Biology subjects

Meng, W.

Publications and source records attributed to Meng, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

CRISPR-based targeted haplotype-resolved assemblies of a megabase region

Constructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved de novo assemblies of targeted genomic regions with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assemblies, our targeted approach achieved comparable completeness and accuracy with greatly reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology.

genomics↗

bioRxiv2021

mRNA Vaccination Induces Durable Immune Memory to SARS-CoV-2 with Continued Evolution to Variants of Concern

SARS-CoV-2 mRNA vaccines have shown remarkable efficacy, especially in preventing severe illness and hospitalization. However, the emergence of several variants of concern and reports of declining antibody levels have raised uncertainty about the durability of immune memory following vaccination. In this study, we longitudinally profiled both antibody and cellular immune responses in SARS-CoV-2 naive and recovered individuals from pre-vaccine baseline to 6 months post-mRNA vaccination. Antibody and neutralizing titers decayed from peak levels but remained detectable in all subjects at 6 months post-vaccination. Functional memory B cell responses, including those specific for the receptor binding domain (RBD) of the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants, were also efficiently generated by mRNA vaccination and continued to increase in frequency between 3 and 6 months post-vaccination. Notably, most memory B cells induced by mRNA vaccines were capable of cross-binding variants of concern, and B cell receptor sequencing revealed significantly more hypermutation in these RBD variant-binding clones compared to clones that exclusively bound wild-type RBD. Moreover, the percent of variant cross-binding memory B cells was higher in vaccinees than individuals who recovered from mild COVID-19. mRNA vaccination also generated antigen-specific CD8+ T cells and durable memory CD4+ T cells in most individuals, with early CD4+ T cell responses correlating with humoral immunity at later timepoints. These findings demonstrate robust, multi-component humoral and cellular immune memory to SARS-CoV-2 and current variants of concern for at least 6 months after mRNA vaccination. Finally, we observed that boosting of pre-existing immunity with mRNA vaccination in SARS-CoV-2 recovered individuals primarily increased antibody responses in the short-term without significantly altering antibody decay rates or long-term B and T cell memory. Together, this study provides insights into the generation and evolution of vaccine-induced immunity to SARS-CoV-2, including variants of concern, and has implications for future booster strategies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/457229v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@16c64b1org.highwire.dtl.DTLVardef@146ca3aorg.highwire.dtl.DTLVardef@86b7edorg.highwire.dtl.DTLVardef@956879_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Changes in the urinary proteome in rats with regular swimming exercise

PurposeUrine can sensitively reflect early pathophysiological changes in the body. The purpose of this study was to determine whether the urine proteome could reflect changes in regular swimming exercise. MethodsIn this study, experimental rats were subjected to daily moderate-intensity swimming exercise for 7 weeks. Urine samples were collected at weeks 2, 5, and 7 and were analyzed by using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). ResultsUnsupervised clustering analysis of all urinary proteins identified at week 2 showed that the swimming group was distinctively different from the control group. Compared to the control group, a total of 112, 61 and 44 differential proteins were identified in the swimming group at weeks 2, 5 and 7, respectively. Randomized grouping statistical analysis showed that more than 85% of the differential proteins identified in this study were caused by swimming exercise rather than random allocation. According to the Human Protein Atlas, the differential proteins that have human orthologs were strongly expressed in the liver, kidney and intestine. Functional annotation analysis revealed that these differential proteins were involved in glucose metabolism and immunity-related pathways. ConclusionOur results revealed that the urinary proteome could reflect significant changes following regular swimming exercise. These findings may suggest an approach to monitoring whether the amount of exercise is appropriate.

biochemistry↗

bioRxiv2021

Sex-specific differences in the function and differentiation of ABCsmark TLR7-driven immunopathogenesis

Sex differences characterize immune responses to viruses and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c- effector populations with pathogenic and proinflammatory potential. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function, and differentiation of ABCs contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.

immunology↗

bioRxiv2020

Activation of the membrane-bound Nrf1 transcription factor by USP19, a tail-anchored ubiquitin-specific protease in the endoplasmic reticulum

The membrane-bound transcription factor Nrf1 (i.e., encoded by Nfe2l1) is activated by sensing glucose deprivation, cholesterol excess, proteasomal inhibition and oxidative stress, and then mediates distinct signaling responses in order to maintain cellular homeostasis. Herein, we found that Nrf1 stability and transactivity are both enhanced by USP19, a ubiquitin-specific protease tail-anchored in the endoplasmic reticulum (ER) through its C-terminal transmembrane domain. Further experiments revealed that USP19 directly interacts with Nrf1 in proximity to the ER and topologically acts as a deubiquitinating enzyme to remove ubiquitin moieties from this protein, and hence allows it to circumvent the potential proteasomal degradation. Such USP19-mediated effect takes place only after Nrf1 is retrotranslocated by p97 out of ER membranes to dislocate the cytoplasmic side. Conversely, knockout of USP19 causes significant decreases in the Nrf1 abundance and its active isoform entering the nucleus, resulting in down-regulation of its target proteasomal subunits. This led to a modest reduction of USP19-/--derived tumor growth in xenograft mice, when compared with wild-type controls. Altogether, these demonstrate that USP19 serves as a novel mechanistic modulator of Nrf1, but not Nrf2, enabling Nrf1 to be rescued from putative ubiquitin-directed ER-associated degradation pathway. In turn, our additional experimental evidence has unraveled that transcriptional expression of endogenous USP19 and its promoter-driven reporter genes is differentially regulated by Nrf2, as well by Nrf1, at distinct layers within a complex hierarchical regulatory network.

biochemistry↗

bioRxiv2020

Increased isoDGR motifs in plasma fibronectin are associated with atherosclerosis through facilitation of vascular fibrosis

Abnormal matrix deposition on vessels and recruitment of inflammatory cells into the arterial wall are critical events in atherosclerotic plaque formation. Fibronectin protein is a key matrix component that exhibits high levels of deamidation in atherosclerotic plaques and blood plasma, but it is unclear how this structural change impacts on endothelial function or modifies interactions with recruited leukocytes. This study aimed to determine how deamidation-induced isoDGR motifs in fibronectin influence extracellular matrix accumulation on endothelial cells, and to investigate possible effects on integrin outside-in signalling in matrix-bound monocytes which are key mediators of human atherosclerosis. Blood plasma fibrinogen and fibronectin displayed marked accumulation of isoDGR motifs in ischemic heart disease (IHD) as determined by ELISA analysis of patients undergoing coronary artery bypass grafting compared with age-matched healthy controls. Biochemical and functional assays confirmed that isoDGR-containing fibronectin promoted activation of integrin {beta}1 in monocytes and facilitated protein deposition and fibrillogenesis on endothelial cell layers. In addition, isoDGR interactions with integrins on the monocyte cell surface triggered an ERK:AP-1 signalling cascade that induced potent secretion of chemotactic mediators (including CCL2, CCL4, IL-8, and TNF), that promoted further leukocyte recruitment to the assembling plaque. Fibronectin deamidation forms isoDGR motifs that increase binding to {beta}1 integrins on the surface of endothelial cells and monocytes. Subsequent activation of integrin outside-in signalling pathways elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix and likely constitutes a key early event in progression to IHD.

biochemistry↗

bioRxiv2020

Immunologic perturbations in severe COVID-19/SARS-CoV-2 infection

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified broad changes in neutrophils, NK cells, and monocytes during severe COVID-19, suggesting excessive mobilization of innate lineages. We found marked activation within T and B cells, highly oligoclonal B cell populations, profound plasmablast expansion, and SARS-CoV-2-specific antibodies in many, but not all, severe COVID-19 cases. Despite this heterogeneity, we found selective clustering of severe COVID-19 cases through unbiased analysis of the aggregated immunological phenotypes. Our findings demonstrate broad immune perturbations spanning both innate and adaptive leukocytes that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation. One Sentence SummaryBroad immune perturbations in severe COVID-19

immunology↗

bioRxiv2020

A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

BackgroundCommon types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203,309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. MethodsCases in the UK Biobank were determined by a question which asked the participants if they had experienced pain in the neck or shoulder in the previous month influencing daily activities. Controls were the UK Biobank participants who reported no pain anywhere in the last month. A genome-wide association study was performed adjusting for age, sex, BMI and 9 population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. ResultsWe identified 3 genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 x 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 x 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 x 10-8 for rs62053992. In the replication stage, among 4 significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). None of the single nucleotide polymorphisms (SNPs) were replicated in the TwinsUK cohort (P > 0.05). ConclusionsWe have identified 3 loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain. SignificanceThis is the first genome-wide association study on neck or shoulder pain. We have identified 3 genetic loci (an intergenic region in chromosome 17, the FOXP2 gene in chromosome 7, and the LINC01572 gene in chromosome 16) that are associated with neck or shoulder pain using the UK Biobank cohort, among which the FOXP2 gene and the LINC01572 gene were weakly replicated by the Generation Scotland: Scottish Family Health Study (P < 0.05). The SNP heritability was 0.11, indicating neck or shoulder pain is a heritable trait. The tissue expression analysis suggested that neck or shoulder pain was related to multiple brain tissues, indicating the involvement of neuron function. The results will inform further research in the characterisation of the mechanisms of neck or shoulder pain.

genetics↗

bioRxiv2019

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development.

Chronic viral infections disrupt B cell responses leading to impaired affinity maturation and delayed control of viremia. Previous studies have identified early pre-germinal center (GC) B cell attrition but the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, we used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, these studies define GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

immunology↗

bioRxiv2019

Dynamics of murine brain protein synthesis in vivo identify the hippocampus, cortex and cerebellum as highly active metabolic sites

Identification of proteins that are synthesized de novo in response to specific microenvironmental cues is critical to understanding the molecular mechanisms that underpin key physiological processes and pathologies. Here we report that a brief period of pulsed SILAC diet (Stable Isotope Labelling by Amino acids in Cell culture) enables determination of biological functions corresponding to actively translating proteins in the mouse brain. Our data demonstrate that the hippocampus, cortex and cerebellum are highly active sites of protein synthesis, rapidly expressing key mediators of nutrient sensing and lipid metabolism, as well as critical regulators of synaptic function, axon guidance, and circadian entrainment. Together, these findings confirm that protein metabolic activity varies significantly between brain regions in vivo and indicate that pSILAC-based approaches can identify specific anatomical sites and biological pathways likely to be suitable for drug targeting in neurodegenerative disorders.\n\nAbbreviationsApoA1: Apolipoprotein A1, ApoA4: Apolipoprotein A4, ApoE: Apolipoprotein E, ApoJ/Clu: Apolipoprotein J/Clusterin, App: Amyloid-{beta} precursor/A4 protein: App, HDL: high density lipoprotein, Lrp1: Low density lipoprotein receptor-related protein 1, pSILAC: pulsed SILAC, pSIVOM: pulsed-SILAC in vivo labelling in mouse, SILAC: Stable Isotope Labelling by Amino acids in Cell culture)

neuroscience↗

bioRxiv2019

Urine proteome changes in rats with approximately ten tumor cells subcutaneous inoculation.

Biomarkers are changes associated with the disease. Without homeostatic control, urine accumulates very early changes and is an ideal biomarker source. Usually, we performed urinary biomarker studies involving at least thousands of tumor cells. But no tumor starts from a thousand tumor cells. Can we observe any urine proteome changes in rats with approximately ten tumor cells subcutaneous inoculation? Here, we serially diluted Walker-256 carcinosarcoma cells to a concentration of 102/mL and subcutaneously inoculated 0.1 mL of these cells into nine rats. Urine proteomes on days 0, 13 and 21 were profiled by LC-MS/MS analysis and studied with unsupervised clustering analysis. Samples at three time points were almost clustered together, indicating a good consistency in these nine rats. Differential proteins on days 13 and 21 were mainly associated with cell adhesion, autophagic cell death, changes in extracellular matrix organization, angiogenesis, and the pentose phosphate pathway. All of these enriched functional processes were reported to contribute to tumor progression and could not be enriched through random allocation analysis. Our results indicated that 1) the urine proteome reflects changes associated with cancer even with approximately ten tumor cells in the body and that 2) the urine proteome reflects pathophysiological changes in the body with extremely high sensitivity and provides potential for a very early screening process of clinical patients.

biochemistry↗

bioRxiv2019

Dynamic changes in the urine proteome in two ovarian cancer rat models

Ovarian cancer is the most lethal gynecological malignancy in women, and it is likely to metastasize and has a poor prognosis. The early and reliable diagnosis and monitoring of ovarian cancer is very important. Without a homeostasis mechanism, urine can reflect early systemic changes in the body and has a great potential to be used for the early detection of cancer. This study tested whether early changes could be detected in two ovarian cancer rat models. Two rat models were established by either intraperitoneal (i.p.) or orthotopic (o.t.) injection of NuTu-19 ovarian cancer cells in female Fischer344 rats. Urine samples from ovarian cancer rats were collected at five time points during cancer development, and urinary proteins from the rats were profiled by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Compared with pre-injection samples, 49 differential proteins that have human orthologues were significantly changed in the orthotopically injected model. Among them, 24 of the differential proteins have previously been reported to be associated with ovarian cancer, six of which were reported to be biomarkers of ovarian cancer. On the 7th day after orthotopic injection, four differential proteins (APOA1, OX2G, CHMP5, HEXB) were identified before obvious metastases appeared. In the intraperitoneal injection model, 76 differential proteins were changed during the course of ovarian cancer development. The results show that urine proteins could enable the early detection and monitoring of ovarian cancer progression and could lay a foundation for further exploration of the biomarkers of ovarian cancer.

biochemistry↗

bioRxiv2019

CRISPR-Cas9 screening of KSHV-transformed cells identifies XPO1 as a vulnerable target of cancer cells

The abnormal proliferation of cancer cells is driven by deregulated oncogenes or tumor suppressors, of which the cancer vulnerable genes are attractive therapeutic targets. Targeting mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export is effective for inhibiting growth transformation of cancer cells. We performed a CRISPR-Cas9 screening in a unique model of matched primary and oncogenic KSHV-transformed cells, and identified genes that were pro-growth and growth-suppressive of both cells, of which exportin XPO1 was demonstrated to be critical for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by siRNA knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells, and cell lines of other cancers including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest through p53 activation but the mechanism of p53 activation differed among different types of cancer cells. p53 activation depended on the formation of PML nuclear bodies in gastric cancer and liver cancer cells. Mechanistically, XPO1 inhibition induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Taken together, we have identified novel pro-growth and growth-suppressive genes of primary and cancer cells, and demonstrated XPO1 as a vulnerable target of cancer cells. XPO1 inhibition induces cell arrest through a novel PML-and p62-dependent mechanism of p53 activation in some types of cancer cells.\n\nImportanceUsing a model of oncogenic virus KSHV driven cellular transformation of primary cells, we have performed a genome-wide CRISPR-Cas9 screening to identify vulnerable genes of cancer cells. This screening is unique in that this virus-induced oncogenesis model does not depend on any cellular genetic alterations, and has matched primary and KSHV-transformed cells, which are not available for similar screenings in other types of cancer. We have identified genes that are both pro-growth and growth-suppressive in primary and transformed cells, some of which could represent novel proto-oncogenes and tumor suppressors. In particular, we have demonstrated exportin XPO1 as a critical factor for the survival of transformed cells. Using a XPO1 inhibitor KPT-8602 and by siRNA-mediated knockdown, we have confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells, as well as gastric and liver cancer cells. XPO1 inhibition induces cell cycle arrest by activating p53 but the mechanism of p53 activation differed among different types of cancer cells. p53 activation is dependent on the formation of PML nuclear bodies in gastric and liver cancer cells. Mechanistically, XPO1 inhibition induces relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. These results illustrate XPO1 as a vulnerable target of cancer cells, and reveal a novel mechanism for blocking cancer cell proliferation by XPO1 inhibition as well as a novel PML-and p62-mediated mechanism of p53 activation in some types of cancer cells.

cancer biology↗

bioRxiv2019

A genome-wide association study identifies that the GDF5 and COL27A1 genes are associated with knee pain in UK Biobank (N = 171, 516)

ObjectiveKnee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo).\n\nMethodsWe performed a genome-wide association study of knee pain in the UK Biobank, where knee pain was ascertained through self-report and defined as \"knee pain in the last month interfering with usual activities\". A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 x 10-8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of knee pain using Genome-wide Complex Trait Analysis (GCTA).\n\nResultsWe identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 x 10-12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 x 10-8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 x 10-18; rs2808772: P -11 = 2.56 x 10-1). The narrow sense heritability of knee pain was 0.08.\n\nConclusionIn this first reported genome-wide association meta-analysis of knee pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with knee pain.

genetics↗

bioRxiv2019

Early urinary protein changes in the tumor-forming process of the NuTu-19 lung metastasis

The early detection of cancer is essential for effective intervention. Urine, which lacks homeostatic control, has been used to reflect early systemic changes in subcutaneous cancer models. However, urine has not been used to predict whether tumors will be formed in animal models. In this study, a cancer model was established by the tail-vein injection of 2 million NuTu-19 tumor cells. Approximately half of the rats formed lung metastatic carcinoma tumors. Urine samples were randomly selected from 4 tumor-forming rats and 4 non-tumor-forming rats on day 0/12/27/39/52 and analyzed by label-free proteomic quantitative analysis. Compared to day 0, a total of 180 and 118 urinary proteins in tumor-forming and non-tumor-forming rats, respectively, showed significant changes. Functional enrichment analysis of the differential proteins in tumor-forming rats revealed similar events during cancer metastasis cascades and tumor progression, such as the migration of tumor cell lines, coagulation system, TGF-{beta} signaling, the STAT3 pathway and the adhesion of myeloid cells and alveolar macrophages. The differential proteins in non-tumor-forming rats were associated with agranulocyte/granulocyte adhesion and diapedesis, glutathione biosynthesis, IL-12 signaling and vitamin metabolism. After validation by parallel reaction monitoring (PRM) targeted proteomics quantitative analysis, a total of 22 urinary proteins showed significant changes in the early phase of the lung tumor formation process, 5 of which have been associated with the mechanisms of lung cancer, while 3 have been suggested as lung cancer biomarkers. Another 14 urinary proteins showed significant changes in the early phase in non-tumor-forming rats. Our results indicate that urine proteins could differentiate early tumor-forming and non-tumor-forming status.

cancer biology↗

bioRxiv2018

Dynamic urinary proteomic analysis in a Walker 256 intracerebral tumor model

Patients with primary and metastatic brain cancer have an extremely poor prognosis, mostly due to the late diagnosis of disease. Urine, which lacks homeostatic mechanisms, is an ideal biomarker source that accumulates early and highly sensitive changes to provides information about the early stage of disease. A rat model mimicking the local tumor growth process in the brain was established with intracerebral Walker 256 (W256) cell injection. Urine samples were collected on days 3, 5 and 8 after injection and then analyzed by LC-MS/MS. In the intracerebral W256 model, no obvious clinical manifestations changes or abnormal MRI signals were found on days 3 and 5; at these time points, nine proteins were changed significantly in the urine of all 8 tumor rats. On day 8, when tumors were detected by MRI, twenty-five differential proteins were identified, including 10 proteins that have been reported to be closely related to tumor metastasis or brain tumors. The differential urinary proteomes were compared with those from the subcutaneous W256 model and the intracerebral C6 model. Few differential proteins overlapped. Specific differential protein patterns were observed among the three models, indicating that the urinary proteome can reflect the difference when tumor cells with different growth characteristics are inoculated into the brain and when identical tumor cells are inoculated into different areas, specifically, the subcutis and the brain.

cancer biology↗

bioRxiv2018

Genetic correlations between pain phenotypes and depression and neuroticism

Correlations between pain phenotypes and psychiatric traits such as depression and the personality trait of neuroticism are not fully understood. The purpose of this study was to identify whether eight pain phenotypes, depressive symptoms, major depressive disorders, and neuroticism are correlated for genetic reasons. Eight pain phenotypes were defined by a specific pain-related question in the UK Biobank questionnaire. First we generated genome-wide association summary statistics on each pain phenotype, and estimated the common SNP-based heritability of each trait using GCTA. We then estimated the genetic correlation of each pain phenotype with depressive symptoms, major depressive disorders and neuroticism using the the cross-trait linkage disequilibrium score regression (LDSC) method integrated in the LD Hub. Third, we used the LDSC software to calculate genetic correlations among pain phenotypes. All pain phenotypes were heritable, with pain all over the body showing the highest heritability (h2=0.31, standard error=0.072). All pain phenotypes, except hip pain and knee pain, had significant and positive genetic correlations with depressive symptoms, major depressive disorders and neuroticism. The largest genetic correlations occurred between neuroticism and stomach or abdominal pain (rg=0.70, P=2.4 x 10-9). In contrast, hip pain and knee pain showed weaker evidence of shared genetic architecture with these negative emotional traits. In addition, many pain phenotypes had positive and significant genetic correlations with each other indicating shared genetic mechanisms. Pain at a variety of body sites is heritable and genetically correlated with depression and neuroticism. This suggests that pain, neuroticism and depression share partially overlapping genetic risk factors.

genetics↗

bioRxiv2018

Deciphering the rules which mRNA structures differs from vivo and vitro in Saccharomyces cerevisiae by deep neural networks

The structure of mRNA in vivo is influenced by various factors involved in the translation process, resulting in significant differentiation of mRNA structure from that in vitro. Because multiple factors cause the differentiation of in vivo and in vitro mRNA structures, it was difficult to perform a more accurate analysis of mRNA structures in previous studies. In this study, we have proposed a novel application of a deep neural network (DNN) model to predict the structural stability of mRNA in vivo by fitting six quantifiable features that may affect mRNA folding: ribosome density, minimum folding free energy, GC content, mRNA abundance, ribosomal initial density and position of mRNA structure. Simulated mutations of the mRNA structure were designed and then fed into the trained DNN model to compute their structural stability. We found unique effects of these six features on mRNA structural stability in vivo. Strikingly, the ribosome density of the structural region is the most important factor affecting the structural stability of mRNA in vivo, and the strength of the mRNA structure in vitro should have a relatively small effect on its structural stability in vivo. The recruitment of DNNs provides a new paradigm to decipher the differentiation of mRNA structure in vivo and in vitro. This improved knowledge on the mechanisms of factors influencing mRNA structural stability will facilitate the design and functional analysis of mRNA structure in vivo.

bioinformatics↗