Sarah N. Zvornicanin, Ala M. Shaqra, Julia Flynn, Lauren E. Intravaia, Heidi Carias Martinez, Weiping Jia, Devendra Kumar Gupta, Stephanie Moquin, Dustin Dovala, Daniel N. Bolon, Brian A. Kelch, Celia A. Schiffer, Nese Kurt Yilmaz
The coronaviral main protease (Mpro) has been the subject of various biochemical and structural studies and a drug target against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. SARS-CoV-2 Mpro is active as a dimer, but despite apparent cooperativity in catalytic activity, how the two distal active sites communicate and modulate binding and/or catalysis is unclear. Here, we have investigated the interplay between cooperativity, dimerization, and substrate cleavage in SARS-CoV-2 Mpro through a combination of enzymatic assays, crystal structures, and protein characterization. To disentangle the contribution of each active site to the observed enzymatic activity, we developed a cleavage assay involving heterodimers of active and inactive (catalytic residue mutated or inhibitor-bound) monomers. Notably, we found that heterodimerization increased cleavage efficiency per active monomer. In addition, we mapped a network of critical residues bridging the two active sites and probed this network through engineered mutations. By dissecting the cooperativity and communication between the active sites, we provide insights into the Mpro reaction cycle and functional significance of its dimeric architecture.
{"title":"Cooperativity and communication between the active sites of the dimeric SARS-CoV-2 main protease","authors":"Sarah N. Zvornicanin, Ala M. Shaqra, Julia Flynn, Lauren E. Intravaia, Heidi Carias Martinez, Weiping Jia, Devendra Kumar Gupta, Stephanie Moquin, Dustin Dovala, Daniel N. Bolon, Brian A. Kelch, Celia A. Schiffer, Nese Kurt Yilmaz","doi":"10.1126/sciadv.aeb0769","DOIUrl":"10.1126/sciadv.aeb0769","url":null,"abstract":"<div >The coronaviral main protease (M<sup>pro</sup>) has been the subject of various biochemical and structural studies and a drug target against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. SARS-CoV-2 M<sup>pro</sup> is active as a dimer, but despite apparent cooperativity in catalytic activity, how the two distal active sites communicate and modulate binding and/or catalysis is unclear. Here, we have investigated the interplay between cooperativity, dimerization, and substrate cleavage in SARS-CoV-2 M<sup>pro</sup> through a combination of enzymatic assays, crystal structures, and protein characterization. To disentangle the contribution of each active site to the observed enzymatic activity, we developed a cleavage assay involving heterodimers of active and inactive (catalytic residue mutated or inhibitor-bound) monomers. Notably, we found that heterodimerization increased cleavage efficiency per active monomer. In addition, we mapped a network of critical residues bridging the two active sites and probed this network through engineered mutations. By dissecting the cooperativity and communication between the active sites, we provide insights into the M<sup>pro</sup> reaction cycle and functional significance of its dimeric architecture.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984100","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}
Paul Miclea, Vendula Nagy-Marková, Robin Van den Eynde, Wim Vandenberg, Alina Sakhi, Alexey Bondar, Jitka Myšková, Peter Dedecker, Josef Lazar
Genetically encoded fluorescent biosensors convert specific biomolecular events into optically detectable signals. However, imaging biomolecular processes often requires modifying the proteins involved, and many molecular processes are still to be imaged. Here, we present a biosensor design that uses a hitherto overlooked detection principle: directionality of optical properties of fluorescent proteins. The biosensors (termed FLIPs) offer an extremely simple design, high sensitivity, multiplexing capability, ratiometric readout, and other advantages, without requiring modifications to their targets. We demonstrate the sensor performance by real-time imaging activity of G protein–coupled receptors (GPCRs), G proteins, arrestins, and other membrane-associated proteins, as well as by identifying a previously undescribed, pronounced, endocytosis-associated conformational change in a GPCR–β-arrestin complex. In combination with an original tri-scanning linear dichroism confocal microscope, FLIPs allow unparalleled imaging of activity of nonmodified, endogenously expressed G proteins. Thus, FLIPs establish a powerful molecular platform for imaging cell signaling, allowing numerous future developments and insights.
{"title":"FLIPs: Genetically encoded molecular biosensors for functional imaging of cell signaling by linear dichroism microscopy","authors":"Paul Miclea, Vendula Nagy-Marková, Robin Van den Eynde, Wim Vandenberg, Alina Sakhi, Alexey Bondar, Jitka Myšková, Peter Dedecker, Josef Lazar","doi":"10.1126/sciadv.adz5662","DOIUrl":"10.1126/sciadv.adz5662","url":null,"abstract":"<div >Genetically encoded fluorescent biosensors convert specific biomolecular events into optically detectable signals. However, imaging biomolecular processes often requires modifying the proteins involved, and many molecular processes are still to be imaged. Here, we present a biosensor design that uses a hitherto overlooked detection principle: directionality of optical properties of fluorescent proteins. The biosensors (termed FLIPs) offer an extremely simple design, high sensitivity, multiplexing capability, ratiometric readout, and other advantages, without requiring modifications to their targets. We demonstrate the sensor performance by real-time imaging activity of G protein–coupled receptors (GPCRs), G proteins, arrestins, and other membrane-associated proteins, as well as by identifying a previously undescribed, pronounced, endocytosis-associated conformational change in a GPCR–β-arrestin complex. In combination with an original tri-scanning linear dichroism confocal microscope, FLIPs allow unparalleled imaging of activity of nonmodified, endogenously expressed G proteins. Thus, FLIPs establish a powerful molecular platform for imaging cell signaling, allowing numerous future developments and insights.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984105","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}
Soroush Darvish-Ghane, Pankaj Gaur, Graham C. R. Ellis-Davies
We use two-color uncaging of glutamate and γ-aminobutyric acid (GABA) on layer 5 (L5) pyramidal neurons of the cingulate cortex to define how inhibitory control of excitation is determined by dendritic geometry. Traditionally, GABAergic input was considered as the gatekeeper; thus, receptors closest to the soma were ideally placed to veto excitation. However, recently modeling has advanced several counterintuitive hypotheses. Since laser uncaging can be directed at will to any position, we used photostimulation to show that inhibition near the sealed end of dendrites distal to excitation is more effective than inhibition near the soma in modulating excitation. Further, dendritic inhibition was found to be branch specific. Last, we demonstrate that inhibitory input from multiple thin basal dendrites can centripetally elevate to effectively tune distant excitation at the soma. These findings provide direct experimental evidence supporting theoretical predictions based on dendritic cable properties, revealing the critical role of dendritic geometry in shaping the interaction between excitatory and inhibitory neurotransmission.
{"title":"Geometric principles of dendritic integration of excitation and inhibition in cortical neurons","authors":"Soroush Darvish-Ghane, Pankaj Gaur, Graham C. R. Ellis-Davies","doi":"10.1126/sciadv.adx2045","DOIUrl":"10.1126/sciadv.adx2045","url":null,"abstract":"<div >We use two-color uncaging of glutamate and γ-aminobutyric acid (GABA) on layer 5 (L5) pyramidal neurons of the cingulate cortex to define how inhibitory control of excitation is determined by dendritic geometry. Traditionally, GABAergic input was considered as the gatekeeper; thus, receptors closest to the soma were ideally placed to veto excitation. However, recently modeling has advanced several counterintuitive hypotheses. Since laser uncaging can be directed at will to any position, we used photostimulation to show that inhibition near the sealed end of dendrites distal to excitation is more effective than inhibition near the soma in modulating excitation. Further, dendritic inhibition was found to be branch specific. Last, we demonstrate that inhibitory input from multiple thin basal dendrites can centripetally elevate to effectively tune distant excitation at the soma. These findings provide direct experimental evidence supporting theoretical predictions based on dendritic cable properties, revealing the critical role of dendritic geometry in shaping the interaction between excitatory and inhibitory neurotransmission.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984116","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}
Shuaiyu Jin, Feihong Liu, Ilya Razdolski, Tsz Wing Lo, Yaorong Wang, Zhiwei Peng, Kuan Liang, Ye Zhu, Wang Yao, Anatoly V. Zayats, Dangyuan Lei
Manipulation of excitonic emission properties is important for numerous photonic applications. Of particular interest are developing easy-to-implement yet effective approaches for controlling the radiation dynamics and directionality of spin-forbidden dark excitons (XD) in two-dimensional semiconductors. Here, we investigate the spectral, temporal, and directional characteristics of room-temperature XD emission from a tungsten diselenide monolayer coupled to a dissipative plasmonic nanocavity. Under resonant plasmon-exciton coupling, the radiative decay rate of XD is accelerated by nearly four orders of magnitude, and correspondingly, the XD lifetime is shortened to a subnanosecond level, making it comparable to that of bright excitons. Fitting the measured lifetimes with a Purcell-formalism–based cavity quantum electrodynamics model allows estimating of the intrinsic room-temperature XD lifetime to be about 24 ± 2.3 microseconds. Furthermore, the measured radiation patterns of the dark excitons show that subtle variations in the nanocavity orientation can effectively tailor the XD emission directionality, important for quantum technologies and optoelectronics applications.
{"title":"Plasmonic tuning of dark-exciton radiation dynamics and far-field emission directionality in monolayer WSe2","authors":"Shuaiyu Jin, Feihong Liu, Ilya Razdolski, Tsz Wing Lo, Yaorong Wang, Zhiwei Peng, Kuan Liang, Ye Zhu, Wang Yao, Anatoly V. Zayats, Dangyuan Lei","doi":"10.1126/sciadv.aea5781","DOIUrl":"10.1126/sciadv.aea5781","url":null,"abstract":"<div >Manipulation of excitonic emission properties is important for numerous photonic applications. Of particular interest are developing easy-to-implement yet effective approaches for controlling the radiation dynamics and directionality of spin-forbidden dark excitons (X<sub>D</sub>) in two-dimensional semiconductors. Here, we investigate the spectral, temporal, and directional characteristics of room-temperature X<sub>D</sub> emission from a tungsten diselenide monolayer coupled to a dissipative plasmonic nanocavity. Under resonant plasmon-exciton coupling, the radiative decay rate of X<sub>D</sub> is accelerated by nearly four orders of magnitude, and correspondingly, the X<sub>D</sub> lifetime is shortened to a subnanosecond level, making it comparable to that of bright excitons. Fitting the measured lifetimes with a Purcell-formalism–based cavity quantum electrodynamics model allows estimating of the intrinsic room-temperature X<sub>D</sub> lifetime to be about 24 ± 2.3 microseconds. Furthermore, the measured radiation patterns of the dark excitons show that subtle variations in the nanocavity orientation can effectively tailor the X<sub>D</sub> emission directionality, important for quantum technologies and optoelectronics applications.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984119","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}
Aaron Ming Zhi Tan, Cenk Celik, Stella Yue Ting Lee, Mark Veleba, Caroline S. Manzano, Rahim M. K. Abdul, Guillaume Thibault, Kimberly A. Kline
Enterococcus faecalis is an opportunistic pathogen that thrives in biofilm-associated infections and delays wound healing, yet how it impairs host tissue responses is unclear. Here, we identified extracellular electron transport (EET) as a previously unrecognized source of reactive oxygen species (ROS) in E. faecalis and showed that this activity directly triggers the unfolded protein response (UPR) in epithelial cells and delays epithelial cell migration. ROS detoxification with catalase suppressed E. faecalis–induced UPR and rescued epithelial cell migration, while exogenous hydrogen peroxide was sufficient to restore UPR activation in EET-deficient strains. UPR disruption by pharmacological inhibition also impaired cell migration, highlighting a critical role for UPR homeostasis in wound repair. Our findings establish EET as a virulence mechanism that links bacterial redox metabolism to host cell stress and impaired repair, offering previously unidentified avenues for therapeutic intervention in chronic infections.
{"title":"Enterococcus faecalis redox metabolism activates the unfolded protein response to impair wound healing","authors":"Aaron Ming Zhi Tan, Cenk Celik, Stella Yue Ting Lee, Mark Veleba, Caroline S. Manzano, Rahim M. K. Abdul, Guillaume Thibault, Kimberly A. Kline","doi":"10.1126/sciadv.aeb5297","DOIUrl":"10.1126/sciadv.aeb5297","url":null,"abstract":"<div ><i>Enterococcus faecalis</i> is an opportunistic pathogen that thrives in biofilm-associated infections and delays wound healing, yet how it impairs host tissue responses is unclear. Here, we identified extracellular electron transport (EET) as a previously unrecognized source of reactive oxygen species (ROS) in <i>E. faecalis</i> and showed that this activity directly triggers the unfolded protein response (UPR) in epithelial cells and delays epithelial cell migration. ROS detoxification with catalase suppressed <i>E. faecalis</i>–induced UPR and rescued epithelial cell migration, while exogenous hydrogen peroxide was sufficient to restore UPR activation in EET-deficient strains. UPR disruption by pharmacological inhibition also impaired cell migration, highlighting a critical role for UPR homeostasis in wound repair. Our findings establish EET as a virulence mechanism that links bacterial redox metabolism to host cell stress and impaired repair, offering previously unidentified avenues for therapeutic intervention in chronic infections.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984120","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}
Xinkuo Li, Chenduan Chen, Ke Sun, Linhan Li, Zhu Xiao, Zhou Li, Yuanzheng Yue, Jianrong Qiu, Dezhi Tan
Encapsulating perovskite nanocrystals (PNCs) in glass enables enhanced stability of PNCs and numerous applications such as random lasers. However, preparing PNCs and tuning their properties in glass is energy consuming because of high processing temperature and long processing time, and continuous-wave (CW) random lasers have not been achieved. Here, we report modulation of the structure, photoluminescence, and lasing properties of PNCs in glass at temperatures well below the glass transition temperature with a short processing period. We generate tunable PNCs in glass via nanophase separation and ion exchange in the perovskite domains. PNCs-in-glass hierarchical structures are created by controlling nanophase separation and crystallization of PNCs. Substantially increased scattering in the hierarchical structures enables stable CW single-mode random lasing with an ultralow threshold of 52.6 milliwatts per square centimeter. We achieve flexible CW random lasers by incorporating hierarchical structures into the polydimethylsiloxane film. The random lasers are used in speckle-free laser imaging and dynamic holographic displays.
{"title":"Perovskite nanocrystals-in-glass hierarchical structures enable stable continuous-wave random lasers","authors":"Xinkuo Li, Chenduan Chen, Ke Sun, Linhan Li, Zhu Xiao, Zhou Li, Yuanzheng Yue, Jianrong Qiu, Dezhi Tan","doi":"10.1126/sciadv.adz8460","DOIUrl":"10.1126/sciadv.adz8460","url":null,"abstract":"<div >Encapsulating perovskite nanocrystals (PNCs) in glass enables enhanced stability of PNCs and numerous applications such as random lasers. However, preparing PNCs and tuning their properties in glass is energy consuming because of high processing temperature and long processing time, and continuous-wave (CW) random lasers have not been achieved. Here, we report modulation of the structure, photoluminescence, and lasing properties of PNCs in glass at temperatures well below the glass transition temperature with a short processing period. We generate tunable PNCs in glass via nanophase separation and ion exchange in the perovskite domains. PNCs-in-glass hierarchical structures are created by controlling nanophase separation and crystallization of PNCs. Substantially increased scattering in the hierarchical structures enables stable CW single-mode random lasing with an ultralow threshold of 52.6 milliwatts per square centimeter. We achieve flexible CW random lasers by incorporating hierarchical structures into the polydimethylsiloxane film. The random lasers are used in speckle-free laser imaging and dynamic holographic displays.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984115","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}
Estimating the eigenstate properties of quantum systems is a long-standing, challenging problem for both classical and quantum computing. Existing universal quantum algorithms typically rely on ideal and efficient query models (e.g., time evolution operator or block encoding of the Hamiltonian), which, however, become suboptimal for actual implementation at the quantum circuit level. Here, we present a full-stack design of quantum algorithms for estimating the eigenenergy and eigenstate properties, which can achieve high precision and good scaling with system size. The gate complexity per circuit for estimating generic Hamiltonians’ eigenstate properties is , which has a logarithmic dependence on the inverse precision ε. For lattice Hamiltonians, the circuit depth of our design achieves near-optimal system-size scaling, even with local qubit connectivity. Our full-stack algorithm has low overhead in circuit compilation, which thus results in a small actual gate count (cnot and non-Clifford gates) for lattice and molecular problems compared to advanced eigenstate algorithms. The algorithm is implemented on IBM quantum devices using up to 2000 two-qubit gates and 20,000 single-qubit gates and achieves high-precision eigenenergy estimation for Heisenberg-type Hamiltonians, demonstrating its noise robustness.
{"title":"High-precision and low-depth quantum algorithm design for eigenstate problems","authors":"Jinzhao Sun, Pei Zeng, Tom Gur, M. S. Kim","doi":"10.1126/sciadv.aeb1622","DOIUrl":"10.1126/sciadv.aeb1622","url":null,"abstract":"<div >Estimating the eigenstate properties of quantum systems is a long-standing, challenging problem for both classical and quantum computing. Existing universal quantum algorithms typically rely on ideal and efficient query models (e.g., time evolution operator or block encoding of the Hamiltonian), which, however, become suboptimal for actual implementation at the quantum circuit level. Here, we present a full-stack design of quantum algorithms for estimating the eigenenergy and eigenstate properties, which can achieve high precision and good scaling with system size. The gate complexity per circuit for estimating generic Hamiltonians’ eigenstate properties is <span><math><mrow><mover><mi>O</mi><mo>˜</mo></mover><mrow><mo>(</mo><mtext>log</mtext><msup><mi>ε</mi><mrow><mo>−</mo><mn>1</mn></mrow></msup><mo>)</mo></mrow></mrow></math></span>, which has a logarithmic dependence on the inverse precision ε. For lattice Hamiltonians, the circuit depth of our design achieves near-optimal system-size scaling, even with local qubit connectivity. Our full-stack algorithm has low overhead in circuit compilation, which thus results in a small actual gate count (<span>cnot</span> and non-Clifford gates) for lattice and molecular problems compared to advanced eigenstate algorithms. The algorithm is implemented on IBM quantum devices using up to 2000 two-qubit gates and 20,000 single-qubit gates and achieves high-precision eigenenergy estimation for Heisenberg-type Hamiltonians, demonstrating its noise robustness.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984109","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}
Mei Feng, Hong Liu, Lu Zheng, Yang Liu, Hao Zhuang, Hao Xu, Tingting Zhang, Zhen Wu, Xiaolong Qian, Huikai Li, Tengfei Xiao, Yisheng Pan, Shaokun Shu, Ning Zhang
The nongenetic mechanisms by which cancer cells escape cell cycle inhibition remain inadequately understood. Here, we uncover an epigenetic pathway driving adaptive resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in hepatobiliary cancers using integrative approach combining genome-wide CRISPR screenings with transcriptional, epigenetic, and proteomic profiling. Sustained CDK4/6 inhibition triggers BAP1-dependent chromatin remodeling that induces a stem cell–like epigenetic state. Specifically, BAP1 removes ubiquitin modification (H2AK119ub) at the TCF4 promoter, activating WNT and EMT signaling to enhance cellular plasticity and survival under therapy. Notably, genetic and pharmacologic inhibition of BAP1 markedly improves abemaciclib efficacy in multiple mouse models and patient-derived organoids (PDOs). These findings establish BAP1 as a key regulator of tumor plasticity and adaptive resistance through epigenetic reprogramming and suggest a promising strategy for overcoming adaptive therapeutic CDK4/6i resistance by targeting quiescent, drug-resistant cancer cells.
{"title":"Genome-wide screenings identify BAP1 as a synthetic-lethality target with CDK4/6 inhibitors","authors":"Mei Feng, Hong Liu, Lu Zheng, Yang Liu, Hao Zhuang, Hao Xu, Tingting Zhang, Zhen Wu, Xiaolong Qian, Huikai Li, Tengfei Xiao, Yisheng Pan, Shaokun Shu, Ning Zhang","doi":"10.1126/sciadv.aeb4348","DOIUrl":"10.1126/sciadv.aeb4348","url":null,"abstract":"<div >The nongenetic mechanisms by which cancer cells escape cell cycle inhibition remain inadequately understood. Here, we uncover an epigenetic pathway driving adaptive resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in hepatobiliary cancers using integrative approach combining genome-wide CRISPR screenings with transcriptional, epigenetic, and proteomic profiling. Sustained CDK4/6 inhibition triggers BAP1-dependent chromatin remodeling that induces a stem cell–like epigenetic state. Specifically, BAP1 removes ubiquitin modification (H2AK119ub) at the <i>TCF4</i> promoter, activating WNT and EMT signaling to enhance cellular plasticity and survival under therapy. Notably, genetic and pharmacologic inhibition of BAP1 markedly improves abemaciclib efficacy in multiple mouse models and patient-derived organoids (PDOs). These findings establish BAP1 as a key regulator of tumor plasticity and adaptive resistance through epigenetic reprogramming and suggest a promising strategy for overcoming adaptive therapeutic CDK4/6i resistance by targeting quiescent, drug-resistant cancer cells.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984112","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}
Anode-free lithium metal batteries (AFLMBs) demonstrate promising high energy density yet suffer from irregular Li deposition, parasitic reactions, and severe volume expansion. The current anode modulation strategies such as tailored solid electrolyte interphase (SEI) and lithiophilic host architectures can hardly simultaneously resolve all above issues, especially at high-capacity Li deposition. Here, we design a Li-rich, hollow ionic-electronic conductor (HIEC) interlayer, which integrates metallic Li encapsulation and interfacial protection, thus guiding highly reversible thick Li deposition (5 milliampere-hours per square centimeter). In addition, the built-in electron-deficient domains in the HIEC facilitate the formation of the hierarchical SEI and further mitigate active Li corrosion. These synergistic effects of the interlayer enable stable cycling in batteries under both anode-less and anode-free configurations, attaining >99% coulombic efficiency under industrial-level cathode loading and lean electrolyte conditions. This study highlights the significance of interlayers in integrating the SEI and host functions and provides a viable and scalable solution for energy-dense batteries.
{"title":"Manipulating metal growth in hollow ionic-electronic conductor for anode-free lithium metal batteries","authors":"Lianqiang Peng, Xiaotian Wang, Xu Liu, Zihang Xi, Yawen Li, Jie Zhang, Yujie Ning, Qing Zhao","doi":"10.1126/sciadv.adt2630","DOIUrl":"10.1126/sciadv.adt2630","url":null,"abstract":"<div >Anode-free lithium metal batteries (AFLMBs) demonstrate promising high energy density yet suffer from irregular Li deposition, parasitic reactions, and severe volume expansion. The current anode modulation strategies such as tailored solid electrolyte interphase (SEI) and lithiophilic host architectures can hardly simultaneously resolve all above issues, especially at high-capacity Li deposition. Here, we design a Li-rich, hollow ionic-electronic conductor (HIEC) interlayer, which integrates metallic Li encapsulation and interfacial protection, thus guiding highly reversible thick Li deposition (5 milliampere-hours per square centimeter). In addition, the built-in electron-deficient domains in the HIEC facilitate the formation of the hierarchical SEI and further mitigate active Li corrosion. These synergistic effects of the interlayer enable stable cycling in batteries under both anode-less and anode-free configurations, attaining >99% coulombic efficiency under industrial-level cathode loading and lean electrolyte conditions. This study highlights the significance of interlayers in integrating the SEI and host functions and provides a viable and scalable solution for energy-dense batteries.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984118","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}
Xianghan Sun, Liqiao Tian, Hongwei Fang, Desmond E. Walling, Jaia Syvitski, Lei Huang, Deren Li, Chunmiao Zheng, Lian Feng
Carbon release from high-latitude regions is intensifying, with profound consequences for the Arctic carbon cycle. Here, we provide a comprehensive analysis of changes in fluvial particulate organic carbon (POC) concentrations (CPOC) and fluxes (FPOC) during ice-free seasons of pan-Arctic rivers from 1985 to 2022 on the basis of satellite observations. Across 578,000 kilometers of river length, 18% of the total length experienced a significant increase in CPOC, which exceeds the 11% that exhibited declines, resulting in a net rise. Most increases occurred after 2005, contributing to a 12.6% (0.49 teragrams per year) increase in total FPOC to the Arctic Ocean between 1985 to 2005 and 2006 to 2022. Regional contrasts highlight distinct possible drivers: increased precipitation in the North American Arctic and atmospheric warming in the Eurasian Arctic. Deepening of the permafrost active layer is also significantly correlated with CPOC increases. These findings highlight climate-driven fluvial POC export as a key contributor to the Arctic carbon budget and provide a high-resolution, satellite-based dataset that can inform carbon cycle models and data assimilation efforts.
{"title":"Mapping pan-Arctic riverine particulate organic carbon from space (1985 to 2022)","authors":"Xianghan Sun, Liqiao Tian, Hongwei Fang, Desmond E. Walling, Jaia Syvitski, Lei Huang, Deren Li, Chunmiao Zheng, Lian Feng","doi":"10.1126/sciadv.ady6314","DOIUrl":"10.1126/sciadv.ady6314","url":null,"abstract":"<div >Carbon release from high-latitude regions is intensifying, with profound consequences for the Arctic carbon cycle. Here, we provide a comprehensive analysis of changes in fluvial particulate organic carbon (POC) concentrations (<i>C</i><sub>POC</sub>) and fluxes (<i>F</i><sub>POC</sub>) during ice-free seasons of pan-Arctic rivers from 1985 to 2022 on the basis of satellite observations. Across 578,000 kilometers of river length, 18% of the total length experienced a significant increase in <i>C</i><sub>POC</sub>, which exceeds the 11% that exhibited declines, resulting in a net rise. Most increases occurred after 2005, contributing to a 12.6% (0.49 teragrams per year) increase in total <i>F</i><sub>POC</sub> to the Arctic Ocean between 1985 to 2005 and 2006 to 2022. Regional contrasts highlight distinct possible drivers: increased precipitation in the North American Arctic and atmospheric warming in the Eurasian Arctic. Deepening of the permafrost active layer is also significantly correlated with <i>C</i><sub>POC</sub> increases. These findings highlight climate-driven fluvial POC export as a key contributor to the Arctic carbon budget and provide a high-resolution, satellite-based dataset that can inform carbon cycle models and data assimilation efforts.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 3","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984106","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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