Biology subjects

Dai, J.

Publications and source records attributed to Dai, J..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

Pre-mutagenic and mutagenic changes imprinted on the genomes of mammalian cells after irradiation with a nail polish dryer

Ultraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of mammalian cells. These results have far-reaching implications in regard to public health and to preventing skin cancer due to consumer-based exposure to ultraviolet light from artificial sources.

cancer biology↗

bioRxiv2021

Unsupervised discovery of dynamic cell phenotypic states from transmitted light movies

Identification of cell phenotypic states within heterogeneous populations, along with elucidation of their switching dynamics, is a central challenge in modern biology. Conventional single-cell analysis methods typically provide only indirect, static phenotypic readouts. Transmitted light images, on the other hand, provide direct morphological readouts and can be acquired over time to provide a rich data source for dynamic cell phenotypic state identification. Here, we describe an end-to-end deep learning platform, UPSIDE (for Unsupervised Phenotypic State IDEntification), for discovering cell states and their dynamics from transmitted light movies. UPSIDE uses the variational auto-encoder architecture to learn latent cell representations, that are then clustered for state identification, decoded for feature interpretation, and linked across movie frames for transition rate inference. Using UPSIDE, we identified distinct blood cell types in a heterogeneous dataset. From acute myeloid leukemia cell movies, we then identified stem-cell associated morphological states and their inter-conversion rates. UPSIDE opens up use of transmitted light movies for systematic exploration of cell state heterogeneity and dynamics in biology and medicine.

bioinformatics↗

bioRxiv2021

ATGs ubiquitination is required for circumsporozoite protein to subvert host innate immunity against malaria liver stage

Although exoerythrocytic forms (EEFs) of liver stage malaria parasite in parasitophorous vacuole (PV) encountered with robust host innate immunity, EEFs can still survive and successfully complete infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly inhibited the killing of exo-erythrocytic forms (EEFs) by interferon-gamma (IFN-{gamma}). Attenuation of IFN-{gamma}-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes via its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection.

microbiology↗

bioRxiv2020

Hydrogel-coating improves the in-vivo stability of electrochemical aptamer-based biosensors

The ability to track the levels of specific molecules, such as drugs, metabolites, and biomarkers, in the living body, in real time and for long durations would improve our understanding of health and our ability to diagnose, treat and monitor disease. To this end, we are developing electrochemical aptamer-based (E-AB) biosensors, a general platform supporting high-frequency, real-time molecular measurements in the living body. Here we report that the addition of an agarose hydrogel protective layer to E-AB sensors significantly improves their baseline stability when deployed in the complex, highly time-varying environments found in vivo. The improved stability is sufficient that these hydrogel-protected sensors achieved good baseline stability when deployed in situ in the veins, muscles, bladder, or tumors of living rats without the use of the drift correction approaches traditionally required in such placements. Finally, this improved stability is achieved without any significant, associated "costs" in terms of detection limits, response times, or biocompatibility.

bioengineering↗

bioRxiv2020

Cell group analysis reveals changes in upper-layer neurons associated with schizophrenia

Genome-wide association studies (GWAS) of schizophrenia (SCZ) have revealed over 100 risk loci. We investigated whether these SCZ-associated variants regulate gene expression by cell type. Using a fully unsupervised deconvolution method, we calculated gene expression by clusters of estimated cell types (cell-groups, CGs). Five CGs emerged in the dorsolateral prefrontal cortices (DLPFC) of 341 donors with and without SCZ. By mapping expression quantitative trait loci (eQTL) per CG, we partitioned the heritability of SCZ risk in GWAS by CGs. CG-specific expressions and eQTLs were replicated in both a deconvoluted bulk tissue data set with a different method and also in sorted-cell expression data. Further, we characterized CG-specific gene differential expression and cell proportion changes in SCZ brains. We found upper-layer neurons in the DLPFC to be associated with SCZ based on enrichment of SCZ heritability in eQTLs, disease-related transcriptional signatures, and decreased cell proportion. Our study suggests that neurons and related anomalous circuits in the upper layers of the DLPFC may have a major contribution to SCZ risk.

genomics↗

bioRxiv2020

Epstein-Barr virus promotes survival through germinal center light zone chromatin architecture

BFL-1 is an understudied anti-apoptotic protein upregulated in cancer and Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (LCLs). We have previously shown that BFL-1 is regulated through viral EBNA3A-mediated alterations in B-cell chromatin conformation (Price et al., 2017). Here, we extend those findings to define cis- and trans-acting factors that regulate BFL-1 in LCLs and reliance on BFL-1 for survival from extrinsic apoptosis. Beyond LCLs, BFL-1 is expressed in B cells maturing in the germinal center (GC). We therefore characterized the gene expression profiles and chromatin landscape of maturing human tonsillar B-cell subsets. While chromatin accessibility at the BFL-1 locus increases as naive B cells enter the GC reaction, BFL-1 expression increases during the transition from dark zone to light zone (LZ) correlating with association between enhancer regions and the transcriptional start site. The relationship between LCLs and LZ B cells suggests that EBV phenocopies GC biology to enhance their survival in establishing latent infection.

immunology↗

bioRxiv2020

Sub-second heat inactivation of coronavirus

Heat treatment denatures viral proteins that comprise the virion, making virus incapable of infecting a host. Coronavirus (CoV) virions contain single-stranded RNA genomes with a lipid envelope and 4 proteins, 3 of which are associated with the lipid envelope and thus are thought to be easily denatured by heat or surfactant-type chemicals. Prior studies have shown that a temperature of as low as 75 {degrees}C and treatment duration of 15 min can effectively inactivate CoV. The applicability of a CoV heat inactivation method greatly depends on the length of time of a heat treatment and the temperature needed to inactivate the virus. With the goal of finding conditions where sub-second heat exposure of CoV can sufficiently inactivate CoV, we designed and developed a simple system that can measure sub-second heat inactivation of CoV. The system is composed of capillary stainless-steel tubing immersed in a temperature-controlled oil bath followed by an ice bath, through which virus solution can be flowed at various speeds. Flowing virus solution at different speeds, along with a real-time temperature monitoring system, allows the virus to be accurately exposed to a desired temperature for various durations of time. Using mouse hepatitis virus (MHV), a beta-coronavirus, as a model system, we identified that 85.2 {degrees}C for 0.48 s exposure is sufficient to obtain > 5 Log10 reduction in viral titer (starting titer: 5 x 107 PFU/mL), and that when exposed to 83.4 {degrees}C for 0.95 s, the virus was completely inactivated (zero titer, > 6 Log10 reduction). IMPORTANCEThree coronaviruses (CoVs) have now caused global outbreaks within the past 20 years, with the COVID19 pandemic caused by SARS-CoV-2 still ongoing. Methods that can rapidly inactivate viruses, especially CoVs, can play critical roles in ensuring public safety and safeguarding personal health. Heat treatment of viruses to inactive them can be an efficient and inexpensive method, with the potential to be incorporated into various human-occupied spaces. In this work, a simple system that can heat-treat viruses for extremely short period was developed and utilized to show that sub-second exposure of CoV to heat is sufficient to inactivate CoV. This opens up the possibility of developing instruments and methods of disinfecting CoV in diverse settings, including rapid liquid disinfection and airborne virus disinfection. The developed method can also be broadly utilized to assess heat sensitivity of viruses other viral pathogens of interest and develop sub-second rapid heat inactivation approaches.

bioengineering↗

bioRxiv2020

Single-cell characterization of transcriptomic heterogeneity in lymphoblastoid cell lines

Lymphoblastoid Cell Lines (LCLs) are generated by transforming primary B cells with Epstein-Barr Virus (EBV) and are used extensively as model systems in viral oncology, immunology, and human genetics research. In this study, we characterized single-cell transcriptomic profiles of five LCLs and present a simple discrete-time simulation to explore the influence of stochasticity on LCL clonal evolution. Single-cell RNA sequencing revealed substantial phenotypic heterogeneity within and across LCLs with respect to immunoglobulin isotype; virus-modulated host pathways involved in survival, proliferation, and differentiation; viral replication state; and oxidative stress. This heterogeneity is likely attributable to intrinsic variance in primary B cells and host-pathogen dynamics. Stochastic simulations demonstrate that initial primary cell heterogeneity, random sampling, time in culture, and even mild differences in phenotype-specific fitness can contribute substantially to dynamic diversity in populations of nominally clonal cells.

immunology↗

bioRxiv2020

Curcumin promotes progression of AApoAII amyloidosis and peroxisome proliferation in mice by activating the PPARα signaling pathway

Curcumin is a polyphenol compound that exhibits multiple physiological activities. To elucidate the mechanisms by which curcumin affects systemic amyloidosis, we investigated amyloid deposition and molecular changes in a mouse model of amyloid apolipoprotein A-II (AApoAII) amyloidosis, in which mice were fed a curcumin-supplemented diet. Curcumin supplementation for 12 weeks significantly increased AApoAII amyloid deposition relative to controls, especially in the liver and spleen. Liver weights and plasma ApoA-II and high-density lipoprotein concentrations were significantly elevated in curcumin-supplemented groups. RNA-sequence analysis revealed that curcumin intake affected hepatic lipid metabolism via the peroxisome proliferator-activated receptor (PPAR) pathway, especially PPAR activation, resulting in increased Apoa2 mRNA expression. The increase in liver weights was due to activation of PPAR and peroxisome proliferation. Taken together, these results demonstrate that curcumin is a PPAR activator and may affect expression levels of proteins involved in amyloid deposition to influence amyloidosis and metabolism in a complex manner.

molecular biology↗

bioRxiv2020

Analysis of single-cell RNA-seq data from ovarian cancer samples before and after chemotherapy links stress-related transcriptional profile withchemotherapy resistance

Chemotherapy resistance is the greatest contributor to cancer mortality and the most urgent unmet challenge in oncology. In order to reveal transcriptomics changes due to platinum-based chemotherapy we analyzed single-cell RNA-seq data from fresh tissue samples taken at the time of diagnosis and after neoadjuvant chemotherapy from 11 high-grade serous ovarian cancer (HGSOC) patients. With a novel clustering method accounting for patient-specific variability and technical confounders, we identified 12 clusters. Of these, a stress-related transcriptional profile was enriched during chemotherapy and associated significantly to poor progression-free survival (PFS) and disease-free interval (DFI) in deconvoluted bulk RNA-seq data analysis of treatment-naive samples in TCGA cohort. Pan-cancer cell line analysis suggests that patients with high stress-related transcriptional profile may benefit from MEK1/2 inhibitors instead of platinum. Further, high proportion of stromal components and high interaction score between tumor and stromal suggest the tumor cells with high-stress profile actively interact with and potentially recruit stromal cells to their microenvironment already prior to chemotherapy, potentially facilitating protection from chemotherapeutic treatments. In summary, we have identified a stress-related transcriptional profile, which is present at the time of diagnosis, enriched during platinum treatment, independent predictor for poor PFS and DFI, and, based on in vitro data, targetable with MEK1/2 inhibitors. Translational relevanceWe discovered a stress-related transcriptional profile that is significantly enriched in fresh tissue samples after chemotherapy and is significantly associated with poor progression-free survival in an independent patient cohort. The survival association is independent of age, tumor purity or BRCAness. Therefore, this chemotherapy resistance associated profile is intrinsic and could thus be targeted already in treatment-naive patients. The translation potential of the stress-related transcriptomics profile was further supported by pan-cancer cell line analysis that showed that cell lines with high stress-related transcriptional profile are not affected by platinum, corroborating our results, whereas they were more sensitive to MEK1/2 inhibitors. Taken together, the stress-related transcriptional profile, quantifiable with a set of 35 marker genes, provides a basis for improved prediction of platinum response as well as novel avenues to treat this patient group more effectively.

bioinformatics↗

bioRxiv2020

Bi-allelic variants in TSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

Dystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenile- onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between presynaptic RIMBP1 dysfunction and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

genetics↗

bioRxiv2020

Intrinsic connectivity of the prefrontal cortex and striato-limbic system respectively differentiate Major Depressive from Generalized Anxiety Disorder

Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) are highly prevalent and debilitating disorders. The high overlap on the symptomatic and neurobiological level led to ongoing debates about their diagnostic and neurobiological uniqueness. The present study aims to identify common and disorder-specific neuropathological mechanisms and treatment targets in MDD and GAD. The present study combined categorial and dimensional disorder models with a fully data-driven intrinsic network level analysis (Intrinsic Connectivity Contrast, ICC) to resting state fMRI data acquired in 108 partn = 35 and n = 38 unmedicated patients with first-episode GAD, MDD respectively and n=35 healthy controls). Convergent evidence from categorical and dimensional analyses revealed MDD-specific decreased whole-brain connectivity profiles of the medial prefrontal and dorsolateral prefrontal cortex while GAD was specifically characterized by decreased whole-brain connectivity profiles of the putamen and decreased communication of this region with the amygdala. Together, findings from the present data-driven analysis suggest that intrinsic communication of frontal regions engaged in executive functions and emotion regulation represent depression-specific neurofunctional markers and treatment targets whereas dysregulated intrinsic communication of the striato-amygdala system engaged in reinforcement-based and emotional learning processes represent GAD-specific markers and a promising treatment target.

neuroscience↗

bioRxiv2020

HDAC inhibitors decrease TLR7/9-mediated human plasmacytoid dendritic cell activation by interfering with IRF-7 and NF-қB signaling

Histone deacetylase inhibitors (HDACi) are epigenome modulating molecules that target histone and non-histone proteins and have been successfully used to target many types of cancer and immunological disorders. While HDACis effects on nuclear histone deacetylases are well characterized, their effect on non-nuclear, cytoplasmic molecules requires further investigation. In the current study we characterized the effects of class I/II HDACi, specifically, TSA, MS-275, and SAHA, on plasmacytoid dendritic cell (pDC) biology upon viral activation via the TLR7/9 pathway. TSA, MS-275, and SAHA, down-modulated the induction of IFN- and TNF- upon Influenza A virus (IAV; TLR7 signaling) and Herpes Simplex 1 (HSV-1; TLR9 signaling) stimulation in primary pDC. The HDACi inhibitory effect was more prominent for IAV-mediated responses than for HSV-1. While IFN- induction was not associated with inhibition of IRF-7 upregulation in the presence of TSA or MS-275, IRF-7 upregulation was affected by SAHA, but only for IAV. Furthermore, TSA, but not MS-275, inhibited TLR7/9-induced expression of maturation markers, CD40, and CD86, but not CD40. In addition, HDACi treatment increased virally-induced shedding of CD62L. Mechanistically, TSA, MS-275, SAHA significantly decreased early IRF-7 and NF-{kappa}B nuclear translocation, which was preceded by a decline in phosphorylation of IRF-7 at Ser477/479 and NF-{kappa}B p-p65, except for MS-275. In summary, we propose that broad HDACi, but not class I HDACi, treatment can negatively impact early TLR7/9-mediated signaling, namely, the disruption of IRF-7 and NF-{kappa}B activation and translocation that lead to deleterious effects on pDC function.

immunology↗

bioRxiv2020

Co-evolution of Eukaryotic-like Vps4 and ESCRT-III Subunits in the Asgard Archaea

The emergence of the endomembrane system is a key step in the evolution of cellular complexity during eukaryogenesis. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery is essential and required for the endomembrane system functions in eukaryotic cells. Recently, genes encoding eukaryote-like ESCRT protein components have been identified in the genomes of Asgard archaea, a newly proposed archaeal superphylum that is thought to include the closest extant prokaryotic relatives of eukaryotes. However, structural and functional features of Asgard ESCRT remain uncharacterized. Here we show that Vps4, Vps2/24/46, and Vps20/32/60, the core functional components of the Asgard ESCRT, co-evolved eukaryote-like structural and functional features. Phylogenetic analysis shows that Asgard Vps4, Vps2/24/46, and Vps20/32/60 are closely related to their eukaryotic counterparts. Molecular dynamic simulation and biochemical assays indicate that Asgard Vps4 contains a eukaryote-like Microtubule Interacting and Transport (MIT) domain that binds the distinct type-1 MIT Interacting Motif and type-2 MIT Interacting Motif in Vps2/24/46, and Vps20/32/60, respectively. The Asgard Vps4 partly, but much more efficiently than homologs from other archaea, complements the vps4 null mutant of Saccharomyces cerevisiae, further supporting the functional similarity between the membrane remodeling machineries of Asgard archaea and eukaryotes. Thus, this work provides evidence that the ESCRT complexes from Asgard archaea and eukaryotes are evolutionarily related and functionally similar. Thus, despite the apparent absence of endomembranes in Asgard archaea, the eukaryotic ESCRT seems to have been directly inherited from an Asgard ancestor, to become a key component of the emerging endomembrane system. IMPORTANCEThe discovery of Asgard archaea has changed the exiting ideas on the origins of Eukaryotes. Researchers propose that eukaryotic cells evolve from Asgard archaea. This hypothesis partly stems from the presence of multiple eukaryotic signature proteins in Asgard archaea, including homologues of ESCRT proteins that are essential components of the endomembrane system in eukaryotes. However, structural and functional features of Asgard ESCRT remain unknown. Our study provides evidence that Asgard ESCRT is functionally comparable to the eukaryotic counterparts suggesting that, despite the apparent absence of endomembranes in archaea, eukaryotic ESCRT was inherited from an Asgard archaeal ancestor, alongside the emergence of endomembrane system during eukaryogenesis.

microbiology↗

bioRxiv2020

SARS-CoV-2 proteome microarray for mapping COVID-19 antibody interactions at amino acid resolution

COVID-19 has quickly become a worldwide pandemic, which has significantly impacted the economy, education, and social interactions. Understanding the humoral antibody response to SARS-CoV-2 proteins may help identify biomarkers that can be used to detect and treat COVID-19 infection. However, no immuno-proteomics platform exists that can perform such proteome-wide analysis. To address this need, we created a SARS-CoV-2 proteome microarray to analyze antibody interactions at amino acid resolution by spotting peptides 15 amino acids long with 5-amino acid offsets representing full-length SARS-CoV-2 proteins. Moreover, the array processing time is short (1.5 hours), the dynamic range is ~2 orders of magnitude, and the lowest limit of detection is 94 pg/mL. Here, the SARS-CoV-2 proteome array reveals that antibodies commercially available for SARS-CoV-1 proteins can also target SARS-CoV-2 proteins. These readily available reagents could be used immediately in COVID-19 research. Second, IgM and IgG immunogenic epitopes of SARS-CoV-2 proteins were profiled in the serum of ten COVID-19 patients. Such epitope biomarkers provide insight into the immune response to COVID-19 and are potential targets for COVID-19 diagnosis and vaccine development. Finally, serological antibodies that may neutralize viral entry into host cells via the ACE2 receptor were identified. Further investigation into whether these antibodies can inhibit the propagation of SARS-CoV-2 is warranted. Antibody and epitope profiling in response to COVID-19 is possible with our peptide-based SARS-COV-2 proteome microarray. The data gleaned from the array could provide invaluable information to the scientific community to understand, detect, and treat COVID-19.

biochemistry↗

bioRxiv2020

AfRip3, a RIP3-like kinase, is identified as a key modulator of necroptotic death in Aspergillus fumigatus

Aspergillus fumigatus exhibits autophagic and necroptotic process when its GPI anchor synthesis is suppressed. A putative kinase (AFUA_6G02590) is found to be overexpressed in response to GPI anchor suppression and identified as a RIP3-like protein, namely AfRip3. To elucidate its function, in this study a Afrip3-overexpressing strain OE-Afrip3 was constructed. Although OE-Afrip3 strain exhibited an increased cell death, neither apoptotic nor autophagic process was activated. Our evidences demonstrated that overexpression of Afrip3 gene in A. fumigatus only led to necroptosis, while the Afrip3-knockout mutant was unable to activate necroptotic process. Further analysis revealed that both JNK and SMase pathways were activated in OE-Afrip3 strain, by which an increase of reactive oxygen species (ROS) was induced. We also showed that expression of Afrip3 gene was induced by Ca2+. In addition, eEF1B{gamma} and adenylylsulfate kinase (ASK) were identified as potential candidates to interact with AfRip3. These results indicate that AfRip3 is a key modulator that activates necroptotic process in A. fumigatus, which can be induced by Ca2+ and in turn activate JNK (c-Jun NH2-terminal kinase) and SMase (sphingomyelinase) pathway. Our findings suggest that necroptotic pathway in A. fumigatus is distinct from that in mammalian cell and may provide a new strategy for development of anti-fungal drug. Author summaryAspergillus fumigatus is a human fungal pathogen and causes invasive aspergillosis (IA) in immunocompromised patients with high mortality (30-95%). Development of novel therapies is urgently needed. In this study, we confirm AfRip3 (AFUA_6G02590), a RIP3-like protein, is a key modulator that activates necroptotic process in A. fumigatus. We also find that cytosolic Ca2+ can induce the expression of Afrip3 and activated AfRip3 in turn activate JNK (c-Jun NH2-terminal kinase) and SMase (sphingomyelinase) pathway. Our findings suggest that necroptotic pathway in A. fumigatus is distinct from that in mammalian cell and may provide a new strategy for development of anti-fungal drug.

microbiology↗

bioRxiv2020

Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy

Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. Herein, we report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1-/- cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.

microbiology↗

bioRxiv2019

Single-Cell Map of Diverse Immune Phenotypes in the Metastatic Brain Tumor Microenvironment of Non Small Cell Lung Cancer

Cancer immunotherapies have shown sustained clinical success in treating primary non-small-cell lung cancer (NSCLC). However, patients with brain metastasis are excluded from the trials because the brain is viewed traditionally as an immune-privileged organ. The composition and properties of tumor-infiltrating myeloid cells in metastatic brain tumors are mostly unknown. To depict the baseline landscape of the composition, gene signature, and functional states of these immune cells, we performed - single-cell RNA sequencing (scRNAseq) for 12,196cellsafter data preprocessing, including 2,241 immunecells from three surgically removed brain lesions of treatment-naive NSCLC patients. We found a lack of T lymphocyte infiltration and activation, as well as the vast expansion of tumor-associated macrophage(TAM) in the brain lesions of NSCLC patients. By comparing our scRNAseq dataset with published data from early and late-stage primary NSCLC tumors, we showed that this compromised T cell response is unique to brain lesions. We identified a unique alternative activation (M2) gene expression pattern of the TAM in the brain metastasis and a lack of known T cell co-stimulator expression. Accumulation of M2 polarized TAM may, therefore, cause the comprised anti-tumor T cell response in metastatic brain lesions. These findings can contribute to the design of new immunotherapy strategies for NSCLC patients with brain metastasis.

cancer biology↗