Biology subjects

Xu, J.

Publications and source records attributed to Xu, J..

At least 811 records · Page 45Linked to original sources

bioRxiv2019

Developing a dengue forecast model using Long Short Term Memory neural networks method

BackgroundDengue Fever (DF) is a tropical mosquito-borne disease that threatens public health and causes enormous economic burdens worldwide. In China, DF expanded from coastal region to inner land, and the incidence sharply increased in the last few years. In this study, we conduct the analysis of dengue using the Long Short Term Memory (LSTM) recurrent neural networks. This is an artificial intelligence technology, to develop a precise dengue forecast model.\n\nMethodology/Principal FindingsThe model is developed from monthly dengue cases and local meteorological data of 2005-2018 among top 20 Chinese cities with a record of the highest dengue incidence. The first 13 year data were used to construct the LSTM and to predict the dengue outbreaks in 2018. The results are compared with the estimated dengue cases of other previously published models. Model performance and prediction accuracy were assessed using Root Mean Square Error (RMSE). With the LSTM method, the prediction measurements of average RMSE drop by 54.79% and 34.76% as compared with the Susceptible Infected Recovered (SIR) model and Zero Inflated Generalized Additive Model (ZIGAM). Our results showed that if only local data were used to develop forecast models, the LSTM neural networks would fail to capture the transmission characteristics of dengue virus in areas with fewer dengue cases. Contrarily, transfer learning (TL) can improve the accuracy of prediction of the LSTM neural network model in areas with fewer dengue incidences.\n\nConclusion and significanceThe LSTM model is beneficial in predicting dengue incidence as compared with other previously published forecasting models. The findings provide a more precise forecast dengue model, which can help the local government and health-related departments respond early to dengue epidemics.\n\nAuthor summaryIn China, DF is a public health concern that poses a great economic burden on local governments. However, the incidence has sharply increased in recent years with growth in the sub-regions. With this issue, it will be challenging to develop an accurate and timely dengue forecast model. LSTM recurrent neural networks, deep learning methods and virus propagation rules by learning from observational data offer more advantages in predicting the prevalence of infectious disease dynamics than the traditional statistical model. The 2005-2017 data of the top 20 Chinese cities with the highest dengue incidence were used to construct the LSTM model, advantageous in predicting dengue in most cities. Moreover, the model helped to predict the dengue outbreaks in 2018 and used to compare the estimated dengue cases with the RMSE results of other previously published models. A thorough search of the literature shows that this is the first established dengue forecast model using the LSTM method, which is effective in predicting the trend of dengue dynamics.

bioinformatics↗

bioRxiv2019

DeepMF: Deciphering the Latent Patterns in Omics Profiles with a Deep Learning Method

With recent advances in high-throughput technologies, matrix factorization techniques are increasingly being utilized for mapping quantitative omics profiling matrix data into low-dimensional embedding space, in the hope of uncovering insights in the underlying biological processes. Nevertheless, current matrix factorization tools fall short in handling noisy data and missing entries, both deficiencies that are often found in real-life data. Here, we propose DeepMF, a deep neural network-based factorization model. DeepMF disentangles the association between molecular feature-associated and sample-associated latent matrices, and is tolerant to noisy and missing values. It exhibited feasible subtype discovery efficacy on mRNA, miRNA, and protein profiles of medulloblastoma cancer, leukemia cancer, breast cancer, and small-blue-round-cell cancer, achieving the highest clustering accuracy of 76%, 100%, 92%, and 100% respectively. When analyzing data sets with 70% missing entries, DeepMF gave the best recovery capacity with silhouette values of 0.47, 0.6, 0.28, and 0.44, outperforming other state-of-the-art MF tools on the cancer data sets Medulloblastoma, Leukemia, TCGA BRCA, and SRBCT. Its embedding strength as measured by clustering accuracy is 88%, 100%, 84%, and 96% on these data sets, which improves on the current best methods 76%, 100%, 78%, and 87%. DeepMF demonstrated robust denoising, imputation, and embedding ability. It offers insights to uncover the underlying biological processes such as cancer subtype discovery. Our implementation of DeepMF can be found at https://gitlab.deepomics.org/jiaox96/DeepMF.

bioinformatics↗

bioRxiv2019

Stromal ISLR promotes intestinal regeneration and cancer by suppressing epithelial Hippo signaling

The YAP signaling activation in epithelial cells is essential for intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here we report a stroma-epithelia YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can directly binds to a transmembrane protocadherin FAT1 on the surface of epithelial cells. This binding suppressed the Hippo signaling by disrupting MST1-FAT1 association, resulting in YAP signaling activation. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration, and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings uncovered a molecular mechanism governing signals for communication between stroma and epithelium during tissue regeneration and tumorigenesis.

cancer biology↗

bioRxiv2019

Cryo-EM structure of the human Mixed Lineage Leukemia-1 complex bound to the nucleosome

Mixed Lineage Leukemia (MLL) family histone methyltransferases are the key enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanism by which the MLL complexes recognize histone H3K4 within the nucleosome core particle (NCP) remains unclear. Here, we report the single-particle cryo-electron microscopy (cryo-EM) structure of the human MLL1 core complex bound to the NCP. The MLL1 core complex anchors on the NCP through RbBP5 and ASH2L, which interacts extensively with nucleosomal DNA as well as the surface close to histone H4 N-terminal tail. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, allowing symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

biochemistry↗

bioRxiv2019

Crl activates transcription by stabilizing the active conformation of the master stress factor σS

{sigma}S is a master transcription initiation factor that protects bacterial cells from various harmful environmental stresses and antibiotic pressure. Although its mechanism remains unclear, it is known that full activation of {sigma}S-mediated transcription requires a {sigma}S-specific activator, Crl. In this study, we determined a 3.80 [A] cryo-EM structure of an E. coli transcription activation complex (E. coli Crl-TAC) comprising E. coli {sigma}S-RNAP holoenzyme, Crl, and a nucleic-acid scaffold. The structure reveals that Crl interacts with the domain 2 of {sigma}S ({sigma}S2), sharing no interaction with promoter DNA. Subsequent hydrogen-deuterium exchange mass spectrometry (HDX-MS) results indicate that Crl stabilizes key structural motifs of {sigma}S2 to promote the assembly of {sigma}S-RNAP holoenzyme and also to facilitate formation of the RNA polymerase-promoter DNA open complex (RPo). Our study demonstrates a unique DNA contact-independent mechanism of transcription activation, thereby defining a previously unrecognized mode of transcription activation in cells.

biochemistry↗

bioRxiv2019

Allicin regulates energy homeostasis through brown adipose tissue

Background/objectivesDisorder of energy homeostasis can lead to a variety of metabolic diseases, especially obesity. Brown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a main bioactive ingredient in garlic, has multiple biology and pharmacological function. However, the role of Allicin, in the regulation of metabolic organ, especially the role of activation of BAT, has not been well studied. Here, we analyzed the role of Allicin in whole-body metabolism and the activation of BAT.\n\nResultsAllicin had a significant effect in inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in diet-introduced obesity (DIO) mice. Then we find that Allicin can strongly activate brown adipose tissue (BAT). The activation of brown adipocyte treated with Allicin was also confirmed in mouse primary brown adipocytes.\n\nConclusionAllicin can ameliorate obesity through activating brown adipose tissue. Our findings provide a promising therapeutic approach for the treatment of obesity and metabolic disorders.

molecular biology↗

bioRxiv2019

An integrative ENCODE resource for cancer genomics

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.

genomics↗

bioRxiv2019

Higher-order patterns of aquatic species spread through the global shipping network

The introduction and establishment of non-indigenous species (NIS) through global ship movements is a significant threat to marine ecosystems and economies. While ballast-vectored invasions have been partly addressed by some national policies and an international agreement regulating the concentrations of organisms in ballast water, biofouling-vectored invasions remain a large risk. Development of additional realistic and cost-effective ship-borne NIS policies requires an accurate estimation of NIS spread risk from both ballast water and biofouling. In this paper, we demonstrate that first-order Markov assumptions limit accurate modeling of NIS spread risks through the global shipping network. In contrast, we show that higher-order patterns overcome this limitation by revealing indirect pathways of NIS transfer. We accomplish this by developing Species Flow Higher-Order Networks (SF-HON), which we developed independently for ballast and biofouling, for comparison with first-order Markovian models of ballast and biofouling. We evaluated SF-HON predictions using the largest available datasets of invasive species for Europe and the United States. We show that not only does SF-HON yield more accurate NIS spread risk predictions than first-order models and existing higher-order models, but also that there are important differences in NIS spread via the ballast and biofouling vectors. Our work provides information that policymakers can use to develop more efficient and targeted prevention strategies for ship-borne NIS spread management, especially as management of biofouling is of increasing concern.

ecology↗

bioRxiv2019

PALM-Seq: simultaneous sequencing of cell-free long RNA and small RNA

Cell-free RNA, including both long RNA and small RNA, has been considered important for its biological functions and potential clinical usage, but the major challenge is to effectively sequence them at the same time. Here we present PolyAdenylation Ligation Mediated-Seq (PALM-Seq), an integrated sequencing method for cell-free long and small RNA. Through terminal modification and addition of 3 polyadenylation and 5 adaptor, we could get mRNA, long non-coding RNA, microRNA, tRNA, piRNA and other RNAs in a single library. With target RNA depletion, all these RNAs could be sequenced with relatively low depth. Using PALM-Seq, we identified pregnant-related mRNAs, long non-coding RNAs and microRNAs in female plasma. We also applied PALM-Seq to sequence RNA from amniotic fluids, leukocytes and placentas, and could find RNA signatures associated with specific sample type. PALM-Seq provides an integrated, cost-effective and simple method to characterize the landscape of cell-free RNA, and can stimulate further progress in cell-free RNA study and usage.

molecular biology↗

bioRxiv2019

Using a bar-coded AAV capsid library to select for novel clinically relevant gene therapy vectors

ABSTRACTWhile gene transfer using recombinant adeno-associated viral (rAAV) vectors have shown success in some clinical trials, there remain many tissues that are not well transduced. Because of the recent success in reprogramming islet derived cells into functional {beta}-cells in animal models, we constructed two highly complex barcoded replication competent capsid shuffled libraries and selected for high transducing variants on primary human islets. We describe a chimeric capsid (AAV-KP1) that penetrated and transduced primary human islet cells and human embryonic stem cell derived {beta}-cells with up to 10-fold higher efficiency compared to previously studied best in class AAV vectors. Remarkably, this chimeric capsid was also able to transduce both mouse and human hepatocytes at very high levels in a humanized-chimeric mouse model, thus providing a versatile vector which has the potential to be used in both preclinical testing and human clinical trials for both liver-based diseases and diabetes.

genetics↗

bioRxiv2019

Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL

Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. The pathological drivers for ccRCC are still poorly understood. One of them is the Ras family of small GTPases that function as \"molecular switches\" in many diseases including ccRCC. Among them, Di-Ras2 encodes a 26-kDa GTPase that shares 60% homology to Ras and Rap. Yet little is known about the biological function(s) of Di-Ras2. In this study, we found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel-Lindau (VHL). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the MAPK signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, VHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene and biomarker in ccRCC, and these data provide a new perspective of the relationship between VHL and the MAPK pathway in ccRCC tumorigenesis.

cancer biology↗

bioRxiv2019

No evidence for motor recovery-related cortical reorganization after stroke using resting-state fMRI

Cortical reorganization has been suggested as mechanism for recovery after stroke. It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state fMRI. Here we report the largest longitudinal data-set in terms of overall sessions in 19 patients with subcortical stroke and 11 controls. Patients were imaged up to 5 times over one year. We found no evidence for post-stroke cortical reorganization despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here we argue instead that they are consistent with other emerging reasons to challenge the idea of motor recovery-related cortical reorganization post-stroke when conceived as changes in connectivity between cortical areas.

neuroscience↗

bioRxiv2019

Different Expressions of IL-1 TNF-α P-selectin mRNA by Endothelial Cells after Vein Thrombosis

[Abstract]O_ST_ABSObjectiveC_ST_ABSExperiments were designed to compare the expressions of IL-1 TNF- P-selectin mRNA by porcine endothelial cells after vein thrombosis.\n\nMethodsIVC under the renal vein of 20 porcines were ligated to induce thrombosis modes. These thrombosed veins were divided into three groups:group A-one day after thrombosis, group B-four days after thrombosis and group C-seven days after thrombosis. The other pigs were given the shame operation as a contro group (group D). The mRNA levels of IL-1 TNF- and P-selectin expressed by porcine endothelial cells in three groups were analy sed by semi quantitative RT-PCR. Endothelial cells were harvested with collagenase II.\n\nResultsThe purity of endothelial cells harvested was 99.42 {+/-}0.07. The expression of IL-1 was detained only in group A while TNF-reached its peak in group B(P <0.05) and P-selectin increased gradually with the days passing by(P <0.05).\n\nConclusionEndothelial cells are not only the target cells of inflammatory mediators, but also can express a variety of active factors to promote venous thrombosis. Expression of TNF- mRNA is increased gradually in the early period of vein thrombosis while P-selectin in the acute period; IL-1 mRNA was transiently expressed only in the early stage of thrombosis.

microbiology↗

bioRxiv2019

Assessment of the gene expression profiles of leukocytes from different isolations

BACKGROUNDResearch on peripheral leukocyte gene expression in human health and disease is growing rapidly. However, how to process sample efficiently, simply and stably, and how to reflect human physiological state preferably remains critical issues in large cohort studies.\n\nMETHODSWe used RNA-seq to explore the differences of gene expression profiles among whole blood (WB) and three groups of leukocytes from buffy coat (BC) extraction, red blood cell (RBC) lysis and peripheral blood mononuclear cell (PBMC) isolation.\n\nRESULTSThe residual globin mRNA in leukocytes from RBC lysis (1.00% {+/-}1.23%) and PBMC isolation (0.06% {+/-} 0.03%) was much less than that in leukocytes from BC extraction (17.48% {+/-} 6.95%) and WB (24.46% {+/-} 6.43%), resulting in higher transcriptome mapping rates and larger numbers of detected genes. The expression of 616 genes associated with leukocyte function was slightly higher in leukocytes from RBC lysis than that from BC extraction and WB, but barely detected in leukocytes from PBMC isolation.\n\nCONCLUSIONSWe suggest that sample processing based on RBC lysis could allow better applications of gene expression profiling of peripheral leukocytes in large cohort studies.

molecular biology↗

bioRxiv2019

TET1 and TDG suppress intestinal tumorigenesis by down regulating the inflammatory and immune response pathways

IntroductionAberrant DNA methylation is frequently observed in colorectal cancer (CRC), but the underlying mechanisms are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and DNA repair enzyme Thymine DNA Glycosylase (TDG) are involved in active DNA demethylation by generating and removing, respectively, novel oxidized cytosine species. Mutations of TET1 and TDG, and alterations of the levels of oxidized cytosine species have been identified in human CRC cases, but the biological significance of the TET-TDG demethylation axis in intestinal tumorigenesis is unclear.\n\nMaterial and MethodsWe generated ApcMin mice with additional inactivation of Tet1 and/or Tdg, and characterized the methylome and transcriptome of intestinal adenomas by DREAM and RNA sequencing, respectively.\n\nResultsTet1- and/or Tdg-deficient ApcMin mice show enhanced intestinal tumorigenesis in comparison to wild type Tet1 and Tdg ApcMin mice. Specifically, Tet1 and/or Tdg-deficient ApcMin adenomas manifested increased size or features of erosion and stroma activation. Methylome analysis revealed progressive loss of global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-deficient ApcMin mice, and hypermethylation of CpG islands in Tet1-deficient ApcMin mice. In addition, RNA sequencing showed upregulation of genes in inflammatory and immune response pathways in Tet1-and Tdg-mutant colonic adenomas compared to control ApcMin adenomas.\n\nConclusionsTaken together, these findings demonstrate the important role of active DNA demethylation mediated by TET-TDG in reducing intestinal tumor formation, by modulating the epigenome and inflammatory/immune responses. This study highlights a novel mechanism of epigenetic deregulation during intestinal tumorigenesis with diagnostic, therapeutic and prognostic implications.

cancer biology↗

bioRxiv2019

Enhancer-dependence of gene expression increases with developmental age

How overall principles of gene regulation (the \"logic\") may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic and topological profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1 and Myb occupancy. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes employ distal enhancers for long-range regulation through enhancer-promoter looping, confirmed by Gata1 HiChIP. Genome editing demonstrated distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer-dependence of transcription, we observed a progressive reliance on enhancer control with increasing age of ontogeny among diverse primary cells and tissues of mouse and human origin. Our findings highlight fundamental and conserved differences in regulatory logic at distinct developmental stages, characterized by simpler promoter-centric regulation in embryonic cells and combinatorial enhancer-driven control in adult cells.\n\nHighlightsO_LIRegulation of embryonic-specific erythroid genes is promoter-centric through Gata1\nC_LIO_LIAdult-specific control is combinatorial enhancer-driven and requires Myb\nC_LIO_LIAdult specific genes have increased enhancer-promoter chromatin interactions\nC_LIO_LIEnhancer-dependence increases progressively with increasing developmental age\nC_LI

molecular biology↗

bioRxiv2019

Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis

Aberrant chromatin structure is a hallmark in cancer cells and has long been used for clinical diagnosis of cancer. However, underlying higher-order chromatin folding during malignant transformation remains elusive, due to the lack of molecular scale resolution. Using optimized stochastic optical reconstruction microscopy (STORM) for pathological tissue (PathSTORM), we uncovered a gradual decompaction and fragmented higher-order chromatin folding throughout all stages of carcinogenesis in multiple tumor types, even prior to the tumor formation. Our integrated imaging, genomic, and transcriptomic analyses reveal the functional consequences in enhanced formation of transcription factories, spatial juxtaposition with relaxed nanosized chromatin domains and impaired genomic stability. We also demonstrate the potential of imaging higher-order chromatin decompaction to detect high-risk precursors that cannot be distinguished by conventional pathology. Taken together, our findings reveal the gradual decompaction and fragmentation of higher-order chromatin structure as an enabling characteristic in early carcinogenesis to facilitate malignant transformation, which may improve cancer diagnosis, risk stratification, and prevention.\n\nSIGNIFICANCEGenomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability. Although much progress has been made on understanding biochemical characteristics of epigenetic modifications in cancer, the higher-order folding of chromatin structure remains largely unknown. Using optimized super-resolution microscopy, we uncover de-compacted and fragmented chromatin folding in tumor initiation and stepwise progression in multiple tumor types, even prior to the presence of tumor cells. This study underlines the significance of unfolding higher-order chromatin structure as an enabling characteristic to promote tumorigenesis, which may facilitate the development and evaluation of new preventive strategies. The potential of imaging higher-order chromatin folding to improve cancer detection and risk stratification is demonstrated by detecting high-risk precursors that cannot be distinguished by conventional pathology.

cancer biology↗

bioRxiv2019

Functional classification of noncoding RNAs associated with distinct histone modifications by PIRCh-seq

Many long noncoding RNAs (lncRNAs) regulate gene transcription through binding to histone modification complexes. Therefore, a comprehensive study of nuclear RNAs in a histone modification-specific manner is critical to understand their regulatory mechanisms. Here we develop a method named Profiling Interacting RNAs on Chromatin by deep sequencing (PIRCh-seq), in which we profile chromatin-associated transcriptome in 5 different cell types using antibodies recognizing histone H3 and 6 distinct histone modifications associated with active or repressive chromatin states. PIRCh-seq identified chromatin-associated RNAs with substantially less contamination by nascent transcripts, as compared to existing methods. We classified chromatin-enriched lncRNAs into 6 functional groups based on the patterns of their association with specific histone modifications. LncRNAs were enriched with different chromatin modifications in different cell types, suggesting lncRNAs regulation may also be cell type-specific. By integrating profiles of RNA secondary structure and RNA m6A modification, we found that RNA bases which bind to chromatin tend to be more single stranded. We discovered hundreds of allele-specific RNA-chromatin interactions, nominating specific single nucleotide variants that alter RNA association with chromatin. These results provide a unique resource to globally study the functions of chromatin-associated lncRNAs and elucidate the basic mechanisms of chromatin-RNA interaction.

cell biology↗