Medicine and Health Sciences Commons^™

Intrinsic Disorder In Transmembrane Proteins: Roles In Signaling And Topology Prediction, Jérôme Bürgi, Bin Xue, Vladimir N Uversky, F Gisou Van Der Goot

Molecular Biosciences Faculty Publications

Intrinsically disordered regions (IDRs) are peculiar stretches of amino acids that lack stable conformations in solution. Intrinsic Disorder containing Proteins (IDP) are defined by the presence of at least one large IDR and have been linked to multiple cellular processes including cell signaling, DNA binding and cancer. Here we used computational analyses and publicly available databases to deepen insight into the prevalence and function of IDRs specifically in transmembrane proteins, which are somewhat neglected in most studies. We found that 50% of transmembrane proteins have at least one IDR of 30 amino acids or more. Interestingly, these domains preferentially localize …

Identification Of Ecdysone Hormone Receptor Agonists As A Therapeutic Approach For Treating Filarial Infections, Amruta S Mhashilkar, Sai L Vankayala, Canhui Liu, Fiona Kearns, Priyanka Mehrotra, George Tzertzinis, Subba R Palli, H. Lee Woodcock Iii, Thomas R Unnasch

Chemistry Faculty Publications

BACKGROUND: A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets.

METHODOLOGY/ PRINCIPAL FINDINGS: Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. …

The Exceptionally High Reactivity Of Cys 621 Is Critical For Electrophilic Activation Of The Sensory Nerve Ion Channel Trpa1, Parmvir K. Bahia, Thomas A. Parks, Katherine R. Stanford, David A. Mitchell, Sameer Varma, Stanley M. Stevens Jr., Thomas E. Taylor-Clark

Molecular Biosciences Faculty Publications

Activation of the sensory nerve ion channel TRPA1 by electrophiles is the key mechanism that initiates nociceptive signaling, and leads to defensive reflexes and avoidance behaviors, during oxidative stress in mammals. TRPA1 is rapidly activated by subtoxic levels of electrophiles, but it is unclear how TRPA1 outcompetes cellular antioxidants that protect cytosolic proteins from electrophiles. Here, using physiologically relevant exposures, we demonstrate that electrophiles react with cysteine residues on mammalian TRPA1 at rates that exceed the reactivity of typical cysteines by 6,000-fold and that also exceed the reactivity of antioxidant enzymes. We show that TRPA1 possesses a complex reactive cysteine …

Reengineering Of Mesh Thesauri For Term Selection To Optimize Literature Retrieval And Knowledge Reconstruction In Support Of Stem Cell Research, Yan Su, James E. Andrews, Hong Huang, Yue Wang, Liangliang Kong, Peter Cannon, Ping Xu

School of Information Faculty Publications

BACKGROUND: PubMed is a widely used database for scientists to find biomedical-related literature. Due to the complexity of the selected research subject and its interdisciplinary nature, as well as the exponential growth in the number of disparate pieces of biomedical literature, it is an overwhelming challenge for scientists to define the right search strategies and quickly locate all related information. Specialized subsets and groupings of controlled vocabularies, such as Medical Subject Headings (MeSH), can enhance information retrieval in specialized domains, such as stem cell research. There is a need to develop effective search strategies and convenient solutions for knowledge organization …

Molecular Mechanism Of Protein Kinase Recognition And Sorting By The Hsp90 Kinome-Specific Cochaperone Cdc37, Dimitra Keramisanou, Adam Aboalroub, Ziming Zhang, Wenjun Liu, Devon Marshall, Andrea Diviney, Randy W. Larsen, Ralf Landgraf, Ioannis Gelis

Chemistry Faculty Publications

Despite the essential functions of Hsp90, little is known about the mechanism that controls substrate entry into its chaperone cycle. We show that the role of Cdc37 cochaperone reaches beyond that of an adaptor protein and find that it participates in the selective recruitment of only client kinases. Cdc37 recognizes kinase specificity determinants in both clients and nonclients and acts as a general kinase scanning factor. Kinase sorting within the client-to-nonclient continuum relies on the ability of Cdc37 to challenge the conformational stability of clients by locally unfolding them. This metastable conformational state has high affinity for Cdc37 and forms …

Fear Conditioning And Extinction In Youth With Obsessive-Compulsive Disorder, Joseph F. Mcguire, Scott P. Orr, Monica S. Wu, Adam B. Lewin, Brent J. Small, Vicky Phares, Tanya K. Murphy, Sabine Wilhelm, Daniel S. Pine, Daniel Geller, Eric A. Storch

Psychology Faculty Publications

BACKGROUND: Fear acquisition and extinction are central constructs in the cognitive-behavioral model of obsessive-compulsive disorder (OCD), which underlies exposure-based cognitive-behavioral therapy (CBT). Youth with OCD may have impairments in fear acquisition and extinction that carry treatment implications. We examined these processes using a differential conditioning procedure.

METHODS: Forty-one youth (19 OCD, 22 community comparisons) completed a battery of clinical interviews, rating scales, and a differential conditioning task that included habituation, acquisition, and extinction phases. Skin conductance response (SCR) served as the primary dependent measure.

RESULTS: During habituation, no difference between groups was observed. During acquisition, differential fear conditioning was observed …

Transdiagnostic Psychiatric Symptoms And Event-Related Potentials Following Rewarding And Aversive Outcomes, Jeffrey S. Bedwell, Geoffrey Potts, Diane C. Gooding, Benjamin J. Trachik, Chi C. Chan, Christopher C. Spencer

Psychology Faculty Publications

There is a need for a better understanding of transdiagnostic psychiatric symptoms that relate to neurophysiological abnormalities following rewarding and aversive feedback in order to inform development of novel targeted treatments. To address this need, we examined a transdiagnostic sample of 44 adults (mean age: 35.52; 57% female), which consisted of individuals with broadly-defined schizophrenia-spectrum disorders (n = 16), bipolar disorders (n = 10), other mood and anxiety disorders (n = 5), and no history of a psychiatric disorder (n = 13). Participants completed a Pavlovian monetary reward prediction task during 32-channel electroencephalogram recording. We assessed the event-related potentials (ERPs) …

Comorbid Substance Use Diagnoses And Partner Violence Among Offenders Receiving Pharmacotherapy For Opioid Dependence, Cory A. Crane, Robert C. Schlauch, Susan Devine, Caroline J. Easton

Psychology Faculty Publications

While previous studies find mixed evidence of an association between opioid use and intimate partner violence perpetration among community samples, initial evidence has detected increased rates of partner violence among individuals receiving pharmacological intervention for opioid dependence. The current study evaluated the role of current comorbid substance use diagnoses, a robust risk factor for violent behavior, on the likelihood of perpetrating partner violence among a high risk sample of offenders receiving pharmacological intervention for opioid dependence. The authors analyzed self-report data provided by 81 (55 male) opioid dependent offenders during a court-ordered substance use interview. Approximately one-third of the sample …