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Taghert P.H.,Washington University Medical School
Current Biology | Year: 2011

Circadian (∼24 hour) pacemaking mechanisms exist within single cells. Which cellular properties contrive to produce a precise clockworks, and which cell properties are downstream of it? The literature is conflicted as to whether membrane excitability contributes to the mechanism. Now, a new conditional genetic strategy argues excitability is largely dispensable. © 2011 Elsevier Ltd. All rights reserved.

Zhou D.,Washington University Medical School | Kim S.H.,Urbana University | Carroll V.M.,Urbana University | Dence C.S.,Washington University Medical School | Katzenellenbn J.A.,Urbana University
Organic and Biomolecular Chemistry | Year: 2014

The development of methods for the facile conjugation and radiolabeling of poly(amido)amine (PAMAM) dendrimers would be of great benefit in evaluating biomedical applications of these intriguing molecularly defined polymers. Two anionic N-hydroxysuccinimide (NHS) esters (7 and 10) were developed and radio-labeled with fluorine-18 using Cu(I)-catalyzed click reactions. The radiolabeling of a primary amine-terminated PAMAM generation-6 (G6) dendrimer with [18F]7 or [18F]10 was complete in water or methanol within 5 min at room temperature. This highly efficient conjugation reaction benefits from a high, localized concentration of these NHS esters on the surface of PAMAM dendrimers, due to the electrostatic attraction between the anionic NHS esters and the positively-charged PAMAM dendrimers. The large medium effect (pH, salt, solvent) observed for these conjugation reactions is consistent with this mechanism. This novel strategy of utilizing electrostatic interactions provides a novel, facile, and efficient method for the conjugation and radiolabeling of PAMAM dendrimers that also has potential for radiolabeling other appropriate nanoparticles. © The Royal Society of Chemistry 2014.

Duvall L.B.,Washington University Medical School | Taghert P.H.,Washington University Medical School
Current Biology | Year: 2011

The 24 hour molecular oscillator requires precisely calibrated degradation of core clock proteins, like PERIOD. New studies shed light on a sequential series of PERIOD phosphorylation events that first inhibits, then accelerates PERIOD degradation. © 2011 Elsevier Ltd.

Visvikis O.,Massachusetts General Hospital | Ihuegbu N.,Washington University Medical School | Labed S.A.,Massachusetts General Hospital | Luhachack L.G.,Massachusetts General Hospital | And 5 more authors.
Immunity | Year: 2014

Animal host defense against infection requires the expression of defense genes at the right place and the right time. Understanding such tight control of host defense requires the elucidation of the transcription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S.aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is apreviously unappreciated, evolutionarily ancient transcription factor in the host response to infection. © 2014 Elsevier Inc.

Vanderheyden W.M.,University of Michigan | Vanderheyden W.M.,Washington University Medical School | Gerstner J.R.,University of Pennsylvania | Tanenhaus A.,University of Wisconsin - Madison | And 2 more authors.
PLoS ONE | Year: 2013

Given the relationship between sleep and plasticity, we examined the role of Extracellular signal-regulated kinase (ERK) in regulating baseline sleep, and modulating the response to waking experience. Both sleep deprivation and social enrichment increase ERK phosphorylation in wild-type flies. The effects of both sleep deprivation and social enrichment on structural plasticity in the LNvs can be recapitulated by expressing an active version of ERK (UAS-ERK SEM) pan-neuronally in the adult fly using GeneSwitch ( Gsw) Gsw-elav-GAL4. Conversely, disrupting ERK reduces sleep and prevents both the behavioral and structural plasticity normally induced by social enrichment. Finally, using transgenic flies carrying a cAMP response Element (CRE)-luciferase reporter we show that activating ERK enhances CRE-Luc activity while disrupting ERK reduces it. These data suggest that ERK phosphorylation is an important mediator in transducing waking experience into sleep. © 2013 Vanderheyden et al.

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