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Chen, G.

Publications and source records attributed to Chen, G..

At least 343 records · Page 19Linked to original sources

Second messengers and divergent HD-GYP enzymes regulate 3’,3’-cGAMP signaling

3,3-cyclic GMP-AMP (cGAMP) is the third cyclic dinucleotide (CDN) to be discovered in bacteria. No activators of cGAMP signaling have yet been identified, and the signaling pathways for cGAMP have appeared narrowly distributed based upon the characterized synthases, DncV and Hypr GGDEFs. Here we report that the ubiquitous second messenger cyclic AMP (cAMP) is an activator of the Hypr GGDEF enzyme GacB from Myxococcus xanthus. Furthermore, we show that GacB is inhibited directly by cyclic di-GMP, which provides evidence for cross-regulation between different CDN pathways. Finally, we reveal that the HD-GYP enzyme PmxA is a cGAMP-specific phosphodiesterase (GAP) that promotes resistance to osmotic stress in M. xanthus. A signature amino acid change in PmxA was found to reprogram substrate specificity and was applied to predict the presence of non-canonical HD-GYP phosphodiesterases in many bacterial species, including phyla previously not known to utilize cGAMP signaling.

biochemistry↗

PERK inhibition mitigates restenosis and thrombosis - a potential low-thrombogenic anti-restenotic paradigm

BackgroundDrug-eluting stents (DES) represent the main-stream management of restenosis following treatments of occlusive cardiovascular diseases. However, DES cannot eliminate instent restenosis yet exacerbate thrombogenic risks. To achieve dual inhibition of restenotic smooth muscle cell (SMC) de-differentiation/proliferation and thrombogenic endothelial cell (EC) dysfunction, a common target in both cell types, has been long-sought after. We evaluated the potential of protein kinase RNA-like endoplasmic reticulum kinase (PERK) as such a target for low-thrombogenic anti-restenotic intervention.\n\nMethods and ResultsWe used a rat angioplasty model of restenosis and a FeCl3-induced mouse model of thrombosis. Loss-or gain-of-function was achieved by PERK inhibition (GSK2606414, siRNA) or overexpression (adenovirus). Restenosis was robustly mitigated by GSK2606414 administered either via injected (i.v.) lesion-homing platelet membrane-coated nanoclusters or a perivascular hydrogel; it was enhanced by PERK transgene. Whereas PERK inhibition blocked, its overexpression exacerbated PDGF-induced human aortic SMC de-differentiation (reduced smooth muscle -actin or SMA) and proliferation (BrdU incorporation). Further, PERK activity promoted STAT3 activation but inhibited SRF transcriptional (luciferase) activity; its protein co-immunoprecipitated with STAT3 and also MRTF-A, the SRF activator for SMA transcription. Importantly, PERK inhibition also prevented TNF-induced impairment of human EC growth and upregulation of thrombogenic tissue factor, both in vitro and ex vivo. In vivo, oral gavage of GSK2606414 preserved ~50% of the normal blood flow 60 min after FeCl3-induced vascular injury.\n\nConclusionsPERK inhibition is dual beneficial in mitigating restenosis and thrombosis, thus implicating a potential design for anti-restenotic intervention to overcome the thrombogenicity of DES.

pathology↗

Impact of Prior Cancer on Outcomes in Nasopharyngeal Carcinoma

BackgroundPrior cancer is a common exclusion criterion in nasopharyngeal carcinoma (NPC) trials. However, whether a prior cancer diagnosis affects trial outcomes is still unknown. We aimed to determine the impact of prior cancer on survival in NPC. MethodsWe identified patients diagnosed with NPC between 2004 and 2009 in the Surveillance, Epidemiology, and End Results (SEER) database. Variables were compared by chi-squared test and t-test as appropriate. Propensity score-adjusted Kaplan-Meier methods and Cox proportional hazard models were used to evaluate the impact of prior cancer on overall survival (OS). ResultsAmong 3,131 eligible NPC patients, 349 (11.15%) patients had a history of prior cancer. The Kaplan-Meier curves did not show a statistically significantly different OS (p=0.19). Subgroup analyses stratified by timing of prior cancer and AJCC TNM stage of index cancer displayed the same tendency, prior cancer didnt adversely affect OS compared with patients without prior cancer (p>0.05). Furthermore, in propensity score-adjusted COX models analysis, patients with prior cancer had the same/non-inferior OS (hazard ratio [HR] = 1.12, 95% confidence interval= 0.88 to 1.42). ConclusionsAmong patients with nasopharyngeal carcinoma, prior cancer does not convey an adverse effect on clinical outcomes, regardless of the timing of prior cancer and AJCC TNM stage of index cancer. Broader inclusion trial criteria could be adopted in nasopharyngeal carcinoma patients with a history of prior cancer. However, further studies are still needed to confirm.

epidemiology↗

Genetic risk for major depressive disorder and loneliness in gender-specific associations with coronary artery disease

ImportanceEpidemiological evidence indicates that major depressive disorder (MDD) and loneliness both reduce life expectancies, but mechanisms underlying the excess morbidity are unclear. Electronic health records (EHRs) linked to genetic data offer new opportunities to address this knowledge gap.\n\nObjectiveTo determine the medical morbidity pattern associated with genetic risk factors for MDD and loneliness, two common psychological traits with adverse health outcomes.\n\nDesignPhenome-wide association study using EHRs spanning 1990 to 2017 from the Vanderbilt University Medical Center biobank, BioVU. Top associations with coronary artery disease (CAD) were replicated in the Atherosclerosis Risk in Communities (ARIC) cohort.\n\nSettingHospital-based EHR study, with replication in a population-based cohort study.\n\nParticipants18,385 genotyped adult patients in BioVU. Replication in ARIC included 7,197 genotyped participants. All participants were of European ancestry.\n\nExposuresPolygenic scores for MDD and loneliness were developed for each individual using previously published meta-GWAS summary statistics.\n\nMain Outcomes and MeasuresThe phenome-wide association study included 882 clinical diagnoses ascertained via billing codes in the EHR. ARIC included 1598 incident CAD cases.\n\nResultsBioVU patients had a median EHR length of 9.91 years. In the phenome-wide association study, polygenic scores for MDD and loneliness were significantly associated with psychiatric and cardiac phenotypes. Targeted analyses of CAD in 3,893 cases and 4,197 controls in BioVU found odds ratios of 1.11 (95% CI, 1.04-1.18; P=8.43x10-4) and 1.13 (95% CI, 1.07-1.20; P=4.51x10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Comparable hazard ratios in ARIC were 1.07 (95% CI, 0.99-1.14; P=0.07) and 1.07 (1.01-1.15; P=0.03). Across both studies, the increased risk persisted in women after adjusting for multiple conventional risk factors, a polygenic score for CAD, and psychiatric symptoms (available in BioVU). Controlling for genetic risk factors shared between MDD and loneliness, the polygenic score for loneliness conditioned on MDD remained associated with CAD risk, but the polygenic score for MDD conditioned on loneliness did not.\n\nConclusions and RelevanceGenetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in women. Continued research into the biological and clinical connections between the heart and mind is warranted.

genetics↗

Accurate loop calling for 3D genomic data with cLoops

Sequencing-based 3D genome mapping technologies can identify loops formed by interactions between regulatory elements hundreds of kilobases apart. Existing loop-calling tools are mostly restricted to a single data type, with accuracy dependent on a pre-defined resolution contact matrix or called peaks, and can have prohibitive hardware costs. Here we introduce cLoops ( see loops) to address these limitations. cLoops is based on the clustering algorithm cDBSCAN that directly analyzes the paired-end tags (PETs) to find candidate loops and uses a permuted local background to estimate statistical significance. These two data-type-independent processes enable loops to be reliably identified for both sharp and broad peak data, including but not limited to ChIA-PET, Hi-C, HiChIP and Trac-looping data. Loops identified by cLoops showed much less distance-dependent bias and higher enrichment relative to local regions than existing tools. Altogether, cLoops improves accuracy of detecting of 3D-genomic loops from sequencing data, is versatile, flexible, efficient, and has modest hardware requirements, and is freely available at: https://github.com/YaqiangCao/cLoops.

bioinformatics↗

One Model to Rule Them All: An Integrative Approach to Matrix-Based Analyses in Neuroimaging Connectomics

Network modeling in neuroimaging holds promise in probing the interrelationships among brain regions and potential clinical applications. Two types of matrix-based analysis (MBA) are usually seen in neuroimaging connectomics: one is the functional attribute matrix (FAM) of, for example, correlations, that measures the similarity of BOLD response patterns among a list of predefined regions of interest (ROIs). Another type of MBA involves the structural attribute matrix (SAM), e.g., describing the properties of white matter between any pair of gray-matter regions such as fractional anisotropy, mean diffusivity, axial and radial diffusivity. There are different methods that have been developed or adopted to summarize such matrices across subjects, including general linear models (GLMs) and various versions of graph theoretic analysis. We argue that these types of modeling strategies tend to be \"inefficient\" in statistical inferences and have many pitfalls, such as having strong dependence on arbitrary thresholding under conventional statistical frameworks.\n\nHere we offer an alternative approach that integrates the analyses of all the regions, region pairs (RPs) and subjects into one framework, called Bayesian multilevel (BML) modeling. In this approach, the intricate relationships across regions as well as across RPs are quantitatively characterized. This integrative approach avoids the multiple testing issue that typically plagues the conventional statistical analysis in neuroimaging, and it provides a principled way to quantify both the effect and its uncertainty at each region as well as for each RP. As a result, a unique feature of BML is that the effect at each region and the corresponding uncertainty can be estimated, revealing the relative strength or importance of each region; in addition, the effect at each RP is obtained along with its uncertainty as statistical evidence. Most importantly, the BML approach can be scrutinized for consistency through validation and comparisons with alternative assumptions or models. We demonstrate the BML methodology with a real dataset with 16 ROIs from 41 subjects, and compare it to the conventional GLM approach in terms of model efficiency, performance and inferences. Furthermore, we emphasize the notion of full results reporting through \"highlighting,\" instead of through the common practice of \"hiding.\" The associated program will be available as part of the AFNI suite for general use.

neuroscience↗

Social relationships, social isolation, and the human gut microbiota

Social relationships shape human health and mortality via behavioral, psychosocial, and physiological mechanisms, including inflammatory and immune responses. Though not tested in human studies, recent primate studies indicate that the gut microbiome may also be a biological mechanism linking relationships to health. Integrating microbiota data into the 60-year-old Wisconsin Longitudinal Study, we found that socialness with family and friends is associated with differences in the human fecal microbiota. Analysis of spouse (N = 94) and sibling pairs (N = 83) further revealed that spouses have more similar microbiota and more bacterial taxa in common than siblings, with no observed differences between sibling and unrelated pairs. These differences held even after accounting for dietary factors. The differences between unrelated individuals and married couples was driven entirely by couples who reported close relationships; there were no differences in similarity between couples reporting somewhat close relationships and unrelated individuals. Moreover, the microbiota of married individuals, compared to those living alone, has greater diversity and richness, with the greatest diversity among couples reporting close relationships, which is notable given decades of research documenting the health benefits of marriage. These results suggest that human interactions, especially sustained, close marital relationships, influence the gut microbiota.

microbiology↗

Cortex-wide neural interfacing via transparent polymer skulls

Neural computations occurring simultaneously in multiple cerebral cortical regions are critical for mediating cognition, perception and sensorimotor behaviors. Enormous progress has been made in understanding how neural activity in specific cortical regions contributes to behavior. However, there is a lack of tools that allow simultaneous monitoring and perturbing neural activity from multiple cortical regions. To fill this need, we have engineered \"See-Shells\" - digitally designed, morphologically realistic, transparent polymer skulls that allow long-term (>200 days) optical access to 45 mm2 of the dorsal cerebral cortex in the mouse. We demonstrate the ability to perform mesoscopic imaging, as well as cellular and subcellular resolution two-photon imaging of neural structures up to 600 {micro}m through the See-Shells. See-Shells implanted on transgenic mice expressing genetically encoded calcium (Ca2+) indicators allow tracking of neural activities from multiple, non-contiguous regions spread across millimeters of the cortex. Further, neural probes can access the brain through perforated See-Shells, either for perturbing or recording neural activity from localized brain regions simultaneously with whole cortex imaging. As See-Shells can be constructed using readily available desktop fabrication tools and modified to fit a range of skull geometries, they provide a powerful tool for investigating brain structure and function.

neuroscience↗

Optimizing guide RNA selection and CRISPR/Cas9 methodology for efficient generation of deletions in C. elegans.

The Caenorhabditis elegans Gene Knockout (KO) Consortium is tasked with obtaining null mutations in each of the more than 20,000 open reading frames (ORFs) of this organism. To date, approximately15,000 ORFs have associated putative null alleles. A directed approach using CRISPR/Cas9 methodology is the most promising technique to complete the task. While there has been substantial success in using CRISPR/Cas9 in C. elegans, there has been little emphasis on optimizing the method for generating large insertions/deletions in this organism. To enhance the efficiency of using CRISPR/Cas9 to generate gene knockouts in C. elegans we have developed an online species-specific guide RNA selection tool (http://genome.sfu.ca/crispr). When coupled with previously developed selection vectors, optimization for homology arm length, and the use of purified Cas9 protein, we demonstrate a robust, efficient and effective protocol for generating deletions. Debate and speculation in the larger scientific community about off- target effects due to non-specific Cas9 cutting has prompted us to investigate through whole genome sequencing the occurrence of single nucleotide variants and indels accompanying targeted deletions. We did not detect any off-site variants above the natural spontaneous mutation rate and therefore conclude this modified protocol does not generate off-target events to any significant degree in C. elegans.

genetics↗

Interleukin-17 regulates neuron-glial communications, inhibitory synaptic transmission and neuropathic pain after chemotherapy

The proinflammatory cytokine Interleukin-17 (IL-17) is produced mainly by Th17 cells and has been implicated in pain regulation. However, synaptic mechanisms by which IL-17 regulates pain transmission are unknown. Here we report that glia-produced IL-17 suppresses inhibitory synaptic transmission in spinal cord pain circuit and drives chemotherapy-induced neuropathic pain. We observed respective expression of IL-17 and its receptor IL-17R in spinal cord astrocytes and neurons. Patch clamp recording in spinal cord slices revealed that IL-17 not only enhanced EPSCs but also suppressed IPSCs and GABA-induced currents in lamina IIo somatostatin-expressing neurons. Spinal IL-17 was upregulated after paclitaxel treatment, and intrathecal IL-17R blockade reduced paclitaxel-induced neuropathic pain. In dorsal root ganglia, respective IL-17 and IL-17R expression in satellite glial cells and neurons was sufficient and required for inducing neuronal hyperexcitability after paclitaxel. Together, our data show that IL-17/IL-17R mediate both central and peripheral neuron-glial interactions in chemotherapy-induced peripheral neuropathy.

neuroscience↗

A tail of two sides: Artificially doubled false positive rates in neuroimaging due to the sidedness choice with t-tests

One-sided t-tests are widely used in neuroimaging data analysis. While such a test may be applicable when investigating specific regions and prior information about directionality is present, we argue here that it is often mis-applied, with severe consequences for false positive rate (FPR) control. Conceptually, a pair of one-sided t-tests conducted in tandem (e.g., to test separately for both positive and negative effects), effectively amounts to a two-sided t-test. However, replacing the two-sided test with a pair of one-sided tests without multiple comparisons correction essentially doubles the intended FPR of statements made about the same study; that is, the actual family-wise error (FWE) of results at the whole brain level would be 10% instead of the 5% intended by the researcher. Therefore, we strongly recommend that, unless otherwise explicitly justified, two-sided t-tests be applied instead of two simultaneous one-sided t-tests.

neuroscience↗

FMRI processing with AFNI: Some comments and corrections on \"Exploring the Impact of Analysis Software on Task fMRI Results\"

A recent study posted on bioRxiv by Bowring, Maumet and Nichols aimed to compare results of FMRI data that had been processed with three commonly used software packages (AFNI, FSL and SPM). Their stated purpose was to use \"default\" settings of each softwares pipeline for task-based FMRI, and then to quantify overlaps in final clustering results and to measure similarity/dissimilarity in the final outcomes of packages. While in theory the setup sounds simple (implement each packages defaults and compare results), practical realities make this difficult. For example, different softwares would recommend different spatial resolutions of the final data, but for the sake of comparisons, the same value must be used across all. Moreover, we would say that AFNI does not have an explicit default pipeline available: a wide diversity of datasets and study designs are acquired across the neuroimaging community, often requiring bespoke tailoring of basic processing rather than a \"one-size-fits-all\" pipeline. However, we do have strong recommendations for certain steps, and we are also aware that the choice of a given step might place requirements on other processing steps. Given the very clear reporting of the AFNI pipeline used in Bowring et al. paper, we take this opportunity to comment on some of these aspects of processing with AFNI here, clarifying a few mistakes therein and also offering recommendations. We provide point-by-point considerations of using AFNIs processing pipeline design tool at the individual level, afni_proc.py, along with supplementary programs; while specifically discussed in the context of the present usage, many of these choices may serve as useful starting points for broader processing. It is our intention/hope that the user should examine data quality at every step, and we demonstrate how this is facilitated in AFNI, as well.

neuroscience↗

Functional repair after ischemic injury through high efficiency in situ astrocyte-to-neuron conversion

Mammalian brains have largely lost internal neural regeneration capability except for a few discrete neurogenic niches. After brain injury, the cerebral cortex is especially difficult to repair due to its extremely low rate of adult neurogenesis. Previous studies have converted glial cells into neurons, but the total number of neurons generated is rather limited, casting doubt about its therapeutic potential. Here, we demonstrate that high-efficiency neuroregeneration can be achieved in adult mammalian brains by making use of an engineered AAV Cre-FLEX system to convert a large number of reactive astrocytes into functional neurons. Specifically, using a combination of GFAP::Cre and FLEX-NeuroD1 AAV system, we were able to regenerate enough new neurons from astrocytes to cover about 40% of the neurons lost from an ischemic injury (400 NeuN+ new neurons/mm2), compared to previously reported an average of <1% of cortical neurons (2-8 NeuN+ neurons/mm2) in an ischemic-injured adult mammalian cortex. Importantly, this in situ astrocyte-to-neuron conversion process also improved survival of injured pre-existing neurons, (additional 400 neurons/mm2), leading to a repaired motor cortex with layered cortical structures. Moreover, NeuroD1-converted neurons not only form functional neural circuits but also rescue motor and memory deficits after ischemic injury. Our results establish the proof-of-principle that a highly efficient in situ astrocyte-to-neuron conversion approach provides a novel treatment for neurological disorders that are in need of new neurons.

neuroscience↗

Genome-wide survey and expression analysis of the SLAC/SLAH gene family in pear (Pyrus bretschneideri) and other members of the Rosaceae

S-type anion channels (SLAC/SLAHs), which play important roles in plant anion (such as nitrate and chloride) transport, growth and development, abiotic stress responses and hormone signaling. However, there is far less information about this family in Rosaceae species. We performed a genome-wide analysis and identified SLAC/SLAH gene family members in pear (Pyrus bretschneideri) and four other species of Rosaceae (Malus domestica, Prunus persica, Fragaria vesca and Prunus mume). A total of 21 SLAC/SLAH genes were identified from the five Rosaceae species. Based on the structural characteristics and a phylogenetic analysis of these genes, the SLAC/SLAH gene family could be classified into three main groups (I, II and III). The evolutionary analysis showed that the SLAC/SLAH gene family was comparatively conserved during the evolution of Rosaceae species. Transcriptome data demonstrated that PbrSLAC/SLAH genes were detected in all parts of the pear. However, PbrSLAC1 showed a higher expression level in leaf, while PbrSLAH2/3 was mainly expressed in roots. In addition, PbrSLAC/SLAH genes were only located on the plasma membrane in transient expression experiments in Arabidopsis protoplasts cells. These results provide valuable information that increases our understanding of the evolution, expression and functions of the SLAC/SLAH gene family in higher plants.

bioinformatics↗

The first set of universal nuclear protein-coding loci markers for avian phylogenetic and population genetic studies

Multiple nuclear markers provide genetic polymorphism data for molecular systematics and population genetic studies. They are especially required for the coalescent-based analyses that can be used to accurately estimate species trees and infer population demographic histories. However, in avian evolutionary studies, these powerful coalescent-based methods are hindered by the lack of a sufficient number of markers. In this study, we designed PCR primers to amplify 136 nuclear protein-coding loci (NPCLs) by scanning the published Red Junglefowl (Gallus gallus) and Zebra Finch (Taeniopygia guttata) genomes. To test their utility, we amplified these loci in 41 bird species representing 23 Aves orders. The sixty-three best-performing NPCLs, based on high PCR success rates, were selected which had various mutation rates and were evenly distributed across 17 avian autosomal chromosomes and the Z chromosome. To test phylogenetic resolving power of these markers, we conducted a Neoavian phylogenies analysis using 63 concatenated NPCL markers derived from 48 whole genomes of birds. The resulting phylogenetic topology, to a large extent, is congruence with results resolved by previous whole genome data. To test the level of intraspecific polymorphism in these makers, we examined the genetic diversity in four populations of the Kentish Plover (Charadrius alexandrinus) at 17 of NPCL markers chosen at random. Our results showed that these NPCL markers exhibited a level of polymorphism comparable with mitochondrial loci. Therefore, this set of pan-avian nuclear protein-coding loci has great potential to facilitate studies in avian phylogenetics and population genetics.

evolutionary biology↗

Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion

Nerve injury often causes neuronal loss and glial proliferation, disrupting the delicate balance between neurons and glial cells in the brain. Recently, we have developed an innovative technology to convert internal reactive glial cells into functional neurons inside the mouse brain. Here, we further demonstrate that such glia-to-neuron conversion can rebalance neuron-glia ratio and reverse glial scar back to neural tissue. Specifically, using a severe stab injury model in the mouse cortex, we demonstrated that ectopic expression of NeuroD1 in reactive astrocytes significantly reduced glial reactivity and transformed toxic A1 astrocytes into less harmful astrocytes before neuronal conversion. Importantly, astrocytes were not depleted after neuronal conversion but rather repopulated due to its intrinsic proliferation capability. Remarkably, converting reactive astrocytes into neurons also significantly reduced microglia-mediated neuroinflammation. Moreover, accompanying regeneration of new neurons together with repopulation of new astrocytes, blood-brain-barrier was restored and synaptic density was rescued in the injury sites. Together, these results demonstrate that glial scar can be reversed back to neural tissue through rebalancing neuron:glia ratio after glia-to-neuron conversion.

neuroscience↗

Combining high-throughput micro-CT-RGB phenotyping and genome-wide association study to dissect the genetic architecture of tiller growth in rice

Traditional phenotyping of rice tillers is time consuming and labor intensive and lags behind the rapid development of rice functional genomics. Thus, dynamic phenotyping of rice tiller traits at a high spatial resolution and high-throughput for large-scale rice accessions is urgently needed. In this study, we developed a high-throughput micro-CT-RGB (HCR) imaging system to non-destructively extract 730 traits from 234 rice accessions at 9 time points. We used these traits to predict the grain yield in the early growth stage, and 30% of the grain yield variance was explained by 2 tiller traits in the early growth stage. A total of 402 significantly associated loci were identified by GWAS, and dynamic and static genetic components were found across the nine time points. A major locus associated with tiller angle was detected at nine time points, which contained a major gene TAC1. Significant variants associated with tiller angle were enriched in the 3'-UTR of TAC1. Three haplotypes for the gene were found and tiller angles of rice accessions containing haplotype H3 were much smaller. Further, we found two loci contained associations with both vigor-related HCR traits and yield. The superior alleles would be beneficial for breeding of high yield and dense planting.\n\nHighlightCombining high-throughput micro-CT-RGB phenotyping facility and genome-wide association study to dissect the genetic architecture of rice tiller development by using the indica subpopulation.

genetics↗

Spatial cell firing during virtual navigation of open arenas by head-restrained mice

We present a mouse virtual reality (VR) system which restrains head-movements to horizontal rotations, potentially compatible with multi-photon imaging. We show that this system allows expression of the spatial navigational behaviour and neuronal firing patterns characteristic of real open arenas (R). Place and grid, but not head-direction, cell firing had broader spatial tuning in VR than R. Theta frequency increased less with running speed in VR than in R, while firing rates increased similarly in both. Place, but not grid, cell firing was more directional in VR than R. These results suggest that the scale of grid and place cell firing patterns, and the frequency of theta, reflect translational motion inferred from both virtual (visual and proprioceptive) cues and uncontrolled static (vestibular translation and extra-maze) cues, while firing rates predominantly reflect visual and proprioceptive motion. They also suggest that omni-directional place cell firing in R reflects local-cues unavailable in VR.

neuroscience↗