Biology subjects

Qian, F.

Publications and source records attributed to Qian, F..

At least 19 recordsLinked to original sources

bioRxiv2026

PKD2 structural destabilization drives primary cilia degeneration and ADPKD pathogenicity.

Abstract/SummaryHuman variants in renal polycystins (PKD1, PKD2) are responsible for most forms of autosomal dominant polycystic kidney disease (ADPKD), a common genetic disorder without curative drug treatment. Renal polycystins form ion channels in primary cilia, but our understanding of their molecular dysregulation caused by disease-associated variants is limited. Using cryo-electron microscopy (cryo-EM), primary cilia electrophysiology and super-resolution analysis, we investigated the mechanistic impact and pathogenic potential of the disease-associated PKD2 missense variant (D511V) located within the channels voltage sensor domain (VSD). Our findings define how this mutation neutralizes critical transmembrane charge interactions, which attenuates PKD2 protein stability resulting in abolished ciliary channel trafficking and function in membranes. To assess the pathogenic effect of this variant in vivo, we generated novel mouse strains carrying the analogous PKD2 mutation in combination with a conditional floxed allele (Pkd2D509V/fl) that exhibit renal tubule primary cilia degeneration and develop rapid renal cysts. Our results establish a clear direct correlation between the in vitro molecular dysfunction and phenotypic in vivo consequences while providing a valuable tool to evaluate ADPKD therapeutic interventions. Translational StatementADPKD is a genetic kidney disorder affecting millions of patients globally and is primarily caused by variants in renal polycystin genes (PKD1, PKD2). Polycystins function as ion channel subunits in primary cilia but the mechanistic impact and cystogenic propensity of disease-associated variants remain poorly defined. The authors employ advanced methodologies including cryo-EM to uncover distinct structurally destabilizing effects of a human PKD2 mutation, while generating a new mouse model which genetically expresses the same variant and recapitulates the human disease. The findings define primary cilia degeneration results from PKD2 hypostasis and establish new tools to assess ADPKD therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/734313v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1cd02ceorg.highwire.dtl.DTLVardef@73410eorg.highwire.dtl.DTLVardef@b40691org.highwire.dtl.DTLVardef@11b5a93_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2026

An in vivo model of Amyloid-Related Imaging Abnormalities (ARIA) predicts ARIA incidence of anti-Aβ antibodies seen in clinical trials

Amyloid-related imaging abnormality (ARIA) is the most common adverse event associated with amyloid-beta (A{beta}) immunotherapy. The neuropathology underlying active ARIA lesions has been studied in only a few rare fatal cases. A faithful translational model of ARIA should allow a better understanding of pathogenic mechanisms and enable development of mitigation strategies. Since bapineuzumab induced the most frequent and severe forms of ARIA in humans, we assessed the ability of its murine precursor, 3D6, to induce ARIA-like lesions by applying clinically-validated MRI sequences in a mouse model with extensive amyloid deposition. Using this paradigm we documented ARIA-like changes based on their imaging features, location, and temporal evolution and established postmortem histopathologic correlates. We observed that ARIA-like lesions were ubiquitously induced with 3D6, including T2-hyperintense leptomeningeal effusions, T2-hyperintense parenchymal lesions and T2* hypointense parenchymal lesions. Histological assays demonstrated meningovascular inflammation as well as vascular mural permeation and microvascular lesions, including microhemorrhages and microinfarcts. Compared to 3D6-treated mice, animals treated with mouse analogues of aducanumab and gantenerumab showed less frequent radiologic and histopathologic ARIA-like lesions with delayed onset. Our results align well with the differential incidence of ARIA observed in humans treated with different anti-A{beta} antibodies. Collectively, our studies demonstrate that: i) anti-A{beta} antibodies chronically administered to 5xFAD mice can induce MRI lesions reminiscent of human ARIA; ii) this paradigm allows identification of transient lesions other than microhemorrhages, and (iii) the incidence and severity of ARIA-like lesions induced with three clinically tested antibodies faithfully recapitulates that seen in humans. One Sentence SummaryMRI and histological correlation in a preclinical ARIA mouse model treated with anti-A{beta} antibodies that recapitulates results seen in humans.

neuroscience↗

bioRxiv2025

Extra-ciliary role for polycystins in regulation of Ezrin and renal tubular morphology

Full understanding of the functions of the polycystin proteins, PC1 and PC2, in renal epithelial cells is obscured by signaling complexity and renal injury that occurs in Autosomal Dominant Polycystic Kidney Disease (ADPKD). The polycystins likely function as a complex in the primary cilium, yet previous work hinted at a critical role for PC1 function outside of the primary cilium (extra-ciliary) during tubule development. Here, we investigate an extra-ciliary role for the polycystins in regulating renal cell and tubular morphology. First, we found acute loss of polycystins significantly increased the circularity of renal epithelial cells and tubuloids grown in 3D culture. Next, we demonstrated that both PC1 and PC2 can immunoprecipitate Ezrin, an ERM protein important for apical compartment shape. In human ADPKD renal cystic tissue, and after acute inducible knockout of Pkd1 or Pkd2, we found that Ezrin protein abundance is significantly reduced, with the remaining Ezrin protein mis-localized. Immunofluorescence in 2D cells and 3D tubuloids suggested acute polycystin loss specifically reduced the active form of Ezrin at the apical surface, leaving inactive Ezrin colocalized with ZO1 in the cell junctions. A specific ERM phosphorylation inhibitor, NSC668394, phenocopied the increased circularity observed in the Pkd1 knockout spheroids, as did inhibition of PKC activity, implicating the polycystin complex in regulating Ezrin phosphorylation. Our data strongly support a role for the polycystin complex in regulating renal cell and tubular shape via interactions with the ERM protein Ezrin, interactions that do not require trafficking to the primary cilium.

cell biology↗

bioRxiv2025

Aducanumab Binding to Aβ1-42 Fibrils Alters Dynamics of the N-Terminal Tail While Preserving the Fibril Core

Aducanumab, a human IgG1 antibody with plaque-clearing effects and modest clinical benefit, binds selectively to aggregated A{beta} via the N-terminal region. Yet, the molecular details of how the antibody engages A{beta}1-42 fibrils remain unresolved. Using magic-angle spinning nuclear magnetic resonance, we show that binding of aducanumab preserves the overall architecture of the A{beta}1-42 fibril core while inducing significant structural and dynamic perturbations in the N-terminal region. Antibody binding markedly reduces flexibility in this domain, with the appearance of sidechain resonances from residues D1, E3, and histidine (likely H6) in dipolar-based experiments. These sidechains--previously observed only in scalar-coupling spectra of the unbound state--indicate rigidification of residues that were dynamic. The interaction extends to S8 and Y10, indicating broader fibril engagement than the minimal epitope (residues 3-7) defined in fragment-based studies. Perturbations in the C-terminal segment (G37-A42) are consistent with its spatial proximity to the antibody-bound N-termini of neighboring monomers. Cryo-TEM images reveal fibrils bundling in the presence of aducanumab, consistent with lateral association via antibody cross-linking, supporting a model where surface coating and steric hindrance suppress secondary nucleation. This mode of action restricts monomer access to catalytic sites on fibril surface, resulting in partial inhibition ([~]three-fold reduction) of secondary nucleation. The effect depends on high avidity and relatively high stoichiometry, but is ultimately limited by antibody size relative to N-terminal spacing along the fibril. These findings provide atomic-level insights into aducanumabs binding mode and supply a structural framework for understanding antibody-mediated fibril recognition and for guiding next-generation therapies targeting A{beta} aggregates in Alzheimers disease. Significance StatementUnderstanding how therapeutic antibodies interact with amyloid-{beta} (A{beta}) fibrils is crucial for developing effective Alzheimers disease treatments. Magic angle spinning NMR provides atomic-level insights into the binding of aducanumab to mature A{beta}1-42 fibrils. Aducanumab binding preserves the fibrils core structure but slows the dynamics of the N-terminal domain of A{beta}. This interaction, which spans D1 to S8 and extends to Y10 on the fibril surface, is consistent with a mechanism in which N-terminal binding by the antibody interferes with aggregation steps like secondary nucleation. These findings detail how aducanumab engages its target fibril and provides insights relevant to other clinically approved antibodies and next-generation therapies that recognize the A{beta} N-terminal region.

biophysics↗

bioRxiv2025

HSD17B7 is required for Auditory Function by Regulating Cholesterol Synthesis in Sensory Hair Cells

Cholesterol homeostasis is fundamental to cellular function, and its disruption underlies a wide range of human diseases. However, the contribution of cholesterol biosynthesis to auditory physiology remains poorly understood. HSD17B7 (17{beta}-Hydroxysteroid dehydrogenase type 7) catalyzes the conversion of zymosterone to zymosterol, a key step in the post-lanosterol cholesterol biosynthetic pathway. Here, we found that Hsd17b7 is highly enriched in sensory hair cells of zebrafish and mice. The deficiency of Hsd17b7 deficiency reduced intracellular cholesterol levels in HEI-OC1 cells and zebrafish hair cells, thereby compromising MET and acoustic startle responses. A heterozygous nonsense variant (c.544G>T; p.E182*) in HSD17B7 was identified in an individual with bilateral profound hearing loss. mRNA of c.544G>T HSD17B7 failed to rescue the impaired MET and acoustic startle response of hsd17b7 mutants. Mechanistically, the mutation decreases mRNA abundance and significantly reduces protein. Moreover, expression of the p.E182* mutation disrupted the interaction between HSD17B7 and the ER retention receptor RER1, leading to aberrant subcellular localization and altered cholesterol distribution, thereby exacerbating HC dysfunction. Together, our findings suggest a conserved and essential role for HSD17B7-mediated cholesterol biosynthesis in sensory hair cell function and identify HSD17B7 as a candidate gene for sensorineural hearing loss.

developmental biology↗

bioRxiv2025

Kidney cystogenesis in embryonic- and adult-onset ADPKD is suppressed from lack of adenylyl cyclase targeting to cilia

Multiple cellular pathways are dysregulated in autosomal dominant polycystic kidney disease (ADPKD), but mechanisms initiating cyst formation are unknown. ADPKD is caused by mutations in Pkd1/Pkd2 genes that encode for polycystins that localize to primary cilia. The primary cilium is a miniscule subcellular compartment for generating signaling outputs that profoundly affect cellular function. Severe cystogenesis from polycystin loss is mostly cilia dependent. However, the polycystin-repressed ciliary signals that promote cyst growth are unknown and have been challenging to uncouple from downstream cystogenic pathways. Here we aimed at differentiating ciliary adenylyl cyclase signaling from total cellular changes in second messenger cAMP implicated in cystogenesis. We studied an Ankyrin repeat and MYND domain protein, ANKMY2 that we previously implicated in maturation and ciliary localization of adenylyl cyclases in fibroblasts. We studied kidney-specific conditional knockout mouse models of Ankmy2/Pkd1 and ciliary localization of adenylyl cyclases in kidney epithelial cells. We found suppression of early postnatal renal cystogenesis and prolonged survival in an embryonic onset Pkd1 deletion model from ANKMY2 loss. Phosphorylated CREB formation, from elevated cellular cAMP levels, remained unaffected. Cyst load in male mice in an adult inducible conditional Pkd1 deletion model was suppressed from ANKMY2 loss. Mechanistically, ANKMY2 determined ciliary trafficking of adenylyl cyclases in kidney epithelial cells without disrupting cilia. Further, ANKMY2 loss prevented ciliary length increase in ADPKD mouse models irrespective of cyst load or sex. Cilia length increase was seen preceding cystogenesis. Our results suggest that targeting of adenylyl cyclases to renal epithelial cilia promotes PC1/2-inhibited cilia-dependent cyst activation distinct from cyst progression involving cellular cAMP.

cell biology↗

bioRxiv2024

Co-recognition of histone acetylation and H3K4 trimethylation by GTE4-EML complex in Arabidopsis

Although histone acetylation and H3K4 trimethylation (H3K4me3) are well-known histone marks associated with active transcription, how they cooperate to regulate transcription remains largely unclear in plants. Our study revealed that the Bromodomain and Extra-terminal (BET) protein GTE4 binds to acetylated histone and forms a complex with the redundant H3K4me3-binding EMSY-Likeproteins EML1 or EML2 (EML1/2) in Arabidopsis thaliana. The eml1 eml2 (eml1/2) double mutant exhibited a morphological phenotype similar to the gte4 mutant, and most of the gte4-mediated differentially expressed genes were co-regulated in the eml1/2 mutant. Through chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), we found that GTE4 and EML2 co-occupy protein-coding genes enriched with both histone acetylation and H3K4me3, exhibiting a synergistic effect on the association of the GTE4-EML complex with chromatin. The association of GTE4 with chromatin requires both the Bromodomain and the EML-interacting domain. This study identified a previously uncharacterized complex and uncovered how it cooperatively recognizes histone acetylation and H3K4me3 to facilitate gene transcription at the whole-genome level in Arabidopsis.

molecular biology↗

bioRxiv2024

An Amygdalar-Vagal-Glandular Circuit Controls the Intestinal Microbiome

Psychological states can regulate intestinal mucosal immunity by altering the gut microbiome. However, the link between the brain and microbiome composition remains elusive. We show that Brunners glands in the duodenal submucosa couple brain activity to intestinal bacterial homeostasis. Brunners glands mediated the enrichment of gut probiotic species in response to stimulation of abdominal vagal fibers. Cell-specific ablation of the glands triggered transmissible dysbiosis associated with an immunodeficiency syndrome that led to mortality upon gut infection with pathogens. The syndrome could be largely prevented by oral or intra-intestinal administration of probiotics. In the forebrain, we identified a vagally-mediated, polysynaptic circuit connecting the glands of Brunner to the central nucleus of the amygdala. Intra-vital imaging revealed that excitation of central amygdala neurons activated Brunners glands and promoted the growth of probiotic populations. Our findings unveil a vagal-glandular neuroimmune circuitry that may be targeted for the modulation of the gut microbiome. The glands of Brunner may be the critical cells that regulate the levels of Lactobacilli species in the intestine.

neuroscience↗

bioRxiv2023

DLG1 functions upstream of SDCCAG3 and IFT20 to control targeting of polycystin-2 to the primary cilium

Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney caused ciliary elongation and cystogenesis, and cell-based proximity labelling proteomics and fluorescence microscopy showed alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20 and polycystin-2 (PC2) were reduced in cilia of DLG1 deficient cells compared to control cells. This phenotype was recapitulated in vivo and rescuable by re-expression of wildtype DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggested that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

cell biology↗

bioRxiv2023

H3-OPT: Accurate prediction of CDR-H3 loop structures of antibodies with deep learning

Accurate prediction of the structurally diverse complementarity determining region heavy chain 3 (CDR-H3) loop structure remains a primary and long-standing challenge for antibody modeling. Here, we present the H3-OPT toolkit for predicting the 3D structures of monoclonal antibodies and nanobodies. H3-OPT combines the strengths of AlphaFold2 with a pre-trained protein language model, and provides a 2.24 [A] average RMSDC between predicted and experimentally determined CDR-H3 loops, thus outperforming other current computational methods in our non-redundant high-quality dataset. The model was validated by experimentally solving three structures of anti-VEGF nanobodies predicted by H3-OPT. We examined the potential applications of H3-OPT through analyzing antibody surface properties and antibody-antigen interactions. This structural prediction tool can be used to optimize antibody-antigen binding, and to engineer therapeutic antibodies with biophysical properties for specialized drug administration route.

bioinformatics↗

bioRxiv2023

Nitric oxide regulates metabolism in murine stress erythroid progenitors to promote recovery during inflammatory anemia.

Inflammation skews bone marrow hematopoiesis increasing the production of myeloid effector cells at the expense of steady-state erythropoiesis. A compensatory stress erythropoiesis response is induced to maintain homeostasis until inflammation is resolved. In contrast to steady-state erythroid progenitors, stress erythroid progenitors (SEPs) utilize signals induced by inflammatory stimuli. However, the mechanistic basis for this is not clear. Here we reveal a nitric oxide (NO)-dependent regulatory network underlying two stages of stress erythropoiesis, namely proliferation, and the transition to differentiation. In the proliferative stage, immature SEPs and cells in the niche increased expression of inducible nitric oxide synthase (Nos2 or iNOS) to generate NO. Increased NO rewires SEP metabolism to increase anabolic pathways, which drive the biosynthesis of nucleotides, amino acids and other intermediates needed for cell division. This NO-dependent metabolism promotes cell proliferation while also inhibiting erythroid differentiation leading to the amplification of a large population of non-committed progenitors. The transition of these progenitors to differentiation is mediated by the activation of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or Nrf2). Nrf2 acts as an anti-inflammatory regulator that decreases NO production, which removes the NO-dependent erythroid inhibition and allows for differentiation. These data provide a paradigm for how alterations in metabolism allow inflammatory signals to amplify immature progenitors prior to differentiation. Key pointsO_LINitric-oxide (NO) dependent signaling favors an anabolic metabolism that promotes proliferation and inhibits differentiation. C_LIO_LIActivation of Nfe2l2 (Nrf2) decreases NO production allowing erythroid differentiation. C_LI

developmental biology↗

bioRxiv2022

Quartet RNA reference materials and ratio-based reference datasets for reliable transcriptomic profiling

As an indispensable tool for transcriptome-wide analysis of differential gene expression, RNA sequencing (RNAseq) has demonstrated great potential in clinical applications. However, the lack of multi-group RNA reference materials of biological relevance and the corresponding reference datasets for assessing the reliability of RNAseq hampers its wide clinical applications wherein the underlying biological differences among study groups are often small. As part of the Quartet Project for quality control and data integration of multiomic profiling, we established four RNA reference materials derived from immortalized B-lymphoblastoid cell lines from four members of a monozygotic twin family. Additionally, we constructed ratio-based transcriptome-wide reference datasets using multi-batch RNAseq datasets, providing "ground truth" for benchmarking. Moreover, Quartet-sample-based quality metrics were developed for assessing reliability of RNAseq technology in terms of intra-batch proficiency and cross-batch reproducibility. The small intrinsic biological differences among the Quartet samples enable sensitive assessment of performance of transcriptomic measurements. The Quartet RNA reference materials combined with the reference datasets can be served as unique resources for assessing data quality and improving reliability of transcriptomic profiling.

genetics↗

bioRxiv2022

Intra-peritoneal transplantation for efficient and easy generation of experimental acute myeloid leukemia in mice

ObjectiveThere is an unmet need for novel therapies to treat acute myeloid leukemia (AML) and the associated relapse that involves leukemia stem cells (LSCs). An experimental AML rodent model to test therapies based on successfully transplanting these cells via retro-orbital injections in recipient mice is fraught with challenges. The aim of this study was to develop an easy, reliable, and consistent method to generate a robust murine model of AML using an intra-peritoneal route. MethodsBone marrow cells were transduced with a retrovirus expressing human MLL-AF9 fusion oncoprotein. Efficiency of lineage negative (Lin-) and Lin-Sca-1+c-Kit+ (LSK) populations as donor LSCs in the development of primary AML was tested. We developed a new method to generate AML by intra-peritoneal injection and discuss the pros and cons of intra-peritoneal and retro-orbital injections in serial transplantations. ResultsBoth Lin- and LSK cells transduced with human MLL-AF9 virus engrafted well in the bone marrow and spleen of recipients, leading to a full-blown AML. Intra-peritoneal injection of donor cells established AML in recipients upon serial transplantation.Infiltration of AML cells was detected in the blood, bone marrow, spleen, and liver of recipients by flow cytometry, qPCR, and histological analyses. ConclusionsO_LIIntra-peritoneal injection is an efficient method of AML induction using serial transplantation of donor cells. C_LIO_LIDelayed homing to bone marrow, seen in intra-peritoneal injection that impedes the progression of AML, can be easily overcome by increasing the number of transplanted donor cells. C_LIO_LIIncreasing the number of transplanted donor cells can also help shorten the duration of onset of AML. C_LIO_LISorting of LSK population within donor cells is not necessary in the generation of MLL-AF9-induced primary AML given that Lin- population are equally efficient as LSK donor cells in primary transplantation of AML in mice. C_LI

cancer biology↗

bioRxiv2021

AGL16 regulates genome-wide gene expression and flowering time with partial dependency on SOC1 in Arabidopsis

Flowering transition is pivotal and tightly regulated by complex gene-regulatory-networks, in which AGL16 plays important roles. But the molecular function and binding property of AGL16 is not fully explored in vivo. With ChIP-seq and comparative transcriptomics approaches, we characterized the AGL16 targets spectrum and tested its close molecular and genetic interactions with SOC1, the key flowering integrator. AGL16 bound to promoters of more than 2000 genes via CArG-box motifs that were highly similar to that of SOC1. Being consistent with this, AGL16 formed protein complex and shared a common set of targets with SOC1. However, only very few genes showed differential expression in the agl16-1 loss-of-function mutant, whereas in the soc1-2 knockout background, AGL16 repressed and activated the expression of 375 and 182 genes, respectively, with more than a quarter of the DEGs were also bound by AGL16. AGL16 targeted potentially to about seventy flowering time genes involved in multiple pathways. Corroborating with these, AGL16 repressed the flowering time stronger in soc1-2 than in Col-0 background. These data reveals that AGL16 regulates gene expression and flowering time with a partial dependency on SOC1 activity. Moreover, AGL16 participated in the regulation of water loss and seed dormancy. Our study thus defines the AGL16 molecular spectrum and provides insights underlining the molecular coordination of flowering and environmental adaptation.

plant biology↗

bioRxiv2021

Indoleamine 2,3-dioxygenase upregulates PD-1 expression on ovarian tumor infiltrating CD8+ T cells via kynurenine activation of the aryl hydrocarbon receptor

The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.

immunology↗

bioRxiv2020

Neural network aided approximation and parameterinference of stochastic models of gene expression

Non-Markov models of stochastic biochemical kinetics often incorporate explicit time delays to effectively model large numbers of intermediate biochemical processes. Analysis and simulation of these models, as well as the inference of their parameters from data, are fraught with difficulties because the dynamics depends on the systems history. Here we use an artificial neural network to approximate the time-dependent distributions of non-Markov models by the solutions of much simpler time-inhomogeneous Markov models; the approximation does not increase the dimensionality of the model and simultaneously leads to inference of the kinetic parameters. The training of the neural network uses a relatively small set of noisy measurements generated by experimental data or stochastic simulations of the non-Markov model. We show using a variety of models, where the delays stem from transcriptional processes and feedback control, that the Markov models learnt by the neural network accurately reflect the stochastic dynamics across parameter space.

systems biology↗

bioRxiv2020

CATA: a comprehensive chromatin accessibility database for cancer

Chromatin accessibility is a crucial epigenetic concept that plays a biological role in oncology. As humans become more involved in cancer research, a comprehensive database is required to identify and annotate tumor chromatin accessible regions (CARs). Here, CATA was developed to provide cancer-related CAR annotation. Currently, CATA possesses 2,991,163 CARs, relevant clinical data, and transcription factor binding predictions for cancer CARs from 410 tumor samples of 24 cancer types. Furthermore, CARs were annotated by SNPs, risk SNPs, eQTLs, linkage disequilibrium SNPs, transcription factors, CNV, SNV, enhancer, and 450K methylation sites in our database. By combining all these resources, we believe that CATA will provide better service for researchers on oncology. Our database is accessible at http://bio.licpathway.net/cata/Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗