Six degrees of freedom(6DoF)input interfaces are essential formanipulating virtual objects through translation or rotation in three-dimensional(3D)space.A traditional outside-in tracking controller requires the instal...Six degrees of freedom(6DoF)input interfaces are essential formanipulating virtual objects through translation or rotation in three-dimensional(3D)space.A traditional outside-in tracking controller requires the installation of expensive hardware in advance.While inside-out tracking controllers have been proposed,they often suffer from limitations such as interaction limited to the tracking range of the sensor(e.g.,a sensor on the head-mounted display(HMD))or the need for pose value modification to function as an input interface(e.g.,a sensor on the controller).This study investigates 6DoF pose estimation methods without restricting the tracking range,using a smartphone as a controller in augmented reality(AR)environments.Our approach involves proposing methods for estimating the initial pose of the controller and correcting the pose using an inside-out tracking approach.In addition,seven pose estimation algorithms were presented as candidates depending on the tracking range of the device sensor,the tracking method(e.g.,marker recognition,visual-inertial odometry(VIO)),and whether modification of the initial pose is necessary.Through two experiments(discrete and continuous data),the performance of the algorithms was evaluated.The results demonstrate enhanced final pose accuracy achieved by correcting the initial pose.Furthermore,the importance of selecting the tracking algorithm based on the tracking range of the devices and the actual input value of the 3D interaction was emphasized.展开更多
Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biolog...Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.展开更多
Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function.However,random orientation of cell membrane coating does not...Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function.However,random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites,especially when applied to intracellular regions of transmembrane proteins.Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem.Herein,inside-out cell membrane camouflaged magnetic nanoparticles(IOCMMNPs)were accurately constructed via bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2.Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic Fe_(3)O_(4)nanoparticles to prepare IOCMMNPs.The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay.Ultimately,two compounds,senkyunolide A and ligustilidel,were successfully captured,and their potential antiproliferative activities were further testified by pharmacological experiments.It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.展开更多
Noble metal nanoparticles with hollow interiors and customizable shell com- positions have immense potential for a wide variety of applications. Herein, we present a facile, general, and cost-effective strategy for th...Noble metal nanoparticles with hollow interiors and customizable shell com- positions have immense potential for a wide variety of applications. Herein, we present a facile, general, and cost-effective strategy for the synthesis of noble metal nanoparticles with hollow structures, which is based on the inside-out diffusion of Ag in solid-state core-shell nanoparticles. This approach starts with the preparation of core-shell nanoparticles with Ag residing in the core region, which are then loaded on a solid substrate and aged in air to allow the inside-out diffusion of Ag from the core region, leading to the formation of monometallic or alloy noble metal nanoparticles with a hollow interior. The synthesis was carried out at room temperature and could be achieved on different solid substrates. In particular, the inside-out diffusion of Ag calls for specific concern with respect to the evaluation of the catalytic performance of the Ag-based core--shell nanoparticles since it may potentially interfere with the physical and chemical properties of the core-shell particles.展开更多
A prototype of cross-membrane signal transduction is that extracellular binding of cell surface receptors to their ligands induces intracellular signalling cascades.However,much less is known about the process in the ...A prototype of cross-membrane signal transduction is that extracellular binding of cell surface receptors to their ligands induces intracellular signalling cascades.However,much less is known about the process in the opposite direction,called inside-out signalling.Recent studies show that it plays a more important role in regulating the functions of many cell surface receptors than we used to think.In particular,in cadherin-mediated cell adhesion,recent experiments indicate that intracellular binding of the scaffold protein p120-catenin(p120ctn)can promote extracellular clustering of cadherin and alter its adhesive function.The underlying mechanism,however,is not well understood.To explore possible mechanisms,we designed a new multiscale simulation procedure.Using all-atom molecular dynamics simulations,we found that the conformational dynamics of the cadherin extracellular region can be altered by the intracellular binding of p120ctn.More intriguingly,by integrating all-atom simulation results into coarse-grained random sampling,we showed that the altered conformational dynamics of cadherin caused by the binding of p120ctn can increase the probability of lateral interactions between cadherins on the cell surface.These results suggest that p120ctn could allosterically regulate the cis-dimerization of cadherin through two mechanisms.First,p120ctn controls the extracellular conformational dynamics of cadherin.Second,p120ctn oligomerization can further promote cadherin clustering.Therefore,our study provides a mechanistic foundation for the inside-out signalling in cadherin-mediated cell adhesion,while the computational framework can be generally applied to other cross-membrane signal transduction systems.展开更多
The small GTPase Rap1 induces integrin activation via an inside-out signaling pathway mediated by the Rapl-interacting adaptor mol- ecule （RIAM）. Blocking this pathway may suppress tumor metastasis and other disease...The small GTPase Rap1 induces integrin activation via an inside-out signaling pathway mediated by the Rapl-interacting adaptor mol- ecule （RIAM）. Blocking this pathway may suppress tumor metastasis and other diseases that are related to hyperactive integrins. However, the molecular basis for the specific recognition of RIAM by Rap1 remains largely unknown. Herein we present the crystal structure of an active, GTP-bound GTPase domain of Rap1 in complex with the Ras association （RA）-pleckstrin homology （PH） structural module of RIAM at 1.65 A. The structure reveals that the recognition of RIAM by Rap1 is governed by side-chain interactions. Several side chains are critical in determining specificity of this recognition, particularly the Lys31 residue in Rap1 that is oppositely charged compared with the Glu31/Asp31 residue in other Ras GTPases. Lys31 forms a salt bridge with RIAM residue Glu212, making it the key specificity determinant of the interaction. We also show that disruption of these interactions results in reduction of Rapl：RIAM association, leadingto a loss of co-clustering and cell adhesion. Our findings elucidate the molecular mechanism by which RIAM med- iates Rapl-induced integrin activation. The crystal structure also offers new insight into the structural basis for the specific recruitment of RA-PH module-containing effector proteins by their smaU GTPase partners.展开更多
Attic cholesteatoma with antral extension in tight sclerotic mastoid cavities is a common presentation that creates difficult decision-making intraoperatively.Drilling through a sclerotic and small mastoid cavity,keep...Attic cholesteatoma with antral extension in tight sclerotic mastoid cavities is a common presentation that creates difficult decision-making intraoperatively.Drilling through a sclerotic and small mastoid cavity,keeping the canal wall intactis often difficult and increases the risk of serious injury.Consequently,a canal-wall-down mastoidectomy is often performed.The endoscopic transcanal modified canal-wall-down mastoidectomy approach al lows the benefits of an open cavity for cholesteatoma resection and the benefits of a closed cavity for better long-term care and a more normal ear canal and middle ear reconstruction.展开更多
文摘Six degrees of freedom(6DoF)input interfaces are essential formanipulating virtual objects through translation or rotation in three-dimensional(3D)space.A traditional outside-in tracking controller requires the installation of expensive hardware in advance.While inside-out tracking controllers have been proposed,they often suffer from limitations such as interaction limited to the tracking range of the sensor(e.g.,a sensor on the head-mounted display(HMD))or the need for pose value modification to function as an input interface(e.g.,a sensor on the controller).This study investigates 6DoF pose estimation methods without restricting the tracking range,using a smartphone as a controller in augmented reality(AR)environments.Our approach involves proposing methods for estimating the initial pose of the controller and correcting the pose using an inside-out tracking approach.In addition,seven pose estimation algorithms were presented as candidates depending on the tracking range of the device sensor,the tracking method(e.g.,marker recognition,visual-inertial odometry(VIO)),and whether modification of the initial pose is necessary.Through two experiments(discrete and continuous data),the performance of the algorithms was evaluated.The results demonstrate enhanced final pose accuracy achieved by correcting the initial pose.Furthermore,the importance of selecting the tracking algorithm based on the tracking range of the devices and the actual input value of the 3D interaction was emphasized.
文摘Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.
基金the National Natural Science Foundation of China(No.82073807)。
文摘Cell membrane camouflaged nanoparticles have been widely used in the field of drug leads discovery attribute to their unique biointerface targeting function.However,random orientation of cell membrane coating does not guarantee effective and appropriate binding of drugs to specific sites,especially when applied to intracellular regions of transmembrane proteins.Bioorthogonal reactions have been rapidly developed as a specific and reliable method for cell membrane functionalization without disturbing living biosystem.Herein,inside-out cell membrane camouflaged magnetic nanoparticles(IOCMMNPs)were accurately constructed via bioorthogonal reactions to screen small molecule inhibitors targeting intracellular tyrosine kinase domain of vascular endothelial growth factor recptor-2.Azide functionalized cell membrane acted as a platform for specific covalently coupling with alkynyl functionalized magnetic Fe_(3)O_(4)nanoparticles to prepare IOCMMNPs.The inside-out orientation of cell membrane was successfully verified by immunogold staining and sialic acid quantification assay.Ultimately,two compounds,senkyunolide A and ligustilidel,were successfully captured,and their potential antiproliferative activities were further testified by pharmacological experiments.It is anticipated that the proposed inside-out cell membrane coating strategy endows tremendous versatility for engineering cell membrane camouflaged nanoparticles and promotes the development of drug leads discovery platforms.
文摘Noble metal nanoparticles with hollow interiors and customizable shell com- positions have immense potential for a wide variety of applications. Herein, we present a facile, general, and cost-effective strategy for the synthesis of noble metal nanoparticles with hollow structures, which is based on the inside-out diffusion of Ag in solid-state core-shell nanoparticles. This approach starts with the preparation of core-shell nanoparticles with Ag residing in the core region, which are then loaded on a solid substrate and aged in air to allow the inside-out diffusion of Ag from the core region, leading to the formation of monometallic or alloy noble metal nanoparticles with a hollow interior. The synthesis was carried out at room temperature and could be achieved on different solid substrates. In particular, the inside-out diffusion of Ag calls for specific concern with respect to the evaluation of the catalytic performance of the Ag-based core--shell nanoparticles since it may potentially interfere with the physical and chemical properties of the core-shell particles.
基金supported by the National Institutes of Health under grant number 1R01GM117104supported by the National Institutes of Health under grant numbers R01GM120238 and R01GM122804supported by a start-up grant from Albert Einstein College of Medicine.Computational support was provided by Albert Einstein College of Medicine High Performance Computing Center and by the National Science Foundation through the Extreme Science and Engineering Discovery Environment(XSEDE)undergrant numberTG-MCB200014.
文摘A prototype of cross-membrane signal transduction is that extracellular binding of cell surface receptors to their ligands induces intracellular signalling cascades.However,much less is known about the process in the opposite direction,called inside-out signalling.Recent studies show that it plays a more important role in regulating the functions of many cell surface receptors than we used to think.In particular,in cadherin-mediated cell adhesion,recent experiments indicate that intracellular binding of the scaffold protein p120-catenin(p120ctn)can promote extracellular clustering of cadherin and alter its adhesive function.The underlying mechanism,however,is not well understood.To explore possible mechanisms,we designed a new multiscale simulation procedure.Using all-atom molecular dynamics simulations,we found that the conformational dynamics of the cadherin extracellular region can be altered by the intracellular binding of p120ctn.More intriguingly,by integrating all-atom simulation results into coarse-grained random sampling,we showed that the altered conformational dynamics of cadherin caused by the binding of p120ctn can increase the probability of lateral interactions between cadherins on the cell surface.These results suggest that p120ctn could allosterically regulate the cis-dimerization of cadherin through two mechanisms.First,p120ctn controls the extracellular conformational dynamics of cadherin.Second,p120ctn oligomerization can further promote cadherin clustering.Therefore,our study provides a mechanistic foundation for the inside-out signalling in cadherin-mediated cell adhesion,while the computational framework can be generally applied to other cross-membrane signal transduction systems.
文摘The small GTPase Rap1 induces integrin activation via an inside-out signaling pathway mediated by the Rapl-interacting adaptor mol- ecule （RIAM）. Blocking this pathway may suppress tumor metastasis and other diseases that are related to hyperactive integrins. However, the molecular basis for the specific recognition of RIAM by Rap1 remains largely unknown. Herein we present the crystal structure of an active, GTP-bound GTPase domain of Rap1 in complex with the Ras association （RA）-pleckstrin homology （PH） structural module of RIAM at 1.65 A. The structure reveals that the recognition of RIAM by Rap1 is governed by side-chain interactions. Several side chains are critical in determining specificity of this recognition, particularly the Lys31 residue in Rap1 that is oppositely charged compared with the Glu31/Asp31 residue in other Ras GTPases. Lys31 forms a salt bridge with RIAM residue Glu212, making it the key specificity determinant of the interaction. We also show that disruption of these interactions results in reduction of Rapl：RIAM association, leadingto a loss of co-clustering and cell adhesion. Our findings elucidate the molecular mechanism by which RIAM med- iates Rapl-induced integrin activation. The crystal structure also offers new insight into the structural basis for the specific recruitment of RA-PH module-containing effector proteins by their smaU GTPase partners.
文摘Attic cholesteatoma with antral extension in tight sclerotic mastoid cavities is a common presentation that creates difficult decision-making intraoperatively.Drilling through a sclerotic and small mastoid cavity,keeping the canal wall intactis often difficult and increases the risk of serious injury.Consequently,a canal-wall-down mastoidectomy is often performed.The endoscopic transcanal modified canal-wall-down mastoidectomy approach al lows the benefits of an open cavity for cholesteatoma resection and the benefits of a closed cavity for better long-term care and a more normal ear canal and middle ear reconstruction.
