bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxygen-responsive p53 tetramer-octamer switch controls cell fate
Authors: Taxak Shashank , Pati Uttam 
Published: November 2019

ABSTRACTSolid tumors require an efficient decision-making mechanism to progress through a gradient of hypoxia. Here, we show that an oxygen-sensory p53 tetramer-octamer switch makes cell decision for survival or death in variable hypoxia. Trapping homo-oligomers from biosynthesis cycle, we found a metastable p53 tetramer in cells. Under the operation of switch, tetramer segregates the p53 character of a tumor suppressor and promoter. The p53 switch generates a pattern of its on-off state in time that is specific to the strength of hypoxia. A bidirectional tetramer-octamer conversion in on state decides the restoration of basal state by forward and programs apoptosis upon the reverse shift via p53-MDM2 loop. However, reversible dimertetramer transitions in off state trigger chaperoning of HIF-1 complex by tetramer in forward and oncogenic gain-of-function by prion-like dimers in reverse direction. Temporal on-off patterns calibrate stabilized p53 pool by defining the abundance of dimer, tetramer and octamer that ultimately decides diverse cellular outcomes in hypoxia. Through multi-chromophore FRET, we further show that chaperoning of HIF-1 may modulate angiogenesis through a possible flip-flop of the p53T-HIF-1 complex upon DNA. Our results demonstrate how p53 can sense oxygen and act upon its homo-oligomerization states to control cell fate in hypoxic tumors.
The role of integrin αvand CD44 in GBM migration in human brain
Authors: Binder Zev A. , Ji Kim Sarah Hyun , Wu Pei-Hsun , Giri Anjil , Gallia Gary L. , Pardo Carlos A. , Wirtz Denis 
Published: November 2019

AbstractGlioblastoma (GBM) is the most common primary adult malignant brain tumor. Recurrence is driven invading tumor cells that escape surgical resection and demonstrate resistance to standard-of-care chemotherapy and radiotherapy. A large body of research has been conducted on tumor cell motility. However, typicalin vitromodels make use of polystyrene culture dishes, which exhibit significantly different physical parameters than brain tissue. Here we report on the use of human organotypic brain slices as anex vivoapproach for the dynamic study of GBM cell motility.Temporal lobectomy tissue from epilepsy patients was obtained and cut into 350µm thick slices. After the tissue slices had a week’s incubation for recovery, fluorescently labeled tumor cells were seeded. We then tracked individual tumor cells using time-lapse fluorescent confocal microscopy. Quantification of motility characteristics, including mean squared displacement, total path length, and consistency, allowed for comparison of different conditions, including knockdown of cell surface proteins integrin αv(ITGAV) and CD44.Human organotypics demonstrated minimal variability across specimen in terms of motility parameters, including total path length, averaged instantaneous velocity, and consistency. Knockdown of the traditional motility protein ITGAV showed little effect on overall motility while knockdown of CD44 resulted in a significant reduction in both averaged instantaneous velocity and total path length. When the same parameters were examined using Matrigel, ITGAV and CD44 both showed decreased motility, highlighting the impact of the physical environment on cell behavior. Finally, cell motility in mouse organotypic slices was decreased when compared to human organotypic slices.Here we demonstrate the use of human organotypic brain slices in the study of GBM cell invasion. This model system offers a physiologically-relevant environment in which to examine the dynamic process of cell motility.
Testing Models of the Visual Word Form Area Using Combined ERP and fMRI Using the Special Properties of Chinese Characters
Authors: Xiang Dan , Dien Joseph , Bolger Donald J. 
Published: November 2019

AbstractThe visual word form area or VWFA has been of special interest for studies of reading and dyslexia and yet there are conflicting models regarding its function. Here we put the Local Combination Detector, Lexicon, and Interactive accounts to the test, using a combination of event-related potentials and functional magnetic resonance imaging. We do so using both pseudoword and reversed radical false word manipulations with Chinese characters, making use of its special properties. We recorded event-related potentials with 68 channels while twenty native Chinese speakers were making rhyme and meaning judgments on single Chinese characters and BOLD signals were collected in a 3T magnet using multi-plane EPI with a further fifteen native Chinese speakers. The word N170 showed a prolongation for reversed radical false characters while the VWFA also showed an effect of reversal, albeit only for pseudocharacters. Furthermore, an N450 rhyming effect was observed in the phonological task compared to the semantic task, but only via an interaction with reversal. The source analysis of the N450 co-registered with a Supplementary Motor Area activation. The combination of these observations suggests that the ventral orthographic pathway is partially order insensitive and that full phonological encoding occurs relatively late, supporting and expanding a model of dyslexia. Overall, they best support a version of the Lexicon account of the VWFA.
Two Ways to Change Your Mind: Effects of Intentional Strength and Motor Costs on Changes of Intention
Authors: Löffler Anne , Sylaidi Anastasia , Fountas Zafeirios , Haggard Patrick 
Published: November 2019

AbstractChanges of Mind are a striking example of the human ability to flexibly reverse decisions after commitment to an initial choice, and to change actions according to circumstances. Previous studies of Changes of Mind largely focused on perceptual choices. Here we investigate reversals ofvoluntary, endogenousaction decisions. In a novel version of the random-dot motion task, participants moved to a target that matched both the perceived dot-motion direction and an internally-generated intention (which colour target to move to). Movement trajectories revealed whether and when participants 1) perceived a change in dot-motion direction, or additionally 2) changed the colour that they chose to move to (‘Change of Intention’). Changes of Intention were less frequent in participants with strong colour intentions, as indicated by high performance costs in trials where perceptual information conflicted with the endogenous intention (Exp. 1). Additionally, Changes of Intention were more frequent when motor costs of intention pursuit were high (Exp. 2). These findings were simulated using an attractor network model that continuously integrates voluntary intentions, sensory evidence, and motor costs. This argues in favour of a unifying framework for dynamic decision-making processes, in which voluntary actions emerge from a dynamic combination of internal action tendencies and external environmental factors.
Sex differences in cognitive performance, style and domain relationships in mosquitofish (Gambusia affinis)
Authors: Wallace Kelly J. , Rausch Richie T. , Ramsey Mary E. , Cummings Molly E. 
Published: November 2019

AbstractGiven that the sexes often differ in their ecological and sexual selection pressures, sex differences in cognitive properties are likely. While research on sexually dimorphic cognitionoften focuses on performance, it commonly overlooks how sexes diverge across multiple cognitive tasks (cognitive domains) and in behaviors associated with cognitive performance (cognitive style). We tested male and female western mosquitofish (Gambusia affinis) in three cognitive tasks: associative learning (numerical discrimination), cognitive flexibility (detour task), and spatio-temporal learning (shuttlebox). We characterized statistical relationships between cognitive performances and cognitive style during the associative learning task with measures of anxiety, boldness, exploration, reaction time, and activity. We found sex differences in performance, cognitive style, and the relationships between cognitive domains. Females outperformed males in spatio-temporal learning task, while the sexes performed equally in associate learning and cognitive flexibility assays. Females (but not males) exhibited a ‘fast-exploratory’ cognitive style during associative learning trials. Meanwhile, only males showed a significant positive relationship between domains (associative learning and cognitive flexibility). We propose that these sexually dimorphic cognitive traits result from strong sexual conflict in this taxon; and emphasize the need to explore suites of sex-specific cognitive traits and broader comparative work examining sexual selection and cognition.HighlightsMales and females perform at similar levels in associative learning and cognitive flexibility assays, but females tend to outperform males on a spatio-temporal learning task.Female performance in associative learning trials (numerical discrimination task) can be predicted by cognitive style behaviors (exploration, reaction time, and activity); whereas male performance cannot.Males, but not females, show a predictive relationship between associative learning and cognitive flexibility performance.Our results demonstrate that sex differences in cognition extend beyond performance into cognitive style and domain relationships, suggesting that investigations into animal personality and cognition require more comprehensive characterization.
Repurposing disulfiram (Tetraethylthiuram Disulfide) as a potential drug candidate againstBorrelia burgdorferi in vitro and in vivo
Authors: Potula Hari-Hara SK , Shahryari Jahanbanoo , Inayathullah Mohammed , Malkovskiy Andrey Victorovich , Kim Kwang-Min , Rajadas Jayakumar 
Published: November 2019

ABSTRACTLyme disease caused by theBorrelia burgdorferi(Bb or B. burgdorferi) is a most common vector-borne, multi-systemic disease in USA. Although, most Lyme disease patients can be cured with a course of antibiotic treatment, a significant percent of patient population fail to be disease-free post-treatment, necessitating the development of more effective therapeutics. We previously found several drugs including disulfiram having with good activity againstB. burgdorferi. In current study, we evaluated the potential of repurposing the FDA approved disulfiram drug for itsborreliacidal activity. Ourin vitroresults indicate disulfiram shows excellentborreliacidal activity against both the log and stationary phaseB. burgdorferi. Subsequent mice studies have determined that the disulfiram eliminatedB. burgdorfericompletely from hearts and urinary bladder by day 28 post infection, demonstrating the practical application and efficacy of disulfiram againstB. burgdorferi in vivo. Moreover, disulfiram treated mice showed reduced expression of inflammatory markers and protected against histopathology and organ damage. Furthermore, disulfiram treated mice showed significantly lower amounts of total antibody titers (IgM and IgG) at day 21 and total IgG2b at day 28 post infection. Mechanistically, cellular analysis of lymph nodes revealed a decrease in percentage of CD19+ B cells and increase in total percentage of CD3+ T cells, CD3+ CD4+ T helpers, and naïve and effector memory cells in disulfiram-treated mice. Together, we demonstrate that disulfiram has the potential and could be repurposed as an effective antibiotic for treating Lyme disease in near future.
AutoGenome: An AutoML Tool for Genomic Research
Authors: Liu Denghui , Xu Chi , He Wenjun , Xu Zhimeng , Fu Wenqi , Zhang Lei , Yang Jie , Peng Guangdun , Han Dali , Bai Xiaolong , Qiao Nan 
Published: November 2019

AbstractDeep learning have made great successes in traditional fields like computer vision (CV), natural language processing (NLP) and speech processing. Those achievements greatly inspire researchers in genomic study and make deep learning in genomics a very hot topic. Convolutional neural network (CNN) and recurrent neural network (RNN) are frequently used for genomic sequence prediction problems; multiple layer perception (MLP) and auto-encoders (AE) are frequently used for genomic profiling data like RNA expression data and gene mutation data. Here, we introduce a new neural network architecture, named residual fully-connected neural network (RFCN) and demonstrate its advantage for modeling genomic profiling data. We further incorporate AutoML algorithms and implement AutoGenome, an end-to-end automated genomic deep learning framework. By utilizing the proposed RFCN architectures, automatic hyper-parameter search and neural architecture search algorithms, AutoGenome can train high-performance deep learning models for various kinds of genomic profiling data automatically. To make researchers better understand the trained models, AutoGenome can assess the feature importance and export the most important features for supervised learning tasks, and the representative latent vectors for unsupervised learning tasks. We envision AutoGenome to become a popular tool in genomic studies.
Interactions between cytoplasmic and nuclear genomes confer sex-specific effects on lifespan inDrosophila melanogaster
Authors: Vaught Rebecca C. , Voigt Susanne , Dobler Ralph , Clancy David J. , Reinhardt Klaus , Dowling Damian K. 
Published: November 2019

ABSTRACTA large body of studies has demonstrated that genetic variation that resides outside of the cell nucleus can affect the organismal phenotype. The cytoplasm is home to the mitochondrial genome and, at least in arthropods, often hosts intracellular endosymbiotic bacteria such asWolbachia. While numerous studies have implicated epistatic interactions between cytoplasmic and nuclear genetic variation as key to mediating patterns of phenotypic expression, two outstanding questions remain. Firstly, the relative contribution of mitochondrial genetic variation to other cytoplasmic sources of variation in shaping the phenotypic outcomes of cyto-nuclear interactions remains unknown. Secondly, it remains unclear whether the outcomes of cyto-nuclear interactions will manifest differently across the two sexes, as might be predicted given that cytoplasmic genomes are screened by natural selection only through females as a consequence of their maternal inheritance. Here, we address these questions, creating a fully-crossed set of replicated cyto-nuclear populations derived from three geographically distinct populations ofDrosophila melanogaster, and measuring the lifespan of males and females from each population. We report cyto-nuclear interactions for lifespan, with the outcomes of these interactions differing across the sexes, and reconcile these findings with information on the full mitochondrial sequences andWolbachiainfection status of each of the populations.
An open database of resting-state fMRI in awake rats
Authors: Liu Yikang , Perez Pablo D. , Ma Zilu , Ma Zhiwei , Dopfel David , Cramer Samuel , Tu Wenyu , Zhang Nanyin 
Published: November 2019

AbstractRodent models are essential to translational research in health and disease. Investigation in rodent brain function and organization at the systems level using resting-state functional magnetic resonance imaging (rsfMRI) has become increasingly popular, owing to its high spatial resolution and whole-brain coverage. Due to this rapid progress, shared rodent rsfMRI databases can be of particular interest and importance to the scientific community, as inspired by human neuroscience and psychiatric research that are substantially facilitated by open human neuroimaging datasets. However, such databases in rats are still lacking. In this paper, we share an open rsfMRI database acquired in 90 rats with a well-established awake imaging paradigm that avoids anesthesia interference. Both raw and preprocessed data are made publically available. Procedures in data preprocessing to remove artefacts induced by the scanner, head motion, non-neural physiological noise are described in details. We also showcase inter-regional functional connectivity and functional networks calculated from the database.
Conductance-based Adaptive Exponential integrate-and-fire model
Authors: Górski Tomasz , Depannemaecker Damien , Destexhe Alain 
Published: November 2019

AbstractThe intrinsic electrophysiological properties of single neurons can be described by a broad spectrum of models, from the most realistic Hodgkin-Huxley type models with numerous detailed mechanisms to the phenomeno-logical models. The Adaptive Exponential integrate-and-fire (AdEx) model has emerged as a convenient “middle-ground” model. With a low computational cost, but keeping biophysical interpretation of the parameters, it has been extensively used for simulations of large neural networks. However, because of its current-based adaptation, it can generate unrealistic behaviors. We show the limitations of the AdEx model and to avoid them, we introduce the Conductance-based Adaptive Exponential integrate-and-fire model (CAdEx). We give an analysis of the dynamics of the CAdEx model and show the variety of firing patterns it can produce. We propose the CAdEx model as a richer alternative to perform network simulations with simplified models reproducing neuronal intrinsic properties.
Transcriptome-wide association analysis of 211 neuroimaging traits identifies new genes for brain structures and yields insights into the gene-level pleiotropy with other complex traits
Authors: Zhao Bingxin , Shan Yue , Yang Yue , Li Tengfei , Luo Tianyou , Zhu Ziliang , Li Yun , Zhu Hongtu 
Published: November 2019

AbstractStructural and microstructural variations of human brain are heritable and highly polygenic traits, with hundreds of associated genes founded in recent genome-wide association studies (GWAS). Using gene expression data, transcriptome-wide association studies (TWAS) can prioritize these GWAS findings and also identify novel gene-trait associations. Here we performed TWAS analysis of 211 structural neuroimaging phenotypes in a discovery-validation analysis of six datasets. Using a cross-tissue approach, TWAS discovered 204 associated genes (86 new) exceeding Bonferroni significance threshold of 1.37*10−8(adjusted for testing multiple phenotypes) in the UK Biobank (UKB) cohort, and validated 18 TWAS or previous GWAS-detected genes. The TWAS-significant genes of brain structures had been linked to a wide range of complex traits in different domains. Additional TWAS analysis of 11 cognitive and mental health traits detected 69 overlapping significant genes with brain structures, further characterizing the genetic overlaps among these brain-related traits. Through TWAS gene-based polygenic risk scores (PRS) prediction, we found that TWAS PRS gained substantial power in association analysis compared to conventional variant-based PRS, and up to 6.97% of phenotypic variance (p-value=7.56*10−31) in testing datasets can be explained by UKB TWAS-derived PRS. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.
A novel vaccine targeting the viral protease cleavage sites protects Mauritian cynomolgus macaques against vaginal SIVmac251 infection
Authors: Li Hongzhao , Omange Robert W. , Liang Binhua , Toledo Nikki , Hai Yan , Liu Lewis R. , Schalk Dane , Crecente-Campo Jose , Dacoba Tamara G. , Lambe Andrew B. , Lim So-Yon , Li Lin , Kashem Mohammad Abul , Wan Yanmin , Correia-Pinto Jorge F. , Liu Xiao Qing , Balshaw Robert F. , Li Qingsheng , Schultz-Darken Nancy , Alonso Maria J. , Whitney James B. , Plummer Francis A. , Luo Ma 
Published: November 2019

AbstractAfter over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers a novel approach to developing an effective HIV vaccine.One Sentence SummaryThe anti-PCS T cell responses and the immune environment induced by the novel PCS vaccine are key correlates of vaccine efficacy
Hippocampal spatial memory representations in mice are heterogeneously stable
Authors: Levy Samuel J , Kinsky Nathaniel R , Mau William , Sullivan David W , Hasselmo Michael E 
Published: November 2019

AbstractThe population of hippocampal neurons actively coding space continually changes across days as mice repeatedly perform tasks. Many hippocampal place cells become inactive while other previously silent neurons become active, challenging the belief that stable behaviors and memory representations are supported by stable patterns of neural activity. Active cell replacement may disambiguate unique episodes that contain overlapping memory cues, and could contribute to reorganization of memory representations. How active cell replacement affects the evolution of representations of different behaviors within a single task is unknown. We trained mice to perform a Delayed Non-Match to Place (DNMP) task over multiple weeks, and performed calcium imaging in area CA1 of the dorsal hippocampus using head-mounted miniature microscopes. Cells active on the central stem of the maze “split” their calcium activity according to the animal’s upcoming turn direction (left or right), the current task phase (study or test), or both task dimensions, even while spatial cues remained unchanged. We found that different splitter neuron populations were replaced at unequal rates, resulting in an increasing number of cells modulated by turn direction and a decreasing number of cells with combined modulation by both turn direction and task phase. Despite continual reorganization, the ensemble code stably segregated these task dimensions. These results show that hippocampal memories can heterogeneously reorganize even while behavior is unchanging.Significance statementSingle photon calcium imaging using head-mounted miniature microscopes in freely moving animals, has enabled researchers to measure the long term stability of hippocampal pyramidal cells during repeated behaviors. Previous studies have demonstrated instability of neural circuit components including dendritic spines and axonal boutons. It is now known that single units in the neuronal population exhibiting behaviorally relevant activity eventually become inactive and that previously silent neurons can quickly acquire task-relevant activity. The function of such population dynamics is unknown. We show here that population dynamics differ for cells coding distinct task dimensions, suggesting such dynamics are part of a mechanism for latent memory reorganization. These results add to a growing body of work showing that maintenance of episodic memory is an ongoing and dynamic process.