bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes
Authors: Huckins Laura M. , Dobbyn Amanda , McFadden Whitney , Wang Weiqing , Ruderfer Douglas M. , Hoffman Gabriel , Rajagopal Veera , Nguyen Hoang T. , Roussos Panos , Fromer Menachem , Kramer Robin , Domenci Enrico , Gamazon Eric ,   CommonMind Consortium, the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, iPSYCH Consortium, Ditte Demontis, Børglum Anders , Devlin Bernie , Sieberts Solveig K. , Cox Nancy , Im Hae Kyung , Sklar Pamela , Stahl Eli A.
Published: December 2017

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.

We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).

We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.
Inter- and intracellular colonization of Arabidopsis roots by endophytic actinobacteria and the impact of plant hormones on their antimicrobial activity
Authors: van der Meij Anne , Willemse Joost , Schneijderberg Martinus A. , Geurts René , Raaijmakers Jos M. , van Wezel Gilles P.
Published: December 2017

Many actinobacteria live in close association with eukaryotes like fungi, insects, animals and plants. Plant-associated actinobacteria display (endo)symbiotic, saprophytic or pathogenic life styles, and can make up a substantial part of the endophytic community. Here, we characterised endophytic actinobacteria isolated from root tissue ofArabidopsis thaliana(Arabidopsis) plants grown in soil from a natural ecosystem. Many of these actinobacteria belong to the family ofStreptomycetaceaewithStreptomyces olivochromogenesandStreptomyces claviferas well represented species. When seeds of Arabidopsis were inoculated with spores ofStreptomycesstrain coa1, which shows high similarity toS. olivochromogenes, roots were colonised intercellularly and, unexpectedly, also intracellularly. Subsequent exposure of endophytic isolates to plant hormones typically found in root and shoot tissues of Arabidopsis led to altered antibiotic production againstEscherichia coliandBacillus subtilis. Taken together, our work reveals remarkable colonization patterns of endophytic streptomycetes with specific traits that may allow a competitive advantage inside root tissue.
k-mer grammar uncovers maize regulatory architecture
Authors: Mejía-Guerra María Katherine , Buckler Edward S
Published: December 2017

Only a small percentage of the genome sequence is involved in regulation of gene expression, but to biochemically identify this portion is expensive and laborious. In species like maize, with diverse intergenic regions and lots of repetitive elements, this is an especially challenging problem. While regulatory regions are rare, they do have characteristic chromatin contexts and sequence organization (the grammar) with which they can be identified. We developed a computational framework to exploit this sequence arrangement. The models learn to classify regulatory regions based on sequence features -k-mers. To do this, we borrowed two approaches from the field of natural language processing: (1) “bag-of-words” which is commonly used for differentially weighting key words in tasks like sentiment analyses, and (2) a vector-space model using word2vec (vector-k-mers), that captures semantic and linguistic relationships between words. We built “bag-of-k-mers” and “vector-k-mers” models that distinguish between regulatory and non-regulatory regions with an accuracy above 90%. Our “bag-of-k-mers” achieved higher overall accuracy, while the “vector-k-mers” models were more useful in highlighting key groups of sequences within the regulatory regions. These models now provide powerful tools to annotate regulatory regions in other maize lines beyond the reference, at low cost and with high accuracy.
Airway IRF7hiversus IRF7lomolecular response patterns determine clinical phenotypes in children with acute wheezing
Authors: Khoo Siew-Kim , Read James , Franks Kimberley , Zhang Guicheng , Bizzintino Joelene , Coleman Laura , McCrae Christopher , Öberg Lisa , Troy Niamh , Prastanti Franciska , Everard Janet , Oo Stephen , Borland Meredith L , Maciewicz Rose A , Le Souëf Peter N , Laing Ingrid A , Bosco Anthony
Published: December 2017

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hiversus IRF7lomolecular phenotypes, the former exhibiting robust upregulation of Th1/type I interferon responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signalling and downregulation of interferon gamma. The two phenotypes also produced distinct clinical phenotypes. For IRF7loversus IRF7hi: symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p=0.011) and nearly three times as long for cough (p<0.001); the odds ratio of admission to hospital was increased more than four-fold (p=0.018); and time to recurrence was shorter (p=0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hiversus IRF7lophenotypes with associated differences in clinical phenotypes.

Abbreviations

AHR, airway hyperresponsiveness; ARG1, Arginase 1, CSF3, Colony Stimulating Factor 3; CD38, Cluster of Differentiation 38; CD163, Cluster of Differentiation 163; cDCs, conventional (or myeloid) dendritic cells; DDX60, DExD/H-Box Helicase 60; ED, Emergency Department; EGF, Epidermal Growth Factor; ERK, Extracellular signal-Regulated Kinase; FCER1G, Fc Fragment Of IgE Receptor Ig; HMBS, Hydroxymethylbilane Synthase; IFNg, Interferon Gamma; IFNL1, Interferon Lambda 1; IL-1R2, Interleukin 1 Receptor Type 2; IRF7, Interferon Regulatory Factor 7; ISG15, Interferon-stimulated gene 15; MDA5, Melanoma Differentiation-Associated protein 5; MX1, Myxovirus Resistance Protein 1; NAD, nicotinamide adenine dinucleotide; NCR1, Natural cytotoxicity triggering receptor 1; OSM, Oncostatin M; PD-L1, Programmed Death-Ligand 1; PPIA, Peptidylprolyl Isomerase A; PPIB Peptidylprolyl Isomerase B; RSAD2, Radical S-adenosyl methionine domain-containing protein 2; RSV, respiratory syncytial virus; RT-qPCR, quantitative reverse transcription PCR; RV, rhinovirus; sPLA2, secretory Phospholipase A2; TGFb, Transforming Growth Factor beta; THBS1, Thrombospondin 1; TNF, Tumor Necrosis Factor; TLR2, Toll-like Receptor 2.
Development of anin vitropre-mRNA splicing assay using plant nuclear extract
Authors: Albaqami Mohammed , Reddy Anireddy S. N.
Published: December 2017

Background

Pre-mRNA splicing is an essential post-transcriptional process in all eukaryotes.In vitrosplicing systems using nuclear or cytoplasmic extracts from mammalian cells, yeast, andDrosophilahave provided a wealth of mechanistic insights into assembly and composition of the spliceosome, splicing regulatory proteins and mechanisms of pre-mRNA splicing in non-plant systems. The lack of anin vitrosplicing system prepared from plant cells has been a major limitation in splicing research in plants.

Results

Here we report anin vitrosplicing assay system using plant nuclear extract. Several lines of evidence indicate that nuclear extract (NE) derived fromArabidopsisseedlings can convert pre-mRNA substrate (LHCB3) into a spliced product. These include: i) generation of an RNA product that corresponds to the size of expected mRNA, ii) a junction-mapping assay using S1 nuclease revealed that the two exons are spliced together, iii) the reaction conditions are similar to those found with non-plant extracts and iv) finally mutations in conserved donor and acceptor sites abolished the production of the spliced product.

Conclusions

This first report on the plantin vitrosplicing assay opens new avenues to investigate plant spliceosome assembly and composition, and splicing regulatory mechanisms specific to plants.
A Web-resource for Nutrient Use Efficiency related Genes, QTLs, and microRNA in important cereals and model plants
Authors: Kumar Anuj , Pandeya Ajay , Malik Girik , Hima Kumari P , Anil Kumar S , Sharma Mansi , Gahlaut Vijay , Gajula MNV Prasad , Suravajhala Prashanth , Singh Krishna Pal , Balyan Harindra Singh , Gupta Pushpendra K
Published: December 2017

Cereals are the key contributors to global food security. Genes involved in uptake (transport), assimilation and utilization of macro- and micro-nutrients are responsible for their content in grain and straw. Although many cereal genomic databases are available, currently there is no cohesive web-resource of manually curated nutrient use efficiency (NtUE) related genes and QTLs, etc. In this study, we present a web-resource containing information on NtUE related genes/QTLs and the corresponding available microRNAs for some of these genes in four major cereal crops [wheat (Triticum aestivum), rice (Oryza sativa), maize (Zea mays), barley (Hordeum vulgare)], two alien species (Triticum urartu and Aegilops tauschii) related to wheat, and two model species including Brachypodium distachyon and Arabidopsis thaliana. Gene annotations integrated in the current web-resource were collected from the existing databases and the available literature. The primary goal of developing this web-resource is to provide descriptions of the NtUE related genes and their functional annotation. MicroRNA targeting some of the NtUE related genes and the quantitative trait loci (QTLs) for NtUE related traits are also included. The available information in the web-resource should help the users to readily search the desired information.

Web-resource URL

http://bioclues.org/NtUE/
LRX Proteins play a crucial role in pollen grain and pollen tube cell wall development
Authors: Fabrice Tohnyui Ndinyanka , Vogler Hannes , Draeger Christian , Munglani Gautam , Gupta Shibu , Herger Aline G. , Knox Paul , Grossniklaus Ueli , Ringli Christoph
Published: December 2017

Leucine-rich repeat extensins (LRXs) are chimeric proteins containing an N-terminal leucine-rich repeat (LRR) and a C-terminal extensin domain. LRXs are involved in cell wall formation in vegetative tissues and required for plant growth. However, the nature of their role in these cellular processes remains to be elucidated. Here, we used a combination of molecular techniques, light microscopy, and transmission electron microscopy to characterize mutants of pollen-expressedLRXsinArabidopsis thaliana. Mutations in multiple pollen-expressedlrxgenes causes severe defects in pollen germination and pollen tube (PT) growth, resulting in a reduced seed set. Physiological experiments demonstrate that manipulating Ca2+availability partially suppresses the PT growth defects, suggesting that LRX proteins influence Ca2+-related processes. Furthermore, we show that LRX protein localizes to the cell wall, and its LRR-domain (which likely mediates protein-protein interactions) is associated with the plasma membrane. Mechanical analyses by cellular force microscopy and finite element method-based modelling revealed significant changes in the material properties of the cell wall and the fine-tuning of cellular biophysical parameters in the mutants compared to the wild type. The results indicate that LRX proteins might play a role in cell wall-plasma membrane communication, influencing cell wall formation and cellular mechanics.
YAMP: a containerised workflow enabling reproducibility in metagenomics research
Authors: Visconti Alessia , Martin Tiphaine C. , Falchi Mario
Published: December 2017

YAMP is a user-friendly workflow that enables the analysis of whole shotgun metagenomic data while using containerisation to ensure computational reproducibility and facilitate collaborative research. YAMP can be executed on any UNIX-like system, and offers seamless support for multiple job schedulers as well as for Amazon AWS cloud. Although YAMP has been developed to be ready-to-use by non-experts, bioinformaticians will appreciate its flexibility, modularisation, and simple customisation.

The YAMP script, parameters, and documentation are available athttps://github.com/alesssia/YAMP.
A Rice Dual-localized Pentatricopeptide Repeat Protein is involved in Organellar RNA Editing with MORFs
Authors: Xiao Haijun , Xu Yanghong , Ni Chenzi , Zhang Qiannan , Zhong Feiya , Huang Jishuai , Zhu Yingguo , Hu Jun
Published: December 2017

Flowering plants engage in diverse RNA editing events in mitochondrion and chloroplast on post-transcriptional process. Although several PPRs and MORFs were identified as RNA editing factors, the underlying mechanism of PPRs and the cooperation among them are still obscure. Here, we identified a rice dual-localized PPR mutant Ospgl1. Loss-of-function of OsPGLl resulted in defect of chloroplast RNA editing at ndhD-878 and mitochondrial RNA editing at ccmFc-543, which can be restored via complementary validation. Despite the synonymous editing on ccmFc-543, loss of editing at ndhD-878 caused failure of conversion from serine to leucine, leading to the dysfunction of chloroplast and defective in photosynthetic complex, further studies demonstrated OsPGL1 directly bound to both two transcripts. The interaction between three MORFs (MORF2/8/9) and OsPGL1 were confirmed in vitro and in vivo, implied OsPGL1 functioned on RNA editing via an editosome. It also suggested MORFs assisted and contributed to the flexible PPR-RNA recognition model during RNA editing through the cooperation with PPRs. These results provide new insight into the relationship between RNA editing and plant development on chloroplast.

Highlight

We firstly characterized a dual-localized PPR protein which is required for RNA editing in mitochondrion and chloroplast simultaneously. OsPGL1 binds to two distinguish target transcripts directly and cooperated with MORFs.
Ca2+-induced mitochondrial ROS regulate the early embryonic cell cycle
Authors: Han Yue , Ishibashi Shoko , Iglesias-Gonzalez Javier , Chen Yaoyao , Love Nick R. , Amaya Enrique
Published: December 2017

While it has long been appreciated that reactive oxygen species (ROS) can act as second messengers in both homeostastic and stress response signaling pathways, potential roles for ROS during early vertebrate development have remained largely unexplored. Here we show that fertilization inXenopusembryos triggers a rapid increase in ROS levels, which oscillates with each cell division. Furthermore, we show that the fertilization induced Ca2+wave is both necessary and sufficient to induce ROS production in activated or fertilized eggs. Using chemical inhibitors, we identified mitochondria as the major source of fertilization induced ROS production. Inhibition of mitochondrial ROS production in early embryos results in cell cycle arrest, in part, via ROS dependent regulation of Cdc25C activity. This study reveals for the first time, a role for oscillating ROS levels in the regulation of the early cell cycle inXenopusembryos.

Highlights

ROS, including hydrogen peroxide, are produced after fertilization inXenopus

Ca2+signaling after fertilization induces ROS production in mitochondria

Mitochondria are the major source of oscillating ROS levels

ROS regulate Cdc25C activity and the early cell cycle
Asymmetrical localization of Nup107-160 subcomplex components within the nuclear pore complex in fission yeast
Authors: Asakawa Haruhiko , Kojidani Tomoko , Yang Hui-Ju , Ohtsuki Chizuru , Osakada Hiroko , Matsuda Atsushi , Iwamoto Masaaki , Chikashige Yuji , Nagao Koji , Obuse Chikashi , Hiraoka Yasushi , Haraguchi Tokuko
Published: December 2017

The nuclear pore complex (NPC) forms a gateway for nucleocytoplasmic transport. The outer ring protein complex of the NPC (the Nup107-160 subcomplex in humans) is a key component for building the NPC. Nup107-160 subcomplexes are believed to be symmetrically localized on the nuclear and cytoplasmic sides of the NPC. However, in S. pombe immunoelectron and fluorescence microscopic analyses revealed that the homologous components of the human Nup107-160 subcomplex had an asymmetrical localization: constituent proteins spNup132 and spNup107 were present only on the nuclear side (designated the spNup132 subcomplex), while spNup131, spNup120, spNup85, spNup96, spNup37, spEly5 and spSeh1 were localized only on the cytoplasmic side (designated the spNup120 subcomplex), suggesting the complex was split into two pieces at the interface between spNup96 and spNup107. This contrasts with the symmetrical localization reported in other organisms. Fusion of spNup96 (cytoplasmic localization) with spNup107 (nuclear localization) caused cytoplasmic relocalization of spNup107. In this strain, half of the spNup132 proteins, which interact with spNup107, changed their localization to the cytoplasmic side of the NPC, leading to defects in mitotic and meiotic progression similar to an spNup132 deletion strain. These observations suggest the asymmetrical localization of the outer ring spNup132 and spNup120 subcomplexes of the NPC is necessary for normal cell cycle progression in fission yeast.

Author summary

The nuclear pore complexes (NPCs) form gateways to transport intracellular molecules between the nucleus and the cytoplasm across the nuclear envelope. The Nup107-160 subcomplex, that forms nuclear and cytoplasmic outer rings, is a key complex responsible for building the NPC by symmetrical localization on the nuclear and cytoplasmic sides of the nuclear pore. This structural characteristic was found in various organisms including humans and budding yeasts, and therefore believed to be common among “all” eukaryotes. However, in this paper, we revealed an asymmetrical localization of the homologous components of the human Nup107-160 subcomplex in fission yeast by immunoelectron and fluorescence microscopic analyses: in this organism, the Nup107-160 subcomplex is split into two pieces, and each of the split pieces is differentially distributed to the nuclear and cytoplasmic side of the NPC: one piece is only in the nuclear side while the other piece is only in the cytoplasmic side. This contrasts with the symmetrical localization reported in other organisms. In addition, we confirmed that the asymmetrical configuration of the outer ring structure is necessary for cell cycle progression in fission yeast. This study provides notions of diverse structures and functions of NPCs evolved in eukaryotes.
Value generalization in human avoidance learning
Authors: Norbury Agnes , Robbins Trevor W. , Seymour Ben
Published: December 2017

Generalization during aversive decision-making allows us to avoid a broad range of potential threats following experience with a limited set of exemplars. However, over-generalization, resulting in excessive and inappropriate avoidance, has been implicated in a variety of psychological disorders. Here, we use reinforcement learning modelling to dissect out different contributions to the generalization of instrumental avoidance in two groups of human volunteers (N=26,N=482). We found that generalization of avoidance could be parsed into perceptual and value-based processes, and further, that value-based generalization could be subdivided into that relating to aversive and neutral feedback - with corresponding circuits including primary sensory cortex, anterior insula, and ventromedial prefrontal cortex, respectively. Further, generalization from aversive, but not neutral, feedback was associated with self-reported anxiety and intrusive thoughts. These results reveal a set of distinct mechanisms that mediate generalization in avoidance learning, and show how specific individual differences within them can yield anxiety.
Neural circuits for long-range color filling-in
Authors: Gerardin Peggy , Abbatecola Clément , Devinck Frédéric , Kennedy Henry , Dojat Michel , Knoblauch Kenneth
Published: December 2017

Surface color appearance depends on both local surface chromaticity and global context. How are these inter-dependencies supported by cortical networks? Combining functional imaging and psychophysics, we examined if color from long-range filling-in engages distinct pathways from responses caused by a field of uniform chromaticity. We find that color from filling-in is best classified and best correlated with appearance by two dorsal areas, V3A and V3B/KO. In contrast, a field of uniform chromaticity is best classified by ventral areas hV4 and LO. Dynamic causal modeling revealed feedback modulation from area V3A to areas V1 and LO for filling-in, contrasting with feedback from LO modulating areas V1 and V3A for a matched uniform chromaticity. These results indicate a dorsal stream role in color filling-in via feedback modulation of area V1 coupled with a cross-stream modulation of ventral areas suggesting that local and contextual influences on color appearance engage distinct neural networks.
On the motion of spikes: a model of multifractality as observed in the neuronal activity of the human basal ganglia
Authors: Andres Daniela Sabrina
Published: December 2017

Neuronal signals are usually characterized in terms of their discharge rate. However, this description is inadequate to account for the complex temporal organization of spike trains. In particular multifractality is a hallmark of the neuronal activity of the human, parkinsonian basal ganglia, which is not accounted for in most models. Here I develop a new conceptualization of neuronal activity, enabling the analysis of spike trains in terms of a velocity field. Firstly, I show that structure functions of increasing order can be used to recover the multifractal spectrum of spike trains obtained from the globus pallidus interna (GPi) of patients with Parkinson’s disease. Further, I propose a neural field model to study the observed multifractality. The model describes the motion of spikes in terms of a velocity field, including a diffusive term to consider the physical properties of the electric field that is associated to neuronal activity. As the model is perturbed with colored noise, the following is observed: 1. multifractality is present for a wide range of diffusion coefficients; and 2. multifractal temporal properties are mirrored into space. These results predict that passive electric properties of neuronal activity are far more relevant to the human brain than what has been usually considered.
Circulating selenium and prostate cancer risk: a Mendelian randomization analysis
Authors: Yarmolinsky James , Bonilla Carolina , Haycock Philip C , Langdon Ryan JQ , Lotta Luca A , Langenberg Claudia , Relton Caroline L , Lewis Sarah J , Evans David M ,   the PRACTICAL consortium, Smith George Davey , Martin Richard M
Published: December 2017

In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 μg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic risk score comprising eleven single-nucleotide polymorphisms robustly (P<5x10−8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72,729 men in the PRACTICAL Consortium (44,825 cases, 27,904 controls), 114 μg/L higher genetically-elevated circulating selenium was not associated with prostate cancer (OR: 1.01; 95% CI: 0.89-1.13). Concordant with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR: 1.21; 95% CI: 0.98-1.49) and type 2 diabetes (OR: 1.18; 95% CI: 0.97-1.43; in a type 2 diabetes GWAS meta-analysis with up to 49,266 cases, 249,906 controls). Mendelian randomization mirrored the outcome of selenium supplementation in SELECT and may offer an approach for the prioritization of interventions for follow-up in large-scale randomized controlled trials.
Transcriptome-wide association studies accounting for colocalization using Egger regression
Authors: Barfield Richard , Feng Helian , Gusev Alexander , Wu Lang , Zheng Wei , Pasaniuc Bogdan , Kraft Peter
Published: December 2017

Integrating genome-wide association (GWAS) and expression quantitative trait locus (eQTL) data into transcriptome-wide association studies (TWAS) based on predicted expression can boost power to detect novel disease loci or pinpoint the susceptibility gene at a known disease locus. However, it is often the case that multiple eQTL genes colocalize at disease loci, making the identification of the true susceptibility gene challenging, due to confounding through linkage disequilibrium (LD). To distinguish between true susceptibility genes (where the genetic effect on phenotype is mediated through expression) and colocalization due to LD, we examine an extension of the Mendelian Randomization Egger regression method that allows for LD while only requiring summary association data for both GWAS and eQTL. We derive the standard TWAS approach in the context of Mendelian Randomization and show in simulations that the standard TWAS does not control Type I error for causal gene identification when eQTLs have pleiotropic or LD-confounded effects on disease. In contrast, LD Aware MR-Egger regression can control Type I error in this case while attaining similar power as other methods in situations where these provide valid tests. However, when the direct effects of genetic variants on traits are correlated with the eQTL associations, all of the methods we examined including LD Aware MR-Egger regression can have inflated Type I error. We illustrate these methods by integrating gene expression within a recent large-scale breast cancer GWAS to provide guidance on susceptibility gene identification.
RetSynth: Solving all optimal retrosynthesis solutions using dynamically constrained integer linear programming
Authors: Whitmore Leanne S. , Pinar Ali , George Anthe , Hudson Corey M.
Published: December 2017

Motivation

Naive determination of all the optimal pathways to production of a target chemical on an arbitrarily defined chassis organism is computationally intractable. Methods like linear integer programming can provide a singular solution to this problem, but fail to provide all optimal pathways.

Results

Here we present RetSynth, an algorithm for determining all optimal biological retrosynthesis solutions, given a starting biological chassis and target chemical. By dynamically scaling constraints, additional pathway search scales relative to the number of fully independent branches in the optimal pathways, and not relative to the number of reactions in the database or size of the metabolic network. This feature allows all optimal pathways to be determined for a very large number of chemicals and for a large corpus of potential chassis organisms.

Availability

This algorithm is distributed as part of the RetSynth software package, under a BSD 2-clause license at https://www.github.com/sandialabs/RetSynth/
Acute myeloid/T-lymphoblastic leukemia (AMTL): A distinct category of acute leukemias with common pathogenesis in need of improved therapy
Authors: Gutierrez Alejandro , Kentsis Alex
Published: December 2017

Advances in the immunophenotypic and cytogenetic classification of acute leukemias have led to improved clinical outcomes for a substantial fraction of patients. However, resistance to chemotherapy remains a major barrier to cure for patients with specific subsets of acute myeloid and lymphoblastic leukemias. Here, we propose that a molecularly distinct subtype of acute leukemia with shared myeloid and T-cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukemia (AMTL), and has been divided between 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-cell lymphoid lineages. This new diagnostic group is supported by the i) shared hematopoietic ontogeny in which myeloid differentiation potential is specifically retained during early T-cell lymphoid development, ii) recognition of cases of AML with hallmarks of T-cell development such as clonal rearrangements of the T-cell receptor genes, and iii) identification of common gene mutations in subsets of AML and T-ALL cases. This proposed diagnostic entity overlaps with early T-cell precursor (ETP) T-ALL and T-cell/myeloid mixed phenotype acute leukemias (MPAL), and also includes a subset of leukemias currently classified as AML with hallmarks of T-lymphoblastic development. AMTLs express variable levels of both T-cell and myeloid-specific markers, such as CD3 and myeloperoxidase, and additionally have shared gene mutations including WT1, PHF6, RUNX1 and BCL11B. The proposed classification of AMTL as a distinct entity should enable prospective diagnosis and development of improved therapies for patients whose treatment is inadequate with current approaches.
Computational Design of Asymmetric Three-dimensional RNA Structures and Machines
Authors: Yesselman Joseph D. , Eiler Daniel , Carlson Erik D. , Ooms Alexandra N. , Kladwang Wipapat , Shi Xuesong , Costantino David A. , Herschlag Daniel , Jewett Michael C. , Kieft Jeffrey S. , Das Rhiju
Published: December 2017

The emerging field of RNA nanotechnology seeks to create nanoscale 3D machines by repurposing natural RNA modules, but successes have been limited to symmetric assemblies of single repeating motifs. We present RNAMake, a suite that automates design of RNA molecules with complex 3D folds. We first challenged RNAMake with the paradigmatic problem of aligning a tetraloop and sequence-distal receptor, previously only solved via symmetry. Single-nucleotide-resolution chemical mapping, native gel electrophoresis, and solution x-ray scattering confirmed that 11 of the 16 ‘miniTTR’ designs successfully achieved clothespin-like folds. A 2.55 Å diffraction-resolution crystal structure of one design verified formation of the target asymmetric nanostructure, with large sections achieving near-atomic accuracy (< 2.0 Å). Finally, RNAMake designed asymmetric segments to tether the 16S and 23S rRNAs together into a synthetic singlestranded ribosome that remains uncleaved by ribonucleases and supports life in Escherichia coli, a challenge previously requiring several rounds of trial-and-error.
Migration alters oscillatory dynamics and promotes survival in connected bacterial populations
Authors: Gokhale Shreyas , Conwill Arolyn , Ranjan Tanvi , Gore Jeff
Published: December 2017

Migration influences population dynamics on networks, thereby playing a vital role in scenarios ranging from species extinction to epidemic propagation. While low migration rates prevent local populations from becoming extinct, high migration rates enhance the risk of global extinction by synchronizing the dynamics of connected populations. Here, we investigate this trade-off using two mutualistic strains of E. coli that exhibit population oscillations when co-cultured. In experiments, as well as in simulations using a mechanistic model, we observe that high migration rates lead to in-phase synchronization whereas intermediate migration rates perturb the oscillations and change their period. Further, our simulations predict, and experiments show, that connected populations subjected to more challenging antibiotic concentrations have the highest probability of survival at intermediate migration rates. Finally, we identify altered population dynamics, rather than recolonization, as the primary cause of extended survival.
Evidence against tetrapod-wide digit identities and for a limited frame shift in bird wings
Authors: Stewart Thomas A. , Liang Cong , Cotney Justin L. , Noonan James P. , Sanger Thomas J. , Wagner Günter P.
Published: December 2017

In crown group tetrapods, individual digits are homologized in relation to a pentadactyl ground plan. However, testing hypotheses of digit homology is challenging because it is unclear whether digits develop with distinct and conserved gene regulatory states. Here we show dramatic evolutionary dynamism in the gene expression profiles of digits, challenging the notion that five digit identities are conserved across amniotes. Transcriptomics of developing limbs shows diversity in the patterns of genetic differentiation of digits, although the anterior-most digit of the pentadactyl limb has a unique, conserved expression profile. Further, we identify a core set of transcription factors that are differentially expressed among the digits of amniote limbs; their spatial expression domains, however, vary between species. In light of these results, we reevaluate the frame shift hypothesis of avian wing evolution and conclude that only the identity of the anterior-most digit has shifted position, suggesting a 1,3,4 digit identity in the bird wing.
Specific cholesterol binding drives drastic structural alterations in Apolipoprotein A1
Authors: Ray Arjun , Ghosh Asmita , Chakraborty Rahul , Upadhyay Santosh Kumar , Maiti Souvik , Sengupta Shantanu , Thukral Lipi
Published: December 2017

Proteins typically adopt a multitude of flexible and rapidly interconverting conformers, many of which are governed by specific protein interaction domains. While disc-shaped oligomeric HDL and its major protein component ApoA1 have been the focus of several investigations, yet the structural properties of monomeric ApoA1 remain poorly understood. Using tens of independent molecular simulations (>50 µs), we reveal that ApoA1 adopts a compact conformation. Upon addition of a physiological concentration of cholesterol to ApoA1, the monomeric protein spontaneously formed a circular conformation. Remarkably, these drastic structural perturbations are driven by a specific cholesterol binding site at the C-terminal and a novel cholesterol binding site at the N-terminal. We propose a mechanism whereby ApoA1 opens in a stagewise manner and mutating the N-terminal binding site destroys the open 'belt-shaped' topology. Complementary experiments confirm that the structural changes are induced by specific association of cholesterol with ApoA1, not by the non-specific hydrophobic effect.
Aging in a relativistic biological space-time
Authors: Maestrini D. , Abler D. , Adhikarla V. , Armenian S. , Branciamore S. , Carlesso N. , Kuo Y-H. , Marcucci G. , Sahoo P. , Rockne R.
Published: December 2017

Here we present a theoretical and mathematical perspective on the process of aging. We extend the concepts of physical space and time to an abstract, mathematically-defined space, which we associate with a concept of “biological space-time” in which biological clocks operate. We hypothesize that biological dynamics, represented as trajectories in biological space-time, may be used to model and study different rates of biological aging. As a consequence of this hypothesis, we show how the dilation or contraction of time resulting from accelerated or decelerated biological dynamics may be used to study precipitous or protracted aging. We show specific examples of how these principles may be used to model different rates of aging, with an emphasis on cancer in aging. We discuss the implications of this theory, including novel concepts that may improve our interpretation of biological aging.
Characterizing the effects of sex, APOE ɛ4, and literacy on mid-life cognitive trajectories: Application of Information-Theoretic model-averaging and multi-model inference techniques to the Wisconsin Registry for Alzheimer’s Prevention Study
Authors: Koscik Rebecca L. , Norton Derek L. , Allison Samantha L. , Jonaitis Erin M. , Clark Lindsay R. , Mueller Kimberly D. , Hermann Bruce P. , Engelman Corinne D. , Gleason Carey E. , Sager Mark A. , Chappell Richard J. , Johnson Sterling C.
Published: December 2017

Objective

In this paper we apply Information-Theoretic (IT) model averaging to characterize a set of complex interactions in a longitudinal study on cognitive decline. Prior research has identified numerous genetic (including sex), education, health and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find models that best fit the observed data; these techniques risk interpretations that only the selected predictors are important. In reality, several models may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates); inference from traditional model selection approaches can lead to overly confident conclusions.

Method

Here we use longitudinal cognitive data from ~1550 late-middle aged adults the Wisconsin Registry for Alzheimer’s Prevention study to examine the effects of sex, Apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a model set with combinations of interactions among sex, APOE, literacy, and age.

Results

For a list-learning test, model-averaged results showed better performance for women vs men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an effect on cognitive performance in this age range (~40-70).

Conclusions

These results illustrate the utility of the IT approach and point to literacy as a potential modifier of decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work.
Accurate estimation of neural population dynamics without spike sorting
Authors: Trautmann Eric M. , Stavisky Sergey D. , Lahiri Subhaneil , Ames Katherine C. , Kaufman Matthew T. , Ryu Stephen I. , Ganguli Surya , Shenoy Krishna V.
Published: December 2017

A central goal of systems neuroscience is to relate an organism’s neural activity to behavior. Neural population analysis often begins by reducing the dimensionality of the data to focus on the patterns most relevant to a given task. A major practical hurdle to data analysis is spike sorting, and this problem is growing rapidly as the number of neurons measured increases. Here, we investigate whether spike sorting is necessary to estimate neural dynamics. The theory of random projections suggests that we can accurately estimate the geometry of low-dimensional manifolds from a small number of linear projections of the data. We re-analyzed data from three previous studies and found that neural dynamics and scientific conclusions are quite similar using multi-unit threshold crossings in place of sorted neurons. This finding unlocks existing data for new analyses and informs the design and use of new electrode arrays for laboratory and clinical use.
Distinct descending motor cortex pathways and their roles in movement
Authors: Economo Michael N. , Viswanathan Sarada , Tasic Bosiljka , Bas Erhan , Winnubst Johan , Menon Vilas , Graybuck Lucas T. , Nguyen Thuc Nghi , Wang Lihua , Gerfen Charles R. , Chandrashekar Jayaram , Zeng Hongkui , Looger Loren L. , Svoboda Karel
Published: December 2017

Activity in motor cortex predicts specific movements, seconds before they are initiated. This preparatory activity has been observed in L5 descending ‘pyramidal tract’ (PT) neurons. A key question is how preparatory activity can be maintained without causing movement, and how preparatory activity is eventually converted to a motor command to trigger appropriate movements. We used single cell transcriptional profiling and axonal reconstructions to identify two types of PT neuron. Both types share projections to multiple targets in the basal ganglia and brainstem. One type projects to thalamic regions that connect back to motor cortex. In a delayed-response task, these neurons produced early preparatory activity that persisted until the movement. The second type projects to motor centers in the medulla and produced late preparatory activity and motor commands. These results indicate that two motor cortex output neurons are specialized for distinct roles in motor control.
Spontaneous Pre-encoding Activation of Neural Patterns Predicts Memory
Authors: Sadeh Talya , Chen Janice , Goshen-Gottstein Yonatan , Moscovitch Morris
Published: December 2017

It is well-established that whether information will be remembered or not depends on the extent to which the learning context is reinstated during post-encoding rest and/or at retrieval. It has yet to be determined, however, if the fundamental importance of reinstatement to memory extends to periods of spontaneous neurocognitive activity prior to learning. We thus asked whether memory performance can be predicted by the extent to which spontaneous pre-encoding neural patterns resemble patterns elicited during encoding. Individuals studied and retrieved lists of words while undergoing fMRI-scanning. Multivoxel hippocampal patterns during resting periods prior to encoding resembled hippocampal patterns at encoding most strongly for items that were subsequently remembered. Furthermore, across subjects, the magnitude of similarity correlated with a behavioural measure of episodic recall. The results indicate that the neural scaffold of a memory trace is spontaneously laid even before ever perceiving the to-be-encoded information.

Significance Statement

It is well-established that memory performance depends on the degree to which the learning-context is reinstated during post-learning rest or during retrieval. However, does memory also depend on the context prior to learning—namely, on processes occurring spontaneously before ever perceiving the to-be-learned information? To answer this question, we scanned participants using fMRI while they were learning and recalling word-lists and, crucially, also during resting periods before each list. Patterns of brain activity in memory-related regions which were elicited spontaneously during these resting periods resembled patterns during learning. Furthermore, the greater this resemblance, the better was memory performance. We demonstrate that memory can be predicted by the degree to which patterns of neural activity prior to learning are reinstated during learning.
Automated detection of bacterial growth on 96-well plates for high-throughput drug susceptibility testing of Mycobacterium tuberculosis
Authors: Fowler Philip W. , Gibertoni Cruz Ana Luíza , Hoosdally Sarah J. , Jarrett Lisa , Borroni Emanuele , Chiacchiaretta Matteo , Rathod Priti , Walker Timothy M. , Robinson Esther , Peto Timothy E. A. , Maria Cirillo Daniela , Smith E. Grace , Crook Derrick W.
Published: December 2017

M. tuberculosis grows slowly and is challenging to work with experimentally compared with many other bacteria. Although microtitre plates have the potential to enable high-throughput phenotypic testing of M. tuberculosis, they can be difficult to read and interpret. Here we present a software package, the Automated Mycobacterial Growth Detection Algorithm (AMyGDA), that measures how much M. tuberculosis is growing in each well of a 96-well microtitre plate. The plate used here has serial dilutions of 14 anti-tuberculosis drugs, thereby permitting the minimum inhibitory concentrations (MICs) to be elucidated. The two participating laboratories each inoculated ten 96-well plates with the standard H37Rv reference strain and, after two weeks incubation, measured the MICs for all 14 drugs on each plate and took a photograph. By analysing the images, we demonstrate that AMyGDA is reproducible, and that the MICs measured are comparable to those measured by a laboratory scientist. AMyGDA software will be used by the Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) to measure the drug susceptibility profile of a large number (> 30,000) of samples of M. tuberculosis from patients over the next few years.
Grafting or Pruning in the Animal Tree: Lateral Gene Transfer and Gene Loss?
Authors: Dunning Hotopp Julie C.
Published: December 2017

Lateral gene transfer (LGT) into multicellular eukaryotes with differentiated tissues, particularly gonads, continues to be met with skepticism by many prominent evolutionary and genomic biologists. A detailed examination of 26 animal genomes identifed putative LGTs in invertebrate and vertebrate genomes, concluding that there are fewer predicted LGTs in vertebrates/chordates than invertebrates, but there is still evidence of LGT into chordates, including humans. More recently, a reanalysis a subset of these putative LGTs into vertebrates concluded that there is not horizontal gene transfer in the human genome. One of the genes in dispute is an N-acyl-aromatic-L-amino acid amidohydrolase (ENSG00000132744), which encodes ACY3, which was initially identified as a putative bacteria-chordate LGT but was later debunked has a significant BLAST match to a more recently deposited genome of Saccoglossus kowalevskii, a flatworm, Metazoan, and hemichordate. Using BLAST searches, HMM searches, and phylogenetics to better understand the evidence for lateral gene transfer, gene loss, and rate variation in ACY3/ASPA homologues, the most parsimonious explanation for the distribution of ACY3/ASPA genes in eukaryotes likely involves both gene loss and lateral gene transfer, albeit lateral gene transfer that occurred hundreds of millions of years ago prior to the divergence of gnathostomes and even longer and prior to the divergence of bilateria. Given the many known, well-characterized, and adaptive lateral gene transfers from bacteria to insects and nematodes, lateral gene transfers at these time scales in the ancestors of humans is expected.