Pub Date : 2025-01-15DOI: 10.1126/scitranslmed.adk3690
Wesley Brandao, Nimansha Jain, Zhuoran Yin, Kilian L. Kleemann, Madison Carpenter, Xin Bao, Javier R. Serrano, Eric Tycksen, Ana Durao, Jen-Li Barry, Caroline Baufeld, Dilansu Guneykaya, Xiaoming Zhang, Alexandra Litvinchuk, Hong Jiang, Neta Rosenzweig, Kristen M. Pitts, Michael Aronchik, Taha Yahya, Tian Cao, Marcelo Kenzo Takahashi, Rajesh Krishnan, Hayk Davtyan, Jason D. Ulrich, Mathew Blurton-Jones, Ilya Ilin, Howard L. Weiner, David M. Holtzman, Oleg Butovsky
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre–neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.
{"title":"Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy","authors":"Wesley Brandao, Nimansha Jain, Zhuoran Yin, Kilian L. Kleemann, Madison Carpenter, Xin Bao, Javier R. Serrano, Eric Tycksen, Ana Durao, Jen-Li Barry, Caroline Baufeld, Dilansu Guneykaya, Xiaoming Zhang, Alexandra Litvinchuk, Hong Jiang, Neta Rosenzweig, Kristen M. Pitts, Michael Aronchik, Taha Yahya, Tian Cao, Marcelo Kenzo Takahashi, Rajesh Krishnan, Hayk Davtyan, Jason D. Ulrich, Mathew Blurton-Jones, Ilya Ilin, Howard L. Weiner, David M. Holtzman, Oleg Butovsky","doi":"10.1126/scitranslmed.adk3690","DOIUrl":"10.1126/scitranslmed.adk3690","url":null,"abstract":"<div >Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre–neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 781","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adr2218
Olivia M. Swanson, Qianyi E. Zhang, Elizabeth Van Itallie, Ming Tian, Alecia R. Brown, Caitlin Harris, Anyway Brenda Kapingidza, Brianna Rhodes, Lena M. Smith, Sravani Venkatayogi, Kenneth Cronin, McKenzie Frazier, Rob Parks, Maggie Bar, Chuancang Jiang, Joshua S. Martin Beem, Hwei-Ling Cheng, Jillian Davis, Kelly McGovern, Amanda Newman, Robert J. Edwards, Derek Cain, S. Munir Alam, Kevin Wiehe, Kevin O. Saunders, Priyamvada Acharya, Fred Alt, Barton F. Haynes, Mihai L. Azoitei
Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation of diverse precursors, followed by successive boosts that guide these responses to enhanced breadth through the acquisition of somatic mutations. Because HIV bnAbs contain mutations in their B cell receptors (BCRs) that are rarely generated during conventional B cell maturation, HIV vaccine immunogens must robustly engage and expand B cells with BCRs that contain these improbable mutations. Here, we engineered an immunogen that activates diverse precursors of an HIV V3-glycan bnAb and promotes their acquisition of a functionally critical improbable mutation. This immunogen was validated biochemically, structurally, and in three different humanized immunoglobulin mouse models that were designed to test HIV immunogens. These results provide a blueprint for rationally designing priming immunogens that explicitly target the elicitation of antibodies with functional yet improbable mutations.
{"title":"An engineered immunogen activates diverse HIV broadly neutralizing antibody precursors and promotes acquisition of improbable mutations","authors":"Olivia M. Swanson, Qianyi E. Zhang, Elizabeth Van Itallie, Ming Tian, Alecia R. Brown, Caitlin Harris, Anyway Brenda Kapingidza, Brianna Rhodes, Lena M. Smith, Sravani Venkatayogi, Kenneth Cronin, McKenzie Frazier, Rob Parks, Maggie Bar, Chuancang Jiang, Joshua S. Martin Beem, Hwei-Ling Cheng, Jillian Davis, Kelly McGovern, Amanda Newman, Robert J. Edwards, Derek Cain, S. Munir Alam, Kevin Wiehe, Kevin O. Saunders, Priyamvada Acharya, Fred Alt, Barton F. Haynes, Mihai L. Azoitei","doi":"10.1126/scitranslmed.adr2218","DOIUrl":"10.1126/scitranslmed.adr2218","url":null,"abstract":"<div >Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation of diverse precursors, followed by successive boosts that guide these responses to enhanced breadth through the acquisition of somatic mutations. Because HIV bnAbs contain mutations in their B cell receptors (BCRs) that are rarely generated during conventional B cell maturation, HIV vaccine immunogens must robustly engage and expand B cells with BCRs that contain these improbable mutations. Here, we engineered an immunogen that activates diverse precursors of an HIV V3-glycan bnAb and promotes their acquisition of a functionally critical improbable mutation. This immunogen was validated biochemically, structurally, and in three different humanized immunoglobulin mouse models that were designed to test HIV immunogens. These results provide a blueprint for rationally designing priming immunogens that explicitly target the elicitation of antibodies with functional yet improbable mutations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adp9607
Simone Romeni, Elena Losanno, Daniele Emedoli, Luigi Albano, Filippo Agnesi, Carlo Mandelli, Lina Raffaella Barzaghi, Edoardo Pompeo, Cinzia Mura, Federica Alemanno, Andrea Tettamanti, Paola Castellazzi, Chiara Ciucci, Veronica Fossati, Laura Toni, Heike Caravati, Andrea Bandini, Ubaldo Del Carro, Federica Agosta, Massimo Filippi, Sandro Iannaccone, Pietro Mortini, Silvestro Micera
Spinal cord injury (SCI) causes severe motor and sensory deficits, and there are currently no approved treatments for recovery. Nearly 70% of patients with SCI experience pathological muscle cocontraction and spasticity, accompanied by clinical signs such as patellar hyperreflexia and ankle clonus. The integration of epidural electrical stimulation (EES) of the spinal cord with rehabilitation has substantial potential to improve recovery of motor functions; however, abnormal muscle cocontraction and spasticity may limit the benefit of these interventions and hinder the effectiveness of EES in promoting functional movements. High-frequency excitation block introduced in peripheral nerve stimulation could reduce abnormal activity and lead to more physiological activation patterns. Here, we evaluated the application of high-frequency EES (HF-EES) in alleviating undesired muscular cocontraction and spasticity in two patients with motor incomplete SCI implanted with a commercial 32-channel EES paddle commonly used for pain therapy. To design custom HF-EES protocols, we first mapped the muscles targeted by different EES configurations. Our results showed that HF-EES substantially reduced patellar reflex in one participant and eliminated both patellar reflex and ankle clonus in the other participant. By combining HF-EES and low-frequency EES (LF-EES) to enhance functional movements with intensive rehabilitation, we observed notable improvements in lower limb kinematics, muscle strength, and clinical lower limb motor assessments over the trial period. This study suggests that HF-EES could be an important supplementary tool in SCI treatment, emphasizing the importance of personalized rehabilitation approaches and advanced tools to optimize EES treatments and offering hope for individuals with SCI-related motor deficits.
{"title":"High-frequency epidural electrical stimulation reduces spasticity and facilitates walking recovery in patients with spinal cord injury","authors":"Simone Romeni, Elena Losanno, Daniele Emedoli, Luigi Albano, Filippo Agnesi, Carlo Mandelli, Lina Raffaella Barzaghi, Edoardo Pompeo, Cinzia Mura, Federica Alemanno, Andrea Tettamanti, Paola Castellazzi, Chiara Ciucci, Veronica Fossati, Laura Toni, Heike Caravati, Andrea Bandini, Ubaldo Del Carro, Federica Agosta, Massimo Filippi, Sandro Iannaccone, Pietro Mortini, Silvestro Micera","doi":"10.1126/scitranslmed.adp9607","DOIUrl":"10.1126/scitranslmed.adp9607","url":null,"abstract":"<div >Spinal cord injury (SCI) causes severe motor and sensory deficits, and there are currently no approved treatments for recovery. Nearly 70% of patients with SCI experience pathological muscle cocontraction and spasticity, accompanied by clinical signs such as patellar hyperreflexia and ankle clonus. The integration of epidural electrical stimulation (EES) of the spinal cord with rehabilitation has substantial potential to improve recovery of motor functions; however, abnormal muscle cocontraction and spasticity may limit the benefit of these interventions and hinder the effectiveness of EES in promoting functional movements. High-frequency excitation block introduced in peripheral nerve stimulation could reduce abnormal activity and lead to more physiological activation patterns. Here, we evaluated the application of high-frequency EES (HF-EES) in alleviating undesired muscular cocontraction and spasticity in two patients with motor incomplete SCI implanted with a commercial 32-channel EES paddle commonly used for pain therapy. To design custom HF-EES protocols, we first mapped the muscles targeted by different EES configurations. Our results showed that HF-EES substantially reduced patellar reflex in one participant and eliminated both patellar reflex and ankle clonus in the other participant. By combining HF-EES and low-frequency EES (LF-EES) to enhance functional movements with intensive rehabilitation, we observed notable improvements in lower limb kinematics, muscle strength, and clinical lower limb motor assessments over the trial period. This study suggests that HF-EES could be an important supplementary tool in SCI treatment, emphasizing the importance of personalized rehabilitation approaches and advanced tools to optimize EES treatments and offering hope for individuals with SCI-related motor deficits.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adk8623
A. Scott McCall, Sergey Gutor, Hari Tanjore, Ankita Burman, Taylor Sherrill, Micah Chapman, Carla L. Calvi, David Han, Jane Camarata, Raphael P. Hunt, David Nichols, Nicholas E. Banovich, William E. Lawson, Jason J. Gokey, Jonathan A. Kropski, Timothy S. Blackwell
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional “aberrant” epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER–traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.
{"title":"Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models","authors":"A. Scott McCall, Sergey Gutor, Hari Tanjore, Ankita Burman, Taylor Sherrill, Micah Chapman, Carla L. Calvi, David Han, Jane Camarata, Raphael P. Hunt, David Nichols, Nicholas E. Banovich, William E. Lawson, Jason J. Gokey, Jonathan A. Kropski, Timothy S. Blackwell","doi":"10.1126/scitranslmed.adk8623","DOIUrl":"10.1126/scitranslmed.adk8623","url":null,"abstract":"<div >Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional “aberrant” epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (<i>Scgb1a1-CreER</i>–traced) progenitors and exhibited transcriptional programs of <i>Hif2a</i> activation. In mice treated with repetitive intratracheal bleomycin, deletion of <i>Epas1</i> (Hif2a) but not <i>Hif1a</i>, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adn9832
Mona Mohammadhosseini, Trevor Enright, Adam Duvall, Alex Chitsazan, Hsin-Yun Lin, Aysegul Ors, Brett A. Davis, Olga Nikolova, Erica Bresciani, Jamie Diemer, Kathleen Craft, Ana Catarina Menezes, Matthew Merguerian, Shawn Chong, Katherine R. Calvo, Natalie T. Deuitch, Shira Glushakow-Smith, Kira Gritsman, Lucy A. Godley, Marshall S. Horwitz, Sioban Keel, Lucio H. Castilla, Emek Demir, Hisham Mohammed, Paul Liu, Anupriya Agarwal
Familial platelet disorder (FPD) is associated with germline RUNX1 mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing (n = 10) combined with functional analysis of samples from patients with RUNX1-FPD (n > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with RUNX1-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. RUNX1-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with RUNX1-FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in RUNX1-FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed RUNX1-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in RUNX1-FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with RUNX1-FPD and prevent myeloid progression.
{"title":"Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder","authors":"Mona Mohammadhosseini, Trevor Enright, Adam Duvall, Alex Chitsazan, Hsin-Yun Lin, Aysegul Ors, Brett A. Davis, Olga Nikolova, Erica Bresciani, Jamie Diemer, Kathleen Craft, Ana Catarina Menezes, Matthew Merguerian, Shawn Chong, Katherine R. Calvo, Natalie T. Deuitch, Shira Glushakow-Smith, Kira Gritsman, Lucy A. Godley, Marshall S. Horwitz, Sioban Keel, Lucio H. Castilla, Emek Demir, Hisham Mohammed, Paul Liu, Anupriya Agarwal","doi":"10.1126/scitranslmed.adn9832","DOIUrl":"10.1126/scitranslmed.adn9832","url":null,"abstract":"<div >Familial platelet disorder (FPD) is associated with germline <i>RUNX1</i> mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing (<i>n</i> = 10) combined with functional analysis of samples from patients with <i>RUNX1</i>-FPD (<i>n</i> > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with <i>RUNX1</i>-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. <i>RUNX1</i>-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with <i>RUNX1</i>-FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in <i>RUNX1</i>-FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed <i>RUNX1</i>-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in <i>RUNX1</i>-FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with <i>RUNX1</i>-FPD and prevent myeloid progression.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adk3434
Payam Gharibani, Efrat Abramson, Shruthi Shanmukha, Matthew D. Smith, Wesley H. Godfrey, Judy J. Lee, Jingwen Hu, Maryna Baydyuk, Marie-France Dorion, Xiaojing Deng, Yu Guo, Andrew J. Calle, Soonmyung A. Hwang, Jeffrey K. Huang, Peter A. Calabresi, Michael D. Kornberg, Paul M. Kim
In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance among demyelination, neurodegeneration, and myelin repair. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the lack of therapies aimed at promoting remyelination and slowing disease progression for individuals with MS. Here, we found that the protein kinase C (PKC)–modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, shifts the transcriptional programs of microglia and CNS-associated macrophages from a proinflammatory phenotype to a regenerative phenotype in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevented the activation of neuroinflammatory reactive astrocytes while also promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment of mice with bryo-1 augmented remyelination after a focal demyelinating injury. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin-regenerative and supportive agents in MS and other neurologic diseases.
{"title":"The protein kinase C modulator bryostatin-1 therapeutically targets microglia to attenuate neuroinflammation and promote remyelination","authors":"Payam Gharibani, Efrat Abramson, Shruthi Shanmukha, Matthew D. Smith, Wesley H. Godfrey, Judy J. Lee, Jingwen Hu, Maryna Baydyuk, Marie-France Dorion, Xiaojing Deng, Yu Guo, Andrew J. Calle, Soonmyung A. Hwang, Jeffrey K. Huang, Peter A. Calabresi, Michael D. Kornberg, Paul M. Kim","doi":"10.1126/scitranslmed.adk3434","DOIUrl":"10.1126/scitranslmed.adk3434","url":null,"abstract":"<div >In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance among demyelination, neurodegeneration, and myelin repair. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the lack of therapies aimed at promoting remyelination and slowing disease progression for individuals with MS. Here, we found that the protein kinase C (PKC)–modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, shifts the transcriptional programs of microglia and CNS-associated macrophages from a proinflammatory phenotype to a regenerative phenotype in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevented the activation of neuroinflammatory reactive astrocytes while also promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment of mice with bryo-1 augmented remyelination after a focal demyelinating injury. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin-regenerative and supportive agents in MS and other neurologic diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1126/scitranslmed.adl2103
Ana Martins, Fanni Judák, Zoltán Farkas, Petra Szili, Gábor Grézal, Bálint Csörgő, Márton Simon Czikkely, Elvin Maharramov, Lejla Daruka, Réka Spohn, Dávid Balogh, Andreea Daraba, Szilvia Juhász, Máté Vágvölgyi, Attila Hunyadi, Yihui Cao, Zhenquan Sun, Xuechen Li, Balázs Papp, Csaba Pál
Several antibiotic candidates are in development against Gram-positive bacterial pathogens, but their long-term utility is unclear. To investigate this issue, we studied the laboratory evolution of resistance to antibiotics that have not yet reached the market. We found that, with the exception of compound SCH79797, antibiotic resistance generally readily evolves in Staphylococcus aureus. Cross-resistance was detected between such candidates and antibiotics currently in clinical use, including vancomycin, daptomycin, and the promising antibiotic candidate teixobactin. These patterns were driven by overlapping molecular mechanisms through mutations in regulatory systems. In particular, teixobactin-resistant bacteria displayed clinically relevant multidrug resistance and retained their virulence in an invertebrate infection model, raising concerns. More generally, we demonstrate that putative resistance mutations against candidate antibiotics are already present in natural bacterial populations. Therefore, antibiotic resistance in nature may evolve readily from the selection of preexisting genetic variants. Our work highlights the importance of predicting future evolution of resistance to antibiotic candidates at an early stage of drug development.
{"title":"Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance","authors":"Ana Martins, Fanni Judák, Zoltán Farkas, Petra Szili, Gábor Grézal, Bálint Csörgő, Márton Simon Czikkely, Elvin Maharramov, Lejla Daruka, Réka Spohn, Dávid Balogh, Andreea Daraba, Szilvia Juhász, Máté Vágvölgyi, Attila Hunyadi, Yihui Cao, Zhenquan Sun, Xuechen Li, Balázs Papp, Csaba Pál","doi":"10.1126/scitranslmed.adl2103","DOIUrl":"10.1126/scitranslmed.adl2103","url":null,"abstract":"<div >Several antibiotic candidates are in development against Gram-positive bacterial pathogens, but their long-term utility is unclear. To investigate this issue, we studied the laboratory evolution of resistance to antibiotics that have not yet reached the market. We found that, with the exception of compound SCH79797, antibiotic resistance generally readily evolves in <i>Staphylococcus aureus</i>. Cross-resistance was detected between such candidates and antibiotics currently in clinical use, including vancomycin, daptomycin, and the promising antibiotic candidate teixobactin. These patterns were driven by overlapping molecular mechanisms through mutations in regulatory systems. In particular, teixobactin-resistant bacteria displayed clinically relevant multidrug resistance and retained their virulence in an invertebrate infection model, raising concerns. More generally, we demonstrate that putative resistance mutations against candidate antibiotics are already present in natural bacterial populations. Therefore, antibiotic resistance in nature may evolve readily from the selection of preexisting genetic variants. Our work highlights the importance of predicting future evolution of resistance to antibiotic candidates at an early stage of drug development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 780","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1126/scitranslmed.adp9805
Li Xiong, Xin Yang, Huashan Liu, Xianrui Wu, Tanxing Cai, Ming Yuan, Liang Huang, Chi Zhou, Xiaobin Zheng, Wenxin Li, Ziwei Zeng, Shujuan Li, Ping Lan, Liang Kang, Zhenxing Liang
The tumorigenesis of colorectal cancer (CRC) often follows the normal-adenoma-carcinoma (N-A-C) sequence. However, the molecular mechanisms underlying colorectal adenoma carcinogenesis remain largely unknown. Here, we analyzed transcriptomic profile changes in normal, advanced adenoma, and carcinoma tissues from patients with CRC, revealing that glutamic-pyruvic transaminase 1 (GPT1) in colorectal tissues was down-regulated during the N-A-C process and correlated with poor CRC prognosis. Mechanistically, GPT1 was transcriptionally activated by Krüppel-like factor 4 (KLF4). GPT1 reprogrammed metabolism and suppressed CRC tumorigenesis in cells and mouse models not only through enzyme-dependent α-ketoglutarate (α-KG) production and WNT signaling inhibition but also through enzyme-independent disruption of the folate cycle through binding with methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L). Furthermore, we identified poliumoside as a GPT1 activator that restrained CRC progression in cells, patient-derived CRC organoids, and patient-derived xenograft (PDX) models of CRC. Our study uncovers a role for GPT1 in CRC tumorigenesis and shows that poliumoside is a potential drug for the prevention and treatment of CRC.
{"title":"Glutamic-pyruvic transaminase 1 deficiency–mediated metabolic reprogramming facilitates colorectal adenoma-carcinoma progression","authors":"Li Xiong, Xin Yang, Huashan Liu, Xianrui Wu, Tanxing Cai, Ming Yuan, Liang Huang, Chi Zhou, Xiaobin Zheng, Wenxin Li, Ziwei Zeng, Shujuan Li, Ping Lan, Liang Kang, Zhenxing Liang","doi":"10.1126/scitranslmed.adp9805","DOIUrl":"10.1126/scitranslmed.adp9805","url":null,"abstract":"<div >The tumorigenesis of colorectal cancer (CRC) often follows the normal-adenoma-carcinoma (N-A-C) sequence. However, the molecular mechanisms underlying colorectal adenoma carcinogenesis remain largely unknown. Here, we analyzed transcriptomic profile changes in normal, advanced adenoma, and carcinoma tissues from patients with CRC, revealing that glutamic-pyruvic transaminase 1 (<i>GPT1</i>) in colorectal tissues was down-regulated during the N-A-C process and correlated with poor CRC prognosis. Mechanistically, <i>GPT1</i> was transcriptionally activated by Krüppel-like factor 4 (KLF4). GPT1 reprogrammed metabolism and suppressed CRC tumorigenesis in cells and mouse models not only through enzyme-dependent α-ketoglutarate (α-KG) production and WNT signaling inhibition but also through enzyme-independent disruption of the folate cycle through binding with methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L). Furthermore, we identified poliumoside as a GPT1 activator that restrained CRC progression in cells, patient-derived CRC organoids, and patient-derived xenograft (PDX) models of CRC. Our study uncovers a role for GPT1 in CRC tumorigenesis and shows that poliumoside is a potential drug for the prevention and treatment of CRC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 779","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1126/scitranslmed.adi6148
Varun Bahl, Reut Rifkind, Eric Waite, Zenab Hamdan, Catherine Lee May, Elisabetta Manduchi, Benjamin F. Voight, Michelle Y. Y. Lee, Mark Tigue, Nicholas Manuto, Benjamin Glaser, Dana Avrahami, Klaus H. Kaestner
Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for α cell–intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 (G6PC2) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the G6PC2 promoter are located in open chromatin not just in β but also in α cells and documented allele-specific G6PC2 expression of linked variants in human α cells. Using α cell–specific gene ablation of G6pc2 in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid–stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that G6PC2 affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.
{"title":"G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells","authors":"Varun Bahl, Reut Rifkind, Eric Waite, Zenab Hamdan, Catherine Lee May, Elisabetta Manduchi, Benjamin F. Voight, Michelle Y. Y. Lee, Mark Tigue, Nicholas Manuto, Benjamin Glaser, Dana Avrahami, Klaus H. Kaestner","doi":"10.1126/scitranslmed.adi6148","DOIUrl":"10.1126/scitranslmed.adi6148","url":null,"abstract":"<div >Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). A critical role for α cell–intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the glucose-6-phosphatase catalytic subunit 2 (<i>G6PC2</i>) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the <i>G6PC2</i> promoter are located in open chromatin not just in β but also in α cells and documented allele-specific <i>G6PC2</i> expression of linked variants in human α cells. Using α cell–specific gene ablation of <i>G6pc2</i> in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid–stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that <i>G6PC2</i> affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 779","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1126/scitranslmed.adr8373
Grace E. Mantus, Ankita J. Chopde, Jason Gorman, Lauren Y. Cominsky, Amine Ourahmane, Adrian Creanga, Geoffrey D. Shimberg, Rebecca A. Gillespie, David J. Van Wazer, Tongqing Zhou, Suprabhath R. Gajjala, Connor Williams, Emma Maestle, Douglas S. Reed, Leonid Serebryannyy, Pamela Costner, Lasonji Holman, Joseph P. Casazza, Richard A. Koup, Lesia K. Dropulic, Peter D. Kwong, Adrian B. McDermott, Masaru Kanekiyo, Sarah F. Andrews
The conserved influenza hemagglutinin stem, which is a target of cross-neutralizing antibodies, is now used in vaccine strategies focused on protecting against influenza pandemics. Antibody responses to group 1 stem have been extensively characterized, but little is known about group 2. Here, we characterized the stem-specific repertoire of individuals vaccinated with one of three group 2 influenza subtypes (H3, H7, or H10). Epitope mapping revealed two epitope supersites on the group 2 stem. Antibodies targeting the central epitope were broadly cross-reactive, whereas antibodies targeting the lower epitope had narrower breadth but higher potency against H3 subtypes. The ratio of B cells targeting each of the supersites varied with the vaccine subtype, leading to differences in the cross-reactivity of the B cell response. Our findings suggest that vaccine strategies targeting both group 2 stem epitopes would be complementary, eliciting broader and more potent protection against both seasonal and pandemic influenza strains.
{"title":"Vaccination with different group 2 influenza subtypes alters epitope targeting and breadth of hemagglutinin stem–specific human B cells","authors":"Grace E. Mantus, Ankita J. Chopde, Jason Gorman, Lauren Y. Cominsky, Amine Ourahmane, Adrian Creanga, Geoffrey D. Shimberg, Rebecca A. Gillespie, David J. Van Wazer, Tongqing Zhou, Suprabhath R. Gajjala, Connor Williams, Emma Maestle, Douglas S. Reed, Leonid Serebryannyy, Pamela Costner, Lasonji Holman, Joseph P. Casazza, Richard A. Koup, Lesia K. Dropulic, Peter D. Kwong, Adrian B. McDermott, Masaru Kanekiyo, Sarah F. Andrews","doi":"10.1126/scitranslmed.adr8373","DOIUrl":"10.1126/scitranslmed.adr8373","url":null,"abstract":"<div >The conserved influenza hemagglutinin stem, which is a target of cross-neutralizing antibodies, is now used in vaccine strategies focused on protecting against influenza pandemics. Antibody responses to group 1 stem have been extensively characterized, but little is known about group 2. Here, we characterized the stem-specific repertoire of individuals vaccinated with one of three group 2 influenza subtypes (H3, H7, or H10). Epitope mapping revealed two epitope supersites on the group 2 stem. Antibodies targeting the central epitope were broadly cross-reactive, whereas antibodies targeting the lower epitope had narrower breadth but higher potency against H3 subtypes. The ratio of B cells targeting each of the supersites varied with the vaccine subtype, leading to differences in the cross-reactivity of the B cell response. Our findings suggest that vaccine strategies targeting both group 2 stem epitopes would be complementary, eliciting broader and more potent protection against both seasonal and pandemic influenza strains.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 779","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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