CellPub Date : 2023-11-09Epub Date: 2023-10-20DOI: 10.1016/j.cell.2023.09.016
Richa Mishra, Melanie Hannebelle, Vishal P Patil, Anaëlle Dubois, Cristina Garcia-Mouton, Gabriela M Kirsch, Maxime Jan, Kunal Sharma, Nicolas Guex, Jessica Sordet-Dessimoz, Jesus Perez-Gil, Manu Prakash, Graham W Knott, Neeraj Dhar, John D McKinney, Vivek V Thacker
{"title":"Mechanopathology of biofilm-like Mycobacterium tuberculosis cords.","authors":"Richa Mishra, Melanie Hannebelle, Vishal P Patil, Anaëlle Dubois, Cristina Garcia-Mouton, Gabriela M Kirsch, Maxime Jan, Kunal Sharma, Nicolas Guex, Jessica Sordet-Dessimoz, Jesus Perez-Gil, Manu Prakash, Graham W Knott, Neeraj Dhar, John D McKinney, Vivek V Thacker","doi":"10.1016/j.cell.2023.09.016","DOIUrl":"10.1016/j.cell.2023.09.016","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"5135-5150.e28"},"PeriodicalIF":64.5,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49674690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-11-09Epub Date: 2023-10-06DOI: 10.1016/j.cell.2023.09.011
Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M Terracciano, Uwe Sauer, Markus H Heim, Michael N Hall
{"title":"Arginine reprograms metabolism in liver cancer via RBM39.","authors":"Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M Terracciano, Uwe Sauer, Markus H Heim, Michael N Hall","doi":"10.1016/j.cell.2023.09.011","DOIUrl":"10.1016/j.cell.2023.09.011","url":null,"abstract":"<p><p>Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"5068-5083.e23"},"PeriodicalIF":64.5,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41107978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-10-26Epub Date: 2023-09-07DOI: 10.1016/j.cell.2023.08.017
Yaxi Wang, Larry A Gallagher, Pia A Andrade, Andi Liu, Ian R Humphreys, Serdar Turkarslan, Kevin J Cutler, Mario L Arrieta-Ortiz, Yaqiao Li, Matthew C Radey, Jeffrey S McLean, Qian Cong, David Baker, Nitin S Baliga, S Brook Peterson, Joseph D Mougous
{"title":"Genetic manipulation of Patescibacteria provides mechanistic insights into microbial dark matter and the epibiotic lifestyle.","authors":"Yaxi Wang, Larry A Gallagher, Pia A Andrade, Andi Liu, Ian R Humphreys, Serdar Turkarslan, Kevin J Cutler, Mario L Arrieta-Ortiz, Yaqiao Li, Matthew C Radey, Jeffrey S McLean, Qian Cong, David Baker, Nitin S Baliga, S Brook Peterson, Joseph D Mougous","doi":"10.1016/j.cell.2023.08.017","DOIUrl":"10.1016/j.cell.2023.08.017","url":null,"abstract":"<p><p>Patescibacteria, also known as the candidate phyla radiation (CPR), are a diverse group of bacteria that constitute a disproportionately large fraction of microbial dark matter. Its few cultivated members, belonging mostly to Saccharibacteria, grow as epibionts on host Actinobacteria. Due to a lack of suitable tools, the genetic basis of this lifestyle and other unique features of Patescibacteira remain unexplored. Here, we show that Saccharibacteria exhibit natural competence, and we exploit this property for their genetic manipulation. Imaging of fluorescent protein-labeled Saccharibacteria provides high spatiotemporal resolution of phenomena accompanying epibiotic growth, and a transposon-insertion sequencing (Tn-seq) genome-wide screen reveals the contribution of enigmatic Saccharibacterial genes to growth on their hosts. Finally, we leverage metagenomic data to provide cutting-edge protein structure-based bioinformatic resources that support the strain Southlakia epibionticum and its corresponding host, Actinomyces israelii, as a model system for unlocking the molecular underpinnings of the epibiotic lifestyle.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4803-4817.e13"},"PeriodicalIF":45.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10633639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10188842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-10-26Epub Date: 2023-10-06DOI: 10.1016/j.cell.2023.09.004
Philipp Schwartenbeck, Alon Baram, Yunzhe Liu, Shirley Mark, Timothy Muller, Raymond Dolan, Matthew Botvinick, Zeb Kurth-Nelson, Timothy Behrens
{"title":"Generative replay underlies compositional inference in the hippocampal-prefrontal circuit.","authors":"Philipp Schwartenbeck, Alon Baram, Yunzhe Liu, Shirley Mark, Timothy Muller, Raymond Dolan, Matthew Botvinick, Zeb Kurth-Nelson, Timothy Behrens","doi":"10.1016/j.cell.2023.09.004","DOIUrl":"10.1016/j.cell.2023.09.004","url":null,"abstract":"<p><p>Human reasoning depends on reusing pieces of information by putting them together in new ways. However, very little is known about how compositional computation is implemented in the brain. Here, we ask participants to solve a series of problems that each require constructing a whole from a set of elements. With fMRI, we find that representations of novel constructed objects in the frontal cortex and hippocampus are relational and compositional. With MEG, we find that replay assembles elements into compounds, with each replay sequence constituting a hypothesis about a possible configuration of elements. The content of sequences evolves as participants solve each puzzle, progressing from predictable to uncertain elements and gradually converging on the correct configuration. Together, these results suggest a computational bridge between apparently distinct functions of hippocampal-prefrontal circuitry and a role for generative replay in compositional inference and hypothesis testing.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4885-4897.e14"},"PeriodicalIF":64.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10914680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41108545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-10-26Epub Date: 2023-10-06DOI: 10.1016/j.cell.2023.09.007
Ofer Zimmerman, Maxwell I Zimmerman, Saravanan Raju, Christopher A Nelson, John M Errico, Emily A Madden, Autumn C Holmes, Ahmed O Hassan, Laura A VanBlargan, Arthur S Kim, Lucas J Adams, Katherine Basore, Bradley M Whitener, Sathvik Palakurty, Hannah G Davis-Adams, Chengqun Sun, Theron Gilliland, James T Earnest, Hongming Ma, Gregory D Ebel, Christian Zmasek, Richard H Scheuermann, William B Klimstra, Daved H Fremont, Michael S Diamond
{"title":"Vertebrate-class-specific binding modes of the alphavirus receptor MXRA8.","authors":"Ofer Zimmerman, Maxwell I Zimmerman, Saravanan Raju, Christopher A Nelson, John M Errico, Emily A Madden, Autumn C Holmes, Ahmed O Hassan, Laura A VanBlargan, Arthur S Kim, Lucas J Adams, Katherine Basore, Bradley M Whitener, Sathvik Palakurty, Hannah G Davis-Adams, Chengqun Sun, Theron Gilliland, James T Earnest, Hongming Ma, Gregory D Ebel, Christian Zmasek, Richard H Scheuermann, William B Klimstra, Daved H Fremont, Michael S Diamond","doi":"10.1016/j.cell.2023.09.007","DOIUrl":"10.1016/j.cell.2023.09.007","url":null,"abstract":"<p><p>MXRA8 is a receptor for chikungunya (CHIKV) and other arthritogenic alphaviruses with mammalian hosts. However, mammalian MXRA8 does not bind to alphaviruses that infect humans and have avian reservoirs. Here, we show that avian, but not mammalian, MXRA8 can act as a receptor for Sindbis, western equine encephalitis (WEEV), and related alphaviruses with avian reservoirs. Structural analysis of duck MXRA8 complexed with WEEV reveals an inverted binding mode compared with mammalian MXRA8 bound to CHIKV. Whereas both domains of mammalian MXRA8 bind CHIKV E1 and E2, only domain 1 of avian MXRA8 engages WEEV E1, and no appreciable contacts are made with WEEV E2. Using these results, we generated a chimeric avian-mammalian MXRA8 decoy-receptor that neutralizes infection of multiple alphaviruses from distinct antigenic groups in vitro and in vivo. Thus, different alphaviruses can bind MXRA8 encoded by different vertebrate classes with distinct engagement modes, which enables development of broad-spectrum inhibitors.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4818-4833.e25"},"PeriodicalIF":45.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41109552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-10-26Epub Date: 2023-10-03DOI: 10.1016/j.cell.2023.08.032
Ajinkya Patil, Amy R Strom, Joao A Paulo, Clayton K Collings, Kiersten M Ruff, Min Kyung Shinn, Akshay Sankar, Kasey S Cervantes, Tobias Wauer, Jessica D St Laurent, Grace Xu, Lindsay A Becker, Steven P Gygi, Rohit V Pappu, Clifford P Brangwynne, Cigall Kadoch
{"title":"A disordered region controls cBAF activity via condensation and partner recruitment.","authors":"Ajinkya Patil, Amy R Strom, Joao A Paulo, Clayton K Collings, Kiersten M Ruff, Min Kyung Shinn, Akshay Sankar, Kasey S Cervantes, Tobias Wauer, Jessica D St Laurent, Grace Xu, Lindsay A Becker, Steven P Gygi, Rohit V Pappu, Clifford P Brangwynne, Cigall Kadoch","doi":"10.1016/j.cell.2023.08.032","DOIUrl":"10.1016/j.cell.2023.08.032","url":null,"abstract":"<p><p>Intrinsically disordered regions (IDRs) represent a large percentage of overall nuclear protein content. The prevailing dogma is that IDRs engage in non-specific interactions because they are poorly constrained by evolutionary selection. Here, we demonstrate that condensate formation and heterotypic interactions are distinct and separable features of an IDR within the ARID1A/B subunits of the mSWI/SNF chromatin remodeler, cBAF, and establish distinct \"sequence grammars\" underlying each contribution. Condensation is driven by uniformly distributed tyrosine residues, and partner interactions are mediated by non-random blocks rich in alanine, glycine, and glutamine residues. These features concentrate a specific cBAF protein-protein interaction network and are essential for chromatin localization and activity. Importantly, human disease-associated perturbations in ARID1B IDR sequence grammars disrupt cBAF function in cells. Together, these data identify IDR contributions to chromatin remodeling and explain how phase separation provides a mechanism through which both genomic localization and functional partner recruitment are achieved.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4936-4955.e26"},"PeriodicalIF":45.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10792396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41101040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-10-26Epub Date: 2023-10-07DOI: 10.1016/j.cell.2023.09.003
Zijun Lan, Zihan Song, Zhijuan Wang, Ling Li, Yiqun Liu, Shuaihua Zhi, Ruihan Wang, Jizong Wang, Qiyun Li, Andrea Bleckmann, Li Zhang, Thomas Dresselhaus, Juan Dong, Hongya Gu, Sheng Zhong, Li-Jia Qu
{"title":"Antagonistic RALF peptides control an intergeneric hybridization barrier on Brassicaceae stigmas.","authors":"Zijun Lan, Zihan Song, Zhijuan Wang, Ling Li, Yiqun Liu, Shuaihua Zhi, Ruihan Wang, Jizong Wang, Qiyun Li, Andrea Bleckmann, Li Zhang, Thomas Dresselhaus, Juan Dong, Hongya Gu, Sheng Zhong, Li-Jia Qu","doi":"10.1016/j.cell.2023.09.003","DOIUrl":"10.1016/j.cell.2023.09.003","url":null,"abstract":"<p><p>Pollen-pistil interactions establish interspecific/intergeneric pre-zygotic hybridization barriers in plants. The rejection of undesired pollen at the stigma is crucial to avoid outcrossing but can be overcome with the support of mentor pollen. The mechanisms underlying this hybridization barrier are largely unknown. Here, in Arabidopsis, we demonstrate that receptor-like kinases FERONIA/CURVY1/ANJEA/HERCULES RECEPTOR KINASE 1 and cell wall proteins LRX3/4/5 interact on papilla cell surfaces with autocrine stigmatic RALF1/22/23/33 peptide ligands (sRALFs) to establish a lock that blocks the penetration of undesired pollen tubes. Compatible pollen-derived RALF10/11/12/13/25/26/30 peptides (pRALFs) act as a key, outcompeting sRALFs and enabling pollen tube penetration. By treating Arabidopsis stigmas with synthetic pRALFs, we unlock the barrier, facilitating pollen tube penetration from distantly related Brassicaceae species and resulting in interspecific/intergeneric hybrid embryo formation. Therefore, we uncover a \"lock-and-key\" system governing the hybridization breadth of interspecific/intergeneric crosses in Brassicaceae. Manipulating this system holds promise for facilitating broad hybridization in crops.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4773-4787.e12"},"PeriodicalIF":45.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41107509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Amyloplast sedimentation repolarizes LAZYs to achieve gravity sensing in plants.","authors":"Jiayue Chen, Renbo Yu, Na Li, Zhaoguo Deng, Xinxin Zhang, Yaran Zhao, Chengfu Qu, Yanfang Yuan, Zhexian Pan, Yangyang Zhou, Kunlun Li, Jiajun Wang, Zhiren Chen, Xiaoyi Wang, Xiaolian Wang, Shu-Nan He, Juan Dong, Xing Wang Deng, Haodong Chen","doi":"10.1016/j.cell.2023.09.014","DOIUrl":"10.1016/j.cell.2023.09.014","url":null,"abstract":"<p><p>Gravity controls directional growth of plants, and the classical starch-statolith hypothesis proposed more than a century ago postulates that amyloplast sedimentation in specialized cells initiates gravity sensing, but the molecular mechanism remains uncharacterized. The LAZY proteins are known as key regulators of gravitropism, and lazy mutants show striking gravitropic defects. Here, we report that gravistimulation by reorientation triggers mitogen-activated protein kinase (MAPK) signaling-mediated phosphorylation of Arabidopsis LAZY proteins basally polarized in root columella cells. Phosphorylation of LAZY increases its interaction with several translocons at the outer envelope membrane of chloroplasts (TOC) proteins on the surface of amyloplasts, facilitating enrichment of LAZY proteins on amyloplasts. Amyloplast sedimentation subsequently guides LAZY to relocate to the new lower side of the plasma membrane in columella cells, where LAZY induces asymmetrical auxin distribution and root differential growth. Together, this study provides a molecular interpretation for the starch-statolith hypothesis: the organelle-movement-triggered molecular polarity formation.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4788-4802.e15"},"PeriodicalIF":45.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10615846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41118588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-10-26Epub Date: 2023-10-17DOI: 10.1016/j.cell.2023.09.020
Manish K Yadav, Jagannath Maharana, Ravi Yadav, Shirsha Saha, Parishmita Sarma, Chahat Soni, Vinay Singh, Sayantan Saha, Manisankar Ganguly, Xaria X Li, Samanwita Mohapatra, Sudha Mishra, Htet A Khant, Mohamed Chami, Trent M Woodruff, Ramanuj Banerjee, Arun K Shukla, Cornelius Gati
{"title":"Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors.","authors":"Manish K Yadav, Jagannath Maharana, Ravi Yadav, Shirsha Saha, Parishmita Sarma, Chahat Soni, Vinay Singh, Sayantan Saha, Manisankar Ganguly, Xaria X Li, Samanwita Mohapatra, Sudha Mishra, Htet A Khant, Mohamed Chami, Trent M Woodruff, Ramanuj Banerjee, Arun K Shukla, Cornelius Gati","doi":"10.1016/j.cell.2023.09.020","DOIUrl":"10.1016/j.cell.2023.09.020","url":null,"abstract":"<p><p>The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. However, the molecular mechanism of ligand recognition, activation, and signaling bias of these receptors remains mostly elusive. Here, we present nine cryo-EM structures of C3aR and C5aR1 activated by their natural and synthetic agonists, which reveal distinct binding pocket topologies of complement anaphylatoxins and provide key insights into receptor activation and transducer coupling. We also uncover the structural basis of a naturally occurring mechanism to dampen the inflammatory response of C5a via proteolytic cleavage of the terminal arginine and the G-protein signaling bias elicited by a peptide agonist of C3aR identified here. In summary, our study elucidates the innerworkings of the complement anaphylatoxin receptors and should facilitate structure-guided drug discovery to target these receptors in a spectrum of disorders.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4956-4973.e21"},"PeriodicalIF":64.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7615941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49674691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2023-10-26Epub Date: 2023-10-16DOI: 10.1016/j.cell.2023.09.023
Adam L Boxer, Reisa Sperling
{"title":"Accelerating Alzheimer's therapeutic development: The past and future of clinical trials.","authors":"Adam L Boxer, Reisa Sperling","doi":"10.1016/j.cell.2023.09.023","DOIUrl":"10.1016/j.cell.2023.09.023","url":null,"abstract":"<p><p>Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"4757-4772"},"PeriodicalIF":45.5,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41232511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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