bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating and interpreting nonlinear receptive fields of sensory responses with deep neural network models
Authors: Keshishian Menoua , Akbari Hassan , Khalighinejad Bahar , Herrero Jose , Mehta Ashesh D. , Mesgarani Nima 
Published: November 2019

AbstractSensory processing by neural circuits includes numerous nonlinear transformations that are critical to perception. Our understanding of these nonlinear mechanisms, however, is hindered by the lack of a comprehensive and interpretable computational framework that can model and explain nonlinear signal transformations. Here, we propose a data-driven framework based on deep neural network regression models that can directly learn any nonlinear stimulus-response mapping. A key component of this approach is an analysis method that reformulates the exact function of the trained neural network as a collection of stimulus-dependent linear functions. This locally linear receptive field interpretation of the network function enables straightforward comparison with conventional receptive field models and uncovers nonlinear encoding properties. We demonstrate the efficacy of this framework by predicting the neural responses recorded invasively from the auditory cortex of neurosurgical patients as they listened to speech. Our method significantly improves the prediction accuracy of auditory cortical responses particularly in nonprimary areas. Moreover, interpreting the functions learned by neural networks uncovered three distinct types of nonlinear transformations of speech that varied considerably in primary and nonprimary auditory regions. By combining two desired properties of a computational sensory-response model; the ability to capture arbitrary stimulus-response mappings and maintaining model interpretability, this data-driven method can lead to better neurophysiological models of the sensory processing.
Neurocomputational mechanisms underlying immoral decisions benefiting self or others
Authors: Qu Chen , Hu Yang , Tang Zixuan , Derrington Edmund , Dreher Jean-Claude 
Published: November 2019

AbstractImmoral behavior often consists of weighing transgression of a moral norm against maximizing personal profits. One important question is to understand why immoral behaviors vary based on who receives specific benefits and what are the neurocomputational mechanisms underlying such moral flexibility. Here, we used model-based fMRI to investigate how immoral behaviors change when benefiting oneself or someone else. Participants were presented with offers requiring a tradeoff between a moral cost (i.e., profiting a morally bad cause) and a benefit for either oneself or a charity. Participants were more willing to obtain ill-gotten profits for themselves than for a charity, driven by a devaluation of the moral cost when deciding for their own interests. The subjective value of an immoral offer, computed as a linear summation of the weighed monetary gain and moral cost, recruited the ventromedial prefrontal cortex regardless of beneficiaries. Moreover, paralleling the behavioral findings, this region enhanced its functional coupling with mentalizing-related regions while deciding whether to gain morally-tainted profits for oneself vs. charity. Finally, individual differences in moral preference differentially modulated choice-specific signals in the dorsolateral prefrontal cortex according to who benefited from the decisions. These findings provide insights for understanding the neurobiological basis of moral flexibility.
Dissemination of linezolid-resistance through sex pheromone plasmid transfer in Enterococcs faecalis
Authors: Zou Jiaqi , Tang Zhaobing , Yan Jia , Liu Hang , Chen Yingzhu , Zhang Dawei , Zhao Jinxin , Tang Yu , Zhang Jing , Xia Yun 
Published: November 2019

AbstractDespite recent recognition of the ATP-binding cassette protein OptrA as an important mediator of linezolid-resistance in Enterococcus faecalis worldwide, the mechanisms of optrA gene acquisition and transfer remain poorly understood. In this study, we performed comprehensive molecular and phenotypic profiling of 44 optrA-carrying E. faecalis clinical isolates with linezolid-resistance. Pulse-field gel electrophoresis and DNA hybridization revealed the presence of optrA in the plasmid in 26 (59%) isolates and in the chromosome in 18 (41%) isolates. Conjugation experiments showed a successful transfer of optrA in 88.5% (23/26) of isolates carrying optrA in plasmids while no transfer occurred in any isolates carrying optrA in the chromosome (0/18). All 23 transconjugants exhibited in vitro resistance to linezolid and several other antibiotics, and were confirmed to contain optrA and other resistance genes. Plasmid typing demonstrated a predominance (18/23 or 78%) of rep9–type plasmids (pCF10 prototype) known to be the best studied sex pheromone responsive plasmids. Full plasmid genome sequencing of one isolate revealed the presence of drug resistance genes (optrA and fexA) and multiple sex pheromone response genes in the same plasmid, which represents the first sex pheromone responsive plasmid carrying optrA from a clinical isolate. PCR-based genotyping revealed the presence of three key sex pheromone response genes (prgA, prgB and prgC) in almost all 23 optrA-carrying isolates tested. Finally, functional studies of these isolates by clumping induction assay detected different degrees of clumping in most of the 23 isolates. Our analysis strongly suggests that optrA-mediated linezolid-resistance can be widely disseminated through sex pheromone plasmid transfer.
Nicotine e-cigarette vapor inhalation effects on nicotine & cotinine plasma levels and somatic withdrawal signs in adult male Wistar rats
Authors: Montanari Christian , Kelley Leslie K , Kerr Tony M , Cole Maury , Gilpin Nicholas W. 
Published: November 2019

AbstractRationaleNon-contingent chronic nicotine exposure procedures have evolved rapidly in recent years, culminating in Electronic Nicotine Delivery Systems (ENDS or e-cigarettes) to deliver vaporized drugs to rodents in standard housing chambers.ObjectivesThe aim of the current work was to use ENDS to test concentration-dependent effects of nicotine e-cigarette vapor inhalation on blood-nicotine concentrations, blood-cotinine concentrations, and somatic withdrawal signs over time in rats.MethodsMale Wistar rats were exposed to vapor containing various concentrations of nicotine (20, 40, 80 mg/mL) for 11 days through ENDS, and blood concentrations of nicotine and cotinine, the major proximate metabolite of nicotine, as well as spontaneous and precipitated somatic withdrawal signs were measured over time (across days of exposure and over hours after termination of vapor exposure).ResultsExposing male Wistar rats to non-contingent nicotine vapor inhalation through ENDS produces somatic withdrawal symptoms and measurable blood-nicotine and blood-cotinine levels that change according to 1) concentration of nicotine in vape solution, 2) number of days of nicotine vapor exposure, 3) time since termination of nicotine vapor exposure, and 4) relative to the withdrawal signs, whether withdrawal was spontaneous or precipitated (by mecamylamine).ConclusionsThe data presented here provide parameters that can be used as a reasonable starting point for future work that employs ENDS to deliver non-contingent nicotine vapor in rats, although many parameters can and should be altered to match the specific goals of future work.
Antiretroviral APOBEC3 Cytidine Deaminases Alter HIV-1 Provirus Integration Site Profiles
Authors: Ajoge Hannah O. , Renner Tyler M. , Bélanger Kasandra , Kohio Hinissan P. , Coleman Macon D. , Langlois Marc-André , Barr Stephen D. 
Published: November 2019

ABSTRACTAPOBEC3 (A3) proteins are host-encoded deoxycytidine deaminases that provide an innate immune barrier to retroviral infection, notably against HIV-1. While the catalytic activity of these proteins can induce catastrophic hypermutation in proviral DNA leading to near-total restriction of infection, sublethal levels of deamination contribute to the genetic evolution of HIV-1. So far, little is known about how A3 might impact HIV-1 integrations into human chromosomal DNA. Using a deep sequencing approach, we analyzed the influence A3F and A3G on HIV-1 integration site selections. DNA editing was detected at the extremities of the long terminal repeat regions of the virus. Both catalytic active and non-catalytic A3 enzymes decreased insertions into gene coding sequences and increased integration sites into SINE elements, oncogenes and transcription-silencing non-B DNA features. Our data implicate A3 as host factors that influence HIV-1 integration site selection and promote insertions into genomic sites that are transcriptionally less active.GRAPHICAL ABSTRACTSchematic depicting the influence of APOBEC3 (A3) proteins on HIV integration site targeting.Left, in the absence of A3, HIV has a strong preference for integrating into genes.Right, both catalytic active and non-catalytic A3 mutants decrease integration into genes and increase integration into SINE elements and in transcription-silencing non-B DNA features.
Matrix Inversion and Subset Selection (MISS): A novel pipeline for mapping of diverse cell types across the murine brain
Authors: Mezias Christopher , Torok Justin , Maia Pedro D. , Markley Eric , Raj Ashish 
Published: November 2019

ABSTRACTThe advent of increasingly sophisticated imaging platforms has allowed for the visualization of the murine nervous system at single-cell resolution. However, current experimental approaches have not yet produced whole-brain maps of a comprehensive set of neuronal and nonneuronal types that approaches the cellular diversity of the mammalian cortex. Here we aim to fill in this gap in knowledge with an open-source computational pipeline, Matrix Inversion with Subset Selection (MISS), that can infer quantitatively validated distributions of diverse collections of neural cell types at 200μm resolution using a combination of single-cell RNAseq and in situ hybridization datasets. We rigorously demonstrate the accuracy of MISS against literature expectations. Importantly, we show that gene subset selection, a procedure by which we filter out low-information genes prior to performing deconvolution, is a critical pre-processing step that distinguishes MISS from its predecessors and facilitates the production of cell type maps with significantly higher accuracy. We also show that MISS is generalizable by generating high-quality cell type maps from a second, independently curated single-cell RNAseq dataset. Together, our results illustrate the viability of computational approaches for determining the spatial distributions of a wide variety of cell types from genetic data alone.
Nanopore sequencing of DNA concatemers reveals higher-order features of chromatin structure
Authors: Ulahannan Netha , Pendleton Matthew , Deshpande Aditya , Schwenk Stefan , Behr Julie M. , Dai Xiaoguang , Tyer Carly , Rughani Priyesh , Kudman Sarah , Adney Emily , Tian Huasong , Wilkes David , Mosquera Juan Miguel , Stoddart David , Turner Daniel J. , Juul Sissel , Harrington Eoghan , Imielinski Marcin 
Published: November 2019

AbstractHigher-order chromatin structure arises from the combinatorial physical interactions of many genomic loci. To investigate this aspect of genome architecture we developed Pore-C, which couples chromatin conformation capture with Oxford Nanopore Technologies (ONT) long reads to directly sequence multi-way chromatin contacts without amplification. In GM12878, we demonstrate that the pairwise interaction patterns implicit in Pore-C multi-way contacts are consistent with gold standard Hi-C pairwise contact maps at the compartment, TAD, and loop scales. In addition, Pore-C also detects higher-order chromatin structure at 18.5-fold higher efficiency and greater fidelity than SPRITE, a previously published higher-order chromatin profiling technology. We demonstrate Pore-C’s ability to detect and visualize multi-locus hubs associated with histone locus bodies and active / inactive nuclear compartments in GM12878. In the breast cancer cell line HCC1954, Pore-C contacts enable the reconstruction of complex and aneuploid rearranged alleles spanning multiple megabases and chromosomes. Finally, we apply Pore-C to generate a chromosome scalede novoassembly of the HG002 genome. Our results establish Pore-C as the most simple and scalable assay for the genome-wide assessment of combinatorial chromatin interactions, with additional applications for cancer rearrangement reconstruction andde novogenome assembly.
Secondary environmental variation creates a shifting evolutionary watershed for the methyl-parathion hydrolase enzyme
Authors: Anderson Dave W. , Baier Florian , Yang Gloria , Tokuriki Nobuhiko 
Published: November 2019

AbstractEnzymes can evolve new catalytic activity when their environments change to present them with novel substrates. Despite this seemingly straightforward relationship, factors other than the direct catalytic target can also impact enzyme adaptation. Here, we characterize the adaptive landscape separating an ancestral dihydrocoumarin hydrolase from a methyl parathion hydrolase descendant under eight different environments supplemented with alternative divalent metals. This variation shifts an evolutionary watershed, causing the outcome of adaptation to depend on the environment in which it occurs. The resultant landscapes also vary in terms both the number and the genotype(s) of “fitness peaks” as a result of genotype-by-environment (G×E) interactions and environment-dependent epistasis (G×G×E). This suggests that adaptive landscapes may be fluid and that molecular adaptation is highly contingent not only on obvious factors (such as catalytic targets) but also on less obvious secondary environmental factors that can direct it toward distinct outcomes.
A cell-free biosynthesis platform for modular construction of protein glycosylation pathways
Authors: Kightlinger Weston , Duncker Katherine E. , Ramesh Ashvita , Thames Ariel H. , Natarajan Aravind , Yang Allen , Stark Jessica C. , Lin Liang , Mrksich Milan , DeLisa Matthew P. , Jewett Michael C. 
Published: November 2019

AbstractGlycosylation plays important roles in cellular function and endows protein therapeutics with beneficial properties. However, constructing biosynthetic pathways to study and engineer protein glycosylation remains a bottleneck. To address this limitation, we describe a modular, versatile cell-free platform for glycosylation pathway assembly by rapid in vitromixing and expression (GlycoPRIME). In GlycoPRIME, crude cell lysates are enriched with glycosyltransferases by cell-free protein synthesis and then glycosylation pathways are assembled in a mix-and-match fashion to elaborate a single glucose priming handle installed by an N-linked glycosyltransferase. We demonstrate GlycoPRIME by constructing 37 putative protein glycosylation pathways, creating 23 unique glycan motifs. We then use selected pathways to design a one-pot cell-free system to synthesize a vaccine protein with an α-galactose motif and engineered Escherichia coli strains to produce human antibody constant regions with minimal sialic acid motifs. We anticipate that our work will facilitate glycoscience and make possible new glycoengineering applications.
Complete genome sequence of Oryctes rhinoceros Nudivirus isolated from Coconut Rhinoceros Beetle in the Solomon Islands
Authors: Etebari Kayvan , Filipović Igor , Rašić Gordana , Devine Gregor J. , Tsatsia Helen , Furlong Michael J. 
Published: November 2019

AbstractOryctes Nudivirus (OrNV) has been an effective biocontrol agent against the insect pest Oryctes rhinoceros (Coleoptera: Scarabaeidae) for decades, but there is evidence that resistance could be evolving in some host populations. We detected OrNv infection in O. rhinoceros from the Solomon Islands and used Oxford Nanopore Technologies (ONT) long-read sequencing to determine the full length of the virus genomic sequence isolated from an individual belonging to a mitochondrial lineage (CRB-G) that was previously reported as resistant to OrNV. The complete circular genome of the virus consisted of 125,917 nucleotides, encoding 130 open reading frames (ORFs) for proteins in the range ~5 kDa (51aa) to ~140 kDa (1280aa). This Solomon Islands isolate has high (99.85%) nucleotide sequence identity to the previously sequenced isolate PV505 from Southern Luzon, Philippines, and has 138 amino acid modifications when compared with the originally described full genome sequence of the Ma07 strain from Malaysia.
A Unified Molecular Signature of Systemic Lupus Erythematosus Revealed by Integrated, Multi-Cohort Transcriptomic Analysis
Authors: Haynes Winston A. , Haddon D. James , Diep Vivian K. , Khatri Avani , Bongen Erika , Yiu Gloria , Balboni Imelda , Bolen Christopher R. , Mao Rong , Utz Paul J. , Khatri Purvesh 
Published: November 2019

AbstractSystemic lupus erythematosus (SLE) is a complex autoimmune disease that follows an unpredictable disease course and affects multiple organs and tissues. We performed an integrated, multi-cohort analysis of 7,471 transcriptomic profiles from 40 independent studies to identify robust gene expression changes associated with SLE. We identified a 93-gene signature (SLE MetaSignature) that is differentially expressed in the blood of SLE patients compared to healthy volunteers; distinguishes SLE from other autoimmune, inflammatory, and infectious diseases; and persists across diverse tissues and cell types. The SLE MetaSignature correlated significantly with disease activity and other clinical measures of inflammation. We prospectively validated the SLE MetaSignature in an independent cohort of pediatric SLE patients using a microfluidic RT-qPCR array. We found that 14 of the 93 genes in the SLE MetaSignature were independent of interferon-induced and neutrophil-related transcriptional profiles that have previously been associated with SLE. Pathway analysis revealed dysregulation associated with nucleic acid biosynthesis and immunometabolism in SLE. We further refined a neutropoeisis signature and identified under-appreciated transcripts related to immune cells and oxidative stress. Our multi-cohort, transcriptomic analysis has uncovered under-appreciated genes and pathways associated with SLE pathogenesis, with the potential to advance clinical diagnosis, biomarker development, and targeted therapeutics for SLE.
The ‘Threat of Scream’ paradigm: A tool for studying sustained physiological and subjective anxiety
Authors: Beaurenaut Morgan , Tokarski Elliot , Dezecache Guillaume , Grèzes Julie 
Published: November 2019

AbstractProgress in understanding the emergence of pathological anxiety depends on the availability of paradigms effective in inducing anxiety in a simple, consistent and sustained way. Much progress has been made using the Threat-of-Shock paradigm (TOS), which generates anxiety through the delivery of unpredictable electric shocks to participants. However, TOS may be problematic when testing vulnerable populations. Moreover, it is not clear whether anxiety can be sustained throughout experiments of long duration. Here, we bring support for an alternative approach called the Threat-of-Scream paradigm (TOSc), in which the tactile delivery of shocks is replaced by the auditory delivery of distress screams. We report on an one-hour long study (plus its replication) in which participants were exposed to blocks before which they were told that they could hear aversive screams at any time (threat blocks), vs. blocks before which they were told that no scream will be heard (safe blocks). Both the experiment and its replication showed higher subjective reports of anxiety, higher skin conductance level, and positive correlation between the two measures, in threat compared to safe blocks. Anxiety measures were sustained throughout the experiments, suggesting little emotional and physiological habituation. Our results suggest that the delivery of low intensity distress screams can be an efficient, stable and cheap methodology to assess the impact of sustained anxiety on a diversity of cognitive functions and populations. We therefore believe the TOSc will become an essential part of the psychological toolkit, particularly so for researchers interested in the emergence of pathological anxiety.
Study on the influence of G82S RAGE polymorphism on RAGE-Amyloid interaction in AD pathology
Authors: C Rani Cathrine. , Lukose Bincy , Rani P. 
Published: November 2019

AbstractReceptor for advanced glycation end products (RAGE) has been implicated in the pathophysiology of AD due to its ability to bind amyloid-beta and mediate inflammatory response. G82S RAGE polymorphism is associated with AD but the molecular mechanism for this association is not understood. Our previous in silico study indicated a higher binding affinity for mutated G82S RAGE, which could be caused due to changes in N linked glycosylation at residue N81. To confirm this hypothesis, in the present study molecular dynamics (MD) simulations were used to simulate the wild type (WT) and G82S glycosylated structures of RAGE to identify the global structural changes and to find the binding efficiency with Aβ42 peptide. Binding pocket analysis of the MD trajectory showed that cavity/binding pocket in mutant G82S glycosylated RAGE variants is more exposed and accessible to external ligands compared to WT RAGE, which can enhance the affinity of RAGE for Aβ. To validate the above concept, an in vitro binding study was carried using SHSY5Y cell line expressing recombinant WT and mutated RAGE variant individually to which HiLyte Fluor labeled Aβ42 was incubated at different concentrations. Saturated binding kinetics method was adopted to determine the Kd values for Aβ42 binding to RAGE. The Kd value for Aβ42-WT and Aβ42-mutant RAGE binding were 92±40 nM (95% CI-52 to 152nM; R2-0.92) and 45±20 nM (95% CI −29 to 64nM; R2-0.93), respectively. The Kd value of <100nM observed for both variants implicates RAGE as a high-affinity receptor for Aβ42 and mutant RAGE has higher affinity compared to WT. The alteration in binding affinity is responsible for activation of the inflammatory pathway as implicated by enhanced expression of TNFα and IL6 in mutant RAGE expressing cell line which gives a mechanistic view for the G82S RAGE association with AD.