Puneet Rawat, Melanie R. Shapiro, Leeana D. Peters, Michael Widrich, Koshlan Mayer-Blackwell, Keshav Motwani, Milena Pavlović, Ghadi al Hajj, Amanda L. Posgai, Chakravarthi Kanduri, Giulio Isacchini, Maria Chernigovskaya, Lonneke Scheffer, Kartik Motwani, Leandro Octavio Balzano-Nogueira, Camryn M. Pettenger-Willey, Sebastiaan Valkiers, Laura M. Jacobsen, Michael J. Haller, Desmond A. Schatz, Clive H. Wasserfall, Ryan O. Emerson, Andrew J. Fiore-Gartland, Mark A. Atkinson, Günter Klambauer, Geir Kjetil Sandve, Victor Greiff, Todd M. Brusko
Type 1 diabetes (T1D) is a T cell–mediated disease with a strong immunogenetic human leukocyte antigen (HLA) dependence. HLA allelic influence on the T cell receptor (TCR) repertoire shapes thymic selection and controls activation of diabetogenic clones yet remains largely unresolved in T1D. We sequenced the circulating TCRβ chain repertoire from 2250 HLA-typed participants across three cross-sectional cohorts, including individuals with T1D and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in individuals with T1D. We leveraged deep learning to identify T1D-associated TCR subsequence motifs that were also observed in independent TCR cohorts residing in pancreas-draining lymph nodes of individuals with T1D. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and groundwork for TCR-based diagnostics and therapeutics.
{"title":"Identification of a type 1 diabetes–associated T cell receptor repertoire signature from the human peripheral blood","authors":"Puneet Rawat, Melanie R. Shapiro, Leeana D. Peters, Michael Widrich, Koshlan Mayer-Blackwell, Keshav Motwani, Milena Pavlović, Ghadi al Hajj, Amanda L. Posgai, Chakravarthi Kanduri, Giulio Isacchini, Maria Chernigovskaya, Lonneke Scheffer, Kartik Motwani, Leandro Octavio Balzano-Nogueira, Camryn M. Pettenger-Willey, Sebastiaan Valkiers, Laura M. Jacobsen, Michael J. Haller, Desmond A. Schatz, Clive H. Wasserfall, Ryan O. Emerson, Andrew J. Fiore-Gartland, Mark A. Atkinson, Günter Klambauer, Geir Kjetil Sandve, Victor Greiff, Todd M. Brusko","doi":"10.1126/sciadv.adx7448","DOIUrl":"10.1126/sciadv.adx7448","url":null,"abstract":"<div >Type 1 diabetes (T1D) is a T cell–mediated disease with a strong immunogenetic human leukocyte antigen (HLA) dependence. HLA allelic influence on the T cell receptor (TCR) repertoire shapes thymic selection and controls activation of diabetogenic clones yet remains largely unresolved in T1D. We sequenced the circulating TCRβ chain repertoire from 2250 HLA-typed participants across three cross-sectional cohorts, including individuals with T1D and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in individuals with T1D. We leveraged deep learning to identify T1D-associated TCR subsequence motifs that were also observed in independent TCR cohorts residing in pancreas-draining lymph nodes of individuals with T1D. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and groundwork for TCR-based diagnostics and therapeutics.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176699","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}
Jamie E. Hibbert, Kent W. Jorgenson, Ramy K.A. Sayed, Hector G. Paez, Marius Meinhold, Corey G.K. Flynn, Anthony N. Lange, Garrison T. Lindley, Philip M. Flejsierowicz, Troy A. Hornberger
Mechanical loading drives skeletal muscle growth, yet the mechanisms that regulate this process remain undefined. Here, we show that an increase in mechanical loading induces muscle fiber growth through two distinct mechanisms. Radial growth, reflected by an increase in fiber cross-sectional area, is mediated through a rapamycin-sensitive signaling pathway, whereas longitudinal growth, marked by the in-series addition of sarcomeres, is mediated through a rapamycin-insensitive signaling pathway. To gain further insight into the events that drive longitudinal growth, we combined BONCAT-based labeling of synthesized proteins with high-resolution imaging and determined that the in-series addition of sarcomeres is mediated by a process that involves transverse splitting at the Z-lines of preexisting sarcomeres. Collectively, our findings not only challenge the long-standing view that mechanically induced growth is uniformly governed by mTORC1 but also lay the framework for a revised understanding of the molecular and structural events that drive this process.
{"title":"Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism","authors":"Jamie E. Hibbert, Kent W. Jorgenson, Ramy K.A. Sayed, Hector G. Paez, Marius Meinhold, Corey G.K. Flynn, Anthony N. Lange, Garrison T. Lindley, Philip M. Flejsierowicz, Troy A. Hornberger","doi":"10.1126/sciadv.aec5134","DOIUrl":"10.1126/sciadv.aec5134","url":null,"abstract":"<div >Mechanical loading drives skeletal muscle growth, yet the mechanisms that regulate this process remain undefined. Here, we show that an increase in mechanical loading induces muscle fiber growth through two distinct mechanisms. Radial growth, reflected by an increase in fiber cross-sectional area, is mediated through a rapamycin-sensitive signaling pathway, whereas longitudinal growth, marked by the in-series addition of sarcomeres, is mediated through a rapamycin-insensitive signaling pathway. To gain further insight into the events that drive longitudinal growth, we combined BONCAT-based labeling of synthesized proteins with high-resolution imaging and determined that the in-series addition of sarcomeres is mediated by a process that involves transverse splitting at the Z-lines of preexisting sarcomeres. Collectively, our findings not only challenge the long-standing view that mechanically induced growth is uniformly governed by mTORC1 but also lay the framework for a revised understanding of the molecular and structural events that drive this process.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176713","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}
Yunxiang Song, Zongda Li, Xinrui Zhu, Norman Lippok, Miro Erkintalo, Marko Lončar
The ability to generate efficient and coherent frequency combs using photonic integrated circuits offers tremendous potential for a range of applications. X-cut thin-film lithium niobate (TFLN) is promising for developing next-generation microcomb-driven photonic systems, providing a diversity of functionalities through combined and electro-optic effects. Normal-dispersion Kerr combs are critically needed because of their standout advantages, yet this dispersion regime remains unexplored on x-cut TFLN. Here, we design and demonstrate microresonators suitable for the robust generation of normal-dispersion Kerr combs. We show Kerr combs that substantially surpass state-of-the-art microcombs on x-cut TFLN in key performance metrics and an ultrabroad frequency comb whose existence is underpinned by both normal-dispersion Kerr dynamics and stimulated Raman scattering. Our work will unlock high-speed and low-energy-consumption photonic circuits for communications and signal processing enabled by a monolithic microcomb technology while also stimulating investigations of previously unknown nonlinear states that may synergize hybrid material nonlinearities.
{"title":"High-efficiency and broadband Kerr comb generation in normal-dispersion x-cut lithium niobate microresonators","authors":"Yunxiang Song, Zongda Li, Xinrui Zhu, Norman Lippok, Miro Erkintalo, Marko Lončar","doi":"10.1126/sciadv.aeb5758","DOIUrl":"10.1126/sciadv.aeb5758","url":null,"abstract":"<div >The ability to generate efficient and coherent frequency combs using photonic integrated circuits offers tremendous potential for a range of applications. X-cut thin-film lithium niobate (TFLN) is promising for developing next-generation microcomb-driven photonic systems, providing a diversity of functionalities through combined <span><math><mrow><msup><mi>χ</mi><mrow><mo>(</mo><mn>3</mn><mo>)</mo></mrow></msup></mrow></math></span> and electro-optic effects. Normal-dispersion Kerr combs are critically needed because of their standout advantages, yet this dispersion regime remains unexplored on x-cut TFLN. Here, we design and demonstrate microresonators suitable for the robust generation of normal-dispersion Kerr combs. We show Kerr combs that substantially surpass state-of-the-art microcombs on x-cut TFLN in key performance metrics and an ultrabroad frequency comb whose existence is underpinned by both normal-dispersion Kerr dynamics and stimulated Raman scattering. Our work will unlock high-speed and low-energy-consumption photonic circuits for communications and signal processing enabled by a monolithic microcomb technology while also stimulating investigations of previously unknown nonlinear states that may synergize hybrid material nonlinearities.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176690","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}
Bernat Durà Faulí, Lennard Kwakernaak, Martin van Hecke
Elastic instabilities such as buckling and snapping have evolved into a powerful design principle, enabling memory, sequential shape morphing, and computing in metamaterials and devices. Modifying the postbuckling configurations or their snapping transitions would greatly expand design possibilities, yet general principles for controlling elastic instabilities are lacking. Here, we show that adding a partial cut, or slit, to a flexible beam enables precise control of postbuckling behavior: Under compression, slit-beams first buckle and then snap, leading to tristability within the hysteretic regime. A truss model explains these phenomena by uncovering the interplay of geometric and slit-induced nonlinearities. Leveraging these insights, we realize multislit beams with programmable behavior, unlocking a vast design space featuring giant hysteresis, quadstability, multistep snapping, tristability at zero compression, and compression-induced snapping between left- and right-buckled states. Our strategy is general, simple to design and implement, and enables mechanical metamaterials and devices with advanced memory and sequential behavior.
{"title":"Hysteretic slit-snapping and multistability in buckled beams with partial cuts","authors":"Bernat Durà Faulí, Lennard Kwakernaak, Martin van Hecke","doi":"10.1126/sciadv.aeb9750","DOIUrl":"10.1126/sciadv.aeb9750","url":null,"abstract":"<div >Elastic instabilities such as buckling and snapping have evolved into a powerful design principle, enabling memory, sequential shape morphing, and computing in metamaterials and devices. Modifying the postbuckling configurations or their snapping transitions would greatly expand design possibilities, yet general principles for controlling elastic instabilities are lacking. Here, we show that adding a partial cut, or slit, to a flexible beam enables precise control of postbuckling behavior: Under compression, slit-beams first buckle and then snap, leading to tristability within the hysteretic regime. A truss model explains these phenomena by uncovering the interplay of geometric and slit-induced nonlinearities. Leveraging these insights, we realize multislit beams with programmable behavior, unlocking a vast design space featuring giant hysteresis, quadstability, multistep snapping, tristability at zero compression, and compression-induced snapping between left- and right-buckled states. Our strategy is general, simple to design and implement, and enables mechanical metamaterials and devices with advanced memory and sequential behavior.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176711","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}
Lipid metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the precise molecular mechanisms underlying lipid-mediated oncogenesis and the specific lipid metabolic enzymes involved remain largely elusive. Here, we identify elongation of very-long-chain fatty acid protein 6 (Elovl6) as a critical regulator in CRC progression. Clinical data reveal significant down-regulation of Elovl6 in colon cancer tissues, with low expression levels correlating with unfavorable patient prognosis. We demonstrate that Elovl6 exerts potent tumor-suppressive effects, significantly inhibiting cellular proliferation in vitro and attenuating tumor growth in vivo. Mechanistically, it maintains intestinal microbial homeostasis by preventing the expansion of opportunistic pathogens while simultaneously orchestrating metabolic reprogramming through modulation of phospholipid biosynthesis pathways. Notably, we find that stearic acid, a key Elovl6-derived metabolite, promotes mitochondrial fusion by stabilizing mitofusin 1 protein. These findings not only position Elovl6 as a promising therapeutic target but also suggest that dietary supplementation with stearic acid could represent a viable strategy for CRC prevention and treatment.
{"title":"Elovl6 inhibits colorectal cancer progression through stearic acid–mediated mitochondrial fusion and metabolic reprogramming","authors":"Zhiqian Bi, Xiaoyao Chang, Shengyun Zhu, Shuilian Fu, Yuzhe Zhang, Tingting Wang, Feng Wang, Hongqin Zhuang, Zi-Chun Hua","doi":"10.1126/sciadv.adz2892","DOIUrl":"10.1126/sciadv.adz2892","url":null,"abstract":"<div >Lipid metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the precise molecular mechanisms underlying lipid-mediated oncogenesis and the specific lipid metabolic enzymes involved remain largely elusive. Here, we identify elongation of very-long-chain fatty acid protein 6 (Elovl6) as a critical regulator in CRC progression. Clinical data reveal significant down-regulation of Elovl6 in colon cancer tissues, with low expression levels correlating with unfavorable patient prognosis. We demonstrate that Elovl6 exerts potent tumor-suppressive effects, significantly inhibiting cellular proliferation in vitro and attenuating tumor growth in vivo. Mechanistically, it maintains intestinal microbial homeostasis by preventing the expansion of opportunistic pathogens while simultaneously orchestrating metabolic reprogramming through modulation of phospholipid biosynthesis pathways. Notably, we find that stearic acid, a key Elovl6-derived metabolite, promotes mitochondrial fusion by stabilizing mitofusin 1 protein. These findings not only position Elovl6 as a promising therapeutic target but also suggest that dietary supplementation with stearic acid could represent a viable strategy for CRC prevention and treatment.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176717","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}
Hadi Zadeh-Haghighi, Caleb R. Siguenza, Robert P. Smith, Christoph Simon, Travis J. A. Craddock
Weak magnetic fields have been shown to influence biological processes; however, the underlying mechanisms remain unknown as the energies involved are far below thermal energies challenging classical explanations. Microtubule cytoskeletal fibers offer an ideal system to test weak magnetic field effects due to their self-assembling capabilities, sensitivity to magnetic fields, and their central role in cellular processes. In this study, we use a combination of experiments and simulations to explore how nuclear spin dynamics affect microtubule polymerization by examining interactions between magnesium isotope substitution and weak magnetic fields. Our experiments reveal an isotope-dependent effect explicitly arising from nuclear spin properties. This nuclear spin-driven effect is enhanced under an applied weak 3-millitesla magnetic field. Our theoretical radical pair model achieves quantitative agreement with our experimental observations. These results support a connection between quantum spin dynamics and microtubule assembly, providing further insights into how weak magnetic fields may influence biomolecular functions.
{"title":"Tubulin polymerization dynamics are influenced by magnetic isotope effects consistent with the radical pair mechanism","authors":"Hadi Zadeh-Haghighi, Caleb R. Siguenza, Robert P. Smith, Christoph Simon, Travis J. A. Craddock","doi":"10.1126/sciadv.ady8317","DOIUrl":"10.1126/sciadv.ady8317","url":null,"abstract":"<div >Weak magnetic fields have been shown to influence biological processes; however, the underlying mechanisms remain unknown as the energies involved are far below thermal energies challenging classical explanations. Microtubule cytoskeletal fibers offer an ideal system to test weak magnetic field effects due to their self-assembling capabilities, sensitivity to magnetic fields, and their central role in cellular processes. In this study, we use a combination of experiments and simulations to explore how nuclear spin dynamics affect microtubule polymerization by examining interactions between magnesium isotope substitution and weak magnetic fields. Our experiments reveal an isotope-dependent effect explicitly arising from nuclear spin properties. This nuclear spin-driven effect is enhanced under an applied weak 3-millitesla magnetic field. Our theoretical radical pair model achieves quantitative agreement with our experimental observations. These results support a connection between quantum spin dynamics and microtubule assembly, providing further insights into how weak magnetic fields may influence biomolecular functions.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176716","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}
Mrinalini Ranjan, Kun-Han Lin, Brian D. Mueller, Sonja M. Wojcik, Mareike Lohse, Thomas C. Südhof, Erik M. Jorgensen, Erwin Neher, Noa Lipstein, Nils Brose, Holger Taschenberger
Synaptic strength and plasticity are fine-tuned by neuromodulation and use-dependent second-messenger signaling. Presynaptic diacylglycerol (DAG), Ca2+, and Ca2+-calmodulin signaling converge on the essential synaptic vesicle (SV) priming protein Munc13-1 via its regulatory C1, C2B, and CaM-binding domains. Using brainstem-specific heterozygous mice expressing a DAG-binding-deficient Munc13-1 variant (Munc13-1H567K), we compared synaptic transmission in situ at glutamatergic calyx of Held synapses carrying either a single Munc13-1H567K or a single Munc13-1wt allele. Munc13-1H567K/− synapses show enhanced initial strength but impaired steady-state release and slower recovery from depression. These deficits result from an increased initial abundance of fully primed SVs and a loss of activity-dependent acceleration of SV priming. Posttetanic potentiation (PTP) is strongly reduced in Munc13-1H567K/− synapses and either increased or attenuated by C2B mutations that enhance or weaken Ca2+-phospholipid binding. Our data identify Munc13-1 as a target of presynaptic TrkB–phospholipase C–γ signaling and demonstrate that C1 and C2B domain-dependent regulation of Munc13-1 determines synaptic strength and shapes short-term plasticity and PTP.
{"title":"Munc13-1 couples DAG and Ca2+ signaling to dynamic vesicle priming, synaptic short-term plasticity, and posttetanic potentiation","authors":"Mrinalini Ranjan, Kun-Han Lin, Brian D. Mueller, Sonja M. Wojcik, Mareike Lohse, Thomas C. Südhof, Erik M. Jorgensen, Erwin Neher, Noa Lipstein, Nils Brose, Holger Taschenberger","doi":"10.1126/sciadv.aea0449","DOIUrl":"10.1126/sciadv.aea0449","url":null,"abstract":"<div >Synaptic strength and plasticity are fine-tuned by neuromodulation and use-dependent second-messenger signaling. Presynaptic diacylglycerol (DAG), Ca<sup>2+</sup>, and Ca<sup>2+</sup>-calmodulin signaling converge on the essential synaptic vesicle (SV) priming protein Munc13-1 via its regulatory C<sub>1</sub>, C<sub>2</sub>B, and CaM-binding domains. Using brainstem-specific heterozygous mice expressing a DAG-binding-deficient Munc13-1 variant (Munc13-1<sup>H567K</sup>), we compared synaptic transmission in situ at glutamatergic calyx of Held synapses carrying either a single Munc13-1<sup>H567K</sup> or a single Munc13-1<sup>wt</sup> allele. Munc13-1<sup>H567K/−</sup> synapses show enhanced initial strength but impaired steady-state release and slower recovery from depression. These deficits result from an increased initial abundance of fully primed SVs and a loss of activity-dependent acceleration of SV priming. Posttetanic potentiation (PTP) is strongly reduced in Munc13-1<sup>H567K/−</sup> synapses and either increased or attenuated by C<sub>2</sub>B mutations that enhance or weaken Ca<sup>2+</sup>-phospholipid binding. Our data identify Munc13-1 as a target of presynaptic TrkB–phospholipase C–γ signaling and demonstrate that C<sub>1</sub> and C<sub>2</sub>B domain-dependent regulation of Munc13-1 determines synaptic strength and shapes short-term plasticity and PTP.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176721","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}
Across metazoans, the insulin/insulin-like signaling (IIS) pathway is assumed to promote organ growth. We found that genes within the IIS pathway evolved opposite roles in organ growth across wing-dimorphic insects, playing opposite roles in regulating the developmental switch between short and long wings. In the firebug, the InR-Chico-PI3K-PDK1-Tsc1/2-TORC1 cascade redirects the switch from short to long wings by inactivating IIS, whereas in the planthopper, the InR-Chico-PI3K-Akt-FoxO cascade redirects this same switch by activating IIS. Activation or inactivation of IIS results in low ecdysteroid titers in both species by regulating different genes within the ecdysteroid biosynthesis pathway, which in turn induces long wing development. Our findings reveal a negative relationship between IIS and organ growth and a mechanism for how a hormone pathway can translate opposing IIS activities into the same developmental switch across species.
{"title":"Opposing insulin signals underlie the same developmental switch across hemipteran insects","authors":"Jin-Li Zhang, Yong-Kang Liu, Yi Wan, Hui-Jie Wu, Ni-Tong Xu, Zhuo-Qi Liu, Heng-Guang Huang, Jia-Peng Yang, Xin-Yang Liu, Xu-Mei Luo, Yi-Song Li, Qi-Sheng Song, Frederik H. Nijhout, Ehab Abouheif, Hai-Jun Xu","doi":"10.1126/sciadv.aea4413","DOIUrl":"10.1126/sciadv.aea4413","url":null,"abstract":"<div >Across metazoans, the insulin/insulin-like signaling (IIS) pathway is assumed to promote organ growth. We found that genes within the IIS pathway evolved opposite roles in organ growth across wing-dimorphic insects, playing opposite roles in regulating the developmental switch between short and long wings. In the firebug, the InR-Chico-PI3K-PDK1-Tsc1/2-TORC1 cascade redirects the switch from short to long wings by inactivating IIS, whereas in the planthopper, the InR-Chico-PI3K-Akt-FoxO cascade redirects this same switch by activating IIS. Activation or inactivation of IIS results in low ecdysteroid titers in both species by regulating different genes within the ecdysteroid biosynthesis pathway, which in turn induces long wing development. Our findings reveal a negative relationship between IIS and organ growth and a mechanism for how a hormone pathway can translate opposing IIS activities into the same developmental switch across species.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176706","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}
Debora Mazzetti, Michal O. Nowicki, Himanshu Soni, Joshua D. Bernstock, Maya Groff, Luisa Esposito, Diego A. Hernandez, Lucia Altucci, Anna Krichevsky, Geoffrey Fell, E. Antonio Chiocca, Hiroshi Nakashima, Marco Mineo, Pierpaolo Peruzzi
RNA medicine is a promisingly expanding field in modern health care, but its use in genetically complex diseases, like cancer, has been challenging, mainly due to their reliance on multiple abnormal pathways. Here, we describe a microRNA-based platform that exploits previously unrecognized features of microRNA processing. Leveraging a microprocessor-dependent, cleave-activation strategy, this design allows us to expand biological impact by simultaneously up- and down-regulating desired microRNAs, while using them as structural enablers for other short, noncoding RNAs, such as aptamers. We demonstrate its biological potential in a glioblastoma model, where the simultaneous bidirectional modulation of five among the most deregulated microRNAs results in critical mass interference against the tumor. In parallel, microRNA-mediated chaperoning of an anti-p50 aptamer within the platform allows us to selectively block the nuclear factor κB pathway, a difficult-to-drug target. This work highlights the potential of chimeric microRNA clusters as an emerging therapeutic concept for cancer and other similarly multifactorial diseases.
{"title":"Accessory microRNA byproducts expand RNA interference via microprocessor-mediated cleavage activation","authors":"Debora Mazzetti, Michal O. Nowicki, Himanshu Soni, Joshua D. Bernstock, Maya Groff, Luisa Esposito, Diego A. Hernandez, Lucia Altucci, Anna Krichevsky, Geoffrey Fell, E. Antonio Chiocca, Hiroshi Nakashima, Marco Mineo, Pierpaolo Peruzzi","doi":"10.1126/sciadv.adz8331","DOIUrl":"10.1126/sciadv.adz8331","url":null,"abstract":"<div >RNA medicine is a promisingly expanding field in modern health care, but its use in genetically complex diseases, like cancer, has been challenging, mainly due to their reliance on multiple abnormal pathways. Here, we describe a microRNA-based platform that exploits previously unrecognized features of microRNA processing. Leveraging a microprocessor-dependent, cleave-activation strategy, this design allows us to expand biological impact by simultaneously up- and down-regulating desired microRNAs, while using them as structural enablers for other short, noncoding RNAs, such as aptamers. We demonstrate its biological potential in a glioblastoma model, where the simultaneous bidirectional modulation of five among the most deregulated microRNAs results in critical mass interference against the tumor. In parallel, microRNA-mediated chaperoning of an anti-p50 aptamer within the platform allows us to selectively block the nuclear factor κB pathway, a difficult-to-drug target. This work highlights the potential of chimeric microRNA clusters as an emerging therapeutic concept for cancer and other similarly multifactorial diseases.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176718","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}
Kun Yang, Chao Zhang, Chengwei Wu, Qian Du, Bingzhi Li, Zhen Fang, Liang Li, Peng Wang, Wen Shang, Jianbo Wu, Tianru Wu, Hui Wang, Tao Deng, Wenpei Gao
Accurate temperature measurement with a high spatial resolution is essential for understanding thermal behavior in integrated nanoscale devices and especially at heterogeneous interfaces. However, existing techniques are often limited by insufficient spatial resolution. Here, we showcase the direct and noncontact temperature measurement with a nanometer spatial resolution using transmission electron microscopy. The experimental probe is the combination of a scanning nanobeam with precession electron diffraction, which offers the collection of kinematic diffraction intensity from a local area at the nanometer scale. With a precalculated, sample- and geometry-specific structure factor–based correction, the linear fitting of diffraction intensities allows the determination of the Debye-Waller factor and, thus, temperature with a precision of 10−4 square angstrom per °C. Using graphene as a model material, this work reveals the influence of sample tilt, lattice thermal expansion, and sample thickness on Debye-Waller factor and offers a route to improving the measurement precision along with spatial resolution. The approach establishes a broadly applicable strategy for nanoscale thermometry in low-dimensional and heterogeneous materials.
{"title":"Nanoscale temperature mapping through thermal vibration characterization using scanning precession electron diffraction","authors":"Kun Yang, Chao Zhang, Chengwei Wu, Qian Du, Bingzhi Li, Zhen Fang, Liang Li, Peng Wang, Wen Shang, Jianbo Wu, Tianru Wu, Hui Wang, Tao Deng, Wenpei Gao","doi":"10.1126/sciadv.aeb9234","DOIUrl":"10.1126/sciadv.aeb9234","url":null,"abstract":"<div >Accurate temperature measurement with a high spatial resolution is essential for understanding thermal behavior in integrated nanoscale devices and especially at heterogeneous interfaces. However, existing techniques are often limited by insufficient spatial resolution. Here, we showcase the direct and noncontact temperature measurement with a nanometer spatial resolution using transmission electron microscopy. The experimental probe is the combination of a scanning nanobeam with precession electron diffraction, which offers the collection of kinematic diffraction intensity from a local area at the nanometer scale. With a precalculated, sample- and geometry-specific structure factor–based correction, the linear fitting of diffraction intensities allows the determination of the Debye-Waller factor and, thus, temperature with a precision of 10<sup>−4</sup> square angstrom per °C. Using graphene as a model material, this work reveals the influence of sample tilt, lattice thermal expansion, and sample thickness on Debye-Waller factor and offers a route to improving the measurement precision along with spatial resolution. The approach establishes a broadly applicable strategy for nanoscale thermometry in low-dimensional and heterogeneous materials.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 7","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176720","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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