bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining predictive coding with neural oscillations optimizes on-line speech processing
Authors: Hovsepyan Sevada , Olasagasti Itsaso , Giraud Anne-Lise
Published: November 2018

Speech comprehension requires segmenting continuous speech to connect iton-linewith discrete linguistic neural representations. This process relies on theta-gamma oscillation coupling, which tracks syllables and encodes them in decipherable neural activity. Speech comprehension also strongly depends on contextual cues predicting speech structure and content. To explore the effects of theta-gamma coupling on bottom-up/top-down dynamics during on-line speech perception, we designed a generative model that can recognize syllable sequences in continuous speech. The model uses theta oscillations to detect syllable onsets and align both gamma-rate encoding activity with syllable boundaries and predictions with speech input. We observed that the model performed best when theta oscillations were used to align gamma units with input syllables, i.e. when bidirectional information flows were coordinated, and internal timing knowledge was exploited. This work demonstrates that notions of predictive coding and neural oscillations can usefully be brought together to account for dynamicon-linesensory processing.
Long-term balancing selection drives evolution of immunity genes inCapsella
Authors: Koenig Daniel , Hagmann Jörg , Li Rachel , Bemm Felix , Slotte Tanja , Neuffer Barbara , Wright Stephen I. , Weigel Detlef
Published: November 2018

Genetic drift is expected to remove polymorphism from populations over long periods of time, with the rate of polymorphism loss being accelerated when species experience strong reductions in population size. Adaptive forces that maintain genetic variation in populations, or balancing selection, might counteract this process. To understand the extent to which natural selection can drive the retention of genetic diversity, we document genomic variability after two parallel species-wide bottlenecks in the genusCapsella. We find that ancestral variation preferentially persists at immunity related loci, and that the same collection of alleles has been maintained in different lineages that have been separated for several million years. Our data point to long term balancing selection as an important factor shaping the genetics of immune systems in plants and as the predominant driver of genomic variability after a population bottleneck.
The crystal structure and localization ofTrypanosoma bruceiinvariant surface glycoproteins suggest a more permissive VSG coat in the tsetse-transmitted metacyclic stage
Authors: Casas-Sánchez Aitor , Perally Samïrah , Ramaswamy Raghavendran , Haines Lee R. , Rose Clair , Yunta Cristina , Aguilera-Flores Marcela , Lehane Michael J. , Almeida Igor C. , Boulanger Martin J. , Acosta-Serrano Alvaro
Published: November 2018

Trypanosoma bruceispp. develop into mammalian-infectious metacyclic trypomastigotes inside the tsetse salivary glands. Besides acquiring a variant surface glycoprotein (VSG) coat, nothing is known about expression of invariant surface antigens by the metacyclic stage. Proteomic analysis of saliva fromT. brucei-infected flies revealed a novel family of hypothetical GPI-anchored surface proteins herein named Metacyclic Invariant Surface Proteins (MISP). MISP are encoded by five homolog genes and share ~80% protein identity. The crystal structure of MISP N-terminus at 1.82 Å resolution revealed a triple helical bundle that shares key features with other trypanosome surface proteins. However, molecular modelling combined with live fluorescent microscopy suggest that MISP N-termini are extended above the metacyclic VSG coat, exposing immunogenic epitopes. Collectively, we suggest that the metacyclic cell surface architecture appears more permissive than bloodstream forms in terms of expression of invariant GPI-anchored glycoproteins, which could be exploited for the development of novel vaccines against African trypanosomiases.
The (p)ppGpp-binding GTPase Era promotes rRNA processing and cold shock survival inStaphylococcus aureus
Authors: Wood Alison , Irving Sophie E. , Bennison Daniel J. , Corrigan Rebecca M.
Published: November 2018

Ribosome assembly cofactors are widely conserved across all domains of life. One such group, the ribosome-associated GTPases (RA-GTPase), act as molecular switches to coordinate ribosome assembly. We previously identified theStaphylococcus aureusRA-GTPase Era as a target for the stringent response alarmone (p)ppGpp, although the function of Era in ribosome assembly is unclear. Era is highly conserved throughout the bacterial kingdom and is essential in many species. Here we show that Era is not essential inS. aureusbut is important for 30S ribosomal subunit assembly. Protein interaction studies reveal that Era interacts with the endonuclease YbeY and the DEAD-box RNA helicase CshA. We determine that both Era and CshA are required for growth at suboptimal temperatures, virulence and 16S rRNA processing. Era and CshA also form direct interactions with the (p)ppGpp synthetase RelSA, with RelSA positively impacting the GTPase activity of Era. We propose that Era acts to direct enzymes involved in rRNA maturation and ribosome subunit assembly to their site of action, an activity that is regulated by components of the stringent response.

Author summary

The bacterial ribosome is an essential cellular component and as such is the target for a number of currently used antimicrobials. Correct assembly of this complex macromolecule requires a number of accessory enzymes, the functions of which are poorly characterised. Here we examine the function of Era, a GTPase enzyme involved in 30S ribosomal subunit biogenesis in the important human pathogenS. aureus. We uncover that Era is not an essential enzyme inS. aureus, as it is in many other species, but is important for correct ribosome assembly. In a bid to uncover the cellular function of this enzyme, we identify a number of protein interaction partners with roles in ribosomal RNA maturation and degradation, supporting the idea that Era acts as an intermediary protein facilitating ribosomal biogenesis. We also uncover a link between Era and the (p)ppGpp synthetase RelSA, revealing an additional level of control of rRNA levels by the stringent response. With this study we elaborate on the functions of GTPases in ribosomal assembly, processes that are controlled at multiple points by the stringent response.
Naught all zeros in sequence count data are the same
Authors: Silverman Justin D. , Roche Kimberly , Mukherjee Sayan , David Lawrence A.
Published: November 2018

Genomic studies feature multivariate count data from high-throughput DNA sequencing experiments, which often contain many zero values. These zeros can cause artifacts for statistical analyses and multiple modeling approaches have been developed in response. Here, we apply common zero-handling models to gene-expression and microbiome datasets and show models disagree on average by 46% in terms of identifying the most differentially expressed sequences. Next, to rationally examine how different zero handling models behave, we developed a conceptual framework outlining four types of processes that may give rise to zero values in sequence count data. Last, we performed simulations to test how zero handling models behave in the presence of these different zero generating processes. Our simulations showed that simple count models are sufficient across multiple processes, even when the true underlying process is unknown. On the other hand, a common zero handling technique known as “zero-inflation” was only suitable under a zero generating process associated with an unlikely set of biological and experimental conditions. In concert, our work here suggests several specific guidelines for developing and choosing state-of-the-art models for analyzing sparse sequence count data.
miR-425 suppresses EMT and inhibits the development of TNBC (triple-negative breast cancer) by targeting TGF-β 1/SMAD 3 signaling pathway
Authors: Liu Yingping , Qiao Hongfei , Chen Jinglong
Published: November 2018

Background

EMT has the crucial effect on the progression and metastasis of tumor. This work will elucidate the role of miR-425 in EMT and development of TNBC.

Methods

The differential miRNA expression among non-tumor, para-tumor (adjacent tissue of tumor) and tumor tissues was analyzed. The luciferase activities of TGF-β1 3’ UTR treated with miR-425 were determined. Then human breast cancer cell lines were dealt with mimics or inhibitors of miR-425, and then the cell proliferation and migration, invasion ability were assessed. The expression of TGF-β1 and markers of epithelial cell and mesenchymal cell were analyzed. The influences of miR-425 on development of TNBC through inducing EMT by targeting TGF-β 1 and TGF-β1/SMAD3 signaling pathway in TNBC cell lines were investigated. Furthermore, Xenograft mice were used to explore the potential roles of miR-425 on EMT and development of TNBC in vivo.

Results

Compared with non-tumor tissues, 9 miRNAs were upregulated and 3 miRNAs were down-regulated in tumor tissues. The relative expression of miR-425 in tumor tissues was obviously much lower than that in para-tumor and non-tumor tissues. MiR-425 suppressed TGF-β1 expression, additionally inhibited expression of mesenchymal cell markers, while exerted effects on cell proliferation and migration of TNBC cell lines. Moreover, the agomir of miR-425 could protect against development process in murine TNBC xenogarft model.

Conclusions

Our results demonstrated that miR-425 targets to TGF-β1, and was a crucial suppressor on EMT and development of TNBC through inhibiting TGF-β1/SMAD3 signaling pathway. It suggested that aim at TGF-β1/SMAD3 signaling pathway by enhancing relative miR-425 expression, was a feasible therapy strategy for TNBC.
Quantitative Analysis Reveals Reciprocal Regulations Underlying Recovery Dynamics of Thymocytes and Thymic Environment
Authors: Kaneko Kazumasa B. , Tateishi Ryosuke , Miyao Takahisa , Akiyama Nobuko , Yokota Ryo , Akiyama Taishin , Kobayashi Tetsuya J.
Published: November 2018

Thymic crosstalk, a set of reciprocal regulations between thymocytes and thymic environment, is relevant for orchestrating the appropriate development of thymocytes as well as the recovery of the thymus from various exogenous insults. Nevertheless, the dynamic and regulatory aspects of the thymic crosstalk have not yet been clarified. In this work, we inferred the interactions shaping the thymic crosstalk and its resultant dynamics between the thymocytes and the thymic epithelial cells (TECs) by quantitative analysis and modelling of the recovery dynamics induced by irradiation. The analysis identified regulatory interactions consistent with the known molecular evidence and revealed their dynamic roles in the recovery process. Moreover, the analysis also predicted, and a subsequent experiment verified a new regulation of CD4+CD8+ double positive (DP) thymocytes, which temporarily increases their proliferation rate upon the decrease in their population size. Our model established the pivotal step towards a dynamic understanding of the thymic crosstalk as a regulatory network system.
Selection at behavioral, developmental and metabolic genes is associated with the northward expansion of a successful tropical colonizer
Authors: Bourgeois Yann , Boissinot Stéphane
Published: November 2018

What makes a species able to colonize novel environments? This question is key to understand the dynamics of adaptive radiations and ecological niche shifts, but the mechanisms that underlie expansion into novel habitats remain poorly understood at a genomic scale. Lizards from the genusAnolisare typically tropical and the green anole(Anolis carolinensis)constitutes an exception since it expanded into temperate North America from subtropical Florida. Thus, we used the green anole as a model to investigate signatures of selection associated with colonization of a new environment, namely temperate North America. To this end, we analyzed 29 whole genome sequences, representing the entire genetic diversity of the species. We used a combination of recent methods to quantify both positive and balancing selection in northern populations, including FSToutlier methods, machine learning and ancestral recombination graphs. We naively scanned for genes of interest and assessed the overlap between multiple tests. Strikingly, we identified many genes involved in behavior, suggesting that the recent successful colonization of northern environments may have been linked to behavioral shifts as well as physiological adaptation. These results were robust to recombination, gene length and clustering. Using a candidate genes strategy, we determined that genes involved in response to cold or behavior displayed more frequently signals of selection, while controlling for local recombination rate and gene length. In addition, we found signatures of balancing selection at immune genes in all investigated genetic groups, but also at genes involved in neuronal and anatomical development in Florida.
Deciphering the Regulatory Landscape of γδ T Cell Development by Single-Cell RNA-Sequencing
Authors: Sagar  , Pokrovskil Maria , Herman Josip S. , Naik Shruti , Sock Elisabeth , Lausch Ute , Wegner Michael , Tanriver Yakup , Littman Dan R. , Grün Dominic
Published: November 2018

Recent studies have established γδ T cells as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases and tissue homeostasis. However, differentiation of γδ T cells in the adult thymus remains poorly understood, due to the rare frequency of this lineage. Here, we infer high-resolution developmental trajectories of this rare population by single-cell RNA-sequencing. We reveal previously unknown subtypes and identify the transcription factor c-MAF as a novel key regulator of IL-17-producing γδ T cell (γδT17) differentiation. c-MAF knockout mice exhibit a complete block in γδT17 differentiation, absence of these cells from peripheral organs, and protection from an autoimmune phenotype in a psoriasis model. Single-cell RNA-sequencing of Sox13 and Rorc knockout mice pinpoints c-MAF as an essential missing link between these lineage-specifying factors. These findings significantly enhance our understanding of γδ T cell ontogeny. Our experimental strategy provides a blueprint for deciphering differentiation of rare cell types.
Learning probabilistic representations with randomly connected neural circuits
Authors: Maoz Ori , Tkacčik Gašper , Esteki Mohamad Saleh , Kiani Roozbeh , Schneidman Elad
Published: November 2018

The brain represents and reasons probabilistically about complex stimuli and motor actions using a noisy, spike-based neural code. A key building block for such neural computations, as well as the basis for supervised and unsupervised learning, is the ability to estimate the surprise or likelihood of incoming high-dimensional neural activity patterns. Despite progress in statistical modeling of neural responses and deep learning, current approaches either do not scale to large neural populations or cannot be implemented using biologically realistic mechanisms. Inspired by the sparse and random connectivity of real neuronal circuits, we present a new model for neural codes that accurately estimates the likelihood of individual spiking patterns and has a straightforward, scalable, efficiently learnable, and realistic neural implementation. This model’s performance on simultaneously recorded spiking activity of >100 neurons in the monkey visual and prefrontal cortices is comparable or better than that of current models. Importantly, the model can be learned using a small number of samples, and using a local learning rule that utilizes noise intrinsic to neural circuits. Slower, structural changes in random connectivity, consistent with rewiring and pruning processes, further improve the efficiency and sparseness of the resulting neural representations. Our results merge insights from neuroanatomy, machine learning, and theoretical neuroscience to suggest random sparse connectivity as a key design principle for neuronal computation.
Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei
Authors: Jiang Shan , Williams Katherine , Kong Xiangduo , Zeng Weihua , Ma Xinyi , Tawil Rabi , Yokomori Kyoko , Mortazavi Ali
Published: November 2018

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. However, DUX4 is lowly expressed in patient samples and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed pooled RNA-seq differentiation time-course in FSHD2 patient-derived primary myoblasts and identified early-and late-induced sets of FSHD-associated genes. Using single-cell and single-nucleus RNA-seq on FSHD2 myoblasts and myotubes respectively, we captured DUX4 expression in single-nuclei and found that only some DUX4 targets are coexpressed. We identified two populations of FSHD myotube nuclei with distinct transcriptional profiles. One population is highly enriched with DUX4 and FSHD related genes, including the DUX4 paralog DUXA (“FSHD-Hi”). The other population has no expression of DUX4 and expresses low amounts of FSHD related genes (“FSHD-Lo”), but is marked by the expression of CYTL1 and CHI3L1. “FSHD-Hi” myotube nuclei upregulated a set of transcription factors (TFs) that may form a self-sustaining network of gene dysregulation, which perpetuates this disease after DUX4 is no longer expressed.
Speech Synthesis from ECoG using Densely Connected 3D Convolutional Neural Networks
Authors: Angrick Miguel , Herff Christian , Mugler Emily , Tate Matthew C. , Slutzky Marc W. , Krusienski Dean J. , Schultz Tanja
Published: November 2018

Objective

Direct synthesis of speech from neural signals could provide a fast and natural way of communication to people with neurological diseases. Invasively-measured brain activity (electrocorticography; ECoG) supplies the necessary temporal and spatial resolution to decode fast and complex processes such as speech production. A number of impressive advances in speech decoding using neural signals have been achieved in recent years, but the complex dynamics are still not fully understood. However, it is unlikely that simple linear models can capture the relation between neural activity and continuous spoken speech.

Approach

Here we show that deep neural networks can be used to map ECoG from speech production areas onto an intermediate representation of speech (logMel spectrogram). The proposed method uses a densely connected convolutional neural network topology which is well-suited to work with the small amount of data available from each participant.

Main results

In a study with six participants, we achieved correlations up tor= 0.69 between the reconstructed and original logMel spectrograms. We transfered our prediction back into an audible waveform by applying a Wavenet vocoder. The vocoder was conditioned on logMel features that harnessed a much larger, pre-existing data corpus to provide the most natural acoustic output.

Significance

To the best of our knowledge, this is the first time that high-quality speech has been reconstructed from neural recordings during speech production using deep neural networks.
Quantitative PCR provides a simple and accessible method for quantitative microbiome profiling
Authors: Jian Ching , Luukkonen Panu , Yki-Järvinen Hannele , Salonen Anne , Korpela Katri
Published: November 2018

The use of relative next generation sequencing (NGS) abundance data can lead to misinterpretations of microbial community structures as the increase of one taxon leads to concurrent decrease of the other(s). To overcome compositionality, we provide a quantitative NGS solution, which is achieved by adjusting the relative 16S rRNA gene amplicon NGS data with quantitative PCR (qPCR-based) total bacterial counts. By comparing the enumeration of dominant bacterial groups on different taxonomic levels in human fecal samples using taxon-specific 16S rRNA gene-targeted qPCR we show that quantitative NGS is able to estimate absolute bacterial abundances accurately. We also observed a higher degree of correspondence in the estimated microbe-metabolite relationship when quantitative NGS was applied. Being conceptually and methodologically analogous to amplicon-based NGS, our qPCR-based method can be readily incorporated into the standard, high-throughput NGS sample processing pipeline for more accurate description of interactions within and between the microbes and host.
BAPC-assistedCRISPR/Cas9 System: Targeted Delivery into Adult Ovaries for Heritable Germline Gene Editing (Arthropoda: Hemiptera)
Authors: Hunter Wayne B. , Gonzalez Maria T. , Tomich John
Published: November 2018

Innovative gene targeting strategies are often limited in application across arthropod species due to problems with successful delivery. In hemipterans, embryonic injections often used to deliver CRISPR components fail due to nearly complete embryo mortality. The Asian citrus psyllid,Diaphorina citri, Kuwayama, (Hemiptera: Liviidae), is the vector for a pathogenic bacterium,CandidatusLiberibacter asiaticus, CLas, which is devastating the U.S. citrus industries. The disease called, Huanglongbing, HLB, (aka. Citrus greening disease), is transmitted during psyllid feeding. Infection causes severe tree decline, loss of fruits, and eventually tree death. The citrus tree pathogen, CLas, is a fastidious alpha-proteobacterium, which has spread into all citrus growing regions worldwide. The economic losses are estimated in the billions of dollars, in U.S.A., Brazil, and China. Innovative technologies aimed at reducing psyllid populations using targeting RNA suppression, like RNAi, or gene-editing tools, like CRISPR/Cas9 have potential to reduce psyllid vectors and the pathogen in a highly specific manner. Breakthroughs that improve gene editing in psyllids, such as theBAPC-assisted-CRISPR/Cas9 System, enabled delivery by injection of CRISPR/Cas9 components directly into nymphs and adult females. Injection near ovaries produced heritable germline gene editing in subsequent generations. This method opens the world of gene editing across arthropods and bypasses the need for microinjection of eggs. Effective development of therapeutic treatments to reduce insect vectors, and stop pathogen transmission would provide sustainable citrus and grapevine industries.
Induction of Interferon-Stimulated Genes and Cellular Stress Pathways by Morpholinos
Authors: Lai Jason K.H. , Gagalova Kristina , Stainier Didier Y.R.
Published: November 2018

The phenotypes caused by morpholino-mediated interference of gene function in zebrafish are often not observed in the corresponding mutant(s). We took advantage of the availability of a relatively large collection of transcriptomic datasets to identify common signatures that characterize morpholino-injected animals (morphants). In addition to the previously reported activation of tp53 expression, we observed increased expression of the interferon-stimulated genes (ISGs), isg15 and isg20, an extrinsic cell death pathway gene, casp8, and other cellular stress response genes including phlda3, mdm2 and gadd45aa. Studies involving segmentation stage embryos were more likely to show upregulation of these genes. We also found that these genes could be upregulated by an increasing dose of egfl7 morpholino, or high doses of standard control morpholino. Thus, these data suggest that morpholinos can stimulate the innate immune response in zebrafish, as was recently reported in Xenopus.
661W photoreceptor cell line as a cell model for studying retinal ciliopathies
Authors: Wheway Gabrielle , Nazlamova Liliya , Turner Dann , Cross Stephen
Published: November 2018

The retina contains several ciliated cell types, including the retinal pigment epithelium (RPE) and photoreceptor cells. The photoreceptor cilium is one of the most highly modified sensory cilia in the human body. The outer segment of the photoreceptor is a highly elaborate primary cilium, containing stacks or folds of membrane where the photopigment molecules are located. Perhaps unsurprisingly, defects in cilia often lead to retinal phenotypes, either as part of syndromic conditions involving other organs, or in isolation in the so-called retinal ciliopathies.

The study of retinal ciliopathies has been limited by a lack of retinal cell lines. RPE1 retinal pigment epithelial cell line is commonly used in such studies, but the existence of a photoreceptor cell line has largely been neglected in the retinal ciliopathy field. 661W cone photoreceptor cells, derived from mouse, have been widely used as a model for studying macular degeneration, but not described as a model for studying retinal ciliopathies such as retinitis pigmentosa.

Here, we characterise the 661W cell line as a model for studying retinal ciliopathies. We fully characterise the expression profile of these cells over many passages, using whole transcriptome RNA sequencing, and provide this data on Gene Expression Omnibus (GEO) for the advantage of the scientific community. We show that these cells robustly express the majority of markers of cone cell origin, including short wave and medium wave opsin. Western blotting confirms expression of selected markers.

Using immunostaining and confocal microscopy, alongside scanning electron microscopy, we show that these cells grow long primary cilia, reminiscent of photoreceptor outer segments, and localise many cilium proteins to the axoneme, membrane and transition zone. Immunostaining shows that opsins are localised to the base of this primary cilium. We show that siRNA knockdown of cilia genes Ift88 results in loss of cilia, and that this can be assayed by high-throughput screening. We present evidence that the 661W cell line is a useful cell model for studying retinal ciliopathies.
Expression variation analysis for tumor heterogeneity in single-cell RNA-sequencing data
Authors: Davis-Marcisak Emily F. , Orugunta Pranay , Stein-O’Brien Genevieve , Puram Sidharth V. , Torres Evanthia Roussos , Hopkins Alexander , Jaffee Elizabeth M. , Favorov Alexander V. , Afsari Bahman , Goff Loyal A. , Fertig Elana J.
Published: November 2018

Tumor heterogeneity provides a complex challenge to cancer treatment and is a critical component of therapeutic response, disease recurrence, and patient survival. Single-cell RNA-sequencing (scRNA-seq) technologies reveal the prevalence of intra-and inter-tumor heterogeneity. Computational techniques are essential to quantify the differences in variation of these profiles between distinct cell types, tumor subtypes, and patients to fully characterize intra-and inter-tumor molecular heterogeneity. We devised a new algorithm, Expression Variation Analysis in Single Cells (EVAsc), to perform multivariate statistical analyses of differential variation of expression in gene sets for scRNA-seq. EVAsc has high sensitivity and specificity to detect pathways with true differential heterogeneity in simulated data. We then apply EVAsc to several public domain scRNA-seq tumor datasets to quantify the landscape of tumor heterogeneity in several key applications in cancer genomics, i.e. immunogenicity, cancer subtypes, and metastasis. Immune pathway heterogeneity in hematopoietic cell populations in breast tumors corresponded to the amount diversity present in the T-cell repertoire of each individual. In head and neck squamous cell carcinoma (HNSCC) patients, we found dramatic differences in pathway dysregulation across basal primary tumors. Within the basal primary tumors we also identified increased immune dysregulation in individuals with a high proportion of fibroblasts present in the tumor microenvironment. Moreover, cells in HNSCC primary tumors had significantly more heterogeneity across pathways than cells in metastases, consistent with a model of clonal outgrowth. These results demonstrate the broad utility of EVAsc to quantify inter-and intra-tumor heterogeneity from scRNA-seq data without reliance on low dimensional visualization.
Resilience of BST-2/Tetherin structure to single amino acid substitutions
Authors: Roy Ian R. , Sutton Camden K. , Berndsen Christopher E.
Published: November 2018

Human Tetherin, also known as BST-2 or CD317, is a dimeric, extracellular membrane-bound protein that consists of N and C terminal membrane anchors connected by an extracellular domain. BST-2 is involved in binding enveloped viruses, such as HIV, and inhibiting viral release in addition to a role in NF-kB signaling. Viral tethering by Tetherin can be disrupted by the interaction with Vpu in HIV-1 in addition to other viral proteins. The structural mechanism of Tetherin function is not clear and the effects of human Tetherin mutations identified by sequencing consortiums are not known. To address this gap in the knowledge, we used data from the Ensembl database to construct and model known human missense mutations within the ectodomain to investigate how the structure of the ectodomain influences function. From the data, we identified an island of sequence stability within the ectodomain, which corresponds to functionally or structurally important region identified in previous biochemical and biophysical studies. Additionally, most mutations have little effect on structure, suggesting that they would not affect function. These findings are in agreement with biochemical and cellular studies which suggest that mutations that do not disrupt the alpha helices of Tetherin have little apparent effect on function. Thus, Tetherin sequence is likely less important than structure and this apparent flexibility may allow for greater anti-viral activities with a larger number of viruses.
The neuropeptide Galanin is required for homeostatic rebound sleep following increased neuronal activity
Authors: Reichert Sabine , Pavón Arocas Oriol , Rihel Jason
Published: November 2018

Sleep pressure homeostatically increases during wake and dissipates during sleep, but the molecular signals and neuronal substrates that measure homeostatic sleep pressure remain poorly understood. We present a pharmacological assay in larval zebrafish that generates acute, short-term increases in wakefulness followed by sustained rebound sleep after washout. The intensity of global neuronal activity during drug-induced wakefulness predicted the amount of subsequent rebound sleep. Whole brain mapping with the neuronal activity marker phosphorylated extracellular signal–regulated kinase (pERK) identified preoptic Galanin-expressing neurons as selectively active during rebound sleep, and the relative induction of galanin transcripts was predictive of total rebound sleep time. Galanin is required for sleep homeostasis, as galanin mutants almost completely lacked rebound sleep following both pharmacologically induced neuronal activity and physical sleep deprivation. These results suggest that Galanin plays a key role in responding to sleep pressure signals derived from neuronal activity and functions as an output arm of the vertebrate sleep homeostat. (word count: 158).
IFT25 is required for the construction of the trypanosome flagellum
Authors: Huet Diego , Blisnick Thierry , Perrot Sylvie , Bastin Philippe
Published: November 2018

Intraflagellar transport (IFT), the movement of protein complexes responsible for the assembly of cilia and flagella, is remarkably well conserved from protists to humans. However, two IFT components (IFT25 and IFT27) are missing from multiple unrelated eukaryotic species. In mouse, IFT25 and IFT27 are not required for assembly of several cilia with the noticeable exception of the flagellum of spermatozoa. Here we show that theTrypanosoma bruceiIFT25 protein is a proper component of the IFT-B complex and displays typical IFT trafficking. Using bimolecular fluorescence complementation assays, we reveal that IFT25 and IFT27 interact within the flagellum in live cells during the IFT transport process. IFT25-depleted cells construct tiny disorganised flagella that accumulate IFT-B proteins (with the exception of IFT27, the binding partner of IFT25) but not IFT-A proteins. This phenotype is comparable to the one following depletion of IFT27 and shows that IFT25/IFT27 constitute a specific module requested for proper IFT and flagellum construction in trypanosomes. We discuss the possible reasons why IFT25/IFT27 would be required for only some types of cilia.
Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells
Authors: Chadchankar Jayashree , Korboukh Victoria , Doig Peter , Jacobsen Steve J. , Brandon Nicholas J. , Moss Stephen J. , Wang Qi
Published: November 2018

USP14 is a cysteine-protease deubiquitinase associated with the proteasome and plays important catalytic and allosteric roles in proteasomal degradation. USP14 inhibition has been considered a therapeutic strategy for accelerating degradation of aggregation-prone proteins in neurodegenerative diseases and for inhibiting proteasome function to induce apoptotic cell death in cancers. Here we studied the effects of USP14 inhibition in mammalian cells using small molecule inhibitors and an inactive USP14 mutant C114A. Neither the inhibitors nor USP14 C114A changed the level of TDP-43, tau or α-synuclein in HEK293T cells. However, USP14 C114A led to an accumulation of ubiquitinated proteins, which were isolated by ubiquitin immunoprecipitation and identified by mass spectrometry. Among these proteins we confirmed that ubiquitinated β-catenin was accumulated in the cells expressing USP14 C114A with biochemistry and molecular biology experiments. The proteasome binding of USP14 C114A is required for its effect on ubiquitinated proteins. UCHL5 is the other cysteine-protease deubiquitinase associated with the proteasome. Interestingly, the inactive mutant of UCHL5 C88A also caused an accumulation of ubiquitinated proteins in HEK293T cells but did not affect β-catenin. Using ubiquitin immunoprecipitation and mass spectrometry, we identified the accumulated ubiquitinated proteins in UCHL5 C88A expressing cells which are mostly distinct from those accumulated in USP14 C114A expressing cells. Among the identified proteins are well established proteasome substrates and proteasome subunits. Together our data suggest that USP14 and UCHL5 can deubiquitinate distinct substrates at the proteasome and regulate the ubiquitination of the proteasome itself which is tightly linked to its function.
Integrative analysis from the epigenome through translation exposes patterns of dominant nuclear regulation during transient stress
Authors: Lee Travis A , Bailey-Serres Julia
Published: November 2018

Gene regulation is modulated from chromatin to translation. To better understand the integration of nuclear and cytoplasmic gene regulatory dynamics, we performed a multi-omic survey of the epigenome through the translatome of the response ofArabidopsisseedlings to hypoxia and reoxygenation. This included eight assays of chromatin (histones, accessibility, RNAPII and transcription factor binding) and three assays of RNA (nuclear, polyadenylated, and ribosome-associated). Dynamic patterns of nuclear regulation distinguished stress-induced and growth-associated mRNAs. The rapid upregulation of hypoxia-responsive gene transcripts and their preferential translation was accompanied by increased chromatin accessibility, RNAPII engagement and reduced Histone 2A.Z association. The more progressive upregulation of heat stress gene transcripts was characterized by early engagement of RNAPII and elevation of nuclear over polyadenylated RNA. Promoters of the rapidly versus progressively upregulated gene cohorts were enriched forcis-elements of ethylene-responsive and heat shock factor transcription factor families, respectively. By contrast, genes associated with growth including ribosomal proteins underwent distinct histone modifications, yet retained RNAPII engagement and accumulated nuclear transcripts during the stress. Upon reaeration, many of the progressively upregulated and growth-associated gene transcripts were mobilized to ribosomes. Thus, multi-level nuclear regulation distinguishes transcript synthesis, accumulation and translation in response to a transient stress.
Dynamical Task Switching in Cellular Computers
Authors: Goñi-Moreno Angel , Cruz Fernando de la , Rodríguez-Patón Alfonso , Amos Martyn
Published: November 2018

We present a scheme for implementing a version of task switching in engineered bacteria, based on the manipulation of plasmid copy numbers. Our method allows for the embeddingof multiple computations in a cellular population, whilst minimising resource usage inefficiency. We describe the results of computational simulations of our model, and discuss the potential for future work in this area.
6-Phosphogluconate Dehydrogenase Links Cytosolic Carbohydrate Metabolism to Protein Secretion
Authors: Li Haoxin , Ericsson Maria , Rabasha Bokang , Budnik Bogdan , Wagner Bridget , Garraway Levi A. , Schreiber Stuart L.
Published: November 2018

The proteinaceous extracellular matrix (ECM) is vital for cancer cell survival, proliferation, migration, and differentiation. However, little is known regarding metabolic pathways required in the ECM secretion process. By using an unbiased computational approach, we searched for enzymes whose suppression may lead to disruptions in protein secretion. Here, we show that 6-phosphogluconate dehydrogenase (PGD), a cytosolic enzyme involved in carbohydrate metabolism, is required for endoplasmic reticulum (ER) structural integrity and protein secretion. Chemical inhibition or genetic suppression of its activity led to cell stress accompanied by significantly expanded ER volume and can be rescued by compensating glutathione supplies. Our results also suggest that this characteristic ER-dilation phenotype may be a general marker indicating increased ECM protein congestion inside cells and decreased secretion. Thus, PGD exemplifies a nexus of cytosolic carbohydrate metabolism and protein secretion.
Four interpenetrating hydrogen-bonded three-dimensional networks in divanillin
Authors: Imer Marcos R. , Aldabalde Virginia , Pagola Silvina , Streek Jacco van de , Suescun Leopoldo
Published: November 2018

The crystal structure of divainillin (systematic name: 6,6′-dihydroxy-5,5′-dimethoxy-[1,1′-biphenyl]-3,3′-dicarbaldehyde), C16H14O6, was determined from laboratory powder X-ray diffraction data using the software EXPO2013 (direct methods) and WinPSSP (direct-space approach). Divanillin molecules crystallize in the orthorhombic space group Pba2 (No. 32), with two molecules per unit cell (Z′ = 1 \over 2). Each divanillin molecule, with twofold symmetry, is linked through strong alcohol–aldehyde hydrogen bonds to four equivalent molecules, defining a three-dimensional hydrogen-bonding network, with rings made up of six divanillin units (a diamond-like arrangement). Each molecule is also connected through π–π interactions to a translation-equivalent molecule along c. Four consecutive molecules stacked along [001] belong to four different three-dimensional hydrogen-bonding networks defining a quadruple array of interpenetrating networks. This complex hydrogen-bonding array is proposed as an explanation for the aging process experienced by divanillin powders.
Crystal structure of the lead-containing organic–inorganic hybrid: (C18H26N2)3[Pb4I14(DMSO)2]·2DMSO
Authors: Li Li , Zhao Dan , Liu Zhi , Zhang Dingchao , Hu Zhenhao , Li Kunlun , Yang Jing
Published: November 2018

The title compound, tris(1,1′-dibutyl-4,4′-bipyridine-1,1′-diium) bis(dimethyl sulfoxide)di-μ3-iodido-tetra-μ2-iodido-octaiodidotetralead(II) dimethyl sulfoxide disolvate, (C18H26N2)3[Pb4I14(C2H6OS)2]·2C2H6OS, belongs to a class of organic–inorganic hybrid materials with novel functionalities. In this compound, C—H...O and C—H...I hydrogen-bonding interactions, π–π interactions, other short contacts and Pb octahedral chains are present, extending the crystal structure into a three-dimensional supramolecular network.
Spiro[cyclopentane-1,11′-hexacyclo[7.6.0.01,6.06,13.08,12.010,14]pentadecane]-7′,15′-dione
Authors: Kotha Sambasivarao , Gunta Rama , Cheekatla Subba Rao , Mhatre Darshan S.
Published: November 2018

An unusual rearrangement of spiro cage dione to a trishomocubane derivatives is reported by acid-catalysed rearrangement with the aid of BF3·OEt2 in benzene (solvent) reflux conditions. Here, the molecular structure of cage molecule C19H22O2 (major product) consists of five-membered rings, which adopt an envelope conformation and six-membered rings adopt a chair or boat conformation. The Cremer & Pople puckering parameters of all four six-membered rings are calculated.
Multi-objective ant lion optimization algorithm to solve large-scale multi-objective optimal reactive power dispatch problem
Authors: Mouassa Souhil , Bouktir Tarek
Published: November 2018

Purpose

In the vast majority of published papers, the optimal reactive power dispatch (ORPD) problem is dealt as a single-objective optimization; however, optimization with a single objective is insufficient to achieve better operation performance of power systems. Multi-objective ORPD (MOORPD) aims to minimize simultaneously either the active power losses and voltage stability index, or the active power losses and the voltage deviation. The purpose of this paper is to propose multi-objective ant lion optimization (MOALO) algorithm to solve multi-objective ORPD problem considering large-scale power system in an effort to achieve a good performance with stable and secure operation of electric power systems.

Design/methodology/approach

A MOALO algorithm is presented and applied to solve the MOORPD problem. Fuzzy set theory was implemented to identify the best compromise solution from the set of the non-dominated solutions. A comparison with enhanced version of multi-objective particle swarm optimization (MOEPSO) algorithm and original (MOPSO) algorithm confirms the solutions. An in-depth analysis on the findings was conducted and the feasibility of solutions were fully verified and discussed.

Findings

Three test systems – the IEEE 30-bus, IEEE 57-bus and large-scale IEEE 300-bus – were used to examine the efficiency of the proposed algorithm. The findings obtained amply confirmed the superiority of the proposed approach over the multi-objective enhanced PSO and basic version of MOPSO. In addition to that, the algorithm is benefitted from good distributions of the non-dominated solutions and also guarantees the feasibility of solutions.

Originality/value

The proposed algorithm is applied to solve three versions of ORPD problem, active power losses, voltage deviation and voltage stability index, considering large -scale power system IEEE 300 bus.
Organizational justice and turnover intentions: probing the Pakistani print media sector
Authors: Hussain Muzammil , Khan Mohammad Saud
Published: November 2018

Purpose

To survive in this competitive era of modern business environment, organizations have to constantly develop, adapt and react to new challenges. Therefore, it is critical for organizations to create a sense of justice and involve their employees in business activities; thereby achieving the organization’s strategic goals. The purpose of this paper is to investigate the impact of organizational justice (OJ) on job turnover behavior of employees within the print media sector of Pakistan.

Design/methodology/approach

The study employs a quantitative methodology. It uses a sample of 402 employees from the newspaper industry to test hypotheses using regression analysis.

Findings

Results indicate that perceived distributive justice, procedural justice and informational justice have a negative relationship with turnover intentions of employees (as hypothesized) whereas; interpersonal justice did not result in a significant relationship.

Originality/value

The present study is one of the first within a Pakistani context in print media sector, aiming to examine the relationship of OJ (addressing all of its dimensions) and “intentions to leave the organization.”
Predicting future AI failures from historic examples
Authors: Yampolskiy Roman V.
Published: November 2018

Purpose

The purpose of this paper is to explain to readers how intelligent systems can fail and how artificial intelligence (AI) safety is different from cybersecurity. The goal of cybersecurity is to reduce the number of successful attacks on the system; the goal of AI Safety is to make sure zero attacks succeed in bypassing the safety mechanisms. Unfortunately, such a level of performance is unachievable. Every security system will eventually fail; there is no such thing as a 100 per cent secure system.

Design/methodology/approach

AI Safety can be improved based on ideas developed by cybersecurity experts. For narrow AI Safety, failures are at the same, moderate level of criticality as in cybersecurity; however, for general AI, failures have a fundamentally different impact. A single failure of a superintelligent system may cause a catastrophic event without a chance for recovery.

Findings

In this paper, the authors present and analyze reported failures of artificially intelligent systems and extrapolate our analysis to future AIs. The authors suggest that both the frequency and the seriousness of future AI failures will steadily increase.

Originality/value

This is a first attempt to assemble a public data set of AI failures and is extremely valuable to AI Safety researchers.
Teaching social economics
Authors: Farias Christine , Balardini Fabian
Published: November 2018

Purpose

Teaching complex economic theories can be made relevant through everyday life experiences and current economic, social, and environmental crises can be used as vehicles for student learning. The purpose of this paper is to help students understand that the economy should be seen as a social system that evolves over time driven by conflictive and contradictory forces and enable them to develop the critical thinking skills needed to make better choices for a more equitable and sustainable future.

Design/methodology/approach

The paper reviews the historical role played by neoliberalism on education in general and on the teaching of economics in particular. A historical/critical/action-learning approach discusses five pedagogical teaching methods that have been implemented in undergraduate economics courses and demonstrates how teaching social economics can be made possible by bringing the real world into the classroom and taking the classroom into the real world.

Findings

There is an urgent need to rethink the teaching of economics and the economics curriculum from one that stresses self-interest, profit maximization and cost minimization, to one that stresses cooperation, collaboration, fairness, and ethical values rather than economic value, as ways of satisfying society’s needs and addressing systemic issues of inequality, power and greed. Bringing teachers and students together in collaborative learning environments, thereby learning from the mistakes of the past and minimizing the impacts of the present so that future generations can also participate, is the much-needed change in how social economics can be taught post-financial crisis.

Originality/value

This paper is a response to the special issue on the theme teaching social economics during the global financial crisis. The authors have provided insights into their teaching pedgagogy in the context of this topic.