Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood.Here,we used mouse genetics,mechanical loading,and pharmacological approaches to test the possi...Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood.Here,we used mouse genetics,mechanical loading,and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts.We created and compared the skeletal phenotypes of control Pkd1^(flox/)+;Wwtr1^(flox/)+,Pkd1^(Oc-cKO),Wwtr1^(Oc-cKO),and Pkd1/Wwtr1^(Oc-cKO)mice to investigate genetic interactions.Consistent with an interaction between polycystins and Wwtr1 in bone in vivo,Pkd1/Wwtr1^(Oc-cKO)mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKOor Pkd1^(Oc-cKO)mice.Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Pkd1/Wwtr1^(Oc-cKO)mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Moreover,we found that Pkd1/Wwtr1^(Oc-cKO)mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of loadinduced mechanosensing gene expression compared to control mice.Finally,control mice treated with a small molecule mechanomimetic,MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control.In contrast,Pkd1/Wwtr1^(Oc-cKO)mice were resistant to the anabolic effects of MS2.These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.展开更多
In the present study we investigated structural and metabolic modifications of the brain in the Ts65Dn mouse model of Down syndrome(DS)using both in vivo magnetic resonance imaging(MRI)and proton magnetic resonance sp...In the present study we investigated structural and metabolic modifications of the brain in the Ts65Dn mouse model of Down syndrome(DS)using both in vivo magnetic resonance imaging(MRI)and proton magnetic resonance spectroscopy(MRS). MRI was performed for further texture analysis and changes in texture parameters, including mean grey levels, contrast and homogeneity, and they were found in Ts65Dn compared to diploid littermates (2n). These phenotypic changes were different in the hippocampus and cerebellum, since in Ts65Dn mean grey levels increased in the cerebellum and decreased in the hippocampus. In addition, proton NMR spectra revealed differences in metabolite ratios. Levels of N-acetylaspartate(NAA)and glutamate(Glu), were lower compared to total creatine levels (CX), in the Ts65Dn brain. However, the most striking finding was an increase in the concentration of myo-inositol(Ins)and choline(Cho)in the hippocampus, whereas the Ins concentration was reduced in the cerebellum. Overall, these data illustrate that MRI and MRS are valuable assesment tools sufficiently sensitive to detect associated changes in different brain areas, thus providing new insight into the causative role of dosage-sensitive genes in the Ts65Dn DS mouse model.展开更多
Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tiss...Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.展开更多
A multiple-image method is proposed to approximate the reaction-field potential of a source charge inside a finite length cylinder due to the electric polarization of the surrounding membrane and bulk water.When appli...A multiple-image method is proposed to approximate the reaction-field potential of a source charge inside a finite length cylinder due to the electric polarization of the surrounding membrane and bulk water.When applied to a hybrid ion-channel model,this method allows a fast and accurate treatment of the electrostatic interactions of protein with membrane and solvent.To treat the channel/membrane interface boundary conditions of the electric potential,an optimization approach is used to derive image charges by fitting the reaction-field potential expressed in terms of cylindric harmonics.Meanwhile,additional image charges are introduced to satisfy the boundary conditions at the planar membrane interfaces.In the end,we convert the electrostatic interaction problem in a complex inhomogeneous system of ion channel/membrane/water into one in a homogeneous free space embedded with discrete charges(the source charge and image charges).The accuracy of this method is then validated numerically in calculating the solvation self-energy of a point charge.展开更多
Phonons are quasi-particles,observed as lattice vibrations in periodic materials,that often dampen in the presence of structural perturbations.Nevertheless,phonon-like collective excitations exist in highly complex sy...Phonons are quasi-particles,observed as lattice vibrations in periodic materials,that often dampen in the presence of structural perturbations.Nevertheless,phonon-like collective excitations exist in highly complex systems,such as proteins,although the origin of such collective motions has remained elusive.Here we present a picture of temperature and hydration dependence of collective excitations in green fluorescent protein(GFP)obtained by inelastic neutron scattering.Our results provide evidence that such excitations can be used as a measure of flexibility/softness and are possibly associated with the protein’s activity.Moreover,we show that the hydration water in GFP interferes with the phonon propagation pathway,enhancing the structural rigidity and stability of GFP.展开更多
This paper summarizes the mathematical and numerical theories and computational elements of the adaptive fast multipole Poisson-Boltzmann(AFMPB)solver.We introduce and discuss the following components in order:the Poi...This paper summarizes the mathematical and numerical theories and computational elements of the adaptive fast multipole Poisson-Boltzmann(AFMPB)solver.We introduce and discuss the following components in order:the Poisson-Boltzmann model,boundary integral equation reformulation,surface mesh generation,the nodepatch discretization approach,Krylov iterative methods,the new version of fast multipole methods(FMMs),and a dynamic prioritization technique for scheduling parallel operations.For each component,we also remark on feasible approaches for further improvements in efficiency,accuracy and applicability of the AFMPB solver to largescale long-time molecular dynamics simulations.The potential of the solver is demonstrated with preliminary numerical results.展开更多
基金supported by National Institutes of Health(NIH),National Institute of Arthritis and Musculoskeletal and Skin Diseases(Grant RO1-AR071930)National Institute of Diabetes and Digestive and Kidney Diseases(Grant RO1 DK121132)supported by the Office of Science of the U.S.Department of Energy under Contract No.DE-AC05-00OR22725。
文摘Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood.Here,we used mouse genetics,mechanical loading,and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts.We created and compared the skeletal phenotypes of control Pkd1^(flox/)+;Wwtr1^(flox/)+,Pkd1^(Oc-cKO),Wwtr1^(Oc-cKO),and Pkd1/Wwtr1^(Oc-cKO)mice to investigate genetic interactions.Consistent with an interaction between polycystins and Wwtr1 in bone in vivo,Pkd1/Wwtr1^(Oc-cKO)mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKOor Pkd1^(Oc-cKO)mice.Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Pkd1/Wwtr1^(Oc-cKO)mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKOor Wwtr1^(Oc-cKO)mice.Moreover,we found that Pkd1/Wwtr1^(Oc-cKO)mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of loadinduced mechanosensing gene expression compared to control mice.Finally,control mice treated with a small molecule mechanomimetic,MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control.In contrast,Pkd1/Wwtr1^(Oc-cKO)mice were resistant to the anabolic effects of MS2.These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.
文摘In the present study we investigated structural and metabolic modifications of the brain in the Ts65Dn mouse model of Down syndrome(DS)using both in vivo magnetic resonance imaging(MRI)and proton magnetic resonance spectroscopy(MRS). MRI was performed for further texture analysis and changes in texture parameters, including mean grey levels, contrast and homogeneity, and they were found in Ts65Dn compared to diploid littermates (2n). These phenotypic changes were different in the hippocampus and cerebellum, since in Ts65Dn mean grey levels increased in the cerebellum and decreased in the hippocampus. In addition, proton NMR spectra revealed differences in metabolite ratios. Levels of N-acetylaspartate(NAA)and glutamate(Glu), were lower compared to total creatine levels (CX), in the Ts65Dn brain. However, the most striking finding was an increase in the concentration of myo-inositol(Ins)and choline(Cho)in the hippocampus, whereas the Ins concentration was reduced in the cerebellum. Overall, these data illustrate that MRI and MRS are valuable assesment tools sufficiently sensitive to detect associated changes in different brain areas, thus providing new insight into the causative role of dosage-sensitive genes in the Ts65Dn DS mouse model.
文摘Recent studies have demonstrated a new role for Klf10, a Krüppel-like transcription factor, in skeletal muscle, specifically relating to mitochondrial function. Thus, it was of interest to analyze additional tissues that are highly reliant on optimal mitochondrial function such as the cerebellum and to decipher the role of Klf10 in the functional and structural properties of this brain region. In vivo (magnetic resonance imaging and localized spectroscopy, behavior analysis) and in vitro (histology, spectroscopy analysis, enzymatic activity) techniques were applied to comprehensively assess the cerebellum of wild type (WT) and Klf10 knockout (KO) mice. Histology analysis and assessment of locomotion revealed no significant difference in Klf10 KO mice. Diffusion and texture results obtained using MRI revealed structural changes in KO mice characterized as defects in the organization of axons. These modifications may be explained by differences in the levels of specific metabolites (myo-inositol, lactate) within the KO cerebellum. Loss of Klf10 expression also led to changes in mitochondrial activity as reflected by a significant increase in the activity of citrate synthase, complexes I and IV. In summary, this study has provided evidence that Klf10 plays an important role in energy production and mitochondrial function in the cerebellum.
基金funded by the Chinese Ministry of Education(NCET-09-0556)985 Project of SJTU,and U.S.NIH(1R01GM083600-03)+2 种基金funded by the U.S.Department of Energy(DEFG0205ER25678)the NSFC(10828101)funded by the U.S.Department of Energy Field Work Proposal ERKJE84.
文摘A multiple-image method is proposed to approximate the reaction-field potential of a source charge inside a finite length cylinder due to the electric polarization of the surrounding membrane and bulk water.When applied to a hybrid ion-channel model,this method allows a fast and accurate treatment of the electrostatic interactions of protein with membrane and solvent.To treat the channel/membrane interface boundary conditions of the electric potential,an optimization approach is used to derive image charges by fitting the reaction-field potential expressed in terms of cylindric harmonics.Meanwhile,additional image charges are introduced to satisfy the boundary conditions at the planar membrane interfaces.In the end,we convert the electrostatic interaction problem in a complex inhomogeneous system of ion channel/membrane/water into one in a homogeneous free space embedded with discrete charges(the source charge and image charges).The accuracy of this method is then validated numerically in calculating the solvation self-energy of a point charge.
基金supported by NSF No.1616008the Department of Energy(DoE),Office of Basic Energy Sciences,and Wayne State University.X.C was supported by NSAF No.U1930403National Natural Science Foundation of China(NSFC)11875051.Neutron scattering measurements at ORNL’s Spallation Neutron Source were supported by the Scientific User Facilities Division,Office of Basic Energy Sciences,DoE.
文摘Phonons are quasi-particles,observed as lattice vibrations in periodic materials,that often dampen in the presence of structural perturbations.Nevertheless,phonon-like collective excitations exist in highly complex systems,such as proteins,although the origin of such collective motions has remained elusive.Here we present a picture of temperature and hydration dependence of collective excitations in green fluorescent protein(GFP)obtained by inelastic neutron scattering.Our results provide evidence that such excitations can be used as a measure of flexibility/softness and are possibly associated with the protein’s activity.Moreover,we show that the hydration water in GFP interferes with the phonon propagation pathway,enhancing the structural rigidity and stability of GFP.
基金supported by NSF,DOE,HHMI,and NIH(B.Z./X.S./N.P.:NSF 0905164,B.Z./J.H.:NSF 0811130 and NSF 0905473,J.A.M.:NSF MCB1020765 and NIH GM31749)the NSF Center of Theoretical Biological Physics(CTBP)partially funded by the Chinese Academy of Sciences,the State Key Laboratory of Scientific/Engineering Computing,and the China NSF(NSFC1097218).
文摘This paper summarizes the mathematical and numerical theories and computational elements of the adaptive fast multipole Poisson-Boltzmann(AFMPB)solver.We introduce and discuss the following components in order:the Poisson-Boltzmann model,boundary integral equation reformulation,surface mesh generation,the nodepatch discretization approach,Krylov iterative methods,the new version of fast multipole methods(FMMs),and a dynamic prioritization technique for scheduling parallel operations.For each component,we also remark on feasible approaches for further improvements in efficiency,accuracy and applicability of the AFMPB solver to largescale long-time molecular dynamics simulations.The potential of the solver is demonstrated with preliminary numerical results.