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Ligand.Info small-molecule Meta-Database.

Ligand.Info is a compilation of various publicly available databases of small molecules. The total size of the Meta-Database is over 1 million entries. The compound records contain calculated three-dimensional coordinates and sometimes information about biological activity. Some molecules have information about FDA drug approving status or about anti-HIV activity. Meta-Database can be downloaded from the http://Ligand.Info web page. The database can also be screened using a Java-based tool. The tool can interactively cluster sets of molecules on the user side and automatically download similar molecules from the server. The application requires the Java Runtime Environment 1.4 or higher, which can be automatically downloaded from Sun Microsystems or Apple Computer and installed during the first use of Ligand.Info on desktop systems, which support Java (Ms Windows, Mac OS, Solaris, and Linux). The Ligand.Info Meta-Database can be used for virtual high-throughput screening of new potential drugs. Presented examples showed that using a known antiviral drug as query the system was able to find others antiviral drugs and inhibitors.

Databases, Genetic↗

Essential concepts of inflammation and immunity.

Virtually all patients in acute or critical care settings experience some degree of immune system alteration, which places them at risk for serious potential complications, including sepsis and debilitation. Nurses need a good working knowledge of specific areas of immune function to provide a safe environment, adequate patient support, and appropriate early interventions to prevent complications. This article presents information about basic immune function and current and potential uses for new immunodulating agents, such as granulocyte macrophage--colony-stimulating factor.

Antibody Formation↗

A twelve-year study of leptospirosis on Barbados.

Between November 1979 and December 1991, 398 cases of severe leptospirosis were confirmed on Barbados (range for 1980-1991 23-56; mean 32.7; incidence 13.3/100,000/year). For the six-year periods 1980-1985 and 1986-1991 there was no significant change in incidence with time. Incidence is unlikely to change significantly in the next decade. Monthly average case numbers ranged from 1.4 (July) to 4.3 (November). The average (2.8) for June to December (the 7 wetter months) was not significantly higher than that (2.5) for January to May (the 5 drier months). The age range was 7-86. There were three times as many male cases (302) as female (96), and nearly 10 times as many in those < 35. Although the highest number of cases (69) was in males aged 15-24, the highest incidence was in the older age groups, particularly the male 65-74 year-olds, and the female 55-64 year-olds. Leptospirosis was the proven cause of death in 55 (13.8%) hospital patients (annual range 0-13, mean 4.5). Some of a further 39 fatalities might have been cases. Death from leptospirosis was nearly twice as common among the women as among the men. Only one patient under 20 years of age died. Leptospira were isolated and identified from 117 (29.4%) of the 398 sick patients. The infecting organisms were bim (serogroup Autumnalis--75), copenhageni (Icterohaemorrhagiae-26), arborea (Ballum-14) and bajan (Australis-2). These infecting serovars could not be distinguished clinically, but infection was milder in children than in adults. Despite its predominance in surveyed children, serogroup Panama was virtually absent in this study. Rainfall is the major factor affecting the distribution of cases; not surprisingly, sanitation workers and agricultural workers appear to be the groups at highest risk. The general lack of clear-cut risk factors reflects the ubiquity of leptospires in the environment and the fact that the disease is not entirely occupational.

Adolescent↗

[Three-dimensional 3D modeling: First applications in radioanatomy and interventional radiology under CT guidance].

PURPOSE: To model vertebrae in 3D to improve radioanatomic knowledge of the spine with the vascular and nerve environment and simulate CT-guided interventions. METHOD AND MATERIALS: Vertebra acquisitions were made with multidetector CT. We developed segmentation software and specific viewer software using the Delphi programming environment. RESULTS: This segmentation software makes it possible to model 3D high-resolution segments of vertebrae and their environment from multidetector CT acquisitions. Then the specific viewer software provides multiplanar reconstructions of the CT volume and the possibility to select different 3D objects of interest. DISCUSSION: This software package improves radiologists' radioanatomic knowledge through a new 3D anatomy presentation. Furthermore, the possibility of inserting virtual 3D objects in the volume can simulate CT-guided intervention. CONCLUSION: The first volumetric radioanatomic software has been born. Furthermore, it simulates CT-guided intervention and consequently has the potential to facilitate learning interventions using CT guidance.

Algorithms↗

15N NMR and Electrochemical Studies of [Ru(II)(hedta)](-) Complexes of NO, NO(+), NO(2)(-), and NO(-).

[Ru(II)(hedta)L](n)()(-) complexes (hedta(3)(-) = N-(hydroxyethyl)ethylenediaminetriacetate; L = NO(+), n = 0; L = NO, n = 1; L = NO(-), n = 2) have been prepared by the displacement of H(2)O/D(2)O via NO(g) or NO(2)(-). This is the first reported entire set of NO(+), NO, and NO(-) as ligands for the same metal center in a constant oxidation state and with a constant ligand environment (here Ru(II) and the amino carboxylate hedta(3)(-)). From the NO stretching frequencies of isolated salts, the net influence of back-donation by Ru(II) and its sigma-withdrawal was observed to be that the bond order for the NO(+) complex is virtually the same (ca. 2.46) as that for the NO complex (ca. 2.48). The back-donation to NO(-) is also small, as is that to NO, but orbital mixing of NO(-) and Ru(II) is sufficiently important to induce a singlet NO(-) complex. Values for the nu(NO) in cm(-)(1) for the (14)N- and (15)N-labeled complexes, respectively, are as follows: NO(+), 1846, 1827; NO, 1858, 1842; NO(-), 1383, 1370. Combined results of (15)N, (13)C, and (1)H NMR spectra of the complexes in D(2)O show that [Ru(II)(hedta)((15)NO(+))] is a single cis-equatorial isomer with its (15)NO(+) resonance at 249.6 ppm vs [(15)N]formamide. The two-electron-reduced [Ru(II)(hedta)((15)NO(-))](2)(-) complex exists as trans- and cis-equatorial isomers having (15)NO(-) resonances at 609.4 and 607.4 ppm. The (15)N resonances appear at 260.0 ppm for the (15)NO(+) ligand and at 348.8 ppm for the bound (15)NO(2)(-) ligand in the [Ru(II)(hedta)((15)NO(2)(-))((15)NO(+))(D(2)O)] complex. Differential pulse voltammetric waves for the [Ru(II)(hedta)L](n)()(-) series occur at -0.37 V for the Ru(II)(NO(-))/Ru(II)(NO) couple, at -0.10 V for the Ru(II)(NO)/Ru(II)(NO(+)) couple, and at +0.98 V for the Ru(II)(NO(+))/Ru(III)(NO(+)) couple. The coordinated nitrosyl ion/nitro equilibrium (L')Ru(II)(NO(+)) + 2OH(-) right harpoon over left harpoon (L')Ru(II)(NO(2)(-)) + H(2)O (K(NO)()2()-) was observed for L' = hedta(3)(-), as for previous examples with L' = violurate, polypyridyl ligands, and (CN(-))(5) and (NH(3))(5) ligand sets. K(NO)()2()- = 1.44 x 10(13) for L' = hedta(3)(-). log(K(NO)()2()-) is linearly related through the ion-pairing equilibrium constant expression to -z(1)z(2), the charge product of the reacting ions (here the (L')Ru(NO(+)) complex and OH(-)) from -4 through +3, excluding the (NH(3))(m)() ammine series with m = 4 and 5. The opposite behavior of the ammines is attributed to strong solvent H-bonding that changes for reactant and product in the nitrosyl/nitro equilibrium. The pK(a) of coordinated nitrous acid in [Ru(II)(hedta)(HONO)](-) is calculated to be -0.80, a 3.85 log unit enhancement over free HONO due to the Ru(II) charge. An MO explanation is presented to interrelate the {Fe(III)-(NO(-) triplet)} complexes, the {Ru(II)-(NO(-) singlet)} type observed for [Ru(II)(hedta)((15)NO(-))](2)(-), and the NO(+) complexes of other strong-field metals. When both d(z)()()2 and d(x)()()2(-)(y)()()2 metal orbitals reside below the NO pi pair, the electronic repulsions favor a bent NO(-) triplet ligand. If both metal orbitals reside above the NO pi pair, the orbital mixing and back-donation induce a coordinated NO(-) singlet ligand, and if the NO pi pair reside between the two sigma-based d orbitals, an NO(+) ligand and reduced metal center obtain.

Journal Article↗

Comparative analysis of the QUTR transcription repressor protein and the three C-terminal domains of the pentafunctional AROM enzyme.

The AROM protein is a pentadomain protein catalysing steps two to six in the prechorismate section of the shikimate pathway in microbial eukaryotes. On the basis of amino acid sequence alignments and the properties of mutants unable to utilize quinic acid as a carbon source, the AROM protein has been proposed to be homologous throughout its length with the proteins regulating transcription of the genes necessary for quinate catabolism. The QUTR transcription repressor protein has been proposed to be homologous with the three C-terminal domains of the AROM protein and one-fifth of the penultimate N-terminal domain. We report here the results of experiments designed to overproduce the QUTR and AROM proteins and their constituent domains in Escherichia coli, the purpose being to facilitate domain purification and (in the case of AROM), complementation of E. coli aro- mutations in order to probe the degree to which individual domains are stable and functional. The 3-dehydroquinate dehydratase domain of the AROM protein and the 3-dehydroquinate dehydratase-like domain of the QUTR spectroscopy and fluorescence emission spectroscopy. The CD spectra were found to be virtually superimposable. The fluorescence emission spectra of both domains had the signal from the tryptophan residues almost completely quenched, giving a tyrosine-dominated spectrum for both the AROM- and QUTR-derived domains. This unexpected observation was demonstrated to be due to a highly unusual environment provided by the tertiary structure, as addition of the denaturant guanidine hydrochloride gave a typical tryptophan-dominated spectrum for both domains. The spectroscopy experiments had the potential to refute the biologically-based proposal for a common origin for the AROM and QUTR proteins; however, the combined biophysical data are consistent with the hypothesis. We have previously reported that the AROM dehydroquinate synthase and 3-dehydroquinate dehydratase are stable and functional as individual domains, but that the 5-enol-pyruvylshikimate-3-phosphate synthase is only active as part of the complete AROM protein or as a bi-domain fragment with dehydroquinate synthase. Here we report that the aromA gene (encoding the AROM protein) of Aspergillus nidulans contains a 53 nt intron in the extreme C-terminus of the shikimate dehydrogenase domain. This finding accounts for the previously reported observation that the AROM protein was unable to complement aroE- (lacking shikimate dehydrogenase) mutations in E. coli. When the intron is removed the correctly translated AROM protein is able to complement the E. coli aroE- mutation. An AROM-derived shikimate dehydrogenase domain is, however, non-functional, but function is restored in a bi-domain protein with e-dehydroquinate dehydratase. This interaction is not entirely specific, as substitution of the 3-dehydroquinate dehydratase domain with the glutathione S-transferase protein partially restores enzyme activity. Similarly an AROM-derived shikimate kinase domain is non-functional, but is functional as part of the complete AROM protein, or as a bi-domain protein with 3-dehydroquinate dehydratase.

Alcohol Oxidoreductases↗

Successive rapid reductive dehalogenation and mineralization of pentachlorophenol by the indigenous microflora of farmyard manure compost.

AIMS: To determine whether composting with animal manure can be used to effectively remediate soil from a pentachlorophenol (PCP)-contaminated site, and to establish the fate of the degraded xenobiotic. METHODS AND RESULTS: Contaminated soil from a sawmill site was mixed with farm animal manure and composted in a 0.5 m3 silo under fully aerobic conditions. The disappearance and fate of PCP was monitored by gas chromatography (GC-ECD) and extensive mineralization confirmed in experiments with 14C-radiolabelled PCP. The disappearance of PCP was rapid and virtually complete within 6 days, prior to the onset of thermophilic conditions. Dechlorination of the PCP was found to be both reductive and sequential. CONCLUSIONS: PCP removal from contaminated soil by aerobic composting with animal manure is efficient and proceeds via reductive dechlorination to virtually complete mineralization. This contrasts with other chlorophenol composting regimes in which mineralization is achieved but dechlorination intermediates do not accumulate to detectable levels. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study demonstrate that anaerobic reductive dechlorination can proceed in an aerobic composting environment and contribute to efficient pentachlorophenol removal. Farmyard manure composts may represent a rapid, low-cost, low-technology option for treatment of chlorophenol-contaminated soils.

Agriculture↗

Cryocrystallography of ribosomal particles.

Crystals suitable for X-ray study have been prepared from biochemically active ribosome particles or their complexes with tRNA and polypeptide chains. At ambient temperature the useful lifetime of these crystals under synchrotron irradiation is limited to a few minutes. However, upon cooling to cryogenic temperatures around 85 K, the original resolution limit (up to 4.5 A) can be recorded and radiation damage is virtually eliminated. Hence it has become possible to collect a complete data set from one single crystal. Crystals were cooled as rapidly as possible, either in a cold gas stream, or by immersion in liquid propane. Before cooling crystals were transferred either to an inert hydrocarbon environment, or to solutions similar to the crystallizing ones but with a higher viscosity. In several cases soaking in a cryosolvent was required. Crystallographic data were collected with intense synchrotron radiation. Full data sets have been measured for native and derivatized crystals of 50S ribosomal subunits from H. marismortui as well as from their complexes with tRNA and nascent polypeptide chains, from the wild type and a mutant of 50S subunits from B. stearothermophilus, and from crystals of native and derivatized 30S ribosomal subunits from T. thermophilus.

Bacteria↗

Identification of gases responsible for the odour of human flatus and evaluation of a device purported to reduce this odour.

BACKGROUND/AIMS: While the social significance of flatus derives mainly from its odour, previous studies have focused on the non-odoriferous components of rectal gas. The aims of the present study were to determine the role of sulphur-containing gases in flatus odour and test the efficacy of a device purported to reduce this odour. METHODS: Flatus was quantitatively collected via rectal tube from 16 healthy subjects who ingested pinto beans and lactulose to enhance flatus output. The concentrations of sulphur-containing gases in each passage were correlated with odour intensity assessed by two judges. Odour intensity was also determined after treatment of flatus samples with zinc acetate, which binds sulphydryl compounds (hydrogen sulphide and methanethiol), or activated charcoal. Utilising gastight Mylar pantaloons, the ability of a charcoal lined cushion to adsorb sulphur-containing gases instilled at the anus of eight subjects was assessed. RESULTS: The main sulphur-containing flatus component was hydrogen sulphide (1.06 (0.2) mumol/l), followed by methanethiol (0.21 (0.04) mumol/l) and dimethyl sulphide (0.08 (0.01) mumol/l) (means (SEM)). Malodour significantly correlated with hydrogen sulphide concentration (p < or = 0.001). Zinc acetate reduced sulphur gas content but did not totally eliminate odour, while activated charcoal removed virtually all odour. The cushion absorbed more than 90% of the sulphur gases. CONCLUSION: Sulphur-containing gases are the major, but not the only, malodorous components of human flatus. The charcoal lined cushion effectively limits the escape of these sulphur-containing gases into the environment.

Adolescent↗

Chronobiology: biological clocks and rhythms of the skin.

The cyclicity of time affects virtually all aspects of our being and is the basis of the underlying rhythmicity which is typical of our lives. To 'tell time', most living organisms use internal timing mechanisms known as 'biological clocks'. These 'clocks' coordinate our physiological and behavioral functions and interactions with our environment. One of the strongest influences on rhythmicity is the solar day. The study of these temporal rhythms in biological systems has been coined chronobiology. With the present article we aim to give an overview on chronobiology. Examples of chronobiological effects on skin will be described. Particular emphasis will be placed on circadian rhythms (including rhythms that take place within a 24-hour period, including so-called infradian and/or diurnal rhythms) but also on seasonal variations (circaannual rhythms).

Biological Clocks↗

Duplicate copies of genes encoding methanesulfonate monooxygenase in Marinosulfonomonas methylotropha strain TR3 and detection of methanesulfonate utilizers in the environment.

Marinosulfonomonas methylotropha strain TR3 is a marine methylotroph that uses methanesulfonic acid (MSA) as a sole carbon and energy source. The genes from M. methylotropha strain TR3 encoding methanesulfonate monooxygenase, the enzyme responsible for the initial oxidation of MSA to formaldehyde and sulfite, were cloned and sequenced. They were located on two gene clusters on the chromosome of this bacterium. A 5.0-kbp HindIII fragment contained msmA, msmB, and msmC, encoding the large and small subunits of the hydroxylase component and the ferredoxin component, respectively, of the methanesulfonate monooxygenase, while a 6.5-kbp HindIII fragment contained duplicate copies of msmA and msmB, as well as msmD, encoding the reductase component of methanesulfonate. Both sets of msmA and msmB genes were virtually identical, and the derived msmA and msmB sequences of M. methylotropha strain TR3, compared with the corresponding hydroxylase from the terrestrial MSA utilizer Methylosulfonomonas methylovora strain M2 were found to be 82 and 69% identical. The msmA gene was investigated as a functional gene probe for detection of MSA-utilizing bacteria. PCR primers spanning a region of msmA which encoded a unique Rieske [2Fe-2S] binding region were designed. These primers were used to amplify the corresponding msmA genes from newly isolated Hyphomicrobium, Methylobacterium, and Pedomicrobium species that utilized MSA, from MSA enrichment cultures, and from DNA samples extracted directly from the environment. The high degree of identity of these msmA gene fragments, compared to msmA sequences from extant MSA utilizers, indicated the effectiveness of these PCR primers in molecular microbial ecology.

Alphaproteobacteria↗

Fingerprinting of signal transduction pathways using a combination of anti-phosphotyrosine immunoprecipitations and two-dimensional polyacrylamide gel electrophoresis.

Virtually all known cellular processes involve modulation of cellular signaling pathways via changes in protein phosphorylation. With genomics efforts more than doubling the number of proteins available for analysis, a major challenge will be to identify unknown phosphoproteins as they exist in the normal or diseased intracellular environment. Recent advances in proteomic technology have made it possible to examine changes in protein expression with much greater resolution than was previously possible. In this report, we describe a rapid and reproducible method for identifying phosphoproteins upregulated in response to activation of cell surface receptors. Phosphotyrosine-containing proteins were immunoprecipitated from IFNalpha- or IL2-treated primary human lymphocyte extracts using a novel anti-phosphotyrosine immunoprecipitation technique. This technique takes advantage of differing antibody affinities for epitopes on native versus denatured proteins. Following separation from the immunopellets, phosphoproteins are resolved by two-dimensional polyacrylamide gel electrophoresis. With this method, we identified known proteins phosphorylated in response to IL2 or IFNalpha using both silver staining and Western blotting for protein detection/identification. The silver-stained immunoprecipitation profile serves as a fingerprint for phosphorylation events that occur in response to cytokine treatment. By merging these techniques with mass spectrometric microsequencing, new capabilities are achieved. It will then be possible to identify novel signaling proteins that are activated in response to a variety of stimuli, including receptor activation, disease progression, etc.

Blotting, Western↗

In vivo proteomic analysis of the intracellular bacterial pathogen, Francisella tularensis, isolated from mouse spleen.

Understanding the pathogenesis of infectious diseases requires comprehensive knowledge of the proteins expressed by the pathogen during in vivo growth in the host. Proteomics provides the tools for such analyses but the protocols required to purify sufficient quantities of the pathogen from the host organism are currently lacking. Here, we present a rapid immunomagnetic protocol for the separation of Francisella tularensis, a highly virulent bacterium and potential biowarfare agent, from the spleens of infected mice. In less than one hour, bacteria can be isolated in quantities sufficient to carry out meaningful proteomic comparisons with in vitro grown bacteria. Furthermore, the isolates are virtually free from contaminating host proteins. Two-dimensional gel analysis revealed a host induced proteome in which 78 proteins were differentially expressed in comparison to in vitro grown controls. The results obtained clearly demonstrate the complexity of the adaptive response of F. tularensis to the host environment, and the difficulty of mimicking such behavior in vitro.

Animals↗

MAP kinases and hypoxia in the control of VEGF expression.

Vascular endothelial growth factor (VEGF), a potent cytokine secreted by virtually all cells plays a key role in tumor angiogenesis. Disruption of one VEGF allele in mice has revealed a dramatic lethal effect in early embryogenesis, suggesting a very tight regulation of this gene. This commentary reviews the mechanisms whereby VEGF mRNA is controlled within the tumor environment by hypoxia and the MAP kinase signaling cascades. Using hamster fibroblasts as a cellular model, we demonstrated that the Ras-mediated activation of p42/p44 MAP kinases exerts a prominent action at the transcriptional level. In normoxic conditions, p42/p44 MAPKs activate the VEGF promoter at the proximal (-88/-66) region where Sp 1/AP-2 transcriptional factor complexes are recruited. At low O2 tension, the stabilized and nuclear hypoxia inducible factor- 1alpha (HIF-1alpha) is directly phosphorylated by p42/p44 MAPKs, an action which enhances HIF-1-dependent transcriptional activition of VEGF. In addition, MAPKs activated under various cellular stresses (p38MAPK and JNK), contribute to the increased expression of this angiogenic growth and survival factor by stabilizing the VEGF mRNA.

Animals↗

Selective neural representation of objects relevant for navigation.

As people find their way through their environment, objects at navigationally relevant locations can serve as crucial landmarks. The parahippocampal gyrus has previously been shown to be involved in object and scene recognition. In the present study, we investigated the neural representation of navigationally relevant locations. Healthy human adults viewed a route through a virtual museum with objects placed at intersections (decision points) or at simple turns (non-decision points). Event-related functional magnetic resonance imaging (fMRI) data were acquired during subsequent recognition of the objects in isolation. Neural activity in the parahippocampal gyrus reflected the navigational relevance of an object's location in the museum. Parahippocampal responses were selectively increased for objects that occurred at decision points, independent of attentional demands. This increase occurred for forgotten as well as remembered objects, showing implicit retrieval of navigational information. The automatic storage of relevant object location in the parahippocampal gyrus provides a part of the neural mechanism underlying successful navigation.

Adolescent↗

Pharmacogenetics of hypertension treatment: a structured review.

The extent of blood pressure lowering by anti-hypertensive agents is difficult to predict for individual patients, even when evaluated in the context of biochemical or demographic information. Genetic predictors (mainly single nucleotide polymorphisms, SNPs) have been the focus of several recent studies and are gaining much attention. We have conducted a literature search for studies in which the lowering of ambient blood pressure by specific drugs or drug classes in humans was related to specific genotypes. Twenty-eight studies were identified, of which six had a single-dose design, and the remaining 22 studied drug effects after more than 4 weeks of drug administration. Virtually all were association studies. Prospective trials that compared the prognostic value of genetic methods to routine clinical practice were not identified. Almost all studies used a candidate-gene design, usually with a very small number of SNPs (typically one). Gene-gene and gene-environment interactions were studied only rarely. Only one study targeted genes involved in drug metabolism. Most candidate-genes were part of the renin-angiotensin system. By far the most extensively studied has been the angiotensin-converting enzyme insertion/deletion polymorphism (15 studies) but, to date, no clear picture has emerged for this or other genetic variants. Thus, the potential for utility of genetic characterization of individual patients as a predictor of anti-hypertensive response has yet to be realized.

Angiotensinogen↗

Immunocytochemical localization of the vitamin D-induced calcium-binding protein: relocation of antigen during frozen section processing.

The vitamin D-induced calcium-binding protein (CaBP) was localized in chick duodenum by the indirect fluorescent antibody technique after tissue was prepared by three different rapid-freezing methods: freeze-thaw, freeze-drying, and freeze-substitution. Sections prepared by freeze-thawing demonstrated CaBP-specific fluorescence over goblet cells and at the absorptive surface of villi, but not in absorptive cells. Sections from the same or adjacent segments prepared by freeze-drying or freeze-substitution produced virtually the opposite pattern of CaBP distribution. CaBP-specific fluorescence was associated with absorptive cell cytoplasm but not with goblet cells. From the results of experiments in which 6 micrometer freeze-dried sections were rehydrated, it was concluded that in the presence of an aqueous environment CaBP migrated from absorptive cells to discrete localization sites bound to goblet cell mucus, possibly to the calcium present in the mucus. By analogy, it was concluded that CaBP in association with goblet cells and the absorptive surface in sections prepared by the freeze-thaw method represented an artifactual localization. The true in situ localization of CaBP in chick duodenum was that which was present in absorptive cell cytoplasm.

Animals↗

Seeking the competitive advantage: it's more than cost reduction.

Most organizations focus considerable time and energy on reducing operating costs as a way to attain marketplace advantage. This strategy was not inappropriate in the past. To be competitive in the future, however, focus must be placed on other issues, not just cost reduction. The near future will be dominated by service industries, knowledge management, and virtual partnerships, with production optimization and flexibility, innovation, and strong partnerships defining those organizations that attain competitive advantage. Competitive advantage will reside in clarifying the vision and strategic plan, reviewing and redesigning work processes to optimize resources and value-added work, and creating change-ready environments and empowered workforces.

Cost Control↗