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Greene C.S.,Dartmouth Hitchcock Norris Cotton Cancer Center | Greene C.S.,Dartmouth College | Krishnan A.,Princeton University | Wong A.K.,Princeton University | And 12 more authors.
Nature Genetics | Year: 2015

Tissue and cell-type identity lie at the core of human physiology and disease. Understanding the genetic underpinnings of complex tissues and individual cell lineages is crucial for developing improved diagnostics and therapeutics. We present genome-wide functional interaction networks for 144 human tissues and cell types developed using a data-driven Bayesian methodology that integrates thousands of diverse experiments spanning tissue and disease states. Tissue-specific networks predict lineage-specific responses to perturbation, identify the changing functional roles of genes across tissues and illuminate relationships among diseases. We introduce NetWAS, which combines genes with nominally significant genome-wide association study (GWAS) P values and tissue-specific networks to identify disease-gene associations more accurately than GWAS alone. Our webserver, GIANT, provides an interface to human tissue networks through multi-gene queries, network visualization, analysis tools including NetWAS and downloadable networks. GIANT enables systematic exploration of the landscape of interacting genes that shape specialized cellular functions across more than a hundred human tissues and cell types. © 2015 Nature America, Inc. All rights reserved.


Stich S.U.,Catholic University of Louvain | Muller C.L.,Simons Center for Data Analysis | Gartner B.,ETH Zurich
Mathematical Programming | Year: 2016

We consider unconstrained randomized optimization of smooth convex objective functions in the gradient-free setting. We analyze Random Pursuit (RP) algorithms with fixed (F-RP) and variable metric (V-RP). The algorithms only use zeroth-order information about the objective function and compute an approximate solution by repeated optimization over randomly chosen one-dimensional subspaces. The distribution of search directions is dictated by the chosen metric. Variable Metric RP uses novel variants of a randomized zeroth-order Hessian approximation scheme recently introduced by Leventhal and Lewis (Optimization 60(3):329–345, 2011. doi:10.1080/02331930903100141). We here present (1) a refined analysis of the expected single step progress of RP algorithms and their global convergence on (strictly) convex functions and (2) novel convergence bounds for V-RP on strongly convex functions. We also quantify how well the employed metric needs to match the local geometry of the function in order for the RP algorithms to converge with the best possible rate. Our theoretical results are accompanied by numerical experiments, comparing V-RP with the derivative-free schemes CMA-ES, Implicit Filtering, Nelder–Mead, NEWUOA, Pattern-Search and Nesterov’s gradient-free algorithms. © 2015, Springer-Verlag Berlin Heidelberg and Mathematical Optimization Society.


Zhou J.,Princeton University | Troyanskaya O.G.,Princeton University | Troyanskaya O.G.,Simons Center for Data Analysis
Nature Communications | Year: 2016

Interpreting the functional state of chromatin from the combinatorial binding patterns of chromatin factors, that is, the chromatin codes, is crucial for decoding the epigenetic state of the cell. Here we present a systematic map of Drosophila chromatin states derived from data-driven probabilistic modelling of dependencies between chromatin factors. Our model not only recapitulates enhancer-like chromatin states as indicated by widely used enhancer marks but also divides these states into three functionally distinct groups, of which only one specific group possesses active enhancer activity. Moreover, we discover a strong association between one specific enhancer state and RNA Polymerase II pausing, linking transcription regulatory potential and chromatin organization. We also observe that with the exception of long-intron genes, chromatin state transition positions in transcriptionally active genes align with an absolute distance to their corresponding transcription start site, regardless of gene length. Using our method, we provide a resource that helps elucidate the functional and spatial organization of the chromatin code landscape. © 2016, Nature Publishing Group. All rights reserved.


Lai J.,Courant Institute of Mathematical Sciences | Kobayashi M.,Courant Institute of Mathematical Sciences | Greengard L.,Courant Institute of Mathematical Sciences | Greengard L.,Simons Center for Data Analysis
Optics Express | Year: 2014

In this paper, we consider acoustic or electromagnetic scattering in two dimensions from an infinite three-layer medium with thousands of wavelength-size dielectric particles embedded in the middle layer. Such geometries are typical of microstructured composite materials, and the evaluation of the scattered field requires a suitable fast solver for either a single configuration or for a sequence of configurations as part of a design or optimization process. We have developed an algorithm for problems of this type by combining the Sommerfeld integral representation, high order integral equation discretization, the fast multipole method and classical multiple scattering theory. The efficiency of the solver is illustrated with several numerical experiments. © 2014 Optical Society of America.


Machado T.A.,Howard Hughes Medical Institute | Machado T.A.,Columbia University | Pnevmatikakis E.,Columbia University | Pnevmatikakis E.,Simons Center for Data Analysis | And 3 more authors.
Cell | Year: 2015

Summary Spinal circuits can generate locomotor output in the absence of sensory or descending input, but the principles of locomotor circuit organization remain unclear. We sought insight into these principles by considering the elaboration of locomotor circuits across evolution. The identity of limb-innervating motor neurons was reverted to a state resembling that of motor neurons that direct undulatory swimming in primitive aquatic vertebrates, permitting assessment of the role of motor neuron identity in determining locomotor pattern. Two-photon imaging was coupled with spike inference to measure locomotor firing in hundreds of motor neurons in isolated mouse spinal cords. In wild-type preparations, we observed sequential recruitment of motor neurons innervating flexor muscles controlling progressively more distal joints. Strikingly, after reversion of motor neuron identity, virtually all firing patterns became distinctly flexor like. Our findings show that motor neuron identity directs locomotor circuit wiring and indicate the evolutionary primacy of flexor pattern generation. © 2015 Elsevier Inc.


Bharioke A.,Howard Hughes Medical Institute | Chklovskii D.B.,Howard Hughes Medical Institute | Chklovskii D.B.,Simons Center for Data Analysis
PLoS Computational Biology | Year: 2015

Neurons must faithfully encode signals that can vary over many orders of magnitude despite having only limited dynamic ranges. For a correlated signal, this dynamic range constraint can be relieved by subtracting away components of the signal that can be predicted from the past, a strategy known as predictive coding, that relies on learning the input statistics. However, the statistics of input natural signals can also vary over very short time scales e.g., following saccades across a visual scene. To maintain a reduced transmission cost to signals with rapidly varying statistics, neuronal circuits implementing predictive coding must also rapidly adapt their properties. Experimentally, in different sensory modalities, sensory neurons have shown such adaptations within 100 ms of an input change. Here, we show first that linear neurons connected in a feedback inhibitory circuit can implement predictive coding. We then show that adding a rectification nonlinearity to such a feedback inhibitory circuit allows it to automatically adapt and approximate the performance of an optimal linear predictive coding network, over a wide range of inputs, while keeping its underlying temporal and synaptic properties unchanged. We demonstrate that the resulting changes to the linearized temporal filters of this nonlinear network match the fast adaptations observed experimentally in different sensory modalities, in different vertebrate species. Therefore, the nonlinear feedback inhibitory network can provide automatic adaptation to fast varying signals, maintaining the dynamic range necessary for accurate neuronal transmission of natural inputs. © 2015 Bharioke, Chklovskii.


Hu T.,Texas A&M University | Chklovskii D.B.,Simons Center for Data Analysis
ICASSP, IEEE International Conference on Acoustics, Speech and Signal Processing - Proceedings | Year: 2015

Natural stimuli are highly redundant, possessing significant spatial and temporal correlations. While sparse coding has been proposed as an efficient strategy employed by neural systems to encode sensory stimuli, the underlying mechanisms are still not well understood. Most previous approaches model the neural dynamics by the sparse representation dictionary itself and compute the representation coefficients offline. In reality, faced with the challenge of constantly changing stimuli, neurons must compute the sparse representations dynamically in an online fashion. Here, we describe a leaky linearized Bregman iteration (LLBI) algorithm which computes the time varying sparse representations using a biologically motivated network of leaky rectifying neurons. Compared to previous attempt of dynamic sparse coding, LLBI exploits the temporal correlation of stimuli and demonstrate better performance both in representation error and the smoothness of temporal evolution of sparse coefficients. © 2015 IEEE.


Pehlevan C.,Harvard University | Pehlevan C.,Simons Center for Data Analysis | Paoletti P.,University of Liverpool | Mahadevan L.,Harvard University
eLife | Year: 2016

Locomotion in an organism is a consequence of the coupled interaction between brain, body and environment. Motivated by qualitative observations and quantitative perturbations of crawling in Drosophila melanogaster larvae, we construct a minimal integrative mathematical model for its locomotion. Our model couples the excitation-inhibition circuits in the nervous system to force production in the muscles and body movement in a frictional environment, thence linking neural dynamics to body mechanics via sensory feedback in a heterogeneous environment. Our results explain the basic observed phenomenology of crawling with and without proprioception, and elucidate the stabilizing role that proprioception plays in producing a robust crawling phenotype in the presence of biological perturbations. More generally, our approach allows us to make testable predictions on the effect of changing body-environment interactions on crawling, and serves as a step in the development of hierarchical models linking cellular processes to behavior. © Pehlevan et al.


Pehlevan C.,Simons Center for Data Analysis | Chklovskii D.B.,Simons Center for Data Analysis
Advances in Neural Information Processing Systems | Year: 2015

To make sense of the world our brains must analyze high-dimensional datasets streamed by our sensory organs. Because such analysis begins with dimensionality reduction, modeling early sensory processing requires biologically plausible online dimensionality reduction algorithms. Recently, we derived such an algorithm, termed similarity matching, from a Multidimensional Scaling (MDS) objective function. However, in the existing algorithm, the number of output dimensions is set a priori by the number of output neurons and cannot be changed. Because the number of informative dimensions in sensory inputs is variable there is a need for adaptive dimensionality reduction. Here, we derive biologically plausible dimensionality reduction algorithms which adapt the number of output dimensions to the eigenspectrum of the input covariance matrix. We formulate three objective functions which, in the offline setting, are optimized by the projections of the input dataset onto its principal subspace scaled by the eigenvalues of the output covariance matrix. In turn, the output eigenvalues are computed as i) soft-thresholded, ii) hard-thresholded, iii) equalized thresholded eigenvalues of the input covariance matrix. In the online setting, we derive the three corresponding adaptive algorithms and map them onto the dynamics of neuronal activity in networks with biologically plausible local learning rules. Remarkably, in the last two networks, neurons are divided into two classes which we identify with principal neurons and interneurons in biological circuits.


Sano T.,New York University | Huang W.,New York University | Hall J.A.,New York University | Yang Y.,New York University | And 15 more authors.
Cell | Year: 2015

RORγt+ Th17 cells are important for mucosal defenses but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt+ T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt+ T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease. © 2015 Elsevier Inc.

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