Faculty Bibliography

Background:gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. Methods:in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Results:mice, with an increase in the gamma band. Conclusions:mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes.

Biomolecular networks have already found great utility in characterizing complex biological systems arising from pairwise interactions amongst biomolecules. Here, we explore the important and hitherto neglected role of information asymmetry in the genesis and evolution of such pairwise biomolecular interactions. Information asymmetry between sender and receiver genes is identified as a key feature distinguishing early biochemical reactions from abiotic chemistry, and a driver of network topology as biomolecular systems become more complex. In this context, we review how graph theoretical approaches can be applied not only for a better understanding of various proximate (mechanistic) relations, but also, ultimate (evolutionary) structures encoded in such networks from among all types of variations they induce. Among many possible variations, we emphasize particularly the essential role of gene duplication in terms of signaling game theory, whereby sender and receiver gene players accrue benefit from gene duplication, leading to a preferential attachment mode of network growth. The study of the resulting dynamics suggests many mathematical/computational problems, the majority of which are intractable yet yield to efficient approximation algorithms, when studied through an algebraic graph theoretic lens. We relegate for future work the role of other possible generalizations, additionally involving horizontal gene transfer, sexual recombination, endo-symbiosis, etc., which enrich the underlying graph theory even further.

BACKGROUND/AIMS/OBJECTIVE:Ouabain, a well-known plant-derived toxin, is also a hormone found in mammals at nanomolar levels that binds to a site located in the a-subunit of Na⁺,K⁺-ATPase. Our main goal was to understand the physiological roles of ouabain. Previously, we found that ouabain increases the degree of tight junction sealing, GAP junction-mediated communication and ciliogenesis. Considering our previous results, we investigated the effect of ouabain on adherens junctions. METHODS:We used immunofluorescence and immunoblot methods to measure the effect of 10 nM ouabain on the cellular and nuclear content of E-cadherin, β-catenin and γ-catenin in cultured monolayers of Marin Darby canine renal cells (MDCK). We also studied the effect of ouabain on adherens junction biogenesis through sequential Ca²⁺ removal and replenishment. Then, we investigated whether c-Src and ERK1/2 kinases are involved in these responses. RESULTS:Ouabain enhanced the cellular content of the adherens junction proteins E-cadherin, β-catenin and γ-catenin and displaced β-catenin and γ-catenin from the plasma membrane into the nucleus. Ouabain also increased the expression levels of E-cadherin and β-catenin in the plasma membrane after Ca²⁺ replenishment. These effects on adherens junctions were sensitive to PP2 and PD98059, suggesting that they depend on c-Src and ERK1/2 signaling. The translocation of β-catenin and γ-catenin into the nucleus was specific because ouabain did not change the localization of the tight junction proteins ZO-1 and ZO-2. Moreover, in ouabain-resistant MDCK cells, which express a Na⁺,K⁺-ATPase α1-subunit with low affinity for ouabain, this hormone was unable to regulate adherens junctions, indicating that the ouabain receptor that regulates adherens junctions is Na⁺,K⁺-ATPase. CONCLUSION/CONCLUSIONS:Ouabain (10 nM) upregulated adherens junctions. This novel result supports the proposition that one of the physiological roles of this hormone is the modulation of cell contacts.

Stable isotope labeling by amino acids in cell culture (SILAC) is a powerful approach for high-throughput quantitative proteomics. SILAC allows highly accurate protein quantitation through metabolic encoding of whole cell proteomes using stable isotope labeled amino acids. Since its introduction in 2002, SILAC has become increasingly popular. In this chapter we review the methodology and application of SILAC, with an emphasis on three research areas: dynamics of posttranslational modifications, protein-protein interactions, and protein turnover.

Behavioral choices made by the brain during stress depend on glucocorticoid and brain-derived neurotrophic factor (BDNF) signaling pathways acting in synchrony in the mesolimbic (reward) and corticolimbic (emotion) neural networks. Deregulated expression of BDNF and glucocorticoid receptors in brain valuation areas may compromise the integration of signals. Glucocorticoid receptor phosphorylation upon BDNF signaling in neurons represents one mechanism underlying the integration of BDNF and glucocorticoid signals that when off balance may lay the foundation of maladaptations to stress. Here, we propose that BDNF signaling conditions glucocorticoid responses impacting neural plasticity in the mesocorticolimbic system. This provides a novel molecular framework for understanding how brain networks use BDNF and glucocorticoid signaling contingencies to forge receptive neuronal fields in temporal domains defined by behavioral experience, and in mood disorders.