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Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson’s disease Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-29 Mohammed Repon Khan, Xiling Yin, Sung-Ung Kang, Jaba Mitra, Hu Wang, Taekyung Ryu, Saurav Brahmachari, Senthilkumar S. Karuppagounder, Yasuyoshi Kimura, Aanishaa Jhaldiyal, Hyun Hee Kim, Hao Gu, Rong Chen, Javier Redding-Ochoa, Juan Troncoso, Chan Hyun Na, Taekjip Ha, Valina L. Dawson, Ted M. Dawson
Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of proteostasis is thought to be central to pathologic α-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the
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T cell responses to SARS-CoV-2 infection and vaccination are elevated in B cell deficiency and reduce risk of severe COVID-19 Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-29 Reza Zonozi, Lucy C. Walters, Aaron Shulkin, Vivek Naranbhai, Pravarut Nithagon, Gabriel Sauvage, Clarety Kaeske, Katherine Cosgrove, Anusha Nathan, Rhoda Tano-Menka, Alton C. Gayton, Matthew A. Getz, Fernando Senjobe, Daniel Worrall, A. John Iafrate, Caroline Fromson, Sydney B. Montesi, Deepak A. Rao, Jeffrey A. Sparks, Zachary S. Wallace, Jocelyn R. Farmer, Bruce D. Walker, Richelle C. Charles, Karen
Individuals with primary and pharmacologic B cell deficiencies have high rates of severe disease and mortality from coronavirus disease 2019 (COVID-19), but the immune responses and clinical outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination have yet to be fully defined. Here, we evaluate the cellular immune responses after both SARS-CoV-2 infection
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Resident microbes shape the vaginal epithelial glycan landscape Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-29 Kavita Agarwal, Biswa Choudhury, Lloyd S. Robinson, Sydney R. Morrill, Yasmine Bouchibiti, Daisy Chilin-Fuentes, Sara B. Rosenthal, Kathleen M. Fisch, Jeffrey F. Peipert, Carlito B. Lebrilla, Jenifer E. Allsworth, Amanda L. Lewis, Warren G. Lewis
Epithelial cells are covered in carbohydrates (glycans). This glycan coat or “glycocalyx” interfaces directly with microbes, providing a protective barrier against potential pathogens. Bacterial vaginosis (BV) is a condition associated with adverse health outcomes in which bacteria reside in direct proximity to the vaginal epithelium. Some of these bacteria, including Gardnerella , produce glycosyl
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A T cell receptor β chain–directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-29 Jonathan Hsu, Renee N. Donahue, Madan Katragadda, Jessica Lowry, Wei Huang, Karunya Srinivasan, Gurkan Guntas, Jian Tang, Roya Servattalab, Jacques Moisan, Yo-Ting Tsai, Allart Stoop, Sangeetha Palakurthi, Raj Chopra, Ke Liu, E. John Wherry, Zhen Su, James L. Gulley, Andrew Bayliffe, Jeffrey Schlom
Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond. Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an antibody targeting germline Vβ6 and Vβ10 T cell receptors (TCRs) fused to human interleukin-2 (IL-2) and simultaneously engages a nonclonal mode of TCR
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Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2α in skeletal progenitor cells Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-29 Wendi Guo, Jiaul Hoque, Carolina J. Garcia Garcia, Kassandra V. Spiller, Abigail P. Leinroth, Vijitha Puviindran, Cahil K. Potnis, Kiana A. Gunn, Hunter Newman, Koji Ishikawa, Tara N. Fujimoto, Denae W. Neill, Abagail M. Delahoussaye, Nerissa T. Williams, David G. Kirsch, Matthew J. Hilton, Shyni Varghese, Cullen M. Taniguchi, Colleen Wu
Radiotherapy remains a common treatment modality for cancer despite skeletal complications. However, there are currently no effective treatments for radiation-induced bone loss, and the consequences of radiotherapy on skeletal progenitor cell (SPC) survival and function remain unclear. After radiation, leptin receptor–expressing cells, which include a population of SPCs, become localized to hypoxic
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Seeking satiety: From signals to solutions Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-22 Matthias H. Tschöp, Jeffrey M. Friedman
Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to “reduce food and avoid drinking to fullness” and begin “running during the night.” Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight
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Obesity and lifespan, a complex tango Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-22 Alberto Diaz-Ruiz, Nathan L. Price, Luigi Ferrucci, Rafael de Cabo
Obesity and aging share comorbidities, phenotypes, and deleterious effects on health that are associated with chronic diseases. However, distinct features set them apart, with underlying biology that should be explored and exploited, especially given the demographic shifts and the obesity epidemic that the world is facing.
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Hyperleptinemia contributes to antipsychotic drug–associated obesity and metabolic disorders Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-22 Shangang Zhao, Qian Lin, Wei Xiong, Li Li, Leon Straub, Dinghong Zhang, Rizaldy Zapata, Qingzhang Zhu, Xue-Nan Sun, Zhuzhen Zhang, Jan-Bernd Funcke, Chao Li, Shiuhwei Chen, Yi Zhu, Nisi Jiang, Guannan Li, Ziying Xu, Steven C. Wyler, May-Yun Wang, Juli Bai, Xianlin Han, Christine M. Kusminski, Ningyan Zhang, Zhiqiang An, Joel K. Elmquist, Olivia Osborn, Chen Liu, Philipp E. Scherer
Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution
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Evidence for the contribution of the gut microbiome to obesity and its reversal Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-22 Douwe F. de Wit, Nordin M. J. Hanssen, Koen Wortelboer, Hilde Herrema, Elena Rampanelli, Max Nieuwdorp
Obesity has become a worldwide pandemic affecting more than 650 million people and is associated with a high burden of morbidity. Alongside traditional risk factors for obesity, the gut microbiome has been identified as a potential factor in weight regulation. Although rodent studies suggest a link between the gut microbiome and body weight, human evidence for causality remains scarce. In this Review
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Metaflammation in obesity and its therapeutic targeting Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-22 Michael W. Schleh, Heather L. Caslin, Jamie N. Garcia, Mona Mashayekhi, Gitanjali Srivastava, Anna B. Bradley, Alyssa H. Hasty
Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune
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Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-22 Judith Y. Altarejos, Jeffrey Pangilinan, Simona Podgrabinska, Baris Akinci, Maria Foss-Freitas, Adam H. Neidert, Yonaton Ray, Wenjun Zheng, Steven Kim, Vishal Kamat, Meilin Huang, Soo Min, Jason Mastaitis, Giselle Dominguez-Gutierrez, Jee-Hae Kim, Panayiotis Stevis, Tammy Huang, Brian Zambrowicz, William C. Olson, Stephen Godin, Elizabeth Bradley, Andrew D. Gewitz, Mark Baker, Rita Hench, Matthew S
Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic
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Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-15 Yasutaka Yamada, Varadha Balaji Venkadakrishnan, Kei Mizuno, Martin Bakht, Sheng-Yu Ku, Maria Mica Garcia, Himisha Beltran
Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMTs) are highly expressed, and global DNA methylation is dysregulated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and substantially reduced NEPC
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Identification of a small-molecule Tim-3 inhibitor to potentiate T cell–mediated antitumor immunotherapy in preclinical mouse models Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-15 Shuaiya Ma, Ye Tian, Jiali Peng, Chaojia Chen, Xueqi Peng, Fabao Zhao, Zhenyu Li, Mengzhen Li, Fangcheng Zhao, Xue Sheng, Runzhe Zong, Yiquan Li, Jiwei Zhang, Mingyan Yu, Qingfen Zhu, Xiaoyu Tian, Yuyang Li, Markus R. Neckenig, Huiqing Liu, Peng Zhan, Xuetian Yue, Zhuanchang Wu, Lifen Gao, Xiaohong Liang, Xinyong Liu, Chunyang Li, Chunhong Ma
T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC′ cleft of Tim-3, a highly conserved binding site of phosphatidylserine
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Effects of boosting and waning in highly exposed populations on dengue epidemic dynamics Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-15 Rosemary A. Aogo, Jose Victor Zambrana, Nery Sanchez, Sergio Ojeda, Guillermina Kuan, Angel Balmaseda, Aubree Gordon, Eva Harris, Leah C. Katzelnick
Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly immune Nicaraguan children and adults ( n = 4478) experience boosting and waning of antibodies during and after major Zika and dengue epidemics. We develop
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Tension-activated nanofiber patches delivering an anti-inflammatory drug improve repair in a goat intervertebral disc herniation model Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-15 Ana P. Peredo, Sarah E. Gullbrand, Chet S. Friday, Brianna S. Orozco, Bijan Dehghani, Austin C. Jenk, Edward D. Bonnevie, Rachel L. Hilliard, Hannah M. Zlotnick, George R. Dodge, Daeyeon Lee, Julie B. Engiles, Michael W. Hast, Thomas P. Schaer, Harvey E. Smith, Robert L. Mauck
Conventional microdiscectomy treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus, resulting in a high incidence of recurrent herniation and persistent dysfunction. The lack of repair and the acute inflammation that arise after injury can further compromise the disc and result in disc-wide degeneration in the long term. To address this clinical need
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Transcriptome-based identification of tumor-reactive and bystander CD8 + T cell receptor clonotypes in human pancreatic cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-15 Zibo Meng, Aaron Rodriguez Ehrenfried, Chin Leng Tan, Laura K. Steffens, Hannes Kehm, Stefan Zens, Claudia Lauenstein, Alina Paul, Marius Schwab, Jonas D. Förster, Mogjiborahman Salek, Angelika B. Riemer, Heshui Wu, Christoph Eckert, Carl-Stephan Leonhardt, Oliver Strobel, Michael Volkmar, Isabel Poschke, Rienk Offringa
Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8 + T cells in PDAC samples. Here, we charted the tumor-infiltrating T cell repertoire in PDAC by combining single-cell transcriptomics with functional testing
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Parathyroid hormone treatment partially reverses endplate remodeling and attenuates low back pain in animal models of spine degeneration Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-15 Zemin Ling, Janet Crane, Hao Hu, Yan Chen, Mei Wan, Shuangfei Ni, Shadpour Demehri, Bahram Mohajer, Xinsheng Peng, Xuenong Zou, Xu Cao
Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory
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Learning CNS immunopathology from therapeutic interventions Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-08 Nicholas Schwab, Heinz Wiendl
Modulation of immune cell trafficking across the blood-brain barrier has not only introduced a therapeutic avenue for multiple sclerosis (MS) but also represents an example of reverse translational medicine. Data from clinical trials of drugs such as natalizumab and fingolimod have revealed the involvement of different compartments in relapsing versus non-relapsing MS immune biology, contributed to
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Immunological drivers of amyotrophic lateral sclerosis Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-08 Tania F. Gendron, Leonard Petrucelli
Amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease involving complex genetic and environmental factors, is associated with neuroinflammation. Preclinical and clinical studies support immune system involvement in ALS pathogenesis, thereby spurring investigations into potential pathogenic mechanisms, immune response biomarkers, and ALS therapeutics.
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Neuroinflammation: An astrocyte perspective Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-08 Hong-Gyun Lee, Joon-Hyuk Lee, Lucas E. Flausino, Francisco J. Quintana
Astrocytes are abundant glial cells in the central nervous system (CNS) that play active roles in health and disease. Recent technologies have uncovered the functional heterogeneity of astrocytes and their extensive interactions with other cell types in the CNS. In this Review, we highlight the intricate interactions between astrocytes, other CNS-resident cells, and CNS-infiltrating cells as well as
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Central and peripheral innate and adaptive immunity in Parkinson’s disease Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-08 Ashley S. Harms, Ya-Ting Yang, Malú Gámez Tansey
Parkinson’s disease (PD) is a multisystem disorder with characteristics of a chronic inflammatory disease. To develop effective immunomodulatory interventions to combat PD, we need to think innovatively about the implications of orchestrated central and peripheral innate and adaptive immune responses that occur as the disease begins and progresses.
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CNS therapeutics: Immune cells break the barriers Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-08 Karine Thai, Alexandre Prat
Peripheral immune cells can be seen as attractive vectors and drug carriers for central nervous system therapeutics because these cells have unique properties that allow them to migrate across the blood-brain barrier, enabling drug delivery to brain regions that are inaccessible to free drugs.
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Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-01 Jingbo Li, Jiao Liu, Zhuan Zhou, Runliu Wu, Xin Chen, Chunhua Yu, Brent Stockwell, Guido Kroemer, Rui Kang, Daolin Tang
Lipid peroxidation–dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis
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Shifting the trajectory of therapeutic development for neurological and psychiatric disorders Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-01 Dimitri Krainc, William J. Martin, Bradford Casey, Frances E. Jensen, Sarah Tishkoff, William Z. Potter, Steven E. Hyman
Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric
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Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-01 Ismail Cimen, Lucia Natarelli, Zahra Abedi Kichi, James M. Henderson, Floriana M. Farina, Eva Briem, Maria Aslani, Remco T.A. Megens, Yvonne Jansen, Elizabeth Mann-Fallenbuchel, Selin Gencer, Johan Duchêne, Maliheh Nazari-Jahantigh, Emiel P.C. van der Vorst, Wolfgang Enard, Yvonne Döring, Andreas Schober, Donato Santovito, Christian Weber
The CXC chemokine receptor 4 (CXCR4) in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is crucial for vascular integrity. The atheroprotective functions of CXCR4 in vascular cells may be counteracted by atherogenic functions in other nonvascular cell types. Thus, strategies for cell-specifically augmenting CXCR4 function in vascular cells are crucial if this receptor is to be useful
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Fecal microbiota transplantation promotes reduction of antimicrobial resistance by strain replacement Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-01 Michael H. Woodworth, Roth E. Conrad, Marina Haldopoulos, Stephanie M. Pouch, Ahmed Babiker, Aneesh K. Mehta, Kaitlin L. Sitchenko, Charlotte H. Wang, Amanda Strudwick, Jessica M. Ingersoll, Cécile Philippe, Sarah Lohsen, Kumru Kocaman, Blake G. Lindner, Janet K. Hatt, Rheinallt M. Jones, Candace Miller, Andrew S. Neish, Rachel Friedman-Moraco, Geeta Karadkhele, Ken H. Liu, Dean P. Jones, C. Christina
Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation (FMT) can reduce MDRO colonization, but its mechanisms are poorly understood. We conducted a randomized, controlled trial of FMT for MDRO decolonization in renal transplant recipients called PREMIX (NCT02922816). Eleven participants
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Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-01 Minsoo Khang, Ju Hyun Lee, Teresa Lee, Hee-Won Suh, Supum Lee, Alessandra Cavaliere, Amy Rushing, Luiz H. Geraldo, Erika Belitzky, Samantha Rossano, Henk M. de Feyter, Kwangsoo Shin, Anita Huttner, Martine F. Roussel, Jean-Leon Thomas, Richard E. Carson, Bernadette Marquez-Nostra, Ranjit S. Bindra, W. Mark Saltzman
The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate
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The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI Sci. Transl. Med. (IF 17.1) Pub Date : 2023-11-01 Francesco Trepiccione, Anna Iervolino, Mariavittoria D’Acierno, Sabrina Siccardi, Vincenzo Costanzo, Donato Sardella, Luigi R. De La Motte, Luciano D’Apolito, Antonio Miele, Alessandra F. Perna, Giovanna Capolongo, Miriam Zacchia, Sebastian Frische, Rikke Nielsen, Leopoldo Staiano, Irene Sambri, Rossella De Cegli, Robert Unwin, Dominique Eladari, Giovambattista Capasso
Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS
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DGKα/ζ inhibitors combine with PD-1 checkpoint therapy to promote T cell–mediated antitumor immunity Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-25 Michael Wichroski, Joseph Benci, Si-Qi Liu, Louis Chupak, Jie Fang, Carolyn Cao, Cindy Wang, Joelle Onorato, Hongchen Qiu, Yongli Shan, Dana Banas, Ryan Powles, Gregory Locke, Abigail Witt, Caitlyn Stromko, Huilin Qi, Xiaofan Zheng, Scott Martin, Min Ding, Robert Gentles, Nicholas Meanwell, Upender Velaparthi, Richard Olson, Susan Wee, Daniel Tenney, Christopher G. Parker, Benjamin F. Cravatt, Michael
Programmed cell death protein 1 (PD-1) immune checkpoint blockade therapy has revolutionized cancer treatment. Although PD-1 blockade is effective in a subset of patients with cancer, many fail to respond because of either primary or acquired resistance. Thus, next-generation strategies are needed to expand the depth and breadth of clinical responses. Toward this end, we designed a human primary T
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Genetic vulnerability to Crohn’s disease reveals a spatially resolved epithelial restitution program Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-25 Toru Nakata, Chenhao Li, Toufic Mayassi, Helen Lin, Koushik Ghosh, Åsa Segerstolpe, Emma L. Diamond, Paula Herbst, Tommaso Biancalani, Shreya Gaddam, Saurabh Parkar, Ziqing Lu, Alok Jaiswal, Bihua Li, Elizabeth A. Creasey, Ariel Lefkovith, Mark J. Daly, Daniel B. Graham, Ramnik J. Xavier
Effective tissue repair requires coordinated intercellular communication to sense damage, remodel the tissue, and restore function. Here, we dissected the healing response in the intestinal mucosa by mapping intercellular communication at single-cell resolution and integrating with spatial transcriptomics. We demonstrated that a risk variant for Crohn’s disease, hepatocyte growth factor activator (HGFAC)
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Immune responses to gut bacteria associated with time to diagnosis and clinical response to T cell–directed therapy for type 1 diabetes prevention Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-25 Quin Yuhui Xie, Sean Oh, Anthony Wong, Christopher Yau, Kevan C. Herold, Jayne S. Danska
Immune-targeted therapies have efficacy for treatment of autoinflammatory diseases. For example, treatment with the T cell–specific anti-CD3 antibody teplizumab delayed disease onset in participants at high risk for type 1 diabetes (T1D) in the TrialNet 10 (TN-10) trial. However, heterogeneity in therapeutic responses in TN-10 and other immunotherapy trials identifies gaps in understanding disease
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Prenatal Zika virus infection has sex-specific effects on infant physical development and mother-infant social interactions Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-25 Gilda Moadab, Florent Pittet, Jeffrey L. Bennett, Christopher L. Taylor, Olivia Fiske, Anil Singapuri, Lark L. Coffey, Koen K. A. Van Rompay, Eliza Bliss-Moreau
There is enormous variation in the extent to which fetal Zika virus (fZIKV) infection affects the developing brain. Despite the neural consequences of fZIKV infection observed in people and animal models, many open questions about the relationship between infection dynamics and fetal and infant development remain. To further understand how ZIKV affects the developing nervous system and the behavioral
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Exacerbated Zika virus–induced neuropathology and microcephaly in fetuses of dengue-immune nonhuman primates Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-25 Wilfried A. A. Saron, Keerthana Shanmugam, Chi-Ching Tung, Ranjit Kumar Patmanathan, Abhay P. S. Rathore, Danielle E. Anderson, Ashley L. St. John
Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is not fully understood why some fetuses experience severe complications after in utero exposure to ZIKV, whereas others do not. Given the antigenic similarity between ZIKV and the closely related virus dengue (DENV) and the potential
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The tumor microenvironment state associates with response to HPV therapeutic vaccination in patients with respiratory papillomatosis Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-25 Scott M. Norberg, Ke Bai, Cem Sievers, Yvette Robbins, Jay Friedman, Xinping Yang, Meg Kenyon, Elizabeth Ward, Jeffrey Schlom, James Gulley, Amy Lankford, Roshanak Semnani, Helen Sabzevari, Douglas E. Brough, Clint T. Allen
Recurrent respiratory papillomatosis (RRP) is a rare, debilitating neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11 and characterized by growth of papillomas in the upper aerodigestive tract. There is no approved medical therapy, and patients require repeated debulking procedures to maintain voice and airway function. PRGN-2012 is a gorilla adenovirus immune-therapeutic
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Many potential pathways to future pandemic influenza Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-18 David M. Morens, Jaekeun Park, Jeffery K. Taubenberger
Although influenza A viruses have caused pandemics for centuries, future pandemics cannot be predicted with our current understanding and resources. Concern about an H5N1 avian influenza pandemic has caused alarm since 1997, but there are many other possible routes to pandemic influenza.
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Multiomic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-18 Camila Farias Amorim, Victoria M. Lovins, Tej Pratap Singh, Fernanda O. Novais, Jordan C. Harris, Alexsandro S. Lago, Lucas P. Carvalho, Edgar M. Carvalho, Daniel P. Beiting, Phillip Scott, Elizabeth A. Grice
Leishmania braziliensis is a parasitic infection that can result in inflammation and skin injury with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 patients infected with
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Wastewater surveillance facilitates climate change–resilient pathogen monitoring Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-18 Megan B. Diamond, Elizabeth Yee, Manisha Bhinge, Samuel V. Scarpino
Traditional disease surveillance systems are ill-equipped to handle climate change–driven shifts in pathogen dynamics. If paired with wastewater surveillance, a cost-effective and scalable approach for generating high-resolution health data, such next-generation systems can enable effective resource allocation and delivery of targeted interventions.
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Backyard zoonoses: The roles of companion animals and peri-domestic wildlife Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-18 Amandine Gamble, Ximena A. Olarte-Castillo, Gary R. Whittaker
The spillover of human infectious diseases from animal reservoirs is now well appreciated. However, societal and climate-related changes are affecting the dynamics of such interfaces. In addition to the disruption of traditional wildlife habitats, in part because of climate change and human demographics and behavior, there is an increasing zoonotic disease risk from companion animals. This includes
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A ticking time bomb hidden in plain sight Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-18 Sukanya Narasimhan, Durland Fish, Joao H. F. Pedra, Utpal Pal, Erol Fikrig
The deer tick transmits nearly half of the known tick-borne pathogens in the United States, and its expanding geographic range increases the risk of human infection. To decrease the abundance of and infection risk from deer ticks, approaches that include vaccines for human use and for animal hosts are desired.
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Zoonotic mosquito-borne arboviruses: Spillover, spillback, and realistic mitigation strategies Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-18 Rafael K. Campos, Shannan L. Rossi, Robert B. Tesh, Scott C. Weaver
Emerging zoonotic mosquito-borne viruses pose increasing health threats because of growing mosquito population, geographic expansions, and control challenges. We emphasize the need for global preparedness to effectively mitigate the health, societal, and economic impacts of spillover by these viruses through proactive measures of prediction, surveillance, prevention, and treatment.
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Drug discovery in Africa tackles zoonotic and related infections Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-18 Christabel N. Hikaambo, Natalia Shakela, John G. Woodland, Kathryn J. Wicht, Kelly Chibale
Zoonotic and related infections pose an enormous health threat to the world’s second-most populous continent. Despite the challenges faced by drug discovery scientists in Africa, recent progress toward identifying potential medicines across diverse disease areas is a cause for optimism and an indicator of progress in African-led scientific initiatives.
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A single-cell genomic atlas for maturation of the human cerebellum during early childhood Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-12 Seth A. Ament, Marcia Cortes-Gutierrez, Brian R. Herb, Evelina Mocci, Carlo Colantuoni, Margaret M. McCarthy
Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to the risk of developing neurodevelopmental disorders. Here, using single-cell genomics
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Donor-derived regulatory dendritic cell infusion modulates effector CD8 + T cell and NK cell responses after liver transplantation Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-11 Lillian M. Tran, Camila Macedo, Alan F. Zahorchak, Xinyan Gu, Beth Elinoff, Aatur D. Singhi, Brian Isett, Adriana Zeevi, Megan Sykes, Kevin Breen, Avantika Srivastava, Erin M. Ables, Douglas Landsittel, Mindi A. Styn, Abhinav Humar, Fadi G. Lakkis, Diana M. Metes, Angus W. Thomson
Immune cell–based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor
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Lactate oxidase nanocapsules boost T cell immunity and efficacy of cancer immunotherapy Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-11 Zheng Cao, Duo Xu, Jeffrey Harding, Wenting Chen, Xiangsheng Liu, Zi Wang, Lan Wang, Tong Qi, Shilin Chen, Xinheng Guo, Irvin S. Y. Chen, Jimin Guo, Yunfeng Lu, Jing Wen
Cancer immunotherapy has reshaped the landscape of cancer treatment. However, its efficacy is still limited by tumor immunosuppression associated with the excessive production of lactate by cancer cells. Although extensive efforts have been made to reduce lactate concentrations through inhibition of lactate dehydrogenase, such inhibitors disrupt the metabolism of healthy cells, causing severe nonspecific
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Regeneration of neuromuscular synapses after acute and chronic denervation by inhibiting the gerozyme 15-prostaglandin dehydrogenase Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-11 Mohsen A. Bakooshli, Yu Xin Wang, Elena Monti, Shiqi Su, Peggy Kraft, Minas Nalbandian, Ludmila Alexandrova, Joshua R. Wheeler, Hannes Vogel, Helen M. Blau
To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable neuromuscular diseases, or aging. Here, we showed that denervation resulting from transection of the sciatic nerve triggered a marked increase in the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in skeletal
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Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-11 Kavita Y. Sarin, John Kincaid, Brittney Sell, Jahanbanoo Shahryari, Matthew A. J. Duncton, Elaine Morefield, Wenchao Sun, Karol Prieto, Omar Chavez-Chiang, Carlos de Moran Segura, Jonathan Nguyen, Roderick T. Bronson, Scott R. Plotkin, Gerd G. Kochendoerfer, Peter Fenn, Michael A. Wootton, Christopher Powala, Mark P. de Souza, Kenneth Y. Tsai
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi)
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A metabolic role for CD47 in pancreatic β cell insulin secretion and islet transplant outcomes Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-11 Kedar Ghimire, Atharva Kale, Jennifer Li, Sohel M. Julovi, Philip O’Connell, Shane T. Grey, Wayne J. Hawthorne, Jenny E. Gunton, Natasha M. Rogers
Diabetes is a global public health burden and is characterized clinically by relative or absolute insulin deficiency. Therapeutic agents that stimulate insulin secretion and improve insulin sensitivity are in high demand as treatment options. CD47 is a cell surface glycoprotein implicated in multiple cellular functions including recognition of self, angiogenesis, and nitric oxide signaling; however
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A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-04 Jimena Perez-Sanchez, Steven J. Middleton, Luke A. Pattison, Helen Hilton, Mosab Ali Awadelkareem, Sana R. Zuberi, Maria B. Renke, Huimin Hu, Xun Yang, Alex J. Clark, Ewan St. John Smith, David L. Bennett
Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM 4 -GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical
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An mpox virus mRNA-lipid nanoparticle vaccine confers protection against lethal orthopoxviral challenge Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-04 Alec W. Freyn, Caroline Atyeo, Patricia L. Earl, Jeffrey L. Americo, Gwo-Yu Chuang, Harini Natarajan, Tiffany R. Frey, Jason G. Gall, Juan I. Moliva, Ruth Hunegnaw, Guha Asthagiri Arunkumar, Clinton O. Ogega, Arshan Nasir, Genesis Santos, Rafael H. Levin, Anusha Meni, Patricia A. Jorquera, Hamilton Bennett, Joshua A. Johnson, Michael A. Durney, Guillaume Stewart-Jones, Jay W. Hooper, Tonya M. Colpitts
Mpox virus (MPXV) caused a global outbreak in 2022. Although smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the threat of additional zoonotic events and the virus’s evolving ability to drive human-to-human transmission, there is an urgent need for an MPXV-specific vaccine that confers
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Identifying predictors of glioma evolution from longitudinal sequencing Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-04 Quanhua Mu, Ruichao Chai, Bo Pang, Yingxi Yang, Hanjie Liu, Zheng Zhao, Zhaoshi Bao, Dong Song, Zhihan Zhu, Mengli Yan, Biaobin Jiang, Zongchao Mo, Jihong Tang, Jason K. Sa, Hee Jin Cho, Yuzhou Chang, Kaitlin Hao Yi Chan, Danson Shek Chun Loi, Sindy Sing Ting Tam, Aden Ka Yin Chan, Angela Ruohao Wu, Zhaoqi Liu, Wai Sang Poon, Ho Keung Ng, Danny Tat Ming Chan, Antonio Iavarone, Do-Hyun Nam, Tao Jiang
Clonal evolution drives cancer progression and therapeutic resistance. Recent studies have revealed divergent longitudinal trajectories in gliomas, but early molecular features steering posttreatment cancer evolution remain unclear. Here, we collected sequencing and clinical data of initial-recurrent tumor pairs from 544 adult diffuse gliomas and performed multivariate analysis to identify early molecular
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Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-04 Shuang Wang, Scott L. Friedman
Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses a global health threat because of its potential to progress to advanced fibrosis, leading to cirrhosis and liver cancer. Recent advances in single-cell methodologies, refined disease models, and genetic and epigenetic insights have provided a nuanced understanding of MASH fibrogenesis, with substantial
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Multicellular bioprinted skin facilitates human-like skin architecture in vivo Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-04 Adam M. Jorgensen, Anastasiya Gorkun, Naresh Mahajan, Kelsey Willson, Cara Clouse, Claire G. Jeong, Mathew Varkey, Mingsong Wu, Stephen J. Walker, Joseph A. Molnar, Sean V. Murphy, Sang Jin Lee, James J. Yoo, Shay Soker, Anthony Atala
Bioprinting is a promising alternative method to generate skin substitutes because it can replicate the structural organization of the skin into biomimetic layers in vitro. In this study, six primary human skin cell types were used to bioprint a trilayer skin construct consisting of epidermis, dermis, and hypodermis. Transplantation of the bioprinted skin with human cells onto full-thickness wounds
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A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens Sci. Transl. Med. (IF 17.1) Pub Date : 2023-10-04 Jun Yan, Travis B. Nielsen, Peggy Lu, Yuli Talyansky, Matt Slarve, Hernan Reza, Boris Novakovic, Mihai G. Netea, Ashley E. Keller, Troy Warren, Antonio DiGiandomenico, Bret R. Sellman, Brian M. Luna, Brad Spellberg
Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care–associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus
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Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2023-09-27 Yang Liu, Steven Reiken, Haikel Dridi, Qi Yuan, Khalid S. Mohammad, Trupti Trivedi, Marco C. Miotto, Kaylee Wedderburn-Pugh, Leah Sittenfeld, Ynez Kerley, Jill A. Meyer, Jonathan S. Peters, Scott C. Persohn, Amanda A. Bedwell, Lucas L. Figueiredo, Sukanya Suresh, Yun She, Rajesh Kumar Soni, Paul R. Territo, Andrew R. Marks, Theresa A. Guise
Chemotherapy-induced cognitive dysfunction (chemobrain) is an important adverse sequela of chemotherapy. Chemobrain has been identified by the National Cancer Institute as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A
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Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction–associated steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells Sci. Transl. Med. (IF 17.1) Pub Date : 2023-09-27 Connor Quinn, Mario C. Rico, Carmen Merali, Carlos A. Barrero, Oscar Perez-Leal, Victoria Mischley, John Karanicolas, Scott L. Friedman, Salim Merali
Hepatic fibrosis is the primary determinant of mortality in patients with metabolic dysfunction–associated steatohepatitis (MASH). Transforming growth factor–β (TGFβ), a master profibrogenic cytokine, is a promising therapeutic target that has not yet been translated into an effective therapy in part because of liabilities associated with systemic TGFβ antagonism. We have identified that soluble folate
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A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus Sci. Transl. Med. (IF 17.1) Pub Date : 2023-09-27 Longping V. Tse, Yixuan J. Hou, Elizabeth McFadden, Rhianna E. Lee, Trevor D. Scobey, Sarah R. Leist, David R. Martinez, Rita M. Meganck, Alexandra Schäfer, Boyd L. Yount, Teresa Mascenik, John M. Powers, Scott H. Randell, Yi Zhang, Lingshu Wang, John Mascola, Jason S. McLellan, Ralph S. Baric
The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome (MERS)–related coronaviruses (CoVs) remain a pressing concern for global health preparedness. Using metagenomic sequence data and CoV reverse genetics, we recovered a full-length wild-type MERS-like BtCoV/
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Boosting systemic absorption of peptides with a bioinspired buccal-stretching patch Sci. Transl. Med. (IF 17.1) Pub Date : 2023-09-27 Zhi Luo, David Klein Cerrejon, Simon Römer, Nicole Zoratto, Jean-Christophe Leroux
Biopharmaceuticals, including proteins and peptides, have revolutionized the treatment of a wide range of diseases, from diabetes and cardiovascular disorders to virus infections and cancer. Despite their efficacy, most of these macromolecular drugs require parenteral administration because of their high molecular weight and relative instability. Over the past 40 years, only a few oral peptide drugs
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Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis Sci. Transl. Med. (IF 17.1) Pub Date : 2023-09-27 Meghan Mooring, Grace A. Yeung, Panu Luukkonen, Silvia Liu, Muhammad Waqas Akbar, Gary J. Zhang, Oluwashanu Balogun, Xuemei Yu, Rigen Mo, Kari Nejak-Bowen, Masha V. Poyurovsky, Carmen J. Booth, Liza Konnikova, Gerald I. Shulman, Dean Yimlamai
Obesity is increasing worldwide and leads to a multitude of metabolic diseases, including cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH). Cysteine-rich angiogenic inducer 61 (CYR61) is associated with the progression of NASH, but it has been described to have anti- and proinflammatory properties. We sought to examine the role of liver
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TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence Sci. Transl. Med. (IF 17.1) Pub Date : 2023-09-20 Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla B. Heavican-Foral, Elisa Mandato, Huiyun Liu, Geoffrey M. Nelson, Lu Yang, Renee Chen, Katherine A. Donovan, Marcus K. Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit J. Nirmal, Salvia Jain, Catharine Leahy, Kristen L. Jones, Kristen E. Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice
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A bioengineered trachea-like structure improves survival in a rabbit tracheal defect model Sci. Transl. Med. (IF 17.1) Pub Date : 2023-09-20 Hai Tang, Weiyan Sun, Xiucheng Liu, Qing Gao, Yi Chen, Chaoqi Xie, Weikang Lin, Jiafei Chen, Long Wang, Ziwen Fan, Lei Zhang, Yijiu Ren, Yunlang She, Yong He, Chang Chen
A practical strategy for engineering a trachea-like structure that could be used to repair or replace a damaged or injured trachea is an unmet need. Here, we fabricated bioengineered cartilage (BC) rings from three-dimensionally printed fibers of poly(ɛ-caprolactone) (PCL) and rabbit chondrocytes. The extracellular matrix (ECM) secreted by the chondrocytes combined with the PCL fibers formed a “concrete-rebar