Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q² (cross-validated correlation coefficient) = 0.557, R²_ncv (non-cross-validated correlation coefficient) = 0.740, R²_pre (predicted correlation coefficient) = 0.749 and Q² = 0.598, R²_ncv = 0.767, R²_pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.     

Comparative molecular profiling of the PPARα/γ activator aleglitazar: PPAR selectivity, activity and interaction with cofactors

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, through heterodimerization with retinoid X receptor and complex formation with various cofactors. Drugs or treatment regimens that combine the beneficial effects of PPARα and γ agonism present an attractive therapeutic strategy to reduce cardiovascular risk factors. Aleglitazar is a dual PPARα/γ agonist currently in phase III clinical development for the treatment of patients with type 2 diabetes mellitus who recently experienced an acute coronary event. The potency and efficacy of aleglitazar was evaluated in a head-to-head comparison with other PPARα, γ and δ ligands. A comprehensive, 12-concentration dose-response analysis using a cell-based assay showed aleglitazar to be highly potent, with EC(50) values of 5 nM and 9 nM for PPARα and PPARγ, respectively. Cofactor recruitment profiles confirmed that aleglitazar is a potent and balanced activator of PPARα and γ. The efficacy and potency of aleglitazar are discussed in relation to other dual PPARα/γ agonists, in context with the published X-ray crystal structures of both PPARα and γ.     

Insight into pyrolysis of hydrophobic silica aerogels: Kinetics,reaction mechanism and effect on the aerogels

Silica aerogels have promising applications in thermal insulation, but their flammability and reaction mechanisms have rarely been investigated. The pyrolysis kinetics and thermodynamics of hydrophobic silica aerogels under N₂ environment were studied. The kinetic and thermodynamic parameters were obtained by three model-free methods. Based on the calculated kinetic parameters, the pyrolysis mechanism of silica aerogels was discussed by the master plots method. The results indicate th...     

Insight into the synthesis and thermomechanical properties of “short-long” type biobased aliphatic polyesters

A series of biobased “short-long” chain aliphatic polyesters having high molecular weight were successfully synthesized using dimethyl sebacate and diols with different carbon chain lengths via a two-step melt-polycondensation method by using titanium butoxide as a catalyst. The diols chain length and its odd-even effect on the structure–property relationship, crystallinity, and thermomechanical properties of the polyesters were systemically investigated. The synthesized polyesters displayed weight-average molecular weight between 23,600 to 72,900 g/mol and a maximum intrinsic viscosity of 0.933 dL/g. With increasing the diol chain length, the molecular weight of the polyesters increased linearly, except for poly(butylene sebacate) (PBS). Altogether, the “odd-even” effect of the diol chain on the crystalline (T_c)/melting temperature (T_m), and melting/ crystallization enthalpies of the polyester's were observed. Poly(pentylene sebacate) (PPeS) has the highest weight-average molecular weight of 72,900 Da, T_m of ∼55.4°C, degradation temperature (T_d,max) of about 404°C, and highest storage modulus (E′ at 25°C) of 661 MPa compared to other short-chain polyesters. PBS and PPeS showed the appearance of sharp intensity peaks from XRD diffraction patterns, indicating higher crystallinity in the material, in accordance with crystallization enthalpies (ΔH_c) values from the differential scanning calorimetry (DSC) thermograms. These fabricated biobased polymers with 100% bio-content, low melting temperature range, rapid crystallization, and high thermal stability suggest good processability and can offer an alternative option to nonrenewable thermoplastic polyesters for potential applications.     

Ceria and Gold/Ceria Catalysts for the Abatement of Polycyclic Aromatic Hydrocarbons: An In Situ DRIFTS Study

Gold catalysts supported on nano-crystalline ceria prepared by deposition precipitation have been characterised and tested for the total oxidation of naphthalene. Two different precipitation methods were used to prepare the nano-crystalline ceria supports and it was observed that although both supports were active materials for naphthalene oxidation, ceria synthesized by homogeneous precipitation with urea was markedly more active than CeO₂ precipitated by carbonate. The addition of gold to both active CeO₂ catalysts resulted in different effects for the total oxidation of naphthalene. Gold addition promotes the naphthalene conversion to CO₂ when ceria is prepared by precipitation with carbonates, whilst the light off temperature is shifted towards higher temperatures when gold is added to ceria synthesized by the urea method. This behaviour has been related to a change in the support characteristics and a removal of the carbonate surface species, when gold is deposited onto the ceria support.     

Mechanistic Exploration of Methionine 274 Acting as a “Switch” of the Selective Pocket Involved in HDAC8 Inhibition: An in Silico Study

The overexpression of histone deacetylase 8 (HDAC8) causes several diseases, and the selective inhibition of HDAC8 has been touted as a promising therapeutic strategy due to its fewer side effects. However, the mechanism of HDAC8 selective inhibition remains unclear. In this study, flexible docking and in silico mutation were used to explore the structural change of methionine (M274) during HDAC8 binding to inhibitors, along with the reason for this change. Meanwhile, steered and conventional molecular dynamics simulations were employed to explore the stability of the structural change. The findings suggest that M274 acts as a “switch” to control the exposure of the HDAC8-selective pocket. The structure of M274 changes from flipped-out to flipped-in only when L-shaped inhibitors bind to HDAC8. This structural change forms a groove that allows these inhibitors to enter the selective pocket. In other HDACs, a leucine residue replaces M274 in situ, and the same structural change is not observed. The findings reveal the mechanism of selective HDAC8 inhibition and provide guidance for the development of novel selective inhibitors.     

The Use of Thermodynamic and Kinetic Data in Drug Discovery: Decisive Insight or Increasing the Puzzlement?

The prime property to rate the success of hit‐to‐lead‐to‐drug optimization in drug discovery is binding affinity. Rational approaches try to relate this property with structure. Affinity can be linked to the thermodynamic property, Gibbs free energy of binding, which itself factorizes into enthalpy and entropy. With respect to kinetic properties, affinity can be associated with the ratio of k_off and k_on of complex formation. Do these features help to obtain better insight into affinity? The present viewpoint assesses our current understanding of thermodynamics– or kinetics–structure relationships and questions the accuracy of data collected to learn about the thermodynamic and kinetic basis to comprehend affinity.     

Electronic and Steric Control of n→π* Interactions: Stabilization of the α-Helix Conformation without a Hydrogen Bond

The preferred conformations of peptides and proteins are dependent on local interactions that bias the conformational ensemble. The n→π* interaction between consecutive carbonyls promotes compact conformations, including the α-helix and polyproline II helix. In order to further understand the n→π* interaction and to develop methods to promote defined conformational preferences through acyl N-capping motifs, a series of peptides was synthesized in which the electronic and steric properties of the acyl group were modified. Using NMR spectroscopy, van't Hoff analysis of enthalpies, X-ray crystallography, and computational investigations, we observed that more electron-rich donor carbonyls (pivaloyl, iso-butyryl, propionyl) promote stronger n→π* interactions and more compact conformations than acetyl or less electron-rich donor carbonyls (methoxyacetyl, fluoroacetyl, formyl). X-ray crystallography indicates a strong, electronically tunable preference for the α-helix conformation, as observed directly on the φ and ψ torsion angles. Electron-donating acyl groups promote the α-helical conformation, even in the absence of the hydrogen bonding that stabilizes the α-helix. In contrast, electron-withdrawing acyl groups led to more extended conformations. More sterically demanding groups can promote trans amide bonds independent of the electronic effect on n→π* interactions. Chloroacetyl groups additionally promote n→π* interactions through the interaction of the chlorine lone pair with the proximal carbonyl π*. These data provide additional support for an important role of n→π* interactions in the conformational ensemble of disordered or unfolded proteins. Moreover, this work suggests that readily incorporated acyl N-capping motifs that modulate n→π* interactions may be employed rationally to promote conformational biases in peptides, with potential applications in molecular design and medicinal chemistry.     

Selective Oxidation of Ethane Over Mo–V–Al–O Oxide Catalysts: Insight to the Factors Affecting the Selectivity of Ethylene and Acetic Acid and Structure-activity Correlation Studies

Catalysts of general formula, MoVAlO _x were prepared with the initial elemental composition of 1:0.34:0.167 (Mo:V:Al) at a pH value in the range of 1–4. The elemental analysis showed that the final composition of the catalysts is pH dependant. The performance of the catalysts was tested for selective oxidation of ethane to give ethylene and acetic acid. While all of them were active for ethane oxidation with a moderate conversion, the catalyst prepared at pH 2 showed a highest activity with 23% ethane conversion and a combined selectivity of 80.6% to ethylene and acetic acid. The catalyst prepared at pH 4 was least selective to ethylene and acetic acid. Various techniques like powder XRD, SEM, Raman, UV–Vis and EPR were used to characterize the catalysts and to identify the active phases responsible for the selective oxidation of ethane. The powder XRD data showed that the catalysts prepared at pH 1 and 2 contain mainly of MoO₃ and MoV₂O₈ along with traces of Mo₄O₁₁. The amount of MoO₃ was slightly higher in the catalyst prepared at pH 1. However, the catalyst prepared at pH 3 contains mainly of MoV₂O₈ with no trace of MoO₃. The catalyst prepared at pH 4 showed V₂O₅ as the major phase along with MoVAlO₄ phase. The Raman data corroborated the XRD results. EPR and UV–Vis studies indicated the presence of traces of V⁴⁺ in pH 1 and 2 catalysts and significant amount of Mo⁵⁺ in all the catalysts. Thus, the high activity and selectivity to ethylene and acetic acid are attributed to the presence of MoV₂O₈ phase and other reduced species like Mo₄O₁₁ phase supported on MoO₃. The presence of V and Mo ions in a partially reduced form seems to play a crucial role in the selective oxidation of ethane.     

Mineralization of the Pharmaceutical β-Blocker Atenolol by Means of Indirect Electrochemical Advanced Oxidation Process: Parametric and Kinetic Study

Atenolol is a β-blocker that can be found in urban wastewaters and which is not removed efficiently by conventional wastewater treatments. In the present study, electro-Fenton (EF) process was used to assess the degradation and mineralization of pharmaceutical atenolol in aqueous solutions. Electrolyses of 250 mL of atenolol solution (0.17 mM), at initial pH 3, were carried out in an undivided electrolytic cell in galvanostatic mode. Influence of material cathode (graphite, stainless steel, and platinized titanium), applied current (100–500 mA), sulfate dosage (0.01–0.5 M), and catalyst ferrous ions concentration (1–10 mM), on the oxidation efficiency was studied. Atenolol mineralization was monitored by COD dosage. Kinetic analysis indicated that atenolol mineralization followed a pseudo-first order model and the rate constant increased with rising current, ferrous ions concentration (up to 5 mM) and electrolyte concentration. Results showed that graphite cathode, 0.5 M Na₂SO₄ electrolyte, 0.3 A and 5 mM FeSO₄ catalyst were the best conditions for atenolol mineralization. In these optimal conditions, after 240 min more than 87% of the initial COD was removed. The corresponding current efficiency (CE) and specific energy consumption (SEC) were 22.33% and 0.194 kWh/kg COD, respectively. This latter corresponds to 0.078 kWh/m³ of treated wastewater.     

MAS NMR, ESR and TPD studies of Mo/HZSM‐5 catalysts: evidence for the migration of molybdenum species into the zeolitic channels

NH₃‐TPD, MAS NMR and ESR spectroscopies were employed to investigate Mo‐modified HZSM‐5 catalysts prepared by impregnation. It was found that the modification of Mo ions results in a pronounced decrease in the intensity of ¹H MAS NMR resonance originating from Brønsted acid sites in the zeolites and a distinct splitting of Mo⁵⁺ ESR signals, which is attributed to the interaction of Mo with the Al atom of the zeolite framework. This presents distinct evidence that Mo ions migrate from the external surface of the zeolite into the lattice channels during the impregnation and subsequent treatment. The remaining Brønsted acid sites associated with the migrated Mo ions form the bifunctional catalytic centers that may be responsible for the outstanding catalytic performance in methane aromatization.     

Reduction of phosphogypsum for SO2 production: Insights into the release characteristics of SO2 following the solid–solid reaction of CaS and CaSO4 under different atmospheres

Phosphogypsum (PG) severely pollutes the environment and is difficult to recycle. PG is primarily composed of CaSO₄ · 2H₂O. In this study, the characteristics of SO₂ released from the solid–solid reaction between calcium sulphide (CaS) and CaSO₄ were thoroughly investigated using thermodynamic calculations. Experiments were performed by tuning the molar ratio of CaS to CaSO₄, reaction atmosphere (S, CH₄, N₂, and air), and the heating rate. As shown by the phase diagram, high reaction temperatures favour CaO stability, and the corresponding maximum SO₂ equilibrium partial pressure increases. The total SO₂ production significantly increased with increasing molar ratio and slightly increased when the ratio exceeded 1:3. The SO₂ productions were ranked from highest to lowest as follows: S, CH₄, N₂, CO, and air. The total SO₂ production decreased with increasing heating rate. For the reaction between CaS and CaSO₄, a higher molar ratio of CaS to CaSO₄ no less than 1:3, both S and CH₄ reductive atmospheres, and a lower heating rate (2°C/min) favour the total SO₂ emission.     

Cationic Micelles Modulated in the Presence of α,ω-Alkanediols: A SANS,NMR and Conductometric Study

The solution behavior of a typical cationic surfactant, tetradecyltrimethylammonium bromide, in mixed solvent systems composed of water and varying concentrations of α,ω-alkanediols; 1,2-ethanediol (ED), 1,4-butanediol (BD), 1,6-hexanediol (HD) and 1,8-octanediol (OD) was examined via electrical conductance measurements, ¹³C-NMR spectroscopy and small angle neutron scattering (SANS) measurements. The critical micelle concentration (CMC) values and degree of counterion dissociation (α) indicate that both ED and BD oppose micellization, whereas HD and OD enhance micelle formation. Changes in the ¹³C-NMR chemical shifts (∆δ values) reveal that the short chain diols reside almost exclusively in the bulk phase and hence, affect the formation of micelles by altering the solvent properties in the bulk of the solution, whereas HD and OD partition between the pseudomicellar phase and the bulk phase. SANS studies indicated that both the micellar size and aggregation number (N _agg) decrease in the presence of all diols. ED and BD behave like cosolvents and increase the α and CMC values and decrease N _agg. We note that the effect of HD and OD on the properties of the micelles is concentration dependent; at low concentrations, these diols interact with the micelles and behave as cosurfactants (as evidenced by the trends in the micellar properties), while at higher concentrations, they enhance the surfactant solubility and behave as a cosolvent.     

Study on the dewatering process for water treatment residuals: Applicability of freezing–thawing,compression, and electro-osmotic treatment

The applicability of freezing–thawing, compression, and electro-osmotic unit on dewatering water treatment residuals (WTRs) was studied through freezing–thawing conditioning followed by a pressurized electro-osmotic dewatering (PEOD) process. Results showed that 86.12% of bound water was released after freezing–thawing treatment at the optimum freezing temperature of ?10°C and duration of 22?h. At optimized mechanical pressure of 811?kPa and voltage of 30?V, the subsequent PEOD could lead to a water content of 58.70% in WTRs with estimated energy consumption of 0.107?kWh/kg (water removed), and free water was obviously removed by compression, while bound water content (BWC) remained stable. Moreover, freezing–thawing treatment remarkably reduced the PEOD duration from 200 to 20?min. Electro-osmotic treatment could accelerate dewatering rate and improve dewatering efficiency especially for raw WTRs. Therefore, direct compression on raw WTRs could be suited to warm regions, while natural freezing–thawing treatment combined with compression/electrical compression will be selected in cold regions.     

Stereo-Preference in the degradation of the erythro and threo isomers of β-O-4-type lignin model compounds in oxidation processes. part 2: In the reaction with hydroxyl and oxyl anion radicals under hydrogen peroxide bleaching conditions

We examined which isomer, the erythro or threo, of non-phenolic β-O-4-type lignin model compounds is stereo-preferentially attacked by hydroxyl radical and its conjugate base, oxyl anion radical, generated by the decomposition of hydrogen peroxide in the presence of ferric ion and its precipitates under hydrogen peroxide bleaching conditions. The intrinsic stereo-preference of oxyl anion radical was slightly toward the erythro isomer, while hydroxyl radical had a further smaller stereo-preference. These stereo-preferences can be explained by our prior knowledge that oxyl anion radical preferentially attacks the side-chain of the lignin model compounds rather than the aromatic nucleus. The amount of the degraded lignin model compounds became less great with decreasing pH, but reversely and intensively greater in the pH range below 10. This phenomenon can be attributed to the change in the decomposition mechanism of hydrogen peroxide accompanying the pH variation.     

Insights into the adsorption performance and mechanism of Cr(Ⅵ) onto porous nanocomposite prepared from gossans and modified coal interface:Steric,energetic,and thermodynamic parameters interpretations

Herein,iron oxide/hydroxides deposits(gossans) were utilized,for the first time,in the fabrication of magnetite nanoparticles(MNPs) to load modified coal(MC).The as-synthesized MNPs@MC composite was characterized via different techniques and utilized for the Cr(Ⅵ) remediation.Experimental studies supported by theoretical treatment were applied to offer a new overview of the Cr(Ⅵ) adsorption geometry and mechanism at 25-45℃.Experimental results suggested that the Cr(Ⅵ) uptake was mainly governed ...     

Structural evolution of H4PVMo11O40⋅xH2O during calcination and isobutane oxidation: New insights into vanadium sites by a comprehensive in situ approach

H₄PVMo₁₁O₄₀⋅8H₂O was studied during thermal activation as well as during isobutane oxidation by simultaneous in situ-EPR/UV–vis/Raman spectroscopy, in situ-FTIR spectroscopy, and quasi-in situ-¹H and -⁵¹V-MAS-NMR. In as-synthesized form, most V sites are pentavalent, octahedrally coordinated, and located within the intact Keggin anions. Stepwise dehydration in N₂ up to 350 °C leads to partial reduction and disintegration of the V sites from the Keggin units, followed by their condensation on the outer surface of the latter in square-pyramidal form. In water-free H₄PVMo₁₁O₄₀, only V⁵⁺ (not V⁴⁺) is stable inside the Keggin unit. Thus, disintegration of V from the latter is favored by its reduction to the tetravalent state and thus depends on the redox properties of the atmosphere. Active sites in isobutane oxidation are most likely composed of single O₄V^4+/5+O species connected to Mo⁶⁺ via oxygen bridges. Partial deactivation occurs by formation of carbon-containing deposits.     

Phylogenetic-Derived Insights into the Evolution of Sialylation in Eukaryotes: Comprehensive Analysis of Vertebrate β-Galactoside α2,3/6-Sialyltransferases (ST3Gal and ST6Gal)

Cell surface of eukaryotic cells is covered with a wide variety of sialylated molecules involved in diverse biological processes and taking part in cell–cell interactions. Although the physiological relevance of these sialylated glycoconjugates in vertebrates begins to be deciphered, the origin and evolution of the genetic machinery implicated in their biosynthetic pathway are poorly understood. Among the variety of actors involved in the sialylation machinery, sialyltransferases are key enzymes for the biosynthesis of sialylated molecules. This review focus on β-galactoside α2,3/6-sialyltransferases belonging to the ST3Gal and ST6Gal families. We propose here an outline of the evolutionary history of these two major ST families. Comparative genomics, molecular phylogeny and structural bioinformatics provided insights into the functional innovations in sialic acid metabolism and enabled to explore how ST-gene function evolved in vertebrates.     

Pollution Gradients and Chemical Characterization of Particulate Matter from Vehicular Traffic near Major Roadways: Results from the 2009 Queens College Air Quality Study in NYC

We present measurements of traffic-related pollutants made near the Long Island Expressway (LIE, I-495), in Queens, New York. The Aerodyne Research Inc. (ARI) mobile laboratory (AML) was deployed to map spatial and temporal gradients of gas-phase species and particulate matter (PM) associated with vehicular exhaust in the residential areas near the LIE. We observe that pollutant levels build up during the early morning hours under stable boundary layer conditions yet fall off quickly within 150 m downwind of the highway. An ARI soot particle aerosol mass spectrometer (SP-AMS) provided measurements of the size-resolved chemical composition of refractory black carbon (rBC) and the associated coating species. The average size distribution of the traffic related PM is characterized by a rBC mode centered at ～100 nm in vacuum aerodynamic diameter, D _va (rBC mass fraction ～50%). A second rBC mode (rBC mass fraction ～5%) more heavily coated with organic material is also observed at D _va ～500 nm. Positive matrix factorization (PMF) analyses of the traffic-related PM indicates that rBC is mostly associated with hydrocarbon-like organic (HOA) PM. These results are discussed in the context of chemically resolved size distributions and PMF analysis results performed on the SP-AMS stationary data collected at the Queens College site. Finally, we report emission indices (EI) for both fleet-average conditions and single vehicles, including several New York City Metropolitan Transit Authority (MTA) buses, sampled by the AML in “chase” mode during the study.

Copyright 2012 American Association for Aerosol Research