bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative genomic analysis of three salmonid species identifies functional candidate genes involved in resistance to the intracellular bacteriaPiscirickettsia salmonis
Authors: Yáñez José M. , Yoshida Grazyella M. , Parra Ángel , Correa Katharina , Barría Agustín , Bassini Liane N. , Christensen Kris A. , López Maria E. , Carvalheiro Roberto , Lhorente Jean P. , Pulgar Rodrigo
Published: March 2019

Piscirickettsia salmonisis the etiological agent of Salmon Rickettsial Syndrome (SRS), and is responsible for considerable economic losses in salmon aquaculture. The bacteria affect coho salmon (CS) (Oncorhynchus kisutch), Atlantic salmon (AS) (Salmo salar) and rainbow trout (RT) (Oncorhynchus mykiss) in several countries, including: Norway, Canada, Scotland, Ireland and Chile. We used Bayesian genome-wide association (GWAS) analyses to investigate the genetic architecture of resistance toP. salmonisin farmed populations of these species. Resistance to SRS was defined as the number of days to death (DD) and as binary survival (BS). A total of 828 CS, 2,130 RT and 2,601 AS individuals were phenotyped and then genotyped using ddRAD sequencing, 57K SNP Affymetrix® Axiom® and 50K Affymetrix® Axiom® SNP panels, respectively. Both trait of SRS resistance in CS and RT, appeared to be under oligogenic control. In AS there was evidence of polygenic control of SRS resistance. To identify candidate genes associated with resistance, we applied a comparative genomics approach in which we systematically explored the complete set of genes adjacent to SNPs which explained more than 1% of the genetic variance of resistance in each salmonid species (533 genes in total). Thus, genes were classified based on the following criteria: i) shared function of their protein domains among species, ii) shared orthology among species, iii) proximity to the SNP explaining the highest proportion of the genetic variance and, iv) presence in more than one genomic region explaining more than 1% of the genetic variance within species. Our results allowed us to identify 120 candidate genes belonging to at least one of the four criteria described above. Of these, 21 of them were part of at least two of the criteria defined above and are suggested to be strong functional candidates influencingP. salmonisresistance. These genes are related to diverse biological processes, such as: kinase activity, GTP hydrolysis, helicase activity, lipid metabolism, cytoskeletal dynamics, inflammation and innate immune response, which seem essential in the host response againstP. salmonisinfection. These results provide fundamental knowledge on the potential functional genes underpinning resistance againstP. salmonisin three salmonid species.
Consequences of consumer origin and omnivory on stability in experimental food web modules
Authors: Granados Monica , Pagnucco Katie S. , Ricciardi Anthony
Published: March 2019

Food web stability, a fundamental characteristic of ecosystems, is influenced by the nature and strength of species interactions. Theory posits that food webs are stabilized by omnivory and disrupted by novel consumers.

To test the effects of secondary consumer origin and trophic level on basal resource stability, we constructed crayfish-snail-algae modules using four congeneric species of crayfish (Faxonius spp.), two from native populations (F. propinquus and F. virilis) and two from non-native populations (F. limosus and F. rusticus). We performed surgical manipulations of crayfish feeding structures to create omnivore food web and predator food chain modules. We compared the temporal stability of these modules using measures of the coefficient of variation of the basal resource (benthic algae).

Consistent with theoretical and empirical predictions, food web modules with omnivory had the lowest coefficient of variation. However, contrary to prediction, we did not find consistently higher coefficients of variation in modules with non-native species. Rather, across species, we found the lowest coefficient of variation in modules with one of the non-native species (F. rusticus) and one native species (F. virilis), owing to stronger interactions between these crayfish species and their snail and algal food resources.

The results suggest that omnivory is indeed stabilizing and that very weak interactions or very low attack rates of the consumer on the basal resource can be unstable. Thus, we demonstrate that omnivores may have different impacts than predators when introduced into a novel ecosystem, differences that can supersede the effect of species identity.
Genetic evaluation modeling of the Tunisian dairy cattle: assessment of the test-day model (TDM) and lactation model (L305) in accordance to the flock size
Authors: Ressaissi Yosra , Ben Hmouda Mohamed
Published: March 2019

Genetic evaluation in dairy cattle has been commonly carried following the lactation model (L305) and the test-day model (TDM), the purpose of this study was to test the adjustment and the accuracy of these main models in relation to the size of the Tunisian dairy flocks while assessing the effect of genealogical data availability on both approaches. Data were obtained from the Tunisian official milk recording system and cows were classified in accordance to the flock sizes into eight groups. Genetic parameters and breeding values were estimated per size group for 305-days (L305) and daily milk yields (TDM) through two animal models and by using 3 pedigrees of different quality. Contemporary groups were defined as herd*calving year for L305 and as herd*control year for TDM. Genetic evaluation approaches were compared by connecting the different obtained results. Fixed factors were observed to be differently significant per group of flock size explaining a specific variance of the average milk yield and that small flocks are mostly affected by environmental factors. Using TDM and an equilibrated pedigree file, genetic parameters were higher, breeding values were fairly compared leading to a more objective ranking of the cows and a better illustration of genetic variabilities between the flock groups. Low genetic variability and significant contribution of unfavorable environmental conditions were observed within the Tunisian dairy flocks.
Single-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids
Authors: Smits Lisa M. , Magni Stefano , Grzyb Kamil , Antony Paul MA. , Krüger Rejko , Skupin Alexander , Bolognin Silvia , Schwamborn Jens C.
Published: March 2019

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulatein vitrothe organisation and function of a respective organ or part of an organ. Human midbrain organoids (hMOs) have been described to contain midbrain-specific dopaminergic neurons that release the neurotransmitter dopamine. However, the human midbrain contains also additional neuronal cell types, which are functionally interacting with each other. Here, we analysed hMOs at high-resolution by means of single-cell RNA-sequencing (scRNA-seq), imaging and electrophysiology to unravel cell heterogeneity. Our findings demonstrate that hMOs show essential neuronal functional properties as spontaneous electrophysiological activity of different neuronal subtypes, including dopaminergic, GABAergic, and glutamatergic neurons. Recapitulating thesein vivofeatures makes hMOs an excellent tool forin vitrodisease phenotyping and drug discovery.
Shared genetic background between children and adults with attention deficit/hyperactivity disorder
Authors: Rovira Paula , Demontis Ditte , Sánchez-Mora Cristina , Zayats Tetyana , Klein Marieke , Mota Nina Roth , Weber Heike , Garcia-Martínez Iris , Pagerols Mireia , Vilar Laura , Arribas Lorena , Richarte Vanesa , Corrales Montserrat , Fadeuilhe Christian , Bosch Rosa , Español Martin Gemma , Almos Peter , Doyle Alysa E. , Grevet Eugenio Horacio , Grimm Oliver , Halmøy Anne , Hoogman Martine , Hutz Mara , Jacob Christian P. , Kittel-Schneider Sarah , Knappskog Per M. , Lundervold Astri J. , Rivero Olga , Rovaris Diego Luiz , Salatino-Oliveira Angelica , da Silva Bruna Santos , Svirin Evgenij , Sprooten Emma , Strekalova Tatyana ,   ADHD Working Group of the Psychiatric Genomics Consortium,   23andMe Research team, Arias-Vasquez Alejandro , Sonuga-Barke Edmund J.S. , Asherson Philip , Dotto Bau Claiton Henrique , Buitelaar Jan K. , Cormand Bru , Faraone Stephen V. , Haavik Jan , Johansson Stefan E. , Kuntsi Jonna , Larsson Henrik , Lesch Klaus-Peter , Reif Andreas , Rohde Luis Augusto , Casas Miquel , Børglum Anders D. , Franke Barbara , Ramos-Quiroga Josep Antoni , Artigas María Soler , Ribasés Marta
Published: March 2019

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.
Cell Specific Reactivation of Epicardium at the Origin of Fibro-Fatty Remodeling of the Atrial Myocardium
Authors: Suffee Nadine , Moore-Morris Thomas , Mougenot Nathalie , Dilanian Gilles , Berthet Myriam , Jagla Bernd , Proukhnitzky Julie , Prince Pascal Le , Tregouet David A , Pucéat Michel , Hatem Stéphane N
Published: March 2019

Abstract

Epicardium, the mesothelium covering the heart, is composed of multipotent cells and is reactivated following myocardial injury in adults. Herein, we provide evidence for activation of atrial epicardium in aged patients with diseased atria and in murine models of atrial remodeling. Epicardial activation contributed to fibro-fatty infiltration of sub-epicardium that contained a number of cells co-expressing markers of epicardial progenitors and fibroblasts. Indeed, using genetic lineage tracing of adult epicardium, we demonstrate the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of adult epicardial-derived cells (aEPDCs) expressing PDGFRα, niched in the sub-epicardium, were isolated and differentiated into myofibroblast in the presence of angiotensin-II. Furthermore, single cell RNA-seq analysis identified several clusters of aEPDCs and revealed transition from adipogenic to fibrogenic cells. In conclusion, a subset of aEPDCs, pre-programmed towards a specific cell fate, contributes to fibro-fatty infiltration of sub-epicardium of diseased atria.
VIVA (VIsualization of VAriants): A VCF file visualization tool
Authors: Tollefson George A. , Schuster Jessica , Gelin Fernando , Ragavendran Ashok , Restrepo Isabel , Stey Paul , Padbury James , Uzun Alper
Published: March 2019

The volume and pace of data accumulation from high-throughput sequencing studies have been amplified by recent rapid technological advances in biological sciences. Visualization of genomic data is essential for quality control, exploration, and interpretation. Here, we describe a user-friendly visualization tool for variant call format (VCF) files with which the users can interactively evaluate and share genomic data, as well as create publication quality graphics.
Heterogeneous profiles of coupled sleep oscillations in human hippocampus
Authors: Cox Roy , Rüber Theodor , Staresina Bernhard P , Fell Juergen
Published: March 2019

Cross-frequency coupling of sleep oscillations is thought to mediate memory consolidation. While the hippocampus is deemed central to this process, detailed knowledge of which oscillatory rhythms interact in the sleeping human hippocampus is lacking. Combining intracranial hippocampal and non-invasive electroencephalography from twelve neurosurgical patients, we characterized spectral power and coupling during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Hippocampal coupling was extensive, with the majority of channels expressing spectral interactions. NREM consistently showed delta–ripple coupling, but ripples were also modulated by slow oscillations (SOs) and sleep spindles. SO–delta and SO–theta coupling, as well as interactions between delta/theta and spindle/beta frequencies also occurred. During REM, limited interactions between delta/theta and beta frequencies emerged. Moreover, oscillatory organization differed substantially between i) hippocampus and scalp, ii) sites along the anterior-posterior hippocampal axis, and iii) individuals. Overall, these results extend and refine our understanding of hippocampal sleep oscillations.
Properties of individual hippocampal synapses influencing NMDA-receptor activation by spontaneous neurotransmission
Authors: Metzbower Sarah R. , Joo Yuyoung , Benavides David R. , Blanpied Thomas A.
Published: March 2019

NMDA receptor (NMDAR) activation is critical for maintenance and modification of synapse strength. Specifically, NMDAR activation by spontaneous glutamate release has been shown to mediate forms of synaptic plasticity as well as synaptic development. Interestingly, there is evidence that within individual synapses each release mode may be segregated such that postsynaptically there are distinct pools of responsive receptors. In order to examine potential regulators of NMDAR activation due to spontaneous glutamate release in cultured rat hippocampal neurons, we utilized GCaMP6f imaging at single synapses in concert with confocal and super-resolution imaging. Using these single spine approaches, we found that Ca2+entry activated by spontaneous release tends to be carried by GluN2B-NMDARs. Additionally, the amount of NMDAR activation varies greatly both between synapses and within synapses, and is unrelated to spine and synapse size, but does correlate loosely with synapse distance from the soma. Despite the critical role of spontaneous activation of NMDARs in maintaining synaptic function, their activation seems to be controlled factors other than synapse size or synapse distance from the soma. It is most likely that NMDAR activation by spontaneous release influenced variability in subsynaptic receptor position, release site position, vesicle content, and channel properties. Therefore, spontaneous activation of NMDARs appears to be regulated distinctly from other receptor types, notably AMPARs, within individual synapses.

Significance Statement

Understanding the underlying synaptic mechanisms for learning and memory is critically important to the field of neuroscience and for human health. A key neurotransmitter receptor type involved in learning is the NMDA receptor, and exploration of its regulation is vital. In this study, we optimized optical tools to allow detailed characterization of NMDA receptor activity at single synapses, along with analysis of structural features of the imaged synapses. The amount of receptor activation is independent of the size of the synapse, but weakly dependent on synapse position within the dendritic tree. Notably, we found that NMDA receptors activated following spontaneous neurotransmitter release tend be GluN2B-containing receptors. Thus, the unique mechanisms that regulate the number and positioning of these receptors within synapses will have important consequences for control of synaptic development and signaling.
Contribution of self- and other-regarding motives to (dis)honesty
Authors: Shuster Anastasia , Levy Dino J
Published: March 2019

Why would people tell the truth when there is an obvious gain in lying and no risk of being caught? Previous work suggests the involvement of two motives, self-interest and regard for others. However, it remains unknown if these motives are related or independently contribute to (dis)honesty, and what are the neural instantiations of these motives. Using a modified Message Game task, in which a Sender sends a dishonest (yet profitable) or honest (less profitable) message to a Receiver, we found that these two motives contributed to dishonesty independently. Furthermore, the two motives involve distinct brain networks: the LPFC tracked potential value to self, whereas the rTPJ tracked potential losses to other, and individual differences in motives modulated these neural responses. Finally, activity in the vmPFC represented a balance of the two motives unique to each participant. Taken together, our results suggest that (dis)honest decisions incorporate at least two separate cognitive and neural processes – valuation of potential profits to self and valuation of potential harm to others.
Decorating Microbially Produced Protein Nanowires with Peptide Ligands
Authors: Ueki Toshiyuki , Walker David J.F. , Tremblay Pier-Luc , Nevin Kelly P. , Ward Joy E. , Woodard Trevor L. , Nonnenmann Stephen S. , Lovley Derek R.
Published: March 2019

The potential applications of electrically conductive protein nanowires (e-PNs) harvested fromGeobacter sulfurreducensmight be greatly expanded if the outer surface of the wires could be modified to confer novel sensing capabilities or to enhance binding to other materials. We developed a simple strategy for functionalizing e-PNs with surface-exposed peptide ligands. TheG. sulfurreducensgene for the monomer that assembles into e-PNs was modified to add known peptide ligands at the carboxyl terminus of the monomer. Strains ofG. sulfurreducenswere constructed that fabricated synthetic e-PNs with a six-histidine ‘His-tag’ or both the His-tag and a nine-peptide ‘HA-tag’ exposed on the outer surface. Addition of the peptide ligands did not diminish e-PN conductivity. The abundance of HA-tag in e-PNs was controlled by placing expression of the gene for the synthetic monomer with the HA-tag under transcriptional regulation. These studies suggest broad possibilities for tailoring e-PN properties for diverse applications.
Predicting primary production in the southern California Current Ecosystem from chlorophyll, nutrient concentrations, and irradiance
Authors: Stukel Michael R. , Goericke Ralf , Landry Michael R.
Published: March 2019

We investigated the processes driving variability in primary productivity in the California Current Ecosystem (CCE) in order to develop an algorithm for predicting primary productivity from in situ irradiance, nutrient, and chlorophyll (chl) measurements. Primary productivity data from seven process cruises of the CCE Long-Term Ecological Research (CCE LTER) program were used to parameterize the algorithm. An initial algorithm was developed using only irradiance to predict chl-specific productivity was found to have model-data misfit that was correlated with NH4+ concentrations. We thus found that the best estimates of primary productivity were obtained using an equation including NH4+ and irradiance: PP/Chl = V0m×(1-exp(−α×PAR/V0m)×NH4/(NH4+KS), where PP/Chl is chlorophyll-specific primary production in units of mg C d−1 / mg Chl, PAR is photosynthetically active radiation (units of μEi m−2 s−1), NH4+ is in units of μmol L−1, V0m = 66.5 mg C d−1 / mg Chl, α = 1.5, and KS = 0.025 μmol L−1. We then used this algorithm to compute primary productivity rates for the CCE-P1706 cruise on which in situ primary productivity samples were not available. We compared these estimates to independent productivity estimates derived from protistan grazing dilution experiments and found excellent agreement.
Statistical Analysis of Variability in TnSeq Data Across Conditions Using Zero-Inflated Negative Binomial Regression
Authors: Subramaniyam Siddharth , Zaveri Anisha , DeJesus Michael A. , Smith Clare , Baker Richard E. , Ehrt Sabine , Schnappinger Dirk , Sassetti Christopher M. , Ioerger Thomas R.
Published: March 2019

Deep sequencing of transposon mutant libraries (or TnSeq) is a powerful method for probing essentiality of genomic loci under different environmental conditions. Various analytical methods have been described for identifying conditionally essential genes whose tolerance for insertions varies between two conditions. However, for large-scale experiments involving many conditions, a method is needed for identifying genes that exhibit significant variability in insertions across multiple conditions. In this paper, we introduce a novel statistical method for identifying genes with significant variability of insertion counts across multiple conditions based on Zero-Inflated Negative Binomial (ZINB) regression. Using likelihood ratio tests, we show that the ZINB fits TnSeq data better than either ANOVA or a Negative Binomial (in a generalized linear model). We use ZINB regression to identify genes required for infection ofM. tuberculosisH37Rv in C57BL/6 mice. We also use ZINB to perform a retrospective analysis of genes conditionally essential in H37Rv cultures exposed to multiple antibiotics. Our results show that, not only does ZINB generally identify most of the genes found by pairwise resampling (and vastly out-performs ANOVA), but it also identifies additional genes where variability is detectable only when the magnitudes of insertion counts are treated separately from local differences in saturation, as in the ZINB model.
Phase space characterization for gene circuit design
Authors: Muñoz Silva Macarena A. , Matute Tamara , Nuñez Isaac , Valdes Ambrosio , Ruiz Carlos A. , Vidal Peña Gonzalo A. , Federici Fernán , Rudge Timothy J.
Published: March 2019

Genetic circuit design requires characterization of the dynamics of synthetic gene expression. This is a difficult problem since gene expression varies in complex ways over time and across different contexts. Here we present a novel method for characterizing the dynamics of gene expression with a few parameters that account for changes in cellular context (host cell physiology) and compositional context (adjacent genes). The dynamics of gene circuits were characterized by a trajectory through a multi-dimensional phase space parameterized by the expression levels of each of their constituent transcriptional units (TU). These trajectories followed piecewise linear dynamics, with each dynamical regime corresponding to different growth regimes, or cellular contexts. Thus relative expression rates were changed by transitions between growth regimes, but were constant in each regime. We present a plausible two-factor mathematical model for this behavior based on resource consumption. By analyzing different combinations of TUs, we then showed that relative expression rates were significantly affected by the neighboring TU (compositional context), but maintained piecewise linear dynamics across cellular and compositional contexts. Taken together these results show that TU expression dynamics could be predicted by a reference TU up to a context dependent scaling factor. This model provides a framework for design of genetic circuits composed of TUs. A common sharable reference TU may be chosen and measured in the cellular contexts of interest. The output of each TU in the circuit may then be predicted from a simple function of the output of the reference TU in the given cellular context. This will aid in genetic circuit design by providing simple models for the dynamics of gene circuits and their constituent TUs.
A sound-sensitive source of alpha oscillations in human non-primary auditory cortex
Authors: Billig Alexander J. , Herrmann Björn , Rhone Ariane E. , Gander Phillip E. , Nourski Kirill V. , Snoad Beau F. , Kovach Christopher K. , Kawasaki Hiroto , Howard Matthew A. , Johnsrude Ingrid S.
Published: March 2019

The functional organization of human auditory cortex can be probed by characterizing responses to various classes of sound at different anatomical locations. Along with histological studies this approach has revealed a primary field in posteromedial Heschl’s gyrus (HG) with pronounced induced high-frequency (70-150 Hz) activity and short-latency responses that phase-lock to rapid transient sounds. Low-frequency neural oscillations are also relevant to stimulus processing and information flow, however their distribution within auditory cortex has not been established. Alpha activity (7-14 Hz) in particular has been associated with processes that may differentially engage earlier versus later levels of the cortical hierarchy, including functional inhibition and the communication of sensory predictions. These theories derive largely from the study of occipitoparietal sources readily detectable in scalp electroencephalography. To characterize the anatomical basis and functional significance of less accessible temporal-lobe alpha activity we analyzed responses to sentences in seven human adults (four female) with epilepsy who had been implanted with electrodes in superior temporal cortex. In contrast to primary cortex in posteromedial HG, a non-primary field in anterolateral HG was characterized by high spontaneous alpha activity that was strongly suppressed during auditory stimulation. Alpha-power suppression decreased with distance from anterolateral HG throughout superior temporal cortex, and was more pronounced for clear compared to degraded speech. This suppression could not be accounted for solely by a change in the slope of the power spectrum. The differential manifestation and stimulus-sensitivity of alpha oscillations across auditory fields should be accounted for in theories of their generation and function.

Significance Statement

To understand how auditory cortex is organized in support of perception, we recorded from patients implanted with electrodes for clinical reasons. This allowed measurement of activity in brain regions at different levels of sensory processing. Oscillations in the alpha range (7-14 Hz) have been associated with functions including sensory prediction and inhibition of regions handling irrelevant information, but their distribution within auditory cortex is not known. A key finding was that these oscillations dominated in one particular non-primary field, anterolateral Heschl’s gyrus, and were suppressed when subjects listened to sentences. These results build on our knowledge of the functional organization of auditory cortex and provide anatomical constraints on theories of the generation and function of alpha oscillations.
Mechanisms of Economic Decisions under Sequential Offers
Authors: Ballesta Sébastien , Padoa-Schioppa Camillo
Published: March 2019

Binary choices between goods are thought to take place in orbitofrontal cortex (OFC). However, current notions emerged mostly from studies where two offers were presented simultaneously, and other work suggested that choices under sequential offers rely on fundamentally different mechanisms. Here we recorded from the OFC of macaques choosing between two juices offered sequentially. Analyzing neuronal responses across time windows, we discovered different groups of neurons that closely resemble those identified under simultaneous offers, suggesting that decisions in the two modalities are formed in the same neural circuit. Building on this result, we examined four hypotheses on the decision mechanisms. OFC neurons encoded goods and values in a juice-based representation (labeled lines). Contrary to previous assessments, decisions did not involve mutual inhibition between pools of offer value cells. Instead, decisions involved mechanisms of circuit inhibition, whereby each offer value indirectly inhibits neurons encoding the opposite choice outcome. These results reconcile disparate findings and provide a unitary account for the neuronal mechanisms underlying economic decisions.
Structure of a Tc holotoxin pore provides insights into the translocation mechanism
Authors: Roderer Daniel , Hofnagel Oliver , Benz Roland , Raunser Stefan
Published: March 2019

Tc toxins are modular toxin systems that are composed of a pentameric membrane translocator (TcA) and a cocoon (TcB and TcC) encapsulating the toxic enzyme. Binding of Tcs to target cells and a pH shift trigger the conformational transition from the soluble prepore state to the membrane-embedded pore. Subsequently, the toxic enzyme is translocated and released into the cytoplasm. Here, we show in atomic detail an assembled Tc toxin complex fromP. luminescensin the membrane. We find that the five TcA protomers conformationally adapt to fit around the cocoon during prepore-to-pore transition. The architecture of the Tc toxin complex also allows TcB-TcC to bind to an already membrane-embedded TcA pore to form a holotoxin. Mammalian lipids with zwitterionic head groups are preferred over other lipids for Tc toxin integration. The translocated toxic enzyme, which can be partially visualized, transiently interacts with alternating negative charges and hydrophobic stretches.
Deep convolutional neural networks for predicting the quality of single protein structural models
Authors: Hou Jie , Cao Renzhi , Cheng Jianlin
Published: March 2019

Predicting the global quality and local (residual-specific) quality of a single protein structural model is important for protein structure prediction and application. In this work, we developed a deep one-dimensional convolutional neural network (1DCNN) that predicts the absolute local quality of a single protein model as well as two 1DCNNs to predict both local and global quality simultaneously through a novel multi-task learning framework. The networks accept sequential and structural features (i.e. amino acid sequence, agreement of secondary structure and solvent accessibilities, residual disorder properties and Rosetta energies) of a protein model of any size as input to predict its quality, which is different from existing methods using a fixed number of hand-crafted features as input. Our three methods (InteractQA-net, JointQA-net and LocalQA-net) were trained on the structural models of the single-domain protein targets of CASP8, 9, 10 and evaluated on the models of CASP11 and CASP12 targets. The results show that the performance of our deep learning methods is comparable to the state-of-the-art quality assessment methods. Our study also demonstrates that combining local and global quality predictions together improves the global quality prediction accuracy. The source code and executable of our methods are available at:https://github.com/multicom-toolbox/DeepCovQA
Gene content of the fish-hunting cone snail Conus consors
Authors: Andreson Reidar , Roosaare Märt , Kaplinski Lauris , Laht Silja , Kõressaar Triinu , Lepamets Maarja , Brauer Age , Kukuškina Viktorija , Remm Maido
Published: March 2019

Background

Conus consors is a fish-hunting cone snail that lives in the tropical waters of the Indo-Pacific region. Cone snails have attracted scientific interest for the amazing potency of their venom, which consists of a complex mixture of small proteins known as conopeptides, many of which act as ion channel and receptor modulators with high selectivity.

Results

We have analysed publicly available transcriptomic sequences from 8 tissues of Conus consors and complemented the transcriptome data with the data from genomic DNA reads. We identified 17,715 full-length protein sequences from the transcriptome. In addition, we predicted 168 full-length or partial conopeptide sequences and characterized gene structures of several conopeptide superfamilies.
Replicated anthropogenic hybridisations reveal parallel patterns of admixture in marine mussels
Authors: Simon Alexis , Arbiol Christine , Nielsen Einar Eg , Couteau Jérôme , Sussarellu Rossana , Burgeot Thierry , Bernard Ismaël , Coolen Joop W.P. , Lamy Jean-Baptiste , Robert Stéphane , Skazina Maria , Strelkov Petr , Queiroga Henrique , Cancio Ibon , Welch John J. , Viard Frédérique , Bierne Nicolas
Published: March 2019

Human-mediated transport creates secondary contacts between genetically differentiated lineages, bringing new opportunities for gene exchange. When similar introductions occur in different places, they provide informally replicated experiments for studying hybridisation. We here examined 4279Mytilusmussels, sampled in Europe and genotyped with 77 ancestry informative markers. We identified a type of introduced mussels, called ‘dock mussels’, associated with port habitats and displaying a particular genetic signal of admixture betweenM. edulisand the Mediterranean lineage ofM. galloprovincialis. These mussels exhibit similarities in their ancestry compositions, regardless of the local native genetic backgrounds and the distance separating colonised ports. We observed fine-scale genetic shifts at the port entrance, at scales below natural dispersal distance. Such sharp clines do not fit with migration-selection tension zone models, and instead suggest habitat choice and early stage adaptation to the port environment, possibly coupled with connectivity barriers. Variations in the spread and admixture patterns of dock mussels seem to be influenced by the local native genetic backgrounds encountered. We next examined departures from the average admixture rate at different loci, and compared human-mediated admixture events, to naturally admixed populations and experimental crosses. When the sameM. galloprovincialisbackground was involved, positive correlations in the departures of loci across locations were found; but when different backgrounds were involved, no or negative correlations were observed. While some observed positive correlations might be best explained by a shared history and saltatory colonisation, others are likely produced by parallel selective events. Altogether, genome-wide effect of admixture seems repeatable, and more dependent on genetic background than environmental context. Our results pave the way towards further genomic analyses of admixture, and monitoring of the spread of dock mussels both at large and fine spacial scales.
Cryo-EM of dynein microtubule-binding domains shows how an axonemal dynein distorts the microtubule
Authors: Lacey Samuel E. , He Shaoda , Scheres Sjors H. W. , Carter Andrew P.
Published: March 2019

Dyneins are motor proteins responsible for transport in the cytoplasm and the beating of the axoneme in cilia and flagella. They bind and release microtubules via a compact microtubule-binding domain (MTBD) at the end of a long coiled-coil stalk. Here we address how cytoplasmic and axonemal dynein MTBDs bind microtubules at near atomic resolution. We decorated microtubules with MTBDs of cytoplasmic dynein-1 and axonemal dynein DNAH7 and determined their cryo-EM structures using the stand-alone Relion package. We show the majority of the MTBD is remarkably rigid upon binding, with the transition to the high affinity state controlled by the movement of a single helix at the MTBD interface. In addition DNAH7 contains an 18-residue insertion, found in many axonemal dyneins, that reaches over and contacts the adjacent protofilament. Unexpectedly we observe that DNAH7, but not dynein-1, induces large distortions in the microtubule cross-sectional curvature. This raises the possibility that dynein coordination in axonemes is mediated via conformational changes in the microtubule.
A Synergistic Anti-Cancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High-Content Phenotypic Screen
Authors: Dawson John C. , Serrels Bryan , Byron Adam , Muir Morwenna , Makda Ashraff , García-Muñoz Amaya , von Kriegsheim Alex , Carragher Neil O. , Frame Margaret C.
Published: March 2019

We mutated the Focal Adhesion Kinase (FAK) catalytic domain to inhibit binding of the chaperone, Cdc37 and ATP, mimicking the actions of a FAK kinase inhibitor. We re-expressed mutant and wild-type FAK in squamous cell carcinoma (SCC) cells from which endogenous FAK had been deleted, genetically fixing one axis of a FAK inhibitor combination high-content phenotypic screen to discover drugs that may synergize with FAK inhibitors. HDAC inhibitors represented the major class of compounds that potently induced multi-parametric phenotypic changes when FAK was rendered kinase-defective, or inhibited pharmacologically in SCC cells. Indeed, combined FAK and HDAC inhibitors arrest proliferation and induce apoptosis in a sub-set of cancer cell lines in vitro and efficiently inhibits tumor growth in vivo. Mechanistically, HDAC inhibitors potentiate inhibitor-induced FAK inactivation and reverses FAK-associated nuclear YAP in sensitive cancer cell lines. Here we report the discovery of a new clinically actionable synergistic combination between FAK and HDAC inhibitors.

Significance

We describe a chemical-genetic, high-content phenotypic screening approach to discover effective anti-cancer combinations of targeted therapeutics through which we identified a novel, synergistic and clinically actionable, combination of FAK and HDAC inhibitors.
Feedback control promotes synchronisation of the cell-cycle across a population of yeast cells
Authors: Perrino Giansimone , Fiore Davide , Napolitano Sara , Galdi Francesca , Regina Antonella La , di Bernardo Mario , di Bernardo Diego
Published: March 2019

The periodic process of cell replication by division, known as cell-cycle, is a natural phenomenon occurring asynchronously in any cell population. Here, we consider the problem of synchronising cell-cycles across a population of yeast cells grown in a microfluidics device. Cells were engineered to reset their cell-cycle in response to low methionine levels. Automated syringes enable changing methionine levels (control input) in the microfluidics device. However, the control input resets only those cells that are in a specific phase of the cell-cycle (G1 phase), while the others continue to cycle unperturbed. We devised a simplified dynamical model of the cell-cycle, inferred its parameters from experimental data and then designed two control strategies: (i) an open-loop controller based on the application of periodic stimuli; (ii) a closed-loop model predictive controller (MPC) that selects the sequence of control stimuli which maximises a synchronisation index. Both the proposed control strategies were validated in-silico, together with experimental validation of the open-loop strategy.
Mechanisms of motor-independent membrane remodeling driven by dynamic microtubules
Authors: Rodríguez-García Ruddi , Volkov Vladimir A. , Chen Chiung-Yi , Katrukha Eugene A. , Olieric Natacha , Aher Amol , Grigoriev Ilya , López Magdalena Preciado , Steinmetz Michel O. , Kapitein Lukas C. , Koenderink Gijsje , Dogterom Marileen , Akhmanova Anna
Published: March 2019

Microtubule-dependent organization of membranous organelles, such as the endoplasmic reticulum, occurs through motor-based pulling and by coupling microtubule dynamics to membrane remodeling. How highly transient protein-protein interactions occurring at growing microtubule tips can induce load-bearing processive motion is currently unclear. Here, we reconstituted membrane tubulation in a minimal system with giant unilamellar vesicles, dynamic microtubules, End-Binding (EB) proteins and a membrane-targeted protein that interacts with EBs and microtubules. We showed that these components are sufficient to drive membrane remodeling by three mechanisms: membrane tubulation by growing microtubule ends, motor-independent membrane sliding along microtubule shafts and pulling by shrinking microtubules. Experiments and modeling demonstrated that the first two mechanisms can be explained by adhesion-driven biased membrane spreading on microtubules. Force spectroscopy revealed that attachments to growing and shrinking microtubule ends can sustain forces of ∼0.5 and ∼5 pN, respectively. Rapidly exchanging molecules that connect membranes to dynamic microtubules can thus bear sufficient load to induce membrane deformation and motility.
Specific gut microbiome members are associated with distinct immune markers in allogeneic hematopoietic stem cell transplantation
Authors: Masche Anna Cäcilia , Kielsen Katrine , Cilieborg Malene Skovsted , Lund Ole , Holmes Susan , Aarestrup Frank M. , Müller Klaus Gottlob , Pamp Sünje Johanna
Published: March 2019

Background

Increasing evidence reveals the importance of the microbiome in health and disease and inseparable host-microbial dependencies. Host-microbe interactions are highly relevant in patients receiving allogeneic hematopoietic stem cell transplantation, (HSCT), i.e. a replacement of the cellular components of the patients’ immune system with that of a foreign donor. HSCT is employed as curative immunotherapy for a number of non-malignant and malignant hematologic conditions, including acute lymphoblastic leukemia. The procedure can be accompanied by severe side effects such as infections, acute graft-versus-host disease (aGvHD), and death. Here, we performed a longitudinal analysis of immunological markers, immune reconstitution and gut microbiota composition in relation to clinical outcomes in children undergoing HSCT. Such an analysis could reveal biomarkers, e.g. at the time point prior to HSCT, that in the future could be used to predict which patients are of high risk in relation to side effects and clinical outcomes and guide treatment strategies accordingly.

Results

In two multivariate analyses (sparse partial least squares regression and canonical correspondence analysis), we identified three consistent clusters: (1) High concentrations of the antimicrobial peptide human beta-defensin 2 (hBD2) prior to the transplantation in patients with high abundances ofLactobacillaceae, who later developed moderate or severe aGvHD and exhibited high mortality. (2) Rapid reconstitution of NK and B cells in patients with high abundances of obligate anaerobes such asRuminococcaceae, who developed no or mild aGvHD and exhibited low mortality. (3) High inflammation, indicated by high levels of C-reactive protein, in patients with high abundances of facultative anaerobic bacteria such asEnterobacteriaceae. Furthermore, we observed that antibiotic treatment influenced the bacterial community state.

Conclusions

We identify multivariate associations between specific microbial taxa, host immune markers, immune cell reconstitution and clinical outcomes in relation to HSCT. Our findings encourage further investigations into establishing longitudinal surveillance of the intestinal microbiome and relevant immune markers, such as hBD2, in HSCT patients. Profiling of the microbiome may prove useful as a prognostic tool that could help identify patients at risk of poor immune reconstitution and adverse outcomes, such as aGvHD and death, upon HSCT, providing actionable information in guiding precision medicine.
Metabolite sequestration enables rapid recovery from fatty acid depletion in Escherichia coli
Authors: Hartline Christopher J. , Mannan Ahmad A. , Liu Di , Zhang Fuzhong , Oyarzún Diego A.
Published: March 2019

Microbes adapt their metabolism to take advantage of nutrients in their environment. Such adaptations control specific metabolic pathways to match energetic demands with nutrient availability. Upon depletion of nutrients, rapid pathway recovery is key to release cellular resources required for survival in the new nutritional condition. Yet little is known about the regulatory strategies that microbes employ to accelerate pathway recovery in response to nutrient depletion. Using the fatty acid catabolic pathway in Escherichia coli, here we show that fast recovery can be achieved by rapid release of a transcriptional regulator from a metabolite-sequestered complex. With a combination of mathematical modelling and experiments, we show that recovery dynamics depend critically on the rate of metabolite consumption and the exposure time to nutrient. We constructed strains with re-wired transcriptional regulatory architectures that highlight the metabolic benefits of negative autoregulation over constitutive and positive autoregulation. Our results have wide-ranging implications for our understanding of metabolic adaptations, as well as guiding the design of gene circuitry for synthetic biology and metabolic engineering.
Heroin Type, Injecting Behavior, and HIV Transmission. A Simulation Model of HIV Incidence and Prevalence
Authors: Bobashev Georgiy V. , Mars Sarah , Murphy Nicholas , Dreisbach Clinton , Zule William , Ciccarone Daniel
Published: March 2019

Background and Aims

Using mathematical modeling to illustrate and predict how different heroin source-forms: “black tar” (BTH) and powder heroin (PH) can affect HIV transmission in the context of contrasting injecting practices. By quantifying HIV risk by these two heroin source-types we show how each affects the incidence and prevalence of HIV over time. From 1997 to 2010 PH reaching the United States was manufactured overwhelmingly by Colombian suppliers and distributed in the eastern states of the United States. Recently Mexican cartels that supply the western U.S. states have started to produce PH too, replacing Colombian distribution to the east. This raises the possibility that BTH in the western U.S. may be replaced by PH in the future.

Design

We used an agent-based model to evaluate the impact of use of different heroin formulations in high- and low-risk injecting drug user populations who use different types of syringes (high vs. low dead space) and injecting practices. We obtained model parameters from peer-reviewed publications and ethnographic research.

Results

Heating of BTH, additional syringe rinsing, and subcutaneous injection can substantially decrease the risk of HIV transmission. Simulation analysis shows that HIV transmission risk may be strongly affected by the type of heroin used. We reproduced historic differences in HIV prevalence and incidence. The protective effect of BTH is much stronger in high-risk compared with low-risk populations. Simulation of future outbreaks show that when PH replaces BTH we expect a long-term overall increase in HIV prevalence. In a population of injectors with mixed low- and high-risk clusters we find that local HIV outbreaks can occur even when the overall prevalence and incidence are low. The results are dependent on evidence-supported assumptions.

Conclusions

The results support harm-reduction measures focused on a reduction in syringe sharing and promoting protective measures of syringe rinsing and drug solution heating.