Faculty Bibliography

Hybrid systems are dynamical systems with the ability to describe mixed discrete-continuous evolution of a wide range of systems. Consequently, at first glance, hybrid systems appear powerful but recalcitrant, neither yielding to analysis and reasoning through a purely continuous-time modeling as with systems of differential equations, nor open to inferential processes commonly used for discrete state-transition systems such as finite state automata. A convenient and popular model, called hybrid automata, was introduced to model them and has spurred much interest on its tractability as a tool for inference and model checking in a general setting. Intuitively, a hybrid automaton is simply a 'finite-state' automaton with each state augmented by continuous variables, which evolve according to a set of well-defined continuous laws, each specified separately for each state. This article investigates both the notion of hybrid automaton and the model checking problem over such a structure. In particular, it relates first-order theories and analysis results on multivalued maps and reduces the bounded reachability problem for hybrid automata whose continuous laws are expressed by inclusions (x' is an element of f (x,t)) to a decidability problem for first-order formula? over the reals. Furthermore, the paper introduces a class of hybrid automata for which the reachability problem can be decided and shows that the problem of deciding whether a hybrid automaton belongs to this class can be again decided using first-order formulae over the reals. Despite the fact that the bisimulation quotient for this class of hybrid automata can be infinite, we show that our techniques permit effective model checking for a nontrivial fragment of CTL. (C) 2008 Elsevier Inc. All rights reserved

Stress triggers changes in gene expression mediating important adaptive and maladaptive responses. The full repertoire of genes whose expression in the adrenal medulla is altered by stress has not been previously determined. In this study, gene profiling (RAE 230 2.0 Affymetrix) was applied to elucidate global changes in gene expression in adrenal medulla of rats exposed to 2-h immobilization (IMO) stress once or repeatedly for 6 consecutive days. The number of transcripts significantly (P < 0.01) altered with single IMO (651 up, 487 down) was more than with repeated IMO (370 up, 195 down). The annotated transcripts were further analyzed and categorized. The largest numbers of changes were in mRNA levels in the transcription factor and cell signaling categories. Robust changes were also observed in transcripts related to growth factors, apoptosis, neurosecretion/neuropeptides, heat shock proteins, structural proteins, chemokines, cytokines, metabolism/lipid-metabolism, and proteases. Many (>80%) were uniquely induced by single IMO. About half of transcripts changed by repeated IMO were also responsive to single IMO. Pathway analysis was applied to identify direct interactions and common targets among gene products altered by single and repeated IMO. In this paper, we briefly describe the most pronounced changes observed, with emphasis on those that may provide new insight into the common and distinct mechanisms whereby the adrenal medulla responses to a first encounter with stress compared to repeated exposure to the same stressor.

Directed indels, insertions or deletions within paralogous genes, have the potential to root the tree of life. Here we apply the top-down rooting algorithm to indels found in PyrD (dihydroorotate dehydrogenase), a key enzyme involved in the de novo biosynthesis of pyrimidines, and HisA (P-ribosylformimino-AICAR-P-isomerase), an essential enzyme in the histidine biosynthesis pathway. Through the comparison of each indel with its two paralogous outgroups, we exclude the root of the tree of life from the clade that encompasses the Actinobacteria, the double-membrane prokaryotes, and their last common ancestor. In combination with previous indel rooting studies excluding the root from a clade consisting of the Firmicutes, the Archaea, and their last common ancestor, this provides evidence for a unique eubacterial root for the tree of life located between the actinobacterial-double-membrane clade and the archaeal-firmicute clade. Mapping the phylogenetic distributions of genes involved in peptidoglycan and lipid synthesis onto this rooted tree parsimoniously implies that the cenancestral prokaryotic population consisted of organisms enclosed by a single, ester-linked lipid membrane, covered by a peptidoglycan layer.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to mutations in desmosomal proteins, including plakophilin-2 (PKP2). Little is known about the changes in cellular function and structure that follow expression of ARVC-relevant PKP2 mutations. OBJECTIVE: The purpose of this study was to investigate the function and distribution of an ARVC-relevant PKP2 mutant where arginine at position 79 was replaced by a stop codon (R79x). METHODS: Results were compared with those obtained with mutation 179fs (frameshift at position 179). Mutant constructs were introduced by adenoviral infection into neonatal rat ventricular myocytes in culture. RESULTS: Both mutant proteins failed to preferentially localize to sites of cell-cell apposition. Their expression did not disrupt localization of endogenous PKP2, connexin-43 (Cx43), or desmoplakin (DP). However, we observed reduced abundance of Cx43 after R79x expression. Early truncation of PKP2 at position 79 also prevented its physical interaction with both DP and Cx43. Finally, R79x expression correlated with loss of expression of HSP90, a protein relevant to cardiomyocyte apoptosis. CONCLUSION: These results provide the first observations of the cellular/molecular phenotype consequent to these PKP2 mutations and give insight into the possible cellular substrates that lead to ARVC

The goal of the present study was to compare six transposing signal-processing algorithms based on different principles (Fourier-based and modulation based), and to choose the algorithm that best enables identification of environmental sounds, i.e. improves the ability to monitor events in the surroundings. Ten children (12-15 years) and 10 adults (21-33 years) with normal hearing listened to 45 representative environmental (events) sounds processed using the six algorithms, and identified them in three different listening experiments involving an increasing degree of experience. The sounds were selected based on their importance for normal hearing and deaf-blind subjects. Results showed that the algorithm based on transposition of 1/3 octaves (fixed frequencies) with large bandwidth was better (p<0.015) than algorithms based on modulation. There was also a significant effect of experience (p<0.001). Adults were significantly (p<0.05) better than children for two algorithms. No clear gender difference was observed. It is concluded that the algorithm based on transposition with large bandwidth and fixed frequencies is the most promising for development of hearing aids to monitor environmental sounds

Aplasia cutis congenita (ACC) in a symmetric, stellate pattern on the trunk or extremities is classically associated with a fetus papyraceus. We report symmetric truncal ACC in a neonate born of a sextuplet pregnancy that had been reduced to twins. This case highlights truncal ACC as a consequence of modern reproductive medicine

Endometriosis is a common gynecological disease that affects approximately 10% of women of childbearing age. It is characterized by endometrial growth outside the uterus and often results in inflamed lesions, pain, and reduced fertility. Although heightened estrogenic activity and/or reduced progesterone responsiveness are considered to be involved in the etiology of endometriosis, neither the extent of their participation nor the underlying mechanisms are clearly understood. Heterogeneous uterine cell types differentially respond to estrogen and progesterone (P(4)). P(4), primarily acting via its nuclear receptor (PR), activates gene transcription and impacts many reproductive processes. Deletion of Fkbp52, an immunophilin cochaperone for PR, results in uterine-specific P(4) resistance in mice, creating an opportunity to study the unique aspects of P(4) signaling in endometriosis. Here we explored the roles of FKBP52 in this disease using Fkbp52(-/-) mice. We found that the loss of FKBP52 encourages the growth of endometriotic lesions with increased inflammation, cell proliferation, and angiogenesis. We also found remarkable down-regulation of FKBP52 in cases of human endometriosis. Our results provide the first evidence corroborated by genetic studies in mice for a potential role of an immunophilin cochaperone in the etiology of human endometriosis. This investigation is highly relevant for clinical application, particularly because P(4) resistance is favorably indicated in endometriosis and other gynecological diseases.