Mutually connected phase-locked loop networks: dynamical models and design parameters

Distribution of timing signals is an essential factor for the development of digital systems for telecommunication networks, integrated circuits and manufacturing automation. Originally, this distribution was implemented by using the master-slave architecture with a precise master clock generator sending signals to phase-locked loops (PLL) working as slave oscillators. Nowadays, wireless networks with dynamical connectivity and the increase in size and operation frequency of the integrated circuits suggest that the distribution of clock signals could be more efficient if mutually connected architectures were used. Here, mutually connected PLL networks are studied and conditions for synchronous states existence are analytically derived, depending on individual node parameters and network connectivity, considering that the nodes are nonlinear oscillators with nonlinear coupling conditions. An expression for the network synchronisation frequency is obtained. The lock-in range and the transmission error bounds are analysed providing hints to the design of this kind of clock distribution system.

Evaluation of Characterization and Performance Modeling of Cementitiously Stabilized Layers in the Mechanistic-Empirical Pavement Design Guide

Cementitious stabilization of aggregates and soils is an effective technique to increase the stiffness of base and subbase layers. Furthermore, cementitious bases can improve the fatigue behavior of asphalt surface layers and subgrade rutting over the short and long term. However, it can lead to additional distresses such as shrinkage and fatigue in the stabilized layers. Extensive research has tested these materials experimentally and characterized them; however, very little of this research attempts to correlate the mechanical properties of the stabilized layers with their performance. The Mechanistic Empirical Pavement Design Guide (MEPDG) provides a promising theoretical framework for the modeling of pavements containing cementitiously stabilized materials (CSMs). However, significant improvements are needed to bring the modeling of semirigid pavements in MEPDG to the same level as that of flexible and rigid pavements. Furthermore, the MEPDG does not model CSMs in a manner similar to those for hot-mix asphalt or portland cement concrete materials. As a result, performance gains from stabilized layers are difficult to assess using the MEPDG. The current characterization of CSMs was evaluated and issues with CSM modeling and characterization in the MEPDG were discussed. Addressing these issues will help designers quantify the benefits of stabilization for pavement service life.

Conceptual Design of Monocolumn Production and Storage With Dry Tree Capability

A new concept and a preliminary study for a monocolumn floating unit are introduced, aimed at exploring and producing oil in ultradeep waters. This platform, which combines two relevant features-great oil storage capacity and dry tree production capability-comprises two bodies with relatively independent heave motions between them. A parametric model is used to define the main design characteristics of the floating units. A set of design alternatives is generated using this procedure. These solutions are evaluated in terms of stability requirements and dynamic response. A mathematical model is developed to estimate the first order heave and pitch motions of the platform. Experimental tests are carried out in order to calibrate this model. The response of each body alone is estimated numerically using the WAMIT (R) code. This paper also includes a preliminary study on the platform mooring system and appendages. The study of the heave plates presents the gain, in terms of decreasing the motions, achieved by the introduction of the appropriate appendages to the platform. [DOI: 10.1115/1.4001429]

Economic design of an X chart for short-run production

The aim of this paper is to present an economical design of an X chart for a short-run production. The process mean starts equal to mu(0) (in-control, State I) and in a random time it shifts to mu(1) > mu(0) (out-of-control, State II). The monitoring procedure consists of inspecting a single item at every m produced ones. If the measurement of the quality characteristic does not meet the control limits, the process is stopped, adjusted, and additional (r - 1) items are inspected retrospectively. The probabilistic model was developed considering only shifts in the process mean. A direct search technique is applied to find the optimum parameters which minimizes the expected cost function. Numerical examples illustrate the proposed procedure. (C) 2009 Elsevier B.V. All rights reserved.

Inverse aerodynamic design applications using the MGM hybrid formulation

The well-known modified Garabedian-Mcfadden (MGM) method is an attractive alternative for aerodynamic inverse design, for its simplicity and effectiveness (P. Garabedian and G. Mcfadden, Design of supercritical swept wings, AIAA J. 20(3) (1982), 289-291; J.B. Malone, J. Vadyak, and L.N. Sankar, Inverse aerodynamic design method for aircraft components, J. Aircraft 24(2) (1987), 8-9; Santos, A hybrid optimization method for aerodynamic design of lifting surfaces, PhD Thesis, Georgia Institute of Technology, 1993). Owing to these characteristics, the method has been the subject of several authors over the years (G.S. Dulikravich and D.P. Baker, Aerodynamic shape inverse design using a Fourier series method, in AIAA paper 99-0185, AIAA Aerospace Sciences Meeting, Reno, NV, January 1999; D.H. Silva and L.N. Sankar, An inverse method for the design of transonic wings, in 1992 Aerospace Design Conference, No. 92-1025 in proceedings, AIAA, Irvine, CA, February 1992, 1-11; W. Bartelheimer, An Improved Integral Equation Method for the Design of Transonic Airfoils and Wings, AIAA Inc., 1995). More recently, a hybrid formulation and a multi-point algorithm were developed on the basis of the original MGM. This article discusses applications of those latest developments for airfoil and wing design. The test cases focus on wing-body aerodynamic interference and shock wave removal applications. The DLR-F6 geometry is picked as the baseline for the analysis.

Rational Design and 3D-Pharmacophore Mapping of 5 `-Thiourea-Substituted alpha-Thymidine Analogues as Mycobacterial TMPK Inhibitors

Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5`-thiourea-substituted alpha-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r(2) = 0.90, q(2) = 0.83 entire set, r(2) = 0.86, q(2) = 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5`-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptor-dependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.

Influence of Urea, Isopropanol, and Propylene Glycol on Rutin In Vitro Release from Cosmetic Semisolid Systems Estimated by Factorial Design

Rutin, one of the major flavonoids found in an assortment of plants, was reported to act as a sun protection factor booster with high anti-UVA defense, antioxidant, antiaging, and anticellulite, by improvement of the cutaneous microcirculation. This research work aimed at evaluating the rutin in vitro release from semisolid systems, in vertical diffusion cells, containing urea, isopropanol and propylene glycol, associated or not, according to the factorial design with two levels with center point. Urea (alone and in association with isopropanol and propylene glycol) and isopropanol (alone and in association with propylene glycol) influenced significant and negatively rutin liberation in diverse parameters: flux (g/cm2.h); apparent permeability coefficient (cm/h); rutin amount released (g/cm2); and liberation enhancement factor. In accordance with the results, the presence of propylene glycol 5.0% (wt/wt) presented statistically favorable to promote rutin release from this semisolid system with flux = 105.12 8.59 g/cm2.h; apparent permeability coefficient = 7.01 0.572 cm/h; rutin amount released = 648.80 53.01 g/cm2; and liberation enhancement factor = 1.21 0.07.

Optimization of Pothomorphe umbellata (L.) Miquel topical formulations using experimental design

Pothomorphe umbellata is a native plant widely employed in the Brazilian popular medicine. This plant has been shown to exert a potent antioxidant activity on the skin and to delay the onset and reduce the incidence of UVB-induced skin damage and photoaging. The aim of this work was to optimize the appearance, the centrifuge stability and the permeation of emulsions containing R umbellata (0. 1% 4-nerolidylchatecol). Experimental design was used to study ternary mixtures models with constraints and graphical representation by phase diagrams. The constraints reduce the possible experimental domain, and for this reason, this methodology offers the maximum information while requiring the minimum investment. The results showed that the appearance follows a linear model, and that the aqueous phase was the principal factor affecting the appearance; the centrifuge stability parameter followed a mathernatic quadratic model and the interactions between factors produced the most stable emulsions; skin permeation was improved by the oil phase, following a linear model generated by data analysis. We propose as optimized P. umbellata formulation: 68.4% aqueous phase, 26.6% oil phase and 5.0% of self-emulsifying phase. This formulation displayed an acceptable compromise between factors and responses investigated. (c) 2007 Elsevier B.V. All rights reserved.

Novel benzofuroxan derivatives against multidrug-resistant Staphylococcus aureus strains: Design using Topliss` decision tree, synthesis and biological assay

The aim of this study was the design of a set of benzofuroxan derivatives as antimicrobial agents exploring the physicochemical properties of the related substituents. Topliss` decision tree approach was applied to select the substituent groups. Hierarchical cluster analysis was also performed to emphasize natural clusters and patterns. The compounds were obtained using two synthetic approaches for reducing the synthetic steps as well as improving the yield. The minimal inhibitory concentration method was employed to evaluate the activity against multidrug-resistant Staphylococcus aureus strains. The most active compound was 4-nitro-3-(trifluoromethyl)[N`-(benzofuroxan-5-yl) methylene] benzhydrazide (MIC range 12.7-11.4 mu g/mL), pointing out that the antimicrobial activity was indeed influenced by the hydrophobic and electron-withdrawing property of the substituent groups 3-CF(3) and 4-NO(2), respectively. (C) 2011 Elsevier Ltd. All rights reserved.

Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus

Molecular modi. cation is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N`-(benzofuroxan-5-yl) methylene] benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological pro. le. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF(3) substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 mu g/mL, and a ClogP value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates. (C) 2009 Elsevier Ltd. All rights reserved.

Box-Behnken design for the optimization of an enantioselective method for the simultaneous analysis of propranolol and 4-hydroxypropranolol by CE

An experimental design optimization (Box-Behnken design, BBD) was used to develop a CE method for the simultaneous resolution of propranolol (Prop) and 4-hydroxypropranolol enantiomers and acetaminophen (internal standard). The method was optimized using an uncoated fused silica capillary, carboxymethyl-beta-cyclodextrin (CM-beta-CD) as chiral selector and triethylamine/phosphoric acid buffer in alkaline conditions. A BBD for four factors was selected to observe the effects of buffer electrolyte concentration, pH, CM-beta-CD concentration and voltage on separation responses. Each factor was studied at three levels: high, central and low, and three center points were added. The buffer electrolyte concentration ranged from 25 to 75 mM, the pH ranged from 8 to 9, the CM-beta-CD concentration ranged from 3.5 to 4.5%w/v, and the applied run voltage ranged from 14 to 20 W. The responses evaluated were resolution and migration time for the last peak. The obtained responses were processed by Minitab (R) to evaluate the significance of the effects and to find the optimum analysis conditions. The best results were obtained using 4%w/v CM-beta-CD in 25 mM triethylamine/H(3)PO(4) buffer at pH 9 as running electrolyte and 17 kV of voltage. Resolution values of 1.98 and 1.95 were obtained for Prop and 4-hydroxypropranolol enantiomers, respectively. The total analysis time was around of 15 min. The BBD showed to be an adequate design for the development of a CE method, resulting in a rapid and efficient optimization of the pH and concentration of the buffer, cyclodextrin concentration and applied voltage.

Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.

Using Computer-aided Drug Design and Medicinal Chemistry Strategies in the Fight Against Diabetes

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics. ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.

Computer-aided Drug Design of Novel PLA(2) Inhibitor Candidates for Treatment of Snakebite

Phospholipases A(2) (PLA(2)) are enzymes commonly found in snake venoms from Viperidae and Elaphidae families, which are major components thereof. Many plants are used in traditional medicine its active agents against various effects induced by snakebite. This article presents the PLA(2) BthTX-I structure prediction based on homology modeling. In addition, we have performed virtual screening in a large database yielding a set of potential bioactive inhibitors. A flexible docking program was used to investigate the interactions between the receptor and the new ligands. We have performed molecular interaction fields (MIFs) calculations with the phospholipase model. Results confirm the important role of Lys49 for binding ligands and suggest three additional residues as well. We have proposed a theoretically nontoxic, drug-like, and potential novel BthTX-I inhibitor. These calculations have been used to guide the design of novel phospholipase inhibitors as potential lead compounds that may be optimized for future treatment of snakebite victims as well as other human diseases in which PLA(2) enzymes are involved.

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when Compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by LIS, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer. (C) 2009 Elsevier Inc. All rights reserved.