Biology subjects

Luo, X.

Publications and source records attributed to Luo, X..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

Binary Discriminator Facilitates GPT-based Protein Design

Generative pre-trained transformers (GPT) models provide powerful tools for de novo protein design (DNPD). GPT-based DNPD involves three procedures: a) finetuning the model with proteins of interest; b) generating sequence candidates with the finetuned model; and c) prioritizing the sequence candidates. Existing prioritization strategies heavily rely on sequence identity, undermining the diversity. Here, we coupled a protein GPT model with a custom discriminator, which enables selecting candidates of low identity to natural sequences while highly likely with desired functions. We applied this framework to creating novel antimicrobial peptides (AMPs) and malate dehydrogenases (MDHs). Experimental verification pinpointed four broad-spectrum AMPs from 24 candidates. Comprehensive computational analyses on the prioritized MDHs candidates provide compelling evidence for the anticipated function. During experimental validation, 4/10 and 3/10 natural MDHs and generated-prioritized novel candidates, respectively, were expressed and soluble. All the soluble candidates (3/3) are functional in vitro. This framework is time- and data-efficient and may therefore considerably expedite the DNPD process.

bioinformatics↗

bioRxiv2023

Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum

Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) patients are suboptimal due to the inflammatory state of the patients pancreas, oxidative tissue damage during the isolation process, and the harsh engraftment conditions in the livers vasculature, which include ischemia-reperfusion injury, and instant blood-mediated inflammatory reactions. We describe the use of the thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to protect islet redox status and function in vitro and in vivo and to create a viable extrahepatic islet engraftment site in the abdomen. PPCN in aqueous media transitions from a liquid to an elastic hydrogel when exposed to body temperature via temperature-induced macromolecular self-assembly. Islets entrapped in the PPCN hydrogel and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a biologic scaffold (BS). When applied to the omentum of non-human primates (NHPs), PPCN is well-tolerated, safe, and mostly resorbed without fibrosis at 3 months post-implantation. To obtain autologous islets, a partial pancreatectomy was performed, followed by STZ administration to induce diabetes and destroy any remaining endogenous islets. Application of the autologous islets to the momentum using PPCN restored normoglycemia with minimal insulin requirements for over 100 days. These results support the use of PPCN as a scaffold for minimally invasive delivery of islets to the omentum of pancreatitis patients and highlight the importance of scaffold antioxidant properties as a new mechanism to protect islet function and maximize long-term autologous graft performance. One Sentence SummaryOmentum islet transplantation using a thermoresponsive, antioxidative polymer supports autologous islet viability and function in nonhuman primates.

bioengineering↗

bioRxiv2023

Single Cell Expression Analysis of Ductal Carcinoma in Situ Identifies Alterations in Epithelial Integrity

To identify mechanisms underlying the growth of ductal carcinoma in situ (DCIS) and properties that lead to progression to invasive cancer, we performed single-cell RNA-sequencing (scRNA-seq) on DCIS lesions and matched synchronous normal breast tissue. Using inferred copy number variations (CNV), we identified neoplastic epithelial cells from the clinical specimens which contained a mixture of DCIS and normal ducts. Phylogenetic analysis based on the CNVs demonstrated intratumoral clonal heterogeneity was associated with significant gene expression differences. We also classified epithelial cells into mammary cell states and found that individual genetic clones contained a mixture of cell states suggesting an ongoing pattern of differentiation after neoplastic transformation. Cell state proportions were significantly different based on estrogen receptor (ER) expression with ER-DCIS more closely resembling the distribution in the normal breast, particularly with respect to cells with basal characteristics. Using deconvolution from bulk RNA-seq in archival DCIS specimens, we show that specific alterations in cell state proportions are associated with progression to invasive cancer. Loss of an intact basement membrane (BM) is the functional definition of invasive breast cancer (IBC) and scRNA-seq data demonstrated that ongoing transcription of key BM genes occurs in specific subsets of epithelial cell states. Examining BM in archival microinvasive breast cancers and an in vitro model of invasion, we found that passive loss of BM gene expression due to cell state proportion alterations is associated with loss of the structural integrity of the duct leading to an invasive phenotype. Our analyses provide detailed insight into DCIS biology. SIGNIFICANCESingle cell analysis reveals that preinvasive breast cancer is comprised of multiple genetic clones and there is substantial phenotypic diversity both within and between these clones. Ductal carcinoma in situ (DCIS) of the breast is a non-invasive condition commonly identified through mammographic screening. A primary diagnosis of DCIS carries little mortality risk on its own, but its presence is a risk factor for subsequent clonally related invasive breast cancer (IBC) (1-5).

cancer biology↗

bioRxiv2023

G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses KrasG12D/+;Lkb1-/-(KL) but not KrasG12D/+;p53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

cancer biology↗

bioRxiv2023

A resource for probing influences of perinatal factors on neurodevelopment in 3-10-years-old Chinese children

Adverse perinatal factors can disrupt the normal development of the brain, with potential long-term impacts on childrens overall development. Currently, the neuropathological mechanisms by which these factors lead to various neurodevelopmental disorders (NDDs) remain largely unknown. An open resource that integrate perinatal factors with brain and mental health development is essential for investigating NDD-related aetiology. In this Data Descriptor, we introduce a multicentre database containing information on perinatal factors that influence childrens brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors associated with a high incidence of NDDs at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development among children aged 3-10 years are associated with perinatal factors. Ultimately, our goal was to develop an early prediction and screening model for NDDs that leverages normative data to facilitate NDD aetiology research. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD and present preliminary brain-mind associations.

neuroscience↗

bioRxiv2023

OSCAA: A Two-Dimensional Gaussian Mixture Model for Copy Number Variation Association Analysis

Copy number variants (CNVs) are prevalent in the human genome which provide profound effect on genomic organization and human diseases. Discovering disease associated CNVs is critical for understanding the pathogenesis of diseases and aiding their diagnosis and treatment. However, traditional methods for assessing the association between CNVs and disease risks adopt a two-stage strategy conducting quantitative CNV measurements first and then testing for association, which may lead to biased association estimation and low statistical power, serving as a major barrier in routine genome wide assessment of such variation. In this article, we developed OSCAA, a flexible algorithm to discover disease associated CNVs for both quantitative and qualitative traits. OSCAA employs a two-dimensional Gaussian mixture model that is built upon the principal components from copy number intensities, accounting for technical biases in CNV detection while simultaneously testing for their effect on outcome traits. In OSCAA, CNVs are identified and their associations with disease risk are evaluated simultaneously in a single step, taking into account the uncertainty of CNV identification in the statistical model. Our simulations demonstrated that OSCAA outperformed the existing one-stage method and traditional two-stage methods by yielding a more accurate estimate of the CNV-disease association, especially for short CNVs or CNVs with weak signal. In conclusion, OSCAA is a powerful and flexible approach for CNV association testing with high sensitivity and specificity, which can be easily applied to different traits and clinical risk predictions.

genomics↗

bioRxiv2023

Activation of a cortical neurogenesis transcriptional program during NEUROD1-induced astrocyte-to-neuron conversion

NEUROD1-induced astrocyte-to-neuron (AtN) conversion has garnered significant attention as a potential therapeutic intervention to neurological disorders. To gain insight into the molecular regulations underlying this neuronal reprogramming process, we applied single-cell multiomics analyses on in vitro ND1-induced AtN conversion to systematically investigate how ND1 changed the fate of astrocytes at transcriptomic and epigenetic levels. Our findings reveal that the initial immature astrocytes go through an intermediate state where both astrocytic and neuronal genes are activated at early stage of AtN conversion. ND1 directly reshapes the chromatin accessibility landscape of astrocytes to that of neurons, promoting expression of endogenous Neurod1 and other neurogenic genes such as Hes6, Insm1 etc. Interestingly, cell proliferation status is highly correlated with conversion rate, and inhibition of cell division significantly reduces the conversion ratio. Moreover, in comparison with another AtN reprogramming transcription factor, ASCL1, external ND1 can activate endogenous Neurod1 and directly promote neuronal gene transcription; whereas external ASCL1 hardly activates endogenous Ascl1, leading to slower and inefficient conversion. Together, our studies demonstrate that in vitro AtN conversion mimics neurogenic transcriptional program in embryonic neurogenesis.

neuroscience↗

bioRxiv2023

Comparative single-cell regulome reveals evolutionary innovations in neural progenitor cells during primate corticogenesis

The cellular and genetic mechanism underlying the human-specific features of cortex development remains unclear. We generated a cell-type resolved atlas of transcriptome and regulome of the developing macaque and mouse prefrontal cortex, and conducted evolutionary analyses with the published complementary human data. We discovered a primate-specific expansion of two neural progenitor subclasses, glia-committed radial glia (RG) and truncated RG. Specifically, the human neural progenitors show extensive transcriptional rewiring in the growth factor and extracellular matrix pathways. Expression of the human-specific progenitor marker ITGA2 in the cortex of fetal mouse promotes progenitor proliferation and an increased upper-layer neuron proportion. We demonstrate that these transcriptional divergences are primarily driven by the activity changes of the distal regulatory elements in the genome. Markedly, the chromatin regions with human-gained accessibility enrich the human-fixed sequence changes, as well as sequence polymorphisms associated with intelligence and neuropsychiatric disorders. Our results uncover evolutionary innovations in neural progenitors and gene regulatory mechanism during primate cortex evolution.

evolutionary biology↗

bioRxiv2023

Targeting pioneer transcription factor Ascl1 to promote optic nerve regeneration

In adult mammalian central nervous system (CNS) neurons, axon regeneration after injury remains limited due to unfavorable gene regulatory programs. Factors enabling comprehensive epigenetic and transcriptional transitions, for instance, pivotal transcription factors that mediate neurogenesis and morphogenesis may be sufficient to promote CNS axon regeneration. Based on the analyses of multiple public whole-genome RNA and chromatin accessibility sequencing dataset of mouse retina development, as well as previous functional studies on the regeneration-capable dorsal root ganglion neurons, we hypothesize that the overexpression of pioneer transcription factor Achaete-Scute homolog 1 (Ascl1) would promote axon regeneration in the adult mammalian CNS neurons. We employed the optic nerve crush in mice, a common model for studying CNS axon regeneration, neuron survival and glaucoma, to investigate the effect of Ascl1 overexpression on the post-injury optic nerve regeneration. We found that Ascl1 could sufficiently promote regenerated axons past the crush site and significantly preserve the survival of retinal ganglion cells. Mechanistically, we revealed that effects of Ascl1 was mediated by known pro-regeneration factor Sox11 but not others. Together, our study established an effective workflow combined with the integrated computational inference and experimental validation for discovering functionally important target for promoting CNS neuron axon regeneration and survival.

neuroscience↗

bioRxiv2023

Habitat correlates of cave-dwelling: A radiation-scale analysis of skin traits and comparative transcriptomics of the Sinocyclocheilus cavefish

With 78 species, Sinocyclocheilus cavefish constitute the largest cavefish radiation in the world. They exhibit remarkable morphological diversity across three habitat types: surface (Surface morphs, Normal-eyed, variably colored), exclusively-cave-dwelling (Stygobitic morphs, Eyeless, depigmented), and intermediate between cave and surface (Stygophilic morphs, Micro-eyed, partially depigmented). Distinctive traits of Sinocyclocheilus include variations in eye and skin conditions associated with their habitat, despite the role of the skin in sensing environmental changes, its habitat correlates are less understood, compared to the well-studied eye conditions. Here, we analyzed the correlation between Sinocyclocheilus skin morphology and its habitat, utilizing morphological and transcriptomics-based methods. We generated RNA-sequencing data for nine species and integrated those with existing data from five additional species. These 14 species represent the primary clades and major habitats of these cavefish. Data on skin color and scale morphology were generated and 7374 orthologous genes were identified. Using a comparative transcriptomics approach, we identified 1,348 differentially expressed genes (DEGs) in the three morphotypes. GO and KEGG enrichment analyses suggest that these species have evolved different strategies for energy metabolism, immunity, and oxidative stress in different habitats. We also found 329 positive selection genes (PSGs) in the skin of these species that are mainly involved in immunity, apoptosis, and necrosis, indicating potential adaptations to their habitats. The maximum likelihood phylogenetic tree, based on 1369 single-copy orthologous genes of the species, was largely concordant with the currently established RAD-seq and mt-DNA based phylogenies, but with a few exceptions. Species with higher cave dependence present lighter coloration, fewer dark blotches, and diminished scale morphology and coverage. PCA and cluster analysis suggested that cave-dwelling species, characterized by the absence of black blotches, have similar expression patterns, indicating convergence in cave adaptation. Variations in tyrosine metabolism may explain pigmentation differences among species in diverse habitats. Our study highlights the significance of habitat in shaping skin metabolism, pigmentation variation, and morphology while offering insights into the molecular mechanisms driving these habitat-specific adaptations in Sinocyclocheilus. These findings underscore the transcriptional variation in adapting to diverse environments and contribute to future studies on the evolution and ecology of cavefish.

evolutionary biology↗

bioRxiv2023

Spatial pattern and differential expression analysis with spatial transcriptomic data

The emergence of spatial transcriptomic technologies has opened new avenues to investigate gene activities while preserving the spatial context of tissues. Utilizing data generated by such technologies, the identification of spatially variable (SV) genes is an essential step in investigating tissue landscapes and biological processes. Particularly in typical experimental designs such as case-control or longitudinal studies, identifying SV genes between groups is crucial for discovering significant biomarkers or developing targeted therapies for diseases. However, current methods available for analyzing spatial transcriptomic data are still in their infancy, and none of the existing methods are capable of identifying SV genes between groups. To overcome this challenge, we developed SPADE for spatial pattern and differential expression analysis to identify SV gene in spatial transcriptomic data. SPADE is based on a machine learning model of Gaussian process regression with a gene-specific Gaussian kernel, enabling the detection of SV genes both within and between groups. Through extensive simulations and real data analyses, we have demonstrated the superior performance of SPADE compared to existing methods in detecting SV genes within and between groups. The SPADE source code and documentation are publicly available at https://github.com/thecailab/SPADE.

bioinformatics↗

bioRxiv2023

EquiScore: A generic protein-ligand interaction scoring method integrating physical prior knowledge with data augmentation modeling

Developing robust methods for evaluating protein-ligand interactions has been a long-standing problem. Here, we propose a novel approach called EquiScore, which utilizes an equivariant heterogeneous graph neural network to integrate physical prior knowledge and characterize protein-ligand interactions in equivariant geometric space. To improve generalization performance, we constructed a dataset called PDBscreen and designed multiple data augmentation strategies suitable for training scoring methods. We also analyzed potential risks of data leakage in commonly used data-driven modeling processes and proposed a more stringent redundancy removal scheme to alleviate this problem. On two large external test sets, EquiScore outperformed 21 methods across a range of screening performance metrics, and this performance was insensitive to binding pose generation methods. EquiScore also showed good performance on the activity ranking task of a series of structural analogs, indicating its potential to guide lead compound optimization. Finally, we investigated different levels of interpretability of EquiScore, which may provide more insights into structure-based drug design.

bioinformatics↗

bioRxiv2023

An Interleukin 9-Zbtb18 axis promotes germinal center development of memory B cells

Germinal centers (GCs) generate humoral memory in the form of long-lived plasma cells and memory B cells (MBCs). MBC development in GCs entail profound changes in states of cell cycle, localization and survival. Whether and how these changes are extrinsically instructed and intrinsically programmed in GC B cells are not well understood. Here we demonstrate that Il-9 instructs MBC development from GCs during the primary response. Il-9 induces expression of Zbtb18, a transcription repressor that is repressed in the bulk of GC cells but highly expressed in GC memory precursor cells and MBCs. While Zbtb18 is dispensable for activation of naive B cells and for GC formation, it is essential for normal development of GC-derived MBCs. Zbtb18 directly binds to and represses a suite of cyclin and CDK genes to promote quiescence, pro-apoptotic genes Bid and Casp3 to promote survival, and GC-retaining gene S1pr2 to promote GC departure. In the absence of Zbtb18, GCMP cells do not efficiently quit cell cycle to achieve quiescence, do not efficiently downregulate S1pr2 to exit, and they become more prone to die. Our results support that an Il-9-Zbtb18 axis instructs development of functional B-cell memory from GCs.

immunology↗

bioRxiv2023

Post-acute immunological and behavioral sequelae in mice after Omicron infection

Progress in understanding long COVID and developing effective therapeutics is hampered in part by the lack of suitable animal models. Here we used ACE2-transgenic mice recovered from Omicron (BA.1) infection to test for pulmonary and behavioral post-acute sequelae. Through in-depth phenotyping by CyTOF, we demonstrate that naive mice experiencing a first Omicron infection exhibit profound immune perturbations in the lung after resolving acute infection. This is not observed if mice were first vaccinated with spike-encoding mRNA. The protective effects of vaccination against post-acute sequelae were associated with a highly polyfunctional SARS-CoV-2-specific T cell response that was recalled upon BA.1 breakthrough infection but not seen with BA.1 infection alone. Without vaccination, the chemokine receptor CXCR4 was uniquely upregulated on multiple pulmonary immune subsets in the BA.1 convalescent mice, a process previously connected to severe COVID-19. Taking advantage of recent developments in machine learning and computer vision, we demonstrate that BA.1 convalescent mice exhibited spontaneous behavioral changes, emotional alterations, and cognitive-related deficits in context habituation. Collectively, our data identify immunological and behavioral post-acute sequelae after Omicron infection and uncover a protective effect of vaccination against post-acute pulmonary immune perturbations.

microbiology↗

bioRxiv2023

Insight into the genetic diversity, resistance, and virulence of Listeria from the marine environment: reveal the risk of hypervirulent isolates

Listeria monocytogenes is a major human foodborne pathogen and a ubiquitous environmental saprophyte. In this study, we investigated the prevalence and characteristics of Listeria spp. from beach sand in the coastal environment. Three different Listeria spp., Listeria monocytogenes (n=16), Listeria fleishmanii (n=7), and Listeria aquatica (n=3) were isolated from 769 beach sand samples and demonstrated diverse biofilm forming capacity. The L. monocytogenes isolates belonged to four distinct sequence types (ST87, ST121, ST35, and ST85) and contained the majority of virulence genes, some isolates were hypervirulent clones or had close phylogenetic relatedness with clinical cases. The ST87 isolates showed higher ability of biofilm formation in seawater than other STs strains. As a reservoir of microbes from marine environments and human/animal excrement, coastal sand would play an important role in the spread of L. monocytogenes and is an environmental risk for human listeriosis.

microbiology↗

bioRxiv2023

Resolving the developmental mechanisms of coagulation abnormalities characteristic of SARS-CoV2 based on single-cell transcriptome analysis

The COVID-19 outbreak caused by the SARS-CoV-2 virus has developed into a global health emergency. In addition to causing respiratory symptoms following SARS-CoV-2 infection, COVID-19-associated coagulopathy (CAC) is the main cause of death in patients with severe COVID-19. In this study, we performed single-cell sequencing analysis of the right ventricular free wall tissue from healthy donors, patients who died in the hypercoagulable phase of CAC, and patients in the fibrinolytic phase of CAC. Among these, we collected 61,187 cells, which were enriched in 24 immune cell subsets and 13 cardiac-resident cell subsets. We found that in response to SARS-CoV-2 infection, CD9highCCR2highmonocyte-derived mo promoted hyperactivation of the immune system and initiated the extrinsic coagulation pathway by activating CXCR-GNB/G-PI3K-AKT. This sequence of events is the main process contributing the development of coagulation disorders subsequent to SARS-CoV-2 infection. In the characteristic coagulation disorder caused by SARS-CoV-2, excessive immune activation is accompanied by an increase in cellular iron content, which in turn promotes oxidative stress and intensifies intercellular competition. This induces cells to alter their metabolic environment, resulting in an increase in sugar uptake, such as that via the glycosaminoglycan synthesis pathway, in CAC coagulation disorders. In addition, high levels of reactive oxygen species generated in response elevated iron levels promote the activation of unsaturated fatty acid metabolic pathways in endothelial cell subgroups, including vascular endothelial cells. This in turn promotes the excessive production of the toxic peroxidation by-product malondialdehyde, which exacerbates both the damage caused to endothelial cells and coagulation disorders.

microbiology↗

bioRxiv2023

Gene expression plasticity followed by genetic change during colonization a high-elevation environment

Phenotypic plasticity facilitates organismal invasion of novel environments, and the resultant phenotypic change may later be modified by genetic change, so called "plasticity first". Herein we quantify gene expression plasticity and regulatory adaptation in a wild bird (Eurasian Tree Sparrow) from its original lowland (ancestral stage), experimentally implemented hypoxia acclimation (plastic stage) and colonized highland (colonized stage). Using a group of co-expressed genes from the cardiac and flight muscle, respectively, we demonstrate that gene expression plasticity to hypoxia tolerance is more often reversed than reinforced at the colonized stage. By correlating gene expression change with muscle phenotypes, we show that colonized tree sparrows reduce maladaptive plasticity that largely associates with decrease hypoxia tolerance. Conversely, adaptive plasticity that is congruent with increase hypoxia tolerance is often reinforced in the colonized tree sparrows. Genes displaying large levels of reinforcement or reversion plasticity (i.e., 200% of original level) show greater genetic divergence between ancestral and colonized populations. Overall, our work demonstrates that gene expression plasticity at the initial stage of high-elevation colonization can be reversed or reinforced through selection-driven adaptive modification.

evolutionary biology↗

bioRxiv2023

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple "omics" assays (CyTOF, RNAseq/scRNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. RNAseq/scRNAseq and Olink analyses similarly revealed immune dysregulatory mechanisms, along with non-immune associated perturbations, in individuals with LC. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.

immunology↗