Biology subjects

Liao, W.

Publications and source records attributed to Liao, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Investigation of a mathematical model describing global cancer growth and treatment: An inhomogeneous model based on the generalized logistic equation

Tumor growth is manifestation of the evolution of a complex system. Researchers have limited scope of modelling studies on specific aspects or stages of the process. It has led to unsatisfactory explanation of clinical observations. We hereby demonstrated that an inhomogeneous model built on the generalized logistic equation could serve better. It was developed to describe the whole process of tumor progression, clinically observed independence of index tumor growth from spread of the disease and growth deceleration during early stage of solid tumors. It was validated by simulating the coexistence of exponential and sigmoidal growth in chronic lymphocytic leukaemia, theories of tumor heterogeneity, as well as by accommodating notions pertaining to tumor treatment and prognosis. We thought therefore it was an interesting and not unjustifiable description of actual tumor growth in human body and hoped it might encourage more researchers to look at tumor modelling from a clinical perspective.

cancer biology↗

bioRxiv2022

A compendium of genetic regulatory effects across pig tissues

The Farm animal Genotype-Tissue Expression (FarmGTEx, https://www.farmgtex.org/) project has been established to develop a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biology discovery and exploitation in animal breeding and human biomedicine. Here we present results from the pilot phase of PigGTEx (http://piggtex.farmgtex.org/), where we processed 9,530 RNA-sequencing and 1,602 whole-genome sequencing samples from pigs. We build a pig genotype imputation panel, characterize the transcriptional landscape across over 100 tissues, and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We study interactions between genotype and breed/cell type, evaluate tissue specificity of regulatory effects, and elucidate the molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying about 80% of the genetic associations for 207 pig complex phenotypes, and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, corroborating the importance of pigs as a human biomedical model.

genomics↗

bioRxiv2022

Barley powdery mildew effector CSEP0162 targets multivesicular body-associated MON1 important for immunity

Encasements formed around haustoria and biotrophic hyphae as well as hypersensitive reaction (HR) cell death are essential plant immune responses to filamentous pathogens. Here we study a possible reason why these responses are absent in susceptible barley attacked by the powdery mildew fungus. We find that the effector CSEP0162 from this pathogen targets plant MON1, important for fusion of multivesicular bodies to their target membranes. Over-expression of CSEP0162 and silencing of barley MON1 both inhibit encasement formation. We find that the Arabidopsis ecotype No-0 has partial resistance to powdery mildew, and that this is dependent on MON1. Surprisingly, we find the MON1-dependent resistance in No-0 not only include an effective encasement response, but also HR. Similarly, silencing of MON1 in barley also blocked Mla3-mediated HR-based powdery mildew resistance. These data indicate that MON1 is a vital plant immunity component, and we speculate that the barley powdery mildew fungus introduces the effector CSEP0162 to target MON1 and reduce encasement formation and HR. HighlightMON1 is essential for MVB fusion to plasma membrane. We find that MON1 also is important for immunity, and that it is targeted by the barley powdery mildew effector CSEP0162.

plant biology↗

bioRxiv2022

Machine learning guided signal enrichment for ultrasensitive plasma tumor burden monitoring

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole genome sequencing (WGS). We now introduce MRD-EDGE, a composite machine learning-guided WGS ctDNA single nucleotide variant (SNV) and copy number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGE uses deep learning and a ctDNA-specific feature space to increase SNV signal to noise enrichment in WGS by 300X compared to our previous noise suppression platform MRDetect. MRD-EDGE also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1Gb to 200Mb, thereby expanding its applicability to a wider range of solid tumors. We harness the improved performance to track changes in tumor burden in response to neoadjuvant immunotherapy in non-small cell lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal to noise enrichment in MRD-EDGE enables de novo mutation calling in melanoma without matched tumor, yielding clinically informative TF monitoring for patients on immune checkpoint inhibition.

genomics↗

bioRxiv2021

Explainable autoencoder-based representation learning for gene expression data

Modern machine learning methods have been extensively utilized in gene expression data analysis. In particular, autoencoders (AE) have been employed in processing noisy and heterogenous RNA-Seq data. However, AEs usually lead to "black-box" hidden variables difficult to interpret, hindering downstream experimental validation and clinical translation. To bridge the gap between complicated models and biological interpretations, we developed a tool, XAE4Exp (eXplainable AutoEncoder for Expression data), which integrates AE and SHapley Additive exPlanations (SHAP), a flagship technique in the field of eXplainable AI (XAI). It quantitatively evaluates the contributions of each gene to the hidden structure learned by an AE, substantially improving the expandability of AE outcomes. By applying XAE4Exp to The Cancer Genome Atlas (TCGA) breast cancer gene expression data, we identified genes that are not differentially expressed, and pathways in various cancer-related classes. This tool will enable researchers and practitioners to analyze high-dimensional expression data intuitively, paving the way towards broader uses of deep learning. AvailabilityOpen source at https://github.com/QingrunZhangLab/Explainable-Deep-Autoencoder. Contactsqingrun.zhang@ucalgary.ca and wliao@ucalgary.ca.

bioinformatics↗

bioRxiv2021

TGF--dependent Lymphoid Tissue Residency of Stem-like T cells Limits the Response to Tumor Vaccine

Stem-like CD8+ T cells represent the key subset responding to multiple tumor immunotherapies, including tumor vaccination. However, the signals that control the differentiation of stem-like T cells are not entirely known. Most previous investigations on stem-like T cells are focused on tumor infiltrating T cells (TIL). The behavior of stem-like T cells in other tissues remains to be elucidated. Tissue-resident memory T cells (TRM) are often defined as a non-circulating T cell population residing in non-lymphoid tissues. TILs carrying TRM features are associated with better tumor control. Here, we found that stem-like CD8+ T cells differentiated into TRMs in a TGF-{beta} and tumor antigen dependent manner almost exclusively in tumor draining lymph node (TDLN). TDLN-resident stemlike T cells were negatively associated with the response to tumor vaccine. In other words, after tumor vaccine, TDLN stem-like T cells transiently lost TRM features, differentiated into migratory effectors and exerted tumor control.

immunology↗

bioRxiv2021

Acetylated Chromatin Domains Link Chromosomal Organization to Cell- and Circuit-level Dysfunction in Schizophrenia and Bipolar Disorder

To explore modular organization of chromosomes in schizophrenia (SCZ) and bipolar disorder (BD), we applied population-scale correlational structuring of 739 histone H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from the prefrontal cortex (PFC) of 568 cases and controls. Neuronal histone acetylomes and methylomes assembled as thousands of cis-regulatory domains (CRDs), revealing fine-grained, kilo-to megabase scale chromatin organization at higher resolution but firmly integrated into Hi-C chromosomal conformations. Large clusters of domains that were hyperacetylated in disease shared spatial positioning within the nucleus, predominantly regulating PFC projection neuron function and excitatory neurotransmission. Hypoacetylated domains were linked to inhibitory interneuron- and myelination-relevant genes. Chromosomal modular architecture is affected in SCZ and BD, with hyperacetylated domains showing unexpectedly strong convergences defined by cell type, nuclear topography, genetic risk, and active chromatin state across a wide developmental window.

genomics↗

bioRxiv2021

Ciliated protozoa from industrial WWTP activated sludge: a biodiversity survey including trophic interactions and redescription of Bakuella subtropica (Spirotrichea, Hypotrichia) according to Next Generation Taxonomy

Optimization of wastewater treatment with biological processes is a fundamental challenge of modern society. During past years new technologies have been developed for the purpose and prokaryotic organisms involved in the process extensively investigated. Nevertheless, relatively few studies so far analysed the protozoan community in these systems using modern integrative approaches, despite its obvious role in shaping ecological dynamics and, possibly, process efficiency. In the present study, we characterized the ciliate community in biological reactors of an Italian industrial (tannery) wastewater treatment plant (WWTP) applying modified Ludzack-Ettinger (MLE) process. This plant is characterized by moderate salinity, high solids retention time and high concentration of organic compounds, including a significant recalcitrant fraction. We performed the morphological and 18S rDNA characterizations of almost all the 21 ciliates retrieved along a one-year sampling period, and provided preliminary data on species occurrence, community dynamics, and trophic interactions. Only 16 species were observed on the sample collection day and most of them had an occurrence higher than 50%. The most frequently occurring and highly abundant organisms were Aspidisca cf. cicada, Euplotes spp., Paramecium calkinsi, and Phialina sp. Cyclidium cf. marinum was only found on a single date and its presence was possibly related to a summer break-induced perturbation. All the species showed the capability to survive the short oxic/anoxic cycling typical of the studied WWTP process. Intriguingly, some of them (i.e., Bakuella subtropica and Trochiliopsis australis) turned out to be species isolated from brackish natural environment rich in organic load as well. As for B. subtropica, we provided an emended redescription according to the most recent taxonomy standards that include also mitogenomic sequencing.

zoology↗

bioRxiv2021

Genetic characteristics of human papillomavirus type 16, 18, 52 and 58 in southern China

Persistent infections of high-risk human papillomaviruses (HPVs) are the leading cause of cervical cancers. We collected cervical exfoliated cell samples from females in Changsha city, Hunan Province and obtained 358 viral genomes of four major HPV types, including HPV 16 (n=82), 18 (n=35), 52 (n=121) and 58 (n=100). The lineage/sublineage distribution of the four HPVs confirmed previous epidemiological reports, with the predominant prevailing sublineage as A4 (50%), A1 (37%) and A3 (13%) for HPV16, A1 (83%) for HPV18, B2 (86%) for HPV52 and A1 (65%), A3 (19%) and A2 (12%) for HPV58. We also identified two potentially novel HPV18 sublineages, i.e. A6 and A7. Virus mutation analysis further revealed the presence of HPV16 and HPV58 strains associated with potentially high oncogenicity. These findings expanded our knowledge on the HPV genetic diversity in China, providing valuable evidence to facilitate HPV DNA screening, vaccine effectiveness evaluation and control strategy development.

genomics↗

bioRxiv2021

Induction of Dopaminergic Neurons for Neuronal Subtype-Specific Modeling of Psychiatric Disease Risk

Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) yield heterogenous cell populations with variable purity and inconsistent reproducibility between donors, hiPSC clones, and experiments. Here, we report the rapid (5 weeks) and efficient (~90%) induction of induced dopaminergic neurons (iDANs) through transient overexpression of lineage-promoting transcription factors combined with stringent selection across five donors. We observe maturation-dependent increase in dopamine synthesis, together with electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after hyperpolarization potentials, an action potential duration of ~3ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at frequency of ~1.0-1.75 Hz. Transcriptome analysis reveals robust expression of genes involved in fetal midbrain dopaminergic neuron identity. Specifically expressed genes in iDANs, relative to their isogenic glutamatergic and GABAergic counterparts, were linked to the genetic risk architecture of a broad range of psychiatric traits, with iDANs showing particularly strong enrichment in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.

neuroscience↗

bioRxiv2020

IOBR: Multi-omics Immuno-Oncology Biological Research to decode tumor microenvironment and signatures

MotivationRecent advance in next generation sequencing has triggered the rapid accumulation of publicly available multi-omics datasets. The application of integrated omics to exploring robust signatures for clinical translation is increasingly highlighted, attributed to the clinical success of immune checkpoint blockade in diverse malignancies. However, effective tools to comprehensively interpret multi-omics data is still warranted to provide increased granularity into intrinsic mechanism of oncogenesis and immunotherapeutic sensitivity. ResultsWe developed a computational tool for effective Immuno-Oncology Biological Research (IOBR), providing comprehensive investigation of estimation of reported or user-built signatures, TME deconvolution and signature construction base on multi-omics data. Notably, IOBR offers batch analyses of these signatures and their correlations with clinical phenotypes, lncRNA profiling, genomic characteristics and signatures generated from single-cell RNA sequencing data in different cancer settings. Additionally, IOBR also integrates multiple existing microenvironmental deconvolution methodologies and signature construction tools for convenient comparison and selection. Collectively, IOBR is a user-friendly tool, to leverage multi-omics data to facilitate immuno-oncology exploration and unveiling of tumor-immune interactions and accelerating precision immunotherapy.

bioinformatics↗

bioRxiv2020

LncRNA Snhg1-driven self-reinforcing regulatory network promotes cardiomyocyte cytokinesis

Most of current cardiac regenerative approaches result in very limited cell division. Positive feedback loops are vital for cell division, but their role in CM regeneration remains unclear. We aimed to demonstrate that lncRNA Snhg1 formed a positive feedback loop with c-Myc to induce stable CM cytokinesis. We found that Snhg1 expression was increased in human and mouse fetal and myocardial infarction (MI) hearts, particularly in CMs. Snhg1 overexpression elicited stable CM proliferation and improved post-MI cardiac function. Antagonism of Snhg1 in neonatal mice inhibited CM proliferation and impaired cardiac repair after MI. Proliferative effect was confirmed using cardiac-specific transgenic mice. RNA pull-down assays showed that Snhg1 directly bound to PTEN and activated PI3K-Akt pathway, resulting in c-Myc activation. Chromatin immunoprecipitation experiments showed that Snhg1 expression was upregulated by c-Myc binding to the Snhg1 promoter region, indicating a positive feedback loop between c-Myc and Snhg1. In conclusion, c-Myc/Snhg1/PI3k-Akt positive feedback loop drove sustained activation of cell cycle re-entry and induced stable CM cytokinesis, and thus may be an attractive strategy for promoting heart regenerative response. Clinical PerspectivesMost of the current cardiac regenerative approaches result in very limited cell division and little new cardiomyocyte (CM) mass. Positive feedback loops are vital for cell division, but their role in CM regeneration remain unclear. Here, we identified the long noncoding RNA Snhg1 as a driver to induce stable CM division and improve cardiac function after myocardial infarction (MI) by forming a positive feedback loop to sustain PI3K-Akt signaling activation. This finding might provide a novel therapeutic of Snhg1 as a promising regenerative approach to improve the prognosis of patients with heart failure.

developmental biology↗

bioRxiv2020

A potent SARS-CoV-2 neutralizing human monoclonal antibody that reduces viral burden and disease severity in Syrian hamsters

The emergence of COVID-19 has led to a pandemic that has caused millions of cases of disease, variable morbidity and hundreds of thousands of deaths. Currently, only remdesivir and dexamethasone have demonstrated limited efficacy, only slightly reducing disease burden, thus novel approaches for clinical management of COVID-19 are needed. We identified a panel of human monoclonal antibody clones from a yeast display library with specificity to the SARS-CoV-2 spike protein receptor binding domain that neutralized the virus in vitro. Administration of the lead antibody clone to Syrian hamsters challenged with SARS-CoV-2 significantly reduced viral load and histopathology score in the lungs. Moreover, the antibody interrupted monocyte infiltration into the lungs, which may have contributed to the reduction of disease severity by limiting immunopathological exacerbation. The use of this antibody could provide an important therapy for treatment of COVID-19 patients.

microbiology↗

bioRxiv2020

Comparison of motility of H. pylori in broth and mucin reveals the interplay of effect of acid on bacterium and the rheology of the medium it swims in.

To colonize on the gastric epithelium Helicobacter pylori bacteria have to swim across a gradient of pH from 2-7 in the mucus layer. Previous studies of H. pylori motility have shown that at pH below 4 do not swim in porcine gastric mucin (PGM) gels. To separately assess the influence of gelation of PGM and that of pH on motors and pH sensitive receptors of H. pylori, we used phase contrast microscopy to compare the translational and rotational motion of H. pylori in PGM versus Brucella broth (BB10) at different pHs. We observed that decreasing pH leads to decreased fraction of motile swimmers with a decrease in the contribution of fast swimmers to the distributions of swimming speeds and length of trajectories. At all pHs the bacteria swam faster with longer net displacement over the trajectory in BB10 as compared to PGM. While bacteria are stuck in PGM gels at low pH, they swim at low pH in broth, albeit with reduced speed. The body rotation rate and estimated cell body torque are weakly dependent on pH in BB10, whereas in PGM the torque increases with increasing viscosity and bacteria stuck in the low pH gel rotate faster than the motile bacteria. Our results show that H. pylori has optimal swimming under slightly acidic conditions, and exhibits mechanosensing when stuck in low pH mucin gels.

biophysics↗

bioRxiv2020

Hybrid origin of Populus tomentosa Carr. identified through genome sequencing and phylogenomic analysis

Populus tomentosa is widely distributed and cultivated in the Northern and Central China, where it is of great economic and ecological importance. However, the origin of P. tomentosa remains controversial. Here, we used a PacBio+Hi-C+Illumina strategy to sequence and assemble its 740.2 Mb (2n) genome. The assembly accounts for greater than 92.1% of the 800-megabase genome, comprises 38 chromosomes, and contains 59,124 annotated protein-coding genes. Phylogenomic analyses elucidated dynamic genome evolution events among its closely related white poplars, and revealed that tomentosa is comprised of two subgenomes, which we deomonstrate is likely to have resulted from hybridization between Populus adenopoda as the female, and Populus alba var. pyramidalis as the male, around 3.93 Mya. We also detected structural variations and allele-indels across genome. Our study presents a high quality and well assembled genome, unveils the origin of the widely distributed and planted P. tomentosa, and provides a powerful resource for comparative plant biology, breeding, and biotechnology.

genomics↗

bioRxiv2020

Deficiency of cyclin-dependent kinase-like 5 causes spontaneous seizures in neonatal mice

Cyclin-dependent kinase-like 5 (CDKL5), an X-linked gene encoding a serine-threonine kinase, is enriched in the mammalian forebrain and critical for neuronal maturation and synaptic function. Mutations in this gene cause CDKL5 deficiency disorder (CDD) that is characterized by early-onset epileptic seizures, autistic behaviors and intellectual disability. Although numerous CDD symptoms have been recapitulated in mouse models, spontaneous seizures have not been reported in mice with CDKL5 deficiency. Here, we present the first systematic study of spontaneous seizures in a mouse model of CDD. Through wireless electroencephalographic (EEG) recording and simultaneous videotaping, we observed epileptiform discharges accompanied with ictal behaviors in pups lacking CDKL5 at a selective time window during the pre-weaning period. The seizure-like patterns of EEG showed robust increase in total number of spike events, the total number and duration of bursts in Cdkl5 null pups compared to wild-type littermate controls at the age of postnatal day 12 (P12). The mutants displayed not only jerky and spasm-like movements during the prolonged bursts of discharges at P12, but also strengthened ictal grasping in both juvenile stage and adulthood. In addition, loss of CDKL5 remarkably reduced the phosphorylation of K+/Cl- co-transporter 2, which may impede GABA-mediated inhibition, in the cortex of P12 mouse pups. Our study reveals previously unidentified phenotypes of early-onset seizures in CDKL5-deficient mice, highlights the translational value of mouse models of CDD and provides a potential molecular target for early diagnosis and treatment for CDD. Significance StatementCyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene encoding a serine-threonine kinase. Mutations in this gene cause CDKL5 deficiency disorder (CDD), a rare disease characterized by developmental delays, autistic behaviors and early-onset epilepsy. Even though many symptoms of CDD patients have been phenocopied in mice, spontaneous seizures are yet to be reported in mouse models of CDD. Here, for the first time, we identified early-onset seizures and ictal behaviors in neonatal pups of CDKL5-deficient mice. Loss of CDKL5 also selectively reduced protein levels of phosphorylated K+/Cl-cotransporter 2 in neonatal cortex of mice. Our study reveals an indispensible role of CDKL5 in regulating neuronal excitability in developing brains and highlights the translational significance of the CDD mouse models.

neuroscience↗

bioRxiv2020

One New Species of the Genus Dryomys (Rodentia, Glirgae) from Xinjiang China, Dryomys Yarkandensis sp. nov

During an expedition in June 2012 in Shache county of Tarim Basin in southern Xinjiang, China, a new species of the genus Dryomys (Gliridae) has been discovered and named Dryomys yarkandensis sp. nov. It has been found obviously different from D. nitedulai in northern Xinjiang, D. laniger, D. niethammeri and D. nitedulai in Europe, which are also belong to genus Dryomys. The new species Dryomys yarkandensis sp. nov is described below. HolotypeNo. N07, an adult female collected by Chen Zhenhai in June 2012, is deposited Center for disease prevention and control of Xinjiang (Xinjiang CDC). It was obtained from oasis orchard of desert in Tarim Basin (38{degrees}29N, 77{degrees}32E), 1211-1215 m. Genus characterThere is a dark chestnut round eye. The terminal of tail is club shape, covered with dense hairs, and cannot see the scale ring in external texture. Description of the speciesThe eyes is large. The beard is long and the longest could reach 30 mm. The tail is thicker and slightly longer than body length about 10%. The terminal of the tail is fluffy. All the surface is covered with dense hairs. External figureThe color of the new species on the back is lighter than that of D. laniger, D. niethammeri and D. nitedulai in Dryomys. The length of the tail is about 110% of the body length. The length of the ears is 12.8 mm, which is 15% shorter than the other three species of Dryomys. Skull and toothThe ratio between the length of audirory bullae and the breadth of auditory bullae is 1.66 (8.35/5.02), which is larger than the other three species of D. nitedula. The habitats of the new species is harsh, drought and hot in summer but dry and cold in winter. The habitats of D. nitedula in mountain valley in northern Xinjiang is temperate, humidity and low temperature, and there are berries or orchard.

zoology↗

bioRxiv2020

MHC*IMP - Imputation of Alleles for Genes in the Major Histocompatibility Complex

We report the development of MHC*IMP, a method for imputing non-classical HLA and other genes in the human Major Histocompatibility Complex (MHC). We created a reference panel for 25 genes in the MHC using allele calls from Whole Genome Sequencing data, combined with SNP data for the same individuals. We used this to construct an allele imputation model, MHC*IMP, for each gene. Cross-validation showed that MHC*IMP performs very well, with allele prediction accuracy 93% or greater for all but two of the genes, and greater than 95% for all but four.

genomics↗