Ernst R. Dow

The use of neural networks for variable selection in QSAR

Abstract The application of a back-propagation neural network has been found to be an efficient and effective tool to identify pertinent variables for QSAR studies.

Changes in Osteoblast, Chondrocyte, and Adipocyte Lineages Mediate the Bone Anabolic Actions of PTH and Small Molecule GSK‐3 Inhibitor

Parathyroid hormone (PTH) and glycogen synthase kinase‐3 (GSK‐3) inhibitor 603281‐31‐8, administered once daily increased bone formation in vivo. We investigated the molecular mechanisms of the anabolic responses of PTH and 603281‐31‐8 in rat osteopenia model. Female 6‐month‐old rats were ovariectomized (Ovx) and permitted to lose bone for 1 month, followed by treatment with PTH (1–38) at 10 µg/kg/day s.c. or 603281‐31‐8 at 3 mg/kg/day p.o. for 60 days. Twenty‐four hours after the last treatment, RNA from distal femur metaphysis was subjected to gene expression analysis. Differentially expressed genes (P < 0.05) were subjected to pathway analysis to delineate relevant bio‐processes involved in skeletal biology. Genes involved in morphogenesis, cell growth/differentiation, and apoptosis were significantly altered by Ovx and the treatments. Analysis of morphogenesis genes showed an overrepresentation of genes involved in osteogenesis, chondrogenesis, and adipogenesis. A striking finding was that Ovx decreased several markers of osteogenesis/chondrogenesis and increased markers of adipogenesis/lipid metabolism. Treatment with either PTH or the GSK‐3 inhibitor reversed these effects, albeit at different levels. Histological analysis confirmed that osteopenia in Ovx animals was associated with three‐fold increase in marrow adiposity. PTH and GSK‐3 inhibitor restored bone volume, and reversed or normalized marrow adiposity. Ex vivo studies showed that PTH and GSK‐3 inhibitor increased the ratio of colony forming marrow stromal progenitors (CFU‐fs) that were alkaline phosphatase positive (putative osteoblasts). Our results suggest that the bone anabolic actions of PTH and GSK‐3 inhibitor in vivo involve concerted effects on mesenchymal lineages; osteoblasts, chondrocytes, and adipocytes. J. Cell. Biochem. 102: 1504–1518, 2007.

Assessment of Diet-induced Obese Rats as an Obesity Model by Comparative Functional Genomics

Objective: We applied a comparative functional genomics approach to evaluate whether diet‐induced obese (DIO) rats serve as an effective obesity model.

Evolutionary computation for discovery of composite transcription factor binding sites.

Previous research demonstrated the use of evolutionary computation for the discovery of transcription factor binding sites (TFBS) in promoter regions upstream of coexpressed genes. However, it remained unclear whether or not composite TFBS elements, commonly found in higher organisms where two or more TFBSs form functional complexes, could also be identified by using this approach. Here, we present an important refinement of our previous algorithm and test the identification of composite elements using NFAT/AP-1 as an example. We demonstrate that by using appropriate existing parameters such as window size, novel-scoring methods such as central bonusing and methods of self-adaptation to automatically adjust the variation operators during the evolutionary search, TFBSs of different sizes and complexity can be identified as top solutions. Some of these solutions have known experimental relationships with NFAT/AP-1. We also indicate that even after properly tuning the model parameters, the choice of the appropriate window size has a significant effect on algorithm performance. We believe that this improved algorithm will greatly augment TFBS discovery.

Induction of periodic alternating nystagmus in intact goldfish by sinusoidal rotation

DURING movement, the vestibulo-ocular reflex (VOR) normally maintains retinal image stability by making slow-phase eye rotations that counterbalance head rotations. These eye rotations are nystagmic when the on-going slow-phases are interrupted by fast-phase eye rotations that reset eye position. Periodic alternating nystagmus (PAN) is an eye-movement disorder characterized by uncontrollable nystagmus that alternates direction roughly sinusoidally (at about 0.005 Hz). PAN has been observed only in humans with cerebellar disorders and in monkeys with lesions to the cerebellar nodulus and uvula. We show experimentally in intact goldfish that prolonged rotation in darkness for 1 h at specific frequencies (0.05–0.1 Hz) induces PAN, upon which the normal VOR response is superimposed. We show computationally that rotation-induced PAN may result from decreased cerebellar inhibition of VOR brain stem neural pathways.

Analysis and Neural Network Modeling of the Nonlinear Correlates of Habituation in the Vestibulo-ocular Reflex

Through the process of habituation, continued exposure to low-frequency (0.01 Hz) rotation in the dark produced suppression of the low-frequency response of the vestibulo-ocular reflex (VOR) in goldfish. The response did not decay gradually, as might be expected from an error-driven learning process, but displayed several nonlinear and nonstationary features. They included asymmetrical response suppression, magnitude-dependent suppression for lower- but not higher-magnitude head rotations, and abrupt-onset suppressions suggestive of a switching mechanism. Microinjection of lidocaine into the vestibulocerebellum of habituated goldfish resulted in a temporary dishabituation. This suggests that the vestibulocerebellum mediates habituation, presumably through Purkinje cell inhibition of vestibular nuclei neurons. The habituated VOR data were simulated with a feed-forward, nonlinear neural network model of the VOR in which only Purkinje cell inhibition of vestibular nuclei neurons was varied. The model suggests that Purkinje cell inhibition may switch in to introduce nonstationarities, and cause asymmetry and magnitude-dependency in the VOR to emerge from the essential nonlinearity of vestibular nuclei neurons.

Violation of superposition by the vestibulo-ocular reflex of the goldfish

The vestibulo-ocular reflex (VOR) allows animals to move and see simultaneously by stabilizing the eyes in space. Previous experiments have largely confirmed the assumption that the VOR behaves as a linear system. However, a linear system must obey the superposition principle: its response to a periodic stimulus at any frequency must be the same whether that stimulus is presented alone or combined with stimuli at other frequencies. We first habituated the VOR in goldfish to low-frequency stimulation, which reduced low-frequency VOR gain. We then observed that the low-frequency gain increased almost 20-fold when the low-frequency stimulus was combined with a higher-frequency stimulus. This demonstrated for the first time a violation of superposition by the VOR. The VOR dishabituated and obeyed superposition following removal of the cerebellum.

Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab

To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52‐week, randomized, placebo‐controlled, double‐blind studies in which patients were treated with the BAFF‐blocking IgG4 monoclonal antibody tabalumab.

Analysis and modeling of frequency-specific habituation of the goldfish vestibulo-ocular reflex

Modification of the vestibulo-ocular reflex (VOR) by vestibular habituation is an important paradigm in the study of neural plasticity. The VOR is responsible for rotating the eyes to maintain the direction of gaze during head rotation. The response of the VOR to sinusoidal rotation is quantified by its gain (eye rotational velocity/head rotational velocity) and phase difference (eye velocity phase—inverted head velocity phase). The frequency response of the VOR in naïve animals has been previously modeled as a high-pass filter (HPF). A HPF passes signals above its corner frequency with gain 1 and phase 0 but decreases gain and increases phase lead (positive phase difference) as signal frequency decreases below its corner frequency. Modification of the VOR by habituation occurs after prolonged low-frequency rotation in the dark. Habituation causes a reduction in low-frequency VOR gain and has been simulated by increasing the corner frequency of the HPF model. This decreases gain not only at the habituating frequency but further decreases gain at all frequencies below the new corner frequency. It also causes phase lead to increase at all frequencies below the new corner frequency (up to some asymptotic value). We show that habituation of the goldfish VOR is not a broad frequency phenomena but is frequency specific. A decrease in VOR gain is produced primarily at the habituating frequency, and there is an increase in phase lead at nearby higher frequencies and a decrease in phase lead at nearby lower frequencies (phase crossover). Both the phase crossover and the frequency specific gain decrease make it impossible to simulate habituation of the VOR simply by increasing the corner frequency of the HPF model. The simplest way to simulate our data is to subtract the output of a band-pass filter (BPF) from the output of the HPF model of the naïve VOR. A BPF passes signals over a limited frequency range only. A BPF decreases gain and imparts a phase lag and lead, respectively, as frequency increases and decreases outside this range. Our model produces both the specific decrease in gain at the habituating frequency, and the phase crossover centered on the frequency of habituation. Our results suggest that VOR habituation may be similar to VOR adaptation (in which VOR modification is produced by visual-vestibular mismatch) in that both are frequency-specific phenomena.

Abstracting genes to gene ontology terms allows comparison across multiple species

Comparing lists of genes generated from microarray analyses is tedious and subjective. The numbers of genes that change can be in the thousands and each gene typically has multiple functions. Clustering approaches simply produce smaller groups of genes. Furthermore, comparing experiments across species interjects an additional complication to data analysis - the genomes are not the same, making direct gene comparisons difficult or impossible. We were able to partially address this issue by abstracting the genes to gene ontology (GO) terms and testing for significance using a hypergeometric distribution function. To test the algorithm, mouse, rat, and dog were treated with LPS, a bacterial cell wall component that causes an acute phase response, and gene expression changes were compared. The GO terms are displayed using a hyperbolic viewer, allowing the biologist to navigate the data in a known framework. A GO term can be readily identified as significantly enriched in all 3 species, although there are relatively few identical genes.