Biology subjects

Cai, M.

Publications and source records attributed to Cai, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Melanocortin 1 receptor regulates cholesterol and bile acid metabolism in the liver

Melanocortin 1 receptor (MC1-R) is widely expressed in melanocytes and leukocytes, and is thus strongly implicated in the regulation of skin pigmentation and inflammation. MC1-R mRNA has also been found in the rat and human liver, but its functional role has remained elusive. We hypothesized that MC1-R is functionally active in the liver and involved in the regulation of cholesterol and bile acid metabolism. We generated hepatocyte-specific MC1-R knock-out (L-Mc1r-/-) mice and phenotyped the mouse model for lipid profiles, liver histology and bile acid levels. L-Mc1r-/- mice had significantly increased liver weight, which was accompanied by elevated levels of total cholesterol and triglycerides in the liver as well as in the plasma. These mice demonstrated also enhanced liver fibrosis and a disturbance in bile acid metabolism as evidenced by markedly reduced bile acid levels in the plasma and feces. Mechanistically, using HepG2 cells as an in vitro model, we found that selective activation of MC1-R in HepG2 cells reduced cellular cholesterol content and enhanced uptake of low- and high-density lipoprotein particles via a cAMP-independent mechanism. In conclusion, the present results demonstrate that MC1-R signaling in hepatocytes regulates cholesterol and bile acid metabolism and its deficiency leads to hypercholesterolemia and enhanced lipid accumulation and fibrosis in the liver.

physiology↗

bioRxiv2022

NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice

AbstractTransplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation is limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarct, neuronal death and glial scarring, and promoted the motor function recovery. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

neuroscience↗

bioRxiv2022

A 4-bp natural deletion of maize Na+/H+ exchanger gene alters maize salt stress tolerance

Soil salinity is a major environmental constraint severely reducing plant growth and crop productivity worldwide. Knowledge of salt tolerance-related genes can facilitate improving crop salt tolerance and alleviating the threat of increasing saline area to world food security. Here, we identified a major locus SALT TOLERANCE 1 (qST1) conferring maize salt tolerance via bulked segregant RNA-Seq (BSR-Seq). qST1 encodes a plasma membrane Na+/H+ exchanger ZmSOS1 which is the ortholog of Arabidopsis thaliana SOS1 gene. In salt-sensitive variety D9H, the natural variation of 4-bp deletion in the coding sequence of ZmSOS1 gene was the causal allele for salt sensitivity. We identified two ethyl methanesulfonate-induced mutants, zmsos1-1 and zmsos1-2, which were sensitive to salt stress and cant complement salt-sensitive variety under salt stress within an allelism test. Overexpression of ZmSOS1 enhanced maize seedling salt tolerance. ZmSOS1 can increase the salt tolerance of Arabidopsis sos1-1 mutant and can be activated by AtSOS2 and AtSOS3 in yeast cells, suggesting that ZmSOS1 confers salt tolerance through the conserved SOS signaling pathway in maize. The detrimental allele harboring the 4-bp deletion was rarely found in the natural population but appeared in an important heterotic group composed of x1132x-derived inbred lines which have been used widely for breeding dozens of hybrid varieties in China. The 4-bp deletion-based molecular marker has been successfully used to improve salt-sensitive varieties in a backcross and marker-assisted breeding program by screening and purging this deleterious allele.

plant biology↗

bioRxiv2022

RPG interacts with E3-ligase CERBERUS to mediate rhizobial infection in Lotus japonicus

Symbiotic interactions between rhizobia and legumes result in the formation of root nodules, which fix nitrogen that can be used for plant growth. Rhizobia usually invade legume roots through a plant-made tunnel-like structure called an infection thread (IT). Rhizobium-directed polar growth (RPG) encodes a coiled-coil protein that was identified in Medicago truncatula as required for root nodule infection, but the function of RPG remains poorly understood. In this study, we identified and characterized RPG in Lotus japonicus and determined that it is required for IT formation. RPG was induced by Mesorhizobium loti or purified Nodulation factor and displayed an infection-specific expression pattern. Nodule inception (NIN) bound to the RPG promoter and induced its expression. A GFP-RPG protein was localized in puncta subcellular localization in L. japonicus root protoplasts and in root hairs infected by M. loti. The N-terminal predicted C2 lipid-binding domain of RPG was not required for this subcellular localization or for function. CERBERUS, a U-box E3 ligase which is also required for rhizobial infection, was found to be localized in similar puncta. RPG co-localized and directly interacted with CERBERUS at the early endosomes (TGN/EE) compartment and near the nuclei in root hairs after rhizobia inoculation. Our study sheds light on that a RPG-CERBERUS protein complex that is involved in an exocytotic pathway mediating IT polarity growth which is driven by nuclear migration. One sentence summaryPuncta localization RPG-CERBERUS protein complex promote polarity growth of ITs driven by nuclear migration.

cell biology↗

bioRxiv2022

Leveraging the local genetic structure for trans-ancestry association mapping

Over the past two decades, genome-wide association studies (GWASs) have successfully advanced our understanding of genetic basis of complex traits. Despite the fruitful discovery of GWASs, most GWAS samples are collected from European populations, and these GWASs are often criticized for their lack of ancestry diversity. Trans-ancestry association mapping (TRAM) offers an exciting opportunity to fill the gap of disparities in genetic studies between non-Europeans and Europeans. Here we propose a statistical method, LOG-TRAM, to leverage the local genetic architecture for TRAM. By using biobank-scale datasets, we showed that LOG-TRAM can greatly improve the statistical power of identifying risk variants in under-represented populations while producing well-calibrated p-values. We applied LOG-TRAM to the GWAS summary statistics of 29 complex traits/diseases from Biobank Japan (BBJ) and UK Biobank (UKBB), and achieved substantial gains in power (the effective sample sizes increased by 49% in average compared to the BBJ GWASs) and effective correction of confounding biases compared to existing methods. Finally, we demonstrated that LOG-TRAM can be successfully applied to identify ancestry-specific loci and the LOG-TRAM output can be further used for construction of more accurate polygenic risk scores (PRSs) in under-represented populations.

bioinformatics↗

bioRxiv2022

Expansion and Adaptive Evolution of the mTERF Gene Family in Plants

Mitochondrial transcription termination factor (mTERF) genes are encoded in the nucleus and bind to nucleic acids to regulate the replication, transcription and translation of mitochondrial genomes. Plants possess a large family of mTERF genes that play important roles in regulating organellar gene expression and stress response. However, their origin and expansion in land plants has not been examined. Here, we conducted a comprehensive molecular evolution analysis of 611 mTERF genes identified in 18 plant species, including algae, moss, fern, gymnosperm and flowering plants. Higher plants have more mTERF genes compared to lower plants, forming a huge higher plant-specific clade (M-class mTERF genes). M-class mTERF genes occur in clusters, suggesting that tandem duplication contributed to their expansion. Compared to other mTERF genes, M-class mTERF genes have undergone rapid evolution, and several significant positively selected sites were located in nucleic acid-binding sites. The strong correlation between the number of M-class mTERF genes and corresponding mitochondrial genome variation suggests that the rapid evolution of M-class mTERF genes might account for the changes in the complex machinery for expression regulation of plant mitochondrial genomes, providing molecular evidence for the host-parasite interaction hypothesis between the nucleus and mitochondria.

plant biology↗

bioRxiv2021

High-fidelity Cas13 variants for targeted RNA degradation with minimal collateral effect

CRISPR-Cas13 systems have recently been employed for targeted RNA degradation in various organisms. However, collateral degradation of bystander RNAs has imposed a major barrier for their in vivo applications. We designed a dual-fluorescent reporter system for detecting collateral effects and screening Cas13 variants in mammalian cells. Among over 200 engineered variants, several Cas13 variants (including Cas13d and Cas13X) exhibit efficient on-target activity but markedly reduced collateral activity. Furthermore, transcriptome-wide off-targets and cell growth arrest induced by Cas13 are absent for these variants. Importantly, high-fidelity Cas13 variants show comparable RNA knockdown activity with wild-type Cas13 but no detectable collateral damage in transgenic mice and adeno-associated virus-mediated somatic cell targeting. Thus, high-fidelity Cas13 variants with minimal collateral effect are now available for targeted degradation of RNAs in basic research and therapeutic applications.

molecular biology↗

bioRxiv2021

Develop an efficient and specific AAV-based labeling system for Muller glia in mice

Cell degeneration in the retina leads to several ocular diseases and vision loss. Considerable research efforts focus on reprogramming Muller glia (MG) into functional cells to rescue vision as a promising therapeutic strategy, although whether MG can convert into functional bipolar cells, retinal ganglia cells (RGCs), rods or cones in mammals remains controversial. The broad applicability of tracking MG differentiation thus presents a need for improved labeling efficiency and specificity. Here, we compared AAV-based labeling strategies with conventional lineage-tracking by crossing transgenic mouse lines. We found that reporter expression was weak and not MG-specific in mGFAP-Cre transgenic mice. Different AAV serotypes showed a range of efficiency and specificity in labeling MG, leading us to optimize a human GFAP-Cre reporter system packaged in the AAV9 serotype with the WPRE (WPRE, woodchuck hepatitis virus post-transcriptional regulatory element) removed. The hGFAP-Cre- {Delta}WPRE reporter could label 20-73.8% MGs, with non-specific RGC labeling rates ranging from 0-0.08% at doses of 1 x 108 to 1010 vector genomes (vg) per eye, an approximate 40-fold reduction compared with the AAV9-hGFAP-Cre-WPRE labeling system. Furthermore, we validated the availability of the label system to trace MG reprogramming and also detected false-positive results reported previously. The AAV9-hGFAP-Cre-{Delta}WPRE system thus represents a highly efficient and specific labeling system for MG, providing a valuable tool for tracking cell fate in vivo.

neuroscience↗

bioRxiv2021

A live attenuated influenza virus-vectored intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2 infection

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 day and 7 days after single-dose vaccination or 6 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight, caused by either the prototype-like strain or beta variant of SARS-CoV-2. Lasted data showed that the animals could be well protected against beta variant challenge 9 months after vaccination. Notably, the weight loss and lung pathological changes of hamsters could still be significantly reduced when the hamster was vaccinated 24 h after challenge. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to fight against the ongoing COVID-19 pandemic, compensating limitations of current intramuscular vaccines, particularly at the start of an outbreak.

pathology↗

bioRxiv2021

Water Pollution and Administrative Division Adjustments: A Quasi-natural Experiment in Chaohu Lake of China

The adjustment of administrative divisions introduces a series of uncertain impacts on the social and economic development in the administrative region. Previous studies focused more on the economic effects of the adjustment of administrative divisions, while, in this paper, we also take environmental effects into consideration. The administrative division adjustment for Chaohu Lake is used as a quasi-natural experiment to explore the influence of the adjustment on pollution control. The synthetic control method is used in this study to access the effect of administrative division adjustment on the water quality indicators of Chaohu Lake and its internal mechanism. Some conclusions are as follows. First, after the administrative division adjustment, some water quality indicators, such as ammonia nitrogen, have indeed been alleviated; however, other major pollution indicators, such as chemical oxygen demand and dissolved oxygen, have deteriorated to varying degrees. Second, the results also reveal that improper development ideas, industrial excessive expansion, and the swing of economic growth and environmental goals are problems after the adjustment. Returning to the original intention of adjustment, rationalizing the Chaohu Lake management system and designing a sound and feasible accountability mechanism are fundamental measures to reduce pollution.

ecology↗

bioRxiv2020

Sterilizing immunity against SARS-CoV-2 in hamsters conferred by a novel recombinant subunit vaccine

A safe and effective SARS-CoV-2 vaccine is essential to avert the on-going COVID-19 pandemic. Here, we developed a subunit vaccine, which is comprised of CHO-expressed spike ectodomain protein (StriFK) and nitrogen bisphosphonates-modified zinc-aluminum hybrid adjuvant (FH002C). This vaccine candidate rapidly elicited the robust humoral response, Th1/Th2 balanced helper CD4 T cell and CD8 T cell immune response in animal models. In mice, hamsters, and non-human primates, 2-shot and 3-shot immunization of StriFK-FH002C generated 28- to 38-fold and 47- to 269-fold higher neutralizing antibody titers than the human COVID-19 convalescent plasmas, respectively. More importantly, the StriFK-FH002C immunization conferred sterilizing immunity to prevent SARS-CoV-2 infection and transmission, which also protected animals from virus-induced weight loss, COVID-19-like symptoms, and pneumonia in hamsters. Vaccine-induced neutralizing and cell-based receptor-blocking antibody titers correlated well with protective efficacy in hamsters, suggesting vaccine-elicited protection is immune-associated. The StriFK-FH002C provided a promising SARS-CoV-2 vaccine candidate for further clinical evaluation.

microbiology↗

bioRxiv2020

XGSEA: CROSS-species Gene Set Enrichment Analysis via domain adaptation

Gene set enrichment analysis (GSEA) has been widely used to identify gene sets with statistically significant difference between cases and controls against a large gene set. GSEA needs both phenotype labels and expression of genes. However, gene expression are assessed more often for model organisms than minor species. More importantly, gene expression could not be measured under specific conditions for human, due to high healthy risk of direct experiments, such as non-approved treatment or gene knockout, and then often substituted by mouse. Thus predicting enrichment significance (on a phenotype) of a given gene set of a species (target, say human), by using gene expression measured under the same phenotype of the other species (source, say mouse) is a vital and challenging problem, which we call CROSS-species Gene Set Enrichment Problem (XGSEP). For XGSEP, we propose XGSEA (Cross-species Gene Set Enrichment Analysis), with three steps of: 1) running GSEA for a source species to obtain enrichment scores and p-values of source gene sets; 2) representing the relation between source and target gene sets by domain adaptation; and 3) using regression to predict p-values of target gene sets, based on the representation in 2). We extensively validated XGSEA by using four real data sets under various settings, proving that XGSEA significantly outperformed three baseline methods. A case study of identifying important human pathways for T cell dysfunction and reprogramming from mouse ATAC-Seq data further confirmed the reliability of XGSEA. Source code is available through https://github.com/LiminLi-xjtu/XGSEA Author summaryGene set enrichment analysis (GSEA) is a powerful tool in the gene sets differential analysis given a ranked gene list. GSEA requires complete data, gene expression with phenotype labels. However, gene expression could not be measured under specific conditions for human, due to high risk of direct experiments, such as non-approved treatment or gene knockout, and then often substituted by mouse. Thus no availability of gene expression leads to more challenging problem, CROSS-species Gene Set Enrichment Problem (XGSEP), in which enrichment significance (on a phenotype) of a given gene set of a species (target, say human) is predicted by using gene expression measured under the same phenotype of the other species (source, say mouse). In this work, we propose XGSEA (Cross-species Gene Set Enrichment Analysis) for XGSEP, with three steps of: 1) GSEA; 2) domain adaptation; and 3) regression. The results of four real data sets and a case study indicate that XGSEA significantly outperformed three baseline methods and confirmed the reliability of XGSEA.

bioinformatics↗

bioRxiv2020

Proto-sex locus in large yellow croaker provides insights into early evolution of the sex chromosome

Autosomal origins of heterogametic sex chromosomes have been inferred frequently from suppressed recombination and gene degeneration manifested in incompletely differentiated sex chromosomes. However, the initial transition of an autosome region to a proto-sex locus has been not explored in depth. By assembling and analyzing a chromosome-level draft genome, we found a recent (evolved 0.26 million years ago), highly homologous, and dmrt1 containing sex-determination locus with slightly reduced recombination in large yellow croaker (Larimichthys crocea), a teleost species with genetic sex determination (GSD) and with undifferentiated sex chromosomes. We observed genomic homology and polymorphic segregation of the proto-sex locus between sexes. Expression of dmrt1 showed a stepwise increase in the development of testis, but not in the ovary. We infer that the inception of the proto-sex locus involves a few divergences in nucleotide sequences and slight suppression of recombination in an autosome region. In androgen-induced sex reversal of genetic females, in addition to dmrt1, genes in the conserved dmrt1 cluster, and the rest of the sex determination network were activated. We provided evidence that broad functional links were shared by genetic sex determination and environmental sex reversal.

evolutionary biology↗

bioRxiv2019

Highly diverse Asgard archaea participate in organic matter degradation in coastal sediments

Asgard is an archaeal superphylum that might hold the key to understand the origin of eukaryotes, but its diversity and ecological roles remain poorly understood. Here, we reconstructed 15 metagenomic-assembled genomes (MAGs) from coastal sediments covering most known Asgard archaea and a novel group, which is proposed as a new Asgard phylum named as the "Gerdarchaeota". Genomic analyses predict that Gerdarchaeota are facultative anaerobes in utilizing both organic and inorganic carbon. Unlike their closest relatives Heimdallarchaeota, Gerdarchaeota have genes encoding for cellulase and enzymes involving in the tetrahydromethanopterin-based Wood-Ljungdahl pathway. Transcriptomic evidence showed that all known Asgard archaea are capable of degrading organic matter, including peptides, amino acids and fatty acids, in different ecological niches in sediments. Overall, this study broadens the diversity of the mysterious Asgard archaea and provides evidence for their ecological roles in coastal sediments.

microbiology↗

bioRxiv2019

Dual oxidase gene Duox and Toll-like receptor 3 gene TLR3 in the Toll pathway suppress zoonotic pathogens through regulating the intestinal bacterial community homeostasis in Hermetia illucens L.

Black soldier fly (BSF; Hermetia illucens L.) larvae can convert fresh pig manure into protein and fat-rich biomass, which can then be used as livestock feed. Currently, it is the only insect approved for such purposes in Europe, Canada, and the USA. Pig manure is rich in zoonotic pathogens (e.g., Staphylococcus aureus and Salmonella spp.). BSF larvae inhibit these zoonotic pathogens; however, the mechanism is unclear. We employed RNAi, qRT-PCR, and Illumina MiSeq bacterial 16S rDNA high-throughput sequencing molecular techniques to study the interaction between the two immune genes (Duoxin Duox-reactive oxygen species [ROS] immune system and TLR3 in the Toll signaling pathway) and zoonotic pathogens to determine the mechanisms resulting in pathogen suppression. Results indicated that Bsf Duox-TLR3 RNAi increased bacterial load but decreased the relative abundance of Providenciaand Dysgonomonasintestinal symbionts. Concurrently, Bsf Duox-TLR3 RNAi inactivated the NF-{kappa} B signaling pathway, downregulated the expression of antimicrobial peptides, and diminished inhibitory effects on zoonotic pathogen. The resulting dysbiosis stimulated an immune response by activating BsfDuox and promoting ROS, which regulated the composition and structure of the gut bacterial community. Thus, BsfDuox and BsfTLR3 are important factors in regulating the gut key bacteria Providenciaand Dysgonomonas homeostasis while inhibiting target zoonotic pathogens.

microbiology↗

bioRxiv2019

Quantifying the impact of genetically regulated expression on complex traits and diseases

About 90% of risk variants identified from genome-wide association studies (GWAS) are located in non-coding regions, highlighting the regulatory role of genetic variants. We propose a unified statistical framework, IGREX, for quantifying the impact of genetically regulated expression (GREX). This is achieved by estimating proportion of phenotypic variations that can be explained by the GREX component. IGREX only requires summary-level GWAS data and a gene expression reference panel as input. In real data analysis, using 48 tissues from the GTEx project as the reference panel, we applied IGREX to a wide spectrum of phenotypes in GWAS, and observed a significant proportion of phenotypic variations could be attributed to the GREX component. In particular, the results given by IGREX revealed tissue-across and tissue-specific patterns of the GREX effects. We also observed strong association between GREX effect and immune-related proteins, further supporting the relevance between GREX and the immune processes.

bioinformatics↗

bioRxiv2019

Consideration of species-specific diatom indicators of anthropogenic stress in the Great Lakes

Robust inferences of environmental condition come from bioindicators that have strong relationships with stressors and are minimally confounded by extraneous environmental variables. These indicator properties are generally assumed for assemblage-based indicators such as diatom transfer functions that use species abundance data to infer environmental variables. However, failure of assemblage approaches necessitates the interpretation of individual dominant taxa when making environmental inferences. To determine whether diatom species from Laurentian Great Lakes sediment cores have the potential to provide unambiguous inferences of anthropogenic stress, we evaluated fossil diatom abundance against a suite of historical environmental gradients: human population, agriculture, mining, atmospheric nutrient deposition, atmospheric temperature and ice cover. Several diatom species, such as Stephanodiscus parvus, had reliable relationships with anthropogenic stress such as human population. However, many species had little or no indicator value or had confusing relationships with multiple environmental variables, suggesting one should be careful when using those species to infer stress in the Great Lakes. Recommendations for future approaches to refining diatom indicators are discussed, including accounting for the effects of broad species geographic distributions to minimize region-specific responses that can weaken indicator power.

ecology↗

bioRxiv2018

Asgard archaea are diverse, ubiquitous, and transcriptionally active microbes

Asgard is a newly proposed archaeal superphylum. Phylogenetic position of Asgard archaea and its relationships to the origin of eukaryotes is attracting increasingly research interest. However, in-depth knowledge of their diversity, distribution, and activity of Asgard archaea remains limited. Here, we used phylogenetic analysis to cluster the publicly available Asgard archaeal 16S rRNA gene sequences into 13 subgroups, including five previously unknown subgroups. These lineages were widely distributed in anaerobic environments, with the majority of 16S rRNA gene sequences (92%) originating from sediment habitats. Co-occurrence analysis revealed potential relationships between Asgard, Bathyarchaeota, and Marine Benthic Group D archaea. Genomic analysis suggested that Asgard archaea are potentially mixotrophic microbes with divergent metabolic capabilities. Importantly, metatranscriptomics confirmed the versatile lifestyles of Lokiarchaeota and Thorarchaeota, which can fix CO2 using the tetrahydromethanopterin Wood-Ljungdahl pathway, perform acetogenesis, and degrade organic matters. Overall, this study broadens the understandings of Asgard archaea ecology, and also provides the first evidence to support a transcriptionally active mixotrophic lifestyle of Asgard archaea, shedding light on the potential roles of these microorganisms in the global biogeochemical cycling.

microbiology↗