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2432 Janelia Publications

Showing 1791-1800 of 2432 results
Looger Lab
08/01/14 | Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM.
Maiti AK, Kim-Howard X, Motghare P, Pradhan V, Chua KH, Sun C, Arango-Guerrero MT, Ghosh K, Niewold TB, Harley JB, Anaya J, Looger LL, Nath SK
Human Molecular Genetics. 2014 Aug 1;23(15):4161-76. doi: 10.1093/hmg/ddu106

Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10(-90), odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' < 'AG' < 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.

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Gonen Lab
08/01/14 | Editorial overview: Membranes: recent methods in the study of membrane protein structure.
Gonen T, Waksman G
Current Opinion in Structural Biology. 2014 Aug;27:iv-v. doi: 10.1016/j.sbi.2014.09.002
Cui Lab
07/29/14 | A self-adaptive method for creating high efficiency communication channels through random scattering media.
Hao X, Martin-Rouault L, Cui M
Science Reports. 2014 Jul 29;4:5874. doi: 10.1038/srep05874

Controlling the propagation of electromagnetic waves is important to a broad range of applications. Recent advances in controlling wave propagation in random scattering media have enabled optical focusing and imaging inside random scattering media. In this work, we propose and demonstrate a new method to deliver optical power more efficiently through scattering media. Drastically different from the random matrix characterization approach, our method can rapidly establish high efficiency communication channels using just a few measurements, regardless of the number of optical modes, and provides a practical and robust solution to boost the signal levels in optical or short wave communications. We experimentally demonstrated analog and digital signal transmission through highly scattering media with greatly improved performance. Besides scattering, our method can also reduce the loss of signal due to absorption. Experimentally, we observed that our method forced light to go around absorbers, leading to even higher signal improvement than in the case of purely scattering media. Interestingly, the resulting signal improvement is highly directional, which provides a new means against eavesdropping.

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07/29/14 | Automated image-based tracking and its application in ecology.
Dell AI, Bender JA, Branson K, Couzin ID, de Polavieja GG, Noldus LP, Pérez-Escudero A, Perona P, Straw AD, Wikelski M, Brose U
Trends in Ecology and Evolution. 2014 Jul;29(7):417-428. doi: 10.1016/j.tree.2014.05.004

The behavior of individuals determines the strength and outcome of ecological interactions, which drive population, community, and ecosystem organization. Bio-logging, such as telemetry and animal-borne imaging, provides essential individual viewpoints, tracks, and life histories, but requires capture of individuals and is often impractical to scale. Recent developments in automated image-based tracking offers opportunities to remotely quantify and understand individual behavior at scales and resolutions not previously possible, providing an essential supplement to other tracking methodologies in ecology. Automated image-based tracking should continue to advance the field of ecology by enabling better understanding of the linkages between individual and higher-level ecological processes, via high-throughput quantitative analysis of complex ecological patterns and processes across scales, including analysis of environmental drivers.

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Looger LabLavis Lab
07/29/14 | Integrated action of pheromone signals in promoting courtship behavior in male mice.
Haga-Yamanaka S, Ma L, He J, Qiu Q, Lavis LD, Looger LL, Yu CR
eLife. 2014 Jul 29;3:e03025. doi: 10.7554/eLife.03025

The mammalian vomeronasal organ encodes pheromone information about gender, reproductive status, genetic background and individual differences. It remains unknown how pheromone information interacts to trigger innate behaviors. In this study, we identify vomeronasal receptors responsible for detecting female pheromones. A sub-group of V1re clade members recognizes gender-identifying cues in female urine. Multiple members of the V1rj clade are cognate receptors for urinary estrus signals, as well as for sulfated estrogen (SE) compounds. In both cases, the same cue activates multiple homologous receptors, suggesting redundancy in encoding female pheromone cues. Neither gender-specific cues nor SEs alone are sufficient to promote courtship behavior in male mice, whereas robust courtship behavior can be induced when the two cues are applied together. Thus, integrated action of different female cues is required in pheromone-triggered mating behavior. These results suggest a gating mechanism in the vomeronasal circuit in promoting specific innate behavior.DOI: http://dx.doi.org/10.7554/eLife.03025.001.

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Ahrens LabLooger LabKeller LabFreeman Lab
07/27/14 | Light-sheet functional imaging in fictively behaving zebrafish.
Vladimirov N, Mu Y, Kawashima T, Bennett DV, Yang C, Looger LL, Keller PJ, Freeman J, Ahrens MB
Nature Methods. 2014 Jul 27;11(9):883-4. doi: 10.1038/nmeth.3040

The processing of sensory input and the generation of behavior involves large networks of neurons, which necessitates new technology for recording from many neurons in behaving animals. In the larval zebrafish, light-sheet microscopy can be used to record the activity of almost all neurons in the brain simultaneously at single-cell resolution. Existing implementations, however, cannot be combined with visually driven behavior because the light sheet scans over the eye, interfering with presentation of controlled visual stimuli. Here we describe a system that overcomes the confounding eye stimulation through the use of two light sheets and combines whole-brain light-sheet imaging with virtual reality for fictively behaving larval zebrafish.

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Looger LabAhrens LabFreeman LabSvoboda Lab
07/27/14 | Mapping brain activity at scale with cluster computing.
Freeman J, Vladimirov N, Kawashima T, Mu Y, Sofroniew NJ, Bennett DV, Rosen J, Yang C, Looger LL, Ahrens MB
Nature Methods. 2014 Jul 27;11(9):941-950. doi: 10.1038/nmeth.3041

Understanding brain function requires monitoring and interpreting the activity of large networks of neurons during behavior. Advances in recording technology are greatly increasing the size and complexity of neural data. Analyzing such data will pose a fundamental bottleneck for neuroscience. We present a library of analytical tools called Thunder built on the open-source Apache Spark platform for large-scale distributed computing. The library implements a variety of univariate and multivariate analyses with a modular, extendable structure well-suited to interactive exploration and analysis development. We demonstrate how these analyses find structure in large-scale neural data, including whole-brain light-sheet imaging data from fictively behaving larval zebrafish, and two-photon imaging data from behaving mouse. The analyses relate neuronal responses to sensory input and behavior, run in minutes or less and can be used on a private cluster or in the cloud. Our open-source framework thus holds promise for turning brain activity mapping efforts into biological insights.

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07/24/14 | Looking under the lamp post: neither fruitless nor doublesex has evolved to generate divergent male courtship in Drosophila.
Cande J, Stern DL, Morita T, Prud'homme B, Gompel N
Cell Reports. 2014 Jul 24;8(2):363-70. doi: 10.1016/j.celrep.2014.06.023

How do evolved genetic changes alter the nervous system to produce different patterns of behavior? We address this question using Drosophila male courtship behavior, which is innate, stereotyped, and evolves rapidly between species. D. melanogaster male courtship requires the male-specific isoforms of two transcription factors, fruitless and doublesex. These genes underlie genetic switches between female and male behaviors, making them excellent candidate genes for courtship behavior evolution. We tested their role in courtship evolution by transferring the entire locus for each gene from divergent species to D. melanogaster. We found that despite differences in Fru+ and Dsx+ cell numbers in wild-type species, cross-species transgenes rescued D. melanogaster courtship behavior and no species-specific behaviors were conferred. Therefore, fru and dsx are not a significant source of evolutionary variation in courtship behavior.

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07/22/14 | Optimized CRISPR/Cas tools for efficient germline and somatic genome engineering in Drosophila.
Port F, Chen H, Lee T, Bullock SL
Proceedings of the National Academy of Sciences of the United States of America. 2014 Jul 22;111(29):E2967-76. doi: 10.1073/pnas.1405500111

The type II clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system has emerged recently as a powerful method to manipulate the genomes of various organisms. Here, we report a toolbox for high-efficiency genome engineering of Drosophila melanogaster consisting of transgenic Cas9 lines and versatile guide RNA (gRNA) expression plasmids. Systematic evaluation reveals Cas9 lines with ubiquitous or germ-line-restricted patterns of activity. We also demonstrate differential activity of the same gRNA expressed from different U6 snRNA promoters, with the previously untested U6:3 promoter giving the most potent effect. An appropriate combination of Cas9 and gRNA allows targeting of essential and nonessential genes with transmission rates ranging from 25-100%. We also demonstrate that our optimized CRISPR/Cas tools can be used for offset nicking-based mutagenesis. Furthermore, in combination with oligonucleotide or long double-stranded donor templates, our reagents allow precise genome editing by homology-directed repair with rates that make selection markers unnecessary. Last, we demonstrate a novel application of CRISPR/Cas-mediated technology in revealing loss-of-function phenotypes in somatic cells following efficient biallelic targeting by Cas9 expressed in a ubiquitous or tissue-restricted manner. Our CRISPR/Cas tools will facilitate the rapid evaluation of mutant phenotypes of specific genes and the precise modification of the genome with single-nucleotide precision. Our results also pave the way for high-throughput genetic screening with CRISPR/Cas.

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07/21/14 | Abdominal-B neurons control Drosophila virgin female receptivity.
Bussell JJ, Yapici N, Zhang SX, Dickson BJ, Vosshall LB
Current Biology. 2014 Jul 21;24(14):1584-95. doi: 10.1016/j.cub.2014.06.011

BACKGROUND: Female sexual receptivity offers an excellent model for complex behavioral decisions. The female must parse her own reproductive state, the external environment, and male sensory cues to decide whether to copulate. In the fly Drosophila melanogaster, virgin female receptivity has received relatively little attention, and its neural circuitry and individual behavioral components remain unmapped. Using a genome-wide neuronal RNAi screen, we identify a subpopulation of neurons responsible for pausing, a novel behavioral aspect of virgin female receptivity characterized in this study.

RESULTS: We show that Abdominal-B (Abd-B), a homeobox transcription factor, is required in developing neurons for high levels of virgin female receptivity. Silencing adult Abd-B neurons significantly decreased receptivity. We characterize two components of receptivity that are elicited in sexually mature females by male courtship: pausing and vaginal plate opening. Silencing Abd-B neurons decreased pausing but did not affect vaginal plate opening, demonstrating that these two components of female sexual behavior are functionally separable. Synthetic activation of Abd-B neurons increased pausing, but male courtship song alone was not sufficient to elicit this behavior.

CONCLUSIONS: Our results provide an entry point to the neural circuit controlling virgin female receptivity. The female integrates multiple sensory cues from the male to execute discrete motor programs prior to copulation. Abd-B neurons control pausing, a key aspect of female sexual receptivity, in response to male courtship.

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