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Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.25.639746
Emilie L Castranio, Merina Varghese, Elentina K Argyrousi, Kuldeep Tripathi, Linda Söderberg, Erin Bresnahan, David Lerner, Francesca Garretti, Hong Zhang, Jonathan van de Loo, Cheryl D Stimpson, Ronan Talty, Charles Glabe, Efrat Levy, Minghui Wang, Marjan Ilkov, Bin Zhang, Lars Lannfelt, Brigitte Guérin, William D Lubell, Shai Rahimipour, Dara L Dickstein, Sam Gandy, Ottavio Arancio, Michelle E Ehrlich

APP E693Q transgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of Aβ (NFA-Aβ) and APP α-carboxy terminal fragments. The APP E693Q mutation disrupts amyloid fibril formation, and no plaques develop in these mice. In the current study, the aging-related accumulation of NFA-Aβ in APP E693Q mice was revealed by A11 immunohistochemistry and NFA-Aβ-detecting cyclic D,L-α-peptide-FITC microscopy. The presynaptic termini of APP E693Q mice developed aging-related physiological abnormalities in post-tetanic potentiation, synaptic fatigue, and synaptic vesicle replenishment. Single-cell RNA sequencing showed that excitatory neurons exhibited the most altered transcriptomic profile, especially involving "protein translation" and "oxidative phosphorylation". Direct measurements of electron transport chain catalysis revealed reduction in mitochondrial complex I activity in Dutch mice. Microglial transcript analysis revealed no evidence of inflammation. The depletion or neutralization of both fibrillar and NFA-Aβ may be needed for complete elimination of Aβ toxicity.

Teaser: APP E693Q "NFA-Aβ only" mice reveal clinically relevant mechanisms despite the absence of detectable inflammation.

APP E693Q转基因小鼠会出现与衰老相关的学习障碍,并积累内源性生成的Aβ非纤维聚集体(NFA-Aβ)和APP α-羧基末端片段。APP E693Q突变会破坏淀粉样纤维的形成,这些小鼠体内不会出现斑块。在本研究中,通过A11免疫组化和NFA-Aβ检测环D,L-α-肽-FITC显微镜,揭示了APP E693Q小鼠中与衰老相关的NFA-Aβ积累。APP E693Q小鼠的突触前末端出现了与衰老相关的生理异常,包括四尖瓣后电位、突触疲劳和突触囊泡补充。单细胞 RNA 测序显示,兴奋性神经元的转录组变化最大,尤其是在 "蛋白质翻译 "和 "氧化磷酸化 "方面。对电子传递链催化作用的直接测量显示,荷兰小鼠的线粒体复合体 I 活性降低。小胶质细胞转录本分析没有发现炎症迹象。要彻底消除 Aβ 的毒性,可能需要消耗或中和纤维状 Aβ 和 NFA-Aβ:APP E693Q "仅 NFA-Aβ "小鼠揭示了与临床相关的机制,尽管没有检测到炎症。
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引用次数: 0
DNA origami vaccines program antigen-focused germinal centers.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.21.639354
Anna Romanov, Grant A Knappe, Larance Ronsard, Heikyung Suh, Marjan Omer, Asheley P Chapman, Vanessa R Lewis, Katie Spivakovsky, Josue Canales, Boris Reizis, Ryan D Tingle, Christopher A Cottrell, Torben Schiffner, Daniel Lingwood, Mark Bathe, Darrell J Irvine

Recruitment and expansion of rare precursor B cells in germinal centers (GCs) is a central goal of vaccination to generate broadly neutralizing antibodies (bnAbs) against challenging pathogens such as HIV. Multivalent immunogen display is a well-established method to enhance vaccine-induced B cell responses, typically accomplished by using natural or engineered protein scaffolds. However, these scaffolds themselves are targets of antibody responses, with the potential to generate competitor scaffold-specific B cells that could theoretically limit expansion and maturation of "on-target" B cells in the GC response. Here, we rationally designed T-independent, DNA-origami based virus-like particles (VLPs) with optimal antigenic display of the germline targeting HIV Env immunogen, eOD-GT8, and appropriate T cell help to achieve a potent GC response. In preclinical mouse models, these DNA-VLPs expanded significantly higher frequencies of epitope-specific GC B cells compared with a state-of-the-art clinical protein nanoparticle. Optimized DNA-VLPs primed germinal centers focused on the target antigen and rapidly expanded subdominant broadly neutralizing antibody precursor B cells for HIV with a single immunization. Thus, avoiding scaffold-specific responses augments priming of bnAb precursor B cells, and DNA-VLPs are a promising platform for promoting B cell responses towards challenging subdominant epitopes.

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引用次数: 0
Beta cell dysfunction occurs independently of insulitis in type 1 diabetes pathogenesis. 在1型糖尿病的发病机制中,β细胞功能障碍独立于胰岛素炎发生。
Pub Date : 2025-03-01 DOI: 10.1101/2024.12.29.630665
Mollie K Huber, Adrienne E Widener, Alexandra E Cuaycal, Dylan Smurlick, Elizabeth A Butterworth, Nataliya I Lenchik, Jing Chen, Maria Beery, Helmut Hiller, Ellen Verney, Irina Kusmartseva, Marjan Slak Rupnik, Martha Campbell-Thompson, Ivan C Gerling, Mark A Atkinson, Clayton E Mathews, Edward A Phelps

The loss of insulin secretory function associated with type 1 diabetes (T1D) is attributed to the immune-mediated destruction of beta cells. Yet, at onset of T1D, patients often have a significant beta cell mass remaining while T cell infiltration of pancreatic islets is sporadic. Thus, we investigated the hypothesis that the remaining beta cells in T1D are largely dysfunctional using live human pancreas tissue slices prepared from organ donors with recently diagnosed T1D. Beta cells in slices from donors with T1D had significantly diminished Ca2+ mobilization and insulin secretion responses to glucose. Beta cell function was equally impaired in T cell-infiltrated and non-infiltrated islets. Fixed tissue staining and gene expression profiling of laser-capture microdissected islets revealed significant decreases of proteins and genes in the glucose stimulus secretion coupling pathway. From these data, we posit that functional defects occur in the remaining mass of beta cells during human T1D pathogenesis.

在1型糖尿病(T1D)进展过程中,β细胞功能失调,表现出第一阶段胰岛素释放减少。虽然这一时期的β细胞功能障碍已经确定,但其原因和潜在机制仍不清楚。为了解决这一知识空白,活体胰腺组织切片取自自身抗体阴性、无糖尿病(ND)的器官供者、一种或多种胰岛自身抗体(AAb+)阳性的供者,以及诊断为T1D 0-4年的供者(T1D+)。通过免疫标记、Ca2+成像和胰岛素分泌的浸润试验,进行动态成像和生理分泌研究,以评估T细胞浸润对β细胞功能的程度和影响。通过ENTPD3细胞表面染色在活切片中鉴定β细胞。来自ND和AAb+供体的β细胞在高葡萄糖和KCl的作用下表现出正常的胞浆Ca2+动员。来自T1D供体的β细胞对高葡萄糖的Ca2+反应显著降低,但对KCl的反应保持不变。在T1D中,T细胞浸润和非浸润胰岛素阳性胰岛的葡萄糖反应性受损,支持β细胞功能障碍独立于β细胞和T细胞之间密切的空间关联的概念。激光捕获微解剖胰岛的固定组织染色和基因表达谱显示,来自T1D供体的β细胞中葡萄糖代谢为ATP的标记物显著减少,但内质网(ER)应激标记物没有变化。根据这些数据,我们假设在T1D发病过程中β细胞发生功能缺陷,与局部T细胞浸润和β细胞破坏无关。此外,尽管存在大量的β细胞,但这些β细胞代谢缺陷导致了T1D诊断时血糖异常的临床表现。
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引用次数: 0
Maintenance DNA methylation is required for induced regulatory T cell reparative function following viral pneumonia.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.25.640199
Anthony M Joudi, Jonathan K Gurkan, Qianli Liu, Manuel A Torres Acosta, Kathryn A Helmin, Luisa Morales-Nebreda, Nurbek Mambetsariev, Carla Patricia Reyes Flores, Hiam Abdala-Valencia, Elizabeth M Steinert, Samuel E Weinberg, Benjamin D Singer

FOXP3+ natural regulatory T cells (nTregs) promote resolution of inflammation and repair of epithelial damage following viral pneumonia-induced lung injury, thus representing a cellular therapy for patients with acute respiratory distress syndrome (ARDS). Whether in vitro induced Tregs (iTregs), which can be rapidly generated in substantial numbers from conventional T cells, also promote lung recovery is unknown. nTregs require specific DNA methylation patterns maintained by the epigenetic regulator, ubiquitin-like with PHD and RING finger domains 1 (UHRF1). Here, we tested whether iTregs promote recovery following viral pneumonia and whether iTregs require UHRF1 for their pro-recovery function. We found that adoptive transfer of iTregs to mice with influenza virus pneumonia promotes lung recovery and that loss of UHRF1-mediated maintenance DNA methylation in iTregs leads to reduced engraftment and a delayed repair response. Transcriptional and DNA methylation profiling of adoptively transferred UHRF1-deficient iTregs that had trafficked to influenza-injured lungs demonstrated transcriptional instability with gain of effector T cell lineage-defining transcription factors. Strategies to promote the stability of iTregs could be leveraged to further augment their pro-recovery function during viral pneumonia and other causes of ARDS.

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引用次数: 0
High-Resolution Proteomics Unveils Salivary Gland Disruption and Saliva-Hemolymph Protein Exchange in Plasmodium -Infected Mosquitoes.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.28.640873
Thiago Luiz Alves E Silva, Sachi Kanatani, Ana Beatriz Barletta Ferreira, Cindi Schwartz, Octavio A C Talyuli, Janet Olivas, Bianca M Nagata, Zarna Rajeshkumar Pala, Tales Pascini, Derron A Alves, Ming Zhao, Motoshi Suzuki, Lilian P Dorner, Friedrich Frischknecht, Isabelle Coppens, Carolina Barillas-Mury, Jose M C Ribeiro, Photini Sinnis, Joel Vega-Rodriguez

Plasmodium sporozoites, the stage that initiates a malaria infection, must invade the mosquito salivary glands (SGs) before transmitting to a vertebrate host. However, the effects of sporozoite invasion on salivary gland physiology and saliva composition remain largely unexplored. We examined the impact of Plasmodium infection on Anopheles gambiae salivary glands using high-resolution proteomics, gene expression, and morphological analysis. The data revealed differential expression of various proteins, including the enrichment of humoral proteins in infected salivary glands originating from the hemolymph. These proteins diffused into the SGs due to structural damage caused by the sporozoites during invasion. Conversely, saliva proteins diffused out into the circulation of infected mosquitoes. Moreover, infection altered saliva protein composition, as shown by proteomes from saliva collected from mosquitoes infected by P. berghei or P. falciparum , revealing a significant reduction of immune proteins compared to uninfected mosquitoes. This reduction is likely due to the association of these proteins with the surface of sporozoites within the mosquito salivary secretory cavities. The saliva protein profiles from mosquitoes infected with both Plasmodium species were remarkably similar, suggesting a conserved interaction between sporozoites and salivary glands. Our results provide a foundation for understanding the molecular interactions between Plasmodium sporozoites and mosquito salivary glands.

疟原虫孢子虫是疟疾感染的始发阶段,必须先侵入蚊子的唾液腺(SGs)才能传播给脊椎动物宿主。然而,孢子虫入侵对唾液腺生理和唾液成分的影响在很大程度上仍未得到研究。我们利用高分辨率蛋白质组学、基因表达和形态学分析研究了疟原虫感染对冈比亚按蚊唾液腺的影响。数据揭示了各种蛋白质的差异表达,包括在感染的唾液腺中富含源自血淋巴的体液蛋白质。由于孢子虫在入侵过程中造成了结构性破坏,这些蛋白质扩散到了唾液腺中。相反,唾液蛋白质则扩散到受感染蚊子的血液循环中。此外,感染改变了唾液蛋白质的组成,从感染了伯格希氏疟原虫或恶性疟原虫的蚊子唾液中收集的蛋白质组显示,与未感染的蚊子相比,免疫蛋白质显著减少。这种减少可能是由于这些蛋白质与蚊子唾液分泌腔中的孢子表面结合。感染两种疟原虫的蚊子的唾液蛋白质图谱非常相似,这表明孢子虫与唾液腺之间存在一致的相互作用。我们的研究结果为了解疟原虫孢子体与蚊子唾液腺之间的分子相互作用奠定了基础。
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引用次数: 0
Scaling up spatial transcriptomics for large-sized tissues: uncovering cellular-level tissue architecture beyond conventional platforms with iSCALE.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.25.640190
Amelia Schroeder, Melanie Loth, Chunyu Luo, Sicong Yao, Hanying Yan, Daiwei Zhang, Sarbottam Piya, Edward Plowey, Wenxing Hu, Jean R Clemenceau, Inyeop Jang, Minji Kim, Isabel Barnfather, Su Jing Chan, Taylor L Reynolds, Thomas Carlile, Patrick Cullen, Ji-Youn Sung, Hui-Hsin Tsai, Jeong Hwan Park, Tae Hyun Hwang, Baohong Zhang, Mingyao Li

Recent advances in spatial transcriptomics (ST) technologies have transformed our ability to profile gene expression while retaining the crucial spatial context within tissues. However, existing ST platforms suffer from high costs, long turnaround times, low resolution, limited gene coverage, and small tissue capture areas, which hinder their broad applications. Here we present iSCALE, a method that predicts super-resolution gene expression and automatically annotates cellular-level tissue architecture for large-sized tissues that exceed the capture areas of standard ST platforms. The accuracy of iSCALE were validated by comprehensive evaluations, involving benchmarking experiments, immunohistochemistry staining, and manual annotation by pathologists. When applied to multiple sclerosis human brain samples, iSCALE uncovered lesion associated cellular characteristics that were undetectable by conventional ST experiments. Our results demonstrate iSCALE's utility in analyzing large-sized tissues with automatic and unbiased tissue annotation, inferring cell type composition, and pinpointing regions of interest for features not discernible through human visual assessment.

{"title":"Scaling up spatial transcriptomics for large-sized tissues: uncovering cellular-level tissue architecture beyond conventional platforms with iSCALE.","authors":"Amelia Schroeder, Melanie Loth, Chunyu Luo, Sicong Yao, Hanying Yan, Daiwei Zhang, Sarbottam Piya, Edward Plowey, Wenxing Hu, Jean R Clemenceau, Inyeop Jang, Minji Kim, Isabel Barnfather, Su Jing Chan, Taylor L Reynolds, Thomas Carlile, Patrick Cullen, Ji-Youn Sung, Hui-Hsin Tsai, Jeong Hwan Park, Tae Hyun Hwang, Baohong Zhang, Mingyao Li","doi":"10.1101/2025.02.25.640190","DOIUrl":"10.1101/2025.02.25.640190","url":null,"abstract":"<p><p>Recent advances in spatial transcriptomics (ST) technologies have transformed our ability to profile gene expression while retaining the crucial spatial context within tissues. However, existing ST platforms suffer from high costs, long turnaround times, low resolution, limited gene coverage, and small tissue capture areas, which hinder their broad applications. Here we present iSCALE, a method that predicts super-resolution gene expression and automatically annotates cellular-level tissue architecture for large-sized tissues that exceed the capture areas of standard ST platforms. The accuracy of iSCALE were validated by comprehensive evaluations, involving benchmarking experiments, immunohistochemistry staining, and manual annotation by pathologists. When applied to multiple sclerosis human brain samples, iSCALE uncovered lesion associated cellular characteristics that were undetectable by conventional ST experiments. Our results demonstrate iSCALE's utility in analyzing large-sized tissues with automatic and unbiased tissue annotation, inferring cell type composition, and pinpointing regions of interest for features not discernible through human visual assessment.</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/PMC11888418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589497","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
Multi-omic analysis of the ciliogenic transcription factor RFX3 reveals a role in promoting activity-dependent responses via enhancing CREB binding in human neurons.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.27.640588
Jenny Lai, Didem Demirbas, Kaitlyn Phillips, Boxun Zhao, Harrison Wallace, Megan Seferian, Tojo Nakayama, Holly Harris, Aikaterini Chatzipli, Eunjung Alice Lee, Timothy W Yu

Heterozygous loss-of-function (LoF) variants in RFX3, a transcription factor known to play key roles in ciliogenesis, result in autism spectrum disorder (ASD) and neurodevelopmental delay. RFX binding motifs are also enriched upstream of genes found to be commonly dysregulated in transcriptomic analyses of brain tissue from individuals with idiopathic ASD. Still, the precise functions of RFX3 in the human brain is unknown. Here, we studied the impact of RFX3 deficiency using human iPSC-derived neurons and forebrain organoids. Biallelic loss of RFX3 disrupted ciliary gene expression and delayed neuronal differentiation, while monoallelic loss of RFX3 did not. Instead, transcriptomic and DNA binding analyses demonstrated that monoallelic RFX3 loss disrupted synaptic target gene expression and diminished neuronal activity-dependent gene expression. RFX3 binding sites co-localized with CREB binding sites near activity-dependent genes, and RFX3 deficiency led to decreased CREB binding and impaired induction of CREB targets in response to neuronal depolarization. This study demonstrates a novel role of the ASD-associated gene RFX3 in shaping neuronal synaptic development and plasticity.

{"title":"Multi-omic analysis of the ciliogenic transcription factor <i>RFX3</i> reveals a role in promoting activity-dependent responses via enhancing CREB binding in human neurons.","authors":"Jenny Lai, Didem Demirbas, Kaitlyn Phillips, Boxun Zhao, Harrison Wallace, Megan Seferian, Tojo Nakayama, Holly Harris, Aikaterini Chatzipli, Eunjung Alice Lee, Timothy W Yu","doi":"10.1101/2025.02.27.640588","DOIUrl":"10.1101/2025.02.27.640588","url":null,"abstract":"<p><p>Heterozygous loss-of-function (LoF) variants in <i>RFX3</i>, a transcription factor known to play key roles in ciliogenesis, result in autism spectrum disorder (ASD) and neurodevelopmental delay. RFX binding motifs are also enriched upstream of genes found to be commonly dysregulated in transcriptomic analyses of brain tissue from individuals with idiopathic ASD. Still, the precise functions of <i>RFX3</i> in the human brain is unknown. Here, we studied the impact of <i>RFX3</i> deficiency using human iPSC-derived neurons and forebrain organoids. Biallelic loss of <i>RFX3</i> disrupted ciliary gene expression and delayed neuronal differentiation, while monoallelic loss of <i>RFX3</i> did not. Instead, transcriptomic and DNA binding analyses demonstrated that monoallelic <i>RFX3</i> loss disrupted synaptic target gene expression and diminished neuronal activity-dependent gene expression. RFX3 binding sites co-localized with CREB binding sites near activity-dependent genes, and <i>RFX3</i> deficiency led to decreased CREB binding and impaired induction of CREB targets in response to neuronal depolarization. This study demonstrates a novel role of the ASD-associated gene RFX3 in shaping neuronal synaptic development and plasticity.</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/PMC11888390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589524","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
Role of the ETV5/p38 signaling axis in aggressive thyroid cancer cells.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.17.637322
Jerry H Houl, Rozita Bagheri-Yarmand, Muthusamy Kunnimalaiyaan, Paola Miranda Mendez, Joseph L Kidd, Ali Dadbin, Andrea Jurado Ruiz, Parag A Parekh, Ying C Henderson, Nikhil S Chari, Aatish Thennavan Thennavan, Reid T Powell, Clifford C Stephan, Xiao Zhao, Anastasios Maniakas, Roza Nurieva, Naifa L Busaidy, Maria E Cabanillas, Ramona Dadu, Mark Zafereo, Jennifer R Wang, Stephen Y Lai, Marie-Claude Hofmann

Patients with poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) face a much poorer prognosis than those with differentiated thyroid cancers. Around 25% of PDTCs and 35% of ATCs carry the BRAFV600E mutation, which constitutively activates the MAPK pathway, a key driver of cell growth. Although combining BRAF and MEK inhibitors can shrink tumors, resistance often develops. The exact cause of this resistance remains unclear. We previously found that in PDTC and ATC cells the BRAFV600E mutation is strongly linked to the expression of ETV5, a transcription factor downstream of the MAPK pathway. In the current study, we observed a significant association between ETV5 expression and the activation of p38, a central component of the MAPK14 pathway. Upon reduction of ETV5 levels, p38 expression and activation decreased, along with its upstream regulators MKK3/MKK6. This suggests that the MAPK and p38/MAPK14 pathways are interconnected and that p38 has oncogenic properties in these cancers. Using high-throughput screening, we established that combining p38 inhibitors with the BRAF inhibitor dabrafenib showed strong synergy in vitro, including in cells resistant to dabrafenib and trametinib that had acquired a secondary TP53 mutation. We then tested this combination in a genetically engineered mouse model (GEMM) of ATC. Overall, our findings suggest an oncogenic link between the MAPK and p38/MAPK14 pathways and that combining p38 pathway inhibitors with dabrafenib-targeted therapy could improve treatment outcomes for aggressive thyroid cancers. However, more specific and effective p38 inhibitors are required to fully harness this potential.

{"title":"Role of the ETV5/p38 signaling axis in aggressive thyroid cancer cells.","authors":"Jerry H Houl, Rozita Bagheri-Yarmand, Muthusamy Kunnimalaiyaan, Paola Miranda Mendez, Joseph L Kidd, Ali Dadbin, Andrea Jurado Ruiz, Parag A Parekh, Ying C Henderson, Nikhil S Chari, Aatish Thennavan Thennavan, Reid T Powell, Clifford C Stephan, Xiao Zhao, Anastasios Maniakas, Roza Nurieva, Naifa L Busaidy, Maria E Cabanillas, Ramona Dadu, Mark Zafereo, Jennifer R Wang, Stephen Y Lai, Marie-Claude Hofmann","doi":"10.1101/2025.02.17.637322","DOIUrl":"https://doi.org/10.1101/2025.02.17.637322","url":null,"abstract":"<p><p>Patients with poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) face a much poorer prognosis than those with differentiated thyroid cancers. Around 25% of PDTCs and 35% of ATCs carry the BRAFV600E mutation, which constitutively activates the MAPK pathway, a key driver of cell growth. Although combining BRAF and MEK inhibitors can shrink tumors, resistance often develops. The exact cause of this resistance remains unclear. We previously found that in PDTC and ATC cells the BRAFV600E mutation is strongly linked to the expression of ETV5, a transcription factor downstream of the MAPK pathway. In the current study, we observed a significant association between ETV5 expression and the activation of p38, a central component of the MAPK14 pathway. Upon reduction of ETV5 levels, p38 expression and activation decreased, along with its upstream regulators MKK3/MKK6. This suggests that the MAPK and p38/MAPK14 pathways are interconnected and that p38 has oncogenic properties in these cancers. Using high-throughput screening, we established that combining p38 inhibitors with the BRAF inhibitor dabrafenib showed strong synergy in vitro, including in cells resistant to dabrafenib and trametinib that had acquired a secondary TP53 mutation. We then tested this combination in a genetically engineered mouse model (GEMM) of ATC. Overall, our findings suggest an oncogenic link between the MAPK and p38/MAPK14 pathways and that combining p38 pathway inhibitors with dabrafenib-targeted therapy could improve treatment outcomes for aggressive thyroid cancers. However, more specific and effective p38 inhibitors are required to fully harness this potential.</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/PMC11870521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545766","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
Deconvolution to restore cryo-EM maps with anisotropic resolution.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.23.639707
Junrui Li, Yifei Chen, Shawn Zheng, Angus McDonald, John W Sedat, David A Agard, Yifan Cheng

With technological advancements in recent years, single particle cryogenic electron microscopy (cryo-EM) has become a major methodology for structural biology. Structure determination by single particle cryo-EM is premised on randomly orientated particles embedded in thin layer of vitreous ice to resolve high-resolution structural information in all directions. Otherwise, preferentially distributed particle orientations will lead to anisotropic resolution of the structure. Here we established a deconvolution approach, named AR-Decon, to computationally improve the quality of three-dimensional maps with anisotropic resolutions reconstructed from datasets with preferred orientations. We have tested and validated the procedure with both synthetic and experimental datasets and compared its performance with alternative machine-learning based methods.

{"title":"Deconvolution to restore cryo-EM maps with anisotropic resolution.","authors":"Junrui Li, Yifei Chen, Shawn Zheng, Angus McDonald, John W Sedat, David A Agard, Yifan Cheng","doi":"10.1101/2025.02.23.639707","DOIUrl":"10.1101/2025.02.23.639707","url":null,"abstract":"<p><p>With technological advancements in recent years, single particle cryogenic electron microscopy (cryo-EM) has become a major methodology for structural biology. Structure determination by single particle cryo-EM is premised on randomly orientated particles embedded in thin layer of vitreous ice to resolve high-resolution structural information in all directions. Otherwise, preferentially distributed particle orientations will lead to anisotropic resolution of the structure. Here we established a deconvolution approach, named AR-Decon, to computationally improve the quality of three-dimensional maps with anisotropic resolutions reconstructed from datasets with preferred orientations. We have tested and validated the procedure with both synthetic and experimental datasets and compared its performance with alternative machine-learning based methods.</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/PMC11888254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589397","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
Potency and selectivity of a novel pan-RAS inhibitor in 3D bioprinted organoid tumor models.
Pub Date : 2025-03-01 DOI: 10.1101/2025.02.25.640132
Daniela De Nobrega, Logan C Eiler, Parmanand Ahirwar, Urvi P Rawal, Chelsea L Crawford, Donald J Buchsbaum, Adam B Keeton, Yulia Y Maxuitenko, Xi Chen, Gary A Piazza, Allan Tsung, Karim I Budhwani

Background: Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ∼40% of cases. Efficacy of recently approved, mutant-specific KRAS inhibitors is limited by intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms. Here, we evaluate ADT-007 in 3D bioprinted organoid tumors (BOTs) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines.

Methods: Potency and selectivity of ADT-007 were compared to bortezomib, a proteasome inhibitor, and YM155, a survivin inhibitor, using high-content imaging and ATP-based luminescence assays. Mechanistic studies assessed impact on RAS activation and downstream signaling.

Results: ADT-007 exhibited high potency and selectivity in KRAS-mutant BOTs, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity over bortezomib and YM155 with minimal cytotoxicity in RAS-WT BOTs. Mechanistic analysis confirmed ADT-007 inhibited RAS activation and downstream signaling, leading to selective apoptosis induction in KRAS-mutant CRC cells.

Conclusions: The selective potency and specificity of ADT-007 warrants further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BOT models for preclinical drug response assessment. Further validation in patient-derived BOTs is necessary to evaluate potential of ADT-007 in clinical settings.

{"title":"Potency and selectivity of a novel pan-RAS inhibitor in 3D bioprinted organoid tumor models.","authors":"Daniela De Nobrega, Logan C Eiler, Parmanand Ahirwar, Urvi P Rawal, Chelsea L Crawford, Donald J Buchsbaum, Adam B Keeton, Yulia Y Maxuitenko, Xi Chen, Gary A Piazza, Allan Tsung, Karim I Budhwani","doi":"10.1101/2025.02.25.640132","DOIUrl":"10.1101/2025.02.25.640132","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ∼40% of cases. Efficacy of recently approved, mutant-specific KRAS inhibitors is limited by intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms. Here, we evaluate ADT-007 in 3D bioprinted organoid tumors (BOTs) generated from KRAS-mutant and RAS wild-type (WT) CRC cell lines.</p><p><strong>Methods: </strong>Potency and selectivity of ADT-007 were compared to bortezomib, a proteasome inhibitor, and YM155, a survivin inhibitor, using high-content imaging and ATP-based luminescence assays. Mechanistic studies assessed impact on RAS activation and downstream signaling.</p><p><strong>Results: </strong>ADT-007 exhibited high potency and selectivity in KRAS-mutant BOTs, reducing tumor burdens >30% at nanomolar concentrations, and demonstrated superior selectivity over bortezomib and YM155 with minimal cytotoxicity in RAS-WT BOTs. Mechanistic analysis confirmed ADT-007 inhibited RAS activation and downstream signaling, leading to selective apoptosis induction in KRAS-mutant CRC cells.</p><p><strong>Conclusions: </strong>The selective potency and specificity of ADT-007 warrants further investigation of pan-RAS inhibitors for treating RAS-driven cancers. This study also underscores the translational utility of 3D BOT models for preclinical drug response assessment. Further validation in patient-derived BOTs is necessary to evaluate potential of ADT-007 in clinical settings.</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/PMC11888295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589464","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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