journal
https://read.qxmd.com/read/38277467/mis-spliced-transcripts-generate-de-novo-proteins-in-tdp-43-related-als-ftd
#1
JOURNAL ARTICLE
Sahba Seddighi, Yue A Qi, Anna-Leigh Brown, Oscar G Wilkins, Colleen Bereda, Cedric Belair, Yong-Jie Zhang, Mercedes Prudencio, Matthew J Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E Kargbo-Hill, James Hawrot, Daniel M Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I Shah, Mike A Nalls, Jennifer M Colón-Mercado, Joel F Reyes, Veronica H Ryan, Matthew P Nelson, Casey N Cook, Ziyi Li, Laurel Screven, Justin Y Kwan, Puja R Mehta, Matteo Zanovello, Martina Hallegger, Anantharaman Shantaraman, Lingyan Ping, Yuka Koike, Björn Oskarsson, Nathan P Staff, Duc M Duong, Aisha Ahmed, Maria Secrier, Jernej Ule, Steven Jacobson, Daniel S Reich, Jonathan D Rohrer, Andrea Malaspina, Dennis W Dickson, Jonathan D Glass, Alessandro Ori, Nicholas T Seyfried, Manolis Maragkakis, Leonard Petrucelli, Pietro Fratta, Michael E Ward
Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD...
January 26, 2024: Science Translational Medicine
https://read.qxmd.com/read/38416845/a-functional-identification-platform-reveals-frequent-spontaneous-neoantigen-specific-t-cell-responses-in-patients-with-cancer
#2
JOURNAL ARTICLE
Aaron M Miller, Zeynep Koşaloğlu-Yalçın, Luise Westernberg, Leslie Montero, Milad Bahmanof, Angela Frentzen, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Gregory Seumois, Jason Greenbaum, Spencer E Brightman, Karla Soria Zavala, Rukman R Thota, Martin S Naradikian, Samir S Makani, Scott M Lippman, Alessandro Sette, Ezra E W Cohen, Bjoern Peters, Stephen P Schoenberger
The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4+ and CD8+ T cell responses across a range of tumor types and mutational burdens...
February 28, 2024: Science Translational Medicine
https://read.qxmd.com/read/38416844/inflammation-and-epithelial-repair-predict-mortality-hospital-readmission-and-growth-recovery-in-complicated-severe-acute-malnutrition
#3
JOURNAL ARTICLE
Jonathan P Sturgeon, Joice Tome, Cherlynn Dumbura, Florence D Majo, Deophine Ngosa, Kuda Mutasa, Kanekwa Zyambo, Ellen Besa, Kanta Chandwe, Chanda Kapoma, Benjamin Mwapenya, Kusum J Nathoo, Claire D Bourke, Robert Ntozini, Bernard Chasekwa, Melanie Smuk, Mutsa Bwakura-Dangarembizi, Beatrice Amadi, Paul Kelly, Andrew J Prendergast
Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM ( n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia...
February 28, 2024: Science Translational Medicine
https://read.qxmd.com/read/38416843/acetyl-coa-carboxylase-1-controls-a-lipid-droplet-peroxisome-axis-and-is-a-vulnerability-of-endocrine-resistant-er-breast-cancer
#4
JOURNAL ARTICLE
Marina Bacci, Nicla Lorito, Alfredo Smiriglia, Angela Subbiani, Francesca Bonechi, Giuseppina Comito, Ludivine Morriset, Rania El Botty, Matteo Benelli, Joanna I López-Velazco, Maria M Caffarel, Ander Urruticoechea, George Sflomos, Luca Malorni, Michela Corsini, Luigi Ippolito, Elisa Giannoni, Icro Meattini, Vittoria Matafora, Kristina Havas, Angela Bachi, Paola Chiarugi, Elisabetta Marangoni, Andrea Morandi
Targeting aromatase deprives ER+ breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER+ breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors...
February 28, 2024: Science Translational Medicine
https://read.qxmd.com/read/38416842/endothelial-cells-drive-organ-fibrosis-in-mice-by-inducing-expression-of-the-transcription-factor-sox9
#5
JOURNAL ARTICLE
Felix A Trogisch, Aya Abouissa, Merve Keles, Anne Birke, Manuela Fuhrmann, Gesine M Dittrich, Nina Weinzierl, Elvira Wink, Julio Cordero, Adel Elsherbiny, Abel Martin-Garrido, Steve Grein, Shruthi Hemanna, Ellen Hofmann, Luka Nicin, Sofia-Iris Bibli, Rannar Airik, Andreas Kispert, Ralf Kist, Sun Quanchao, Sina W Kürschner, Manuel Winkler, Norbert Gretz, Carolin Mogler, Thomas Korff, Philipp-Sebastian Koch, Stefanie Dimmeler, Gergana Dobreva, Joerg Heineke
Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet and nitric oxide synthase inhibition, pulmonary fibrosis induced by bleomycin treatment, and liver fibrosis due to a choline-deficient diet...
February 28, 2024: Science Translational Medicine
https://read.qxmd.com/read/38416841/apoe-from-patient-derived-astrocytic-extracellular-vesicles-alleviates-neuromyelitis-optica-spectrum-disorder-in-a-mouse-model
#6
JOURNAL ARTICLE
Shihe Jiang, Xindi Li, Yan Li, Zhilin Chang, Meng Yuan, Ying Zhang, Huimin Zhu, Yuwen Xiu, Hengri Cong, Linlin Yin, Zhen-Wei Yu, Junwan Fan, Wenyan He, Kaibin Shi, De-Cai Tian, Jing Zhang, Alexei Verkhratsky, Wei-Na Jin, Fu-Dong Shi
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD...
February 28, 2024: Science Translational Medicine
https://read.qxmd.com/read/38381849/chondrocyte-membrane-coated-nanoparticles-promote-drug-retention-and-halt-cartilage-damage-in-rat-and-canine-osteoarthritis
#7
JOURNAL ARTICLE
Ronghui Deng, Ruifang Zhao, Zining Zhang, Yang Chen, Meng Yang, Yixuan Lin, Jing Ye, Nan Li, Hao Qin, Xin Yan, Jian Shi, Fuzhen Yuan, Shitang Song, Zijie Xu, Yifan Song, Jiangnan Fu, Bingbing Xu, Guangjun Nie, Jia-Kuo Yu
Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we show that poly(lactide- co -glycolic acid) nanoparticles coated in chondrocyte membranes (CM-NPs) were preferentially taken up by rat chondrocytes ex vivo compared with uncoated nanoparticles...
February 21, 2024: Science Translational Medicine
https://read.qxmd.com/read/38381848/lipid-nanoparticles-and-sirna-targeting-plasminogen-provide-lasting-inhibition-of-fibrinolysis-in-mouse-and-dog-models-of-hemophilia-a
#8
JOURNAL ARTICLE
Amy W Strilchuk, Woosuk S Hur, Paul Batty, Yaqiu Sang, Sara R Abrahams, Alyssa S M Yong, Jerry Leung, Lakmali M Silva, Jocelyn A Schroeder, Kate Nesbitt, Bas de Laat, Niki M Moutsopoulos, Thomas H Bugge, Qizhen Shi, Pieter R Cullis, Elizabeth P Merricks, Alisa S Wolberg, Matthew J Flick, David Lillicrap, Timothy C Nichols, Christian J Kastrup
Antifibrinolytic drugs are used extensively for on-demand treatment of severe acute bleeding. Controlling fibrinolysis may also be an effective strategy to prevent or lessen chronic recurring bleeding in bleeding disorders such as hemophilia A (HA), but current antifibrinolytics have unfavorable pharmacokinetic profiles. Here, we developed a long-lasting antifibrinolytic using small interfering RNA (siRNA) targeting plasminogen packaged in clinically used lipid nanoparticles (LNPs) and tested it to determine whether reducing plasmin activity in animal models of HA could decrease bleeding frequency and severity...
February 21, 2024: Science Translational Medicine
https://read.qxmd.com/read/38381847/synthetic-development-of-a-broadly-neutralizing-antibody-against-snake-venom-long-chain-%C3%AE-neurotoxins
#9
JOURNAL ARTICLE
Irene S Khalek, R R Senji Laxme, Yen Thi Kim Nguyen, Suyog Khochare, Rohit N Patel, Jordan Woehl, Jessica M Smith, Karen Saye-Francisco, Yoojin Kim, Laetitia Misson Mindrebo, Quoc Tran, Mateusz Kędzior, Evy Boré, Oliver Limbo, Megan Verma, Robyn L Stanfield, Stefanie K Menzies, Stuart Ainsworth, Robert A Harrison, Dennis R Burton, Devin Sok, Ian A Wilson, Nicholas R Casewell, Kartik Sunagar, Joseph G Jardine
Snakebite envenoming is a major global public health concern for which improved therapies are urgently needed. The antigenic diversity present in snake venom toxins from various species presents a considerable challenge to the development of a universal antivenom. Here, we used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins produced by numerous medically relevant snakes. Our antibody bound diverse toxin variants with high affinity, blocked toxin binding to the nicotinic acetylcholine receptor in vitro, and protected mice from lethal venom challenge...
February 21, 2024: Science Translational Medicine
https://read.qxmd.com/read/38381846/an-anti-mycobacterial-conjugated-oligoelectrolyte-effective-against-mycobacterium-abscessus
#10
JOURNAL ARTICLE
Kaixi Zhang, Jakkarin Limwongyut, Alex S Moreland, Samuel Chan Jun Wei, Tania Jim Jia Min, Yan Sun, Sung Jae Shin, Su-Young Kim, Byung Woo Jhun, Kevin Pethe, Guillermo C Bazan
Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. Mycobacterium abscessus (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Current standard-of-care treatments are not satisfactory, with high failure rate and notable adverse effects. We report here a potent anti-Mab compound from the flexible molecular framework afforded by conjugated oligoelectrolytes (COEs)...
February 21, 2024: Science Translational Medicine
https://read.qxmd.com/read/38381845/lipocalin-2-expression-identifies-an-intestinal-regulatory-neutrophil-population-during-acute-graft-versus-host-disease
#11
JOURNAL ARTICLE
Marie Czech, Sophia Schneider, Nina Peltokangas, Nadia El Khawanky, Sakhila Ghimire, Geoffroy Andrieux, Jan Hülsdünker, Máté Krausz, Michele Proietti, Lukas M Braun, Tamina Rückert, Marlene Langenbach, Dominik Schmidt, Ina Martin, Valentin Wenger, Enrique de Vega, Eileen Haring, Mohsen Pourjam, Dietmar Pfeifer, Annette Schmitt-Graeff, Bodo Grimbacher, Konrad Aumann, Brigitte Kircher, Herbert Tilg, Manuela Raffatellu, Erik Thiele Orberg, Georg Häcker, Justus Duyster, Natalie Köhler, Ernst Holler, David Nachbaur, Melanie Boerries, Romana R Gerner, Dominic Grün, Robert Zeiser
Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations...
February 21, 2024: Science Translational Medicine
https://read.qxmd.com/read/38354229/engineered-t-cells-secreting-anti-bcma-t-cell-engagers-control-multiple-myeloma-and-promote-immune-memory-in-vivo
#12
JOURNAL ARTICLE
Laura Díez-Alonso, Aïda Falgas, Javier Arroyo-Ródenas, Paola A Romencín, Alba Martínez, Marina Gómez-Rosel, Belén Blanco, Anaïs Jiménez-Reinoso, Andrea Mayado, Alba Pérez-Pons, Óscar Aguilar-Sopeña, Ángel Ramírez-Fernández, Alejandro Segura-Tudela, Lorena Perez-Amill, Antonio Tapia-Galisteo, Carmen Domínguez-Alonso, Laura Rubio-Pérez, Maria Jara, Francesc Solé, Oana Hangiu, Laura Almagro, Ángela Albitre, Petronila Penela, Laura Sanz, Eduardo Anguita, Antonio Valeri, Almudena García-Ortiz, Paula Río, Manel Juan, Joaquín Martínez-López, Pedro Roda-Navarro, Beatriz Martín-Antonio, Alberto Orfao, Pablo Menéndez, Clara Bueno, Luis Álvarez-Vallina
Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies...
February 14, 2024: Science Translational Medicine
https://read.qxmd.com/read/38354228/aberrant-atm-signaling-and-homology-directed-dna-repair-as-a-vulnerability-of-p53-mutant-gbm-to-azd1390-mediated-radiosensitization
#13
JOURNAL ARTICLE
Jiajia Chen, Daniel J Laverty, Surabhi Talele, Ashwin Bale, Brett L Carlson, Kendra A Porath, Katrina K Bakken, Danielle M Burgenske, Paul A Decker, Rachael A Vaubel, Jeanette E Eckel-Passow, Rohit Bhargava, Zhenkun Lou, Petra Hamerlik, Brendan Harley, William F Elmquist, Zachary D Nagel, Shiv K Gupta, Jann N Sarkaria
ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0 -G1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro...
February 14, 2024: Science Translational Medicine
https://read.qxmd.com/read/38354227/multispecies-transcriptomics-identifies-sike-as-a-mapk-repressor-that-prevents-nash-progression
#14
JOURNAL ARTICLE
Lan Bai, Weiyi Qu, Xu Cheng, Hailong Yang, Yong-Ping Huang, Zhenya Wang, Cuijuan Han, Rui-Feng Tian, Fengjiao Hu, Ling Yang, Song Tian, Han Tian, Zhiwei Cai, Juan Wan, Jingwei Jiang, Jiajun Fu, Junjie Zhou, Yufeng Hu, Tengfei Ma, Xin Zhang, Yan-Xiao Ji, Jingjing Cai, Zhi-Gang She, Yibin Wang, Peng Zhang, Lingli Huang, Hongliang Li, Xiao-Jing Zhang
Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε ( SIKE ) as a conserved and potent negative controller of MAPK activation...
February 14, 2024: Science Translational Medicine
https://read.qxmd.com/read/38354226/dynamic-load-modulation-predicts-right-heart-tolerance-of-left-ventricular-cardiovascular-assist-in-a-porcine-model-of-cardiogenic-shock
#15
JOURNAL ARTICLE
Kimberly K Lamberti, Steven P Keller, Elazer R Edelman
Ventricular assist devices (VADs) offer mechanical support for patients with cardiogenic shock by unloading the impaired ventricle and increasing cardiac outflow and subsequent tissue perfusion. Their ability to adjust ventricular assistance allows for rapid and safe dynamic changes in cardiac load, which can be used with direct measures of chamber pressures to quantify cardiac pathophysiologic state, predict response to interventions, and unmask vulnerabilities such as limitations of left-sided support efficacy due to intolerance of the right heart...
February 14, 2024: Science Translational Medicine
https://read.qxmd.com/read/38354225/autologous-transplantation-of-p63-lung-progenitor-cells-for-chronic-obstructive-pulmonary-disease-therapy
#16
JOURNAL ARTICLE
Yujia Wang, Zili Meng, Ming Liu, Yueqing Zhou, Difei Chen, Yu Zhao, Ting Zhang, Nanshan Zhong, Xiaotian Dai, Shiyue Li, Wei Zuo
Adult lung resident stem/progenitor cells, including P63+ progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63+ progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63+ progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0...
February 14, 2024: Science Translational Medicine
https://read.qxmd.com/read/38324642/erratum-for-the-research-article-restoring-activity-in-the-thalamic-reticular-nucleus-improves-sleep-architecture-and-reduces-a%C3%AE-accumulation-in-mice-by-r-jagirdar-et-al
#17
JOURNAL ARTICLE
(no author information available yet)
No abstract text is available yet for this article.
February 7, 2024: Science Translational Medicine
https://read.qxmd.com/read/38324641/cd23-igg1-memory-b-cells-are-poised-to-switch-to-pathogenic-ige-production-in-food-allergy
#18
JOURNAL ARTICLE
Miyo Ota, Kenneth B Hoehn, Weslley Fernandes-Braga, Takayuki Ota, Carlos J Aranda, Sara Friedman, Mariana G C Miranda-Waldetario, Jamie Redes, Maria Suprun, Galina Grishina, Hugh A Sampson, Alefiyah Malbari, Steven H Kleinstein, Scott H Sicherer, Maria A Curotto de Lafaille
Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little is known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population of CD23+ IgG1+ memory B cells arising in type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing cells upon activation. The frequency of CD23+ IgG1+ memory B cells correlated with circulating concentrations of IgE in children with peanut allergy. A corresponding population of "type 2-marked" IgG1+ memory B cells was identified in single-cell RNA sequencing experiments...
February 7, 2024: Science Translational Medicine
https://read.qxmd.com/read/38324640/ige-in-allergy-it-takes-two
#19
REVIEW
Anouk von Borstel, Robyn E O'Hehir, Menno C van Zelm
A type 2 memory B cell subset is poised to differentiate into IgE-producing plasma cells in individuals with allergies (Ota et al . and Koenig et al .).
February 7, 2024: Science Translational Medicine
https://read.qxmd.com/read/38324639/integrating-spatial-and-single-cell-transcriptomics-to-characterize-the-molecular-and-cellular-architecture-of-the-ischemic-mouse-brain
#20
JOURNAL ARTICLE
Bing Han, Shunheng Zhou, Yuan Zhang, Sina Chen, Wen Xi, Chenchen Liu, Xu Zhou, Mengqin Yuan, Xiaoyu Yu, Lu Li, Yu Wang, Hui Ren, Jian Xie, Bin Li, Minzi Ju, You Zhou, Ziqi Liu, Zhongli Xiong, Ling Shen, Yuan Zhang, Ying Bai, Jun Chen, Wei Jiang, Honghong Yao
Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777 spots, allowing us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities...
February 7, 2024: Science Translational Medicine
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