Biology subjects

Zheng, C.

Publications and source records attributed to Zheng, C..

140 records · Page 8Linked to original sources

bioRxiv2019

Predicting cancer origins with a DNA methylation-based deep neural network model

Cancer origin determination combined with site-specific treatment of metastatic cancer patients is critical to improve patient outcomes. Existing pathology and gene expression-based techniques often have limited performance. In this study, we developed a deep neural network (DNN)-based classifier for cancer origin prediction using DNA methylation data of 7,339 patients of 18 different cancer origins from The Cancer Genome Atlas (TCGA). This DNN model was evaluated using four strategies: (1) when evaluated by 10-fold cross-validation, it achieved an overall specificity of 99.72% (95% CI 99.69%-99.75%) and sensitivity of 92.59% (95% CI 91.87%-93.30%); (2) when tested on hold-out testing data of 1,468 patients, the model had an overall specificity of 99.83% and sensitivity of 95.95%; (3) when tested on 143 metastasized cancer patients (12 cancer origins), the model achieved an overall specificity of 99.47% and sensitivity of 95.95%; and (4) when tested on an independent dataset of 581 samples (10 cancer origins), the model achieved overall specificity of 99.91% and sensitivity of 93.43%. Compared to existing pathology and gene expression-based techniques, the DNA methylation-based DNN classifier showed higher performance and had the unique advantage of easy implementation in clinical settings.

cancer biology↗

bioRxiv2019

Brainstem organoids from human pluripotent stem cells contain neural crest population

The brainstem controls heartbeat, blood pressure and respiration, which are life-sustaining functions, therefore, disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models have limitations, hampering the elucidation of diseases affecting specific components of the brain. Here, we developed a method to generate human brainstem organoids (hBSOs), containing neural crest stem cells as well as midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, and dopaminergic neurons, demonstrated by specific electrophysiological signatures. Single-cell RNA sequence analysis, together with proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem and neural crest, which raises the possibility of making use of hBSOs in grafting for transplantation, efficient drug screenings and modeling the neural crest diseases.

developmental biology↗

bioRxiv2019

Timing matters: primacy effects of experience on mood revealed using a novel Mood-Machine-Interface

Humans refer to their own mood state regularly in day-to-day as well as in clinical interactions. Theoretical accounts suggest that when reporting on our mood we integrate over the history of our experiences; yet, the temporal structure of this integration remains unexamined. Here we use a computational approach to quantitatively answer this question and show that early events exert a stronger influence on the reported mood compared to recent events. We show that a Primacy model accounts better for mood reports compared to a range of alternative temporal representations, and replicate this result across random, consistent or dynamic structures of reward environments, age groups and both healthy and depressed participants. Moreover, we find evidence for neural encoding of the Primacy, but not the Recency, model in frontal brain regions related to mood regulation. These findings hold implications for the timing of events in experimental or clinical settings and suggest new directions for individualized mood interventions. SignificanceHow we rate our own mood at any given moment is shaped by our experiences; but are the most recent experiences the most influential, as assumed by current theories? Using several sources of experimental data and mathematical modeling, we show that earlier experiences within a context are more influential than recent events, and replicate this finding across task environments, age groups, and in healthy and depressed participants. Additionally, we present neural evidence supporting this primacy model. Our findings show that delineating a temporal structure is crucial in modeling mood and this has key implications for its measurement and definition in both clinical and everyday settings.

neuroscience↗

bioRxiv2019

Lyb-2-4, a unique genomic region of hypervirulent carbapenem-resistant Acinetobacter baumannii

Acinetobacter baumannii is an important human pathogen due to its multi-drug resistance, but is usually with low-grade virulence. Although a mouse model revealed different virulence grades of clinical carbapenem-resistant A. baumannii (CRAB) strains, the genetic basis remains unknown. We collected 61 CRAB isolates from intensive care unit of Shenzhen Peoples Hospital (Shenzhen, China), and analyzed them used whole genome sequencing (WGS), multilocus sequence typing (MLST) and core genome MLST (cgMLST), transmission chain reconstruction and Comparative genomic tools. A mouse pneumonia model was used to confirm the hypervirulent phenotype. Eleven complex types (CT) were identified based on core genome multilocus sequence typing scheme. CT512 showed higher transmissibility and bloodstream infection rates than other CTs. A genomic region Lyb-2-4 was shared by CT512 and CT2092 but not CT2085. The mortality rates of patient infected with CRAB harboring Lyb-2-4 was significantly higher than those infected with CRAB isolates without Lyb-2-4 (77.8% vs 24.5%, p < 0.01). In the mouse model, the survival rates of strains containing the Lyb-2-4 region (LAC-4, 5122 and 2092) were significantly lower than for strains without Lyb-2-4 (7152, 71517, 20859 and ATCC17978). One open reading frame (ORF) was a marker for the presence of Lyb-2-4, and PCR of a segment of this ORF, designated as hvcT, served as a tag for hypervirulent CRAB. Our study should be very useful in advising the clinician to implement medical intervention earlier, and also making the worldwide surveillance of these hypervirulent CRAB strains easier.\n\nIMPORTANCEHypervirulent CRAB strains are expected to pose a threat to human health because infection of these strains is associated with high mortality and multidrug resistance. The rapid hypervirulent CRAB identification assay will facilitate prompt medical intervention. Our findings should provoke surveillance for hypervirulent CRAB strains harboring Lyb-2-4 in other countries. Further research should focus on the mechanism of hypervirulence, the acquisition of this genomic region and the development of control measures to prevent further dissemination.

microbiology↗

bioRxiv2019

The Avocado Genome Informs Deep Angiosperm Phylogeny, Highlights Introgressive Hybridization, and Reveals Pathogen Influenced Gene Space Adaptation

The avocado, Persea americana, is a fruit crop of immense importance to Mexican agriculture with an increasing demand worldwide. Avocado lies in the anciently-diverged magnoliid clade of angiosperms, which has a controversial phylogenetic position relative to eudicots and monocots. We sequenced the nuclear genomes of the Mexican avocado race, P. americana var. drymifolia, and the most commercially popular hybrid cultivar, Hass, and anchored the latter to chromosomes using a genetic map. Resequencing of Guatemalan and West Indian varieties revealed that [~]39% of the Hass genome represents Guatemalan source regions introgressed into a Mexican race background. Some introgressed blocks are extremely large, consistent with the recent origin of the cultivar. The avocado lineage experienced two lineage-specific polyploidy events during its evolutionary history. Although gene-tree/species-tree phylogenomic results are inconclusive, syntenic ortholog distances to other species place avocado as sister to the enormous monocot and eudicot lineages combined. Duplicate genes descending from polyploidy augmented the transcription factor diversity of avocado, while tandem duplicates enhanced the secondary metabolism of the species. Phenylpropanoid biosynthesis, known to be elicited by Colletotrichum (anthracnose) pathogen infection in avocado, is one enriched function among tandems. Furthermore, transcriptome data show that tandem duplicates are significantly up- and down-regulated in response to anthracnose infection, whereas polyploid duplicates are not, supporting the general view that collections of tandem duplicates contribute evolutionarily recent \"tuning knobs\" in the genome adaptive landscapes of given species.\n\nSIGNIFICANCE STATEMENTAvocado is a nutritious, economically important fruit species that occupies an unresolved position near the earliest evolutionary branchings of flowering plants. Our nuclear genome sequences of Mexican and Hass variety avocados inform ancient evolutionary relationships and genome doublings, the admixed nature of Hass, and provide a look at how pathogen interactions have shaped avocados more recent genomic evolutionary history.

genomics↗

bioRxiv2019

Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

Drug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR)-mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here we find that 2-hour sublethal TKI treatment elicits a transient drug-tolerant state in EGFR-mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated epigenetic upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combinational treatment with TKI and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with EGFR TKI response. Collectively, our findings reveal the importance of epigenetically regulated BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer.\n\nHIGHLIGHTSSublethal EGFR TKI treatment induces transient drug-tolerant state and long-term resistance in EGFR-mutant lung cancer cells\n\nEpigenetically regulated BCAT1-mediated metabolic reprogramming orchestrates EGFR TKI-induced drug resistance\n\nCombinational treatment with TKI and ROS-inducing agents overcomes the drug resistance induced by EGFR TKI treatment

cancer biology↗

bioRxiv2019

Trophoblast proliferation, migration, and invasion is regulated by the miR-195/EGFR signaling pathway in recurrent spontaneous abortion patients

OBJECTIVETo investigate the effect of the miR-195/EGFR signaling pathway on trophoblasts in patients with recurrent spontaneous abortion, thus providing a clinical basis for the diagnosis and treatment of recurrent spontaneous abortion.\n\nMETHODSRT-qPCR, western blot, flow cytometry, CCK8, cell scratch assay, transwell, and a dual Luciferase reporter assay were used to detect changes in the miR-195/EGFR signaling pathways in clinical samples and in vitro cultured cells and to explore how these changes affect trophoblasts in affected patients.\n\nRESULTSExpression of miR-195 was elevated in villus tissues of patients with recurrent spontaneous abortion, while the expression levels of EGFR and its downstream genes p38 and AKT phosphorylation were down-regulated. In vitro cultured cell experiments showed that miR-195 inhibited the proliferation, migration, and invasion of trophoblast cells. EGFR is a target gene of miR-195, and miR-195 suppresses the expression of EGFR.\n\nConclusionThe miR-195/EGFR signaling pathway regulates the proliferation, migration, and invasion of trophoblast cells, thus playing an important role in recurrent spontaneous abortion.

cell biology↗

bioRxiv2019

Demographic histories and genome-wide patterns of divergence in incipient species of shorebirds

Understanding how incipient species are maintained with gene flow is a fundamental question in evolutionary biology. Whole genome sequencing of multiple individuals holds great potential to illustrate patterns of genomic differentiation as well as the associated evolutionary histories. Kentish (Charadrius alexandrinus) and the white-faced (C. dealbatus) plovers, which differ in their phenotype, ecology and behaviour, are two incipient species and parapatrically distributed in East Asia. Previous studies show evidence of genetic diversification with gene flow between the two plovers. Under this scenario, it is of great importance to explore the patterns of divergence at the genomic level and to determine whether specific regions are involved in reproductive isolation and local adaptation. Here we present the first population genomic analysis of the two incipient species based on the de novo Kentish plover reference genome and resequenced populations. We show that the two plover lineages are distinct in both nuclear and mitochondrial genomes. Using model-based coalescence analysis, we found that population sizes of Kentish plover increased whereas white-faced plovers declined during the Last Glaciation Period. Moreover, the two plovers diverged allopatrically, with gene flow occurring after secondary contact. This has resulted in low levels of genome-wide differentiation, although we found evidence of a few highly differentiated genomic regions in both the autosomes and the Z-chromosome. This study illustrates that incipient shorebird species with gene flow after secondary contact can exhibit discrete divergence at specific genomic regions and provides basis to further exploration on the genetic basis of relevant phenotypic traits.

evolutionary biology↗

bioRxiv2018

Gating TrkB switch by methylglyoxal enables GLO1 as a target for depression

The endogenous metabolite methylglyoxal (MGO) has recently emerged as a potential mediator of psychiatric disorders, such as anxiety and depression, but its precise mechanism of action remains poorly understood. Here, we find that MGO concentrations are decreased in the prefrontal cortex and hippocampus in rats subjected to chronic stress, and low-dose MGO treatment remarkedly enhances resilience to stress and alleviates depression-like symptoms. This effect is achieved by MGOs promotion on the synaptic plasticity in prefrontal cortex and hippocampus. Both in vitro and in vivo experiments show that MGO provokes the dimerization and autophosphorylation of TrkB and the subsequent activation of downstream Akt/CREB signaling, which leads to a rapid and sustained expression of brain-derived neurotrophic factor (BDNF). We further demonstrate that MGO directly binds to the extracellular domain of TrkB, but not its intracellular domain. In addition, we also identify a natural product luteolin and its derivative lutD as potent inhibitors of Glyoxalase 1 and validate their antidepressant effects in chronic stress rat models. The antidepressant role of endogenous MGO provides a new basis for the understanding and therapeutic intervention design for stress-associated mental disorders.

neuroscience↗

bioRxiv2018

ZAG-1/ZEB and EGL-44/TEAD form a negative feedback loop to safeguard the choice of cell fate

Terminal differentiation generates the specialized features and functions that allow postmitotic cells to acquire their distinguishing characteristics. This process is thought to be controlled by transcription factors called \"terminal selectors\" that directly activate a set of downstream effector genes. In Caenorhabditis elegans the differentiation of both the mechanosensory touch receptor neurons (TRNs) and the multidendritic nociceptor FLP neurons utilize the terminal selectors UNC-86 and MEC-3. The FLP neurons fail to activate TRN genes, however, because a complex of two transcriptional repressors (EGL-44/EGL-46) prevents their expression. Here we show that the ZEB family transcriptional factor ZAG-1 promotes TRN differentiation not by activating TRN genes but by preventing the expression of EGL-44/EGL-46. Since EGL-44/EGL-46 also inhibits the production of ZAG-1, these proteins form a bistable, negative feedback loop that regulates the choice between the two neuronal fates.\n\nSummary statementTranscriptional repressors regulate binary fate choices through reciprocal inhibition during terminal neuronal differentiation. Specifically, ZEB family transcription factor safeguards fate specification of touch receptor neuron by inhibiting TEA domain-containing repressor.

developmental biology↗

bioRxiv2018

Optical Imaging of Metabolic Dynamics in Animals

Direct visualization of metabolic dynamics in living tissues with high spatial and temporal resolution is essential to understanding many biological processes. Here we introduce a platform that combines deuterium oxide (D2O) probing with stimulated Raman scattering microscopy (DO-SRS) to image in situ metabolic activities. Enzymatic incorporation of D2O-derived deuterium into macromolecules generates carbon-deuterium (C-D) bonds, which track biosynthesis in tissues and can be imaged by SRS in situ. Within the broad vibrational spectra of C-D bonds, we discovered lipid-, protein-, and DNA-specific Raman shifts and developed spectral unmixing methods to obtain C-D signals with macromolecular selectivity. DO-SRS enabled us to probe de novo lipogenesis in animals, image protein biosynthesis without tissue bias, and simultaneously visualize lipid and protein metabolism and reveal their different dynamics. DO-SRS, being noninvasive, universally applicable, and cost-effective, can be adapted to a broad range of biological systems to study development, tissue homeostasis, aging, and tumor heterogeneity.

biophysics↗

bioRxiv2018

Integrating cross-linking experiments with ab initio protein-protein docking

Ab initio protein-protein docking algorithms often rely on experimental data to identify the most likely complex structure. We integrated protein-protein docking with the experimental data of chemical cross-linking followed by mass spectrometry. We tested our approach using 12 cases that resulted from an exhaustive search of the Protein Data Bank for protein complexes with cross-links identified in our experiments. We implemented cross-links as constraints based on Euclidean distance or void-volume distance. For most test cases the rank of the top-scoring near-native prediction was improved by at least two fold compared with docking without the cross-link information, and the success rates for the top 5 and top 10 predictions doubled. Our results demonstrate the delicate balance between retaining correct predictions and eliminating false positives. Several test cases had multiple components with distinct interfaces, and we present an approach for assigning cross-links to the interfaces. Employing the symmetry information for these cases further improved the performance of complex structure prediction.\n\nHighlightsO_LIIncorporating low-resolution cross-linking experimental data in protein-protein docking algorithms improves performance more than two fold.\nC_LIO_LIIntegration of protein-protein docking with chemical cross-linking reveals information on the configuration of higher order complexes.\nC_LIO_LISymmetry analysis of protein-protein docking results improves the predictions of multimeric complex structures\nC_LI

bioinformatics↗

bioRxiv2017

Genetic load and mutational meltdown in cancer cell populations

ABSRACTLarge and non-recombining genomes are prone to accumulating deleterious mutations faster than natural selection can purge (Mullers ratchet). A possible consequence would then be the extinction of small populations. Relative to most single-cell organisms, cancer cells, with large and non-recombining genomes, could be particularly susceptible to such \"mutational meltdown\". Curiously, deleterious mutations in cancer cells are rarely noticed despite the strong signals in cancer genome sequences. Here, by monitoring single-cell clones from HeLa cell lines, we characterize deleterious mutations that retard cell proliferation. The main mutational events are copy number variations (CNVs), which happen at an extraordinarily high rate of 0.29 events per cell division. The average fitness reduction, estimated to be 18% per mutation, is also very high. HeLa cell populations therefore have very substantial genetic load and, at this level, natural population would likely experience mutational meltdown. We suspect that HeLa cell populations may avoid extinction only after the population size becomes large. Because CNVs are common in most cell lines and cancer tissues, the observations hint at cancer cells vulnerability, which could be exploited by therapeutic strategies.

evolutionary biology↗

bioRxiv2017

Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans

Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the C. elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an -tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA-7 may be responsible for this destabilization.\n\nTable of Content (TOC) Highlight SummaryDifferent tubulin isotypes perform different functions in the regulation of MT structure and neurite growth, and missense mutations of tubulin genes have three types of distinct effects on MT stability and neurite growth. One -tubulin isotype appears to induce relative instability due to the lack of potential post-translational modification sites.

cell biology↗