卟啉类化合物是一类重要的光化学材料,其衍生物特殊的光电特性在各个领域中得到了广泛的应用。利用密度泛函理论(DFT)研究了(free base porphyrin,FBP)及其异构体(neo-confused porphyrin,NECP)和(n-confused porphyrin,NCP)三种卟啉环...卟啉类化合物是一类重要的光化学材料,其衍生物特殊的光电特性在各个领域中得到了广泛的应用。利用密度泛函理论(DFT)研究了(free base porphyrin,FBP)及其异构体(neo-confused porphyrin,NECP)和(n-confused porphyrin,NCP)三种卟啉环的几何结构和分子轨道能级。采用TDDFT方法计算真空和溶剂场极化连续模型下三者的吸收光谱。计算表明由于N原子位置变化,FBP,NECP和NCP在Soret带和Q带两个特征吸收峰也有不同。按FBP,NECP和NCP顺序,分子轨道能级LUMO依次降低,HOMO轨道依次升高,从而造成吸收光谱红移。HOMO和HOMO-1轨道能级的分裂造成了FBP和NECP的Soret带的多个吸收峰,而NCP的LUMO和LUMO+1的能级差与其HOMO和HOMO-1能级差几乎相等造成Soret带只有一个最高吸收峰。计算结果表明不同溶剂(苯、氯仿、乙腈和水)条件下三者的Soret带和Q带特征吸收峰均有显著变化。为此重点讨论了N原子位置的变化及在不同性质溶剂下FBP,NCP和NECP三类化合物Soret带/Q带吸收光谱性质的变化规律和机理。展开更多
Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transf...Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transformation of‘cold’tumors into‘hot’tumors.The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators.The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15.However,it specifically lacks the binding site of IL-2 receptorαsubunit(CD25),therefore unable to induce the Treg proliferation.In present study,a recombinant vesicular stomatitis virus expressing the Neo-2/15(VSVM51R-Neo-2/15)was generated.Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic.Moreover,treatment with VSVM51R-Neo-2/15 increased the number of activated CD8t T cells but not Treg cells in tumors.More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment,and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity.In addition,combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response.These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors,providing promising attempts for further clinical trials.展开更多
Corynebacterium glutamicum represents an emerging recombinant protein expression factory due to its ideal features for protein secretion,but its applicability is harmed by the lack of an autoinduction system with tigh...Corynebacterium glutamicum represents an emerging recombinant protein expression factory due to its ideal features for protein secretion,but its applicability is harmed by the lack of an autoinduction system with tight regulation and high yield.Here,we propose a new recombinant protein manufacturing platform that leverages ethanol as both a delayed carbon source and an inducer.First,we reanalysed the native inducible promoter PICL from the acetate uptake operon and found that its limited capacity is the result of the inadequate translation initial architecture.The two strategies of bicistronic design and ribozyme-based insulator can ensure the high activity of this promoter.Next,through transcriptional engineering that alters transcription factor binding sites(TFBSs)and the first transcribed sequence,the truncated promoter PA256 with a dramatically higher transcription level was generated.When producing the superfolder green fluorescent protein(sfGFP)under 1%ethanol conditions,PA256 exhibited substantially lower protein accumulation in prophase but an approximately 2.5-fold greater final yield than the strong promoter PH36.This superior expression mode was further validated using two secreted proteins,camelid antibody fragment(VHH)and endoxylanase(XynA).Furthermore,utilizing CRISPRi technology,ethanol utilization blocking strains were created,and PA256 was shown to be impaired in the phosphotransacetylase(PTA)knockdown strains,indicating that ethanol metabolism into the tricarboxylic acid cycle is required for PA256 upregulation.Finally,this platform was applied to produce the“de novo design”protein NEO-2/15,and by introducing the N-propeptide of CspB,NEO-2/15 was effectively secreted with the accumulation 281 mg/L obtained after 24 h of shake-flask fermentation.To the best of our knowledge,this is the first report of NEO-2/15 secretory overexpression.展开更多
In natural language, number-words can be used in two different syntactic ways: adjectivally, i.e., with the syntactic status of an adjective, as in (1) 4Mars has two moons/ and nominally, i.e., with the syntactic stat...In natural language, number-words can be used in two different syntactic ways: adjectivally, i.e., with the syntactic status of an adjective, as in (1) 4Mars has two moons/ and nominally, i.e., with the syntactic status of a noun phrase, as in (2)‘Two is even.’ This syntactic difference is often taken to correspond to a difference in semantic function: adjectival number-words function as predicables, whereas nominal number-words function as singular terms. The view that nominal number-words function as singular terms is typically supported by appeal to certain tests for singular-termhood, tests that stem from the (neo-)Fregean tradition. In this paper, I argue that these tests do not support the view of nominal number-words as singular terms.展开更多
One of the remarkable results of Frege＇s Logicism is Frege＇s Theorem, which holds that one can derive the main truths of Peano arithmetic from Hume＇s Principle （HP） without using Frege＇s Basic Law V. This result...One of the remarkable results of Frege＇s Logicism is Frege＇s Theorem, which holds that one can derive the main truths of Peano arithmetic from Hume＇s Principle （HP） without using Frege＇s Basic Law V. This result was rediscovered by the Neo-Fregeans and their allies. However, when applied in developing a more advanced theory of mathematics, their fundamental principles--the abstraction principles--incur some problems, e.g., that of inflation. This paper finds alternative paths for such inquiry in extensionalism and object theory.展开更多
文摘卟啉类化合物是一类重要的光化学材料,其衍生物特殊的光电特性在各个领域中得到了广泛的应用。利用密度泛函理论(DFT)研究了(free base porphyrin,FBP)及其异构体(neo-confused porphyrin,NECP)和(n-confused porphyrin,NCP)三种卟啉环的几何结构和分子轨道能级。采用TDDFT方法计算真空和溶剂场极化连续模型下三者的吸收光谱。计算表明由于N原子位置变化,FBP,NECP和NCP在Soret带和Q带两个特征吸收峰也有不同。按FBP,NECP和NCP顺序,分子轨道能级LUMO依次降低,HOMO轨道依次升高,从而造成吸收光谱红移。HOMO和HOMO-1轨道能级的分裂造成了FBP和NECP的Soret带的多个吸收峰,而NCP的LUMO和LUMO+1的能级差与其HOMO和HOMO-1能级差几乎相等造成Soret带只有一个最高吸收峰。计算结果表明不同溶剂(苯、氯仿、乙腈和水)条件下三者的Soret带和Q带特征吸收峰均有显著变化。为此重点讨论了N原子位置的变化及在不同性质溶剂下FBP,NCP和NECP三类化合物Soret带/Q带吸收光谱性质的变化规律和机理。
文摘Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transformation of‘cold’tumors into‘hot’tumors.The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators.The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15.However,it specifically lacks the binding site of IL-2 receptorαsubunit(CD25),therefore unable to induce the Treg proliferation.In present study,a recombinant vesicular stomatitis virus expressing the Neo-2/15(VSVM51R-Neo-2/15)was generated.Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic.Moreover,treatment with VSVM51R-Neo-2/15 increased the number of activated CD8t T cells but not Treg cells in tumors.More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment,and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity.In addition,combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response.These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors,providing promising attempts for further clinical trials.
基金This work received funding from the National Natural Science Foundation of China(No.21878124,22078128,and 21938004)the Fundamental Research Funds for the Central Universities(No.JUSRP221032)+1 种基金the 111 Project(No.111-2-06)the national first-class discipline program of Light Industry Technology and Engineering(LITE2018-24).
文摘Corynebacterium glutamicum represents an emerging recombinant protein expression factory due to its ideal features for protein secretion,but its applicability is harmed by the lack of an autoinduction system with tight regulation and high yield.Here,we propose a new recombinant protein manufacturing platform that leverages ethanol as both a delayed carbon source and an inducer.First,we reanalysed the native inducible promoter PICL from the acetate uptake operon and found that its limited capacity is the result of the inadequate translation initial architecture.The two strategies of bicistronic design and ribozyme-based insulator can ensure the high activity of this promoter.Next,through transcriptional engineering that alters transcription factor binding sites(TFBSs)and the first transcribed sequence,the truncated promoter PA256 with a dramatically higher transcription level was generated.When producing the superfolder green fluorescent protein(sfGFP)under 1%ethanol conditions,PA256 exhibited substantially lower protein accumulation in prophase but an approximately 2.5-fold greater final yield than the strong promoter PH36.This superior expression mode was further validated using two secreted proteins,camelid antibody fragment(VHH)and endoxylanase(XynA).Furthermore,utilizing CRISPRi technology,ethanol utilization blocking strains were created,and PA256 was shown to be impaired in the phosphotransacetylase(PTA)knockdown strains,indicating that ethanol metabolism into the tricarboxylic acid cycle is required for PA256 upregulation.Finally,this platform was applied to produce the“de novo design”protein NEO-2/15,and by introducing the N-propeptide of CspB,NEO-2/15 was effectively secreted with the accumulation 281 mg/L obtained after 24 h of shake-flask fermentation.To the best of our knowledge,this is the first report of NEO-2/15 secretory overexpression.
文摘In natural language, number-words can be used in two different syntactic ways: adjectivally, i.e., with the syntactic status of an adjective, as in (1) 4Mars has two moons/ and nominally, i.e., with the syntactic status of a noun phrase, as in (2)‘Two is even.’ This syntactic difference is often taken to correspond to a difference in semantic function: adjectival number-words function as predicables, whereas nominal number-words function as singular terms. The view that nominal number-words function as singular terms is typically supported by appeal to certain tests for singular-termhood, tests that stem from the (neo-)Fregean tradition. In this paper, I argue that these tests do not support the view of nominal number-words as singular terms.
文摘One of the remarkable results of Frege＇s Logicism is Frege＇s Theorem, which holds that one can derive the main truths of Peano arithmetic from Hume＇s Principle （HP） without using Frege＇s Basic Law V. This result was rediscovered by the Neo-Fregeans and their allies. However, when applied in developing a more advanced theory of mathematics, their fundamental principles--the abstraction principles--incur some problems, e.g., that of inflation. This paper finds alternative paths for such inquiry in extensionalism and object theory.
