In situ structures of the segmented genome and RNA polymerase complex inside a dsRNA virus

Nature 527, 7579 (2015). doi:10.1038/nature15767

Authors: Xing Zhang, Ke Ding, Xuekui Yu, Winston Chang, Jingchen Sun & Z. Hong Zhou

Viruses in the Reoviridae, like the triple-shelled human rotavirus and the single-shelled insect cytoplasmic polyhedrosis virus (CPV), all package a genome of segmented double-stranded RNAs (dsRNAs) inside the viral capsid and carry out endogenous messenger RNA synthesis through a transcriptional enzyme complex (TEC). By direct electron-counting cryoelectron microscopy and asymmetric reconstruction, we have determined the organization of the dsRNA genome inside quiescent CPV (q-CPV) and the in situ atomic structures of TEC within CPV in both quiescent and transcribing (t-CPV) states. We show that the ten segmented dsRNAs in CPV are organized with ten TECs in a specific, non-symmetric manner, with each dsRNA segment attached directly to a TEC. The TEC consists of two extensively interacting subunits: an RNA-dependent RNA polymerase (RdRP) and an NTPase VP4. We find that the bracelet domain of RdRP undergoes marked conformational change when q-CPV is converted to t-CPV, leading to formation of the RNA template entry channel and access to the polymerase active site. An amino-terminal helix from each of two subunits of the capsid shell protein (CSP) interacts with VP4 and RdRP. These findings establish the link between sensing of environmental cues by the external proteins and activation of endogenous RNA transcription by the TEC inside the virus.

Abstract

In this paper we initiate the study of job scheduling on related and unrelated machines so as to minimize the maximum flow time or the maximum weighted flow time (when each job has an associated weight). Previous work for these metrics considered only the setting of parallel machines, while previous work for scheduling on unrelated machines only considered \(L_p, p<\infty \) norms. Our main results are: (1) we give an \(\mathcal {O}({\varepsilon }^{-3})\) -competitive algorithm to minimize maximum weighted flow time on related machines where we assume that the machines of the online algorithm can process \(1+{\varepsilon }\) units of a job in 1 time-unit ( \({\varepsilon }\) speed augmentation). (2) For the objective of minimizing maximum flow time on unrelated machines we give a simple \(2/{\varepsilon }\) -competitive algorithm when we augment the speed by \({\varepsilon }\) . For m machines we show a lower bound of \({\varOmega }(m)\) on the competitive ratio if speed augmentation is not permitted. Our algorithm does not assign jobs to machines as soon as they arrive. To justify this “drawback” we show a lower bound of \({\varOmega }(\log m)\) on the competitive ratio of immediate dispatch algorithms. In both these lower bound constructions we use jobs whose processing times are in \(\left\{ 1,\infty \right\} \) , and hence they apply to the more restrictive subset parallel setting. (3) For the objective of minimizing maximum weighted flow time on unrelated machines we establish a lower bound of \({\varOmega }(\log m)\) -on the competitive ratio of any online algorithm which is permitted to use \(s=\mathcal {O}(1)\) speed machines. In our lower bound construction, job j has a processing time of \(p_j\) on a subset of machines and infinity on others and has a weight \(1/p_j\) . Hence this lower bound applies to the subset parallel setting for the special case of minimizing maximum stretch.

Abstract

We show that the quantum query complexity of detecting if an n-vertex graph contains a triangle is \(O(n^{9/7})\) . This improves the previous best algorithm of Belovs (Proceedings of 44th symposium on theory of computing conference, pp 77–84, 2012) making \(O(n^{35/27})\) queries. For the problem of determining if an operation \(\circ : S \times S \rightarrow S\) is associative, we give an algorithm making \(O(|S|^{10/7})\) queries, the first improvement to the trivial \(O(|S|^{3/2})\) application of Grover search. Our algorithms are designed using the learning graph framework of Belovs. We give a family of algorithms for detecting constant-sized subgraphs, which can possibly be directed and colored. These algorithms are designed in a simple high-level language; our main theorem shows how this high-level language can be compiled as a learning graph and gives the resulting complexity. The key idea to our improvements is to allow more freedom in the parameters of the database kept by the algorithm.

Abstract

In an \(\epsilon \) -Nash equilibrium, a player can gain at most \(\epsilon \) by unilaterally changing his behavior. For two-player (bimatrix) games with payoffs in [0, 1], the best-known  \(\epsilon \) achievable in polynomial time is 0.3393 (Tsaknakis and Spirakis in Internet Math 5(4):365–382, 2008). In general, for n-player games an \(\epsilon \) -Nash equilibrium can be computed in polynomial time for an \(\epsilon \) that is an increasing function of n but does not depend on the number of strategies of the players. For three-player and four-player games the corresponding values of \(\epsilon \) are 0.6022 and 0.7153, respectively. Polymatrix games are a restriction of general n-player games where a player’s payoff is the sum of payoffs from a number of bimatrix games. There exists a very small but constant \(\epsilon \) such that computing an \(\epsilon \) -Nash equilibrium of a polymatrix game is \(\mathtt {PPAD}\) -hard. Our main result is that a \((0.5+\delta )\) -Nash equilibrium of an n-player polymatrix game can be computed in time polynomial in the input size and \(\frac{1}{\delta }\) . Inspired by the algorithm of Tsaknakis and Spirakis [28], our algorithm uses gradient descent style approach on the maximum regret of the players. We also show that this algorithm can be applied to efficiently find a \((0.5+\delta )\) -Nash equilibrium in a two-player Bayesian game.

Background: Amplicon re-sequencing based on the automated Sanger method remains popular for detection of single nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms (InDels) for a spectrum of genetics applications. However, existing software tools for detecting intra-individual SNPs and InDels in direct amplicon sequencing of diploid samples are insufficient in analyzing single traces and their accuracy is still limited. Results: We developed a novel computation tool, named DiSNPindel, to improve the detection of intra-individual SNPs and InDels in direct amplicon sequencing of a diploid. Neither reference sequence nor additional sample was required. Using two real datasets, we demonstrated the usefulness of DiSNPindel in its ability to improve largely the true SNP and InDel discovery rates and reduce largely the missed and false positive rates as compared with existing detection methods. Conclusions: The software DiSNPindel presented here provides an efficient tool for intra-individual SNP and InDel detection in diploid amplicon sequencing. It will also be useful for identification of DNA variations in expressed sequence tag (EST) re-sequencing.

Background: Reconstruction of neuron anatomy structure is a challenging and important task in neuroscience. However, few algorithms can automatically reconstruct the full structure well without manual assistance, making it essential to develop new methods for this task. Methods: This paper introduces a new pipeline for reconstructing neuron anatomy structure from 3-D microscopy image stacks. This pipeline is initialized with a set of seeds that were detected by our proposed Sliding Volume Filter (SVF), given a non-circular cross-section of a neuron cell. Then, an improved open curve snake model combined with a SVF external force is applied to trace the full skeleton of the neuron cell. A radius estimation method based on a 2D sliding band filter is developed to fit the real edge of the cross-section of the neuron cell. Finally, a surface reconstruction method based on non-parallel curve networks is used to generate the neuron cell surface to finish this pipeline. Results: The proposed pipeline has been evaluated using publicly available datasets. The results show that the proposed method achieves promising results in some datasets from the DIgital reconstruction of Axonal and DEndritic Morphology (DIADEM) challenge and new BigNeuron project. Conclusion: The new pipeline works well in neuron tracing and reconstruction. It can achieve higher efficiency, stability and robustness in neuron skeleton tracing. Furthermore, the proposed radius estimation method and applied surface reconstruction method can obtain more accurate neuron anatomy structures.

Background: Metabolomics experiments often comprise large numbers of biological samples resulting in huge amounts of data. This data needs to be inspected for plausibility before data evaluation to detect putative sources of error e.g. retention time or mass accuracy shifts. Especially in liquid chromatography-high resolution mass spectrometry (LC-HRMS) based metabolomics research, proper quality control checks (e.g. for precision, signal drifts or offsets) are crucial prerequisites to achieve reliable and comparable results within and across experimental measurement sequences. Software tools can support this process. Results: The software tool QCScreen was developed to offer a quick and easy data quality check of LC-HRMS derived data. It allows a flexible investigation and comparison of basic quality-related parameters within user-defined target features and the possibility to automatically evaluate multiple sample types within or across different measurement sequences in a short time. It offers a user-friendly interface that allows an easy selection of processing steps and parameter settings. The generated results include a coloured overview plot of data quality across all analysed samples and targets and, in addition, detailed illustrations of the stability and precision of the chromatographic separation, the mass accuracy and the detector sensitivity. The use of QCScreen is demonstrated with experimental data from metabolomics experiments using selected standard compounds in pure solvent. The application of the software identified problematic features, samples and analytical parameters and suggested which data files or compounds required closer manual inspection. Conclusions: QCScreen is an open source software tool which provides a useful basis for assessing the suitability of LC-HRMS data prior to time consuming, detailed data processing and subsequent statistical analysis. It accepts the generic mzXML format and thus can be used with many different LC-HRMS platforms to process both multiple quality control sample types as well as experimental samples in one or more measurement sequences.

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b09337

by Dimitrije Marković, Jan Gläscher, Peter Bossaerts, John O’Doherty, Stefan J. Kiebel

For making decisions in everyday life we often have first to infer the set of environmental features that are relevant for the current task. Here we investigated the computational mechanisms underlying the evolution of beliefs about the relevance of environmental features in a dynamical and noisy environment. For this purpose we designed a probabilistic Wisconsin card sorting task (WCST) with belief solicitation, in which subjects were presented with stimuli composed of multiple visual features. At each moment in time a particular feature was relevant for obtaining reward, and participants had to infer which feature was relevant and report their beliefs accordingly. To test the hypothesis that attentional focus modulates the belief update process, we derived and fitted several probabilistic and non-probabilistic behavioral models, which either incorporate a dynamical model of attentional focus, in the form of a hierarchical winner-take-all neuronal network, or a diffusive model, without attention-like features. We used Bayesian model selection to identify the most likely generative model of subjects’ behavior and found that attention-like features in the behavioral model are essential for explaining subjects’ responses. Furthermore, we demonstrate a method for integrating both connectionist and Bayesian models of decision making within a single framework that allowed us to infer hidden belief processes of human subjects.

by Philipp S. Orekhov, Daniel Klose, Armen Y. Mulkidjanian, Konstantin V. Shaitan, Martin Engelhard, Johann P. Klare, Heinz-Jürgen Steinhoff

Motile bacteria and archaea respond to chemical and physical stimuli seeking optimal conditions for survival. To this end transmembrane chemo- and photoreceptors organized in large arrays initiate signaling cascades and ultimately regulate the rotation of flagellar motors. To unravel the molecular mechanism of signaling in an archaeal phototaxis complex we performed coarse-grained molecular dynamics simulations of a trimer of receptor/transducer dimers, namely NpSRII/NpHtrII from Natronomonas pharaonis. Signaling is regulated by a reversible methylation mechanism called adaptation, which also influences the level of basal receptor activation. Mimicking two extreme methylation states in our simulations we found conformational changes for the transmembrane region of NpSRII/NpHtrII which resemble experimentally observed light-induced changes. Further downstream in the cytoplasmic domain of the transducer the signal propagates via distinct changes in the dynamics of HAMP1, HAMP2, the adaptation domain and the binding region for the kinase CheA, where conformational rearrangements were found to be subtle. Overall these observations suggest a signaling mechanism based on dynamic allostery resembling models previously proposed for E. coli chemoreceptors, indicating similar properties of signal transduction for archaeal photoreceptors and bacterial chemoreceptors.

by Tobias Brosch, Heiko Neumann, Pieter R. Roelfsema

The processing of a visual stimulus can be subdivided into a number of stages. Upon stimulus presentation there is an early phase of feedforward processing where the visual information is propagated from lower to higher visual areas for the extraction of basic and complex stimulus features. This is followed by a later phase where horizontal connections within areas and feedback connections from higher areas back to lower areas come into play. In this later phase, image elements that are behaviorally relevant are grouped by Gestalt grouping rules and are labeled in the cortex with enhanced neuronal activity (object-based attention in psychology). Recent neurophysiological studies revealed that reward-based learning influences these recurrent grouping processes, but it is not well understood how rewards train recurrent circuits for perceptual organization. This paper examines the mechanisms for reward-based learning of new grouping rules. We derive a learning rule that can explain how rewards influence the information flow through feedforward, horizontal and feedback connections. We illustrate the efficiency with two tasks that have been used to study the neuronal correlates of perceptual organization in early visual cortex. The first task is called contour-integration and demands the integration of collinear contour elements into an elongated curve. We show how reward-based learning causes an enhancement of the representation of the to-be-grouped elements at early levels of a recurrent neural network, just as is observed in the visual cortex of monkeys. The second task is curve-tracing where the aim is to determine the endpoint of an elongated curve composed of connected image elements. If trained with the new learning rule, neural networks learn to propagate enhanced activity over the curve, in accordance with neurophysiological data. We close the paper with a number of model predictions that can be tested in future neurophysiological and computational studies.

by Mingming Chen, Daqing Guo, Min Li, Tao Ma, Shengdun Wu, Jingling Ma, Yan Cui, Yang Xia, Peng Xu, Dezhong Yao

The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies.

by Àngel Gómez-Sicilia, Mateusz Sikora, Marek Cieplak, Mariano Carrión-Vázquez

Deposits of misfolded proteins in the human brain are associated with the development of many neurodegenerative diseases. Recent studies show that these proteins have common traits even at the monomer level. Among them, a polyglutamine region that is present in huntingtin is known to exhibit a correlation between the length of the chain and the severity as well as the earliness of the onset of Huntington disease. Here, we apply bias exchange molecular dynamics to generate structures of polyglutamine expansions of several lengths and characterize the resulting independent conformations. We compare the properties of these conformations to those of the standard proteins, as well as to other homopolymeric tracts. We find that, similar to the previously studied polyvaline chains, the set of possible transient folds is much broader than the set of known-to-date folds, although the conformations have different structures. We show that the mechanical stability is not related to any simple geometrical characteristics of the structures. We demonstrate that long polyglutamine expansions result in higher mechanical stability than the shorter ones. They also have a longer life span and are substantially more prone to form knotted structures. The knotted region has an average length of 35 residues, similar to the typical threshold for most polyglutamine-related diseases. Similarly, changes in shape and mechanical stability appear once the total length of the peptide exceeds this threshold of 35 glutamine residues. We suggest that knotted conformers may also harm the cellular machinery and thus lead to disease.

by Joel Z. Leibo, Qianli Liao, Fabio Anselmi, Tomaso Poggio

Is visual cortex made up of general-purpose information processing machinery, or does it consist of a collection of specialized modules? If prior knowledge, acquired from learning a set of objects is only transferable to new objects that share properties with the old, then the recognition system’s optimal organization must be one containing specialized modules for different object classes. Our analysis starts from a premise we call the invariance hypothesis: that the computational goal of the ventral stream is to compute an invariant-to-transformations and discriminative signature for recognition. The key condition enabling approximate transfer of invariance without sacrificing discriminability turns out to be that the learned and novel objects transform similarly. This implies that the optimal recognition system must contain subsystems trained only with data from similarly-transforming objects and suggests a novel interpretation of domain-specific regions like the fusiform face area (FFA). Furthermore, we can define an index of transformation-compatibility, computable from videos, that can be combined with information about the statistics of natural vision to yield predictions for which object categories ought to have domain-specific regions in agreement with the available data. The result is a unifying account linking the large literature on view-based recognition with the wealth of experimental evidence concerning domain-specific regions.

by Armin Meier, Johannes Söding

Homology modeling predicts the 3D structure of a query protein based on the sequence alignment with one or more template proteins of known structure. Its great importance for biological research is owed to its speed, simplicity, reliability and wide applicability, covering more than half of the residues in protein sequence space. Although multiple templates have been shown to generally increase model quality over single templates, the information from multiple templates has so far been combined using empirically motivated, heuristic approaches. We present here a rigorous statistical framework for multi-template homology modeling. First, we find that the query proteins’ atomic distance restraints can be accurately described by two-component Gaussian mixtures. This insight allowed us to apply the standard laws of probability theory to combine restraints from multiple templates. Second, we derive theoretically optimal weights to correct for the redundancy among related templates. Third, a heuristic template selection strategy is proposed. We improve the average GDT-ha model quality score by 11% over single template modeling and by 6.5% over a conventional multi-template approach on a set of 1000 query proteins. Robustness with respect to wrong constraints is likewise improved. We have integrated our multi-template modeling approach with the popular MODELLER homology modeling software in our free HHpred server http://toolkit.tuebingen.mpg.de/hhpred and also offer open source software for running MODELLER with the new restraints at https://bitbucket.org/soedinglab/hh-suite.

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b09980

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b09248

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b07848