CircadiOmics: circadian omic web portal.

Circadian rhythms are a foundational aspect of biology. These rhythms are found at the molecular level in every cell of every living organism and they play a fundamental role in homeostasis and a variety of physiological processes. As a result, biomedical research of circadian rhythms continues to expand at a rapid pace. To support this research, CircadiOmics (http://circadiomics.igb.uci.edu/) is the largest annotated repository and analytic web server for high-throughput omic (e.g. transcriptomic, metabolomic, proteomic) circadian time series experimental data. CircadiOmics contains over 290 experiments and over 100 million individual measurements, across >20 unique tissues/organs, and 11 different species. Users are able to visualize and mine these datasets by deriving and comparing periodicity statistics for oscillating molecular species including: period, amplitude, phase, P-value and q-value. These statistics are obtained from BIO_CYCLE and JTK_CYCLE and are intuitively aggregated and displayed for comparison. CircadiOmics is the most up-to-date and cutting-edge web portal for searching and analyzing circadian omic data and is used by researchers around the world.

Bioinformatics and Systems Biology of Circadian Rhythms: BIO_CYCLE and CircadiOmics.

Circadian rhythms are fundamental to biology and medicine and today these can be studied at the molecular level in high-throughput fashion using various omic technologies. We briefly present two resources for the study of circadian omic (e.g. transcriptomic, metabolomic, proteomic) time series. First, BIO_CYCLE is a deep-learning-based program and web server that can analyze omic time series and statistically assess their periodic nature and, when periodic, accurately infer the corresponding period, amplitude, and phase. Second, CircadiOmics is the larges annotated repository of circadian omic time series, containing over 260 experiments and 90 million individual measurements, across multiple organs and tissues, and across 9 different species. In combination, these tools enable powerful bioinformatics and systems biology analyses. The are currently being deployed in a host of different projects where they are enabling significant discoveries: both tools are publicly available over the web at: http://circadiomics.ics.uci.edu/ .

Hippocampal ensembles represent sequential relationships among an extended sequence of nonspatial events.

The hippocampus is critical to the temporal organization of our experiences. Although this fundamental capacity is conserved across modalities and species, its underlying neuronal mechanisms remain unclear. Here we recorded hippocampal activity as rats remembered an extended sequence of nonspatial events unfolding over several seconds, as in daily life episodes in humans. We then developed statistical machine learning methods to analyze the ensemble activity and discovered forms of sequential organization and coding important for order memory judgments. Specifically, we found that hippocampal ensembles provide significant temporal coding throughout nonspatial event sequences, differentiate distinct types of task-critical information sequentially within events, and exhibit theta-associated reactivation of the sequential relationships among events. We also demonstrate that nonspatial event representations are sequentially organized within individual theta cycles and precess across successive cycles. These findings suggest a fundamental function of the hippocampal network is to encode, preserve, and predict the sequential order of experiences.

SPLASH: Learnable activation functions for improving accuracy and adversarial robustness.

We introduce SPLASH units, a class of learnable activation functions shown to simultaneously improve the accuracy of deep neural networks while also improving their robustness to adversarial attacks. SPLASH units have both a simple parameterization and maintain the ability to approximate a wide range of non-linear functions. SPLASH units are: (1) continuous; (2) grounded (f(0)=0); (3) use symmetric hinges; and (4) their hinges are placed at fixed locations which are derived from the data (i.e. no learning required). Compared to nine other learned and fixed activation functions, including ReLU and its variants, SPLASH units show superior performance across three datasets (MNIST, CIFAR-10, and CIFAR-100) and four architectures (LeNet5, All-CNN, ResNet-20, and Network-in-Network). Furthermore, we show that SPLASH units significantly increase the robustness of deep neural networks to adversarial attacks. Our experiments on both black-box and white-box adversarial attacks show that commonly-used architectures, namely LeNet5, All-CNN, Network-in-Network, and ResNet-20, can be up to 31% more robust to adversarial attacks by simply using SPLASH units instead of ReLUs. Finally, we show the benefits of using SPLASH activation functions in bigger architectures designed for non-trivial datasets such as ImageNet.

CircadiOmics: circadian omic web portal.

Circadian rhythms play a fundamental role at all levels of biological organization. Understanding the mechanisms and implications of circadian oscillations continues to be the focus of intense research. However, there has been no comprehensive and integrated way for accessing and mining all circadian omic datasets. The latest release of CircadiOmics (http://circadiomics.ics.uci.edu) fills this gap for providing the most comprehensive web server for studying circadian data. The newly updated version contains high-throughput 227 omic datasets corresponding to over 74 million measurements sampled over 24 h cycles. Users can visualize and compare oscillatory trajectories across species, tissues and conditions. Periodicity statistics (e.g. period, amplitude, phase, P-value, q-value etc.) obtained from BIO_CYCLE and other methods are provided for all samples in the repository and can easily be downloaded in the form of publication-ready figures and tables. New features and substantial improvements in performance and data volume make CircadiOmics a powerful web portal for integrated analysis of circadian omic data.

What time is it? Deep learning approaches for circadian rhythms.

MOTIVATION: Circadian rhythms date back to the origins of life, are found in virtually every species and every cell, and play fundamental roles in functions ranging from metabolism to cognition. Modern high-throughput technologies allow the measurement of concentrations of transcripts, metabolites and other species along the circadian cycle creating novel computational challenges and opportunities, including the problems of inferring whether a given species oscillate in circadian fashion or not, and inferring the time at which a set of measurements was taken. RESULTS: We first curate several large synthetic and biological time series datasets containing labels for both periodic and aperiodic signals. We then use deep learning methods to develop and train BIO_CYCLE, a system to robustly estimate which signals are periodic in high-throughput circadian experiments, producing estimates of amplitudes, periods, phases, as well as several statistical significance measures. Using the curated data, BIO_CYCLE is compared to other approaches and shown to achieve state-of-the-art performance across multiple metrics. We then use deep learning methods to develop and train BIO_CLOCK to robustly estimate the time at which a particular single-time-point transcriptomic experiment was carried. In most cases, BIO_CLOCK can reliably predict time, within approximately 1 h, using the expression levels of only a small number of core clock genes. BIO_CLOCK is shown to work reasonably well across tissue types, and often with only small degradation across conditions. BIO_CLOCK is used to annotate most mouse experiments found in the GEO database with an inferred time stamp. AVAILABILITY AND IMPLEMENTATION: All data and software are publicly available on the CircadiOmics web portal: circadiomics.igb.uci.edu/ CONTACTS: fagostin@uci.edu or pfbaldi@uci.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.