Managing laboratory automation: integration and informatics in drug discovery

Drug discovery today requires the focused use of laboratory automation and other resources in combinatorial chemistry and high-throughput screening (HTS). The ultimate value of both combinatorial chemistry and HTS technologies and the lasting impact they will have on the drug discovery process is a chapter that remains to be written. Central to their success and impact is how well they are integrated with each other and with the rest of the drug discovery processes-informatics is key to this success. This presentation focuses on informatics and the integration of the disciplines of combinatorial chemistry and HTS in modern drug discovery. Examples from experiences at Neurogen from the last five years are described.     

Attentional skills following traumatic brain injury in childhood: a componential analysis

Recent research has documented residual deficits in attention following traumatic brain injury in childhood. The present study aimed to investigate whether such deficits are global, or affect specific components of attention differentially. Four attentional domains were examined using a newly developed test of attention, the Test of Everyday Attention for Children: sustained attention, focussed attention, divided attention, and response inhibition. Eighteen children with a history of traumatic brain injury, aged between 8 and 14 years, and 18 non-injured matched controls participated in the study. Results indicated that attentional skills may be differentially impaired after TBI, with children who have sustained moderate-to-severe TBI exhibiting significant deficits for sustained and divided attention, and response inhibition, but relatively intact focussed attention.     

Growth-related and antennular amputation-induced changes in the olfactory centers of crayfish brain

Freshwater crayfish increase in size throughout their lives, and this growth is accompanied by an increase in the length of the appendages and number of mechanoreceptive and chemoreceptive sensilla on them. We find that in the Australian freshwater crayfish Cherax destructor, neuropil volumes of the olfactory centers increase linearly with body size over the entire size range of animals found in their natural habitat. The number of cell somata of two groups of interneurons associated with the olfactory centers (projection neurons and small local neurons) also increases linearly with the size of the animals. In contrast, axon counts of interneurons that represent a nonolfactory input to the olfactory centers show that these reach a total number in the very early adult stages that then remains constant regardless of the size of the animal. Only the axon diameter of these interneurons increases linearly with body size. Amputation of the antennule and olfactory sensilla reduces the number of projection and local interneurons on the amputated side. No change in the size of the olfactory centers occurs on the unamputated side. Amputation of the olfactory receptor neurons in crayfish therefore leads not only to a degeneration of the receptor cell endings in the olfactory lobe but also to a trans-synaptic response in which the number of higher order neurons decreases. Reconstitution of the antennule and olfactory receptor neurons in small adult crayfish is accompanied by the reestablishment of the normal number of interneurons and neuropil volume in the olfactory centers.     

Cognitive test performance among nondemented elderly African Americans and whites

We examined the neuropsychological test performance of a randomly selected community sample of English-speaking non-Hispanic African American and white elders in northern Manhattan. All participants were diagnosed as nondemented by a neurologist, whose assessment was made independent of neuropsychological test scores. African American elders obtained significantly lower scores on measures of verbal and nonverbal learning and memory, abstract reasoning, language, and visuospatial skill than whites. After using a stratified random sampling technique to match groups on years of education, many of the discrepancies became nonsignificant; however, significant ethnic group differences on measures of figure memory, verbal abstraction, category fluency, and visuospatial skill remained. Discrepancies in test performance of education-matched African Americans and whites could not be accounted for by occupational attainment or history of medical conditions such as hypertension and diabetes. These findings emphasize the importance of using culturally appropriate norms when evaluating ethnically diverse elderly for dementia.     

Do neuropsychological tests have the same meaning in Spanish speakers as they do in English speakers?

Objective: The purpose of this study was to examine whether neuropsychological tests translated into Spanish measure the same cognitive constructs as the original English versions. Method: Older adult participants (N = 2,664), who did not exhibit dementia from the Washington Heights Inwood Columbia Aging Project (WHICAP), a community-based cohort from northern Manhattan, were evaluated with a comprehensive neuropsychological battery. The study cohort includes both English (n = 1,800) and Spanish speakers (n = 864) evaluated in their language of preference. Invariance analyses were conducted across language groups on a structural equation model comprising four neuropsychological factors (memory, language, visual-spatial ability, and processing speed). Results: The results of the analyses indicated that the four-factor model exhibited partial measurement invariance, demonstrated by invariant factor structure and factor loadings but nonequivalent observed score intercepts. Conclusion: The finding of invariant factor structure and factor loadings provides empirical evidence to support the implicit assumption that scores on neuropsychological tests are measuring equivalent psychological traits across these two language groups. At the structural level, the model exhibited invariant factor variances and covariances. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of African-American acculturation on neuropsychological test performance in normal and HIV-positive individuals. The HIV Neurobehavioral Research Center (HNRC) Group

The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.     

The efficacy of toddler-parent psychotherapy to reorganize attachment in the young offspring of mothers with major depressive disorder: A randomized preventive trial.

The development of insecure attachment relationships in the offspring of mothers with major depressive disorder (MDD) may initiate a negative trajectory leading to future psychopathology. Therefore, the provision of theoretically guided interventions designed to promote secure attachment is of paramount importance. Mothers who had experienced MDD since their child's birth were recruited (n = 130) and randomized to toddler-parent psychotherapy (DI) or to a control group (DC). Nondepressed mothers with no current or history of major mental disorder and their toddlers also were recruited for a nondepressed comparison group (NC; n = 68). Children averaged 20.34 months of age at the initial assessment. Higher rates of insecure attachment were present in both the DI and the DC groups at baseline, relative to the NC group. At postintervention, at age 36 months, insecure attachment continued to predominate in the DC group. In contrast, the rate of secure attachment had increased substantially in the DI group and was higher than that for the DC and the NC groups. These results demonstrate the efficacy of toddler-parent psychotherapy in fostering secure attachment relationships in young children of depressed mothers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of time-on-task and concurrent cognitive load on normal visuospatial bias.

Research suggests that the severity of left spatial neglect can be modulated by changes in general alertness. Analogous effects in healthy volunteers now suggest that this may reflect an amplified form of a normal pattern. Recent neuropsychological studies also suggest that concurrent cognitive load may exacerbate rightward bias. In this study, for the first time, the authors examined the effect of both factors on spatial bias in healthy volunteers. Participants performed a task in which as many letters as possible needed to be reported from a briefly presented visual array under three conditions (alone, with a syllable-discrimination secondary task and with a pitch-discrimination secondary task). The results confirmed a significant rightward shift associated with time-on-task across all conditions--the first demonstration of such an effect within a fixation controlled, brief presentation task. While the secondary tasks influenced overall visual performance, there was no discernable effect on bias. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of models on food intake of obese and non-obese female college students.

Compared the effects of a model on the food intake of obese and nonobese females. 20 obese and 20 nonobese female Ss were paired with an experimental confederate who was either obese or nonobese. Analysis of the amount of food eaten revealed an interaction between weight status and type of confederate: obese Ss ate significantly more in the presence of an obese confederate. By contrast, nonobese Ss ate a similar amount in both conditions. There was a significant difference between the amount Ss ate and the amount they reported they had eaten, due largely to the fact that obese Ss underestimated the amount of food they had eaten. (French summary) (13 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Auditory sustained attention is a marker of unilateral spatial neglect

The relationships between performance on a non-spatially-lateralized measure of sustained attention and spatial bias on tests sensitive to unilateral neglect were considered in a group of 44 patients with right hemisphere lesions following stroke. As predicted from earlier studies showing a strong association between unilateral spatial neglect and sustained attention, performance on a brief and monotonous tone-counting measure formed a significant predictor of spatial bias across a variety of measures of unilateral visual neglect. This study provides further evidence for a very close link between two attentional systems hitherto regarded as being quite separate, namely a spatial attention system implicated in unilateral neglect and a sustained attention system. A close connection between these two systems was predicted by Posner, who argued that the right hemisphere-dominant sustained attention system provides a strong modulatory influence on the functioning of the lateralized posterior attention system.