Pub Date : 2024-10-30DOI: 10.1038/s41575-024-01001-3
Maria Carmen Collado, Suzanne Devkota, Tarini Shankar Ghosh
To mark the twentieth anniversary of Nature Reviews Gastroenterology & Hepatology, we asked three experts to comment on how the gut microbiome has transformed our understanding of biology and the strengths and limitations of microbiome research today as well as to look ahead at what the next 20 years of microbiome research and clinical applications might look like. In this Viewpoint, Maria Carmen Collado, Suzanne Devkota and Tarini Shankar Ghosh comment on the past and future of gut microbiome research and clinical applications.
为纪念《Nature Reviews Gastroenterology & Hepatology》创刊二十周年，我们邀请三位专家就肠道微生物组如何改变了我们对生物学的理解、当今微生物组研究的优势和局限性发表评论，并展望未来二十年微生物组研究和临床应用的前景。在本视点中，玛丽亚-卡门-科拉多（Maria Carmen Collado）、苏珊娜-德夫科塔（Suzanne Devkota）和塔里尼-尚卡尔-戈什（Tarini Shankar Ghosh）对肠道微生物组研究和临床应用的过去和未来发表了看法。
{"title":"Gut microbiome: a biomedical revolution","authors":"Maria Carmen Collado, Suzanne Devkota, Tarini Shankar Ghosh","doi":"10.1038/s41575-024-01001-3","DOIUrl":"https://doi.org/10.1038/s41575-024-01001-3","url":null,"abstract":"To mark the twentieth anniversary of Nature Reviews Gastroenterology & Hepatology, we asked three experts to comment on how the gut microbiome has transformed our understanding of biology and the strengths and limitations of microbiome research today as well as to look ahead at what the next 20 years of microbiome research and clinical applications might look like. In this Viewpoint, Maria Carmen Collado, Suzanne Devkota and Tarini Shankar Ghosh comment on the past and future of gut microbiome research and clinical applications.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"37 1","pages":""},"PeriodicalIF":65.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541692","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.2024.09.033
Ivan N. Zheludev, Robert C. Edgar, Maria Jose Lopez-Galiano, Marcos de la Peña, Artem Babaian, Ami S. Bhatt, Andrew Z. Fire
Here, we describe “obelisks,” a class of heritable RNA elements sharing several properties: (1) apparently circular RNA ∼1 kb genome assemblies, (2) predicted rod-like genome-wide secondary structures, and (3) open reading frames encoding a novel “Oblin” protein superfamily. A subset of obelisks includes a variant hammerhead self-cleaving ribozyme. Obelisks form their own phylogenetic group without detectable similarity to known biological agents. Surveying globally, we identified 29,959 distinct obelisks (clustered at 90% sequence identity) from diverse ecological niches. Obelisks are prevalent in human microbiomes, with detection in ∼7% (29/440) and ∼50% (17/32) of queried stool and oral metatranscriptomes, respectively. We establish Streptococcus sanguinis as a cellular host of a specific obelisk and find that this obelisk’s maintenance is not essential for bacterial growth. Our observations identify obelisks as a class of diverse RNAs of yet-to-be-determined impact that have colonized and gone unnoticed in human and global microbiomes.
{"title":"Viroid-like colonists of human microbiomes","authors":"Ivan N. Zheludev, Robert C. Edgar, Maria Jose Lopez-Galiano, Marcos de la Peña, Artem Babaian, Ami S. Bhatt, Andrew Z. Fire","doi":"10.1016/j.cell.2024.09.033","DOIUrl":"https://doi.org/10.1016/j.cell.2024.09.033","url":null,"abstract":"Here, we describe “obelisks,” a class of heritable RNA elements sharing several properties: (1) apparently circular RNA ∼1 kb genome assemblies, (2) predicted rod-like genome-wide secondary structures, and (3) open reading frames encoding a novel “Oblin” protein superfamily. A subset of obelisks includes a variant hammerhead self-cleaving ribozyme. Obelisks form their own phylogenetic group without detectable similarity to known biological agents. Surveying globally, we identified 29,959 distinct obelisks (clustered at 90% sequence identity) from diverse ecological niches. Obelisks are prevalent in human microbiomes, with detection in ∼7% (29/440) and ∼50% (17/32) of queried stool and oral metatranscriptomes, respectively. We establish <em>Streptococcus sanguinis</em> as a cellular host of a specific obelisk and find that this obelisk’s maintenance is not essential for bacterial growth. Our observations identify obelisks as a class of diverse RNAs of yet-to-be-determined impact that have colonized and gone unnoticed in human and global microbiomes.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"63 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541491","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.2024.10.006
Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D. Park, Nelson M. LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K. Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D. Brown
Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.
{"title":"Ovarian cancer-derived IL-4 promotes immunotherapy resistance","authors":"Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T. Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D. Park, Nelson M. LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K. Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D. Brown","doi":"10.1016/j.cell.2024.10.006","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.006","url":null,"abstract":"Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"65 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541493","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.2024.10.004
Brandon R. Munn, Eli J. Müller, Itia Favre-Bulle, Ethan Scott, Joseph T. Lizier, Michael Breakspear, James M. Shine
Brain recordings collected at different resolutions support distinct signatures of neural coding, leading to scale-dependent theories of brain function. Here, we show that these disparate signatures emerge from a heavy-tailed, multiscale functional organization of neuronal activity observed across calcium-imaging recordings collected from the whole brains of zebrafish and C. elegans as well as from sensory regions in Drosophila, mice, and macaques. Network simulations demonstrate that this conserved hierarchical structure enhances information processing. Finally, we find that this organization is maintained despite significant cross-scale reconfiguration of cellular coordination during behavior. Our findings suggest that this nonlinear organization of neuronal activity is a universal principle conserved for its ability to adaptively link behavior to neural dynamics across multiple spatiotemporal scales while balancing functional resiliency and information processing efficiency.
{"title":"Multiscale organization of neuronal activity unifies scale-dependent theories of brain function","authors":"Brandon R. Munn, Eli J. Müller, Itia Favre-Bulle, Ethan Scott, Joseph T. Lizier, Michael Breakspear, James M. Shine","doi":"10.1016/j.cell.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.004","url":null,"abstract":"Brain recordings collected at different resolutions support distinct signatures of neural coding, leading to scale-dependent theories of brain function. Here, we show that these disparate signatures emerge from a heavy-tailed, multiscale functional organization of neuronal activity observed across calcium-imaging recordings collected from the whole brains of zebrafish and <em>C. elegans</em> as well as from sensory regions in <em>Drosophila</em>, mice, and macaques. Network simulations demonstrate that this conserved hierarchical structure enhances information processing. Finally, we find that this organization is maintained despite significant cross-scale reconfiguration of cellular coordination during behavior. Our findings suggest that this nonlinear organization of neuronal activity is a universal principle conserved for its ability to adaptively link behavior to neural dynamics across multiple spatiotemporal scales while balancing functional resiliency and information processing efficiency.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"3 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542102","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 : 2024-10-29DOI: 10.1038/s41575-024-01016-w
Caroline Barranco
Subsets of human tuft cells retain their proliferative capacity throughout life and can act as a damage-induced pool of regenerative stem cells, report Huang et al. in Nature.
Organoids containing all human intestinal cell types were generated by the researchers from a single mature proliferating human tuft cell. Organoids engineered to lack tuft cells did not regenerate after irradiation, unlike those containing tuft cells. Although cells bearing leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) are the most common intestinal stem cell type, they are highly sensitive to injury. Therefore, tuft cells could provide a reserve stem cell pool after loss of LGR5+ cells.
黄等人（Huang et al）在《自然》（Nature）杂志上报告说，人类丛细胞的子集终生保持增殖能力，可作为损伤诱导的再生干细胞池。研究人员从单个成熟增殖的人类丛细胞中生成了包含所有人类肠道细胞类型的器官组织。与含有簇状细胞的有机体不同，缺乏簇状细胞的有机体在辐照后不会再生。虽然含有富亮氨酸重复的G蛋白偶联受体5（LGR5）的细胞是最常见的肠干细胞类型，但它们对损伤高度敏感。因此，在失去LGR5+细胞后，丛细胞可提供后备干细胞池。
{"title":"Intestinal tuft cells can act as injury-resistant stem cells","authors":"Caroline Barranco","doi":"10.1038/s41575-024-01016-w","DOIUrl":"https://doi.org/10.1038/s41575-024-01016-w","url":null,"abstract":"<p>Subsets of human tuft cells retain their proliferative capacity throughout life and can act as a damage-induced pool of regenerative stem cells, report Huang et al. in <i>Nature</i>.</p><p>Organoids containing all human intestinal cell types were generated by the researchers from a single mature proliferating human tuft cell. Organoids engineered to lack tuft cells did not regenerate after irradiation, unlike those containing tuft cells. Although cells bearing leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) are the most common intestinal stem cell type, they are highly sensitive to injury. Therefore, tuft cells could provide a reserve stem cell pool after loss of LGR5<sup>+</sup> cells.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"46 1","pages":""},"PeriodicalIF":65.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536655","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 : 2024-10-29DOI: 10.1016/j.cell.2024.10.005
Liyen Loh, Philippa M. Saunders, Camilla Faoro, Neus Font-Porterias, Neda Nemat-Gorgani, Genelle F. Harrison, Suraju Sadeeq, Luca Hensen, Shu Cheng Wong, Jacqueline Widjaja, E. Bridie Clemens, Shiying Zhu, Katherine M. Kichula, Sudan Tao, Faming Zhu, Gonzalo Montero-Martin, Marcelo Fernandez-Vina, Lisbeth A. Guethlein, Julian P. Vivian, Jane Davies, Paul J. Norman
Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A∗24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1∗114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1∗114+NK cells from First Nations Australian donors are inhibited through binding HLA-A∗24:02. The KIR3DL1∗114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.
{"title":"An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania","authors":"Liyen Loh, Philippa M. Saunders, Camilla Faoro, Neus Font-Porterias, Neda Nemat-Gorgani, Genelle F. Harrison, Suraju Sadeeq, Luca Hensen, Shu Cheng Wong, Jacqueline Widjaja, E. Bridie Clemens, Shiying Zhu, Katherine M. Kichula, Sudan Tao, Faming Zhu, Gonzalo Montero-Martin, Marcelo Fernandez-Vina, Lisbeth A. Guethlein, Julian P. Vivian, Jane Davies, Paul J. Norman","doi":"10.1016/j.cell.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.005","url":null,"abstract":"Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A<sup>∗</sup>24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1<sup>∗</sup>114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1<sup>∗</sup>114<sup>+</sup>NK cells from First Nations Australian donors are inhibited through binding HLA-A<sup>∗</sup>24:02. The KIR3DL1<sup>∗</sup>114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"103 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536565","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}
Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.
慢性瘙痒是一种使人衰弱的症状，严重影响胆汁淤积症等肝病患者的生活质量。胆汁酸（BA）激活人类 G 蛋白偶联受体 MRGPRX4 (hX4) 与促进胆汁淤积性瘙痒有关。然而，其详细的内在机制仍然难以捉摸。在这里，我们发现了胆汁淤积症患者瘙痒症状中升高的 3-硫酸化胆汁酸。我们解析了hX4-Gq与3-磷酸化脱氧胆酸（DCA-3P）复合物的低温电子显微镜结构，3-磷酸化脱氧胆酸是内源性3-硫酸化脱氧胆酸（DCA-3S）的模拟物。该结构揭示了 MRGPR 家族蛋白中前所未有的配体结合口袋，突出了 BA 上的 3-hydroxyl (3-OH) 基团在激活 hX4 中的关键作用。在这一结构信息的指导下，我们设计并开发了化合物 7（C7），一种缺少 3-OH 的 BA 衍生物。值得注意的是，C7 能有效缓解肝病模型中的肝损伤和肝纤维化，同时显著减轻瘙痒的副作用。
{"title":"Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch","authors":"Jun Yang, Tianjun Zhao, Junping Fan, Huaibin Zou, Guangyi Lan, Fusheng Guo, Yaocheng Shi, Han Ke, Huasheng Yu, Zongwei Yue, Xin Wang, Yingjie Bai, Shuai Li, Yingjun Liu, Xiaoming Wang, Yu Chen, Yulong Li, Xiaoguang Lei","doi":"10.1016/j.cell.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.001","url":null,"abstract":"Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"237 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536564","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 : 2024-10-29DOI: 10.1016/j.cell.2024.10.007
Ying Lyu, Soo Jin Kim, Ericka S. Humphrey, Richa Nayak, Yinglu Guan, Qingnan Liang, Kun Hee Kim, Yukun Tan, Jinzhuang Dou, Huandong Sun, Xingzhi Song, Priyadharsini Nagarajan, Kamryn N. Gerner-Mauro, Kevin Jin, Virginia Liu, Rehman H. Hassan, Miranda L. Johnson, Lisa P. Deliu, Yun You, Anurag Sharma, Yejing Ge
Mammalian retrotransposons constitute 40% of the genome. During tissue regeneration, adult stem cells coordinately repress retrotransposons and activate lineage genes, but how this coordination is controlled is poorly understood. Here, we observed that dynamic expression of histone methyltransferase SETDB1 (a retrotransposon repressor) closely mirrors stem cell activities in murine skin. SETDB1 ablation leads to the reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and the assembly of viral-like particles, resulting in hair loss and stem cell exhaustion that is reversible by antiviral drugs. Mechanistically, at least two molecularly and spatially distinct pathways are responsible: antiviral defense mediated by hair follicle stem cells and progenitors and antiviral-independent response due to replication stress in transient amplifying cells. ERV reactivation is promoted by DNA demethylase ten-eleven translocation (TET)-mediated hydroxymethylation and recapitulated by ablating cell fate transcription factors. Together, we demonstrated ERV silencing is coupled with stem cell activity and essential for adult hair regeneration.
{"title":"Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration","authors":"Ying Lyu, Soo Jin Kim, Ericka S. Humphrey, Richa Nayak, Yinglu Guan, Qingnan Liang, Kun Hee Kim, Yukun Tan, Jinzhuang Dou, Huandong Sun, Xingzhi Song, Priyadharsini Nagarajan, Kamryn N. Gerner-Mauro, Kevin Jin, Virginia Liu, Rehman H. Hassan, Miranda L. Johnson, Lisa P. Deliu, Yun You, Anurag Sharma, Yejing Ge","doi":"10.1016/j.cell.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.007","url":null,"abstract":"Mammalian retrotransposons constitute 40% of the genome. During tissue regeneration, adult stem cells coordinately repress retrotransposons and activate lineage genes, but how this coordination is controlled is poorly understood. Here, we observed that dynamic expression of histone methyltransferase SETDB1 (a retrotransposon repressor) closely mirrors stem cell activities in murine skin. SETDB1 ablation leads to the reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and the assembly of viral-like particles, resulting in hair loss and stem cell exhaustion that is reversible by antiviral drugs. Mechanistically, at least two molecularly and spatially distinct pathways are responsible: antiviral defense mediated by hair follicle stem cells and progenitors and antiviral-independent response due to replication stress in transient amplifying cells. ERV reactivation is promoted by DNA demethylase ten-eleven translocation (TET)-mediated hydroxymethylation and recapitulated by ablating cell fate transcription factors. Together, we demonstrated ERV silencing is coupled with stem cell activity and essential for adult hair regeneration.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"132 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536563","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 : 2024-10-28DOI: 10.1103/revmodphys.96.045002
Carl M. Bender, Daniel W. Hook
It is generally assumed that a Hamiltonian for a physically acceptable quantum system (one that has a positive-definite spectrum and obeys the requirement of unitarity) must be Hermitian. However, a <mjx-container ctxtmenu_counter="246" ctxtmenu_oldtabindex="1" jax="CHTML" overflow="linebreak" role="tree" sre-explorer- style="font-size: 100.7%;" tabindex="0"><mjx-math data-semantic-structure="0"><mjx-mi data-semantic-font="script" data-semantic- data-semantic-role="unknown" data-semantic-speech="script upper P upper T" data-semantic-type="identifier"><mjx-c noic="true" style="padding-top: 0.703em;">𝒫</mjx-c><mjx-c style="padding-top: 0.703em;">𝒯</mjx-c></mjx-mi></mjx-math></mjx-container>-symmetric Hamiltonian can also define a physically acceptable quantum-mechanical system even if the Hamiltonian is not Hermitian. The study of <mjx-container ctxtmenu_counter="247" ctxtmenu_oldtabindex="1" jax="CHTML" overflow="linebreak" role="tree" sre-explorer- style="font-size: 100.7%;" tabindex="0"><mjx-math data-semantic-structure="0"><mjx-mi data-semantic-font="script" data-semantic- data-semantic-role="unknown" data-semantic-speech="script upper P upper T" data-semantic-type="identifier"><mjx-c noic="true" style="padding-top: 0.703em;">𝒫</mjx-c><mjx-c style="padding-top: 0.703em;">𝒯</mjx-c></mjx-mi></mjx-math></mjx-container>-symmetric quantum systems is a young and extremely active research area in both theoretical and experimental physics. The purpose of this review is to provide established scientists as well as graduate students with a compact, easy-to-read introduction to this field that will enable them to understand more advanced publications and to begin their own theoretical or experimental research activity. The ideas and techniques of <mjx-container ctxtmenu_counter="248" ctxtmenu_oldtabindex="1" jax="CHTML" overflow="linebreak" role="tree" sre-explorer- style="font-size: 100.7%;" tabindex="0"><mjx-math data-semantic-structure="0"><mjx-mi data-semantic-font="script" data-semantic- data-semantic-role="unknown" data-semantic-speech="script upper P upper T" data-semantic-type="identifier"><mjx-c noic="true" style="padding-top: 0.703em;">𝒫</mjx-c><mjx-c style="padding-top: 0.703em;">𝒯</mjx-c></mjx-mi></mjx-math></mjx-container> symmetry have been applied in the context of many different branches of physics. This review introduces the concepts of <mjx-container ctxtmenu_counter="249" ctxtmenu_oldtabindex="1" jax="CHTML" overflow="linebreak" role="tree" sre-explorer- style="font-size: 100.7%;" tabindex="0"><mjx-math data-semantic-structure="0"><mjx-mi data-semantic-font="script" data-semantic- data-semantic-role="unknown" data-semantic-speech="script upper P upper T" data-semantic-type="identifier"><mjx-c noic="true" style="padding-top: 0.703em;">𝒫</mjx-c><mjx-c style="padding-top: 0.703em;">𝒯</mjx-c></mjx-mi></mjx-math></mjx-container> symmetry by focusing on elementary one-dimensional <mjx-container ctxtmenu_counter="250" ctxtmenu_oldtabin
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Pub Date : 2024-10-28DOI: 10.1016/j.cell.2024.10.003
Hua Wang, Cheng Cheng, James L. Dal Santo, Chen-Hsiang Shen, Tatsiana Bylund, Amy R. Henry, Colin A. Howe, Juyun Hwang, Nicholas C. Morano, Daniel J. Morris, Sergei Pletnev, Ryan S. Roark, Tongqing Zhou, Bryan T. Hansen, Forrest H. Hoyt, Timothy S. Johnston, Shuyi Wang, Baoshan Zhang, David R. Ambrozak, Jordan E. Becker, Peter D. Kwong
An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%–77% breadth (geometric mean 50% inhibitory dilution [ID50] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%–60% (50% inhibitory concentration [IC50] < 50 μg/mL) and total lineage-concentrations estimates of 50–200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide in vivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.
{"title":"Potent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques","authors":"Hua Wang, Cheng Cheng, James L. Dal Santo, Chen-Hsiang Shen, Tatsiana Bylund, Amy R. Henry, Colin A. Howe, Juyun Hwang, Nicholas C. Morano, Daniel J. Morris, Sergei Pletnev, Ryan S. Roark, Tongqing Zhou, Bryan T. Hansen, Forrest H. Hoyt, Timothy S. Johnston, Shuyi Wang, Baoshan Zhang, David R. Ambrozak, Jordan E. Becker, Peter D. Kwong","doi":"10.1016/j.cell.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.003","url":null,"abstract":"An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%–77% breadth (geometric mean 50% inhibitory dilution [ID<sub>50</sub>] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%–60% (50% inhibitory concentration [IC<sub>50</sub>] < 50 μg/mL) and total lineage-concentrations estimates of 50–200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide <em>in vivo</em> molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519571","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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