Pub Date : 2024-12-11DOI: 10.1016/j.cell.2024.11.022
Jake F. Watson, Victor Vargas-Barroso, Rebecca J. Morse-Mora, Andrea Navas-Olive, Mojtaba R. Tavakoli, Johann G. Danzl, Matthias Tomschik, Karl Rössler, Peter Jonas
Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ.
{"title":"Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory","authors":"Jake F. Watson, Victor Vargas-Barroso, Rebecca J. Morse-Mora, Andrea Navas-Olive, Mojtaba R. Tavakoli, Johann G. Danzl, Matthias Tomschik, Karl Rössler, Peter Jonas","doi":"10.1016/j.cell.2024.11.022","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.022","url":null,"abstract":"Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"200 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-11DOI: 10.1016/j.cell.2024.11.011
Yago A. Arribas, Blandine Baudon, Maxime Rotival, Guadalupe Suárez, Pierre-Emmanuel Bonté, Vanessa Casas, Apollinaire Roubert, Paul Klein, Elisa Bonnin, Basma Mchich, Patricia Legoix, Sylvain Baulande, Benjamin Sadacca, Julien Diharce, Joshua J. Waterfall, Catherine Etchebest, Montserrat Carrascal, Christel Goudot, Lluís Quintana-Murci, Marianne Burbage, Sebastian Amigorena
Alternative splicing enhances protein diversity in different ways, including through exonization of transposable elements (TEs). Recent transcriptomic analyses identified thousands of unannotated spliced transcripts with exonizing TEs, but their contribution to the proteome and biological relevance remains unclear. Here, we use transcriptome assembly, ribosome profiling, and proteomics to describe a population of 1,227 unannotated TE exonizing isoforms generated by mRNA splicing and recurrent in human populations. Despite being shorter and lowly expressed, these isoforms are shared between individuals and efficiently translated. Functional analyses show stable expression, specific cellular localization, and, in some cases, modified functions. Exonized TEs are rich in ancient genes, whereas the involved splice sites are recent and can be evolutionarily conserved. In addition, exonized TEs contribute to the secondary structure of the emerging isoforms, supporting their functional relevance. We conclude that TE-spliced isoforms represent a diversity reservoir of functional proteins on which natural selection can act.
{"title":"Transposable element exonization generates a reservoir of evolving and functional protein isoforms","authors":"Yago A. Arribas, Blandine Baudon, Maxime Rotival, Guadalupe Suárez, Pierre-Emmanuel Bonté, Vanessa Casas, Apollinaire Roubert, Paul Klein, Elisa Bonnin, Basma Mchich, Patricia Legoix, Sylvain Baulande, Benjamin Sadacca, Julien Diharce, Joshua J. Waterfall, Catherine Etchebest, Montserrat Carrascal, Christel Goudot, Lluís Quintana-Murci, Marianne Burbage, Sebastian Amigorena","doi":"10.1016/j.cell.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.011","url":null,"abstract":"Alternative splicing enhances protein diversity in different ways, including through exonization of transposable elements (TEs). Recent transcriptomic analyses identified thousands of unannotated spliced transcripts with exonizing TEs, but their contribution to the proteome and biological relevance remains unclear. Here, we use transcriptome assembly, ribosome profiling, and proteomics to describe a population of 1,227 unannotated TE exonizing isoforms generated by mRNA splicing and recurrent in human populations. Despite being shorter and lowly expressed, these isoforms are shared between individuals and efficiently translated. Functional analyses show stable expression, specific cellular localization, and, in some cases, modified functions. Exonized TEs are rich in ancient genes, whereas the involved splice sites are recent and can be evolutionarily conserved. In addition, exonized TEs contribute to the secondary structure of the emerging isoforms, supporting their functional relevance. We conclude that TE-spliced isoforms represent a diversity reservoir of functional proteins on which natural selection can act.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-11DOI: 10.1016/j.cell.2024.11.021
Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai
Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.
{"title":"How NINJ1 mediates plasma membrane rupture and why NINJ2 cannot","authors":"Bibekananda Sahoo, Zongjun Mou, Wei Liu, George Dubyak, Xinghong Dai","doi":"10.1016/j.cell.2024.11.021","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.021","url":null,"abstract":"Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"10 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.cell.2024.11.009
Wenbin Mei, Schayan Faraj Tabrizi, Christopher Godina, Anthea F. Lovisa, Karolin Isaksson, Helena Jernström, Sohail F. Tavazoie
Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis.
识别有转移性复发风险的患者是一项关键的医疗需求。我们在多种乳腺癌患者队列中发现了一种常见的蛋白转化酶subtilisin/kexin type 9 (PCSK9) （rs562556, V474I）的错意种系变异，该变异与生存率降低有关。这种功能获得的单核苷酸变异在小鼠中的遗传模型显示，它可以促进乳腺癌转移。相反，在多种乳腺癌模型中，宿主PCSK9缺失减少了转移性定植。宿主PCSK9通过靶向肿瘤低密度脂蛋白受体相关蛋白1 （LRP1）受体，抑制促进转移的基因XAF1和USP18，促进肺转移起始事件，增强转移增殖能力。抗体介导的PCSK9治疗性抑制在多种模型中抑制乳腺癌转移。在一项大型瑞典早期乳腺癌队列研究中，rs562556纯合子在15年时远处转移性复发的风险为22%，而非纯合子的风险为2%。我们的研究结果表明，一种常见的遗传基因改变控制着乳腺癌的转移，并预测了乳腺癌的生存——揭示了乳腺癌转移的遗传基础。
{"title":"A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor","authors":"Wenbin Mei, Schayan Faraj Tabrizi, Christopher Godina, Anthea F. Lovisa, Karolin Isaksson, Helena Jernström, Sohail F. Tavazoie","doi":"10.1016/j.cell.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.009","url":null,"abstract":"Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (<em>PCSK9</em>) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes <em>XAF1</em> and <em>USP18</em>. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"35 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.cell.2024.11.006
Benedikt Goretzki, Maryam Khoshouei, Martin Schröder, Patrick Penner, Luca Egger, Christine Stephan, Dayana Argoti, Nele Dierlamm, Jimena Maria Rada, Sandra Kapps, Catrin Swantje Müller, Zacharias Thiel, Merve Mutlu, Claude Tschopp, David Furkert, Felix Freuler, Simon Haenni, Laurent Tenaillon, Britta Knapp, Alexandra Hinniger, César Fernández
Broad-complex, tramtrack, and bric-à-brac domain (BTB) and CNC homolog 1 (BACH1) is a key regulator of the cellular oxidative stress response and an oncogene that undergoes tight post-translational control by two distinct F-box ubiquitin ligases, SCFFBXO22 and SCFFBXL17. However, how both ligases recognize BACH1 under oxidative stress is unclear. In our study, we elucidate the mechanism by which FBXO22 recognizes a quaternary degron in a domain-swapped β-sheet of the BACH1 BTB dimer. Cancer-associated mutations and cysteine modifications destabilize the degron and impair FBXO22 binding but simultaneously expose an otherwise shielded degron in the dimer interface, allowing FBXL17 to recognize BACH1 as a monomer. These findings shed light on a ligase switch mechanism that enables post-translational regulation of BACH1 by complementary ligases depending on the stability of its BTB domain. Our results provide mechanistic insights into the oxidative stress response and may spur therapeutic approaches for targeting oxidative stress-related disorders and cancer.
{"title":"Dual BACH1 regulation by complementary SCF-type E3 ligases","authors":"Benedikt Goretzki, Maryam Khoshouei, Martin Schröder, Patrick Penner, Luca Egger, Christine Stephan, Dayana Argoti, Nele Dierlamm, Jimena Maria Rada, Sandra Kapps, Catrin Swantje Müller, Zacharias Thiel, Merve Mutlu, Claude Tschopp, David Furkert, Felix Freuler, Simon Haenni, Laurent Tenaillon, Britta Knapp, Alexandra Hinniger, César Fernández","doi":"10.1016/j.cell.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.006","url":null,"abstract":"Broad-complex, tramtrack, and bric-à-brac domain (BTB) and CNC homolog 1 (BACH1) is a key regulator of the cellular oxidative stress response and an oncogene that undergoes tight post-translational control by two distinct F-box ubiquitin ligases, SCF<sup>FBXO22</sup> and SCF<sup>FBXL17</sup>. However, how both ligases recognize BACH1 under oxidative stress is unclear. In our study, we elucidate the mechanism by which FBXO22 recognizes a quaternary degron in a domain-swapped β-sheet of the BACH1 BTB dimer. Cancer-associated mutations and cysteine modifications destabilize the degron and impair FBXO22 binding but simultaneously expose an otherwise shielded degron in the dimer interface, allowing FBXL17 to recognize BACH1 as a monomer. These findings shed light on a ligase switch mechanism that enables post-translational regulation of BACH1 by complementary ligases depending on the stability of its BTB domain. Our results provide mechanistic insights into the oxidative stress response and may spur therapeutic approaches for targeting oxidative stress-related disorders and cancer.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-06DOI: 10.1016/j.cell.2024.11.002
Svenja K. Tetzlaff, Ekin Reyhan, Nikolas Layer, C. Peter Bengtson, Alina Heuer, Julian Schroers, Anton J. Faymonville, Atefeh Pourkhalili Langeroudi, Nina Drewa, Elijah Keifert, Julia Wagner, Stella J. Soyka, Marc C. Schubert, Nirosan Sivapalan, Rangel L. Pramatarov, Verena Buchert, Tim Wageringel, Elena Grabis, Niklas Wißmann, Obada T. Alhalabi, Varun Venkataramani
Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.
{"title":"Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing","authors":"Svenja K. Tetzlaff, Ekin Reyhan, Nikolas Layer, C. Peter Bengtson, Alina Heuer, Julian Schroers, Anton J. Faymonville, Atefeh Pourkhalili Langeroudi, Nina Drewa, Elijah Keifert, Julia Wagner, Stella J. Soyka, Marc C. Schubert, Nirosan Sivapalan, Rangel L. Pramatarov, Verena Buchert, Tim Wageringel, Elena Grabis, Niklas Wißmann, Obada T. Alhalabi, Varun Venkataramani","doi":"10.1016/j.cell.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.002","url":null,"abstract":"Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain, engaging in widespread functional communication, with cholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor-cell-state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasiveness. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"82 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-04DOI: 10.1016/j.cell.2024.11.003
Jazmín Ramos-Madrigal, Gayle J. Fritz, Bryon Schroeder, Bruce Smith, Fátima Sánchez-Barreiro, Christian Carøe, Anne Kathrine Wiborg Runge, Sarah Boer, Krista McGrath, Filipe G. Vieira, Shanlin Liu, Rute R. da Fonseca, Chunxue Guo, Guojie Zhang, Bent Petersen, Thomas Sicheritz-Pontén, Shyam Gopalakrishnan, M. Thomas P. Gilbert, Nathan Wales
Indigenous maize varieties from eastern North America have played an outsized role in breeding programs, yet their early origins are not fully understood. We generated paleogenomic data to reconstruct how maize first reached this region and how it was selected during the process. Genomic ancestry analyses reveal recurrent movements northward from different parts of Mexico, likely culminating in at least two dispersals from the US Southwest across the Great Plains to the Ozarks and beyond. We find that 1,000-year-old Ozark specimens carry a highly differentiated wx1 gene, which is involved in the synthesis of amylose, highlighting repeated selective pressures on the starch metabolic pathway throughout maize’s domestication. This population shows a close affinity with the lineage that ultimately became the Northern Flints, a major contributor to modern commercial maize.
{"title":"The genomic origin of early maize in eastern North America","authors":"Jazmín Ramos-Madrigal, Gayle J. Fritz, Bryon Schroeder, Bruce Smith, Fátima Sánchez-Barreiro, Christian Carøe, Anne Kathrine Wiborg Runge, Sarah Boer, Krista McGrath, Filipe G. Vieira, Shanlin Liu, Rute R. da Fonseca, Chunxue Guo, Guojie Zhang, Bent Petersen, Thomas Sicheritz-Pontén, Shyam Gopalakrishnan, M. Thomas P. Gilbert, Nathan Wales","doi":"10.1016/j.cell.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.003","url":null,"abstract":"Indigenous maize varieties from eastern North America have played an outsized role in breeding programs, yet their early origins are not fully understood. We generated paleogenomic data to reconstruct how maize first reached this region and how it was selected during the process. Genomic ancestry analyses reveal recurrent movements northward from different parts of Mexico, likely culminating in at least two dispersals from the US Southwest across the Great Plains to the Ozarks and beyond. We find that 1,000-year-old Ozark specimens carry a highly differentiated <em>wx1</em> gene, which is involved in the synthesis of amylose, highlighting repeated selective pressures on the starch metabolic pathway throughout maize’s domestication. This population shows a close affinity with the lineage that ultimately became the Northern Flints, a major contributor to modern commercial maize.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-03DOI: 10.1016/j.cell.2024.11.001
Hye Jin Kang, Brian E. Krumm, Adrien Tassou, Matan Geron, Jeffrey F. DiBerto, Nicholas J. Kapolka, Ryan H. Gumpper, Kensuke Sakamoto, D. Dewran Kocak, Reid H.J. Olsen, Xi-Ping Huang, Shicheng Zhang, Karen L. Huang, Saheem A. Zaidi, MyV.T. Nguyen, Min Jeong Jo, Vsevolod Katritch, Jonathan F. Fay, Grégory Scherrer, Bryan L. Roth
Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.
{"title":"Structure-guided design of a peripherally restricted chemogenetic system","authors":"Hye Jin Kang, Brian E. Krumm, Adrien Tassou, Matan Geron, Jeffrey F. DiBerto, Nicholas J. Kapolka, Ryan H. Gumpper, Kensuke Sakamoto, D. Dewran Kocak, Reid H.J. Olsen, Xi-Ping Huang, Shicheng Zhang, Karen L. Huang, Saheem A. Zaidi, MyV.T. Nguyen, Min Jeong Jo, Vsevolod Katritch, Jonathan F. Fay, Grégory Scherrer, Bryan L. Roth","doi":"10.1016/j.cell.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.001","url":null,"abstract":"Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"13 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-02DOI: 10.1016/j.cell.2024.10.044
Amanda Andersson-Rolf, Kelvin Groot, Jeroen Korving, Harry Begthel, Maaike A.J. Hanegraaf, Michael VanInsberghe, Fredrik Salmén, Stieneke van den Brink, Carmen Lopez-Iglesias, Peter J. Peters, Daniel Krueger, Joep Beumer, Maarten H. Geurts, Anna Alemany, Helmuth Gehart, Françoise Carlotti, Eelco J.P. de Koning, Susana M. Chuva de Sousa Lopes, Alexander van Oudenaarden, Johan H. van Es, Hans Clevers
The mammalian pancreas consists of three epithelial compartments: the acini and ducts of the exocrine pancreas and the endocrine islets of Langerhans. Murine studies indicate that these three compartments derive from a transient, common pancreatic progenitor. Here, we report derivation of 18 human fetal pancreas organoid (hfPO) lines from gestational weeks 8–17 (8–17 GWs) fetal pancreas samples. Four of these lines, derived from 15 to 16 GWs samples, generate acinar-, ductal-, and endocrine-lineage cells while expanding exponentially for >2 years under optimized culture conditions. Single-cell RNA sequencing identifies rare LGR5+ cells in fetal pancreas and in hfPOs as the root of the developmental hierarchy. These LGR5+ cells share multiple markers with adult gastrointestinal tract stem cells. Organoids derived from single LGR5+ organoid-derived cells recapitulate this tripotency in vitro. We describe a human fetal tripotent stem/progenitor cell capable of long-term expansion in vitro and of generating all three pancreatic cell lineages.
{"title":"Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages","authors":"Amanda Andersson-Rolf, Kelvin Groot, Jeroen Korving, Harry Begthel, Maaike A.J. Hanegraaf, Michael VanInsberghe, Fredrik Salmén, Stieneke van den Brink, Carmen Lopez-Iglesias, Peter J. Peters, Daniel Krueger, Joep Beumer, Maarten H. Geurts, Anna Alemany, Helmuth Gehart, Françoise Carlotti, Eelco J.P. de Koning, Susana M. Chuva de Sousa Lopes, Alexander van Oudenaarden, Johan H. van Es, Hans Clevers","doi":"10.1016/j.cell.2024.10.044","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.044","url":null,"abstract":"The mammalian pancreas consists of three epithelial compartments: the acini and ducts of the exocrine pancreas and the endocrine islets of Langerhans. Murine studies indicate that these three compartments derive from a transient, common pancreatic progenitor. Here, we report derivation of 18 human fetal pancreas organoid (hfPO) lines from gestational weeks 8–17 (8–17 GWs) fetal pancreas samples. Four of these lines, derived from 15 to 16 GWs samples, generate acinar-, ductal-, and endocrine-lineage cells while expanding exponentially for >2 years under optimized culture conditions. Single-cell RNA sequencing identifies rare LGR5<sup>+</sup> cells in fetal pancreas and in hfPOs as the root of the developmental hierarchy. These LGR5<sup>+</sup> cells share multiple markers with adult gastrointestinal tract stem cells. Organoids derived from single LGR5<sup>+</sup> organoid-derived cells recapitulate this tripotency <em>in vitro</em>. We describe a human fetal tripotent stem/progenitor cell capable of long-term expansion <em>in vitro</em> and of generating all three pancreatic cell lineages.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"18 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-27DOI: 10.1016/j.cell.2024.10.051
Alessandra Dall’Agnese, Ming M. Zheng, Shannon Moreno, Jesse M. Platt, An T. Hoang, Deepti Kannan, Giuseppe Dall’Agnese, Kalon J. Overholt, Ido Sagi, Nancy M. Hannett, Hailey Erb, Olivia Corradin, Arup K. Chakraborty, Tong Ihn Lee, Richard A. Young
The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases.
{"title":"Proteolethargy is a pathogenic mechanism in chronic disease","authors":"Alessandra Dall’Agnese, Ming M. Zheng, Shannon Moreno, Jesse M. Platt, An T. Hoang, Deepti Kannan, Giuseppe Dall’Agnese, Kalon J. Overholt, Ido Sagi, Nancy M. Hannett, Hailey Erb, Olivia Corradin, Arup K. Chakraborty, Tong Ihn Lee, Richard A. Young","doi":"10.1016/j.cell.2024.10.051","DOIUrl":"https://doi.org/10.1016/j.cell.2024.10.051","url":null,"abstract":"The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"16 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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