Pub Date : 2024-11-05DOI: 10.1016/j.cell.2024.10.012
Shiyun Cao, Sheena Faye Garcia, Huigang Shi, Ellie I. James, Yuki Kito, Hui Shi, Haibin Mao, Sharon Kaisari, Gergely Rona, Sophia Deng, Hailey V. Goldberg, Jackeline Ponce, Beatrix Ueberheide, Luca Lignitto, Miklos Guttman, Michele Pagano, Ning Zheng
Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets’ degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate.
{"title":"Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress","authors":"Shiyun Cao, Sheena Faye Garcia, Huigang Shi, Ellie I. James, Yuki Kito, Hui Shi, Haibin Mao, Sharon Kaisari, Gergely Rona, Sophia Deng, Hailey V. Goldberg, Jackeline Ponce, Beatrix Ueberheide, Luca Lignitto, Miklos Guttman, Michele Pagano, Ning Zheng","doi":"10.1016/j.cell.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.012","url":null,"abstract":"Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets’ degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1038/s41575-024-00996-z
Patrick Tso, Jeremiah Bernier-Latmani, Tatiana V. Petrova, Min Liu
Lymphatic vessels are crucial for fluid absorption and the transport of peripheral immune cells to lymph nodes. However, in the small intestine, the lymphatic fluid is rich in diet-derived lipids incorporated into chylomicrons and gut-specific immune cells. Thus, intestinal lymphatic vessels have evolved to handle these unique cargoes and are critical for systemic dietary lipid delivery and metabolism. This Review covers mechanisms of lipid absorption from epithelial cells to the lymphatics as well as unique features of the gut microenvironment that affect these functions. Moreover, we discuss details of the intestinal lymphatics in gut immune cell trafficking and insights into the role of inter-organ communication. Lastly, we highlight the particularities of fat absorption that can be harnessed for efficient lipid-soluble drug distribution for novel therapies, including the ability of chylomicron-associated drugs to bypass first-pass liver metabolism for systemic delivery. In all, this Review will help to promote an understanding of intestinal lymphatic–systemic interactions to guide future research directions.
{"title":"Transport functions of intestinal lymphatic vessels","authors":"Patrick Tso, Jeremiah Bernier-Latmani, Tatiana V. Petrova, Min Liu","doi":"10.1038/s41575-024-00996-z","DOIUrl":"https://doi.org/10.1038/s41575-024-00996-z","url":null,"abstract":"<p>Lymphatic vessels are crucial for fluid absorption and the transport of peripheral immune cells to lymph nodes. However, in the small intestine, the lymphatic fluid is rich in diet-derived lipids incorporated into chylomicrons and gut-specific immune cells. Thus, intestinal lymphatic vessels have evolved to handle these unique cargoes and are critical for systemic dietary lipid delivery and metabolism. This Review covers mechanisms of lipid absorption from epithelial cells to the lymphatics as well as unique features of the gut microenvironment that affect these functions. Moreover, we discuss details of the intestinal lymphatics in gut immune cell trafficking and insights into the role of inter-organ communication. Lastly, we highlight the particularities of fat absorption that can be harnessed for efficient lipid-soluble drug distribution for novel therapies, including the ability of chylomicron-associated drugs to bypass first-pass liver metabolism for systemic delivery. In all, this Review will help to promote an understanding of intestinal lymphatic–systemic interactions to guide future research directions.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"65 1","pages":""},"PeriodicalIF":65.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Strigolactones (SLs) are hormones essential for plant development and environmental responses. SL perception requires the formation of the complex composed of an SL receptor DWARF14 (D14), F-box protein D3, and transcriptional repressor D53, triggering ubiquitination and degradation of D53 to activate signal transduction. However, mechanisms of SL perception and their influence on plant architecture and environmental responses remain elusive and controversial. Here, we report that key residues at interfaces of the AtD14-D3-ASK1 complex are essential for the activation of SL perception, discover that overexpression of the D3-CTH motif negatively regulates SL perception to enhance tillering, and reveal the importance of phosphorylation and N-terminal disordered (NTD) domain in mediating ubiquitination and degradation of D14. Importantly, low nitrogen promotes phosphorylation and stabilization of D14 to repress rice tillering. These findings reveal a panorama of the activation, termination, and regulation of SL perception, which determines the plasticity of plant architecture in complex environments.
{"title":"Regulatory mechanisms of strigolactone perception in rice","authors":"Qingliang Hu, Huihui Liu, Yajun He, Yanrong Hao, Jijun Yan, Simao Liu, Xiahe Huang, Zongyun Yan, Dahan Zhang, Xinwei Ban, Hao Zhang, Qianqian Li, Jingkun Zhang, Peiyong Xin, Yanhui Jing, Liquan Kou, Dajun Sang, Yonghong Wang, Yingchun Wang, Xiangbing Meng, Jiayang Li","doi":"10.1016/j.cell.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.009","url":null,"abstract":"Strigolactones (SLs) are hormones essential for plant development and environmental responses. SL perception requires the formation of the complex composed of an SL receptor DWARF14 (D14), F-box protein D3, and transcriptional repressor D53, triggering ubiquitination and degradation of D53 to activate signal transduction. However, mechanisms of SL perception and their influence on plant architecture and environmental responses remain elusive and controversial. Here, we report that key residues at interfaces of the AtD14-D3-ASK1 complex are essential for the activation of SL perception, discover that overexpression of the D3-CTH motif negatively regulates SL perception to enhance tillering, and reveal the importance of phosphorylation and N-terminal disordered (NTD) domain in mediating ubiquitination and degradation of D14. Importantly, low nitrogen promotes phosphorylation and stabilization of D14 to repress rice tillering. These findings reveal a panorama of the activation, termination, and regulation of SL perception, which determines the plasticity of plant architecture in complex environments.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.cell.2024.10.010
Kautilya K. Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I. Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R. Thiagarajah, Ivan Zanoni
Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight into how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or type II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to caspase-8 activation and the cleavage of gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has implications for IBD patients or individuals exposed to radiation therapies.
组织损伤和修复是炎症的标志。尽管有大量关于组织损伤机制的信息，但对炎症如何影响修复的机制还缺乏深入了解。在这里，我们研究了干扰素如何影响肠粘膜损伤后的组织修复。我们发现，III 型而非 I 型或 II 型干扰素会通过诱导 Z-DNA 结合蛋白 1（ZBP1）的上调来延迟上皮细胞的再生。肠道损伤后形成的 Z 核酸会被 ZBP1 感知，从而导致 caspase-8 激活和 gasdermin C（GSDMC）的裂解。裂解后的 GSDMC 会导致上皮细胞热解死亡，并分别延缓结肠炎或辐照后大肠或小肠的修复。III 型干扰素/ZBP1/caspase-8/GSDMC 轴在炎症性肠病（IBD）患者中也很活跃。我们的研究结果突显了 III 型干扰素延迟肠道修复的能力，这对 IBD 患者或接受放射治疗的个体具有重要意义。
{"title":"Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair","authors":"Kautilya K. Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I. Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R. Thiagarajah, Ivan Zanoni","doi":"10.1016/j.cell.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.010","url":null,"abstract":"Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight into how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or type II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to caspase-8 activation and the cleavage of gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has implications for IBD patients or individuals exposed to radiation therapies.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"241 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1038/s41575-024-01009-9
Geoffrey A. Preidis, Janet E. Berrington
Probiotics might prevent some necrotizing enterocolitis, late-onset sepsis and mortality in preterm infants. However, clinical practice varies widely, and families are often excluded from shared decision making. This Clinical Outlook highlights current evidence, clinical practice guidelines and the future outlook of probiotics in the neonatal intensive care unit.
{"title":"Probiotics for preterms: sharing complex decision-making","authors":"Geoffrey A. Preidis, Janet E. Berrington","doi":"10.1038/s41575-024-01009-9","DOIUrl":"https://doi.org/10.1038/s41575-024-01009-9","url":null,"abstract":"Probiotics might prevent some necrotizing enterocolitis, late-onset sepsis and mortality in preterm infants. However, clinical practice varies widely, and families are often excluded from shared decision making. This Clinical Outlook highlights current evidence, clinical practice guidelines and the future outlook of probiotics in the neonatal intensive care unit.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"7 1","pages":""},"PeriodicalIF":65.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.cell.2024.10.019
Shuai Ma, Zhejun Ji, Bin Zhang, Lingling Geng, Yusheng Cai, Chao Nie, Jiaming Li, Yuesheng Zuo, Yuzhe Sun, Gang Xu, Beibei Liu, Jiaqi Ai, Feifei Liu, Liyun Zhao, Jiachen Zhang, Hui Zhang, Shuhui Sun, Haoyan Huang, Yiyuan Zhang, Yanxia Ye, Guang-Hui Liu
To systematically characterize the loss of tissue integrity and organ dysfunction resulting from aging, we produced an in-depth spatial transcriptomic profile of nine tissues in male mice during aging. We showed that senescence-sensitive spots (SSSs) colocalized with elevated entropy in organizational structure and that the aggregation of immunoglobulin-expressing cells is a characteristic feature of the microenvironment surrounding SSSs. Immunoglobulin G (IgG) accumulated across the aged tissues in both male and female mice, and a similar phenomenon was observed in human tissues, suggesting the potential of the abnormal elevation of immunoglobulins as an evolutionarily conserved feature in aging. Furthermore, we observed that IgG could induce a pro-senescent state in macrophages and microglia, thereby exacerbating tissue aging, and that targeted reduction of IgG mitigated aging across various tissues in male mice. This study provides a high-resolution spatial depiction of aging and indicates the pivotal role of immunoglobulin-associated senescence during the aging process.
{"title":"Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging","authors":"Shuai Ma, Zhejun Ji, Bin Zhang, Lingling Geng, Yusheng Cai, Chao Nie, Jiaming Li, Yuesheng Zuo, Yuzhe Sun, Gang Xu, Beibei Liu, Jiaqi Ai, Feifei Liu, Liyun Zhao, Jiachen Zhang, Hui Zhang, Shuhui Sun, Haoyan Huang, Yiyuan Zhang, Yanxia Ye, Guang-Hui Liu","doi":"10.1016/j.cell.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.019","url":null,"abstract":"To systematically characterize the loss of tissue integrity and organ dysfunction resulting from aging, we produced an in-depth spatial transcriptomic profile of nine tissues in male mice during aging. We showed that senescence-sensitive spots (SSSs) colocalized with elevated entropy in organizational structure and that the aggregation of immunoglobulin-expressing cells is a characteristic feature of the microenvironment surrounding SSSs. Immunoglobulin G (IgG) accumulated across the aged tissues in both male and female mice, and a similar phenomenon was observed in human tissues, suggesting the potential of the abnormal elevation of immunoglobulins as an evolutionarily conserved feature in aging. Furthermore, we observed that IgG could induce a pro-senescent state in macrophages and microglia, thereby exacerbating tissue aging, and that targeted reduction of IgG mitigated aging across various tissues in male mice. This study provides a high-resolution spatial depiction of aging and indicates the pivotal role of immunoglobulin-associated senescence during the aging process.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"36 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Targeted protein degradation (TPD) utilizes molecular glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that (S)-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.
{"title":"Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders","authors":"Panrui Lu, Yalong Cheng, Lei Xue, Xintong Ren, Xilong Xu, Chenglong Chen, Longzhi Cao, Jiaojiao Li, Qingcui Wu, Shan Sun, Junjie Hou, Wei Jia, Wei Wang, Yan Ma, Zhaodi Jiang, Chao Li, Xiangbing Qi, Niu Huang, Ting Han","doi":"10.1016/j.cell.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.015","url":null,"abstract":"Targeted protein degradation (TPD) utilizes molecular glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that (<em>S</em>)-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"33 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1038/s41575-024-01003-1
David Goldberg, Julius Wilder, Norah Terrault
Morbidity and mortality from cirrhosis are substantial and increasing. Health disparities in cirrhosis and liver transplantation are reflective of inequities along the entire spectrum of chronic liver disease care, from screening and diagnosis to prevention and treatment of liver-related complications. The key populations experiencing disparities in health status and healthcare delivery include racial and ethnic minority groups, sexual and gender minorities, people of lower socioeconomic status and underserved rural communities. These disparities lead to delayed diagnosis of chronic liver disease and complications of cirrhosis (for example, hepatocellular carcinoma), to differences in treatment of chronic liver disease and its complications, and ultimately to unequal access to transplantation for those with end-stage liver disease. Calling out these disparities is only the first step towards implementing solutions that can improve health equity and clinical outcomes for everyone. Multi-level interventions along the care continuum for chronic liver disease are needed to mitigate these disparities and provide equitable access to care.
{"title":"Health disparities in cirrhosis care and liver transplantation","authors":"David Goldberg, Julius Wilder, Norah Terrault","doi":"10.1038/s41575-024-01003-1","DOIUrl":"https://doi.org/10.1038/s41575-024-01003-1","url":null,"abstract":"<p>Morbidity and mortality from cirrhosis are substantial and increasing. Health disparities in cirrhosis and liver transplantation are reflective of inequities along the entire spectrum of chronic liver disease care, from screening and diagnosis to prevention and treatment of liver-related complications. The key populations experiencing disparities in health status and healthcare delivery include racial and ethnic minority groups, sexual and gender minorities, people of lower socioeconomic status and underserved rural communities. These disparities lead to delayed diagnosis of chronic liver disease and complications of cirrhosis (for example, hepatocellular carcinoma), to differences in treatment of chronic liver disease and its complications, and ultimately to unequal access to transplantation for those with end-stage liver disease. Calling out these disparities is only the first step towards implementing solutions that can improve health equity and clinical outcomes for everyone. Multi-level interventions along the care continuum for chronic liver disease are needed to mitigate these disparities and provide equitable access to care.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"35 1","pages":""},"PeriodicalIF":65.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.cell.2024.09.022
Shanghua Gao, Ada Fang, Yepeng Huang, Valentina Giunchiglia, Ayush Noori, Jonathan Richard Schwarz, Yasha Ektefaie, Jovana Kondic, Marinka Zitnik
We envision “AI scientists” as systems capable of skeptical learning and reasoning that empower biomedical research through collaborative agents that integrate AI models and biomedical tools with experimental platforms. Rather than taking humans out of the discovery process, biomedical AI agents combine human creativity and expertise with AI’s ability to analyze large datasets, navigate hypothesis spaces, and execute repetitive tasks. AI agents are poised to be proficient in various tasks, planning discovery workflows and performing self-assessment to identify and mitigate gaps in their knowledge. These agents use large language models and generative models to feature structured memory for continual learning and use machine learning tools to incorporate scientific knowledge, biological principles, and theories. AI agents can impact areas ranging from virtual cell simulation, programmable control of phenotypes, and the design of cellular circuits to developing new therapies.
{"title":"Empowering biomedical discovery with AI agents","authors":"Shanghua Gao, Ada Fang, Yepeng Huang, Valentina Giunchiglia, Ayush Noori, Jonathan Richard Schwarz, Yasha Ektefaie, Jovana Kondic, Marinka Zitnik","doi":"10.1016/j.cell.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.022","url":null,"abstract":"We envision “AI scientists” as systems capable of skeptical learning and reasoning that empower biomedical research through collaborative agents that integrate AI models and biomedical tools with experimental platforms. Rather than taking humans out of the discovery process, biomedical AI agents combine human creativity and expertise with AI’s ability to analyze large datasets, navigate hypothesis spaces, and execute repetitive tasks. AI agents are poised to be proficient in various tasks, planning discovery workflows and performing self-assessment to identify and mitigate gaps in their knowledge. These agents use large language models and generative models to feature structured memory for continual learning and use machine learning tools to incorporate scientific knowledge, biological principles, and theories. AI agents can impact areas ranging from virtual cell simulation, programmable control of phenotypes, and the design of cellular circuits to developing new therapies.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"239 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.cell.2024.09.048
Lina Herhaus, Uxía Gestal-Mato, Vinay V. Eapen, Igor Mačinković, Henry J. Bailey, Cristian Prieto-Garcia, Mohit Misra, Anne-Claire Jacomin, Aparna Viswanathan Ammanath, Ivan Bagarić, Jolina Michaelis, Joshua Vollrath, Ramachandra M. Bhaskara, Georg Bündgen, Adriana Covarrubias-Pinto, Koraljka Husnjak, Jonathan Zöller, Ajami Gikandi, Sara Ribičić, Tobias Bopp, Ivan Dikic
The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.
自噬-溶酶体系统引导着多种货物的降解，也参与了肿瘤的进展。在这里，我们发现免疫相关 GTPase 家族 Q 蛋白（IRGQ）--一种迄今为止尚未定性的蛋白质--在主要组织相容性复合体 I 类（MHC I 类）分子的质量控制中发挥作用。IRGQ 通过其与 GABARAPL2 和 LC3B 的结合模式将折叠错误的 MHC I 类导向溶酶体降解。在缺乏 IRGQ 的情况下，游离的 MHC I 类重链不仅会在细胞内积聚，还会被运输到细胞表面，从而促进免疫反应。由于 CD8+ T 细胞对 IRGQ 基因敲除肿瘤细胞的反应性增加，小鼠和人类肝细胞癌患者在 IRGQ 水平降低的情况下生存率有所提高。因此，我们揭示了 IRGQ 是 MHC I 类质量控制的调节因子，可介导肿瘤免疫逃避。
{"title":"IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion","authors":"Lina Herhaus, Uxía Gestal-Mato, Vinay V. Eapen, Igor Mačinković, Henry J. Bailey, Cristian Prieto-Garcia, Mohit Misra, Anne-Claire Jacomin, Aparna Viswanathan Ammanath, Ivan Bagarić, Jolina Michaelis, Joshua Vollrath, Ramachandra M. Bhaskara, Georg Bündgen, Adriana Covarrubias-Pinto, Koraljka Husnjak, Jonathan Zöller, Ajami Gikandi, Sara Ribičić, Tobias Bopp, Ivan Dikic","doi":"10.1016/j.cell.2024.09.048","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.048","url":null,"abstract":"The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"5 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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