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Vlasits A.L.,University of Washington | Vlasits A.L.,Helen Wills Neuroscience Institute | Simon J.A.,Fred Hutchinson Cancer Research Center | Raible D.W.,University of Washington | And 2 more authors.
Hearing Research | Year: 2012

Loss of mechanosensory hair cells in the inner ear accounts for many hearing loss and balance disorders. Several beneficial pharmaceutical drugs cause hair cell death as a side effect. These include aminoglycoside antibiotics, such as neomycin, kanamycin and gentamicin, and several cancer chemotherapy drugs, such as cisplatin. Discovering new compounds that protect mammalian hair cells from toxic insults is experimentally difficult because of the inaccessibility of the inner ear. We used the zebrafish lateral line sensory system as an in vivo screening platform to survey a library of FDA-approved pharmaceuticals for compounds that protect hair cells from neomycin, gentamicin, kanamycin and cisplatin. Ten compounds were identified that provide protection from at least two of the four toxins. The resulting compounds fall into several drug classes, including serotonin and dopamine-modulating drugs, adrenergic receptor ligands, and estrogen receptor modulators. The protective compounds show different effects against the different toxins, supporting the idea that each toxin causes hair cell death by distinct, but partially overlapping, mechanisms. Furthermore, some compounds from the same drug classes had different protective properties, suggesting that they might not prevent hair cell death by their known target mechanisms. Some protective compounds blocked gentamicin uptake into hair cells, suggesting that they may block mechanotransduction or other routes of entry. The protective compounds identified in our screen will provide a starting point for studies in mammals as well as further research discovering the cellular signaling pathways that trigger hair cell death. © 2012 Elsevier B.V.

Miller E.W.,Helen Wills Neuroscience Institute
Current Opinion in Chemical Biology | Year: 2016

Voltage imaging has the potential to unravel the contributions that rapid changes in membrane voltage make to cellular physiology, especially in the context of neuroscience. In particular, small molecule fluorophores are especially attractive because they can, in theory, provide fast and sensitive measurements of membrane potential dynamics. A number of classes of small molecule voltage indicators will be discussed, including dyes with improved two-photon voltage sensing, near infrared optical profiles for use in in vivo applications, and newly developed electron-transfer based indicators, or VoltageFluors, that can be tuned across a range of wavelengths to enable all-optical voltage manipulation and measurement. Limitations and a 'wish-list' for voltage indicators will also be discussed. © 2016 Elsevier Ltd.

Agency: GTR | Branch: EPSRC | Program: | Phase: Training Grant | Award Amount: 3.94M | Year: 2014

The achievements of modern research and their rapid progress from theory to application are increasingly underpinned by computation. Computational approaches are often hailed as a new third pillar of science - in addition to empirical and theoretical work. While its breadth makes computation almost as ubiquitous as mathematics as a key tool in science and engineering, it is a much younger discipline and stands to benefit enormously from building increased capacity and increased efforts towards integration, standardization, and professionalism. The development of new ideas and techniques in computing is extremely rapid, the progress enabled by these breakthroughs is enormous, and their impact on society is substantial: modern technologies ranging from the Airbus 380, MRI scans and smartphone CPUs could not have been developed without computer simulation; progress on major scientific questions from climate change to astronomy are driven by the results from computational models; major investment decisions are underwritten by computational modelling. Furthermore, simulation modelling is emerging as a key tool within domains experiencing a data revolution such as biomedicine and finance. This progress has been enabled through the rapid increase of computational power, and was based in the past on an increased rate at which computing instructions in the processor can be carried out. However, this clock rate cannot be increased much further and in recent computational architectures (such as GPU, Intel Phi) additional computational power is now provided through having (of the order of) hundreds of computational cores in the same unit. This opens up potential for new order of magnitude performance improvements but requires additional specialist training in parallel programming and computational methods to be able to tap into and exploit this opportunity. Computational advances are enabled by new hardware, and innovations in algorithms, numerical methods and simulation techniques, and application of best practice in scientific computational modelling. The most effective progress and highest impact can be obtained by combining, linking and simultaneously exploiting step changes in hardware, software, methods and skills. However, good computational science training is scarce, especially at post-graduate level. The Centre for Doctoral Training in Next Generation Computational Modelling will develop 55+ graduate students to address this skills gap. Trained as future leaders in Computational Modelling, they will form the core of a community of computational modellers crossing disciplinary boundaries, constantly working to transfer the latest computational advances to related fields. By tackling cutting-edge research from fields such as Computational Engineering, Advanced Materials, Autonomous Systems and Health, whilst communicating their advances and working together with a world-leading group of academic and industrial computational modellers, the students will be perfectly equipped to drive advanced computing over the coming decades.

Sheridan M.A.,Boston University | Sarsour K.,Eli Lilly and Company | Jutte D.,University of California at Berkeley | D'Esposito M.,Helen Wills Neuroscience Institute | And 2 more authors.
PLoS ONE | Year: 2012

The prefrontal cortex (PFC) develops from birth through late adolescence. This extended developmental trajectory provides many opportunities for experience to shape the structure and function of the PFC. To date, a few studies have reported links between parental socioeconomic status (SES) and prefrontal function in childhood, raising the possibility that aspects of environment associated with SES impact prefrontal function. Considering that behavioral measures of prefrontal function are associated with learning across multiple domains, this is an important area of investigation. In this study, we used fMRI to replicate previous findings, demonstrating an association between parental SES and PFC function during childhood. In addition, we present two hypothetical mechanisms by which SES could come to affect PFC function of this association: language environment and stress reactivity. We measured language use in the home environment and change in salivary cortisol before and after fMRI scanning. Complexity of family language, but not the child's own language use, was associated with both parental SES and PFC activation. Change in salivary cortisol was also associated with both SES and PFC activation. These observed associations emphasize the importance of both enrichment and adversity-reduction interventions in creating good developmental environments for all children. © 2012 Sheridan et al.

Agarwal G.,Helen Wills Neuroscience Institute | Isacoff E.,Helen Wills Neuroscience Institute | Isacoff E.,University of California at Berkeley | Isacoff E.,Lawrence Berkeley National Laboratory
Journal of Neurophysiology | Year: 2011

Insect pheromonal glomeruli are thought to track the fine spatiotemporal features of one or a few odorants to aid conspecific localization. However, it is not clear whether they function differently from generalist glomeruli, which respond to many odorants. In this study, we test how DA1, a model pheromonal glomerulus in the fruit fly, represents the spatial and temporal properties of its input, compared with other glomeruli. We combine calcium imaging and electrical stimulation in an isolated brain preparation for a simultaneous, unbiased comparison of the functional organization of many glomeruli. In contrast to what is found in other glomeruli, we find that ipsilateral and contralateral stimuli elicit distinct spatial patterns of activity within DA1. DA1's output shows a greater preference for ipsilateral stimuli in males than in females. DA1 experiences greater and more rapid inhibition than other glomeruli, allowing it to report slight interantennal delays in stimulus onset in a "winner-take-all" manner. DA1's ability to encode spatiotemporal input features distinguishes it from other glomeruli in the fruit fly antennal lobe but relates it to pheromonal glomeruli in other insect species. We propose that DA1 is specialized to help the fly localize and orient with respect to pheromone sources. © 2011 the American Physiological Society.

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