bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restoration of Kv7 channel mediated inhibition reduces cued-reinstatement of cocaine seeking
Authors: Parrilla-Carrero Jeffrey , Buchta William C. , Goswamee Priyodarshan , Culver Oliver , McKendrick Greer , Harlan Benjamin , Moutal Aubin , Penrod Rachel , Khanna Rajesh , Kalivas Peter , Riegel Arthur C. 
Published: March 2018

AbstractCocaine addicts display increased sensitivity to drug-associated cues, due in part to pathological changes in the prelimbic cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a male rat model of relapse to cocaine-seeking, we sampled over 600 neurons to examine spike frequency adaptation (SFA) and after-hyperpolarizations (AHPs), two systems that attenuate low frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a sub-population of PL-PFC neurons, but only with cocaine did the resulting hyper-excitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 minutes prior to reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Lastly, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Taken together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This sub-population of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues.Significance StatementLong after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced after-hyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC prior to reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability.
The CRF-R1 regulation of VTA-GABAergic plasticity is suppressed by CB1 receptor inhibition following chronic exposure to ethanol
Authors: Harlan Benjamin , Becker Howard , Woodward John , Riegel Arthur 
Published: March 2018

AbstractDopamine neurons in the ventral tegmental area (VTA) influence learned behaviors and neuropsychiatric diseases including addiction. The stress peptide corticotrophin-releasing factor (CRF) contributes to relapse to drug and alcohol seeking following withdrawal, although the cellular actions are poorly understood. In this study, we show that presynaptic CRF type 1 receptors (CRF-R1) potentiate GABA release onto mouse VTA dopamine neurons via a PKC-Ca2+signaling mechanism. In na1ve animals, activation of CRF-R1 by bath application of CRF or ethanol enhanced GABAAinhibitory postsynaptic currents (IPSCs). Following three days of withdrawal from four weekly cycles of chronic intermittent ethanol (CIE) vapor exposure, spontaneous IPSC frequency was enhanced while CRF- and ethanol-potentiation of IPSCs was intact. However, withdrawal for 3 weeks or more was associated with reduced spontaneous IPSC frequency and diminished CRF and ethanol responses. Long-term withdrawal was also accompanied by decreased sensitivity to the CB1 receptor agonist WIN55212 as well as greatly enhanced sensitivity to the CB1 antagonist AM-251. Inclusion of BAPTA in the internal recording solution restored the responsiveness to CRF or ethanol and reduced the potentiating actions of AM251. Together, these data suggest that GABAAinhibition of VTA dopamine neurons is regulated by presynaptic actions of CRF and endocannabinoids and that long-term withdrawal from CIE treatment enhances endocannabinoid mediated inhibition, thereby suppressing CRF facilitation of GABA release. Such findings have implications for understanding the impact of chronic alcohol on stress-related, dopamine-mediated alcohol seeking behaviors.
Neuroticism Impairs the Use of Reward Values for Decision-Making inMajor Depression
Authors: Rupprechter Samuel , Stankevicius Aistis , Huys Quentin , Steele J. Douglas , Seriès Peggy 
Published: March 2018

ABSTRACTDepression is a debilitating condition with a high prevalence, but aetiology and pathophysiology are still unclear. Various reward-learning paradigms have been used to show impairments in depression. Both trait pessimism and neuroticism are associated with depression, but their link with the impairments in reward learning and decision-making have not been investigated. A Pavlovian conditioning task was performed by 32 subjects, 15 with depression. Participants had to estimate the probability of some fractal stimuli to be associated with a binary reward, based on a few observations. They then had to make a choice between one of the observed fractals and another target for which the reward probability was explicitly given. Computational modelling was used to succinctly describe participants’ behaviour. Patients performed worse than controls at the task. Computational modelling revealed that this was caused by behavioural impairments during both learning and decision phases. Neuroticism scores across participants were significantly correlated with participants’ inability to follow their internal value estimations. Our results demonstrate behavioural differences in probabilistic reward learning between depressed patients and healthy controls. Neuroticism was associated with the impaired ability to follow internal reward values and consequently with worse decision-making.
Performance of convolutional neural networks for identification of bacteria in 3D microscopy datasets
Authors: Hay Edouard A , Parthasarathy Raghuveer 
Published: March 2018

AbstractThree-dimensional microscopy is increasingly prevalent in biology due to the development of techniques such as multiphoton, spinning disk confocal, and light sheet fluorescence microscopies. These methods enable unprecedented studies of life at the microscale, but bring with them larger and more complex datasets. New image processing techniques are therefore called for to analyze the resulting images in an accurate and efficient manner. Convolutional neural networks are becoming the standard for classification of objects within images due to their accuracy and generalizability compared to traditional techniques. Their application to data derived from 3D imaging, however, is relatively new and has mostly been in areas of magnetic resonance imaging and computer tomography. It remains unclear, for images of discrete cells in variable backgrounds as are commonly encountered in fluorescence microscopy, whether convolutional neural networks provide sufficient performance to warrant their adoption, especially given the challenges of human comprehension of their classification criteria and their requirements of large training datasets. We therefore applied a 3D convolutional neural network to distinguish bacteria and non-bacterial objects in 3D light sheet fluorescence microscopy images of larval zebrafish intestines. We find that the neural network is as accurate as human experts, outperforms random forest and support vector machine classifiers, and generalizes well to a different bacterial species through the use of transfer learning. We also discuss network design considerations, and describe the dependence of accuracy on dataset size and data augmentation. We provide source code, labeled data, and descriptions of our analysis pipeline to facilitate adoption of convolutional neural network analysis for three-dimensional microscopy data.Author summaryThe abundance of complex, three dimensional image datasets in biology calls for new image processing techniques that are both accurate and fast. Deep learning techniques, in particular convolutional neural networks, have achieved unprecedented accuracies and speeds across a large variety of image classification tasks. However, it is unclear whether or not their use is warranted in noisy, heterogeneous 3D microscopy datasets, especially considering their requirements of large, labeled datasets and their lack of comprehensible features. To asses this, we provide a case study, applying convolutional neural networks as well as feature-based methods to light sheet fluorescence microscopy datasets of bacteria in the intestines of larval zebrafish. We find that the neural network is as accurate as human experts, outperforms the feature-based methods, and generalizes well to a different bacterial species through the use of transfer learning.
New perspectives on multilocus ancestry informativeness
Authors: Tal Omri , Tran Tat Dat 
Published: March 2018

AbstractWe present an axiomatic approach formultilocus informativenessmeasures for determining the amount of information that a set of polymorphic genetic markers provides about individual ancestry. We then reveal several surprising properties of a decision-theoretic based measure that is consistent with the set of proposed criteria formultilocus informativeness. In particular, these properties highlight the interplay between information originating from population priors and the information extractable from the population genetic variants. This analysis then reveals a certain deficiency ofmutual informationbasedmultilocus informativenessmeasures when such population priors are incorporated. Finally, we analyse and quantify the inevitable inherent decrease ininformativenessdue to learning from finite population samples.
Phase-Amplitude Coupling of Neural Oscillations can be Effectively Probed with Concurrent TMS-EEG
Authors: Glim Sarah , Okazaki Yuka O. , Nakagawa Yumi , Mizuno Yuji , Hanakawa Takashi , Kitajo Keiichi 
Published: March 2018

AbstractDespite the widespread use of transcranial magnetic stimulation (TMS), knowledge of its neurophysiological mode of action is still incomplete. Recently, TMS has been proposed to synchronise neural oscillators, and to thereby increase the detectability of corresponding oscillations at the population level. As oscillations in the human brain are known to interact within nested hierarchies via phase-amplitude coupling, TMS might also be able to increase the macroscopic detectability of such coupling. In a concurrent TMS-electroencephalography study, we therefore examined the technique’s influence on theta-gamma, alpha-gamma and beta-gamma phase-amplitude coupling by delivering single-pulse TMS (sTMS) and repetitive TMS (rTMS) over the left motor cortex and right visual cortex of healthy participants. The rTMS pulse trains were of 5 Hz, 11 Hz and 23 Hz for the three coupling variations, respectively. Relative to sham stimulation, all conditions showed transient but significant increases in phase-amplitude coupling at the stimulation site. In addition, we observed enhanced coupling over various other cortical sites, with a more extensive propagation during rTMS than during sTMS. By indicating that scalp-recorded phase-amplitude coupling can be effectively probed with TMS, these findings open the door to the technique’s application in manipulative dissections of such coupling during human cognition and behaviour in healthy and pathological conditions.
Assessment and refinement of sample preparation methods for deep and quantitative plant proteome profiling
Authors: Song Gaoyuan , Yingshan Hsu Polly Y , Walley Justin W. 
Published: March 2018

SummaryA major challenge in the field of proteomics is obtaining high quality peptides for comprehensive proteome profiling by liquid chromatography mass spectrometry for many organisms. Here we evaluate and modify a range of sample preparation methods using photosynthetically active Arabidopsis leaf tissues from several developmental timepoints. We find that inclusion of FASP-based on filter digestion improves all protein extraction methods tested. Ultimately, we show that a detergent-free urea-FASP approach enables deep and robust quantification of leaf proteomes. For example, from 4-day-old leaf tissue we profiled up to 11,690 proteins from a single sample replicate. This method should be broadly applicable to researchers working on difficult to process samples from a range of plant and non-plant organisms.AbbreviationsChloroMethanol/Chloroform ExtractionFASPFilter Aided Sample PrepGOGene OntologyIAAIodoacetamideLFQLabel Free QuantificationMS/MSTandem mass spectrometryTFTranscription FactorUAUrea Extraction1D1 Dimensional2D2 Dimensional
A new function for Prokineticin 2: recruitment of SVZ-derived neuroblasts to the injured cortex in a mouse model of traumatic brain injury
Authors: Mundim Mayara Vieira , Zamproni Laura Nicoleti , Sardinha Pinto Agnes Araújo , Galindo Layla Testa , Xavier André Machado , Glezer Isaias , Porcionatto Marimélia 
Published: March 2018

AbstractTraumatic brain injury is an important cause of mortality and morbidity all over the world. After the initial injury there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim not only to counteract these mechanisms but also to replenish the lost cell population in order to achieve a better recovery. The adult mammal brain in not as plastic as the postnatal, but it has at least two neurogenic regions that maintains physiological functions in the brain; the subgranular zone of the dentate gyrus of the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) of the lateral ventricles, that produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs. Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas. Here we report that SVZ cells migrate to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired. We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis by promoting the directional migration of neuroblasts, is induced in the injured cortex. Using PROK2 receptor antagonist and recombinant PROK2 we show for the first time that PROK2 can directionally attract SVZ cells in vitro and in vivo. The data we present here links one more element of the inflammatory process, PROK2 secreted by microglia, to the attempt to regenerate an acutely injured mammalian cortex.AbbreviationsSGZsubgranular zoneSVZsubventricular zoneRMSrostral migratory streamPROK2Prokineticin 2
Molecular dynamics ensemble refinement of the heterogeneous native state of NCBD using chemical shifts and NOEs
Authors: Papaleo Elena , Camilloni Carlo , Teilum Kaare , Vendruscolo Michele , Lindorff-Larsen Kresten 
Published: March 2018

ABSTRACTMany proteins display complex dynamical properties that are often intimately linked to their biological functions. As the native state of a protein is best described as an ensemble of confor-mations, it is important to be able to generate models of native state ensembles with high accuracy. Due to limitations in sampling efficiency and force field accuracy it is, however, challenging to obtain accurate ensembles of protein conformations by the use of molecular simulations alone. Here we show that dynamic ensemble refinement, which combines an accurate atomistic force field with commonly available nuclear magnetic resonance (NMR) chemical shifts and NOEs, can provide a detailed and accurate description of the conformational ensemble of the native state of a highly dynamic protein. As both NOEs and chemical shifts are averaged on timescales up to milliseconds, the resulting ensembles reflect the structural heterogeneity that goes beyond that probed e.g. by NMR relaxation order parameters. We selected the small protein domain NCBD as object of our study since this protein, which has been characterized experimentally in substantial detail, displays a rich and complex dynamical behaviour. In particular, the protein has been described as having a molten-globule like structure, but with a relatively rigid core. Our approach allowed us to describe the conformational dynamics of NCBD in solution, and to probe the structural heterogeneity resulting from both short- and long-time-scale dynamics by the calculation of order parameters on different time scales. These results illustrate the usefulness of our approach since they show that NCBD is rather rigid on the nanosecond timescale, but interconverts within a broader ensemble on longer timescales, thus enabling the derivation of a coherent set of conclusions from various NMR experiments on this protein, which could otherwise appear in contradiction with each other.
Dietary lipids modulate Notch signaling and influence adult intestinal development and metabolism inDrosophila
Authors: Obniski Rebecca , Sieber Matthew , Spradling Allan C. 
Published: March 2018

SummaryTissue homeostasis is a complex balance of developmental signals and environmental cues that dictate stem cell function. However, it remains poorly understood how nutrients interface with developmental pathways. Using the Drosophila midgut as a model we found that during the first four days of adult life, dietary lipids including cholesterol, determine how many enteroendocrine (ee) cells differentiate and persist in the posterior midgut where lipids are preferentially absorbed. The nuclear hormone receptor Hr96 which functions to control sterol trafficking, storage, and utilization, is required for sterol-mediated changes in ee number. Dietary cholesterol influences new intestinal epithelial cell differentiation from stem cells by altering the level and persistance of Notch signaling. Exogenous lipids modulate signaling by changing the stability of the Delta ligand and Notch intracellular domain and their trafficking in endosomal vesicles. Lipid-modulated Notch signaling occurs in other nutrient-dependent tissues such as the ovary, suggesting that Delta trafficking in many cells is sensitive to cellular sterol levels. These diet-mediated alterations in ee number in young animals contribute to a metabolic program adapted to the prevailing nutrient environment that persists after the diet changes. A low sterol diet also slows the proliferation of enteroendocrine tumors initiated by disruptions in the Notch pathway. These studies show that a specific dietary nutrient can modify a key intercellular signaling pathway to shift stem cell differentiation and cause lasting changes in tissue structure and physiology.
An Array of Gut-on-a-Chips for Drug Development
Authors: Ashammakhi Nureddin , Elmusrati Mohammed 
Published: March 2018

AbstractDrug development is a time and cost-consuming long process. Conventionally, this involves the use of two-dimensional (2D) cell culture and animal testing. However, these methods often fail to mimic normal human physiology and drug metabolism, and sometimes complications may occur later because they do not appear in preclinical studies. With recent development of organ-on-a-chip devices, these biomimetic systems try to recapitulate human physiology more than other methods, and promise to largely replace animal studies and reduce costs and complications. Because gut is an important route for drug administration and absorption, gut-on-a-chip platform was developed. To develop a high throughput system, a recent work reported on using a multiplication array of several chip devices, demonstrating the efficiency in studying drug effect on gut barrier function as compared to conventional methods. Huge data was generated, and thus new multidisciplinary approach is needed where data collection, communication and analysis platforms need to be developed. This will enable validation of organ-on-a-chip approach and lay basis for its establishment as efficient and cost-effective tool in drug development. Because of the importance of the work, this commentary highlights important aspects of the topic and try to stimulate new the development of innovations in the field.DisclosureNo conflict of interest.
Genomic Exploration of Within-Host Microevolution Reveals a Distinctive Molecular Signature of PersistentStaphylococcus aureusBacteraemia
Authors: Giulieri Stefano G. , Baines Sarah L. , Guerillot Romain , Seemann Torsten , da Silva Anders Gonçalves , Schultz Mark , Massey Ruth C. , Holmes Natasha E. , Stinear Timothy P. , Howden Benjamin P. 
Published: March 2018

ABSTRACTBackgroundLarge-scale genomic studies of within-host evolution duringStaphylococcus aureusbacteraemia (SAB) are needed to understanding bacterial adaptation underlying persistence and thus refining the role of genomics in management of SAB. However, available comparative genomic studies of sequential SAB isolates have tended to focus on selected cases of unusually prolonged bacteraemia, where secondary antimicrobial resistance has developed. To understand the bacterial genomic evolution during SAB more broadly, we applied whole genome sequencing to a large collection of sequential isolates obtained from patients with persistent or relapsing bacteraemia.ResultsWe show that, while adapation pathways are heterogenous and episode-specific, isolates from persistent bacteraemia have a distinctive molecular signature, characterised by a low mutation frequency and high proportion of non-silent mutations. By performing an extensive analysis of structural genomic variants in addition to point mutations, we found that these often overlooked genetic events are commonly acquired during SAB. We discovered that IS256insertion may represent the most effective driver of within-host microevolution in selected lineages, with up to three new insertion events per isolate even in the absence of other mutations. Genetic mechanisms resulting in significant phenotypic changes, such as increases in vancomycin resistance, development of small colony phenotypes, and decreases in cytotoxicity, included mutations in key genes (rpoB, stp, agrA) and anIS256insertion upstream of thewalKRoperon.ConclusionsThis study provides for the first time a large-scale analysis of within-host evolution during invasiveS. aureusinfection and describes specific patterns of adaptation that will be informative for both understandingS. aureuspathoadaptation and utilising genomics for management of complicatedS. aureusinfections.