Yangyang Feng, Lei Jiao, Xu Zhuang, Yaobing Wang, Jiannian Yao
Ammonia plays a pivotal role in agriculture and meanwhile holds promising potential as an energy vector for the hydrogen economy, where the nitrogen reduction to ammonia is a critical pathway for achieving sustainable development. Over the past hundred years, ammonia synthesis has undergone several breakthrough developments from Haber-Bosch process to photo/electro-catalysis and Li-mediated strategy, but still faces the challenges of low yield rate, selectivity and efficiency. Therefore, there is a pressing demand to develop efficient and green ammonia synthesis from nitrogen. This review summarizes the development of the nitrogen reduction to ammonia, highlighting six milestones during the whole journey. From the development direction, this work finds and extracts the essence of ammonia synthesis, that is the reaction pathways are affected by the energy barrier of reaction intermediates, which can be altered by proton sources, auxiliaries and catalysts. Then this work discusses the detailed overview of the significant development of proton source, auxiliaries and catalysts. Finally, based on the essence, the possible opportunities of ammonia synthesis from nitrogen reduction are presented, including the design of new ammonia synthesis pathways and efficient catalysts. The deep insight of nitrogen reduction to ammonia will provide a design guidance for efficient ammonia synthesis.
{"title":"The Development, Essence and Perspective of Nitrogen Reduction to Ammonia","authors":"Yangyang Feng, Lei Jiao, Xu Zhuang, Yaobing Wang, Jiannian Yao","doi":"10.1002/adma.202410909","DOIUrl":"https://doi.org/10.1002/adma.202410909","url":null,"abstract":"Ammonia plays a pivotal role in agriculture and meanwhile holds promising potential as an energy vector for the hydrogen economy, where the nitrogen reduction to ammonia is a critical pathway for achieving sustainable development. Over the past hundred years, ammonia synthesis has undergone several breakthrough developments from Haber-Bosch process to photo/electro-catalysis and Li-mediated strategy, but still faces the challenges of low yield rate, selectivity and efficiency. Therefore, there is a pressing demand to develop efficient and green ammonia synthesis from nitrogen. This review summarizes the development of the nitrogen reduction to ammonia, highlighting six milestones during the whole journey. From the development direction, this work finds and extracts the essence of ammonia synthesis, that is the reaction pathways are affected by the energy barrier of reaction intermediates, which can be altered by proton sources, auxiliaries and catalysts. Then this work discusses the detailed overview of the significant development of proton source, auxiliaries and catalysts. Finally, based on the essence, the possible opportunities of ammonia synthesis from nitrogen reduction are presented, including the design of new ammonia synthesis pathways and efficient catalysts. The deep insight of nitrogen reduction to ammonia will provide a design guidance for efficient ammonia synthesis.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"63 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.
PD-1/PD-L1阻断疗法对黑色素瘤、肾癌、膀胱癌和肺癌显示出非凡的临床疗效；然而，只有少数结直肠癌（CRC）患者能从这些疗法中获益。由于肿瘤微环境的复杂性，PD-1/PD-L1 阻断疗法对 CRC 的疗效受到了限制。PD-1/PD-L1 阻断免疫疗法是基于以 T 细胞为中心的肿瘤免疫观点。然而，T 细胞应答的发生和维持以及长效记忆 T 细胞的形成都依赖于先天性免疫应答。鉴于先天性免疫在抗肿瘤免疫反应中的关键作用，本综述总结了在激活先天性免疫的同时使用 PD-1/PD-L1 阻断的联合疗法，并探讨了其潜在的细胞机制，旨在利用先天性免疫反应为接受 PD-1/PD-L1 阻断疗法的 CRC 患者诱导持久的肿瘤控制。
{"title":"Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer","authors":"Qi Xie, Xiaolin Liu, Rengyun Liu, Jingxuan Pan, Jing Liang","doi":"10.1186/s12943-024-02166-w","DOIUrl":"https://doi.org/10.1186/s12943-024-02166-w","url":null,"abstract":"PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1007/s00134-024-07713-z
Martin Balik, G. Tavazzi, M. Slama
{"title":"Beta-blockers as antiarrhythmics in septic shock: a light at the end of the tunnel?","authors":"Martin Balik, G. Tavazzi, M. Slama","doi":"10.1007/s00134-024-07713-z","DOIUrl":"https://doi.org/10.1007/s00134-024-07713-z","url":null,"abstract":"","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"164 1","pages":""},"PeriodicalIF":38.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiangjiao Gong, Wenkai Teng, Wei Liu, Hang Xiao, He Li, Honghui Ou, Guidong Yang
Designing a reaction system that integrates reactant capture and transformation in an artificial photosynthesis system to achieve high reaction efficiency remains challenging. Here, an ionic liquid (IL) -polyoxometalate (POM) superstructure photocatalyst (P2HPMo) is reported, where the anisotropy of the superstructure is allowed by adjusting the alkyl chain lengths of ILs. Experimental data and theoretical simulation show that ILs and POM serve as the “sucker” and “reactor” of the reaction system to capture and transform the reactants, respectively. In particular, the addition of quaternary phosphorous IL cations is not only conducive to the adsorption of N2 but also effectively promotes the activation of N2 by manipulating the energy band and electronic structure. Consequently, the synthesized P2HPMo exhibits an ammonia synthesis rate of 98 µmol·gcat−1·h−1, which is one of the highest values available in a sacrificial agent-free system.
{"title":"A Sucker-Reactor Polyoxometalate Assembled Superstructures for Efficient Photocatalytic Nitrogen Fixation","authors":"Xiangjiao Gong, Wenkai Teng, Wei Liu, Hang Xiao, He Li, Honghui Ou, Guidong Yang","doi":"10.1002/adma.202412924","DOIUrl":"https://doi.org/10.1002/adma.202412924","url":null,"abstract":"Designing a reaction system that integrates reactant capture and transformation in an artificial photosynthesis system to achieve high reaction efficiency remains challenging. Here, an ionic liquid (IL) -polyoxometalate (POM) superstructure photocatalyst (P2HPMo) is reported, where the anisotropy of the superstructure is allowed by adjusting the alkyl chain lengths of ILs. Experimental data and theoretical simulation show that ILs and POM serve as the “sucker” and “reactor” of the reaction system to capture and transform the reactants, respectively. In particular, the addition of quaternary phosphorous IL cations is not only conducive to the adsorption of N<sub>2</sub> but also effectively promotes the activation of N<sub>2</sub> by manipulating the energy band and electronic structure. Consequently, the synthesized P2HPMo exhibits an ammonia synthesis rate of 98 µmol·g<sub>cat</sub><sup>−1</sup>·h<sup>−1</sup>, which is one of the highest values available in a sacrificial agent-free system.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"15 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Justus T. Metternich, Sujit K. Patjoshi, Tanuja Kistwal, Sebastian Kruss
Optical sensors are powerful tools to identify and image (biological) molecules. Because of their optoelectronic properties, nanomaterials are often used as building blocks. To transduce the chemical interaction with the analyte into an optical signal, the interplay between surface chemistry and nanomaterial photophysics has to be optimized. Understanding these aspects promises major opportunities for tailored sensors with optimal performance. However, this requires methods to create and explore the many chemical permutations. Indeed, many current approaches are limited in throughput. This affects the chemical design space that can be studied, the application of machine learning approaches as well as fundamental mechanistic understanding. Here, an overview of selection-limited and synthesis-limited approaches is provided to create and identify molecular nanosensors. Bottlenecks are discussed and opportunities of non-classical recognition strategies are highlighted such as corona phase molecular recognition as well as the requirements for high throughput and scalability. Fluorescent carbon nanotubes are powerful building blocks for sensors and their huge chemical design space makes them an ideal platform for high throughput approaches. Therefore, they are the focus of this article, but the insights are transferable to any nanosensor system. Overall, this perspective aims to provide a fresh perspective to overcome current challenges in the nanosensor field.
{"title":"High-Throughput Approaches to Engineer Fluorescent Nanosensors","authors":"Justus T. Metternich, Sujit K. Patjoshi, Tanuja Kistwal, Sebastian Kruss","doi":"10.1002/adma.202411067","DOIUrl":"https://doi.org/10.1002/adma.202411067","url":null,"abstract":"Optical sensors are powerful tools to identify and image (biological) molecules. Because of their optoelectronic properties, nanomaterials are often used as building blocks. To transduce the chemical interaction with the analyte into an optical signal, the interplay between surface chemistry and nanomaterial photophysics has to be optimized. Understanding these aspects promises major opportunities for tailored sensors with optimal performance. However, this requires methods to create and explore the many chemical permutations. Indeed, many current approaches are limited in throughput. This affects the chemical design space that can be studied, the application of machine learning approaches as well as fundamental mechanistic understanding. Here, an overview of selection-limited and synthesis-limited approaches is provided to create and identify molecular nanosensors. Bottlenecks are discussed and opportunities of non-classical recognition strategies are highlighted such as corona phase molecular recognition as well as the requirements for high throughput and scalability. Fluorescent carbon nanotubes are powerful building blocks for sensors and their huge chemical design space makes them an ideal platform for high throughput approaches. Therefore, they are the focus of this article, but the insights are transferable to any nanosensor system. Overall, this perspective aims to provide a fresh perspective to overcome current challenges in the nanosensor field.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"196 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sankalpa Hazra, Tobias Schwaigert, Aiden Ross, Haidong Lu, Utkarsh Saha, Victor Trinquet, Betul Akkopru-Akgun, Benjamin Z. Gregory, Anudeep Mangu, Suchismita Sarker, Tatiana Kuznetsova, Saugata Sarker, Xin Li, Matthew R. Barone, Xiaoshan Xu, John W. Freeland, Roman Engel-Herbert, Aaron M. Lindenberg, Andrej Singer, Susan Trolier-McKinstry, David A. Muller, Gian-Marco Rignanese, Salva Salmani-Rezaie, Vladimir A. Stoica, Alexei Gruverman, Long-Qing Chen, Darrell G. Schlom, Venkatraman Gopalan
Strong coupling between polarization (P) and strain (ɛ) in ferroelectric complex oxides offers unique opportunities to dramatically tune their properties. Here colossal strain tuning of ferroelectricity in epitaxial KNbO3 thin films grown by sub-oxide molecular beam epitaxy is demonstrated. While bulk KNbO3 exhibits three ferroelectric transitions and a Curie temperature (Tc) of ≈676 K, phase-field modeling predicts that a biaxial strain of as little as −0.6% pushes its Tc > 975 K, its decomposition temperature in air, and for −1.4% strain, to Tc > 1325 K, its melting point. Furthermore, a strain of −1.5% can stabilize a single phase throughout the entire temperature range of its stability. A combination of temperature-dependent second harmonic generation measurements, synchrotron-based X-ray reciprocal space mapping, ferroelectric measurements, and transmission electron microscopy reveal a single tetragonal phase from 10 K to 975 K, an enhancement of ≈46% in the tetragonal phase remanent polarization (Pr), and a ≈200% enhancement in its optical second harmonic generation coefficients over bulk values. These properties in a lead-free system, but with properties comparable or superior to lead-based systems, make it an attractive candidate for applications ranging from high-temperature ferroelectric memory to cryogenic temperature quantum computing.
铁电复合氧化物中极化（P）和应变（ɛ）之间的强耦合为显著调整其特性提供了独特的机会。这里展示了通过亚氧化物分子束外延生长的 KNbO3 外延薄膜铁电性的巨大应变调整。虽然块状 KNbO3 表现出三个铁电转换和居里温度（Tc）≈676 K，但根据相场建模预测，低至 -0.6% 的双轴应变可将其 Tc > 975 K（其在空气中的分解温度）推高到 Tc > 1325 K（其熔点）。此外，-1.5% 的应变可使单相在整个温度范围内保持稳定。与温度相关的二次谐波发生测量、同步辐射 X 射线倒易空间映射、铁电测量和透射电子显微镜相结合，揭示了从 10 K 到 975 K 的单一四方相，四方相的重正极化（Pr）增强了≈46%，其光学二次谐波发生系数比块体值增强了≈200%。在无铅系统中具有这些特性，但其性能却与铅基系统相当或更优，这使它成为从高温铁电存储器到低温量子计算等各种应用的理想候选材料。
{"title":"Colossal Strain Tuning of Ferroelectric Transitions in KNbO3 Thin Films","authors":"Sankalpa Hazra, Tobias Schwaigert, Aiden Ross, Haidong Lu, Utkarsh Saha, Victor Trinquet, Betul Akkopru-Akgun, Benjamin Z. Gregory, Anudeep Mangu, Suchismita Sarker, Tatiana Kuznetsova, Saugata Sarker, Xin Li, Matthew R. Barone, Xiaoshan Xu, John W. Freeland, Roman Engel-Herbert, Aaron M. Lindenberg, Andrej Singer, Susan Trolier-McKinstry, David A. Muller, Gian-Marco Rignanese, Salva Salmani-Rezaie, Vladimir A. Stoica, Alexei Gruverman, Long-Qing Chen, Darrell G. Schlom, Venkatraman Gopalan","doi":"10.1002/adma.202408664","DOIUrl":"https://doi.org/10.1002/adma.202408664","url":null,"abstract":"Strong coupling between polarization (<i>P</i>) and strain (ɛ) in ferroelectric complex oxides offers unique opportunities to dramatically tune their properties. Here colossal strain tuning of ferroelectricity in epitaxial KNbO<sub>3</sub> thin films grown by sub-oxide molecular beam epitaxy is demonstrated. While bulk KNbO<sub>3</sub> exhibits three ferroelectric transitions and a Curie temperature (<i>T<sub>c</sub></i>) of ≈676 K, phase-field modeling predicts that a biaxial strain of as little as −0.6% pushes its <i>T<sub>c</sub></i> > 975 K, its decomposition temperature in air, and for −1.4% strain, to <i>T<sub>c</sub></i> > 1325 K, its melting point. Furthermore, a strain of −1.5% can stabilize a single phase throughout the entire temperature range of its stability. A combination of temperature-dependent second harmonic generation measurements, synchrotron-based X-ray reciprocal space mapping, ferroelectric measurements, and transmission electron microscopy reveal a single tetragonal phase from 10 K to 975 K, an enhancement of ≈46% in the tetragonal phase remanent polarization (<i>P<sub>r</sub></i>), and a ≈200% enhancement in its optical second harmonic generation coefficients over bulk values. These properties in a lead-free system, but with properties comparable or superior to lead-based systems, make it an attractive candidate for applications ranging from high-temperature ferroelectric memory to cryogenic temperature quantum computing.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"8 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elliot Thouvenot, Laura Charnay, Noa Burshtein, Jean-Michel Guigner, Léonie Dec, Damarys Loew, Amanda K.A. Silva, Anke Lindner, Claire Wilhelm
Extracellular vesicles (EVs) are emerging as novel therapeutics, particularly in cancer and degenerative diseases. Nevertheless, from both market and clinical viewpoints, high-yield production methods using minimal cell materials are still needed. Herein, a millifluidic cross-slot chip is proposed to induce high-yield release of biologically active EVs from less than three million cells. Depending on the flow rate, a single vortex forms in the outlet channels, exposing transported cellular material to high viscous stresses. Importantly, the chip accommodates producer cells within their physiological environment, such as human mesenchymal stem cells (hMSCs) spheroids, while facilitating their visualization and individual tracking within the vortex. This precise control of viscous stresses at the spheroid level allows for the release of up to 30000 EVs per cell at a Reynolds number of ≈400, without compromising cellular integrity. Additionally, it reveals a threshold initiating EV production, providing evidence for a stress-dependent mechanism governing vesicle secretion. EVs mass-produced at high Reynolds displayed pro-angiogenic and wound healing capabilities, as confirmed by proteomic and cytometric analysis of their cargo. These distinct molecular signatures of these EVs, compared to those derived from monolayers, underscore the critical roles of the production method and the 3D cellular environment in EV generation.
{"title":"High-Yield Bioproduction of Extracellular Vesicles from Stem Cell Spheroids via Millifluidic Vortex Transport","authors":"Elliot Thouvenot, Laura Charnay, Noa Burshtein, Jean-Michel Guigner, Léonie Dec, Damarys Loew, Amanda K.A. Silva, Anke Lindner, Claire Wilhelm","doi":"10.1002/adma.202412498","DOIUrl":"https://doi.org/10.1002/adma.202412498","url":null,"abstract":"Extracellular vesicles (EVs) are emerging as novel therapeutics, particularly in cancer and degenerative diseases. Nevertheless, from both market and clinical viewpoints, high-yield production methods using minimal cell materials are still needed. Herein, a millifluidic cross-slot chip is proposed to induce high-yield release of biologically active EVs from less than three million cells. Depending on the flow rate, a single vortex forms in the outlet channels, exposing transported cellular material to high viscous stresses. Importantly, the chip accommodates producer cells within their physiological environment, such as human mesenchymal stem cells (hMSCs) spheroids, while facilitating their visualization and individual tracking within the vortex. This precise control of viscous stresses at the spheroid level allows for the release of up to 30000 EVs per cell at a Reynolds number of ≈400, without compromising cellular integrity. Additionally, it reveals a threshold initiating EV production, providing evidence for a stress-dependent mechanism governing vesicle secretion. EVs mass-produced at high Reynolds displayed pro-angiogenic and wound healing capabilities, as confirmed by proteomic and cytometric analysis of their cargo. These distinct molecular signatures of these EVs, compared to those derived from monolayers, underscore the critical roles of the production method and the 3D cellular environment in EV generation.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"2 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1186/s12943-024-02157-x
W. J. McDaid, L. Wilson, H. Adderley, A. Martinez-Lopez, M. J. Baker, J. Searle, L. Ginn, T. Budden, M. Aldea, A. Marinello, J. V. Aredo, A. Viros, B. Besse, H. A. Wakelee, F. Blackhall, S. Castillo-Lluva, C. R. Lindsay, A. Malliri
KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC. KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.
{"title":"The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer","authors":"W. J. McDaid, L. Wilson, H. Adderley, A. Martinez-Lopez, M. J. Baker, J. Searle, L. Ginn, T. Budden, M. Aldea, A. Marinello, J. V. Aredo, A. Viros, B. Besse, H. A. Wakelee, F. Blackhall, S. Castillo-Lluva, C. R. Lindsay, A. Malliri","doi":"10.1186/s12943-024-02157-x","DOIUrl":"https://doi.org/10.1186/s12943-024-02157-x","url":null,"abstract":"KRASG12C and KRASG12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms. We contrasted tumor development between KrasG12C and KrasG12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of KrasG12C and KrasG12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRASG12C or KRASG12D-mutant NSCLC. KRASG12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12D GEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12C oncogenicity and downstream pathway activation were comparable with KRASG12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12C models on the MAPK pathway. Specifically, KRASG12D inhibition was enhanced by AKT inhibition in vitro and in vivo. Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"10 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Highly sensitive shortwave infrared (SWIR) detectors are essential for detecting weak radiation (typically below 10−8 W·Sr−1·cm−2·µm−1) with high-end passive image sensors. However, mainstream SWIR detection based on epitaxial photodiodes cannot effectively detect ultraweak infrared radiation due to the lack of inherent gain. Here, we develop a heterojunction-gated field-effect transistor (HGFET) consisting of a colloidal quantum dot (CQD)-based p-i-n heterojunction and a carbon nanotube (CNT) field-effect transistor, which achieves a high inherent gain based on an opto-electric decoupling mechanism for suppressing noise. The stacked heterojunction absorbs infrared radiation and separates electron–hole pairs. Then, the generated photovoltage tunes the drain current of the CNT FET through an Y2O3 gate insulator. As a result, the HGFET significantly detects and amplifies SWIR signals with a high inherent gain while minimally amplifying noise, leading to a recorded specific detectivity above 1014 Jones at 1300 nm and a recorded maximum gain-bandwidth product of 69.2 THz. Direct comparative testing indicates that the HGFET can detect weak infrared radiation at 0.46 nW cm−2 levels; thus, compared to commercial and reported SWIR detectors, this detector is much more sensitive and enables starlight detection or vision. As the fabrication process is very compatible with CMOS readout integrated circuits, the HGFET is a promising SWIR detector for realizing passive night vision imaging sensors with high resolutions that are high-end, highly sensitive, and inexpensive.
{"title":"Opto-Electrical Decoupled Phototransistor for Starlight Detection","authors":"Shaoyuan Zhou, Xinyue Zhang, Ying Wang, Dongyi Lin, Shoubin Zou, Jingwen Wang, Luna Xiao, Dijie Zhang, Jianhua Jiang, Panpan Zhang, Jianbing Zhang, Jiang Tang, Zhiyong Zhang","doi":"10.1002/adma.202413247","DOIUrl":"https://doi.org/10.1002/adma.202413247","url":null,"abstract":"Highly sensitive shortwave infrared (SWIR) detectors are essential for detecting weak radiation (typically below 10<sup>−8</sup> W·Sr<sup>−1</sup>·cm<sup>−2</sup>·µm<sup>−1</sup>) with high-end passive image sensors. However, mainstream SWIR detection based on epitaxial photodiodes cannot effectively detect ultraweak infrared radiation due to the lack of inherent gain. Here, we develop a heterojunction-gated field-effect transistor (HGFET) consisting of a colloidal quantum dot (CQD)-based p-i-n heterojunction and a carbon nanotube (CNT) field-effect transistor, which achieves a high inherent gain based on an opto-electric decoupling mechanism for suppressing noise. The stacked heterojunction absorbs infrared radiation and separates electron–hole pairs. Then, the generated photovoltage tunes the drain current of the CNT FET through an Y<sub>2</sub>O<sub>3</sub> gate insulator. As a result, the HGFET significantly detects and amplifies SWIR signals with a high inherent gain while minimally amplifying noise, leading to a recorded specific detectivity above 10<sup>14</sup> Jones at 1300 nm and a recorded maximum gain-bandwidth product of 69.2 THz. Direct comparative testing indicates that the HGFET can detect weak infrared radiation at 0.46 nW cm<sup>−2</sup> levels; thus, compared to commercial and reported SWIR detectors, this detector is much more sensitive and enables starlight detection or vision. As the fabrication process is very compatible with CMOS readout integrated circuits, the HGFET is a promising SWIR detector for realizing passive night vision imaging sensors with high resolutions that are high-end, highly sensitive, and inexpensive.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"11 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Idiopathic pulmonary fibrosis (IPF) is exacerbated by injurious mechanical forces that destabilize the pulmonary mechanical microenvironment homeostasis, leading to alveolar dysfunction and exacerbating disease severity. However, given the inherent mechanosensitivity of fibrotic lungs, where type II alveolar epithelial cells (AEC IIs) are subjected to persistent stretching and overactivated myofibroblasts experience malignant interactions during mechanotransduction, it becomes imperative to develop effective strategies to modulate the pulmonary mechanical microenvironment. Herein, cyclo (RGDfC) peptide-decorated zeolitic imidazolate framework-8 nanoparticles (named ZDFPR NPs) are constructed to target and repair the aberrant mechanical force levels in pathological lungs. Specifically, reduces mechanical tension in AEC IIs by pH-responsive ZDFPR NPs that release zinc ions and 7, 8-dihydroxyflavone to promote alveolar repair and differentiation. Meanwhile, malignant interactions between myofibroblast contractility and extracellular matrix stiffness during mechanotransduction are disrupted by the fasudil inhibition ROCK signaling pathway. The results show that ZDFPR NPs successfully restored pulmonary mechanical homeostasis and terminated the fibrosis process in bleomycin-induced fibrotic mice. This study not only presents a promising strategy for modulating pulmonary mechanical microenvironment but also pioneers a novel avenue for IPF treatment.
特发性肺纤维化（IPF）会因损伤性机械力而恶化，这些机械力会破坏肺部机械微环境的平衡，导致肺泡功能障碍并加重疾病的严重程度。然而，鉴于纤维化肺固有的机械敏感性，其中 II 型肺泡上皮细胞（AEC II）受到持续的拉伸，过度激活的肌成纤维细胞在机械传导过程中经历恶性相互作用，因此开发有效的策略来调节肺机械微环境变得势在必行。在此，研究人员构建了环(RGDfC)肽装饰的沸石咪唑酸框架-8纳米粒子（命名为ZDFPR NPs），以靶向修复病变肺部异常的机械力水平。具体而言，通过 pH 响应型 ZDFPR NPs 释放锌离子和 7，8-二羟基黄酮，降低 AEC II 的机械张力，促进肺泡修复和分化。同时，在机械传导过程中，肌成纤维细胞收缩性与细胞外基质硬度之间的恶性相互作用会被法舒地尔抑制ROCK信号通路所破坏。结果表明，ZDFPR NPs成功恢复了博莱霉素诱导的纤维化小鼠的肺机械稳态，并终止了其纤维化进程。这项研究不仅为调节肺机械微环境提供了一种前景广阔的策略，还为治疗 IPF 开辟了一条新途径。
{"title":"Modulating Fibrotic Mechanical Microenvironment for Idiopathic Pulmonary Fibrosis Therapy","authors":"Xue-Na Li, Ya-Ping Lin, Meng-Meng Han, Yue-Fei Fang, Lei Xing, Jee-Heon Jeong, Hu-Lin Jiang","doi":"10.1002/adma.202407661","DOIUrl":"https://doi.org/10.1002/adma.202407661","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is exacerbated by injurious mechanical forces that destabilize the pulmonary mechanical microenvironment homeostasis, leading to alveolar dysfunction and exacerbating disease severity. However, given the inherent mechanosensitivity of fibrotic lungs, where type II alveolar epithelial cells (AEC IIs) are subjected to persistent stretching and overactivated myofibroblasts experience malignant interactions during mechanotransduction, it becomes imperative to develop effective strategies to modulate the pulmonary mechanical microenvironment. Herein, cyclo (RGDfC) peptide-decorated zeolitic imidazolate framework-8 nanoparticles (named ZDFPR NPs) are constructed to target and repair the aberrant mechanical force levels in pathological lungs. Specifically, reduces mechanical tension in AEC IIs by pH-responsive ZDFPR NPs that release zinc ions and 7, 8-dihydroxyflavone to promote alveolar repair and differentiation. Meanwhile, malignant interactions between myofibroblast contractility and extracellular matrix stiffness during mechanotransduction are disrupted by the fasudil inhibition ROCK signaling pathway. The results show that ZDFPR NPs successfully restored pulmonary mechanical homeostasis and terminated the fibrosis process in bleomycin-induced fibrotic mice. This study not only presents a promising strategy for modulating pulmonary mechanical microenvironment but also pioneers a novel avenue for IPF treatment.","PeriodicalId":27,"journal":{"name":"Analytical Chemistry","volume":"29 1","pages":""},"PeriodicalIF":29.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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