Qi Hu, Shuning Lv, Hsiaoyi Tsai, Yufeng Xue, Xixiang Jing, Fanrong Lin, Chuanjia Tong, Tengfei Cao, Gilberto Teobaldi, Li-Min Liu
The discovery of ferroelectric phases in HfO 2 offers insights into ferroelectricity. Its unique fluorite structure and complex polarization switching pathways exhibit distinct characteristics, challenging conventional analysis methods. Combining group theory and first-principles calculations, we identify numerous unconventional electric polarization switching pathways in HfO 2 with energy barriers of 0.32 to 0.57 eV as a function of the different shift in the suboxygen lattices. In total, we identify 47 switching pathways for the orthorhombic phase, corresponding to the left cosets of the Fm3¯m group with Pca21 group. Contrary to the conception that the tetracoordinated oxygen (O IV ) layers are inactive, our result demonstrates that both the tricoordinated oxygen (O III ) and O IV can be displaced, leading to polarization switching along any axial direction. The multiple switching pathways in HfO 2 result in both 180° polarization reversal and the formation of 90° domains observed experimentally. Calculations show that specific switching pathways depend on the orientation of the applied electric field relative to the HfO 2 growth surface. This allows HfO 2 to automatically adjust the in-plane polarization direction under an out-of-plane electric field, thereby maximizing the out-of-plane component and contributing to the wake-up process. These findings redefine the roles of O III and O IV layers, clarify unconventional switching pathways, and enhance our understanding of electric field response mechanisms, wake-up, and fatigue in ferroelectrics.
{"title":"Mapping of the full polarization switching pathways for HfO 2 and its implications","authors":"Qi Hu, Shuning Lv, Hsiaoyi Tsai, Yufeng Xue, Xixiang Jing, Fanrong Lin, Chuanjia Tong, Tengfei Cao, Gilberto Teobaldi, Li-Min Liu","doi":"10.1073/pnas.2419685122","DOIUrl":"https://doi.org/10.1073/pnas.2419685122","url":null,"abstract":"The discovery of ferroelectric phases in HfO <jats:sub>2</jats:sub> offers insights into ferroelectricity. Its unique fluorite structure and complex polarization switching pathways exhibit distinct characteristics, challenging conventional analysis methods. Combining group theory and first-principles calculations, we identify numerous unconventional electric polarization switching pathways in HfO <jats:sub>2</jats:sub> with energy barriers of 0.32 to 0.57 eV as a function of the different shift in the suboxygen lattices. In total, we identify 47 switching pathways for the orthorhombic phase, corresponding to the left cosets of the <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:mi>F</mml:mi> <mml:mi>m</mml:mi> <mml:mover accent=\"true\"> <mml:mn>3</mml:mn> <mml:mo>¯</mml:mo> </mml:mover> <mml:mi>m</mml:mi> </mml:mrow> </mml:math> </jats:inline-formula> group with <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:mi>P</mml:mi> <mml:mi>c</mml:mi> <mml:mi>a</mml:mi> <mml:msub> <mml:mn>2</mml:mn> <mml:mn>1</mml:mn> </mml:msub> </mml:mrow> </mml:math> </jats:inline-formula> group. Contrary to the conception that the tetracoordinated oxygen (O <jats:sub>IV</jats:sub> ) layers are inactive, our result demonstrates that both the tricoordinated oxygen (O <jats:sub>III</jats:sub> ) and O <jats:sub>IV</jats:sub> can be displaced, leading to polarization switching along any axial direction. The multiple switching pathways in HfO <jats:sub>2</jats:sub> result in both 180° polarization reversal and the formation of 90° domains observed experimentally. Calculations show that specific switching pathways depend on the orientation of the applied electric field relative to the HfO <jats:sub>2</jats:sub> growth surface. This allows HfO <jats:sub>2</jats:sub> to automatically adjust the in-plane polarization direction under an out-of-plane electric field, thereby maximizing the out-of-plane component and contributing to the wake-up process. These findings redefine the roles of O <jats:sub>III</jats:sub> and O <jats:sub>IV</jats:sub> layers, clarify unconventional switching pathways, and enhance our understanding of electric field response mechanisms, wake-up, and fatigue in ferroelectrics.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"8 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xinqi Zhou, Kayla J. Belavek, Marisol X. Navarro, Kayli N. Martinez, Abigail Hinojosa, Evan W. Miller
Calcium ions (Ca 2+ ) play central roles in cellular physiology. Fluorescent indicators for Ca 2+ ions revolutionized our ability to make rapid, accurate, and highly parallel measurement of Ca 2+ concentrations in living cells. The use of ratio-based imaging with one particular indicator, fura-2, allowed practitioners to correct for a number of experimental confounds, including dye bleaching, variations in sample thickness, and fluctuations in illumination intensity. Ratio-based imaging with fura-2 was the most accurate and reliable method for measuring Ca 2+ concentrations. Two drawbacks to fura-2 exist. First, it requires ultraviolet (UV) excitation, which is more toxic to living cells than visible light. Second, our ability to use fura-2 for accurate, stable, ratio-based determinations of Ca 2+ concentration in living cells is fast becoming a method of the past. This is due, in part, because modern microscopes are phasing out the use of mercury arc lamps that provide the UV excitation needed for fura-2 imaging. To address this problem, we describe the design, synthesis, and cellular application of benzo[ b ]phosphole-based fluorescent Ca 2+ indicators for ratio-based imaging of Ca 2+ in living cells that can be used with modern light emitting diode (LED)-equipped fluorescence microscopes. We report isoCaRed-1Me, a Ca 2+ indicator that enables ratio-based imaging in immortalized cell lines, primary mammalian hippocampal neurons, and human-induced pluripotent stem cell–derived cardiomyocytes. These data show that isoCaRed-1Me will be useful for ratio-based Ca 2+ imaging using modern microscopes.
{"title":"Ratio-based indicators for cytosolic Ca 2+ with visible light excitation","authors":"Xinqi Zhou, Kayla J. Belavek, Marisol X. Navarro, Kayli N. Martinez, Abigail Hinojosa, Evan W. Miller","doi":"10.1073/pnas.2410436122","DOIUrl":"https://doi.org/10.1073/pnas.2410436122","url":null,"abstract":"Calcium ions (Ca <jats:sup>2+</jats:sup> ) play central roles in cellular physiology. Fluorescent indicators for Ca <jats:sup>2+</jats:sup> ions revolutionized our ability to make rapid, accurate, and highly parallel measurement of Ca <jats:sup>2+</jats:sup> concentrations in living cells. The use of ratio-based imaging with one particular indicator, fura-2, allowed practitioners to correct for a number of experimental confounds, including dye bleaching, variations in sample thickness, and fluctuations in illumination intensity. Ratio-based imaging with fura-2 was the most accurate and reliable method for measuring Ca <jats:sup>2+</jats:sup> concentrations. Two drawbacks to fura-2 exist. First, it requires ultraviolet (UV) excitation, which is more toxic to living cells than visible light. Second, our ability to use fura-2 for accurate, stable, ratio-based determinations of Ca <jats:sup>2+</jats:sup> concentration in living cells is fast becoming a method of the past. This is due, in part, because modern microscopes are phasing out the use of mercury arc lamps that provide the UV excitation needed for fura-2 imaging. To address this problem, we describe the design, synthesis, and cellular application of benzo[ <jats:italic>b</jats:italic> ]phosphole-based fluorescent Ca <jats:sup>2+</jats:sup> indicators for ratio-based imaging of Ca <jats:sup>2+</jats:sup> in living cells that can be used with modern light emitting diode (LED)-equipped fluorescence microscopes. We report isoCaRed-1Me, a Ca <jats:sup>2+</jats:sup> indicator that enables ratio-based imaging in immortalized cell lines, primary mammalian hippocampal neurons, and human-induced pluripotent stem cell–derived cardiomyocytes. These data show that isoCaRed-1Me will be useful for ratio-based Ca <jats:sup>2+</jats:sup> imaging using modern microscopes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"41 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael Cremin, Valerie T. Ramirez, Kristina Sanchez, Emmy Tay, Kaitlin Murray, Ingrid Brust-Mascher, Colin Reardon
Immune responses in the intestine are intricately balanced to prevent pathogen entry without inducing immunopathology. The nervous system is well established to interface with the immune system to fine-tune immunity in various organ systems including the gastrointestinal tract. Specialized sensory neurons can detect bacteria, bacterial products, and the resulting inflammation, to coordinate the immune response in the gastrointestinal tract. These sensory neurons release peptide neurotransmitters such as Substance P (SP), to induce both neuronal signaling and localized responses in nonneuronal cells. With this in mind, we assessed the immunoregulatory roles of SP receptor signaling during enteric bacterial infection with the noninvasive pathogen Citrobacter rodentium . Pharmacological antagonism of the SP receptor significantly reduced bacterial burden and prevented colonic crypt hyperplasia. Mice with SP receptor signaling blockade had significantly reduced inflammation and recruitment of T cells in the colon. Reduced colonic T cell recruitment is due to reduced expression of adhesion molecules on colonic endothelial cells in SP receptor antagonist-treated mice. Using SP receptor T cell conditional knockout mice, we further confirmed SP receptor signaling enhanced select aspects of T cell responses. Our data demonstrate that SP receptor signaling can significantly reduce inflammation and prevent host-maladaptive responses without impinging upon host protection.
{"title":"Substance P receptor signaling contributes to host maladaptive responses during enteric bacterial infection","authors":"Michael Cremin, Valerie T. Ramirez, Kristina Sanchez, Emmy Tay, Kaitlin Murray, Ingrid Brust-Mascher, Colin Reardon","doi":"10.1073/pnas.2415287122","DOIUrl":"https://doi.org/10.1073/pnas.2415287122","url":null,"abstract":"Immune responses in the intestine are intricately balanced to prevent pathogen entry without inducing immunopathology. The nervous system is well established to interface with the immune system to fine-tune immunity in various organ systems including the gastrointestinal tract. Specialized sensory neurons can detect bacteria, bacterial products, and the resulting inflammation, to coordinate the immune response in the gastrointestinal tract. These sensory neurons release peptide neurotransmitters such as Substance P (SP), to induce both neuronal signaling and localized responses in nonneuronal cells. With this in mind, we assessed the immunoregulatory roles of SP receptor signaling during enteric bacterial infection with the noninvasive pathogen <jats:italic>Citrobacter rodentium</jats:italic> . Pharmacological antagonism of the SP receptor significantly reduced bacterial burden and prevented colonic crypt hyperplasia. Mice with SP receptor signaling blockade had significantly reduced inflammation and recruitment of T cells in the colon. Reduced colonic T cell recruitment is due to reduced expression of adhesion molecules on colonic endothelial cells in SP receptor antagonist-treated mice. Using SP receptor T cell conditional knockout mice, we further confirmed SP receptor signaling enhanced select aspects of T cell responses. Our data demonstrate that SP receptor signaling can significantly reduce inflammation and prevent host-maladaptive responses without impinging upon host protection.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michelle Spiegel, Leah Clark, Thurston Domina, Emily K. Penner, Paul Hanselman, Paul Y. Yoo, Andrew Penner
Children from families across the income distribution attend public schools, making schools and classrooms potential sites for interaction between more- and less-affluent children. However, limited information exists regarding the extent of economic integration in these contexts. We merge educational administrative data from Oregon with measures of family income derived from IRS records to document student exposure to economically diverse school and classroom peers. Our findings indicate that affluent children in public schools are relatively isolated from their less affluent peers, while low- and middle-income students experience relatively even peer income distributions. Students from families in the top percentile of the income distribution attend schools where 20 percent of their peers, on average, come from the top five income percentiles. A large majority of the differences in peer exposure that we observe arise from the sorting of students across schools; sorting across classrooms within schools plays a substantially smaller role.
{"title":"Peer income exposure across the income distribution","authors":"Michelle Spiegel, Leah Clark, Thurston Domina, Emily K. Penner, Paul Hanselman, Paul Y. Yoo, Andrew Penner","doi":"10.1073/pnas.2410349122","DOIUrl":"https://doi.org/10.1073/pnas.2410349122","url":null,"abstract":"Children from families across the income distribution attend public schools, making schools and classrooms potential sites for interaction between more- and less-affluent children. However, limited information exists regarding the extent of economic integration in these contexts. We merge educational administrative data from Oregon with measures of family income derived from IRS records to document student exposure to economically diverse school and classroom peers. Our findings indicate that affluent children in public schools are relatively isolated from their less affluent peers, while low- and middle-income students experience relatively even peer income distributions. Students from families in the top percentile of the income distribution attend schools where 20 percent of their peers, on average, come from the top five income percentiles. A large majority of the differences in peer exposure that we observe arise from the sorting of students across schools; sorting across classrooms within schools plays a substantially smaller role.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"27 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A standard assumption in game theory is that decision-makers have preplanned strategies telling them what actions to take for every contingency. In contrast, nonstrategic decisions often involve an on-the-spot comparison process, with longer response times (RT) for choices between more similarly appealing options. If strategic decisions also exhibit these patterns, then RT might betray private information and alter game theory predictions. Here, we examined bargaining behavior to determine whether RT reveals private information in strategic settings. Using preexisting and experimental data from eBay, we show that both buyers and sellers take hours longer to accept bad offers and to reject good offers. We find nearly identical patterns in the two datasets, indicating a causal effect of offer size on RT. However, this relationship is half as strong for rejections as for acceptances, reducing the amount of useful private information revealed by the sellers. Counter to our predictions, buyers are discouraged by slow rejections—they are less likely to counteroffer to slow sellers. We also show that a drift-diffusion model (DDM), traditionally limited to decisions on the order of seconds, can account for decisions on the order of hours, sometimes days. The DDM reveals that more experienced sellers are less cautious and more inclined to accept offers. In summary, strategic decisions are inconsistent with preplanned strategies. This underscores the need for game theory to incorporate RT as a strategic variable and broadens the applicability of the DDM to slow decisions.
{"title":"Deliberation during online bargaining reveals strategic information","authors":"Miruna Cotet, Wenjia Joyce Zhao, Ian Krajbich","doi":"10.1073/pnas.2410956122","DOIUrl":"https://doi.org/10.1073/pnas.2410956122","url":null,"abstract":"A standard assumption in game theory is that decision-makers have preplanned strategies telling them what actions to take for every contingency. In contrast, nonstrategic decisions often involve an on-the-spot comparison process, with longer response times (RT) for choices between more similarly appealing options. If strategic decisions also exhibit these patterns, then RT might betray private information and alter game theory predictions. Here, we examined bargaining behavior to determine whether RT reveals private information in strategic settings. Using preexisting and experimental data from eBay, we show that both buyers and sellers take hours longer to accept bad offers and to reject good offers. We find nearly identical patterns in the two datasets, indicating a causal effect of offer size on RT. However, this relationship is half as strong for rejections as for acceptances, reducing the amount of useful private information revealed by the sellers. Counter to our predictions, buyers are discouraged by slow rejections—they are less likely to counteroffer to slow sellers. We also show that a drift-diffusion model (DDM), traditionally limited to decisions on the order of seconds, can account for decisions on the order of hours, sometimes days. The DDM reveals that more experienced sellers are less cautious and more inclined to accept offers. In summary, strategic decisions are inconsistent with preplanned strategies. This underscores the need for game theory to incorporate RT as a strategic variable and broadens the applicability of the DDM to slow decisions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"30 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yen Thi Kim Nguyen, Xueyong Zhu, Julianna Han, Alesandra J. Rodriguez, Weina Sun, Wenli Yu, Peter Palese, Florian Krammer, Andrew B. Ward, Ian A. Wilson
Chimeric hemagglutinins (cHA) appear to be promising for the design and development of universal influenza vaccines. Influenza A group 1 cHAs, cH5/1, cH8/1, and cH11/1, comprising an H1 stem attached to either an H5, H8, or H11 globular head, have been used sequentially as vaccine immunogens in human clinical trials and induced high levels of broadly protective antibodies. Using X-ray crystallography and negative-stain electron microscopy, we determined structures of cH5/1, cH8/1, and cH11/1 HAs in their apo (unliganded) and antibody Fab-bound states. Stem-reactive antibodies 3E1 and 31.b.09 recognize their cognate epitopes in cH5/1, cH8/1, and cH11/1 HAs. However, with cH5/1, the head domains are rotated by 35 to 45° around the threefold axis of the HA trimer compared to native HA with a more splayed-open conformation at the stem base. cH11/1 with 3E1 is structurally more native-like but resembles cH5/1 with 31.b.09, whereas cH8/1 with 31.b.09 exhibited a range of closed-to-open stem configurations with some separation of head and stem domains. Furthermore, all of these group 1 cHAs effectively bound a broad head trimer interface antibody and other broad stem antibodies. Thus, the cHAs exhibit structural plasticity without compromising the stem and head trimer interface epitopes for elicitation of influenza A group 1 cross-reactive antibodies.
{"title":"Structural characterization of influenza group 1 chimeric hemagglutinins as broad vaccine immunogens","authors":"Yen Thi Kim Nguyen, Xueyong Zhu, Julianna Han, Alesandra J. Rodriguez, Weina Sun, Wenli Yu, Peter Palese, Florian Krammer, Andrew B. Ward, Ian A. Wilson","doi":"10.1073/pnas.2416628122","DOIUrl":"https://doi.org/10.1073/pnas.2416628122","url":null,"abstract":"Chimeric hemagglutinins (cHA) appear to be promising for the design and development of universal influenza vaccines. Influenza A group 1 cHAs, cH5/1, cH8/1, and cH11/1, comprising an H1 stem attached to either an H5, H8, or H11 globular head, have been used sequentially as vaccine immunogens in human clinical trials and induced high levels of broadly protective antibodies. Using X-ray crystallography and negative-stain electron microscopy, we determined structures of cH5/1, cH8/1, and cH11/1 HAs in their apo (unliganded) and antibody Fab-bound states. Stem-reactive antibodies 3E1 and 31.b.09 recognize their cognate epitopes in cH5/1, cH8/1, and cH11/1 HAs. However, with cH5/1, the head domains are rotated by 35 to 45° around the threefold axis of the HA trimer compared to native HA with a more splayed-open conformation at the stem base. cH11/1 with 3E1 is structurally more native-like but resembles cH5/1 with 31.b.09, whereas cH8/1 with 31.b.09 exhibited a range of closed-to-open stem configurations with some separation of head and stem domains. Furthermore, all of these group 1 cHAs effectively bound a broad head trimer interface antibody and other broad stem antibodies. Thus, the cHAs exhibit structural plasticity without compromising the stem and head trimer interface epitopes for elicitation of influenza A group 1 cross-reactive antibodies.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"2 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lanjing Ma, Zhongqiu Pang, Haijiao Zhang, Xueling Yang, Shaoqin Zheng, Yi Chen, Weijie Ding, Qing Han, Xi Zhang, Liu Cao, Teng Fei, Qiang Wang, Daming Gao, Aina He, Ke-Bang Hu, Xuexin Li, Ren Sheng
Clear cell renal cell carcinoma (ccRCC) is the predominant human renal cancer with surging incidence and fatality lately. Hyperactivation of hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) signaling are the common signatures in ccRCC. Herein, we employed spontaneous ccRCC model to demonstrate the indispensability of an underappreciated Ser/Thr kinase, CDKL3, in the initiation and progression of ccRCC. Ablation of CDKL3 does not affect normal kidney, but abrogates Akt-mTOR hyperactivity and thoroughly prevents the formation and growth of the HIF-agitated ccRCC in vivo. Remarkable clinical correlations also supported the oncogenic role of CDKL3. Mechanism-wise, cytosolic CDKL3 unexpectedly behaves as the adaptor to physically potentiate mTORC2-dependent Akt activation without functioning through kinase activity. And mTORC2 can phosphorylate and stabilize CDKL3 to form a positive feedback loop to sustain the cancer-favored Akt-mTOR overactivation. Together, we revealed the pathological importance and molecular mechanism of CDKL3-mediated Akt-mTOR axis in ccRCC initiation and progression.
{"title":"Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis","authors":"Lanjing Ma, Zhongqiu Pang, Haijiao Zhang, Xueling Yang, Shaoqin Zheng, Yi Chen, Weijie Ding, Qing Han, Xi Zhang, Liu Cao, Teng Fei, Qiang Wang, Daming Gao, Aina He, Ke-Bang Hu, Xuexin Li, Ren Sheng","doi":"10.1073/pnas.2415244122","DOIUrl":"https://doi.org/10.1073/pnas.2415244122","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is the predominant human renal cancer with surging incidence and fatality lately. Hyperactivation of hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) signaling are the common signatures in ccRCC. Herein, we employed spontaneous ccRCC model to demonstrate the indispensability of an underappreciated Ser/Thr kinase, CDKL3, in the initiation and progression of ccRCC. Ablation of CDKL3 does not affect normal kidney, but abrogates Akt-mTOR hyperactivity and thoroughly prevents the formation and growth of the HIF-agitated ccRCC in vivo. Remarkable clinical correlations also supported the oncogenic role of CDKL3. Mechanism-wise, cytosolic CDKL3 unexpectedly behaves as the adaptor to physically potentiate mTORC2-dependent Akt activation without functioning through kinase activity. And mTORC2 can phosphorylate and stabilize CDKL3 to form a positive feedback loop to sustain the cancer-favored Akt-mTOR overactivation. Together, we revealed the pathological importance and molecular mechanism of CDKL3-mediated Akt-mTOR axis in ccRCC initiation and progression.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"61 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ozge Karayel, Allison Soung, Hem Gurung, Alexander F. Schubert, Susan Klaeger, Marc Kschonsak, Aljazi Al-Maraghi, Ajaz A. Bhat, Ammira S. Alshabeeb Akil, Debra L. Dugger, Joshua D. Webster, Dorothy M. French, Dhullipala Anand, Naharmal Soni, Khalid A. Fakhro, Christopher M. Rose, Seth F. Harris, Ada Ndoja, Kim Newton, Vishva M. Dixit
COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here, we link a homozygous DET1 R26W mutation to lethal developmental abnormalities in humans. Experimental cryo-electron microscopy of the DET1 complex with DDB1 and DDA1, as well as co-immunoprecipitation experiments, revealed that DET1 R26W impairs binding to DDB1, thereby compromising E3 ligase function. Accordingly, human-induced pluripotent stem cells homozygous for DET1 R26W expressed ETV4 and ETV5 highly, and exhibited defective mitochondrial homeostasis and aberrant caspase-dependent cell death when differentiated into neurons. Neuronal cell death was increased further in the presence of Det1 -deficient microglia as compared to WT microglia, indicating that the deleterious effects of the DET1 p.R26W mutation may stem from the dysregulation of multiple cell types. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.
{"title":"Impairment of DET1 causes neurological defects and lethality in mice and humans","authors":"Ozge Karayel, Allison Soung, Hem Gurung, Alexander F. Schubert, Susan Klaeger, Marc Kschonsak, Aljazi Al-Maraghi, Ajaz A. Bhat, Ammira S. Alshabeeb Akil, Debra L. Dugger, Joshua D. Webster, Dorothy M. French, Dhullipala Anand, Naharmal Soni, Khalid A. Fakhro, Christopher M. Rose, Seth F. Harris, Ada Ndoja, Kim Newton, Vishva M. Dixit","doi":"10.1073/pnas.2422631122","DOIUrl":"https://doi.org/10.1073/pnas.2422631122","url":null,"abstract":"COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here, we link a homozygous <jats:italic> DET1 <jats:sup>R26W</jats:sup> </jats:italic> mutation to lethal developmental abnormalities in humans. Experimental cryo-electron microscopy of the DET1 complex with DDB1 and DDA1, as well as co-immunoprecipitation experiments, revealed that DET1 <jats:sup>R26W</jats:sup> impairs binding to DDB1, thereby compromising E3 ligase function. Accordingly, human-induced pluripotent stem cells homozygous for <jats:italic> DET1 <jats:sup>R26W</jats:sup> </jats:italic> expressed ETV4 and ETV5 highly, and exhibited defective mitochondrial homeostasis and aberrant caspase-dependent cell death when differentiated into neurons. Neuronal cell death was increased further in the presence of <jats:italic>Det1</jats:italic> -deficient microglia as compared to WT microglia, indicating that the deleterious effects of the <jats:italic>DET1</jats:italic> p.R26W mutation may stem from the dysregulation of multiple cell types. Mice lacking <jats:italic>Det1</jats:italic> died during embryogenesis, while <jats:italic>Det1</jats:italic> deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"208 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anthony Hurben, Yinchen Hao, Ioan-Augustin Chioar, Liu Yang, Nanny Strandqvist, Michael Saccone, Nicholas S. Bingham, Justin Ramberger, Chris Leighton, Cristiano Nisoli, Peter Schiffer
We have studied the magnetic moments of artificial spin ice arrays of nanomagnets in both undistorted square arrays and in arrays with a topological defect induced by a single disclination. We confirm that the disclination induces global, macroscopic changes in the low-energy collective states of the nanomagnet moment configuration. Specifically, the disclination leads to Faraday lines of effective magnetic flux that run from the center all the way to the edge of the arrays. Moreover, the geometric deformation, induced by the topological defect, curves the geometry such that these Faraday lines are channeled preferentially by the arrays’ curved geometry. Our results demonstrate how the intentional combination of topology and geometry can be designed to control magnetic charges and the flow of local magnetization and thus manipulate associated collective excitations.
{"title":"Fractional magnetic charges and channeling of Faraday lines by disclinations in artificial spin ice","authors":"Anthony Hurben, Yinchen Hao, Ioan-Augustin Chioar, Liu Yang, Nanny Strandqvist, Michael Saccone, Nicholas S. Bingham, Justin Ramberger, Chris Leighton, Cristiano Nisoli, Peter Schiffer","doi":"10.1073/pnas.2415101122","DOIUrl":"https://doi.org/10.1073/pnas.2415101122","url":null,"abstract":"We have studied the magnetic moments of artificial spin ice arrays of nanomagnets in both undistorted square arrays and in arrays with a topological defect induced by a single disclination. We confirm that the disclination induces global, macroscopic changes in the low-energy collective states of the nanomagnet moment configuration. Specifically, the disclination leads to Faraday lines of effective magnetic flux that run from the center all the way to the edge of the arrays. Moreover, the geometric deformation, induced by the topological defect, curves the geometry such that these Faraday lines are channeled preferentially by the arrays’ curved geometry. Our results demonstrate how the intentional combination of topology and geometry can be designed to control magnetic charges and the flow of local magnetization and thus manipulate associated collective excitations.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-11Epub Date: 2025-02-03DOI: 10.1073/pnas.2426535122
Marko Hyvönen
{"title":"Yet another twist to the regulation of the TGF-β family ligands.","authors":"Marko Hyvönen","doi":"10.1073/pnas.2426535122","DOIUrl":"https://doi.org/10.1073/pnas.2426535122","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 6","pages":"e2426535122"},"PeriodicalIF":9.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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