Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) superfamily of proteins, circulates in a complex with vitronectin. Furthermore, these two proteins are co-localized in the ...Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) superfamily of proteins, circulates in a complex with vitronectin. Furthermore, these two proteins are co-localized in the extracellular matrix (ECM) in many different pathophysiological conditions. Though PAI-1 is a well-characterized inhibitor of serine proteases, recent emphasis has also focused on its protease-independent functions. Vitronectin, a multi-domain protein that binds a wide variety of ligands and proteins, exists in the circulation in a preferred monomeric state, while in the extracellular matrix it exists as a multimer resulting from an altered conformation. Though the mechanism for the conformational alterations and compartmentalization in tissues is unknown, there are a number of biomolecules including PAI-1 that appear to cause such changes. Experimental analysis has established that PAI-1 induces association of vitronectin to higher-order species in a concentration-dependent fashion [1]. This report extends our investigations into the mechanism of the interaction between vitronectin and PAI-1 to explore the physiological relevance of these higher-order complexes for cellular adhesion and migration. In this study, we evaluate the effects of the pericellular microenvironment on the functions of the multimeric complexes in a variety of relevant biological settings. Our findings underscore the importance of the variability of components within this microenvironment, including different receptors and ECM components, in governing the way in which the vitronectin/PAI-1 complex mediates cell-matrix interactions.展开更多
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
Geographic patterns in body size are often associated with latitude,elevation,or environmental and climatic variables.This study investigated patterns of body size and cell size of the green anole lizard,Anolis caroli...Geographic patterns in body size are often associated with latitude,elevation,or environmental and climatic variables.This study investigated patterns of body size and cell size of the green anole lizard,Anolis carolinensis,and potential associations with geography or climatic variables.Lizards were sampled from 19 populations across the native range,and body size,red blood cell size and size and number of muscle cells were measured.Climatic data from local weather stations and latitude and longitude were entered into model selection with Akaike’s information criterion to explain patterns in cell and body sizes.Climatic variables did not drive any major patterns in cell size or body size;rather,latitude and longitude were the best predictors of cell and body size.In general,smaller body and cell sizes in Florida anoles drove geographic patterns in A.carolinensis.Small size in Florida may be attributable to�q�the�geological history of the peninsular state or�the�unique ecological factors in this area,including a recently introduced congener.In contrast to previous studies,we found that A.carolinensis does not follow Bergmann’s rule when the influence of Florida is excluded.Rather,the opposite pattern of larger lizards in southern populations is evident in the absence of Florida populations,and mirrors the general pattern in squamates.Muscle cell size was negatively related to latitude and red blood cell size showed no latitudinal trend outside of Florida.Different patterns in the sizes of the 2 cell types confirm the importance of examining multiple cell types when studying geographic variation in cell size.展开更多
A striking characteristic of plant cells is that their organelles can move rapidly through the cell.This movement,commonly referred to as cytoplasmic streaming,has been observed for over 200 years,but we are only now ...A striking characteristic of plant cells is that their organelles can move rapidly through the cell.This movement,commonly referred to as cytoplasmic streaming,has been observed for over 200 years,but we are only now beginning to decipher the mechanisms responsible for it.The identification of the myosin motor proteins responsible for these movements allows us to probe the regulatory events that coordinate organelle displacement with normal cell physiology.This review will highlight several recent developments that have provided new insight into the regulation of organelle movement,both at the cellular level and at the molecular level.展开更多
文摘Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) superfamily of proteins, circulates in a complex with vitronectin. Furthermore, these two proteins are co-localized in the extracellular matrix (ECM) in many different pathophysiological conditions. Though PAI-1 is a well-characterized inhibitor of serine proteases, recent emphasis has also focused on its protease-independent functions. Vitronectin, a multi-domain protein that binds a wide variety of ligands and proteins, exists in the circulation in a preferred monomeric state, while in the extracellular matrix it exists as a multimer resulting from an altered conformation. Though the mechanism for the conformational alterations and compartmentalization in tissues is unknown, there are a number of biomolecules including PAI-1 that appear to cause such changes. Experimental analysis has established that PAI-1 induces association of vitronectin to higher-order species in a concentration-dependent fashion [1]. This report extends our investigations into the mechanism of the interaction between vitronectin and PAI-1 to explore the physiological relevance of these higher-order complexes for cellular adhesion and migration. In this study, we evaluate the effects of the pericellular microenvironment on the functions of the multimeric complexes in a variety of relevant biological settings. Our findings underscore the importance of the variability of components within this microenvironment, including different receptors and ECM components, in governing the way in which the vitronectin/PAI-1 complex mediates cell-matrix interactions.
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.
基金the Department of Ecology&Evolutionary Biology and the University of Tennessee,Knoxville(UTK)for providing research funding and spacefinancial support to R.M.Goodman during this project(also the Biology Division Science Alliance Award and UTK Yates Dissertation Fellowship).
文摘Geographic patterns in body size are often associated with latitude,elevation,or environmental and climatic variables.This study investigated patterns of body size and cell size of the green anole lizard,Anolis carolinensis,and potential associations with geography or climatic variables.Lizards were sampled from 19 populations across the native range,and body size,red blood cell size and size and number of muscle cells were measured.Climatic data from local weather stations and latitude and longitude were entered into model selection with Akaike’s information criterion to explain patterns in cell and body sizes.Climatic variables did not drive any major patterns in cell size or body size;rather,latitude and longitude were the best predictors of cell and body size.In general,smaller body and cell sizes in Florida anoles drove geographic patterns in A.carolinensis.Small size in Florida may be attributable to�q�the�geological history of the peninsular state or�the�unique ecological factors in this area,including a recently introduced congener.In contrast to previous studies,we found that A.carolinensis does not follow Bergmann’s rule when the influence of Florida is excluded.Rather,the opposite pattern of larger lizards in southern populations is evident in the absence of Florida populations,and mirrors the general pattern in squamates.Muscle cell size was negatively related to latitude and red blood cell size showed no latitudinal trend outside of Florida.Different patterns in the sizes of the 2 cell types confirm the importance of examining multiple cell types when studying geographic variation in cell size.
基金supported by a grant from theNational Science Foundation (MCB-0822111) to A.N
文摘A striking characteristic of plant cells is that their organelles can move rapidly through the cell.This movement,commonly referred to as cytoplasmic streaming,has been observed for over 200 years,but we are only now beginning to decipher the mechanisms responsible for it.The identification of the myosin motor proteins responsible for these movements allows us to probe the regulatory events that coordinate organelle displacement with normal cell physiology.This review will highlight several recent developments that have provided new insight into the regulation of organelle movement,both at the cellular level and at the molecular level.
基金supported by the National Science Foundation(Grant number:0817940to HG)the DOE Office of Biological and Environmental Research-Genome to Life Program through the BioEnergy Science Center(BESC)(to FC)+2 种基金the Sun Grant Initiative(to FC)the computer resources(Newton)from University of Tennessee Knoxvillethe NSF TeraGrid resources provided by the University of Texas at Austin
