Peptide-modified delivery systems are enabling the improvement of the targeting specificity,biocompatibility,stability,etc.However,the precise design of a peptide-decorated surface for a designated function has remain...Peptide-modified delivery systems are enabling the improvement of the targeting specificity,biocompatibility,stability,etc.However,the precise design of a peptide-decorated surface for a designated function has remained to be challenging due to a lack of mechanistic understanding of the interactions between surface-bound peptide ligands and their receptors.Enlightened by the recent report on pairwise interactions between peptides in the solution state and surface-immobilized state,we used computational simulations to explore the contributing mechanisms underlining the observed binding affinity characteristics.Molecular dynamics simulations were performed to sample and compare conformations of homo-octapeptides free in solution(mobile peptides)and bound to the surface(N-terminal fixed peptides).We found that peptides converged to more extended and rigid conformations when immobilized to the surface and confirmed that the extended structures could increase the space available to counter-interacting peptides during the peptide–peptide interactions.In addition,studies on interactions between stationary and mobile peptides revealed that main-chain/side-chain and side-chain/side-chain hydrogen bonds play an important role.The presented efforts in this work may provide supportive references for peptide design and modification on the nanoparticle surface as well as guidance for analyzing peptide–receptor interactions through an emphasis on hydrogen bonds during peptide design and an understanding of the influence on the binding affinity by the sequence-dependant conformational changes after peptide immobilization.展开更多
Several clinical studies have reported that hearing loss is correlated with autism in children.However,little is known about the underlying mechanism between hearing loss and autism.p21-activated kinases(PAKs)are a fa...Several clinical studies have reported that hearing loss is correlated with autism in children.However,little is known about the underlying mechanism between hearing loss and autism.p21-activated kinases(PAKs)are a family of serine/threonine kinases that can be activated by multiple signaling molecules,particularly the Rho family of small GTPases.Previous studies have shown that Pak1 mutations are associated with autism.In the present study,we take advantage of Pak1 knockout(Pak1a/a)mice to investigate the role of PAK1 in hearing function.We find that PAK1 is highly expressed in the postnatal mouse cochlea and that PAK1 deficiency leads to hair cell(HC)apoptosis and severe hearing loss.Further investigation indicates that PAK1 deficiency downregulates the phosphorylation of cofilin and ezrin-radixin-moesin and the expression of b II-spectrin,which further decreases the HC synapse density in the basal turn of cochlea and disorganized the HC stereocilia in all three turns of cochlea in Pak1à/àmice.Overall,our work demonstrates that the autism-related gene Pak1 plays a crucial role in hearing function.As the first candidate gene linking autism and hearing loss,Pak1 may serve as a potential target for the clinical diagnosis of autism-related hearing loss.展开更多
The arrangement of oligothiophenes is essential for understanding the relationship between structure and properties particularly in the organic electronic field. The self-assembly behaviors of helical(TMS)2-[7]helicen...The arrangement of oligothiophenes is essential for understanding the relationship between structure and properties particularly in the organic electronic field. The self-assembly behaviors of helical(TMS)2-[7]helicene(T1), naphthalene-cored double(TMS)2-[7]helicene(T2), and saddle-shaped cyclooctatetrathiophene(T3), its derivative α,α,α,α-tetraphenyl-cyclooctatetrathiophene(T4) on solid surface are firstly investigated by using a combination of scanning tunneling microscopy(STM) and density functional theory(DFT) calculation. 1,3,5-Tris(10-carboxydecyloxy)-benzene(TCDB) is selected to build flexible host networks to immobilize these oligothiophenes in order to capture their molecular adsorption images successfully. The observed monodisperse or polydisperse filling and long-range alignment of oligothiophenes are described based on the non-covalent interactions and commensurate structure between olihothiophene and cavity. We speculate that those molecularly defined alignments could lead to significantly understanding the application of such ordered monolayer in organic electronic devices.展开更多
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB36000000)the National Key R&D Program of China(No.2022YFA1203200)the National Natural Science Foundation of China(No.32027801).
文摘Peptide-modified delivery systems are enabling the improvement of the targeting specificity,biocompatibility,stability,etc.However,the precise design of a peptide-decorated surface for a designated function has remained to be challenging due to a lack of mechanistic understanding of the interactions between surface-bound peptide ligands and their receptors.Enlightened by the recent report on pairwise interactions between peptides in the solution state and surface-immobilized state,we used computational simulations to explore the contributing mechanisms underlining the observed binding affinity characteristics.Molecular dynamics simulations were performed to sample and compare conformations of homo-octapeptides free in solution(mobile peptides)and bound to the surface(N-terminal fixed peptides).We found that peptides converged to more extended and rigid conformations when immobilized to the surface and confirmed that the extended structures could increase the space available to counter-interacting peptides during the peptide–peptide interactions.In addition,studies on interactions between stationary and mobile peptides revealed that main-chain/side-chain and side-chain/side-chain hydrogen bonds play an important role.The presented efforts in this work may provide supportive references for peptide design and modification on the nanoparticle surface as well as guidance for analyzing peptide–receptor interactions through an emphasis on hydrogen bonds during peptide design and an understanding of the influence on the binding affinity by the sequence-dependant conformational changes after peptide immobilization.
基金supported by grants from Strategic Priority Research Program of the Chinese Academy of Science(XDA16010303)the National Natural Science Foundation of China(81570921,82030029,81970882,81970884,81900941,81771019,81700913)+2 种基金Natural Science Foundation of Jiangsu Province(BE2019711,BK20190121)the China Postdoctoral Science Foundation(2020M681555)Shenzhen Fundamental Research Program(JCYJ20190814093401920)。
文摘Several clinical studies have reported that hearing loss is correlated with autism in children.However,little is known about the underlying mechanism between hearing loss and autism.p21-activated kinases(PAKs)are a family of serine/threonine kinases that can be activated by multiple signaling molecules,particularly the Rho family of small GTPases.Previous studies have shown that Pak1 mutations are associated with autism.In the present study,we take advantage of Pak1 knockout(Pak1a/a)mice to investigate the role of PAK1 in hearing function.We find that PAK1 is highly expressed in the postnatal mouse cochlea and that PAK1 deficiency leads to hair cell(HC)apoptosis and severe hearing loss.Further investigation indicates that PAK1 deficiency downregulates the phosphorylation of cofilin and ezrin-radixin-moesin and the expression of b II-spectrin,which further decreases the HC synapse density in the basal turn of cochlea and disorganized the HC stereocilia in all three turns of cochlea in Pak1à/àmice.Overall,our work demonstrates that the autism-related gene Pak1 plays a crucial role in hearing function.As the first candidate gene linking autism and hearing loss,Pak1 may serve as a potential target for the clinical diagnosis of autism-related hearing loss.
基金supported by the National Basic Research Program of China(2016YFA0200700)the National Natural Science Foundation of China(21472029,21773041,21672054)
文摘The arrangement of oligothiophenes is essential for understanding the relationship between structure and properties particularly in the organic electronic field. The self-assembly behaviors of helical(TMS)2-[7]helicene(T1), naphthalene-cored double(TMS)2-[7]helicene(T2), and saddle-shaped cyclooctatetrathiophene(T3), its derivative α,α,α,α-tetraphenyl-cyclooctatetrathiophene(T4) on solid surface are firstly investigated by using a combination of scanning tunneling microscopy(STM) and density functional theory(DFT) calculation. 1,3,5-Tris(10-carboxydecyloxy)-benzene(TCDB) is selected to build flexible host networks to immobilize these oligothiophenes in order to capture their molecular adsorption images successfully. The observed monodisperse or polydisperse filling and long-range alignment of oligothiophenes are described based on the non-covalent interactions and commensurate structure between olihothiophene and cavity. We speculate that those molecularly defined alignments could lead to significantly understanding the application of such ordered monolayer in organic electronic devices.
