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MRGPRX4 mediates phospho-drug–associated pruritus in a humanized mouse model Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-08 Daphne Chun-Che Chien, Nathachit Limjunyawong, Can Cao, James Meixiong, Qi Peng, Cheng-Ying Ho, Jonathan F. Fay, Bryan L. Roth, Xinzhong Dong
The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein–coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor
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The translational gap for gene therapies in low- and middle-income countries Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-08 Kevin W. Doxzen, Jennifer E. Adair, Yris Maria Fonseca Bazzo, Daima Bukini, Kenneth Cornetta, Varsha Dalal, Renato Luiz Guerino-Cunha, Suradej Hongeng, Geeta Jotwani, Cissy Kityo-Mutuluuza, Krishnamurti Lakshmanan, Johnny Mahlangu, Julie Makani, Vikram Mathews, Margareth C. Ozelo, Savita Rangarajan, Janine Scholefield, João Batista Silva Júnior, Joseph M. McCune
Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must
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Nothing about us without us: Advocacy and engagement in genetic medicine Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-08 Olabimpe Olayiwola, Adam Castillejo, Michael Louella, Moses Supercharger, Evelyn Harlow, Lynda Dee, Khadidja Abdallah, Cissy Kityo-Mutuluuza, Jennifer E. Adair, Rimas Orentas, Karine Dubé
The development of new genetic medicines to treat sickle cell disease highlights the need for greater collaboration between researchers and people with lived experiences. Drawing on the adage “Nothing about us, without us,” we call for increased investments in community advocacy and engagement.
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Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-08 Benjamin P. Hurrell, Yoshihiro Sakano, Stephen Shen, Doumet Georges Helou, Meng Li, Pedram Shafiei-Jahani, Mohammad Hossein Kazemi, Kei Sakano, Xin Li, Christine Quach, Richard Barbers, Omid Akbari
Group 2 innate lymphoid cells (ILC2s) rapidly induce a type 2 inflammation in the lungs in response to allergens. Here, we focused on the role of iron, a critical nutritional trace element, on ILC2 function and asthma pathogenesis. We found that transferrin receptor 1 (TfR1) is rapidly up-regulated and functional during ILC2 activation in the lungs, and blocking transferrin uptake reduces ILC2 expansion
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Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-08 Ying Yang, Hao Feng, Ying Tang, Zhenguo Wang, Ping Qiu, Xihua Huang, Lin Chang, Jifeng Zhang, Yuqing Eugene Chen, Dogukan Mizrak, Bo Yang
Thoracic aortic aneurysm (TAA) is a life-threatening vascular disease frequently associated with underlying genetic causes. An inadequate understanding of human TAA pathogenesis highlights the need for better disease models. Here, we established a functional human TAA model in an animal host by combining human induced pluripotent stem cells (hiPSCs), bioengineered vascular grafts (BVGs), and gene editing
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Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-01 Yongzhen Wei, Huan Jiang, Fengjuan Li, Chao Chai, Yaping Xu, Mengmeng Xing, Weiliang Deng, He Wang, Yuexin Zhu, Sen Yang, Yongquan Yu, Wenming Wang, Yan Wei, Yu Guo, Jinwei Tian, Jie Du, Zhikun Guo, Yuan Wang, Qiang Zhao
An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell– or fibroblast-specific knockout of Igf1r , the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin
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Vaccination for healthy aging Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-01 David E. Bloom, Simone Pecetta, Francesco Berlanda Scorza, Andrea Carfi, Bruce Carleton, Mariateresa Cipriano, Kathryn Edwards, Gianmarco Gasperini, Richard Malley, Arindam Nandi, Aurelia Nguyen, Lynda Stuart, Steve Black, Rino Rappuoli
As the world’s population grows older, vaccination is becoming a key strategy for promoting healthy aging. Despite scientific progress in adult vaccine development, obstacles such as immunosenescence and vaccine hesitancy remain. To unlock the potential of adult vaccines fully, we must enhance immunization programs, dispel misinformation, and invest in research that deepens our understanding of aging
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Electronic health record signatures identify undiagnosed patients with common variable immunodeficiency disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-01 Ruth Johnson, Alexis V. Stephens, Rachel Mester, Sergey Knyazev, Lisa A. Kohn, Malika K. Freund, Leroy Bondhus, Brian L. Hill, Tommer Schwarz, Noah Zaitlen, Valerie A. Arboleda, Lisa A. Bastarache, Bogdan Pasaniuc, Manish J. Butte
Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes
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Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-01 Brian L. Edlow, Mark Olchanyi, Holly J. Freeman, Jian Li, Chiara Maffei, Samuel B. Snider, Lilla Zöllei, J. Eugenio Iglesias, Jean Augustinack, Yelena G. Bodien, Robin L. Haynes, Douglas N. Greve, Bram R. Diamond, Allison Stevens, Joseph T. Giacino, Christophe Destrieux, Andre van der Kouwe, Emery N. Brown, Rebecca D. Folkerth, Bruce Fischl, Hannah C. Kinney
Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain
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Vaccination with antigenically complex hemagglutinin mixtures confers broad protection from influenza disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-01 Zhaochen Luo, Hector A. Miranda, Kaitlyn N. Burke, M. Ariel Spurrier, Madison Berry, Erica L. Stover, Rachel L. Spreng, Greg Waitt, Erik J. Soderblom, Andrew N. Macintyre, Kevin Wiehe, Nicholas S. Heaton
Current seasonal influenza virus vaccines induce responses primarily against immunodominant but highly plastic epitopes in the globular head of the hemagglutinin (HA) glycoprotein. Because of viral antigenic drift at these sites, vaccines need to be updated and readministered annually. To increase the breadth of influenza vaccine–mediated protection, we developed an antigenically complex mixture of
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Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome Sci. Transl. Med. (IF 17.1) Pub Date : 2024-05-01 Giulia Consiglieri, Francesca Tucci, Maurizio De Pellegrin, Barbara Guerrini, Alessandro Cattoni, Giulia Risca, Stefano Scarparo, Marina Sarzana, Silvia Pontesilli, Renata Mellone, Serena Gasperini, Stefania Galimberti, Paolo Silvani, Chiara Filisetti, Silvia Darin, Giulia Forni, Simona Miglietta, Ludovica Santi, Marcella Facchini, Ambra Corti, Francesca Fumagalli, Maria Pia Cicalese, Valeria Calbi
Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell–gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations
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Antigenic distance between primary and secondary dengue infections correlates with disease risk Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-24 Lin Wang, Angkana T. Huang, Leah C. Katzelnick, Noémie Lefrancq, Ana Coello Escoto, Loréna Duret, Nayeem Chowdhury, Richard Jarman, Matthew A. Conte, Irina Maljkovic Berry, Stefan Fernandez, Chonticha Klungthong, Butsaya Thaisomboonsuk, Piyarat Suntarattiwong, Warunee Vandepitte, Stephen S. Whitehead, Simon Cauchemez, Derek A. T. Cummings, Henrik Salje
Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection even in previously exposed individuals. In addition, for some pathogens, such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease through a mechanism known as antibody-dependent enhancement. However, it remains unclear whether
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Inhibiting Eph/ephrin signaling reduces vascular leak and endothelial cell dysfunction in mice with sepsis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-24 Nemat Khan, Vinod Kumar, Pengcheng Li, RAPIDS Study Group, Luregn J. Schlapbach, Andrew W. Boyd, Mark G. Coulthard, Trent M. Woodruff
Sepsis is a life-threatening disease caused by a dysregulated host response to infection, resulting in 11 million deaths globally each year. Vascular endothelial cell dysfunction results in the loss of endothelial barrier integrity, which contributes to sepsis-induced multiple organ failure and mortality. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ephrin ligands play
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An electroencephalogram microdisplay to visualize neuronal activity on the brain surface Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-24 Youngbin Tchoe, Tianhai Wu, Hoi Sang U, David M. Roth, Dongwoo Kim, Jihwan Lee, Daniel R. Cleary, Patricia Pizarro, Karen J. Tonsfeldt, Keundong Lee, Po Chun Chen, Andrew M. Bourhis, Ian Galton, Brian Coughlin, Jimmy C. Yang, Angelique C. Paulk, Eric Halgren, Sydney S. Cash, Shadi A. Dayeh
Functional mapping during brain surgery is applied to define brain areas that control critical functions and cannot be removed. Currently, these procedures rely on verbal interactions between the neurosurgeon and electrophysiologist, which can be time-consuming. In addition, the electrode grids that are used to measure brain activity and to identify the boundaries of pathological versus functional
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Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-24 Po Hu, Jack Rychik, Juanjuan Zhao, Huajun Bai, Aidan Bauer, Wenbao Yu, Elizabeth B. Rand, Kathryn M. Dodds, David J. Goldberg, Kai Tan, Benjamin J. Wilkins, Liming Pei
The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic
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The subacromial bursa modulates tendon healing after rotator cuff injury in rats Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-24 Brittany P. Marshall, Beth G. Ashinsky, Xavier E. Ferrer, Jennifer A. Kunes, Astia C. Innis, Andrew J. Luzzi, Lynn Ann Forrester, Kevin G. Burt, Andy J. Lee, Lee Song, Lauren E. Lisiewski, Rajesh K. Soni, Clark T. Hung, William N. Levine, David Kovacevic, Stavros Thomopoulos
Rotator cuff injuries result in more than 500,000 surgeries annually in the United States, many of which fail. These surgeries typically involve repair of the injured tendon and removal of the subacromial bursa, a synovial-like tissue that sits between the rotator cuff and the acromion. The subacromial bursa has been implicated in rotator cuff pathogenesis and healing. Using proteomic profiling of
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Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-17 Hoang Van Phan, Alexandra Tsitsiklis, Cole P. Maguire, Elias K. Haddad, Patrice M. Becker, Seunghee Kim-Schulze, Brian Lee, Jing Chen, Annmarie Hoch, Harry Pickering, Patrick van Zalm, Matthew C. Altman, Alison D. Augustine, Carolyn S. Calfee, Steve Bosinger, Charles B. Cairns, Walter Eckalbar, Leying Guan, Naresh Doni Jayavelu, Steven H. Kleinstein, Florian Krammer, Holden T. Maecker, Al Ozonoff,
Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between
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Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-17 Jason D. Roh, Claire Castro, Andy Z. Yu, Sarosh Rana, Sajid Shahul, Kathryn J. Gray, Michael C. Honigberg, Melanie Ricke-Hoch, Yoshiko Iwamoto, Ashish S. Yeri, Robert Kitchen, Justin Baldovino Guerra, Ryan Hobson, Vinita Chaudhari, Bliss Chang, Amy Sarma, Carolin Lerchenmüller, Zeina R. Al Sayed, Carmen Diaz Verdugo, Peng Xia, Niv Skarbianskis, Amit Zeisel, Johann Bauersachs, James L. Kirkland, S.
Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP)
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Nociceptor spontaneous activity is responsible for fragmenting non–rapid eye movement sleep in mouse models of neuropathic pain Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-17 Chloe Alexandre, Giulia Miracca, Victor Duarte Holanda, Ashley Sharma, Kamila Kourbanova, Ashley Ferreira, Maíra A. Bicca, Xiangsunze Zeng, Victoria A. Nassar, Seungkyu Lee, Satvinder Kaur, Sridevi V. Sarma, Pierre Sacré, Thomas E. Scammell, Clifford J. Woolf, Alban Latremoliere
Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund’s complete
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Increased β 2 -adrenergic signaling promotes fracture healing through callus neovascularization in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-17 Denise Jahn, Paul Richard Knapstein, Ellen Otto, Paul Köhli, Jan Sevecke, Frank Graef, Christine Graffmann, Melanie Fuchs, Shan Jiang, Mayla Rickert, Cordula Erdmann, Jessika Appelt, Lawik Revend, Quin Küttner, Jason Witte, Adibeh Rahmani, Georg Duda, Weixin Xie, Antonia Donat, Thorsten Schinke, Andranik Ivanov, Mireille Ngokingha Tchouto, Dieter Beule, Karl-Heinz Frosch, Anke Baranowsky, Serafeim
Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β 2 -adrenergic receptor (ADRB2) as a mediator of skeletal changes in response
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Deep learning assists detection of esophageal cancer and precursor lesions in a prospective, randomized controlled study Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-17 Shao-wei Li, Li-hui Zhang, Yue Cai, Xian-bin Zhou, Xin-yu Fu, Ya-qi Song, Shi-wen Xu, Shen-ping Tang, Ren-quan Luo, Qin Huang, Ling-ling Yan, Sai-qin He, Yu Zhang, Jun Wang, Shu-qiong Ge, Bin-bin Gu, Jin-bang Peng, Yi Wang, Li-na Fang, Wei-dan Wu, Wen-guang Ye, Min Zhu, Ding-hai Luo, Xiu-xiu Jin, Hai-deng Yang, Jing-jing Zhou, Zhen-zhen Wang, Jian-fen Wu, Qiao-qiao Qin, Yan-di Lu, Fei Wang, Ya-hong
Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate
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BCR signaling is required for posttransplant lymphoproliferative disease in immunodeficient mice receiving human B cells Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-10 Ting-ting Zhang, Rene Yu-Hong Cheng, Andee R. Ott, Noelle P. Dahl, Emmaline R. Suchland, Claire M. Stoffers, Gregory D. Asher, Deyin Hou, Christopher D. Thouvenel, Tyler F. Hill, David J. Rawlings, Richard G. James
Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo–differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of
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Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-10 Zilong Bai, Nicholas Bartelo, Maryam Aslam, Elisabeth A. Murphy, Caryn R. Hale, Nathalie E. Blachere, Salina Parveen, Edoardo Spolaore, Edward DiCarlo, Ellen M. Gravallese, Melanie H. Smith, Accelerating Medicines Partnership RA/SLE Network, Mayu O. Frank, Caroline S. Jiang, Haotan Zhang, Christina Pyrgaki, Myles J. Lewis, Shafaq Sikandar, Costantino Pitzalis, Joseph B. Lesnak, Khadijah Mazhar, Theodore
It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples
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Where do the pathogens that cause surgical site infections come from? Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-10 Jack A. Gilbert, John Alverdy
A study from Long et al. shows that many pathogens that cause surgical site infections during spine surgery come from the patient’s own microbiome, suggesting a paradigm shift in the understanding of surgical site infections that questions the effectiveness of current enhanced sterility and antibiotic protocols.
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Contribution of the patient microbiome to surgical site infection and antibiotic prophylaxis failure in spine surgery Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-10 Dustin R. Long, Chloe Bryson-Cahn, Adam Waalkes, Elizabeth A. Holmes, Kelsi Penewit, Celeste Tavolaro, Carlo Bellabarba, Fangyi Zhang, Jeannie D. Chan, Ferric C. Fang, John B. Lynch, Stephen J. Salipante
Despite modern antiseptic techniques, surgical site infection (SSI) remains a leading complication of surgery. However, the origins of SSI and the high rates of antimicrobial resistance observed in these infections are poorly understood. Using instrumented spine surgery as a model of clean (class I) skin incision, we prospectively sampled preoperative microbiomes and postoperative SSI isolates in a
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A mouse model of chronic primary pain that integrates clinically relevant genetic vulnerability, stress, and minor injury Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-10 Yaomin Wang, Shin Hyung Kim, Marguerita E. Klein, Jiegen Chen, Elizabeth Gu, Shad Smith, Andrey Bortsov, Gary D. Slade, Xin Zhang, Andrea G. Nackley
Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse model that integrated clinically relevant genetic (catechol-O-methyltransferase; COMT knockdown) and environmental (stress and injury) factors. Compared
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Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-10 Kimberly Nellenbach, Emily Mihalko, Seema Nandi, Drew W. Koch, Jagathpala Shetty, Leandro Moretti, Jennifer Sollinger, Nina Moiseiwitsch, Ana Sheridan, Sanika Pandit, Maureane Hoffman, Lauren V. Schnabel, L. Andrew Lyon, Thomas H. Barker, Ashley C. Brown
Uncontrolled bleeding after trauma represents a substantial clinical problem. The current standard of care to treat bleeding after trauma is transfusion of blood products including platelets; however, donated platelets have a short shelf life, are in limited supply, and carry immunogenicity and contamination risks. Consequently, there is a critical need to develop hemostatic platelet alternatives.
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Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Sandra Donkervoort, Martijn van de Locht, Dario Ronchi, Janine Reunert, Catriona A. McLean, Maha Zaki, Rotem Orbach, Josine M. de Winter, Stefan Conijn, Daan Hoomoedt, Osorio Lopes Abath Neto, Francesca Magri, Angela N. Viaene, A. Reghan Foley, Svetlana Gorokhova, Véronique Bolduc, Ying Hu, Nicole Acquaye, Laura Napoli, Julien H. Park, Kalyan Immadisetty, Lee B. Miles, Mona Essawi, Salar McModie, Leonardo
Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast (TNNI2) and TnI-slow (TNNI1), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants
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Therapeutic administration of a cross-reactive mAb targeting the fusion glycoprotein of Nipah virus protects nonhuman primates Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Larry Zeitlin, Robert W. Cross, Courtney Woolsey, Brandyn R. West, Viktoriya Borisevich, Krystle N. Agans, Abhishek N. Prasad, Daniel J. Deer, Lauren Stuart, Maria McCavitt-Malvido, Do H. Kim, James Pettitt, James E. CroweJr., Kevin J. Whaley, David Veesler, Antony Dimitrov, Dafna M. Abelson, Thomas W. Geisbert, Christopher C. Broder
No licensed vaccines or therapies exist for patients infected with Nipah virus (NiV), although an experimental human monoclonal antibody (mAb) cross-reactive to the NiV and Hendra virus (HeV) G glycoprotein, m102.4, has been tested in a phase 1 trial and has been provided under compassionate use for both HeV and NiV exposures. NiV is a highly pathogenic zoonotic paramyxovirus causing regular outbreaks
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Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Ziyan Pan, Rasha El Sharkway, Ali Bayoumi, Mayada Metwally, Brian S. Gloss, Robert Brink, David Bo Lu, Christopher Liddle, Saleh A. Alqahtani, Jun Yu, Philip J. O’Connell, Jacob George, Mohammed Eslam
Transforming growth factor–β (TGFβ) drives fibrosis and disease progression in a number of chronic disorders, but targeting this ubiquitously expressed cytokine may not yield a viable and safe antifibrotic therapy. Here, we sought to identify alternative ways to inhibit TGFβ signaling using human hepatic stellate cells and macrophages from humans and mice in vitro, as well as mouse models of liver
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Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Jinchao Hou, Yun Chen, Zhangying Cai, Gyu Seong Heo, Carla M. Yuede, Zuoxu Wang, Kent Lin, Fareeha Saadi, Tihana Trsan, Aivi T. Nguyen, Eleni Constantopoulos, Rachel A. Larsen, Yiyang Zhu, Nicole D. Wagner, Nolan McLaughlin, Xinyi Cynthia Kuang, Alexander D. Barrow, Dian Li, Yingyue Zhou, Shoutang Wang, Susan Gilfillan, Michael L. Gross, Simone Brioschi, Yongjian Liu, David M. Holtzman, Marco Colonna
Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein
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Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Ziyan Pan, Rasha El Sharkway, Ali Bayoumi, Mayada Metwally, Brian S. Gloss, Robert Brink, David Bo Lu, Christopher Liddle, Saleh A. Alqahtani, Jun Yu, Philip J. O’Connell, Jacob George, Mohammed Eslam
Transforming growth factor–β (TGFβ) drives fibrosis and disease progression in a number of chronic disorders, but targeting this ubiquitously expressed cytokine may not yield a viable and safe antifibrotic therapy. Here, we sought to identify alternative ways to inhibit TGFβ signaling using human hepatic stellate cells and macrophages from humans and mice in vitro, as well as mouse models of liver
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Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Sandra Donkervoort, Martijn van de Locht, Dario Ronchi, Janine Reunert, Catriona A. McLean, Maha Zaki, Rotem Orbach, Josine M. de Winter, Stefan Conijn, Daan Hoomoedt, Osorio Lopes Abath Neto, Francesca Magri, Angela N. Viaene, A. Reghan Foley, Svetlana Gorokhova, Véronique Bolduc, Ying Hu, Nicole Acquaye, Laura Napoli, Julien H. Park, Kalyan Immadisetty, Lee B. Miles, Mona Essawi, Salar McModie, Leonardo
Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast ( TNNI2 ) and TnI-slow ( TNNI1 ), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants
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TSPAN8+ myofibroblastic cancer–associated fibroblasts promote chemoresistance in patients with breast cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Guangjian Fan, Bo Yu, Lei Tang, Rongxuan Zhu, Jianhua Chen, Ying Zhu, He Huang, Liying Zhou, Jun Liu, Wei Wang, Zhonghua Tao, Fengchun Zhang, Siwei Yu, Xiaoqing Lu, Yuan Cao, Shaoqian Du, Huihui Li, Junjian Li, Jian Zhang, He Ren, Olivier Gires, Haikun Liu, Xin Wang, Jun Qin, Hongxia Wang
Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+
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Therapeutic administration of a cross-reactive mAb targeting the fusion glycoprotein of Nipah virus protects nonhuman primates Sci. Transl. Med. (IF 17.1) Pub Date : 2024-04-03 Larry Zeitlin, Robert W. Cross, Courtney Woolsey, Brandyn R. West, Viktoriya Borisevich, Krystle N. Agans, Abhishek N. Prasad, Daniel J. Deer, Lauren Stuart, Maria McCavitt-Malvido, Do H. Kim, James Pettitt, James E. Crowe, Kevin J. Whaley, David Veesler, Antony Dimitrov, Dafna M. Abelson, Thomas W. Geisbert, Christopher C. Broder
No licensed vaccines or therapies exist for patients infected with Nipah virus (NiV), although an experimental human monoclonal antibody (mAb) cross-reactive to the NiV and Hendra virus (HeV) G glycoprotein, m102.4, has been tested in a phase 1 trial and has been provided under compassionate use for both HeV and NiV exposures. NiV is a highly pathogenic zoonotic paramyxovirus causing regular outbreaks
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Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Minrui Liang, Nicholas Dickel, Andrea-Hermina Györfi, Bilgesu SafakTümerdem, Yi-Nan Li, Aleix Rius Rigau, Chunguang Liang, Xuezhi Hong, Lichong Shen, Alexandru-Emil Matei, Thuong Trinh-Minh, Cuong Tran-Manh, Xiang Zhou, Ariella Zehender, Alexander Kreuter, Hejian Zou, Georg Schett, Meik Kunz, Jörg H. W. Distler
Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis–associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and
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Multiple sclerosis endophenotypes identified by high-dimensional blood signatures are associated with distinct disease trajectories Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Catharina C. Gross, Andreas Schulte-Mecklenbeck, Olga V. Steinberg, Timo Wirth, Sarah Lauks, Stefan Bittner, Patrick Schindler, Sergio E. Baranzini, Sergiu Groppa, Judith Bellmann-Strobl, Nora Bünger, Claudia Chien, Eva Dawin, Maria Eveslage, Vinzenz Fleischer, Gabriel Gonzalez-Escamilla, Barbara Gisevius, Jürgen Haas, Martin Kerschensteiner, Lucienne Kirstein, Catharina Korsukewitz, Lisa Lohmann,
One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible
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Comparison of the immunogenicity and protective efficacy of ACAM2000, MVA, and vectored subunit vaccines for Mpox in rhesus macaques Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Catherine Jacob-Dolan, Darren Ty, David Hope, Katherine McMahan, Jinyan Liu, Olivia C. Powers, Catherine A. Cotter, Michela Sciacca, Cindy Wu, Erica Borducchi, Emily Bouffard, Hannah Richter, Jason Velasco, Elyse Teow, Mona Boursiquot, Anthony Cook, Karen Feliciano, Jake Yalley-Ogunro, Michael S. Seaman, Laurent Pessiant, Mark G. Lewis, Hanne Andersen, Bernard Moss, Dan H. Barouch
The 2022–2023 mpox outbreak triggered vaccination efforts using smallpox vaccines that were approved for mpox, including modified vaccinia Ankara (MVA; JYNNEOS), which is a safer alternative to live replicating vaccinia virus (ACAM2000). Here, we compare the immunogenicity and protective efficacy of JYNNEOS by the subcutaneous or intradermal routes, ACAM2000 by the percutaneous route, and subunit Ad35
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The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Patrick J. Gleeson, Nicolas Benech, Jonathan Chemouny, Eleftheria Metallinou, Laureline Berthelot, Jennifer da Silva, Julie Bex-Coudrat, Erwan Boedec, Fanny Canesi, Carine Bounaix, Willy Morelle, Maryse Moya-Nilges, John Kenny, Liam O’Mahony, Loredana Saveanu, Bertrand Arnulf, Aurélie Sannier, Eric Daugas, François Vrtovsnik, Patricia Lepage, Harry Sokol, Renato C. Monteiro
Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA
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Comparison of the immunogenicity and protective efficacy of ACAM2000, MVA, and vectored subunit vaccines for Mpox in rhesus macaques Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Catherine Jacob-Dolan, Darren Ty, David Hope, Katherine McMahan, Jinyan Liu, Olivia C. Powers, Catherine A. Cotter, Michela Sciacca, Cindy Wu, Erica Borducchi, Emily Bouffard, Hannah Richter, Jason Velasco, Elyse Teow, Mona Boursiquot, Anthony Cook, Karen Feliciano, Jake Yalley-Ogunro, Michael S. Seaman, Laurent Pessiant, Mark G. Lewis, Hanne Andersen, Bernard Moss, Dan H. Barouch
The 2022–2023 mpox outbreak triggered vaccination efforts using smallpox vaccines that were approved for mpox, including modified vaccinia Ankara (MVA; JYNNEOS), which is a safer alternative to live replicating vaccinia virus (ACAM2000). Here, we compare the immunogenicity and protective efficacy of JYNNEOS by the subcutaneous or intradermal routes, ACAM2000 by the percutaneous route, and subunit Ad35
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Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Minrui Liang, Nicholas Dickel, Andrea-Hermina Györfi, Bilgesu SafakTümerdem, Yi-Nan Li, Aleix Rius Rigau, Chunguang Liang, Xuezhi Hong, Lichong Shen, Alexandru-Emil Matei, Thuong Trinh-Minh, Cuong Tran-Manh, Xiang Zhou, Ariella Zehender, Alexander Kreuter, Hejian Zou, Georg Schett, Meik Kunz, Jörg H. W. Distler
Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis–associated ( ENHO ) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and
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The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Patrick J. Gleeson, Nicolas Benech, Jonathan Chemouny, Eleftheria Metallinou, Laureline Berthelot, Jennifer da Silva, Julie Bex-Coudrat, Erwan Boedec, Fanny Canesi, Carine Bounaix, Willy Morelle, Maryse Moya-Nilges, John Kenny, Liam O’Mahony, Loredana Saveanu, Bertrand Arnulf, Aurélie Sannier, Eric Daugas, François Vrtovsnik, Patricia Lepage, Harry Sokol, Renato C. Monteiro
Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA
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A tough bioadhesive hydrogel supports sutureless sealing of the dural membrane in porcine and ex vivo human tissue Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Kyle C. Wu, Benjamin R. Freedman, Phoebe S. Kwon, Matthew Torre, Daniel O. Kent, Wenya Linda Bi, David J. Mooney
Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply
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An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Michael J. McPherson, Adrian D. Hobson, Axel HernandezJr., Christopher C. Marvin, Wendy Waegell, Christian Goess, Jason Z. Oh, Dan Shi, Martin E. Hayes, Lu Wang, Lu Wang, Diana Schmidt, Zhi Wang, Victoria Pitney, Kimberley McCarthy, Ying Jia, Ce Wang, Bit Na Kang, Shaughn Bryant, Suzanne Mathieu, Melanie Ruzek, Julie Parmentier, Ronilda R. D’Cunha, Yinuo Pang, Lucy Phillips, Nathan J. Brown, Jianwen
Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore
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The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Martin Skov, Titia Q. Ruijs, Thomas S. Grønnebæk, Marianne Skals, Anders Riisager, Jeppe Blichfeldt Winther, Kamilla Løhde Tordrup Dybdahl, Anders Findsen, Jeanette J. Morgen, Nete Huus, Martin Broch-Lips, Ole B. Nielsen, Catherine M.K.E. de Cuba, Jules A.A.C. Heuberger, Marieke L. de Kam, Martijn Tannemaat, Jan J. G. M. Verschuuren, Lars J. S. Knutsen, Nicholas M. Kelly, Klaus G. Jensen, William D
Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl−) ion channel that plays
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Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Jianxing Yin, Xin Ge, Fangshu Ding, Liuguijie He, Keying Song, Zhumei Shi, Zehe Ge, Junxia Zhang, Jing Ji, Xiefeng Wang, Ningwei Zhao, Chuanjun Shu, Fan Lin, Qianghu Wang, Qigang Zhou, Yuandong Cao, Wentao Liu, Dan Ye, Jeremy N. Rich, Xiuxing Wang, Yongping You, Xu Qian
Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic
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Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Emmeran Le Moal, Yuguo Liu, Jasmin Collerette-Tremblay, Simon Dumontier, Paul Fabre, Thomas Molina, Junio Dort, Zakaria Orfi, Nicolas Denault, Joël Boutin, Joris Michaud, Hugo Giguère, Alexandre Desroches, Kien Trân, Benjamin Ellezam, François Vézina, Sonia Bedard, Catherine Raynaud, Frederic Balg, Philippe Sarret, Pierre-Luc Boudreault, Michelle S. Scott, Jean-Bernard Denault, Eric Marsault, Jerome
Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2–related MD, and collagen VI–related myopathy were associated with inefficient mobilization of MuSCs after tissue damage
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Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Jianxing Yin, Xin Ge, Fangshu Ding, Liuguijie He, Keying Song, Zhumei Shi, Zehe Ge, Junxia Zhang, Jing Ji, Xiefeng Wang, Ningwei Zhao, Chuanjun Shu, Fan Lin, Qianghu Wang, Qigang Zhou, Yuandong Cao, Wentao Liu, Dan Ye, Jeremy N. Rich, Xiuxing Wang, Yongping You, Xu Qian
Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic
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The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Martin Skov, Titia Q. Ruijs, Thomas S. Grønnebæk, Marianne Skals, Anders Riisager, Jeppe Blichfeldt Winther, Kamilla Løhde Tordrup Dybdahl, Anders Findsen, Jeanette J. Morgen, Nete Huus, Martin Broch-Lips, Ole B. Nielsen, Catherine M.K.E. de Cuba, Jules A.A.C. Heuberger, Marieke L. de Kam, Martijn Tannemaat, Jan J. G. M. Verschuuren, Lars J. S. Knutsen, Nicholas M. Kelly, Klaus G. Jensen, William D
Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl − ) ion channel that plays
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Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Emmeran Le Moal, Yuguo Liu, Jasmin Collerette-Tremblay, Simon Dumontier, Paul Fabre, Thomas Molina, Junio Dort, Zakaria Orfi, Nicolas Denault, Joël Boutin, Joris Michaud, Hugo Giguère, Alexandre Desroches, Kien Trân, Benjamin Ellezam, François Vézina, Sonia Bedard, Catherine Raynaud, Frederic Balg, Philippe Sarret, Pierre-Luc Boudreault, Michelle S. Scott, Jean-Bernard Denault, Eric Marsault, Jerome
Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2–related MD, and collagen VI–related myopathy were associated with inefficient mobilization of MuSCs after tissue damage
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A tough bioadhesive hydrogel supports sutureless sealing of the dural membrane in porcine and ex vivo human tissue Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Kyle C. Wu, Benjamin R. Freedman, Phoebe S. Kwon, Matthew Torre, Daniel O. Kent, Wenya Linda Bi, David J. Mooney
Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply
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An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Michael J. McPherson, Adrian D. Hobson, Axel Hernandez, Christopher C. Marvin, Wendy Waegell, Christian Goess, Jason Z. Oh, Dan Shi, Martin E. Hayes, Lu Wang, Lu Wang, Diana Schmidt, Zhi Wang, Victoria Pitney, Kimberley McCarthy, Ying Jia, Ce Wang, Bit Na Kang, Shaughn Bryant, Suzanne Mathieu, Melanie Ruzek, Julie Parmentier, Ronilda R. D’Cunha, Yinuo Pang, Lucy Phillips, Nathan J. Brown, Jianwen Xu
Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore
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An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Michael Westberg, Yichi Su, Xinzhi Zou, Pinghan Huang, Arjun Rustagi, Jaishree Garhyan, Puja Bhavesh Patel, Daniel Fernandez, Yan Wu, Chenzhou Hao, Chieh-Wen Lo, Marwah Karim, Lin Ning, Aimee Beck, Panatda Saenkham-Huntsinger, Vivian Tat, Aleksandra Drelich, Bi-Hung Peng, Shirit Einav, Chien-Te K. Tseng, Catherine Blish, Michael Z. Lin
Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants
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Genome-wide repeat landscapes in cancer and cell-free DNA Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Akshaya V. Annapragada, Noushin Niknafs, James R. White, Daniel C. Bruhm, Christopher Cherry, Jamie E. Medina, Vilmos Adleff, Carolyn Hruban, Dimitrios Mathios, Zachariah H. Foda, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu
Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma
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Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Linkang Zhou, Xiaoxue Qiu, Ziyi Meng, Tongyu Liu, Zhimin Chen, Peng Zhang, Henry Kuang, Tong Pan, You Lu, Ling Qi, David P. Olson, X. Z. Shawn Xu, Y. Eugene Chen, Siming Li, Jiandie D. Lin
Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of
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Harnessing regulatory T cells to establish immune tolerance Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Patrick Ho, Ellen Cahir-McFarland, Jason D. Fontenot, Tracey Lodie, Adel Nada, Qizhi Tang, Laurence A. Turka, Jeffrey A. Bluestone
Engineered regulatory T (Treg) cells have emerged as precision therapeutics aimed at inducing immune tolerance while reducing the risks associated with generalized immunosuppression. This Viewpoint highlights the opportunities and challenges for engineered Treg cell therapies in treating autoimmune and other inflammatory diseases.
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Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Jelena Scekic-Zahirovic, Cristina Benetton, Aurore Brunet, XiaoQian Ye, Evgeny Logunov, Vincent Douchamps, Salim Megat, Virginie Andry, Vanessa Wing Yin Kan, Geoffrey Stuart-Lopez, Johan Gilet, Simon J. Guillot, Sylvie Dirrig-Grosch, Charlotte Gorin, Margaux Trombini, Stéphane Dieterle, Jérôme Sinniger, Mathieu Fischer, Frédérique René, Zeynep Gunes, Pascal Kessler, Luc Dupuis, Pierre-François Pradat
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability
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Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Jelena Scekic-Zahirovic, Cristina Benetton, Aurore Brunet, XiaoQian Ye, Evgeny Logunov, Vincent Douchamps, Salim Megat, Virginie Andry, Vanessa Wing Yin Kan, Geoffrey Stuart-Lopez, Johan Gilet, Simon J. Guillot, Sylvie Dirrig-Grosch, Charlotte Gorin, Margaux Trombini, Stéphane Dieterle, Jérôme Sinniger, Mathieu Fischer, Frédérique René, Zeynep Gunes, Pascal Kessler, Luc Dupuis, Pierre-François Pradat
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability
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Hepatic danger signaling triggers TREM2 + macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Linkang Zhou, Xiaoxue Qiu, Ziyi Meng, Tongyu Liu, Zhimin Chen, Peng Zhang, Henry Kuang, Tong Pan, You Lu, Ling Qi, David P. Olson, X. Z. Shawn Xu, Y. Eugene Chen, Siming Li, Jiandie D. Lin
Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2 + macrophages in various disease conditions, and substantial induction of
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Genome-wide repeat landscapes in cancer and cell-free DNA Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Akshaya V. Annapragada, Noushin Niknafs, James R. White, Daniel C. Bruhm, Christopher Cherry, Jamie E. Medina, Vilmos Adleff, Carolyn Hruban, Dimitrios Mathios, Zachariah H. Foda, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu
Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma