The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are s...The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.展开更多
Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics...Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.展开更多
GroupqV monochalcogenides are emerging as a new class of layered materials beyond graphene, transition metal dichalcogenides （TMDCs）, and black phosphorus （BP）. In this paper, we report experimental and theoretica...GroupqV monochalcogenides are emerging as a new class of layered materials beyond graphene, transition metal dichalcogenides （TMDCs）, and black phosphorus （BP）. In this paper, we report experimental and theoretical investigations of the band structure and transport properties of GeSe and its heterostructures. We find that GeSe exhibits a markedly anisotropic electronic transport, with maximum conductance along the armchair direction. Density functional theory calculations reveal that the effective mass is 2.7 times larger along the zigzag direction than the armchair direction; this mass anisotropy explains the observed anisotropic conductance. The crystallographic orientation of GeSe is confirmed by angle- resolved polarized Raman measurements, which are further supported by calculated Raman tensors for the orthorhombic structure. Novel GeSeflVIoS2 p-n heterojunctions are fabricated, combining the natural p-type doping in GeSe and n-type doping in MoS2. The temperature dependence of the measured junction current reveals that GeSe and MoS2 have a type-II band alignment with a conduction band offset of N 0.234 eV. The anisotropic conductance of GeSe may enable the development of new electronic and optoelectronic devices, such as high-efficiency thermoelectric devices and plasmonic devices with resonance frequency continuously tunable through light polarization direction. The unique GeSe/MoS2 p-n junctions with type-II alignment may become essential building blocks of vertical tunneling field-effect transistors for low-power applications. The novel p-type layered material GeSe can also be combined with n-type TMDCs to form heterogeneous complementary metal oxide semiconductor （CMOS） circuits.展开更多
Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2...Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and metabolism.Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism.Sin1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral immunity.At the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,respectively.Therefore,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.展开更多
We present a symbolic-numeric hybrid method, based on sum-of-squares （SOS） relaxation and rational vec- tor recovery, to compute inequality invariants and ranking functions for proving total correctness and generati...We present a symbolic-numeric hybrid method, based on sum-of-squares （SOS） relaxation and rational vec- tor recovery, to compute inequality invariants and ranking functions for proving total correctness and generating pre- conditions for programs. The SOS relaxation method is used to compute approximate invariants and approximate rank- ing functions with floating point coefficients. Then Gauss- Newton refinement and rational vector recovery are applied to approximate polynomials to obtain candidate polynomials with rational coefficients, which exactly satisfy the conditions of invariants and ranking functions. In the end, several exam- ples are given to show the effectiveness of our method.展开更多
基金supported by a grant from the National Natural Science Foundation of China(No.82072210)the Shanghai Municipal Science and Technology Commission,China(No.20ZR1445200)+1 种基金the Chinese Federation of Public Health Foundation(GWLM202001)the Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai(No.GWV-10.1-XK25).
文摘The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.
基金This work received financial support from the National Natural Science Foundation of China(no.82070677 and 82201964)Natural Science and Technology Major Project of the Xiamen(no.3502Z20231034)+1 种基金Natural Science Fund for Distinguished Young Scholars of Fujian Province(no.2023J01310519)Natural Science Foundation of Xiamen(no.3502Z20227283 and 3502Z20227122).
文摘Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.
文摘GroupqV monochalcogenides are emerging as a new class of layered materials beyond graphene, transition metal dichalcogenides （TMDCs）, and black phosphorus （BP）. In this paper, we report experimental and theoretical investigations of the band structure and transport properties of GeSe and its heterostructures. We find that GeSe exhibits a markedly anisotropic electronic transport, with maximum conductance along the armchair direction. Density functional theory calculations reveal that the effective mass is 2.7 times larger along the zigzag direction than the armchair direction; this mass anisotropy explains the observed anisotropic conductance. The crystallographic orientation of GeSe is confirmed by angle- resolved polarized Raman measurements, which are further supported by calculated Raman tensors for the orthorhombic structure. Novel GeSeflVIoS2 p-n heterojunctions are fabricated, combining the natural p-type doping in GeSe and n-type doping in MoS2. The temperature dependence of the measured junction current reveals that GeSe and MoS2 have a type-II band alignment with a conduction band offset of N 0.234 eV. The anisotropic conductance of GeSe may enable the development of new electronic and optoelectronic devices, such as high-efficiency thermoelectric devices and plasmonic devices with resonance frequency continuously tunable through light polarization direction. The unique GeSe/MoS2 p-n junctions with type-II alignment may become essential building blocks of vertical tunneling field-effect transistors for low-power applications. The novel p-type layered material GeSe can also be combined with n-type TMDCs to form heterogeneous complementary metal oxide semiconductor （CMOS） circuits.
基金This study was partially supported by grant PR093728(DoD to B.S.)the National Natural Science Foundation of China(grant numbers 31470845 and 81430033 to B.S.,31422020 to F.L.and 31600704 to H.H.Z.)+2 种基金grant 13JC1404700 from the Program of Science and Technology Commission of Shanghai Municipality(B.S.)the Ministry of Science and Technology of China(Program 2014CB943600,F.L.)Chinese Mega Project on Infectious Diseases(No.2018ZX10302301).
文摘Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and metabolism.Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism.Sin1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral immunity.At the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,respectively.Therefore,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.
文摘We present a symbolic-numeric hybrid method, based on sum-of-squares （SOS） relaxation and rational vec- tor recovery, to compute inequality invariants and ranking functions for proving total correctness and generating pre- conditions for programs. The SOS relaxation method is used to compute approximate invariants and approximate rank- ing functions with floating point coefficients. Then Gauss- Newton refinement and rational vector recovery are applied to approximate polynomials to obtain candidate polynomials with rational coefficients, which exactly satisfy the conditions of invariants and ranking functions. In the end, several exam- ples are given to show the effectiveness of our method.
