Mild Procedure Research Articles

Rh(III)-catalyzed, 1,2,3-triazole-assisted directed C[sbnd]H coupling with diazo diphosphonates

A mild and efficient procedure was developed for the [Cp∗Rh(III)]-catalyzed, 1,2,3-triazole directed CH coupling with diazomethylene-diphosphonates. This protocol provided a step- and atom-economical protocol for CC bond formation and led to structurally diverse 2-(1,2,3-triazol-2-yl)benzyl diphosphonates in good to excellent yields.

Protein-Based Nanoparticles for the Delivery of Enzymes with Antibacterial Activity.

Proteins represent a versatile biopolymer material for the preparation of nanoparticles due to their biocompatibility, biodegradability, and low immunogenicity. This study presents a protein-based nanoparticle system consisting of high surface PEGylated lysozyme polyethylene glycol-modified lysozyme (LYZmPEG ). This protein modification leads to a solubility switch, which allows a nanoparticle preparation using a mild double emulsion method without the need of surfactants. The method allows the encapsulation of large hydrophilic payloads inside of the protein-based nanoparticle system. Native lysozyme (LYZ) was chosen as payload because of its innate activity as natural antibiotic. The mild particle preparation procedure retains the structure and activity of the enzyme which was successfully tested against the gram-positive bacteria strain M. Luteus. In comparison, the particle system shows no toxicity to human cells. This first report of a full protein-based particle material for the transport of large hydrophilic payloads opens up new therapeutic applications for biopolymer-based delivery systems.

Enhancement of Resistance to Protein Fouling of Poly(ether imide) Membrane by Surface Grafting with PEG under Organic Solvent-free Condition

Poly(ether imide) (PEI) membrane with enhanced antifouling property was successfully prepared in a mild and simple procedure. The virgin membrane was firstly functionalized with an aqueous solution of diamino-terminated poly(ethylene oxide) block copolymer (PEG-diamine). Glutaraldehyde was used in a second step as a linker to chemically attach additional PEG-diamine to the primary amine groups grafted on PEI membrane surface. Immobilization of PEG segments was confirmed using Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy and atomic force microscopy. Ultrafiltration experiments revealed that the enhancement of a PEG coverage on the membrane surface provided superior anti-protein-fouling property. Cycles of protein filtration also demonstrated that the antifouling surface was stable over time and excellent ultrafiltration performance could be maintained without the need of harsh cleansing operation.

Chronic Stress Exposure Reduces Parvalbumin Expression in the Rat Hippocampus through an Imbalance of Redox Mechanisms: Restorative Effect of the Antipsychotic Lurasidone

BackgroundPsychiatric disorders are associated with altered function of inhibitory neurotransmission within the limbic system, which may be due to the vulnerability of selective neuronal subtypes to challenging environmental conditions, such as stress. In this context, parvalbumin-positive GABAergic interneurons, which are critically involved in processing complex cognitive tasks, are particularly vulnerable to stress exposure, an effect that may be the consequence of dysregulated redox mechanisms.MethodsAdult Male Wistar rats were subjected to the chronic mild stress procedure for 7 weeks. After 2 weeks, both control and stress groups were further divided into matched subgroups to receive chronic administration of vehicle or lurasidone (3 mg/kg/d) for the subsequent 5 weeks. Using real-time RT-PCR and western blot, we investigated the expression of GABAergic interneuron markers and the levels of key mediators of the oxidative balance in the dorsal and ventral hippocampus.ResultsChronic mild stress induced a specific decrease of parvalbumin expression in the dorsal hippocampus, an effect normalized by lurasidone treatment. Interestingly, the regulation of parvalbumin levels was correlated to the modulation of the antioxidant master regulator NRF2 and its chaperon protein KEAP1, which were also modulated by pharmacological intervention.ConclusionsOur findings suggest that the susceptibility of parvalbumin neurons to stress may represent a key mechanism contributing to functional and structural impairments in specific brain regions relevant for psychiatric disorders. Moreover, we provide new insights on the mechanism of action of lurasidone, demonstrating that its chronic treatment normalizes chronic mild stress-induced parvalbumin alterations, possibly by potentiating antioxidant mechanisms, which may ameliorate specific functions that are deteriorated in psychiatric patients.

A Mild Procedure for Enone Preparation Catalysed by Bovine Serum Albumin in a Green and Easily Available Medium

A simple and mild procedure to obtain α,β-unsaturated ketones from acetone and a set of benzaldehydes is described. The approach applies bovine serum albumin (BSA) catalysis and water or ethanol, this mild reaction medium contrasting with the strong reaction conditions of the classic aldol condensation. Except for the assayed nitrobenzaldehydes, high enone yields (88–97%) were attained. In addition to its mildness, further advantages of this procedure are the use of a green catalyst exhibiting an efficient reuse and the use of eco-friendly and cheap solvents. In order to gain a deeper understanding of the involved catalytic mechanism, computational experiments on BSA structural analysis and molecular docking were carried out.

Instability and Degradation Mechanism of Platinum-Group Metal (PGM)-Based Carbon Supported Electrocatalysts in Alkaline Medium

Direct liquid alkaline fuel cells (DLAFC) are considered high-energy density generators and arouse interest because (i) their energy density can be higher than for closed systems like Li-ion batteries, and (ii) they do not suffer from issues related to H2 compression, storage and delivery as for proton-exchange membrane fuel cells (PEMFC). Moreover, electrocatalyst commonly used for PEMFC suffer from a poor durability in operation [1]. In the case of alkaline fuel cells, despite few studies, the common belief supposes a larger stability of electrocatalysts in alkaline medium compared to acidic medium, owing to the better thermodynamic stability of many metals and oxides at high pH, as predicted by Pourbaix [2]. In reality, some recent studies showed that the state-of-the-art carbon-supported platinum nanocatalysts are subjected to severe degradations upon a mild potential cyclic procedure in 0.1 M NaOH at 25°C [3]. The loss of electrochemical surface area (ECSA) reaches 60 % after 150 cycles in the range 0.1 - 1.23 V vs. RHE at 100 mV s-1. Herein, the same degradation procedure has been performed with Pd/C and PtRu/C: non-negligible ECSA loss (ca. 35 %) is monitored for Pd/C, whereas very harsh degradation is noted for PtRu/C. Identical-location transmission electron microscopy studies (ILTEM) revealed that the main degradation mechanism is, whatever the electrocatalyst, the detachment of the nanoparticles from the carbon substrate (Figure 1 D-E-F). It is suspected that this detachment follows the rupture of the binding between the PGM nanoparticles and the carbon support, triggered by the formation of carbonates originating from PGM-assisted corrosion of the carbon support. The CO-stripping experiments performed in NaOH 0.1 M (Figure 1 A-B-C) confirm that the ability of each electrocatalysts to form CO2 is linked to the observed degradations. This work was partly supported by an ONR-global grant (project ONR N62909-16-1-2137).

Durability of Platinum-Based Carbon-Supported Electrocatalysts in Liquid Versus Solid Polymer Alkaline Electrolytes

Alkaline fuel cells (AFC) are competitors to proton-exchange membrane fuel cells for stationary applications [1]. Because many metals and metal oxides are stable at high pH [2], one may think that AFC electrocatalysts will be more stable in operation than in acidic medium. However, this was proven wrong for carbon-supported Pt and Pd nanoparticles (NPs) aged in liquid alkaline environment: these undergo severe electrochemical surface area losses even for a very mild potential cycling procedure in 0.1 M NaOH [3, 4]. Identical-location transmission electron microscopy (ILTEM) experiments revealed pronounced detachment of the Pt (and Pd) NPs from the carbon support, but minor degradation phenomena for the metal NPs and the carbon support itself. Additional experiments performed in various alkaline electrolytes (LiOH, NaOH, KOH, CsOH) coupled with in situ Fourier-transform infrared spectroscopy enabled to link this detachment to the formation of solid carbonates at the interface between the Pt (Pd) NPs and the carbon support, because the metal nanoparticles assist the local corrosion of the carbon support (firstly into CO2, then CO3 2- anions and finally into M2CO3, M = Li, Na, K or Cs). Figure 1 demonstrates that the loss of Pt NPs is greatly decreased when the alkaline electrolyte is an anion-exchange membrane. In that case, the formation of solid carbonates is severely depreciated, because the counter-cation of the OH- species are immobilized on the polymer backbone and can therefore not precipitate (as Na2CO3 does in NaOH aqueous electrolyte). Although the degradation of the Pt/C NPs is minored when the materials are aged in interface with an AEM, it is not suppressed: Ostwald ripening and Pt redeposition are observed, i.e. the mechanisms of degradation differ in solid versus liquid alkaline environment. Such differences between the fate of Pt-based electrocatalysts were also demonstrated for solid versus liquid acidic electrolytes [5, 6]. This work was partly supported by an ONR-global grant (project ONR N62909-16-1-2137).

P-Toluenesulfonic acid mediated one-pot cascade synthesis and cytotoxicity evaluation of polyfluorinated 2-aryl-2,3-dihydroquinolin-4-ones and their derivatives

Biologically interesting polyfluorinated 2-aryl-2,3-dihydroquinolin-4-ones (5), 3-benzylidene-2-aryl-2,3-dihydroquinolin-4-ones (6) and 7-methyl-6-aryl-5,6-dihydrodibenzo[b,h][1,6] naphthyridines (7) were synthesized using a mild and efficient one-pot procedure starting from 2-aminoacetophenones and trifluorobenzaldehyde in the presence of p-toluenesulfonic acid. Thanks to the use of a high-active polyfluorinated electrophile this synthetic protocol provides rapid access to a variety of bioactive heterocyclic assemblies. Screening of the synthesized compounds for their cytotoxic activity against human tumor cell lines, including breast cancer (MCF-7), lung carcinoma (A-549), and myeloma cancer cells (RPMI 8226) revealed that polyfluorinated compounds 6b–f showed manifest cytotoxic effects (with IC50 = 2.5 ÷ 7 μM for MCF-7 and RPMI 8226 cancer cells).

Spinal Cord Stimulation, MILD Procedure, and Regenerative Medicine, Novel Interventional Nonopioid Therapies in Chronic Pain.

Chronic pain is a highly prevalent condition affecting millions of individuals. In recent years, newer treatments have emerged that are changing the way clinicians treat pain pathogenesis, including novel nonopioid strategies. In this regard, spinal cord stimulation, the MILD procedure, and regenerative medicine have shown promise. This review summarizes recent literature on these three emerging treatment strategies. The results of this review suggest that under certain conditions, spinal cord stimulation, the MILD procedure, and regenerative medicine can be effective treatment modalities.

An efficient synthesis of fully substituted pyrazolo[3,4-b]pyridin-5-amines from α-azidochalcones

A facile, mild and efficient procedure for the synthesis of fully substituted pyrazolo[3,4-b]pyridin-5-amines is reported. A mixture of an α-azidochalcone, a 5-aminopyrazole and t-BuOK was stirred in DMF at ambient temperature for 5 min to afford the corresponding pyrazolo[3,4-b]pyridin-5-amines in good to excellent yields.

Three-component, solvent-free synthesis of Betti base catalyzed by sulfated polyborate

In this work, efficient, mild, and eco-friendly procedure of 1-aminoalkyl-2-phenol/Betti base from one-pot three-component condensations of aldehyde, phenol, and morpholine in the presence of sulfated polyborate catalyst, under a solvent-free condition at 100 °C, is described. The key advantages of the present method are short reaction time, high yields, aqueous work-up procedure, low cost, stable, reusable catalyst, and solvent-free reaction conditions.

Efficient synthesis of organic thioacetates in water.

Thioacetates as precursors of thiols are interesting starting points for synthesizing other organosulfur compounds. Herein, we propose a simple, efficient and fast method to obtain organic thioacetates using water as a solvent. Taking into account the great attention that has been paid toward environmentally friendly synthetic procedures in the past decades, we prove the role and the strength of the thioacetate anion as a nucleophile for nucleophilic displacement reactions in an aqueous medium. The reactions were carried out under pH control, to prevent the decomposition of the mesylate starting materials, using potassium carbonate as a safe and mild base. A simple work up allows products to be obtained with excellent yield and acceptable purity.

Facile Metal Coordination of Active Site Imprinted Nitrogen Doped Carbons for the Conservative Preparation of Non‐Noble Metal Oxygen Reduction Electrocatalysts

AbstractIron‐ or cobalt‐coordinated heteroatom doped carbons are promising alternatives for Pt‐based cathode catalysts in polymer‐electrolyte fuel cells. Currently, these catalysts are obtained at high temperatures. The reaction conditions complicate the selective and concentrated formation of metal–nitrogen active sites. Herein a mild procedure is introduced, which is conservative toward the carbon support and leads to active‐site formation at low temperatures in a wet‐chemical metal‐coordination step. Active‐site imprinted nitrogen doped carbons are synthesized via ionothermal carbonization employing Lewis‐acidic Mg2+ salt. The obtained carbons with large tubular porosity and imprinted N4 sites lead to very active catalysts with a half‐wave potential (E1/2) of up to 0.76 V versus RHE in acidic electrolyte after coordination with iron. The catalyst shows 4e− selectivity and exceptional stability with a half‐wave potential shift of only 5 mV after 1000 cycles. The X‐ray absorption fine structure as well as the X‐ray absorption near edge structure profiles of the most active catalyst closely match that of iron(II)phthalocyanine, proving the formation of active and stable FeN4 sites at 80 °C. Metal‐coordination with other transition metals reveals that Zn–Nx sites are inactive, while cobalt gives rise to a strong performance increase even at very low concentrations.

Laccase-catalyzed, aerobic oxidative coupling of 4-substituted urazoles with sodium arylsulfinates: Green and mild procedure for the synthesis of arylsulfonyl triazolidinediones

The direct aerobic oxidation of 4-substituted urazoles using the laccase enzyme from Trametes versicolor in a phosphate buffer solution at ambient temperature, and subsequent cross-coupling with sodium benzenesulfinates was investigated to afford arylsulfonyl-1,2,4-triazolidine-3,5-dione derivatives in good to high yields.

Understanding the interactions of cellulose fibres and deep eutectic solvent of choline chloride and urea

A deep eutectic solvent composed of choline chloride (ChCl) and urea has been recently introduced as a promising cellulose compatible medium that enables e.g. fibre spinning. This paper clarifies the influence of such a solvent system on the structure and chemical composition of the cellulosic pulp fibres. Special emphasis was placed on the probable alterations of the chemical composition due to the dissolution of the fibre components and/or due to the chemical derivatisation taking place during the DES treatment. Possible changes in fibre morphology were studied with atomic force microscopy and scanning electron microscopy. Chemical compositions of pulp fibres were determined from the carbohydrate content, and by analysing the elemental content. Detailed structural characterisation of the fibres was carried out using spectroscopic methods; namely X-Ray Photoelectron Spectroscopy, solid state Nuclear Magnetic Resonance and Raman Spectroscopy. No changes with respect to fibre morphology were revealed and negligible changes in the carbohydrate composition were noted. The most significant change was related to the nitrogen content of the pulp after the DES treatment. Comprehensive examination using spectroscopic methods revealed that the nitrogen originated from strongly bound ChCl residuals that could not be removed with a mild ethanol washing procedure. According to Raman spectroscopic data and methylene blue adsorption tests, the cationic groups of ChCl seems to be attached to the anionic groups of pulp by electrostatic forces. These findings will facilitate the efficient utilisation of DES as a cellulose compatible medium without significantly affecting the native fibre structure.

Synthesis of New Annulated Pyrazinothienotriazolopyrimidinones and Triazolylthienopyrazines

New pyrazino[2′,3′:4,5]thieno[2,3-e][1,2,3]triazolo[1,5-a]-pyrimidin-5(4H)-ones were synthesized in an efficient, fast, and mild one-pot procedure from methyl 7-azidothieno[2,3-b]pyrazine-6-carboxylate. From the latter, some triazolothieno[2,3-b]pyrazine-6-carboxylates were also obtained with total regioselectivity by [2+3] cycloaddition with alkynes without any metal catalyst.

Superior capacitive properties of polyaniline produced by a one-pot peroxidase/H2O2-triggered polymerization of aniline in the presence of AOT vesicles

The development of novel electrode materials for electrochemical capacitors requires innovative approaches with an imperative to produce highly active materials while holding to simple and scalable synthetic approaches. For the first time we have addressed capacitances of polyaniline (PANI) obtained by enzymatic polymerization. PANI was synthesized in an aqueous system containing aniline, horseradish peroxidase isoenzyme C (HRPC)/hydrogen peroxide (H2O2) as catalyst/oxidant, and 80-100 nm-sized vesicles formed from sodium bis(2-ethylhexyl) sulfosuccinate (AOT). The vesicles served as templates to produce PANI in its emeraldine salt (ES) form. Electrochemical properties of the obtained material were investigated using cyclic voltammetry and galvanostatic charge/discharge experiments. Under galvanostatic conditions and the current load of 1 A g−1 a specific capacitance of 770 F g−1 was measured in 0.5 M H2SO4 solution. We observed that the presence of AOT vesicles in the reaction mixture is crucial for the synthesized polymer product to exhibit redox activity. The applied mild enzymatic PANI-ES synthesis procedure led to a highly stable and processable PANI-AOT vesicle suspension which can be applied directly for the production of active electrodes without any isolation and purification of the reaction products. We believe that the presented results can open a new perspective in the production of conductive polymers for application in electrochemical capacitors.

Individual differences in fear relapse

Vulnerability to anxiety disorders might be due to enhanced acquisition of aversive associations, impaired inhibition of those associations (extinction), and/or vulnerability to the return of fear (relapse). Animal research investigating the processes underpinning fear learning, extinction, and relapse will be critical to further advancing our understanding of anxiety disorders and their treatment. Here we examined whether individual differences in the rate of extinction might be related to vulnerability to relapse. Relapse of fear was examined by testing animals for conditioned freezing using renewal, reinstatement, and spontaneous recovery procedures. Across all three experiments we found that when tested under “milder” relapse conditions (in a novel context, after a mild reinstatement procedure, or 8 days after extinction training) Slow Extinguishers exhibited relapse of fear whereas Fast Extinguishers did not. However, when tested under “stronger” relapse conditions (in the training context, after a strong reinstatement procedure, or 29 days after extinction training) both Fast and Slow Extinguishers exhibited comparable relapse of fear. These results show that Slow Extinguishers are more vulnerable to relapse than Fast Extinguishers. These findings have clinical implications for identifying those most at risk of relapse following treatment and highlight the importance of developing further strategies to reduce relapse.

A synthetic route to novel 3-substituted-2,1-benzisoxazoles from 5-(2-nitrobenzylidene)(thio)barbiturates

2,1-Benzisoxazoles, also called anthranils, are one of the two types of aromatic bicyclic heterocycles having a benzene ring fused with an isoxazole, which are particularly recognized as valuable intermediates in organic synthesis. Nevertheless several methods can be found in the literature to prepare 2,1-benzisoxazoles, we herein report a new, efficient, simple, mild, and alternative procedure to prepare 3-substituted-2,1-benzisoxazoles from 5-(2-nitrobenzylidene)barbiturates in moderate to good yields (51–82%). All the novel benzisoxazoles showed spectral data fully consistent with the assigned structures, which were unequivocally confirmed by single crystal X-ray analysis. A possible mechanism of the reaction is proposed. In addition, a screening of the bioactivity of these benzisoxazoles as xanthine oxidase inhibitors, antioxidants, and cytotoxic compounds was performed. The benzisoxazole formed from barbituric acid revealed moderate xanthine oxidase inhibitory effects (IC 50 = 22.10 μM).

Public health risk assessment with bioaccessibility considerations for soil PAHs at oil refinery vicinity areas in India

Populations living in the vicinity of oil refinery sludge deposition sites may be at greater risk of potential exposure to polycyclic aromatic hydrocarbons (PAHs) through inhalation, ingestion, and direct contact with contaminated media. Three Indian oil refinery sludge deposition sites (at Haldia, Barauni and Guwahati) were chosen for study. Soil samples were collected from three different locations at each site. Mild solvent extraction by butanol and exhaustive extraction by acetone/hexane have been conducted to estimate the bioaccessible PAHs beside the total extractable PAHs content of the soil samples. Concentrations of 13 PAHs in the soils were found to be in a range of 67.02–95.21μg/g and bioaccessible PAHs were in a range of 19.296–36.657μg/g. A probabilistic health risk assessment with bioaccessibility considerations was carried out using Monte Carlo simulations for the estimation of the cancer risk exposed to the PAHs. The 90th percentiles cancer risks with bioaccessibility considerations of soil PAHs for children is 6.506E−05 and for the adults the risk is 6.609E−05. Risk assessments on extracted PAHs from exhaustive solvent extraction can overestimate the risk by 2.87–2.89 folds at 90% confidence level with respect to the biomimetic mild extraction procedure using butanol. According to USEPA above 1×10−6 extra risk of cancer is an alarm towards management. So, public health issues due to PAHs is imminent in these oil refinery vicinity areas. Sensitivity analysis revealed exposure duration (ED) and relative skin adherence factor for soil (AF) as the most influential parameters of the assessment. The profiling and risk assessment study with bioaccessibility considerations of PAHs from soil indicates that high PAHs concentration can lead to higher cancer risk for the vicinity area residents and local government should take immediate management actions.