Poly(ADP-ribose)-polymerase-catalyzed hydrolysis of NAD+: QM/MM simulation of the enzyme reaction

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which uses NAD+ as substrate and catalyzes the transfer of multiple units of ADP-ribose to target proteins. PARP is an attractive target for the discovery of novel therapeutic agents and PARP inhibitors are currently evaluated for the treatment of a variety of pathological conditions such as brain ischemia, inflammation, and cancer. Herein, we use the PARP-catalyzed reaction of NAD+ hydrolysis as a model for gaining insight into the molecular details of the catalytic mechanism of PARP. The reaction has been studied in both the gas-phase and in the enzyme environment through a QM/MM approach. Our results indicate that the cleavage reaction of the nicotinamide-ribosyl bond proceeds through an SN2 dissociative mechanism via an oxacarbenium transition structure. These results confirm the importance of the structural water molecule in the active site and may constitute the basis for the design of transition-state-based PARP inhibitors.     

Kinetic Theories of Geodesic Acoustic Modes: Radial Structure,Linear Excitation by Energetic Particles and Nonlinear Saturation

Geodesic Acoustic Modes (GAMs) are oscillating zonal mode structures unique to toroidal plasmas and are capable of regulating microscopic turbulence and associated transports. In this paper, we investigate three important aspects of GAM dynamics: (1) GAM continuous spectrum and its mode conversion to kinetic GAM (KGAM); (2) linear excitation of energetic particle induced GAM (EGAM) and its coupling to the GAM continuum, and (3) nonlinear saturation of EGAM via wave particle trapping. The analogy between the GAM-EGAM dynamics and the well known beam-plasma instability is also discussed.     

Joint optimization of a flow-shop group scheduling with sequence dependent set-up times and skilled workforce assignment

Flow-shop sequence-dependent group scheduling (FSDGS) problem has been extensively investigated in the literature also due to many manufacturers who implemented the concept of group technology to reduce set-up costs, lead times, work-in-process inventory costs, and material handling costs. On the other hand, skilled workforce assignment (SWA) to machines of a given shop floor may represent a key issue for enhancing the performance of a manufacturing system. As the body of literature addressing the group scheduling problems ignored up to now the effect of human factor on the performance of serial manufacturing systems, the present paper moves in that direction. In particular, an M-machine flow-shop group scheduling problem with sequence-dependent set-up times integrated with the worker allocation issue has been studied with reference to the makespan minimization objective. First, a Mixed Integer Linear Programming model of the proposed problem is reported. Then, a well-known benchmark arisen from the literature is adopted to carry out an extensive comparison campaign among three properly developed metaheuristics based on a genetic algorithm framework. Once the best procedure among those tested is selected, it is compared with an effective optimization procedure recently proposed in the field of FSDGS problems, being this latter properly adapted to run the SWA issue. Finally, a further analysis dealing with the trade-off between manpower cost and makespan improvement is proposed.     

Metal complexes containing allenylidene and higher cumulenylidene ligands: a theoretical perspective

Transition metal complexes containing unsaturated carbenes have enjoyed a recent surge in research interest. In addition to showing potential as molecular wires and as components of opto-electronic materials, they provide multifaceted reactive sites for organic synthesis. In this Account, we describe results of recent theoretical studies that delineate the main features of electronic structure and bonding in allenylidenes and higher cumulenylidene complexes, [L(m)M]═C(═C)(n)═CR(1)R(2) (where L represents the ligand, M the metal, and n ≥ 1). Although free cumulenylidene ligands, :C(═C)(n)═CR(1)R(2), are extremely unstable and reactive species, they can be stabilized by coordination to a transition metal. The σ-donation of the electron lone pair on the terminal carbon atom to an empty metal d-orbital, together with the simultaneous π back-donation from filled metal d(π)-orbitals to empty cumulene π* system orbitals, leads to the formation of a strong M═C bond with multiple character. Density functional theory studies on the model systems [(CO)(5)Cr(═C)(n)CH(2)] and [trans-Cl(PH(3))(4)Ru(═C)(n)CH(2)](+) (where n = 1-9) have been useful in interpreting the structural and spectroscopic properties and the reactivity of this class of complexes. Geometry optimizations significantly contributed to the generalization of the sparse structural data available for allenylidene, butatrienylidene, and pentatetraenylidene complexes to higher cumulenylidene complexes (with up to eight carbon atoms in the chain), which show a clear structural trend. In particular, the geometries of all even-chain cumulenes are consistent with an almost purely cumulenic structure, whereas the geometries of odd-chain cumulenes present a significant polyyne-like carbon-carbon bond length alternation. The calculated bond dissociation energies (BDEs) of the cumulenylidene ligand remain almost constant on lengthening the cumulene chain. These BDEs indicate that there is no thermodynamic upper limit to the cumulene chain length and suggest that the synthetic difficulties in preparing higher cumulenylidenes are due to an increase in reactivity. The calculated charges on the carbon atoms show no significant polarization along the cumulene chain, indicating that charge distribution is not important in determining the regioselectivity of either electrophilic or nucleophilic attack, which is instead determined by frontier orbital factors. The breakdown of the contributions from the metal and the carbon atoms along the chain to the HOMO and LUMO shows that the HOMO has contributions mainly from the metal and the carbon atoms in even positions along the chain (C(2), C(4), C(6), and higher). In contrast, the LUMO has contributions mainly from the carbon atoms in odd positions along the chain (C(1), C(3), C(5), and higher), thus explaining the experimentally observed regioselectivity of electrophilic and nucleophilic attacks, which are directed, respectively, to even and odd positions of the cumulenylidene chain. The study of the electronic structure of cumulenylidenes has allowed us not only to give a consistent rationale for the main structural and spectroscopic properties and for the reactivity of this emerging class of compounds but also to predict the effect of ancillary ligands on the metal center or substituents on the carbon end. The result is a useful guide to new developments in the still-underexplored fields of this fascinating class of compounds.     

Probing thermomechanics at the nanoscale: impulsively excited pseudosurface acoustic waves in hypersonic phononic crystals

High-frequency surface acoustic waves can be generated by ultrafast laser excitation of nanoscale patterned surfaces. Here we study this phenomenon in the hypersonic frequency limit. By modeling the thermomechanics from first-principles, we calculate the system's initial heat-driven impulsive response and follow its time evolution. A scheme is introduced to quantitatively access frequencies and lifetimes of the composite system's excited eigenmodes. A spectral decomposition of the calculated response on the eigemodes of the system reveals asymmetric resonances that result from the coupling between surface and bulk acoustic modes. This finding allows evaluation of impulsively excited pseudosurface acoustic wave frequencies and lifetimes and expands our understanding of the scattering of surface waves in mesoscale metamaterials. The model is successfully benchmarked against time-resolved optical diffraction measurements performed on one-dimensional and two-dimensional surface phononic crystals, probed using light at extreme ultraviolet and near-infrared wavelengths.     

The photoinduced charge transfer mechanism in aligned and unaligned carbon nanotubes

Using time-resolved reflectivity measurements on unaligned and aligned bundled single-wall carbon nanotubes with a pump energy of 1.55 eV, quasi-resonant with the second Van Hove singularity of semiconducting tubes, a positive sign of the transient reflectivity is detected in unaligned nanotubes. In contrast a negative sign is detected in aligned nanotubes. This discovery addresses a long-standing question showing that in unaligned nanotubes the stronger intertube interactions favor the formation of short-lived free charge carriers in semiconducting tubes. A detailed analysis of the transient reflectivity spectral response shows that the free carriers in the photo-excited state of semiconducting tubes move towards metallic tubes in about 400 fs.     

Peer review research assessment: a sensitivity analysis of performance rankings to the share of research product evaluated

In national research assessment exercises that take the peer review approach, research organizations are evaluated on the basis of a subset of their scientific production. The dimension of the subset varies from nation to nation but is typically set as a proportional function of the number of researchers employed at each research organization. However, scientific fertility varies from discipline to discipline, meaning that the representativeness of such a subset also varies according to discipline. The rankings resulting from the assessments could be quite sensitive to the size of the share of articles selected for evaluation. The current work examines this issue, developing empirical evidence of variations in ranking due changes in the dimension of the subset of products evaluated. The field of observation is represented by the scientific production from the hard sciences of the entire Italian university system, from 2001 to 2003.     

Clogging in submerged entry nozzles

Casting high quality steel grades requires the use of a submerged entry nozzle (SEN) to prevent oxygen and nitrogen pick‐up and to achieve favourable steel flow conditions in the mould. Clogging of the SEN leads to instability of the casting operation as well as to a decrease in slab quality. To understand the interactions between liquid steel and the SEN, 156 nozzles from the Sidmar steel plant were investigated with respect to the amount of clogging. A linear relation between the clogging volume and the clogging weight was observed. This indicates that the clogging material's density remains constant during the clogging process for the different steel grades. A distinct relationship was also found between the amount of clogging and the cast steel weight. No relation between the amount of clogging and the superheating of the steel nor the steel flow rate was noticed, however. It was also concluded that for AI killed steels the high Mn (> 3000 ppm) and high C (> 500 ppm) grades cause less clogging than AI killed steel grades with low Mn content (< 3000 ppm) and that Al/Si killed steel grades cause less clogging when compared to AI killed steel grades. When comparing these different steel grades with respect to their total oxygen concentration in the ladle, it appears that steel grades, which have a low total oxygen concentration, cause less clogging in the SEN. Based on these observations three combinations SEN/steel grade were selected for further analysis with electron microscopy.     

Auctioning wind power sites when environmental quality matters

In this work, we propose an index that allows a public authority to order different projects for the construction of onshore wind energy plants and that explicitly takes into account their environmental quality. Wind farm projects are defined as vectors of four attributes: the technical properties of each project, its social impact, its environmental impact, and the share of earnings that proponents offer to the collectivity in compensation for the negative externalities of the wind plant. We define an absolute index that allows the ordering of different proposals and evaluation of the acceptability of each project, providing the monetary value of each point and inducing a truthful revelation of firms' private information. Moreover, we calibrate the index on the basis of data referring to wind plants in Southern Italy and derive the corresponding iso-scoring curves.