bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Model Mechanism Based Explanation of an In Vitro-In Vivo Disconnect for Improving Extrapolation and Translation
Authors: Smith Andrew K. , Xu Yanli , Ropella Glen E.P. , Hunt C. Anthony 
Published: November 2017

AbstractAn improved understanding of in vivo-to-in vitro hepatocyte changes is crucial to interpreting in vitro data correctly and further improving hepatocyte-based in vitro-to-in vivo extrapolations to human targets. We demonstrate using virtual experiments as a means to help untangle plausible causes of inaccurate extrapolations. We start with virtual mice that have biomimetic software livers. Earlier, using those mice, we discovered model mechanisms that enabled achieving quantitative validation targets while also providing plausible causal explanations for temporal characteristics of acetaminophen hepatotoxicity. We isolated virtual hepatocytes, created a virtual culture, and then conducted dose-response experiments in both culture and mice. We expected the two dose-response curves to be displaced. We were surprised that they crossed because it evidenced that simulated acetaminophen metabolism and toxicity are different for virtual culture and mouse contexts even though individual hepatocyte mechanisms were unchanged. Crossing dose-response curves is a virtual example of an in vivo-to-in vitro disconnect. We use detailed results of experiments to explain the disconnect. Individual hepatocytes contribute differently to system level phenomena. In liver, hepatocytes are exposed to acetaminophen sequentially. Relative production of the reactive acetaminophen metabolite is largest (smallest) in pericentral (periportal) hepatocytes. Because that sequential exposure is absent in culture, hepatocytes from different lobular locations do not respond the same. A virtual Culture-to-Mouse translation can stand as a scientifically challengeable theory explaining an in vitro-in vivo disconnect. It provides a framework to develop more reliable interpretations of in vitro observations, which then may be used to improve extrapolations.AbbreviationsaHPCanalog hepatocyteAPAPacetaminophenCVCentral VeinSSsinusoidal segmentNAPQIN-acetyl-p-benzoquinone iminemitoDmitochondrial damage productsnonMDnon-mitochondrial damage products
STIMULUS: Noninvasive Dynamic Patterns of Neurostimulation using Spatio-Temporal Interference
Authors: Cao Jiaming , Grover Pulkit 
Published: November 2017

AbstractUsing a systematic computational and modeling framework, we provide a novelSpatio-Temporal Interference-based stiMULation focUsing Strategy(STIMULUS) for high spatial precision noninvasive neurostimulation deep inside the brain. To do so, we first replicate the results of the recently proposed temporal interference (TI) stimulation (which was only tested in-vivo) in a computational model based on a Hodgkin-Huxley model for neurons and a model of current dispersion in the head. Using this computational model, we obtain a nontrivial extension of the 2-electrode-pair TI proposed originally to multielectrode TI (>2 electrode pairs) that yields significantly higher spatial precision. To further improve precision, we develop STIMULUS techniques for generating spatial interference patterns in conjunction with temporal interference, and demonstrate strict and significant improvements over multielectrode TI. Finally, we utilize the adaptivity that is inherent in STIMULUS to create multisite neurostimulation patterns that can be dynamically steered over time.
Module analysis captures pancancer genetically and epigenetically deregulated cancer driver genes for smoking and antiviral response
Authors: Champion Magali , Brennan Kevin , Croonenborghs Tom , Gentles Andrew J. , Pochet Nathalie , Gevaert Olivier 
Published: November 2017

AbstractThe availability of increasing volumes of multi-omics profiles across many cancers promises to improve our understanding of the regulatory mechanisms underlying cancer. The main challenge is to integrate these multiple levels of omics profiles and especially to analyze them across many cancers. Here we present AMARETTO, an algorithm that addresses both challenges in three steps. First, AMARETTO identifies potential cancer driver genes through integration of copy number, DNA methylation and gene expression data. Then AMARETTO connects these driver genes with co-expressed target genes that they control, defined as regulatory modules. Thirdly, we connect AMARETTO modules identified from different cancer sites into a pancancer network to identify cancer driver genes. Here we applied AMARETTO in a pancancer study comprising eleven cancer sites and confirmed that AMARETTO captures hallmarks of cancer. We also demonstrated that AMARETTO enables the identification of novel pancancer driver genes. In particular, our analysis led to the identification of pancancer driver genes of smoking-induced cancers and ‘antiviral’ interferon-modulated innate immune response.Software availabilityAMARETTO is available as an R package athttps://bitbucket.org/gevaertlab/pancanceramarettoHighlightsWe present an algorithm for pancancer identification of cancer driver genes based on multiomics data fusionGPX2 is a novel driver gene in smoking induced cancers and validated using knockdown of GPX2 in the A549 cell line.OAS2 is a novel driver gene defining cancers with an antiviral signature supported by increased infiltration of tumor-associated macrophages.Research in contextWe present an algorithm that combines multiple sources of molecular data to identify novel genes that are involved in cancer development. We applied this algorithm on multiple cancers in a combined fashion and identified a network of pancancer driver genes. We highlighted two genes in detail GPX2 and OAS2. We showed that GPX2 is an important cancer gene in smoking induced cancers, and validated our predictions using experimental data where GPX2 was inactivated in a lung cancer cell line. Similarly we showed that OAS2 is an important cancer driver gene in cancers that show an antiviral signature.
Cognitive Entities Underpinning Task Episodes
Authors: Farooqui Ausaf A , Manly Tom 
Published: November 2017

Cognitive Entities Underpinning Task EpisodesAccounts of hierarchical cognition suggest that extended task episodes as one task entity and not individually execute their component acts. Such hierarchical execution is frequently thought to occur by first instantiating a sequence representation in working memory that then controls the identity and sequence of component steps. In contrast, we evidence hierarchical execution of extended behavior in situations where the identity and sequence of component steps was unknown and not linked to any sequence representation. Participants executed unpredictable trials wherein, depending on the margin color, they could either choose the smaller value or the font of the two numbers. Crucially, they were biased into construing a recurring instance of three or five trials as one task episode. Behavioral signs of hierarchy, identical to those seen previously with memorized sequence execution, were seen - High trial 1 RT, higher trial 1 RT before longer task episodes, and absence of trial level switch cost specifically across episode boundaries. This showed that hierarchical task sequence representations are not a requisite for hierarchical organization of cognition. Merely construing behavior to be executed as a task episode is enough for the accompanying cognition to be hierarchically organized. Task episodes are executed through the intermediation of episode related programs that are assembled at the beginning and control and organize cognition across time.
Generation of Mouse-Zebrafish Hematopoietic Tissue Chimeric Embryos for Hematopoiesis and Host-Pathogen Interaction Studies
Authors: Parada-Kusz Margarita , Clatworthy Anne , Hagedorn Elliott J. , Penaranda Cristina , Nair Anil V. , Henninger Jonathan E. , Ernst Christoph , Li Brian , Riquelme Raquel , Jijon Humberto , Villablanca Eduardo J. , Zon Leonard I. , Hung Deborah , Allende Miguel L. 
Published: November 2017

ABSTRACTXenografts of the hematopoietic system are extremely useful as disease models and for translational research. Zebrafish xenografts have been widely used to monitor blood cancer cell dissemination and homing due to the optical clarity of embryos and larvae, which allow unrestrictedin vivovisualization of migratory events. To broaden the scope of xenotransplantation studies in zebrafish, we have developed a technique that transiently generates hematopoietic tissue chimeras by transplanting murine bone marrow cells into zebrafish blastulae. This procedure leads to mammalian cell integration into the fish developmental hematopoietic program. Monitoring zebrafish chimeras at different time points post fertilization usingin vivotime-lapse and confocal imaging showed murine cell co-localization with developing primitive and definitive hematopoietic tissues, intravasation into fish circulation, and dynamic hematopoietic cell-vascular endothelial and hematopoietic cell-niche interactions. Immunohistochemistry assays performed in chimeric animals showed that, after engraftment, murine cells expressed antigens related to i) hematopoietic stem and progenitor cells, ii) active cell proliferation, and iii) myeloid cell lineages. Lastly, xenografted zebrafish larvae infected withKlebsiella pneumoniaeshowed murine immune cells trafficking to bacterial foci and interacting with bacterial cells. Overall, these results show that mammalian bone marrow cells xenografted in zebrafish integrate into the host hematopoietic system revealing highly conserved molecular mechanisms of hematopoiesis between zebrafish and mammals. In addition, this procedure introduces a useful and simple method that improves and broadens the scope of hematopoietic tissue xenotransplantation studies in zebrafish.
A new sequencing-based women’s health assay combining self-sampling, HPV detection and genotyping, STI detection, and vaginal microbiome analysis
Authors: Bik Elisabeth M. , Bird Sara W. , Bustamante Juan P. , Leon Luis E. , Nieto Pamela A. , Addae Kwasi , Alegría-Mera Víctor , Bravo Cristian , Bravo Denisse , Cardenas Juan P. , Caughey Adam , Covarrubias Paulo C. , Pérez-Donoso José , Gass Graham , Gupta Sarah L. , Harman Kira , Hongo Donna Marie B. , Jiménez Juan C. , Kraal Laurens , Melis-Arcos Felipe , Morales Eduardo H. , Morton Amanda , Navas Camila F. , Nuñez Harold , Olivares Eduardo , Órdenes-Aenishanslins Nicolás , Ossandon Francisco J. , Phan Richard , Pino Raul , Soto-Liebe Katia , Varas Ignacio , Vera-Wolf Patricia , Walton Nathaniel A. , Almonacid Daniel E. , Goddard Audrey D. , Ugalde Juan A. , Richman Jessica , Apte Zachary S. 
Published: November 2017

AbstractThe composition of the vaginal microbiome, including both the presence of pathogens involved in sexually transmitted infections (STI) as well as commensal microbiota, has been shown to have important associations for a woman’s reproductive and general health. Currently, healthcare providers cannot offer comprehensive vaginal microbiome screening, but are limited to the detection of individual pathogens, such as high-risk human papillomavirus (hrHPV), the predominant cause of cervical cancer. There is no single test on the market that combines HPV, STI, and microbiome screening. Here, we describe a novel inclusive women’s health assay that combines self-sampling with sequencing-based HPV detection and genotyping, vaginal microbiome analysis, and STI-associated pathogen detection. The assay includes genotyping and detection of 14 hrHPV types, 5 low-risk HPV types (lrHPV), as well as the relative abundance of 32 bacterial taxa of clinical importance, includingLactobacillus,Sneathia,Gardnerella, and 4 pathogens involved in STI, with high sensitivity, specificity, and reproducibility. For each of these taxa, healthy ranges were determined in a group of 50 self-reported healthy women. The hrHPV portion of the test was evaluated against the Digene High-Risk HPV HC2 DNA test with vaginal samples obtained from 185 women. Results were concordant for 181/185 of the samples (overall agreement of 97.83%, Cohen’s kappa = 0.93), with sensitivity and specificity values of 94.74% and 98.64%, respectively. Two discrepancies were caused by the Digene assay’s known cross-reactivity with low-risk HPV types, while two additional samples were found to contain hrHPV not detected by Digene. This novel assay could be used to complement conventional cervical cancer screening, because its self-sampling format can expand access among women who would otherwise not participate, and because of its additional information about the composition of the vaginal microbiome and the presence of pathogens.
Biological Sequence Modeling with Convolutional Kernel Networks
Authors: Chen Dexiong , Jacob Laurent , Mairal Julien 
Published: November 2017

AbstractThe growing number of annotated biological sequences available makes it possible to learn genotype-phenotype relationships from data with increasingly high accuracy. When large quantities of labeled samples are available for training a model, convolutional neural networks can be used to predict the phenotype of unannotated sequences with good accuracy. Unfortunately, their performance with medium- or small-scale datasets is mitigated, which requires inventing new data-efficient approaches. In this paper, we introduce a hybrid approach between convolutional neural networks and kernel methods to model biological sequences. Our method enjoys the ability of convolutional neural networks to learn data representations that are adapted to a specific task, while the kernel point of view yields algorithms that perform significantly better when the amount of training data is small. We illustrate these advantages for transcription factor binding prediction and protein homology detection, and we demonstrate that our model is also simple to interpret, which is crucial for discovering predictive motifs in sequences. The source code is freely available athttps://gitlab.inria.fr/dchen/CKN-seq.
Stomach-brain synchrony binds neural representations of the body in a novel, delayed-connectivity resting-state network
Authors: Rebollo Ignacio , Devauchelle Anne-Dominique , Béranger Benoît , Tallon-Baudry Catherine 
Published: November 2017

AbstractResting-state networks offer a unique window into the brain’s functional architecture, but their characterization remains limited to instantaneous connectivity thus far. Here, we describe a novel resting-state network based on the delayed connectivity between the brain and the slow electrical rhythm (0.05 Hz) generated in the stomach. The gastric network cuts across classical resting-state networks with little overlap with autonomic regulation areas. This network is composed of regions with convergent functional properties involved in mapping bodily space through touch, action or vision, as well as mapping external space in bodily coordinates. The network is characterized by a precise temporal sequence of activations within a gastric cycle, beginning with somato-motor cortices and ending with the extrastriate body area and dorsal precuneus. Our results demonstrate that canonical resting-state networks based on instantaneous connectivity represent only one of the possible partitions of the brain into coherent networks based on temporal dynamics.
A Timer for analyzing temporally dynamic changes in transcription during differentiation in vivo
Authors: Bending David , Martín Paz Prieto , Paduraru Alina , Ducker Catherine , Marzaganov Erik , Laviron Marie , Kitano Satsuki , Miyachi Hitoshi , Crompton Tessa , Ono Masahiro 
Published: November 2017

AbstractUnderstanding the mechanisms of cellular differentiation is challenging because differentiation is initiated by signaling pathways that drive temporally dynamic processes, which are difficult to analyse in vivo. We establish a new Tool, Timer-of-cell-kinetics-and-activity (Tocky [toki], time in Japanese). Tocky uses the Fluorescent Timer protein, which spontaneously shifts its emission spectrum from blue-to-red, in combination with computer algorithms to reveal the dynamics of differentiation in vivo. Using a transcriptional target of T cell receptor (TCR)-signaling, we establish Nr4a3-Tocky to follow downstream effects of TCR signaling. Nr4a3-Tocky reveals the temporal sequence of events during regulatory T cell (Treg) differentiation and shows that persistent TCR signals occur during Treg generation. Remarkably, antigen-specific T cells at the site of autoimmune inflammation also show persistent TCR signaling. In addition, by generating Foxp3-Tocky, we reveal the in vivo dynamics of demethylation of the Foxp3 gene. Thus, Tocky is a Tool for cell biologists to address previously inaccessible questions by directly revealing dynamic processes in vivo.SummaryThe authors establish a new Tool, Timer-of-cell-kinetics-and-activity (Tocky) revealing the temporal dynamics of cellular activation and differentiation in vivo. The tool analyses the temporal sequence of molecular processes during cellular differentiation and identifies cells that receive persistent signals in vivo.
Extra-field activity shifts the place field center of mass to encode aversion experience
Authors: Mamad Omar , Agayby Beshoy , Stumpp Lars , Reilly Richard B. , Tsanov Marian 
Published: November 2017

AbstractThe hippocampal place cells encode spatial representation but it remains unclear how they store concurrent positive or negative experiences. Here, we report on place field reconfiguration in response to an innately aversive odor trimethylthiazoline (TMT). The advantage of TMT is the absence of learning curve required for associative fear conditioning. Our study investigated if CA1 place cells, recorded from behaving rats, remap randomly or if their reconfiguration depends on the location of the aversive stimulus perception. Exposure to TMT increased the amplitude of hippocampal beta oscillations in two arms of a maze (TMT arms). We found that a population of place cells with fields located outside the TMT arms increased their activity (extra-field spiking) in the TMT arms during the aversive episodes. These cells exhibited significant shift of the center of mass towards the TMT arms in the subsequent post-TMT recording. The induction of extra-field plasticity was mediated by the basolateral amygdala complex (BLA). Photostimulation of the BLA triggered aversive behavior, synchronized response of hippocampal local field oscillations, augmented theta rhythm amplitude and increased the spiking of place cells for the first 100ms after the light delivery. This occurred only for the extra-field-but not for intra-field spikes. Optogenetic BLA-triggered an increase in extra-field spiking activity correlated to the degree of place field plasticity in the post-ChR2 recording session. Our findings demonstrate that the increased extra-field activity during aversive episodes mediates the degree of subsequent field plasticity.
Theta and alpha oscillations are traveling waves in the human neocortex
Authors: Zhang Honghui , Watrous Andrew J. , Patel Ansh , Jacobs Joshua 
Published: November 2017

SummaryHuman cognition requires the coordination of neural activity across widespread brain networks. Here we describe a new mechanism for large-scale coordination in the human brain: traveling waves of theta and alpha oscillations. Examining direct brain recordings from neurosurgical patients performing a memory task, we found contiguous clusters of cortex in individual patients with oscillations at specific frequencies between 2 to 15 Hz. These clusters displayed spatial phase gradients, indicating that the oscillations were traveling waves that propagated across the cortex at ∼0.25-0.75 m/s. Traveling waves were relevant behaviorally because their propagation correlated with task events and was more consistent when subjects performed the task well. Our findings suggest that traveling waves can be modeled by a network of coupled oscillators because the direction of wave propagation correlated with the spatial orientation of local frequency gradients. These findings suggest a role for traveling waves in supporting brain connectivity by organizing neural processes across space and time.
PPARD regulation in gastric progenitor cells drives gastric tumorigenesis in mice
Authors: Zuo Xiangsheng , Deguchi Yasunori , Xu Weiguo , Wei Daoyan , Tian Rui , Chen Weidong , Moussalli Micheline J. , Liu Yi , Mao Fei , Xu Min , Yang Yaying , Gao Shen , Jaoude Jonathan C. , Liu Fuyao , Gagea Mihai , Broaddus Russell , Xie Keping , Shureiqi Imad 
Published: November 2017

AbstractLittle is known about the cell origin of gastric cancer. Peroxisome proliferator-activated receptor-delta (PPARD) is a druggable ligand-activated nuclear receptor that impacts protumorigenic cellular events. However, PPARD’s role in tumorigenesis, especially gastric tumorigenesis, remains to be defined. We found that targeting PPARD overexpression in murine gastric progenitor cells (GPC), via a villin promoter, spontaneously induced gastric tumorigenesis that progressed to invasive adenocarcinoma. PPARD overexpression in GPC upregulated tumorigenic proinflammatory cytokine and CD44 expression, expanded GPC populationin vivo, enhanced GPC self-renewal and proliferation in organoid cultures, and endowed these cells with tumorigenic properties. Our findings identify PPARD as a driver of gastric tumorigenesis via GPC transformation.