Biology subjects

Nguyen, T.

Publications and source records attributed to Nguyen, T..

At least 181 records · Page 10Linked to original sources

bioRxiv2022

Highly-Automated, High-Throughput Replication of Yeast-based Logic Circuit Design Assessments

We describe an experimental campaign that replicated the performance assessment of logic gates engineered into cells of S. cerevisiae by Gander, et al. Our experimental campaign used a novel high throughput experimentation framework developed under DARPAs Synergistic Discovery and Design (SD2) program: a remote robotic lab at Strateos executed a parameterized experimental protocol. Using this protocol and robotic execution, we generated two orders of magnitude more flow cytometry data than the original experiments. We discuss our results, which largely, but not completely, agree with the original report, and make some remarks about lessons learned.

synthetic biology↗

bioRxiv2022

The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci

Vascular sites have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinning of vascular site-specific disease risk is largely unknown. Vascular tissues have different developmental origins that may influence global chromatin accessibility, and understanding differential chromatin accessibility, gene expression profiles, and gene regulatory networks (GRN) on single cell resolution may give key insight into vascular site-specific disease risk. Here, we performed single cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of healthy adult mouse vascular tissue from three vascular sites, 1) aortic root and ascending aorta, 2) brachiocephalic and carotid artery, and 3) descending thoracic aorta. Through a comprehensive analysis at single cell resolution, we discovered key regulatory enhancers to not only be cell type, but vascular site specific in vascular smooth muscle (SMC), fibroblasts, and endothelial cells. We identified epigenetic markers of embryonic origin with differential chromatin accessibility of key developmental transcription factors such as Tbx20, Hand2, Gata4, and Hoxb family members and discovered transcription factor motif accessibility to be cell type and vascular site specific. Notably, we found ascending fibroblasts to have distinct epigenomic patterns, highlighting SMAD2/3 function to suggest a differential susceptibility to TGF{beta}, a finding we confirmed through in vitro culture of primary adventitial fibroblasts. Finally, to understand how vascular site-specific enhancers may regulate human genetic risk for disease, we integrated genome wide association study (GWAS) data for ascending and descending aortic dimension, and through using a distinct base resolution deep learning model to predict variant effect on chromatin accessibility, ChromBPNet, to predict variant effects in SMC, Fibroblasts, and Endothelial cells within ascending aorta, carotid, and descending aorta sites of origin. We reveal that although cell type remains a primary influence on variant effects, vascular site modifies cell type transcription and highlights genomic regions that are enriched for specific TF motif footprints -- including MEF2A, SMAD3, and HAND2. This work supports a paradigm that the epigenomic and transcriptomic landscape of vascular cells are cell type and vascular site-specific and that site-specific enhancers govern complex genetic drivers of disease risk.

genomics↗

bioRxiv2022

The autism-associated gene SYNGAP1 regulates human cortical neurogenesis

Autism spectrum disorder (ASD) is a genetically heterogeneous disorder linked with rare, inherited and de novo mutations occurring in two main functional gene categories: gene expression regulation and synaptic function1. Accumulating evidence points to dysregulation in cortical neurogenesis as a convergent mechanism in ASD pathophysiology2-8. While asynchronous development has been identified as a shared feature among ASD-risk genes in the category of gene expression regulation, it remains unknown whether this phenotype is also associated with ASD-risk genes in the synaptic function category. Here we show for the first time the expression of the synaptic Ras GTP-ase activating protein 1 (SYNGAP1), one of the top ASD risk genes9, in human cortical progenitors (hCPs). Interestingly, we found that multiple components of the postsynaptic density (PSD) of excitatory synapses, of which SYNGAP1 is one of the most abundant components 10,11, are enriched in the proteome of hCPs. Specifically, we discover that SYNGAP1 is expressed within the apical domain of human radial glia cells (hRGCs) where it lines the wall of the developing cortical ventricular zone colocalizing with the tight junction-associated protein and MAGUK family member TJP1. In a cortical organoid model of SYNGAP1 haploinsufficiency, we show dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination of the cortical plate and accelerated maturation of cortical projection neurons. Overall, the discovery of the expression and function of SYNGAP1 in cortical progenitor cells reframes our understanding of the pathophysiology of SYNGAP1-related disorders and, more broadly, underscores the importance of dissecting the role of synaptic genes associated with neurodevelopmental disorders in distinct cell types across developmental stages.

developmental biology↗

bioRxiv2022

An Entropy Approach for Choosing Gene Expression Cutoff

Annotating cell types using single-cell transcriptome data usually requires binarizing the expression data to distinguish between the background noise vs. real expression or low expression vs. high expression cases. A common approach is choosing a "reasonable" cutoff value, but it remains unclear how to choose it. In this work, we describe a simple yet effective approach for finding this threshold value.

bioinformatics↗

bioRxiv2022

Robust and durable prophylactic protection conferred by RNA interference in preclinical models of SARS-CoV-2

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving [≥]3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.

pharmacology and toxicology↗

bioRxiv2022

Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA

Formation of biomolecular condensates constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, the reported forces generated by such protein-DNA co-condensation are typically below one piconewton (pN), questioning its physiological significance. Moreover, the force-generating capacity of these condensates in the chromatin context remains unknown. Using single-molecule biophysical techniques, we show that Sox2, a nucleosome-binding pioneer TF, forms co-condensates with DNA, thereby exerting considerable mechanical tension on DNA strands both in cis and trans. Sox2 can generate forces up to 7 pN--similar in magnitude to other cellular forces. Sox2:DNA condensates are highly stable, withstanding disruptive forces high enough to melt DNA. We find that the disordered domains of Sox2 are required for maximum force generation but not condensate formation per se. Finally, we show that nucleosomes dramatically attenuate the mechanical stress exerted by Sox2 via sequestering it from coalescing on bare DNA. Our findings reveal that TF-mediated DNA condensation can exert significant mechanical stress which can nonetheless be alleviated by the chromatin organization, suggesting a new function of eukaryotic chromatin in protecting the genome from potentially deleterious nuclear forces.

biophysics↗

bioRxiv2022

Reduced synaptic activity and dysregulated extracellular matrix pathways are common phenotypes in midbrain neurons derived from sporadic and mutation-associated Parkinson's disease patients

Several mutations that cause Parkinsons disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: Neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, shows changes that are central and convergent to PD and suggests a strong involvement of the tetra-partite synapse in PD pathophysiology.

neuroscience↗

bioRxiv2021

A NEUROGENIC GENE EXPRESSION SIGNATURE SUPPORTS HUMAN THERMOGENIC ADIPOSE TISSUE DEVELOPMENT IN VIVO.

Mechanisms that control "beige/brite" thermogenic adipose tissue development may be harnessed to improve human metabolic health. To define these mechanisms, we developed a species-hybrid model in which human mesenchymal progenitor cells were used to develop white or thermogenic/beige adipose tissue in mice. The hybrid adipose tissue developed distinctive features of human adipose tissue, such as larger adipocyte size, despite its neurovascular architecture being entirely of murine origin. Thermogenic adipose tissue recruited a denser, qualitatively distinct vascular network, differing in genes mapping to circadian rhythm pathways, and denser sympathetic innervation. The enhanced thermogenic neurovascular network was associated with human adipocyte expression of THBS4, TNC, NTRK3 and SPARCL1, which enhance neurogenesis, and decreased expression of MAOA and ACHE, which control neurotransmitter tone. Systemic inhibition of MAOA, which is present in human but absent in mouse adipocytes, induced browning of human but not mouse adipose tissue, revealing the physiological relevance of this pathway. Our results reveal species-specific cell type dependencies controlling the development of thermogenic adipose tissue and point to human adipocyte MAOA as a potential target for metabolic disease therapy.

developmental biology↗

bioRxiv2021

Evidence for widespread cytoplasmic structuring into mesoscopic condensates

Eukaryotic cytoplasm organizes itself via both membrane-bound organelles and membrane-less biomolecular condensates (BMCs). Known BMCs exhibit liquid-like properties and are typically visualized on the scale of ~1 m. They have been studied mostly by microscopy, examining select individual proteins. Here, we investigate the global organization of native cytoplasm with quantitative proteomics, using differential pressure filtration, size exclusion, and dilution experiments. These assays reveal that BMCs form throughout the cytosplasm, predominantly at the mesoscale of ~100 nm. Our data indicate that at least 18% of the proteome is organized via such mesoscale BMCs, suggesting that cells widely employ dynamic liquid-like clustering to organize their cytoplasm, at surprisingly small length scales.

biochemistry↗

bioRxiv2021

Duesselpore: a full-stack local web server for rapid and simple analysis of Oxford Nanopore Sequencing data

Genome-wide analysis of transcriptomes offers extensive insights into the molecular mechanisms underlying the physiology of all known species and discover those that are still hidden. Oxford Nanopore Technologies (ONT) has recently been developed as a fast, miniaturized, portable and a cost effective alternative to Next Generation Sequencing. However, RNA-seq data analysis software that exploit ONT portability and allows scientists to easily analyze ONT data everywhere without bioinformatic expertise is not widely available. We developed Duesselpore, an easy-to-follow deep sequencing workflow that runs as a local webserver and allows the analysis of ONT data everywhere without requiring additional bioinformatic tools or internet connection. Duesselpore output includes differentially expressed genes and further downstream analyses, such as variance heatmap, disease and gene ontology plots, gene concept network plots and exports customized pathways for different cellular processes. We validated Duesselpore by analyzing the transcriptomic changes induced by PCB126, a dioxin-like PCB and a potent aryl hydrocarbon receptor (AhR) agonist in human HaCaT keratinocytes, a well characterized model system. Duesselpore was specifically developed to analyze ONT data but we also implemented NGS data analysis. Duesselpore is compatible with Microsoft and Mac operating systems, allows convenient, reliable and cost-effective analysis of ONT and NGS data.

bioinformatics↗

bioRxiv2021

Loss of epigenetic regulation disrupts lineage integrity, reactivatesmultipotency and promotes breast cancer

Systematically investigating the scores of genes mutated in cancer and discerning real drivers from inconsequential bystanders is a prerequisite for Precision Medicine, but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent long-tail breast cancer genes, which revealed epigenetic regulation as major tumor suppressive mechanism. We report that core or accessory components of the COMPASS histone methylase complex including KMT2C, KDM6A, BAP1 and ASXL2 ("EpiDrivers") cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that Cre-mediated activation of PIK3CAH1047R elicited an aberrant alveolar lactation program in luminal cells, which was exacerbated upon loss of EpiDrivers. Remarkably, EpiDriver loss in basal cells also triggered an alveolar-like lineage conversion and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. As EpiDrivers are mutated in 39% of human breast cancers, lineage infidelity and lactation mimicry may significantly contribute to early steps of breast cancer progression. Statement of significanceInfrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In-vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of lactation genes as potential early events in tumorigenesis.

cancer biology↗

bioRxiv2021

Differential nuclear import sets the timing of protein access to the embryonic genome

The development of a fertilized egg to an embryo requires the proper temporal control of gene expression1-6. During cell differentiation, timing is often controlled via cascades of transcription factors (TFs)7,8. However, in early development, transcription is often inactive, and many TF levels are constant, suggesting that unknown mechanisms govern the observed rapid and ordered onset of gene expression9. Here, we find that in early embryonic development, access of maternally deposited nuclear proteins to the genome is temporally ordered via importin affinities, thereby timing the expression of downstream targets. We quantify changes in the nuclear proteome during early development and find that nuclear proteins, such as TFs and RNA polymerases, enter nuclei sequentially. Moreover, we find that the timing of the access of nuclear proteins to the genome corresponds to the timing of downstream gene activation. We show that the affinity of proteins to importin is a major determinant in the timing of protein entry into embryonic nuclei. Thus, we propose a mechanism by which embryos encode the timing of gene expression in early development via biochemical affinities. This process could be critical for embryos to organize themselves before deploying the regulatory cascades that control cell identities. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/464816v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@1e9438org.highwire.dtl.DTLVardef@1950f92org.highwire.dtl.DTLVardef@131716corg.highwire.dtl.DTLVardef@10d6d24_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2021

Single-cell analysis of basal cell carcinoma reveals heat shock proteins promote tumor growth in response to WNT5A-mediated inflammatory signals

How basal cell carcinoma (BCC) interacts with its tumor microenvironment to promote growth is unclear. Here we use singe-cell RNA sequencing to define the human BCC ecosystem and discriminate between normal and malignant epithelial cells. We identify spatial biomarkers of both tumors and their surrounding stroma that reinforce the heterogeneity of each tissue type. Combining pseudotime, RNA velocity, cellular entropy, and regulon analysis in stromal cells reveal a cancer-specific rewiring of fibroblasts where STAT1, TGF-{beta}, and inflammatory signals induce a non-canonical WNT5A program that maintains the stromal inflammatory state. Cell-cell communication modeling suggests that tumors respond to the sudden burst of fibroblast-specific inflammatory signaling pathways by producing heat shock proteins, which we validated in situ. Finally, dose-dependent treatment with an HSP70 inhibitor suppresses in vitro BCC cell growth and Hedgehog signaling and in vivo tumor growth in a BCC mouse model, validating HSP70s essential role in tumor growth and reinforcing the critical nature of tumor microenvironment crosstalk in BCC progression.

cancer biology↗

bioRxiv2021

Ex Vivo and In Vivo CD46 Receptor Utilization by Species D Human Adenovirus Serotype 26 (HAdV26)

Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against SARS-CoV-2 and HIV-1. Yet, its primary receptor portfolio remains controversial, potentially including sialic acid, CAR, integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned by the inability to co-crystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domains CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (IM) injection, but not after intranasal (IN) administration. Ad26 transduction was 10-fold lower than Ad5 after intratumoral (IT) injection of CD46-expressing tumors. Ad26 transduction of liver was 1000-fold lower than Ad5 after intravenous (IV) injection. These data demonstrate the use of CD46 by Ad26 under certain situations, but also show that the receptor has little consequence by other routes of administration. Finally, IV injection of high doses of Ad26 into CD46 mice induced release of liver enzymes in the bloodstream and reduced white blood cell counts, but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during COVID-19 vaccination with this serotype of adenovirus. IMPORTANCEHuman species D Ad26 is being pursued as a low seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection, and its role in virus biology, vaccine efficacy, and importantly, in vaccine safety.

pharmacology and toxicology↗

bioRxiv2021

A whole-brain monosynaptic input connectome to neuron classes in mouse visual cortex

Identification of the structural connections between neurons is a prerequisite to understanding brain function. We developed a pipeline to systematically map brain-wide monosynaptic inputs to specific neuronal populations using Cre-driver mouse lines and the recombinant rabies tracing system. We first improved the rabies virus tracing strategy to accurately identify starter cells and to efficiently quantify presynaptic inputs. We then mapped brain-wide presynaptic inputs to different excitatory and inhibitory neuron subclasses in the primary visual cortex and seven higher visual areas. Our results reveal quantitative target-, layer- and cell-class-specific differences in the retrograde connectomes, despite similar global input patterns to different neuronal populations in the same anatomical area. The retrograde connectivity we define is consistent with the presence of the ventral and dorsal visual information processing streams and reveals further subnetworks within the dorsal stream. The hierarchical organization of the entire visual cortex can be derived from intracortical feedforward and feedback pathways mediated by upper- and lower-layer input neurons, respectively. This study expands our knowledge of the brain-wide inputs regulating visual areas and demonstrates that our improved rabies virus tracing strategy can be used to scale up the effort in dissecting connectivity of genetically defined cell populations in the whole mouse brain.

neuroscience↗

bioRxiv2021

Data Representation in the DARPA SD2 Program

1Modern scientific enterprises are often highly complex and multidisciplinary, particularly in areas like synthetic biology where the subject at hand is itself inherently complex and multidisciplinary. Collaboration across many organizations is necessary to efficiently tackle such problems [6, 15], but remains difficult. The challenge is further amplified by automation that increases the pace at which new information can be produced, and particularly so for matters of fundamental research, where concepts and definitions are inherently fluid and may rapidly change as an investigation evolves [7]. The DARPA program Synergistic Discovery and Design (SD2) aimed to address these challenges by organizing the development of data-driven methods to accelerate discovery and improve design robustness, with one of the key domains under study being synthetic biology. The program was specifically organized such that teams provided complementary types of expertise and resources, and without any team being in a dominant organizational position, such that subject-matter investigations would necessarily require peer-level collaboration across multiple team boundaries. With more than 100 researchers across more than 20 organizations, several of which ran experimental facilities with high-throughput automation, participants were forced to confront challenges around effective data sharing. The default architecture for scientific collaboration is essentially one of anarchy, with ad-hoc bilateral relations between pairs of collaborators or experimental phases (Figure 1(a)). This was by necessity the case during early phases of the SD2 program as well, in which incorporating new tools into pipelines was ad-hoc and time-consuming, and data was generally disconnected from genetic designs and experimental plans. The other typical approach for collaboration is one of "command and control", in which a dominant organization determines the data sharing content and format for all participants (Figure 1(b)). This can be efficient, but tends to be limited in flexibility and extensibility, rendering it unsuitable for research collaboration, as indeed was found when we attempted this approach during the first year of the SD2 program. We addressed these problems with the application of distributed standards to create a "flexible rendezvous" model of collaboration (Figure 1(c)), enabling information flow to track evolving collaborative relationships, improving the sharing and utility of information across the community and supporting accelerated rates of experimentation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/460644v1_fig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@fc7371org.highwire.dtl.DTLVardef@1ff2733org.highwire.dtl.DTLVardef@66af53org.highwire.dtl.DTLVardef@1809640_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Architectures for data sharing: bilateral relations (a), command and control (b), and flexible rendezvous (c). C_FIG

synthetic biology↗

bioRxiv2021

RTICBM-74 is a Brain-Penetrant CB1 Receptor Allosteric Modulator that Reduces Alcohol Intake in Rats

The endocannabinoid system is implicated in the neuronal mechanisms of alcohol use disorder (AUD), with the cannabinoid receptor subtype 1 (CB1) representing a promising target for AUD therapeutic interventions. We have previously shown negative allosteric modulators (NAMs) of the CB1 receptor attenuated the reinstatement of other drugs of abuse including cocaine and methamphetamine in rats; however, their effects on alcohol-related behaviors have not been investigated. Here, we tested the pharmacokinetic properties of one such CB1 NAM, RTICBM-74, and its effects on alcohol self-administration in rats. RTICBM-74 showed low aqueous solubility and high protein binding but had excellent half-life and low clearance against rat liver microsomes and hepatocytes, and excellent brain penetrance in rats. RTICBM-74 pretreatment specifically reduced alcohol intake across a range of doses in male or female Wistar or Long-Evans rats that were trained to self-administer alcohol. These effects were similar to the CB1 antagonist/inverse agonist rimonabant which was tested as a positive control. Importantly, RTICBM-74 was effective at reducing alcohol intake at doses that did not affect locomotion or sucrose self-administration. Our findings suggest that CB1 NAMs such as RTICBM-74 have promising therapeutic potential in treatment of AUD. SIGNIFICANCE STATEMENTThe present work shows that a metabolically stable and brain penetrant CB1 receptor negative allosteric modulator (NAM) reduces alcohol self-administration in rats without affecting locomotion or sucrose self-administration, suggesting potential therapeutic relevance for the treatment of AUD.

neuroscience↗

bioRxiv2021

Single cell multi-omics reveals early elevated function and multiple fates within human progenitor exhausted CD8+ T cells

T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of subjects with primary infection using single cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-{gamma} response against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome we discovered progenitors of early-exhaustion with intermediate expression of PD-1. Intra clonal analysis revealed distinct trajectories with multiple fates suggesting evolutionary plasticity of precursor cells. These findings challenge current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T-cell differentiation in human infections. One sentence summaryProgenitors of T-cell exhaustion in acute HCV infection

immunology↗