Molecular structures and dynamics of the stepwise activation mechanism of a matrix metalloproteinase zymogen: challenging the cysteine switch dogma

Activation of matrix metalloproteinase zymogen (pro-MMP) is a vital homeostatic process, yet its molecular basis remains unresolved. Using stopped-flow X-ray spectroscopy of the active site zinc ion, we determined the temporal sequence of pro-MMP-9 activation catalyzed by tissue kallikrein protease in milliseconds to several minutes. The identity of three intermediates seen by X-ray spectroscopy was corroborated by molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. The cysteine-zinc interaction that maintains enzyme latency is disrupted via active-site proton transfers that mediate transient metal-protein coordination events and eventual binding of water. Unexpectedly, these events ensue as a direct result of complexation of pro-MMP-9 and kallikrein and occur before proteolysis and eventual dissociation of the pro-peptide from the catalytic site. Here we demonstrate the synergism among long-range protein conformational transitions, local structural rearrangements, and fine atomic events in the process of zymogen activation.     

Design, synthesis, and evaluation of a mechanism-based inhibitor for gelatinase A

[structure: see text] Matrix metalloproteinases (MMPs), of which 26 are known, have been implicated in a number of pathological conditions, including tumor metastasis. We have previously described the first mechanism-based inhibitor for MMPs (J. Am. Chem. Soc. 2000, 122, 6799-6800), which in chemistry mediated by the active site zinc ion selectively and covalently inhibits MMP-2, -3, and -9. Computational analyses indicated that this selectivity in inhibition of MMPs could be improved by design of new variants of the inhibitor class. We report herein the syntheses of methyl 2-(4-{4-[(2-thiiranylpropyl)sulfonyl]phenoxy}phenyl)acetate (3) and 2-(4-{4-[(2-thiiranylpropyl)sulfonyl]phenoxy}phenyl)acetic acid (4), and show that compound 3 serves as a mechanism-based inhibitor exclusively for MMP-2. This molecule should prove useful in delineating the functions of MMP-2 in biological systems.     

Investment optimization on port’s development by fuzzy integer programming

In this research, the main purpose is to formulate a model to determine the optimum investment on port development from national investment prospective; on the other hand, costs and benefits are calculated from consumer and investor’s viewpoint. The formulated model is an integer-programming model. The emphasis is on how to formulate an investment optimization problem where cargo operation, investment costs, cargo-handling capacity, cargo transportation network, and the world maritime fleet constraints are included. Fuzzy numbers are used for cargo forecast study results. The output of the model is the type of design ships and design berths which are needed in each sub period, so that the port planner (the government) will find out the optimum development plan of port in each sub period when there is uncertainty in cargo handling forecast (fuzzy numbers).     

Key side products due to reactivity of dimethylmaleoyl moiety as amine protective group

Dimethylmaleoyl (DMM) moiety has become an important amine protective group in sugar chemistry. We disclose herein that DMM-containing D-glucosamine analogues, because of their electrophilic nature, are prone to reactions with strong nucleophiles, such as hydrazine, resulting in a set of undesired side products that are difficult to detect, yet proved to be problematic for organic synthesis.     

Diamond-Free Subsets in the Linear Lattices

Four distinct elements a, b, c, and d of a poset form a diamond if \(a< b and \(a . A subset of a poset is diamond-free if no four elements of the subset form a diamond. Even in the Boolean lattices, finding the size of the largest diamond-free subset remains an open problem. In this paper, we consider the linear lattices—poset of subspaces of a finite dimensional vector space over a finite field of order q—and extend the results of Griggs et al. (J. Combin. Theory Ser. A 119(2):310–322, 2012) on the Boolean lattices, to prove that the number of elements of a diamond-free subset of a linear lattice can be no larger than \(2+\frac {1}{q+1}\) times the width of the lattice, so that this fraction tends to 2 as \(q \longrightarrow \infty \) . In addition, using an algebraic technique, we introduce so-called diamond matchings, and prove that for linear lattices of dimensions up to 5, the size of a largest diamond-free subset is equal to the sum of the largest two rank numbers of the lattice.     

Mixed mode axisymmetric annular cracks in a finite layer: Off angle crack initiation

The solutions of axisymmetric Volterra type climb and glide edge dislocations are obtained in a layer by means of the Hankel transforms. Utilizing the same procedure, Green’s function solution is obtained for a layer under self-equilibration normal ring traction. The distributed dislocation technique is used to construct integral equations for a system of co-axial annular cracks where the layer is under axisymmetric normal loads. These equations are solved numerically to obtain dislocation density on the cracks surfaces. The results are employed to determine stress intensity factors for annular and penny-shaped cracks and the interaction between two co-axial penny-shaped cracks is studied. Moreover, the stress intensity factors of the interacting cracks are determined such that they can be further used in conjunction with strain energy density (SED) failure criterion to obtain the possible direction of crack initiation that may not be apparent under mixed mode conditions.     

An experimental and numerical investigation of the dynamics of microconfined droplets in systems with one viscoelastic phase

The dynamics of single droplets in a bounded shear flow is experimentally and numerically investigated for blends that contain one viscoelastic component. Results are presented for systems with a viscosity ratio of 1.5 and a Deborah number for the viscoelastic phase of 1. The numerical algorithm is a volume-of-fluid method for tracking the placement of the two liquids. First, we demonstrate the validation of the code with an existing boundary integral method and with experimental data for confined systems containing Newtonian components. This is followed by numerical simulations and experimental data for the combined effect of geometrical confinement and component viscoelasticity on the droplet dynamics after startup of shear flow at a moderate capillary number. The viscoelastic liquids are Boger fluids, which are modeled with the Oldroyd-B constitutive model and the Giesekus model. Confinement substantially increases the viscoelastic stresses and the elongation rates in and around the droplet. We show that the latter can be dramatic for the use of the Oldroyd-B model in confined systems with viscoelastic components. A sensitivity analysis for the choice of the model parameters in the Giesekus constitutive equation is presented.     

Introducing a modified gradient vector method for optimization of accident prediction non-linear functions

In this paper, a new optimization method has been proposed for accident prediction non-linear models. This has been achieved by eliminating the Hessian matrix from the equation of optimal pace length in the gradient vector method. One advantage is that it is independent of the starting point in optimization processes and it provides convergence at the highest top as well. This method has been tested on an accident prediction model and its preference over the gradient vector method has been proven.     

Chromone and flavonoid alkaloids: occurrence and bioactivity

The chromone and flavonoid alkaloids represent an unusual group of structurally diverse secondary metabolites, derived from the convergence of multiple biosynthetic pathways that are widely distributed through the plant and animal kingdoms. Many of them have been discovered through bioassay-guided chemical investigations of traditional medicines, suggesting potential therapeutic significance. Their unique structures and varied pharmacological activities may provide important new leads for the discovery of drugs with novel mechanisms of action. Potential therapeutic indications are as diverse as cancer and viral infections, inflammation and immunomodulation, neurological and psychiatric conditions, and diabetes.