bluuebunny/crossref_metadata_2025_split huggingface dataset:
The limbic circuit for response vigour
Authors: Porr Bernd , Gomes Pedro , Andreassen Thor 
Published: April 2019

AbstractMotivation can be defined as the amount of energy an animal puts into actions to achieve goals. This not a static property but can be learned. Recently, abstract models have been developed for this kind of learning which propose that tonic dopamine is responsible to energise behaviour. However the underlying circuitry is still not understood and it is still unclear how tonic dopamine acts on the motor system to energise behaviour. In this paper we present a limbic system model of response invigoration which is based on neurophysiological data and anatomical connections. We argue that the indirect pathway from NAcc core D2 neurons via the ventral pallidum to the SNr conveys response vigour, while the direct pathway from NAcc core D1 neurons is responsible for action selection. Once this detailed anatomically mapped circuit has been established we then condense this realistic model into an abstract model which then shows that tonic DA acts in a multiplicative way on the motor output and thus is able to energise behaviour. We demonstrate the model with both a simulated and real robot experiment.
Noise-Reducing Negative-Feedback Optogenetic Circuits in Mammalian Cells
Authors: Guinn Michael Tyler , Balázsi Gábor 
Published: April 2019

AbstractGene autorepression is widely present in nature and is also employed in synthetic biology, partly to reduce gene expression noise in cells. Optogenetic systems have recently been employed for controlling gene expression levels in mammalian cells, but most have utilized activator-based proteins, neglecting negative feedback. Here, we engineer optogenetic negative-feedback gene circuits in mammalian cells to achieve noise-reduction for precise gene expression control. We build a toolset of these noise-reducing Light-Inducible Tuner (LITer) gene circuits using the TetR repressor fused with a Tet-Inhibitory peptide (TIP) or a degradation tag through the light-sensitive LOV2 protein domain. These LITers provide nearly a range of 4-fold gene expression control and up to five-fold noise reduction from existing optogenetic systems. Moreover, we use the LITer gene circuit architecture to control gene expression of the cancer oncogene KRAS(G12V) and study its downstream effects through phospho-ERK levels and cellular proliferation. Overall, these novel LITer optogenetic platforms should enable precise spatiotemporal perturbations for studying multicellular phenotypes in developmental biology, oncology, and other biomedical fields of research.
Predicting the partition of behavioral variability in speed perception with naturalistic stimuli
Authors: Chin Benjamin M. , Burge Johannes 
Published: April 2019

AbstractA core goal of visual neuroscience is to predict human perceptual performance from natural signals. Performance in any natural task can be impacted by at least three sources of uncertainty: stimulus variability, internal noise, and sub-optimal computations. Determining the relative importance of these factors has been a focus of interest for decades, but most successes have been achieved with simple tasks and simple stimuli. Drawing quantitative links directly from natural signals to perceptual performance has proven a substantial challenge. Here, we develop an image-computable (pixels in, estimates out) Bayesian ideal observer that makes optimal use of the statistics relating image movies to speed. The optimal computations bear striking resemblance to descriptive models proposed to account for neural activity in area MT. We develop a model based on the ideal, stimulate it with naturalistic signals, predict the behavioral signatures of each performance-limiting factor, and test the predictions in an interlocking series of speed discrimination experiments. The critical experiment collects human responses to repeated presentations of each unique image movie. The model, highly constrained by the earlier experiments, tightly predicts human response consistency without free parameters. This result implies that human observers use near-optimal computations to estimate speed, and that human performance is near-exclusively limited by natural stimulus variability and internal noise. The results demonstrate that human performance can be predicted from a task-specific statistical analysis of naturalistic stimuli, show that image-computable ideal observer analysis can be generalized from simple to natural stimuli, and encourage similar analyses in other domains.
Lethal mutagenesis of Rift Valley fever virus induced by favipiravir
Authors: Borrego Belén , de Ávila Ana I. , Domingo Esteban , Brun Alejandro 
Published: April 2019

ABSTRACTRift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies, and a decrease of specific infectivity, hallmarks of lethal mutagenesis.
SICaRiO: Short Indel Call filteRing with bOosting
Authors: Bhuyan Md Shariful Islam , Pe’er Itsik , Rahman M. Sohel 
Published: April 2019

AbstractDespite impressive improvement in the next-generation sequencing technology, reliable detection of indels is still a difficult endeavour. Recognition of true indels is of prime importance in many applications, such as, personalized health care, disease genomics, population genetics etc. Recently, advanced machine learning techniques have been successfully applied to classification problems with large-scale data. In this paper, we present SICaRiO, a gradient boosting classifier for reliable detection of true indels, trained with gold-standard dataset from genome-in-a-bottle (GIAB) consortium. Our filtering scheme significantly improves the performance of each variant calling pipeline used in GIAB and beyond. SICaRiO uses genomic features which can be computed from publicly available resources, hence, we can apply it on any indel callsets not having sequencing pipeline-specific information (e.g., read depth). This study also sheds lights on prior genomic contexts responsible for indel calling error made by sequencing platforms. We have compared prediction difficulty for three indel categories over different sequencing pipelines. We have also ranked genomic features according to their predictivity in determining false indel calls.
Robust and replicable measurement for prepulse inhibition of the acoustic startle response
Authors: Miller Eric A. , Kastner David B. , Grzybowski Michael N. , Dwinell Melinda R. , Geurts Aron M. , Frank Loren M. 
Published: April 2019

AbstractMeasuring animal behavior in the context of experimental manipulation is critical for modeling and understanding neuro-psychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral paradigm used extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this metric remains uncertain. Here we deconstruct the phenomenon of PPI. We first confirm several limitations of the traditional PPI metric, including that the underlying startle response has a non-Gaussian distribution and that the traditional PPI metric changes with different stimulus condition. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound perception. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared to wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In addition, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.
Phenotypic and Genetic Markers of Psychopathology in a Population-Based Sample of Older Adults
Authors: Gard Arianna M. , Ware Erin B. , Hyde Luke W. , Schmitz Lauren , Faul Jessica , Mitchell Colter 
Published: April 2019

AbstractAlthough psychiatric phenotypes are hypothesized to organize into a two-factor internalizing – externalizing structure, few studies have evaluated the structure of psychopathology in older adults, nor explored whether genome-wide polygenic scores (PGSs) are associated with psychopathology in a domain-specific manner. We used data from 6,216 individuals of European ancestry from the Health and Retirement Study, a large population-based sample of older adults in the United States. Confirmatory factor analyses were applied to validated measures of psychopathology and PGSs were derived from well-powered GWAS. Genomic SEM was implemented to construct latent PGSs for internalizing, externalizing, and general psychopathology. Phenotypically, the data were best characterized by a single general factor of psychopathology, a factor structure that was replicated across genders and age groups. Although externalizing PGSs (cannabis use, antisocial behavior, alcohol dependence, ADHD) were not associated with any phenotypes, PGSs for MDD, neuroticism, and anxiety disorders were associated with both internalizing and externalizing phenotypes. Moreover, the latent internalizing PGS and the latent one-factor PGS, derived using weights from Genomic SEM, explained 1% more variance in the general factor of psychopathology than any of the individual PGSs. Results support the following conclusions: genetic risk factors for and phenotypic markers of psychiatric disorders are transdiagnostic in European ancestries, GWAS-derived PGSs fail to capture genetic variation associated with disease specificity in European ancestries, and blunt phenotypic measurement in GWAS may preclude our ability to evaluate the structure and specificity of genetic contributions to psychiatric disorders.
Dorsal-to-ventral neocortical expansion is physically primed by ventral streaming of early embryonic preplate neurons
Authors: Saito Kanako , Okamoto Mayumi , Watanabe Yuto , Noguchi Namiko , Nagasaka Arata , Nishina Yuta , Shinoda Tomoyasu , Sakakibara Akira , Miyata Takaki 
Published: April 2019

SummaryMammalian neocortex exhibits a disproportionally “luxurious” representation of somatotopies in its lateral region, which depends on dorsal-to-ventral expansion of the pallium during development. Despite recent studies elucidating the molecular mechanisms underlying the cortical arealization/patterning, we know very little about how the cortex expands ventrally and the nature of the underlying force-generating events. We found that neurons born earliest (at embryonic day 10 [E10]) in the mouse pallium migrated ventrally and then extended corticofugal axons, which together formed a morphogenetic flow of the preplate that persists until E13. These neurons exerted pulling and pushing forces at the process and the soma, respectively. Ablation of these E10-born neurons attenuated both deflection of radial glial fibers (by E13) and extension of the cortical plate (by E14), which should occur ventrally, and subsequently shrank the postnatal neocortical map dorsally. This previously unrecognized preplate stream physically primes neocortical expansion and somatotopic map formation.
Object Colours, Material Properties and Animal Signals
Authors: Wilkins Lucas , Osorio Daniel 
Published: April 2019

AbstractColour is commonly regarded as an absolute measure of object properties, but most work on visual communication signals is concerned with colour differences, typically scaled by just noticeable differences (JNDs). Object colour solids represent the colour gamut of reflective materials for an eye. The geometry of colour solids reveals general relationships between colours and object properties which can explain why certain colours are significant to animals and evolve as signals. We define a measure of colour vividness, such that points on the surface are maximally vivid and the ‘grey’ centre is minimally vivid. We show that a vivid colour for one animal is likely to vivid for others, and highly vivid colours are less easily mimicked than less vivid colours. Further, vivid colours such as black, white, red, blue and light, unsaturated shades are produced pure or orderly materials. This kind of material needs to created and maintained against entropic processes that would otherwise degrade or destroy them. Vivid coloration is therefore indicative of ecological affordance or biological function, so that it is valuable to have attentional biases towards these colours regardless of any specific significance.
Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases
Authors: Zhang Chi , Stockwell Simon R. , Elbanna May , Ketteler Robin , Freeman Jamie , Al-Lazikani Bissan , Eccles Suzanne , De Haven Brandon Alexis , Raynaud Florence , Hayes Angela , Clarke Paul A. , Workman Paul , Mittnacht Sibylle 
Published: April 2019

AbstractDeregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer yet inhibitors against these kinases currently show use in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and what may undermine such dependency is poorly understood. Here we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2-activation, involving as a critical mechanistic events loss of the CDK inhibitor p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.
Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility
Authors: Chakraborty Arijita , Jenjaroenpun Piroon , McCulley Andrew , Li Jing , El Hilali Sami , Haarer Brian , Hoffman Elizabeth A. , Belak Aimee , Thorland Audrey , Hehnly Heidi , Chen Chun-long , Kuznetsov Vladimir A. , Feng Wenyi 
Published: April 2019

ABSTRACTFragile X syndrome (FXS) is the most prevalent inherited intellectual disability caused by mutations in the Fragile X Mental Retardation 1 (FMR1) gene. The protein product of FMR1, FMRP, is known as a translational repressor whose nuclear function is not understood. Here we report that FMRP is a genome maintenance protein. We show that FX cells exhibit elevated level of chromosome breaks, both spontaneous and replication stress-induced. We demonstrate that FMRP is required for abating R-loop accumulation, thereby preventing chromosome breakage. Through mapping FMRP-bound chromatin loci in normal cells and correlating with FX-specific chromosome breaks, we identified novel FXS-susceptible genes. We show that FX cells have reduced expression of the uridine diphosphoglucuronosyl transferase 1 family enzymes, suggesting defective xenobiotics glucuronidation and consequential neurotoxicity in FXS.
Tunability of DNA polymerase stability during eukaryotic DNA replication
Authors: Lewis Jacob S. , Spenkelink Lisanne M. , Schauer Grant D. , Yurieva Olga , Mueller Stefan H. , Natarajan Varsha , Kaur Gurleen , Maher Claire , Kay Callum , O’Donnell Michael E. , van Oijen Antoine M. 
Published: April 2019

SummaryStructural and biochemical studies have revealed the basic principles of how the replisome duplicates genomic DNA, but little is known about its dynamics during DNA replication. We reconstitute the 34 proteins needed to form the S. cerevisiae replisome and show how changing local concentrations of the key DNA polymerases tunes the ability of the complex to efficiently recycle these proteins or to dynamically exchange them. Particularly, we demonstrate redundancy of the Pol α DNA polymerase activity in replication and show that Pol α primase and the lagging-strand Pol δ can be re-used within the replisome to support the synthesis of large numbers of Okazaki fragments. This unexpected malleability of the replisome might allow it to deal with barriers and resource challenges during replication of large genomes.
Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus
Authors: Bayraktar Gonca , Yuanxiang PingAn , Gomes Guilherme M , Confettura Aessandro D , Raza Syed A , Stork Oliver , Tajima Shoji , Yildirim Ferah , Kreutz Michael R. 
Published: April 2019

AbstractDNA-methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3a1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDAR drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3a1 and results in deficits of promoter methylation of activity-dependent genes, synaptic plasticity as well as memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively the data show that GluN2A containing NMDAR control synapse-to-nucleus signaling that links plasticity-relevant signals to activity-dependent DNA-methylation involved in memory formation.
D-Cycloserine as Adjunct to Brief Computerised CBT for Spider Fear: Effects on Fear, Behaviour, and Cognitive Biases
Authors: Kappelmann Nils , Suesse Mareike , Steudte-Schmiedgen Susann , Kaldewaij Reinoud , Browning Michael , Michael Tanja , Rinck Mike , Reinecke Andrea 
Published: April 2019

AbstractIn anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response, so they might constitute important treatment targets. This study investigated (i) whether information-processing biases changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS). Spider-fearful individuals were randomized to receiving 250mg of DCS (n=21) or placebo (n=17) and spider fear was assessed using self-report, behavioural, and information-processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures. Linear mixed-effects analyses indicated improvements on self-report and behavioural spider fear following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive biases at 1-day were not predictive of 1-month follow-up spider fear. These findings provide no evidence for information-processing biases relating to CBT response or augmentation with DCS.
sMode of action of the antimicrobial peptide Mel4 is independent of Staphylococcus aureus cell membrane permeability
Authors: Yasir Muhammad , Dutta Debarun , Willcox Mark D.P. 
Published: April 2019

AbstractMel4 is a novel cationic peptide with potent activity against Gram-positive bacteria. The current study examined the anti-staphylococcal mechanism of action of Mel4 and its precursor peptide melimine. The interaction of peptides with lipoteichoic acid (LTA) and with the cytoplasmic membrane using DiSC(3)-5, Sytox green, Syto-9 and PI dyes were studied. Release of ATP and DNA/RNA from cells exposed to the peptides were determined. Bacteriolysis and autolysin-activated cell death were determined by measuring decreases in OD620nm and killing of Micrococcus luteus cells by cell-free media. Both peptides bound to LTA and rapidly dissipated the membrane potential (within 30 seconds) without affecting bacterial viability. Disturbance of the membrane potential was followed by the release of ATP (50% of total cellular ATP) by melimine and by Mel4 (20%) after 2 minutes exposure (p<0.001). Mel4 resulted in staphylococcal cells taking up PI with 3.9% cells predominantly stained after 150 min exposure, whereas melimine showed 34% staining. Unlike melimine, Mel4 did not release DNA/RNA. Cell-free media from Mel4 treated cells hydrolysed peptidoglycan and produced greater zones of inhibition against M. luteus lawn than melimine treated samples. These findings suggest that pore formation is unlikely to be involved in Mel4-mediated membrane destabilization for Staphylococcci, since there was no significant Mel4-induced PI staining and DNA/RNA leakage. It is likely that the S. aureus killing mechanism of Mel4 involves the release of autolysins followed by cell death. Whereas, membrane interaction is the primary bactericidal activity of melimine, which includes membrane depolarisation, pore formation, release of cellular contents leading to cell death.This work is original, has not been published and is not being considered for publication elsewhere. Part of this manuscript has been presented as a poster presentation in Gordon Research Conference Italy in 2019. There are no conflicts of interest for any of the authors that could have influenced the results of this work. Prof. Mark Willcox holds the patent the for the melimine peptide.