Open-ring Structures Research Articles

Revisiting the nature and pharmacodynamics of tacrolimus metabolites

The toxicity of tacrolimus metabolites and their potential pharmacodynamic (PD) interactions with tacrolimus might respectively explain the surprising combination of higher toxicity and lower efficacy of tacrolimus despite normal blood concentrations, described in extensive metabolizers. To evaluate such interactions, we produced tacrolimus metabolites in vitro and characterized them by high resolution mass spectrometry (HRMS, for all) and nuclear magnetic resonance (NMR, for the most abundant, M-I). We quantified tacrolimus metabolites and checked their structure in patient whole blood and peripheral blood mononuclear cells (PBMC). We explored the interactions of M-I with tacrolimus in silico, in vitro and ex vivo. In vitro metabolization produced isoforms of tacrolimus and of its metabolites M-I and M-III, whose HRMS fragmentation suggested an open-ring structure. M-I and M-III open-ring isomers were also observed in patient blood. By contrast, NMR could not detect these open-ring forms. Transplant patients expressing CYP3A5 exhibited higher M-I/TAC ratios in blood and PBMC than non-expressers. Molecular Dynamics simulations showed that: all possible tacrolimus metabolites and isomers bind FKPB12; and the hypothetical open-ring structures induce looser binding between FKBP12 and calcineurins, leading to lower CN inhibition. In vitro, tacrolimus bound FKPB12 with more affinity than purified M-I, and the pool of tacrolimus metabolites and purified M-I had only weak inhibitory activity on IL2 secretion and not at all on NFAT nuclear translocation. M-I showed no competitive effect with tacrolimus on either test. Finally, M-I or the metabolite pool did not significantly interact with tacrolimus MLR suppression, thus eliminating a pharmacodynamic interaction.

Light-Driven Dynamic Hierarchical Architecture of Three-Dimensional Self-Assembled Cholesteric Liquid Crystal Droplets.

Cholesteric liquid crystals have attracted much attention in biosensors, in communication systems, security identification, hierarchical materials assembly, and microlasers, due to their complex and interesting structures accompanied by particular optical properties making them low-cost, label-free and sensitive. However, the reports of CLC droplets with stable topological configurations are still very limited, which hinders the fast development and broad application of CLC droplet-based devices. In this paper, we manifest light-driven changes in the topological configuration of cholesteric liquid crystals droplets, examined experimentally. Photoresponsive azo-LC doped CLC droplets were manipulated by irradiation by UV light to form novel topological configurations with stable 3D structures. The phenomenon behind the configuration changes is the light-induced cholesteric-isotropic phase transition that takes place in liquid crystals. Several topological configurations of CLC droplets have been demonstrated such as closed-ring structures with cone-shaped centers and concentric elliptical centers, and open-ring structures formed under unidirectional illumination of UV light. Structures with parallel CLC pitch lines at the center and with a central point singularity are also formed under multidirectional illumination. The competition of the elastic energy and surface energy of the CLC droplets results in the formation of the new topological configurations. All proposed configurations are stable and controllable by light, which enable CLC droplets with novel topological structures with new characteristics and provide a lot of potential applications in biosensors and microlasers.

Structural stability of open vortex beams

Normally, intensity patterns of vortex beams are closed rings such as Laguerre–Gaussian beams and Bessel–Gaussian beams. Recent studies showed that the vortex beams with open ring structures, namely, open vortex beams (OVBs), have non-trivial orbital angular momentum (OAM) spectra and optical forces and can be employed in many applications such as metrology and quantum information. However, the structural stability of OVBs, including the topological charge conservation and the intensity invariance, has not been studied yet. Here, we theoretically propose a generalized model of OVBs, using both geometrical ray-like trajectories and coherent wave-packets, and the structural stability of OVBs is validated by the geometrical envelope of ray bundles. Moreover, we experimentally demonstrated that such OVBs can be generated by a partial fork-grating (PFG). Our study reveals structural characteristics of OVBs, which lays a foundation for the OVB's potential applications in optical manipulation, optical metrology, etc.

Trapped ion mobility spectrometry time-of-flight mass spectrometry for high throughput and high resolution characterization of human milk oligosaccharide isomers

The microbiome and immune system of infants are shaped by various bioactive components of human breastmilk, notably human milk oligosaccharides (HMOs). HMOs represent the third component of breastmilk and exhibit extremely high structural diversity with many isomers. Here, we propose a high throughput and high resolution approach to characterize main oligosaccharides present in breastmilk with high identification level thanks to ion mobility spectrometry. Four pairs of standard HMO isomers, that are (LNT/LNnT), (LNFP I/LNFP V), (3′-SL/6′-SL) and (2′-FL/3-FL), were first investigated under both positive and negative ionization mode using direct introduction-trapped ion mobility spectrometry-time-of-flight mass spectrometry (TIMS-TOF). By examining all the ionic species formed (i.e. protonated and deprotonated ions as well as adduct species), every isomer pair could be distinguished through the separation of at least one species, even with a small difference in collision cross section values (as small as 1.5%) thanks to the flexible resolution capacity of the TIMS instrument. Although multiple mobility peaks resulting from different glycan anomeric conformers, open-ring and/or different ionic isomer structures (i.e. various charge site locations), could be observed for some HMO species. The reduction at the reducing-end of HMOs did not significantly facilitate the isomer distinction. Finally, the unambiguous identification of the studied HMOs in a breastmilk sample showed the potential of the approach combining ion mobility separation and MS/MS experiments for high throughput distinction of HMO isomers in complex breastmilk samples without laborious sample preparation.

Simulation and Experimental Study of Terahertz Wave Transmission Characteristics Based on Periodic Metal Open Resonant Ring Structures

Different open resonant ring structures with substrate of polyimide were designed. The transmission characteristics of the structures for terahertz wave were investigated by simulation and experiment. The results show that the transmission peak of the structures moves to high frequency with increase of thickness of the metal layer. With increase of substrate thickness, the transmission peak moved to low frequency and the transmissivity decreased. The influence of number of “C” shape open resonant rings in the unit structure on the transmission characteristics of terahertz wave was also studied. It is found that when the number of “C” shape open resonant rings increases from one to two, more transmission peaks appeared in the frequency of 0.2–2 THz. The transmissivity of the designed structures was tested by terahertz time-domain spectrometer (THz-TDS). The experimental results showed good agreement to the simulation results.

Theoretical study on the photocyclization reactivity mechanism in a diarylethene derivative with multicolour fluorescence modulation

For a photochromic spiro-diarylethene derivative (Spiro-DAE), its photocyclization reaction and multicolour fluorescence modulation performances were investigated based on a series of density functionals calculations in this work. Some elementary properties such as geometric and electronic structures at ground and the first excited state (S1), absorption and emission spectra in respective open-ring and closed-ring structures were compared, which indicate the cyclization reaction may occur at S1. It is further verified by the lower activation barrier (3.4 kcal/mol) of the transition state at S1 potential energy surface. The photochromic reaction rates for both cyclization and cycloreversion processes were quantitatively estimated, which suggests the much smaller radiative and internal conversion rates contribute to the higher photocyclization rate and thus efficiency. Furthermore, we suspect that the dihydroacridine fragment may make important contribution to the cyclization reaction occurring at S1 considering its contribution to electronic structure.

Ultrasonic cavitation tailored wastewater purification and desalination using thick sand of highly permeable deep aquifer

Pulp and paper industry generates large wastewater volumes containing recalcitrant and toxic compounds in various forms. These compounds are highly toxic and standard primary/secondary treatments are unable to filter heavy metal contaminants besides organic species. An emerging demand of advance level treatment is the motivation of current work that explores possibility of using thick sand of deep aquifers as an adsorbent to remove inorganic and organic contaminants simultaneously from wastewater besides desalination. Popular ultrasonic cavitation is used to accelerate degradation of toxic organic effluent into less toxic open ring structures besides curing heavy metals to form new bonds during adsorption. Because of extreme local environment due to cavitation, heavy metals coagulate in silicon-aluminum atomic meshes and carbon nano tubes for less toxic new crystalline structure. Significant changes in physico-chemical investigations like pH, chemical oxygen demand and colour towards drinkable water standards indicate effective adsorption resulting into wastewater purification.

Bioconversion of alkaloids to high-value chemicals: Comparative analysis of newly isolated lupanine degrading strains

This work explores the potential for development of a lupanine valorization process evaluating different isolated microorganisms for their capacity to metabolize the alkaloid. Ecotoxicological assessment demonstrated that lupanine is toxic for Vibrio fischeri and Daphnia magna exhibiting EC50 values of 89 mg L−1 and 47 mg L−1 respectively, while acting both as growth inhibitor for a monocotyledonous and as promoter for a dicotyledonous plant. Among the eight aerobic and anaerobic strains isolated and identified Rhodococcus rhodochrous LPK211 achieved 81% removal for 1.5 g L−1 lupanine, while no end-products were detected by NMR constituting a promising microorganism for lupanine biodegradation. Moreover, Rhodococcus ruber LPK111 and Rhodococcus sp. LPK311 exhibited 66% and 71% of removal respectively, including potential formation of lupanine N-oxide. Pseudomonas putida LPK411 reached 80% of lupanine removal and generated three fermentation products potentially comprising 17-oxolupanine and lupanine derivatives with open ring structures enabling the development of alkaloid valorization processes.

Ab initio molecular dynamics of thiophene: the interplay of internal conversion and intersystem crossing.

The fast and slow components of the relaxation of photoexcited thiophene have been investigated by means of SHARC (surface hopping including arbitrary couplings) molecular dynamics based on multiconfiguration electronic structure calculations. Triplet states are included to ascertain their role in the relaxation process. After thiophene is excited to the S1 state, ultrafast dynamics (τfast = 96 fs) initiates a ring opening due to cleavage of a carbon sulfur bond and simultaneous ring puckering. This time constant is in agreement with previous experimental and theoretical studies. The subsequent dynamics of the open-ring structures is characterized by the interplay of internal conversion and intersystem crossing. For the open-ring structures, the S0, S1, T1 and T2 states are nearly degenerate and the spin-orbit couplings are large. The underlying potential energy surface is flat and long-lived open-ring structures in the singlet as well as in the triplet states are formed. Both the participation of triplet states and the shape of the energy surface explain the experimentally observed slow ring closure in the ground state.

PH-Responsive near-infrared fluorescent cyanine dyes for molecular imaging based on pH sensing.

Indocyanine green (ICG) derivatives having nucleophilic substituents were synthesized as pH-responsive near-infrared dyes. pH-responsive dyes 1-C with closed-ring structures smoothly internalized and converted to emissive open-ring structures 1-O in response to relatively low pHs in acidic intracellular compartments of HeLa cells.

Miniature UWB Filter Using Three-Quarters Wavelength Resonator with Direct-Connected Feed Method

A miniature ultra-wideband (UWB) bandpass filter using three-quarters wavelength resonators is presented in this paper. Direct-connected feed method is employed between the input/output ports and the resonators in order to overcome the shortcomings due to the gap-coupled feed method and produce two transmission zeros in the lower and upper stopbands. On the other hand, two quarter-wavelength matching transmission lines are introduced to the input/output ports to improve the reflection loss characteristic in the passband of the filter. In addition, the resonators are folded to be open ring structures, which are more miniaturized than the conventional linear structure. As a consequence, the filter is compact in size and exhibits good performance. The filter is successfully realized in theory and verified by full wave EM simulation, and simulated frequency response results show that the fabricated filter has an insertion loss of better than 1dB in the passband and two rejections of greater than 25dB in most of the stopbands.

Resolution adapted finite element modeling of radio frequency interactions on conductive resonant structures in MRI

Prediction of interactions between the radiofrequency electromagnetic field in magnetic resonance scanners and electrically conductive material surrounded by tissue plays an increasing role for magnetic resonance safety. Testing of conductive implants or instruments is usually performed by standardized experimental setups and temperature measurements at distinct geometrical points, which cannot always reflect worst-case situations. A finite element method based on Matlab (The Mathworks, Natick, MA) and the finite element method program Comsol Multiphysics (Stockholm, Sweden) with a spatially highly variable mesh size solving Maxwell's full-wave equations was applied for a comprehensive simulation of the complete geometrical arrangement of typical birdcage radiofrequency coils loaded with small conductive structures in a homogenous medium. Conductive implants like rods of variable length and closed and open ring structures, partly exhibiting electromagnetic resonance behavior, were modeled and evaluated regarding the distribution of the B(1)- and E-field, induced currents and specific absorption rates. Numerical simulations corresponded well with experiments using a spin-echo sequence for visualization of marked B(1)-field inhomogeneities. Even resonance effects in conductive rods and open rings with suitable geometry were depicted accurately. The proposed method has high potential for complementation or even replacement of common experimental magnetic resonance compatibility measurements.

Degradation of 17α-ethinylestradiol by ozonation — Identification of the by-products and assessment of their estrogenicity and toxicity

The presence of the synthetic estrogen 17α-ethinylestradiol (EE2) in waters at low levels is a concern due to its ability to act as an endocrine disruptor. Ozone (O 3) is commonly used in water treatment and reacts with EE2 to form by-products having characteristics that are mostly unknown. The aim of this study was to identify the by-products of E2 and EE2 ozonation and determine their estrogenicity and toxicity relative to the parent compound. Ozonation by-products were identified via LC–MS analysis. The estrogenicity was measured using the YES assay, and toxicity was determined by monitoring effects on histology of fetal rat testes and testosterone secretion by these tissues. Two EE2 by-products were identified with open phenolic ring structures (masses 302 and 344 u). The Yeast Estrogen Screening (YES) assay showed a decreased but incomplete removal of estrogenicity after ozonation of EE2. Histological analysis of fetal testes revealed that neither E2 nor EE2, with or without ozonation, had any effect on seminiferous cord formation; however, a remarkable negative effect on testosterone secretion was observed, with EE2 by-products after ozonation showing the most rapid and extensive inhibition. These results show that the removal of EE2 via reaction with O 3 resulted in the formation of by-products that are less estrogenic (as demonstrated by the YES assay), but have a greater negative impact on testosterone secretion. Thus, the disappearance of the parent compound is not a sufficient endpoint, as the by-products created may be more toxic. Care should be taken when implementing oxidation applications such as ozone during waste water treatment.

Water trimer cation

By using density functional theory (DFT) and high-level ab initio theory, we have investigated the structure, interaction energy, electronic property, and IR spectra of the water trimer cation [(H2O) 3 + ]. Two structures of the water trimer cation [the H3O+ containing linear (3Lp) structure versus the ring (3OO) structure] are compared. For the complete basis set (CBS) limit of coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)], the 3Lp structure is 11.9 kcal/mol more stable than the 3OO structure. This indicates that the ionization of water clusters produce the hydronium cation moiety (H3O+) and the hydroxyl radical. It is interesting to note that the calculation results of the water trimer cation vary seriously depending on the calculation level. At the level of Moller–Plesset second-order perturbation (MP2) theory, the stability of 3OO is underestimated due to the underestimated O…O hemibonding energy. This stability is also underestimated even for the CCSD(T) single point calculations on the MP2-optimized geometry. For the 3OO structure, the MP2 and CCSD(T) calculations give closed-ring structures with a hemi-bond between two O atoms, while the DFT calculations show open-ring structures due to the overestimated O…O hemibonding energy. Thus, in order to obtain reliable stabilities and frequencies of the water trimer cation, the CCSD(T) geometry optimizations and frequency calculations are necessary. In this regard, the DFT functionals need to be improved to take into account the proper O…O hemibonding energy.

Chaperonins from an Antarctic archaeon are predominantly monomeric: crystal structure of an open state monomer

Archaea are abundant in permanently cold environments. The Antarctic methanogen, Methanococcoides burtonii, has proven an excellent model for studying molecular mechanisms of cold adaptation. Methanococcoides burtonii contains three group II chaperonins that diverged prior to its closest orthologues from mesophilic Methanosarcina spp. The relative abundance of the three chaperonins shows little dependence on organism growth temperature, except at the highest temperatures, where the most thermally stable chaperonin increases in abundance. In vitro and in vivo, the M. burtonii chaperonins are predominantly monomeric, with only 23-33% oligomeric, thereby differing from other archaea where an oligomeric ring form is dominant. The crystal structure of an N-terminally truncated chaperonin reveals a monomeric protein with a fully open nucleotide binding site. When compared with closed state group II chaperonin structures, a large-scale ≈ 30° rotation between the equatorial and intermediate domains is observed resulting in an open nucleotide binding site. This is analogous to the transition observed between open and closed states of group I chaperonins but contrasts with recent archaeal group II chaperonin open state ring structures. The predominance of monomeric form and the ability to adopt a fully open nucleotide site appear to be unique features of the M. burtonii group II chaperonins.

Excess and deviation properties of {(glycylglycine + ZnCl 2) in aqueous methanol} mixtures

The excess molar volumes ( V E), viscosity deviations (Δ η), deviations in isentropic compressibility (Δ κ S) and excess molar refractivity (Δ R m E ) for {(glycylglycine + ZnCl 2) in aqueous methanol} mixture have been calculated from the experimental values. The bridging water molecules bend the chains into stable open ring structures together with intermolecular hydrogen bonding and interstitial accommodation leading to negative V E values. The positive Δ η values indicate a structure breaking effect of aqueous glycylglycine–ZnCl 2 upon contact with methanol molecules. It is also noted that chelation of zinc to glycylglycinate is through carboxylic group and not the amino group. The negative Δ κ S values suggest the formation of an open ring structure lowering the entropy of the solution. Due to weak interaction between solute and solvent, the molecular structure of individual molecule does not change significantly and leads to negative Δ R m E values. Finally, the results have lead to a good understanding of the thermodynamics properties of the studied liquid mixture.

Probing Open Conformation of GroEL Rings by Cross-linking Reveals Single and Double Open Ring Structures of GroEL in ADP and ATP

Two heptamer rings of chaperonin GroEL undergo opening-closing conformational transition in the reaction cycle with the aid of GroES and ATP. We introduced Cys into the GroEL subunit at Ala-384 and Ser-509, which are very close between adjacent GroEL subunits in the open heptamer ring but far apart in the closed heptamer ring. The open ring-specific inter-subunit cross-linking between these Cys indicated that the number of rings in open conformation in GroEL was two in ATP (GroEL(OO)), one in ADP (GroEL(O)), and none in the absence of nucleotide. ADP showed an inhibitory effect on ATP-induced generation of GroEL(OO). The isolated GroEL(O) and GroEL(OO), which lost any bound nucleotide, could bind GroES to form a bullet-shaped 1:1 GroEL-GroES complex and a football-shaped 1:2 GroEL-GroES complex, respectively, even without the addition of any nucleotide. Substrate protein was unable to form a stable complex with GroEL(OO) and did not stimulate ATPase activity of GroEL. These results favor a model of the GroEL reaction cycle that includes a football complex as a critical intermediate.

Atomic resolution study of the interfacial bonding at Si3N4/CeO2−δ grain boundaries

Using a combination of atomic-resolution Z-contrast imaging and electron energy-loss spectroscopy (EELS) in the scanning transmission electron microscope, we examine the atomic and electronic structures at the interface between Si3N4 (101¯0) and CeO2−d intergranular film (IGF). Ce atoms are observed to segregate to the interface in a two-layer periodic arrangement, which is significantly different from the structure observed in a previous study. Our EELS experiments show (i) oxygen in direct contact with the terminating Si3N4 open-ring structures, (ii) a change in the Ce valence from a nominal oxidation state of +3 to almost +4 moving from the interface into the IGF, and (iii) a uniform concentration of Si in the film.

Proton and hydrogen atom adducts to cytosine. An experimental and computational study

Cytosine cations were generated by chemical ionization and fast-atom bombardment of cytosine, and their dissociations in the gas phase were studied by tandem mass spectrometry and quantum chemistry calculations at levels of theory up to CCSD(T)/aug-cc-pVTZ. Metastable cytosine cations undergo loss of NH 3, H 2O, and [CHNO] molecules as major dissociations. Mechanisms for these dissociations were established by a combination of MS 3, deuterium labeling, and calculations. Several tautomers of protonated cytosine were identified to exist as local energy minima. The tautomers are predicted to undergo facile prototropic isomerizations at internal energies below the lowest ion-dissociation thresholds. The lowest-energy elimination of ammonia proceeds from open-ring structures and is accompanied by exchange of the N-3 and N-7 positions in cytosine, so that either nitrogen atom can be lost in the ammonia molecule. Cytosine radicals corresponding to hydrogen atom adducts are stable when formed by femtosecond electron transfer to the cations. A fraction of the radicals dissociate by loss of hydrogen atom to form cytosine tautomers. Ring-cleavage dissociations leading to the loss of CO and HNCO are less abundant, and are predicted to proceed from excited electronic states accessed by vertical electron transfer.

Cooperative Effects: Stabilization of the Isoguanine Trimer

Isoguanine (isoG) trimers have been theoretically studied using the density functional theory to reveal the role of H-bonding in the formation of different base aggregations. Similar to the isoG tetrads, the isoG trimer also adopts diverse conformations. Cooperative effects for the H-bonding in the cyclic isoG trimers have been found to be important. As a result of the strong cooperativity, the conformer characterized by the highest symmetry is the most stable among the possible trimers. Vibration mode analysis reveals the influence of the cooperative effects on the H-bond stretching motion. An atoms-in-molecules study of the H-bonds in the isoG trimers suggests that the electronic density topology of the bifurcated H-bond is insensitive to the cooperative effects. The values of the binding energy, the vibration frequency, and the electronic density topology of the noncyclic isoG trimers demonstrate that there is no cooperativity in these open ring structures.