Domain Interface Research Articles

Magnons Transmission Across Soliton Domain in 2D Triangular Ferromagnetic Waveguides

In this work, we investigate the scattering phenomena at the inhomogeneous boundary of a magnetic interface in two-dimensional (2D)-triangular ferromagnetic waveguide. We especially examine two ferromagnetic interfaces, named heavy and superheavy solitons in 2D-triangular lattices. The system is supported on a nonmagnetic substrate. Therefore, each spin site in the lattice can be considered free from magnetic interactions with its environment. The spin excitations in the modeled system are studied by the field matching theory (FMT). Their magnons transmission/reflection, localized spin states as well as the local density of spin states (LDOS) are calculated and analyzed. They are derived as elements of a Landauer type scattering matrix. The magnonic spectra are calculated specifically for two distinct interfaces, which join the two semi-infinite perfect 2D-triangular waveguides. The inter-atomic magnetic exchange is varied on the interface domain to investigate the consequences of magnetic softening and hardening for the calculated magnetic properties. The numerical results show the interference effects between the incident magnons and the localized spin states on the interface domain, with characteristic magnetic resonances that vary according to each configuration. The numerical results yield an understanding for the relation between the coherent magnon propagation and the interface configuration in the perfect 2D-triangular system.

Existence and weak–strong uniqueness of solutions to the Cahn–Hilliard–Navier–Stokes–Darcy system in superposed free flow and porous media

We study a diffuse interface model for two-phase flows of similar densities in superposed free flow and porous media. The model consists of the Navier–Stokes–Cahn–Hilliard system in free flow and the Darcy–Cahn–Hilliard system in porous media coupled through a set of domain interface boundary conditions. These domain interface boundary conditions include the nonlinear Lions interface condition and the linear Beavers–Joseph–Saffman–Jones interface condition. We establish global existence of weak solutions in three dimension. We also show that the strong solution if exists agrees with the weak solutions.

Degradation of p53 by HPV16-E6 variants isolated from cervical cancer specimens of Moroccan women.

Cervical cancer is the second most diagnosed cancer in Moroccan women. The main etiological factor for developing cervical cancer is the persistent infection with HPV16. Genetic studies have reported the occurrence of amino acid variations within the E6 oncoprotein that promotes host cell transformation by targeting p53 for degradation. To verify the biological effects of E6 polymorphisms towards p53 degradation, HPV16-E6 prototype and 7 variants isolated from cervical cancer biopsies of Moroccan women were evaluated for their activities by transient expression assays using pcDNA3.1-E6 constructs in C33A cell line. Expression of E6 genes in transfected cells was detected with reverse transcription PCR (RT-PCR), then, p53 levels were evaluated by western blot analysis. Significant dissimilarities in p53 degradation activities of HPV16-E6 prototype and intratypic variants were noticed. As compared to the prototype, the highest p53 degradation were exhibited by the African variants Af2-a/r, Af1-d/G295 and Af2-a/G285 (p<0.001), followed by the European variants E- C442/G350 and E-G350/r (p<0.01), then, the North American variant NA1-b/r (p<0.05). The inter-variant differences were statistically significant between Af2-a/r variant and the North American variants NA1-b/r and NA1 (p<0.05). Thus, the Af2-a/r variant was significantly more active in degrading p53 in our in vitro experiments (p<0.0001). Our findings support the fact that HPV16-E6 variations have a biological impact on degrading p53, and so, represent a significant carcinogenic potential for developing cervical cancer.

Crystal structures of UDP-N-acetylmuramic acid L-alanine ligase (MurC) from Mycobacterium bovis with and without UDP-N-acetylglucosamine.

Peptidoglycan comprises repeating units of N-acetylmuramic acid, N-acetylglucosamine and short cross-linking peptides. After the conversion of UDP-N-acetylglucosamine (UNAG) to UDP-N-acetylmuramic acid (UNAM) by the MurA and MurB enzymes, an amino acid is added to UNAM by UDP-N-acetylmuramic acid L-alanine ligase (MurC). As peptidoglycan is an essential component of the bacterial cell wall, the enzymes involved in its biosynthesis represent promising targets for the development of novel antibacterial drugs. Here, the crystal structure of Mycobacterium bovis MurC (MbMurC) is reported, which exhibits a three-domain architecture for the binding of UNAM, ATP and an amino acid as substrates, with a nickel ion at the domain interface. The ATP-binding loop adopts a conformation that is not seen in other MurCs. In the UNAG-bound structure of MbMurC, the substrate mimic interacts with the UDP-binding domain of MbMurC, which does not invoke rearrangement of the three domains. Interestingly, the glycine-rich loop of the UDP-binding domain of MbMurC interacts through hydrogen bonds with the glucose moiety of the ligand, but not with the pyrophosphate moiety. These findings suggest that UNAG analogs might serve as potential candidates for neutralizing the catalytic activity of bacterial MurC.

Molecular Docking and Dynamics Simulation of a Screening Library from Life Chemicals Database for Potential Protein-Protein Interactions (PPIs) Inhibitors against SARS-CoV-2 Spike Protein

The ongoing pandemic of coronavirus 2 represents a major challenge for global public health authorities. Coronavirus disease 2019 can be fatal especially in elderly people and those with comorbidities. Currently, several vaccines against coronavirus 2 are under application in multiple countries with emergency use authorization. In the same time, many vaccine candidates are under development and assessment. It is worth noting that the design of some of these vaccines depends on the expression of receptor binding domain for viral spike protein to induce host immunity. As such, blocking the spike protein interface with antibodies, peptides or small molecular compounds can impede the ability of coronavirus 2 to invade host cells by intervention with interactions between viral spike protein and cellular angiotensin converting enzyme 2. In this virtual screening study, we have used predictive webservers, molecular docking and dynamics simulation to evaluate the ability of 3000 compounds to interact with interface residues of spike protein receptor binding domain. This library of chemicals was focused by Life Chemicals as potential protein-protein interactions inhibitor. Here, we report that hit compound 7, with IUPAC name of 3‐cyclohexyl‐N‐(4‐{[(1R,9R) ‐6‐oxo‐7,11‐ diazatricyclo [7.3.1.02,7] trideca‐2,4‐dien‐11‐yl] sulfonyl} phenyl) propenamide, may have the capacity to interact with interface of receptor binding domain for viral spike protein and thereby reduce cellular entry of the virus. However, in vitro and in vivo assessments may be required to validate these virtual findings.

A new quasi-static delamination model with rate-dependence in interface damage and its operation under cyclic loading

A computational model for analysis of interface damage is introduced. It provides results for initiation and growth of cracks along a damaged interface in a multi-domain structure which is considered to be exposed to a periodically repeating load. First, the simulation of damage processes takes into account various possible relations between interface stresses and domain deformation leading to separation of subdomains in the structure expressed in a form typical for cohesive zone models. Second, equipped by a kind of viscosity associated to the evolution of the interface damage, the simulations with the proposed model considering repeating loading–unloading conditions make this damage process to have a fatigue-like nature, where the cracks appear for smaller loads and their magnitudes, while applied in cycles, compared to purely increasing loads. The computations provide evidences of such behaviour and suitability of the proposed model in situations where a structure is exposed to reoccurring load cycles.

A Tryptophan 'Gate' in the CRISPR-Cas3 Nuclease Controls ssDNA Entry into the Nuclease Site, That When Removed Results in Nuclease Hyperactivity.

Cas3 is a ssDNA-targeting nuclease-helicase essential for class 1 prokaryotic CRISPR immunity systems, which has been utilized for genome editing in human cells. Cas3-DNA crystal structures show that ssDNA follows a pathway from helicase domains into a HD-nuclease active site, requiring protein conformational flexibility during DNA translocation. In genetic studies, we had noted that the efficacy of Cas3 in CRISPR immunity was drastically reduced when temperature was increased from 30 °C to 37 °C, caused by an unknown mechanism. Here, using E. coli Cas3 proteins, we show that reduced nuclease activity at higher temperature corresponds with measurable changes in protein structure. This effect of temperature on Cas3 was alleviated by changing a single highly conserved tryptophan residue (Trp-406) into an alanine. This Cas3W406A protein is a hyperactive nuclease that functions independently from temperature and from the interference effector module Cascade. Trp-406 is situated at the interface of Cas3 HD and RecA1 domains that is important for maneuvering DNA into the nuclease active site. Molecular dynamics simulations based on the experimental data showed temperature-induced changes in positioning of Trp-406 that either blocked or cleared the ssDNA pathway. We propose that Trp-406 forms a ‘gate’ for controlling Cas3 nuclease activity via access of ssDNA to the nuclease active site. The effect of temperature in these experiments may indicate allosteric control of Cas3 nuclease activity caused by changes in protein conformations. The hyperactive Cas3W406A protein may offer improved Cas3-based genetic editing in human cells.

Engineering the Distinct Structure Interface of Subnano-alumina Domains on Silica for Acidic Amorphous Silica-Alumina toward Biorefining.

Amorphous silica–aluminas (ASAs) are important solid catalysts and supports for many industrially essential and sustainable processes, such as hydrocarbon transformation and biorefining. However, the wide distribution of acid strength on ASAs often results in undesired side reactions, lowering the product selectivity. Here we developed a strategy for the synthesis of a unique class of ASAs with unvarying strength of Brønsted acid sites (BAS) and Lewis acid sites (LAS) using double-flame-spray pyrolysis. Structural characterization using high-resolution transmission electron microscopy (TEM) and solid-state nuclear magnetic resonance (NMR) spectroscopy showed that the uniform acidity is due to a distinct nanostructure, characterized by a uniform interface of silica–alumina and homogeneously dispersed alumina domains. The BAS population density of as-prepared ASAs is up to 6 times higher than that obtained by classical methods. The BAS/LAS ratio, as well as the population densities of BAS and LAS of these ASAs, could be tuned in a broad range. In cyclohexanol dehydration, the uniform Brønsted acid strength provides a high selectivity to cyclohexene and a nearly linear correlation between acid site densities and cyclohexanol conversion. Moreover, the concerted action of these BAS and LAS leads to an excellent bifunctional Brønsted–Lewis acid catalyst for glucose dehydration, affording a superior 5-hydroxymethylfurfural yield.

Self-connected multi-domain topology optimization of structures with multiple dissimilar microstructures

Multi-domain topology optimization allows the design of lattice structures with multiple dissimilar microstructures. However, how to handle the connectivity issue between the dissimilar microstructures is a very important and difficult topic. In this paper, a self-connected material interpolation is proposed to handle the topology optimization of structures with multiple dissimilar-but-connected microstructures. Due to this interpolation, the material in the interface domains between the dissimilar microstructures can be separately defined, which enables us to carefully design the material of interface to guarantee good connectivity. An advantage of this way is that the connectivity requirement is only considered for these microstructures in the small interface domain while other microstructures can be freely designed in the remaining relatively much bigger design domain. In this paper, the connectivity requirement is realized by simply using a non-design solid domain in the interface microstructures. Based on the proposed interpolation, a two-scale multi-objective optimization formulation is proposed for concurrently designing the topologies and the lattice materials. In addition to the traditional mechanical performance, a geometric feature, i.e., the mass of the interface, is also taken as an objective in this method to control the material usage of interface. Several examples with parameterized lattice microstructures are provided to illustrate the effectiveness of the proposed method.

SHANK3 Conformation Regulates Direct Actin Binding and Crosstalk With Rap1 Signaling

Actin-rich cellular protrusions direct versatile biological processes from cancer cell invasion to dendritic spine development. The stability, morphology and specific biological function of these protrusions are regulated by crosstalk between three main signaling axes: integrins, actin regulators and small GTPases. SHANK3 is a multifunctional scaffold protein, interacting with several actin-binding proteins, and a well-established autism risk gene. Recently, SHANK3 was demonstrated to sequester integrin-activating small GTPases Rap1 and R-Ras to inhibit integrin activity via its N-terminal SPN domain. Here, we demonstrate that in addition to scaffolding actin regulators and actin binding proteins, SHANK3 interacts directly with actin through its SPN domain. Molecular simulations and targeted mutagenesis of the SPN-ARR interface reveal that actin binding is inhibited by an intramolecular closed conformation of SHANK3, where the adjacent ARR domain covers the actin-binding interface of the SPN domain. Actin and Rap1 compete with each other for binding to SHANK3 and mutation of the SHANK3-actin binding site, resulting in reduced actin binding, augments inhibition of Rap1-mediated integrin activity. This dynamic crosstalk has functional implications for cell morphology and integrin activity in cancer cells, dendritic spine morphology in neurons and autism-linked phenotypes in vivo.

Competing spin wave emission mechanisms revealed by time-resolved x-ray microscopy

Spin wave emission and propagation in magnonic waveguides represent a highly promising alternative for beyond-CMOS computing. It is therefore all the more important to fully understand the underlying physics of the emission process. Here, we use time-resolved scanning transmission x-ray microscopy to directly image the formation process of the globally excited local emission of spin waves in a permalloy waveguide at the nanoscale. Thereby, we observe spin wave emission from the corner of the waveguide as well as from a local oscillation of a domain-wall-like structure within the waveguide. Additionally, an isofrequency contour analysis is used to fully explain the origin of quasicylindrical spin wave excitation from the corner and its concurrent nonreflection and nonrefraction at the domain interface. This study is complemented by micromagnetic simulations which perfectly fit the experimental findings. Thus, we clarify the fundamental question of the emission mechanisms in magnonic waveguides which lay the basis for future magnonic operations.

Structure, substrate specificity, and catalytic mechanism of human D-2-HGDH and insights into pathogenicity of disease-associated mutations

D-2-hydroxyglutarate dehydrogenase (D-2-HGDH) catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) into 2-oxoglutarate, and genetic D-2-HGDH deficiency leads to abnormal accumulation of D-2-HG which causes type I D-2-hydroxyglutaric aciduria and is associated with diffuse large B-cell lymphoma. This work reports the crystal structures of human D-2-HGDH in apo form and in complexes with D-2-HG, D-malate, D-lactate, L-2-HG, and 2-oxoglutarate, respectively. D-2-HGDH comprises a FAD-binding domain, a substrate-binding domain, and a small C-terminal domain. The active site is located at the interface of the FAD-binding domain and the substrate-binding domain. The functional roles of the key residues involved in the substrate binding and catalytic reaction and the mutations identified in D-2-HGDH-deficient diseases are analyzed by biochemical studies. The structural and biochemical data together reveal the molecular mechanism of the substrate specificity and catalytic reaction of D-2-HGDH and provide insights into the pathogenicity of the disease-associated mutations.

Simplicity in mean-field phase behavior of two-component miktoarm star copolymers.

Using self-consistent field theory, we systematically explore the microphase separation in the class of two-component miktoarm star copolymers containing a single conjunction point between different blocks by considering an extended list of candidate microphases. We plot mean-field phase diagrams in the plane of segregation strength and composition for an array of representative star copolymers. Three principal phase diagram topologies, dictated by different phase stabilities, are exposed, displaying a hierarchy in complexity by increasing the molecular asymmetry. Our investigation indicates that the phase diagram topology depends on the ratios of arm numbers and Kuhn segment lengths, which highlights the role of the coordination number ratio between different polymers at the domain interface. These findings reveal the simplicity of the general phase behavior and suggest a complete list of stable microphases for the entire class, which provide useful insight into studying copolymers with more complicated architectures and conformational properties.

Genomic surveillance of Nevada patients revealed prevalence of unique SARS-CoV-2 variants bearing mutations in the RdRp gene

Patients with signs of COVID-19 were tested through diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from the nasopharyngeal/nasal swabs. To determine the variants of SARS-CoV-2 circulating in the state of Nevada, specimens from 200 COVID-19 patients were sequenced through our robust sequencing platform, which enabled sequencing of SARS-CoV-2 from specimens with even very low viral loads, without the need of culture-based amplification. High genome coverage allowed the identification of single and multi-nucleotide variants in SARS-CoV-2 in the community and their phylogenetic relationships with other variants present during the same period of the outbreak. We report the occurrence of a novel mutation at 323aa (314aa of orf1b) of nsp12 (RNA-dependent RNA polymerase) changed to phenylalanine (F) from proline (P), in the first reported isolate of SARS-CoV-2, Wuhan-Hu-1. This 323F variant was present at a very high frequency in Northern Nevada. Structural modeling determined this mutation in the interface domain, which is important for the association of accessory proteins required for the polymerase. In conclusion, we report the introduction of specific SARS-CoV-2 variants at very high frequency in distinct geographic locations, which is important for understanding the evolution and circulation of SARS-CoV-2 variants of public health importance, while it circulates in humans.

Optimized binding of substituted quinoline ALLINIs within the HIV-1 integrase oligomer

During the integration step, human immunodeficiency virus type 1 integrase (IN) interacts with viral DNA and the cellular cofactor LEDGF/p75 to effectively integrate the reverse transcript into the host chromatin. Allosteric human immunodeficiency virus type 1 integrase inhibitors (ALLINIs) are a new class of antiviral agents that bind at the dimer interface of the IN catalytic core domain and occupy the binding site of LEDGF/p75. While originally designed to block IN-LEDGF/p75 interactions during viral integration, several of these compounds have been shown to also severely impact viral maturation through an IN multimerization mechanism. In this study, we tested the hypothesis that these dual properties of ALLINIs could be decoupled toward late stage viral replication effects by generating additional contact points between the bound ALLINI and a third subunit of IN. By sequential derivatization at position 7 of a quinoline-based ALLINI scaffold, we show that IN multimerization properties are enhanced by optimizing hydrophobic interactions between the compound and the C-terminal domain of the third IN subunit. These features not only improve the overall antiviral potencies of these compounds but also significantly shift the ALLINIs selectivity toward the viral maturation stage. Thus, we demonstrate that to fully maximize the potency of ALLINIs, the interactions between the inhibitor and all three IN subunits need to be simultaneously optimized.

Non-visual composing and coding

Both music creation tools and novice coding environments often use highly visual interfaces to aid in writing, editing, and navigation. Such designs fail to include blind users and may be totally inaccessible. This work sets out to develop a novel domain specific language, interface, and curriculum in partnership with students and teachers at the Filomen M. D'Agostino Greenberg (FMDG) School, a community music school that reaches blind and visually impaired musicians of all ages and skill levels. The project will consist of an iterative co-design phase and an implementation/evaluation phase in which a small number of students at the school will use the technology during a music composition course to create original works.

Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases

Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas the nonhomologous isozyme in many parasitic species is cofactor independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure–activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized Caenorhabditis elegans iPGM, measured as fold enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ in the iPGM phosphatase domain and (2) shape complementarity surrounding the macrocyclic core at the phosphotransferase–phosphatase domain interface. Our results show that the high-affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex.

A diffuse domain method for two-phase flows with large density ratio in complex geometries

Abstract

Local and Global Motions Underlying Antibiotic Binding in Bacterial Ribosome.

The bacterial ribosome is one of the most important targets in the treatment of infectious diseases. As antibiotic resistance in bacteria poses a growing threat, a significant amount of effort is concentrated on exploring new drug-binding sites where testable predictions are of significance. Here, we study the dynamics of a ribosomal complex and 67 small and large subunits of the ribosomal crystal structures (64 antibiotic-bound, 3 antibiotic-free) from Deinococcus radiodurans, Escherichia coli, Haloarcula marismortui, and Thermus thermophilus by the Gaussian network model. Interestingly, a network of nucleotides coupled in high-frequency fluctuations reveals known antibiotic-binding sites. These sites are seen to locate at the interface of dynamic domains that have an intrinsic dynamic capacity to interfere with functional globular motions. The nucleotides and the residues fluctuating in the fast and slow modes of motion thus have promise for plausible antibiotic-binding and allosteric sites that can alter antibiotic binding and resistance. Overall, the present analysis brings a new dynamic perspective to the long-discussed link between small-molecule binding and large conformational changes of the supramolecule.

Paradoxical Filler Size Effect on Composite Wear: Filler–Matrix Interaction and Its Tribochemical Consequences

The addition of 0.2–5% nanoscale (40–80 nm) α-phase or microscale (40 μm) γ-phase Al2O3 particles in PTFE effectively reduce the matrix wear rate by 99.99%, whereas microscale (> 0.5 μm) α-Al2O3 or nanoscale (40–80 nm) γ-Al2O3 only reduce PTFE wear by ~ 90% under identical loading, dispersion and testing conditions. This paradoxical material system best illustrates the complexity of tribology and the importance of filler–matrix interactions at small scales. We studied the independent effect of the Al2O3/PTFE interface area and alumina structure by systematically varying the particle size over two orders of magnitude for both α- and γ-Al2O3/PTFE composites. Detailed characterizations of filler size, surface area and tribofilm’s chemical composition were conducted. The results found: (1) DLS median particle sizes conformed reasonably to vendor reported values and percentages of microscale filler aggregates correlated weakly with wear rates, (2) electron microscopy of the as-worn composite surface suggested a strong relation between the characteristic size of ‘unreinforced’ polymer domain and composite wear rate, (3) third bodies (i.e., transfer films, debris) played an important role in counterface abrasion, (4) wear rate correlated strongly with filler’s specific surface area and ultralow wear was only maintained ~ 0.3–10 m2/g nominal specific filler–matrix area values, (5) ultralow wear coincided with perfluorinated carboxylic salt rich tribofilms which supported a previously proposed wear reduction mechanism that mechanochemically degraded PTFE chelate with alumina and cause crosslinked and wear-resistant tribofilms, (6) tribofilm Al-F bond signal increased with filler surface area and high wear coincided with excessive tribofilm Al-F signal for γ-Al2O3/PTFE systems. Based on these results and literature hypothesis, we proposed that (1) the 1 μm α-Al2O3 provided the least filler–matrix interface and largest unreinforced polymer domain in PTFE, which lead to the least crosslinked and compartmentalized tribofilms; (2) in γ-alumina filled composites, Al-F bond forms as a product of mechanochemically degraded PTFE but also blocks chelation between the degraded PTFE and alumina fillers, (3) the 20 nm γ-Al2O3 provided the most filler–matrix interface which leads to excessive aluminum fluoride that blocked the filler–matrix chelation, prevented the tribofilm crosslinking and lead to high wear rates. This hypothesis was additionally supported by small molecule experiments in this study. However, this study provides no direct insight into how sensitive the filler–matrix tribochemical interaction is to filler phase or aggregate strength (strong, weak or fully dense).