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OBJECTIVES: Identifying drugs or chemicals that represent hazards to human development is a continuous challenge. Of the approximately 60,000 chemicals in commercial use only 5% have been evaluated for developmental toxicity. Identification of inexpensive, rapid, validated techniques to demonstrate chemical hazards for the human embryo or fetus is the objective of this research. STUDY DESIGN: This research explored identification of structure activity predictors associated with human developmental toxicity by means of MULTICASE (multiple computer-automated structure evaluation), an algorithm that evaluates associations between chemicals and their constituent fragments and a biologic response. This algorithm allows identification of chemicals (and specific substructures) that may be human developmental toxicants. Developmental toxicity data were compiled from two sources (the Teratogen Information System and Food and Drug Administration guidelines) and analyzed to identify structural determinants (biophores) associated with human developmental toxicity. RESULTS: This analysis identified 17 biophores associated with human developmental toxicity. Testing the biophores against the learning set demonstrated 99% concordance, 100% sensitivity, and 98% specificity. Cross-validation studies were conducted, in which the original database was randomly separated into five learning and test sets; these demonstrated a mean concordance of 73%, with a mean sensitivity of 63% and a mean specificity of 79%. CONCLUSIONS: The MULTICASE structure-activity model is useful for identifying potential human developmental toxicants, as well as serving as a starting point for mechanistic investigations.

Models investigating relationships between chemical structures and biological activities are receiving increased recognition for the identification of chemicals with the potential for inducing adverse health effects. The relationships can be either qualitative (noted as SAR) or quantitative (noted as QSAR). The objective of the present study was to define an effective process for evaluating such models. The predictivity of SAR/QSAR models derived from the U.S. National Toxicology Program Rodent Carcinogenicity Bioassay endeavor by CASE/MultiCASE was evaluated by several different approaches: leave-one-out tests, 10-fold cross-validations and by the use of an independent test set. The goodness-of-fit for the data used in the model building, the predictivity for the chemicals not contained in the model, and the consistency of the predictions for a group of chemicals by different SAR/QSAR sub-models were examined systematically. Individual prediction indices generated by CASE/MultiCASE, arbitrary combinations thereof, as well as weighted combinations using Bayes' theorem, were utilized to derive predictions of Carcinogenicity. Combinations derived using Bayes' theorem provided the most predictive model. The closeness between sub-models based on the leave-one-out procedure and the full model (all chemicals used for model building) makes it the most reliable process for the estimation of a model's predictivity. However, the similarity between the predictions of the leave-one-out models and the 10-fold cross-validation models indicates that the latter process provides an acceptable approach.

MultiCASE (version 2.80), a structure-activity relationship expert system, was applied to a series of structurally diverse compounds evaluated for sensory irritant properties. The resulting biophores (molecular fragments responsible for the observed activity) were interpreted in terms of their physicochemical properties. Aromatic, charge-charge, and lipophilic interactions with a hypothetical receptor site are proposed. Fragment overlaps were observed with other databases of toxicological interest. The MultiCASE model is useful for predictive purposes and for providing information of a mechanistic nature. Furthermore, the identified biophores can serve as starting points for in-depth exploration of the correlation between physicochemical properties and biological activity.

Methyl tert -butyl ether (MTBE), ethyl tert -butyl ether (ETBE), tert -amyl methyl ether (TAME), and diisopropyl ether (DIPE) were evaluated with CASE/MULTICASE structure relational models in order...

We report the results of a systematic investigation of the phase diagram of the iron-based superconductor system, Ba${}_{1\ensuremath{-}x}$Na${}_{x}$Fe${}_{2}$As${}_{2}$, from $x=0.1$ to $x=1.0$ using high-resolution neutron and x-ray diffraction and magnetization measurements. We find that the coincident structural and magnetic phase transition to an orthorhombic structure with space group $Fmmm$ and a striped antiferromagnet with space group ${F}_{C}m{m}^{\ensuremath{'}}{m}^{\ensuremath{'}}$ in Ba${}_{1\ensuremath{-}x}$Na${}_{x}$Fe${}_{2}$As${}_{2}$ is of first order. A complete suppression of the magnetic phase is observed by $x$ $=$ 30$%$, and bulk superconductivity occurs at a critical concentration near 15$%$. We compare our findings to the previously reported results of the hole-doped Ba${}_{1\ensuremath{-}x}$K${}_{x}$Fe${}_{2}$As${}_{2}$ solid solution in order to resolve the differing effects of band filling and $A$-site cation size on the properties of the magnetic and superconducting ground states. The substantial size difference between Na and K causes various changes in the lattice trends, yet the overarching property phase diagram from the Ba${}_{1\ensuremath{-}x}$K${}_{x}$Fe${}_{2}$As${}_{2}$ phase diagram carries over to the Ba${}_{1\ensuremath{-}x}$Na${}_{x}$Fe${}_{2}$As${}_{2}$ solid solution. We note that the composition dependence of the $c$ axis turns over from positive to negative around $x$ $=$ 0.35, unlike the K-substituted materials. We show that this can be understood by invoking steric effects; primarily the Fe${}_{2}$As${}_{2}$ layer shape is dictated mostly by the electronic filling, which secondarily induces an interlayer spacing adjusted to compensate for the given cation volume. This exemplifies the primacy of even subtle features in the Fe${}_{2}$As${}_{2}$ layer in controlling both the structure and properties in the uncollapsed 122 phases.

We present an investigation of the lattice dynamics of the charge density wave (CDW) compound 2$H$-NbSe${}_{2}$. We analyze the precise nature of the wave vector-dependent electron-phonon coupling (EPC) and derive the bare dispersion of the CDW soft phonon mode using inelastic x-ray scattering combined with ab initio calculations. Experimentally, phonon modes along the \ensuremath{\Gamma}\ensuremath{-}$M$ line, i.e., q $=$ ($h$,0,0), with 0 \ensuremath{\le} $h$ \ensuremath{\le} 0.5 and the same longitudinal symmetry (${\ensuremath{\Sigma}}_{1}$) as the CDW soft mode, were investigated up to 32 meV. In agreement with our calculations, we observe significant EPC in the optic modes at $h$ \ensuremath{\le} 0.2. We analyze the EPC in the optic, as well as acoustic, mode and show that the q dependences stem from scattering processes between two bands at the Fermi surface that both have a Nb 4$d$ character. Finally, we demonstrate that the soft mode dispersion at $T$ $=$ 33 K (=${T}_{\mathrm{CDW}}$) can be well described on the basis of a strongly q-dependent EPC matrix element and an acousticlike bare phonon dispersion in agreement with observations near room temperature.

In the present study, the effects of data base size on predictivity, informational content and structural overlap of derived Structure-Activity Relationship (SAR) models were investigated. It was found that indices of predictivity (i.e., sensitivity, specificity, and concordance between experimental and predicted results (OCP)) increased with increasing size of the data base until the range is 300–400 chemicals, at which point they plateau. The greater the size of the data base, the greater the informational content of the model; however, the rate of this increase is no longer optimal when the size of the data base exceeds 400 chemicals.

A knowledge-based system (MULTICASE) was applied to the elucidation of the structural basis of the induction of aneuploidy and growth inhibition by a group of chlorinated alkanes and alkenes in Aspergillus nidulans. It was found that while there were commonalities in the structural determinants associated with fungicidal and fungostatic activities, there were none between these and the structures associated with the induction of aneuploidy. Moreover, there did not appear to be a commonality between the structures associated with the induction of aneuploidy and those associated with the induction of mutations in Salmonella.

Clinical case reports can be important sources of information for alerting health professionals to the existence of possible health hazards. Isolated case reports, however, are weak evidence of causal relationships between exposure and disease because they do not provide an indication of the frequency of a particular exposure leading to a disease event. A database of chemicals causing allergic contact dermatitis (ACD) was compiled to discern structure-activity relationships. Clinical reports repre sented a considerable fraction of the data. Multiple Computer Automated Structure Evaluation (MultiCASE) was used to create a structure-activity model to be used in predicting the ACD activity of untested chemicals. We examined how the predictive ability of the model was influenced by including the case report data in the model. In addition, the model was used to predict the activity of chemicals identified from clinical case reports. The following results were obtained: • When chemicals which were identified as dermal sensitizers by only one or two case reports were included in the model, the specificity of the model was reduced. • Less than one half of these chemicals were predicted to be active by the most highly evidenced model. • These chemicals possessed substructures not pre viously encountered by any of the models. We conclude that chemicals classified as sensitizers based on isolated clinical case reports be excluded from our model of ACD. The approach described here for evaluating activity of chemicals based on sparse evidence should be considered for use with other endpoints of toxicity when data are correspondingly limited.

The expert structure-activity relational system CASE/MULTICASE was used to obtain an assessment of the possible carcinogenicity of selligueain A, a plant-derived sweetener. Based upon a series of authoritative data bases it was predicted that this chemical had some marginal potential for being a ‘non-genotoxic’ rodent carcinogen. The relevance of this potential to possible human health risks is problematic. Still, given the fact that successful sweetener may be widely consumed, should this chemical be developed further, experimental determinations of its potential carcinogenicity appear in order.

An analysis of the structure of diethylstilbestrol (DES) indicates that neither DES nor any of its metabolites are potential mutagens. Moreover, the present analyses suggest (a) that the observed carcinogenic spectrum of DES reflects the activity of metabolic intermediates and (b) that the carcinogenicity of DES in mice is due to the presence of a 6 A geometric descriptor that appears to be related to an estrogen receptor.

The computational analysis data presented indicate a significant mechanistic association between the ability of a chemical to cause tubulin polymerization perturbation (TPP), via direct interaction with the protein, and the in vivo induction of micronuclei (MN). Since it is known that TPP is not a genotoxic event, the analyses suggest that the induction of MN by a non-genotoxic mechanism is a significant alternate pathway.

We evaluated the carcinogenic potential of Dacthal, an important herbicide, and its biodegradation product, tetrachloro-terephthalic acid, on the basis of their chemical and biological properties as well as by a variety of computational tools. We concluded that tetrachloroterephthalic acid does not present any substantial carcinogenic risk and that the observed rodent carcinogenicity of Dacthal is probably due to its impurities.

Twenty-four organic compounds currently undergoing testing within cancer bioassays under the aegis of the U.S. National Toxicology Program (NTP) were submitted to the computer automated structure evaluation (CASE) and multiple computer automated structure evaluation (MULTICASE) system for predictions of activity. Individual predictions resulting from the NTP combined rodent, NTP mouse, Carcinogenic Potency Database (CPDB) combined rodent, and CPDB mouse databases were combined using Bayes' theorem to yield an overall probability of rodent carcinogenicity. Based upon an arbitrary probability cut-off of 0.50, nine compounds were predicted to be rodent carcinogens. The predicted carcinogens are chloroprene, 1-chloro-2-propanol, codeine, emodin, furfuryl alcohol, isobutyraldehyde, primaclone, sodium xylenesulfonate, and t-butylhydroquinone.

An analysis of the chemical structure of tamoxifen, toremifene and their metabolites indicates that metabolism to a DNA-reactive hydroxylamine intermediate is possible. The parent compounds and many of their metabolites are predicted to be rodent carcinogens. Moreover, many of these metabolites contain a 6 A or 8.4 A distance descriptor biphore. These geometric descriptors may be related to an ability of these chemicals to bind to an estrogen receptor. The prediction of the carcinogenicity of toremifene is not in accord with studies published thus far. However, the reports available have not excluded this possibility, since the protocols used have not addressed it systematically.

The ability of a number of prediction systems was examined to determine how well they could predict Salmonella mutagenicity. The prediction systems included two computer-based systems (CASE© and TOPKAT©), the measurement of a physiochemical parameter (k e ) and the use of structural alerts by an expert chemist. The computer-based systems operators and the chemist were supplied with the structures of 100 chemicals that had been tested for mutagenicity in the Salmonella test ; the actual chemicals were needed for the physiochemical measurement. None of the participants was provided with the chemical names or Salmonella test results prior to submitting their predictions. The three systems that predicted the mutagenicity from the structure of the chemicals produced equivalent results (71-76% concordance with the Salmonella results) ; the physiochemical system produced a lower (60-61%) concordance.

Rodent carcinogenicities for a group of 30 chemicals which form the subject of the Second NIEHS Predictive-Toxicology Evaluation Experiment are predicted based on their subchronic organ toxicities. Predictions are made by rules learned by the rule learning (RL) induction program.

A distance descriptor (6A) originally associated with non-genotoxic mouse carcinogens has been found to be present in some, but not all, estrogens and antiestrogens. It is hypothesized that this descriptor describes a ligand binding site on an estrogen receptor. Evidence is presented that those estrogens and antiestrogens not containing the 6A distance bind to a different receptor. It is conceivable that binding to the receptor that recognizes the 6A distance is associated with carcinogenicity.

Allergic contact dermatitis (ACD) is a widespread concern in which sensitization occurs to low molecular weight chemicals. Currently, animal and human assays are used to identify chemicals with potential to cause ACD. MultiCASE, a computer based structure-activity relational system was employed to evaluate a data base of contact sensitizers and identify structural determinants (biophores) associated with sensitization. The data base was derived from reports of animal and human studies and consisted of 1034 chemicals of which 317 were classified as sensitizers (extreme, strong, moderate, or weak), 22 chemicals had marginal (questionable) activity, and 695 were inactive. MultiCASE identified 49 biophores with related expanded fragments which accounted for the activity of all active chemicals. The major biophores consisted of: 1) a nitrogen double-bonded to a carbon or a nitrogen; 2) substituted aromatic structures; 3) thiol and disulfide containing fragments; and 4) electrophilic moieties. Modulators of each biophore, which either augmented or decreased potency, included additional structural fragments, two dimensional distance descriptors, as well as physico-chemical characteristics. Internal evaluation of the data base indicated the sensitivity was 99.6%, and the specificity of the data set was 99.4%. Prediction of the activity of chemicals not in the learning set gave a concordance of 90.2% with experimental results. These findings demonstrate the ability of MultiCASE to identify contact sensitizers and suggest its ability to screen chemicals for their potential to produce ACD.

Taking into account insights into the reality of human decision-making, is an important challenge for today’s policymakers. Are there `cheaper´, more efficient and possibly as well more effective, non-financial ways of influencing the behaviour of private and corporate citizens, nudging them towards socially desired choices, for example, in the domain of energy consumption? Can such mechanisms complement or substitute for monetary incentives in fostering sustainable decision-making in policy relevant areas such as energy consumption? If so, what mechanisms might be feasible to implement in actual policymaking? Against this background, the Dutch Ministry of Economic Affairs (Ministerie van Economische Zaken) wants to know which “nudges†are the most suitable for application in the field of energy conservation. To this end, in this report we (1) take stock what is known about the effects of non-monetary incentives in general, and legacy reminders in particular, in increasing individuals’ regard for collective interests and for intergenerational beneficence, in particular in the domain of energy consumption (literature review); (2) investigate in a laboratory setting the effects of selected non-monetary incentives on a selection of relevant decision tasks (laboratory experiments); and (3) apply the insights from the literature review and laboratory experiments to specific instruments of policy-making in the Netherlands.

The paper investigates the effect of four differently framed payment contracts on the agent's effort provision and performance in a real effort experiment. The four incentive payments are framed as a base wage and bonuses (one immediately pays bonuses, the other only after an initial performance-independent part), penalties or a combination of bonuses and penalties. The base wage that is offered, induces the reference point. The participants provide real effort and are paid for finding pairs in a customized Memory game. The bonus-only frame elicits the highest effort, whereas frames with penalties lag behind. Ability positively complements the effect of effort on performance. The combination of penalties and bonuses minimises the costs of the principal only for low levels of performance employing heterogeneous agents. For higher performance levels, framing a base wage with bonuses is cost-effective.

The potential of praziquantel (PZ) to induce cancers in rodents was evaluated using a structure-activity relational expert system (CASE/MULTICASE). The analyses indicated that based upon structural features PZ had the potential for being a "nongenotoxic" carcinogen. The potential risk to humans of nongenotoxic carcinogens is considered to be much less than that posed by "genotoxic" ones. Moreover, PZ has demonstrated therapeutic effectiveness against parasitic diseases that affect millions of individuals. Additionally, PZ was developed to replace antiparasitic agents which mere genotoxic rodent carcinogens. Thus, on balance, the beneficial effects of PZ appear to outweigh its potential for causing harm to humans.

The objectives of our work are to develop methodologies capable of identifying the potential environmental health hazards of chemicals. These techniques are particularly useful when it is necessary to evaluate molecules that have not been synthesized as yet, or for which there is little or no toxicological information known. With the help of MULTICASE, an artificial intelligence program capable of uncovering the relationship between the presence of specific substructures in a molecule and its toxicity, and TOX II, a program capable of identifying the existence of such substructures in a new molecule, it is now possible to predict with a reasonable degree of certainty whether a new molecule will be toxic. TOX II will uncover any functionality previously found to be related to toxicity in any organic molecule. The evaluation is extensive and may include its automatically generated metabolites. The scope of TOX II is vast as more than 70 toxicological endpoints can be evaluated.

It is shown that the use of a combination of two programs, MULTICASE and META can help assess the carcinogenic risk factor posed by the disposal of industrial organic materials in the ecosystem. MULTICASE is a knowledge-based computer system that had been trained to identify molecular substructures believed to be conducive to carcinogenic potential and META is an expert system trained to predict the aerobic biodegradation products of organic molecules. The programs can be used to assess the health hazard of the discarded chemicals by evaluating their chemical structure, their biodegradability and the structures of the predicted biodegradation products. Several examples of the application of the methodology are described in this paper.

The mean electronegativity of chemicals tested for mutagenicity, genotoxicity, clastogenicity and toxicity was determined. It was found that, as expected, chemicals with ‘structural alerts’ for DNA reactivity, and/or capable of inducing mutations in Salmonella and/or unscheduled DNA synthesis in hepatocytes, as a group, were significantly more electronegative than the molecules lacking these attributes. Molecules capable of inducing somatic mutations and recombinations in Drosophila melanogaster also exhibited this characteristic although it was of borderline statistical significance. Inducers of chromosomal aberrations and sister-chromatid exchanges in cultured CHO cells showed the same trend, however the differences between inducers and non-inducers were not statistically significant. In contrast to the above, inducers of bone marrow micronuclei, as a group, were significantly less electronegative than non-inducers. This is a property they shared with chemicals that exhibited systemic or cellular toxicity or that induced lethality in minnows. These findings suggest that in addition to genotoxicity, cellular and/or systemic toxicity may also contribute to the induction of micronuclei.

A computer program has been developed that can predict the most probable metabolites formed from aerobic biodegradation of chemicals. Predictions are based on an expert evaluation of the parent chemical's molecular structure. The program was designed to recognize molecular fragments within complete chemical structures that are sites of microbial attack. The system is based on a dictionary of transformation rules, consisting of a compilation of molecular transformation operators relevant to microbial attack. The user inputs chemical structures, and the output is a visual or printed display of the potential metabolites resulting from the appropriate metabolic pathways. New chemicals can be evaluated, since the program recognizes structural fragments rather than complete molecular structures.

Structural analyses of azadirachtin, a promising biopesticide recently introduced into the United States, indicates that this natural product has the potential for acting as a "genotoxic" carcinogen. In view of the fact that genotoxic carcinogens are regarded as presenting a potential carcinogenic risk to humans, the present finding suggests that the possible metabolism of azadirachtin to DNA-reactive products be evaluated experimentally.

Using an event study methodology, this paper assesses the competitive effects of remedies implemented by the European Commission in 11 horizontal mergers in the ICT industry between 1990 and 2010. The estimates of merger announcement effects for both merging parties and competitors have predominantly insignificant residuals, suggesting that collusion and anti-competitive effects are not implied by the market reactions to merger announcements. Remedies, both behavioural and structural, appear to be largely ineffective in negating the competition concerns of the Commission, even if properly applied to anti-competitive mergers. Moreover, behavioural remedies appear to transfer rents from merging parties to competitors. These findings suggest that static economic models are ineffective in analysing dynamic markets, possibly as a result of inadequate market definitions.

Developmental toxicity, an area of public concern, suffers from the lack of accessible, reliable, peer-reviewed compilations of data and substantial gaps in testing. These deficits frequently make it necessary for regulatory agencies to use other toxicological end points to regulate developmental toxicants. We have utilized a database of chemicals identified as developmental toxicants in rats, mice, rabbits, and humans and an expert system which learns the association between molecular structure and biological response (Computer Automated Structure Evaluation; CASE) to explore structure-activity relationships in developmental toxicity. Developmental toxicity was defined as death, growth retardation, or structural or functional malformations. In analyzing the data CASE selects its own molecular descriptors from a learning set of active and inactive molecules. Using randomly constructed learner and tester sets, the concordance of the predictions with the actual data was between 77 and 82%. CASE identified 13 major structural fragments associated with developmental toxicity in mice, 15 in rats, 9 in rabbits, and 7 in humans. These analyses indicate that there is indeed a structural basis for developmental toxicity which may be used to predict the developmental hazard of untested or inadequately tested chemicals.

The CASE (computer automated structure evaluation) structure-activity relational expert system was used to analyze the toxicity of a database of chemical sets to environmental bacteria (aerobic heterotrophs, nitrosomonas, methanogens, and photobacteria [Microtox [reg sign]test]). The analyses revealed that the data sets related to each of the antimicrobial activities, albeit containing a relatively small number of chemicals, are characterized by structural determinants significantly associated with the probability of antimicrobial activity, as well as with antibacterial potency. Although there were a number of similarities among the structural determinants associated with each of these antimicrobial activities, there were also features unique to each assay that presumably reflect species-specific targets of bactericidal activity. Overall the assay for antimethanogenic activity appears to be the most informative as well as the one most predictive of the activity in the other three assays.

The assumptions and considerations underlying the use of structure-activity studies in the field of genotoxicity are discussed and reviewed. The MULTI-CASE program, recently introduced as a second generation CASE program is described and its special features higlighted. Some of the problems relevant to the use of structure-activity tools are also discussed. A list of these problems is a follows: • Problems with non-congeneric dtata bases, • Problems with expert systems, • Problems with the size of the data bases, • Problem with “structural alerts”, • Problems with QSAR, • Problems with Metabolic transformations, and • Problems with short-term assays.

In 1969 Innes et al. reported that 9% of 127 industrial chemicals and pesticides (including 7 positive controls) tested in a mouse bioassay were carcinogenic by oral administration. This is much lower than the prevalence of approximately 50% that has been found recently by the cancer bioassays conducted under the aegis of the U.S. National Toxicology Program (NTP) or reported in Carcinogen Potency Data Base compiled by Gold and collaborators. Using the CASE structure-activity relational expert system and the NTP cancer bioassay results as a learning set, we found that the predicted prevalence of carcinogens among the chemicals tested by Innes et al. is 62.7%. It is concluded that the bioassay protocol used by Innes et al. is less sensitive than the subsequently adopted bioassay procedures.

The mutagenicity, metabolism, DNA adduction and induction of unscheduled DNA synthesis (UDS) of 1-nitropyrene and 1,8-dinitropyrene were investigated in the human hepatoma cell line HepG2. Previous results had demonstrated that 1-nitropyrene was both mutagenic at the hgprt locus and induced UDS in these cells. In the present study, we find that the dinitropyrenes, although highly mutagenic in Salmonella typhimurium, are not mutagenic and do not induce UDS in the HepG2. Although the rate of 1,8-dinitropyrene nitroreduction was less than that of 1-nitropyrene nitroreduction, this did not explain the lack of mutagenicity and UDS induction by the dinitropyrenes. Therefore, it is proposed that the arylhydroxylamine O-esterificase is not expressed in these cells. Since cytochrome P450-mediated C-oxidation is the predominant metabolic pathway in vivo, we sought to determine if an increase in the ratio of cytochrome P450-mediated C-oxidation over nitroreduction would result in increased or decreased DNA adducts in the HepG2. The administration of 2.5 microM 3-methylcholanthrene to the HepG2 increased the ratio of C-oxidation/nitroreduction from 2.8 +/- 1.9 to 50.4 +/- 46.1. This was accompanied by a decrease in the C8-guanyl adduct of 1-nitropyrene (via nitroreduction) from 18.7 +/- 7.0 to 4.8 +/- 1.7 fmoles/micrograms DNA, without any further increase in other 1-nitropyrene DNA adducts. These results suggest that the cytochrome P450-mediated metabolism of 1-nitropyrene to epoxides, phenols, and dihydrodiols is not an activation pathway in the HepG2 cells, and may explain the weak carcinogenicity of 1-nitropyrene in vivo, where cytochrome P450-mediated C-oxidation predominates. Images Figure 4.

The CASE (Computer-Automated Structure Evaluation) methodology has been applied to an investigation of the basis of the genotoxicity (sfiA induction) of 79 nitroarenofurans and related molecules examined with the E. coli PQ37 genotoxicity assay (SOS chromotest). CASE identified 9 major activating structural fragments (biophores) responsible for the probability of genotoxicity (SAR). With respect to quantitative features, CASE identified 8 major molecular subunits related to the genotoxic potency (QSAR). Both the SAR as well as the QSAR analysis indicate that a nitro group on position 2 of the furan ring is important for activity provided one or more aromatic rings are attached to the furan ring, i.e. 2-nitrobenzofuran, 2-nitronaphthofuran, 2-nitroanthrafuran and 8-nitropyrenofuran. Additionally, a small substituent at position 3 of the furan ring, i.e. the methyl group of R7371, the ethyl group of R7427 and the butyl group of R7429, enhance the activity of 2-nitronaphtho[2,1-b]furan (R6597), whereas longer aliphatic chains decrease activity. Moreover, the activity of the nitro group at position 2 of the furan ring was increased by substitution of a methoxy group at position 7 of the R6597 structure. Additionally the n-octanol/water partition coefficient (log P) was found to be an important descriptor for the genotoxic potency in E. coli PQ37. Using the identified descriptors CASE correctly predicted the probability of genotoxicity of all of the genotoxicants and non-genotoxicants in the data base. The calculated genotoxic potency was equally good: 94% of all predicted results were within plus/minus one order of magnitude of the experimental result. Using CASE in the predictive mode, the program correctly predicted the probability of sfiA induction in E. coli of 95.8% of 24 "unknown" nitroarenofurans which were not part of the learning set (QSAR with r = 0.88-0.97).

Recent findings indicate that platelet-derived growth factor (PDGF) plays a role in the generation of reactive oxygen species (ROS) as second messengers in smooth muscle cells (SMC). To identify the source and signal transduction pathway of ROS formation in SMC, we investigated PDGF-induced ROS formation. Stimulation of SMC with PDGF resulted in a rapid increase of ROS production. Using an inactivating antibody, we identified the increase to be dependent on p22phox, a NAD(P)H-oxidase subunit. ROS release was completely inhibited by the Gi protein inhibitor PTX as well as an antibody against Galphai1,2, however, not by antibodies against Galphai3/0, Gas, and Gbeta1beta2. The effect of PDGF on ROS production in SMC membranes could likewise be mimicked by the use of a recombinant Galphai2 subunit but not by Galphai3, Galphai0, Gas, and Gbetagamma subunits. Immunoaffinity chromatography demonstrated coupling of Galphai1,2 to the PDGF a-receptor, which, after preincubation of the SMC membranes with PDGF, was increased in the absence of GTPgammaS but decreased in the presence of GTPgammaS and prevented by PTX treatment. These data define a novel G protein-dependent mechanism by which PDGF signaling is transduced through direct coupling of the Gai1,2 subunit of the trimeric G proteins to the PDGF tyrosine kinase receptor.

A 70-year-old female patient was admitted with progressive dyspnea and peripheral edema. The patient had a medical history of myocardial hypertrophy, diastolic dysfunction and concomitant pulmonary hypertension (PH).The physical exam was suggestive of cardiac decompensation. Echocardiography showed myocardial hypertrophy, an enlarged left atrium as well as enlarged right-sided heart chambers. A prominent tricuspid regurgitation jet was present, and the estimated systolic right ventricular pressure was 65 mmHg. Invasive hemodynamic measurements showed a marked pressure elevation in the pulmonary circulation (mean PAP 51 mmHg), combined with an elevated left ventricular end-diastolic pressure (LVEDP) of 30 mmHg and a profound increase in the transpulmonary gradient (TPG, 21 mmHg).The synopsis of these findings led to the diagnosis of postcapillary PH with a prominent precapillary involvement and cardiac decompensation. Due to signs of volume overload, an adequate diuretic therapy was initiated. The patient was recompensated and lost 7 kg of weight, which was associated with substantial clinical improvement. At invasive follow-up hemodynamic measurement, the patient's PAP was substantially decreased and almost reached normal values. The previously diagnosed precapillary involvement had disappeared.PH is a frequent phenomenon in patients with systolic and diastolic heart failure, and might initially appear as a combination of pre- and postcapillary involvement. The patients' volume status has a major influence on pulmonary hemodynamics. An adequate therapy of the underlying heart failure, especially an adequate diuresis, may have marked beneficial effects on pulmonary hemodynamics. Hemodynamic measurements should always be performed in compensated status.

We report an inelastic neutron scattering investigation of phonons with energies up to 159 meV in the conventional superconductor YNi(2)B(2)C. Using the sweep mode, a newly developed time-of-flight technique involving the continuous rotation of a single crystal specimen, allowed us to measure a four-dimensional volume in (Q, E) space and, thus, determine the dispersion surface and linewidths of the A(1g) (≈102 meV) and A(u) (≈159 meV) type phonon modes over the whole Brillouin zone. Despite of having linewidths of Γ=10 meV, A(1g) modes do not strongly contribute to the total electron-phonon coupling constant λ. However, experimental linewidths show a remarkable agreement with ab initio calculations over the complete phonon energy range, demonstrating the accuracy of such calculations in a rare comparison to a comprehensive experimental data set.

We report inelastic neutron scattering measurements of the resonant spin excitations in Ba(1-x)K(x)Fe(2)As(2) over a broad range of electron band filling. The fall in the superconducting transition temperature with hole doping coincides with the magnetic excitations splitting into two incommensurate peaks because of the growing mismatch in the hole and electron Fermi surface volumes, as confirmed by a tight-binding model with s(±)-symmetry pairing. The reduction in Fermi surface nesting is accompanied by a collapse of the resonance binding energy and its spectral weight, caused by the weakening of electron-electron correlations.

We report an inelastic neutron scattering study of acoustic phonons in the charge and orbitally ordered bilayer manganite LaSr(2)Mn(2)O(7). For excitation energies less than 15 meV, we observe an abrupt increase (decrease) of the phonon energies (linewidths) of a transverse acoustic phonon branch at q = (h, h, 0), h ≤ 0.3, upon entering the low temperature charge and orbital ordered state (T(COO) = 225 K). This indicates a reduced electron-phonon coupling due to a decrease of electronic states at the Fermi level leading to a partial removal of the Fermi surface below T(COO) and provides direct experimental evidence for a link between electron-phonon coupling and charge order in manganites.

We report inelastic x-ray scattering measurements of the temperature dependence of phonon dispersion in the prototypical charge-density-wave (CDW) compound 2H-NbSe2. Surprisingly, acoustic phonons soften to zero frequency and become overdamped over an extended region around the CDW wave vector. This extended phonon collapse is dramatically different from the sharp cusp in the phonon dispersion expected from Fermi surface nesting. Instead, our experiments, combined with ab initio calculations, show that it is the wave vector dependence of the electron-phonon coupling that drives the CDW formation in 2H-NbSe2 and determines its periodicity. This mechanism explains the so far enigmatic behavior of CDW in 2H-NbSe2 and may provide a new approach to other strongly correlated systems where electron-phonon coupling is important.

We analyze the effect of liquidated damage rules in exclusive contracts that are negotiated in a sequential bargaining process between one seller and two buyers with endogenous outside options. We show that assumptions on the distribution of bargaining power influence the size of the payment of damages and determine which contractual party benefits from including liquidated damage rules. Furthermore, we show that the effect of the payment of damages on the efficiency of the consummated deals depends on the possibility to sign more than one contract. Only if this is not possible, damage rules may prevent the breaking and entering of contracts and thus lead to inefficient deals in the market of corporate control, or allow for ‘naked’ exclusion in the context of supplier contracts with externalities.

Die Lungenembolie ist als meist thrombembolisch bedingte Verlegung einer oder mehrerer Pulmonalarterien mit der Folge einer plotzlich einsetzenden Gasaustauschstorung und einer akuten Druckbelastung des rechten Ventrikels definiert. Steigt der systolische Druck in der A. pulmonalis auf uber 30 mmHg oder der Mitteldruck auf uber 20 mmHg an, so spricht man vom akuten Cor pulmonale.

The structural determinants associated with inhibition of bacterial growth (Microtox assay), as well as those associated with other toxicological activities, were identified using the CASE/Multi-CASE structure-activity relational system. CASE/Multi-CASE also possesses the ability to compare structural determinants associated with different biological phenomena. The extent of the homology between structural determinants can be used to evaluate common mechanisms of action. Using this approach, significant commonalities between structural determinants associated with the Microtox assay and those associated with toxicity to mammals and fish were found, suggesting that there may be a mechanistic relationship between these toxicological activities. The findings indicate that, within these structural similarities, the Microtox assay can be used as an indicator of potential toxicity to mammals and fish.

The genotoxicities in vitro and in vivo of the mouse-skin carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) have been compared with those of its weakly carcinogenic 4,5-sulphur analogue, 6,11-dimethylbenzo[b]naphtho-[2,3-d]thiophene (S-DMBA). The only datasets that correlated with the relative carcinogenicity of these agents to the skin were those conducted using topically exposed mouse skin. Thus, both chemicals induced lacZ- mutations in the skin of lacZ+ transgenic mice, and both produced DNA adducts on mouse-skin DNA as assessed using the 32P-postlabeling technique. In each case, DMBA gave a stronger response than did S-DMBA. In contrast to these responses, only DMBA was active in the mouse bone-marrow micronucleus assay and in the C3H10T1/2 in vitro cell transformation assay. Both chemicals were mutagenic to Salmonella and of approximately equal potency. The molecular geometry of DMBA and S-DMBA are compared, and divergent CASE predictions of activity in the Salmonella assay and skin-painting bioassay are discussed. The importance of conducting predictive genotoxicity assays in systems close to those in which carcinogenicity is to be assessed is emphasized by these data.

The CASE program, an expert structure-activity relational system, was used to identify the structural determinants associated with inhibition of the human isozyme P4502D, toxicity of cultured murine Balb 3T3 cells, induction of alpha 2u-globulin-associated nephropathy in male rats, systemic toxicity in mice and rats, and acute toxicity in minnows. Comparison of the structural determinants thus identified revealed a significant mechanistic overlap between the determinants of cellular toxicity and systemic toxicity in mice, rats, and minnows.

An analysis of a number of data bases revealed a dichotomy between the lipophilicity of groups of agents capable of inducing genotoxicity in vitro and in vivo. Thus agents with the potential for reacting with cellular DNA, inducing mutations in Salmonella and clastogenicity in cultured cells were characteristically significantly more hydrophilic than agents which did not induce such effects. On the other hand, in vivo inducers of clastogenicity (micronuclei) were significantly more lipophilic than non-inducers. Cellular and systemic toxicants were also more lipophilic than non-toxicants.

The computer-automated structure evaluation (CASE) methodology has been used to investigate the correlation between chemical structure and rate of biodegradation. A training set consisting of 283 diverse organic chemicals of known biodegradation activity was evaluated. Computer-automated structure evaluation identified six major activating fragments that contained oxygen in a carbonyl or hydroxyl group, suggesting that the presence of oxygen plays a significant role in biodegradation. The training set predicts the biodegradation categories correctly 74% of the time for an independent validation set of 27 chemicals. By also using a data base of diverse chemicals whose activity was based on acclimated inocula, two prediction results were obtained for each of the 27 chemicals of an independent validation set. Analysis of the results showed that the chemicals could be grouped into five prediction categories. Two of these categories included chemicals for which both data bases predicted exactly the same activity, whereas a third category contained two chemicals for which no conclusion was made. The other two categories include chemicals of intermediate activity, that is, chemicals that can undergo slow or fast biodegradation, depending on the conditions. In addition, the identification of activating structural fragments has provided information on mechanisms for biodegradation in the environment.

A method is described for using the fragments identified by the CASE structure-activity relational expert system to identify the type of chemicals that require further testing in mutagenicity and clastogenicity assays. Inclusion of such chemicals will increase the informational content of databases with respect to structural features that are under-represented in currently available data bases. The method is applied to existing databases (mutagenicity in Salmonella, chromosomal aberrations in Chinese hamster ovary cells, unscheduled DNA synthesis in rat hepatocytes, in vivo induction of micronuclei, somatic mutations in Drosophila melanogaster) to identify structural determinants that are absent.