Proposed Activation Mechanism Research Articles

Shock Activation Mechanism of Aluminum Nano-Particles outside High Explosives

Abstract Adding aluminum nanoparticles (ANPs) to explosive charges can effectively increase the total explosion energy and work capacity. A novel explosive charge was researched where ANPs were placed outside the high explosive. And the shock activation mechanism for the ANPs was proposed. The proposed shock activation mechanism suggests that under shock loadings, ANPs ignite due to the combined effects of shock work and plastic work. To investigate this mechanism, four turns of explosion experiments were conducted with varying layer thicknesses of ANPs in an enclosed space. The quasi-static pressure was measured to characterize the activation efficiency of the ANPs. The experimental results revealed that the reaction degree of the ANPs ranged from 55.9% to 67.2%, indicating that ANPs reached a relatively high reaction degree despite being placed outside the high explosives. Furthermore, the reaction degree decreased monotonically from 67.2% to 55.9% as the Al layer thickness increased from 1.3% to 6.3% of the explosive diameter. This observation suggests that the activation efficiency of the ANPs decreased with increasing layer thickness. These experimental findings show that the shock activation mechanism can effectively explain the activation of ANPs placed outside of explosives. The proposed shock activation mechanism is indeed valid and provides a promising approach to enhance the explosion energy and work capacity by incorporating ANPs in the charge configuration.

(Invited) Performance As Electrode for Electric Double-Layer Capacitor of Activated Carbon Derived from Bamboo Residue after Steam Treatment Activated By Alkaline Metal Hydroxide

Introduction Biomass-derived activated carbon can be the electrode material for high performance EDLCs, owing to its high surface area, porosity, and excellent conductivity1). The performance of EDLC electrode can be presumed to depend on pore size distribution from the theory of electric double layer. In Japan, the disorderly expansion of bamboo forest is serious problem because it causes economical damage. Therefore, we have already proposed “cascading usage of bamboo”, the extraction of saccharides by hydrolysis and the usage of solid residue as the precursor for EDLC electrode, as the promising candidate of the solution for the bamboo problem2). The alkaline metal hydroxide, such as KOH and NaOH, is known to be the activator for preparing activated carbon, and the pore size distribution could be presumed to depend on the kind of alkaline metal hydroxide from the proposed activation mechanism. In this study, the solid residue of steam-treated bamboo is used as a precursor for activated carbon for the activation by KOH or NaOH, and the performance as EDLC electrode of the activated carbons is investigated in detail. Experimental Moso bamboo powder and water were separately set in a container for autoclave (HU-100, Sanai Science Co., Ltd.). The container was heated at 200°C for 2.5 hours, which was chosen based on previous work3). The treated bamboo was dispersed in distilled water at room temperature for 1 hour for the extraction of sugars. The solid residue after filtration was heated at 500oC for 1 hour with N2 gas flowing for carbonization. The carbonized sample was mixed with KOH or NaOH, and then the mixture was heated at 800°C for 1 hour with N2 gas flowing. The activated sample washed with heated distilled water for several times and then dried. Raman Spectroscopy (NRS-5100, JASCO Corporation) utilizing a 532 nm laser for excitation was utilized to examine the degree of graphitization within the sample structures. The morphology of the samples was examined by Field Emission Scanning Electron Microscope (FE-SEM) from Japan Electronics Co., Ltd (Model JSM-6701F). The adsorption isotherms of the samples for N2 (at 77 K) and CO2 (at 298 K) was measured by a commercial apparatus (BELSORP-miniII, MicrotracBEL). The electrochemical performance, such as cyclic Voltammetry (CV), Electrochemical Impedance Spectroscopy (EIS), and galvanostatic charge/discharge measurement, of the sample was evaluated by using two-electrode cell with 1 M (C2H5)4NBF4 (TEABF4)/PC as electrolyte. Results and Discussions The yield, which is (weight after activation)/(weight before activation), decreased at higher weight ratios of KOH or NaOH, and the yield for NaOH activation was lower than that for KOH activation. The Raman spectra of the samples indicated that the samples have amorphous structure. The SEM images showed that the activated samples kept the microstructure derived from plant tissue. The N2 adsorption isotherms at 77 K for all the activated samples exhibited type I, indicating a microporous structure. However, the NaOH-activated samples displayed gentler slopes at low relative pressure, suggesting wider micropore size distribution. That is, the micropore size distribution depended on the kind of alkaline metal hydroxide.The capacitance values calculated from discharge process at 10 mA g-1 from 2.5-0 V was ca. 25 F g-1, which is comparable to the reported values. The capacitance values calculated from CV curves of NaOH-activated sample, 37.6 F g-1 at 1 mV s-1, was slightly higher than that of KOH-activated sample. Moreover, the decrement of the capacitance value at higher scan rate was trend to be suppressed for NaOH-activated samples. The capacitive contribution calculated according to the Dunn method4) indicated that NaOH-activated carbon showed a higher degree of capacitive contribution (74 %). The wider pore size distribution of NaOH-activated sample could contribute the suppression of the decrement of the capacitance value at higher scan rate. Conclusions The chemical activation by hydroxide of alkaline metal, such as KOH and NaOH, was performed to the solid residue after the extraction of steam-treated bamboo. From the results of the capacitance value, the suppression of the decrement of the capacitance value, and the capacitive contribution, the performance as EDLC electrode of NaOH-activated sample was better than that of KOH-activated sample. The wider pore size distribution for NaOH-activated sample could be one of the reasons for the higher performance. References 1) K.Ö. Köse et al. (2018) International Journal of Hydrogen Energy, 43:18607–16.2) T. Tsubota et al., (2018) Journal of Porous Materials, 25: 1541-1548.3) D.A. Khuong et al. (2023) Materials Chemistry and Physics, 304:127853.4) D. Dubey et al. (2023) Journal of Energy Storage, 58:106441. Figure 1

Metal-Free Activation of Molecular Oxygen by Quaternary Ammonium-Based Ionic Liquid: A Detail Mechanistic Study.

Most oxidation processes in common organic synthesis and chemical biology require transition metal catalysts or metalloenzymes. Herein, we report a detailed mechanistic study of a metal-free oxygen (O2) activation protocol on benzylamine/alcohols using simple quaternary alkylammonium-based ionic liquids to produce products such as amide, aldehyde, imine, and in some cases, even aromatized products. NMR and various control experiments established the product formation and reaction mechanism, which involved the conversion of molecular oxygen into a hydroperoxyl radical via a proton-coupled electron transfer process. Detection of hydrogen peroxide in the reaction medium using colorimetric analysis supported the proposed mechanism of oxygen activation. Furthermore, first-principles calculations using density functional theory (DFT) revealed that reaction coordinates and transition state spin densities have a unique spin conversion of triplet oxygen leading to formation of singlet products via a minimum energy crossing point. In addition to DFT, domain-based local pair natural orbital coupled cluster, (DLPNO-CCSD(T)), and complete active space self-consistent field, CASSCF(20,14) methods complemented the above findings. Partial density of states analysis showed stabilization of π* orbital of oxygen in the presence of ionic liquid, making it susceptible to hydrogen abstraction in a mild, metal-free condition. Inductively coupled plasma atomic emission spectroscopic (ICP-AES) analysis of reactant and ionic liquids clearly showed the absence of any significant transition metal contamination. The current results described the origin of O2 activation within the context of molecular orbital (MO) theory and opened up a new avenue for the use of ionic liquids as inexpensive, multifunctional and high-performance alternative to metal-based catalysts for O2 activation.

TMEM63 mechanosensitive ion channels: Activation mechanisms, biological functions and human genetic disorders

The transmembrane 63 (TMEM63) family of proteins are originally identified as homologs of the osmosensitive calcium-permeable (OSCA) channels in plants. Mechanosensitivity of OSCA and TMEM63 proteins are recently demonstrated in addition to their proposed activation mechanism by hyper/hypo-osmolarity. TMEM63 proteins exist in all animals, with a single member in Drosophila (TMEM63) and three members in mammals (TMEM63 A/B/C). In humans, monoallelic variants of TMEM63A have been reported to cause transient hypomyelination during infancy, or severe hypomyelination and global developmental delay. Heterozygous variants of TMEM63B are found in patients with intellectual disability and abnormal motor function and brain morphology. Biallelic variants of TMEM63C are associated with hereditary spastic paraplegias accompanied by mild or no intellectual disability. Physiological functions of TMEM63 proteins clearly recognized so far include detecting food grittiness and environmental humidity in Drosophila, and supporting hearing in mice by regulating survival of cochlear hair cells. In this review, we summarize current knowledge about the activation mechanisms and biological functions of TMEM63 channels, and provide a concise reference for researchers interested in investigating more physiological and pathogenic roles of this family of proteins with ubiquitous expression in the body.

A phase transition reduces the threshold for nicotinamide mononucleotide-based activation of SARM1, an NAD(P) hydrolase, to physiologically relevant levels

Axonal degeneration is a hallmark feature of neurodegenerative diseases. Activation of the NAD(P)ase sterile alpha and toll-interleukin receptor motif containing protein 1 (SARM1) is critical for this process. In resting neurons, SARM1 activity is inhibited, but upon damage, SARM1 is activated and catalyzes one of three NAD(P)+ dependent reactions: (1) NAD(P)+ hydrolysis to form ADP-ribose (ADPR[P]) and nicotinamide; (2) the formation of cyclic-ADPR (cADPR[P]); or (3) a base exchange reaction with nicotinic acid (NA) and NADP+ to form NA adenine dinucleotide phosphate. Production of these metabolites triggers axonal death. Two activation mechanisms have been proposed: (1) an increase in the nicotinamide mononucleotide (NMN) concentration, which leads to the allosteric activation of SARM1, and (2) a phase transition, which stabilizes the active conformation of the enzyme. However, neither of these mechanisms have been shown to occur at the same time. Using invitro assay systems, we show that the liquid-to-solid phase transition lowers the NMN concentration required to activate the catalytic activity of SARM1 by up to 140-fold. These results unify the proposed activation mechanisms and show for the first time that a phase transition reduces the threshold for NMN-based SARM1 activation to physiologically relevant levels. These results further our understanding of SARM1 activation and will be important for the future development of therapeutics targeting SARM1.

Deciphering the Allosteric Activation Mechanism of SIRT6 Using Molecular Dynamics Simulations.

As a member of the histone deacetylase protein family, the NAD+-dependent SIRT6 plays an important role in maintaining genomic stability and regulating cell metabolism. Interestingly, SIRT6 has been found to have a preference for hydrolyzing long-chain fatty acyls relative to deacetylation, and it can be activated by fatty acids. However, the mechanisms by which SIRT6 recognizes different substrates and can be activated by small molecular activators are still not well understood. In this study, we carried out extensive molecular dynamic simulations to shed light on these mechanisms. Our results revealed that the binding of the myristoylated substrate stabilizes the catalytically favorable conformation of NAD+, while the binding of the acetyl-lysine substrate leads to a loose binding of NAD+ in SIRT6. Based on these observations, we proposed a reasonable allosteric binding mode for myristic acid, which can enhance the catalytic activity of SIRT6 by stabilizing the binding of NAD+ with His131 as well as the acetylated substrate. Furthermore, our molecular dynamics simulations demonstrated that synthetic SIRT6 activators, such as UBCS039, MDL-801, and 12q, block the flipping of ribose in NAD+ and therefore can stabilize substrate-NAD+-His131 interactions in a manner similar to fatty acids. In summary, our newly proposed activation mechanism of SIRT6 highlights the importance of protein-substrate interactions, which would facilitate the rational design of new SIRT6 activators.

Biased signalling is structurally encoded as an autoproteolysis event in adhesion G protein-coupled receptor Latrophilin-3/ADGRL3.

Adhesion G protein-coupled receptors (aGPCRs) possess a unique topology, including the presence of a GPCR proteolysis site (GPS), which, upon autoproteolysis, generates two functionally distinct fragments that remain non-covalently associated at the plasma membrane. A proposed activation mechanism for aGPCRs involves the exposure of a tethered agonist, which depends on cleavage at the GPS. However, this hypothesis has been challenged by the observation that non-cleavable aGPCRs exhibit constitutive activity, thus making the function of GPS cleavage widely enigmatic. In this study, we sought to elucidate the function of GPS-mediated cleavage through the study of G protein coupling with Latrophilin-3/ADGRL3, a prototypical aGPCR involved in synapse formation and function. Using BRET-based G protein biosensors, we reveal that an autoproteolysis-deficient mutant of ADGRL3 retains constitutive activity. Surprisingly, we uncover that cleavage deficiency leads to a signalling bias directed at potentiating the activity of select G proteins such as Gi2 and G12/13. These data unveil the underpinnings of biased signalling for aGPCRs defined by GPS autoproteolysis.

Mechanistic insight into active species formation during Fenton-like processes by regulating dissimilar charged groups on Fe3O4 nanospheres

Iron-mediated activation of peroxymonosulfate (PMS) had long been of great interest for the effective oxidation of micropollutants. However, how the chemical environment of iron oxides influence active species formation in heterogeneous Fenton processes was poorly understood. Herein, Fe3O4-X nanospheres (X = –NH2, –COOH) were synthesized for coordination chemical environment regulation. The DFT calculation showed the models of Fe3O4-X modified by –NH2 and –COOH in four-coordination and six-coordination environments. Among them, Fe3O4-COOH in four-coordination environment had the lowest formation energy and highest adsorption energy combined with PMS, with a most stable system. In the adsorption model of four-coordination Fe3O4-COOH, the d-orbitals and s-orbitals energy levels of Fe atoms underwent drastic changes compared with those before adsorption, H atoms on the carboxyl group and O atoms on the PMS formed a new HO– that attached to Fe atoms, with a strong coupling between them. The simulation results confirmed the proposed activation mechanism of Fe3O4-COOH activating PMS to generate SO4·- and HO–, and then partial SO4·- reacted with HO– to generate ·OH, and finally the two radicals attacked tetracycline (TC) together. In Fe3O4-COOH/PMS system, Fe3O4-COOH/PMS system can convert more Fe2+ into Fe3+, which also means that more Fe2+ reacts with PMS to produce Fe3+ and SO4·-. The TC degradation efficiency of the Fe3O4-COOH/PMS system was 93%, higher than that of the Fe3O4-NH2/PMS system after 30 min of reaction. Consequently, this work contributes to the mechanistic insight into active species regulation during Fenton-like processes by manipulating surface groups.

Molecular structure-dependent contribution of reactive species to organic pollutant degradation using nanosheet Bi2Fe4O9 activated peroxymonosulfate

Iron-based catalysts have attracted increasing attention in heterogeneous activation of peroxymonosulfate (PMS). However, the activity of most iron-based heterogenous catalysts is not satisfactory for practical application and the proposed activation mechanisms of PMS by iron-based heterogenous catalyst vary case by case. This study prepared Bi2Fe4O9 (BFO) nanosheet with super high activity toward PMS, which was comparable to its homogeneous counterpart at pH 3.0 and superior to its homogeneous counterpart at pH 7.0. Fe sites, lattice oxygen and oxygen vacancies on BFO surface were believed to be involved in the activation of PMS. By using electron paramagnetic resonance (EPR), radical scavenging tests, 57Fe Mössbauer and 18O isotope-labeling technique, the generation of reactive species including sulfate radicals, hydroxyl radicals, superoxide and Fe (IV) were confirmed in BFO/PMS system. However, the contribution of reactive species to the elimination of organic pollutants very much depends on their molecular structure. The effect of water matrices on the elimination of organic pollutants also hinges on their molecular structure. This study implies that the molecular structure of organic pollutants governs their oxidation mechanism and their fate in iron-based heterogeneous Fenton-like system and further broadens our knowledge on the activation mechanism of PMS by iron-based heterogeneous catalyst.

Remdesivir-induced conduction abnormalities: A molecular model-based explanation.

Purpose: Remdesivir use in COVID-19 is associated with cardiac conduction abnormalities from unclear mechanisms. A proposed mechanism is the bioaccumulation of the intermediate metabolite GS-441524 resulting in exogenous activation of cardiac adenosine A1 due to the structural similarity between adenosine and GS-441524. The prolonged half-life of GS-441524 can result in sustained activation of adenosine A1 receptors. In this study, we used molecular modeling of adenosine, GS-441524 and the adenosine A1 receptor to assess the potential mechanistic association of the proposed mechanism. Methods: Adenosine and GS-441524 structures were acquired from the PubChem database. Ligand docking was carried out using UCSF Chimera. Models were chosen based on greatest binding affinity and minimum root mean square deviation. Figures of resulting structural models were prepared using UCSF Chimera or PyMOL 2.3.5. Results: By modeling the interaction between the A1 G protein complex and both adenosine and GS-441524, we found that the proposed mechanism of exogenous A1 receptor activation is feasible based on docking compatibility. Conclusion: The proposed mechanism of exogenous cardiac A1 receptor activation from bioaccumulation of GS-441524 as a cause of observed cardiac conduction abnormalities with the use of remdesivir in COVID-19 is viable. Further studies are needed to assess causality.

Thermal-mechanical-photo-activation effect on silica micro/nanofiber surfaces: origination, reparation and utilization.

The exploration relevant to the surface changes on optical micro- and nanofibers (MNFs) is still in infancy, and the reported original mechanisms remain long-standing puzzles. Here, by recognizing the combined interactions between fiber heating, mechanically tapering, and high-power pulsed laser guiding processes in MNFs, we establish a general thermal-mechanical-photo-activation mechanism that can explain the surface changes on MNFs. Our proposed activation mechanism can be well supported by the systematical experimental results using high-intensity nanosecond/femtosecond pulsed lasers. Especially we find large bump-like nanoscale cavities on the fracture ends of thin MNFs. Theoretically, on the basis of greatly increased bond energy activated by the fiber heating and mechanically tapering processes, the energy needed to break the silicon-oxygen bond into dangling bonds is significantly reduced from its intrinsic bandgap of ∼9 eV to as low as ∼4.0 eV, thus high-power pulsed lasers with much smaller photon energy can induce obvious surface changes on MNFs via multi-photon absorption. Finally, we demonstrate that using surfactants can repair the MNF surfaces and exploit them in promising applications ranging from sensing and optoelectronics to nonlinear optics. Our results pave the way for future preventing the performances from degradation and enabling the practical MNF-based device applications.

Increased Acid Exposure on Pretransplant Impedance-pH Testing Is Associated With Chronic Rejection After Lung Transplantation.

The goal of this study was to assess the relationship between pretransplant measures of reflux and longer-term outcomes of chronic allograft rejection in lung transplant recipients. Bronchiolitis obliterans syndrome (BOS) is a primary measure of morbidity and mortality following lung transplantation, and a manifestation of chronic lung allograft dysfunction (CLAD). Acid reflux has been associated with early allograft injury through a proposed mechanism of aspiration and activation of the inflammatory cascade, but its association with chronic rejection is unclear. This was a retrospective cohort study of lung transplant recipients undergoing impedance-pH testing off proton pump inhibitor from 2007 to 2016. Patients with pretransplant antireflux surgery were excluded. Time-to-event analysis using the Cox proportional hazards model was applied to assess the relationship between pretransplant reflux measures and the development of BOS, defined histologically and clinically. A secondary analysis was completed using CLAD as the outcome variable. Fifty-one subjects (59% men, mean age: 56, mean follow-up: 2.2 y) met inclusion criteria for the study. The BOS endpoint was reached in 13 subjects (28%). In time-to-event analyses, BOS was associated with increased acid exposure, defined as >4.2% of time with pH<4 [hazard ratio (HR): 4.18; 95% confidence interval (CI): 1.31-13.4; P=0.01], and elevated DeMeester score >14.7 (HR: 3.08; 95% CI: 1.02-9.26; P=0.04), with confirmation from Kaplan-Meier analyses. The secondary analysis demonstrated a similar association between increased acid exposure and CLAD (HR: 3.28; 95% CI: 1.09-9.88; P=0.03), which persisted on multivariate models. Increased acid exposure on pretransplant reflux testing was associated with the development of BOS and CLAD, both measures of chronic allograft rejection, after lung transplantation, and may provide clinically relevant information to improve lung allograft survival through aggressive reflux management.

Insights into the activation of silica-supported metallocene olefin polymerization catalysts by methylaluminoxane

Metallocene-based olefin polymerization catalysts often require large excesses of co-catalyst for optimal catalyst activation. In this work, mechanistic insights into the activation of supported metallocenes by methylaluminoxane as co-catalyst are acquired. UV–vis diffuse reflectance (DR) spectroscopy of five metallocene catalysts with varying co-catalyst loading reveals the presence of different metallocene species on the surface of the catalyst particles. Deconvolution of the obtained spectra, in combination with an extensive TD–DFT study of UV–vis DR spectra of metallocene structures results in a proposed activation mechanism. We find that with increasing MAO loading, more AlMe2+-bound metallocenes are observed with a shift towards the trimethylaluminum-stabilized cationic methylated metallocene compound. This shift can be directly correlated with a higher activity in the olefin polymerization reaction. Based on this finding, we propose a universal metallocene activation mechanism in which the cationic methylated metallocene is the active species. This species is formed through initial interaction with AlMe2+, followed by ligand exchange with MAO and stabilized in complex with trimethylaluminum as a dormant species.

The conserved threonine-rich region of the HCF-1PRO repeat activates promiscuous OGT:UDP-GlcNAc glycosylation and proteolysis activities

O-Linked GlcNAc transferase (OGT) possesses dual glycosyltransferase–protease activities. OGT thereby stably glycosylates serines and threonines of numerous proteins and, via a transient glutamate glycosylation, cleaves a single known substrate—the so-called HCF-1PRO repeat of the transcriptional co-regulator host-cell factor 1 (HCF-1). Here, we probed the relationship between these distinct glycosylation and proteolytic activities. For proteolysis, the HCF-1PRO repeat possesses an important extended threonine-rich region that is tightly bound by the OGT tetratricopeptide-repeat (TPR) region. We report that linkage of this HCF-1PRO-repeat, threonine-rich region to heterologous substrate sequences also potentiates robust serine glycosylation with the otherwise poor Rp-αS-UDP-GlcNAc diastereomer phosphorothioate and UDP-5S-GlcNAc OGT co-substrates. Furthermore, it potentiated proteolysis of a non-HCF-1PRO-repeat cleavage sequence, provided it contained an appropriately positioned glutamate residue. Using serine- or glutamate-containing HCF-1PRO-repeat sequences, we show that proposed OGT-based or UDP-GlcNAc–based serine-acceptor residue activation mechanisms can be circumvented independently, but not when disrupted together. In contrast, disruption of both proposed activation mechanisms even in combination did not inhibit OGT-mediated proteolysis. These results reveal a multiplicity of OGT glycosylation strategies, some leading to proteolysis, which could be targets of alternative molecular regulatory strategies.

Water-Activated VOPO4 for Magnesium Ion Batteries.

Rechargeable Mg batteries, using high capacity and dendrite-free Mg metal anodes, are promising energy storage devices for large scale smart grid due to low cost and high safety. However, the performance of Mg batteries is still plagued by the slow reaction kinetics of their cathode materials. Recent discoveries demonstrate that water in cathode can significantly enhance the Mg-ion diffusion in cathode by an unknown mechanism. Here, we propose the water-activated layered-structure VOPO4 as a novel cathode material and examine the impact of water in electrode or organic electrolyte on the thermodynamics and kinetics of Mg-ion intercalation/deintercalation in cathodes. Electrochemical measurements verify that water in both VOPO4 lattice and organic electrolyte can largely activate VOPO4 cathode. Thermodynamic analysis demonstrates that the water in the electrolyte will equilibrate with the structural water in VOPO4 lattice, and the water activity in the electrolyte alerts the mechanism and kinetics for electrochemical Mg-ion intercalation in VOPO4. Theoretical calculations and experimental results demonstrate that water reduces both the solid-state diffusion barrier in the VOPO4 electrode and the desolvation penalty at the interface. To achieve fast reaction kinetics, the water activity in the electrolyte should be larger than 10-2. The proposed activation mechanism provides guidance for screening and designing novel chemistry for high performance multivalent-ion batteries.

Evaluation of Nitrobenzyl Derivatives of Camptothecin as Anti-Cancer Agents and Potential Hypoxia Targeting Prodrugs.

As part of our initial efforts into developing a tumor-targeting therapy, C-10 substituted derivatives of a camptothecin analog (SN-38) have been synthesized (2-, 3- and 4-nitrobenzyl) for use as potential hypoxia-activated prodrugs and evaluated for their cytotoxicity, topoisomerase I inhibition and electrochemical (reductive) properties. All three derivatives were found to possess reduced toxicity towards human leukemia K562 cells compared to SN-38, validating a condition for prodrug action. Using an MTS assay, IC50’s were found to be 3.0, 25.9, 12.2 and 58.0 nM for SN-38, 2-nitro-, 3-nitro- and 4-nitrobenzyl-C10-substituted-SN-38, respectively, representing an 8-, 4- and 19-fold decrease in cytotoxicity. Using a topoisomerase I assay, one of the analogs (4-nitrobenzyl) was shown to inhibit the ability of this enzyme to relax supercoiled pBR322 DNA, at a similar concentration to the clinically-approved active metabolite SN-38. Cyclic voltammetry detailed the reductive nature of the analogs, and was used to infer the potential of these compounds to serve as hypoxia-targeting prodrugs. The electrochemical results also validated the quasi-reversible nature of the first reduction step, and served as a proof-of-principle that hypoxia-targeting prodrugs of SN-38 can participate in a redox-futile cycle, the proposed mechanism of activation and targeting. Chemical reduction of the 4-nitrobenzyl analog led to the formation/release of SN-38 and validated the prodrug ability of the C-10 substituted derivative.

Activation of persulfate by modified drinking water treatment residuals for sulfamethoxazole degradation

In this work, drinking water treatment residuals (WTRs), an iron-rich safety byproducts, was modified via facile reduction calcination and subsequently proved as an effective persulfate (PS) activator for degradation of sulfamethoxazole (SMX). Various parameters affecting SMX degradation efficiency were tested, and the results showed that 80% of SMX (50 μM) was removed within 60 min in the presence of 2.0 mM PS and 0.2 g L−1 modified WTRs at pH 5.3 under ambient temperature. Radical scavenging and electron spin-resonance spectroscopy tests indicated that sulfate radical was a much more powerful active oxygen specie than hydroxyl radical for the SMX degradation in the WTRs/PS system. To understand the proposed activation mechanism, X-ray diffraction and X-ray photoelectron spectroscopy were applied to reveal the change of modified WTRs before and after use. This process confirmed that the activation mechanism was in situ homogenous and heterogeneous reaction simultaneously. Furthermore, liquid chromatography coupled with ion trap time-of-flight mass spectrometry was applied to identify the intermediates of SMX to understand the possible pathway. This work provides a novel value-added reuse approach for WTRs as an efficient and cost-effective heterogeneous activator for PS.

Crystal Structure of Carbonic Anhydrase II in Complex with an Activating Ligand: Implications in Neuronal Function.

Carbonic anhydrase (CA) plays a key role in neuronal signaling, providing bicarbonate and proton ions for GABAergic and glutamatergic neuronal function. Activation of CA isoforms expressed in neurons have been shown to have implications in the prognosis of Alzheimer's disease and dementia, while inhibitors of CAs are clinically used in the treatment of epilepsy, emphasizing the importance of this family of enzymes in both disease and normal neuronal function. Previously, compounds have been reported to enhance activity of CAs in an aging rat model, but their mechanism of action was not known. We report the 1.6Å resolution structure of an imidazole-based CA activator in complex with the ubiquitously-expressed human CA II. Based on the structure, a proposed mechanism of CA activation by the compound and its potential applications in the neurobiology of aging are discussed.

Investigating the molecular mechanism of positive and negative allosteric modulators in the calcium-sensing receptor dimer

Allosteric modulators that are targeting the calcium-sensing receptor (CaSR) hold great therapeutic potential, and elucidating the molecular basis for modulation would thus benefit the development of novel therapeutics. In the present study, we aimed at investigating the mechanism of allosteric modulation in CaSR by testing dimers carrying mutations in the allosteric site of one or both of the subunits. To ensure measurements on a well-defined dimer composition, we applied a trans-activation system in which only the specific heterodimer of two loss-of-function mutants responded to agonist. Although one of these mutants was potentiated by a positive allosteric modulator, we showed that receptor activity was further potentiated in a trans-activation heterodimer containing a single allosteric site, however only when the allosteric site was located in the subunit responsible for G protein coupling. On the contrary, preventing activation in both subunits was necessary for obtaining full inhibition by a negative allosteric modulator. These findings correlate with the proposed activation mechanism of the metabotropic glutamate receptors (mGluRs), in which only a single transmembrane domain is activated at a time. CaSR and mGluRs belong to the class C G protein-coupled receptors, and our findings thus suggest that the activation mechanism is common to this subfamily.

Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis.

RhoBTB proteins constitute a subfamily of atypical Rho GTPases represented in mammals by RhoBTB1, RhoBTB2, and RhoBTB3. Their characteristic feature is a carboxyl terminal extension that harbors two BTB domains capable of assembling cullin 3-dependent ubiquitin ligase complexes. The expression of all three RHOBTB genes has been found reduced or abolished in a variety of tumors. They are considered tumor suppressor genes and recent studies have strengthened their implication in tumorigenesis through regulation of the cell cycle and apoptosis. RhoBTB3 is also involved in retrograde transport from endosomes to the Golgi apparatus. One aspect that makes RhoBTB proteins atypical among the Rho GTPases is their proposed mechanism of activation. No specific guanine nucleotide exchange factors or GTPase activating proteins are known. Instead, RhoBTB might be activated through interaction with other proteins that relieve their auto-inhibited conformation and inactivated through auto-ubiquitination and destruction in the proteasome. In this review we discuss our current knowledge on the molecular mechanisms of action of RhoBTB proteins and the implications for tumorigenesis and other pathologic conditions.