Reversible Complex Research Articles

Discovery of Mitochondrial Complex I Inhibitors as Anticancer and Radiosensitizer Drugs Based on Compensatory Stimulation of Lactate Release

Cancer cells may stimulate glycolytic flux when O2 becomes insufficient. Increase in L-lactate release therefore appears as an escape mechanism to drugs targeting mitochondrial respiration but also represents a response that may be exploited to screen for compounds blocking either mitochondrial carriers of oxidizable substrates or the electron transport chain. Here, we developed a screening procedure based on the capacity of cancer cells to release L-lactate to gain insights on the development of mitochondrial complex I inhibitors. For this purpose, we synthesized derivatives of carboxyamidotriazole, a compound previously described as a potential OXPHOS inhibitor. Two series of derivatives were generated by cycloaddition between benzylazide and either cyanoacetamides or alkynes. A primary assay measuring L-lactate release as a compensatory mechanism upon OXPHOS inhibition led us to identify 15 hits among 28 derivatives. A secondary assay measuring O2 consumption in permeabilized cancer cells confirmed that 12 compounds among the hits exhibited reversible complex I inhibitory activity. Anticancer effects of a short list of 5 compounds identified to induce more L-lactate release than reference compound were then evaluated on cancer cells and tumor-mimicking 3D spheroids. Human and mouse cancer cell monolayers exhibiting high level of respiration in basal conditions were up to 3-fold more sensitive than less oxidative cancer cells. 3D tumor spheroids further revealed potency differences between selected compounds in terms of cytotoxicity but also radiosensitizing activity resulting from local reoxygenation. In conclusion, this study documents the feasibility to efficiently screen in 96-well plate format for mitochondrial complex I inhibitors based on the capacity of drug candidates to induce L-lactate release.

Concurrent magma mixing and crystallization processes revealed by clinopyroxene macrocrysts from Lamont guyot lavas in NW Pacific

Minerals in volcanic rocks have been commonly used to reconstruct the physicochemical conditions of crystallization and magma chamber processes (magma mixing and recharge) prior to eruption which are fundamental to deduce the petrogenesis of volcanic rocks. Here we present mineral chemistry including in situ major-trace element and Sr isotopic data for clinopyroxene (Cpx) and plagioclase macrocrysts from lavas collected from Lamont guyot in the Wake seamount group, NW Pacific. The Cpx macrocrysts display normal and reverse zoning or complex zoning (e.g., combination of reverse, normal, sector and/or patchy zoning). The normally-zoned Cpx macrocrysts are euhedral and in Fe Mg equilibrium with the host rock compositions. In contrast, the cores of reversely- and complexly-zoned Cpx macrocrysts are in textural (e.g., resorption texture) and chemical (very low Mg#) disequilibrium with their host rock compositions. These reversed cores, however, form coherent compositional trends with and display parallel trace element patterns to the normally zoned Cpx crystals, suggesting that these resorbed cores are most likely antecrysts which crystallized from progenitor melts. The continuously changing major-trace element contents with Cpx Mg# values can be explained by crystallization of these Cpx crystals from melts that progressively fractionate Cpx, plagioclase and Fe Ti oxides. Together with those of the complexly-zoned plagioclase, the complex zoning patterns and large ranges of La/Yb and Sm/Yb ratios at a restricted Cpx Mg# range record magmatic processes of fractional crystallization and mixing in the magma plumbing system. The Cpx crystals from a single lava sample have various 87 Sr/ 86 Sr ratios (0.7025–0.7042) extending from HIMU (high μ = 238 U/ 204 Pb) to FOZO (focal zone) mantle components suggesting that the large 87 Sr/ 86 Sr variation in Cpx could be explained by mixing between HIMU and FOZO components. Our data suggest that frequent recharging of melts derived from different mantle sources and concurrent mixing and crystallization are important processes that shape the currently observed compositional variation of Lamont guyot lavas. • Textural and compositional zoning of Cpx from Lamont seamount lavas, NW Pacific • Cpx shows large trace element and 87 Sr/ 86 Sr variations at a restricted Mg# range. • Reverse and complex zoning textures of Cpx record magma recharge and mixing. • Mixing of multiple batches of HIMU- and FOZO-derived melts. • Concurrent mixing and crystallization played a key role in forming the Cpx crystals.

Heteroprotein complex coacervation of lactoferrin and osteopontin: Phase behaviour and thermodynamics of formation

This research describes the formation of reversible heteroprotein complex coacervates between the bioactive milk proteins lactoferrin (LF) and osteopontin (OPN) within specific combinations of pH (∼4–6), ionic strength (≤30 mM added NaCl), protein stoichiometry (LF:OPN mass mixing ratios of ∼ 2–8) and total protein concentration (≤∼8% w/v). Electrostatic attraction between these proteins is possible across a wide range of pH values due to the acidic isoelectric point of OPN (∼ pH 3.5) and the basic isoelectric point of LF (∼ pH 8.7). Thermodynamic analysis of the OPN-LF interaction indicated that the protein-protein binding had enthalpic and entropic contributions which resulted in liquid-liquid phase separation given the appropriate combination of intrinsic and extrinsic conditions. The complex coacervates were found to be a concentrated protein phase (∼27% protein, w/w) which was highly hydrated (>70% moisture, w/w) and occurred spontaneously within LF: OPN ratios naturally found in human milk. The structure, biological functionality, and applications of heteroprotein complexes and/or complex coacervates between LF and OPN will be explored in separate work.

Reversible complexation mediated polymerization of methacrylates using amine catalysts in aqueous heterogeneous systems

Reversible complexation mediated polymerization of methacrylates using amine catalysts in aqueous heterogeneous systems

Metal Confined in 2D Membranes for Molecular Recognition and Sieving towards Ethylene/Ethane Separation.

Membranes with nanochannels have exhibited great potential in molecular separations, while it remains a great challenge to separate molecules with very close physical properties and kinetic diameters (e.g., ethylene/ethane) owing to the lack of size-sieving property and specific affinity. Herein, a metal confined 2Dsub-nanometer channel is reported to successfully discriminate ethylene over ethane via molecular recognition and sieving. Transition metal cations are paired with polyelectrolyte anions to achieve high dissociation activity, forming reversible complexation with ethylene. Aberration-corrected transmission electron microscopy observes that the metals with size of ≈2nm are uniformly confined in graphene oxide (GO) interlayer channels with average height of ≈0.44nm, thereby cooperating the size-sieving effect with a molecular recognition ability toward ethylene and stimulating its selective transport over ethane. The resulting ultrathin (≈60nm) membrane exhibits superior ethylene/ethane separation performance far beyond the polymeric upper-bound. Density functional theory (DFT) and molecular dynamic simulations reveal that the metal@2D interlayer channel provides a molecular recognition pathway for selective gas transport. The proposed metal confined in 2D channel with molecular recognition and sieving properties would have broad application in other related fields such as single-atom catalysis, sensor and energy conversion.

Estimate near-surface velocity with reversals using deep learning and full-waveform inversion: A field-data-driven method

Estimating shallow velocity from land seismic data is challenging due to complexities in the near surface. One such complexity arises from velocity reversals, which can be caused by anomalous high/low-velocity layer intrusions into the otherwise increasing velocity-depth trend. Velocity reversal imposes significant challenges for conventional velocity model building methods to accurately estimate near surface models. Turning ray tomography or tomostatics relies on accurate picking of first breaks, which becomes infeasible when velocity reversals generate shingling events. In this paper, we proposed a field-data-driven deep learning framework, which combines field-specific training, deep learning and full-waveform inversion, to estimate the near surface velocity model from land seismic data. Instead of training over purely random synthetic data, we propose to incorporate a-priori knowledge about the field under study to generate field-specific data set for training the proposed deep neural network. In addition, we combine the deep learning model with full-waveform inversion to further improve the near-surface velocity model. Synthetic and field data examples show that the proposed framework can successfully handle the velocity reversal complexity in land seismic data and achieve promising performance on estimating near surface velocity models.

Recent Advances in Host-Guest Supramolecular Hydrogels for Biomedical Applications.

The recognition-directed host-guest interaction is recognized as a valuable tool for creating supramolecular polymers. Functional hydrogels constructed through the dynamic and reversible host-guest complexation are endowed with a great many appealing features, such as superior self-healing, injectability, flexibility, stimuli-responsiveness and biocompatibility, which are crucial for biological and medicinal applications. With numerous topological structures and host-guest combinations established previously, recent breakthroughs in this area mostly focus on further improvement and fine-tuning of various properties for practical utilizations. The current contribution provides a comprehensive overview of the latest developments in host-guest supramolecular hydrogels, with a particular emphasis on the innovative molecular-level design strategies and hydrogel formation methodologies targeting at a wide range of active biomedical domains, including drug delivery, 3D printing, wound healing, tissue engineering, artificial actuators, biosensors, etc. Furthermore, a brief conclusion and discussion on the steps forward to bring these smart hydrogels to clinical practice is also presented.

Scaffolding viral protein NC nucleates phase separation of the HIV-1 biomolecular condensate.

Membraneless biomolecular condensates (BMCs) contribute to the replication of a growing number of viruses but remain to be functionally characterized. Previously, we demonstrated that pan-retroviral nucleocapsid (NC) proteins phase separated into condensates regulating virus assembly. Here we discover that intrinsically disordered human immunodeficiency virus-type 1 (HIV-1) core proteins condense with the viral genomic RNA (vRNA) to assemble as BMCs attaining a geometry characteristic of viral reverse transcription complexes. We explore the predisposition, mechanisms, and pharmacologic sensitivity of HIV-1 core BMCs in living cells. HIV-1 vRNA-interacting NC condensates were found to be scaffolds onto which client capsid, reverse transcriptase, and integrase condensates assemble. HIV-1 core BMCs exhibit fundamental characteristics of BMCs and are drug-sensitive. Lastly, protease-mediated maturation of Gag and Gag-Pol precursor proteins yield abundant and visible BMCs in cells. This study redefines HIV-1 core components as fluid BMCs and advances our understanding of the nature of viral cores during ingress.

Reversible Complexation Mediated Living Radical Polymerization Using Tetraalkylammonium Chloride Catalysts.

This work reports the first use of organic chloride salts as catalysts for reversible complexation mediated living radical polymerization. Owing to the strong halogen-bond forming ability of Cl- , the studied four tetraalkylammonium chloride catalysts (R4 N+ Cl- ) successfully control the polymerizations of methyl methacrylate, yielding polymers with low dispersities up to high monomer conversion (>90%). Benzyldodecyldimethylammonium chloride is further exploited to other methacrylates and yields low-dispersity block copolymers. The advantages of the chloride salt catalysts are wide monomer scope, good livingness, accessibility to block copolymers, and good solubility in organic media. Because of the good solubility, the use of the chloride salt catalysts can prevent agglomeration of catalysts on reactor walls in organic media, which is an industrially attractive feature. Among halide anions, chloride anion is the most abundant and least expensive halide anion, and therefore, the use of the chloride salt catalysts may lower the cost of the polymerization.

Bacterial retrons encode phage-defending tripartite toxin-antitoxin systems.

Retrons are prokaryotic genetic retroelements encoding a reverse transcriptase that produces multi-copy single-stranded DNA1 (msDNA). Despite decades of research on the biosynthesis of msDNA2, the function and physiological roles of retrons have remained unknown. Here we show that Retron-Sen2 of Salmonellaenterica serovarTyphimurium encodes an accessory toxin protein, STM14_4640, which we renamed as RcaT. RcaT is neutralized by the reverse transcriptase-msDNA antitoxin complex, and becomes active upon perturbation of msDNA biosynthesis. The reverse transcriptase is required for binding to RcaT, and the msDNA is required for the antitoxin activity. The highly prevalent RcaT-containing retron family constitutes anew type of tripartite DNA-containing toxin-antitoxin system. To understand the physiological roles of such toxin-antitoxin systems, we developed toxin activation-inhibition conjugation (TAC-TIC), a high-throughput reverse genetics approach that identifies the molecular triggers and blockers of toxin-antitoxin systems. By applying TAC-TIC to Retron-Sen2, we identified multiple trigger and blocker proteins of phage origin. We demonstrate that phage-related triggers directly modify the msDNA, thereby activating RcaT and inhibiting bacterial growth. By contrast, prophage proteins circumvent retrons by directly blocking RcaT. Consistently, retron toxin-antitoxin systems act as abortive infection anti-phage defence systems, in line with recent reports3,4. Thus, RcaT retrons are tripartite DNA-regulated toxin-antitoxin systems, which use the reverse transcriptase-msDNA complex both as an antitoxin and as a sensor of phage protein activities.

Understanding the Electrolyte/Electrode Interfacial Interactions for the Development of High-Performance Aqueous Redox-Enhanced Electrochemical Capacitors

Research in electrochemical energy storage is converging to target systems with battery-level energy density, and capacitor-level cycling stability and power density. One approach is to utilize redox-active electrolytes that add faradaic charge storage to increase energy density of supercapacitors. Aqueous redox-active electrolytes are simple to prepare and to up-scale; and, can be synergistically optimized to fully utilize the dynamic charge/discharge and storage properties of micro/mesoporous carbon based electrode systems. However, aqueous redox-enhanced electrochemical capacitors (redox ECs) have performed relatively poorly, primarily due to the cross-diffusion of soluble redox couples, reduced cycle life, and low operating voltages.In this presentation, we show that these challenges can be met by the use of liquid-to-solid phase transitions of redox electrolyte molecules, and their reversible confinement in the pores ( > 2 nm) of high-surface-area electrodes. This approach is demonstrated by the use of bromide catholyte and modified hydrophobic cations (e.g., viologens and tetrabutylammonium) that together induce reversible solid-state complexation of Br2/Br3 –. This mechanism solves the cross-diffusion issue of redox ECs without using costly ion-selective membranes, and has the added benefit of stabilizing the reactive bromine generated during charging.Using the concepts learned from this 1st generation configuration, we further developed high-performance aqueous-based redox ECs by (1) synthesizing differently functionalized/substituted viologen molecules and (2) optimizing the interfacial interactions between the viologens and hierarchically porous-structured carbon electrodes. In the second part of this presentation, we show systematic approaches to explore optimal parameters to improve the energy storage capacity of the device.

Reactive extraction of acetic acid by using tri-butyl-phosphate with different diluents

Acetic acid is a valuable chemical component that can be produced by processing waste streams using biotechnology. It is a significant carboxylic acid largely used in chemical, pharmaceutical, food and other industries. The production of organic acids from waste renewable resources using fermentation is a very promising technology but recovery of these dilute acids is a huge challenge. The present work is based on the reversible complexation, extraction equilibria of the system (aqueous solution + extractant/diluents) which were measured at T=298K using various concentration of acetic acid (0.2 mol.kg−1 to 1 mol.kg−1) and the extractant tri-n-butyl phosphate (10-40% by volume) in different diluents (Jatropha oil, Karanja oil and used cooking oil). Furthermore, single pure solvents (not containing extractant) and solvents with extractant were used for the physical and chemical extractions. The results of extraction experiments were calculated and reported as distribution coefficient (KD), extraction efficiency (E%) and loading ratio (LR). The extraction of acetic acid from aqueous solutions using tri-n-butyl phosphate with methyl ester of Jatropha oil, Karanja oil and used cooking oil, respectively, resulted in a degree of extraction which reported as the highest reactive extraction efficiency of acetic acid is 73.22% by using 40% tri-n-butyl phosphate by volume and methyl ester of Jatropha oil.

Synthesis and Characterization of Metallopolymer Networks Featuring Triple Shape-Memory Ability Based on Different Reversible Metal Complexes.

This study presents the synthesis and characterization of metallopolymer networks with a triple shape-memory ability. A covalently crosslinked polymer network featuring two different additional ligands in its side chains is synthesized via free radical polymerization (FRP). The subsequent addition of different metal salts leads to the selective formation of complexes with two different association constants (Ka), proven via isothermal titration calorimetry (ITC). Those two supramolecular crosslinks feature different activation temperatures and can act as two individual switching units enabling the fixation and recovery of two temporary shapes. The presented samples were investigated in a detailed fashion via differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and FT-Raman spectroscopy. Furthermore, thermo-mechanical analyses (TMA) revealed excellent dual and triple shape-memory abilities of the presented metallopolymer networks.

Covalently Immobilizable Tris(Pyridino)-Crown Ether for Separation of Amines Based on Their Degree of Substitution.

A great number of biologically active compounds contain at least one amine function. Appropriate selectivity can only be accomplished in a few cases upon the substitution of these groups, thus functionalization of amines generally results in a mixture of them. The separation of these derivatives with very similar characteristics can only be performed on a preparative scale or by applying pre-optimized HPLC methods. A tris(pyridino)-crown ether was designed and synthetized for overcoming these limitations at a molecular level. It is demonstrated, that this selector molecule is able to distinguish protonated primary, secondary and tertiary amines by the formation of reversible complexes with different stabilities. This degree of substitution-specific molecular recognition of amines opens the door to develop separation processes primarily focusing on the purification of biologically active compounds in a nanomolar scale.

Interaction Behaviours between Soliton and Cnoidal Periodic Waves for Nonlocal Complex Modified Korteweg–de Vries Equation

The reverse space-time nonlocal complex modified Kortewewg–de Vries (mKdV) equation is investigated by using the consistent tanh expansion (CTE) method. According to the CTE method, a nonauto-Bäcklund transformation theorem of nonlocal complex mKdV is obtained. The interactions between one kink soliton and other different nonlinear excitations are constructed via the nonauto-Bäcklund transformation theorem. By selecting cnoidal periodic waves, the interaction between one kink soliton and the cnoidal periodic waves is derived. The specific Jacobi function-type solution and graphs of its analysis are provided in this paper.

Losartan Interactions with 2-Hydroxypropyl-β-CD.

Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) could improve its pharmacological profile. Thus, its molecular interactions are studied using a combination of Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR) and Molecular Dynamics (MD). First, its complexation is shown through Differential Scanning Calorimetry as lyophilization provided distinct thermal properties in comparison to the mixture. The complexation is further proved by utilizing the chemical shift changes in the complexation and T1 values. Furthermore, the reversible favorable complexation was shown by MD calculations. Such physical chemical properties provide evidence that this formulation must be further explored through biological experiments.

Air-Tolerant Reversible Complexation Mediated Polymerization (RCMP) Using Aldehyde.

An air-tolerant reversible complexation mediated polymerization (RCMP) technique, which can be carried out without prior deoxygenation, is developed. The system contains a monomer, an alkyl iodide initiating dormant species, air (oxygen), an aldehyde, N-hydroxyphthalimide (NHPI), and a base. Oxygen is consumed via the NHPI-catalyzed conversion of the aldehyde (RCHO) to a carboxylic acid (RCOOH). The generated RCOOH is further converted to a carboxylate anion (RCOO- ) by the base. The RCOO- generated in situ works as an RCMP catalyst; the polymerization proceeds with the monomer, alkyl iodide dormant species, and RCOO- catalyst. Thus, the system is not only air-tolerant but also does not require additional RCMP catalysts, which is a notable feature of this system. (NHPI is used as an oxidation catalyst for converting RCHO to RCOOH.) This technique is amenable to methyl methacrylate, butyl methacrylate, benzyl methacrylate, 2-hydroxyethyl methacrylate, and styrene, yielding polymers with relatively low-dispersity (Mw /Mn =1.20-1.49), where Mw and Mn are the weight- and number-average molecular weights, respectively.

Design of an Efficient Reverse Converter for Moduli Sets

The appropriate selection of moduli has a significant impact on the reverse converter's speed and complexity. The modified converter depends upon the arithmetic designs that are implemented without the read - only memories and lookup tables. The Carry Save Adder and Carry Propagate Adder are used in the reverse converter and modulo adder gives higher speed and less hardware complexity. The proposed converter has been implemented to get the conversion time and area as supported by the reverse converter of 12-bits and maximum up to 100-bits.

Material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood:based on computer-aided drug design

Angelicae Sinensis Radix excels in activating blood, but the scientific mechanism has not been systematically analyzed, thus limiting the development of the medicinal. This study employed the computer-aided drug design methods, such as structural similarity-based target reverse prediction, complex network analysis, molecular docking, binding free energy calculation, cluster analysis, and ADMET(absorption, distribution, metabolism, excretion, toxicity) calculation, and enzyme activity assay in vitro, to explore the components and mechanism of Angelicae Sinensis Radix in activating blood. Target reverse prediction and complex network analysis yielded 40 potential anticoagulant targets of the medicinal. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis indicated that the targets mainly acted on the complement and coagulation cascade signaling pathway to exert the anticoagulant function. Among them, the key enzymes thrombin(THR) and coagulation factor Xa(FXa) in coagulation cascade and thrombosis were the drug targets for thromboembolic diseases. At the same time, molecular docking and cluster analysis showed that the medicinal had high selectivity for FXa. According to binding free energy score, 8 potential active components were selected for enzyme activity assay in vitro. The results demonstrated that 8 components inhibited THR and FXa, and the inhibition was stronger on FXa than on THR. The pharmacophore model of 8 active compounds was constructed, which suggested that the components had the common pharmacophore AAHH. The ADMET calculation result indicated that they had good pharmacokinetic properties and were safe. Based on target reverse prediction, complex network analysis, molecular docking and binding free energy calculation, anticoagulant activity in vitro, spatial binding conformation of molecules and targets, pharmacophore model construction, and ADMET calculation, this study preliminarily clarified the material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood from the perspective of big data, and calculated the pharmacology and toxicology parameters of the active components. Our study, for the first time, revealed that the medicinal had obvious selectivity and pertinence for different coagulation proteins, reflecting the unique effect of different Chinese medicinals and the biological basis. Therefore, this study can provide clues for precision application of Angelicae Sinensis Radix and the development of the blood-activating components with modern technology.

In-situ growth of boronic acid-decorated metal-organic framework on Fe3O4 nanospheres for specific enrichment of cis-diol containing nucleosides

In this study, a novel core-shell structured magnetic metal-organic framework nanospheres (Fe3O4@PD@BA-Zr-MOF) were fabricated by in-situ growth of boronic acid-decorated porphyrin-based metal-organic frameworks on polydopamine (PD) functionalized Fe3O4 nanospheres for highly efficient enrichment of cis-diol containing nucleosides by magnetic solid phase extraction (MSPE). PD as a molecular linker promotes the nucleation and crystal growth of boronic acid-decorated porphyrin-based metal-organic framework (BA-Zr-MOF), which was synthesized via a dual-ligand strategy by using Zr4+ as a metal unit as well as meso-tetra (4-carboxylphenyl) porphyrin (TCPP) and 1, 4-phenylenebisboronic acid (BA) as dual organic ligands. It is worth noting that the nitrogen-rich skeleton of TCPP and abundant boric acid groups in MOF allows for effective and selective enrichment of cis-diol containing compounds by hydrophilic interaction and boron affinity. Also, Zr4+ well assembled into the MOF is beneficial to extraction via metal oxide affinity interaction due to reversible covalent complex formation/dissociation between Zr and cis-diol compounds. The morphology, structure and saturation magnetization of Fe3O4@PD@BA-Zr-MOF were systematically characterized. The as-prepared adsorbent coupled with high performance liquid chromatography was used for analysis of four nucleosides including cytidine, uridine, guanosine, and adenosine in urine sample with the detection limits in range of 0.002–0.005 μg mL−1 and the quantitative limits in range of 0.008–0.018 μg mL−1. The as-fabricated Fe3O4@PD@BA-Zr-MOF nanospheres shows high selectivity, low detection limit, excellent reusability and reproducibility for nucleosides enrichment. The large specific surface area and quick magnetic response performance endow the affinity magnetic nanospheres with outstanding enrichment capability for rapid extraction. The adsorbent of Fe3O4@PD@BA-Zr-MOF nanospheres has great potential for identification and analysis of trace cis-diol containing nucleosides in biological samples.