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Robinson, J.

Publications and source records attributed to Robinson, J..

49 records · Page 3Linked to original sources

Thermal stimulation temperature is encoded as a firing rate in a Hydra nerve ring

Many animals that lose neural tissue due to injury or disease have the ability to maintain their behavioral abilities by regenerating new neurons or reorganizing existing neural circuits. However, most small model organisms used for neuroscience like nematodes and flies lack this high degree of neural plasticity. These animals often show significant behavioral deficits if they lose even a single neuron. Here we show that the small freshwater cnidarian Hydra vulgaris can maintain stable sensory motor behaviors even after losing half of the neurons in its body. Specifically, we find that both the behavioral and neural response to a rapid change in temperature is maintained if we make their nervous system roughly 50% smaller by caloric restriction or surgery. These observations suggest that Hydra provides a rich model for studying how animals maintain stable sensory-motor responses within dynamic neural circuit architectures, and may lead to general principles for neural circuit plasticity and stability. Significance StatementThe ability of the nervous system to restore its function following injury is key to survival for many animals. Understanding this neural plasticity in animals across the phylogenetic tree would help reveal fundamental principles of this important ability. To our knowledge, the discovery of a set of neurons in the jellyfish polyp Hydra vulgaris that stably support a response to thermal stimulation is the first demonstration of large-scale neural plasticity in a genetically tractable invertebrate model organism. The small size and transparency of Hydra suggests that it will be possible to study large-scale neural circuit plasticity in an animal where one can simultaneously image the activity of every neuron.

neuroscience↗

Differential gene expression and functional pathway enrichment in fetal colon cell line CCD 841 CoN (CRL-1790) transfected with miR-mimics miR-18b, miR-142-3p, miR-155, and miR-890.

This report is a bioinformatic analysis of samples from NCBI GEO database series GS132501. It includes previously un-reported data for miR-mimic over-expression of the miRNAs miR-18b, miR-155, miR-142-3p, and miR-890 in the ATCC CRL-1790 cell line. Data analysis was performed using Nanostring nSolver 4.0 and Advanced Analysis Module 2.0 plugin (Nanostring MAN-10030-03). Bioinformatic methods utilized include pathway scoring, differential expression (DE), and gene-set enrichment (GSE) analyses. Findings, with full supplementary data, provide a community resource for effects of dysregulation of these miRNAs in a colon epithelial-like cell line.

molecular biology↗

Comparative pathway enrichment analysis in gastrointestinal cell lines Caco-2, HT-29, HEPG2, and colon fibroblasts using a custom expression panel for tight-junction and cytoskeletal regulatory genes.

This brief report details results from a comparative analysis of Nanostring expression data between cell lines HEPG2, Caco-2, HT-29, and colon fibroblasts. Raw and normalized data are available publicly in the NCBI GEO/Bioproject databases. Results identify cell-line specific variations in gene expression relevant to intestinal epithelial function.

cell biology↗

Disentangling causal relationships between inflammatory markers and depression: a bidirectional Mendelian randomization analysis

BackgroundThe inflammatory markers C-reactive protein (CRP), interleukin-1 receptor antagonist (IL1-Ra), and interleukin-6 (IL-6) have been associated with depression risk in observational studies. The causal nature of these associations is unclear as conventional observational designs are susceptible to reverse causation and residual confounding. Bidirectional Mendelian randomization (MR) analysis uses genetic variants to proxy for risk factors to help elucidate the presence, magnitude, and direction of causal relationships between traits. MethodsWe performed bidirectional two-sample MR to examine causal associations between circulating CRP, IL1-Ra, and IL-6 and major depressive disorder (MDD) in 135,458 cases and 344,901 controls in the Psychiatric Genetics Consortium. Genetic instruments to proxy inflammatory markers and liability to MDD were constructed by obtaining single-nucleotide polymorphisms (SNPs) associated with these phenotypes in genome-wide association study meta-analyses. Wald ratios and inverse-variance weighted random-effects models were employed to generate causal effect estimates and various sensitivity analyses were performed to examine violations of MR assumptions. ResultsThere was evidence supporting a causal effect of circulating IL-6 on risk of MDD (per natural-log increase: OR 0.85, 95% CI: 0.75-0.96, P=0.007). Higher circulating levels of IL-6 as influenced by variants in the IL6R gene region represent lower cellular binding of IL-6 to its receptor and therefore the present results suggest that IL-6 increases the risk of MDD. We found limited evidence supporting a causal effect of CRP (1.06, 95% CI 0.93-1.22; P=0.36) or IL1-Ra (OR 0.95, 95% CI: 0.87-1.03, P=0.20) on risk of MDD. Reverse direction MR analyses suggested limited evidence for a causal effect of genetic liability to MDD on any of the inflammatory markers examined. ConclusionsThese findings support a causal role of IL-6-related pathways in development of major depressive disorder and suggest the possible efficacy of interleukin-6 inhibition as a therapeutic target for depression.

genomics↗

Accurate assembly of the olive baboon (Papio anubis) genome using long-read and Hi-C data

Besides macaques, baboons are the most commonly used nonhuman primate in biomedical research. Despite this importance, the genomic resources for baboons are quite limited. In particular, the current baboon reference genome Panu_3.0 is a highly fragmented, reference-guided (i.e., not fully de novo) assembly, and its poor quality inhibits our ability to conduct downstream genomic analyses. Here we present a truly de novo genome assembly of the olive baboon (Papio anubis) that uses data from several recently developed single-molecule technologies. Our assembly, Panubis1.0, has an N50 contig size of ~1.46 Mb (as opposed to 139 Kb for Panu_3.0), and has single scaffolds that span each of the 20 autosomes and the X chromosome. We highlight multiple lines of evidence (including Bionano Genomics data, pedigree linkage information, and linkage disequilibrium data) suggesting that there are several large assembly errors in Panu_3.0, which have been corrected in Panubis1.0.

genomics↗

Complete blood count with differential: An effective diagnostic for IBS subtype in the context of BMI?

The Complete Blood Count with Differential hematological assay is a mainstay diagnostic for point-of-care clinical diagnoses for a spectrum of diseases including infection, inflammation, anemia, and leukemia, and CBC-D profiles are under investigation as early prognostic biomarkers for leukemias and other diseases. Chronic abdominal pain (CAP) and irritable bowel syndrome (IBS) are prevalent gastrointestinal disorders in the United States, with obesity among the most common comorbidities. Often, IBS-like gastrointestinal (GI) symptoms persist after resolution of known inflammation and/or enteropathogenic infection, and current literature contains significant discussion of the extent to which IBS is within the biological spectrum of inflammatory disease. Obesity is also associated with generalized signatures of inflammation and may confound accurate diagnoses. We performed ANOVA, multiple means comparisons, statistical analyses of CBC data from our \"Brain-Gut Natural History\" (BGNH) clinical cohort, with additional ELISA assays for lipopolysaccharide binding protein (LBP), IL-10, cortisol, and ACTH, signatures of immune-inflammatory response and Hypothalamic-Pituitary-Adrenal (HPA) axis activity, respectively. BGNH cohort includes healthy and overweight individuals diagnosed with IBS diarrhea-(IBS-D) and constipation-predominant (IBS-C) subtypes. We identified several potentially significant markers for IBS-D and IBS-C, notably IL-10, mean platelet volume (MPV), with LBP and monocyte percent also showing some statistical significance. Weight also showed significant results for overweight vs. normal weight, regardless of IBS subtype, particularly for Cortisol. CBC-D predictive profiles for IBS subtype and weight were identified using discriminant functions analysis and show that predictivity of marker profiles have poor performance relative to their normal weight subsets. Further refinement of this analysis will be performed utilizing increased sample size, additional molecular profiles, and enhanced statistical analysis.

immunology↗

Estimating statistical power for event-related potential studies using the late positive potential

The late positive potential (LPP) is a common measurement used to study emotional processes of subjects in event-related potential (ERP) paradigms. Despite its extensive use in affective neuroscience, there is presently no gold standard for how to appropriately power ERP studies using the LPP in within-subject and between-subjects experimental designs. The present study investigates how the number of trials, number of subjects, and magnitude of the effect size affect statistical power in analyses of the LPP. Using Monte Carlo simulations of ERP experiments with varying numbers of trials, subjects, and effect sizes, we measured the probability of obtaining a statistically significant effect in 1,489 different experiments repeated 1,000 times each. Predictably, our results showed that statistical power increases with increasing numbers of trials and subjects and at larger effect sizes. In addition, we found that higher levels of statistical power can be achieved with lower numbers of subjects and trials and at lower effect sizes in within-subject than in between-subjects designs. Furthermore, we found that, as subjects are added to an experiment, the slope of the relationship between effect size and statistical power increases and shifts to the left until the power asymptotes to nearly 100% at higher effect sizes. This suggests that adding more subjects greatly increases statistical power at lower effect sizes (<1 {micro}V) compared with more robust (>1.5 {micro}V) effect sizes.

neuroscience↗

Satiety, Thermosensation and Mechanosensation Regulate a Spontaneous C. elegans Sleep State

One remarkable feature of the nervous system is its ability to rapidly and spontaneously switch between activity states. In the extreme example of sleep, animals arrest locomotion, reduce their sensitivity to sensory stimuli, and dramatically alter their neural activity. Small organisms are useful models to better understand these sudden changes in neural states because we can simultaneously observe whole-brain activity, monitor behavior and precisely regulate the external environment. Here, we show a spontaneous sleep-like behavior in C. elegans that is associated with a distinct global-brain state and regulated by both the animals internal physiological state and input from multiple sensory circuits. Specifically, we found that when confined in microfluidic chambers, adult worms spontaneously transition between periods of normal activity and short quiescent bouts, with behavioral state transitions occurring every few minutes. This quiescent state, which we call Sleep, meets the behavioral requirements of C. elegans sleep, is dependent on known sleep-promoting neurons ALA and RIS, and is associated with a global down-regulation of neural activity. Consistent with prior studies of C. elegans sleep, we found that Sleep is regulated by satiety and temperature. In addition, we show for the first time that quiescence can be either driven or suppressed by thermosensory input, and that animal restraint induces quiescence through mechanosensory pathways. Together, these results establish a rich model system for studying how neural and behavioral state transitions are influenced by multiple physiological and environmental conditions. Significance StatementUnique brain states govern animal behaviors like sleep and wakefulness; however, how the brain regulates these dramatic state transitions is not well understood. Brain activity can be influenced by a complex interaction between sensory circuits that monitor the external environment, neural circuits that control behavior, and internal chemical signaling. Here, we describe a platform to study behavioral states in a context that allows us to record whole-brain activity while controlling the environment and monitoring animal behavior. Specifically, we identify a pattern of sleep bouts in the roundworm C. elegans that occur when they are confined to microscopic fluidic chambers. This behavior platform provides a powerful system to study how neural circuits interact with chemical signaling to drive brain state transitions.

neuroscience↗

Analysis of 100 high coverage genomes from a pedigreed captive baboon colony

Baboons (genus Papio) are broadly studied in the wild and in captivity. They are widely used as a non-human primate model for biomedical studies, and the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute has maintained a large captive baboon colony for more than 50 years. Unlike other model organisms though, the genomic resources for baboons are severely lacking. This has hindered the progress of studies using baboons as a model for basic biology or human disease. Here, we describe a dataset of 100 high-coverage whole-genome sequences obtained from the mixed colony of olive (P. anubis) and yellow (P. cynocephalus) baboons housed at the SNPRC. These data provide a comprehensive catalog of common genetic variation in baboons, as well as a fine-scale genetic map. We show how the data can be used to learn about ancestry and admixture, and to correct errors in the colony records. Finally, we investigated the consequences of inbreeding within the SNPRC colony and found clear evidence for increased rates of juvenile mortality and increased homozygosity of putatively deleterious alleles in inbred individuals.

genomics↗

A 14-day Dexamethasone timecourse exposure in Caco-2 monolayers results in differential expression of tight-junction and cytoskeleton regulatory pathway genes

Glucocorticoid (GC) hormones are modulators of endogenous stress responses and are important pharmaceuticals for inflammatory and autoimmune diseases. The gastrointestinal epithelium is a significant tissue target of Glucocorticoids; perturbation of epithelial barrier function during the endogenous stress response plays a major role in the pathophysiology of inflammatory bowel disease. Epithelial permeability and barrier function are mediated by the tight junction protein complex, with a network of molecular/cellular interactions occurring between the actin cytoskeleton, RhoGTPase, Akt/PI3K and growth factor receptor, and inflammatory cytokine signaling, influencing the establishment of a partial EMT phenotype. To improve our understanding of GC-responsive gene expression in a gastrointestinal epithelial context, we tested polarized Caco-2 monolayer cultures during at 30-day timecourse, with 15-days of continuous Dexamethasone exposure. Trans-epithelial resistance (TEER) was recorded to provide a physiological quantification of barrier function during the timecourse treatments. Presence of intracellular glucocorticoid hormone activates the human glucocorticoid receptor (GCR, human NR3C1 gene) transcription factor, resulting in transcriptional activation and repression of various GCR-responsive genes. We tested for differential gene expression with a multiplexed panel of 250 gene expression panel using the Nanostring nCounter(R) system. Gene panel selection was based on membership of genes in canonical KEGG pathways for tight-junction, adherens junction, focal adhesion, actin cytoskeleton regulation, and colorectal cancer. Our TEER results confirm, as previously reported, that long-term Dexamethasone exposure results in decreased permeability in Caco-2 monolayers ~day 20-25. Culture age and Dexamethasone exposure both contributed to differential gene expression for cell-cell junction, protein kinases, survival and cancer associated genes, reported here in the context of their corresponding KEGG pathway representations. The findings give evidence for GC and time-associated patterns of transcriptional response and provide further insight into long-term glucocorticoid-associated physiological effects on the gastrointestinal epithelia. Future research utilizing more advanced cell culture methods will use this data-set as a reference.

cell biology↗

Microfluidics for Electrophysiology, Imaging, and Behavioral Analysis of Hydra

The cnidarian Hydra vulgaris provides an exciting opportunity to discover the relationship between animal behavior and the activity of every neuron in highly plastic, diffuse network of spiking cells. However, Hydras deformable and contractile body makes it difficult to manipulate the local environment while recording neural activity. Here, we present a suite of microfluidic technologies capable of simultaneous electrical, chemical, and optical interrogation of these soft, deformable organisms. Specifically, we demonstrate devices that can immobilize Hydra for hours-long simultaneous electrical and optical recording, and chemical stimulation of behaviors revealing neural activity during muscle contraction. We further demonstrate quantitative locomotive and behavioral tracking made possible by confining the animal to quasi-two-dimensional micro-arenas. Together, these proof-of-concept devices show that microfluidics provide a platform for scalable, quantitative cnidarian neurobiology. The experiments enabled by this technology may help reveal how highly plastic networks of neurons provide robust control of animal behavior.

neuroscience↗

Juicebox.js provides a cloud-based visualization system for Hi-C data

Contact mapping experiments such as Hi-C explore how genomes fold in 3D. Here, we introduce Juicebox.js, a cloud-based web application for exploring the resulting datasets. Like the original Juicebox application, Juicebox.js allows users to zoom in and out of such datasets using an interface similar to Google Earth. Furthermore, Juicebox.js encodes the exact state of the browser in a shareable URL. Creating a public browser for a new Hi-C dataset does not require coding and can be accomplished in under a minute.

bioinformatics↗

Placental gene expression mediates the interaction between obstetrical history and genetic risk for schizophrenia

Defining the environmental context in which genes enhance susceptibility can provide insight into the pathogenesis of complex disorders, like schizophrenia. Here we show that the intrauterine and perinatal environment modulates the association of schizophrenia with genomic risk, as measured with polygenic risk scores (PRS) based primarily on GWAS significant variants. Genomic risk interacts with intrauterine and perinatal complications (Early Life Complications, ELCs) in each of three independent samples from USA, Italy and Germany (overall n= 1693, p= 6e-05). In each sample, the liability of schizophrenia explained by PRS is nominally more than five times greater in the presence of a history of ELCs compared with its absence. In each sample, patients with positive ELC histories have higher PRS than patients without ELCs, which is further confirmed in two additional patient samples from Germany and Japan (overall n=2038, p= 1e-04). The gene set based on the schizophrenia loci interacting with ELCs is highly expressed in multiple placental compartments and dynamically regulated in placenta from complicated in comparison with normal pregnancies. The same genes are differentially up-regulated in placentae from male compared with female offspring. The interaction between genomic risk and ELCs is mainly driven by GWAS significant loci enriched for genes highly expressed in the various placenta samples. Molecular pathway analyses based on the genes not driving this interaction reflect previous analyses about schizophrenia risk-genes, while genes highly and differentially expressed in placentae implicate an orthogonal biology involving cellular stress. These results suggest that the most significant genetic variants detected by current schizophrenia GWAS contribute to risk in part by converging on a developmental trajectory sensitive to events affecting placentation, which may underlie the male preponderance of schizophrenia and offer new insights into primary prevention.

genetics↗