当前,AI大模型逐渐被应用于蛋白质科学和生物信息学中,但其复杂性常常使人们无法解释神经网络如何从复杂的生物数据中提取和理解关键特征.为了理解这类计算模型如何拥有推断生物大分子的结构、功能和相互作用的能力,在前人关于预测治疗...当前,AI大模型逐渐被应用于蛋白质科学和生物信息学中,但其复杂性常常使人们无法解释神经网络如何从复杂的生物数据中提取和理解关键特征.为了理解这类计算模型如何拥有推断生物大分子的结构、功能和相互作用的能力,在前人关于预测治疗性抗体结合特异性的研究基础上进一步拓展,提出了基于通道注意力机制可解释的残差卷积神经网络.该网络能够有效预测具有不同氨基酸序列的抗体特异性结合概率,网络交叉验证的AUC(Area under Curve)达到0.943,与传统方法相比有显著提高.其次,通过非线性变换和积分梯度的方法获得各位点对于结合能力的贡献,从而推断出抗体序列的残基分布模式.提出的方法可以获得氨基酸序列背后潜在的信息,也能显著减小特异性抗体预测未知的突变空间,证明该网络不仅性能更优,对于理解复杂的神经网络背后的逻辑也有所帮助.展开更多
Biocatalysis,which involves using enzymes to address synthetic challenges of significance to humans,has rapidly developed into a pivotal technology for chemical innovation.Over the past decade,there has been a notable...Biocatalysis,which involves using enzymes to address synthetic challenges of significance to humans,has rapidly developed into a pivotal technology for chemical innovation.Over the past decade,there has been a notable increase in the use of metalloproteins as catalysts for abiotic,synthetically valuable carbene and nitrene transfer reactions.This trend highlights the adaptability of protein-based catalysts and our growing ability to harness this potential for novel enzyme chemistry.This review focuses on the most recent advancements in metalloenzyme-catalyzed carbene and nitrene transfer reactions,including cyclopropanation,carbene Y–H and C–H insertions,Doyle-Kirmse reactions,aldehyde olefinations,nitrene azide-to-aldehyde conversions,and nitrene C–H insertion.A variety of protein scaffolds have been engineered to offer varied levels of reactivity and selectivity towards pharmaceutically relevant compounds.The application of these new catalysts in preparative-scale synthesis underscores their emerging biotechnological significance.Furthermore,insights into key intermediate and determining factors in stereochemistry are offering valuable guidance for engineering metalloproteins,thereby expanding the scope and utility of these non-natural activities.展开更多
Contrary to the solar system,most exoplanet systems detected hitherto are close-in and compact.One typical system is TRAPPIST-1,which has seven nearly co-planar terrestrial planets all within the orbit of Mercury,incl...Contrary to the solar system,most exoplanet systems detected hitherto are close-in and compact.One typical system is TRAPPIST-1,which has seven nearly co-planar terrestrial planets all within the orbit of Mercury,including three in the habitable zone.To evaluate the differences in developing sophisticated gravity theories from the solar system,we use N-body integrations to simulate ephemeris and reproduce some important astronomy phenomena observed on the potentially habitable planet TRAPPIST-1e.Retrograde motions of other planets last 1-2 orders of magnitude shorter than in the solar system,but occur much more frequently.Transit events of all inner planets can be observed steadily.Except for Kepler's first law,which is hard to notice for low eccentricities of planets,the other two laws can then be precisely verified in 102 days,because the areas swept by planets vary by0.01%and the observed semimajor axes and periods result in constants with theoretical and observation accuracies both2%.However,the mean motion correlation implies that the Great Inequality is not always apparent between one pair of planets like Jupiter and Saturn.Furthermore,general relativity can hardly be discovered because it gives rise to perihelion precession of inner planets only~0.1%of gravity precession,dozens of times smaller than Mercury.Our results support the possibility of developing part of gravity theories by potential exo-civilizations in compact systems like TRAPPIST-1.展开更多
Modulating the dipole polarization loss in the single-atom region and establishing its direct relationship with the electromagnetic wave absorption(EWA)performance remain an unmet challenge.Here,a dual-ligand modulati...Modulating the dipole polarization loss in the single-atom region and establishing its direct relationship with the electromagnetic wave absorption(EWA)performance remain an unmet challenge.Here,a dual-ligand modulation strategy,i.e.,partially changing coordination atoms in the single-metal region(sMr),is introduced to effectively break the coordination symmetry of conjugated metal-organic frameworks(cMOFs),finally enhancing EWA property of cMOFs materials.Further,the asymmetrical sMr is experimentally found to elicit the dipole polarization loss,overcoming the handicaps of other electromagnetic wave loss mechanisms,which directly contribution to enhance EWA performance of this series of cMOFs.This strategy is further confirmed by replacing metal centers.Among studied series of cMOFs,Cu_(2.25)/Co_(0.75)(HHTP1.67HITP0.33)achieves excellent EWA performance with an effective absorption bandwidth of 5.00 GHz and a reflection loss of66.03 dB.We introduce a dual-ligand modulation strategy targeting single-metal regions within cMOFs here,aiming to achieve superior EWA performance through atomic-scale dipole polarization loss modulation.We hope our study can inspire more exploration to realize high-performance EWA materials.展开更多
Objectives:Mitochondrial Ca^(2+)uniporter(MCU)provides a Ca^(2+)influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca^(2+)rise stimulates ATP production and cell growth.MCU is h...Objectives:Mitochondrial Ca^(2+)uniporter(MCU)provides a Ca^(2+)influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca^(2+)rise stimulates ATP production and cell growth.MCU is highly expressed in various cancer cells including breast cancer cells,thereby increasing the capacity of mitochondrial Ca^(2+)uptake,ATP production,and cancer cell proliferation.The objective of this study was to examine MCU inhibition as an anti-cancer mechanism.Methods:The effects of MCU-i4,a newly developed MCU inhibitor,on cell viability,apoptosis,cytosolic Ca^(2+),mitochondrial Ca^(2+)and potential,glycolytic rate,generation of ATP,and reactive oxygen species,were examined in breast cancer BT474 cells.Results:MCU-i4 caused apoptotic cell death,and it decreased and increased,respectively,mitochondrial and cytosolic Ca^(2+)concentration.Inhibition of MCU by MCU-i4 revealed that cytosolic Ca^(2+)elevation resulted from endoplasmic reticulum(ER)Ca^(2+)release via inositol 1,4,5-trisphosphate receptors(IP3R)and ryanodine receptors(RYR).Unexpectedly,MCU-i4 enhanced glycolysis and ATP production;it also triggered a large production of reactive oxygen species(ROS)and mitochondrial membrane potential collapse.Conclusion:Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS.It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis.Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.展开更多
文摘当前,AI大模型逐渐被应用于蛋白质科学和生物信息学中,但其复杂性常常使人们无法解释神经网络如何从复杂的生物数据中提取和理解关键特征.为了理解这类计算模型如何拥有推断生物大分子的结构、功能和相互作用的能力,在前人关于预测治疗性抗体结合特异性的研究基础上进一步拓展,提出了基于通道注意力机制可解释的残差卷积神经网络.该网络能够有效预测具有不同氨基酸序列的抗体特异性结合概率,网络交叉验证的AUC(Area under Curve)达到0.943,与传统方法相比有显著提高.其次,通过非线性变换和积分梯度的方法获得各位点对于结合能力的贡献,从而推断出抗体序列的残基分布模式.提出的方法可以获得氨基酸序列背后潜在的信息,也能显著减小特异性抗体预测未知的突变空间,证明该网络不仅性能更优,对于理解复杂的神经网络背后的逻辑也有所帮助.
文摘Biocatalysis,which involves using enzymes to address synthetic challenges of significance to humans,has rapidly developed into a pivotal technology for chemical innovation.Over the past decade,there has been a notable increase in the use of metalloproteins as catalysts for abiotic,synthetically valuable carbene and nitrene transfer reactions.This trend highlights the adaptability of protein-based catalysts and our growing ability to harness this potential for novel enzyme chemistry.This review focuses on the most recent advancements in metalloenzyme-catalyzed carbene and nitrene transfer reactions,including cyclopropanation,carbene Y–H and C–H insertions,Doyle-Kirmse reactions,aldehyde olefinations,nitrene azide-to-aldehyde conversions,and nitrene C–H insertion.A variety of protein scaffolds have been engineered to offer varied levels of reactivity and selectivity towards pharmaceutically relevant compounds.The application of these new catalysts in preparative-scale synthesis underscores their emerging biotechnological significance.Furthermore,insights into key intermediate and determining factors in stereochemistry are offering valuable guidance for engineering metalloproteins,thereby expanding the scope and utility of these non-natural activities.
基金supported by the National Key R&D Program of China(2019YFA0706601)the National Natural Science Foundation of China(grant Nos.11973028,11933001,1803012,12150009,and 42005045)+3 种基金Science and Technology Foundation of Zhejiang Ocean University(No.2021C21021)Key Laboratory of Modern Astronomy and Astrophysics(Nanjing University),Ministry of Educationthe science research grants from the Civil Aerospace Technology Research Project(D010102)as well as the China Manned Space Project with NO.CMS-CSST-2021-B12 and CMSCSST-2021-B09.
文摘Contrary to the solar system,most exoplanet systems detected hitherto are close-in and compact.One typical system is TRAPPIST-1,which has seven nearly co-planar terrestrial planets all within the orbit of Mercury,including three in the habitable zone.To evaluate the differences in developing sophisticated gravity theories from the solar system,we use N-body integrations to simulate ephemeris and reproduce some important astronomy phenomena observed on the potentially habitable planet TRAPPIST-1e.Retrograde motions of other planets last 1-2 orders of magnitude shorter than in the solar system,but occur much more frequently.Transit events of all inner planets can be observed steadily.Except for Kepler's first law,which is hard to notice for low eccentricities of planets,the other two laws can then be precisely verified in 102 days,because the areas swept by planets vary by0.01%and the observed semimajor axes and periods result in constants with theoretical and observation accuracies both2%.However,the mean motion correlation implies that the Great Inequality is not always apparent between one pair of planets like Jupiter and Saturn.Furthermore,general relativity can hardly be discovered because it gives rise to perihelion precession of inner planets only~0.1%of gravity precession,dozens of times smaller than Mercury.Our results support the possibility of developing part of gravity theories by potential exo-civilizations in compact systems like TRAPPIST-1.
基金supported by the National Natural Science Foundation of China(52172091,52172295)Defense Industrial Technology Development Program(JCKY2023605C002)+3 种基金Basic Research Program of Jiangsu(BK20232013)the National Key Laboratory on Electromagnetic Environmental Effects and Electro-optical Engineering(NO.61422062301)The Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX23_0371,KYCX24_0571,KYCX25_0602)Opening Project of Science and Technology on Reliability Physics and Application Technology of Electronic Component Laboratory(ZHD202305).
文摘Modulating the dipole polarization loss in the single-atom region and establishing its direct relationship with the electromagnetic wave absorption(EWA)performance remain an unmet challenge.Here,a dual-ligand modulation strategy,i.e.,partially changing coordination atoms in the single-metal region(sMr),is introduced to effectively break the coordination symmetry of conjugated metal-organic frameworks(cMOFs),finally enhancing EWA property of cMOFs materials.Further,the asymmetrical sMr is experimentally found to elicit the dipole polarization loss,overcoming the handicaps of other electromagnetic wave loss mechanisms,which directly contribution to enhance EWA performance of this series of cMOFs.This strategy is further confirmed by replacing metal centers.Among studied series of cMOFs,Cu_(2.25)/Co_(0.75)(HHTP1.67HITP0.33)achieves excellent EWA performance with an effective absorption bandwidth of 5.00 GHz and a reflection loss of66.03 dB.We introduce a dual-ligand modulation strategy targeting single-metal regions within cMOFs here,aiming to achieve superior EWA performance through atomic-scale dipole polarization loss modulation.We hope our study can inspire more exploration to realize high-performance EWA materials.
基金China Medical University and China Medical University Hospital,Taiwan for providing fundings(CMU111-S-20,CMU112-S-59,DMR-112-067)ECS thanks An Nan Hospital for support(ANHRF112-04).
文摘Objectives:Mitochondrial Ca^(2+)uniporter(MCU)provides a Ca^(2+)influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca^(2+)rise stimulates ATP production and cell growth.MCU is highly expressed in various cancer cells including breast cancer cells,thereby increasing the capacity of mitochondrial Ca^(2+)uptake,ATP production,and cancer cell proliferation.The objective of this study was to examine MCU inhibition as an anti-cancer mechanism.Methods:The effects of MCU-i4,a newly developed MCU inhibitor,on cell viability,apoptosis,cytosolic Ca^(2+),mitochondrial Ca^(2+)and potential,glycolytic rate,generation of ATP,and reactive oxygen species,were examined in breast cancer BT474 cells.Results:MCU-i4 caused apoptotic cell death,and it decreased and increased,respectively,mitochondrial and cytosolic Ca^(2+)concentration.Inhibition of MCU by MCU-i4 revealed that cytosolic Ca^(2+)elevation resulted from endoplasmic reticulum(ER)Ca^(2+)release via inositol 1,4,5-trisphosphate receptors(IP3R)and ryanodine receptors(RYR).Unexpectedly,MCU-i4 enhanced glycolysis and ATP production;it also triggered a large production of reactive oxygen species(ROS)and mitochondrial membrane potential collapse.Conclusion:Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS.It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis.Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.
