Maximum Alignment Research Articles

Pharmacophore Identification and Validation Study of CK2 Inhibitors Using CoMFA/CoMSIA

Protein kinase CK2, also known as casein kinase-2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase-2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three-dimensional quantitative structure-activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best-fitted model was identified and the same alignment was used for 3D-QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (R(2)(CV) = 0.58, R(2) = 0.82 and r(2)(pred) = 0.62) and the comparative molecular similarity index analysis (R(2)(CV) = 0.74, R(2) = 0.98 and r(2)(pred) = 0.81) gave reasonable results. Besides pharmacophore-based alignment, the maximum common substructure-based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore-based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H-bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring.

QSAR Studies of CYP2D6 Inhibitor Aryloxypropanolamines Using 2D and 3D Descriptors

Thirty six aryloxypropanolamine compounds with cytochrome 2D6 (CYP2D6) inhibitory activity were subjected to molecular shape analysis and molecular field analysis studies to explore the required molecular shape features as well as information on putative interactions with the active site of the enzyme. In addition to the 3D QSAR models, impact of two-dimensional (2D; thermodynamic, structural and topological including E-state parameters) descriptors towards the inhibitory activity was also studied. The whole data set was divided into training (n = 26) and test (n = 10) sets by K-means clustering technique. The chemometric tools used for molecular shape analysis and molecular field analysis were GFA and G/PLS techniques respectively. The G/PLS model derived in molecular field analysis using maximum common subgroup alignment was found to be the best model based on highest external (R(2)(pred) = 0.912) predictive power with lowest RMSEP value (0.363). The molecular field analysis-derived models suggest the requirement of U-shape conformation for optimum interactions as well as importance of different substituents on the aryloxypropanol fragment like indolylalkyl substituent. The molecular shape analysis models indicate the importance of distribution of positive and negative charges on the surface of the molecules. The QSAR models with 2D descriptors reveal the importance of bulk, branching and presence of different fragments.

STRATEGIC ALIGNMENT AND PURCHASING EFFICACY: AN EXPLORATORY ANALYSIS OF THEIR IMPACT ON FINANCIAL PERFORMANCE

Purchasing and supply management (PSM) has become a discipline of major strategic importance for effectively competing in today's global marketplace. Literature recognizes that the full value‐creation potential of the purchasing function can only be realized if its decisions and activities are aligned with the organization's overall strategic orientation. Despite general agreement on this matter, research and practice lacks knowledge on how exactly such an alignment can be achieved and what performance implications it has. Therefore, this article empirically investigates the alignment–performance link in PSM in a comprehensive manner. Drawing on the theory of production competence, we suggest that the relative fit between business strategy and purchasing strategy, labeled as strategic alignment, and between purchasing strategy and purchasing practices, referred to as purchasing efficacy, is key to achieving superior financial performance. Results from profile deviation analysis on data collected globally from 141 strategic business units (SBUs) with revenues greater than US$S3 billion support our hypotheses. Findings provide clear guidance to managers on how to design their purchasing strategies and practices to achieve maximum alignment and thus to effectively contribute to the SBU's financial success.

Sequence Alignment with an Appropriate Substitution Matrix

A widely used algorithm for computing an optimal local alignment between two sequences requires a parameter set with a substitution matrix and gap penalties. It is recognized that a proper parameter set should be selected to suit the level of conservation between sequences. We describe an algorithm for selecting an appropriate substitution matrix at given gap penalties for computing an optimal local alignment between two sequences. In the algorithm, a substitution matrix that leads to the maximum alignment similarity score is selected among substitution matrices at various evolutionary distances. The evolutionary distance of the selected substitution matrix is defined as the distance of the computed alignment. To show the effects of gap penalties on alignments and their distances and help select appropriate gap penalties, alignments and their distances are computed at various gap penalties. The algorithm has been implemented as a computer program named SimDist. The SimDist program was compared with an existing local alignment program named SIM for finding reciprocally best-matching pairs (RBPs) of sequences in each of 100 protein families, where RBPs are commonly used as an operational definition of orthologous sequences. SimDist produced more accurate results than SIM on 50 of the 100 families, whereas both programs produced the same results on the other 50 families. SimDist was also used to compare three types of substitution matrices in scoring 444,461 pairs of homologous sequences from the 100 families.

Polymer cell culture substrates with micropatterned carbon nanotubes

This article presents study of the interactions between cells and micropatterned carbon nanotubes on a polymer cell culture substrate. The polymer substrates with patterned carbon nanotubes were fabricated using an imprint process, whereby the nanotubes were pressed into a polymer layer at high temperature. The patterned substrates featured 28 different nanotube patterns of microscale lanes and circles, where the feature sizes ranged from 9 to 76 microm. Osteoblast-like cells were seeded on the substrates and cell alignment was quantified via fluorescent and electron microscopy. Many patterns were fabricated on each polymer substrate, allowing 28 different experiments on each cell culture substrate, which were tested over 10,000 cells. The cell response to the patterned nanotubes showed a maximum alignment to the microlane patterns of 55 +/- 6% and no significant alignment to microcircle patterns. This work enables the study of cell response to a wider range of patterns featuring both the micro and nano length scales.

The Italian CBI 2: New corporate banking services to optimise the financial value chain

In recent times, the payments industry has been deeply affected by technological evolution, which has affected every industrial sector: security, integrity, authenticity of transactions, end-to-end, flexibility, integration with corporate systems and automatic reconciliation are words which have been in use for years, and now is the time to shift them into concrete solutions, as expected by the market. Moreover, the need for European Union harmonisation of payment methods, prices and standards has led to the creation of the single euro payments area (SEPA), which represents a major opportunity for multinational enterprises and banks who operate at a cross-border level. The Association for Interbank Corporate Banking (ACBI), thanks to its numbers (over 620,000 corporates connected and most of the Italian banking system), has ridden the wave and is now becoming a real benchmark for the corporate banking community thanks to the launch of a new Internet-based Virtual Private Network, the use of XML syntax, the integration between the financial cycle (payments) and the supply chain (trade relationships and documents, eg e-invoice). The new services cite the maximum alignment with ISO 20022 standards (UNIversal Financial Industry message scheme) providing bank customers with a set of specific Additional Optional Services built over the core scheme of existing services (eg credit transfer), offering new end-to-end functions, such as the trade documents exchange, and financing traditional solutions which have been now converted to electronic, such as the invoice financing request. But how does it work? And what value added do the new mentioned functions generate for companies? This paper explains in detail all these topics, by describing the experience of the ACBI, the critical factor of success, lessons learned and the value that the model could have in other countries and zones, given the widespread impact on the Italian market.

Laser-induced field-free alignment of the OCS molecule

We investigate the dynamical alignment of jet-cooled OCS molecules induced by a short laser pulse. The alignment is measured through the orientational contribution of the optical Kerr effect using a second weak laser pulse as a probe. Maximum alignment is observed at conditions close to saturation of ionization. The results are analysed with a quantum mechanical model solving for the rotational dynamics.

Regular expression constrained sequence alignment

We introduce regular expression constrained sequence alignment as the problem of finding the maximum alignment score between given strings S 1 and S 2 over all alignments such that in these alignments there exists a segment where some substring s 1 of S 1 is aligned to some substring s 2 of S 2 , and both s 1 and s 2 match a given regular expression R, i.e. s 1 , s 2 ∈ L ( R ) where L ( R ) is the regular language described by R. For complexity results we assume, without loss of generality, that n = | S 1 | ⩾ | m | = | S 2 | . A motivation for the problem is that protein sequences can be aligned in a way that known motifs guide the alignments. We present an O ( n m r ) time algorithm for the regular expression constrained sequence alignment problem where r = O ( t 4 ) , and t is the number of states of a nondeterministic finite automaton N that accepts L ( R ) . We use in our algorithm a nondeterministic weighted finite automaton M that we construct from N. M has O ( t 2 ) states where the transition-weights are obtained from the given costs of edit operations, and state-weights correspond to optimum alignment scores we compute using the underlying dynamic programming solution for sequence alignment. If we are given a deterministic finite automaton D accepting L ( R ) with t d states then our construction creates a deterministic finite automaton M d with t d 2 states. In this case, our algorithm takes O ( t d 2 n m ) time. Using M d results in faster computation than using M when t d < t 2 . If we only want to compute the optimum score, the space required by our algorithm is O ( t 2 n ) ( O ( t d 2 m ) if we use a given M d ). If we also want to compute an optimal alignment then our algorithm uses O ( t 2 m + t 2 | s 1 | | s 2 | ) space ( O ( t d 2 m + t d 2 | s 1 | | s 2 | ) space if we use a given M d ) where s 1 and s 2 are substrings of S 1 and S 2 , respectively, s 1 , s 2 ∈ L ( R ) , and s 1 and s 2 are aligned together in the optimal alignment that we construct. We also show that our method generalizes for the case of the problem with affine gap penalties, and for finding optimal regular expression constrained local sequence alignments.

Cluster infall in the concordance ΛCDM model

We perform statistical analyses of the infall of dark matter on to clusters in numerical simulations within the concordance ACDM (cold dark matter) model. By studying the infall profile around clusters of different mass, we find a linear relation between the mass and maximum infall velocities which reach ∼900 km s -1 for the most massive groups. The maximum infall velocity and the group mass follow a suitable power-law fit of the form V max inf = (M/m 0 ) γ . By comparing the measured infall velocity to the linear infall model with an exponential cut-off introduced by Croft et al., we find that the best agreement is obtained for a critical overdensity δ c = 45. We study the dependence of the direction of infall with respect to the cluster centres, and find that in the case of massive groups, the maximum alignment occurs at scales r ∼ 6h -1 Mpc. We obtain a logarithmic power-law relation between the average infall angle and the group mass. We also study the dependence of the results on the local dark matter density, finding a remarkable difference in the dynamical behaviour of low- and high-density particles.

Evolutionary algorithms in the optimization of dynamic molecular alignment

We numerically study the optimization of dynamic molecular alignment by shaped femtosecond pulses. It is found that an accurate synchronization of the applied field to the molecular response is needed to obtain maximum alignment. Simple approaches based on low-dimensional parametrizations of the electric field are shown to be clearly inferior, especially in the strongly nonperturbative regime.

Solution Structure of Human Peptidyl Prolyl Isomerase-like Protein 1 and Insights into Its Interaction with SKIP

The human PPIL1 (peptidyl prolyl isomerase-like protein 1) is a specific component of human 35 S U5 small nuclear ribonucleoprotein particle and 45 S activated spliceosome. It is recruited by SKIP, another essential component of 45 S activated spliceosome, into spliceosome just before the catalytic step 1. It stably associates with SKIP, which also exists in 35 S and activated spliceosome as a nuclear matrix protein. We report here the solution structure of PPIL1 determined by NMR spectroscopy. The structure of PPIL1 resembles other members of the cyclophilin family and exhibits PPIase activity. To investigate its interaction with SKIP in vitro, we identified the SKIP contact region by GST pulldown experiments and surface plasmon resonance. We provide direct evidence of PPIL1 stably associated with SKIP. The dissociation constant is 1.25 x 10(-7) M for the N-terminal peptide of SKIP-(59-129) with PPIL1. We also used chemical shift perturbation experiments to show the possible SKIP binding interface on PPIL1. These results illustrated that a novel cyclophilin-protein contact mode exists in the PPIL1-SKIP complex during activation of the spliceosome. The biological implication of this binding with spliceosome rearrangement during activation is discussed.

Comparing alignment methods for inferring the history of the new world lizard genus Mabuya (Squamata: Scincidae)

The rapid increase in the ability to generate molecular data, and the focus on model-based methods for tree reconstruction have greatly advanced the use of phylogenetics in many fields. The recent flurry of new analytical techniques has focused almost solely on tree reconstruction, whereas alignment issues have received far less attention. In this paper, we use a diverse sampling of gene regions from lizards of the genus Mabuya to compare the impact, on phylogeny estimation, of new maximum likelihood alignment algorithms with more widely used methods. Sequences aligned under different optimality criteria are analyzed using partitioned Bayesian analysis with independent models and parameter settings for each gene region, and the most strongly supported phylogenetic hypothesis is then used to test the hypothesis of two colonizations of the New World by African scincid lizards. Our results show that the consistent use of model-based methods in both alignment and tree reconstruction leads to trees with more optimal likelihood scores than the use of independent criteria in alignment and tree reconstruction. We corroborate and extend earlier evidence for two independent colonizations of South America by scincid lizards. Relationships within South American Mabuya are found to be in need of taxonomic revision, specifically complexes under the names M. heathi, M. agilis, and M. bistriata (sensu, M.T. Rodrigues, Papeis Avulsos de Zoologia 41 (2000) 313).

Dynamics of laser-induced molecular alignment in the impulsive and adiabatic regimes: A direct comparison

Quantum-mechanical calculations are performed of the dynamic alignment of linear molecules induced by a strong nonresonant laser field. Within this framework we have treated in a unified fashion the alignment with laser pulses of varying duration from the short pulse impulsive limit $({\ensuremath{\tau}}_{\text{pulse}}⪡{T}_{\mathrm{rot}})$ to the long pulse adiabatic limit $({\ensuremath{\tau}}_{\text{pulse}}g{T}_{\mathrm{rot}})$. The temporal behavior of the alignment in both these limits, and in the intermediate pulse duration regime, have been analyzed. For the impulsive limit the dependence of the degree of maximum alignment upon the laser pulse duration was examined and the intensity-dependent optimum pulse duration explained. A comparison between the degree of alignment under the same conditions of pulse intensity and rotational temperature was performed between the impulsive and adiabatic cases. The adiabatic case was found to always provide a better degree of alignment for a given intensity which we show is due to the zero relative phasing between the component states of the superposition that form the pendular states. We have explicitly calculated the angular distribution of an ensemble of linear molecules as it evolves through a rotational revival; a rich structure is found that may be useful in guiding future experiments that utilize the field free alignment in a revival.

Topographic guidance of endothelial cells on silicone surfaces with micro‐ to nanogrooves: Orientation of actin filaments and focal adhesions

To mimic the uniformly elongated endothelium in natural linear vessels, bovine aortic endothelial cells (BAECs) are cultured on micro- to nanogrooved, model poly(dimethylsiloxane) (PDMS) substrates preadsorbed with about 300 ng/cm(2) of fibronectin. BAEC alignment, elongation, and projected area were investigated for channel depths of 200 nm, 500 nm, 1 microm, and 5 microm, as well as smooth surfaces. Except for the 5 microm case, the ridge and channel widths were held nearly constant about 3.5 microm. With increasing channel depth, the percentage of aligned BAECs increased by factors of 2, 2, 1.8, and 1.7 for 1, 4, 24, and 48 h. Maximum alignment, about 90%, was observed for 1 microm deep channels at 1 h. The alignment of BAECs on grooved PDMS was maintained at least until cells reached near confluence. F-actin and vinculin at focal adhesions also aligned with channel direction. Analysis of confocal microscopy images showed that focal adhesions localized at corners and along the sidewalls of 1-microm deep channels. In contrast, focal adhesions could not form on the bottom of the 5-microm deep channels. Cell proliferation was similar on grooved and smooth substrates. In summary, PDMS substrates engraved with micro- and nanochannels provide a powerful method for investigating the interplay between topography and cell/cytoskeletal alignment.

Generating Triaxial Reinforced Epoxy/Montmorillonite Nanocomposites with Uniaxial Magnetic Fields

The next step forward, transforming polymer nanocomposites from filled-polymer replacements to designed and engineered materials, necessitates the development of techniques to transform the random or ill-defined nanoscale morphologies into compositionally and spatially engineered hierarchal structures, paralleling that which underpins conventional continuous-fiber-reinforced composites. By exploiting an orthogonal magnetic susceptibility of montmorillonites (MMTs) from different deposits, a three-dimensional morphology composed of orthogonal alignment of aluminosilicate layers is generated from a mixture of montmorillonites and a uniaxial external magnetic field. Depending on the source, MMTs exhibit remnant magnetization arising from antiferro- and ferrimagnetic impurities and align with layers parallel or perpendicular to the field. Within a few minutes, application of static magnetic fields (1.2 or 11.7 T) induces stable alignment of organically modified MMT within an epoxy resin at room temperature. Structural relaxation is orders of magnitude slower, enabling the alignment to be captured during the subsequent cure. Thermal mechanical measurements demonstrate that morphology manipulation impacts the coefficient of thermal expansion (CTE), decreasing CTE the most in the direction of maximum MMT alignment. Knowledge of the detailed mechanism that leads to a change of the magnetic easy axis within layered silicates opens up opportunities to design novel synthetic layered silicates with unusual magnetic properties.

Treatment of intra-articular fractures

本期 是以关节内骨折为主要内容的重点刊,涉及下肢的胫骨平台骨折、髌骨骨折、 Pilon骨折、跟骨骨折及上肢的肩胛盂骨折、桡骨远端骨折的手术治疗.关节内骨折,特别是高能量的损伤由于骨折移位、关节塌陷及软组织损伤等增加了治疗的难度.治疗上根据关节内骨折的特点应做到:对骨折损伤正确判断,把握手术时机,应用微创技术,尽可能达到骨折的解剖复位及对线,最大限度恢复关节功能.特别强调关节内骨折的治疗要个体化。

Tunnel construction right below a controlled industrial waste landfill

The 1340-m Kozuka Tunnel, located in a section between Shin-Tamana Station (provisional name) and Kumamoto Station along the Kagoshima route of the Kyushu Shinkansen line, is being excavated using heading and bench and New Austrian Tunneling Method (NATM) methods. A controlled industrial waste landfill operated by the Kumamoto municipal government is located right above the midpoint of the Tunnel. The clearance below the landfill with an embankment height of about 40 m is about 4 m. A weak boundary layer between the Aso pyroclastic deposit and Ko-kinpozan rock needs to be excavated. Thus, construction conditions are extremely severe over a length of about 60 m. Adverse effects of tunnel excavation on the bottom (waterproof membrane) of the landfill and leakage of turbid water from industrial waste would have immeasurable impact on surrounding environments. In the section under such unique conditions, a pipe roof (composed of 13 steel pipes of a 800-mm diameter and a 66-m length) was applied, and side drifts and NATM were adopted. In order to select an optimum pipe roofing method before tunneling, the geology in the section under the landfill and the location of the waterproof membrane under the landfill were explored using horizontal boreholes and ground-penetrating radars. As a result, the Unclemole-Super method was adopted because it could satisfy such requirements as excavating the strata containing hard boulders with diameters of 1.0-2.0 m, preventing collapse of excavated face for installing the pipe roof and limiting the alignment error under 1/500 of the pipe length. The pipe roof was completed successfully with the maximum alignment error being 1/2200 of the roofing pipe length. The Tunnel is now being excavated using side drifts and NATM. Construction is strictly monitored. Standard settlements have been defined and settlements are being measured by inclinometers installed in the pipes. This paper describes pipe roof construction and construction control plans that are being implemented while the Tunnel is being excavated using side drifts and NATM. (A). Reprinted with permission from Elsevier. For the covering abstract see ITRD E124500.

Distinct relative F0 levels elicit categorical effects in F0 maximum and minimum alignment

A standard assumption in intonation research is that the presence and timing of fundamental frequency (F0) maxima and minima relative to segments are crucial phonetic characteristics of intonation patterns. The present experiment tests an alternative hypothesis that the representation of intonation patterns is based on the relative pitch levels of syllables in sequence. Synthetic stimuli were created using the phrase Some lemonade with an overall rising/falling or falling/rising intonation pattern. Cues to the presence and timing of F0 maxima and minima were eliminated by replacing the F0 across lemon- with level F0 contours and replacing the sonorant consonants before and after each target vowel nucleus with Gaussian noise. Four continua were created by shifting the F0 levels of one or both syllables in equal 0.5- or 0.75-semitone increments. Thirteen subjects imitated randomized stimuli presented over headphones. Results showed that alignment of maxima and minima in imitations was predictably related to relative F0 level: F0 maxima (minima) were aligned early in the segmental string when the first target syllable in the stimulus was higher (lower) than the following syllable; otherwise, maxima and minima were aligned late. These results provide support for models of intonation based on relative pitch levels.

3D-QSAR studies of pyruvate dehydrogenase kinase inhibitors based on a divide and conquer strategy

PDHK is a highly specific enzyme, which inhibits PDC thereby reducing the conversion of pyruvate to AcetylCoA leading to increased glucose and lactate level contributing to various pathological disease states. 3D-QSAR CoMFA studies were performed on diverse PDHK inhibitors based on maximum common substructural alignments of different classes of molecules with the selected reference molecule using a divide and conquer strategy. Statistically robust CoMFA model was obtained with a cross-validated correlation coefficient of 0.561 and conventional correlation coefficient of 0.990. Predictive correlation coefficient r 2 pred was found to be 0.875.

Alignment of molecules in pulsed resonant laser fields.

We investigate by numerical simulations the dynamics of alignment of linear molecules in resonant pulsed laser fields and its dependence on pulse length, field strength, and molecular parameters. We propose an analytical short-time approximation for the time-dependent wave packets. We provide a theoretical basis for the occurrence of saturation in the rotational pumping. We present a formula to predict the time at which the maximum alignment occurs. We discuss the magnitude of the laser-induced alignment and we relate it to a theoretical upper limit.