bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling Functional Genetic Alteration in Cancer Reveals New Candidate Driver Genes
Authors: Brandes Nadav , Linial Nathan , Linial Michal 
Published: January 2018

AbstractCompiling the catalogue of genes actively involved in tumorigenesis (known as cancer drivers) is an ongoing endeavor, with profound implications to the understanding of tumorigenesis and treatment of the disease. An abundance of computational methods have been developed to screening the genome for candidate driver genes based on genomic data of somatic mutations in tumors. Most methods rely on detecting genes displaying excessive mutation rates compared to some background model. This approach is susceptible to false discoveries, due to its sensitivity to the assumptions of the background model, such as the need to account for hyper-mutated samples, cancer types and genomic loci. We present a fundamentally different approach. Instead of focusing on the number of mutations, we examine their content, and their expected effects on the functions of genes. We use a machine-learning model to predict functional effect scores of somatic mutations. For each gene, we compare the distribution of observed effect scores with the distribution expected at random, and report genes showing significant bias. By applying our framework on the ~20k protein-coding human genes, we detected 593 genes showing significant bias towards harmful mutations in the context of cancer. In contrast, we found only 6 significant genes biased in the opposite direction. The list of 593 genes, constructed without any prior knowledge of their role in cancer, shows an overwhelming overlap with known cancer driver genes, but also highlights many overlooked genes. These overlooked genes are promising candidates for novel cancer drivers. Our model is generic and is not restricted to the context of cancer. Applying the same framework to data of human-population genetic variation reveals the opposite trend. Unlike cancer, which is dominated by a bias towards harmful mutations, long-term evolution in healthy individuals results a bias towards less harmful mutations. The underlying assumptions of our framework are minimal, making it ideal for analyzing genetic data in search of genes subjected to positive or negative selection. It is fully open sourced and available for installation and use. Our framework presents a substantial development towards the application of state-of-the-art machine-learning algorithms in genetic studies.
Protein-coding variation and introgression of regulatory alleles drive plumage pattern diversity in the rock pigeon
Authors: Vickrey Anna I. , Bruders Rebecca , Kronenberg Zev , Mackey Emma , Bohlender Ryan J. , Maclary Emily T. , Osborne E.J. , Johnson Kevin P. , Huff Chad D. , Yandell Mark , Shapiro Michael D. 
Published: January 2018

ABSTRACTBirds and other vertebrates display stunning variation in pigmentation patterning, yet the genes controlling this diversity remain largely unknown. Rock pigeons (Columba livia) are fundamentally one of four color pattern phenotypes, in decreasing order of melanism: T-check, checker, bar (ancestral), or barless. Using whole-genome scans, we identifiedNDPas a candidate gene for this variation. Allele-specific expression differences inNDPindicatecis-regulatory differences between ancestral and melanistic alleles. Sequence comparisons suggest that derived alleles originated in the speckled pigeon (Columba guinea), providing a striking example of introgression of alleles that are favored by breeders and are potentially advantageous in the wild. In contrast, barless rock pigeons have an increased incidence of vision defects and, like two human families with hereditary blindness, carry start-codon mutations inNDP. In summary, we find unexpected links between color pattern, introgression, and vision defects associated with regulatory and coding variation at a single locus.
The Homeostatic Logic of Reward
Authors: Morville Tobias , Friston Karl , Burdakov Denis , Siebner Hartwig R. , Hulme Oliver J. 
Published: January 2018

AbstractEnergy homeostasis depends on behavior to predictively regulate metabolic states within narrow bounds. Here we review three theories of homeostatic control and ask how they provide insight into the circuitry underlying energy homeostasis. We offer two contributions. First, we detail how control theory and reinforcement learning are applied to homeostatic control. We show how these schemes rest on implausible assumptions; either via circular definitions, unprincipled drive functions, or by ignoring environmental volatility. We argue active inference can elude these shortcomings while retaining important features of each model. Second, we review the neural basis of energetic control. We focus on a subset of arcuate subpopulations that project directly to, and are thus in a privileged position to opponently modulate, dopaminergic cells as a function of energetic predictions over a spectrum of time horizons. We discuss how this can be interpreted under these theories, and how this can resolve paradoxes that have arisen. We propose this circuit constitutes a homeostatic-reward interface that underwrites the conjoint optimisation of physiological and behavioural homeostasis.
Crumble: reference free lossy compression of sequence quality values
Authors: Bonfield James K , McCarthy Shane A , Durbin Richard 
Published: January 2018

AbstractMotivationThe bulk of space taken up by NGS sequencing CRAM files consists of per-base quality values. Most of these are unnecessary for variant calling, offering an opportunity for space saving.ResultsOn the CHM1+CHM13 test set, a 17 fold reduction in quality storage can be achieved while maintaining variant calling accuracy.AvailabilityCrumble is OpenSource and can be obtained from https://github.com/jkbonfield/crumble.Contactjkb@sanger.ac.ukSupplementary informationSupplementary data are available.
An empirical, 21st century evaluation of phrenology
Authors: Jones O. Parker , Alfaro-Almagro F. , Jbabdi S. 
Published: January 2018

AbstractPhrenology was a nineteenth century endeavour to link personality traits with scalp morphology, which has been both influential and fiercely criticised, not least because of the assumption that scalp morphology can be informative of underlying brain function. Here we test the idea empirically rather than dismissing it out of hand. Whereas nineteenth century phrenologists had access to coarse measurement tools (digital technology referring then to fingers), we were able to re-examine phrenology using 21stcentury methods and thousands of subjects drawn from the largest neuroimaging study to date. High-quality structural MRI was used to quantify local scalp curvature. The resulting curvature statistics were compared against lifestyle measures acquired from the same cohort of subjects, being careful to match a subset of lifestyle measures to phrenological ideas of brain organisation, in an effort to evoke the character of Victorian times. The results represent the most rigorous evaluation of phrenological claims to date.
Conditioning nausea in a laboratory setting: A pilot study
Authors: Van Hedger Kathryne , Cavallo Joel S. , Ruiz Nicholas A. , de Wit Harriet 
Published: January 2018

AbstractCancer patients can experience nausea as they approach the place where they have received chemotherapy treatment. This nausea is likely the result of Pavlovian conditioning, where the previously neutral environment acquires conditioned properties, in this case conditioned nausea, because its association with feeling ill. To investigate this phenomenon under controlled conditions, we studied the acquisition of conditioned nausea using a distinct environment paired with an emetic drug in healthy young adults. We measured two indices of conditioning: i) conditioned place aversion, and ii) conditioned drug-like (nausea) responses. Healthy volunteers (N=32) first rated their preference for two testing rooms, and then underwent four conditioning sessions in which they received either syrup of ipecac (5 ml) or placebo. A Paired Group (PG; N=17) always received ipecac in their initially preferred room and placebo in the other, while an Unpaired Group (UG; N=15) received ipecac and placebo in both rooms. Conditioned responses were assessed with i) time spent in each room, ii) room liking and preference, and iii) feelings of nausea in each room. There was no evidence of conditioned place aversion as measured by either time spent or ratings of room liking. However, the PG did report a small increase in nausea in the ipecac-paired room. Although the conditioned responses in this study were not robust, this procedure is a first step towards studying conditioned aversive drug responses in humans, which will enable development of future studies to prevent or treat anticipatory nausea.
GSK3 Controls Migration of the Neural Crest Lineage
Authors: Malagon Sandra G. Gonzalez , Muñoz Anna M. Lopez , Doro Daniel , Bolger Triòna G. , Poon Evon , Tucker Elizabeth R. , Al-Lami Hadeel Adel , Krause Matthias , Phiel Christopher , Chesler Louis , Liu Karen J. 
Published: January 2018

AbstractMigration of the neural crest lineage is critical to its physiological function. Mechanisms controlling neural crest migration are comparatively unknown, due to difficulties accessing this cell populationin vivo. Here, we uncover novel requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in neural crest cells and that this activation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with pathologically increased ALK activity express high levels of pY-GSK3 and migration of these cells can be inhibited by GSK3 or ALK blockade. In normal neural crest cells, loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK-3 results in failure of migration. All together, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.
Methionine metabolism influences the genomic architecture of H3K4me3 with the link to gene expression encoded in peak width
Authors: Dai Ziwei , Mentch Samantha J. , Gao Xia , Nichenametla Sailendra N. , Locasale Jason W. 
Published: January 2018

AbstractNutrition and metabolism are known to influence chromatin biology and epigenetics by modifying the levels of post-translational modifications on histones, yet how changes in nutrient availability influence specific aspects of genomic architecture and connect to gene expression is unknown. To investigate this question we considered, as a model, the metabolically-driven dynamics of H3K4me3, a histone methylation mark that is known to encode information about active transcription, cell identity, and tumor suppression. We analyzed the genome-wide changes in H3K4me3 and gene expression in response to alterations in methionine availability under conditions that are known to affect the global levels of histone methylation in both normal rodent physiology and in human cancer cells. Surprisingly, we found that the location of H3K4me3 peaks at specific genomic loci was largely preserved under conditions of methionine restriction. However, upon examining different geometrical features of peak shape, it was found that the response of H3K4me3 peak width encoded almost all aspects of H3K4me3 biology including changes in expression levels, and the presence of cell identity and cancer associated genes. These findings reveal simple yet new and profound principles for how nutrient availability modulates specific aspects of chromatin dynamics to mediate key biological features.
SLO potassium channels antagonize premature decision making in C. elegans
Authors: Aoki Ichiro , Tateyama Michihiro , Shimomura Takushi , lhara Kunio , Kubo Yoshihiro , Nakano Shunji , Mori Ikue 
Published: January 2018

SummaryAnimals have to modify their behavior at the right timing to respond to changes in environments. Yet, the molecular and neural mechanisms regulating the timing of behavioral transition remain largely unknown. Performing forward genetics on a plasticity of thermotaxis behavior in C. elegans, we demonstrated that SLO potassium channels together with a cyclic nucleotide-gated channel CNG-3 determine the timing of the transition of temperature preference after shift of cultivation temperature. We further revealed that SLO and CNG-3 channels regulate the alteration in responsiveness of thermosensory neurons. Our results suggest that the regulation of sensory adaptation is a major determinant of the latency for animals to make decisions in changing behavior.HighlightsSlo-1 and SLO-2 K+ channels decelerated transition of temperature preference in thermotaxis behavior after upshift of cultivation temperatureSLO K+ channels slowed down the adaptation of AFD thermosensory neuron to new cultivation temperatureA cyclic nucleotide-gated channel CNG-3 functioned together with SLO-2Thermotaxis serves as could be a model system for early onset epilepsies
Synaptic transmission may provide an evolutionary benefit to HIV through modulation of latency
Authors: Vargas-Garcia Cesar , Zurakowski Ryan , Singh Abhyudai 
Published: January 2018

AbstractTransmission of HIV is known to occur by two mechanisms in vivo: the free virus pathway, where viral particles bud off an infected cell before attaching to an uninfected cell, and the cell-cell pathway, where infected cells form virological synapses through close contact with an uninfected cell. It has also been shown that HIV replication includes a positive feedback loop controlled by the viral protein Tat, which may act as a stochastic switch in determining whether an infected cell enters latency. In this paper, we introduce a simple mathematical model of HIV replication containing both the free virus and cell-cell pathways. Using this model, we demonstrate that the high multiplicity of infection in cell-cell transmission results in a suppression of latent infection, and that this modulation of latency through balancing the two transmission mechanisms can provide an evolutionary benefit to the virus. This benefit increases with decreasing overall viral fitness, which may provide a within-host evolutionary pressure toward more cell-cell transmission in late-stage HIV infection.
Building online genomics applications using BioPyramid
Authors: Stephenson Liam , Wakeham Yoshua , Seidenman Nick , Choi Jarny 
Published: January 2018

AbstractBioPyramid is a python package, which can serve as a scaffold for building an online genomics application. BioPyramid contains a number of components designed to reduce the time and effort in building such an application from scratch, including gene annotation, dataset models and visualisation tools. The user can rapidly deploy a data portal with the example dataset included, and start customising components as required. BioPyramid is implemented in python and javascript and freely available at http://github.com/jarny/biopyramid.
Characterization of mannitol metabolism genes inSaccharinaexplains its key role in mannitol biosynthesis and evolutionary significance in Laminariales
Authors: Chi Shan , Liu Tao , Liu Cui , Jin Yuemei , Yin Hongxin , Xu Xin , Li Yue 
Published: January 2018

AbstractAs a unique photosynthetic product in brown algae, mannitol exhibits high synthesis and accumulation inSaccharina japonica. Mannitol acts as a carbon-storage compound and is an osmoprotectant, imparting increased tolerance to osmotic stress. However, the underlying biochemical and molecular mechanisms in macroalgae have not been studied. Analysis of genomic and transcriptomic data has shown that mannitol metabolism inS. japonicais a circular pathway composed of four steps. In this study, oneS. japonicamannitol-1-phosphate dehydrogenase (M1PDH2) and two mannitol-1-phosphatase (M1Pase) proteins were recombinantly expressed to analysis enzyme biochemical properties. RNA sequencing and droplet digital polymerase chain reaction were used to analyze the gene expression patterns of mannitol metabolism in different generations, tissues, sexes, and abiotic stresses. Our findings revealed insights into the mannitol synthesis pathways in brown algae. All genes were constitutively expressed in all samples, allowing maintenance of basic mannitol anabolism and dynamic maintenance of the “saccharide pool”in vivoas the main storage and antistress mechanism. Enzyme assays confirmed that the recombinant proteins produced mannitol, with the specific activity of SjaM1Pase1 being 1.8–4831 times that of other algal enzymes. Combined with the transcriptional analysis, SjaM1Pase1 was shown to be the dominant gene of mannitol metabolism. Mannitol metabolism genes in multicellular filamentous (gametophyte) and large parenchyma thallus (sporophyte) generations had different expression levels and responded differently under environmental stresses (hyposaline and hyperthermia) in gametophytes and sporophytes. The considerable variation in enzyme characteristics and expression of mannitol synthesis genes suggest their important ecophysiological significance in the evolution of complex systems (filamentous and thallus) and environmental adaptation of Laminariales.
Coordinated activity of sleep and arousal neurons for stabilizing sleep/wake states in Drosophila
Authors: Ni Jinfei D. , Ogunmowo Tyler H. , Hackbart Hannah , Elsheikh Ahmed , Gurav Adishthi S. , Verdegaal Andrew A. , Montell Craig 
Published: January 2018

SummaryThe output arm of the sleep homeostat in Drosophila is a group of neurons with projections to the dorsal fan-shaped body (dFSB) of the central complex in the brain. However, neurons that regulate the sleep homeostat remain poorly understood. Using neurogenetic approaches combined with ex vivo Ca2+ imaging, we identify two groups of sleep-regulatory neurons that modulate the activity of the sleep homeostat in an opposing fashion. The sleep-promoting neurons activate the sleep homeostat with glutamate, whereas the arousal-promoting neurons down-regulate the sleep homeostat’s output with dopamine. Co-activating these two inputs leads to frequent shifts between sleep and wake states. We also show that dFSB sleep homeostat neurons release the neurotransmitter GABA that inhibits octopaminergic arousal neurons. Taken together, we suggest coordinated neuronal activity of sleep- and arousal-promoting neurons is essential for stabilizing sleep/wake states.HighlightsGlutamate released by AstA neurons activates dFSBAstAR1 sleep-promoting neuronsDopamine down-regulates the activity of dFSBAstAR1 neuronsSimultaneous glutamate and dopamine input causes rapid sleep and awake swingsGABA released by dFSBAstAR1 neurons promotes sleep by inhibiting arousal neurons
Open source tools for temporally controlled rodent behavior suitable for electrophysiology and optogenetic manipulations
Authors: Solari Nicola , Sviatkó Katalin , Laszlovszky Tamás , Hegedüs Panna , Hangya Balázs 
Published: January 2018

AbstractUnderstanding how the brain controls behavior requires observing and manipulating neural activity in awake behaving animals. Neuronal firing is timed at millisecond precision. Therefore, to decipher temporal coding, it is necessary to monitor and control animal behavior at the same level of temporal accuracy. However, it is technically challenging to deliver sensory stimuli and reinforcers as well as to read the behavioral responses they elicit with millisecond precision. Presently available commercial systems often excel in specific aspects of behavior control, but they do not provide a customizable environment allowing flexible experimental design while maintaining high standards for temporal control necessary for interpreting neuronal activity. Moreover, delay measurements of stimulus and reinforcement delivery are largely unavailable. We combined microcontroller-based behavior control with a sound delivery system for playing complex acoustic stimuli, fast solenoid valves for precisely timed reinforcement delivery and a custom-built sound attenuated chamber using high-end industrial insulation materials. Together this setup provides a physical environment to train head-fixed animals, enables calibrated sound stimuli and precisely timed fluid and air puff presentation as reinforcers. We provide latency measurements for stimulus and reinforcement delivery and an algorithm to perform such measurements on other behavior control systems. Combined with electrophysiology and optogenetic manipulations, the millisecond timing accuracy will help interpret temporally precise neural signals and behavioral changes. Additionally, since software and hardware provided here can be readily customized to achieve a large variety of paradigms, these solutions enable an unusually flexible design of rodent behavioral experiments.
Dynamics of ribosomes and release factors during translation termination inE. coli
Authors: Adio Sarah , Sharma Heena , Senyushkina Tamara , Karki Prajwal , Maracci Cristina , Wohlgemuth Ingo , Holtkamp Wolf , Peske Frank , Rodnina Marina V. 
Published: January 2018

AbstractRelease factors RF1 and RF2 promote hydrolysis of peptidyl-tRNA during translation termination. The GTPase RF3 promotes recycling of RF1 and RF2. Using single molecule FRET together with ensemble kinetics, we show that ribosome termination complexes that carry two factors, RF1–RF3 or RF2–RF3, are dynamic and fluctuate between non-rotated and rotated states, while each factor alone has its distinct signature on the ribosome dynamics and conformation. Dissociation of RF1 depends on peptide release and the presence of RF3, whereas RF2 can dissociate spontaneously. RF3 binds in the GTP-bound state and can rapidly dissociate without GTP hydrolysis from termination complex carrying RF1. GTP cleavage helps RF3 release from ribosomes stalled in the rotated state in the absence of RF1. Our data suggest how the stochastic assembly of the ribosome–RF1–RF3–GTP complex, peptide release, and ribosome fluctuations promote termination of protein synthesis and recycling of the release factors.
Theta and gamma oscillations in the rat hippocampus during attentive lever pressing
Authors: Lipponen A , Tanila H , Gurevicius K 
Published: January 2018

AbstractThe hippocampus is known to be pivotal for spatial memory but emerging evidence suggests its contribution to temporal memories as well. However, it is not clear how the hippocampus represents time and how it synchronizes spatial and temporal presentations into a coherent memory. We assessed the specific role of hippocampal theta and gamma oscillations and their interaction in short-term timing of motor reactions. Rats were trained to maintain lever pressing for 2.5 s and then to quickly release the lever and retrieve water reward from a nearby water port guided by a cue light. In essence, this task allows observation of hippocampal rhythms during timed anticipation when no overt movements take place. Then we implanted wire electrodes to five hippocampal layers for recording local field potentials during the task. Consistent with earlier reports, theta showed a declining trend during the lever press. We also found that fast-gamma declined in tandem with theta while slow-gamma showed an opposite trend. Theta-phase to gamma-amplitude cross-frequency coupling measured with modulation index (MI) varied significantly between the three task phases. Interestingly, also changes in MI were opposite for fast- and slow-gamma. The MI was also related to the task performance, so that during omission trials the MI for fast-gamma in CA1 was smaller than during trials with premature lever release. In addition, the MI in dentate hilus was higher during all error trials than during correctly performed trials. Collectively, these data suggest an important role of synchronization of hippocampal theta and gamma rhythms to timing of cued motor reactions.