Biology subjects

Xu, R.

Publications and source records attributed to Xu, R..

At least 163 records · Page 9Linked to original sources

bioRxiv2020

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

BackgroundImmune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet. MethodsA total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation in LGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition. ResultsPD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in different LGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration. Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes. ConclusionsHigh expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

bioinformatics↗

bioRxiv2020

Comparative Genome Analysis of Scutellaria baicalensis and Scutellaria barbata Reveals the Evolution of Active Flavonoid Biosynthesis

Scutellaria baicalensis and Scutellaria barbata, common medicinal plants of the Lamiaceae family, produce specific flavonoid compounds with antioxidant and antitumor activities, including baicalein, scutellarein, norwogonin, wogonin, and their glycosides. Here, we reported two chromosome-level genome assemblies of S. baicalensis and S. barbata with significant quantitative chromosomal variation (2n = 18 and 2n = 26, respectively). The divergence of S. baicalensis and S. barbata occurred far earlier than previously reported, and a whole-genome duplication event was identified. The insertion of long terminal repeat elements after speciation might be responsible for the observed chromosomal expansion and rearrangement. The comparative genome analysis of congeneric species elucidated the species-specific evolution of chrysin and apigenin biosynthetic genes, such as the S. baicalensis-specific tandem duplication of the phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS) genes, and the S. barbata-specific duplication of 4-CoA ligase (4CL) genes. In addition, the paralogous duplication, collinearity, and expression diversity of CYP82D subfamily members revealed the functional divergence of flavone hydroxylase genes between S. baicalensis and S. barbata. These Scutellaria genomes highlight the common and species-specific evolution of flavone biosynthetic genes, promoting the development of molecular breeding and the study of the biosynthesis and regulation of bioactive compounds.

genomics↗

bioRxiv2020

Analysis of metagenome-assembled genomes from the mouse gut microbiota reveals distinctive strain-level characteristics

The laboratorial mouse harbors a unique gut microbiota with potential value for human microbiota-associated studies. Mouse gut microbiota has been explored at the genus and species levels, but features rarely been showed at the strain level. The identification of 833,051 and 658,438 nonredundant genes of faeces and gut content samples from the laboratorial C57/BL mice showed over half of these genes were newly found compared to the previous mouse gut microbial gene catalogue. Metagenome-assembled genomes (MAGs) was used to reconstruct 46 nonredundant MAGs belonging to uncultured specieses. These MAGs included members across all phyla in mouse gut (i.e. Firmicutes, Bacteroidetes, Proteobacteria, Deferribacteres, Verrucomicrobia, and Tenericutes) and allowed a strain-level delineating of the mouse gut microbiota. Comparison of MAGs with human gut colonies revealed distinctive genomic and functional characteristics of mouses Bacteroidetes and Firmicutes strains. Genomic characteristics of rare phyla in mouse gut microbiota were demonstrated by MAG approach, including strains of Mucispirillum schaedleri, Parasutterella excrementihominis, Helicobacter typhlonius, and Akkermansia muciniphila. ImportanceThe identification of nonredundant genes suggested the existence of unknown microbes in the mouse gut samples. The metagenome-assembled genomes (MAGs) instantiated the specificity of mouse gut species and revealed an intestinal microbial correlation between mouse and human. The cultivation of faeces and gut contents sample validated the existence of MAGs and estimate their accuracy. Full-length 16S ribosomal RNA gene sequencing enabled taxonomic characterization. This study highlighted a unique ecosystem in the gut of laboratorial mice that obviously differed with the human gut flora at the strain level. The outcomes may be beneficial to researches based on laboratorial mouse models.

microbiology↗

bioRxiv2020

Colorectal cancer marker identification using the aging immune system-related blood cell DNA methylome

ObjectiveThere is a body of evidence that the aging immune system is linked to cancer. Here, we hypothesized that ubiquitination might play a key gatekeeper role in immune system aging and tumorigenesis in CRC. Therefore, we will systematically study the DNA methylation of ubiquitination genes and screen candidate CRC marker that are correlated with both aging and immune cell compositions. DesignThrough aging- and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune cell proportion in the circulating whole blood of healthy individuals. Then, by collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we used nucleic acid mass spectrometry to test whether ubiquitination genes can be used as candidate markers for the early screening of CRC. ResultsThe biological analyses for aging- and CD4 T cell proportion-derived differential genes showed that they are associated with ubiquitination. Among them, DZIP3 was significantly associated with both aging (P-value = 3.86E-06) and CD4 T cell proportion (P-value = 1.97E-05) in circulating blood. Then, we validated that the 1st exon DNA methylation of DZIP3 could predict the onset of early stage CRC (AUC = 0.833, OR = 8.82) and all pTNM stages of CRC (AUC = 0.782, OR = 5.70). ConclusionsThe epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. DNA methylation characteristic of DZIP3 can be used as a promising marker of CRC early screening. Summary boxO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIThe aging immune system is associated with cancer. C_LIO_LIUbiquitination plays potent roles in regulating a variety of signals in both innate and adaptive immune cells. C_LIO_LIThe abnormalities of ubiquitination are closely related to the occurrence of various tumors. C_LIO_LIBlood cell DNA methylome analysis provides a promising tool to probe the key components of immune cell dysregulation in aging and tumorigenesis. C_LI What are the new findings?O_LIThe aging- and immune cell proportion-derived differential genes are associated with ubiquitination. C_LIO_LIThe epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. C_LIO_LIDNA methylation characteristic of DZIP3, an E3 ubiquitin ligase with no reports on its function in immune cells and tumorigenesis, can be used as a promising markers of CRC early screening. C_LI How might it impact on clinical practice in the foreseeable future?O_LIThe in-depth study for DNA methylome of ubiquitination will open up a new path for the study of CRC pathogenesis, diagnosis and treatment. C_LIO_LIIn addition, DZIP3-focused screening technique only needs to extract the whole blood of individuals for MassARRAY analysis; the samples are easy to obtain, and the results are objective. Therefore, this method may have important applications in clinical CRC screening. C_LI

cancer biology↗

bioRxiv2020

Mining the Selective Remodeling of DNA Methylation in Promoter Regions to Identify Robust Gene-Level Associations with Phenotype

Epigenetics is an essential biological frontier linking genetics to the environment, where DNA methylation is one of the most studied epigenetic events. In recent years, through the epigenome-wide association study (EWAS), researchers have identified thousands of phenotype-related methylation sites. However, the overlap between identified phenotype-related DNA methylation sites are often quite small, and it might clue to methylation remodeling has a certain degree of randomness within the genome. Thus, the identification of robust gene-phenotype associations is crucial for interpreting pathogenesis. How to integrate the methylation values of different sites on the same gene and to mining the DNA methylation at the gene level remains a challenge. A recent study found that the DNA methylation difference of the gene body and promoter region has a strong correlation with gene expression. In this study, we proposed a Statistical difference of DNA Methylation between Promoter and Other Body Region (SIMPO) algorithm to extract DNA methylation values at the gene level. First, by choosing to smoke as an environmental exposure factor, our method led to significant improvements in gene overlaps (from 5% to 17%) between different datasets. In addition, the biological significance of these genes ([~]23%) are significantly better than those identified by traditional probe-based methods ([~]18%, P-value = 5.18e-03). Then, we selected two disease content (e.g., insulin resistance and Parkinsons disease) to show that the biological efficiency of disease-related gene identification increased from 15.43% to 44.44% (P-value = 1.20e-28). Thus, our results declare that mining the selective remodeling of DNA methylation in promoter regions can identify robust gene-level associations with phenotype, and the characteristic remodeling of a given genes promoter region can reflect the essence of disease.

bioinformatics↗

bioRxiv2020

Characterization of the Intestinal Absorption of Morroniside from Cornus officinalis Sieb. et Zucc via a Caco-2 Cell Monolayer Model

Morroniside is biologically active polyphenols found in Cornus officinalis Sieb. et Zucc (CO) which exhibits a broad spectrum of pharmacological activities, such as protecting nerves, preventing diabetic liver damageand renal damage. However, little data is available regarding its mechanism ofintestinal absorption. Here, ahuman intestinal epithelial cell model Caco-2 cell in vitro cultured was applied to study on the absorption and transport of morroniside, the effects of time, donor concentration,pH, temperature and inhibitors,the absorption and transport of morroniside were investigated.The bidirectional permeability of morroniside from the apical (AP) to the basolateral (BL) side and in the revese direction was studied. When administrated was setat three tested concentrations (5, 25 and 100M), the P app value in AP-to-BL direction was ranged from 1.59 to 2.66x10 -6 cm/s. Inthe reverse direction, BL-to-AP, the value was ranged from 2.67to 4.10 x10 -6 cm/s.The data indicated that morroniside transport was both pH- and temperature- dependent. The morronisides permeability process affected bytreatment with various inhibitors, such as the multidrug resistance protein inhibitors MK571 and benzbromarone, the breast cancer resistance protein inhibitor apigenin.It can be found that the mechanisms of intestinal absorption of morroniside may involve multiple transport pathways like passive diffusion as well as efflux protein-mediated active transportespecially the multidrug resistance protein2 and breast cancer resistance protein.After CO was added, P app AB increased significantly by about 125.26%, it can therefore be assumed that some ingredients in the crude material promote morronisides absorption in the small intestine.

pharmacology and toxicology↗

bioRxiv2019

Predicting cancer origins with a DNA methylation-based deep neural network model

Cancer origin determination combined with site-specific treatment of metastatic cancer patients is critical to improve patient outcomes. Existing pathology and gene expression-based techniques often have limited performance. In this study, we developed a deep neural network (DNN)-based classifier for cancer origin prediction using DNA methylation data of 7,339 patients of 18 different cancer origins from The Cancer Genome Atlas (TCGA). This DNN model was evaluated using four strategies: (1) when evaluated by 10-fold cross-validation, it achieved an overall specificity of 99.72% (95% CI 99.69%-99.75%) and sensitivity of 92.59% (95% CI 91.87%-93.30%); (2) when tested on hold-out testing data of 1,468 patients, the model had an overall specificity of 99.83% and sensitivity of 95.95%; (3) when tested on 143 metastasized cancer patients (12 cancer origins), the model achieved an overall specificity of 99.47% and sensitivity of 95.95%; and (4) when tested on an independent dataset of 581 samples (10 cancer origins), the model achieved overall specificity of 99.91% and sensitivity of 93.43%. Compared to existing pathology and gene expression-based techniques, the DNA methylation-based DNN classifier showed higher performance and had the unique advantage of easy implementation in clinical settings.

cancer biology↗

bioRxiv2019

The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism

The I{kappa}B kinase {varepsilon} (IKK{varepsilon}) is a key molecule at the crossroads of inflammation and cancer. Known for its role as an activator of NF{kappa}B and IRF3 signalling leading to cytokine secretion, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKK{varepsilon} remodels cellular metabolism is currently unknown. Here we used a combination of metabolomics and phosphoproteomics to show that IKK{varepsilon} orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and serine biosynthesis. Acting independently of its canonical signalling role, IKK{varepsilon} upregulates the serine biosynthesis pathway (SBP) mainly by limiting glucose and pyruvate derived anaplerosis of the TCA cycle. In turn, this elicits activation of the transcription factor ATF4 and upregulation of the SBP genes. Importantly, pharmacological inhibition of the IKK{varepsilon}-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a set of basal ER negative and highly proliferative human breast cancer tumours, IKK{varepsilon} and PSAT1 expression levels are positively correlated corroborating the link between IKK{varepsilon} and the SBP in the clinical context.

cancer biology↗

bioRxiv2019

The \"Locus of Learning\" Problem: Effects of Stimulus and Task Structure on Temporal Perceptual Learning

The ability to discriminate sub-second intervals can be improved with practice, a process known as temporal perceptual learning (TPL). A central question in TPL is whether training improves the low-level sensory representation of a temporal interval or optimizes a set of task-specific response strategies. Here, we trained three groups of participants over five days on a single-interval temporal discrimination task using either fixed intervals (FI) or random intervals (RI). Before and after training, discrimination thresholds were also obtained on an untrained task. Our results revealed that only the FI group showed improvements with five days of training, but this learning did not generalize from the trained task to the untrained task in any group. These results highlight task-specificity in TPL and suggest that training-dependent improvements in timing ability might reflect an active reweighting of decision units, in addition to refinements in the sensory representation of a learned interval.

neuroscience↗

bioRxiv2019

Structural basis of recruitment of RBM39 to DCAF15 by a sulfonamide molecular glue E7820

E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. In order to understand their mechanism of action, we carried out kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the 1 helix of RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other protein of interests.

biophysics↗

bioRxiv2019

Mice Lacking FXR Are Susceptible to Liver Ischemia-Reperfusion Injury

Activation of bile acid (BA) receptor, farnesoid X receptor (FXR) has been shown to inhibit inflammatory responses and improve tissue ischemia-reperfusion injury (IRI). This study investigated the effect of FXR deficiency on liver IRI, using a liver warm IRI mouse model. We demonstrate that liver IRI resulted in decreased FXR expression in the liver of WT mice. FXR-/-mice displayed greater liver damage and inflammatory responses than WT mice, characterized by significant increases in liver weight, serum AST and ALT, hepatocyte apoptosis and liver inflammatory cytokines. Liver IRI increased expression of X box binding protein 1 (XBP1) and FGF21 in WT liver, but not in FXR-/- liver, which conversely increased CHOP expression, suggesting a loss of ER stress protection in the absence of FXR. FXR deficiency increased circulating total BAs and altered BA composition with reduced TUDCA and hepatic BA synthesis markers. FXR deficiency also reshaped gut microbiota composition with increased Bacteroidetes and Proteobacteria and decreased Firmicutes. Curiously, Bacteroidetes were positively and Firmicutes were negatively correlated with serum ALT levels. Administration of FXR agonist CDCA inhibited NF-{kappa}B activity and TNF expression in vitro and improved liver IRI in vivo. Our findings demonstrate that FXR signaling plays an important role in the modulation of liver IRI.

physiology↗

bioRxiv2019

Microstimulation of primate neocortex targeting striosomes induces negative decision-making

Affective judgment and decision-making are strongly modulated by the pregenual anterior cingulate (pACC) and caudal orbitofrontal (cOFC) cortical regions. By combining MRI-guided electrical microstimulation with viral tracing methods in non-human primates, we demonstrate that circumscribed pACC and cOFC microstimulation sites that induce negative decision-making preferentially project to striosomes in the anterior striatum. These results outline a behaviorally important circuit from pACC/cOFC to striosomes causally modulating decision-making under emotional conflict.

neuroscience↗

bioRxiv2019

Effect of adiposity on leukocyte telomere length in US adults by race/ethnicity: The National Health and Nutrition Examination Survey

ObjectiveObesity is associated with telomere attrition - a marker of cellular and biological aging. The US has the highest proportion of obesity and is comprised of a racially/ethnic diverse population. Little is known about the relationship between obesity and telomere attrition according to race/ethnicity in the US. Our objective is to examine the differential association.\n\nDesign and settingThe effect of body mass index (BMI), % total body fat (TBF) and waist circumference (WC) on leukocyte telomere length (LTL) were examined as adiposity measures according to race/ethnicity and sex specific race/ethnicity using separate adjusted linear regressions on a sample of 4,919 respondents aged 20-84 years from cross-sectional 1999-2002 data using the US National Health and Nutrition Examination Survey. Mediation analyses assessed health behaviors associated with relationship between adiposity measures and LTL.\n\nMain outcome measureLTL\n\nResultsAfrican Americans (AA) experienced a 28% and 11% decrease in LTL associated with increasing BMI and WC, (p=.02 and .03) respectively. Mexican Americans (MA) experienced a 33% decrease in LTL associated with increasing %TBF (p=.04). Whites experienced a 19%, 23%, and .08% decrease in LTL associated with increasing BMI, %TBF, and WC, (p=.05, .003, .02) respectively. White men experienced a 26% decrease in LTL due to increasing BMI (p=.05). AA women experienced a 41%, 44%, and 16% decrease in LTL due to increasing BMI, %TBF, and WC, respectively (p=.007, .02, .04). White women experienced a 29% decrease in LTL associated with increasing %TBF (p=.006). Selected health behaviors were associated with the relationship between adiposity measures and LTL.\n\nConclusionOverall, AA and Whites have worse cellular and biological aging related to collective adiposity measures. According to sex, AA women experienced more deleterious cellular and biological aging. Findings suggest tailored interventions to improve adverse behaviors that contribute to obesity may improve telomere attrition in US adults.

epidemiology↗

bioRxiv2019

Verify Hub Genes of expression profile in aortic dissection

BackgroundTo assess the mRNAs expression profile and explore the hub mRNAs and potential molecular mechanisms in the pathogenesis of human thoracic aortic dissection (TAD). Methodology: mRNA microarray expression signatures of TAD tissues (n=6) and no TAD tissues (NT;n=6) were analyzed by Arraystar human mRNAs microarray. Real-time PCR (qRT-PCR) were used to validate the result of mRNAs microarray. Bioinformatic tools including gene ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analysis were utilized. The protein-protein interaction networks were constructed based on data from the STRING database. Molecular Complex Detection (MCODE) and cytohubba analysis were used to infer the most hug gene and pathways. Results: The top 10 hub genes CDK1, CDC20, CCNB2, CCNB1, MAD2L1, AURKA, C3AR1, NCAPG,CXCL12 and ASPM were identified from the PPI network. Module analysis revealed that TAD was associated with cell cycle, oocyte meiosis, p53 signaling pathway, progesterone-mediated oocyte maturation. The qRT-PCR result showed that the expression of all hug genes was significantly increased in TAD samples (p < 0.05). Conclusions: These candidate genes could be used as potential diagnostic biomarkers and therapeutic targets of TAD.\n\nAuthor summaryMany basic characteristics underlying the establishment of aortic dissection have not been studied in detail. The presented work sought to understand the pathogenesis of human thoracic aortic dissection by employing bioinformatic tools to explore the hub mRNAs and potential molecular mechanisms of thoracic aortic dissection. Many pathway were thought to have relevant with this disease, but the most important pathway was not define. We used bio-mathematical analysis to explore the potential functions in thoracic aortic dissection and identified the hub genes and explored the intrinsic molecular mechanisms involved in thoracic aortic dissection between two microarray analysis. Finally, we indentified the cell cycle maybe the key pathway in thoracic aortic dissection.

bioinformatics↗

bioRxiv2019

Xenotransplantation of Human PSC-derived Microglia Creates a Chimeric Mouse Brain Model that Recapitulates Features of Adult Human Microglia

Microglia, the brain-resident macrophages, exhibit highly dynamic functions in neurodevelopment and neurodegeneration. Human microglia possess unique features as compared to mouse microglia, but our understanding of human microglial functions is largely limited by an inability to obtain human microglia under homeostatic states. We developed a human pluripotent stem cell (hPSC)-based microglial chimeric mouse brain model by transplanting hPSC-derived primitive macrophage precursors into neonatal mouse brains. The engrafted human microglia widely disperse in the brain and replace mouse microglia in corpus callosum at 6 months post-transplantation. Single-cell RNA-sequencing of the microglial chimeric mouse brains reveals that xenografted hPSC-derived microglia largely retain human microglial identity, as they exhibit signature gene expression patterns consistent with physiological human microglia and recapitulate heterogeneity of adult human microglia. Importantly, the engrafted hPSC-derived microglia exhibit dynamic response to cuprizone-induced demyelination and species-specific transcriptomic differences in the expression of neurological disease-risk genes in microglia. This model will serve as a novel tool to study the role of human microglia in brain development and degeneration.

neuroscience↗

bioRxiv2019

Effects of topical PaiTeLing in nude mice implanted with human condyloma acuminatum tissue infected with HPV 6, 31, and 81: comparison with imiquimod and interferon-α-2b

BACKGROUNDThe standard treatment for condyloma acuminatum is topical imiquimod. In the current study, we used a mouse model to compare the effects of an herbal medication PaiTeLing. METHODSLesion tissue was obtained from a woman with genital condyloma acuminatum. DNA genotyping revealed HPV6, 31, and 81. Tissue prism (0.5 cm3) was implanted to BALB/C nude mice, 22 days after the implantation, mice began to receive topical treatment with imiquimod, interferon--2b gel, or PaiTeLing over the site of implantation for 2 consecutive weeks. Mice receiving tissue implantation but no other intervention was included as a control. Skin tissue was collected for H&E staining and anti-CD207 immunohistochemistry. Blood was collected to determine a panel of cytokines. RESULTSH&E staining showed lower number of koilocytes and higher number of Langerhans cells in the treatment groups, particularly in mice receiving imiquimod or PaiTeLing. Blood levels of TNF, IL-2, INF-{gamma} and IL-12p70 were increased in the treatment groups, particularly in mice receiving imiquimod or PaiTeLing. CONCLUSIONImmune response in nude mice infected with HPV6, 31, and 81 is enhanced by treatment with imiquimod, interferon--2b and PaiTeLing. Effects of imiquimod and PaiTeLing seems to be stronger than interferon--2b.

immunology↗

bioRxiv2018

Genome sequencing analysis identifies high-risk Epstein-Barr virus subtypes for nasopharyngeal carcinoma

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and associated with multiple cancers including nasopharyngeal carcinoma (NPC). The role of EBV viral genomic variation in NPC development and its striking endemicity in southern China has been poorly explored. Through large-scale genome sequencing and association study of EBV isolates from China, we identified two non-synonymous EBV variants within BALF2 strongly associated with NPC risk (conditional P value 1.75x10-6 for SNP162476_C and 3.23x10-13 for SNP163364_T), whose cumulative effects contributed to 83% of the overall risk in southern China. Phylogenetic analysis of the risk variants revealed a unique origin in southern China followed by clonal expansion. EBV BALF2 haplotype carrying the risk variants were shown to reduce viral lytic DNA replication, as a result potentially promoting viral latency. Our discovery has not only provided insight to the unique endemic pattern of NPC occurrence in southern China, but also paved the way for the identification of individuals at high risk of NPC and effective intervention program to reduce the disease burden in southern China.

genetics↗

bioRxiv2018

Reversing Abnormal Neural Development by Inhibiting OLIG2 in Down Syndrome Human iPSC Brain Organoids and Neuronal Mouse Chimeras

Down syndrome (DS) is a common neurodevelopmental disorder, and cognitive defects in DS patients may arise form imbalances in excitatory and inhibitory neurotransmission. Understanding the mechanisms underlying such imbalances may provide opportunities for therapeutic intervention. Here, we show that human induced pluripotent stem cells (hiPSCs) derived from DS patients overproduce OLIG2+ ventral forebrain neural progenitors. As a result, DS hiPSC-derived cerebral organoids excessively produce specific subclasses of GABAergic interneurons and cause impaired recognition memory in neuronal chimeric mice. Increased OLIG2 expression in DS cells directly upregulates interneuron lineage-determining transcription factors. shRNA-mediated knockdown of OLIG2 largely reverses abnormal gene expression in early-stage DS neural progenitors, reduces interneuron production in DS organoids and chimeric mouse brains, and improves behavioral deficits in DS chimeric mice. Thus, altered OLIG2 expression may underlie neurodevelopmental abnormalities and cognitive defects in DS patients.

neuroscience↗