Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design

LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different gram-negative pathogens. We report that inhibitors with a diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale. These observations highlight the need for a molecular understanding of inherent structural features and conformational plasticity of LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics against gram-negative infections.     

Anion induced diversification from heptanuclear to tetranuclear clusters: syntheses, structures and magnetic properties

Three new polynuclear complexes, [Co(7)(bm)(12)]·(ClO(4))(2)·13H(2)O (1), [Co(4)(bm)(4)Cl(4)(C(3)H(7)OH)(4)] (2), and [Co(4)(bm)(4)(μ-HCO(2))(2)(μ(2)-HCO(2))(2)(C(3)H(7)OH)(2)] (3) (Hbm = (1H-Benzimidazol)-methanol), have been synthesized and characterized by elemental analysis, IR, powder X-ray diffraction and X-ray single-crystal diffraction. Compound 1 features a centrosymmetric wheel-like heptanuclear Co(II) cluster. Compound 2 having a I4(1)/a space group exhibits a tetranuclear Co(II) cluster with a cubane topology in which the central Co(II) ion and oxygen atoms from bm occupy the alternate vertices of the cube. However, compound 3 has a tetranuclear Co(II) cluster with a C2/c space group different from that of compound 2. These results show that the geometries and sizes of the corresponding anions as well as their coordinating and hydrogen-bonding properties are essential in determining the final structures of the assemblies. Magnetic properties of 1-3 in the 2-300 K have also been discussed. The {Co(7)} (1) and {Co(4)} (2) cores display dominant ferromagnetic interactions while the {Co(4)} (3) core displays dominant anti-ferromagnetic interactions.     

Interplay of olefin metathesis and multiple hydrogen bonding interactions: covalently cross-linked zippers

Hydrogen-bonded zippers bearing terminal alkene groups were treated with Grubbs' catalyst, leading to covalently cross-linked zippers without violating H-bonding sequence specificity. The yield of a cross-linked zipper depended on the stability of its H-bonded precursor, with a weakly associating pair giving reasonable yields only at high concentrations while strongly associating pairs showed nearly quantitative yields. The integration of thermodynamic (H-bonding) and kinetic (irreversible C═C bond formation) processes suggests the possibility of developing many different covalent association units for constructing molecular structures based on a self-assembling way.     

Fe3O4 nanoparticle-supported copper(I) pybox catalyst: magnetically recoverable catalyst for enantioselective direct-addition of terminal alkynes to imines

An Fe(3)O(4) nanoparticle-supported copper(I) pybox catalyst, which exhibits excellent reactivity and yields products with good enantioselectivity, was developed. As a proof of concept, six optically active propargyl amines were obtained in excellent yields. The catalyst can be magnetically removed and recycled easily six times without a decrease in activity or enantioselectivity.     

Folding-promoted TBACl-mediated chemo- and regioselective demethylations of methoxybenzene-based macrocyclic pentamers

Tetrabutylammonium chloride (TBACl) salt alone has not been shown previously to be capable of removing methoxy groups. It is demonstrated here that the use of TBACl achieves efficient folding-promoted chemo- and regioselective demethylations, eliminating up to two out of five methyl groups situated in similar macrocyclic chemical microenvironments.     

Bilayer matrix composed of polycation/DNA complex and sodium alginate gel as a tumor cell catcher

A bilayer matrix consisting of TABP-SS/DNA complexes and sodium alginate gel is formed via electrostatic interaction. In vitro cell adhesion, proliferation and transfection of the bilayer matrix are investigated in HepG2, HeLa and COS7 cells. Results show that this matrix can only promote tumor cell attachment and growth. Compared with normal cells, the bilayer matrix exhibits significantly higher transfection efficacy in tumor cells. Cell co-culture competitive transfection assay shows that the cell uptake of TABP-SS/DNA complexes is significantly enhanced in tumor cells rather than normal cells under the co-culture competitive condition, which confirms that TABP-SS/DNA complexes have strong tumor cell selectivity and tumor targeting transfection ability.     

A link-free method for testing the significance of predictors

One important step in regression analysis is to identify significant predictors from a pool of candidates so that a parsimonious model can be obtained using these significant predictors only. However, most of the existing methods assume linear relationships between response and predictors, which may be inappropriate in some applications. In this article, we discuss a link-free method that avoids specifying how the response depends on the predictors. Therefore, this method has no problem of model misspecification, and it is suitable for selecting significant predictors at the preliminary stage of data analysis. A test statistic is suggested and its asymptotic distribution is derived. Examples are used to demonstrate the proposed method.     

Incomplete quenching of heat equations with coupled singular logarithms boundary fluxes

This paper deals with quenching phenomena for a heat equations with coupled singular logarithms boundary fluxes. Under appropriate hypotheses, the non-simultaneous quenching of the solution for the system is proved, and the estimates of quenching rates are given. Then we give a natural continuation of the solution (u,v) after the quenching time when the equations occurs non-simultaneous quenching. Moreover, we identify the heat equations verified by the continuation beyond quenching time, i.e., the equations occurs incomplete quenching.     

Convergence analysis and performance of the extended artificial physics optimization algorithm

This paper presents extended artificial physics optimization (EAPO), a population-based, stochastic, evolutionary algorithm (EA) for multidimensional search and optimization. EAPO extends the physicomimetics-based Artificial Physics Optimization (APO) algorithm by including each individual’s best fitness history. Including the history improves EAPO’s search capability compared to APO. EAPO and APO invoke a gravitational metaphor in which the force of gravity may be attractive or repulsive, the aggregate effect of which is to move individuals toward local and global optima. A proof of convergence is presented that reveals the conditions under which EAPO is guaranteed to converge. Discrete-time linear system theory is used to develop a second-order difference equation for an individual’s stochastic position vector as a function of time step. Stable solutions require eigenvalues inside the unit circle, leading to explicit convergence criteria relating the run parameters {m_i, w, G}. EAPO is tested against several benchmark functions with excellent results. The algorithm converges more quickly than APO and with better diversity.     

模糊有界变差函数全变差的积分表示与距离导数

定义和讨论了模糊数值函数的距离导数,给出了模糊有界变差函数全变差的积分表示.发现模糊绝对连续函数是几乎处处距离可导的,距离导数的积分等于其原函数的总变差,从而给出了模糊有界变差函数全变差的积分表示.