Articles de revues sur le sujet « Novel Nano-structures -Ab-initio Study »

A density functional theory (DFT) based multi-step simulation method is used to characterize the detailed molecular structure and inter/intra- molecular interactions of two benchmark liquid crystals (LC) 5CB, 8CB and a novel tri-biphenyl ring bent core LC material. The method uses hybrid DFT at the B3LYP/6-31G* level to obtain molecular structure and Raman data. These results are fed to a crystal packing simulation to find possible crystal structures. A pico-second quantum mechanics/molecular mechanics (QM/MM) simulation model is built for the selected structures with lower overall energy as well as optimal density. The stabilized crystal structures are then extended into a super cell, heated and simulated using a mixed force field and nano-second molecular dynamics (MD). The described simulation process sequence provides predictions of molecular Raman spectrum, LC density, isotropic depolarization ratio, ratio of differential polarizability, order parameters, molecular structures, and rotating Raman spectrum of the different mesophases. The Raman spectra, order parameters and depolarization ratios all agree well with existing experimental and previous simulation results. The study of the novel tri-biphenyl ring bent core LC system shows that the ratio of differential polarizability depends on intra-molecular interactions. The findings presented in this manuscript contribute to the on-going efforts to establish links between LC molecular structures and their properties, including optical behavior.

Antimicrobial peptides (AMPs) are small amphipathic peptides that exhibit bactericidal activity against a wide range of pathogenic microorganisms and are considered to be potential substitutes for antibiotics effective against microbial infection. PSK, an 84-amino-acid AMP recently isolated from Chrysomya megacephala larvae, probably belongs to the mitochondrial ATPase inhibitor family according to its sequence. No member of this family from an insect has been structurally characterized to date. In this study, the crystal structure of full-length PSK determined by molecular replacement using an ab initio modeled ensemble as a search model and a solution structure obtained from small-angle X-ray scattering (SAXS) measurements are reported. The crystal structure reveals a distinct fold compared with those of homologous peptides, in that PSK comprises two antiparallel α-helices rather than a single long helix, which is in good agreement with the SAXS-based ab initio model. However, the peptide exists as a monomer in solution, even though a stable dimer was observed in the crystal structure. This apparent contradiction may reflect different oligomerization states that may be implicated in its bioactivity. The data presented here have established a solid basis for further mechanistic studies of this novel insect AMP.

Boric acid, borate esters, and hydroxy derivatives are biologically active molecules. Thus, performing molecular dynamics simulations of these molecules is vital in terms of drug design, but it is difficult to find directly generated Amber parameters based on an ab initio method for these kinds of molecules in the literature. In this study, Amber parameters for such molecules containing boron were generated based on ab initio calculations using the paramfit program, which applies a combination of genetic and simplex algorithms, and the Visual Force Field Derivation Toolkit (VFFDT) program containing the Seminario method. The minimized structure, after obtaining novel parameters and using the sander program, was compared with the experimental crystallographic structures, and it was observed that the root-mean-square deviation (RMSD) value between the experimental structure and minimized structure agreed reasonably well. In addition, the molecule was heated, and the molecular dynamics simulation was successfully obtained with the novel parameters.

Research Highlights • Electronic, magnetic, elastic and thermoelectric properties of RbCrC alloy are investigated. • Material is half-metallic, ductile and anisotropic in nature. • The total magnetic moment (3[Formula: see text][Formula: see text]B) obeys the Slater–Pauling rule. • The HM RbCrC compound is identified as potential candidate for spintronic applications. • ZT calculated values of 0.89 and 0.94 make RbCrC a promising thermoelectric material candidate for use in future devices. The aim of this work is to investigate the half-metallicity behavior, elastic, thermodynamic and thermoelectric (TE) properties of the Heusler compound RbCrC using the generalized gradient approximation (GGA-PBE96) and the modified Becke–Johnson (mBJ) approach. The electronic band structures and density of states reveal that RbCrC is a half-metallic ferromagnet (HMF). The calculated total magnetic moment of 3[Formula: see text][Formula: see text]B follows the Slater–Pauling rule ([Formula: see text]). The half-metallicity character can be maintained in the 5.4–7.4 Å lattice constants range and the 0.8–1.2 [Formula: see text]/[Formula: see text] ratio range. Existence of half-metallic ferromagnetism in RbCrC makes it a promising material for practical applications in the spintronic field. Also, the RbCrC exhibits a ductile and anisotropic behavior. The quasi-harmonic Debye model (QHDM) is used to calculate the thermodynamic properties. The BoltzTraP code which is based on semi-classical Boltzmann theory (SCBT) is applied for calculating TE properties. According to the obtained figure of merit values (ZT between 0.89 and 0.94 from 50 K to 800 K), the RbCrC alloy remains a good candidate for thermoelectric applications.

The Nb4AlC3 MAX phase can be regarded as a TMC structure with stacking faults, which has great potential as a novel solid hydrogen storage material. Herein, we used ab initio calculations for understanding the hydrogen incorporation into Nb4AlC3 MAX phases, including equilibrium structural characteristics, energy changes, electronic structures, bonding characteristics, and diffusion paths. According to the calculated results, H has thermal stability in the interstice of the Nb-Al layer, and the most probable insertion site is an octahedron (3-site) composed of three Nb atoms and three Al atoms. When C vacancies are introduced, the Nb-C layer has a specific storage capacity for H. In addition, Al vacancies can also be used as possible sites for H incorporation. Moreover, the introduction of vacancies significantly increase the hydrogen storage capacity of the MAX phase. According to the electronic structure and bonding characteristics, the excellent hydrogen storage ability of the Nb4AlC3 structure may be due to the formation of ionic bonds between H and Nb/Al. It is worth noting that the H-Al bond in the 1-site is a covalent bond and an ionic bond key mixture. The linear synchronous transit optimization study shows that only H diffusion in Al vacancies is not feasible. In conclusion, the Nb-Al layer in Nb4AlC3 can provide favorable conditions for the continuous insertion and subsequent extraction of H, while the vacancy structure is more suitable for H storage. Our work provides solid theoretical results for understanding the hydrogen incorporation into Nb4AlC3 MAX phases that can be helpful for the design of advanced hydrogen storage materials.

Recent studies of TiO2/TiS2 nanostructures with various morphologies have been reported, usually showing improved properties with applications from electronics and catalysis to solar cells and medicine. However, there is a limited number of studies on the crystal structures of TiO2/TiS2 compounds with corresponding properties. In this research, relevant crystal structures of TiO1–x S x (x = 0, 0.25, 0.5, 0.75 and 1) solid solutions were investigated using an ab initio method. For each composition, crystal structures adopting anatase, rutile and CdI2 structure type were calculated on LDA-PZ and GGA-PBE levels of theory. Novel phase transitions and predicted structures are presented, and apart from several interesting metastable structures, a very interesting pressure-induced phase transition is found in the TiOS compound. Furthermore, electronic properties were studied through the dependence of semiconducting properties on dopant concentration. The first description of the electronic properties of the mixed TiO1–x S x compounds in crystal form has been presented, followed by a detailed study of the structure–property relationship, which will possibly have numerous industrial and technological applications.

Proteins are evolution’s mechanisms of choice. The study of nano-mechanical systems must encompass an understanding of the geometry and conformation of protein molecules. Proteins are open or closed loop kinematic chains of miniature rigid bodies connected by revolute joints. The Kinematics community is in a unique position to extend the boundaries of knowledge in nano biomechanical systems. In this work, we have presented a comprehensive methodology for kinematics notation and direct kinematics for protein molecules. These methods utilize the zero-position analysis method and draws upon other recent advances in robot manipulation theories. The procedures involved in finding the coordinates of every atom in the protein chain as a function of the dihedral and Rotamer angles are computationally the most efficient formulation developed to date. The notation and the methodologies of this paper are incorporated in the computer software package PROTOFOLD and will be made available to individuals interested in using it. PROTOFOLD is a software package that implements novel and comprehensive methodologies for ab initio prediction of the final three-dimensional conformation of a protein, given only its linear structure. In addition to the new kinematics methodologies mentioned above, we have also included all the basic kinematic parameter values that are needed in any kinematic analysis involving proteins. While these values are based on a body of knowledge recorded in the protein data bank, they are presented in a form conducive to kinematics.

Conjugated polymers and oligomers have great potentials in various fields, especially in materials and biological sciences because of their intriguing electronic and optoelectronic properties. In recent years, the through-space conjugation system has emerged as a new assembled pattern of multidimensional polymers. Here, a novel series of structurally condensed multicolumn/multilayer 3D polymers and oligomers have been designed and synthesized through one-pot Suzuki polycondensation (SPC). The intramolecularly stacked arrangement of polymers can be supported by either X-ray structural analysis or computational analysis. In all cases, polymers were obtained with modest to good yields, as determined by GPC and 1H-NMR. MALDI-TOF analysis has proven the speculation of the step-growth process of this polymerization. The computational study of ab initio and DFT calculations based on trimer and pentamer models gives details of the structures and the electronic transition. Experimental results of optical and AIE research confirmed by calculation indicates that the present work would facilitate the research and applications in materials.

A series of six seven-coordinate pentagonal-bipyramidal (PBP) erbium complexes, with acyclic pentadentate [N3O2] Schiff-base ligands, 2,6-diacetylpyridine bis-(4-methoxybenzoylhydrazone) [H2DAPMBH], or 2,6-diacethylpyridine bis(salicylhydrazone) [H4DAPS], and various apical ligands in different charge states were synthesized: [Er(DAPMBH)(C2H5OH)Cl] (1); [Er(DAPMBH)(H2O)Cl]·2C2H5OH (2); [Er(DAPMBH)(CH3OH)Cl] (3); [Er(DAPMBH)(CH3OH)(N3)] (4); [(Et3H)N]+[Er(H2DAPS)Cl2]− (5); and [(Et3H)N]+[Y0.95Er0.05(H2DAPS)Cl2]− (6). The physicochemical properties, crystal structures, and the DC and AC magnetic properties of 1–6 were studied. The AC magnetic measurements revealed that most of Compounds 1–6 are field-induced single-molecule magnets, with estimated magnetization energy barriers, Ueff ≈ 16–28 K. The experimental study of the magnetic properties was complemented by theoretical analysis based on ab initio and crystal field calculations. An experimental and theoretical study of the magnetism of 1–6 shows the subtle impact of the type and charge state of the axial ligands on the SMM properties of these complexes.

In this work, we carried out the density functional theory (DFT) calculations in order to understand the molecular structures and thermal trans–cis isomerization of 3,3′-diamino-4,4′-azofurazan (DAAzF) and 3,3′-diamino-4,4′-azoxyfurazan (DAAF). We found that the azo group oxidation of DAAzF leading to the formation of DAAF induced evidently the twist of azofurazan molecule and weakened one of CN bonds connecting the furazan rings and azo group. This means that DAAzF is more stable than DAAF. In addition, the oxidation of azo group has a significant influence on the energy difference between trans- and cis-isomer of azofurazan. The energy difference between the isomers of DAAF is only about half of that of DAAzF. Furthermore, the thermal trans–cis isomerization of DAAzF and DAAF was found to follow a different mechanism: an inversion mechanism for DAAzF and a rotation mechanism for DAAF. By analyzing the reversible trans–cis isomerization process, we firstly proposed that a self-desensitization effect could be responsible for the low sensitivity of azofurazan. This new desensitization mechanism may be useful in the design of novel high energetic density material.

The structure and properties of the arginine-glycine-aspartate (RGD) sequence of the 1FUV peptide at 0 K and body temperature (310 K) are systematically investigated in a dry and aqueous environment using more accurate ab initio molecular dynamics and density functional theory calculations. The fundamental properties, such as electronic structure, interatomic bonding, partial charge distribution, and dielectric response function at 0 and 310 K are analyzed, comparing them in dry and solvated models. These accurate microscopic parameters determined from highly reliable quantum mechanical calculations are useful to define the range and strength of complex molecular interactions occurring between the RGD peptide and the integrin receptor. The in-depth bonding picture analyzed using a novel quantum mechanical metric, the total bond order (TBO), quantifies the role played by hydrogen bonds in the internal cohesion of the simulated structures. The TBO at 310 K decreases in the dry model but increases in the solvated model. These differences are small but extremely important in the context of conditions prevalent in the human body and relevant for health issues. Our results provide a new level of understanding of the structure and properties of the 1FUV peptide and help in advancing the study of RGD containing other peptides.

We study the nature of chemical bonding of the thorium atom with novel BN-based nanomaterials: fullerenes B[Formula: see text]N[Formula: see text], B[Formula: see text]N[Formula: see text], B[Formula: see text]N[Formula: see text], and the BN analog of coronene—B[Formula: see text]N[Formula: see text]H[Formula: see text], used as a representative molecular fragment of the two dimensional hexagonal BN-sheet. Our ab initio calculations are performed within the dispersion-corrected density functional approach with a hybrid exchange-correlation potential. The smallest 20-atom BN-fullerenes B[Formula: see text]N[Formula: see text], B[Formula: see text]N[Formula: see text] proposed by us are shown to be stable and should be observable experimentally. Thorium is found at the center of these structures pushing the outer shell of atoms farther away. The shape of the B[Formula: see text]N[Formula: see text]-cage in Th@B[Formula: see text]N[Formula: see text] is conserved, while the shape of the B[Formula: see text]N[Formula: see text] molecule in Th@B[Formula: see text]N[Formula: see text] is largely deformed. The initially planar structure of B[Formula: see text]N[Formula: see text]H[Formula: see text] in the presence of thorium becomes corrugated, demonstrating pronounced off-plane displacements under the thorium atom. Other four-valent metals (Ti, Zr, and Hf) also cause off-plane displacements of B and N atoms albeit to a much smaller scale. In the 60-atom fullerene B[Formula: see text]N[Formula: see text], which is the BN analog of C[Formula: see text], two conformations of Th@B[Formula: see text]N[Formula: see text] are found: one is with thorium facing the hexagon with one B–B and one N–N covalent bonds and a second, lying 0.79 eV higher, with thorium close to the center of pentagon with one B–B covalent bond.

Background: 4-(n-Octyloxy)aniline is a known component in the elaboration of organic materials with mesogenic properties such as N-substituted Schiff bases, perylene bisimide assemblies with a number of 2-amino-4,6-bis[4-(n-octyloxy)phenylamino]-s-triazines, amphiphilic azobenzene-containing linear-dendritic block copolymers and G-0 monomeric or dimeric dendritic liquid crystals with photochromic azobenzene mesogens. The present ab initio study explores a previously unknown use of 4-(n-octyloxy)aniline in the synthesis, structure and supramolecular behaviour of new dendritic melamines. Results: Starting from 4-(n-octyloxy)aniline, seven G-2 melamine-based dendrimers were obtained in 29–79% overall yields. Their iterative convergent- and chemoselective synthesis consisted of SN2-Ar aminations of cyanuric chloride and final triple N-acylations and Williamson etherifications (→ G-2 covalent trimers) or stoichiometric carboxyl/amino 1:3 neutralisations (→ G-2 ionic trimers). These transformations connected G-1 chloro- and amino-termini dendrons to m-trivalent cores (triazin-2,4,6-triyl and benzene-1,3,5-triyl units) or tripodands (central building blocks), such as N-substituted melamines with 4-hydroxyphenyl or phenyl-4-oxyalkanoic motifs. Owing to the diversity of cores and central building blocks, the structural assortment of the dendritic series was disclosed by solvation effects (affecting reactivity), rotational stereodynamism and self-organisation phenomena (determining a vaulted and/or propeller macromolecular shape in solution). DFT calculations (in solution), (VT) NMR and IR (KBr) spectroscopy supported these assignments. TEM analysis revealed the ability of the title compounds towards self-assembling into homogeneously packed spherical nano-aggregates. Conclusions: The (non)covalent synthesis and step-by-step structural elucidation of novel G-2 melamine dendrimers based on 4-(n-octyloxy)aniline are reported. Our study demonstrates the crucial influence of the nature (covalent vs ionic) of the dendritic construction in tandem with that of its central building blocks on the aptitude of dendrimers to self-organise in solution and to self-assembly in the solid state.

Hyaluronic acid (HA) is the main non-sulfated glycosaminoglycan of the extracellular matrix that is synthesized by fibroblasts and other specialized connective tissue cells. The accumulation of HA on different tissues is a characteristic of disorders that are associated with progressive tissue fibrosis. HA is also known to play a critical role in tumorigenesis and tumor metastasis. It is overproduced by many types of tumors and promotes tumor progression and multidrug resistance. There is a great necessity for the development of an easy and cost-effective detection method for the monitoring of HA for both the diagnosis and efficient treatment of related disorders. In the present study, an innovative immune device was designed for the rapid and sensitive recognition of HA in human plasma samples. For this purpose, an efficient alloy (Pt@Au) was fabricated on the surface of the gold electrode. Thus, a novel substrate was used for the preparation of an efficient transducer, which is necessary for the immobilization of biotinylated antibodies. CHA was applied for the electrochemical deposition of Pt@Au nano-alloy on Au electrodes. Additionally, the morphological study of the used nanocomposite was assessed using FESEM at a working voltage of 3 kV, and the chemical structures of the electrode were analyzed using the EDS apparatus. For the first time, a biocompatible alloy-based substrate was prepared for the study of antigen–antibody identification. The developed immunosensor has a linear response within the range of 0.156–160 ng.mL−1 with a limit of detection of 0.039 ng.mL−1 in human plasma samples. This research study offers a novel promising technique for HA analyses and is anticipated to be used in the early diagnosis of some disorders related to abnormal levels of HA in human bio-fluids. Thus, a constructed (pt@Au) nano-alloy provides a useful interface for the dense loading of AB. This excellent design loads high sensations of the biosensor for the selective detection of HA in real samples (human bio-fluids).

The AMPA receptor GluA2 belongs to the family of ionotropic glutamate receptors, which are responsible for most of the fast excitatory neuronal signalling in the central nervous system. These receptors are important for memory and learning, but have also been associated with brain diseases such as Alzheimer's disease and epilepsy. Today, one drug is on the market for the treatment of epilepsy targeting AMPA receptors, i.e. a negative allosteric modulator of these receptors. Recently, crystal structures and cryo-electron microscopy (cryo-EM) structures of full-length GluA2 in the resting (apo), activated and desensitized states have been reported. Here, solution structures of full-length GluA2 are reported using small-angle neutron scattering (SANS) with a novel, fully matched-out detergent. The GluA2 solution structure was investigated in the resting state as well as in the presence of AMPA and of the negative allosteric modulator GYKI-53655. In solution and at neutral pH, the SANS data clearly indicate that GluA2 is in a compact form in the resting state. The solution structure resembles the crystal structure of GluA2 in the resting state, with an estimated maximum distance (D max) of 179 ± 11 Å and a radius of gyration (R g) of 61.9 ± 0.4 Å. An ab initio model of GluA2 in solution generated using DAMMIF clearly showed the individual domains, i.e. the extracellular N-terminal domains and ligand-binding domains as well as the transmembrane domain. Solution structures revealed that GluA2 remained in a compact form in the presence of AMPA or GYKI-53655. At acidic pH only, GluA2 in the presence of AMPA adopted a more open conformation of the extracellular part (estimated D max of 189 ± 5 Å and R g of 65.2 ± 0.5 Å), resembling the most open, desensitized class 3 cryo-EM structure of GluA2 in the presence of quisqualate. In conclusion, this methodological study may serve as an example for future SANS studies on membrane proteins.

The transition to a sustainable society is vital and requires electrification. Sodium and potassium ion-based electrolytes will likely play an important role in energy storage as these elements are very abundant. The latter cations and chloride are especially interesting since life on the planet is somehow based on biological transfers of these ions through cell membranes. K+ is the key charge carrier in plants. Here, we characterize electrochemically, electrostatically, and structurally novel electrolytes, K3ClO and K2.99Ba0.005ClO, and compare their performance with Na3ClO and Na2.99Ba0.005ClO in symmetric and asymmetric structural electrode-less cells, such as K/K2.99Ba0.005ClO in a cellulose membrane/K, Na/Na2.99Ba0.005ClO in a cellulose membrane/Na, Al/K2.99Ba0.005ClO composite/Cu, and Al/Na2.99Ba0.005ClO composite/Cu, at temperatures that range from −45 to 65 °C. An ab initio molecular dynamics structural study followed by band structure determination using density functional theory and hybrid simulations allowed us to compare the amorphous character of the structures, bandgap, and electron localization function for both K3ClO at 25 °C and Na3ClO at 37 °C, temperatures at which preliminary studies indicate that these compounds are already amorphous. As in Na+-based electrolytes, the ferroelectric character of the K+-based electrolytes is well recognizable, especially at −45 °C, where the relative real permittivity achieves 1013 in K/K2.99Ba0.005ClO in cellulose membrane/K symmetric cells for an ionic conductivity of ∼120 mS/cm. As in Na+-based electrodes-less structural battery cells, self-charge and self-cycling phenomena are also demonstrated reinforcing the ferroelectric nature of the A3ClO (A = Li, Na, and K) family of electrolytes. These studies may contribute to understanding the K+ and Na+ transfer behavior in energy harvesting and storage as well as the biologic world.

Motivated by the possibility of scaling down of various electronic devices at the nanolevel, we have chosen a simple p-n junction like device in silicon structure. An aggregation of seventy-eight silicon atoms, passivated by oxygen is considered. We compute the electronic structure of such a cluster and then the density of states and the optical spectra for this aggregate are compared with a modified one. The modification is introduced by substituting phosphorus and boron atom within this cluster of silicon atoms in both sides in order to make a p-n junction like situation. A variant of this p-n junction like structure is introduced by adding a layer of oxygen between the phosphorus and boron regions. Comparison of the electronic structures of all these systems reveals several interesting properties.

Background COVID-19, caused by the novel SARS-CoV-2, is considered the most threatening respiratory infection in the world, with over 40 million people infected and over 0.934 million related deaths reported worldwide. It is speculated that epidemiological and clinical features of COVID-19 may differ across countries or continents. Genomic comparison of 48,635 SARS-CoV-2 genomes has shown that the average number of mutations per sample was 7.23, and most SARS-CoV-2 strains belong to one of 3 clades characterized by geographic and genomic specificity: Europe, Asia, and North America. Objective The aim of this study was to compare the genomes of SARS-CoV-2 strains isolated from Italy, Sweden, and Congo, that is, 3 different countries in the same meridian (longitude) but with different climate conditions, and from Brazil (as an outgroup country), to analyze similarities or differences in patterns of possible evolutionary pressure signatures in their genomes. Methods We obtained data from the Global Initiative on Sharing All Influenza Data repository by sampling all genomes available on that date. Using HyPhy, we achieved the recombination analysis by genetic algorithm recombination detection method, trimming, removal of the stop codons, and phylogenetic tree and mixed effects model of evolution analyses. We also performed secondary structure prediction analysis for both sequences (mutated and wild-type) and “disorder” and “transmembrane” analyses of the protein. We analyzed both protein structures with an ab initio approach to predict their ontologies and 3D structures. Results Evolutionary analysis revealed that codon 9628 is under episodic selective pressure for all SARS-CoV-2 strains isolated from the 4 countries, suggesting it is a key site for virus evolution. Codon 9628 encodes the P0DTD3 (Y14_SARS2) uncharacterized protein 14. Further investigation showed that the codon mutation was responsible for helical modification in the secondary structure. The codon was positioned in the more ordered region of the gene (41-59) and near to the area acting as the transmembrane (54-67), suggesting its involvement in the attachment phase of the virus. The predicted protein structures of both wild-type and mutated P0DTD3 confirmed the importance of the codon to define the protein structure. Moreover, ontological analysis of the protein emphasized that the mutation enhances the binding probability. Conclusions Our results suggest that RNA secondary structure may be affected and, consequently, the protein product changes T (threonine) to G (glycine) in position 50 of the protein. This position is located close to the predicted transmembrane region. Mutation analysis revealed that the change from G (glycine) to D (aspartic acid) may confer a new function to the protein—binding activity, which in turn may be responsible for attaching the virus to human eukaryotic cells. These findings can help design in vitro experiments and possibly facilitate a vaccine design and successful antiviral strategies.

The ternary alloy ZnSxSe1-x wurtziod can be designed by simulation of DFT when varies the contents of S and Se atom. Study change band gaps of alloy wurtziod and density state. Density functional theory considers of the best approximations which associated with accuracy to simulate the geometrical, electronic characteristics and lines active of Raman. The clusters Zn7S3Se4 wurtziods at nano limited that obtains from wurtzite structure, note that band gaps of alloys decrease with the previous results for ZnS and ZnSe ,also when increase concentrations of Se . Nanotubes of Zn7S3Se4 wurtziods can be noted in the geometrical structures, also in this work found that longitudinal optical shifted toward blue. Investigation of Bond lengths with their densities of alloys Zn7S3Se4 wurtziods and the comparative with practical values.

Due to their bandgap engineering capabilities for optoelectronics applications, the study of nano-graphene has been a topic of interest to researchers in recent years. Using a first-principles study based on density functional theory (DFT) and thermal DFT, we investigated the electronic structures and optical properties of bilayer graphene quantum dots (GQDs). The dielectric tensors, absorption spectra, and the refractive indexes of the bilayer GQDs were obtained for both in-plane and out-of-plane polarization. In addition, we calculated the absorption spectra via time-dependent DFT (TD-DFT) in the linear response regime. The TDDFT results show that a blue shift occurs in the absorption spectrum, which is consistent with the experimental results. In this investigation, we consider triangular and hexagonal GQDs of various sizes with zigzag and armchair edges. Our simulations show that unlike monolayer GQDs, for which light absorption for out-of-plane polarization occurs in the ultraviolet wavelength range of 85–250 nm, the out-of-plane polarization light absorption peaks in the bilayer GQDs appear in the near-infrared range of 500–1600 nm, similar to those in bilayer graphene sheets. The out-of-plane polarization light absorption peaks in the near-infrared range make bilayer GQDs suitable for integrated optics and optical communication applications.

Nanomaterials bridge the gaps between crystalline materials, thin films, and molecules, and are of great importance in the design of new classes of materials, since the existence of many modifications of a nano-object for the same overall composition allows us to tune the properties of the nanomaterial. However, the structural analysis of nano-size systems is often difficult and their structural stability is frequently relatively low. Thus, a study of their energy landscape is needed to determine or predict possible structures, and analyse their stability, via the determination of the minima on the landscape and the generalized barriers separating them. In this contribution, we introduce the major concepts of energy landscapes for chemical systems, and present summaries of four applications to nano-materials: a MgO monolayer on a sapphire substrate, possible quasitwo- dimensional carbon-silicon networks, the ab initio energy landscape of Cu4Ag4-clusters, and the possible arrangements of ethane molecules on an ideally smooth substrate.

Quantum-mechanical calculations are applied to examine magnetic and electronic properties of phases appearing in binary Fe-Al-based nanocomposites. The calculations are carried out using the Vienna Ab-initio Simulation Package which implements density functional theory and generalized gradient approximation. The focus is on a disordered solid solution with 18.75 at. % Al in body-centered-cubic ferromagnetic iron, so-called α -phase, and an ordered intermetallic compound Fe 3 Al with the D0 3 structure. In order to reveal the impact of the actual atomic distribution in the disordered Fe-Al α -phase three different special quasi-random structures with or without the 1st and/or 2nd nearest-neighbor Al-Al pairs are used. According to our calculations, energy decreases when eliminating the 1st and 2nd nearest neighbor Al-Al pairs. On the other hand, the local magnetic moments of the Fe atoms decrease with Al concentration in the 1st coordination sphere and increase if the concentration of Al atoms increases in the 2nd one. Furthermore, when simulating Fe-Al/Fe 3 Al nanocomposites (superlattices), changes of local magnetic moments of the Fe atoms up to 0.5 μ B are predicted. These changes very sensitively depend on both the distribution of atoms and the crystallographic orientation of the interfaces.

Breast cancer in women is one of the most common life-threatening malignancies. Despite of the development for the improved treatment, there are still many limitations to overcome. Among them, cancer stem cells (CSCs) are well known for tumor formation, development, cellular heterogeneity, and cancer recurrence. Therefore, to completely cure breast cancer, treatment of both cancer and CSC is required. To selectively target CSCs, we generated a liposome-based smart nano complex using CEACAM 6 (CD66c) antibody (Ab), a novel cell-surface biomarker of breast-derived CSCs (BCSCs) discovered in our previous research. Selective and increased cellular uptake was observed in BCSCs treated with CD66c Ab-conjugated rhodamine-labeled liposomes (CDRHOL) depending on the expression level of CD66c. CD66c Ab-conjugated doxorubicin (DOX)-loaded liposomes (CDDOXL) selectively showed increased cell killing effects in BCSCs with high CD66c expression levels. In an in vivo animal study, CDRHOL showed enhanced accumulation in xenografted BCSC tumors with low delivery into non-target organs. Moreover, mice treated with CDDOXL have assessed the decreased induction ability of immune response by low expression levels of pro-inflammatory cytokines and reduced liver toxicity by histopathological analysis. Finally, the improved antitumor effect of CDDOXL was evaluated in a metastatic BCSC mouse model via systemic administration. Collectively, our study is the first to demonstrate that a multi-functional nano complex using a novel surface biomarker of BCSC may be a more effective therapeutic agent for the treatment of cancer and CSCs.

In this work, we study the structural and electronic properties of boron nitride bilayers sandwiched between graphene sheets. Different stacking, twist angles, doping, as well as an applied external gate voltage, are reported to induce important changes in the electronic band structure near the Fermi level. Small electronic lateral gaps of the order of few meV can appear near the Dirac points K. We further discuss how the bandstructures change applying a perpendicular external electric field, showing how its application lifts the degeneracy of the Dirac cones and, in the twisted case, moves their crossing points away from the Fermi energy. Then, we consider the possibility of co-doping, in an asymmetric way, the two external graphene layers. This is a situation that could be realized in heterostructures deposited on a substrate. We show that the co-doping acts as an effective external electric field, breaking the Dirac cones degeneracy. Finally, our work demonstrates how, by playing with field strength and p-n co-doping, it is possible to tune the small lateral gaps, pointing towards a possible application of C/BN sandwich structures as nano-optical terahertz devices.

Introduction Coagulation Factor VIII (FVIII) is a serine protease cofactor that directly interacts with coagulation factors IXa and X on activated platelets, and enhances FIXa activity toward FX by 105. von Willebrand Factor (VWF), via its D'D3 domains, interacts with FVIII and prevents premature deposition on phospholipids until activation by thrombin. Thrombin cleavage at Arg1689 of FVIII promotes VWF dissociation by disrupting the FVIII a3 high affinity interaction with the VWF D' domain. VWF extends the half-life of circulating FVIII from less than 3 hours to ~11 hours in humans. While crystal structures of FVIII and VWF D'D3 alone have been solved, the atomic details of a formed complex are unknown. We sought to determine the FVIII-VWF D'D3 complex structure by using BIVV001, our investigational new drug currently in clinical trials for the treatment of Hemophilia A. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein consisting of single chain B-domain deleted (BDD) human FVIII, the Fc domain of human immunoglobulin G1 (IgG1), the FVIII-binding D'D3 domain of human von Willebrand factor, and 2 XTEN polypeptide linkers. The Fc, VWF, and XTEN linker portions of the molecule are each designed to extend the half-life of FVIII. We anticipated that the tethering of FVIII to D'D3 through the Fc dimer in BIVV001 would stabilize the complex for structural studies. Given the large size of BIVV001, at 312 kDa, we thought it an ideal target for structure determination by single particle cryo-EM. Methods We collected a total of 3955 micrographs of BIVV001 embedded in vitreous ice at 81,000x magnification using a Titan Krios electron microscope equipped with a Gatan BioQuantum K3 energy filter and camera operating in super-resolution mode. Preferential particle orientation was a major challenge that was overcome through a variety of methods. Micrograph movies were motion-corrected and summed, and over 2 million candidate particle coordinates were extracted. Repeated rounds of reference-free 2D classification resulted in a set of 1.2 million particles that generated a reasonable ab initio/de novo 3D model. Initial full 3D refinements of this model produced a map at approximately 5 Å resolution, into which available crystal structures can be readily fit. Subsequent iterative 3D refinement and 3D classification resulted in a final map at high resolution, into which an atomic model was built. Results The structure of BIVV001 was solved by single particle cryo-EM. D' of VWF interacts with the front face of the C1 and A3 domains of FVIII, consistent with a lower resolution, negative stain EM map (Yee et al. 2015. Blood). Interface residues on FVIII identified in an HDX-MS dataset (Chiu et al. 2015. Blood.) largely correspond to this high affinity interaction. D' protrudes upward from the VWF D3 domain, which sits centrally located between the C1 and C2 domains of FVIII at a 45° tilt. By occupying this position, D3 likely sterically blocks the FVIII C domains from binding to membrane. The VWD3 module of the D3 domain contacts the base of the C1 domain, whereas C8-3 binds to the bottom of the C2 domain. The conserved Ca2+ site in VWD3 identified previously (Dong et al. 2019. Blood.) is in the interface with C1. This is consistent with Yee et al., where docking placed D3 below the C domains. In that study, a lack of density between FVIII and VWF D3 in the 3D reconstruction, due to flexibility, prevented the detailed analysis that is possible here. In this study, flexibility in this region is also apparent, as C2 is less well ordered than the rest of FVIII and VWF D3 is the least well-ordered portion of the resolved structure. The XTEN linkers are not visible in the final map and were not apparent in any 2D class averages. The Fc is absent in most 2D class averages, due to a lack of consistent positioning relative to FVIII. In the rare cases where the Fc is visible, it adopts a preferred position on the back side of FVIII below the A3 protrusion. Conclusions The structure of BIVV001 has been solved by cryo-electron microscopy to high resolution. Alignment with previous results and the averaging out of BIVV001 elaborations suggests the structure obtained here likely represents WT FVIII-D'D3. This structure demonstrates how VWF D'D3 prevents premature FVIII deposition on phospholipids. The structural basis of type 2N von Willebrand Disease mutations in D'D3 can be readily interpreted. Next steps include solving a FVIII-D'D3 dimer structure at high resolution. Disclosures Fuller: Sanofi: Employment. Batchelor:Sanofi: Employment. Knockenhauer:Sanofi: Employment. Biemann:Sanofi: Employment. Peters:Sanofi: Employment.

Glycosaminoglycans (GAGs) are a family of chemically heterogeneous polysaccharides that play important roles in physiological and pathological processes. Owing to the structural complexity of GAGs, their sophisticated chemical structures and biological functions have not been extensively studied. Lyases that cleave GAGs are important tools for structural analysis. Although various GAG lyases have been identified, exolytic lyases with unique enzymatic property are urgently needed for GAG sequencing. In the present study, a putative exolytic GAG lyase from a marine bacterium was recombinantly expressed and characterized in detail. Since it showed exolytic lyase activity toward hyaluronan (HA), chondroitin sulfate (CS), and dermatan sulfate (DS), it was designated as HCDLase. This novel exolyase exhibited the highest activity in Tris–HCl buffer (pH 7.0) at 30°C. Especially, it showed a specific activity that released 2-aminobenzamide (2-AB)-labeled disaccharides from the reducing end of 2-AB-labeled CS oligosaccharides, which suggest that HCDLase is not only a novel exolytic lyase that can split disaccharide residues from the reducing termini of sugar chains but also a useful tool for the sequencing of CS chains. Notably, HCDLase could not digest 2-AB-labeled oligosaccharides from HA, DS, or unsulfated chondroitin, which indicated that sulfates and bond types affect the catalytic activity of HCDLase. Finally, this enzyme combined with CSase ABC was successfully applied for the sequencing of several CS hexa- and octasaccharides with complex structures. The identification of HCDLase provides a useful tool for CS-related research and applications.

Any listing of important scientific figures in 20th century crystallography would certainly include William Nunn Lipscomb, Jr. He is notable for both the breadth and depth of his research and because of many former students and fellows who are still active in science. Beginning with graduate work in the 40s at Caltech with Linus Pauling, his scientific career spanned almost 7 decades and produced more than 660 publications. "The Colonel" as he was known by his students was a genius in choosing important and challenging areas in which to study. He is widely known for his work on borane chemistry, theoretical chemistry and protein structure and function. His work on the chemical structure and bonding of boron cage compounds led to insights into electron deficient bonding that resulted in the award of the Nobel Prize in Chemistry in 1976. He championed the use of various quantum-mechanical approaches, both empirical and ab initio, to address questions in chemistry and biochemistry. He is particularly known for work using partial retention of differential diatomic overlap (PRDDO), and early work leading to the development of extended Hückel methods. He was a pioneer in using quantum chemistry to address questions in enzymology. His group produced the structures of several proteins including carboxypeptidase A, the 3rd enzyme structure solved after lysozyme and ribonuclease A, and also the structure of the dodecameric enzyme, aspartate transcarbamylase. The structures of the T and R forms of this protein were the first detailed descriptions of the homotropic allosteric transition ever reported for an enzyme. Additionally, Professor Lipscomb mentored a huge number of important scientists whose work continues throughout the world today. Notably two former graduate students, Tom Steitz and Roald Hoffman have received Nobel Prizes. The list of other notable group members is too long to include here but includes Don Wiley, David Christianson, Eric Gouaux, Doug Rees, Michael Rossman, and Norbert Sträter among many, many others. I was fortunate to be a graduate student with him in the 1980s and am very grateful for his influence and mentorship. With so many important scientific contributions spread over such a long time span William Lipscomb's scientific legacy is certain to endure.

Abstract The composition and structure of interstellar dust are important and complex for the study of the evolution of stars and the interstellar medium (ISM). However, there is a lack of corresponding experimental data and model theories. By theoretical calculations based on ab-initio method, we have predicted and geometry optimized the structures of Carbon-rich (C-rich) dusts, carbon (12C), iron carbide (FeC), silicon carbide (SiC), even silicon (28Si), iron (56Fe), and investigated the optical absorption coefficients and emission coefficients of these materials in 0D (zero-dimensional), 1D, and 2D nanostructures. Comparing the nebular spectra of the supernovae (SN) with the coefficient of dust, we find that the optical absorption coefficient of the 2D 12C, 28Si, 56Fe, SiC and FeC structure corresponds to the absorption peak displayed in the infrared band (5–8) μm of the spectrum at 7554 days after the SN1987A explosion. It also corresponds to the spectrum of 535 days after the explosion of SN2018bsz, when the wavelength was in the range of (0.2–0.8) and (3–10) μm. Nevertheless, 2D SiC and FeC correspond to the spectrum of 844 days after the explosion of SN2010jl, when the wavelength is within (0.08–10) μm. Therefore, FeC and SiC may be the second type of dust in SN1987A corresponding to infrared band (5–8) μm of dust and may be in the ejecta of SN2010jl and SN2018bsz. The nano-scale C-rich dust size is ∼0.1 nm in SN2018bsz, which is 3 orders of magnitude lower than the value of 0.1 μm. In addition, due to the ionization reaction in the supernova remnant (SNR), we also calculated the Infrared Radiation (IR) spectrum of dust cations. We find that the cation of the 2D layered (SiC)2+ has a higher IR spectrum than those of the cation (SiC)1+ and neutral (SiC)0+.

A series of new congeners, 1-[2-(1-adamantyl)ethyl]-1H-benzimidazole (AB) and 1-[2-(1-adamantyl)ethyl]-4,5,6,7-tetrahalogeno-1H-benzimidazole (Hal=Cl, Br, I; tClAB, tBrAB, tIAB), have been synthesized and studied. These novel multi-target ligands combine a benzimidazole ring known to show antitumor activity and an adamantyl moiety showing anti-influenza activity. Their crystal structures were determined by X-ray, while intermolecular interactions were studied using topological Bader’s Quantum Theory of Atoms in Molecules, Hirshfeld Surfaces, CLP and PIXEL approaches. The newly synthesized compounds crystallize within two different space groups, P-1 (AB and tIAB) and P21/c (tClAB and tBrAB). A number of intramolecular hydrogen bonds, C-H···Hal (Hal=Cl, Br, I), were found in all halogen-containing congeners studied, but the intermolecular C-H···N hydrogen bond was detected only in AB and tIAB, while C-Hal···π only in tClAB and tBrAB. The interplay between C−H···N and C−H···Hal hydrogen bonds and a shift from the strong (C−H···Cl) to the very weak (C−H···I) attractive interactions upon Hal exchange, supplemented with Hal···Hal overlapping, determines the differences in the symmetry of crystalline packing and is crucial from the biological point of view. The hypothesis about the potential dual inhibitor role of the newly synthesized congeners was verified using molecular docking and the congeners were found to be pharmaceutically attractive as Human Casein Kinase 2, CK2, inhibitors, Membrane Matrix 2 Protein, M2, blockers and Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2, inhibitors. The addition of adamantyl moiety seems to broaden and modify the therapeutic indices of the 4,5,6,7-tetrahalogeno-1H-benzimidazoles.

Radioactive iodine-capturing materials are urgently needed for the emerging challenges in nuclear waste disposal. The various pore structures of covalent organic frameworks (COFs) render them promising candidates for efficient iodine adsorption. However, the detailed structure–property relationship of COFs in iodine adsorption remains elusive. Herein, two polymorphic COFs with significantly different crystalline structures are obtained based on the same building blocks with varied molecular ratios. The two COFs both have high crystallinity, high specific surface area, and excellent chemical and thermal stability. Compared with the [C4+C4] topology (PyT-2) with an AA stacking form, the [C4+C2] topology (PyT-1) with an AB stacking form has more twisted pore channels and complex ink-bottle pores. At ambient conditions, PyT-1 and PyT-2 both exhibit good adsorption properties for iodine capture either in a gaseous or liquid medium. Remarkably, PyT-1 presents an excellent maximum adsorption capacity (0.635 g g−1), and the adsorption limit of PyT-2 is 0.445 g g−1 in an n-hexane solution with an iodine concentration of 400 mg L−1, which is highly comparable to the state-of-the-art iodine absorption performance. This study provides a guide for the future molecular design strategy toward novel iodine adsorbents.

Abstract Background One of the NIH high-priority HIV/AIDS research objectives is to discover novel therapeutics aimed at developing safe, tolerable, strategies that targets cellular protein to induce long-term antiviral suppression. This current research aims at designing a novel targeted nano-formulation combining cell targeting and antiretroviral therapy to provide double protection against HIV-1. Methods CCR5 targeted combination antiretroviral drugs (cARV) loaded nanoparticles (NPs) were synthesized based on water-in-oil-in-water (W-O-W) emulsion methodology. For targeting CCR5+ T cells, a modified high affinity CCR5 monoclonal Ab (XFCCR5 mAb), was isolated from XF-CCR5 hybridoma cells. The XFCCR5 mAbs were covalently conjugated through their C-terminus by replacing the NHS group on FTC+DTG NPs with covalent amide bond. The CCR5 mAb binding was evaluated by SDS–PAGE methods. The CCR5-specific binding affinity of XFCCR5-FTC+DTG NP in compared with XFCCR5 monoclonal antibody (mAb) was evaluated by flow cytometry using CD4+CCR5+ TZM-bl cell line and PBMCs. The intracellular pharmacokinetic (PK) profile in TZMbl cells was evaluated by LC-MS/MS analysis, whereas in vitro efficacy was evaluated based on Steady-Glo® Luciferase Assay System using TZM-bl cells. Results XFCCR5-FTC+DTG NPs obtained averaged 173 ± 23 nm (mean ± SEM, n = 3) with 2.2 ± 0.47 mg XFCCR5 mAb bound per mg cARV NP. The formulation % entrapment efficiency of DTG and FTC respectively, to be 55 ± 1.6% and 42.6 ± 5.6%. The specific binding affinity (Km) of XFCCR5-FTC+DTG NP and XFCCR5 mAb were estimated to be 0.0057 and 0.0377, higher compared with wild-type anti-CCR5 mAb with higher Km value 0.303. Finally, the 4-day HIV-infection protection study result illustrates IC50 in case of XFCCR5-FTC+DTG NP and XFCCR5 NP to be as low as 0.0069 and 0.0031 µg/mL, respectively, compared with 1.771 µg/mL for XFCCR5 mAb (Figure 1, TZM-bl and Figure 2, PBMCs). Conclusion This nano-formulation aimed at duel protection by preventing HIV binding to CCR5+CD4+T cell due to CCR5 receptor blocking. These result support protection against HIV and maintenance of cARV drug levels. This novel formulation could be supportive of immune-alternative to achieve functional-cure against HIV. Disclosures All authors: No reported disclosures.

Acinetobacter baumanniihas emerged as an important opportunistic pathogen equipped with a growing number of antibiotic resistance genes. Our study investigated the molecular epidemiology and antibiotic resistance features of 28 consecutive carbapenem-resistant clinical isolates ofA. baumanniicollected throughout Sweden in 2012 and 2013. The isolates mainly belonged to clonal complexes (CCs) with an extensive international distribution, such as CC2 (n= 16) and CC25 (n= 7). Resistance to carbapenems was related toblaOXA-23(20 isolates),blaOXA-24/40-like(6 isolates),blaOXA-467(1 isolate), and ISAba1-blaOXA-69(1 isolate). Ceftazidime resistance was associated withblaPER-7in the CC25 isolates. Two classical point mutations were responsible for resistance to quinolones in all the isolates. Isolates with high levels of resistance to aminoglycosides carried the 16S rRNA methylasearmAgene. The isolates also carried a variety of genes encoding aminoglycoside-modifying enzymes. Several novel structures involved in aminoglycoside resistance were identified, including Tn6279, ΔTn6279, Ab-ST3-aadB, and different assemblies of Tn6020and TnaphA6. Importantly, a number of circular forms related to the IS26or ISAba125composite transposons were detected. The frequent occurrence of these circular forms in the populations of several isolates indicates a potential role of these circular forms in the dissemination of antibiotic resistance genes.

Accurate selectivity estimation for string predicates is a long-standing research challenge in databases. Supporting pattern matching on strings (such as prefix, substring, and suffix) makes this problem much more challenging, thereby necessitating a dedicated study. Traditional approaches often build pruned summary data structures such as tries followed by selectivity estimation using statistical correlations. However, this produces insufficiently accurate cardinality estimates resulting in the selection of sub-optimal plans by the query optimizer. Recently proposed deep learning based approaches leverage techniques from natural language processing such as embeddings to encode the strings and use it to train a model. While this is an improvement over traditional approaches, there is a large scope for improvement. We propose Astrid, a framework for string selectivity estimation that synthesizes ideas from traditional and deep learning based approaches. We make two complementary contributions. First, we propose an embedding algorithm that is query-type (prefix, substring, and suffix) and selectivity aware. Consider three strings 'ab', 'abc' and 'abd' whose prefix frequencies are 1000, 800 and 100 respectively. Our approach would ensure that the embedding for 'ab' is closer to 'abc' than 'abd'. Second, we describe how neural language models could be used for selectivity estimation. While they work well for prefix queries, their performance for substring queries is sub-optimal. We modify the objective function of the neural language model so that it could be used for estimating selectivities of pattern matching queries. We also propose a novel and efficient algorithm for optimizing the new objective function. We conduct extensive experiments over benchmark datasets and show that our proposed approaches achieve state-of-the-art results.

I summarize our recent works on using differential observables to explore the physics potential of future [Formula: see text] colliders in the framework of Higgs effective field theory. This proceeding is based upon Refs. 1 and 2. We study angular observables in the [Formula: see text] channel at future circular [Formula: see text] colliders such as CEPC and FCC-ee. Taking into account the impact of realistic cut acceptance and detector effects, we forecast the precision of six angular asymmetries at CEPC (FCC-ee) with center-of-mass energy [Formula: see text] GeV and 5 (30) ab[Formula: see text] integrated luminosity. We then determine the projected sensitivity to a range of operators relevant for the Higgsstrahlung process in the dimension-6 Higgs EFT. Our results show that angular observables provide complementary sensitivity to rate measurements when constraining various tensor structures arising from new physics. We further find that angular asymmetries provide a novel means of constraining the “blind spot” in indirect limits on supersymmetric scalar top partners. We also discuss the possibility of using [Formula: see text]-fusion at [Formula: see text] machines at different energies to probe new operators.

Lower extremity dysfunction is often associated with hip muscle strength deficiencies. Detailed knowledge of the muscle forces generated in the hip under specific external loading conditions enables specific structures to be trained. The aim of this study was to find the most effective movement type and loading direction to enable the training of specific parts of the hip muscles using a standing posture and a pulley system. In a novel approach to release the predictive power of musculoskeletal modelling techniques based on inverse dynamics, flexion/extension and ab-/adduction movements were virtually created. To demonstrate the effectiveness of this approach, three hip orientations and an external loading force that was systematically rotated around the body were simulated using a state-of-the art OpenSim model in order to establish ideal designs for training of the anterior and posterior parts of the M. gluteus medius (GM). The external force direction as well as the hip orientation greatly influenced the muscle forces in the different parts of the GM. No setting was found for simultaneous training of the anterior and posterior parts with a muscle force higher than 50% of the maximum. Importantly, this study has demonstrated the use of musculoskeletal models as an approach to predict muscle force variations for different strength and rehabilitation exercise variations.

A series of ester-linked diamines, with different lengths and substituents, was synthesized to obtain poly(ester imide)s (PEsIs) having improved properties. A substituent-free ester-linked diamine (AB-HQ) was poorly soluble in N-methyl-2-pyrrolidone at room temperature, which forced the need for polyaddition by adding tetracarboxylic dianhydride solid into a hot diamine solution. This procedure enabled the smooth progress of polymerization, however, accompanied by a significant decrease in the molecular weights of poly(amic acid)s (PAAs), particularly when using hydrolytically less stable pyromellitic dianhydride. On the other hand, the incorporation of various substituents (–CH3, –OCH3, and phenyl groups) to AB-HQ was highly effective in improving diamine solubility, which enabled the application of the simple polymerization process without the initial heating of the diamine solutions, and led to PAAs with sufficiently high molecular weights. The introduction of bulkier phenyl substituent tends to increase the coefficients of thermal expansion (CTE) of the PEsI films, in contrast to that of the small substituents (–CH3, –OCH3). The effects of ester-linked diamines, consisting of longitudinally further extended structures, were also investigated. However, this approach was unsuccessful due to the solubility problems of these diamines. Consequently, the CTE values of the PEsIs, obtained using longitudinally further extended diamines, were not as low as we had expected initially. The effects of substituent bulkiness on the target properties, and the dominant factors for water uptake (WA) and the coefficients of hygroscopic expansion (CHE), are also discussed in this study. The PEsI derived from methoxy-sustituted AB-HQ analog and 3,3′,4,4′-biphenyltetracarboxylic dianhydride achieved well-balanced properties, i.e., a very high Tg (424 °C), a very low CTE (5.6 ppm K−1), a low WA (0.41%), a very low CHE value (3.1 ppm/RH%), and sufficient ductility, although the 26 μm-thick film narrowly missed certification of the V-0 standard in the UL-94V test. This PEsI film also displayed a moderate εr (3.18) and a low tan δ (3.14 × 10−3) at 10 GHz under 50% RH and at 23 °C. Thus, this PEsI system is a promising candidate as a novel dielectric substrate material for use in the next generation of high-performance flexible printed circuit boards operating at higher frequencies (≥10 GHz).

Polysaccharides are abundant in natural resources and perform numerous physiological functions. Polysaccharide structures often lack chromophore groups; thus, current analytical methods cannot distinguish polysaccharide metabolites in the body or polysaccharide prototypes in biological samples. Thus, the measurement of polysaccharides in blood, bodily fluid, and cell-culture medium is difficult. Our early-stage research resulted in the isolation of two homogeneous polysaccharides from Pseudostellaria heterophylla, PHP0.5MSC-F and PHPH-1-2, which have anti-hyperglycemia and insulin resistance improvement effects for type 2 diabetes. In this study, the reducing terminal sugars of PHP0.5MSC-F and PHPH-1-2 were labeled with 2-aminobenzamide (2-AB) to prepare novel fluorescent probes for HPLC-coupled fluorescence detection (HPLC-FLD). Quantitative analysis was performed in reference to T40, and the detection limit for PHP0.5MSC-F was found to be 8.84 μg/mL with a linear range of 29.45–683.28 μg/mL. In reference to T70, the detection limit for PHPH-1-2 was found to be 13.89 μg/mL with a linear range of 46.29–462.76 μg/mL. This method was used to measure the bidirectional transport of polysaccharides across caco-2 cells from apical to basolateral (AP→BL) or from basolateral to apical (BL→AP) directions and to evaluate the polysaccharide bioavailability. The drug absorption capacity was determined based on the apparent permeability coefficient (Papp), and the Papp values for the two polysaccharides were found to be greater than 1 × 10−6 cm/s, which suggests easy absorption. Regarding bidirectional transport, the AP→BL Papp values were greater than the BL→AP values; thus, PHP0.5MSC-F and PHPH-1-2 mainly underwent passive transference. The two membrane permeable polysaccharides were not P-gp efflux transporter substrates. The absorption mechanism of PHP0.5MSC-F complies with passive diffusion under a concentration gradient, whereas PHPH-1-2 mainly utilizes a clathrin-mediated endocytic pathway to enter caco-2 cells. This innovative HPLC-FLD method can help to track polysaccharide internalization in vitro and in vivo to facilitate cellular uptake and biodistribution exploration.

ABSTRACTElastmeric materials are of great importance in both academic and industrial field due to the soft and highly stretchable properties. Thus, many theories and models are proposed to correlate the physical properties and structural parameters. However, in general, it is difficult to validate these models experimentally. Thus, to this day, we do not know the requirement conditions for each model or even the validity of each model. The validation of these models has been inhibited by the inherent heterogeneity of polymer networks.Recently, we, for the first time, succeeded in fabricating polymer network with extremely suppressed heterogeneity with a novel molecular design of prepolymers. The homogeneous polymer network, called Tetra-PEG gel, is prepared by AB-type crosslink-coupling of mutually reactive tetra-arm prepolymers. In this study, we examined the models of elastic modulus and fracture energy using Tetra-PEG gel as a model system. We controlled the structural parameters with tuning the molecular weight and concentration of prepolymers, and reaction conversion of the reaction. This series of controlled network structures, for the first time, enabled us to quantitatively examine these models. We performed the stretching and tearing measurements for these polymer gels. As for the elastic modulus, we observed the shift of the models from the phantom to affine network models around the overlapping concentration of prepolymers. As for the fracture energy, we confirmed the validity of the Lake-Thomas model, which is the most popular model predicting fracture energies of elastomers.

Abstract Regulatory T cells (Treg) play a critical role in controlling immune responses in diseases such as cancer or autoimmunity. Activated Treg express the membrane protein GARP (LRRC32) in complex with the latent form of the immunosuppressive cytokine TGF-β (L-TGF-β). In this study, we confirmed that active TGF-β was generated from its latent form in an integrin-dependent manner and induced TGF-β receptor signaling in activated human Treg. We studied a series of Abs targeting the L-TGF-β/GARP complex with distinct binding modes. We found that TGF-β receptor signaling could be inhibited by anti–TGF-β and by some, but not all, Abs against the L-TGF-β/GARP complex. Cryogenic electron microscopy structures of three L-TGF-β/GARP complex–targeting Abs revealed their distinct epitopes and allowed us to elucidate how they achieve blockade of TGF-β activation. Three different modes of action were identified, including a novel unusual mechanism of a GARP-binding Ab. However, blockade of GARP or TGF-β by Abs did not influence the suppressive activity of human Treg in vitro. We were also not able to confirm a prominent role of GARP in other functions of human Treg, such as FOXP3 induction and Treg stability. These data show that the GARP/TGF-β axis can be targeted pharmacologically in different ways, but further studies are necessary to understand its complexity and to unleash its therapeutic potential.

ABSTRACTThe cytolethal distending toxin (Cdt), produced by some clinically important Gram-negative bacterial species, is related to the family of AB-type toxins. Three heterologous proteins (CdtA, CdtB, and CdtC) and a genotoxin mode of action distinguish the Cdt from others in this toxin class. Crystal structures of several species-specific Cdts have provided a basis for predicting subunit interactions and functions. In addition, empirical studies have yielded significant insights into thein vivointeractions of the Cdt subunits. However, there are still critical gaps in information about the intoxication process. In this study, a novel protein tagging technology was used to localize the subunits in Chinese hamster ovary cells (CHO-K1). A tetracysteine motif was engineered in each subunit, and in subunits with mutations in predicted functional domains, to permit detection with the fluorescein arsenical hairpin binding (FlAsH) dye Lumio green. Live-cell imaging, in conjunction with confocal microscopy, was used to capture the locations of the individual subunits in cells intoxicated, under various conditions, with hybrid heterotrimers. Using this approach, we observed the following. (i) The CdtA subunit remains on the cell surface of CHO cells in association with cholesterol-containing and cholesterol-depleted membrane. (ii) The CdtB subunit is exclusively in the cytosol and, after longer exposure times, localizes to the nucleus. (iii) The CdtC subunit is present on the cell surface and, to a greater extent, in the cytosol. These observations suggest that CdtC, but not CdtA, functions as a chaperone for CdtB entry into cells.

Abstract Background For decades since its discovery, the idiotype protein (Id) expressed on the surface of B-cell malignancies has been pursued as a tumor-specific target in therapeutic antibody and vaccine development programs. The challenge in vaccine development has been to present the Id antigen so as to stimulate an effective anti-tumor response. Advances in our understanding of the immune system have revealed the importance of innate receptors, particularly the toll-like receptor (TLR) family, in stimulating adaptive immunity. Further understanding of virus-induced immunity reveals features such as viral trafficking to lymph nodes and presentation of antigens in an ordered array that facilitate immune response generation. Our strategy combines this knowledge with advanced protein engineering in order to produce a stabilized virus-like particle (sVLP) that displays Id in the context of innate immune stimulants. Multiple studies using the 38C13 lymphoma model were performed to evaluate and maximize the efficacy of Id-VLP vaccines using the historical "gold standard" Id-KLH as a reference. Methods VLP vaccines were constructed by conjugating the tumor-associated Id antigen and immune stimulants, GM-CSF, CpG DNA, and flagellin, to the exterior surface of either the MS2 or Hepatitis B core (HBc) VLP. The bioconjugates were engineered to maintain biologic activity of the immune stimulants and present unperturbed heavy and light chain variable regions. A total of 14 different vaccines displaying 3 different 38C13 Id formats, IgM, F(ab')2 and scFv, with or without one or more of the three immune stimulant were produced. For example, with the scFv Id format VLP vaccines, 7 of the 8 possible combinations of immune stimulants were made. Three in vivo experiments were performed to evaluate vaccine compositions. C3H mice were vaccinated three times within a one-month period with control or experimental vaccines. Following vaccination, the mice were challenged with 38C13 Id-bearing tumor cells administered by intraperitoneal or subcutaneous routes. Sera samples were collected prior to, during, and after vaccination for analysis of total and isotype-specific anti-Id antibody titer. Results The first study compared MS2- and HBc-based VLP vaccines. While both viral structures exhibited immune inhibition on their own, the HBc VLP vaccine conjugated with GM-CSF and CpG elicited a strong and protective humoral immune response as compared to experimental controls. This was confirmed in a second study where different HBc VLP vaccines explored additional combinations of immune stimulants and the different Id formats. While all HBc VLP vaccines elicited strong and protective immune responses, the VLP with scFv Id format and CpG provided better protection against tumor challenge than the Id-KLH conjugate. (70% vs 30% event-free survival). The third study further examined the scFv Id format and immune stimulants on stabilized HBc-based vaccines where disulfide bonds were introduced between dimers within the axes of symmetry to create a VLP structure in which every atom is indirectly covalently bonded to every other atom. Once again, the scFv Id-CpG-sVLP vaccine elicited a strong and protective response. Conclusions Collectively, these studies provide strong rationale for the selected BB-001 composition (scFv Id-CpG-HBc sVLP) as a vaccine for Id-bearing lymphomas, as well as solid evidence that HBc sVLPs are a versatile and effective platform for further vaccine development. While all HBc-based Id vaccines with immune stimulants were statistically significantly superior to placebo groups in terms of efficacy and/or immune response, the simpler VLP vaccine with the TLR9 agonist CpG outperformed the combinations with GM-CSF and/or flagellin. The subcutaneous tumor challenge was more demanding, and showed a statistically significant survival advantage for BB-001(70%) versus Id-KLH (30%). Consistent with previous 38C13 studies, humoral immune response was critical for protection from challenge. Evidence of antibody class switching in the humoral immune response was also observed. Disclosures Theriault: Bullet Biotechnology, Inc.: Employment, Equity Ownership. Levy:Bullet Biotechnology, Inc.: Consultancy. Swartz:Bullet Biotechnology, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction Multiple myeloma (MM) remains an incurable malignancy despite important recent advances in treatments. Neo-vascularization entails a crucial aspect of interactions between neoplastic plasma cells (PCs) and their microenvironment. Without it, MM would be unable to grow and progress, and would probably regress to a low-mass steady-state comparable to monoclonal gammopathy of undetermined significance (MGUS). To overcome drug resistance and improve clinical response to novel therapeutic approaches halting both PC growth and the increased bone marrow (BM) microvascular density are needed. In this setting, monoclonal antibodies against MM-specific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate membrane target structures expressed across all MM cells. The Eph receptors, a large family of receptor tyrosine kinases, have been implicated in many processes involved in malignancy, including alteration of the tumour microenvironment, and in angiogenesis, in both of which EphA3 likely plays an active role. Interestingly, the over-expression of EphA3 is sufficient to confer tumorigenic potential, although probably further mechanisms can occur to abnormally activate the receptor. A first-in-class engineered IgG1 antibody targeting the EphA3 was developed and it is now under phase I clinical trials in USA and Australia for the treatment of EphA3 over-expressing hematological myeloid malignancies refractory to conventional treatment. Methods We investigated the EphA3 role in MM patients in order to define whether it may represent a potential new molecular target for a novel therapeutic approach with a specific anti EphA3 monoclonal antibody. The EphA3 expression was studied through a comparative proteomic analysis between BM endothelial cells (ECs) of patients with MM (MMECs) or with MGUS (MGECs), of control subjects (normal ECs). Moreover, the effects of anti EphA3 antibody in MM were studied in vitro and in vivo in a MM xenograft mouse model. After written informed consent, BM aspirates were collected from 26 MM and 6MGUS patients. Normal ECs were derived from 5 BM aspirates of subjects with anemia due to iron or vitamin B12 deficiency. We analyzed both mRNA and protein levels of EphA3 in normal ECs, MGECs and MMECs and in MM cell lines by absolute RT-PCR and by WB coupled to immunofluorescence and FACS analysis respectively. Immunoistochemistry was also performed on MM BM biopsies. The biological effects of EphA3 targeting were studied in vitro silencing (siRNA) the EphA3 mRNA in MMECs and using the anti EphA3 antibody testing them in series of in vitro functional assays including viability, apoptosis, adhesion, migration, wound healing and angiogenesis tests. We further examined the inhibitory capacity of anti-EphA3 Ab on tumor growth in SCID mice bearing MM tumor cell xenografts. Finally, we assessed morphology, vessel density, and apoptosis of excised xenotransplanted tumors. Results Briefly, our data showed that EphA3 mRNA and protein levels are progressively increased from ECs to MGECs, reaching the highest values in MMECs. EphA3 stained intensely and diffusely MM microvessels and PC in MM BM biopsies. The EphA3siRNA MMECs revealed a protein level reduction of approximately 80% when compared to the control. We not detected viability or apoptotic defects, whereas in vitro adhesion, migration and angiogenesis inhibition was evident when compared to the not silenced counterpart. The anti EphA3 antibody inhibited MMECs migration and reduced in vitro MM angiogenesis. In particular, tumour masses developed in xenograft mice treated with anti-EphA3 Abs were smaller in size and showed foci of ischemic-hemorrhagic necrosis, in association with a significant (P < 0.05) reduction in the number of intact tumor microvessels. The proliferative activity was not significantly different from that observed in tumors from untreated or control isotype treated mice, while the apoptotic index was significantly (P < 0.05) increased in comparison with tumors from both groups of mice. Conclusions In this study we have characterized the role of the EphA3in MM patients, providing in vitro and in vivo experimental evidences that support the possibility of using EphA3 as a new molecular target for MM. Disclosures: No relevant conflicts of interest to declare.

The polscope uses novel electrooptical hardware and digital processing to image macromolecular structures in cells on the basis of their birefringence (Sato et al. 1975 J. Cell Biol. 76, 501-517). Imaging of the spindle in living oocytes with the polscope is based on birefringence of an inherent physical property of the microtubules. De-polymerization of microtubules arrests meiosis and induces abnormal meiosis generating chromosomally abnormal oocytes which are not capable of being fertilized and developing. In this study we examined whether spindles in living mouse oocytes can be safely imaged/examined by the polscope and investigated the influence of sub-optimal temperature on spindle detection/visualization. For oocyte collection, 6- to 8-week-old CB6F1 female mice were superovulated with PMSG (10 IU, i.p.; Sigma, USA) and 46 to 48 h later they were injected with hCG (10 IU, i.p.; Sigma). Oocytes were collected 20 to 23 h after hCG treatment in MOPS buffered medium (G-MOPS"; Vitrolife, Sweden AB, Kungsbacka, Sweden) supplemented with human serum albumin (HAS"; Vitrolife). Cumulus cells were removed from the zonae pellucidae by exposure to a solution of 40 IU/mL hyaluronidase (HYASE"; Vitrolife). For spindle examination, each oocyte was placed in a 5-�L drop of G-MOPS medium, covered with oil (Ovoil; Vitrolife), and examined in a Delta T.C.O. dish with a specially coated glass bottom (Willco-Dish, Willco Wells, Amsterdam, The Netherlands). Oocytes were imaged by a Nikon Diaphot microscope with a video camera, objective lens, and controller, combined with a computerized imaging analysis system (CRI, Great Britain). For evaluation of the effect of sub-optimal temperature on the visualization/detection of the spindle, mouse oocytes were cultured for a short period of time at sub optimal temperatures (18 to -20�C/25 min and -10 to -15�C/2 min). After that, the oocytes were immediately checked for presence and condition of the meiotic spindle and re-checked after 30-min culture at 37�C with 6% CO2, 5% O2, 89% N2 and maximal humidity in air. There was no difference in the detect ability of the spindle in mouse oocytes with or without polar body (PB+: 21/24, 87%; PB-: 29/32, 90%). We found that the treatment with sub-optimal temperature has an effect to the spindle visualization. Immediately after treatment, the spindle could be detected in 80% of the oocytes (16/20). However, after 30-min culture, the meiotic spindle was detectable in only 25% of the treated oocytes (5/20; P < 0.05). Sub optimal temperature at first increased the birefringence of the meiotic spindle for a short period of time; then the spindle became completely undetectable. The increased sensitivity of the meiotic spindle to low temperature is one of the biggest obstacles to the oocyte cryopreservation. Our results provide further evidence that the spindle in mammalian oocytes is very sensitive to temperature fluctuations. The increase in the birefringence was the first sign that the structure of microtubules and other cytoskeletal factors forming the spindle had changed. Investigations are underway to learn more about the capability of the meiotic spindle to become reorganized.

Abstract Background Despite numerous new and improved therapies, a majority of NHL patients eventually succumb to relapse. An approach to increase survival and decrease normal tissue toxicity in hematopoietic cell transplantation (HCT) regimens has been to replace high-dose total body irradiation with targeted RIT. Although radiolabeled MAbs targeting CD20 as conditioning prior to HCT have proven feasible and may provide curative radiation doses for NHL, targeting CD45 may be superior because of increased antigen expression, longer anti-CD45 MAb retention at target sites, and potentially less impact from antigen blocking by prior anti-CD20 treatment. In addition, replacing commonly employed beta emitters with the more radiobiologically favorable alpha (α) emitter 211At may be more effective for anti-CD45 RIT and HCT conditioning. This study aims to investigate the MAb dose of 211At-anti-CD45 RIT that provides efficient pharmacokinetics and optimal targeting of hematopoietic cells, with minimal normal tissue toxicity, using a canine model of relapsed NHL that closely resembles human disease in terms of clinical presentation, histology, and biological behavior. Methods Five normal dogs (7.7–12.8 kg) were injected i.v. with 211At-anti-CD45 MAb (B10-conjugated CA12.10C12) starting at a MAb dose of 0.75 mg/kg for dogs 1–4 (0.5 mg/kg was non-saturating in previous studies) and increasing to 1.0 mg/kg for dog 5. Blood was sampled from 5 min to 22 h post injection (p.i.) and measured for 211At activity. MAb clearance was assessed by ELISA. Dogs 1 and 2 were euthanized 22 and 19 h after 211At injection (0.395 and 0.745 mCi/kg) and tissues were harvested for comparing the % of injected radioactivity per gram (ID/g) in target organs and normal tissues. Dogs 3–5 received autologous HCT 3 days after 211At-anti-CD45 RIT (0.310–0.395 mCi/kg) and biopsies of lymph nodes and bone marrow were performed at 2 and/or 19 h p.i. Complete blood counts were obtained at baseline, daily for the first 2 months or until full hematopoietic recovery, then once a week until end of study. Electrolytes, BUN, creatinine, and liver enzymes were measured at baseline and then every other week for 3 months. Flow cytometry and immunohistochemistry (IHC) was used to assess CD45 binding and sub-organ MAb localization with saturation being determined by comparison of mean fluorescence intensity (MFI) of target cells stained with FITC-conjugated goat anti-mouse F(ab’)2 (FMF) or FITC-conjugated anti-CD45 (CD45F). In addition to IHC, localization of 211At-anti-CD45-MAb was evaluated using two novel digital autoradiography techniques: α-camera and iQID. Both systems enable quantitative ex vivo imaging of α-particles in tissue, allowing dosimetry and assessment of 211At distribution down to the cellular level. Results Biological half-lives for circulating 211At and anti-CD45 MAb were calculated using single-phase exponential fit to 2.8 ± 0.5 and 3.2 ± 1.3 h, respectively. CD45F staining of peripheral blood mononuclear cells showed that 0.75 mg/kg of MAb was saturating for blood lymphocytes, but gated on all cells the MFI was lower using 1.0 mg/kg, indicating a decrease in available CD45 sites at the higher dose. Lymph nodes remained sub-saturated at 1.0 mg/kg. A dramatic effect was seen on bone marrow lymphocytes with antigen saturation (low CD45F MFI) at 2 h p.i. and few cells (halved FMF MFI) remaining 19 h after treatment. Successful marrow targeting and ablation was supported by α-imaging of cryosectioned bone marrow, showing evenly distributed 211At in remaining cells. Lymph nodes showed efficient targeting of peripheral follicle-like structures at 19 and 22 h p.i., with lower activity seen in central areas (dogs 1–3). At 2 h p.i. (dog 4), the activity distribution was more homogeneous, indicating elimination of centrally located CD45-expressing cells between 2 and 19 h p.i. In dog 5, the 2-h lymph node biopsy displayed a heterogeneous 211At distribution as seen in dogs 1–3, hypothetically due to faster penetration and enhanced cell kill with increased 211At-MAb dose. Conclusion Administration of 1.0 mg/kg of 211At-anti-CD45 MAb resulted in saturation of CD45 sites in bone marrow with ablation of marrow cells. While the lymph nodes were not saturated, there was highly effective targeting of the lymph node follicles. Further studies are needed to assess if targeting 211At to CD45 may be effective for therapy of NHL. Disclosures: No relevant conflicts of interest to declare.

The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. 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ABSTRACTPredicting crystal structure is one of the most fundamental problems in materials science and a key early step in computational materials design. Ab initio simulation methods are a powerful tool for predicting crystal structure, but are too slow to explore the extremely large space of possible structures for new alloys. Here we describe ongoing work on a novel method (Data Mining of Quantum Calculations, or DMQC) that applies data mining techniques to existing ab initio data in order to increase the efficiency of crystal structure prediction for new alloys. We find about a factor of three speedup in ab intio prediction of crystal structures using DMQC as compared to naïve random guessing. This study represents an extension of work done by Curtarolo, et al. [1] to a larger library of data.