Biology subjects

Lei, X.

Publications and source records attributed to Lei, X..

79 records · Page 5Linked to original sources

bioRxiv2019

MRGPRX4 is a novel bile acid receptor in cholestatic itch

Patients with liver diseases often suffer from chronic itch or pruritus, yet the itch-causing pruritogen(s) and their cognate receptor(s) remain largely elusive. Using transcriptomics and GPCR activation assays, we found that an orphan, primate specific MRGPRX4 is expressed in human dorsal root ganglia (hDRG) and selectively activated by bile acids. In situ hybridization and immunohistochemistry revealed that MRGPRX4 is expressed in [~]7% of hDRG neurons and co-localizes with HRH1, a known itch-inducing GPCR. Bile acids elicited a robust Ca2+ response in a subset of cultured hDRG neurons, and intradermal injection of bile acids and an MRGPRX4 specific agonist induced significant itch in healthy human subjects. Surprisingly, application of agonist for TGR5, a known sequence conserved bile acid receptor previously implicated in cholestatic itch, failed to elicit Ca2+ response in cultured hDRG neurons, nor did it induce pruritus in human subjects. In situ hybridization and immunostaining results revealed that hTGR5 is selectively expressed in satellite glial cells, unlike mTGR5 (in mouse DRG neurons), likely accounting for the inter-species difference functionally. Finally, we found that patients with cholestatic itch have significantly higher plasma bile acid levels compared to non-itchy patients and the bile acid levels significantly decreased after itch relief. This elevated bile acid level in itchy patients is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch, providing a promising new drug target for anti-itch therapies.

neuroscience↗

bioRxiv2019

Inhibiting TG2 sensitize lung cancer to radiotherapy through interfering TOPOIIα-mediated DNA repair

Radiotherapy is an indispensable strategy for lung cancer, however, treatment failure or reoccurrence is often found in patients due to the developing radioresistance. Novel approaches are required for radiosensitizing to improve the therapeutic efficacy. In present study, we found that transglutaminase 2 (TG2) confers radioresistance in non-small cell lung cancer (NSCLC) cells through regulating TOPOII and promoting DNA repair. Our data showed that TG2 inhibitor or knockdown increased NSCLC radiosensitivity in vivo and in vitro. We found that TG2 translocated into nucleus and located to DSB sites, surprisingly, knockdown TG2 or glucosamine inhibited the phosphorylation of ATM, ATR and DNA-Pkcs. Through IP-MS assay and functional experiments, we identified that TOPOII as an downstream factor of TG2. Moreover, we found that TGase domain account for the interaction with TOPOII. Finally, we found that TG2 expression was correlated with poor survival in lung adenocarcinoma instead of squamous cell carcinoma. In conclusion, we demonstrated that inhibiting TG2 sensitize NSCLC to IR through interfere TOPOII mediated DNA repair, suggesting TG2 as a potential radiosensitizing target in NSCLC.

cancer biology↗

bioRxiv2018

Ancient DNAs and the Neolithic Chinese super-grandfather Y haplotypes

Previous studies identified 3 Neolithic Han Chinese super-grandfather Y haplotypes, O2a2b1a1a-F5, O2a2b1a2a1-F46, and O2a1b1a1a1a-F11, but their relationships with the archaeological and written records remain unexplored. We here report genome wide DNA data for 12 ancient samples (0.02x-1.28x) from China ranging from 6500 to 2500 years before present (YBP). They belonged to 4 different genetic groups, designated as Dashanqian (DSQ) of Xiajiadian Culture in the Northeast, Banpo (BP) of middle Yangshao Culture in the Central West, Zhengzhou Xishan (ZX) of Miaodigou Culture in the Central Plains, and Others. Present day F5 samples were closer in autosomal distances to the ZX and DSQ groups while F11, C, O1, and O2 samples were closer to the BP group. We also sequenced the Y chromosome of one of these ancient samples K12 from DSQ and found both K12 and a previously reported ~4000 year old sample MG48 from Northwest China to have the O2a2b1a1a1a2a-F2137 haplotype, belonging to the most prolific branch O2a2b1a1a1-F438 immediately under F5. We further found close relationships between ZX and DSQ and between ZX and ancient M117 Tibetans or present day Southwest Dai Chinese carrying the F5 subtype O2a2b1a1a6, implicating radiations of F5 subtypes from the putative place of F5 origin in ZX. These results are remarkably consistent with archaeological and written records.

evolutionary biology↗

bioRxiv2018

Genetic continuity in the last seven Millennia in human hepatitis B viruses

Hepatitis B virus (HBV) is a major human pathogen and yet the evolution history of HBV has largely remained uncertain. With a better theoretical understanding of genetic diversity, we here used a new method to examine the previously published ancient and present day HBV genomes. We identified an informative region in the HBV polymerase that is slow evolving and used it to study genetic distances among HBVs. Three ancient human HBV isolates from 4488-7074 years ago in Germany were identified as genotype G that is also presently common in the same country. We constructed a new phylogenetic tree of HBVs that placed genotype D as the most basal branch with an inferred age of ~20500 years, which is remarkably consistent with the worldwide distribution and a most parsimonious migration route of HBV genotypes today. These results help resolve the evolutionary history of HBV and provide a useful method for studying the phylogenetics of HBV and other viruses in general.

evolutionary biology↗

bioRxiv2017

Accumulation of Minor Alleles of Common SNPs in Schizophrenia

Schizophrenia is a common neuropsychiatric disorder with a lifetime risk of 1%. A number of large scale genome wide association studies have identified numerous individual risk single nucleotide polymorphisms (SNPs) whose precise roles in schizophrenia remain unknown. Accumulation of many of these risk alleles has been found to be a more important risk factor. Consistently, recent studies showed a role for enrichment of minor alleles (MAs) in complex diseases. Here we studied the role of MAs in general in schizophrenia using public datasets. Relative to matched controls, schizophrenia cases showed higher minor allele content (MAC), especially for the sporadic cases. By linkage analysis, we identified 82 419 SNPs that could be used to predict 2.2% schizophrenia cases with 100% certainty. Pathway enrichment analysis of these SNPs identified 17 pathways, 15 of which are known to be linked with Schizophrenia with the remaining 2 associated with other mental disorders. These results suggest a role for a collective effect of MAs in schizophrenia and provide a method to genetically screen for schizophrenia.\n\nAbbreviations

pathology↗

bioRxiv2017

Collective effects of common SNPs and improved risk prediction in lung cancer

Lung cancer is the leading cause of cancer deaths in both men and women in the US. While most sporadic lung cancer cases are related to environmental factors such as smoking, genetic susceptibility may also play an important role and a number of lung cancer associated single nucleotide polymorphisms (SNPs) have been identified although many remain to be found. The collective effects of genome wide minor alleles of common SNPs, or the minor allele content (MAC) in an individual, have been linked with quantitative variations of complex traits and diseases. Here we studied MAC in lung cancer using previously published SNP datasets and found higher MAC in cases relative to matched controls. A set of 25883 SNPs with MA (MAF < 0.5) more common in cases (P < 0.1) was found to have the best predictive accuracy. A weighted risk score calculated by using this set can predict 2.6% of lung cancer cases (100% specificity). These results identify a novel genetic risk element or higher MAC in lung cancer susceptibility and provide a useful genetic method to identify a small fraction of lung cancer cases.

cancer biology↗

bioRxiv2017

Modern human origins: multiregional evolution of autosomes and East Asia origin of Y and mtDNA

The neutral theory has been used as a null model for interpreting nature and produced the Recent Out of Africa model of anatomically modern humans. Recent studies, however, have established that genetic diversities are mostly at maximum saturation levels maintained by selection, therefore challenging the explanatory power of the neutral theory and rendering the present molecular model of human origins untenable. Using improved methods and public data, we have revisited human evolution and found sharing of genetic variations among racial groups to be largely a result of parallel mutations rather than recent common ancestry and admixture as commonly assumed. We derived an age of 1.86-1.92 million years for the first split in modern human populations based on autosomal diversity data. We found evidence of modern Y and mtDNA originating in East Asia and dispersing via hybridization with archaic humans. Analyses of autosomes, Y and mtDNA all suggest that Denisovan and Neanderthal were archaic Africans with Eurasian admixtures and ancestors of South Asia Negritos and Aboriginal Australians. Verifying our model, we found more ancestry of Southern Chinese from Hunan in Africans relative to other East Asian groups examined. These results suggest multiregional evolution of autosomes and replacements of archaic Y and mtDNA by modern ones originating in East Asia, thereby leading to a coherent account of modern human origins.

evolutionary biology↗