20 Works

Inference of nonlinear receptive field subunits with spike-triggered clustering

Nishal Shah, Nora Brackbill, Colleen Rhoades, Alexandra Kling, Georges Goetz, Alan Litke, Alexander Sher, Eero Simoncelli & E.J. Chichilnisky
Responses of sensory neurons are often modeled using a weighted combination of rectified linear subunits. Since these subunits often cannot be measured directly, a flexible method is needed to infer their properties from the responses of downstream neurons. We present a method for maximum likelihood estimation of subunits by soft-clustering spike-triggered stimuli, and demonstrate its effectiveness in visual neurons. Subunits estimated from parasol retinal ganglion cells (RGCs) in macaque retina partitioned the receptive field into...

Data from: Nuclear microenvironments modulate transcription from low-affinity enhancers

Albert Tsai, Anand K. Muthusamy, Mariana R. P. Alves, Luke D. Lavis, Robert H. Singer, David L. Stern, Justin Crocker, Anand K Muthusamy, Luke D Lavis, Robert H Singer, David L Stern & Mariana RP Alves
Transcription factors bind low-affinity DNA sequences for only short durations. It is not clear how brief, low-affinity interactions can drive efficient transcription. Here we report that the transcription factor Ultrabithorax (Ubx) utilizes low-affinity binding sites in the Drosophila melanogaster shavenbaby (svb) locus and related enhancers in nuclear microenvironments of high Ubx concentrations. Related enhancers colocalize to the same microenvironments independently of their chromosomal location, suggesting that microenvironments are highly differentiated transcription domains. Manipulating the affinity...

Data from: The kinetochore prevents centromere-proximal crossover recombination during meiosis

Nadine Vincenten, Lisa-Marie Kuhl, Isabel Lam, Ashwini Oke, Alastair R. W. Kerr, Andreas Hochwagen, Jennifer C. Fung, Scott Keeney, Gerben Vader & Adèle L. Marston
During meiosis, crossover recombination is essential to link homologous chromosomes and drive 22 faithful chromosome segregation. Crossover recombination is non-random across the genome, 23 and centromere-proximal crossovers are associated with an increased risk of aneuploidy, 24 including Trisomy 21 in humans. Here, we identify the conserved Ctf19/CCAN kinetochore sub- 25 complex as a major factor that minimizes potentially deleterious centromere-proximal crossovers 26 in budding yeast. We uncover multi-layered suppression of pericentromeric recombination by the 27...

Data from: Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast

Eduardo M. Torres, Noah Dephoure, Sunyoung Hwang, Ciara O’Sullivan, Stacie E. Dodgson, Steve P. Gygi, Angelika Amon, Ciara O'Sullivan, Eduardo M Torres & Stacie E Dodgson
Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by aneuploidy are not well characterized. Here, we examined the consequences of aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our...

Data from: High-throughput synapse-resolving two-photon fluorescence microendoscopy for deep-brain volumetric imaging in vivo

Guanghan Meng, Yajie Liang, Sarah Sarsfield, Wan-Chen Jiang, Rongwen Lu, Joshua Tate Dudman, Yeka Aponte & Na Ji
Optical imaging has become a powerful tool for studying brains in vivo. The opacity of adult brains makes microendoscopy, with an optical probe such as a gradient index (GRIN) lens embedded into brain tissue to provide optical relay, the method of choice for imaging neurons and neural activity in deeply buried brain structures. Incorporating a Bessel focus scanning module into two-photon fluorescence microendoscopy, we extended the excitation focus axially and improved its lateral resolution. Scanning...

Data from: Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing-bisphosphonates

Zhou Yu, Lauren E. Surface, Chong Yon Park, Max A Horlbeck, Gregory A Wyant, Monther Abu-Remaileh, Timothy R. Peterson, David M. Sabatini, Jonathan S. Weissman, Erin K. O'Shea, Lauren E Surface, Erin K O'Shea, David M Sabatini, Jonathan S Weissman & Timothy R Peterson
Nitrogen-containing-bisphosphonates (N-BPs) are widely prescribed to treat osteoporosis and other bone-related diseases. Although previous studies established that N-BPs function by inhibiting the mevalonate pathway in osteoclasts, the mechanism by which N-BPs enter the cytosol from the extracellular space to reach their molecular target is not understood. Here we implemented a CRISPRi-mediated genome-wide screen and identified SLC37A3 (solute carrier family 37 member A3) as a gene required for the action of N-BPs in mammalian cells. We...

Data from: Tensor analysis reveals distinct population structure that parallels the different computational roles of areas M1 and V1

Jeffrey S. Seely, Matthew T. Kaufman, Stephen I. Ryu, Krishna V. Shenoy, John P. Cunningham & Mark M. Churchland
Cortical firing rates frequently display elaborate and heterogeneous temporal structure. One often wishes to compute quantitative summaries of such structure—a basic example is the frequency spectrum—and compare with model-based predictions. The advent of large-scale population recordings affords the opportunity to do so in new ways, with the hope of distinguishing between potential explanations for why responses vary with time. We introduce a method that assesses a basic but previously unexplored form of population-level structure: when...

Data from: The Oxytricha trifallax macronuclear genome: a complex eukaryotic genome with 16,000 tiny chromosomes

Estienne C. Swart, John R. Bracht, Vincent Magrini, Patrick Minx, Xiao Chen, Yi Zhou, Jaspreet S. Khurana, Aaron D. Goldman, Mariusz Nowacki, Klaas Schotanus, Seolkyoung Jung, Robert S. Fulton, Amy Ly, Sean McGrath, Kevin Haub, Jessica L. Wiggins, Donna Storton, John C. Matese, Lance Parsons, Wei-Jen Chang, Michael S. Bowen, Nicholas A. Stover, Thomas A. Jones, Sean R. Eddy, Thomas G. Doak … & Laura F. Landweber
The macronuclear genome of the ciliate Oxytricha trifallax displays an extreme and unique eukaryotic genome architecture with extensive genomic variation. During sexual genome development, the expressed, somatic macronuclear genome is whittled down to the genic portion of a small fraction (~5%) of its precursor “silent” germline micronuclear genome by a process of “unscrambling” and fragmentation. The tiny macronuclear “nanochromosomes” typically encode single, protein-coding genes (a small portion, 10%, encode 2–8 genes), have minimal noncoding regions,...

Data from: Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data

Pengcheng Zhou, Shanna L. Resendez, Jose Rodriguez-Romaguera, Jessica C. Jimenez, Shay Q. Neufeld, Andrea Giovannucci, Johannes Friedrich, Eftychios A Pnevmatikakis, Garret D. Stuber, Rene Hen, Mazen A. Kheirbek, Bernardo L. Sabatini, Robert E. Kass, Liam Paninski, Robert E Kass, Garret D Stuber, Jessica C Jimenez, Shanna L Resendez, Mazen A Kheirbek, Shay Q Neufeld & Bernardo L Sabatini
In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We...

Data from: Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching

Felix Horns, Christopher Vollmers, Derek Croote, Sally F. Mackey, Gary E. Swan, Cornelia L. Dekker, Mark M. Davis, Stephen R. Quake, Stephen R Quake, Gary E Swan, Mark M Davis, Sally F Mackey & Cornelia L Dekker
Antibody class switching is a feature of the adaptive immune system which enables diversification of the effector properties of antibodies. Even though class switching is essential for mounting a protective response to pathogens, the in vivo patterns and lineage characteristics of antibody class switching have remained uncharacterized in living humans. Here we comprehensively measured the landscape of antibody class switching in human adult twins using antibody repertoire sequencing. The map identifies how antibodies of every...

Data from: Genetic architecture and functional characterization of genes underlying the rapid diversification of male external genitalia between Drosophila simulans and Drosophila mauritiana

Kentaro M. Tanaka, Corinna Hopfen, Matthew R. Herbert, Christian Schlötterer, David L. Stern, John P. Masly, Alistair P. McGregor, Maria D. S. Nunes, J. P. Masly, D. L. Stern, K. M. Tanaka, M. R. Herbert, A. P. McGregor & M. D. S. Nunes
Male sexual characters are often among the first traits to diverge between closely related species and identifying the genetic basis of such changes can contribute to our understanding of their evolutionary history. However, little is known about the genetic architecture or the specific genes underlying the evolution of male genitalia. The morphology of the claspers, posterior lobes and anal plates exhibit striking differences between Drosophila mauritiana and Drosophila simulans. Using QTL and introgression-based high-resolution mapping,...

Data from: Optogenetic dissection of descending behavioral control in Drosophila

Jessica Cande, Shigehiro Namiki, Jirui Qiu, Wyatt Korff, Gwyneth M. Card, Joshua W. Shaevitz, David L. Stern, Gordon J. Berman, Gordon J Berman, Joshua W Shaevitz, Gwyneth M Card & David L Stern
In most animals, the brain makes behavioral decisions that are transmitted by descending neurons to the nerve cord circuitry that produces behaviors. In insects, only a few descending neurons have been associated with specific behaviors. To explore how descending neurons control an insect's movements, we developed a novel method to systematically assay the behavioral effects of activating individual neurons on freely behaving terrestrial D. melanogaster. We calculated a two-dimensional representation of the entire behavior space...

Data from: Experimental evolution of Legionella pneumophila in mouse macrophages leads to strains with altered determinants of environmental survival

Alexander W. Ensminger, Yosuf Yassin, Alexander Miron & Ralph R. Isberg
The Gram-negative bacterium, Legionella pneumophila, is a protozoan parasite and accidental intracellular pathogen of humans. We propose a model in which host cycling through multiple protozoan hosts in the environment holds L. pneumophila in a state of evolutionary stasis as a broad host-range pathogen. Using an experimental evolution approach, we tested this hypothesis by restricting L. pneumophila to growth within mouse macrophages for hundreds of generations. Whole-genome resequencing and high-throughput genotyping identified several parallel adaptive...

Data from: Engineering ER-stress dependent non-conventional mRNA splicing

Weihan Li, Voytek Okreglak, Jirka Peschek, Philipp Kimmig, Meghan Zubradt, Jonathan S. Weissman, Peter Walter & Jonathan S Weissman
The endoplasmic reticulum (ER) protein folding capacity is balanced with the protein folding burden to prevent accumulation of un- or misfolded proteins. The ER membrane-resident kinase/RNase Ire1 maintains ER protein homeostasis through two fundamentally distinct processes. First, Ire1 can initiate a transcriptional response through a non-conventional mRNA splicing reaction to increase the ER folding capacity. Second, Ire1 can decrease the ER folding burden through selective mRNA decay. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, the two...

Data from: Pioneer cells established by the [SWI+] prion can promote dispersal and out-crossing in yeast

Gregory A. Newby & Susan Lindquist
To thrive in an ever-changing environment, microbes must widely distribute their progeny to colonize new territory. Simultaneously, they must evolve and adapt to the stresses of unpredictable surroundings. In both of these regards, diversity is key—if an entire population moved together or responded to the environment in the same way, it could easily go extinct. Here, we show that the epigenetic prion switch [SWI+] establishes a specialized subpopulation with a “pioneer” phenotypic program in Saccharomyces...

Data from: Improving transcriptome assembly through error correction of high-throughput sequence reads

Matthew D. MacManes & Michael B. Eisen
The study of functional genomics, particularly in non-model organisms, has been dramatically improved over the last few years by the use of transcriptomes and RNAseq. While these studies are potentially extremely powerful, a computationally intensive procedure, the de novo construction of a reference transcriptome must be completed as a prerequisite to further analyses. The accurate reference is critically important as all downstream steps, including estimating transcript abundance are critically dependent on the construction of an...

Data from: Genome-wide errant targeting by Hairy

Kurtulus Kok, Ahmet Ay, Li M. Li, David N. Arnosti, David N Arnosti & Li M Li
Metazoan transcriptional repressors regulate chromatin through diverse histone modifications. Contributions of individual factors to the chromatin landscape in development is difficult to establish, as global surveys reflect multiple changes in regulators. Therefore, we studied the conserved Hairy/Enhancer of Split family repressor Hairy, analyzing histone marks and gene expression in Drosophila embryos. This long-range repressor mediates histone acetylation and methylation in large blocks, with highly context-specific effects on target genes. Most strikingly, Hairy exhibits biochemical activity...

Data from: Synchronized excitability in a network enables generation of internal neuronal sequences

Yingxue Wang, Zachary Roth & Eva Pastalkova
Hippocampal place field sequences are supported by sensory cues and network internal mechanisms. In contrast, sharp-wave (SPW) sequences, theta sequences, and episode field sequences are internally generated. The relationship of these sequences to memory is unclear. SPW sequences have been shown to support learning and have been assumed to also support episodic memory. Conversely, we demonstrate these SPW sequences were present in trained rats even after episodic memory was impaired and after other internal sequences...

Data from: Gene flow mediates the role of sex chromosome meiotic drive during complex speciation

Colin D. Meiklejohn, Emily L. Landeen, Kathleen E. Gordon, Thomas Rzatkiewicz, Sarah B. Kingan, Anthony J. Geneva, Jeffrey P. Vedanayagam, Christina A. Muirhead, Daniel Garrigan, David L. Stern, Daven C. Presgraves, Emily L Landeen, Sarah B Kingan, Anthony J Geneva, Jeffrey P Vedanayagam, Christina A Muirhead, Daven C Presgraves, David L Stern, Colin D Meiklejohn & Kathleen E Gordon
During speciation, sex chromosomes often accumulate interspecific genetic incompatibilities faster than the rest of the genome. The drive theory posits that sex chromosomes are susceptible to recurrent bouts of meiotic drive and suppression, causing the evolutionary build-up of divergent cryptic sex-linked drive systems and, incidentally, genetic incompatibilities. To assess the role of drive during speciation, we combine high-resolution genetic mapping of X-linked hybrid male sterility with population genomics analyses of divergence and recent gene flow...

Data from: Impaired spatial memory codes in a mouse model of Rett syndrome

Sara E. Kee, Xiang Mou, Huda Y. Zoghbi, Daoyun Ji & Huda Y Zoghbi
The Mecp2+/-mouse model recapitulates many phenotypes of patients with Rett syndrome (RTT), including learning and memory deficits. It is unknown, however, how the disease state alters memory circuit functions in vivoin RTT mice. Here we recorded from hippocampal place cells, which are thought to encode spatial memories, in freely moving RTT mice and littermate controls. We found that place cells in RTT mice are impaired in their experience-dependent increase of spatial information. This impairment is...

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