Biology subjects

Wei, D.

Publications and source records attributed to Wei, D..

88 records · Page 5Linked to original sources

bioRxiv2019

Suppression of membranous LRP5 recycling, WNT/β-catenin signaling, and colorectal tumorigenesis by 15-LOX-1 peroxidation of PI3P_linoleic acid

Aberrant Wnt/{beta}-catenin activation is a major driver of colorectal cancer (CRC), which is typically initiated by APC mutations. Additional modifiable factors beyond APC mutations have been recognized to be important for further potentiation of aberrant {beta}-catenin activation to promote colorectal tumorigenesis. These factors have yet to be clearly identified. Western-type diets are increasingly enriched in linoleic acid (LA). LA-enriched diet however promotes chemically-induced colorectal tumorigenesis in rodent models. Furthermore, the main metabolizing enzyme of LA, 15-lipoxygenase-1 (15-LOX-1), is transcriptionally silenced in CRC. Whether LA and 15-LOX-1 affect Wnt/{beta}-catenin signaling to modulate colorectal tumorigenesis is poorly understood. Herein, we report that high dietary LA promoted colorectal tumorigenesis in mice with intestinally targeted APC mutation (Apc{Delta}580) by upregulating a Wnt receptor, LRP5 expression, and {beta}-catenin activation. 15-LOX-1 transgenic expression in intestinal epithelial cells suppressed LRP5 expression, {beta}-catenin activation and subsequently CRC in these mice. In particular, 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time that 15-LOX-1 metabolism of LA in PI3P to regulate LRP5 membrane abundance is a modifiable factor of Wnt/{beta}-catenin aberrant signaling that could be potentially therapeutically targeted to suppress colorectal tumorigenesis and progression.

cancer biology↗

bioRxiv2019

PAG neurons encode a simplified action-selective signal during aggression

SummaryWhile the ventromedial hypothalamus, ventrolateral area (VMHvl) is now well established as a critical locus for the generation of conspecific aggression, its role is complex, with populations of neurons responding during the motivational, sensory, and action phases of aggression, and also during social interactions with the opposite sex. It has been previously unclear how the brain uses this complex multidimensional signal and generates a discrete action: the attack. Here we find that the largest posterior target of the VMHvl, the lateral periaqueductal gray (lPAG) encodes a simplified attack-selective signal during aggression. Single units in the lPAG exhibit greater selectivity for the attack action during aggression than VMHvl neurons and a subpopulation of neurons in the PAG exhibit short-latency, time-locked spiking relative to the activity of jaw muscles for biting during attack. In addition, channelrhodopsin assisted circuit mapping reveals a preferential projection from VMHvl glutamatergic cells to lPAG glutamatergic cells. Using projection-specific fiber photometry, we find that this excitatory projection conveys male-biased signals from the VMHvl to downstream glutamatergic PAG neurons that integrate ongoing male-related activity over several seconds, which suggests that action-selectivity is generated by a combination of both pre and postsynaptic filtering mechanisms.

neuroscience↗

bioRxiv2019

Molecular Insights on exquisitely Selective SrtA inhibitors towards active site loop forming open/close lid conformations in SrtA from Bacillus anthracis

The present study clearly explains the dependency of inhibitory activities in SrtA inhibitors is closely related to protein conformational changes of SrtA from Bacillus anthracis B. anthracisSortase A (SrtA) protein anchors proteins by recognizing a cell wall sorting signal containing the amino acid sequence LPXTG In order to analyze conformational changes and the role of SrtA enzyme, especially the loop motions which situated proximal to the active site molecular dynamic simulation was carried out for 100ns. Particular loop is examined for its various conformations from the MD trajectories and the open/close lid conformations are considered for the enzyme activity validations. Experimentally verified SrtA inhibitors activity was analyzed through 3D-QSAR and Molecular docking approaches. Results indicate that, biological activity of SrtA inhibitors is closely related to the closed lid conformation of SrtA from Bacillus anthracis. This work may lead to a better understanding of the mechanism of action and aid to design a novel and more potent SrtA inhibitors.

bioinformatics↗

bioRxiv2019

Assessment of the optimum fertilizer rates and planting density for soybean production in China

Fertilization rate and planting density are important factors affecting crop yield. A large number of soybean [Glycine max (L.) Merr] field experimental data (1998-2017) were collected through different database sources to evaluate the optimum fertilizer rate and planting density for high yield of spring and summer soybean in China. The yield of spring and summer soybean gradually increased over year, with their average yields were 2610 and 2724 kg ha-1, respectively. Based on the fitted quadratic curve, the optimal rate of nitrogen (N), phosphorus (P), and potassium (K) fertilizers for high yield of summer soybean was 96 kg N ha-1, 80 kg P2O5 ha-1, and 126 kg K2O ha-1, and the corresponding yields were 3038, 2801 and 2305 kg ha-1, respectively. The optimal rate of N, P and K fertilizers for spring soybean was 71 kg N ha-1, 108 kg P2O5 ha-1 and 74 kg K2O ha-1, and the corresponding yields were 2932, 2834 and 2678 kg ha-1, respectively. The optimum density was 27x104 and 34x104 plants ha-1 under high yield for summer and spring soybean, respectively. Stepwise regression analysis showed that the P fertilizer had the greatest influence on the spring soybean yield followed by K fertilizer and planting density. For summer soybean, population density had the major effect on yield followed by P fertilizer. Overall, the P fertilization and planting density should be payed attention to increase soybean yield in different regions of China.

plant biology↗

bioRxiv2019

DTI-CDF: a CDF model towards the prediction of DTIs based on hybrid features

Drug-target interactions play a crucial role in target-based drug discovery and exploitation. Computational prediction of DTIs has become a popular alternative strategy to the experimental methods for identification of DTIs of which are both time and resource consuming. However, the performances of the current DTIs prediction approaches suffer from a problem of low precision and high false positive rate. In this study, we aimed to develop a novel DTIs prediction method, named DTI-CDF, for improving the prediction precision based on a cascade deep forest model which integrates hybrid features, including multiple similarity-based features extracted from the heterogeneous graph, fingerprints of drugs, and evolution information of target protein sequences. In the experiments, we built five replicates of 10 fold cross-validations under three different experimental settings of data sets, namely, corresponding DTIs values of certain drugs (SD), targets (ST), or drug-target pairs (SP) in the training set are missed, but existed in the test set. The experimental results show that our proposed approach DTI-CDF achieved significantly higher performance than the state-of-the-art methods.

bioinformatics↗

bioRxiv2019

CAMIO for deletion analysis of endogenous DNA sequences in multicellular organisms

The genome is the blueprint for an organism. Interrogating the genome, especially locating critical cis-regulatory elements, requires deletion analysis. This is conventionally performed using synthetic constructs, making it cumbersome and non-physiological. Thus, we created Cas9-mediated Arrayed Mutagenesis of Individual Offspring (CAMIO) to achieve high-throughput analysis of native DNA. CAMIO utilizes CRISPR that is spatially restricted to generate independent deletions. Controlled by recombination, a single guide RNA is stochastically chosen from a set targeting a specific DNA region. Combining two sets increases variability, leading to either indels at 1-2 target sites or inter-target deletions. Cas9 restriction to male germ cells elicits autonomous double-strand-break repair, consequently creating offspring with diverse mutations. Thus, from a single population cross, we can obtain a deletion matrix covering a large expanse of DNA at both coarse and fine resolution. We demonstrate the ease and power of CAMIO by mapping 5UTR sequences crucial for chinmos post-transcriptional regulation.

genomics↗

bioRxiv2019

Adaptive substitutions underlying cardiac glycoside insensitivity in insects exhibit epistasis in vivo.

Predicting how species will respond to selection pressures requires understanding the factors that constrain their evolution. We use genome engineering of Drosophila to investigate constraints on the repeated evolution of unrelated herbivorous insects to toxic cardiac glycosides, which primarily occurs via a small subset of possible functionally-relevant substitutions to Na+,K+-ATPase. Surprisingly, we find that frequently observed adaptive substitutions at two sites, 111 and 122, are lethal when homozygous and adult heterozygotes exhibit dominant neural dysfunction. We identify a phylogenetically correlated substitution, A119S, that partially ameliorates the deleterious effects of substitutions at 111 and 122. Despite contributing little to cardiac glycoside-insensitivity in vitro, A119S, like substitutions at 111 and 122, substantially increases adult survivorship upon cardiac glycoside exposure. Our results demonstrate the importance of epistasis in constraining adaptive paths. Moreover, by revealing distinct effects of substitutions in vitro and in vivo, our results underscore the importance of evaluating the fitness of adaptive substitutions and their interactions in whole organisms.

evolutionary biology↗

bioRxiv2018

Comparative transcriptome and proteome profiling of the chlorophyll metabolism pathway in four cultivars of Magnolia officinalis

Magnolia officinalis is an important herb in Chinese medicine that has good therapeutic effects on gastrointestinal motility and helps regulate the spleen and stomach. Magnolia officinalis Rehd.et Wils. (abbreviated as CH) Magnolia officinalis Rehd.et Wils. var. biloba DaAoye (abbreviated as DA) Magnolia officinalis Rehd.et Wils. var. biloba XiaoAoye (abbreviated as XA)Magnolia officinalis Rehd.et Wils. var. biloba Liuye (abbreviated as LY) are the four main cultivars in Dujiangyan city, Sichuan province in China, and DA has better medicinal effects and higher levels of green pigment than the other three cultivars. Proteomics research not only provides new insights into protein expression patterns but also enables the identification of many attractive candidates for further research on the effects of pesticides on chlorophyll metabolism in Magnolia officinalis. Transcriptome and proteome analysis of the four main Magnolia officinalis cultivars in Sichuan province in China identified 125,100 unigenes and 6,012 proteins. Proteomic data and parallel reaction monitoring (PRM) revealed that porphobilinogen deaminase, uroporphyrinogen decarboxylase, oxygen-dependent coproporphyrinogen-III oxidase, protoporphyrinogen oxidase 1, magnesium protoporphyrin IX methyltransferase, magnesium-protoporphyrin IX monomethyl ester oxidative cyclase, and protochlorophyllide reductase-like protein, all of which are involved in chlorophyll synthesis, have higher expression levels in DA than in the other three cultivars. This finding is consistent with the observation that DA has the highest concentration of chlorophyll (37.56 mg/g Fw) of the four cultivars. This research is beneficial to the understanding of the differences in the growth of the four cultivars on the molecular level.

bioinformatics↗

bioRxiv2018

Nanoscale fracture of defective popgraphene monolayer

A new carbon allotrope, namely popgraphene, has been recently demonstrated to possess high potentials for nanodevice applications. Here, the fracture of defective popgraphene was studied using molecular dynamics simulations and continuum modeling. Three scenarios of defects were considered, including an individual point defect, distributed point defects, and nanocracks. It was found that the fracture stress of popgraphene with an individual point defect was governed by both the geometry of the defect and the critical bond where fracture initiates. Moreover, the fracture stress of popgraphene with distributed point defects was discovered to be inversely proportional to the defect density, showing a nice linear trend. Furthermore, for popgraphene with a nanocrack, it failed in a brittle fashion and exhibited a negligible lattice trapping effect. Griffith criterion was subsequently employed with the consideration of crack deflection to accurately predict the dependence of fracture stress on crack size. The present study lays a mechanistic foundation for nanoscale applications of popgraphene and offers a better understanding of the roles of defects in fracture of low-dimensional materials.

biophysics↗

bioRxiv2018

KPNA2 promotes cellular proliferation and inhibits apoptosis in the Saos-2 osteosarcoma cell line

Karyopherin 2 plays a critical role in tumorigenesis and tumor progression. However, nothing is currently known about the effects of KPNA2 on osteosarcomas. This study aimed to investigate differential KPNA2 protein and mRNA expression in human osteosarcoma tumor cells and normal bone tissue. We also sought to determine whether KPNA2 can influence the proliferation and apoptosis of the Saos-2 osteosarcoma cell line. Immunohistochemistry (IHC) was used to investigate KPNA2 protein expression. Real-time quantitative PCR (qPCR) was used to detect levels of KPNA2 mRNA expression, and lentivirus-mediated short-hairpin RNAs (shRNAs) were used to knock down KPNA2 expression in Saos-2 cells. The MTT assay and multiparametric high-content screening (HCS) were used to measure cell proliferation and growth, respectively. Flow cytometry was conducted to detect cell cycle distribution and apoptosis. The results revealed significantly higher KPNA2 expression levels in osteosarcoma tissues than in normal bone tissues; furthermore, KPNA2 mRNA was also highly expressed in three osteosarcoma cell lines. After transducing Saos-2 cells with KPNA2-shRNA lentivirus, the proliferative rate was notably decreased compared to that of the negative control (NC) lentivirus group (P<0.05). Flow cytometry results indicated that KPNA2 may arrest cell cycle progression and regulate the growth of these cells. The results for apoptosis indicated an apoptotic rate of 13.38{+/-}0.48% in KPNA2-shRNA cells, which was significantly higher than the rate for cells in the control group (5.13 {+/-}0.33%). Therefore, this study showed that KPNA2 is highly expressed in osteosarcoma tissues and that reduced KPNA2mRNA levels inhibited proliferation and promoted apoptosis in an osteosarcoma cell line.

cancer biology↗

bioRxiv2018

Pleotropic effects of PPARD accelerate colorectal tumor progression and invasion

Colorectal carcinogenesis (CRC) progression requires additional molecular mechanisms to APC mutations/aberrant {beta}-catenin signaling. PPARD is a druggable ligand-activated nuclear receptor that regulates essential genes involved in cell fate. PPARD is upregulated in intestinal epithelial cells (IECs) of human colorectal adenomas and adenocarcinomas. The mechanistic significance of PPARD upregulation in CRC remains unknown. Here we show that targeted PPARD overexpression in IECs of mice strongly augmented {beta}-catenin activation via BMP7/TAK1 signaling, promoted intestinal tumorigenesis in Apcmin mice, and accelerated CRC progression and invasiveness in mice with IEC-targeted Apc{Delta}580 mutation. Human CRC invasive fronts had higher PPARD expression than their paired adenomas. A PPARD agonist (GW501516) enhanced APC{Delta}580 mutation-driven CRC, while a PPARD antagonist (GSK3787) suppressed it. Functional proteomics analyses and subsequent validation studies uncovered PPARD upregulation of multiple pro-invasive pathways that drive CRC progression (e.g. PDGFR{beta}, AKT1, CDK1 and EIF4G1). Our results identify novel mechanisms by which PPARD promotes CRC invasiveness and provide the rational for the development of PPARD antagonists to suppress CRC.

cancer biology↗

bioRxiv2018

Enterovirus 71 structural viral protein 1 promotes mouse Schwann cell autophagy via endoplasmic reticulum stress-mediated peripheral myelin protein 22 upregulation

Enterovirus 71 (EV71) accounts for the majority of hand, foot and mouth disease-related deaths due to fatal neurological complications. The clinical observations and animal models found the early invasion of nervous system, and the demyelinating phenomenon was observed. As one of the receptors of EV71 structural viral protein 1 (VP1), SCARB2 mainly exists on the myelin sheath. EV71 VP1 can promote viral replication through inducing autophagy in neuron cells. This study aims to investigate the role and mechanism of VP1 in autophagy of mouse Schwann cells (MSCs). An EV71 VP1-expressing vector (pEGFP-C3-VP1) was generated and transfected into MSCs. Transmission electron microscopy (TEM) and Western blot analysis of the autophagy marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) were used to assess autophagy in the cells. Real-time PCR and immunofluorescent staining were performed to determine the expression of PMP22. Small interfering RNA against PMP22 was employed to investigate the role of PMP22 in MSCs autophagy. Selective endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) was employed to determine whether PMP22 is mediated by ER stress. Our results demonstrated that VP1 played a promotive role in MSC autophagy. Overexpression of VP1 upregulated PMP22. PMP22 deficiency downregulated LC3B and thus inhibited autophagy. Furthermore, PMP22 expression was significantly suppressed by SAL. VP1 promotes MSC autophagy through upregulating ER stress-mediated PMP22 expression. VP1/ER stress/ PMP22 axis in autophagy may be a potential therapeutic target for EV71 infection-induced fatal neuronal damage.

cell biology↗

bioRxiv2018

A chemoproteomic portrait of the oncometabolite fumarate

Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth and survival. Understanding these mechanisms and developing biomarkers to identify their presence thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of the covalent targets of fumarate, an oncometabolite whose accumulation marks the genetic cancer predisposition syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). First, we validate the ability of known and novel chemoproteomic probes to report on fumarate reactivity in vitro. Next, we apply these probes in concert with LC-MS/MS to identify cysteine residues sensitive to either fumarate treatment or fumarate hydratase (FH) mutation in untransformed and human HLRCC cell models, respectively. Mining this data to understand the structural determinants of fumarate reactivity reveals an unexpected anti-correlation with nucleophilicity, and the discovery of a novel influence of pH on fumarate-cysteine interactions. Finally, we show that many fumarate-sensitive and FH-regulated cysteines are found in functional protein domains, and perform mechanistic studies of a fumarate-sensitive cysteine in SMARCC1 that lies at a key protein-protein interface in the SWI-SNF tumor suppressor complex. Our studies provide a powerful resource for understanding the influence of fumarate on reactive cysteine residues, and lay the foundation for future efforts to exploit this distinct aspect of oncometabolism for cancer diagnosis and therapy.

cancer biology↗

bioRxiv2017

PPARD regulation in gastric progenitor cells drives gastric tumorigenesis in mice

Little is known about the cell origin of gastric cancer. Peroxisome proliferator-activated receptor-delta (PPARD) is a druggable ligand-activated nuclear receptor that impacts protumorigenic cellular events. However, PPARDs role in tumorigenesis, especially gastric tumorigenesis, remains to be defined. We found that targeting PPARD overexpression in murine gastric progenitor cells (GPC), via a villin promoter, spontaneously induced gastric tumorigenesis that progressed to invasive adenocarcinoma. PPARD overexpression in GPC upregulated tumorigenic proinflammatory cytokine and CD44 expression, expanded GPC population in vivo, enhanced GPC self-renewal and proliferation in organoid cultures, and endowed these cells with tumorigenic properties. Our findings identify PPARD as a driver of gastric tumorigenesis via GPC transformation.

cancer biology↗

bioRxiv2017

Structural and functional MRI from a cross-sectional Southwest University Adult lifespan Dataset (SALD)

Recently, the field of developmental neuroscience has aimed to uncover the developmental trajectory of the human brain and understand the changes that occur as a function of aging. Here we present an adult lifespan dataset of functional magnetic resonance imaging (fMRI) data including structural MRI and resting-state functional MRI. 494 healthy adults (age range: 19-80 years; Males=187) were recruited and completed two multi-modal MRI scan sessions in the Brain Imaging Central of Southwest University, Chongqing, China. The goals of the dataset are to give researchers the opportunity to map the developmental trajectory of structural and functional changes of human brain and to replicate previous findings.

neuroscience↗

bioRxiv2017

Deubiquitylation and stabilization of p21 by USP11 is critical for cell cycle progression and DNA damage responses

p21WAF1/CIP1 is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligases complex is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21 and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCFSKP2, CRL4CDT2 and APC/CCDT20 in a cell cycle-independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation and pinpoint a crucial role of the USP11-p21 axis in regulating cell cycle progression and DNA damage responses.

cell biology↗