Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Chem-tox informatics: data mining using a medicinal chemistry building block approach.

Relating chemical structure to biological activity is not a new endeavor, however, the ability to do this on large datasets is just emerging. To cope with the enormous amounts of data being generated, an assortment of computational methods has been developed in the fields of chemoinformatics and computational toxicology. Many of the molecular descriptors used in these approaches are abstract, theoretical constructs that are difficult to understand and visualize. Having easily recognized chemical features, such as those in several new programs, will allow chemists to use toxicological information (or any biological information) when designing new libraries. These improved chem-tox informatics systems will have an impact on library design, hit and lead optimization, development candidate testing and regulatory review.

LeadScope: software for exploring large sets of screening data.

Modern approaches to drug discovery have dramatically increased the speed and quantity of compounds that are made and tested for potential potency. The task of collecting, organizing, and assimilating this information is a major bottleneck in the discovery of new drugs. We have developed LeadScope a novel, interactive computer program for visualizing, browsing, and interpreting chemical and biological screening data that can assist pharmaceutical scientists in finding promising drug candidates. The software organizes the chemical data by structural features familiar to medicinal chemists. Graphs are used to summarize the data, and structural classes are highlighted that are statistically correlated with biological activity.

A plaque index for occlusal surfaces and fissures. Measurement of repeatability and plaque removal.

Plaque indices have largely been developed for buccal and lingual tooth surfaces. There has been minimal interest in plaque accumulation on occlusal surfaces despite the predilection for caries at these sites. A numerical plaque index (0-5) is described based on the presence and distribution of plaque in the fissures and over the occlusal surfaces of permanent molar and premolar teeth. The repeatability of a single examiner in scoring the index was performed using 4 groups of 10 subjects. Each group of volunteers suspended tooth cleaning for 48 h and the index scored after disclosing plaque deposits. The index was rescored 60-90 min later. Plaque area was also determined by drawing the outline of plaque onto grids. Except for one condition of repeatability for one group, the 4 conditions of repeatability in scoring the index were met for all 4 groups of subjects. The sensitivity of the index and area recordings to detect plaque removed by brushing was then evaluated. A group of 10 subjects had plaque scored by index and area after suspending toothcleaning for 48 h. Subjects were then randomly allocated to brush or not brush their teeth and plaque rescored. The experiment was then repeated and brushing or not brushing crossed over. Highly significant differences between brushing and no brushing plaque indices and areas were determined. In conclusion, the occlusal fissure plaque index was easy to apply, repeatable and sufficiently sensitive to detect plaque removed by brushing. The index could find use as an additional measure of oral hygiene, in clinical trials on plaque control and possibly epidemiological studies relating to caries.

The cardiopulmonary cost of backward walking at selected speeds.

Backward walking has been advocated as a method of maintaining cardiovascular conditioning in patients undergoing knee rehabilitation because it may decrease patellofemoral joint compressive forces. The primary purpose of this study was to determine the relationship between the rate of oxygen consumption (VO2) and backward walking speed. Twenty-five healthy males, aged 18-35 years, participated in this study. The rate of oxygen consumption and heart rate were measured at the backward walking speeds of 0.89, 1.12, 1.34, 1.56, and 1.79 m/sec (2.0, 2.5, 3.0, 3.5, and 4.0 miles/hour, respectively). Analysis revealed a direct, curvilinear relationship between VO2 and backward walking speed. This research provides information that can be used to prescribe a backward walking rehabilitation program which may be appropriate to maintain aerobic fitness levels during rehabilitation of patients with patellofemoral pain syndrome.

SPROUT: recent developments in the de novo design of molecules.

SPROUT is a computer program for constrained structure generation. It is designed to generate molecules for a range of applications in molecular recognition. The program uses a number of approximations that enable a wide variety of diverse structures to be generated. Practical use of the program is demonstrated in two examples. The first demonstrates the ability of the program to generate candidate inhibitors for a receptor site of known 3D structure, specifically the GDP binding site of p21. In the second example, structures are generated to fit a pharmacophore hypothesis that models morphine agonists.

Female sexual behavior in the golden hamster following kainic acid lesions in the lateral septal area.

Patterns of female sexual behavior in the hamster are qualitatively different from that observed in the rat. Hamsters demonstrate tonic immobility and a sustained lordotic response that can last for several minutes following minimal stimulation from the male while in rats, the lordotic response is highly dependent upon continued stimulation from the male and lasts for only a few seconds following a mount or intromission. Also, the hamster requires both estrogen and progesterone priming in order to display female sexual behavior but the rat can show lordotic behavior following treatment with estrogen alone. Electrolytic lesions in the lateral septal area of female rats produce a facilitation in female sexual behavior and increase behavioral sensitivity to estrogen. However, lesions in the lateral septal area of rats produced by the neurotoxin kainic acid (KA) result in deficits in female sexual behavior following estrogen and progesterone treatment. Given these species differences in sexual behavior, we have examined the effects of KA lesions in the lateral septal area of hamsters on female sexual behavior. Adult female golden hamsters were ovariectomized and tested for female sexual behavior prior to receiving brain surgery. For all behavior tests, animals were injected SC with 60 micrograms of estradiol benzoate/kg per day for two days and 0.5 mg of progesterone three hours prior to the behavior test on day three. Behavior tests consisted of placing the test animal in a male's home cage for 10 minutes and recording the latency to the first lordosis, length of the longest single bout of lordosis and total lordosis duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Further evidence for hypothalamic asymmetry in endocrine control of the ovary.

The differential release of FSH and LH associated with hemigonadectomy (hemi-x) of prepubertal male rats can be blocked by unilateral hypothalamic deafferentation located on the side ipsilateral, but not contralateral, to the hemi-x. Also, ovarian compensatory hypertrophy (OCH) in prepubertal female rats can be blocked by ipsilateral, but not contralateral, hypothalamic hemi-islands. Both these endocrine phenomenon are limited to knife cuts on a particular side of the brain. These results suggest that there are neural connections with the gonads which are involved in endocrine regulation and that hypothalamic control of the endocrine system may be asymmetrically organized. In support of this, the present study shows that in adult female rats, unilateral injections of the excitotoxin kainic acid (1.0 microgram in 1.0 microliter) into the retrochiasmatic area of the hypothalamus can block OCH if the injections are located on the side ipsilateral to the hemi-x. This phenomenon was more apparent if the lesions and hemi-x were located on the right side. In addition, neither hemi-x nor kainic acid injections alone had any effect on vaginal cycles, whereas the combination of these two treatments reduced the incidence of estrus. However, these effects on vaginal cycles were not specifically associated with lesions or hemi-x on a particular side, thus excluding this as an explanation of the different endocrine effects of kainic acid on the two sides of the brain. These results support the evidence for a direct neural contribution to endocrine control and further suggest a functional difference in the two-halves of the hypothalamus in neuroendocrine regulation.

Serum lipoproteins and atherosclerosis in animals.

The lipoproteins have been examined in more than 300 serum or plasma samples taken during life or at post mortem from a fairly wide range of mammals, birds and reptiles. The material, which was collected over a period of several years, was subjected to a limited range of lipid analyses, but all specimens were submitted to electrophoresis with paper or cellulose acetate membrane as supporting medium. The lipoprotein pattern in mammals appears to be basically similar to that in man, but there are wide variations in lipid concentrations; the highest levels being found in bears, seals and primates. High concentrations were also observed in many birds and a few reptiles, but the lipoprotein patterns in these vertebrates differ from those in mammals and are further greatly modified by oviparity. Semi-quantitative data on the degree of atherosclerosis were available on the animals that died. There was only a crude positive correlation between the intensity of the arterial disease and high serum beta-lipoprotein levels, and it was concluded that the latter are probably of only secondary importance in the development of spontaneous atherosclerosis in animals.