Biology subjects

Liang, H.

Publications and source records attributed to Liang, H..

At least 127 records · Page 7Linked to original sources

bioRxiv2020

Total recall: episodic memory retrieval,choice, and memory confidence in the rat

Episodic memory enables recollection of past experiences to guide future behavior. Humans know which memories to trust (high confidence) and which to doubt (low confidence). How memory retrieval, memory confidence, and memory-guided decisions are related, however, is not understood. Additionally, whether animals can assess confidence in episodic memories to guide behavior is unknown. We developed a spatial episodic memory task in which rats were incentivized to gamble their time: betting more following a correct choice yielded greater reward. Rat behavior reflected memory confidence, with higher temporal bets following correct choices. We applied modern machine learning to identify a memory decision variable, and built a generative model of memories evolving over time that accurately predicted both choices and confidence reports. Our results reveal in rats an ability thought to exist exclusively in primates, and introduce a unified model of memory dynamics, retrieval, choice, and confidence.

neuroscience↗

bioRxiv2020

Mammalian-unique eIF4E2 maintains GSK3β proline kinase activity to resist senescence against hypoxia

Cellular senescence is a stable state of cell cycle arrest elicited by various stresses. Hypoxia modulates senescence, but its consequences and implications in living organisms remains unknown. Here we identified the eIF4E2-GSK3{beta} pathway regulated by hypoxia to maintain p53 proline-directed phosphorylation (S/T-P) to prevent senescence. We previously knew that GSK3{beta} activates p53 translation through phosphorylation of RBM38 Ser195 (-Pro196). Unexpectedly, eIF4E2 directly binds to GSK3{beta} via a conserved motif, mediating Ser195 phosphorylation. Phosphoproteomics revealed that eIF4E2-GSK3{beta} specifically regulates proline-directed phosphorylation. Peptide e2-I or G3-I that disrupts this pathway dephosphorylates p53 at multiple S/T-P, which accelerate senescence by transcriptional suppressing TOPBP1 and TRX1. Consistently, peptides induce liver senescence that is rescued by TOPBP1 expression, and mediate senescence-dependent tumor regression. Furthermore, hypoxia inhibits eIF4E2-GSK3{beta}. Inspiringly, eIF4E2-GSK3{beta} is unique to mammals, which maintains mice viability and prevents liver senescence against physiological hypoxia. Interestingly, this mammalian eIF4E2 protects heart of zebrafish against hypoxia. Together, we identified a mammalian -unique eIF4E2-GSK3{beta} pathway preventing senescence and guarding against hypoxia in vivo.

cell biology↗

bioRxiv2020

Enabling in vivo Analysis Via Nanoparticle-mediated Intracellular Assay Probe Delivery: Using RAS as the Prototype

Many experimental protocols must be executed in vitro due to a lack of cell-permeable analysis probes. For instance, the cellular signaling moderator RAS proteins alternate between the active GTP-binding and the inactive GDP-binding states. Though many GTP analogs can serve as probes for RAS activity analysis, their cell impermeability renders in vivo analysis impossible. On the other hand, the lipid/calcium/phosphate (LCP) nanoparticle has enabled efficient intracellular delivery of a nucleotide analog as a chemotherapy agent. Thus, using RAS analysis and LCP nanoparticle as the prototype, we tackled the cell-impermeability issue via nanoparticle-mediated intracellular delivery of the analysis probe. Briefly, BODIPY-FT-GTP-{gamma}-S, a GTP analog that becomes fluorescent only upon protein binding, was chosen as the analysis probe, so that GTP binding can be quantified by fluorescent activity. BODIPY-FT-GTP-{gamma}-S-loaded LCP-nanoparticle was synthesized for efficient intracellular BODIPY-FT-GTP-{gamma}-S delivery. Binding of the delivered BODIPY-FT-GTP-{gamma}-S to the RAS proteins were consistent with previously reported observations; the RAS GTP binding activity was reduced in serum-starved cells; and a transient activation peak of the binding activity was observed upon subsequent serum reactivation of the cells. In a word, nanoparticle-mediated probe delivery enabled an in vivo RAS analysis method. The approach should be applicable to a wide variety of analysis protocols.

biochemistry↗

bioRxiv2020

Large-scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines

Perturbation biology is a powerful approach to developing quantitative models of cellular behaviors and gaining mechanistic insights into disease development. In recent years, large-scale resources for phenotypic and mRNA responses of cancer cell lines to perturbations have been generated. However, similar large-scale protein response resources are not available, resulting in a critical knowledge gap for elucidating oncogenic mechanisms and developing effective cancer therapies. Here we generated and compiled perturbed expression profiles of ~210 clinically relevant proteins in >12,000 cancer cell-line samples in response to >150 drug compounds using reverse-phase protein arrays. We show that integrating protein response signals substantially increases the predictive power for drug sensitivity and aids in gaining insights into mechanisms of drug resistance. We build a systematic map of protein-drug connectivity and develop an open-access, user-friendly data portal for community use. Our study provides a valuable information resource for a broad range of quantitative modeling and biomedical applications. HighlightsO_LIA large collection of cancer cell line protein responses to drug perturbations C_LIO_LIPerturbed protein responses greatly increase predictive power for drug sensitivity C_LIO_LIBuild a systematic map of protein-drug connectivity based on response profiles C_LIO_LIDevelop a user-friendly, interactive data portal for community use C_LI

systems biology↗

bioRxiv2020

Quantitative study of unsaturated transport of glycerol through aquaglyceroporin that has high affinity for glycerol

Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=37 SRC="FIGDIR/small/152512v1_ufig1.gif" ALT="Figure 1"> View larger version (9K): org.highwire.dtl.DTLVardef@19dcc7forg.highwire.dtl.DTLVardef@dce74dorg.highwire.dtl.DTLVardef@d599b4org.highwire.dtl.DTLVardef@15e24f5_HPS_FORMAT_FIGEXP M_FIG C_FIG ABSTRACTThe structures of several aquaglyceroporins have been resolved to atomic resolution showing two or more glycerols bound inside a channel and confirming a glycerol-facilitators affinity for its substrate glycerol. However, the kinetics data of glycerol transport experiments all point to unsaturated transport that is characteristic of low substrate affinity in terms of the Michaelis-Menten kinetics. In this article, we present an in silico-in vitro research focused on AQP3, one of the human aquaglyceroporins that is natively expressed in the abundantly available erythrocytes. We conducted 2.1 s in silico simulations of AQP3 embedded in a model erythrocyte membrane with intracellular-extracellular asymmetries in leaflet lipid compositions and compartment salt ions. From the equilibrium molecular dynamics (MD), we elucidated the mechanism of glycerol transport at high substrate concentrations. From the steered MD simulations, we computed the Gibbs free-energy profile throughout the AQP3 channel. From the free-energy profile, we quantified the kinetics of glycerol transport that is unsaturated due to glycerol-glycerol interaction mediated by AQP3 resulting in the concerted movement of two glycerol molecules for the transport of one glycerol molecule across the cell membrane. We conducted in vitro experiments on glycerol uptake into human erythrocytes for a wide range of substrate concentrations and various temperatures. The experimental data quantitatively validated our theoretical-computational conclusions on the unsaturated glycerol transport through AQP3 that has high affinity for glycerol.

biophysics↗

bioRxiv2020

Synonymous sites in SARS-CoV-2 genes display trends affecting translational efficiency

A novel coronavirus, SARS-CoV-2, has caused a pandemic of COVID-19. The evolutionary trend of the virus genome may have implications for infection control policy but remains obscure. We introduce an estimation of fold change of translational efficiency based on synonymous variant sites to characterize the adaptation of the virus to hosts. The increased translational efficiency of the M and N genes suggests that the population of SARS-CoV-2 benefits from mutations toward favored codons, while the ORF1ab gene has slightly decreased the translational efficiency. In the coding region of the ORF1ab gene upstream of the -1 frameshift site, the decreasing of the translational efficiency has been weakening parallel to the growth of the epidemic, indicating inhibition of synthesis of RNA-dependent RNA polymerase and promotion of replication of the genome. Such an evolutionary trend suggests that multiple infections increased virulence in the absence of social distancing.

evolutionary biology↗

bioRxiv2020

A Chemical-genetics and Nanoparticle Enabled Approach for in vivo Protein Kinase Analysis

The human kinome contains >500 protein kinases, and regulates up to 30% of the proteome. Kinase study is currently hindered by a lack of in vivo analysis approaches due to two factors: our inability to distinguish the kinase reaction of interest from those of other kinases in live cells and the cell impermeability of the ATP analogs. Herein, we tackled this issue by combining the widely used chemical genetic method developed by Dr. Kevan Shokat and colleagues with nanoparticle-mediated intracellular delivery of the ATP analog. The critical AKT1 protein kinase, which has been successfully studied with the method, was used as our initial prototype. Briefly, enlargement of the ATP binding pocket, by mutating the gate-keeper Methionine residue to a Glycine, prompted the mutant AKT1 to preferentially use the bulky ATP analog N6-Benzyl-ATP-{gamma}-S (A*TP{gamma}S) and, thus, differentiating AKT1-catalyzed and other phosphorylation events. The lipid/calcium/phosphate (LCP) nanoparticle was used for efficient intracellular delivery of A*TP{gamma}S, overcoming the cell impermeability issue. The mutant, but not wild-type, AKT1 used the delivered A*TP{gamma}S for autophosphorylation and phosphorylating its substrates in live cells. Thus, an in vivo protein kinase analysis method has been developed. The strategy should be widely applicable to other protein kinases.

cell biology↗

bioRxiv2020

Characterization of miRNAs encoded by Autographa californica nucleopolyhedrovirus

Two Autographa californica nucleopolyhedrovirus (AcMNPV) encoded miRNAs, AcMNPV-miR-1 and -miR-3, have been reported in 2013 and 2019. Here, we present an integrated investigation of AcMNPV-encoded miRNAs. Six candidate miRNAs were predicted through small RNA deep sequencing and bioinformatics, of which, five validated by experiments. Three miRNAs perfectly matched the coding sequence of viral genes. The other two are located in coding sequences of viral genes. Targets in both virus and host were predicted and subsequently tested using dual-luciferase reporter assay. The validated targets were found mainly in AcMNPV, except for the targets of AcMNPV-miR-4, which are all host genes. Based on reporter assays, the five miRNAs predominantly function by down-regulating their targets, though individual target is slightly up-regulated. The transcription start sites of these miRNAs were analyzed. Our results suggest that AcMNPV-encoded miRNAs function as fine modulators of the interactions between host and virus by regulating viral and/or host genes. Author summaryVirus-encoded miRNAs have been widely reported as modulators participating in almost all biological processes. However, among Baculoviridae, which consists of a large family of dsDNA viruses that infect numerous beneficial insects and agricultural pests, only several have been reported encoding miRNAs. To clarify the roles of AcMNPV-encoded miRNAs in host-pathogen interactions, we employed RNA deep sequencing and series of experimental approaches identifying AcMNPV-encoded miRNAs, followed by target validation and function deduction. Among them, AcMNPV-miR-1 and AcMNPV-miR-3 have been reported in 2013 and 2019, respectively. This study reveals the sites of these miRNAs in the genome, both in coding sequences and complements, suggesting diverse functions. These miRNAs target genes in the virus itself and in the host, largely by suppressing expression, with some enhancing it. The transcription initiations of the miRNAs were analyzed. Our results provide some insight into the finely regulated process of baculovirus infection.

microbiology↗

bioRxiv2020

In silico simulations of erythrocyte aquaporins with quantitative in vitro validation

Modelling water and membrane lipids is an essential element in the computational research of biophysical/biochemical processes such as water transport across the cell membrane. In this study, we examined the accuracies of two popular water models, TIP3P and TIP4P, in the molecular dynamics simulations of erythrocyte aquaporins (AQP1 and AQP3). We modelled the erythrocyte membrane as an asymmetric lipid bilayer with appropriate lipid compositions of its inner and outer leaflet, in comparison with a symmetric lipid bilayer of a single lipid type. We computed the AQP1/3 permeabilities with the transition state theory with full correction for recrossing events. We also conducted cell swelling assays for water transport across the erythrocyte membrane. The experimental results agree with the TIP3P water-erythrocyte membrane model, in confirmation of the expected accuracy of the erythrocyte membrane model, the TIP3P water model, and the CHARMM parameters for water-protein interactions.

biophysics↗

bioRxiv2020

Constructing an ethanol utilization pathway in Escherichia coli to produce acetyl-CoA derived compounds

Engineering microbes to utilize non-conventional substrates could create short and efficient pathways to convert substrate into product. In this study, we designed and constructed a two-step heterologous ethanol utilization pathway (EUP) in Escherichia coli by using acetaldehyde dehydrogenase (encoded by ada) from Dickeya zeae and alcohol dehydrogenase (encoded by adh2) from Saccharomyces cerevisiae. This EUP can convert ethanol into acetyl-CoA without ATP consumption, and generate two molecules of NADH per molecule of ethanol. We optimized the expression of these two genes and found that ethanol consumption could be improved by expressing them in a specific order (ada-adh2) with a constitutive promoter (PgyrA). The engineered E. coli strain with EUP consumed approximately 8 g/L of ethanol in 96 hours when it was used as sole carbon source. Subsequently, we combined EUP with the biosynthesis of polyhydroxybutyrate (PHB), a biodegradable polymer derived from acetyl-CoA. The engineered E. coli strain carrying EUP and PHB biosynthetic pathway produced 1.1 g/L of PHB from 10 g/L of ethanol and 1 g/L of aspartate family amino acids in 96 hours. We also engineered E. coli strain to produced 24 mg/L of prenol from 10 g/L of ethanol in 48 hours, supporting the feasibility of converting ethanol into different classes of acetyl-CoA derived compounds. HighlightsO_LIEngineered Escherichia coli strains to grow on ethanol as sole carbon source C_LIO_LIDemonstrated that ethanol was converted into acetyl-CoA (AcCoA) through two pathways (acetaldehyde-acetate-AcCoA and acetaldehyde-AcCoA) C_LIO_LIConverted ethanol into two acetyl-CoA derived products with low structural similarity (polyhydroxybutyrate and prenol) C_LIO_LIDiscovered that supplementation of the aspartate family amino acids can substantially improve cell growth on ethanol C_LI

bioengineering↗

bioRxiv2020

Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro

COVID-19 has become a global pandemic that threatens millions of people worldwide. There is an urgent call for developing effective drugs against the virus (SARS-CoV-2) causing this disease. The main protease of SARS-CoV-2, 3C-like protease (3CLpro), is highly conserved across coronaviruses and is essential for the maturation process of viral polyprotein. Scutellariae radix (Huangqin in Chinese), the root of Scutellaria baicalensis has been widely used in traditional Chinese medicine to treat viral infection related symptoms. The extracts of S. baicalensis have exhibited broad spectrum antiviral activities. We studied the anti-SARS-CoV-2 activity of S. baicalensis and its ingredient compounds. We found that the ethanol extract of S. baicalensis inhibits SARS-CoV-2 3CLpro activity in vitro and the replication of SARS-CoV-2 in Vero cells with an EC50 of 0.74 g/ml. Among the major components of S. baicalensis, baicalein strongly inhibits SARS-CoV-2 3CLpro activity with an IC50 of 0.39 M. We further identified four baicalein analogue compounds from other herbs that inhibit SARS-CoV-2 3CLpro activity at microM concentration. Our study demonstrates that the extract of S. baicalensis has effective anti-SARS-CoV-2 activity and baicalein and analogue compounds are strong SARS-CoV-2 3CLpro inhibitors.

pharmacology and toxicology↗

bioRxiv2020

Identification of the associated expression patterns as potential predictive markers for cancer prognosis

Dysregulated gene expression can develop as a consequence of uncontrolled alterations of tumor cells. Analysis of these abnormal alterations will improve our understanding of the tumor development and reveal the corresponding clinical associations. It is well known that multiple genetic abnormalities could be observed in the same tumor, however, the interactions between those abnormal events are rarely analyzed. To address this problem, we constructed a novel gene expression correlation network by integrating the transcriptomes of 5,001 cancer patients from 22 cancer types. We investigated how the change of associated expression pattern (AEP), which describe certain associations between gene expression, could affect the cancer patients prognosis. Consequently, we identified an AEP composed of mitosis-related gene expressions, which is significantly correlated with overall survival in most cancer types. In particular, the AEPs could present the association between gene expressions and show distinct effects on prognosis prediction for cancer patients, suggesting that AEP analysis is indispensable to uncover the complex interactions of abnormal gene expressions in tumor development.

bioinformatics↗

bioRxiv2020

Analyzing Presymptomatic Tissue to Gain Insights into the Molecular and Mechanistic Origins of Late-Onset Degenerative Trinucleotide Repeat Disease

How genetic defects trigger the molecular changes that cause late-onset disease is important for understanding disease progression and therapeutic development. Fuchs endothelial corneal dystrophy (FECD) is an RNA-mediated disease caused by a trinucleotide CUG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at 1-2 copies per cell, posing a challenge to understand how a rare RNA can cause disease. Late-onset FECD is a uniquely advantageous model for studying how RNA triggers disease because; 1) Affected tissue is routinely removed during surgery; 2) The expanded CUG mutation is one of the most prevalent disease-causing mutations, making it possible to obtain pre-symptomatic tissue from eye bank donors to probe how gene expression changes precede disease; and 3) The affected tissue is a homogeneous single cell monolayer, facilitating accurate transcriptome analysis. Here we use RNA sequencing (RNAseq) to compare tissue from individuals who are pre-symptomatic (Pre_S) to tissue from patients with late stage FECD (FECD_REP). The abundance of mutant repeat intronic RNA in Pre_S and FECD_REP tissue is elevated due to increased half-life in a corneal cell-specific manner. In Pre_S tissue, changes in splicing and extracellular matrix gene expression foreshadow the changes observed in advanced disease and predict the activation of the fibrosis pathway and immune system seen in late-stage patients. The absolute magnitude of splicing changes is similar in presymptomatic and late stage tissue. Our data identify gene candidates for early drivers of disease and biomarkers that may represent diagnostic and therapeutic targets for FECD. We conclude that changes in alternative splicing and gene expression are observable decades prior to the diagnosis of late-onset trinucleotide repeat disease.

molecular biology↗

bioRxiv2020

Dissecting the nanoscale lipid profile of caveolae

Caveolae are specialized domains of the vertebrate cell surface with a well-defined morphology and crucial roles in cell migration and mechanoprotection. Unique compositions of proteins and lipids determine membrane architectures. The precise caveolar lipid profile and the roles of the major caveolar structural proteins, caveolins and cavins, in selectively sorting lipids have not been defined. Here we used quantitative nanoscale lipid mapping together with molecular dynamic simulations to define the caveolar lipid profile. We show that caveolin1 (CAV1) and cavin1 individually sort distinct plasma membrane lipids. Intact caveolar structures composed of both CAV1 and cavin1 further generate a unique lipid nano-environment. The caveolar lipid sorting capability includes selectivities for lipid headgroups and acyl chains. Because lipid headgroup metabolism and acyl chain remodelling are tightly regulated, this selective lipid sorting may allow caveolae to act as transit hubs to direct communications among lipid metabolism, vesicular trafficking and signalling.

biochemistry↗

bioRxiv2020

MSIsensor-pro: fast, accurate and matched-normal-sample-free detection of microsatellite instability

We developed MSIsensor-pro (https://github.com/xjtu-omics/msisensor-pro), an open-source single sample microsatellite instability (MSI) scoring method for research and clinical applications. MSIsensor-pro introduces a multinomial distribution model to quantify polymerase slippages for each tumor sample and a discriminative sites selection method to enable MSI detection without matched normal samples. For samples of various sequencing depths and tumor purities, MSIsensor-pro significantly outperformed the current leading methods in terms of both accuracy and computational cost.

bioinformatics↗

bioRxiv2019

FtsW exhibits distinct processive movements driven by either septal cell wall synthesis or FtsZ treadmilling in E. coli

During bacterial cell division, synthesis of new septal peptidoglycan (sPG) is crucial for successful cytokinesis and cell pole morphogenesis. FtsW, a SEDS (Shape, Elongation, Division and Sporulation) family protein and an indispensable component of the cell division machinery in all walled bacterial species, was recently identified in vitro as a new monofunctional peptidoglycan glycosyltransferase (PGTase). FtsW and its cognate monofunctional transpeptidase (TPase) class B penicillin binding protein (PBP3 or FtsI in E. coli) may constitute the essential, bifunctional sPG synthase specific for new sPG synthesis. Despite its importance, the septal PGTase activity of FtsW has not been documented in vivo. How its activity is spatiotemporally regulated in vivo has also remained unknown. Here we investigated the septal PGTase activity and dynamics of FtsW in E. coli cells using a combination of single-molecule imaging and genetic manipulations. We show that FtsW exhibits robust activity to incorporate an N-acetylmuramic acid analog at septa in the absence of other known PGTases, confirming FtsW as the essential septum-specific PGTase in vivo. Notably, we identified two populations of processive moving FtsW molecules at septa. A fast-moving population is driven by the treadmilling dynamics of FtsZ and independent of sPG synthesis. A slow-moving population is driven by active sPG synthesis and independent of FtsZs treadmilling dynamics. We further identified that FtsN, a potential sPG synthesis activator, plays an important role in promoting the slow-moving, sPG synthesis-dependent population. Our results support a two-track model, in which inactive sPG synthase molecules follow the fast treadmilling "Z-track" to be distributed along the septum; FtsN promotes their release from the "Z-track" to become active in sPG synthesis on the slow "sPG-track". This model explains how the spatial information is integrated into the regulation of sPG synthesis activity and suggests a new mechanistic framework for the spatiotemporal coordination of bacterial cell wall constriction.

biophysics↗

bioRxiv2019

Personalized Network Modeling of the Pan-Cancer Patient and Cell Line Interactome

AO_SCPCAPBSTRACTC_SCPCAPO_ST_ABSPurposeC_ST_ABSPersonalized network inference on diverse clinical and in vitro model systems across cancer types can be used to delineate specific regulatory mechanisms, uncover drug targets and pathways, and develop individualized predictive models in cancer.\n\nDatasets and methodsWe developed TransPRECISE, a multi-scale Bayesian network modeling framework, to analyze the pan-cancer patient and cell line interactome to identify differential and conserved intra-pathway activities, globally assess cell lines as representative models for patients and develop drug sensitivity prediction models. We assessed pan-cancer pathway activities for a large cohort of patient samples (>7700) from The Cancer Proteome Atlas across [≥]30 tumor types and a set of 640 cancer cell lines from the M.D. Anderson Cell Lines Project spanning16 lineages, and [≥]250 cell lines response to >400 drugs.\n\nResultsTransPRECISE captured differential and conserved proteomic network topologies and pathway circuitry between multiple patient and cell line lineages: ovarian and kidney cancers shared high levels of connectivity in the hormone receptor and receptor tyrosine kinase pathways, respectively, between the two model systems. Our tumor stratification approach found distinct clinical subtypes of the patients represented by different sets of cell lines: head and neck patient tumors were classified into two different subtypes that are represented by head and neck and esophagus cell lines, and had different prognostic patterns (456 vs. 654 days of median overall survival; P=0.02). The TransPRECISE-based sample-specific pathway scores achieved high predictive accuracy for drug sensitivities in cell lines across multiple drugs (median AUC >0.8).\n\nConclusionOur study provides a generalizable analytical framework to assess the translational potential of preclinical model systems and guide pathway-based personalized medical decision-making, integrating genomic and molecular data across model systems.

bioinformatics↗

bioRxiv2019

Extraction of genome-wide reads distribution pattern through whole genome sequencing of cell-free DNA for tracking tissue-of-origin in cancer patients

Somatic mosaicism is widespread among tissues and could indicate distinct tissue origins of circulating cell-free DNA (cfDNA), DNA fragments released by lytic cells into the blood. By investigating the alignment patterns of whole genome sequencing reads with the genomic DNA of different tissues, we found that the read distributions formed type-specific patterns in some regions as a result of somatic mosaicism. We then utilized this information to construct a tissue-of-origin mapping model and evaluated its predictive performance on whole genome sequencing data from tissue and cfDNA samples. In total, 1,545 tissue samples associated with 13 cancer types were included, and identification of the tissue of origin achieved a specificity of 82% and a sensitivity of 80%. Furthermore, a total of 30 cfDNA samples from lung cancer and liver cancer patients and healthy controls were analyzed to predict their tissues of origin with a specificity of 87% and a sensitivity of 87%. Our results show that read distribution patterns from whole genome sequencing could be used to identify cfDNA tissues of origin with high accuracy, suggesting the potential application of our model to early cancer detection and diagnosis.

bioinformatics↗