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Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae after acute COVID-19 Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-17 Chaofan Li, Wei Qian, Xiaoqin Wei, Harish Narasimhan, Yue Wu, Mohd Arish, In Su Cheon, Jinyi Tang, Gislane de Almeida Santos, Ying Li, Kamyar Sharifi, Ryan Kern, Robert Vassallo, Jie Sun
Postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) represent an urgent public health challenge and are estimated to affect more than 60 million individuals globally. Although a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood-based studies,
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Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-17 Deborah M. Eaton, Benjamin W. Lee, Matthew A. Caporizzo, Amit Iyengar, Christina Y. Chen, Keita Uchida, Guillaume Marcellin, Yoann Lannay, Alexia Vite, Kenneth C. Bedi, Claire F. Brady, Julia N. Smolyak, Danika Meldrum, Jessica Dominic, Noah Weingarten, Mrinal Patel, Andrew Belec, Khaled Hached, Pavan Atluri, Siem Van Der Laan, Benjamin L. Prosser, Kenneth B. Margulies
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored
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Knockdown of swine leukocyte antigen expression in porcine lung transplants enables graft survival without immunosuppression Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-17 Constanca Figueiredo, Chen Chen-Wacker, Jawad Salman, Marco Carvalho-Oliveira, Thierry Siemeni Monthé, Klaus Höffler, Tamina Rother, Karolin Hacker, Emilio Valdivia, Olena Pogozhykh, Sabine Hammer, Wiebke Sommer, Yuliia Yuzefovych, Nadine Wenzel, Axel Haverich, Gregor Warnecke, Rainer Blasczyk
Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this
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Extracellular vesicle–packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-17 Shangyou Zheng, Chonghui Hu, Qing Lin, Tingting Li, Guolin Li, Qing Tian, Xiang Zhang, Tianhao Huang, Yuancheng Ye, Rihua He, Changhao Chen, Yu Zhou, Rufu Chen
Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence
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Molecular dissection of cobra venom highlights heparinoids as an antidote for spitting cobra envenoming Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-17 Tian Y. Du, Steven R. Hall, Felicity Chung, Sergey Kurdyukov, Edouard Crittenden, Karishma Patel, Charlotte A. Dawson, Adam P. Westhorpe, Keirah E. Bartlett, Sean A. Rasmussen, Cesar L. Moreno, Christopher E. Denes, Laura-Oana Albulescu, Amy E. Marriott, Joel P. Mackay, Mark C. Wilkinson, José María Gutiérrez, Nicholas R. Casewell, G. Gregory Neely
Snakebites affect about 1.8 million people annually. The current standard of care involves antibody-based antivenoms, which can be difficult to access and are generally not effective against local tissue injury, the primary cause of morbidity. Here, we used a pooled whole-genome CRISPR knockout screen to define human genes that, when targeted, modify cell responses to spitting cobra venoms. A large
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Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-10 Brian J. Mog, Nikita Marcou, Sarah R. DiNapoli, Alexander H. Pearlman, Tushar D. Nichakawade, Michael S. Hwang, Jacqueline Douglass, Emily Han-Chung Hsiue, Stephanie Glavaris, Katharine M. Wright, Maximilian F. Konig, Suman Paul, Nicolas Wyhs, Jiaxin Ge, Michelle S. Miller, P. Azurmendi, Evangeline Watson, Drew M. Pardoll, Sandra B. Gabelli, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler
Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen–binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high
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An open-label, randomized controlled trial to assess a ketogenic diet in critically ill patients with sepsis Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-10 Tim Rahmel, David Effinger, Thilo Bracht, Leonore Griep, Björn Koos, Barbara Sitek, Max Hübner, Simon Hirschberger, Jale Basten, Nina Timmesfeld, Michael Adamzik, Simone Kreth
Patients with sepsis experience metabolic and immunologic dysfunction that may be amplified by standard carbohydrate-based nutrition. A ketogenic diet (KD) may offer an immunologically advantageous alternative, although clinical evidence is limited. We conducted a single-center, open-label, randomized controlled trial to assess whether a KD could induce stable ketosis in critically ill patients with
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Harmine and exendin-4 combination therapy safely expands human β cell mass in vivo in a mouse xenograft system Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-10 Carolina Rosselot, Yansui Li, Peng Wang, Alexandra Alvarsson, Kara Beliard, Geming Lu, Randy Kang, Rosemary Li, Hongtao Liu, Virginia Gillespie, Nikolaos Tzavaras, Kunal Kumar, Robert J. DeVita, Andrew F. Stewart, Sarah A. Stanley, Adolfo Garcia-Ocaña
Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing β cells are reduced in number in most people with diabetes, but most individuals still have some residual β cells. However, none of the many diabetes drugs in common use increases human β cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical
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Hemodynamic evaluation of biomaterial-based surgery for Tetralogy of Fallot using a biorobotic heart, in silico, and ovine models Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-10 Manisha Singh, François Roubertie, Caglar Ozturk, Paul Borchiellini, Adeline Rames, Jean Bonnemain, Samuel Dutra Gollob, Sophie X. Wang, Jérôme Naulin, Dounia El Hamrani, Nathalie Dugot-Senant, Isalyne Gosselin, Célia Grenet, Nicolas L’Heureux, Ellen T. Roche, Fabien Kawecki
Tetralogy of Fallot is a congenital heart disease affecting newborns and involves stenosis of the right ventricular outflow tract (RVOT). Surgical correction often widens the RVOT with a transannular enlargement patch, but this causes issues including pulmonary valve insufficiency and progressive right ventricle failure. A monocusp valve can prevent pulmonary regurgitation; however, valve failure resulting
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Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-10 Wenliang Zhu, Wan Du, Arun Prabhu Rameshbabu, Ariel Miura Armstrong, Stewart Silver, Yehree Kim, Wei Wei, Yilai Shu, Xuezhong Liu, Morag A. Lewis, Karen P. Steel, Zheng-Yi Chen
Mutations in microRNA-96 ( MIR96 ) cause autosomal dominant deafness-50 (DFNA50), a form of delayed-onset hearing loss. Genome editing has shown efficacy in hearing recovery through intervention in neonatal mice, yet editing in the adult inner ear is necessary for clinical applications, which has not been done. Here, we developed a genome editing therapy for the MIR96 mutation 14C>A by screening different
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Nasal tau immunotherapy clears intracellular tau pathology and improves cognitive functions in aged tauopathy mice Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-03 Sagar Gaikwad, Nicha Puangmalai, Minal Sonawane, Mauro Montalbano, Rachel Price, Malini S. Iyer, Anamika Ray, Sandra Moreno, Rakez Kayed
Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD). These aggregates are prevalent within intracellular compartments. Current tau immunotherapies have shown limited efficacy in clearing intracellular tau aggregates and improving cognition in clinical trials. In this study, we developed toxic tau conformation–specific monoclonal antibody-2
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Prostate tissue ablation and drug delivery by an image-guided injectable ionic liquid in ex vivo and in vivo models Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-03 Yusuf M. Demirlenk, Hassan Albadawi, Zefu Zhang, Dila Atar, Enes Cevik, Hyeongseop Keum, Jinjoo Kim, Suliman Rehman, Seyda Gunduz, Erin Graf, Joseph L. Mayer, Pedro R. Dos Santos, Rahmi Oklu
Benign prostatic hyperplasia and prostate cancer are often associated with lower urinary tract symptoms, which can severely affect patient quality of life. To address this challenge, we developed and optimized an injectable compound, prostate ablation and drug delivery agent (PADA), for percutaneous prostate tissue ablation and concurrently delivered therapeutic agents. PADA is an ionic liquid composed
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Lupus IgA1 autoantibodies synergize with IgG to enhance plasmacytoid dendritic cell responses to RNA-containing immune complexes Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-03 Hayley R. Waterman, Matthew J. Dufort, Sylvia E. Posso, Minjian Ni, Lucy Z. Li, Chengsong Zhu, Prithvi Raj, Kelly D. Smith, Jane H. Buckner, Jessica A. Hamerman
Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes
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Tissue-based T cell activation and viral RNA persist for up to 2 years after SARS-CoV-2 infection Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-03 Michael J. Peluso, Dylan Ryder, Robert R. Flavell, Yingbing Wang, Jelena Levi, Brian H. LaFranchi, Tyler-Marie Deveau, Amanda M. Buck, Sadie E. Munter, Kofi A. Asare, Maya Aslam, Walter Koch, Gyula Szabo, Rebecca Hoh, Monika Deswal, Antonio E. Rodriguez, Melissa Buitrago, Viva Tai, Uttam Shrestha, Scott Lu, Sarah A. Goldberg, Thomas Dalhuisen, Joshua J. Vasquez, Matthew S. Durstenfeld, Priscilla Y
The mechanisms of postacute medical conditions and unexplained symptoms after SARS-CoV-2 infection [Long Covid (LC)] are incompletely understood. There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles. We performed whole-body positron emission tomography imaging in a well-characterized cohort of 24 participants at time points ranging from
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PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections Sci. Transl. Med. (IF 15.8) Pub Date : 2024-07-03 Ryan M. Shepard, Anghesom Ghebremedhin, Isaraphorn Pratumchai, Sally R. Robinson, Courtney Betts, Jingjing Hu, Roman Sasik, Kathleen M. Fisch, Jaroslav Zak, Hui Chen, Marc Paradise, Jason Rivera, Mohammad Amjad, Satoshi Uchiyama, Hideya Seo, Alejandro D. Campos, Denise Ann Dayao, Saul Tzipori, Cesar Piedra-Mora, Soumita Das, Farnaz Hasteh, Hana Russo, Xin Sun, Le Xu, Laura Crotty E. Alexander, Jason
Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected
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Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-26 John V. Pluvinage, Thomas Ngo, Camille Fouassier, Maura McDonagh, Brandon B. Holmes, Christopher M. Bartley, Sravani Kondapavulur, Charlotte Hurabielle, Aaron Bodansky, Vincent Pai, Sam Hinman, Ava Aslanpour, Bonny D. Alvarenga, Kelsey C. Zorn, Colin Zamecnik, Adrian McCann, Andoni I. Asencor, Trung Huynh, Weston Browne, Asritha Tubati, Michael S. Haney, Vanja C. Douglas, Martineau Louine, Bruce A
Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in
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TRPML1 triggers ferroptosis defense and is a potential therapeutic target in AKT-hyperactivated cancer Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-26 Hai-Liang Zhang, Bing-Xin Hu, Zhi-Peng Ye, Zhi-Ling Li, Shan Liu, Wen-Qing Zhong, Tian Du, Dong Yang, Jia Mai, Li-Chao Li, Yu-Hong Chen, Xian-Ying Zhu, Xuan Li, Gong-Kan Feng, Xiao-Feng Zhu, Rong Deng
Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated
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New government drug repurposing programs: Opportunities and uncertainties Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-26 Johnathon Liddicoat, Ashleigh Hamidzadeh, Kathleen Liddell, Marco Schito, David Simon, Mateo Aboy, Timo Minssen
Drug repurposing can be cheaper and faster than developing new compounds. Yet, it remains underused, partially because of regulatory and intellectual property challenges. Policy-makers in the United States and Europe have created seven drug development programs that aim to overcome these challenges using a variety of different strategies.
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AZD3152 neutralizes SARS-CoV-2 historical and contemporary variants and is protective in hamsters and well tolerated in adults Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-26 Yingyun Cai, Seme Diallo, Kim Rosenthal, Kuishu Ren, Daniel J. Flores, Andrew Dippel, Vaheh Oganesyan, Nydia van Dyk, Xiaoru Chen, Erin Cantu, Rakesh Choudhary, Michal Sulikowski, Hibret Adissu, Bhavna Chawla, Swagata Kar, Chang Liu, Aiste Dijokaite-Guraliuc, Juthathip Mongkolsapaya, Saravanan Rajan, Yueh-Ming Loo, Rohini Beavon, Chris Webber, Lee-Jah Chang, Steven Thomas, Lindsay Clegg, Huixia Zhang
The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2–neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain
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MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-26 Simon Perrin, Sanela Protic, Vincent Bretegnier, Ingrid Laurendeau, Oriane Duchamp de Lageneste, Nicolas Panara, Odile Ruckebusch, Marine Luka, Cécile Masson, Théodora Maillard, Fanny Coulpier, Stéphanie Pannier, Philippe Wicart, Smail Hadj-Rabia, Katarzyna J. Radomska, Mohammed Zarhrate, Mickael Ménager, Dominique Vidaud, Piotr Topilko, Béatrice Parfait, Céline Colnot
Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS–mitogen-activated protein kinase (MAPK) signaling pathway.
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Proteomic analysis of Alzheimer’s disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-26 Eric B. Dammer, Anantharaman Shantaraman, Lingyan Ping, Duc M. Duong, Ekaterina S. Gerasimov, Suda Parimala Ravindran, Valborg Gudmundsdottir, Elisabet A. Frick, Gabriela T. Gomez, Keenan A. Walker, Valur Emilsson, Lori L. Jennings, Vilmundur Gudnason, Daniel Western, Carlos Cruchaga, James J. Lah, Thomas S. Wingo, Aliza P. Wingo, Nicholas T. Seyfried, Allan I. Levey, Erik C. B. Johnson
Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aβ and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated
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A subpopulation of tissue remodeling monocytes stimulates revascularization of the ischemic limb Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-19 Ashish S. Patel, Francesca E. Ludwinski, Alexander Kerr, Simon Farkas, Puja Kapoor, Laura Bertolaccini, Ramon Fernandes, Paul R. Jones, Donal McLornan, Lefteris Livieratos, Prakash Saha, Alberto Smith, Bijan Modarai
Despite decades of effort aimed at developing clinically effective cell therapies, including mixed population mononuclear cells, to revascularize the ischemic limb, there remains a paucity of patient-based studies that inform the function and fate of candidate cell types. In this study, we showed that circulating proangiogenic/arteriogenic monocytes (PAMs) expressing the FcγIIIA receptor CD16 were
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Inhibiting AGTR1 reduces AML burden and protects the heart from cardiotoxicity in mouse models Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-19 Yi Pan, Chen Wang, WenXuan Zhou, Yao Shi, XiaDuo Meng, Yasir Muhammad, Richard D. Hammer, Bei Jia, Hong Zheng, De-Pei Li, Zhenguo Liu, Gerhard Hildebrandt, XunLei Kang
Clinical treatment of acute myeloid leukemia (AML) largely relies on intensive chemotherapy. However, the application of chemotherapy is often hindered by cardiotoxicity. Patient sequence data revealed that angiotensin II receptor type 1 ( AGTR1 ) is a shared target between AML and cardiovascular disease (CVD). We found that inhibiting AGTR1 sensitized AML to chemotherapy and protected the heart against
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Diet shapes the metabolite profile in the intact human ileum, which affects PYY release Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-19 Aygul Dagbasi, Claire Byrne, Dominic Blunt, Jose Ivan Serrano-Contreras, Georgia Franco Becker, Jesus Miguens Blanco, Stephane Camuzeaux, Edward Chambers, Nathan Danckert, Cathrina Edwards, Andres Bernal, Maria Valdivia Garcia, Aylin Hanyaloglu, Elaine Holmes, Yue Ma, Julian Marchesi, Laura Martinez-Gili, Lilian Mendoza, Martina Tashkova, Natalia Perez-Moral, Isabel Garcia-Perez, Andres Castillo Robles
The human ileum contains a high density of enteroendocrine L-cells, which release the appetite-suppressing hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in response to food intake. Recent evidence highlighted the potential role of food structures in PYY release, but the link between food structures, ileal metabolites, and appetite hormone release remains unclear owing
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A bioadhesive pacing lead for atraumatic cardiac monitoring and stimulation in rodent and porcine models Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-19 Jue Deng, Jingjing Wu, Xiaoyu Chen, Tiffany L. Sarrafian, Claudia E. Varela, William Whyte, Chuan Fei Guo, Ellen T. Roche, Leigh G. Griffiths, Hyunwoo Yuk, Christoph S. Nabzdyk, Xuanhe Zhao
Current clinically used electronic implants, including cardiac pacing leads for epicardial monitoring and stimulation of the heart, rely on surgical suturing or direct insertion of electrodes to the heart tissue. These approaches can cause tissue trauma during the implantation and retrieval of the pacing leads, with the potential for bleeding, tissue damage, and device failure. Here, we report a bioadhesive
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Topical JAK inhibition ameliorates EGFR inhibitor–induced rash in rodents and humans Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-19 Qing You, Leying Chen, Shuaihu Li, Min Liu, Meng Tian, Yuan Cheng, Liangyong Xia, Wenxi Li, Yang Yao, Yinan Li, Ying Zhou, Yurui Ma, Dazhao Lv, Longfei Zhao, Hejie Wang, Zhaoyu Wu, Jiajun Hu, Juegang Ju, Chuanlong Jia, Nan Xu, Jie Luo, Shiyi Zhang
Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput
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Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-12 Miriam Manook, Danae Olaso, Imran Anwar, Isabel DeLaura, Janghoon Yoon, Yeeun Bae, Andrew Barbas, Brian Shaw, Dimitrios Moris, Mingqing Song, Alton B. Farris, Kathryn Stiede, Michele Youd, Stuart Knechtle, Jean Kwun
Genetic modification of porcine donors, combined with optimized immunosuppression, has been shown to improve outcomes of experimental xenotransplant. However, little is known about outcomes in sensitized recipients, a population that could potentially benefit the most from the clinical implementation of xenotransplantation. Here, five highly allosensitized rhesus macaques received a porcine kidney
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Microglia promote maladaptive plasticity in autonomic circuitry after spinal cord injury in mice Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-12 Faith H. Brennan, Emily A. Swarts, Kristina A. Kigerl, Katherine A. Mifflin, Zhen Guan, Benjamin T. Noble, Yan Wang, Kristina G. Witcher, Jonathan P. Godbout, Phillip G. Popovich
Robust structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry after severe high-level spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli elicit uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology. How hyperexcitable sympathetic circuitry forms is unknown, but local
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Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-12 Ahmed Khalaf, Lucie de Beauchamp, Eric Kalkman, Kevin Rattigan, Ekaterini Himonas, Joe Jones, Daniel James, Engy Shokry Abd Shokry, Mary T. Scott, Karen Dunn, Saverio Tardito, Mhairi Copland, David Sumpton, Emma Shanks, G. Vignir Helgason
In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors
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Anti–PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-12 Janaki Manoja Vinnakota, Rachael C. Adams, Dimitrios Athanassopoulos, Dominik Schmidt, Francesca Biavasco, Alexander Zähringer, Daniel Erny, Marius Schwabenland, Marlene Langenbach, Valentin Wenger, Henrike Salié, James Cook, Omar Mossad, Geoffroy Andrieux, Rick Dersch, Sebastian Rauer, Sandra Duquesne, Gianni Monaco, Phillipp Wolf, Thomas Blank, Philipp Häne, Melanie Greter, Burkhard Becher, Philipp
Cancer treatment with anti–PD-1 immunotherapy can cause central nervous system immune-related adverse events (CNS-irAEs). The role of microglia in anti–PD-1 immunotherapy–induced CNS-irAEs is unclear. We found that anti–PD-1 treatment of mice caused morphological signs of activation and major histocompatibility complex (MHC) class II up-regulation on microglia. Functionally, anti–PD-1 treatment induced
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Heterotypic immunity from prior SARS-CoV-2 infection but not COVID-19 vaccination associates with lower endemic coronavirus incidence Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-12 David J. Bean, Janet Monroe, Yan Mei Liang, Ella Borberg, Yasmeen Senussi, Zoe Swank, Sujata Chalise, David Walt, Janice Weinberg, Manish Sagar
Immune responses from prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination mitigate disease severity, but they do not fully prevent subsequent infections, especially from genetically divergent strains. We examined the incidence of and immune differences against human endemic coronaviruses (eCoVs) as a proxy for response against future genetically heterologous
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Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-05 Yan Mao, Zhen Jin, Jing Yang, Dengqiu Xu, Lei Zhao, Abdukahar Kiram, Yujing Yin, Danxia Zhou, Zongchao Sun, Liwei Xiao, Zheng Zhou, Likun Yang, Tingting Fu, Zhisheng Xu, Yuhuan Jia, Xinyi Chen, Feng-Nan Niu, Xihua Li, Zezhang Zhu, Zhenji Gan
Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction–related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function
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Comparative analysis of Bcl-2 family protein overexpression in CAR T cells alone and in combination with BH3 mimetics Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-05 Felix Korell, Michael L. Olson, Diego Salas-Benito, Mark B. Leick, Rebecca C. Larson, Amanda Bouffard, Harrison Silva, Alessandro Gasparetto, Trisha R. Berger, Michael C. Kann, Markus Mergen, Tamina Kienka, Marc Wehrli, Nicholas J. Haradhvala, Stefanie R. Bailey, Anthony Letai, Marcela V. Maus
Approximately 50% of patients with hematologic malignancies relapse after chimeric antigen receptor (CAR) T cell treatment; mechanisms of failure include loss of CAR T persistence and tumor resistance to apoptosis. We hypothesized that both of these challenges could potentially be overcome by overexpressing one or more of the Bcl-2 family proteins in CAR T cells to reduce their susceptibility to apoptosis
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Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-05 Jian Liu, David A. Copland, Alison J. Clare, Mathias Gorski, Burt T. Richards, Louis Scott, Sofia Theodoropoulou, Ursula Greferath, Katherine Cox, Gongyu Shi, Oliver H. Bell, Kepeng Ou, Jenna Le Brun Powell, Jiahui Wu, Luis Martinez Robles, Yingxin Li, Lindsay B. Nicholson, Peter J. Coffey, Erica L. Fletcher, Robyn Guymer, Monte J. Radeke, Iris M. Heid, Gregory S. Hageman, Ying Kai Chan, Andrew D.
Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor–associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3 , which encodes IRAK-M, were associated with an increased likelihood
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Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration Sci. Transl. Med. (IF 15.8) Pub Date : 2024-06-05 Marvin Reich, Matthew J. Simon, Beate Polke, Iñaki Paris, Georg Werner, Christian Schrader, Lena Spieth, Sonnet S. Davis, Sophie Robinson, Gabrielly Lunkes de Melo, Lennart Schlaphoff, Katrin Buschmann, Stefan Berghoff, Todd Logan, Brigitte Nuscher, Lis de Weerd, Dieter Edbauer, Mikael Simons, Jung H. Suh, Thomas Sandmann, Mihalis S. Kariolis, Sarah L. DeVos, Joseph W. Lewcock, Dominik Paquet, Anja
Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD- GRN ). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient
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An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-29 Alison J. Davis, Natasja Brooijmans, Jason D. Brubaker, Faith Stevison, Timothy P. LaBranche, Faris Albayya, Paul Fleming, Brian L. Hodous, Joseph L. Kim, Sean Kim, Riadh Lobbardi, Michael Palmer, Michael P. Sheets, John Vassiliadis, Ruduan Wang, Brett D. Williams, Douglas Wilson, Lan Xu, Xing Julia Zhu, Keith Bouchard, Jeffrey W. Hunter, Chris Graul, Elliot Greenblatt, Amira Hussein, Morgan Lyon,
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor–like kinase 2 (ALK2), the most common variant being ALK2 R206H . In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues
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Functional ultrasound imaging of human brain activity through an acoustically transparent cranial window Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-29 Claire Rabut, Sumner L. Norman, Whitney S. Griggs, Jonathan J. Russin, Kay Jann, Vasileios Christopoulos, Charles Liu, Richard A. Andersen, Mikhail G. Shapiro
Visualization of human brain activity is crucial for understanding normal and aberrant brain function. Currently available neural activity recording methods are highly invasive, have low sensitivity, and cannot be conducted outside of an operating room. Functional ultrasound imaging (fUSI) is an emerging technique that offers sensitive, large-scale, high-resolution neural imaging; however, fUSI cannot
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Primary exposure to Zika virus is linked with increased risk of symptomatic dengue virus infection with serotypes 2, 3, and 4, but not 1 Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-29 José Victor Zambrana, Chloe M. Hasund, Rosemary A. Aogo, Sandra Bos, Sonia Arguello, Karla Gonzalez, Damaris Collado, Tatiana Miranda, Guillermina Kuan, Aubree Gordon, Angel Balmaseda, Leah C. Katzelnick, Eva Harris
Infection with any of the four dengue virus serotypes (DENV1–4) can protect against or enhance subsequent dengue depending on preexisting antibodies and infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) is associated with increased risk of DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by DENV1–4 in
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Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-29 Daniel Fowler, Marta Barisa, Alba Southern, Callum Nattress, Elizabeth Hawkins, Eleni Vassalou, Angeliki Kanouta, John Counsell, Enrique Rota, Petra Vlckova, Benjamin Draper, Tessa De Mooij, Andrea Farkas, Helena Brezovjakova, Alfie T. Baker, Katia Scotlandi, Maria C. Manara, Chris Tape, Kerry Chester, John Anderson, Jonathan Fisher
T cell–based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent
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Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-23 Yan Xia, Cuihua Xia, Yi Jiang, Yu Chen, Jiaqi Zhou, Rujia Dai, Cong Han, Zhongzheng Mao, PsychENCODE Consortium, Chunyu Liu, Chao Chen, Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, Jose Juan Almagro Armenteros, Brian J. Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul A. Bharadwaj, Arjun Bhattacharya, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A. Champagne, Tanima Chatterjee
Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2,160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism
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The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-22 David R. Martinez, Fernando R. Moreira, Nicholas J. Catanzaro, Meghan V. Diefenbacher, Mark R. Zweigart, Kendra L. Gully, Gabriela De la Cruz, Ariane J. Brown, Lily E. Adams, Boyd Yount, Thomas J. Baric, Michael L. Mallory, Helen Conrad, Samantha R. May, Stephanie Dong, D. Trevor Scobey, Cameron Nguyen, Stephanie A. Montgomery, Jason K. Perry, Darius Babusis, Kimberly T. Barrett, Anh-Hoa Nguyen, Anh-Quan
Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need
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Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6 Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-22 Christiane R. Stadler, Ursula Ellinghaus, Leyla Fischer, Hayat Bähr-Mahmud, Martin Rao, Claudia Lindemann, Anuhar Chaturvedi, Caroline Scharf, Imke Biermann, Bernhard Hebich, Alexandra Malz, Georg Beresin, Georg Falck, Aline Häcker, Astrid Houben, Michael Erdeljan, Kristina Wolf, Maximilian Kullmann, Philip Chang, Özlem Türeci, Uğur Şahin
We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)–formulated RNA (RNA-LNP) encoding a T cell–engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus
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Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-22 Jeremy M. Sullivan, Anna M. Bagnell, Jonathan Alevy, Elvia Mena Avila, Ljubica Mihaljević, Pamela C. Saavedra-Rivera, Lingling Kong, Jennifer S. Huh, Brett A. McCray, William H. Aisenberg, Aamir R. Zuberi, Laurent Bogdanik, Cathleen M. Lutz, Zhaozhu Qiu, Katharina A. Quinlan, Peter C. Searson, Charlotte J. Sumner
Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease
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Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-22 Zhuo Chen, Eiichiro Satake, Marcus G. Pezzolesi, Zaipul I. Md Dom, Devorah Stucki, Hiroki Kobayashi, Anna Syreeni, Adam T. Johnson, Xiwei Wu, Emma H. Dahlström, Jaxon B. King, Per-Henrik Groop, Stephen S. Rich, Niina Sandholm, Andrzej S. Krolewski, Rama Natarajan
Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals
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Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-22 Christopher A. Cottrell, Xiaozhen Hu, Jeong Hyun Lee, Patrick Skog, Sai Luo, Claudia T. Flynn, Katherine R. McKenney, Jonathan Hurtado, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Elise Landais, Sebastian Raemisch, Xuejun Chen, Sabyasachi Baboo, Sunny Himansu, Jolene K. Diedrich, Hongying Duan, Cheng Cheng, Torben Schiffner, Daniel L. V. Bader, Daniel W. Kulp, Ryan Tingle, Erik Georgeson
A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be
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Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-15 Yi-Mei Wang, Chia-Wei Liu, Shun-Ying Chen, Liang-Yin Lu, Wen-Chuan Liu, Jia-Huei Wang, Chun-Lun Ni, Shi-Bing Wong, Ami Kumar, Jye-Chang Lee, Sheng-Han Kuo, Shun-Chi Wu, Ming-Kai Pan
Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2 dupE3 mouse model to investigate whether
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SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-15 Iris S. Luk, Caroline M. Bridgwater, Angela Yu, Liberalis D. Boila, Mariana Yáñez-Bartolomé, Aaron E. Lampano, Taylor S. Hulahan, Myriam Boukhali, Meena Kathiresan, Teresa Macarulla, Heidi L. Kenerson, Naomi Yamamoto, David Sokolov, Ian A. Engstrom, Lucas B. Sullivan, Paul D. Lampe, Jonathan A. Cooper, Raymond S. Yeung, Tian V. Tian, Wilhelm Haas, Supriya K. Saha, Sita Kugel
Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal
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Comparative analysis of SARS-CoV-2 neutralization titers reveals consistency between human and animal model serum and across assays Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-15 Barbara Mühlemann, Samuel H. Wilks, Lauren Baracco, Meriem Bekliz, Juan Manuel Carreño, Victor M. Corman, Meredith E. Davis-Gardner, Wanwisa Dejnirattisai, Michael S. Diamond, Daniel C. Douek, Christian Drosten, Isabella Eckerle, Venkata-Viswanadh Edara, Madison Ellis, Ron A. M. Fouchier, Matthew Frieman, Sucheta Godbole, Bart Haagmans, Peter J. Halfmann, Amy R. Henry, Terry C. Jones, Leah C. Katzelnick
The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires ongoing monitoring to judge the ability of newly arising variants to escape the immune response. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal serum samples. We compared 18 datasets generated using human, hamster
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Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-15 Vitor M. Pereira, Pedro Lylyk, Nicole Cancelliere, Pedro N. Lylyk, Ivan Lylyk, Vania Anagnostakou, Carlos Bleise, Hidehisa Nishi, Mark Epshtein, Robert M. King, Mohammed Salman Shazeeb, Ajit S. Puri, Conrad W. Liang, Ricardo A. Hanel, Julian Spears, Thomas R. Marotta, Demetrius K. Lopes, Matthew J. Gounis, Giovanni J. Ughi
Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate
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Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis Sci. Transl. Med. (IF 15.8) Pub Date : 2024-05-15 Shi Yong Neo, Le Tong, Joni Chong, Yaxuan Liu, Xu Jing, Mariana M. S. Oliveira, Yi Chen, Ziqing Chen, Keene Lee, Nutsa Burduli, Xinsong Chen, Juan Gao, Ran Ma, Jia Pei Lim, Jianxin Huo, Shengli Xu, Evren Alici, Stina L. Wickström, Felix Haglund, Johan Hartman, Arnika K. Wagner, Yihai Cao, Rolf Kiessling, Kong Peng Lam, Lisa S. Westerberg, Andreas Lundqvist
Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell–to–myeloid cell interactions remain largely
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MRGPRX4 mediates phospho-drug–associated pruritus in a humanized mouse model Sci. Transl. Med. (IF 15.8) 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 15.8) 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 15.8) 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 15.8) 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 15.8) 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 15.8) 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 15.8) 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 15.8) 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 15.8) 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 15.8) 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