bluuebunny/crossref_metadata_2025 huggingface dataset:
Horizontal transfer of prokaryotic cytolethal distending toxin B genes to eukaryotes
Authors: Verster Kirsten I. , Wisecaver Jennifer H. , Duncan Rebecca P. , Karageorgi Marianthi , Gloss Andrew D. , Armstrong Ellie , Price Donald K. , Menon Aruna R. , Ali Zainab M. , Whiteman Noah K.
Published: February 2019

Cytolethal distending toxins (CDTs) are tripartite eukaryotic genotoxins encoded in diverse bacterial and phage genomes. The cdtB subunit is a DNAse that causes eukaryotic cell cycle arrest and apoptosis, and in one context, is associated with resistance against parasitoid wasp infections. Here we report the discovery of functional cdtB copies in the nuclear genomes of insect species from two distantly related insect orders, including fruit flies (Diptera: Drosophilidae) and aphids (Hemiptera: Aphididae). Insect cdtB copies are most closely related to bacteriophage copies, were horizontally transferred to insect genomes > 40 million years ago and encode a protein that retains ancestral DNase activity. This phage-derived toxin has been domesticated by diverse insects and we hypothesize that it is used as a defensive weapon against parasitoid wasps.

One Sentence Summary

We report horizontal transfer of the gene cytolethal distending toxin B, which encodes a DNase, into eukaryotic genomes from bacteriophage.

Significance

Cytolethal distending toxins (CDTs) are secreted by diverse pathogenic bacterial species to kill animal cells. The cdtB subunit enters cell nuclei, damaging the DNA and leading to mitotic arrest and apoptosis. In the pea aphid, a bacterial endosymbiont provides protection against wasp attack, possibly via cdtB. We discovered that this same endosymbiont-encoded lineage of cdtB was transferred to the genomes of Diptera and Hemiptera species and retains ancestral DNase activity. This is the first report of cdtB outside of bacteria or phages. A toxin that first evolved to kill eukaryotic cells has been co-opted by insects, potentially to their benefit.
Insular Cortex Projections to Nucleus Accumbens Core Mediate Social Approach to Stressed Juvenile Rats
Authors: Rogers-Carter Morgan M. , Djerdjaj Anthony , Gribbons Katherine B. , Varela Juan A. , Christianson John P.
Published: February 2019

Social interactions are shaped by features of the interactants including age, emotion, sex and familiarity. Age-specific responses to social affect are evident when an adult male rat is presented with a pair of unfamiliar male conspecifics, one of which is stressed via 2 footshocks and the other naïve to treatment. Adult test rats prefer to interact with stressed juvenile (PN30) conspecifics, but avoid stressed adult (PN50) conspecifics. This pattern depends upon the insular cortex (IC) which is anatomically connected to the nucleus accumbens core (NAc). The goal of this work was to test the necessity of IC projections to NAc during social affective behavior. Here, bilateral pharmacological inhibition of the NAc with tetrodotoxin (1µM; 0.5ul/side) abolished the preference for stressed PN30, but did not alter interactions with PN50 conspecifics. Using a combination of retrograding tracing and c-Fos immunohistochemistry, we report that social interactions with stressed PN30 conspecifics elicit greater Fos immunoreactivity in IC → NAc neurons than interactions with naïve PN30 conspecifics. Chemogenetic stimulation of IC terminals in the NAc increased social exploration with juvenile, but not adult, conspecifics, while chemogenetic inhibition of this tract blocked the preference to investigate stressed PN30 conspecifics, which expands upon our previous finding that optogenetic inhibition of IC projection neurons mediated approach and avoidance. These new findings suggest that outputs of IC to the NAc modulate social approach, which provides new insight to the neural circuitry underlying social decision-making.

Significance Statement

Social decision-making underlies an animal’s behavioral response to others in a range of social contexts. Previous findings indicate the insular cortex (IC) and the nucleus accumbens (NAc) play important roles in a range of social behaviors, and human neuroimaging implicates both IC and NAc in autism and other psychiatric disorders characterized by aberrant social cognition. To test whether IC projections to the NAc are involved in social decision making, circuit-specific chemogenetic manipulations demonstrated that the IC → NAc pathway mediates social approach toward distressed juvenile, but not adult, conspecifics. This finding is the first to implicate this circuit in rodent socioemotional behaviors and may be a neuroanatomical substrate for integration of emotion with social reward.
Helicobacter pylori Senses Bleach as a Chemoattractant Using a Cytosolic Chemoreceptor
Authors: Perkins Arden , Tudorica Dan A. , Amieva Manuel R. , Remington S. James , Guillemin Karen
Published: February 2019

The gastric pathogenHelicobacter pylorirequires a non-canonical cytosolic chemoreceptor transducer-like protein D (TlpD) for efficient colonization of the mammalian stomach. Here we reconstituted a complete chemotransduction signaling complexin vitrowith TlpD and the chemotaxis proteins CheW and CheA, enabling quantitative assays for potential chemotaxis ligands. We found that TlpD is selectively sensitive at micromolar concentrations to bleach (hypochlorous acid, HOCl), a potent antimicrobial produced by neutrophil myeloperoxidase during inflammation. Counterintuitively, HOCl acts as a chemoattractant by reversibly oxidizing a conserved cysteine within a 3His/1Cys Zn-binding motif in TlpD that inactivates the chemotransduction signaling complex. We found thatH. pyloriis resistant to killing by millimolar concentrations of HOCl and responds to bleach in the micromolar range by increasing its smooth swimming behavior, leading to chemoattraction to HOCl sources. We found that related protein domains fromSalmonella entericaandEscherichia colishowed a similar reactivity toward bleach. We propose that this family of proteins enables host-associated bacteria to sense sites of tissue inflammation, a strategy thatH. pyloriuses to aid in colonizing and persisting in inflamed gastric tissue.
Age and sex-dependent patterns of gut microbial diversity in human adults
Authors: de la Cuesta-Zuluaga Jacobo , Kelley Scott T. , Chen Yingfeng , Escobar Juan S. , Mueller Noel T. , Ley Ruth E. , McDonald Daniel , Huang Shi , Swafford Austin D. , Knight Rob , Thackray Varykina G.
Published: February 2019

Gut microbial diversity changes throughout the human lifespan and is known to be affected by host sex. We investigated the association of age, sex and gut bacterial alpha diversity in three large cohorts of adults from four geographical regions: US and UK cohorts in the American Gut Project, and two independent cohorts of Colombians and Chinese. In three of the four cohorts, we observed a strong positive association between age and alpha diversity in young adults that plateaued after age 40. We also found pronounced sex-dependent differences in younger but not middle-aged adults, and women had higher alpha diversity than men. In contrast, no association of alpha diversity with age or sex was observed in the Chinese cohort. These associations were maintained after adjusting for cardiometabolic parameters in the Colombian cohort and antibiotic usage in the AGP cohort, suggesting that these factors do not affect the association of alpha diversity with age and sex. We also used a machine learning approach to predict individual age based on the gut microbiome. Consistent with our alpha diversity-based findings, women had significantly higher predicted age than men in the US and UK cohort, with a reduced difference above age 40. This was not observed in the Colombian cohort and only in the group of middle-age adults in the Chinese cohort. Together, our results provide new insights into the influence of age and sex on biodiversity of the human gut microbiota during adulthood while highlighting similarities and differences across diverse cohorts.
Physiological and Evolutionary Implications of Tetrameric Photosystem I in Cyanobacteria
Authors: Li Meng , Calteau Alexandra , Semchonok Dmitry A. , Witt Thomas A. , Nguyen Jonathan T. , Sassoon Nathalie , Boekema Egbert J. , Whitelegge Julian , Gugger Muriel , Bruce Barry D.
Published: February 2019

Photosystem I (PSI) were reported as trimeric complexes in most characterized cyanobacteria, yet monomers in plants and algae PSI. Recent reports on tetrameric PSI raised questions regarding its structural basis, physiological role, phylogenetic distribution and evolutionary significance. In this study, by examining PSI in 61 cyanobacteria, we show that tetrameric PSI, correlating with a uniquepsaLgene and genomic structure, is widespread in the heterocyst-forming cyanobacteria and their close relatives. Physiological studies on these cyanobacteria revealed that tetrameric PSI is favored under high light, with an increased content of novel PSI-bound carotenoids (myxoxanthophyll, canthaxanthan and echinenone). Together this work suggests that tetrameric PSI is an adaptation to high light, along with results showing that change in PsaL leads to trimeric PSI monomerization, supporting the hypothesis of tetrameric PSI being the evolutionary intermediate in the transition from cyanobacterial trimeric PSI to monomeric PSI in plants and algae.
Cold-induced switch in direction of chloroplast relocation occurs independently of changes in endogenous phototropin expression
Authors: Fujii Yuta , Ogasawara Yuka , Takahashi Yamato , Sakata Momoko , Tamura Saori , Kodama Yutaka
Published: February 2019

When exposed to fluctuating light intensity, chloroplasts move towards weak light (accumulation response), and away from strong light (avoidance response). In addition, cold treatment (5°C) induces the avoidance response even under weak light conditions (cold-avoidance response). These three responses are mediated by the phototropin (phot), which is a blue-light photoreceptor and has also been found to act as a thermosensory protein that perceives temperature variation. Our previous report indicated that cold-induced changes in phot biochemical activity initiate the cold-avoidance response. In this study, we further explored the induction mechanism of the cold-avoidance response in the liverwort Marchantia polymorpha and examined the relationship between changes in the amount of phot and the induction of the cold-avoidance response. The switch between the accumulation and avoidance responses occurs at a so-called ‘transitional’ light intensity. Our physiological experiments revealed that a cold-mediated decrease in the transitional light intensity leads to the induction of the cold-avoidance response. While artificial overexpression of phot decreased the transitional light intensity as much as cold treatment did, the amount of endogenous phot remained unchanged by cold treatment in wild-type M. polymorpha. Taken together, these findings show that the cold-avoidance response is initiated by a cold-mediated reduction of the transitional light intensity, independent of the amount of endogenous phot. This study provides a clue to understand the mechanism underlying the switch in direction of chloroplast relocation in response to light and temperature.
Homotypic and heterotypic trans-assembly of human Rab-family small GTPases in reconstituted membrane tethering
Authors: Segawa Kazuya , Tamura Naoki , Mima Joji
Published: February 2019

Membrane tethering is a highly regulated event that occurs during the initial physical contact between membrane-bounded transport carriers and their target subcellular membrane compartments, thereby ensuring the spatiotemporal specificity of intracellular membrane trafficking. Although Rab-family small GTPases and specific Rab-interacting effectors, such as coiled-coil tethering proteins and multisubunit tethering complexes, are known to be involved in membrane tethering, how these protein components directly act upon the tethering event remains enigmatic. Here, we investigated the molecular basis of membrane tethering by comprehensively and quantitatively evaluating the intrinsic capacities of 10 representative human Rab-family proteins (Rab1a, 3a, 4a, 5a, 6a, 7a, 9a, 11a, 27a, and 33b) to physically tether two distinct membranes via homotypic and heterotypic Rab-Rab assembly in a chemically defined reconstitution system. All of the Rabs tested, except Rab27a, specifically caused homotypic membrane tethering at physiologically relevant Rab densities on membrane surfaces (e.g., Rab-to-lipid molar ratios of 1:100-1:3,000). Notably, endosomal Rab5a retained its intrinsic potency to drive efficient homotypic tethering even at concentrations below the Rab-to-lipid ratio of 1:3,000. Comprehensive reconstitution studies further uncovered that heterotypic combinations of human Rab-family isoforms, including Rab1a/6a, Rab1a/9a, and Rab1a/33b, can directly and selectively mediate membrane tethering. Rab1a and Rab9a, in particular, synergistically triggered very rapid and efficient membrane tethering reactions through their heterotypic trans-assembly on two opposing membranes. Thus, our findings establish that, in the physiological context, homotypic and heterotypic trans-assembly of Rab-family small GTPases can provide the essential molecular machinery necessary to drive membrane tethering in eukaryotic endomembrane systems.
Comparative genome analysis of 12 Shigella sonnei strains: virulence, resistance, and their interactions
Authors: Zhu Zuobin , Wang Liang , Gu Feng , Li Ying , Zhang Heng , Chen Ying , Shi Jiajia , Ma Ping , Gu Bing
Published: February 2019

Shigellosis is a highly infectious disease that are mainly transmitted via faecal-oral contact of the bacteria Shigella. Four species have been identified in Shigella genus, among which S. flexneri is used to be the most prevalent species globally and commonly isolated from developing countries. However, it is being replaced by S. sonnei that is currently the main causative agent for dysentery pandemic in many emerging industrialized countries such as Asia and the Middle East with unclear reasons. For a better understanding of S. sonnei virulence and antibiotic resistance, we sequenced 12 clinical S. sonnei strains with varied antibiotic-resistance profiles collected from four cities in Jiangsu Province, China. Phylogenomic analysis clustered antibiotic sensitive and resistant S. sonnei into two distinct groups while pangenome analysis reveals the presence and absence of featured genes in each group. Screening of 31 classes of virulence factors found out that type 2 secretion system is doubled in resistant strains. Further principle component analysis based on the interactions between virulence and resistance indicated that abundant virulence factors are associated with higher resistant phenotypes. The result present here is based on statistical analysis of a small sample size and serves basically as a guidance for further experimental and theoretical studies.
Rhodopsin-based voltage imaging tools for use in excitable cells of Caenorhabditis elegans
Authors: Hashemi Negin Azimi , Bergs Amelie C. F. , Scheiwe Rebecca , Costa Wagner Steuer , Liewald Jana F. , Gottschalk Alexander
Published: February 2019

Genetically encoded voltage indicators (GEVIs) based on microbial rhodopsins utilize the voltage-sensitive fluorescence of the all-trans retinal (ATR) cofactor, while in electrochromic (eFRET) sensors, donor fluorescence drops when the rhodopsin acts as depolarization-sensitive acceptor. We systematically assessed Arch(D95N), Archon, and QuasAr, as well as the eFRET sensors MacQ-mCitrine and QuasAr-mOrange, in C. elegans. ATR-bearing rhodopsins reported on voltage changes in body wall muscles (BWMs) and the pharynx, the feeding organ, where Arch(D95N) showed ca. 125 % ΔF/F increase per 100 mV. The ATR fluorescence is very dim, however, using the retinal analog dimethylaminoretinal (DMAR), it was boosted 250-fold. eFRET sensors provided sensitivities of 45 % to 78 % ΔF/F per 100 mV, induced by BWM action potentials (APs). All sensors reported differences in muscle depolarization induced by a voltage-gated Ca2+-channel mutant. Optogenetically evoked de-or hyperpolarization of motor neurons increased or eliminated AP activity and caused a rise or drop in BWM sensor fluorescence. Last, we could analyze voltage dynamics across the entire pharynx, showing uniform depolarization but compartmentalized repolarization of anterior and posterior parts. Our work establishes all-optical, non-invasive electrophysiology in intact C. elegans.
Auditory prediction errors and auditory white matter microstructure as predictors of psychotic experiences in healthy individuals
Authors: Randeniya R. , Oestreich L.K.L. , Garrido M.I.
Published: February 2019

Our sensory systems actively predict sensory information based on previously learnt patterns. An inability to accurately predict forthcoming information results in prediction errors. Individuals with schizophrenia consistently show reduced auditory prediction errors as well as reduced microstructure in auditory white matter pathways. However, it is not clear if also healthy individuals with psychotic experiences demonstrate such deficits. Participants underwent electroencephalography (EEG) recordings while listening to a simple two-tone duration deviant oddball paradigm (N=103) and a stochastic oddball paradigm (N=89). A subset of participants (N=89) also underwent diffusion-weighted magnetic resonance imaging (MRI), from which fractional anisotropy (FA), a measure of overall white matter microstructure, was obtained for auditory pathways namely the auditory interhemispheric pathway, as well as the left and right arcuate fasciculi. We investigated both structural and functional predictors of positive psychotic experiences in healthy participants as measured by the Community Assessment for Psychic Experiences positive dimension (CAPE+) scores. Prediction errors evoked by the classical oddball paradigm failed to reveal significant effects, whereas the stochastic oddball paradigm revealed significant clusters at typical mismatch negativity periods predictive of CAPE+ scores. Furthermore, we show that white matter microstructure from auditory pathways in addition to mismatches significantly predict CAPE+ scores. We suggest that structural and functional prediction error measures together may have potential in predicting psychotic experiences in the healthy population.
Spatially constrained tumour growth affects the patterns of clonal selection and neutral drift in cancer genomic data
Authors: Chkhaidze Kate , Heide Timon , Werner Benjamin , Williams Marc J. , Huang Weini , Caravagna Giulio , Graham Trevor A. , Sottoriva Andrea
Published: February 2019

Quantification of the effect of spatial tumour sampling on the patterns of mutations detected in next-generation sequencing data is largely lacking. Here we use a spatial stochastic cellular automaton model of tumour growth that accounts for somatic mutations, selection, drift and spatial constrains, to simulate multi-region sequencing data derived from spatial sampling of a neoplasm. We show that the spatial structure of a solid cancer has a major impact on the detection of clonal selection and genetic drift from bulk sequencing data and single-cell sequencing data. Our results indicate that spatial constrains can introduce significant sampling biases when performing multi-region bulk sampling and that such bias becomes a major confounding factor for the measurement of the evolutionary dynamics of human tumours. We present a statistical inference framework that takes into account the spatial effects of a growing tumour and allows inferring the evolutionary dynamics from patient genomic data. Our analysis shows that measuring cancer evolution using next-generation sequencing while accounting for the numerous confounding factors requires a mechanistic model-based approach that captures the sources of noise in the data.

Sequencing the DNA of cancer cells from human tumours has become one of the main tools to study cancer biology. However, sequencing data are complex and often difficult to interpret. In particular, the way in which the tissue is sampled and the data are collected, impact the interpretation of the results significantly. We argue that understanding cancer genomic data requires mathematical models and computer simulations that tell us what we expect the data to look like, with the aim of understanding the impact of confounding factors and biases in the data generation step. In this study, we develop a spatial simulation of tumour growth that also simulates the data generation process, and demonstrate that biases in the sampling step and current technological limitations severely impact the interpretation of the results. We then provide a statistical framework that can be used to overcome these biases and more robustly measure aspects of the biology of tumours from the data.
Intrinsic control of muscle attachment sites matching
Authors: Carayon Alexandre , Bataillé Laetitia , Lebreton Gaëlle , Dubois Laurence , Pelletier Aurore , Carrier Yannick , Wystrach Antoine , Vincent Alain , Frendo Jean-Louis
Published: February 2019

How a stereotypic muscle pattern is established, and adapted to fit locomotion behaviour is a fascinating question. Here we set up the targeted deletion of cis-regulatory modules (CRMs) controlling the transcription ofDrosophilamuscle identity transcription factors (iTF) to generate larval muscle identity mutants. By focusing on one muscle transcription and morphology, we show that selection of muscle attachment sites and the precision of muscle/muscle matching is intrinsic to muscle identity. It involves propagation of the iTF expression code from a founder myoblast to the other syncytial nuclei after fusion. Live imaging indicates that the precise staggered muscle attachment pattern involves attraction to tendon cells and homotypic repulsion. Unbalance leads to the formation of abnormal, branched muscles. Single muscle morphology shifts induce subtle locomotor behaviour. Together this work highlights that CRM deletion is an effective setting for creating muscle-specific defects and branched muscles, as new paradigms to study the development of human myopathies affecting subsets of muscles.

Highlights

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First muscle-identity mutants, via deletion of specific cis-regulatory modules

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Reprogramming of syncytial nuclei is key to muscle morphological identity

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Selection of muscle attachment sites; attraction and retraction intrinsic to muscle identity

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Genetically controlled formation of branched muscles, a new paradigm for functional studies

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Single muscle morphology shift induces subtle locomotor behaviour modification
Chasing the full free energy landscape of neuroreceptor/ligand unbinding by metadynamics simulations
Authors: Capelli Riccardo , Bochicchio Anna , Piccini GiovanniMaria , Casasnovas Rodrigo , Carloni Paolo , Parrinello Michele
Published: February 2019

Predicting the complete free energy landscape associated with protein-ligand unbinding would greatly help designing drugs with highly optimized pharmacokinetics. Here we investigate the unbinding of the iperoxo agonist to its target human neuroreceptor M2, embedded in a neuronal membrane. By feeding out-of-equilibrium molecular simulations data in a classification analysis, we identify the few essential reaction coordinates of the process. The full landscape is then reconstructed using an exact enhanced sampling method, well-tempered metadynamics in its funnel variant. The calculations reproduce well the measured affinity, provide a rationale for mutagenesis data and show that the ligand can escape via two different routes. The allosteric modulator LY2119620 turns out to hamper both escapes routes, thus slowing down the unbinding process, as experimentally observed. This computationally affordable protocol is totally general and it can be easily applied to determine the full free energy landscape of membrane receptors/drug interactions.
Genetic, epigenetic and pharmacological influences modulating tissue specific regulation of the cannabinoid receptor-1 gene (CB1); implications for cannabinoid pharmacogenetics
Authors: Hay Elizabeth A. , Cowie Philip , McEwan Andrew , Wilson Dana , Ross Ruth , Barrett Perry , Pertwee Roger G. , MacKenzie Alasdair
Published: February 2019

Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1(encoded by the CNR1 gene) have been compromised by differences in patient response. Towards addressing the hypothesis that genetic and epigenetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we isolated the human CNR1 promotor (CNR1prom) and demonstrate its activity in primary cells and transgenic mice. We also provide evidence of CNR1prom in CB1autoregulation and its repression by DNA-methylation. We further characterised a conserved regulatory sequence (ECR1) in CNR1 intron 2 that contained a polymorphism in linkage disequilibrium with disease associated SNPs. Deletion of ECR1 from mice using CRISPR genome editing significantly reduced CNR1 expression in the hippocampus. These mice also displayed reduced ethanol intake and hypothermia response to CB1agonism. Moreover, human specific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in hippocampal cells than did the ancestral T-allele. We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity. In the context of the known roles of CB1the current study suggests a mechanism through which ECR1(C) may be neuroprotective in the hippocampus against stress. The cell-specific approaches used in our study to determine the functional effects of genetic and epigenetic changes on the activity of tissue-specific regulatory elements at the CNR1 locus represent an important step in gaining a mechanistic understanding of cannabinoid pharmacogenetics.
An Objective Technology-based Assessment of Arm and Hand Sensorimotor Disability in Neurological Disorders
Authors: Kanzler Christoph M. , Rinderknecht Mike D. , Schwarz Anne , Lamers Ilse , Gagnon Cynthia , Held Jeremia , Feys Peter , Luft Andreas R. , Gassert Roger , Lambercy Olivier
Published: February 2019

Background

Detailed assessments of upper limb disability are essential to understand and monitor sensorimotor recovery. Usually, multiple timeconsuming assessments are required to define a holistic sensorimotor profile of proximal (shoulder-elbow) and distal (wrist-hand) impairments and their impact on the capacity to perform activities. We propose and evaluate a novel physiologically-motivated computational framework for objectively assessing sensorimotor profiles in neurological patients using a single, rapid technology-based assessment involving goal-directed arm and hand movements.

Methods

The Virtual Peg Insertion Test (VPIT) was administered to 121 healthy and 80 neurological subjects. The framework provides 25 kinematic and kinetic metrics expected to describe 12 sensorimotor components representative of ataxia and paresis and their influence on task performance, as well as one overall disability measure. The feasibility (protocol duration), structural validity (factor analysis and correlations ρ between sensorimotor components), concurrent validity (correlation with Action Research Arm Test; ARAT), and discriminant validity (comparing healthy controls and patients, and patients with different disability levels) were evaluated.

Results

The median VPIT protocol duration was 16.5min in neurological patients. The sensor-based metrics could unambiguously be grouped into 12 mostly independent (median |ρ|=0.14) components. Ten components showed significant differences between healthy and impaired subjects and nine components indicated clear trends across disability levels, without any ceiling effects. The VPIT overall disability measure and ARAT were moderately correlated (ρ=−0.53, p<0.001).

Conclusions

This work demonstrates the possibility to rapidly, holistically, and objectively assess proximal and distal sensorimotor impairments and their influence on the capacity to perform activities with a single assessment.
Marine-freshwater prokaryotic transitions require extensive changes in the proteome
Authors: Cabello-Yeves Pedro J. , Rodriguez-Valera Francisco
Published: February 2019

The comparison of microbial genomes found in either freshwater or marine habitats indicated that in some cases (SynechococcusandCa. Pelagibacter) there were notable differences in the global isoelectric point (pI) of proteins. We have analysed global metagenomic proteomes and have added more prokaryotes to extend the pI comparison. Without exception, in a set that included archaea and multiple bacterial phyla, the proteome pI distribution varied, with more acidic values in marine and neutral/basic in freshwater microbes. Four pairs of highly related prokaryotes of marine and freshwater origin revealed marked differences manifested mostly in the residues located at the protein surface. This study has also shown that the magnitude of the change depended on protein location (secreted > cytoplasmic > transmembrane) and affected proteins encoded at both core and flexible genome. Our results point to a very extensive variation taking place in microbes when they move from marine (salt-rich) to freshwater habitats. These adaptations would require long evolutionary times to produce changes involving many genes in the core genome. They also point to significant differences in the physiology, probably at the level of membrane functioning, bioenergetics, intracellular ion concentration and pH (or all of them).
In planta chromatin immunoprecipitation in Zymoseptoria tritici reveals chromatin-based regulation of putative effector gene expression
Authors: Soyer Jessica L. , Grandaubert Jonathan , Haueisen Janine , Schotanus Klaas , Stukenbrock Eva H.
Published: February 2019

During infection, pathogens secrete effectors, key elements of pathogenesis. In several phytopathogenic fungi, synchronous waves of effector genes are expressed during plant infection to manipulate and silence plant defenses. In Zymoseptoria tritici, causing septoria leaf blotch of wheat, at least two waves of effector genes are expressed, during the asymptomatic phase and at the switch to necrotrophy. The underlying factors responsible for the fine-tuned regulation of effector gene expression in this pathogen are unknown. Previously, a detailed map of the chromatin structure in vitro of Z. tritici was generated by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) targeting histone modifications typical for euchromatin (di-methylation of the lysine 4 of the histone H3, H3K4me2) or heterochromatin (tri-methylation of the lysine 9 and 27 of the histone H3, H3K9me3 and H3K27me3). Based on the hypothesis that changes in the histone modifications contribute to the transcriptional control of pathogenicity-related genes, we tested whether different sets of genes are associated with different histone modifications in vitro. We correlated the in vitro histone maps with in planta transcriptome data and show that genes located in heterochromatic domains in vitro are highly up-regulated at the switch toward necrotrophy. We combined our integrated analyses of genomic, transcriptomic and epigenomic data with ChIP-qPCR in planta and thereby provide further evidence for the involvement of histone modifications in the transcriptional dynamic of putative pathogenicity-related genes of Z. tritici.
Deficit in motor skill learning-dependent synaptic plasticity at motor cortex to Dorso Lateral Striatum synapses in a mouse model of Huntington's disease
Authors: Glangetas Christelle , Espinosa Pedro , Bellone Camilla
Published: February 2019

Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symptoms. Although the loss of Medium Spiny Neurons (MSNs) in the striatum has been associated with motor deficits, premanifest patients already present cognitive deficiencies and show early signs of motor disabilities. Here in a YAC128 HD mouse model, we identified impairment in motor skill learning at the age of 11 to 14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the Dorso Lateral part of the Striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill learning is accompanied by a dynamic change in AMPA/NMDA ratio in wild type mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill learning dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for Huntington's disease.
Size- and stage-dependence in cause-specific mortality of migratory brown trout
Authors: Nater Chloé Rebecca , Vindenes Yngvild , Aass Per , Cole Diana , Langangen Øystein , Moe Jannicke , Rustadbakken Atle , Turek Daniel , Vøllestad Leif Asbjørn , Ergon Torbjørn
Published: February 2019

Evidence-based management of natural populations under strong human influence frequently requires not only estimates of survival but also knowledge about how much mortality is due to anthropogenic versus natural causes. This is the case particularly when individuals vary in their vulnerability to different causes of mortality due to traits, life-history stages, or locations. Here, we estimated harvest and background (other cause) mortality of a landlocked migratory salmonid over half a century. In doing so, we quantified among-individual variation in vulnerability to cause-specific mortality resulting from differences in body size and spawning location relative to a hydropower dam. We constructed a multistate mark-recapture model to estimate harvest and background mortality hazard rates as functions of a discrete state (spawning location) and an individual time-varying covariate (body size). We further accounted for among-year variation in mortality and migratory behavior and fit the model to a unique 50-year time-series of mark-recapture-recovery data on brown trout (Salmo trutta) in Norway. Harvest mortality was highest for intermediate-sized trout, and outweighed background mortality for most of the observed size range. Background mortality decreased with body size for trout spawning below the dam and increased for those spawning above. All vital rates varied substantially over time, but a trend was evident only in estimates of fishers' reporting rate, which decreased from over 50% to less than 10% throughout the study period. We highlight the importance of body size for cause-specific mortality and demonstrate how this can be estimated using a novel hazard rate parameterisation for mark-recapture models. Our approach allows estimating effects of individual traits and environment on cause-specific mortality without confounding, and provides an intuitive way to estimate temporal patterns within and correlation among different mortality sources.
Patient satisfaction with nursing care in Ethiopia: A systematic review and meta-analysis
Authors: Mulugeta Henok , Wagnew Fasil , Dessie Getenet , Biresaw Henok , Habtewold Tesfa Dejenie
Published: February 2019

Background

Patient satisfaction with nursing care has been considered as the most important predictor of the overall patient satisfaction with hospital service and quality of health care service at large. However, the national level of patient satisfaction with nursing care remains unknown. Hence, the objective of this systematic review and meta-analysis was to estimate patient satisfaction with nursing care in Ethiopia.

Methods

Studies were accessed through an electronic web-based search strategy from PubMed, Cochrane Library, Google Scholar, Embase, PsycINFO and CINAHL by using combination search terms. Qualities of each included article assessed by using a modified version of the Newcastle-Ottawa Scale for cross-sectional studies. All statistical analyses were done using STATA version 14 software. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed for reporting results.

Results

Of 1,166 records screened, 15 studies with 6091 participants were included. The estimated pooled level of patient satisfaction with nursing care in Ethiopia was 55.15% (95% CI (47.35, 62.95%)). Based on the subgroup analysis, the estimated level of patient satisfaction was 61.84% (95% CI: 44.49, 79.2) in Addis Ababa, 54.24 %(95%CI: 46.84, 61.65) in Amhara region, 44.06% (95%CI: 38.09, 50.03) in SNNP, and 53.02 %(95% CI: 50.03, 56.00) in other regions. Patients who have one nurse in charge [(OR 1.08(0.45, 2.62)], with no history of previous hospitalization [(OR 1.37(0.82, 2.31)], living in the urban area [(OR 1.07(0.70, 1.65)], / and those who have no comorbid disease [(OR 1.08(0.48, 2.62)] were more likely to be satisfied with nursing care than their counterparts even though it was not statistically significant.

Conclusion

This meta-analysis revealed that about one in two patients were not satisfied with the nursing care provided in Ethiopia. Therefore, Ministry of Health should give more emphasis to the quality of nursing care in order to increase patient satisfaction which is important to improve the overall quality of healthcare service.
Modelling Subject Variability in the Spatial and Temporal Characteristics of Functional Modes
Authors: Harrison Samuel J. , Bijsterboch Janine D. , Segerdahl Andrew R. , Fitzgibbon Sean P. , Farahibozorg Seyedeh-Rezvan , Duff Eugene P. , Smith Stephen M. , Woolrich Mark W.
Published: February 2019

Recent work has highlighted the scale and ubiquity of subject variability in observations from functional MRI data (fMRI). Furthermore, it is highly likely that errors in the estimation of either the spatial presentation of, or the coupling between, functional regions can confound cross-subject analyses, making accurate and unbiased representations of functional data essential for interpreting any downstream analyses.

Here, we extend the framework of probabilistic functional modes (PFMs) [Harrison et al. 2015] to capture cross-subject variability not only in the mode spatial maps, but also in the functional coupling between modes and in mode amplitudes. A new implementation of the inference now also allows for the analysis of modern, large-scale data sets, and the combined inference and analysis package, PROFUMO, is available from git.fmrib.ox.ac.uk/samh/profumo. Using simulated data, resting-state data from 1,000 subjects collected as part of the Human Connectome Project [Van Essen et al. 2013], and an analysis of 14 subjects in a variety of continuous task-states [Kieliba et al. 2019], we demonstrate how PFMs are able to capture, within a single model, a rich description of how the spatio-temporal structure of resting-state fMRI activity varies across subjects.

We also compare the new PFM model to the well established independent component analysis with dual regression (ICA-DR) pipeline. This reveals that, under PFM assumptions, much more of the (behaviorally relevant) cross-subject variability in fMRI activity should be attributed to the variability in spatial maps, and that, after accounting for this, functional coupling between modes primarily reflects current cognitive state. This has fundamental implications for the interpretation of cross-sectional studies of functional connectivity that do not capture cross-subject variability to the same extent as PFMs.
Long-term mark-recapture and growth data for large-sized migratory brown trout (Salmo trutta) from Lake Mjøsa, Norway
Authors: Moe S. Jannicke , Nater Chloé R. , Rustadbakken Atle , Vøllestad L. Asbjørn , Lund Espen , Qvenild Tore , Hegge Ola , Aass Per
Published: February 2019

Background

Long-term data from marked animals provide a wealth of opportunities for studies with high relevance to both basic ecological understanding and successful management in a changing world. The key strength of such data is that they allow to quantify individual variation in vital rates (e.g. survival, growth, reproduction) and then link it mechanistically to dynamics at the population level. However, maintaining the collection of individual-based data over long time periods comes with large logistic efforts and costs, and studies spanning over decades are therefore rare. This is the case particularly for migratory aquatic species, many of which are in decline despite their high ecological, cultural, and economical value.

New information

This paper describes two unique publicly available time series of individual-based data originating from a 51-year mark-recapture study of a land-locked population of large-sized migratory brown trout (Salmo trutta) in Norway: the Hunder trout. In the period 1966-2015, nearly 14,000 adult Hunder trout have been captured and individually marked during their spawning migration from Lake Mjøsa to the river Gubrandsdalslågen. Almost a third of those individuals were later recaptured alive during a later spawning run and/or captured by fishermen and reported dead or alive. This has resulted in the first data series: a mark-recapture-recovery dataset spanning half a century and more than 18,000 capture records. The second data series consists of additional data on juvenile and adult growth and life-history schedules from half of the marked individuals, obtained by means of scale sample analysis. The two datasets offer a rare long-term perspective on individuals and population dynamics and provide unique opportunities to gain insights into questions surrounding management, conservation, and restoration of migratory salmonid populations and freshwater ecosystems.
Neural organization of speech production: A lesion-based study of error patterns in connected speech
Authors: Stark Brielle C , Basilakos Alexandra , Hickok Gregory , Rorden Chris , Bonilha Leonardo , Fridriksson Julius
Published: February 2019

While numerous studies have explored single-word naming, few have evaluated the behavioral and neural correlates of more naturalistic language, like connected speech, which we produce every day. Here, in a retrospective analysis of 120 participants at least six months following left hemisphere stroke, we evaluated the distribution of word errors (paraphasias) and associated brain damage during connected speech (picture description) and object naming. While paraphasias in connected speech and naming shared underlying neural substrates, analysis of the distribution of paraphasias suggested that lexical-semantic load is likely reduced during connected speech. Using voxelwise lesion-symptom mapping (VLSM), we demonstrated that verbal (real word: semantically related and unrelated) and sound (phonemic and neologistic) paraphasias during both connected speech and naming loaded onto the left hemisphere ventral and dorsal streams of language, respectively. Furthermore, for the first time using both connected speech and naming data, we localized semantically related paraphasias to more anterior left hemisphere temporal cortex and unrelated paraphasias to more posterior left temporal and temporoparietal cortex. The connected speech results, in particular, highlight a gradient of specificity as one translates visual recognition from left temporo-occipital cortex to posterior and subsequently anterior temporal cortex. The robustness of VLSM results for sound paraphasias derived during connected speech was notable, in that analyses performed on sound paraphasias from the connected speech task, and not the naming task, demonstrated significant results following removal of lesion volume variance and related apraxia of speech variance. Therefore, connected speech may be a particularly sensitive task on which to evaluate further lexical-phonological processing in the brain. The results presented here demonstrate the related, though different, distribution of paraphasias during connected speech, confirm that paraphasias arising in connected speech and single-word naming likely share neural origins, and endorse the need for continued evaluation of the neural substrates of connected speech processes.
A simplified spiking model of grid-cell scale and intrinsic frequencies
Authors: Santos-Pata Diogo , Zucca Riccardo , López-Carral Héctor , Verschure Paul F. M. J.
Published: February 2019

The hexagonal tessellation pattern of grid cells scales up progressively along the dorsal-to-ventral axis of the medial entorhinal cortex (MEC) layer II. This scaling gradient has been hypothesized to originate either from inter population synaptic dynamics as postulated by attractor networks, from projected theta frequencies to different axis levels, as in oscillatory models, or from cellular dynamics dependent on hyperpolarization-activated cation currents. To test the hypothesis that intrinsic cellular properties account for the scale gradient as well as the different oscillatory frequencies observed along the dorsal-to-ventral axis, we have modeled and analyzed data from a population of grid cells simulated with spiking neurons interacting through low-dimensional attractor dynamics. To investigate the causal relationship between oscillatory frequencies and grid scale increase, we analyzed the dominant frequencies of the membrane potential for cells with distinct after-spike dynamics. We observed that intrinsic neuronal membrane properties of simulated cells could induce an increase of grid scale when modulated by after-spike reset values. Differences in the membrane potential oscillatory frequency were observed along the simulated dorsal-to-ventral axis, suggesting that, rather than driving to the increase of grid scale as proposed by interference models of grid cells, they are the result of intrinsic cellular properties of neurons at each axis level. Overall, our results suggest that the after-spike dynamics of cation currents may play a major role in determining the grid cells’ scale and that oscillatory frequencies are a consequence of intrinsic cellular properties that are specific to different levels of the dorsal-to-ventral axis in the MEC layer II.
Potential link between selection for high GC content and repair of double strand breaks in prokaryotic genomes
Authors: Weissman Jake L. , Fagan William F. , Johnson Philip L.F.
Published: February 2019

Genomic GC content varies widely among microbes for reasons unknown. While mutation bias partially explains this variation, prokaryotes near-universally have a higher GC content than predicted solely by this bias. Debate surrounds the relative importance of the remaining explanations of selection versus biased gene conversion favoring GC alleles. Some environments (e.g. soils) are associated with a high genomic GC content of their inhabitants, which implies that this content may be a selective adaptation to particular habitats. Here, we report a novel association between the presence of the non-homologous end joining DNA doublestrand break repair pathway and GC content; this observation suggests that high GC content may be an adaptation to facilitate repair of double strand breaks when homologous recombination is not possible. We discuss potential mechanisms accounting for the observed association, and provide preliminary evidence that sites experiencing higher rates of doublestrand breaks are under selection for increased GC content relative to the genomic background.