Biology subjects

Zhou, J.

Publications and source records attributed to Zhou, J..

54 records · Page 3Linked to original sources

bioRxiv2018

Inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates seizures by enhancing A-type potassium currents

The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report that Hsp70 exerts an unexpected deleterious role in kainic acid (KA)-induced seizures, and inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates both acute and chronic seizures via enhancing A-type potassium currents primarily formed by Kv4 -subunits and auxiliary KChIPs. Proteosomal degradation of Kv4-KChIP4a channel complexes is enhanced by Hsp70, which can be reversed by the Hsp70 inhibitors, 2-phenylethynesulfonamide (PES) and VER-155008 (VER). In cultured hippocampal neurons, either PES or VER can increase A-type Kv4 current to suppress neuronal hyperexcitability. Mechanistically, Hsp70-CHIP complexes directly bind to the N-terminus of auxiliary KChIP4a and target Kv4-KChIP4a complexes to the proteasome. Our findings reveal a previously unrecognized role of Hsp70 in mediating degradation of Kv4-KChIP4a complexes and regulating neuronal excitability, thus highlighting a therapeutic potential for hyperexcitability-related neurological disorders through Hsp70 inhibition.

neuroscience↗

bioRxiv2017

Comparing the differentiation potential of Brachyury+ mesodermal cells generated from 3-D and 2-D culture systems

Mesodermal populations can be generated in vitro from mouse embryonic stem cells (mESCs) using three-dimensional (3-D) aggregates called embryoid bodies or two-dimensional (2-D) monolayer culture systems. Here, we investigated whether Brachyury-expressing mesodermal cells generated using 3-D or 2-D culture systems are equivalent, or instead, have different properties. Using a Brachyury-GFP/E2-Crimson reporter mESC line, we isolated Brachyury-GFP+ mesoderm cells using flow-activated cell sorting and compared their gene expression profiles and ex vivo differentiation patterns. Quantitative RT-PCR analysis showed significant up-regulation of Cdx2, Foxf1 and Hoxb1 in the Brachyury-GFP+ cells isolated from the 3-D system compared with those isolated from the 2-D system. Furthermore, using an ex vivo mouse kidney rudiment assay, we found that irrespective of their source, Brachyury-GFP+ cells failed to integrate into developing nephrons, which are derived from the intermediate mesoderm. However, Brachyury-GFP+ cells isolated under 3-D conditions appeared to differentiate into endothelial-like cells within the kidney rudiments, whereas the Brachyury-GFP+ isolated from the 2-D conditions only did so to a limited degree. The high expression of Foxf1 in the 3-D Brachyury-GFP+ cells combined with their tendency to differentiate into endothelial-like cells suggests these mesodermal cells may represent lateral plate mesoderm.

developmental biology↗

bioRxiv2017

Decoding the regulatory logic of the Drosophila male stem cell system

In the past decade, the importance of the niche to provide regulatory inputs to balance stem cell self-renewal and differentiation has become clear. However, the regulatory interplay between stem cells and their niche at the whole genome level is still poorly understood. To elucidate the mechanisms controlling stem cells and their progenies as they progress through their developmental program at the transcriptional level, we recorded the regulatory program of two independent cell lineages in the Drosophila testis stem cell model. To this end, we identified genes active in the soma or germline as well as genome-wide binding profiles of two essential transcription factors, Zfh-1 and Abd-A, expressed in somatic support cells and crucial for fate acquisition of both cell lineages. Our data identified key roles for TOR signalling, signal processing V-ATPase proton pumps and the nuclear transport engaged nucleoporins and we demonstrate their importance in controlling germline maintenance, proliferation and differentiation from the support side. To make our dataset publicly available and support quick and intuitive data mining, we generated an interactive online analysis tool. Applying our tool for comparative analysis, we uncovered conserved core gene sets of adult stem cells across species boundaries. We have tested the functional relevance of these genes in the Drosophila testis and intestine and find a striking overrepresentation of stem cell defects when the corresponding genes were depleted. In summary, our dataset and interactive platform represents a versatile tool for identifying novel gene networks active in diverse stem cell types and provides a valuable resource for elucidating the multifaceted regulatory inputs required to guide proper stem cell behaviour.

developmental biology↗

bioRxiv2017

Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease

The existence of cerebral blood flow (CBF) reductions in Alzheimers disease (AD) patients and related mouse models has been known for decades, but the underlying mechanisms and the resulting impacts on cognitive function and AD pathogenesis remain poorly understood. In the APP/PS1 mouse model of AD we found that an increased number of cortical capillaries had stalled blood flow as compared to wildtype animals, largely due to leukocytes that adhered in capillary segments and blocked blood flow. These capillary stalls were an early feature of disease development, appearing before amyloid deposits. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to an immediate increase in CBF and to rapidly improved performance in spatial and working memory tasks. Our work has thus identified a cellular mechanism that explains the majority of the CBF reduction seen in a mouse model of AD and has also demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing the leukocyte adhesion that plugs capillaries may provide a novel strategy for improving cognition in AD patients.

neuroscience↗

bioRxiv2017

Base-resolution mapping reveals distinct m1A methylome in nuclear- and mitochondrial-encoded transcripts

Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N1-methyladenosine (m1A) is a recently identified mRNA modification; however, little is known about its precise location, regulation and function. Here, we develop a base-resolution m1A profiling method, based on m1A-induced misincorporation during reverse transcription, and report distinct classes of m1A methylome in the human transcriptome. m1A in 5-UTR, particularly those at the first nucleotide of mRNA, associate with increased translation efficiency. A different subset of m1A exhibit a GUUCRA tRNA-like motif, are evenly distributed in the transcriptome and are dependent on the methyltransferase TRMT6/61A. Additionally, we show for the first time that m1A is prevalent in the mitochondrial-encoded transcripts. Manipulation of m1A level via TRMT61B, a mitochondria-localizing m1A methyltransferase, demonstrates that m1A in mitochondrial mRNA interferes with translation. Collectively, our approaches reveal distinct classes of m1A methylome and provide a resource for functional studies of m1A-mediated epitranscriptomic regulation.

biochemistry↗

bioRxiv2017

Phylostratigraphic analysis of tumor and developmental transcriptomes reveals relationship between oncogenesis, phylogenesis and ontogenesis

The question of the existence of cancer is inadequately answered by invoking somatic mutations or the disruptions of cellular and tissue control mechanisms. As such uniformly random events alone cannot account for the almost inevitable occurrence of an extremely complex process such as cancer. In the different epistemic realm, an ultimate explanation of cancer is that cancer is a reversion of a cell to an ancestral pre-Metazoan state, i.e. a cellular form of atavism. Several studies have suggested that genes involved in cancer have evolved at particular evolutionary time linked to the unicellular-multicellular transition. Here we used a refined phylostratigraphic analysis of evolutionary ages of the known genes/pathways associated with cancer and the genes differentially expressed between normal and cancer tissue as well as between embryonic and mature (differentiated) cells. We found that cancer-specific transcriptomes and cancer-related pathways were enriched for genes that evolved in the pre-Metazoan era and depleted of genes that evolved in the post-Metazoan era. By contrast an opposite relation was found for cell maturation: the age distribution frequency of the genes expressed in differentiated epithelial cells were enriched for post-Metazoan genes and depleted of pre-Metazoan ones. These findings support the atavism theory that cancer cells manifest the reactivation of an ancient ancestral state featuring unicellular modalities. Thus our bioinformatics analyses suggest that not only does oncogenesis recapitulate ontogenesis, and ontogenesis recapitulates phylogenesis, but also oncogenesis recapitulates phylogenesis. This more encompassing perspective may offer a natural organizing framework for genetic alterations in cancers and point to new treatment options that target the genes controlling the atavism transition.\n\nOne Sentence SummaryTracing cancer gene evolutionary ages revealed that cancer reverts to a pre-existing early Metazoan state.

cancer biology↗

bioRxiv2017

Leaf-GP: An Open and Automated Software Application for Measuring Growth Phenotypes for Arabidopsis and Wheat

BackgroundPlants demonstrate dynamic growth phenotypes that are determined by genetic and environmental factors. Phenotypic analysis of growth features over time is a key approach to understand how plants interact with environmental change as well as respond to different treatments. Although the importance of measuring dynamic growth traits is widely recognised, available open software tools are limited in terms of batch processing of image datasets, multiple trait analysis, software usability and cross-referencing results between experiments, making automated phenotypic analysis problematic.\n\nResultsHere, we present Leaf-GP (Growth Phenotypes), an easy-to-use and open software application that can be executed on different platforms. To facilitate diverse scientific user communities, we provide three versions of the software, including a graphic user interface (GUI) for personal computer (PC) users, a command-line interface for high-performance computer (HPC) users, and an interactive Jupyter Notebook (also known as the iPython Notebook) for computational biologists and computer scientists. The software is capable of extracting multiple growth traits automatically from large image datasets. We have utilised it in Arabidopsis thaliana and wheat (Triticum aestivum) growth studies at the Norwich Research Park (NRP, UK). By quantifying growth phenotypes over time, we are able to identify diverse plant growth patterns based on a variety of key growth-related phenotypes under varied experimental conditions.\n\nAs Leaf-GP has been evaluated with noisy image series acquired by different imaging devices and still produced reliable biologically relevant outputs, we believe that our automated analysis workflow and customised computer vision based feature extraction algorithms can facilitate a broader plant research community for their growth and development studies. Furthermore, because we implemented Leaf-GP based on open Python-based computer vision, image analysis and machine learning libraries, our software can not only contribute to biological research, but also exhibit how to utilise existing open numeric and scientific libraries (including Scikit-image, OpenCV, SciPy and Scikit-learn) to build sound plant phenomics analytic solutions, efficiently and effectively.\n\nConclusionsLeaf-GP is a comprehensive software application that provides three approaches to quantify multiple growth phenotypes from large image series. We demonstrate its usefulness and high accuracy based on two biological applications: (1) the quantification of growth traits for Arabidopsis genotypes under two temperature conditions; and (2) measuring wheat growth in the glasshouse over time. The software is easy-to-use and cross-platform, which can be executed on Mac OS, Windows and high-performance computing clusters (HPC), with open Python-based scientific libraries preinstalled. We share our modulated source code and executables (.exe for Windows; .app for Mac) together with this paper to serve the plant research community. The software, source code and experimental results are freely available at https://github.com/Crop-Phenomics-Group/Leaf-GP/releases.

plant biology↗

bioRxiv2017

CropQuant: An automated and scalable field phenotyping platform for crop monitoring and trait measurements to facilitate breeding and digital agriculture

Automated phenotyping technologies are capable of providing continuous and precise measurements of traits that are key to todays crop research, breeding and agronomic practices. In additional to monitoring developmental changes, high-frequency and high-precision phenotypic analysis can enable both accurate delineation of the genotype-to-phenotype pathway and the identification of genetic variation influencing environmental adaptation and yield potential. Here, we present an automated and scalable field phenotyping platform called CropQuant, designed for easy and cost-effective deployment in different environments. To manage infield experiments and crop-climate data collection, we have also developed a web-based control system called CropMonitor to provide a unified graphical user interface (GUI) to enable realtime interactions between users and their experiments. Furthermore, we established a high-throughput trait analysis pipeline for phenotypic analyses so that lightweight machine-learning modelling can be executed on CropQuant workstations to study the dynamic interactions between genotypes (G), phenotypes (P), and environmental factors (E). We have used these technologies since 2015 and reported results generated in 2015 and 2016 field experiments, including developmental profiles of five wheat genotypes, performance-related traits analyses, and new biological insights emerged from the application of the CropQuant platform.

plant biology↗

bioRxiv2017

Speed breeding: a powerful tool to accelerate crop research and breeding

The growing human population and a changing environment have raised significant concern for global food security, with the current improvement rate of several important crops inadequate to meet future demand [1]. This slow improvement rate is attributed partly to the long generation times of crop plants. Here we present a method called speed breeding, which greatly shortens generation time and accelerates breeding and research programs. Speed breeding can be used to achieve up to 6 generations per year for spring wheat (Triticum aestivum), durum wheat (T. durum), barley (Hordeum vulgare), chickpea (Cicer arietinum), and pea (Pisum sativum) and 4 generations for canola (Brassica napus), instead of 2-3 under normal glasshouse conditions. We demonstrate that speed breeding in fully-enclosed controlled-environment growth chambers can accelerate plant development for research purposes, including phenotyping of adult plant traits, mutant studies, and transformation. The use of supplemental lighting in a glasshouse environment allows rapid generation cycling through single seed descent and potential for adaptation to larger-scale crop improvement programs. Cost-saving through LED supplemental lighting is also outlined. We envisage great potential for integrating speed breeding with other modern crop breeding technologies, including high-throughput genotyping, genome editing, and genomic selection, accelerating the rate of crop improvement.

plant biology↗

bioRxiv2017

The pomegranate (Punica granatum L.) genome provides insights into fruit quality and ovule developmental biology

Pomegranate (Punica granatum L.) with an uncertain taxonomic status has an ancient cultivation history, and has become an emerging fruit due to its attractive features such as the bright red appearance and the high abundance of medicinally valuable ellagitannin-based compounds in its peel and aril. However, the absence of genomic resources has restricted further elucidating genetics and evolution of these interesting traits. Here we report a 274-Mb high-quality draft pomegranate genome sequence, which covers approximately 81.5% of the estimated 336 Mb genome, consists of 2,177 scaffolds with an N50 size of 1.7 Mb, and contains 30,903 genes. Phylogenomic analysis supported that pomegranate belongs to the Lythraceae family rather than the monogeneric Punicaceae family, and comparative analyses showed that pomegranate and Eucalyptus grandis shares the paleotetraploidy event. Integrated genomic and transcriptomic analyses provided insights into the molecular mechanisms underlying the biosynthesis of ellagitannin-based compounds, the color formation in both peels and arils during pomegranate fruit development, and the unique ovule development processes that are characteristic of pomegranate. This genome sequence represents the first reference in Lythraceae, providing an important resource to expand our understanding of some unique biological processes and to facilitate both comparative biology studies and crop breeding.

genomics↗

bioRxiv2017

Compressive Temporal Summation in Human Visual Cortex

Combining sensory inputs over space and time is fundamental to vision. Population receptive field models have been successful in characterizing spatial encoding throughout the human visual pathways. A parallel question--how visual areas in the human brain process information distributed over time--has received less attention. One challenge is that the most widely used neuroimaging method--fMRI--has coarse temporal resolution compared to the time-scale of neural dynamics. Here, via carefully controlled temporally modulated stimuli, we show that information about temporal processing can be readily derived from fMRI signal amplitudes in male and female subjects. We find that all visual areas exhibit sub-additive summation, whereby responses to longer stimuli are less than the linear prediction from briefer stimuli. We also find fMRI evidence that the neural response to two stimuli is reduced for brief interstimulus intervals (indicating adaptation). These effects are more pronounced in visual areas anterior to V1-V3. Finally, we develop a general model that shows how these effects can be captured with two simple operations: temporal summation followed by a compressive nonlinearity. This model operates for arbitrary temporal stimulation patterns and provides a simple and interpretable set of computations that can be used to characterize neural response properties across the visual hierarchy. Importantly, compressive temporal summation directly parallels earlier findings of compressive spatial summation in visual cortex describing responses to stimuli distributed across space. This indicates that for space and time, cortex uses a similar processing strategy to achieve higher-level and increasingly invariant representations of the visual world.\n\nSignificance statementCombining sensory inputs over time is fundamental to seeing. Two important temporal phenomena are summation, the accumulation of sensory inputs over time, and adaptation, a response reduction for repeated or sustained stimuli. We investigated these phenomena in the human visual system using fMRI. We built predictive models that operate on arbitrary temporal patterns of stimulation using two simple computations: temporal summation followed by a compressive nonlinearity. Our new temporal compressive summation model captures (1) subadditive temporal summation, and (2) adaptation. We show that the model accounts for systematic differences in these phenomena across visual areas. Finally, we show that for space and time, the visual system uses a similar strategy to achieve increasingly invariant representations of the visual world.

neuroscience↗

bioRxiv2017

Microbial community assembly differs by mineral type in the rhizosphere

Inputs of root carbon (C) fuel growth of nearby soil microorganisms. If these microbes associate with soil minerals, then mineral-microbiome complexes near roots could be a gateway towards stabilization of soil carbon and may influence the quantity and quality of persistent SOM. To investigate the interactions between roots, soil minerals, and microbes, we incubated three types of minerals (ferrihydrite, kaolinite, quartz) and a native soil mineral fraction near roots of a common Californian annual grass, Avena barbata, growing in its resident soil. We followed microbial colonization of these minerals for 2.5 months - the plants lifespan. Bacteria and fungi that colonized mineral surfaces during this experiment differed across mineral types and differed from those in the background soil, implying microbial colonization was the result of processes in addition to passive movement with water to mineral surfaces. Null model analysis revealed that dispersal limitation was a dominant factor structuring mineral-associated microbial communities for all mineral types. Once bacteria arrived at a mineral surface, capacity for rapid growth appeared important, as ribosomal copy number was significantly correlated with relative enrichment on minerals. Glomeromycota (a phylum associated with arbuscular mycorrhizal fungi) appeared to preferentially associate with ferrihydrite surfaces. The mechanisms enabling colonization of soil minerals may be foundational to the overall soil microbiome composition and partially responsible for the persistence of C entering soil via plant roots.

microbiology↗

bioRxiv2017

PGC-1α coordinates with Bcl-2 to control cell cycle in U251 cells through reducing ROS

B-cell lymphoma 2 (Bcl-2) has a dual function, acting both as an oncogene and an anti-tumor gene. It is well known that Bcl-2 exerts its tumor promoting function through the mitochondrial pathway. However, the mechanism by which Bcl-2 suppresses tumor formation is not well understood. We have previously shown that Bcl-2 inhibits cell cycle progression from the G0/G1 to the S phase after serum starvation, and that quiescent Bcl-2 expressing cells maintained a significant lower level of mitochondrial reactive oxygen species (ROS) than the control cells. Based on the fact that ROS mediate cell cycle progression, and are controlled by peroxisome proliferator-activated receptor-{gamma} co-activator 1 (PGC-1), a key molecule induced by prolonged starvation and involved in mitochondrial metabolism, we hypothesized that PGC-1 might be related with the cell cycle function of Bcl-2. Here, we showed that PGC-1 was upregulated upon Bcl-2 overexpression and downregulated following Bcl-2 knockdown during serum starvation. Knockdown of PGC-1 activated Bcl-2 expression. Taken together, our results suggest that after serum depletion, PGC-la might coordinate with Bcl-2 to reduce ROS, which in turn delay cell cycle progression.\n\nSummary statementPGC-1 coordinate with Bcl-2 delay cell cycle progression to reduce ROS after serum depletion in human glioma U251 cells.

biochemistry↗

bioRxiv2017

The Pax9/Wnt pathway regulates secondary palate formation in mice

Clefts of the palate and/or lip arise in about 1/700 human live births and are caused by multiple genetic and environmental factors. Studies of mouse knockout models of cleft palate have improved our understanding of the molecular control of palatogenesis. While it is known that Pax9 regulates palatogenesis through Bmp, Fgf and Shh signaling, there is still much to learn about its precise relationship with other pathways. Here we show that alterations of Wnt expression and decreased Wnt activity in Pax9-/- palatal shelves are a result of Pax9s ability to directly bind and repress the promoters of Dkk1 and Dkk2, proteins that antagonize Wnt signaling. The delivery of small-molecule Dkk inhibitors (Wnt agonists) into the tail-veins of pregnant Pax9+/- mice from E10.5 to E14.5 restored Wnt signaling, promoted cell proliferation, bone formation and restored the fusion of palatal shelves in Pax9-/- embryos. In contrast, other organ defects in Pax9 mutants were not corrected. These data uncover a unique molecular relationship between Pax9 and Wnt genes in palatogenesis and offer a new approach for treating cleft palates in humans.\n\nSummary StatementThese studies demonstrate that the Pax9/Wnt genes regulate murine palatogenesis. This unique molecular relationship is proven by the correction of cleft defects in Pax9-deficient mice through Wnt agonist therapies.

developmental biology↗

bioRxiv2017

Systematic changes in temporal summation across human visual cortex

Neuronal responses in visual cortex show a diversity of complex temporal properties. These properties include sub-additive temporal summation, response reduction with repeated or sustained stimuli (adaptation), and slower dynamics at low stimulus contrast. Here, we hypothesize that these seemingly disparate effects can be explained by a single, shared computational mechanism. We propose a model consisting of a linear stage, followed by history-dependent gain control. The model accounts for these various temporal phenomena, tested against an unusually diverse set of measurements - intracranial electrodes in patients, fMRI, and macaque single unit spiking. The model further enables us to uncover a systematic and rich variety of temporal encoding strategies across visual cortex: First, temporal receptive field shape differs both across and within visual field maps. Second, later visual areas show more rapid and pronounced adaptation. Our study provides a new framework to understand the transformation between visual input and dynamical cortical responses.\n\nAuthor SummaryThe nervous system extracts meaning from the distribution of light over space and time. Spatial vision has been a highly successful research area, and the spatial receptive field has served as a fundamental and unifying concept that spans perception, computation, and physiology. While there has also been a large interest in temporal vision, the temporal domain has lagged the spatial domain in terms of quantitative models of how signals are transformed across the visual hierarchy. Here we present a model of temporal dynamics of neuronal responses in human cerebral cortex. We show that the model can accurately predict responses at the millisecond scale using intracortical electrodes in patient volunteers, and that the same model generalizes to multiple types of other measurements, including functional MRI and action potentials from monkey cortex. Further, we show that a single model can account for a variety of temporal phenomena, including short-term adaptation and slower dynamics at low stimulus contrast. By developing a computational model and showing that it successfully generalizes across measurement types, cortical areas, and stimuli, we provide new insights into how time-varying images are encoded and transformed into dynamic cortical responses.

neuroscience↗

bioRxiv2017

Research on Mitochondrial DNA Mutations in Patients with SCA3/MJD

Spinocerebellar ataxia type 3 (SCA3) is a degenerative neurological disorders caused by trinucleotide repeat expansion within the ataxin-3 gene. It is characterized by multi-system involvement and diverse clinical phenotypes, which cannot be fully explained the length of the CAG repeats. One possible explanation for the phenotypic heterogeneity could be the presence of mitochondrial DNA mutations that modify disease severity. To explore the role of Mitochondrial DNA(mtDNA) variations in SCA3 pathogenesis, we analyzed polymorphisms of six mitochondrial genes, MT-LT1, MT-ND1, MT-CO2, MT-TK, MT-ATP8 and MT-ATP6, in 102 unrelated SCA3/MJD patients and 100 healthy controls. The results showed that there were 24 variations of those mtDNA genes in the SCA3 patients and only 10 in the unrelated healthy controls. There was no difference of the relative mtDNA copy number variation between the SCA3 patients and healthy controls (93.20 vs. 89.66, P>0.05). In the group of SCA3 patients, the relative mtDNA copy number showed a negative correlation between the number of CAG repeats (r=-0.210, P < 0.05), but did not correlate with the age at diagnosis, the age of onset, disease duration, ICARS scores and SARA scores. Our research demonstrated that the frequency of mutated mtDNA in SCA3 patients was higher than that in the healthy group. The mtDNA relative copy number in SCA3 patients was not significantly different compared to the healthy group. Thus, the copy number might not be treated as a biomedical indicator when measuring the severity of illness in SCA3 patients.

genetics↗

bioRxiv2017

A Network Integration Approach for Drug-Target Interaction Prediction and Computational Drug Repositioning from Heterogeneous Information

The emergence of large-scale genomic, chemical and pharmacological data provides new opportunities for drug discovery and repositioning. Systematic integration of these heterogeneous data not only serves as a promising tool for identifying new drug-target interactions (DTIs), which is an important step in drug development, but also provides a more complete understanding of the molecular mechanisms of drug action. In this work, we integrate diverse drug-related information, including drugs, proteins, diseases and side-effects, together with their interactions, associations or similarities, to construct a heterogeneous network with 12,015 nodes and 1,895,445 edges. We then develop a new computational pipeline, called DTINet, to predict novel drug-target interactions from the constructed heterogeneous network. Specifically, DTINet focuses on learning a low-dimensional vector representation of features for each node, which accurately explains the topological properties of individual nodes in the heterogeneous network, and then predicts the likelihood of a new DTI based on these representations via a vector space projection scheme. DTINet achieves substantial performance improvement over other state-of-the-art methods for DTI prediction. Moreover, we have experimentally validated the novel interactions between three drugs and the cyclooxygenase (COX) protein family predicted by DTINet, and demonstrated the new potential applications of these identified COX inhibitors in preventing inflammatory diseases. These results indicate that DTINet can provide a practically useful tool for integrating heterogeneous information to predict new drug-target interactions and repurpose existing drugs. The source code of DTINet and the input heterogeneous network data can be downloaded from http://github.com/luoyunan/DTINet.

bioinformatics↗

bioRxiv2017

Cyclic-di-GMP is required for corneal infection by Pseudomonas aeruginosa and modulates host immunity

Biofilms are extremely tolerant toward antimicrobial treatment and host immune clearance due to their distinct physiology and protection by extracellular polymeric substances. Bis-(3{acute}-5{acute})-cyclic dimeric guanosine monophosphate (c-di-GMP) is an essential messenger that regulates biofilm formation by a wide range of bacteria. However, there is a lack of physiological characterization of biofilms in vivo as well as the roles of c-di-GMP signaling in mediating host-biofilm interactions. Here, we employed dual RNA-Seq to characterize the host and pathogen transcriptomes during Pseudomonas aeruginosa infection using a mouse keratitis model. In vivo P. aeruginosa biofilms maintained a distinct physiology compared with in vitro P. aeruginosa biofilms, with enhanced virulence and iron uptake capacity. C-di-GMP synthesis was enhanced in P. aeruginosa cells in vivo, potentially due to down-regulation of the expression of several phosphodiesterases (e.g., DipA, NbdA). Increased intracellular c-di-GMP levels were required for long-term ocular colonization of P. aeruginosa and impaired host innate immunity.

microbiology↗