Structural Analysis of the Complex of Human Transthyretin with 3′,5′-Dichlorophenylanthranilic Acid at 1.5 Å Resolution

Human transthyretin (hTTR) can form amyloid deposits that accumulate in nerves and organs, disrupting cellular function. Molecules such as tafamidis that bind to and stabilize the TTR tetramer can reduce such amyloid formation. Here, we studied the interaction of VCP-6 (2-((3,5-dichlorophenyl)amino)benzoic acid) with hTTR. VCP-6 binds to hTTR with 5 times the affinity of the cognate ligand, thyroxine (T₄). The structure of the hTTR:VCP-6 complex was determined by X-ray crystallography at 1.52 Å resolution. VCP-6 binds deeper in the binding channel than T₄ with the 3′,5′-dichlorophenyl ring binding in the ‘forward’ mode towards the channel centre. The dichlorophenyl ring lies along the 2-fold axis coincident with the channel centre, while the 2-carboxylatephenylamine ring of VCP-6 is symmetrically displaced from the 2-fold axis, allowing the 2-carboxylate group to form a tight intermolecular hydrogen bond with Nζ of Lys15 and an intramolecular hydrogen bond with the amine of VCP-6, stabilizing its conformation and explaining the greater affinity of VCP-6 compared to T₄. This arrangement maintains optimal halogen bonding interactions in the binding sites, via chlorine atoms rather than iodine of the thyroid hormone, thereby explaining why the dichloro substitution pattern is a stronger binder than either the diiodo or dibromo analogues.     

Chemical Fractionations of Lead and Zinc in the Contaminated Soil Amended with the Blended Biochar/Apatite

Heavy metal contamination in agricultural land is an alarming issue in Vietnam. It is necessary to develop suitable remediation methods for environmental and farming purposes. The present study investigated the effectiveness of using peanut shell-derived biochar to remediate the two heavy metals Zn and Pb in laboratory soil assays following Tessier’s sequential extraction procedure. The concentration of heavy metals was analyzed using Inductively coupled plasma mass spectrometry (ICP-MS). This study also compared the effectiveness of the blend of biochar and apatite applied and the mere biochar amendment on the chemical fractions of Pb and Zn in the contaminated agricultural soil. Results have shown that the investigated soil was extremely polluted by Pb (3047.8 mg kg⁻¹) and Zn (2034.3 mg kg⁻¹). In addition, the pH, organic carbon, and electrical conductivity values of amended soil samples increased with the increase in the amendment’s ratios. The distribution of heavy metals in soil samples was in the descending order of carbonate fraction (F2) > residue fraction (F5) > exchangeable fraction (F1) > Fe/Mn oxide fraction (F3) > organic fraction (F4) for Pb and F5 ≈ F2 > F1 > F3 > F4 for Zn. The peanut shell-derived biochar produced at 400 °C and 600 °C amended at a 10% ratio (PB4:10 and PB6:10) could significantly reduce the exchangeable fraction Zn from 424.82 mg kg⁻¹ to 277.69 mg kg⁻¹ and 302.89 mg kg⁻¹, respectively, and Pb from 495.77 mg kg⁻¹ to 234.55 mg kg⁻¹ and 275.15 mg kg⁻¹, respectively, and immobilize them in soil. Amending the biochar and apatite combination increased the soil pH, then produced a highly negative charge on the soil surface and facilitated Pb and Zn adsorption. This study shows that the amendment of biochar and biochar blended with apatite could stabilize Pb and Zn fractions, indicating the potential of these amendments to remediate Pb and Zn in contaminated soil.     

Analytical study of comprehensive and targeted multidimensional gas chromatography incorporating modulated cryogenic trapping

This paper reports the results of an analytical study comparing capillary gas chromatography (GC) operated in the normal mode with 2 new GC techniques, comprehensive GC (GC x GC) and targeted (or selective) multidimensional GC, which use a longitudinally modulated cryogenic system (LMCS), recently developed in our laboratory. A high-temperature application of derivatized sterols, of interest in fecal pollution monitoring, was chosen for this work. A directly connected coupled-column ensemble was used, comprising a nonpolar column and a moderately polar column. With LMCS, effluent from the first column is zone-compressed in a cryogenic trap and then pulsed to a short second column, producing narrower peaks with sharp, tall peak responses at the detector. The modulator is operated at a constant frequency, e.g., 0.25 s(-1), to produce the GC x GC result, or is moved in a predefined manner so that whole peaks are selectively trapped and subsequently pulsed through to the second column in the targeted mode. Standard solutions containing a mixture of 7 sterols and 5-alpha-cholestane internal standard were used. Detection sensitivity is increased by a factor of >25 with the use of LMCS. The estimated limit of detection was about 0.1 microg/mL when normal GC with flame ionization detection (GC/FID) and a 1.0 microL splitless injection volume were used, compared with 0.02 and 0.004 microg/mL for the LMCS operated in GC x GC and selective modes, respectively. Calibration curves for GC/FID were linear over the 0.1-2.0 microg/mL range tested. Reproducibilities for the GC x GC and normal GC modes were comparable; generally, relative standard deviations (RSD) were on the order of 3-4%, based on raw peak responses. Improved reproducibility was found for selective LMCS operation, at an RSD of around 2%; with internal standardization, better results were achieved. The coupled-column arrangement allowed complete separation of sterol peaks from overlapping impurity peaks in a number of instances with LMCS modes, and its use should improve data quality over that of normal GC operation, in which the overlapping peaks interfere with measurement of peak response in the normal mode.     

Halogenated catechols from cycloaddition reactions of η-(2-ethoxyvinylketene)iron(0) complexes with 1-haloalkynes

1-Chloroalkynes and 1-bromohexyne undergo cycloaddition reactions with ethoxyvinylketeneiron(0) complexes to form chloro and bromocatechols. With most substituents, the halogen is incorporated ortho to the phenolic hydroxyl group regioselectively. With chloroethyne, chlorohexyne, and methyl chloropropiolate, the reverse regioselection is observed. Ab initio calculations reveal that the products are, in most cases, nearly isoenergetic, which indicates that the intermediate ketene-alkyne adduct geometry must be important in determining the product distribution.     

Kinetics of the hydrogen abstraction CHO + Alkane → HCHO + Alkyl reaction class: an application of the reaction class transition state theory

The kinetics of the hydrogen abstraction at alkanes by formyl radicals is investigated using the reaction class transition state theory (RC-TST) approach combined with the linear energy relationship (LER) or the barrier height grouping (BHG). The rate constants of a reaction in this class can be estimated through those of the reference reaction, CHO + C₂H₆, which are obtained from rate constants of the reaction that involves the smallest species, namely CHO + CH₄, using the explicit RC-TST scaling. The thermal rate constants of this smallest reaction are evaluated at the canonical variational transition state theory (CVT) with the corrections from the small-curvature tunneling (SCT) and hindered rotation (HR) treatments. Our analyses indicate that less than 40% systematic errors, on the average, exist in the predicted rate constants using both the LER approach, where only reaction energy is needed, and the BHG approach, where no additional information is needed; while comparing to explicit rate calculations the differences are less than 60%. Contribution to Mark S. Gordon 65th Birthday Festschrift Issue.     

Enantioselective Michael addition of diethyl cyanomethylphosphonate to chalcones using bifunctional cinchona-derived organocatalysts: synthesis of chiral precursors of α-substituted β-aminophosphonates

An enantioselective Michael addition of diethyl cyanomethyl phosphonate to chalcones catalysed by bifunctional catalysts based on cinchona alkaloids has been developed, producing enantiomerically enriched cyanophosphonate precursors of α-substituted β-aminophosphonates.     

Mechanisms of and effect of coadsorption on water dissociation on an oxygen vacancy of the MgO(100) surface

The dissociation mechanism of a water molecule at an oxygen vacancy on the MgO(100) surface was studied by using the embedded cluster method at the DFT/B3 LYP level, while the energetic information was refined by using the IMOMO method at the CCSD level. We found that a water molecule initially adsorbs on one of the magnesium ions surrounding the vacancy site with a binding energy of 15.98 kcal mol(-1). It then can dissociate on the MgO(100) surface along two possible dissociation pathways. One pathway produces a hydroxyl group bonded to the original magnesium with a proton filling the vacancy via a transition state with a barrier of 4.67 kcal mol(-1) relative to the adsorbed water configuration. The other pathway yields two hydroxy groups; the hydroxy group originally belonging to the water molecule fills the vacancy, while the hydrogen atom binds with the surface oxygen to form the other hydroxy group. Hydrogen atoms of these hydroxy groups can recombine to form a hydrogen molecule and the surface is healed. Although the barrier (14.09 kcal mol(-1)) of the rate-controlling step of the latter pathway is higher than that of the former one, the energies of all of its stationary points are lower than that of the separated reactants (H(2)O+cluster). The effects of water coadsorption are modeled by placing an additional water molecule near the active center, which suggests that the more coadsorbed water molecules further stabilize the hydroxy species and prevent the hydrogen molecule formation through the latter pathway. The results support the photoemission spectral evidence of water dissociation on the defective MgO(100) surface at low water coverage.     

Relative Pareto minimizers for multiobjective problems: existence and optimality conditions

In this paper we introduce and study enhanced notions of relative Pareto minimizers for constrained multiobjective problems that are defined via several kinds of relative interiors of ordering cones and occupy intermediate positions between the classical notions of Pareto and weak Pareto efficiency/minimality. Using advanced tools of variational analysis and generalized differentiation, we establish the existence of relative Pareto minimizers for general multiobjective problems under a refined version of the subdifferential Palais-Smale condition for set-valued mappings with values in partially ordered spaces and then derive necessary optimality conditions for these minimizers (as well as for conventional efficient and weak efficient counterparts) that are new in both finite-dimensional and infinite-dimensional settings. Our proofs are based on variational and extremal principles of variational analysis; in particular, on new versions of the Ekeland variational principle and the subdifferential variational principle for set-valued and single-valued mappings in infinite-dimensional spaces.     

On subelliptic manifolds

A smooth complex quasi-affine algebraic variety Y is flexible if its special group SAut(Y) of automorphisms (generated by the elements of one-dimensional unipotent subgroups of Aut(Y)) acts transitively on Y, and an algebraic variety is stably flexible if its product with some affine space is flexible. An irreducible algebraic variety X is locally stably flexible if it is a union of a finite number of Zariski open sets each of which is stably flexible. The main result of this paper states that the blowup of a locally stably flexible variety along a smooth algebraic subvariety (not necessarily equidimensional or connected) is subelliptic, and, therefore, it is an Oka manifold.     

The regularity and exponential decay of solution for a linear wave equation associated with two-point boundary conditions

This paper is concerned with the existence and the regularity of global solutions to the linear wave equation associated the boundary conditions of two-point type. We also investigate the decay properties of the global solutions to this problem by the construction of a suitable Lyapunov functional. Finally, we present some numerical results.