structure-activity-relationship studies

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Pharmacological evaluation of NF279 as a P2 receptor antagonist : structure-activity relationship studies of analogues of the P2 receptor antagonists Suramin and NF023 at native P2 receptor subtypes and ecto-nucleotidases

Pharmacological evaluation of NF279 as a P2 receptor antagonist : structure-activity relationship studies of analogues of the P2 receptor antagonists Suramin and NF023 at native P2 receptor subtypes and ecto-nucleotidases

Heterogeneity of P2 receptors mediating contraction of the ratVD has been reported, based on the observation that in contrast to contraction evoked by a,b-mATP contractile responses to ATP were not totally blocked by suramin and iso-PPADS (Bültmann and Starke, 1994b). However, results obtained in a recent study confirmed earlier presumptions that the lack of effect of these antagonists might at least in part to be due to their dual activity: blocking P2 receptors and inhibiting ATP degradation by ecto-nucleotidases (Bültmann et al., 1999b), a phenomenon that has already been described for suramin and is referred to as “self-cancellation” (Crack et al., 1994). Nevertheless, the existence of additional subtypes of contraction-mediating P2 receptors cannot be totally ruled out by this explanation. Recently, UTP which has previously been shown to be inactive in pre-contracted ratVD (Khakh et al., 1994), was reported to elicit contraction of the tissue, when Evans blue was present to prevent enzymatic degradation of the nucleotide (Bültmann et al., 1999a). Contraction elicited by UTP was shown to be insensitive to desensitisation by a,b-mATP and persisted in the absence of extracellular calcium, indicating that contractile responses to uracil nucleotides were most likely to be mediated by a G protein-coupled P2Y receptor subtype. The fact that the UTP-induced contraction was inhibited by suramin together with a rank order of agonist potency of ATP ³ UTP > UDP = ADP led to the conclusion, that UTP might interact with P2Y 2 receptors in the ratVD preparation (Bültmann et
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Chemistry and Structure-Activity Relationships of Herbicide Safeners 

Chemistry and Structure-Activity Relationships of Herbicide Safeners 

Physiology and Weed Science, Blacksburg, Virginia 24061, U.S.A. Z. Naturforsch. 46c, 798-804 (1991); received March 26, 1991 Safeners, Chemical Properties, Structure-Activity Relationships The discovery and commercial success o f safeners against thiolcarbamate herbicide injury to corn has stimulated a rapid progress and opened new possibilities for further research and development in the last decade. Compounds with new chemistry, increased efficacy, and a broader selectivity spectrum were synthesized and developed for agricultural use. Structure- activity relationship studies helped to optimize their chemical properties and to understand their biological modes of action. Several examples indicate close similarity between chemical structures possessing herbicidal and safener properties. In some cases this differentiation may be marginal, as shown in crops pretreated with low herbicide doses leading to safening effects. In other examples, however, structural optima for safening and herbicidal efficacy can be clearly differentiated.
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Extensive structure‐activity relationship study of albicidin’s C‐terminal dipeptidic p‐aminobenzoic acid moiety

Extensive structure‐activity relationship study of albicidin’s C‐terminal dipeptidic p‐aminobenzoic acid moiety

Abstract: Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pro- nounced activity, particularly against Gram-negative bacte- ria, turns it into a promising lead structure for an antibac- terial drug. Hence, structureactivity relationship studies are key for the in-depth understanding of structural fea- tures/moieties affecting gyrase inhibition, antibacterial ac- tivity and overcoming resistance. The 27 newly synthe- sized albicidins give profound insights into possibilities for variations of the C-terminus. Furthermore, in the present study, a novel derivative has been identified as overcom- ing resistance posed by the Klebsiella-protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as a triazole amide bond isostere be- tween building blocks D and E.
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Structure-Activity Relationship Study of Host-Specific Phytotoxins (AM-Toxin Analogs) Using a New Assay Method with Leaves from Apple Meristem Culture 

Structure-Activity Relationship Study of Host-Specific Phytotoxins (AM-Toxin Analogs) Using a New Assay Method with Leaves from Apple Meristem Culture 

M. Miyashita et al. • Structure-Activity R elationship o f AM -Toxin A nalogs 1033 tured leaves was induced by AM -toxin I at levels as low as 1 0 “ 10 m for the susceptible cultivar (Indo). Necrosis appeared along the veins of meri- stem cultured leaves after treatm ent with low con­ centrations of AM -toxin I, and the entire part of leaves were necrotized following treatm ent with high concentrations of AM -toxin I. The necrosis of leaves was induced by AM -toxin I at 10-5 m for meristem cultures of the m oderately resistant cultivar (Jonathan) and no necrosis was observed even at 10~4 m for the resistant cultivar (Gala). These results are in good agreem ent with previous studies using tree leaves. The MC values obtained from the use of tree leaves in previous studies (Kohmoto et al., 1977; Shimohigashi et al., 1977; Tabira et al., 1998) are listed for com parison in Table II. In the previous studies no necrosis was induced by AM -toxin I at concentrations less than 2 x 1 0 ~ 9 m , indicating that the assay m ethod using meristem cultured leaves is 2 0 times more sensi­ tive to AM -toxin I.
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Neutron spectroscopy and crystallography to understand the structure-dynamics relationship in enzymes

Neutron spectroscopy and crystallography to understand the structure-dynamics relationship in enzymes

identified in the in silico studies [76]. As seen in figure 1.8, these oxygen entry pathways are close to the active site. Hence, apart from the long range structural changes, another possible reason for the effect of the two mutations (E573Q, I342F) on the activity of ECAO in spite of these being 20-30 ˚ A from the active site can be that these mutations affect the dynamics of the enzyme. This change in dynamics may affect the trafficking of molecular oxygen in E573Q mutant in such a way that its entry channel is blocked leading to inactivation of ECAO. In order to understand the influence of the two mutations on the structure which can then be correlated with the function and hence the change in the activity of ECAO, the X-ray structures of single (E573Q) and double (E573Q/I342F) mutants of ECAO were solved [77]. Surprisingly, no major structural changes were observed in the two mutants. Some of the subtle changes include the change in the side chain conformation of the residue MET-699 which maybe related to hindrance of the pathway of molecular oxygen entry as MET-699 is in close proximity to one of the oxygen entry channels. It was also found that the water which replaces the calcium ion bound in wild-type enzyme is present only in subunit A and not in B. To summarize, the subtle structural changes in the two mutants were insufficient to explain the effect of the mutations on the activity of ECAO. This effect can be attributed either to the changes in long-range electrostatic interactions resulting in the alteration of the protonation state of TPQ or the associated residues, hence inaccessible to X-ray crystallography or to the change in structural dynamics of the enzyme resulting in altered conformational sampling either of the residues involved in O 2 or amine entry channel or those involved in the
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Rational design, structure-activity relationship, and immunogenicity of hypoallergenic Pru p 3 variants

Rational design, structure-activity relationship, and immunogenicity of hypoallergenic Pru p 3 variants

Owing to the fact that PV showed favorable storage capacities as well as strongly reduced IgE binding activity, immunological in vivo studies were focusing on this molecule. WT was included as reference and endotoxin levels measured in both protein prepa- rations were ࣘ3 EU. In order to optimize immunogenicity, ad- sorption conditions to aluminum hydroxide (H) and aluminum phosphate (P) were assessed in vitro (Figure S3, Supporting In- formation). Longer incubation time increased the binding rate of PV, while the adsorption of WT already reached a plateau after shorter incubation period. Based on these results, in vivo experi- ments’ formulation of PV was performed o/n at 4 °C, while WT was incubated for 1 h at RT.
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Quantitative Structure Activity Relationship of Diphenylamines as Inhibitors of Photosynthetic Electron Transport and Photophosphorylation 

Quantitative Structure Activity Relationship of Diphenylamines as Inhibitors of Photosynthetic Electron Transport and Photophosphorylation 

QSAR studies on inhibitors of photosynthetic electron transport have been mainly perform ed on inhibitors of the DCMU type, which are com m ercial­ ly used as herbicides. In these cases, mostly the apparent dissociation constant pka , partition coef­ ficient P, Hammett o value and T aft’s steric constant

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Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

In 2016, an X-ray co-crystal structure of the natural product muraymycin D2 7 in complex with MraY from Aquifex aeolicus was reported by Chung et al. [ 22 , 23 ]. These structural insights into the target interaction of muraymycins allowed an identification of possible key interactions which were used to rationalize the design of synthetic muraymycin analogues for SAR studies [ 24 ]. A comparison of the aforementioned co-crystal structure with the previously reported crystal structure of the ligand-free apo enzyme [ 25 ] revealed a large conformational change due to inhibitor binding, hinting to a pronounced conformational plasticity of MraY. In this context, the formation of a well-defined binding pocket for the uridine-derived GlyU moiety was observed (Figure 2 ). This was regarded as one of the main reasons for the high binding affinity of naturally occurring nucleoside antibiotics despite their structural deviation from the natural substrate, i.e., UDP-MurNAc pentapeptide 1 [ 22 , 23 , 25 ]. Very recently, a more comprehensive model for MraY binding of diverse classes of nucleoside antibiotics, again based on X-ray crystallographic studies, has been reported [ 26 ].
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Structure-stability-activity studies on low Ir content mixed metal oxides for the electrochemical water oxidation in acidic media

Structure-stability-activity studies on low Ir content mixed metal oxides for the electrochemical water oxidation in acidic media

As laid out above, research should not continue hunting for the next record activity but focus on anode catalysts that allow ultra-low iridium loadings with sufficient conductivity and stability. Mixed metal oxides or a variant of supported iridium oxides are the most promising candidates to achieve this goal. 86 Low-temperature iridium oxides exhibit superior performance over their high-temperature, crystalline counterparts whereas the latter show increased stability in return. 115 Several studies indicate that this inverse relationship can be broken for some catalysts, though. In order to achieve active and stable catalysts several approaches have been investigated so far. High-temperature, stable oxides can be tuned to achieve higher activities, e.g. by Ni enrichment and subsequent leaching, but this turns out to strongly decrease the stability at the same time. 99 Here, the counter-approach is applied. We start from a low-temperature oxide with high intrinsic activity and stabilize its structure by Nb incorporation. Simultaneously, the more abundant Nb (0.66 ppm vs. 0.001 ppm in the earth’s crust) 270 would reduce the overall catalyst cost (Nb 271 : 40 US$ kg -1 vs. Ir 272 : ~44,000 € kg -1 ). Furthermore, Kadakia et al. suggested Nb as stabilizing agent for high-temperature oxides in their study on trimetallic IrNbSn oxide catalysts. 31 In order to access the low-temperature mixed oxide, the decomposition temperatures of the limited available Nb precursors was scanned by thermogravimetric analysis. Thereby, ammonium niobium oxalate hydrate was found to be a good match to the decomposition temperature of common iridium precursors (see Fig. 43).
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Inhibition of Photosynthesis by 4-Nitro-6-alkylphenols: Structure-Activity Studies in Wild Type and Five Mutants of Chlamydomonas reinhardtii Thylakoids 

Inhibition of Photosynthesis by 4-Nitro-6-alkylphenols: Structure-Activity Studies in Wild Type and Five Mutants of Chlamydomonas reinhardtii Thylakoids 

In Tables I and II also the descriptors n, logP, C LOGP, C M R , and L are given. Inspection o f the data from Tables I and II suggests th at there might be a parabolic relationship between the p / 50 values and these param eters. T h at this is indeed the case is shown by Fig. 1 and 2 which present correlations of the second or third pow er of the partition co­ efficient logP, an experim ental param eter. In the graphs, only the relationships for the eleven 2-bromo-4-nitro-6-alkylphenols are shown. The 2,4-dinitrophenols give similar pictures, and the same holds true with the other calculated descrip­ tors in Tables I and II: the num ber o f carbon atom s in the alkyl chain n, the param eters C L O G P and C M R from the Pom ona database obtained by in­ crement addition, and the S TER IM O L param eter L. All these descriptors have in com m on th at they increase homogeneously with the num ber o f car­ bon atoms. The problem o f colinearity in m ost o f
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Peroxidizing Herbicides (II): Structure-Activity Relationship and Molecular Design 

Peroxidizing Herbicides (II): Structure-Activity Relationship and Molecular Design 

598 T rends A rticle • K. W akabayashi and P. Böger ■ Peroxidizing H erb icid es (II) The Second Generation of Peroxidizing Herbicides The first generation of peroxidizing herbicides, such as oxadiazon, chlorophthalim and oxyfluor- fen, have handed down their unique phytotoxic properties to more than 20 different peroxidizing herbicides or candidates of a second generation including DPEs, Cyls. pyrazoles, triazoles, triazo- lidines, thiadiazolidines, oxazolidines and so on, which have been developed mostly in the second half of the 1980's (Figs. 7, 8 and 9). By studies in our laboratories many of these compounds have experimentally been confirmed to be peroxidizing herbicides by inhibiting protox, causing photooxi- dative ethane formation and a strong bleaching effect in the light, although their structures are quite different. Some candidates, e.g. KPP-300, KPP-314, S-23142, flumipropyn, flumioxazin, flu- thiacet-methyl (KIH-9201), NS-1556, thidiazimin, ET-751, PPG-1013 and SUAM-16476, are cur­ rently developed as practical herbicides. In Figures 7 to 9 these and further structures of candidates
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New Peroxidizing Herbicides: Activity Compared with X-Ray Structure 

New Peroxidizing Herbicides: Activity Compared with X-Ray Structure 

336 H. K o h n o et al. • X -R ay S tru c tu re o f Som e Peroxidizing H erbicides spectrophotom etrically in methanolic extracts. Determ ination o f ethane formation was per­ formed as described previously [11]. The ^50 values for chlorophyll content was calculated by adapted Dixon plots according to Lam bert et al. [12, 13]. The “activity value” for ethane form ation was esti­ mated through double-reciprocal plots similar to

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Multiplexed single-molecule force spectroscopy and activity studies on cellulosomes

Multiplexed single-molecule force spectroscopy and activity studies on cellulosomes

DTAF), and patterned in lines onto a cover slip (see Experimen- tal Section). The sample was then imaged under liquid in the TIRF microscope. Under blue illumination (See “TIRF-cellulose”, Figure 4 a and e), patterned bands of labeled cellulose fibers were clearly visible at the top and bottom of the image, and reproduced the fibrous structure of the Cladophora cellulose in the TIRF image. The cellulose-free band forms the black stripe in the center of the image. Next, Tr enzymes and HyReS system including Rhod dye at 35 nm were added to the liquid, and images were collected over time under green illumination (Figure 4 b–d). At time t = 0, the gel had not yet formed and no Rhod signal was observable in the TIRF image (Figure 4 B). By time t = 60 min., HyReS polymerization had incorporated Rhod into the hydrogel and the signal became observable in the TIRF image, mainly at locations where the cellulose was de- posited, reproducing the substrate pattern with high fidelity (Figure 4 d). This result indicated that reaction of the oligosac- charide hydrolysis products with the HyReS system compo- nents and initiation of polymerization occurred quickly enough to be localized to their site of production before the compo- nents could diffuse away from the fiber surface. Negative con- trol experiments lacking the Tr enzyme mixtures (Figure 4 e–h) showed only low non-specific signal that did not co-localize with the patterned substrate locations. The HyReS system therefore served as an imaging method and provided a fluores- cent readout that increased from a low background to a high signal directly in response to hydrolysis of the substrate. To the best of our knowledge, such a localized chemical imaging system for cellulolytic activity has never been shown before using fluorescence detection. Such a method could provide distinct advantages in studies on cellulase synergy and sus- ceptibility of cellulose substrates to degradation at specific lo- cations (e.g., branch points, fibril ends, and/or crystalline faces).
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Analysis of studies on Time-Driven Activity Based Costing (TDABC)

Analysis of studies on Time-Driven Activity Based Costing (TDABC)

There are several case studies on the implementation of TDABC, having been observed its advantages, namely that it is a model of easy construction, easy integration with software management and a easy approach for obtaining information about the consumption of resources by cost objects (Pernot, Roodhooft & Abbeele, 2007). Through the TDABC, it is possible to study the effectiveness of the processes in terms of available capacity versus effective capacity utilization. The authors of this approach (Kaplan & Anderson, 2007) argue that the use of time equations result in a simpler and less costly computation model than the ABC method. Among other advantages, TDABC allows assessing the value added of each activity, simulating the use of resources and testing processes of capacity rationalization considering the unused capacity. But some limitations were also noted in some case studies in which, for example, the fact that it may be required a huge amount of data for estimating time equations (Varila, Seppanem & Suomala, 2007).
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Bleaching Activity of New 2-Phenylpyridazinones: Structure-Activity Relationship 

Bleaching Activity of New 2-Phenylpyridazinones: Structure-Activity Relationship 

Substituted phenylpyridazinones can act as “bleaching” herbicides, i.e., they interfere with ca­ rotenoid biosynthesis and prevent the subsequent build-up of chlorophyll and other constituents of the thylakoid [1]. This phytotoxic effect depends on various substituents [2 -4 , see the latter for review]. In a recent publication, bleaching activity of such com pounds was quantitatively assayed by measuring their interference with the greening process, using a sensitive Scenedesmus m utant [3]. As pointed out previously [5], this algal model system allows for fast and reliable data on structure-activity relation­ ships. We found that the prom inent effect of the substituents is by influencing the charge distribu­ tion of the phenylpyridazinone molecule. Pigm ent bleaching improved firstly by substituents with increasing am values at position 4, secondly with decreasing ov values at position 5 of the pyrida- zinone ring, and thirdly by substituents with in­ creasing am or Up values at the m eta position o f the phenyl moiety ([3]; see formula in Table).
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The relationship between organizational structure and market orientation: An empirical aproach

The relationship between organizational structure and market orientation: An empirical aproach

With this approach, the development of a strategy aimed at the market requires the development of new organizational forms (Achrol, 1991). The most traditional concept of organization-characterized by a vertical and specialized structure - is being substituted by new forms of organization in those businesses that have adopted a market orientation. The hierarchical organization - in which the market department is a separate function - is “obsolete” according to these new approaches. The marketing responsibility must be dispersed throughout the organization in such a way that customer satisfaction is the fundamental goal of each of its members (Webster, 1994, p. 206). As a consequence, the structures become flatter, specialization is substituted by multifunctional processes, activities that do not turn out to be critical are externalized and work networks with other organizations are fostered (Cravens et al., 1998). “A great marketing department can be the antithesis of a market-oriented company, especially if it is part of a bureaucratic hierarchical structure dominated by rules, policies and procedures” (Webster, 1994, p. 271). For a large and bureaucratic organization, to respond rapidly to the changes caused by technological developments and the modifications of their customers' preferences will turn out to be problematic (Cravens et al., 1994).
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The relationship between childhood trauma and personality traits structure in adulthood

The relationship between childhood trauma and personality traits structure in adulthood

In the same line of scientific inquiry, this study looks back at the Kosovar preschoolers who underwent war in the years 1998-99, and examines the way their personalities have been shaped in their adult life, with the aim of finding out if the war trauma has played any role with regard to such developments. The way that personality reacts and manages traumatic events adds more ramifications to the already complex nature of the human personality. In this study, personality refers to a theoretical structure borne out of frequencies within language. The Five Factor Model of Personality by McCrae (1992) (the factors being: neuroticism, extraversion - introversion, agreeableness, openness to experience, and conscientiousness) that is used here, will serve as the theoretical negative against which the data will be extrapolated and analyzed within this study project. This model, also known as the ‘big five’, is a description of personality traits based on how most people described each other in the past and how they codified these descriptions in language. The most popular words, especially adverbs, eventually gained gravity and were to be ever more present in the everyday language.
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Structure-property relationship of aliphatic segmented poly(ester amide)s

Structure-property relationship of aliphatic segmented poly(ester amide)s

A number of experimental techniques can be used to characterize the microdomain structure of multiphase polymers at molecular level. They include, for example, transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), fluorescence spectroscopy, and solid state NMR spectroscopy. Among the available techniques, the solid state NMR became an extremely powerful and useful analytical tool for such characterizations in the last few decades. The power of this technique lies in its ability to obtain various kind of information by simply combining different NMR techniques. In particular, it can probe the microphase separation and extract domain thickness with the help of spin-diffusion experiments. These type of experiments in which the proton magnetisation is selectively suppressed in one of the phases with the help of dipolar filters 27-30 and then allowed to re-equilibrate due to a dipolar mediated flip-flop process were successfully applied to various type of systems including polyolefins 24 , nylon fibres 29,30 , block copolymers 29-32 , but also much more complex systems such as confined biomolecules. 33 Generally, the estimated domain sizes by the proton spin- diffusion agree very well with those estimated by X-ray. 24
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Synthesis, structure and catalytic activity of new lanthanide alkynylamidinates

Synthesis, structure and catalytic activity of new lanthanide alkynylamidinates

72 Reactions of p-chloroaniline with both carbodiimides (Table 9, entries 7 and 8) provided the expected guanylation products 41 and 42 under the standard conditions in quantitative yields (99%), reflecting again the exceptionally high catalytic activity of the neodymium complex 7. In both cases, quantitative conversion was observed after only 30 min. Both p-chlorophenyl- substituted guanidines could be easily isolated in a highly pure form by recrystallization from acetonitrile. In all cases (36  42), acetonitrile was found to be the solvent of choice for obtaining high-purity guanidine products. In addition to their 1 H and 13 C NMR data, the molecular structures of the trisubstituted guanidine products 40 and 41 were also authenticated by X-ray diffraction. The molecular structures are depicted in Figure 40.
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The relationship between organizational structure and market orientation: An empirical aproach

The relationship between organizational structure and market orientation: An empirical aproach

To conclude, companies are creating new flexible organizational forms that respond to their customers' needs and the market's requirements. “The key feature is the understanding of their customers' needs and the value offer to their customers” (Cravens et al., 1994, p. 19). As Achrol pointed out (1991, p. 80), "the firm of the future will need to be very permeable between its departments. Its departments and hierarchy will be confusingly defined, the hierarchy will be minimum and indirect and individuals will have much more autonomy". In this context, what emerges is a new form of organization based on a flexible network of independent organizations through vertical links with suppliers and users and horizontal links with competitors (Cravens et al., 1994). The consequences of these new designs can be difficult to understand and may even turn out to be contradictory. Hence, it has been noted that these networks may represent a problem to attain and maintain a market orientation and a customer focus . This is because the complexity associated with the networks can mean an obstacle for the employees to identify the end customers, as well as their requirements. Moreover, it can limit organizational learning (Cravens et al., 1996). The organizational structure can be described on the basis of different variables, though the literature (Aiken and Hage, 1966; Hall et al., 1967; Zaltman et al., 1973; Champion, 1975; Evers et al., 1976; Van de Ven, 1976; Dewar and Hage, 1978; Robbins, 1987a; Hall, 1996) indicate formalization, centralization and complexity as its fundamental and commonly-studied dimensions. A fourth component – integration -tends to be added to these factors (Lawrence and Lorsch, 1967; Galbraith, 1973; Mintzberg, 1998).
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