Biology subjects

Zeng, W.

Publications and source records attributed to Zeng, W..

At least 91 records · Page 5Linked to original sources

bioRxiv2020

Structure of intact human MCU supercomplex with the auxiliary MICU subunits

The mitochondrial Ca2+ uniporter (MCU) supercomplex is essential for mitochondrial Ca2+ uptake. Here, we present high-resolution cryo-EM structures of human MCU-EMRE supercomplex (MES, 3.41 [A]) and MCU-EMRE-MICU1-MICU2 supercomplex (MEMMS, 3.64 [A]). MES adopts a V-shaped dimer architecture comprising two hetero-octamers, and a pair of MICU1-MICU2 hetero-dimers form a bridge across the two halves of MES to constitute an O-shaped architecture of MEMMS. The MES and MEMMS pore profiles are almost identical, with Ca2+ in the selectivity filters and no obstructions, indicating both channels are conductive. Contrary to the current model in which MICUs block the MCU pore, MICU1-MICU2 dimers are located on the periphery of the MCU pores and do not occlude them. However, MICU1-MICU2 dimers may modulate MCU gating by affecting the matrix gate through the EMRE lever.

molecular biology↗

bioRxiv2020

Transmission dynamics of 2019 novel coronavirus (2019-nCoV)

RationaleSeveral studies have estimated basic production number of novel coronavirus pneumonia (NCP). However, the time-varying transmission dynamics of NCP during the outbreak remain unclear. ObjectivesWe aimed to estimate the basic and time-varying transmission dynamics of NCP across China, and compared them with SARS. MethodsData on NCP cases by February 7, 2020 were collected from epidemiological investigations or official websites. Data on severe acute respiratory syndrome (SARS) cases in Guangdong Province, Beijing and Hong Kong during 2002-2003 were also obtained. We estimated the doubling time, basic reproduction number (R0) and time-varying reproduction number (Rt) of NCP and SARS. Measurements and main resultsAs of February 7, 2020, 34,598 NCP cases were identified in China, and daily confirmed cases decreased after February 4. The doubling time of NCP nationwide was 2.4 days which was shorter than that of SARS in Guangdong (14.3 days), Hong Kong (5.7 days) and Beijing (12.4 days). The R0 of NCP cases nationwide and in Wuhan were 4.5 and 4.4 respectively, which were higher than R0 of SARS in Guangdong (R0=2.3), Hongkong (R0=2.3), and Beijing (R0=2.6). The Rt for NCP continuously decreased especially after January 16 nationwide and in Wuhan. The R0 for secondary NCP cases in Guangdong was 0.6, and the Rt values were less than 1 during the epidemic. ConclusionsNCP may have a higher transmissibility than SARS, and the efforts of containing the outbreak are effective. However, the efforts are needed to persist in for reducing time-varying reproduction number below one. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSSince December 29, 2019, pneumonia infection with 2019-nCoV, now named as Novel Coronavirus Pneumonia (NCP), occurred in Wuhan, Hubei Province, China. The disease has rapidly spread from Wuhan to other areas. As a novel virus, the time-varying transmission dynamics of NCP remain unclear, and it is also important to compare it with SARS. What This Study Adds to the FieldWe compared the transmission dynamics of NCP with SARS, and found that NCP has a higher transmissibility than SARS. Time-varying production number indicates that rigorous control measures taken by governments are effective across China, and persistent efforts are needed to be taken for reducing instantaneous reproduction number below one.

systems biology↗

bioRxiv2019

Functional Vagotopy in the Cervical Vagus Nerve of the Domestic Pig: Implications for Vagus Nerve Stimulation

Given current clinical interest in vagus nerve stimulation, there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the domestic pig, whose vagus nerve organization and size approximates the human cervical vagus nerve. We provide data on key features across the cervical vagus nerve including diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for vagus nerve stimulation with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the cervical vagus nerve. This often leads to a distinct bimodal organization, or vagotopy that may be advantageous to exploit in design of electrodes/stimulation paradigms. Finally, we placed our data in context of historic and recent histology spanning mouse, rat, canine, pig, non-human primate and human models, thus providing a comprehensive resource to understand similarities and differences across species.

neuroscience↗

bioRxiv2019

Characterization of xyloglucan-specific fucosyltransferase activity in Golgi-enriched microsomal preparations from wheat seedlings

Xyloglucan (XyG) is a major hemicellulosic polymer in primary cell walls of dicotyledonous plants but represents only a minor constituent of cell walls from graminaceous monocotyledons (Poaceae). Our current information on XyG biosynthesis in vitro comes exclusively from studies on dicotyledonous plants. While XyG has been reported in grass cell walls, there are no studies of XyG biosynthesis in vitro in grasses. In this report, we investigated XyG structure and biosynthesis in etiolated wheat seedlings and showed that their walls contain small amounts (4-14%) of XyG. Furthermore, structural analysis using electrospray ionization mass spectrometry (ESI-MS) and high pH anion exchange chromatography (HPAEC) revealed that wheat XyG may be of XXGGG-type. Interestingly, detergent extracts from root microsomes were able to fucosylate tamarind XyG in vitro in a similar way as fucosyltransferase activity from Arabidopsis thaliana (AtFUT1) and pea (PsFUT1). Endoglucanase digestion of the [14C]fucosylated-tamarind XyG formed by the wheat fucosyltransferase activity released radiolabeled oligosaccharides that co-eluted with authentic fucoslyated XyG oligosaccharides (XXFG and XLFG). Although wheat fucosyltransferase activity was low, it appeared to be specific to XyG and required divalent ions (Mg2+ or Mn2+) for full activity. Together, these results suggest that the XyG fucosylation mechanism is conserved between monocots and dicots.

biochemistry↗

bioRxiv2019

Vaccine-specific immune responses against Mycobacterium ulcerans infection in a low-dose murine challenge model

The neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue with Mycobacterium ulcerans. There is no effective BU vaccine. Here, we assessed an experimental prime-boost vaccine in a low-dose murine tail infection model. We used the enoyl-reductase (ER) domain of the M. ulcerans mycolactone polyketide synthases electrostatically coupled with a previously described TLR-2 agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14-20 colony forming units (CFU) of an engineered bioluminescent strain of M. ulcerans. Mice receiving either the experimental ER vaccine or Mycobacterium bovis Bacille Calmette-Guerin (BCG) were equally well protected, with both groups faring significantly better than non-vaccinated animals (p<0.05). A suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were then used to interrogate the immune response data to develop disease-prognostic models. High levels of IL-2 and low IFN-{gamma} produced in the spleen best predicted control of infection across all vaccine groups. Univariate logistic regression then revealed vaccine-specific profiles of protection. High titres of ER-specific IgG serum antibodies together with IL-2 and IL-4 in the draining lymph node (DLN) were associated with protection induced by the experimental ER vaccine. In contrast, high titres of IL-6, TNF-, IFN-{gamma} and IL-10 in the DLN and low IFN{gamma} titres in the spleen were associated with protection following BCG vaccination. This study suggests an effective BU vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of infection.

immunology↗

bioRxiv2019

FAP overexpression induce Epithelial-Mesenchymal Transition (EMT) in oral squamous cell carcinoma by down-regulating DPP9 gene.

FAP acts as a tumor promoter via epithelial-mesenchymal transition (EMT) in human oral squamous cell carcinoma (OSCC). The present study was designed to investigate the interaction proteins with FAP and explore the precise mechanism of FAP promoting EMT in OSCC. IP-MS analysis confirmed that DPP9 was an interacting protein of FAP. DPP9 was down-regulated in OSCC tissue samples compared with MNT using immunohistochemistry and quantitative-PCR detection. Lower DPP9 was correlated with unfavorable overall survival of patients with OSCC. Repressing DPP9 accelerates the proliferation of OSCC cells in vitro and in vivo. Mechanistically, overexpression of FAP downregulate the expression of the DPP9 and the effect of FAP on OSCC proliferation, migration, invasion and EMT could be reversed by up-regulated DPP9. Our study suggests that FAP could induce EMT and promote carcinogenesis in oral squamous cell carcinoma by down-regulating DPP9 gene. That will hint different dimension on therapy for patients with OSCC.

molecular biology↗

bioRxiv2019

Is Vagus Stimulation Brain Washing?

Vagal nerve stimulation (VNS) is an FDA approved treatment method for intractable epilepsy, treatment resistant depression, cluster headaches and migraine with over 100,000 patients having received vagal nerve implants to date. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood and an area of active research. In parallel, the glymphatic and meningeal lymphatic systems have recently been proposed and experimentally validated to explain how the brain maintains a healthy homeostasis without a traditionally defined lymphatic system. In particular, the glymphatic system relates to the interchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) whose net effect is to wash through the brain parenchyma removing metabolic waste products and misfolded proteins from the interstitium. Of note, clearance is sensitive to adrenergic signaling, and a primary driver of CSF influx into the parenchyma appears to be cerebral arterial pulsations and respiration. As VNS has well-documented effects on cardiovascular and respiratory physiology as well as brain adrenergic signaling, we hypothesized that VNS delivered at clinically derived parameters would increase CSF influx in the brain. To test this hypothesis, we injected a low molecular weight (3 kD) lysine-fixable fluorescent tracer (TxRed) into the CSF system of mice with a cervical vagus nerve cuff implant and measured the amount of CSF penetrance following VNS. We found that the clinical VNS group showed a significant increase in CSF dye penetrance as compared to the naive control and sham groups. This study demonstrates that VNS therapeutic strategies already being applied in the clinic today may induce intended effects and/or unwanted side effects by altering CSF/ISF exchange in the brain. This may have broad ranging implications in the treatment of various CNS pathologies.\n\nOne Sentence SummaryCervical vagus nerve stimulation using clinically derived parameters enhances movement of cerebrospinal fluid into the brain parenchyma presenting a previously unreported effect of vagus nerve stimulation with potential clinical utility.

neuroscience↗

bioRxiv2019

A technology-agnostic long-read analysis pipeline for transcriptome discovery and quantification

Alternative splicing is widely acknowledged to be a crucial regulator of gene expression and is a key contributor to both normal developmental processes and disease states. While cost-effective and accurate for quantification, short-read RNA-seq lacks the ability to resolve full-length transcript isoforms despite increasingly sophisticated computational methods. Long-read sequencing platforms such as Pacific Biosciences (PacBio) and Oxford Nanopore (ONT) bypass the transcript reconstruction challenges of short reads. Here we introduce TALON, the ENCODE4 pipeline for platform-independent analysis of long-read transcriptomes. We apply TALON to the GM12878 cell line and show that while both PacBio and ONT technologies perform well at full-transcript discovery and quantification, each displayed distinct technical artifacts. We further apply TALON to mouse hippocampus and cortex transcriptomes and find that 422 genes found in these regions have more reads associated with novel isoforms than with annotated ones. We demonstrate that TALON is a capable of tracking both known and novel transcript models as well as their expression levels across datasets for both simple studies and in larger projects. These properties will enable TALON users to move beyond the limitations of short-read data to perform isoform discovery and quantification in a uniform manner on existing and future long-read platforms.

genomics↗

bioRxiv2019

Identification of NAD-dependent xylitol dehydrogenase from Gluconobacter oxydans WSH-003

Gluconobacter oxydans plays important role in conversion of D-sorbitol to L-sorbose, which is an essential intermediate for industrial-scale production of vitamin C. In the fermentation process, some D-sorbitol could be converted to D-fructose and other byproducts by uncertain dehydrogenases. Genome sequencing has revealed the presence of diverse genes encoding dehydrogenases in G. oxydans. However, the characteristics of most of these dehydrogenases remain unclear. Therefore, analyses of these unknown dehydrogenases could be useful for identifying those related to the production of D-fructose and other byproducts. Accordingly, dehydrogenases in G. oxydans WSH-003, an industrial strain used for vitamin C production, were examined. An NAD-dependent dehydrogenase, which was annotated as xylitol dehydrogenase 2, was identified, codon-optimized, and expressed in Escherichia coli BL21 (DE3) cells. The enzyme exhibited high preference for NAD+ as the cofactor, while no activity with NADP+, FAD, or PQQ was noted. Although this enzyme presented high similarity with NAD-dependent xylitol dehydrogenase, it showed high activity to catalyze D-sorbitol to D-fructose. Unlike the optimum temperature and pH for most of the known NAD-dependent xylitol dehydrogenases (30{degrees}C-40{degrees}C and about 6-8, respectively), those for the identified enzyme were 57{degrees}C and 12, respectively. The Km and Vmax of the identified dehydrogenase towards L-sorbitol were 4.92 M and 196.08 M/min, respectively. Thus, xylitol dehydrogenase 2 can be useful for cofactor NADH regeneration under alkaline conditions or its knockout can improve the conversion ratio of D-sorbitol to L-sorbose.\n\nImportanceProduction of L-sorbose from D-sorbitol by Gluconobacter oxydans is the first step for industrial scale production of L-ascorbic acid. G. oxydans contains a lot of different dehydrogenases, among which only several are responsible for the conversion of D-sorbitol to L-sorbose, while others may responsible for the accumulation of byproducts, thus decreased the yield of L-sorbose on D-sorbitol. Therefore, a new xylitol dehydrogenase has been identified from 44 dehydrogenases of G. oxydans. Optimum temperature and pH of the xylitol dehydrogenase are different to most of the known ones. Knock-out of the dehydrogenase may improve the conversion ratio of D-sorbitol to L-sorbose. Besides, the enzyme exhibits high preference for NAD+ and have potential to be used for cofactor regeneration.

bioengineering↗

bioRxiv2019

A Truly Injectable Neural Stimulation Electrode Made From an In-Body Curing Polymer/Metal Composite

Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, we have developed a novel electrode that begins as an uncured, flowable pre-polymer that can be injected around a neuroanatomical target to minimize surgical manipulation. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, we performed detailed electrochemical and microscopy characterization of its material properties and validated the feasibility of using it to electrically stimulate the nervous system in rats and swine. The silicone-metal-particle composite performed very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSCC) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of being simpler than traditional electrode designs, less invasive, and more cost-effective, the Injectrode has the potential to increase the adoption of neuromodulation therapies for existing and new indications.

bioengineering↗

bioRxiv2019

An Array of 60,000 Antibodies for Proteome-Scale Antibody Generation and Target Discovery

Antibodies are essential for elucidating the roles of genes decoded by genome sequencing. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed the Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 mAbs against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic feature of an antibody. Distinctive combinations of 10,000-20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-target pairs were discovered for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for human membrane proteins and ChIP-seq mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues discovered internalizing tumor antigens for antibody-drug conjugates. By discovering high affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.

systems biology↗

bioRxiv2018

Dynamics of microRNA expression during mouse prenatal development

MicroRNAs (miRNAs) play a critical role as post-transcriptional regulators of gene expression. The ENCODE project profiled the expression of miRNAs in a comprehensive set of tissues during a time-course of mouse embryonic development and captured the expression dynamics of 785 miRNAs. We found distinct tissue and developmental stage specific miRNA expression clusters, with an overall pattern of increasing tissue specific expression as development proceeds. Comparative analysis of conserved miRNAs in mouse and human revealed stronger clustering of expression patterns by tissue types rather than by species. An analysis of messenger RNA gene expression clusters compared with miRNA expression clusters identifies the potential role of specific miRNA expression clusters in suppressing the expression of mRNAs specific to other developmental programs in the tissue where these microRNAs are expressed during embryonic development. Our results provide the most comprehensive timecourse of miRNA expression as an integrated part of the ENCODE reference dataset for mouse embryonic development.

genomics↗

bioRxiv2018

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. However, DUX4 is lowly expressed in patient samples and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed pooled RNA-seq differentiation time-course in FSHD2 patient-derived primary myoblasts and identified early-and late-induced sets of FSHD-associated genes. Using single-cell and single-nucleus RNA-seq on FSHD2 myoblasts and myotubes respectively, we captured DUX4 expression in single-nuclei and found that only some DUX4 targets are coexpressed. We identified two populations of FSHD myotube nuclei with distinct transcriptional profiles. One population is highly enriched with DUX4 and FSHD related genes, including the DUX4 paralog DUXA ("FSHD-Hi"). The other population has no expression of DUX4 and expresses low amounts of FSHD related genes ("FSHD-Lo"), but is marked by the expression of CYTL1 and CHI3L1. "FSHD-Hi" myotube nuclei upregulated a set of transcription factors (TFs) that may form a self-sustaining network of gene dysregulation, which perpetuates this disease after DUX4 is no longer expressed.

genomics↗

bioRxiv2018

Bioluminscent Mycobacterium ulcerans, a tool to study host-pathogen interactions in a murine tail model of Buruli ulcer

Buruli ulcer is a neglected tropical disease caused by infection with Mycobacterium ulcerans. In this study we used a previously reported strain of M. ulcerans, genetically engineered to constitutively produce bioluminescence, to follow the progression of Buruli ulcer in mice using an in-vivo imaging (IVIS(R)) system. We aimed to characterize a mouse tail infection model for pathogenesis, as well as for pre-clinical vaccine and drug development research for Buruli ulcer. Immune parameters, such as antibody titers and cytokine levels, were determined throughout the course of the infection and histology specimens were examined for comparison with human pathology. Nine out of ten (90%) BALB/c mice infected subcutaneously with 105 M. ulcerans JKD8049 (containing pMV306 hsp16+luxG13) exhibited light emission from the site of infection over the course of the experiment indicating M. ulcerans growth in-vivo. Five out of ten (50%) animals developed clinical signs of disease. Antibody titers were overall low and their onset was late, as measured by responses to both heterogenous (bacterial whole cell lysate) and single antigen (Hsp18) targets. IFN-{gamma}, and IL-10 are reported to play a vital role in host control of Buruli ulcer and these cytokines were elevated in animals with pathology. For mice with advanced pathology, histology revealed clusters of acid-fast bacilli within subcutaneous tissue 300-400 m beneath the epidermis of the tail, with macrophage infiltration and granuloma-formation resembling human Buruli ulcer. This study has shown the utility of using bioluminescent M. ulcerans and IVIS(R) in a mouse tail infection model to study Buruli ulcer infection.\n\nAuthor summaryBuruli ulcer is one of the so called neglected tropical diseases. It is an infectious disease, mainly occurring in West Africa but also in Australia. It manifests as skin lesion and ulcer. Up to date, the way of transmission is inadequately understood. Also, there is no vaccine to protect against the disease. Buruli ulcer is treatable with a course of antibiotics that need to be given for the duration of two months. More laboratory research is needed to elucidate the mechanism of transmission, develop a vaccine and improve and shorten antibiotic therapy. For this, animal (mouse) models of disease are used. The aim of this study was to refine and improve the mouse tail infection model of Buruli ulcer. For this, we used a genetically modified Mycobacterium ulcerans strain that emits light. After infection of animals, light emitted from the bacteria was read out with an in-vivo imaging (IVIS) camera. This allowed us to monitor the location of bacteria in the living animal over time without the need to kill the animal. We also measured parameters of the immune system such as antibodies and cytokines as a baseline for future studies into immunology, vaccine development and pathology of Buruli ulcer. We successfully improved and characterized the mouse tail infection model in Buruli ulcer with the use of modern technology using light emitting bacteria and the IVIS camera.

microbiology↗

bioRxiv2018

Aerobic removal of microcystin-LR by a novel native effective bacterial community designated as YFMCD4 isolated from Lake Taihu

Microcystins (MCs) are a group of monocyclic heptapeptide hepatotoxins produced by species of cyanobacteria. MC-LR is the most toxic and frequently detected MCs variant in water, which poses a great threat to the natural ecosystem and public health. Its important to seek environment-friendly and cost-efficient methods to remove MC-LR. To investigate the MC-degrading capacities of a novel indigenous bacterial community designated as YFMCD4 and the influence of environmental factors including various temperatures, MC concentrations and pH on the MC-degrading activities, the concentration of MC-LR was measured by high performance liquid chromatography. In addition, the MC-degrading mechanism containing the degradation pathway and products of YFMCD4 was studied using HPLC coupled with an ultra-high resolution LTQ Orbitrap Velos Pro ETD mass spectrometry equipped with electrospray ionization interface. The data showed MC-LR can be removed at the maximum rate of 0.5 {micro}g/(ml{middle dot}h) by YFMCD4 containing Alcaligenes faecalis and Stenotrophomonas acidaminiohila. The MC-degrading rates of YFMCD4 were significantly affected by different temperatures, pH and MC-LR concentrations. Two intermediates of a tetrapeptide and Adda appeared in the degradation process. These results illustrate that the novel bacterial community YFMCD4 can remove MC-LR effectively and completely, which indicates YFMCD4 possesses a significant potential to be used in bioremediation of water bodies contaminated by MC-LR.

ecology↗

bioRxiv2018

Integrating distal and proximal information to predict gene expression via a densely con-nected convolutional neural network

MotivationInteractions among such cis-regulatory elements as enhancers and promoters are main driving forces shaping context-specific chromatin structure and gene expression. Although there have been computational methods for predicting gene expression from genomic and epigenomic information, most of them overlook long-range enhancer-promoter interactions, due to the difficulty in precisely linking regulatory enhancers to target genes. Recently, a novel high-throughput experimental approach named HiChIP has been developed and generating comprehensive data on high-resolution interactions between promoters and distal enhancers. On the other hand, plenty of studies have suggested that deep learning achieves state-of-the-art performance in epigenomic signal prediction, and thus promoting the understanding of regulatory elements. In consideration of these two factors, we integrate proximal promoter sequences and HiChIP distal enhancer-promoter interactions to accurately model gene expression.\n\nResultsWe propose DeepExpression, a densely connected convolutional neural network to predict gene expression using both promoter sequences and enhancer-promoter interactions. We demonstrate that our model consistently outperforms baseline methods not only in the classification of binary gene expression status but also in the regression of continuous gene expression levels, in both cross-validation experiments and cross-cell lines predictions. We show that sequential promoter information is more informative than experimental enhancer information while enhancer-promoter interactions are most beneficial from those within {+/-}100 kbp around the TSS of a gene. We finally visualize motifs in both promoter and enhancer regions and show the match of identified sequence signatures and known motifs. We expect to see a wide spectrum of applications using HiChIP data in deciphering the mechanism of gene regulation.\n\nAvailabilityDeepExpression is freely available at https://github.com/wanwenzeng/DeepExpression.\n\nContactruijiang@tsinghua.edu.cn, ywang@amss.ac.cn\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2018

Selecting precise reference normal tissue samples for cancer research using a deep learning approach

BackgroundNormal tissue samples are often employed as a control for understanding disease mechanisms, however, collecting matched normal tissues from patients is difficult in many instances. In cancer research, for example, the open cancer resources such as TCGA and TARGET do not provide matched tissue samples for every cancer or cancer subtype. The recent GTEx project has profiled samples from healthy individuals, providing an excellent resource for this field, yet the feasibility of using GTEx samples as the reference remains unanswered.\n\nMethodsWe analyze RNA-Seq data processed from the same computational pipeline and systematically evaluate GTEx as a potential reference resource. We use those cancers that have adjacent normal tissues in TCGA as a benchmark for the evaluation. To correlate tumor samples and normal samples, we explore top varying genes, reduced features from principal component analysis, and encoded features from an autoencoder neural network. We first evaluate whether these methods can identify the correct tissue of origin from GTEx for a given cancer and then seek to answer whether disease expression signatures are consistent between those derived from TCGA and from GTEx.\n\nResultsAmong 32 TCGA cancers, 18 cancers have less than 10 matched adjacent normal tissue samples. Among three methods, autoencoder performed the best in predicting tissue of origin, with 12 of 14 cancers correctly predicted. The reason for misclassification of two cancers is that none of normal samples from GTEx correlate well with any tumor samples in these cancers. This suggests that GTEx has matched tissues for the majority cancers, but not all. While using autoencoder to select proper normal samples for disease signature creation, we found that disease signatures derived from normal samples selected via an autoencoder from GTEx are consistent with those derived from adjacent samples from TCGA in many cases. Interestingly, choosing top 50 mostly correlated samples regardless of tissue type performed reasonably well or even better in some cancers.\n\nConclusionsOur findings demonstrate that samples from GTEx can serve as reference normal samples for cancers, especially those do not have available adjacent tissue samples. A deep-learning based approach holds promise to select proper normal samples.

bioinformatics↗

bioRxiv2018

Integrative analysis of single cell genomics data by coupled nonnegative matrix factorizations

When different types of functional genomics data are generated on single cells from different samples of cells from the same heterogeneous population, the clustering of cells in the different samples should be coupled. We formulate this \"coupled clustering\" problem as an optimization problem, and propose the method of coupled nonnegative matrix factorizations (coupled NMF) for its solution. The method is illustrated by the integrative analysis of single cell RNA-seq and single cell ATAC-seq data.\n\nSignificance StatementsBiological samples are often heterogeneous mixtures of different types of cells. Suppose we have two single cell data sets, each providing information on a different cellular feature and generated on a different sample from this mixture. Then, the clustering of cells in the two samples should be coupled as both clusterings are reflecting the underlying cell types in the same mixture. This \"coupled clustering\" problem is a new problem not covered by existing clustering methods. In this paper we develop an approach for its solution based the coupling of two nonnegative matrix factorizations. The method should be useful for integrative single cell genomics analysis tasks such as the joint analysis of single cell RNA-seq and single cell ATAC-seq data.

bioinformatics↗