Biology subjects

Dai, Y.

Publications and source records attributed to Dai, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Iron deprivation activates aboveground cell wall biosynthesis in Populus and the role of PtrbHLH011

Lack of mechanistic understanding of the environmental plasticity of secondary cell wall (SCW) biosynthesis hinders the massive bioenergy production on marginal lands. Growing bioenergy crops on marginal lands is appealing to minimize competition for arable land. However, abiotic stresses, particularly iron deficiency stress, are widespread to perturb SCW biosynthesis. In poplar, a major bioenergy crop, we demonstrated that iron deprivation activates stem SCW biosynthesis and identified transcription factor PtrbHLH011 as a possible underlying regulator. PtrbHLH011 is a potent repressor of SCW, whose overexpression resulted in a reduction of stem SCW by over 65%. Our genomic and molecular studies discovered that PtrbHLH011 binds to the AAAGACA sequence and represses essential genes for SCW biosynthesis, flavonoid biosynthesis, and iron homeostasis. Wood formation and iron deprivation downregulates PtrbHLH011 to release the transcriptional repression. Our findings reveal a regulatory mechanism coordinating SCW biosynthesis in response to environmental iron availability and suggest that PtrbHLH011 manipulation may help engineer bioenergy crops with improved performance under marginal conditions.

plant biology↗

bioRxiv2024

Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis

The acidic tumor microenvironment favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether acidic environments select for cancer stem cell (CSC) properties. Bulk RNA-seq of Panc-1 human pancreatic cancer cells adapted to extracellular pH 6.5 revealed upregulation of CSC markers including CD44, EpCam, Nestin and aldehyde dehydrogenases, and CSC pathway enrichment. We therefore assessed CSC characteristics of acid-adapted (AA) and non-adapted (Ctrl) PaTu8988s and MiaPaca-2 pancreatic cancer cells. Compared to Ctrl, AA cells exhibited increased ALDH- and {beta}-catenin activity and pancreatosphere-forming efficiency, classical CSC characteristics. Panc-1, PaTu8988s and MiaPaCa-2 AA cells differed in CSC marker expression, and AA cells did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing identified the acid adaptation-induced emergence of a population with clear CSC characteristics. Finally, in an orthotopic mouse model, AA Panc-1 cells drove strongly increased aggressiveness and liver metastasis compared to Ctrl cells. We conclude that acid-adaptation of pancreatic cancer cells leads to enrichment of a CSC phenotype with unusual traits, providing new insight into how acidic tumor microenvironments favor cancer aggressiveness.

cancer biology↗

bioRxiv2024

A phosphorylation signal activates genome-wide transcriptional control by BfmR, the global regulator of Acinetobacter resistance and virulence.

The nosocomial pathogen Acinetobacter baumannii is a major threat to human health. The sensor kinase-response regulator system, BfmS-BfmR, is essential to multidrug resistance and virulence in the bacterium and represents a potential antimicrobial target. Important questions remain about how the system controls resistance and pathogenesis. Although BfmR knockout alters expression of >1000 genes, its direct regulon is undefined. Moreover, how phosphorylation controls the regulator is unclear. Here, we address these problems by combining mutagenesis, ChIP-seq, and in vitro phosphorylation to study the functions of phospho-BfmR. We show that phosphorylation is required for BfmR-mediated gene regulation, antibiotic resistance, and sepsis development in vivo. Consistent with activating the protein, phosphorylation induces dimerization and target DNA affinity. Integrated analysis of genome-wide binding and transcriptional profiles of BfmR led to additional key findings: (1) Phosphorylation dramatically expands the number of genomic sites BfmR binds; (2) DNA recognition involves a direct repeat motif widespread across promoters; (3) BfmR directly regulates 303 genes as activator (eg, capsule, peptidoglycan, and outer membrane biogenesis) or repressor (pilus biogenesis); (4) BfmR controls several non-coding sRNAs. These studies reveal the centrality of a phosphorylation signal in driving A. baumannii disease and disentangle the extensive pathogenic gene-regulatory network under its control.

microbiology↗

bioRxiv2024

Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote asymptomatic colonization

Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize womens vaginocervix without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both pro- (IL-1{beta} and TNF-) and anti-inflammatory (IL-10) cytokines during the first 24-h. Cytokine induction required GC expression of an Opa isoform that binds the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-{kappa}B activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-{kappa}B activation, which reduced GC-induced IL-1{beta} and TNF-, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, reduced GC-induced IL-10 secretion. These results show that GC induce local IL-10 secretion at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding while suppressing inflammation activation, providing a potential mechanism for GC asymptomatic infection in women.

cell biology↗

bioRxiv2024

Norepinephrine Signals Through Astrocytes To Modulate Synapses

AbstractLocus coeruleus (LC)-derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and Ca2+ dynamics fully gate the effect of NE on synapses as the astrocyte-specific deletion of adrenergic receptors and three independent astrocyte-silencing approaches all render synapses insensitive to NE. Additionally, we find that NE suppression of synaptic strength results from an ATP-derived and adenosine A1 receptor-mediated control of presynaptic efficacy. An accompanying study from Chen et al. reveals the existence of an analogous pathway in the larval zebrafish and highlights its importance to behavioral state transitions. Together, these findings fuel a new model wherein astrocytes are a core component of neuromodulatory systems and the circuit effector through which norepinephrine produces network and behavioral adaptations, challenging an 80-year-old status quo.

neuroscience↗

bioRxiv2024

Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model

Physical exercise represents a primary defense against age-related cognitive decline and neurodegenerative disorders like Alzheimers disease (AD). To impartially investigate the underlying mechanisms, we conducted single-nucleus transcriptomic and chromatin accessibility analyses (snRNA-seq and ATAC-seq) on the hippocampus of mice carrying AD-linked NL-G-F mutations in the amyloid precursor protein gene (APPNL-G-F) following prolonged voluntary wheel-running exercise. Our study reveals that exercise mitigates amyloid-induced changes in both transcriptomic expression and chromatin accessibility through cell type-specific transcriptional regulatory networks. These networks converge on the activation of growth factor signaling pathways, particularly the epidermal growth factor receptor (EGFR) and insulin signaling, correlating with an increased proportion of immature dentate granule cells and oligodendrocytes. Notably, the beneficial effects of exercise on neurocognitive functions can be blocked by pharmacological inhibition of EGFR and the downstream phosphoinositide 3-kinases (PI3K). Furthermore, exercise leads to elevated levels of heparin-binding EGF (HB-EGF) in the blood, and intranasal administration of HB-EGF enhances memory function in sedentary APPNL-G-F mice. These findings offer a panoramic delineation of cell type-specific hippocampal transcriptional networks activated by exercise and suggest EGF-related growth factor signaling as a druggable contributor to exercise-induced memory enhancement, thereby suggesting therapeutic avenues for combatting AD-related cognitive decline.

animal behavior and cognition↗

bioRxiv2024

Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH

Heme is an iron-containing cofactor essential for life. In eukaryotes heme is generated in the mitochondria and must leave this organelle to reach protein targets in other cell compartments. Mitochondrial heme binding by cytosolic GAPDH was recently found essential for heme distribution in eukaryotic cells. Here, we sought to uncover how mitochondrial heme reaches GAPDH. Experiments involving a human cell line and a novel GAPDH reporter construct whose heme binding in live cells can be followed by fluorescence revealed that the mitochondrial transmembrane protein FLVCR1b exclusively transfers mitochondrial heme to GAPDH through a direct protein-protein interaction that rises and falls as heme transfers. In the absence of FLVCR1b, neither GAPDH nor downstream hemeproteins received any mitochondrial heme. Cell expression of TANGO2 was also required, and we found it interacts with FLVCR1b to likely support its heme exporting function. Finally, we show that purified GAPDH interacts with FLVCR1b in isolated mitochondria and triggers heme transfer to GAPDH and its downstream delivery to two client proteins. Identifying FLVCR1b as the sole heme source for GAPDH completes the path by which heme is exported from mitochondria, transported, and delivered into protein targets within eukaryotic cells.

cell biology↗

bioRxiv2024

STARDUST: a pipeline for the unbiased analysis of astrocyte regional calcium dynamics

Calcium imaging has become a popular way to probe astrocyte activity, but few analysis methods holistically capture discrete calcium signals that occur across the astrocyte domain. Here, we introduce STARDUST, a pipeline for the Spatio-Temporal Analysis of Regional Dynamics & Unbiased Sorting of Transients from fluorescence recordings of astrocytes, and provide step-by-step guidelines. STARDUST yields fluorescence time- series from data-defined regions of activity and performs systematic signal detection and feature extraction, enabling the in-depth and unbiased study of astrocyte calcium signals. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/588196v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@c6a97aorg.highwire.dtl.DTLVardef@a0b0fdorg.highwire.dtl.DTLVardef@1c3dd73org.highwire.dtl.DTLVardef@1ffa9ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Pseudovibriamides from Pseudovibrio marine sponge bacteria promote swarming motility via transcriptional modulation

Pseudovibrio -Proteobacteria have been repeatedly isolated from marine sponges and proposed to be beneficial to the host. Bacterial motility is known to contribute to host colonization. We have previously identified pseudovibriamides A and B, produced in culture by Pseudovibrio brasiliensis Ab134, and shown that pseudovibriamide A promotes flagellar motility. Pseudovibriamides are encoded in a hybrid nonribosomal peptide synthetase-polyketide synthase gene cluster that also includes several accessory genes. Pseudovibriamide A is a linear heptapeptide and pseudovibriamide B is a nonadepsipeptide derived from pseudovibriamide A. Here we define the borders of the pseudovibriamides gene cluster, assign function to biosynthetic genes using reverse genetics and test the hypothesis that pseudovibriamides impact motility by modulating gene transcription. RNA-seq transcriptomic analyses of strains having different compositions of pseudovibriamides suggested that both pseudovibriamides A and B affect genes potentially involved in motility, and that a compensatory mechanism is at play in mutants that produce only pseudovibriamide A, resulting in comparable swarming motility as the wild type. The data gathered suggest that pseudovibriamides A and B have opposite roles in modulating a subset of genes, with pseudovibriamide B having a primary effect in gene activation, and pseudovibriamide A on inhibition. Finally, we observed many differentially expressed genes (up to 29% of the total gene number) indicating that pseudovibriamides have a global effect on transcription that goes beyond motility. ImportanceMarine sponges are found throughout the oceans from tropical coral reefs to polar sea floors, playing crucial roles in marine ecosystems. Pseudovibrio bacteria have been proposed to contribute to sponge health. We have previously shown that pseudovibriamides produced by Pseudovibrio brasiliensis promote bacterial motility, a behavior that is beneficial to bacterial survival and to host colonization. The gene cluster that encodes pseudovibriamide biosynthesis is found in two thirds of Pseudovibrio genomes. This gene cluster is also present in Pseudomonas bacteria that interact with terrestrial plants and animals. Here we first assign function to pseudovibriamide biosynthetic genes using reverse genetics. We then show that pseudovibriamides play a major role in transcriptional regulation, affecting up to 29% of P. brasiliensis genes, including motility genes. Thus, this work gives insights into pseudovibriamide biosynthesis and provides evidence that they are signaling molecules relevant to bacterial motility and to other yet to be identified phenotypes.

microbiology↗

bioRxiv2024

Single-cell genomics and regulatory networks for 388 human brains

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized [~]250 disease-risk genes and drug targets with associated cell types. Summary Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/585576v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@70b24org.highwire.dtl.DTLVardef@6c9eddorg.highwire.dtl.DTLVardef@131fae2org.highwire.dtl.DTLVardef@4e0f1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Single-cell multiomics reveals a gene regulatory circuit promoting leukemia cell differentiation

Cancer differentiation therapy aims to induce maturation of neoplastic cells, yet how cell fate is determined in oncogenic cellular contexts is poorly understood. Here we integrate chromatin accessibility and transcriptome analysis at single-cell levels to investigate the mechanism driving the differentiation trajectory of the PML/RAR+ acute promyeloid leukemia (APL) cell line model, NB4, under the induction of all-trans-retinoid acid (ATRA). We show that differentiating NB4 cells navigate through an intermediate cell fate decision point that leads to either terminal granulopoiesis or a transient immature-lymphocyte-like state. Functional perturbation studies indicate that ATRA signaling activates discrete PML/RAR-target enhancers to induce a positive feedforward gene regulatory circuit involving two myeloid-lineage transcription factors, SPI1 and CEBPE, which is both necessary and sufficient to activate a myelocytic gene expression program in NB4. Further, ectopic expression of SPI1 and CEBPE also promotes myelocytic differentiation in non-APL leukemia cell lines HL60 and K562. Together, these results shed light on the differentiation trajectory of therapy-induced cell decisions of APL and suggest a gene regulatory circuit that may be broadly exploited to promote terminal differentiation of leukemia.

cancer biology↗

bioRxiv2024

Selective attention modulates feature accumulation speed during perception and memory retrieval

Mounting evidence indicates that information processing in the visual hierarchy follows a sequential progression from low-level perceptual to high-level conceptual features during visual perception, with the reverse order during memory retrieval. However, the nature of this hierarchical processing and its modulation by selective attention remains unclear. By integrating a deep neural network with the drift-diffusion model on reaction time data, we identified parallel processing of perceptual and conceptual features during perception, rather than sequential processing. The slower reaction times observed in conceptual tasks compared to perceptual tasks were primarily driven by the larger decision boundary and longer non-decision time associated with conceptual features, which could not be compensated by their faster evidence accumulation rates. Using single-trial multivariate decoding of MEG (magnetoencephalography) data to examine the timing of neural representations of different features, we found that selective attention reversed the onset times of perceptual and conceptual features in the occipital and parietal lobes during perception. This led to earlier detection of conceptual features compared to perceptual features in the animacy and size tasks. During retrieval, the colour task exhibited earlier peak times for perceptual features compared to conceptual features in the frontal lobe, indicating that perceptual features were reconstructed with the highest fidelity before conceptual features. These findings provide novel insights into the hierarchical nature of information processing during perception and retrieval, emphasizing the crucial role of selective attention in modulating the speed of feature information accumulation.

neuroscience↗

bioRxiv2023

Mapping the shared and unique structural asymmetry abnormalities of young children with autism and developmental delay/intellectual disability with normative models and their multimodal cascade

To understand the neural mechanism of autism spectrum disorder (ASD) concurrent with developmental delay/intellectual disability (DD/ID), it is essential to comprehensively take genetic, brain, and behavioural measurements as a whole and focus on subjects at early age. However, such research is still lacking. Here, using the sMRI data of 1030 children under 8 years old, we employed developmental normative models to explore the atypical development of gray matter volume (GMV) asymmetry in individuals with ASD without DD/ID, ASD with DD/ID and DD/ID, and their associations with neurophysiological measures and transcription profiles. By computing the individual deviations from typical controls, we observed an ASD-specific abnormal GMV laterality pattern that was more rightwards in the inferior parietal cortex and precentral cortex and noted abnormal within-group heterogeneity in the temporal pole. Specifically, ASD with DD/ID children exhibited more regional abnormalities; ASD without DD/ID children showed higher within-group variability; while children with DD/ID showed no significant abnormalities. However, there were no significant differences among the three groups. The GMV laterality of ASD without DD/ID children was associated with ASD symptoms, whereas that of ASD with DD/ID children was associated with both ASD symptoms and verbal IQ. Last, the GMV laterality of the ASD with DD/ID, ASD without DD/ID, and DD/ID groups was associated with shared and unique gene expression profiles, but the associations of the latter two groups with intellectual genes showed opposite effects. Our findings illustrated the atypical development of regional structural lateralization in autistic children, which is associated with upstream genes and downstream behavioural performance. The differences and similarity between ASD and DD/ID additionally improve our standing to the neural mechanism of neurodevelopmental disorders comorbidity.

neuroscience↗

bioRxiv2023

High-resolution ultrastructure and morphology of marine ammonia-oxidizing archaea Nitrosopumilus maritimus SCM1 revealed by Cryo-ET and STEM-EDS

Nitrososphaerota, formerly known as Thaumarchaeota, constitute a diverse and widespread group of ammonia-oxidizing archaea (AOA) inhabiting ubiquitously in marine and terrestrial environments, playing a pivotal role in global nitrogen cycling. Despite their significance in Earths ecosystems, the cellular organization of AOA remains largely unexplored, leading to a significant question unanswered of how the machinery of these organisms underpins metabolic functions. In this study, we combined chromatic-aberration-corrected cryo-electron tomography (cryo-ET), scanning transmission electron microscopy (STEM), and energy dispersive X-ray spectroscopy (EDS) to unveil the cellular organization and elemental composition of Nitrosopumilus maritimus SCM1, a representative member of marine Nitrososphaerota. Our tomograms show the native ultrastructural morphology of SCM1 and one to several dense storage granules in the cytoplasm. STEM-EDS analysis identifies two types of storage granules in which one type is possibly composed of polyphosphate, while the other type is polyhydroxyalkanoate. Collectively, these findings provide visual evidence for the resilience of AOA in the vast oligotrophic marine environment.

microbiology↗

bioRxiv2023

Chaperone-mediated autophagy is an overlooked pathway for mutant α1 antitrypsin Z degradation

Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSC70 for substrate recognition. In 1-antitrypsin deficiency (AATD), a disease characterized by the hepatic build-up of 1-Antitrypsin Z mutant (ATZ), CMAs role had been unclear. This work demonstrates the critical role that CMA plays in preventing ATZ accumulation; suppressing CMA worsens ATZ accumulation, whilst activating it through chemical stimulation or LAMP2A overexpression promotes ATZ breakdown. Specifically, ATZs 121QELLR125 motif is critical for HSC70 recognition and LAMP2As charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of ATZ. This selective activation of CMA operates independently from other autophagy pathways and alleviate ATZ aggregates caused cellular stress. These findings highlight CMAs critical function in cellular protein quality control of ATZ and place it as a novel target for AATD treatment approaches.

cell biology↗

bioRxiv2023

Abnormal white matter development during early childhood in autism and developmental disability

The abnormal maturation of white matter microstructure in autism spectrum disorder (ASD) compared with typical developing (TD) and developmental delay/intellectual disorder (DD/ID) during early childhood and their associations with clinical implications remain unclear. Here, we characterized spatial and temporal patterns of white matter development in 364 children (including ASD, DD/ID and TD) under 8 years old using neurite orientation dispersion and density imaging. Using neurite density index (NDI), we consistently detected three white matter clusters across all the groups through clustering analysis, indicating the conserved spatial layout in atypical development. Further, three developmental stages with successively lower growth rates were identified in ASD, similar to those in TD but delayed overall. Meanwhile, DD/ID children showed the slowest growth rates and lacked staging features. Finally, for ASD children, the NDI was correlated with cognitive impairments at the fast developmental stage but associated with social deficits during the moderate-to-slow stage.

neuroscience↗

bioRxiv2023

Global control of cellular physiology by biomolecular condensates through modulation of electrochemical equilibria

Control of the electrochemical environment in living cells is typically attributed to ion channels. Here we show that the formation of biomolecular condensates can modulate the electrochemical environment in cells, which affects processes globally within the cell and interactions of the cell with its environment. Condensate formation results in the depletion or enrichment of certain ions, generating intracellular ion gradients. These gradients directly affect the electrochemical properties of a cell, including the cytoplasmic pH and hyperpolarization of the membrane potential. The modulation of the electrochemical equilibria between the intra- and extra-cellular environments by biomolecular condensates governs charge-dependent uptake of small molecules by cells, and thereby directly influences bacterial survival under antibiotic stress. The shift of the intracellular electrochemical equilibria by condensate formation also drives a global change of the gene expression profile. The control of the cytoplasmic environment by condensates is correlated with their volume fraction, which can be highly variable between cells due to the stochastic nature of gene expression at the single cell level. Thus, condensate formation can amplify cell-cell variability of the environmental effects induced by the shift of cellular electrochemical equilibria. Our work reveals new biochemical functions of condensates, which extend beyond the biomolecules driving and participating in condensate formation, and uncovers a new role of biomolecular condensates in cellular regulation.

cell biology↗

bioRxiv2023

Molecular pathways and cellular subsets associated with adverse clinical outcomes in overlapping immune-related myocarditis and myositis

Immune checkpoint therapies (ICTs) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we obtained heart and skeletal muscle biopsies for single-cell RNA sequencing in living patients with cancers treated with ICTs admitted to the hospital with myocarditis and /or myositis (overlapping myocarditis plus myositis, n=10; myocarditis-only, n=1) compared to ICT-exposed patients ruled out for toxicity utilized as controls (n=9) within 96 hours of clinical presentation. Analyses of 58,523 cells revealed clonally expanded CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of tissue-resident myeloid cells expressed Fc{gamma}RIIIa, which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d that were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL-1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results are the first to recognize these myeloid subsets in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/556590v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@b5895forg.highwire.dtl.DTLVardef@4dec8corg.highwire.dtl.DTLVardef@1e50cb9org.highwire.dtl.DTLVardef@a653fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗