Three anti-inflammatory polysaccharides from Lonicera japonica Thunb.:insights into the structure-function relationships

This study demonstrates the feasibility of producing three polysaccharides(neutral LJP-1,acidic LJP-2 and acidic LJP-3)with significant in vitro and in vivo anti-inflammatory activities from the flowers of Lonicera japonica.The three polysaccharides differed in chemical composition,molecular weight(Mw)distribution,glycosidic linkage pattern,functional groups and morphology.They exhibited excellent protective effects(in a dose-dependent manner)in lipopolysaccharide-injured RAW264.7 macrophages and Cu SO4-damaged zebrafish via reducing NO production and inhibiting the overexpressions of inflammation-related transcription factors,inflammatory proteins and cytokines in the NF-κB/MAPK signaling pathways.Their antiinflammatory effects varied owing to their different molecular characteristics and chemical compositions.Overall,LJP-2 at 400μg/m L was the most effective.LJP-2 consisted mainly of→5)-α-L-Araf(1→,→4)-α-LGalp A(1→and→2)-α-L-Rhap(1→residues with terminal T-β-D-Glcp.Thus,honeysuckle flowers are good sources of anti-inflammatory polysaccharides,and precise fractionation enables the production of potent antiinflammatory agents for the development of functional foods and healthcare products.

Structure-function integrated magnesium alloys and their composites

Magnesium-based materials not only exhibit desirable characteristics such as low density and high specific strength, but also possess exceptional functional properties, including high damping capacity, high thermal conductivity, high electromagnetic interference shielding capacity, flame retardancy, and dissolvability. However, achieving a balance between strength and functional properties remains a significant challenge in Mg alloys community. Typically, strength depends on the pinning effect of defects, such as solute atoms and second phases,which hinder dislocation motion. On the other hand, optimal functional properties usually necessitate relative perfect crystal structures, as the presence of solute atoms and second phases can have adverse effects on damping capacity and thermal conductivity. Balancing these conflicting requirements is difficult. The trade-off between strength and functional properties of the Mg alloys should be broken to meet the urgent need in aerospace, automotive, 3C(computers, communications, and consumer electronics) and energy industries for high performance structural-functional integrated Mg-based materials. This review summarizes recent progress in understanding the mechanisms and influencing factors for the functional properties of Mg alloys. The mechanisms underlying the trade-off between strength and functional properties of Mg alloys is discussed. The latest developed structural-functional integrated Mg alloys and their composites are summarized, including high strength Mg-based materials with high damping capacity/high thermal conductivity/strong electromagnetic shielding capability/excellent flame-resistance/high dissolution rate. The future works of developing structure-function integrated Mg-based materials are proposed.

Extending the solid solution range of sodium ferric pyrophosphate:Off‐stoichiometric Na_(3)Fe(2.5)(P_(2)O_(7))_(2)as a novel cathode for sodium‐ion batteries

Iron‐based pyrophosphates are attractive cathodes for sodium‐ion batteries due to their large framework,cost‐effectiveness,and high energy density.However,the understanding of the crystal structure is scarce and only a limited candidates have been reported so far.In this work,we found for the first time that a continuous solid solution,Na_(4−α)Fe_(2+α)_(2)(P_(2)O_(7))_(2)(0≤α≤1,could be obtained by mutual substitution of cations at center‐symmetric Na3 and Na4 sites while keeping the crystal building blocks of anionic P2O7 unchanged.In particular,a novel off‐stoichiometric Na_(3)Fe(2.5)(P_(2)O_(7))_(2)is thus proposed,and its structure,energy storage mechanism,and electrochemical performance are extensively investigated to unveil the structure–function relationship.The as‐prepared off‐stoichiometric electrode delivers appealing performance with a reversible discharge capacity of 83 mAh g^(−1),a working voltage of 2.9 V(vs.Na^(+)/Na),the retention of 89.2%of the initial capacity after 500 cycles,and enhanced rate capability of 51 mAh g^(−1)at a current density of 1600 mA g^(−1).This research shows that sodium ferric pyrophosphate could form extended solid solution composition and promising phase is concealed in the range of Na_(4−α)Fe_(2+α)_(2)(P_(2)O_(7))_(2),offering more chances for exploration of new cathode materials for the construction of high‐performance SIBs.

Structure-function Relationships in Human Hypoxanthine-guanine Phosphoribosyltransferase(HGPRT) by Random Mutagenesis

Hypoxanthine-guanine phosphoribosyltransferase （ HGPRT, EC 2.4.2.8） is a key enzyme of the purine salvage pathway, which allows recycling of purine bases into DNA and RNA. It is widely distributed in nature and has been studied both in prokaryotes and eukaryotes. In humans, a complete lack of HGPRT activity causes the Lesch-Nyhan syndrome, which is characterized by hyperuricaemia and neural disorders,

Structure-function relationship of antimicrobial peptide cathelicidin Pc-CATH1

Cathelicidin Pc-CATH1 is a cathelicidin-derived myeloid antimicrobial peptide identified from Phasianus colchicus with strong antimicrobial activity against most of bacteria and fungi tested,including the clinically isolated(IS)drug-resistant strains.Considering the uniform distribution of net positive charge in both C-and N-terminus sequence of cathelicidin Pc-CATH1 and most of hydrophobic amino acid(aa)residues positioned in middle of the sequence,the antimicrobial peptide was used to investigate the structure-function relationship by truncating gradually N-or C-terminus amino acid residue.More than 10 modified peptide homo-logues(20-26 aa length)of cathelicidin Pc-CATH1 were found to keep strong antimicrobial abilities.The possible relationships between bioactivities including antimicrobial and hemolytic abilities,components of secondary structure,hydrophobicity,amphipathicity,net charge,and sequence length were investigated.The current work provided suggestions for structural and functional modification of linear,α-helical antimicrobial peptides containing no disulfided bridges.

Thoughts of a travelling ecologist 14. Structure-function conflation in environmental risk assessment and monitoring

Recently,I attended a conference organised by the European Food Safety Authority in the beautiful and prosperous Italian city of Parma.The overall topic of the conference was risk assessment,and the program included a section on aspects of environmental risk assessment.In various areas,including the evalution of the effects of pesticide applications,invasive organisms or genetically modified plants(Arpaia et al.,2014)preparing an environmental risk assessment is an obviously relevant exercise.

GO/HTPB composite liner for anti-migration of small molecules

Hydroxyl-terminated polybutadiene/toluene diisocyanate(HTPB/TDI)system is widely used in composite solid propellants.The migrations of plasticizers and water molecules from solid propellants and surrounding environment to the inhibitor have always been the important issues.This study focuses on the preparation,characterization and anti-migration behavior of graphene oxide(GO)/HTPB nanocomposite liner.The GO/HTPB(GH)composite liners affect the migration of small molecules through a tighter cross-linked structure and weakening function of small molecule adsorption.The anti-migration performance of the liner at different temperatures was analyzed,and the influence of the added amount of GO on the anti-migration performance and adhesion performance was also systematically studied.The overall performance of the liner is optimized when the amount of GO filler is 0.3 wt%.After adding 0.3 wt%GO,the concentration of dioctyl sebacate(DOS)migrated into the liner is decreased by 23.28%,and the concentration of water molecules is decreased by 51.89%,indicating that the introduction of GO can significantly improve the anti-migration performance of the liner.In addition,the bond strength is greatly increased from 0.25 MPa to 0.95 MPa,which meets the application requirements of the current propellant system.This research provides an important way for the preparation of structure-function synergistic anti-migration composite liners.

Subspecific variation in sperm morphology and performance in the Long-tailed Finch (Poephila acuticauda)

Background: Evolutionary biology endeavours to explain biological diversity,and as such it is critical to develop an understanding of the adaptive and functional significance of trait variation.Spermatozoa exhibit remarkable levels of morphological diversification.However,our understanding of the evolutionary causes and functional significance of this variation is limited,especially at the intraspecific level.Methods: We quantified variation in sperm morphology and performance between two subspecies of Long-tailed Finch(Poephila acuticauda acuticauda and P.a.hecki),a small grassfinch found in tropical northern Australia.Despite a zone of secondary contact,these subspecies are maintained as two distinct forms: P.a.acuticauda occurs in the western part of the species' range and has a yellow bill,while P.a.hecki exhibits a red bill and is found in the eastern part of the range.Results: We found small,but significant differences in sperm size between these subspecies(P.a.acuticauda had longer and narrower sperm than P.a.hecki),which was surprising given the recent evolutionary origins of these two taxa(i.e.0.3 million years ago).Additionally,both subspecies exhibited high values of between- and within-male variation in sperm morphology,though in the case of sperm midpiece length this variation was significantly lower in P.a.acuticauda relative to P.a.hecki.Conclusions: We suggest these observed differences in sperm morphology are the result of genetic drift and reflect historical processes associated with divergence between the eastern and western populations of these two subspecies.Finally,we discuss the potential implications of our findings for the process of population divergence and reproductive isolation.

Mechano-Chemical Regulation of VWF-A Activity in Flow

Von Willebrand Factor(VWF),a multimeric plasma glycoprotein,is synthesized in endothelial cells and megakaryocytes.In adhesion and aggregation of circulating platelets towards to the sites of vascular injury,VWF captures and activates the circulating platelets through interaction with platelet GPlba.As a triplet complex of A1A2A3,the VWF-A domain is a closed conformation with a low affinity to GPlba,but mutations or pathological hemodynamic environment of high fluid shear stress can induce the closed A domain to become an extended one.However,the key events in the force-and/or mutation-induced activation of VWF-A under flows remains unclear.Therefore,with techniques of AFM and PPFC,we here examined transformation of conformation and function of VWF-A under various wall shear stresses,for understanding regulation of force on VWF-A activation.Interesting,AFM scanning imaging data showed that VWF-A molecules on substrate pretreated by perfusing distilled water at various wall shear stresses shortened first and then lengthened as increasing of the pre-loaded wall shear stress,and the threshold of the wall shear stress is about 100 dyn/cm2,demonstrating that increasing pre-loaded wall shear stress would make the treated-A1A2A3 conformation gradually transform from a loose spherical structure to a compact one first and then become an open or extended one.The adhesion frequency of GPlba-coated Polystyrene microspheres(3-μm radius)on the VWF-A-coated substrates decreased first and then increased with the preloaded wall shear stress,which has a same threshold mentioned above.These results suggested that,force-induced activation of VWF-A occurs just at high wall shear stresses(>100 dyn/cm2).The mechanical stability of the closed A1A2A3 conformation would be weakened by the gain of function(GOF)mutant R1 308 L of A1 and enhanced by the loss of function(LOF)mutant G1324S,as it should be.To further reveal the molecular mechanism of the force-induced enhancing or weakening of VWF-A activation,we performed AFM experiment to investigate interaction of A1(WT A1 and its two mutants,the GOF mutant R1 308 L and the LOF mutant G1324S)with A2 and A3,respectively.The adhesive frequency of A1 with A2was larger than that of A1 with A3,showing that A1 was in favor of A2 rather than A3.And,the lifetimes of A1-A2 and A1-A3bond were biphasic force-dependent,showing a'Catch-slip bond'transform in binding of A1 to A2 or A3.It suggested that under the low wall shear stresses,force could inhibit VWF activity through a catch bond mechanism,which enhanced the stability of the closed A1A2A3 conformation,but under high wall shear stresses,the force would enhance VWF activity through a slip bond mechanism,which promoted conformational transform of VWF-A from closed to extended one through reducing the stability of the closed A1A2A3 structure.Our results showed that the GOF mutant R1 308 L would down-regulate the binding affinity of A1 to A2,leading to a low barrier in opening of the closed VWF-A structure.In contrast,the LOF mutant G1324S would enhance the stability of the closed VWF-A conformation by up-regulating the binding affinity of A1 to A2,leading to inhibition of VWF activity.

Molecular Dynamic Simulation of Kindlin F3 Domain with Integrin β3-tail

Integrin activation,the transition from a low to a high affinity state,regulates the numerous cellular responses consequent to integrin engagement by extracellular matrix proteins.Kindlin proteins,play crucial roles in the integrin-signaling pathway by directly interacting with and activating integrins,which mediate the cell-extracellular matrix adhesion and signaling.As a widely distributed PTB domain protein and a major member of the kindlin family,kindlin2 interacts withβ3-tail,bridges talin-activated integrins to promote integrin aggregation,and enhances talin-induced integrin activation.Thus,kindlin2 is identified as a coactivator of integrins.Unlike talins,kindlin2 cannot directly alter the conformation of the integrin transmembrane helix and fail to activate integrin alone.Nevertheless,although it is widely accepted that kindlins and talins synergistically promote integrin activation,the underlying mechanism is unclear.Thus,the study of the force dissociation of the kindlin2/β3-tail complex and the conformation stabilization under different mechanical micro-environments should be of great significance for the further understanding of the structural basis of its synergistically activation of integrin.To reveal the molecular dynamics mechanism of interaction between kindlin2 andβ3-tail,we perform molecular dynamics(MD)simulations for this complex with different computing strategies interaction.In MD simulations,the available crystal structures of Kindlin-2/β3-tail complex(Protein Data Bank code 5XQ1)was downloaded from the PDB database.Two software packages,VMD for visualization and modeling and NAMD 2.13 for energy minimizations and MD simulations,were used here.The steadystate conformation of the complex was obtained from the equilibrium simulation.The dissociation event was observed by the constant velocity simulation,and the mechanical stability of the complex was observed by the constant force simulation.Our results showed that,during the equilibrium of the kindlin2-F3/β34ail complex,the residue MET612,LYS613 and TRP615 on the F3 domain of kindlin2 contributed to hydrogen-bonding with the corresponding residues onβ3 integrin.These bonds exhibit moderate or strong stability through steered molecular dynamics(SMD)simulation.During the constant velocity simulation,the complex exhibits a variety of unfolding pathways against tension applications,which are mainly distinguished by the disruption of hydrogen-bonds between the F3 domain a1/a2 helixes andβ1/β2 sheets.During the constant force simulation,the different phases of the composite force dissociation have different dissociation probabilities,which shows the biphasic force-dependent characteristics.And,the key residues in the pulling were recognized according not only to the number of interacting residue pairs,but also to their bond strength.Using molecular dynamics simulation,we showed the steady state of the kindlin2-F3/β3-tail complex under different tensile forces,and observe the dynamic process of molecular interaction.A possible underlying biophysical mechanism is that,the dissociation of Kindlin2-F3/β3-tail complex is biphasic force-dependent,and the conformations under different stretching states have different binding affinities.This study not only provides insights into the structural basis and mechanical regulation mechanisms of the kindlin/integrin interaction,in understanding in kindlin/integrin-related signaling in different cellular biological processes,but also provides new ideas for novel drug design and the treatment of related diseases.

Emanuel Strehler’s work on calcium pumps and calcium signaling

Cells are equipped with mechanisms to control tightly the influx, efflux and resting level of free calcium (Ca 2+ ). Inappropriate Ca 2+ signaling and abnormal Ca 2+ levels are involved in many clinical disorders including heart disease, Alzheimer's disease and stroke. Ca 2+ also plays a major role in cell growth, differentiation and motility; disturbances in these processes underlie cell transformation and the progression of cancer. Accordingly, research in the Strehler laboratory is focused on a better understanding of the molecular "toolkit" needed to ensure proper Ca 2+ homeostasis in the cell, as well as on the mechanisms of localized Ca 2+ signaling. A longterm focus has been on the plasma membrane calcium pumps (PMCAs), which are linked to multiple disorders including hearing loss, neurodegeneration, and heart disease. Our work over the past 20 years or more has revealed a surprising complexity of PMCA isoforms with different functional characteristics, regulation, and cellular localization. Emerging evidence shows how specific PMCAs contribute not only to setting basal intracellular Ca 2+ levels, but also to local Ca 2+ signaling and vectorial Ca 2+ transport. A second major research arearevolves around the calcium sensor protein calmodulin and an enigmatic calmodulin-like protein (CALML3) that is linked to epithelial differentiation. One of the cellular targets of CALML3 is the unconventional motor protein myosin-10, which raises new questions about the role of CALML3 and myosin-10 in cell adhesion and migration in normal cell differentiation and cancer.

Structure-activity correlationship and folding of recombinant Escherichia coli dihydro folate reductase (DHFR) enzyme through biochemical and biophysical approaches

The design of any antagonist or inhibitor for any enzyme requires the knowledge of structure- function relationship of the protein and the optimum conformational states for maximum and minimum activities. Furthermore, designing of the inhibitors or drugs against an enzyme becomes easier if there is information available about various well characterized intermediate conformation of the molecule. In vivo folding pathway of any recombinant protein is an important parameter for understanding its ability to fold by itself inside the cell, which always dictates the downstream processing for the purification. In the present manuscript we have discussed about the in vivo and in vitro folding, and structure-function relationship of Dihydrofolate reductase enzyme. This is an important enzyme involved in the cell growth and hence inhibition or inactivation of the enzyme may reduce the cell growth. It was observed that the equilibrium unfolding transition of DHFR proceeds through the formation of intermediates having higher exposed surface hydrophobicity, unchanged enzymatic activity and minimum changes in the secondary structural elements. Because of enhanced surface hydrophobicity, and unchanged enzymatic activity, these intermediates could be a nice target for designing drugs against DHFR.

Structural and functional design of geopolymer adsorbents:a review

The water pollution derived from the discharge of heavy metals,antibiotics,dyes and surfactants wastewater,etc.has seriously affected human survival and ecological security.As an efficient and low-cost physical wastewater treatment process,the adsorption is a continuous hot spot in related scientific research and applications.Geopolymers are non-crystal or semi-crystalline materials with high-efficiency adsorption performance due to the alkali metal ions that balance the electronegative aluminosilicate skeleton can be efficiently replaced by other cations in the aqueous environment.The related studies of different application conditions,service objects and morphological differences of geopolymer adsorbents based on structure-function design have been in-depth exploration and investigation.This review aims to summarize the research progres s of the structure-function design based on the geopolymerization mechanism and kinetics and service requirements.An overview of service characteristics and progress of geopolymers in the wastewater treatment field(e.g.,dyes,heavy metals,radionuclides,surfactants,antibiotics,ammonium,phosphorus,nitrogen and CO_(2),etc.)are systematically discussed.And the evolution and development of morphological differences and the relationship of structure-function design of geopolymer adsorbents were compared and reviewed.Finally,the challenge worth overcoming,the trends worth considering and perspectives worth developing are highlighted.

Recent Advances in Mn,Fe,Co,and Ni-Catalyzed Organic Reactions

This paper reviewed the recent research progress of organic reactions catalyzed by four typical earthabundant and 3d metal catalysts:Mn,Fe,Co,and Ni complexes and mainly focused on the reactions in which these 3d metal catalysts exhibited obvious advantages over other catalysts.The mechanism that makes these 3d metal catalysts show unusual properties is another focus of this paper.An outlook on 3d metal complexes-catalyzed organic reactions was also considered.

Large-scale data-driven and physics-based models offer insights into the relationships among the structures,dynamics,and functions of chromosomes

The organized three-dimensional chromosome architecture in the cell nucleus provides scaffolding for precise regulation of gene expression.When the cell changes its identity in the cell-fate decision-making process,extensive rearrangements of chromo-some structures occur accompanied by large-scale adaptations of gene expression,underscoring the importance of chromosome dynamics in shaping genome function.Over the last two decades,rapid development of experimental methods has provided unprecedented data to characterize the hierarchical structures and dynamic properties of chromosomes.In parallel,these enormous data offer valuable opportunities for developing quantitative computational models.Here,we review a variety of large-scale polymer models developed to investigate the structures and dynamics of chromosomes.Different from the underlying modeling strategies,these approaches can be classified into data-driven(‘top-down’)and physics-based(‘bottom-up’)categories.We discuss their contributions to offering valuable insights into the relationships among the structures,dynamics,and functions of chromosomes and propose the perspective of developing data integration approaches from different experimental technologies and multidisciplinary theoretical/simulation methods combined with different modeling strategies.

RNA Regulations and Functions Decoded by Transcriptome-wide RNA Structure Probing

RNA folds into intricate structures that are crucial for its functions and regulations. To date, a multitude of approaches for probing structures of the whole transcriptome, i.e., RNA struc- turomes, have been developed. Applications of these approaches to different cell lines and tissues have generated a rich resource for the study of RNA structure-function relationships at a systems biology level. In this review, we first introduce the designs of these methods and their applications to study different RNA structuromes. We emphasize their technological differences especially their unique advantages and caveats. We then summarize the structural insights in RNA functions and regulations obtained from the studies of RNA structuromes. And finally, we propose potential directions for future improvements and studies.

Analysis of the ligand-binding domain of macrophage colony-stimulating receptor

RNAs have been extracted from human placenta. Extracellular regions of M-CSFR, D1-3, D2-3 and D3 motifs have been amplified with RT-PCR. The proteins have been expressed in E.coli. Enzyme-linked immusorbent assay (EIA) shows that recombinant D1-3 possesses binding ability 3 times that of D2-3. Kd, the dissociation constant of the former is 11 nmol/L, and that of latter is 39 nmol/L. D3 lacks binding ability. These data suggest that D2-3 is the main site for M-CSF binding, D1 is an assistant site and also contributes to the conformation of site for ligand binding.

STUDIES ON THE CRYSTAL STRUCTURE OF (D-Ala)-B0 PORCINE INSULIN AT 1.9 RESOLUTION

The crystal structure of (D-Ala)-B0 porcine insulin has been determined, using data to 1.9 and atomic parameters of 2 Zn porcine insulin as a starting model, and through the use of the difference method and the restrained least square method, to a final R-factor of 0.211 and r. m. s. deviation of 0.057 for the bond lengths. The electron densities of B0 residues were very clear. Introduction of B0 residues into the molecules had reduced the thermal vibration of the N-terminus of B-chain for both molecules Ⅰ and Ⅱ and made the molecules pack closer in the crystal The obvious differences between the crystal structures of 2 Zn and (D-Ala)-B0 porciue insulin were the conformations of partial polar groups around the possible receptor binding surface and the assembly mode of two helixes of A-chain in molecule I. In the local environment of the N-terminus of Bchain there were great differences between the crystal structures of(D-Ala)-B0 porcine insulin, (Trp)-B1 porcine insulin and Des B1(Phe) bovine insulin.

Biomineralization proteins： from vertebrates to bacteria

Biomineralization processes are frequently found in nature. Living organisms use various strategies to create highly ordered and hierarchical mineral structures under physiologic conditions in which the temperatures and pressures are much lower than those required to form the same mineralized structures by chemical synthesis. Although the mechanism of biomineralization remains elusive, proteins have been found responsible for the formation of such mineral structures in many cases. These proteins are active components in the process of biomineralization. The mechanisms by which their function can vary from providing active organic matrices that control the formation of specific mineral structures to being catalysts that facilitate the crystallization of certain metal ions. This review summarizes the current understanding of the functions of several representative biomineralization proteins from vertebrates to bacteria in the hopes of providing useful insight and guidance for further elucidation of mechanisms of biomineralization processes in living organisms.

Construction of continuous heat conductive channel,a double harvest strategy to enhance thermal conductance and bending strength of C/SiC composites

The development of efficient and quick method to prepare structure-function integrative C/SiC composites is always a major challenge in this feld.Herein,the thermal conductivity and bending strength of C/SiC composites were enhanced simultaneously via continuous high heat conductive channels constructed by continuous wave laser machining and pitch-based high thermal conductivity carbon fber in thickness direction.Results revealed that the thermal conductivity of the modifed C/SiC composites is three times higher than that of referential C/SiC composites due to its highly ordered heat conducive channel in the thickness direction.Importantly,the bending strength of modifed C/SiC composites increased to 457MPa.To better understand the enhance mechanism,the micro-structure for both the composites and heat conductive channel was systematically analyzed.The results demonstrated that the rivet effect of heat conductive channel and the formed two phases structure on the fbers dispersed partial of load and fnally enhanced the property of the composites.In a word,this method holds a nice applicable future in constructing structure-function integrative C/SiC composites.