensional plane to characterize patterns of interaction and spatial correlations between lipid-lipid and lipid-biopolymer interfaces. The toolbox contains two hubs implemented using MDAKits architecture, one for membranes and one for biopolymers, that can be used independently or together. Three case studies demonstrate the versatility of the toolbox with detailed tutorials in GitHub. The toolbox and tutorials will be periodically updated with other functionalities and resolutions to expand our understanding of the structure-function relationship of biomolecules in two-dimensions.

{"title":"2Danalysis: A toolbox for analysis of lipid membranes and biopolymers in two-dimensional space.","authors":"Ricardo X Ramirez, Antonio M Bosch, Ruben Perez, Horacio V Guzman, Viviana Monje","doi":"10.1101/2025.02.27.640563","DOIUrl":"10.1101/2025.02.27.640563","url":null,"abstract":"<p><p>Molecular simulations expand our ability to learn about the interplay of biomolecules. Biological membranes, composed of diverse lipids with varying physicochemical properties, are highly dynamic environments involved in cellular functions. Proteins, nucleic acids, glycans and bio-compatible polymers are the machinery of cellular processes both in the cytosol and at the lipid membrane interface. Lipid species directly modulate membrane properties, and affect the interaction and function of other biomolecules. Natural molecular diffusion results in changes of local lipid distribution, affecting the membrane properties. Projecting biophysical and structural membrane and biopolymer properties to a two-dimensional plane can be beneficial to quantify molecular signatures in a reduced dimensional space to identify relevant interactions at the interface of interest, i.e. the membrane surface or biopolymer-surface interface. Here, we present a toolbox designed to project membrane and biopolymer properties to a two-dimensional plane to characterize patterns of interaction and spatial correlations between lipid-lipid and lipid-biopolymer interfaces. The toolbox contains two hubs implemented using MDAKits architecture, one for membranes and one for biopolymers, that can be used independently or together. Three case studies demonstrate the versatility of the toolbox with detailed tutorials in GitHub. The toolbox and tutorials will be periodically updated with other functionalities and resolutions to expand our understanding of the structure-function relationship of biomolecules in two-dimensions.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Smoothie: Efficient Inference of Spatial Co-expression Networks from Denoised Spatial Transcriptomics Data.
Pub Date : 2025-03-02 DOI: 10.1101/2025.02.26.640406
Chase Holdener, Iwijn De Vlaminck

Finding correlations in spatial gene expression is fundamental in spatial transcriptomics, as co-expressed genes within a tissue are linked by regulation, function, pathway, or cell type. Yet, sparsity and noise in spatial transcriptomics data pose significant analytical challenges. Here, we introduce Smoothie, a method that denoises spatial transcriptomics data with Gaussian smoothing and constructs and integrates genome-wide co-expression networks. Utilizing implicit and explicit parallelization, Smoothie scales to datasets exceeding 100 million spatially resolved spots with fast run times and low memory usage. We demonstrate how co-expression networks measured by Smoothie enable precise gene module detection, functional annotation of uncharacterized genes, linkage of gene expression to genome architecture, and multi-sample comparisons to assess stable or dynamic gene expression patterns across tissues, conditions, and time points. Overall, Smoothie provides a scalable and versatile framework for extracting deep biological insights from high-resolution spatial transcriptomics data.

{"title":"Smoothie: Efficient Inference of Spatial Co-expression Networks from Denoised Spatial Transcriptomics Data.","authors":"Chase Holdener, Iwijn De Vlaminck","doi":"10.1101/2025.02.26.640406","DOIUrl":"10.1101/2025.02.26.640406","url":null,"abstract":"<p><p>Finding correlations in spatial gene expression is fundamental in spatial transcriptomics, as co-expressed genes within a tissue are linked by regulation, function, pathway, or cell type. Yet, sparsity and noise in spatial transcriptomics data pose significant analytical challenges. Here, we introduce Smoothie, a method that denoises spatial transcriptomics data with Gaussian smoothing and constructs and integrates genome-wide co-expression networks. Utilizing implicit and explicit parallelization, Smoothie scales to datasets exceeding 100 million spatially resolved spots with fast run times and low memory usage. We demonstrate how co-expression networks measured by Smoothie enable precise gene module detection, functional annotation of uncharacterized genes, linkage of gene expression to genome architecture, and multi-sample comparisons to assess stable or dynamic gene expression patterns across tissues, conditions, and time points. Overall, Smoothie provides a scalable and versatile framework for extracting deep biological insights from high-resolution spatial transcriptomics data.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Formaldehyde Exposure Induces Systemic Epigenetic Alterations in Histone Methylation and Acetylation.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.25.640236
Jiahao Feng, Chih-Wei Liu, Jingya Peng, Yun-Chung Hsiao, Danqi Chen, Chunyuan Jin, Kun Lu

Formaldehyde (FA) is a pervasive environmental organic pollutant and a Group 1 human carcinogen. While FA has been implicated in various cancers, its genotoxic effects, including DNA damage and DNA-protein crosslinking, have proven insufficient to fully explain its role in carcinogenesis, suggesting the involvement of epigenetic mechanisms. Histone post-translational modifications (PTMs) on H3 and H4, critical for regulating gene expression, may contribute to FA-induced pathogenesis as lysine and arginine residues serve as targets for FA-protein adduct formation. This study aimed to elucidate the effects of FA on histone methylation and acetylation patterns. Human bronchial epithelial cells (BEAS-2B) were exposed to low-dose (100 μM) and high-dose (500 μM) FA for 1 hour, and their histone extracts were analyzed using high-resolution liquid chromatography-tandem mass spectrometry-based proteomics, followed by PTM-combined peptide analysis and single PTM site/type comparisons. We identified 40 peptides on histone H3 and 16 on histone H4 bearing epigenetic marks. Our findings revealed that FA exposure induced systemic alterations in H3 and H4 methylation and acetylation, including hypomethylation of H3K4 and H3K79 and changes in H3K9, H3K14, H3K18, H3K23, H3K27, H3K36, H3K37, and H3R40, as well as modifications in H4K5, H4K8, H4K12, and H4K16. These FA-induced histone modifications exhibited strong parallels with epigenetic alterations observed in cancers, leukemia, and Alzheimer's disease. This study provides novel evidence of FA epigenetic toxicity, offering new insights into the potential mechanisms underlying FA-driven pathogenesis.

{"title":"Formaldehyde Exposure Induces Systemic Epigenetic Alterations in Histone Methylation and Acetylation.","authors":"Jiahao Feng, Chih-Wei Liu, Jingya Peng, Yun-Chung Hsiao, Danqi Chen, Chunyuan Jin, Kun Lu","doi":"10.1101/2025.02.25.640236","DOIUrl":"10.1101/2025.02.25.640236","url":null,"abstract":"<p><p>Formaldehyde (FA) is a pervasive environmental organic pollutant and a Group 1 human carcinogen. While FA has been implicated in various cancers, its genotoxic effects, including DNA damage and DNA-protein crosslinking, have proven insufficient to fully explain its role in carcinogenesis, suggesting the involvement of epigenetic mechanisms. Histone post-translational modifications (PTMs) on H3 and H4, critical for regulating gene expression, may contribute to FA-induced pathogenesis as lysine and arginine residues serve as targets for FA-protein adduct formation. This study aimed to elucidate the effects of FA on histone methylation and acetylation patterns. Human bronchial epithelial cells (BEAS-2B) were exposed to low-dose (100 μM) and high-dose (500 μM) FA for 1 hour, and their histone extracts were analyzed using high-resolution liquid chromatography-tandem mass spectrometry-based proteomics, followed by PTM-combined peptide analysis and single PTM site/type comparisons. We identified 40 peptides on histone H3 and 16 on histone H4 bearing epigenetic marks. Our findings revealed that FA exposure induced systemic alterations in H3 and H4 methylation and acetylation, including hypomethylation of H3K4 and H3K79 and changes in H3K9, H3K14, H3K18, H3K23, H3K27, H3K36, H3K37, and H3R40, as well as modifications in H4K5, H4K8, H4K12, and H4K16. These FA-induced histone modifications exhibited strong parallels with epigenetic alterations observed in cancers, leukemia, and Alzheimer's disease. This study provides novel evidence of FA epigenetic toxicity, offering new insights into the potential mechanisms underlying FA-driven pathogenesis.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel environment exposure drives temporally defined and region-specific chromatin accessibility and gene expression changes in the hippocampus.
Pub Date : 2025-03-01 DOI: 10.1101/2024.10.31.621351
Lisa Traunmüller, Erin E Duffy, Hanqing Liu, Stella Sanalidou, Elena G Assad, Senmiao Sun, Naeem S Pajarillo, Nancy Niu, Eric C Griffith, Michael E Greenberg

The interaction of mammals with a novel environment (NE) results in structural and functional changes in multiple brain areas, including the hippocampus. This experience-dependent circuit reorganization is driven in part by changes in gene expression however, the dynamic sensory experience-driven chromatin states and the diverse cell type specific gene expression programs that are regulated by novel experiences are not well described. We employed single- nucleus multiomics (snRNA- and ATAC-seq) and bulk RNA-seq of the hippocampal DG, CA3, and CA1 regions to characterize the temporal evolution of cell-type-specific chromatin accessibility and gene expression changes that occur in 14 different cell types of the hippocampus upon exposure of mice to a novel environment. We observe strong hippocampal regional specificity in excitatory neuron chromatin accessibility and gene expression as well as great diversity in the inhibitory neuron and non-neuronal transcriptional responses. The novel environment-regulated genes in each cell type were enriched for genes that encode secreted factors, and cell-type-specific expression of their cognate receptors identified promising candidates for the modulation of learning and memory processes. Our characterization of the effect of novel experience on chromatin revealed thousands of cell-type-specific changes in chromatin accessibility. Coordinated analysis of chromatin accessibility and gene expression changes within individual cell types identified Fos/AP-1 as a key driver of novel experience-induced changes in chromatin accessibility and cell-type-specific gene expression. Together, these data provide a rich resource of hippocampal chromatin accessibility and gene expression profiles across diverse cell types in response to novel experience, a physiological stimulus that affects learning and memory.

{"title":"Novel environment exposure drives temporally defined and region-specific chromatin accessibility and gene expression changes in the hippocampus.","authors":"Lisa Traunmüller, Erin E Duffy, Hanqing Liu, Stella Sanalidou, Elena G Assad, Senmiao Sun, Naeem S Pajarillo, Nancy Niu, Eric C Griffith, Michael E Greenberg","doi":"10.1101/2024.10.31.621351","DOIUrl":"10.1101/2024.10.31.621351","url":null,"abstract":"<p><p>The interaction of mammals with a novel environment (NE) results in structural and functional changes in multiple brain areas, including the hippocampus. This experience-dependent circuit reorganization is driven in part by changes in gene expression however, the dynamic sensory experience-driven chromatin states and the diverse cell type specific gene expression programs that are regulated by novel experiences are not well described. We employed single- nucleus multiomics (snRNA- and ATAC-seq) and bulk RNA-seq of the hippocampal DG, CA3, and CA1 regions to characterize the temporal evolution of cell-type-specific chromatin accessibility and gene expression changes that occur in 14 different cell types of the hippocampus upon exposure of mice to a novel environment. We observe strong hippocampal regional specificity in excitatory neuron chromatin accessibility and gene expression as well as great diversity in the inhibitory neuron and non-neuronal transcriptional responses. The novel environment-regulated genes in each cell type were enriched for genes that encode secreted factors, and cell-type-specific expression of their cognate receptors identified promising candidates for the modulation of learning and memory processes. Our characterization of the effect of novel experience on chromatin revealed thousands of cell-type-specific changes in chromatin accessibility. Coordinated analysis of chromatin accessibility and gene expression changes within individual cell types identified Fos/AP-1 as a key driver of novel experience-induced changes in chromatin accessibility and cell-type-specific gene expression. Together, these data provide a rich resource of hippocampal chromatin accessibility and gene expression profiles across diverse cell types in response to novel experience, a physiological stimulus that affects learning and memory.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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