Yaniv Kurman, Neta Lahav, Roman Schuetz, Avner Shultzman, Charles Roques-Carmes, Alon Lifshits, Segev Zaken, Tom Lenkiewicz, Rotem Strassberg, Orr Be’er, Yehonadav Bekenstein, Ido Kaminer
Scintillation materials convert high-energy radiation to optical light through a complex multistage process. The last stage of the process is spontaneous light emission, which usually governs and limits the scintillator emission rate and light yield. For decades, scintillator research focused on developing faster-emitting materials or external photonic coatings for improving light yields. Here, we experimentally demonstrate a fundamentally different approach: enhancing the scintillation rate and yield via the Purcell effect, utilizing optical environment engineering to boost spontaneous emission. This enhancement is universally applicable to any scintillating material and dopant when the material’s nanoscale geometry is engineered. We design a thin multilayer nanophotonic scintillator, demonstrating Purcell-enhanced scintillation with 50% enhancement in emission rate and 80% enhancement in light yield. The emission is robust to fabrication disorder, further highlighting its potential for x-ray applications. Our results show prospects for bridging nanophotonics and scintillator science toward reduced radiation dosage and increased resolution for high-energy particle detection.
闪烁材料通过一个复杂的多级过程将高能辐射转化为光学光。该过程的最后一个阶段是自发光发射，它通常控制并限制着闪烁体的发射率和光产率。几十年来，闪烁体研究的重点是开发更快的发射材料或外部光子涂层，以提高光产率。在这里，我们通过实验证明了一种根本不同的方法：通过珀塞尔效应提高闪烁率和光产率，利用光环境工程提高自发辐射。当对材料的纳米级几何结构进行设计时，这种增强效果普遍适用于任何闪烁材料和掺杂剂。我们设计了一种薄型多层纳米光子闪烁体，展示了珀塞尔增强闪烁，发射率提高了 50%，光产率提高了 80%。这种发射对制造失序很稳定，进一步凸显了它在 X 射线应用方面的潜力。我们的研究结果表明，纳米光子学和闪烁体科学之间有望架起一座桥梁，从而降低辐射剂量，提高高能粒子探测的分辨率。
{"title":"Purcell-enhanced x-ray scintillation","authors":"Yaniv Kurman, Neta Lahav, Roman Schuetz, Avner Shultzman, Charles Roques-Carmes, Alon Lifshits, Segev Zaken, Tom Lenkiewicz, Rotem Strassberg, Orr Be’er, Yehonadav Bekenstein, Ido Kaminer","doi":"10.1126/sciadv.adq6325","DOIUrl":"10.1126/sciadv.adq6325","url":null,"abstract":"<div >Scintillation materials convert high-energy radiation to optical light through a complex multistage process. The last stage of the process is spontaneous light emission, which usually governs and limits the scintillator emission rate and light yield. For decades, scintillator research focused on developing faster-emitting materials or external photonic coatings for improving light yields. Here, we experimentally demonstrate a fundamentally different approach: enhancing the scintillation rate and yield via the Purcell effect, utilizing optical environment engineering to boost spontaneous emission. This enhancement is universally applicable to any scintillating material and dopant when the material’s nanoscale geometry is engineered. We design a thin multilayer nanophotonic scintillator, demonstrating Purcell-enhanced scintillation with 50% enhancement in emission rate and 80% enhancement in light yield. The emission is robust to fabrication disorder, further highlighting its potential for x-ray applications. Our results show prospects for bridging nanophotonics and scintillator science toward reduced radiation dosage and increased resolution for high-energy particle detection.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq6325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa Demoen, Filip Matthijssens, Lindy Reunes, Bruno Palhais, Béatrice Lintermans, Sara T’Sas, Igor Fijalkowski, Joachim Taminau, Muluembet Z. Akele, Siska Van Belle, Tom Taghon, Dieter Deforce, Filip Van Nieuwerburgh, Geert Berx, Panagiotis Ntziachristos, Zeger Debyser, Kaat Durinck, Tim Pieters, Steven Goossens, Pieter Van Vlierberghe
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in KMT2A-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
{"title":"A dual role for PSIP1/LEDGF in T cell acute lymphoblastic leukemia","authors":"Lisa Demoen, Filip Matthijssens, Lindy Reunes, Bruno Palhais, Béatrice Lintermans, Sara T’Sas, Igor Fijalkowski, Joachim Taminau, Muluembet Z. Akele, Siska Van Belle, Tom Taghon, Dieter Deforce, Filip Van Nieuwerburgh, Geert Berx, Panagiotis Ntziachristos, Zeger Debyser, Kaat Durinck, Tim Pieters, Steven Goossens, Pieter Van Vlierberghe","doi":"10.1126/sciadv.ado6765","DOIUrl":"10.1126/sciadv.ado6765","url":null,"abstract":"<div >T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in <i>KMT2A</i>-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of <i>Psip1</i> accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado6765","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spencer D. Shelton, Sara House, Luiza Martins Nascentes Melo, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B. Llamas, Siva Sai Krishna Venigalla, Cameron J. Menezes, Gabriele Allies, Jonathan Krystkiewicz, Jonas Rösler, Sven W. Meckelmann, Peihua Zhao, Florian Rambow, Dirk Schadendorf, Zhiyu Zhao, Jennifer G. Gill, Ralph J. DeBerardinis, Sean J. Morrison, Alpaslan Tasdogan, Prashant Mishra
Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.
{"title":"Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis","authors":"Spencer D. Shelton, Sara House, Luiza Martins Nascentes Melo, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B. Llamas, Siva Sai Krishna Venigalla, Cameron J. Menezes, Gabriele Allies, Jonathan Krystkiewicz, Jonas Rösler, Sven W. Meckelmann, Peihua Zhao, Florian Rambow, Dirk Schadendorf, Zhiyu Zhao, Jennifer G. Gill, Ralph J. DeBerardinis, Sean J. Morrison, Alpaslan Tasdogan, Prashant Mishra","doi":"10.1126/sciadv.adk8801","DOIUrl":"10.1126/sciadv.adk8801","url":null,"abstract":"<div >Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adk8801","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yueyue Gui, Qingfei Sun, Kexin Li, Longjia Lin, Han Zhou, Jiehua Ma, Chao Li
Aerobic vaginitis (AV) is a long-standing inflammatory disease that affects female patients. The use of antibiotics is a common means for AV treatment, but it will indiscriminately kill both pathogenic bacteria and beneficial strains, which easily causes vaginal dysbacteriosis and infection recurrence. Herein, we describe a bioinspired strategy for fabricating gelated cell sheet–supported lactobacillus biofilms (GCS-LBs) for AV treatment. Compared with common planktonic probiotic formulations, probiotic biofilms forming on a robust GCS exhibit enhanced stress tolerance and better colonization capacity in the mouse vagina. Moreover, DNA nanodevices are decorated on the GCS and dynamically report the microenvironment change of biofilms for timely evaluating bacterium activity, both in vitro and in vivo. Consequently, GCS-LBs are used for treating AV in an Escherichia coli–infected mouse model, which shows enhanced therapeutic efficacy compared with conventional antibiotic or lactobacillus monotherapy. Overall, the GCS-LB shows promise as a potent multifunctional tool to combat bacterial infection.
{"title":"Bioinspired gelated cell sheet–supported lactobacillus biofilm for aerobic vaginitis diagnosis and treatment","authors":"Yueyue Gui, Qingfei Sun, Kexin Li, Longjia Lin, Han Zhou, Jiehua Ma, Chao Li","doi":"10.1126/sciadv.adq2732","DOIUrl":"10.1126/sciadv.adq2732","url":null,"abstract":"<div >Aerobic vaginitis (AV) is a long-standing inflammatory disease that affects female patients. The use of antibiotics is a common means for AV treatment, but it will indiscriminately kill both pathogenic bacteria and beneficial strains, which easily causes vaginal dysbacteriosis and infection recurrence. Herein, we describe a bioinspired strategy for fabricating gelated cell sheet–supported lactobacillus biofilms (GCS-LBs) for AV treatment. Compared with common planktonic probiotic formulations, probiotic biofilms forming on a robust GCS exhibit enhanced stress tolerance and better colonization capacity in the mouse vagina. Moreover, DNA nanodevices are decorated on the GCS and dynamically report the microenvironment change of biofilms for timely evaluating bacterium activity, both in vitro and in vivo. Consequently, GCS-LBs are used for treating AV in an <i>Escherichia coli</i>–infected mouse model, which shows enhanced therapeutic efficacy compared with conventional antibiotic or lactobacillus monotherapy. Overall, the GCS-LB shows promise as a potent multifunctional tool to combat bacterial infection.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq2732","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Megan Cole, Panayiotis Anastasiou, Claudia Lee, Xiaofei Yu, Andrea de Castro, Jannes Roelink, Chris Moore, Edurne Mugarza, Martin Jones, Karishma Valand, Sareena Rana, Emma Colliver, Mihaela Angelova, Katey S. S. Enfield, Alastair Magness, Asher Mullokandov, Gavin Kelly, Tanja D. de Gruijl, Miriam Molina-Arcas, Charles Swanton, Julian Downward, Febe van Maldegem
Kirsten rat sarcoma virus (KRAS)–G12C inhibition causes remodeling of the lung tumor immune microenvironment and synergistic responses to anti–PD-1 treatment, but only in T cell infiltrated tumors. To investigate mechanisms that restrain combination immunotherapy sensitivity in immune-excluded tumors, we used imaging mass cytometry to explore cellular distribution in an immune-evasive KRAS mutant lung cancer model. Cellular spatial pattern characterization revealed a community where CD4+ and CD8+ T cells and dendritic cells were gathered, suggesting localized T cell activation. KRAS-G12C inhibition led to increased PD-1 expression, proliferation, and cytotoxicity of CD8+ T cells, and CXCL9 expression by dendritic cells, indicating an effector response. However, suppressive regulatory T cells (Tregs) were also found in frequent contact with effector T cells within this community. Lung adenocarcinoma clinical samples showed similar communities. Depleting Tregs led to enhanced tumor control in combination with anti–PD-1 and KRAS-G12C inhibitor. Combining Treg depletion with KRAS inhibition shows therapeutic potential for increasing antitumoral immune responses.
Kirsten 大鼠肉瘤病毒（KRAS）-G12C 抑制可导致肺肿瘤免疫微环境的重塑以及对抗 PD-1 治疗的协同反应，但仅限于 T 细胞浸润的肿瘤。为了研究制约免疫排斥肿瘤联合免疫疗法敏感性的机制，我们使用成像质谱仪探索了免疫侵袭性 KRAS 突变肺癌模型中的细胞分布。细胞空间模式表征显示，CD4 + 和 CD8 + T 细胞以及树突状细胞聚集在一个群落中，这表明T细胞被局部激活。KRAS-G12C 抑制导致 CD8 + T 细胞的 PD-1 表达、增殖和细胞毒性以及树突状细胞的 CXCL9 表达增加，表明出现了效应反应。然而，在这个群体中还发现抑制性调节 T 细胞（T regs）与效应 T 细胞频繁接触。肺腺癌临床样本也显示出类似的群落。在联合使用抗-PD-1和KRAS-G12C抑制剂的情况下，消耗T细胞可增强对肿瘤的控制。将Treg耗竭与KRAS抑制相结合，显示了增强抗肿瘤免疫反应的治疗潜力。
{"title":"Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor–induced immune responses","authors":"Megan Cole, Panayiotis Anastasiou, Claudia Lee, Xiaofei Yu, Andrea de Castro, Jannes Roelink, Chris Moore, Edurne Mugarza, Martin Jones, Karishma Valand, Sareena Rana, Emma Colliver, Mihaela Angelova, Katey S. S. Enfield, Alastair Magness, Asher Mullokandov, Gavin Kelly, Tanja D. de Gruijl, Miriam Molina-Arcas, Charles Swanton, Julian Downward, Febe van Maldegem","doi":"10.1126/sciadv.adl6464","DOIUrl":"10.1126/sciadv.adl6464","url":null,"abstract":"<div >Kirsten rat sarcoma virus (KRAS)–G12C inhibition causes remodeling of the lung tumor immune microenvironment and synergistic responses to anti–PD-1 treatment, but only in T cell infiltrated tumors. To investigate mechanisms that restrain combination immunotherapy sensitivity in immune-excluded tumors, we used imaging mass cytometry to explore cellular distribution in an immune-evasive KRAS mutant lung cancer model. Cellular spatial pattern characterization revealed a community where CD4<sup>+</sup> and CD8<sup>+</sup> T cells and dendritic cells were gathered, suggesting localized T cell activation. KRAS-G12C inhibition led to increased PD-1 expression, proliferation, and cytotoxicity of CD8<sup>+</sup> T cells, and CXCL9 expression by dendritic cells, indicating an effector response. However, suppressive regulatory T cells (T<sub>regs</sub>) were also found in frequent contact with effector T cells within this community. Lung adenocarcinoma clinical samples showed similar communities. Depleting T<sub>regs</sub> led to enhanced tumor control in combination with anti–PD-1 and KRAS-G12C inhibitor. Combining T<sub>reg</sub> depletion with KRAS inhibition shows therapeutic potential for increasing antitumoral immune responses.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adl6464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fengdeng Liu, Zhifei Yang, David Abramovitch, Silu Guo, K. Andre Mkhoyan, Marco Bernardi, Bharat Jalan
Exploration and advancements in ultrawide bandgap (UWBG) semiconductors are pivotal for next-generation high-power electronics and deep-ultraviolet (DUV) optoelectronics. Here, we used a thin heterostructure design to facilitate high conductivity due to the low electron mass and relatively weak electron-phonon coupling, while the atomically thin films ensured high transparency. We used a heterostructure comprising SrSnO3/La:SrSnO3/GdScO3 (110), and applied electrostatic gating, which allow us to effectively separate charge carriers in SrSnO3 from dopants and achieve phonon-limited transport behavior in strain-stabilized tetragonal SrSnO3. This led to a modulation of carrier density from 1018 to 1020 cm−3, with room temperature mobilities ranging from 40 to 140 cm2 V−1 s−1. The phonon-limited mobility, calculated from first principles, closely matched experimental results, suggesting that room temperature mobility could be further increased with higher electron density. In addition, the sample exhibited 85% optical transparency at a 300-nm wavelength. These findings highlight the potential of heterostructure design for transparent UWBG semiconductor applications, especially in DUV regime.
超宽带隙（UWBG）半导体的探索和进步对于下一代大功率电子器件和深紫外（DUV）光电子器件至关重要。在这里，我们采用了一种薄型异质结构设计，由于电子质量低和电子-声子耦合相对较弱，因而具有高导电性，而原子级薄膜则确保了高透明度。我们使用了一种由 SrSnO 3 /La:SrSnO 3 /GdScO 3 (110) 组成的异质结构，并应用了静电门控技术，从而有效地分离了 SrSnO 3 中的电荷载流子和掺杂剂，并在应变稳定的四方 SrSnO 3 中实现了声子限制传输行为。这导致载流子密度从 10 18 cm -3 调制到 10 20 cm -3，室温迁移率从 40 cm 2 V -1 s -1 到 140 cm 2 V -1 s -1 不等。根据第一原理计算出的声子限制迁移率与实验结果非常吻合，这表明室温迁移率可以随着电子密度的增加而进一步提高。此外，该样品在 300 纳米波长下的光学透明度达到 85%。这些发现凸显了异质结构设计在透明 UWBG 半导体应用方面的潜力，尤其是在 DUV 阶段。
{"title":"Deep-ultraviolet transparent conducting SrSnO3 via heterostructure design","authors":"Fengdeng Liu, Zhifei Yang, David Abramovitch, Silu Guo, K. Andre Mkhoyan, Marco Bernardi, Bharat Jalan","doi":"10.1126/sciadv.adq7892","DOIUrl":"10.1126/sciadv.adq7892","url":null,"abstract":"<div >Exploration and advancements in ultrawide bandgap (UWBG) semiconductors are pivotal for next-generation high-power electronics and deep-ultraviolet (DUV) optoelectronics. Here, we used a thin heterostructure design to facilitate high conductivity due to the low electron mass and relatively weak electron-phonon coupling, while the atomically thin films ensured high transparency. We used a heterostructure comprising SrSnO<sub>3</sub>/La:SrSnO<sub>3</sub>/GdScO<sub>3</sub> (110), and applied electrostatic gating, which allow us to effectively separate charge carriers in SrSnO<sub>3</sub> from dopants and achieve phonon-limited transport behavior in strain-stabilized tetragonal SrSnO<sub>3</sub>. This led to a modulation of carrier density from 10<sup>18</sup> to 10<sup>20</sup> cm<sup>−3</sup>, with room temperature mobilities ranging from 40 to 140 cm<sup>2</sup> V<sup>−1</sup> s<sup>−1</sup>. The phonon-limited mobility, calculated from first principles, closely matched experimental results, suggesting that room temperature mobility could be further increased with higher electron density. In addition, the sample exhibited 85% optical transparency at a 300-nm wavelength. These findings highlight the potential of heterostructure design for transparent UWBG semiconductor applications, especially in DUV regime.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq7892","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yingyun Yang, Dahan Wen, Feng Lin, Xiaowei Song, Ruiyang Pang, Weihao Sun, Donglin Yu, Ziyi Zhang, Tao Yu, Jie Kong, Lei Zhang, Xinyuan Cao, Wanying Liao, Dingding Wang, Qianyi Yang, Junbo Liang, Ning Zhang, Kailong Li, Chunyang Xiong, Yuying Liu
Increasing evidence highlights the importance of immune mechanoregulation in establishing and sustaining tumor-specific cytotoxicity required for desirable immunotherapeutic outcomes. However, the molecular connections between mechanobiological inputs and outputs and the designated immune activities remain largely unclear. Here, we show that partial inhibition of non-muscle myosin II (NM II) augmented the traction force exerted by T cells and potentiated T cell cytotoxicity against tumors. By using T cells from mice and patients with cancer, we found that NM II is required for the activity of NKX3-2 in maintaining the expression of ADGRB3, which shapes the filamentous actin (F-actin) organization and ultimately attributes to the reduced traction force of T cells in the tumor microenvironment. In animal models, suppressing the NM II–NKX3-2–ADGRB3 pathway in T cells effectively suppressed tumor growth and improved the efficacy of the checkpoint-specific immunotherapy. Overall, this work provides insights into the biomechanical regulation of T cell cytotoxicity that can be exploited to optimize clinical immunotherapies.
越来越多的证据表明，免疫机械调节在建立和维持理想免疫治疗效果所需的肿瘤特异性细胞毒性方面非常重要。然而，机械生物学输入和输出与指定免疫活动之间的分子联系在很大程度上仍不清楚。在这里，我们发现非肌肉肌球蛋白 II（NM II）的部分抑制增强了 T 细胞施加的牵引力，并增强了 T 细胞对肿瘤的细胞毒性。通过使用小鼠和癌症患者的 T 细胞，我们发现 NM II 是 NKX3-2 维持 ADGRB3 表达活性的必要条件，而 ADGRB3 可塑造丝状肌动蛋白（F-actin）组织，并最终导致 T 细胞在肿瘤微环境中的牵引力降低。在动物模型中，抑制 T 细胞中的 NM II-NKX3-2-ADGRB3 通路可有效抑制肿瘤生长，提高检查点特异性免疫疗法的疗效。总之，这项研究深入揭示了T细胞细胞毒性的生物力学调控，可用于优化临床免疫疗法。
{"title":"Suppression of non-muscle myosin II boosts T cell cytotoxicity against tumors","authors":"Yingyun Yang, Dahan Wen, Feng Lin, Xiaowei Song, Ruiyang Pang, Weihao Sun, Donglin Yu, Ziyi Zhang, Tao Yu, Jie Kong, Lei Zhang, Xinyuan Cao, Wanying Liao, Dingding Wang, Qianyi Yang, Junbo Liang, Ning Zhang, Kailong Li, Chunyang Xiong, Yuying Liu","doi":"10.1126/sciadv.adp0631","DOIUrl":"10.1126/sciadv.adp0631","url":null,"abstract":"<div >Increasing evidence highlights the importance of immune mechanoregulation in establishing and sustaining tumor-specific cytotoxicity required for desirable immunotherapeutic outcomes. However, the molecular connections between mechanobiological inputs and outputs and the designated immune activities remain largely unclear. Here, we show that partial inhibition of non-muscle myosin II (NM II) augmented the traction force exerted by T cells and potentiated T cell cytotoxicity against tumors. By using T cells from mice and patients with cancer, we found that NM II is required for the activity of NKX3-2 in maintaining the expression of ADGRB3, which shapes the filamentous actin (F-actin) organization and ultimately attributes to the reduced traction force of T cells in the tumor microenvironment. In animal models, suppressing the NM II–NKX3-2–ADGRB3 pathway in T cells effectively suppressed tumor growth and improved the efficacy of the checkpoint-specific immunotherapy. Overall, this work provides insights into the biomechanical regulation of T cell cytotoxicity that can be exploited to optimize clinical immunotherapies.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp0631","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wonmin Choi, Mara Fattah, Yutong Shang, Matthew P. Thompson, Kendal P. Carrow, Di Hu, Zunren Liu, Michael J. Avram, Keith Bailey, Or Berger, Xin Qi, Nathan C. Gianneschi
Recently, it has been shown that blocking the binding of valosin-containing protein (VCP) to mutant huntingtin (mtHtt) can prevent neuronal mitochondrial autophagy in Huntington’s disease (HD) models. Herein, we describe the development and efficacy of a protein-like polymer (PLP) for inhibiting this interaction in cellular and in vivo models of HD. PLPs exhibit bioactivity in HD mouse striatal cells by successfully inhibiting mitochondrial destruction. PLP is notably resilient to in vitro enzyme, serum, and liver microsome stability assays, which render analogous control oligopeptides ineffective. PLP demonstrates a 2000-fold increase in circulation half-life compared to peptides, exhibiting an elimination half-life of 152 hours. In vivo efficacy studies in HD transgenic mice (R6/2) confirm the superior bioactivity of PLP compared to free peptide through behavioral and neuropathological analyses. PLP functions by preventing pathologic VCP/mtHtt binding in HD animal models; exhibits enhanced efficacy over the parent, free peptide; and implicates the PLP as a platform with potential for translational central nervous system therapeutics.
最近的研究表明，在亨廷顿氏病（HD）模型中，阻断含缬氨酸蛋白（VCP）与突变型杭丁蛋白（mtHtt）的结合可以防止神经元线粒体自噬。在此，我们介绍了一种类蛋白聚合物（PLP）的开发及其在细胞和体内 HD 模型中抑制这种相互作用的功效。PLP 在 HD 小鼠纹状体细胞中表现出生物活性，成功抑制了线粒体的破坏。PLP 对体外酶、血清和肝微粒体稳定性试验具有显著的适应性，而这些试验使类似的对照寡肽失效。与肽相比，PLP 的循环半衰期延长了 2000 倍，消除半衰期为 152 小时。对 HD 转基因小鼠（R6/2）进行的体内药效研究通过行为和神经病理学分析证实，与游离肽相比，PLP 具有更强的生物活性。在 HD 动物模型中，PLP 通过防止病理 VCP/mtHtt 结合而发挥作用；与母体游离肽相比，PLP 表现出更强的疗效；这意味着 PLP 是一种具有转化中枢神经系统疗法潜力的平台。
{"title":"Proteomimetic polymer blocks mitochondrial damage, rescues Huntington’s neurons, and slows onset of neuropathology in vivo","authors":"Wonmin Choi, Mara Fattah, Yutong Shang, Matthew P. Thompson, Kendal P. Carrow, Di Hu, Zunren Liu, Michael J. Avram, Keith Bailey, Or Berger, Xin Qi, Nathan C. Gianneschi","doi":"10.1126/sciadv.ado8307","DOIUrl":"10.1126/sciadv.ado8307","url":null,"abstract":"<div >Recently, it has been shown that blocking the binding of valosin-containing protein (VCP) to mutant huntingtin (mtHtt) can prevent neuronal mitochondrial autophagy in Huntington’s disease (HD) models. Herein, we describe the development and efficacy of a protein-like polymer (PLP) for inhibiting this interaction in cellular and in vivo models of HD. PLPs exhibit bioactivity in HD mouse striatal cells by successfully inhibiting mitochondrial destruction. PLP is notably resilient to in vitro enzyme, serum, and liver microsome stability assays, which render analogous control oligopeptides ineffective. PLP demonstrates a 2000-fold increase in circulation half-life compared to peptides, exhibiting an elimination half-life of 152 hours. In vivo efficacy studies in HD transgenic mice (R6/2) confirm the superior bioactivity of PLP compared to free peptide through behavioral and neuropathological analyses. PLP functions by preventing pathologic VCP/mtHtt binding in HD animal models; exhibits enhanced efficacy over the parent, free peptide; and implicates the PLP as a platform with potential for translational central nervous system therapeutics.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado8307","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Highly efficient bifacial organic solar cells (OSCs) have not been reported due to limited thickness of the active layer in conventional configurations, not allowing for efficient harvesting of front sunlight and albedo light. Here, bifacial OSCs are reported with efficiency higher than the monofacial counterparts. The incorporation of pyramid-based asymmetrical optical transmission (AOT) array to a transparent silver electrode suppresses the escaping of front sunlight without sacrificing the harvesting of albedo light. Parasitic absorption induced by the excitation of surface plasmons in an AOT electrode is further reduced by doping organic emitter in electron transport layer and capping high dielectric constant film to silver. The rear electrode achieves a front transmittance of 7% and a rear transmission of 86%. At a conventional albedo of 0.2, the synergistic effect of AOT and minimized optical loss endow the bifacial OSCs with power conversion efficiency of 20.4%. This work paves the way for the utilization of albedo light in OSCs.
{"title":"20.4% Power conversion efficiency from albedo-collecting organic solar cells under 0.2 albedo","authors":"Hao Ren, Jing-De Chen, Ye-Fan Zhang, Jia-Liang Zhang, Wei-Shuo Chen, Yan-Qing Li, Jian-Xin Tang","doi":"10.1126/sciadv.adp9439","DOIUrl":"10.1126/sciadv.adp9439","url":null,"abstract":"<div >Highly efficient bifacial organic solar cells (OSCs) have not been reported due to limited thickness of the active layer in conventional configurations, not allowing for efficient harvesting of front sunlight and albedo light. Here, bifacial OSCs are reported with efficiency higher than the monofacial counterparts. The incorporation of pyramid-based asymmetrical optical transmission (AOT) array to a transparent silver electrode suppresses the escaping of front sunlight without sacrificing the harvesting of albedo light. Parasitic absorption induced by the excitation of surface plasmons in an AOT electrode is further reduced by doping organic emitter in electron transport layer and capping high dielectric constant film to silver. The rear electrode achieves a front transmittance of 7% and a rear transmission of 86%. At a conventional albedo of 0.2, the synergistic effect of AOT and minimized optical loss endow the bifacial OSCs with power conversion efficiency of 20.4%. This work paves the way for the utilization of albedo light in OSCs.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp9439","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mengjie Zhang, Lei Yan, Yash Amonkar, Adam Nayak, Upmanu Lall
Climate variability influences renewable electricity supply and demand and hence system reliability. Using the hidden states of the sea surface temperature of tropical Pacific Ocean that reflect El Niño–Southern Oscillation (ENSO) dynamics that is objectively identified by a nonhomogeneous hidden Markov model, we provide a first example of the potential predictability of monthly wind and solar energy and heating and cooling energy demand for 1 to 6 months ahead for Texas, United States, a region that has a high penetration of renewable electricity and is susceptible to disruption by climate-driven supply-demand imbalances. We find a statistically significant potential for oversupply or undersupply of energy and anomalous heating/cooling demand depending on the ENSO state and the calendar month. Implications for financial securitization and the potential application of forecasts are discussed.
{"title":"Potential climate predictability of renewable energy supply and demand for Texas given the ENSO hidden state","authors":"Mengjie Zhang, Lei Yan, Yash Amonkar, Adam Nayak, Upmanu Lall","doi":"10.1126/sciadv.ado3517","DOIUrl":"10.1126/sciadv.ado3517","url":null,"abstract":"<div >Climate variability influences renewable electricity supply and demand and hence system reliability. Using the hidden states of the sea surface temperature of tropical Pacific Ocean that reflect El Niño–Southern Oscillation (ENSO) dynamics that is objectively identified by a nonhomogeneous hidden Markov model, we provide a first example of the potential predictability of monthly wind and solar energy and heating and cooling energy demand for 1 to 6 months ahead for Texas, United States, a region that has a high penetration of renewable electricity and is susceptible to disruption by climate-driven supply-demand imbalances. We find a statistically significant potential for oversupply or undersupply of energy and anomalous heating/cooling demand depending on the ENSO state and the calendar month. Implications for financial securitization and the potential application of forecasts are discussed.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado3517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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