Biology subjects

Cheng, S.

Publications and source records attributed to Cheng, S..

179 records · Page 10Linked to original sources

bioRxiv2019

The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

BACKGROUNDAfter long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.\n\nMETHODSImmunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling.\n\nRESULTSYAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development.\n\nCONCLUSIONSThe expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.

cancer biology↗

bioRxiv2019

An ancestral signalling pathway is conserved in plant lineages forming intracellular symbioses

Plants are the foundation of terrestrial ecosystems and their colonization of land was facilitated by mutualistic associations with arbuscular mycorrhizal fungi. Following that founding event, plant diversification has led to the emergence of a tremendous diversity of mutualistic symbioses with microorganisms, ranging from extracellular associations to the most intimate intracellular associations, where fungal or bacterial symbionts are hosted inside plant cells. Through analysis of 271 transcriptomes and 122 plant genomes, we demonstrate that the common symbiosis signalling pathway controlling the association with arbuscular mycorrhizal fungi and with nitrogen-fixing bacteria specifically co-evolved with intracellular endosymbioses, including ericoid and orchid mycorrhizae in angiosperms and ericoid-like associations of bryophytes. In contrast, species forming exclusively extracellular symbioses like ectomycorrhizae or associations with cyanobacteria have lost this signalling pathway. This work unifies intracellular symbioses, revealing conservation in their evolution across 450 million years of plant diversification.

plant biology↗

bioRxiv2019

Deep spectral learning for label-free optical imaging oximetry with uncertainty quantification

Measurement of blood oxygen saturation (sO2) by optical imaging oximetry provides invaluable insight into local tissue functions and metabolism. Despite different embodiments and modalities, all label-free optical imaging oximetry utilize the same principle of sO2-dependent spectral contrast from hemoglobin. Traditional approaches for quantifying sO2 often rely on analytical models that are fitted by the spectral measurements. These approaches in practice suffer from uncertainties due to biological variability, tissue geometry, light scattering, systemic spectral bias, and variations in experimental conditions. Here, we propose a new data-driven approach, termed deep spectral learning (DSL) for oximetry to be highly robust to experimental variations, and more importantly to provide uncertainty quantification for each sO2 prediction. To demonstrate the robustness and generalizability of DSL, we analyze data from two visible light optical coherence tomography (vis-OCT) setups across two separate in vivo experiments in rat retina. Predictions made by DSL are highly adaptive to experimental variabilities as well as the depth-dependent backscattering spectra. Two neural-network-based models are tested and compared with the traditional least-squares fitting (LSF) method. The DSL-predicted sO2 shows significantly lower mean-square errors than the LSF. For the first time, we have demonstrated en face maps of retinal oximetry along with pixel-wise confidence assessment. Our DSL overcomes several limitations in the traditional approaches and provides a more flexible, robust, and reliable deep learning approach for in vivo non-invasive label-free optical oximetry.

bioengineering↗

bioRxiv2019

A Pandas complex adapted for piRNA-guided transposon silencing

The repression of transposons by the Piwi-interacting RNA (piRNA) pathway is essential to protect animal germ cells. In Drosophila ovaries, Panoramix (Panx) enforces transcriptional silencing by binding to the target-engaged Piwi-piRNA complex, although the precise mechanisms by which this occurs remain elusive. Here, we show that Panx functions together with a germline specific paralogue of a nuclear export factor, dNxf2, and its cofactor dNxt1 (p15), as a ternary complex to suppress transposon expression. Structural and functional analyses demonstrate that dNxf2 binds Panx via its UBA domain, which plays an important role in transposon silencing. Unexpectedly, dNxf2 interacts directly with dNxf1 (TAP), a general nuclear export factor. As a result, dNxf2 prevents dNxf1 from binding to the FG repeats of the nuclear pore complex, a process required for proper RNA export. Transient tethering of dNxf2 to nascent transcripts leads to their nuclear retention. Therefore, we propose that dNxf2 may function as a Pandas (Panoramix-dNxf2 dependent TAP/p15 silencing) complex, which counteracts the canonical RNA exporting machinery and restricts transposons to the nuclear peripheries. Our findings may have broader implications for understanding how RNA metabolism modulates epigenetic gene silencing and heterochromatin formation.

molecular biology↗

bioRxiv2019

Draft genome sequence of the Solanum aethiopicum provides insights into disease resistance, drought tolerance and the evolution of the genome

BackgroundS. aethiopicum is a close relative to S. melongena and has been routinely used to improve disease resistance in S. melongena. However, these efforts have been greatly limited by the lack of a reference genome and the clear understanding of the genes involved during biotic and abiotic stress response. ResultsWe present here a draft genome assembly of S. aethiopicum of 1.02 Gb in size, which is predominantly occupied by repetitive sequences (76.2%), particularly long terminal repeat elements. We annotated 37,681 gene models including 34,905 protein-coding genes. We observed an expansion of resistance genes through two rounds of amplification of LTR-Rs, occurred around 1.25 and 3.5 million years ago, respectively. The expansion also occurred in gene families related to drought tolerance. A number of 14,995,740 SNPs are identified by re-sequencing 65 S. aethiopicum genotypes including "Gilo" and "Shum" accessions, 41,046 of which are closely linked to resistance genes. The domestication and demographic history analysis reveals selection of genes involved in drought tolerance in both "Gilo" and "Shum" groups. A pan-genome of S. aethiopicum with a total of 36,250 protein-coding genes was assembled, of which 1,345 genes are missing in the reference genome. ConclusionsOverall, the genome sequence of S. aethiopicum increases our understanding of the genomic mechanisms of its extraordinary disease resistance and drought tolerance. The SNPs identified are available for potential use by breeders. The information provided here will greatly accelerate the selection and breeding of the African eggplant as well as other crops within the Solanaceae family.

genomics↗

bioRxiv2019

De novo assembly of the Mongolian gerbil genome and transcriptome

BACKGROUNDThe Mongolian gerbil (Meriones unguiculatus) has historically been used as a model organism for the auditory and visual systems, stroke/ischemia, epilepsy and aging related research since 1935 when laboratory gerbils were separated from their wild counterparts. In this study we report genome sequencing, assembly, and annotation further supported by transcriptome data from 27 different tissues samples. FINDINGSThe genome was assembled using Illumina HiSeq 2000 and resulted in a final genome size of 2.54 Gbp with contig and scaffold N50 values of 31.4 Kbp and 500.0 Kbp, respectively. Based on the k-mer estimated genome size of 2.48 Gbp, the assembly appears to be complete. The genome annotation was supported by transcriptome data that identified 36 019 predicted protein-coding genes across 27 tissue samples. A BUSCO search of 3023 mammalian groups resulted in 86% of curated single copy orthologs present among predicted genes, indicating a high level of completeness of the genome. CONCLUSIONSWe report a de novo assembly of the Mongolian gerbil genome that was further enhanced by annotation of transcriptome data from several tissues. Sequencing of this genome increases the utility of the gerbil as a model organism, opening the availability of now widely used genetic tools. The data sets supporting the results of this article are available in the China National GeneBank CNSA repository, Accession id: CNP0000340.

genomics↗

bioRxiv2019

Low-dose IFN-γ induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer

Interferon-{gamma} (IFN-{gamma}) is conventionally recognized as an inflammatory cytokine that play a central role in antitumor immunity. Clinically, although has been used clinically to treat a variety of malignancies, low-level IFN-{gamma} in the tumor microenvironment (TME) increases the risk of tumor metastasis during immunotherapy. Accumulating evidence has suggested that IFN-{gamma} can induce cancer progression. The mechanisms underlying the controversial role of IFN-{gamma} regulating tumor development remain unclear. Herein, we firstly revealed a dose-dependent effect of IFN-{gamma} in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Mechanically, low-level IFN-{gamma} endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high-level IFN-{gamma} activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells induced by the low dose of IFN-{gamma} both in vitro and in vivo. Our study first defines the role of low-level IFN-{gamma} in conferring tumor stemness and clearly elucidate the distinct signaling pathways activated by IFN-{gamma} in a dose-dependent manner, providing new insights into cancer treatment, particularly patients with low-level IFN-{gamma} expression in the TME.

cancer biology↗

bioRxiv2019

From the clinic to the bench and back again in one dog year: identifying new treatments for sarcoma using a cross-species personalized medicine pipeline

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identifying personalized treatments; however, for rare cancers, such as sarcomas, access to patient samples can be extremely limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up less than 1% of all cancers in humans, sarcomas represent at least 15% of all cancers in dogs. Dogs with naturally-occurring sarcomas also have intact immune systems, an accelerated pace of cancer progression, and share the same environment as humans, making them ideal models that bridge key gaps between mouse models and human sarcomas.\n\nHere, we develop a framework for a personalized medicine pipeline that integrates drug screening, validation, and genomics to identify new therapies. We tested this paradigm through the study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. By integrating patient-derived cancer models, in vitro drug screens, and in vivo validation we identified proteasome inhibitors as a potential therapy for Teddy. After showing an initial response to the proteasome inhibitor, bortezomib, Teddy developed rapid resistance, and tumor growth resumed. Whole exome sequencing revealed substantial genetic heterogeneity across Teddys multiple recurrent tumors and metastases, suggesting that intra-patient heterogeneity was responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas can offer rapid insights into the process of developing personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.

cancer biology↗

bioRxiv2019

Frequency of mutations in 21 hereditary breast and ovarian cancer susceptibility genes among high-risk Chinese individuals

PurposeTo determine the prevalence and clinical prediction factors associated with deleterious mutations among 882 high-risk Chinese individuals who underwent multigene panel testing for hereditary breast and ovarian cancer (HBOC) risk assessment.\n\nExperimental DesignSubjects were selected from individuals referred for genetic testing using a 21-gene panel (Oseq-BRCA) between January 2015 and March 2018. The distribution and prevalence of deleterious mutations were analyzed for the full cohort as well as subtypes.\n\nResultsOverall, 176 deleterious mutations were observed in 19.50% (n = 172) individuals. Of these, 26 mutations are not reported in public databases and literatures. In the ovarian cancer only subgroup, 115 deleterious mutations were identified in 429 patients (48.6%). Patients with ovarian cancer with mutations were enriched for a family history of breast or ovarian cancers (p < 0.05). In the breast cancer only subgroup, 31 deleterious mutations were identified in 261 patients. Most mutations occurred in BRCA1 (8; 25.8%) and BRCA2 (11; 35.5%). An additional 12 deleterious mutations (38.7%) were found in 7 other susceptibility genes. An increased frequency of mutation rate (57.9%) was observed in the subgroup of subjects with histories of both breast and ovarian cancer.\n\nConclusions19.50% of individuals carried a deleterious mutation in HBOC susceptibility genes in our cohort. Subgroup of subjects with histories of both breast and ovarian cancer had the highest prevalence of mutations. Our results highlighted the genetic heterogeneity of HBOC and the efficiency of multigene panel in performing risk assessment.

cancer biology↗

bioRxiv2018

A new family of neural wiring receptors across bilaterians defined by phylogenetic, biochemical and structural evidence

The evolution of complex nervous systems was accompanied by the expansion of groups of protein families, most notably cell adhesion molecules, surface receptors and their ligands. These proteins mediate axonal guidance, synapse targeting, and other neuronal wiring-related functions. Recently, members of a set of thirty interacting cell surface proteins belonging to two newly defined families of the immunoglobulin superfamily (IgSF) in fruit flies were discovered to label different subsets of neurons in the brain and ventral nerve cord. They have been shown to be involved in synaptic targeting and morphogenesis, retrograde signaling, and neuronal survival. Here we show that these proteins, denoted as Dprs and DIPs, belong to a family of two and three-Ig domain molecules in bilaterians generally known for neuronal wiring functions. In protostomes, the ancestral Dpr/DIP gene has duplicated to form heterophilic partners, such as Dprs and DIPs, while in deuterostomes, they have evolved to create the IgLON family of neuronal receptors. In support of this phylogeny, we show that IgLONs interact with each other, and that their complexes can be broken by mutations designed using homology models based on Dpr and DIP structures. Similarly, the nematode orthologs ZIG-8 and RIG-5 can form heterophilic and homophilic complexes structurally matching Dpr-DIP and DIP-DIP complexes. The evolutionary, biochemical and structural relationships we demonstrate here provides insights into neural development and the rise of complexity in metazoans.\n\nSignificance StatementCell surface receptors assign and display unique identities to neurons, and direct proper and robust wiring of neurons to create functional neural circuits. Recent work has identified two new classes of receptors in fruit flies, called the Dpr and DIP families with 30 members, which interact in 38 pairwise combinations. These proteins are implicated in neural identity, wiring and survival in many parts of the fly nervous system. Here, using evolutionary, biochemical and structural evidence, we show that Dprs and DIPs are members of an ancient bilaterian family of receptors. Members of this family share functional roles relevant to wiring across species, and are likely crucial in the emergence of the bilaterian nervous systems common to vertebrate and invertebrate animals.

biochemistry↗

bioRxiv2018

Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre- and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment \"in patient\" TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target.\n\nOne Sentence SummaryCellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer both in vitro and in patient.

cancer biology↗

bioRxiv2018

GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.\n\nMethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n=15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.\n\nResultsWe identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top association in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was for intronic SNP rs3922344 (P= 8.56x10-26) in SCN5A/SCN10A. Three additional previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.\n\nConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

genetics↗

bioRxiv2018

Sensing Plant Physiology and Environmental Stress by Automatically Tracking Fj and Fi Features in PSII Chlorophyll Fluorescence Induction

Following a step excitation, chlorophyll fluorescence (ChlF) from photosystem II of a dark-adapted plant leaf exhibits the well-known OJIP pattern. The OJIP induction has been widely applied in plant science, agriculture engineering, and environmental engineering. While the J and I phases are related to transitions of photochemical reaction redox states, characteristic fluorescence intensities for the two phases (Fj and Fi) are often treated as fixed time points in routine measurement and thus do not account for variations in plant and experimental conditions, which (1) neglects the time differences, potentially useful information for characterizing plant status and environmental factors, and (2) leads to errors in measured Fj and Fi values. In this work, a method for consistent measurement of Fj and Fi was developed through polynomial fitting and curvature analysis. The method measures the curvatures in the OJIP curve and automatically tracks the characteristic transition points under variable sample and experimental conditions. Experiments were carried out to demonstrate the concept and classification capabilities of the developed method. This research established a new framework to analyze ChlF and enhanced the applications of ChlF.

plant biology↗

bioRxiv2018

Transcriptome analysis of Culter alburnus gonad tissues for discovery of sex-related genes

Culter alburnus is an important commercially fish species for freshwater breeding in China, and the females grow faster than the males. However, the molecular genetic mechanism of sex determination in C.alburnus is still poorly characterized. Here, we performed de novo assembly of a transcriptome from adult fish tissues of different gender using short read sequencing technology (Illumina). Our results showed that a total of 364,650 unigenes using Trinity software were obtained, giving rise to an average of 561.92 bp per read. Among them, 70,215 sequences matched known genes, including 5,892 male-biased unigenes and 942 female-biased unigenes. Many sex-related genes and pathways were identified based on annotation information. These results would provide new insights into the genetic mechanism of C.alburnus sex determination and also establish an important foundation for further research on aquaculture breeding.

bioinformatics↗

bioRxiv2018

Spatial transcriptomics and in silico random pooling identify novel dopamine neuron subtype markers

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinsons Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation and well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were downregulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

neuroscience↗

bioRxiv2017

Integrative Single-Cell Analysis By Transcriptional And Epigenetic States In Human Adult Brain

Detailed characterization of the cell types comprising the highly complex human brain is essential to understanding its function. Such tasks require highly scalable experimental approaches to examine different aspects of the molecular state of individual cells, as well as the computational integration to produce unified cell state annotations. Here we report the development of two highly scalable methods (snDrop-Seq and scTHS-Seq), that we have used to acquire nuclear transcriptome and DNA accessibility maps for thousands of single cells from the human adult visual and frontal cortex. This has led to the best-resolved human neuronal subtypes to date, identification of a majority of the non-neuronal cell types, as well as the cell-type specific nuclear transcriptome and DNA accessibility maps. Integrative analysis allowed us to identify transcription factors and regulatory elements shaping the state of different brain cell types, and to map genetic risk factors of human brain common diseases to specific pathogenic cell types and subtypes.

genomics↗

bioRxiv2017

Generation And Comparative Analysis Of Full-Length Transcriptomes In Sweetpotato And Its Putative Wild Ancestor I. trifida

Sweetpotato [Ipomoea batatas (L.) Lam.] is one of the most important crops in many developing countries and provides a candidate source of bioenergy. However, neither high-quality reference genome nor large-scale full-length cDNA sequences for this outcrossing hexaploid are still lacking, which in turn impedes progress in research studies in sweetpotato functional genomics and molecular breeding. In this study, we apply a combination of second- and third-generation sequencing technologies to sequence full-length transcriptomes in sweetpotato and its putative ancestor I. trifida. In total, we obtained 53,861/51,184 high-quality transcripts, which includes 34,963/33,637 putative full-length cDNA sequences, from sweetpotato/I. trifida. Amongst, we identified 104,540/94,174 open reading frames, 1476/1475 transcription factors, 25,315/27,090 simple sequence repeats, 417/531 long non-coding RNAs out of the sweetpotato/I. trifida dataset. By utilizing public available genomic contigs, we analyzed the gene features (including exon number, exon size, intron number, intron size, exon-intron structure) of 33,119 and 32,793 full-length transcripts in sweetpotato and I. trifida, respectively. Furthermore, comparative analysis between our transcript datasets and other large-scale cDNA datasets from different plant species enables us assessing the quality of public datasets, estimating the genetic similarity across relative species, and surveyed the evolutionary pattern of genes. Overall, our study provided fundamental resources of large-scale full-length transcripts in sweetpotato and its putative ancestor, for the first time, and would facilitate structural, functional and comparative genomics studies in this important crop.

plant biology↗