Biology subjects

Wei, J.

Publications and source records attributed to Wei, J..

13 recordsLinked to original sources

bioRxiv2018

Profiling the surface proteome identifies actionable biology for TSC1 mutant cells beyond mTORC1 signaling

Loss of the TSC1/TSC2 complex leads to constitutively high mTORC1 signaling; however, pharmacological inhibition of mTORC1 in this setting produces a broad spectrum of clinical responses. We report herein several cell surface proteins upregulated by inactivation of TSC1 that present therapeutic alternatives or adjuvants to direct mTORC1 inhibition. A proteomics screen revealed that TSC1 loss most dramatically induced the expression of neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). The survival of TSC1 null human cancer cells was dependent on NEP expression, and TSC1 mutation sensitized cells to biochemical inhibition of APN. Remarkably, NEP and APN upregulation occurred via a TSC2- and mTORC1-independent mechanism; therefore, the antiproliferative effects of mTORC1 inhibition could be augmented by co-suppression of APN activity.\n\nStatement of significanceThese data introduce a non-canonical biological role for TSC1 beyond regulating mTORC1 signaling, which also enabled several immediately translatable therapeutic strategies for clinically problematic cells with TSC1 mutations.

cancer biology↗

bioRxiv2018

Application of clinical genomic sequencing among Chinese advanced cancer patients to guide precision medicine decisions

PurposeA number of studies have suggested that high-throughput genomic analyses might improve the outcomes of cancer patients. However, whether integrative information about genomic sequencing and related clinical interpretation may benefit Chinese cancer patients with stage IV disease to date has not investigated.\n\nMethodsTargeted gene panel and whole exome of tumor/blood samples in > 1,000 Chinese cancer patients were sequenced. Then we provided patients and their oncologists with the sequencing results and a clinical recommendation roadmap based on evidence-based medicine, defined as CWES. Only patients with stage IV disease who failed the previous treatment upon receiving the CWES reports were included for analyzing the impact of CWES on clinical outcomes in 1-year follow-ups.\n\nResultsWe identified the mutational signatures of 953 Chinese cancer patients, with some being unique. Approximately 88.6% of patients had clinically actionable somatic genomic alterations. We successfully followed up 22 stage IV patients. Of these, 11 patients treatment followed the CWES reports defined as group A. Eleven patients received the next treatment, but did not follow the CWES suggestions, and are defined as group B. The types of therapies before CWES were similar in the two groups. The median PFS of group A was 12 months and 45% patients failed this round of therapy. The median PFS of group B was 4 months and 91% of patients failed the treatment.\n\nConclusionThe current study suggested that CWES has the potential to help explore the clinical benefits in multiple line therapies among advanced stage tumor patients.

cancer biology↗

bioRxiv2018

Comprehensive analysis of potential immunotherapy genomic biomarkers in 1,000 Chinese patients with cancer

BackgroundTumor mutation burden (TMB), DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and PD-L1 amplification (PD-L1 AMP) may predict the efficacy of PD-1/PD-L1 blockade. In this study, we aimed to characterize the distributions of these biomarkers in over 1,000 Chinese patients with cancer.\n\nMethodsTMB, MSI, dMMR, and PD-L1 AMP were determined based on whole-exome sequencing of tumor/blood samples from > 1,000 Chinese patients with cancer.\n\nResultsIncidence rates among 953 Chinese patients with cancer showing high TMB (TMB-H), high MSI (MSI-H), dMMR and PD-L1 AMP were 35%, 4%, 0.53% and 3.79%, respectively. We found higher rates of TMB-H among hepatocellular carcinoma, breast cancer, and esophageal cancer patients than was reported for The Cancer Genome Atlas data. Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild-type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC). The frequency of tumors with MSI-H was highest in CRC (14%) and gastric cancer (4%). PD-L1 AMP occurred most frequently in lung squamous cell carcinoma (14.3%) and HER2-positive breast cancer (8.8%). Most MSI-H and dMMR cases exhibited TMB-H, but the overlap among the other biomarkers was low.\n\nConclusionWhile MSI and dMMR are associated with higher mutational loads, correlations between TMB-H and other biomarkers, between MSI-H and dMMR, and between PD-L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers. Thus, it is recommended that all four biomarkers be assessed for certain cancers before administration of PD-1/PD-L1 blockade treatment.

cancer biology↗

bioRxiv2018

Inference of Chromosome-length Haplotypes Using Genomic Data of Three to Five Single Gametes

Knowledge of chromosome-length haplotypes will not only advance our understanding of the relationship between DNA and phenotypes, but also promote a variety of genetic applications. Here we present Hapi, an innovative method for chromosomal haplotype inference using only 3 to 5 gametes. Hapi outperformed all existing haploid-based phasing methods in terms of accuracy, reliability, and cost efficiency in both simulated and real gamete datasets. This highly cost-effective phasing method will make large-scale haplotype studies feasible to facilitate human disease studies and plant/animal breeding. In addition, Hapi can detect meiotic crossovers in gametes, which has promise in the diagnosis of abnormal recombination activity in human reproductive cells.

bioinformatics↗

bioRxiv2018

White spot syndrome virus infection induces Caspase 1-mediated antiviral cell death in crustacean

In vertebrates, pyroptosis is an intensely inflammatory form of programmed cell death which is dependent on Caspase 1 activation and release of cytoplasmic cytokines including IL-1{beta}. This death pathway is critical for controlling pathogenic infection by mobilizing immune cells and stimulating the development of adaptive immune response. In invertebrates, however, due to the lack of adaptive immune response, it is still elusive whether Caspase 1-dependent cell death pathway exists. In this study, our data showed that Caspase 1-mediated cell death was activated by white spot syndrome virus (WSSV) infection to control the virus in shrimp. Caspase 1 had a higher expression level in hemocytes and lymphoid-like organ in shrimp and WSSV infection was significantly promoted upon the inhibition of Caspase 1 enzymatic activity. IL-1{beta}-like protein was identified as the substrate of Caspase 1 and its interaction with Caspase 1 was validated ectopically and endogenously. Moreover, IL-1{beta} like protein was released into extracellular contents under WSSV infection and Prophenoloxidase system was activated, resulting in the reduction of WSSV copies in vivo. Our data unraveled a previously unidentified mechanism through which Caspase 1-dependent cell death controlled virus infection in shrimp. Therefore, our study opened the possibility that an invertebrate cytokine network might be operative and regulate host defenses against virus infection as in vertebrates.\n\nAuthor SummaryThe elimination of infected cells by programmed cell death is considered as one of the most important anti-pathogen responses. Pyroptosis is one form of programmed cell death, which is mediated by Caspase 1 activation. Activated Caspase 1 can process the inactive precursors of interleukin 1{beta} (IL-1{beta}) into mature inflammatory cytokines to induce potent immune responses. Meanwhile, pyroptosis also induces morphologic changes, DNA fragmentation and chromatin condensation to destroy infected cells. However, due to the lack of efficient adaptive immune responses, it is still unclear whether Caspase 1-mediated cell death also exits and plays such an important role in defending hosts from pathogen invasion in invertebrates. In our data, Caspase 1 gene was characterized and Caspase 1-mediated cell death pathway was validated in shrimp. The Caspase 1-mediated cell death pathway was enhanced by white spot syndrome virus (WSSV) infection to control the virus in shrimp. IL-1{beta}-like protein was cleaved by Caspase 1 and released into extracellular contents under WSSV infection to activate Prophenoloxidase system, leading to the reduction of WSSV copies in shrimp in vivo. On the other hand, silencing of Caspase 1 or IL-1{beta}-like gene facilitated virus infection in shrimp. Our study indicated that Casapase-1-mediated cell death played an important antiviral role in shrimp against WSSV infection and opened the possibility that an invertebrate cytokine network might be operative.

immunology↗

bioRxiv2018

Baculovirus utilizes cholesterol transporter Niemann-Pick C1 for host cell entry

The dual roles of baculovirus for the control of natural insect populations as an insecticide, and for foreign gene expression and delivery, have called for a comprehensive understanding of the molecular mechanisms governing viral infection. Here, we demonstrate that the Bombyx mori Niemann-Pick C1 (BmNPC1) is essential for baculovirus infection in insect cells. Both pretreatment of Bombyx mori embryonic cells (BmE) with NPC1 antagonists (imipramine or U18666A) and down-regulation of NPC1 expression resulted in a significant reduction in baculovirus BmNPV (Bombyx mori nuclear polyhedrosis virus) infectivity. Furthermore, we show that the major glycoprotein gp64 of BmNPV, responsible for both receptor binding and fusion, is able to interact predominantly with the BmNPC1 C domain, with an enhanced binding capacity at low pH conditions, indicating that NPC1 most likely plays a role during viral fusion in endosomal compartments. Our results, combined with previous studies identifying an essential role of hNPC1 in filovirus infection, suggest that the glycoprotein of several enveloped viruses possess a shared strategy of exploiting host NPC1 proteins during virus intracellular entry events.\n\nIMPORTANCEBmNPV is one of the most important members of the Baculoviridae; many viruses in this family have been frequently employed as viral vectors for foreign gene delivery or expression and as biopesticides, but their host receptors still remain unclear. Here, we describe that the intracellular cholesterol transporter BmNPC1 is indispensable for BmNPV infection in insect cells, and it interacts with the major viral glycoprotein gp64. Our study on the role of BmNPC1 in baculovirus infection has further expanded the list of the enveloped viruses that require host NPC1 proteins for entry, and will ultimately help us to uncover the molecular mechanism of the involvement of NPC1 proteins in the entry process of many enveloped viruses.

microbiology↗

bioRxiv2018

Early candidate biomarkers in urine of Walker-256 lung metastasis rat model.

Cancer metastasis accounts for the majority of deaths by cancer. Detection of cancer metastasis at its early stage is important for the management and prediction of cancer progression. Urine, which is not regulated by homeostatic mechanisms, reflects systemic changes in the whole body and can potentially be used for the early detection of cancer metastasis. In this study, a lung metastasis of a Walker-256 rat model was established by tail-vein injection of Walker-256 cells. Urine samples were collected at days 2, 4, 6 and 9 after injection, and the urinary proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The urinary protein patterns changed significantly with the development of Walker-256 lung metastasis. On the fourth day, lung metastasis nodules appeared. On the sixth day, clinical symptoms started. On days 2, 4, 6 and 9, 11, 25, 34 and 44 differential proteins were identified in 7 lung metastatic rats by LC-MS/MS. Seventeen of these 62 differential proteins were identified on the second day, and 18 of them were identified on the fourth day. The differential urinary proteins changed significantly two days before lung metastasis nodules appeared. Differential urinary proteins differed in Walker-256 lung metastasis rat models and Walker-256 subcutaneous rat models. A total of 9 differential proteins (NHRF1, CLIC1, EZRI, AMPN, ACY1A, HSP7C, BTD, NID2, and CFAD) were identified in 7 lung metastatic rats at one or more common time points, and these 9 differential proteins were not identified in the subcutaneous rat model. Seven of these 9 differential proteins were associated with both breast cancer and lung cancer, eight of the nine were identified on the second day, and 8 of the nine can be identified on the fourth day; these early changes in urine were also identified with differential abundances at late stages of lung metastasis. Our results indicate that (1) the urine proteome changed significantly, even on the second day after tail-vein injection of Walker-256 cells and that (2) the urinary differential proteins were different in Walker-256 lung metastatic tumors and Walker-256 subcutaneous tumors. Our results provide the potential to detect early breast cancer lung metastasis, monitor its progression and differentiate it from the same cancer cells grown at other locations.

biochemistry↗

bioRxiv2018

Soil microbial habitats in an extreme desert Mars-analogue environment

Sediments in the hyper-arid core of the Atacama Desert are a terrestrial analogue to Mars regolith. Understanding the distribution and drivers of microbial life in the sediment may give critical clues on how to search for biosignatures on Mars. Here, we identify the spatial distribution of highly specialised bacterial communities in previously unexplored depth horizons of subsurface sediments. We deployed an autonomous rover in a mission-relevant Martian drilling scenario with manual sample validation. Subsurface communities were delineated by depth related to sediment moisture. Geochemical analysis indicated soluble salts and minerology that influenced water bio-availability, particularly in deeper sediments. Colonization was also patchy and uncolonized sediment was associated with indicators of extreme osmotic challenge. The study identifies linkage between biocomplexity, moisture and geochemistry in Mars-like sediments at the limit of habitability and demonstrates feasibility of the rover-mounted drill for future Mars sample recovery.

microbiology↗

bioRxiv2018

Optimizing Trait Predictability in Hybrid Rice Using Superior Prediction Models and Selective Omic Datasets

Hybrid breeding has dramatically boosted yield and its stability in rice. Genomic prediction further benefits rice breeding by increasing selection intensity and accelerating breeding cycles. With the rapid advancement of technology, other omic data, such as metabolomic data and transcriptomic data, are readily available for predicting genetic values (or breeding values) for agronomically important traits. In the current study, we searched for the best prediction strategy for four traits (yield, 1000 grain weight, number of grains per panicle and number of tillers per plant) of hybrid rice by evaluating all possible combinations of omic datasets with different prediction methods. We conclude that, in rice, the predictions using the combination of genomic and metabolomic data generally produce better results than single-omics predictions or predictions based on other combined omic data. Inclusion of transcriptomic data does not improve predictability possibly because transcriptome does not provide more information for the trait than the sum of genome and metabolome; rather, the computational complexity is substantially increased if transcriptomic data is included in the models. Best linear unbiased prediction (BLUP) appears to be the most efficient prediction method compared to the other commonly used approaches, including LASSO, SSVS, SVM-RBF, SVP-POLY and PLS. Our study has provided a guideline for selection of hybrid rice in terms of which types of omic datasets and which method should be used to achieve higher trait predictability.

genetics↗

bioRxiv2018

Influenza A Virus Negative Strand RNA is Translated for CD8+ T Cell Immunosurveillance

To probe the limits of CD8+ T cell immunosurveillance, we inserted the model peptide SIINFEKL into influenza A virus (IAV) negative strand gene segments. Although IAV genomic RNA is widely considered as non-coding, there is a conserved, relatively long open reading frame present in the genomic strand of segment eight, encoding a potential protein termed NEG8. The biosynthesis of NEG8 from IAV has yet to be demonstrated. While we failed to detect NEG8 protein expression in IAV infected cells, cell surface Kb-SIINFEKL complexes are generated when SIINFEKL is genetically appended to the predicted COOH-terminus of NEG8, as shown by activation of OT-I T cells in vitro and in vivo. Moreover, recombinant IAV encoding SIINFEKL embedded in the negative strand of the NA-stalk coding sequence also activates OT-I T cells in vivo. Together, our findings demonstrate both the translation of sequences on the negative strand of a single stranded RNA virus and its relevance anti-viral immunosurveillance.\n\nSignificanceEvery gene encodes complementary information on the opposite strand that can potentially be used for immunosurveillance. In this study, we show that the influenza A virus \"non-coding\" strand translated into polypeptides during a viral infection of either cultured cells or mice that can be recognized by CD8+ T cells. Our findings raise the possibility that influenza virus uses its negative strand to generate proteins useful to the virus. More generally, it adds to a growing literature showing that immunosurveillance extends to gene sequences generally thought not to be converted into proteins. The relevance of translating this \"dark\" information extends from viral immunity to cancer immunotherapy and autoimmunity.

immunology↗

bioRxiv2018

Early candidate urine biomarkers for detecting Alzheimer’s disease before beta amyloid plaque deposition in an APP (swe)/PSEN1dE9 transgenic mouse model

Alzheimers disease (AD) is an incurable age-associated neurodegenerative disorder that is characterized by irreversible progressive cognitive deficits and extensive brain damage. The identification of candidate biomarkers before beta amyloid plaque deposition occurs is therefore of great importance for the early intervention of AD. Urine, which is not regulated by homeostatic mechanisms, theoretically accumulates changes associated with AD earlier than cerebrospinal fluid and blood. In this study, an APP (swe)/PSEN1dE9 transgenic mouse model was used to identify candidate biomarkers for early AD. Urine samples were collected from 4-, 6-, and 8-month-old transgenic mouse models, and the urinary proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The levels of 33 proteins differed significantly between wild-type and 4-month-old mice, which had not started to deposit beta amyloid plaque. Among these proteins, 16 have been associated with the mechanisms of AD, while 9 have been suggested as AD biomarkers. Our results indicated that urine proteins enable detecting AD before beta amyloid plaque deposition, which may present an opportunity for intervention.

molecular biology↗

bioRxiv2017

GDCRNATools: an R/Bioconductor package for integrative analysis of lncRNA, miRNA, and mRNA data in GDC

The large-scale multidimensional omics data in the Genomic Data Commons (GDC) provides opportunities to investigate the crosstalk among different RNA species and their regulatory mechanisms in cancers. Easy-to-use bioinformatics pipelines are needed to facilitate such studies. We have developed a user-friendly R/Bioconductor package, named GDCRNATools, to facilitate downloading, organizing, and analyzing RNA data in GDC with an emphasis on deciphering the lncRNA-mRNA related competing endogenous RNAs (ceRNAs) regulatory network in cancers. Many widely used bioinformatics tools and databases are utilized in our package. Users can easily pack preferred downstream analysis pipelines or integrate their own pipelines into the workflow. Interactive shiny web apps built in GDCRNATools greatly improve visualization of results from the analysis.\n\nAvailabilityGDCRNATools is an R/Bioconductor package that is freely available at https://github.com/Jialab-UCR/GDCRNATools

bioinformatics↗

bioRxiv2017

Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. Here, we sought to investigate the contribution of CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on MZ pairs discordant for autism spectrum disorder (ASD) using the PsychChip array. In our collection, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. When analyzing the burden of rare CNVs among pairs concordant and discordant for ASD/NDD in comparison with typically developed (TD) pairs, no differences were found. However, we did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p=0.02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood and, in the majority of MZ twins, do not explain the discordance of NDDs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.

genetics↗