Biology subjects

Peterson, C.

Publications and source records attributed to Peterson, C..

26 records · Page 2Linked to original sources

bioRxiv2020

A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein

SARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease--COVID-19-- within several months of its initial identification. Comparable to the first SARS-CoV, this novel coronaviruss surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics. Molecular information on the SARS-CoV-2 S glycoprotein remains limited. Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 [A]. We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins. One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity. We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses. This epitope is inaccessible in the "closed" prefusion S structure, but is accessible in "open" conformations. This first-ever resolution of a human antibody in complex with SARS-CoV-2 and the broad reactivity of this set of antibodies to a conserved betacoronavirus epitope will allow antigenic assessment of vaccine candidates, and provide a framework for accelerated vaccine, immunotherapeutic and diagnostic strategies against SARS-CoV-2 and related betacoronaviruses. HIGHLIGHTSHigh resolution structure of the SARS-CoV-2 Receptor-Binding-Domain (RBD). Recognition of the SARS-CoV-2 RBD by SARS-CoV antibodies. Structure of the SARS-COV-2 RBD in complex with antibody CR3022. Identification of a cryptic site of vulnerability on the SARS-CoV-2 Spike.

immunology↗

bioRxiv2019

OCTAVVS: A graphical toolbox for high-throughput preprocessing and analysis of vibrational spectroscopy imaging data

Modern vibrational spectroscopy techniques enable rapid collection of thousands of spectra in a single hyperspectral image, allowing researchers to resolve spatially heterogeneous samples down to a resolution of a few m. A number of algorithms have been developed to correct for effects such as atmospheric absorption, light scattering by cellular structures and varying baseline levels. Following such preprocessing, spectra are commonly decomposed and clustered to reveal informative patterns and subtle spectral changes. Several of these steps are slow, labor-intensive and require programming skills to make use of published algorithms and code. We here present a free and platform-independent graphical toolbox that allows rapid processing of large sets of spectroscopic images, including atmospheric correction and an algorithm for resonant Mie scattering with improved speed and stability. The software includes modules for decomposition into constituent spectra using the popular MCR-ALS algorithm, augmented by region-of-interest selection, as well as clustering and cluster annotation.

biochemistry↗

bioRxiv2019

Specialization to cell-free or cell-associated spread by BAC-cloned HCMV strains not determined by the UL128-131 and RL13 loci

It is widely held that clinical isolates of human cytomegalovirus (HCMV) are highly cell-associated, and mutations affecting the UL128-131 and RL13 loci that arise in culture lead to the appearance of a cell-free spread phenotype. The BAC-clone Merlin (ME), expresses abundant UL128-131, is RL13-impaired and produces low infectivity virions in fibroblasts, whereas TB40/e (TB) and TR are low in UL128-131, RL13-intact and produce virions of much higher infectivity. Despite these differences, quantification of spread by flow cytometry revealed remarkably similar spread efficiencies in fibroblasts. In epithelial cells, ME spread more efficiently, consistent with robust UL128-131 expression. Strikingly, ME spread far better than TB or TR in the presence of neutralizing antibodies on both cell types, indicating that ME is not simply deficient at cell-free spread, but is particularly efficient at cell-to-cell spread, whereas TB and TR cell-to-cell spread is poor. Sonically disrupted ME-infected cells contained scant infectivity, suggesting that the efficient cell-to-cell spread mechanism of ME depends on features of the intact cells such as junctions or intracellular trafficking processes. Even when UL128-131 was transcriptional repressed, cell-to-cell spread of ME was still more efficient than TB or TR. Moreover, RL13 expression comparably reduced both cell-free and cell-to-cell spread of all three strains, suggesting that it acts at a stage of assembly and/or egress common to both routes of spread. Thus, HCMV strains can be highly specialized for either for cell-free or cell-to-cell spread and these phenotypes are determined by factors beyond the UL128-131 or RL13 loci. IMPORTANCEBoth cell-free and cell-to-cell spread are likely important for the natural biology of HCMV. In culture, strains clearly differ in their capacity for cell-free spread as a result of differences in the quantity and infectivity of extracellular released progeny. However, it has been unclear whether "cell-associated" phenotypes are simply the result of poor cell-free spread, or are indicative of particularly efficient cell-to-cell spread mechanisms. By measuring the kinetics of spread at early time points, we were able to show that HCMV strains can be highly specialized to either cell-free or cell-to-cell mechanisms, and this was not strictly linked the efficiency of cell-free spread. Our results provide a conceptual approach to evaluating intervention strategies for their ability to limit cell-free or cell-to-cell spread as independent processes.

microbiology↗

bioRxiv2019

Multi-scale dynamical modelling of T-cell development from an early thymic progenitor state to lineage commitment

Thymic development of committed pro-T-cells from multipotent hematopoietic precursors offers a unique opportunity to dissect the molecular circuitry establishing cell identity in response to environmental signals. This transition encompasses programmed shutoff of stem/progenitor genes, upregulation of T-cell specification genes, extensive proliferation, and commitment after a delay. We have incorporated these factors, as well as new single cell gene expression and developmental kinetics data, into a three-level dynamic model of commitment based upon regulation of the commitment gene Bcl11b. The first level is a core gene regulatory network architecture determined by transcription factor perturbation data, the second a stochastically controlled epigenetic gate, and the third a proliferation model validated by growth and commitment kinetics measured at single-cell levels. Using expression values consistent with single molecule RNA-FISH measurements of key transcription factors, this single-cell model exhibits state switching consistent with measured population and clonal proliferation and commitment times. The resulting multi-scale model provides a powerful mechanistic framework for dissecting commitment dynamics.

systems biology↗

bioRxiv2019

Depletion of resident muscle stem cells inhibits muscle fiber hypertrophy induced by lifelong physical activity

BackgroundA reduction in skeletal muscle stem cell (satellite cell) content with advancing age is thought to directly contribute to the progressive loss of skeletal muscle mass and function with aging (sarcopenia). However, we reported that the depletion of satellite cells throughout adulthood did not affect the onset or degree of sarcopenia observed in sedentary old mice. The current study was designed to determine if lifelong physical activity would alter the requirements for satellite cells during aging.\n\nMethodsWe administered vehicle or tamoxifen to adult (5 months old) female Pax7-DTA mice for 5 consecutive days to effectively deplete satellite cells. Following a 2-month washout period, mice were assigned to physically active (free access to a running wheel) or sedentary (locked running wheel) conditions. Thirteen months later, at a mean age of 20 months, mice were sacrificed for subsequent analysis.\n\nResultsSatellite cell depletion throughout adulthood negatively impacted physical function and limited muscle fiber hypertrophy in response to lifelong physical activity. To further interrogate these findings, we performed transcriptome-wide analyses on the hind limb muscles that experienced hypertrophic growth (plantaris and soleus) in response to lifelong physical activity. Our findings demonstrate that satellite cell function is muscle type-specific; fusion with fibers is apparent in oxidative muscles, while initiation of Gi2 signaling appears to require satellite cells in glycolytic muscles to induce muscle growth..\n\nConclusionsThese findings suggest that satellite cells, or their secretory products, are viable therapeutic targets to preserve physical function with aging and promote muscle growth in older adults who regularly engage in physical activity.

physiology↗

bioRxiv2017

Revisiting the erythroid-myeloid lineage decision - a data-driven dynamical model analysis

It is widely conjectured that the mutually antagonizing pair of transcription factors GATA1 and PU.1, deter-mines the choice between the erythroid and myeloid lineages in hematopoiesis. In theoretical approaches, this appears natural with a bistable switch driving the decision. Recent extensive binding and gene expression experiments with some focus on the triad GATA1, GATA2 and PU.1 indicate that GATA2 may be more involved in this lineage decision than previously anticipated. Here, we analyze these experimental data by modeling regulatory sub-networks with deterministic rate equations. Using network dynamical parameters determined by the data, we deduce from increasing the self-interaction bindings in silico among the triad genes that GATA2 and PU.1 exhibit non-linear behavior with one unstable and one stable state. This is in contrast to GATA1, which shows smoother behavior. We extend the network to include the downstream regulators FOG1 and CEBPA, and extract the nature of the corresponding regulatory interactions, excitatory or suppressing, between this pair and the triad by fitting to experimental gene expression time series. Based on this extended network, we simulate and explore different knockout scenarios, providing insight into the role of these regulators in the process of lineage specification, as well as predictions for future experimental validation. We address the mechanism of GATA switching as a mechanism of lineage differentiation by investigating the dynamics of FOG1 regulation by GATA2 and GATA1. Overall, this analysis strongly suggests that within this network, GATA2 is the key driver of erythroid lineage specification through its repression of PU.1, whereas GATA1 appears to be more relevant for the downstream differentiation events.

systems biology↗

bioRxiv2017

Do Candidate Genes Affect the Brain’s White Matter Microstructure? Large-Scale Evaluation of 6,165 Diffusion MRI Scans

AbstractSusceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU,CNTNAP2, COMT, DISC1, DTNBP1, ErbB4, HFE, NRG1, NTKR3, and ZNF804A - have been reported to affect white matter (WM) microstructure in the healthy human brain, as assessed through diffusion tensor imaging (DTI). However, effects of single nucleotide polymorphisms (SNPs) in these genes explain only a small fraction of the overall variance and are challenging to detect reliably in single cohort studies. To date, few studies have evaluated the reproducibility of these results. As part of the ENIGMA-DTI consortium, we pooled regional fractional anisotropy (FA) measures for 6,165 subjects (CEU ancestry N=4,458) from 11 cohorts worldwide to evaluate effects of 15 candidate SNPs by examining their associations with WM microstructure. Additive association tests were conducted for each SNP. We used several meta-analytic and mega-analytic designs, and we evaluated regions of interest at multiple granularity levels. The ENIGMA-DTI protocol was able to detect single-cohort findings as originally reported. Even so, in this very large sample, no significant associations remained after multiple-testing correction for the 15 SNPs investigated. Suggestive associations (1.3x10-4 < p < 0.05, uncorrected) were found for BDNF, COMT, and ZNF804A in specific tracts. Meta-and mega-analyses revealed similar findings. Regardless of the approach, the previously reported candidate SNPs did not show significant associations with WM microstructure in this largest genetic study of DTI to date; the negative findings are likely not due to insufficient power. Genome-wide studies, involving large-scale meta-analyses, may help to discover SNPs robustly influencing WM microstructure.

neuroscience↗

bioRxiv2016

Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate

By analyzing multi-tissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalogue of expression quantitative trait loci (eQTLs) in a non-human primate model. This catalogue contains more genome-wide significant eQTLs, per sample, than comparable human resources, and reveals sex and age-related expression patterns. Findings include a master regulatory locus that likely plays a role in immune function, and a locus regulating hippocampal long non-coding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

genetics↗