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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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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
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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 (T reg ) 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 T reg cell therapies in treating autoimmune and other inflammatory diseases.
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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 (M pro ) 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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Immunocytokines with target cell–restricted IL-15 activity for treatment of B cell malignancies Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Latifa Zekri, Ilona Hagelstein, Melanie Märklin, Boris Klimovich, Mary Christie, Cornelia Lindner, Sofie Kämereit, Nisha Prakash, Stefanie Müller, Sophie Stotz, Andreas Maurer, Carsten Greve, Bastian Schmied, Daniel Atar, Hans-Georg Rammensee, Gundram Jung, Helmut R. Salih
Despite the advances in cancer treatment achieved, for example, by the CD20 antibody rituximab, an urgent medical need remains to optimize the capacity of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) that determines therapeutic efficacy. The cytokine IL-15 stimulates proliferation, activation, and cytolytic capacity of NK cells, but broad clinical use is prevented by short
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B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Angela A. Wang, Felix Luessi, Tradite Neziraj, Elisabeth Pössnecker, Michelle Zuo, Sinah Engel, Nicholas Hanuscheck, Alexandra Florescu, Eryn Bugbee, Xianjie I. Ma, Fatima Rana, Dennis Lee, Lesley A. Ward, Jens Kuhle, Johannes Himbert, Muriel Schraad, Erwin van Puijenbroek, Christian Klein, Eduard Urich, Valeria Ramaglia, Anne-Katrin Pröbstel, Frauke Zipp, Jennifer L. Gommerman
Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby T H 17 cells promote brain leptomeningeal immune cell aggregates, we found that
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Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 TaeHyun Kim, Benjamin T. James, Martin C. Kahn, Cristina Blanco-Duque, Fatema Abdurrob, Md Rezaul Islam, Nicolas S. Lavoie, Manolis Kellis, Li-Huei Tsai
Patients with cancer undergoing chemotherapy frequently experience a neurological condition known as chemotherapy-related cognitive impairment, or “chemobrain,” which can persist for the remainder of their lives. Despite the growing prevalence of chemobrain, both its underlying mechanisms and treatment strategies remain poorly understood. Recent findings suggest that chemobrain shares several characteristics
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Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Qiuhua Yang, Yongfeng Cai, Qian Ma, Albert Xiong, Peishan Xu, Zhidan Zhang, Jiean Xu, Yaqi Zhou, Zhiping Liu, Dingwei Zhao, John Asara, Wei Li, Huidong Shi, Ruth B. Caldwell, Akrit Sodhi, Yuqing Huo
Anti–vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis
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Immunocytokines with target cell–restricted IL-15 activity for treatment of B cell malignancies Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Latifa Zekri, Ilona Hagelstein, Melanie Märklin, Boris Klimovich, Mary Christie, Cornelia Lindner, Sofie Kämereit, Nisha Prakash, Stefanie Müller, Sophie Stotz, Andreas Maurer, Carsten Greve, Bastian Schmied, Daniel Atar, Hans-Georg Rammensee, Gundram Jung, Helmut R. Salih
Despite the advances in cancer treatment achieved, for example, by the CD20 antibody rituximab, an urgent medical need remains to optimize the capacity of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) that determines therapeutic efficacy. The cytokine IL-15 stimulates proliferation, activation, and cytolytic capacity of NK cells, but broad clinical use is prevented by short
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Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Sergi Clotet-Freixas, Olga Zaslaver, Max Kotlyar, Chiara Pastrello, Andrew T. Quaile, Caitriona M. McEvoy, Aninda D. Saha, Sofia Farkona, Alex Boshart, Katarina Zorcic, Slaghaniya Neupane, Kieran Manion, Maya Allen, Michael Chan, Xuqi Chen, Arthur P. Arnold, Peggy Sekula, Inga Steinbrenner, Anna Köttgen, Allison B. Dart, Brandy Wicklow, Jon M. McGavock, Tom D. Blydt-Hansen, Clara Barrios, Marta Riera
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis
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Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9 Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Felix A. Trogisch, Aya Abouissa, Merve Keles, Anne Birke, Manuela Fuhrmann, Gesine M. Dittrich, Nina Weinzierl, Elvira Wink, Julio Cordero, Adel Elsherbiny, Abel Martin-Garrido, Steve Grein, Shruthi Hemanna, Ellen Hofmann, Luka Nicin, Sofia-Iris Bibli, Rannar Airik, Andreas Kispert, Ralf Kist, Sun Quanchao, Sina W. Kürschner, Manuel Winkler, Norbert Gretz, Carolin Mogler, Thomas Korff, Philipp-Sebastian
Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet
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Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9 Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Felix A. Trogisch, Aya Abouissa, Merve Keles, Anne Birke, Manuela Fuhrmann, Gesine M. Dittrich, Nina Weinzierl, Elvira Wink, Julio Cordero, Adel Elsherbiny, Abel Martin-Garrido, Steve Grein, Shruthi Hemanna, Ellen Hofmann, Luka Nicin, Sofia-Iris Bibli, Rannar Airik, Andreas Kispert, Ralf Kist, Sun Quanchao, Sina W. Kürschner, Manuel Winkler, Norbert Gretz, Carolin Mogler, Thomas Korff, Philipp-Sebastian
Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet
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A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Aaron M. Miller, Zeynep Koşaloğlu-Yalçın, Luise Westernberg, Leslie Montero, Milad Bahmanof, Angela Frentzen, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Gregory Seumois, Jason Greenbaum, Spencer E. Brightman, Karla Soria Zavala, Rukman R. Thota, Martin S. Naradikian, Samir S. Makani, Scott M. Lippman, Alessandro Sette, Ezra E. W. Cohen, Bjoern Peters, Stephen P. Schoenberger
The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to
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Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Jonathan P. Sturgeon, Joice Tome, Cherlynn Dumbura, Florence D. Majo, Deophine Ngosa, Kuda Mutasa, Kanekwa Zyambo, Ellen Besa, Kanta Chandwe, Chanda Kapoma, Benjamin Mwapenya, Kusum J. Nathoo, Claire D. Bourke, Robert Ntozini, Bernard Chasekwa, Melanie Smuk, Mutsa Bwakura-Dangarembizi, Beatrice Amadi, Paul Kelly, Andrew J. Prendergast
Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis
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Acetyl-CoA carboxylase 1 controls a lipid droplet–peroxisome axis and is a vulnerability of endocrine-resistant ER + breast cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Marina Bacci, Nicla Lorito, Alfredo Smiriglia, Angela Subbiani, Francesca Bonechi, Giuseppina Comito, Ludivine Morriset, Rania El Botty, Matteo Benelli, Joanna I. López-Velazco, Maria M. Caffarel, Ander Urruticoechea, George Sflomos, Luca Malorni, Michela Corsini, Luigi Ippolito, Elisa Giannoni, Icro Meattini, Vittoria Matafora, Kristina Havas, Angela Bachi, Paola Chiarugi, Elisabetta Marangoni, Andrea
Targeting aromatase deprives ER + breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER + breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets
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APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Shihe Jiang, Xindi Li, Yan Li, Zhilin Chang, Meng Yuan, Ying Zhang, Huimin Zhu, Yuwen Xiu, Hengri Cong, Linlin Yin, Zhen-Wei Yu, Junwan Fan, Wenyan He, Kaibin Shi, De-Cai Tian, Jing Zhang, Alexei Verkhratsky, Wei-Na Jin, Fu-Dong Shi
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with
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An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Kaixi Zhang, Jakkarin Limwongyut, Alex S. Moreland, Samuel Chan Jun Wei, Tania Jim Jia Min, Yan Sun, Sung Jae Shin, Su-Young Kim, Byung Woo Jhun, Kevin Pethe, Guillermo C. Bazan
Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. Mycobacterium abscessus (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Current standard-of-care treatments are not satisfactory, with high failure rate and notable adverse effects
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Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Irene S. Khalek, R. R. Senji Laxme, Yen Thi Kim Nguyen, Suyog Khochare, Rohit N. Patel, Jordan Woehl, Jessica M. Smith, Karen Saye-Francisco, Yoojin Kim, Laetitia Misson Mindrebo, Quoc Tran, Mateusz Kędzior, Evy Boré, Oliver Limbo, Megan Verma, Robyn L. Stanfield, Stefanie K. Menzies, Stuart Ainsworth, Robert A. Harrison, Dennis R. Burton, Devin Sok, Ian A. Wilson, Nicholas R. Casewell, Kartik Sunagar
Snakebite envenoming is a major global public health concern for which improved therapies are urgently needed. The antigenic diversity present in snake venom toxins from various species presents a considerable challenge to the development of a universal antivenom. Here, we used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins
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Lipid nanoparticles and siRNA targeting plasminogen provide lasting inhibition of fibrinolysis in mouse and dog models of hemophilia A Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Amy W. Strilchuk, Woosuk S. Hur, Paul Batty, Yaqiu Sang, Sara R. Abrahams, Alyssa S.M. Yong, Jerry Leung, Lakmali M. Silva, Jocelyn A. Schroeder, Kate Nesbitt, Bas de Laat, Niki M. Moutsopoulos, Thomas H. Bugge, Qizhen Shi, Pieter R. Cullis, Elizabeth P. Merricks, Alisa S. Wolberg, Matthew J. Flick, David Lillicrap, Timothy C. Nichols, Christian J. Kastrup
Antifibrinolytic drugs are used extensively for on-demand treatment of severe acute bleeding. Controlling fibrinolysis may also be an effective strategy to prevent or lessen chronic recurring bleeding in bleeding disorders such as hemophilia A (HA), but current antifibrinolytics have unfavorable pharmacokinetic profiles. Here, we developed a long-lasting antifibrinolytic using small interfering RNA
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Chondrocyte membrane–coated nanoparticles promote drug retention and halt cartilage damage in rat and canine osteoarthritis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Ronghui Deng, Ruifang Zhao, Zining Zhang, Yang Chen, Meng Yang, Yixuan Lin, Jing Ye, Nan Li, Hao Qin, Xin Yan, Jian Shi, Fuzhen Yuan, Shitang Song, Zijie Xu, Yifan Song, Jiangnan Fu, Bingbing Xu, Guangjun Nie, Jia-Kuo Yu
Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we
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Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Marie Czech, Sophia Schneider, Nina Peltokangas, Nadia El Khawanky, Sakhila Ghimire, Geoffroy Andrieux, Jan Hülsdünker, Máté Krausz, Michele Proietti, Lukas M. Braun, Tamina Rückert, Marlene Langenbach, Dominik Schmidt, Ina Martin, Valentin Wenger, Enrique de Vega, Eileen Haring, Mohsen Pourjam, Dietmar Pfeifer, Annette Schmitt-Graeff, Bodo Grimbacher, Konrad Aumann, Brigitte Kircher, Herbert Tilg
Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)–expressing neutrophil population in mice with intestinal aGVHD
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Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Jiajia Chen, Daniel J. Laverty, Surabhi Talele, Ashwin Bale, Brett L. Carlson, Kendra A. Porath, Katrina K. Bakken, Danielle M. Burgenske, Paul A. Decker, Rachael A. Vaubel, Jeanette E. Eckel-Passow, Rohit Bhargava, Zhenkun Lou, Petra Hamerlik, Brendan Harley, William F. Elmquist, Zachary D. Nagel, Shiv K. Gupta, Jann N. Sarkaria
ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390
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Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Laura Díez-Alonso, Aïda Falgas, Javier Arroyo-Ródenas, Paola A. Romencín, Alba Martínez, Marina Gómez-Rosel, Belén Blanco, Anaïs Jiménez-Reinoso, Andrea Mayado, Alba Pérez-Pons, Óscar Aguilar-Sopeña, Ángel Ramírez-Fernández, Alejandro Segura-Tudela, Lorena Perez-Amill, Antonio Tapia-Galisteo, Carmen Domínguez-Alonso, Laura Rubio-Pérez, Maria Jara, Francesc Solé, Oana Hangiu, Laura Almagro, Ángela Albitre
Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising
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Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Lan Bai, Weiyi Qu, Xu Cheng, Hailong Yang, Yong-Ping Huang, Zhenya Wang, Cuijuan Han, Rui-Feng Tian, Fengjiao Hu, Ling Yang, Song Tian, Han Tian, Zhiwei Cai, Juan Wan, Jingwei Jiang, Jiajun Fu, Junjie Zhou, Yufeng Hu, Tengfei Ma, Xin Zhang, Yan-Xiao Ji, Jingjing Cai, Zhi-Gang She, Yibin Wang, Peng Zhang, Lingli Huang, Hongliang Li, Xiao-Jing Zhang
Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across
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Autologous transplantation of P63 + lung progenitor cells for chronic obstructive pulmonary disease therapy Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Yujia Wang, Zili Meng, Ming Liu, Yueqing Zhou, Difei Chen, Yu Zhao, Ting Zhang, Nanshan Zhong, Xiaotian Dai, Shiyue Li, Wei Zuo
Adult lung resident stem/progenitor cells, including P63 + progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63 + progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63 + progenitor cells were isolated from the airway
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Dynamic load modulation predicts right heart tolerance of left ventricular cardiovascular assist in a porcine model of cardiogenic shock Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Kimberly K. Lamberti, Steven P. Keller, Elazer R. Edelman
Ventricular assist devices (VADs) offer mechanical support for patients with cardiogenic shock by unloading the impaired ventricle and increasing cardiac outflow and subsequent tissue perfusion. Their ability to adjust ventricular assistance allows for rapid and safe dynamic changes in cardiac load, which can be used with direct measures of chamber pressures to quantify cardiac pathophysiologic state
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DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser 56 to diminish pancreatic β cell function upon overnutrition Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Yuting Lu, Junyu Xu, Yufeng Li, Ruoran Wang, Chengqiu Dai, Bingqian Zhang, Xinwen Zhang, Lei Xu, Yunhua Tao, Ming Han, Ren Guo, Qingqian Wu, Linshi Wu, Zhuoxian Meng, Minjia Tan, Jingya Li
Impeded autophagy can impair pancreatic β cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic β cells protected β
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Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Maria Carmina Castiello, Chiara Brandas, Samuele Ferrari, Simona Porcellini, Nicolò Sacchetti, Daniele Canarutto, Elena Draghici, Ivan Merelli, Matteo Barcella, Gabriele Pelosi, Valentina Vavassori, Angelica Varesi, Aurelien Jacob, Serena Scala, Luca Basso Ricci, Marianna Paulis, Dario Strina, Martina Di Verniere, Lucia Sergi Sergi, Marta Serafini, Steven M. Holland, Jenna R. E. Bergerson, Suk See
Recombination activating genes ( RAGs ) are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence
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IgE in allergy: It takes two Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Anouk von Borstel, Robyn E. O’Hehir, Menno C. van Zelm
A type 2 memory B cell subset is poised to differentiate into IgE-producing plasma cells in individuals with allergies (Ota et al . and Koenig et al .).
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CD23 + IgG1 + memory B cells are poised to switch to pathogenic IgE production in food allergy Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Miyo Ota, Kenneth B. Hoehn, Weslley Fernandes-Braga, Takayuki Ota, Carlos J. Aranda, Sara Friedman, Mariana G. C. Miranda-Waldetario, Jamie Redes, Maria Suprun, Galina Grishina, Hugh A. Sampson, Alefiyah Malbari, Steven H. Kleinstein, Scott H. Sicherer, Maria A. Curotto de Lafaille
Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little is known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population of CD23 + IgG1 + memory B cells arising in type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing cells upon activation. The frequency of
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Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Bing Han, Shunheng Zhou, Yuan Zhang, Sina Chen, Wen Xi, Chenchen Liu, Xu Zhou, Mengqin Yuan, Xiaoyu Yu, Lu Li, Yu Wang, Hui Ren, Jian Xie, Bin Li, Minzi Ju, You Zhou, Ziqi Liu, Zhongli Xiong, Ling Shen, Yuan Zhang, Ying Bai, Jun Chen, Wei Jiang, Honghong Yao
Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777
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Type 2–polarized memory B cells hold allergen-specific IgE memory Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Joshua F. E. Koenig, Niels Peter H. Knudsen, Allyssa Phelps, Kelly Bruton, Ilka Hoof, Gitte Lund, Danielle Della Libera, Anders Lund, Lars Harder Christensen, David R. Glass, Tina D. Walker, Allison Fang, Susan Waserman, Manel Jordana, Peter S. Andersen
Allergen-specific immunoglobulin E (IgE) antibodies mediate pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. Here, we report a population of type 2–polarized MBCs defined as CD23 hi , IL-4Rα hi , and CD32 low at both the transcriptional and surface protein levels
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TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Gan Zhao, Lulu Xue, Aaron I. Weiner, Ningqiang Gong, Stephanie Adams-Tzivelekidis, Joanna Wong, Maria E. Gentile, Ana N. Nottingham, Maria C. Basil, Susan M. Lin, Terren K. Niethamer, Joshua M. Diamond, Christian A. Bermudez, Edward Cantu, Xuexiang Han, Yaqi Cao, Mohamad-Gabriel Alameh, Drew Weissman, Edward E. Morrisey, Michael J. Mitchell, Andrew E. Vaughan
Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated
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Rescuing lung development through embryonic inhibition of histone acetylation Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Giangela Stokes, Zhuowei Li, Nicole Talaba, William Genthe, Maria B. Brix, Betty Pham, Mark D. Wienhold, Gracia Sandok, Rebecca Hernan, Julia Wynn, Haiyang Tang, Diana M. Tabima, Allison Rodgers, Timothy A. Hacker, Naomi C. Chesler, Pan Zhang, Rabi Murad, Jason X. -J. Yuan, Yufeng Shen, Wendy K. Chung, David J. McCulley
A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying
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Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Pablo A. Valdes, Chih-Chieh (Jay) Yu, Jenna Aronson, Debarati Ghosh, Yongxin Zhao, Bobae An, Joshua D. Bernstock, Deepak Bhere, Michelle M. Felicella, Mariano S. Viapiano, Khalid Shah, E. Antonio Chiocca, Edward S. Boyden
Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here, we present an ExM variant, decrowding expansion pathology (dExPath), that can expand proteins away from each other in human brain pathology specimens,
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Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Francesco Limone, Alexander Couto, Jin-Yuan Wang, Yingying Zhang, Blake McCourt, Cerianne Huang, Adina Minkin, Marghi Jani, Sarah McNeer, James Keaney, Gaëlle Gillet, Rodrigo Lopez Gonzalez, Wendy A. Goodman, Irena Kadiu, Kevin Eggan, Aaron Burberry
A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional
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Integrating the gut microbiome and pharmacology Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Andrew A. Verdegaal, Andrew L. Goodman
The gut microbiome harbors trillions of organisms that contribute to human health and disease. These bacteria can also affect the properties of medical drugs used to treat these diseases, and drugs, in turn, can reshape the microbiome. Research addressing interdependent microbiome-host-drug interactions thus has broad impact. In this Review, we discuss these interactions from the perspective of drug
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Bone morphogenetic protein 9 is a candidate prognostic biomarker and host-directed therapy target for sepsis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Haobo Bai, Qian Lu, Chunxiang Wu, Fang Xu, Jiayu Liu, Ke Wang, Hao Ding, Yibing Yin, Yi Liu, Xiaofei Lai, Ju Cao
Defining next-generation immune therapeutics for the treatment of sepsis will involve biomarker-based therapeutic decision-making. Bone morphogenetic protein 9 (BMP9) is a cytokine in the transforming growth factor–β superfamily. Here, circulating BMP9 concentrations were quantified in two independent cohorts of patients with sepsis. Decreased concentrations of serum BMP9 were observed in the patients
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Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-26 Sahba Seddighi, Yue A. Qi, Anna-Leigh Brown, Oscar G. Wilkins, Colleen Bereda, Cedric Belair, Yong-Jie Zhang, Mercedes Prudencio, Matthew J. Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E. Kargbo-Hill, James Hawrot, Daniel M. Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I. Shah, Mike A. Nalls, Jennifer M. Colón-Mercado, Joel F. Reyes, Veronica H. Ryan, Matthew P. Nelson, Casey
Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that
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Single-cell atlas of human infrapatellar fat pad and synovium implicates APOE signaling in osteoarthritis pathology Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Su’an Tang, Lutian Yao, Jianzhao Ruan, Jingliang Kang, Yumei Cao, Xiaoyu Nie, Weiren Lan, Zhaohua Zhu, Weiyu Han, Yongguang Liu, Jing Tian, Patrick Seale, Ling Qin, Changhai Ding
The infrapatellar fat pad (IPFP) and synovium play essential roles in maintaining knee joint homeostasis and in the progression of osteoarthritis (OA). The cellular and transcriptional mechanisms regulating the function of these specialized tissues under healthy and diseased conditions are largely unknown. Here, single-cell and single-nuclei RNA sequencing of human IPFP and synovial tissues were performed
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The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Aurélien Voissière, Carlos Gomez-Roca, Sylvie Chabaud, Céline Rodriguez, Axelle Nkodia, Justine Berthet, Laure Montane, Anne-Sophie Bidaux, Isabelle Treilleux, Lauriane Eberst, Catherine Terret, Iphigénie Korakis, Gwenaelle Garin, David Pérol, Jean-Pierre Delord, Christophe Caux, Bertrand Dubois, Christine Ménétrier-Caux, Nathalie Bendriss-Vermare, Philippe A. Cassier
Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R–directed tyrosine kinase inhibitor (TKI), and durvalumab (anti–PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating
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SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Yijia Li, Manish C. Choudhary, James Regan, Julie Boucau, Anusha Nathan, Tessa Speidel, May Yee Liew, Gregory E. Edelstein, Yumeko Kawano, Rockib Uddin, Rinki Deo, Caitlin Marino, Matthew A. Getz, Zahra Reynolds, Mamadou Barry, Rebecca F. Gilbert, Dessie Tien, Shruti Sagar, Tammy D. Vyas, James P. Flynn, Sarah P. Hammond, Lewis A. Novack, Bina Choi, Manuela Cernadas, Zachary S. Wallace, Jeffrey A.
Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the immune defects that predispose an individual to persistent coronavirus disease 2019 (COVID-19) remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants
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Machine learning to detect the SINEs of cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Christopher Douville, Kamel Lahouel, Albert Kuo, Haley Grant, Bracha Erlanger Avigdor, Samuel D. Curtis, Mahmoud Summers, Joshua D. Cohen, Yuxuan Wang, Austin Mattox, Jonathan Dudley, Lisa Dobbyn, Maria Popoli, Janine Ptak, Nadine Nehme, Natalie Silliman, Cherie Blair, Katharine Romans, Christopher Thoburn, Jennifer Gizzi, Robert E. Schoen, Jeanne Tie, Peter Gibbs, Lan T. Ho-Pham, Bich N. H. Tran,
We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested
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Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Seyedeh Maryam Zekavat, Saman Doroodgar Jorshery, Franziska G. Rauscher, Katrin Horn, Sayuri Sekimitsu, Satoshi Koyama, Trang T. Nguyen, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Andreas Kühnapfel, Yusrah Shweikh, Yixuan Ye, Vineet Raghu, Hongyu Zhao, Marzyeh Ghassemi, Tobias Elze, Ayellet V. Segrè, Janey L. Wiggs, Lucian Del Priore, Markus Scholz, Jay C. Wang, Pradeep Natarajan, Nazlee Zebardast
The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype
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Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Eva Lana-Elola, Rifdat Aoidi, Miriam Llorian, Dorota Gibbins, Callan Buechsenschuetz, Claudio Bussi, Helen Flynn, Tegan Gilmore, Sheona Watson-Scales, Marie Haugsten Hansen, Darryl Hayward, Ok-Ryul Song, Véronique Brault, Yann Herault, Emmanuel Deau, Laurent Meijer, Ambrosius P. Snijders, Maximiliano G. Gutierrez, Elizabeth M. C. Fisher, Victor L. J. Tybulewicz
Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS is a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology is the result of a third copy of one or more of the approximately 230 genes on Hsa21, but the identity of the causative dosage–sensitive genes and hence mechanisms underlying this cardiac
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Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-17 Shakti K. Bhattarai, Muxue Du, Abigail L. Zeamer, Benedikt M. Morzfeld, Tasia D. Kellogg, Kaya Firat, Anna Benjamin, James M. Bean, Matthew Zimmerman, Gertrude Mardi, Stalz Charles Vilbrun, Kathleen F. Walsh, Daniel W. Fitzgerald, Michael S. Glickman, Vanni Bucci
Despite their therapeutic benefits, antibiotics exert collateral damage on the microbiome and promote antimicrobial resistance. However, the mechanisms governing microbiome recovery from antibiotics are poorly understood. Treatment of Mycobacterium tuberculosis , the world’s most common infection, represents the longest antimicrobial exposure in humans. Here, we investigate gut microbiome dynamics
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Fusion peptide–directed antibodies: Humoral armor against HIV-1 infection Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-17 P. J. Klasse
Infused neutralizing antibodies to the fusion peptide of the HIV envelope glycoprotein protected macaques from mucosal viral challenge (Pegu et al. ).
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Splicing neoantigen discovery with SNAF reveals shared targets for cancer immunotherapy Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-17 Guangyuan Li, Shweta Mahajan, Siyuan Ma, Erin D. Jeffery, Xuan Zhang, Anukana Bhattacharjee, Meenakshi Venkatasubramanian, Matthew T. Weirauch, Emily R. Miraldi, H. Leighton Grimes, Gloria M. Sheynkman, Tamara Tilburgs, Nathan Salomonis
Immunotherapy has emerged as a crucial strategy to combat cancer by “reprogramming” a patient’s own immune system. Although immunotherapy is typically reserved for patients with a high mutational burden, neoantigens produced from posttranscriptional regulation may provide an untapped reservoir of common immunogenic targets for new targeted therapies. To comprehensively define tumor-specific and likely
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Antibodies targeting the fusion peptide on the HIV envelope provide protection to rhesus macaques against mucosal SHIV challenge Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-17 Amarendra Pegu, Sarah E. Lovelace, Megan E. DeMouth, Michelle D. Cully, Daniel J. Morris, Yingying Li, Keyun Wang, Stephen D. Schmidt, Misook Choe, Cuiping Liu, Xuejun Chen, Elise Viox, Ariana Rowshan, Justin D. Taft, Baoshan Zhang, Kai Xu, Hongying Duan, Li Ou, John-Paul Todd, Rui Kong, Hui Li, George M. Shaw, Nicole A. Doria-Rose, Peter D. Kwong, Richard A. Koup, John R. Mascola
The fusion peptide (FP) on the HIV-1 envelope (Env) trimer can be targeted by broadly neutralizing antibodies (bNAbs). Here, we evaluated the ability of a human FP-directed bNAb, VRC34.01, along with two vaccine-elicited anti-FP rhesus macaque mAbs, DFPH-a.15 and DF1W-a.01, to protect against simian-HIV (SHIV) BG505 challenge. VRC34.01 neutralized SHIV BG505 with a 50% inhibitory concentration (IC
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Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-17 Julie C. Ullman, Kevin T. Mellem, Yannan Xi, Vyas Ramanan, Hanne Merritt, Rebeca Choy, Tarunmeet Gujral, Lyndsay E.A. Young, Kerrigan Blake, Samnang Tep, Julian R. Homburger, Adam O’Regan, Sandya Ganesh, Perryn Wong, Terrence F. Satterfield, Baiwei Lin, Eva Situ, Cecile Yu, Bryan Espanol, Richa Sarwaikar, Nathan Fastman, Christos Tzitzilonis, Patrick Lee, Daniel Reiton, Vivian Morton, Pam Santiago
Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule
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TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-17 Jordan D. Marks, Virginia Estades Ayuso, Yari Carlomagno, Mei Yue, Tiffany W. Todd, Ying Hao, Ziyi Li, Zachary T. McEachin, Anantharaman Shantaraman, Duc M. Duong, Lillian M. Daughrity, Karen Jansen-West, Wei Shao, Anna Calliari, Jesus Gonzalez Bejarano, Michael DeTure, Bailey Rawlinson, Monica Castanedes Casey, Meredith T. Lilley, Megan H. Donahue, Vidhya Maheswari Jawahar, Bradley F. Boeve, Ronald
Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery
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Deciphering maternal-fetal cross-talk in the human placenta during parturition using single-cell RNA sequencing Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-10 Valeria Garcia-Flores, Roberto Romero, Adi L. Tarca, Azam Peyvandipour, Yi Xu, Jose Galaz, Derek Miller, Tinnakorn Chaiworapongsa, Piya Chaemsaithong, Stanley M. Berry, Awoniyi O. Awonuga, David R. Bryant, Roger Pique-Regi, Nardhy Gomez-Lopez
Labor is a complex physiological process requiring a well-orchestrated dialogue between the mother and fetus. However, the cellular contributions and communications that facilitate maternal-fetal cross-talk in labor have not been fully elucidated. Here, single-cell RNA sequencing (scRNA-seq) was applied to decipher maternal-fetal signaling in the human placenta during term labor. First, a single-cell
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Prospective study design and data analysis in UK Biobank Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-10 Naomi E. Allen, Ben Lacey, Deborah A. Lawlor, Jill P. Pell, John Gallacher, Liam Smeeth, Paul Elliott, Paul M. Matthews, Ronan A. Lyons, Anthony D. Whetton, Anneke Lucassen, Matthew E. Hurles, Michael Chapman, Andrew W. Roddam, Natalie K. Fitzpatrick, Anna L. Hansell, Rebecca Hardy, Riccardo E. Marioni, Valerie B. O’Donnell, Julie Williams, Cecilia M. Lindgren, Mark Effingham, Jonathan Sellors, John
Population-based prospective studies, such as UK Biobank, are valuable for generating and testing hypotheses about the potential causes of human disease. We describe how UK Biobank’s study design, data access policies, and approaches to statistical analysis can help to minimize error and improve the interpretability of research findings, with implications for other population-based prospective studies
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Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-10 Yi-Yin Tai, Qiujun Yu, Ying Tang, Wei Sun, Neil J. Kelly, Satoshi Okawa, Jingsi Zhao, Tae-Hwi Schwantes-An, Caroline Lacoux, Stephanie Torrino, Yassmin Al Aaraj, Wadih El Khoury, Vinny Negi, Mingjun Liu, Catherine G. Corey, Frances Belmonte, Sara O. Vargas, Brian Schwartz, Bal Bhat, B. Nelson Chau, Jason H. Karnes, Taijyu Satoh, Robert J. Barndt, Haodi Wu, Victoria N. Parikh, Jianrong Wang, Yingze
Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)–dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N -methyltransferase 2E-antisense 1 ( KMT2E-AS1 ) and histone
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mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-10 Sonam Gurung, Oskar Vilhelmsson Timmermand, Dany Perocheau, Ana Luisa Gil-Martinez, Magdalena Minnion, Loukia Touramanidou, Sherry Fang, Martina Messina, Youssef Khalil, Justyna Spiewak, Abigail R. Barber, Richard S. Edwards, Patricia Lipari Pinto, Patrick F. Finn, Alex Cavedon, Summar Siddiqui, Lisa Rice, Paolo G. V. Martini, Deborah Ridout, Wendy Heywood, Ian Hargreaves, Simon Heales, Philippa B
The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis
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Rapid-acting antidepressant drugs modulate affective bias in rats Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-10 Justyna K. Hinchcliffe, Sarah A. Stuart, Christian M. Wood, Julia Bartlett, Katie Kamenish, Roberto Arban, Christopher W. Thomas, Aslihan Selimbeyoglu, Shaun Hurley, Bastian Hengerer, Gary Gilmour, Emma S. J. Robinson
How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we