Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b09519

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b08259

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b09596

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b08279

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b10182

Background: Many functional RNA molecules fold into pseudoknot structures, which are often essential for the formation of an RNA’s 3D structure. Currently the design of RNA molecules, which fold into a specific structure (known as RNA inverse folding) within biotechnological applications, is lacking the feature of incorporating pseudoknot structures into the design. Hairpin-(H)- and kissing hairpin-(K)-type pseudoknots cover a wide range of biologically functional pseudoknots and can be represented on a secondary structure level. Results: The RNA inverse folding program antaRNA, which takes secondary structure, target GC-content and sequence constraints as input, is extended to provide solutions for such H- and K-type pseudoknotted secondary structure constraint.We demonstrate the easy and flexible interchangeability of modules within the antaRNA framework by incorporating pKiss as structure prediction tool capable of predicting the mentioned pseudoknot types. The performance of the approach is demonstrated on a subset of the Pseudobase ++ dataset. Conclusions: This new service is available via a standalone version and is also part of the Freiburg RNA Tools webservice. Furthermore, antaRNA is available in Galaxy and is part of the RNA-workbench Docker image.

Genomics: Acorn worms in a nutshell

Nature 527, 7579 (2015). doi:10.1038/nature16315

Authors: Casey W. Dunn

The genome sequences of two members of the hemichordate group of marine invertebrates bring the evolution of their relatives, including vertebrates, into sharper focus. See Article p.459

Circadian clocks: A receptor for subtle temperature changes

Nature 527, 7579 (2015). doi:10.1038/nature16316

Authors: François Rouyer & Abhishek Chatterjee

The protein IR25a is best known for its role as an odour receptor in flies, but an analysis reveals that it also acts to synchronize the circadian clock by sensing small temperature fluctuations. See Letter p.516

Hemichordate genomes and deuterostome origins

Nature 527, 7579 (2015). doi:10.1038/nature16150

Authors: Oleg Simakov, Takeshi Kawashima, Ferdinand Marlétaz, Jerry Jenkins, Ryo Koyanagi, Therese Mitros, Kanako Hisata, Jessen Bredeson, Eiichi Shoguchi, Fuki Gyoja, Jia-Xing Yue, Yi-Chih Chen, Robert M. Freeman, Akane Sasaki, Tomoe Hikosaka-Katayama, Atsuko Sato, Manabu Fujie, Kenneth W. Baughman, Judith Levine, Paul Gonzalez, Christopher Cameron, Jens H. Fritzenwanker, Ariel M. Pani, Hiroki Goto, Miyuki Kanda, Nana Arakaki, Shinichi Yamasaki, Jiaxin Qu, Andrew Cree, Yan Ding, Huyen H. Dinh, Shannon Dugan, Michael Holder, Shalini N. Jhangiani, Christie L. Kovar, Sandra L. Lee, Lora R. Lewis, Donna Morton, Lynne V. Nazareth, Geoffrey Okwuonu, Jireh Santibanez, Rui Chen, Stephen Richards, Donna M. Muzny, Andrew Gillis, Leonid Peshkin, Michael Wu, Tom Humphreys, Yi-Hsien Su, Nicholas H. Putnam, Jeremy Schmutz, Asao Fujiyama, Jr-Kai Yu, Kunifumi Tagawa, Kim C. Worley, Richard A. Gibbs, Marc W. Kirschner, Christopher J. Lowe, Noriyuki Satoh, Daniel S. Rokhsar & John Gerhart

Acorn worms, also known as enteropneust (literally, ‘gut-breathing’) hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By

Sweet and bitter taste in the brain of awake behaving animals

Nature 527, 7579 (2015). doi:10.1038/nature15763

Authors: Yueqing Peng, Sarah Gillis-Smith, Hao Jin, Dimitri Tränkner, Nicholas J. P. Ryba & Charles S. Zuker

Taste is responsible for evaluating the nutritious content of food, guiding essential appetitive behaviours, preventing the ingestion of toxic substances, and helping to ensure the maintenance of a healthy diet. Sweet and bitter are two of the most salient sensory percepts for humans and other animals; sweet taste allows the identification of energy-rich nutrients whereas bitter warns against the intake of potentially noxious chemicals. In mammals, information from taste receptor cells in the tongue is transmitted through multiple neural stations to the primary gustatory cortex in the brain. Recent imaging studies have shown that sweet and bitter are represented in the primary gustatory cortex by neurons organized in a spatial map, with each taste quality encoded by distinct cortical fields. Here we demonstrate that by manipulating the brain fields representing sweet and bitter taste we directly control an animal’s internal representation, sensory perception, and behavioural actions. These results substantiate the segregation of taste qualities in the cortex, expose the innate nature of appetitive and aversive taste responses, and illustrate the ability of gustatory cortex to recapitulate complex behaviours in the absence of sensory input.

Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature

Nature 527, 7579 (2015). doi:10.1038/nature16148

Authors: Chenghao Chen, Edgar Buhl, Min Xu, Vincent Croset, Johanna S. Rees, Kathryn S. Lilley, Richard Benton, James J. L. Hodge & Ralf Stanewsky

Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2–4 °C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known ‘hot’ and ‘cold’ sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels.

Abstract

Computing high dimensional volumes is a hard problem, even for approximation. Several randomized approximation techniques for #P-hard problems have been developed in the three decades, while some deterministic approximation algorithms are recently developed only for a few #P-hard problems. Motivated by a new technique for a deterministic approximation, this paper is concerned with the volume computation of 0-1 knapsack polytopes, which is known to be #P-hard. This paper presents a new technique based on approximate convolutions for a deterministic approximation of volume computations, and provides a fully polynomial-time approximation scheme for the volume computation of 0-1 knapsack polytopes. We also give an extension of the result to multi-constrained knapsack polytopes with a constant number of constraints.

Abstract

One difficult aspect of the protein-folding problem is characterizing the non-specific interactions that define packing in protein tertiary structure. To better understand tertiary structure, this work extends the knob-socket model by classifying the interactions of a single knob residue packed into a set of contiguous sockets, or a pocket made up of 4 or more residues. The knob-socket construct allows for a symbolic two-dimensional mapping of pockets. The two-dimensional mapping of pockets provides a simple method to investigate the variety of pocket shapes in order to understand the geometry of protein tertiary surfaces. The diversity of pocket geometries can be organized into groups of pockets that share a common core, which suggests that some interactions in pockets are ancillary to packing. Further analysis of pocket geometries displays a preferred configuration that is right-handed in α-helices and left-handed in β-sheets. The amino acid composition of pockets illustrates the importance of non-polar amino acids in packing as well as position specificity. As expected, all pocket shapes prefer to pack with hydrophobic knobs; however, knobs are not selective for the pockets they pack. Investigating side-chain rotamer preferences for certain pocket shapes uncovers no strong correlations. These findings allow a simple vocabulary based on knobs and sockets to describe protein tertiary packing that supports improved analysis, design and prediction of protein structure. This article is protected by copyright. All rights reserved.

by Manuel Schottdorf, Wolfgang Keil, David Coppola, Leonard E. White, Fred Wolf

The architecture of iso-orientation domains in the primary visual cortex (V1) of placental carnivores and primates apparently follows species invariant quantitative laws. Dynamical optimization models assuming that neurons coordinate their stimulus preferences throughout cortical circuits linking millions of cells specifically predict these invariants. This might indicate that V1’s intrinsic connectome and its functional architecture adhere to a single optimization principle with high precision and robustness. To validate this hypothesis, it is critical to closely examine the quantitative predictions of alternative candidate theories. Random feedforward wiring within the retino-cortical pathway represents a conceptually appealing alternative to dynamical circuit optimization because random dimension-expanding projections are believed to generically exhibit computationally favorable properties for stimulus representations. Here, we ask whether the quantitative invariants of V1 architecture can be explained as a generic emergent property of random wiring. We generalize and examine the stochastic wiring model proposed by Ringach and coworkers, in which iso-orientation domains in the visual cortex arise through random feedforward connections between semi-regular mosaics of retinal ganglion cells (RGCs) and visual cortical neurons. We derive closed-form expressions for cortical receptive fields and domain layouts predicted by the model for perfectly hexagonal RGC mosaics. Including spatial disorder in the RGC positions considerably changes the domain layout properties as a function of disorder parameters such as position scatter and its correlations across the retina. However, independent of parameter choice, we find that the model predictions substantially deviate from the layout laws of iso-orientation domains observed experimentally. Considering random wiring with the currently most realistic model of RGC mosaic layouts, a pairwise interacting point process, the predicted layouts remain distinct from experimental observations and resemble Gaussian random fields. We conclude that V1 layout invariants are specific quantitative signatures of visual cortical optimization, which cannot be explained by generic random feedforward-wiring models.

by Alejandro Ochoa, John D. Storey, Manuel Llinás, Mona Singh

E-values have been the dominant statistic for protein sequence analysis for the past two decades: from identifying statistically significant local sequence alignments to evaluating matches to hidden Markov models describing protein domain families. Here we formally show that for “stratified” multiple hypothesis testing problems—that is, those in which statistical tests can be partitioned naturally—controlling the local False Discovery Rate (lFDR) per stratum, or partition, yields the most predictions across the data at any given threshold on the FDR or E-value over all strata combined. For the important problem of protein domain prediction, a key step in characterizing protein structure, function and evolution, we show that stratifying statistical tests by domain family yields excellent results. We develop the first FDR-estimating algorithms for domain prediction, and evaluate how well thresholds based on q-values, E-values and lFDRs perform in domain prediction using five complementary approaches for estimating empirical FDRs in this context. We show that stratified q-value thresholds substantially outperform E-values. Contradicting our theoretical results, q-values also outperform lFDRs; however, our tests reveal a small but coherent subset of domain families, biased towards models for specific repetitive patterns, for which weaknesses in random sequence models yield notably inaccurate statistical significance measures. Usage of lFDR thresholds outperform q-values for the remaining families, which have as-expected noise, suggesting that further improvements in domain predictions can be achieved with improved modeling of random sequences. Overall, our theoretical and empirical findings suggest that the use of stratified q-values and lFDRs could result in improvements in a host of structured multiple hypothesis testing problems arising in bioinformatics, including genome-wide association studies, orthology prediction, and motif scanning.

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b09826

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b10221

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b06382

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b10184