Biology subjects

Qiu, L.

Publications and source records attributed to Qiu, L..

13 recordsLinked to original sources

bioRxiv2018

The convergent evolution of caste in ants and honey bees is based on a shared core of ancient reproductive genes and many plastic genes

Eusociality has convergently evolved multiple times, but the genomic basis of caste-based division of labor and degree to which independent origins of eusociality have utilized common genes remain largely unknown. Here we characterize caste-specific transcriptomic profiles across development and adult body segments from pharaoh ants (Monomorium pharaonis) and honey bees (Apis mellifera), representing two independent origins of eusociality. We identify a substantial shared core of genes upregulated in the abdomens of queen ants and honey bees that also tends to be upregulated in mated female flies, suggesting that these genes are part of a conserved insect reproductive groundplan. Outside of this shared groundplan, few genes are differentially expressed in common. Instead, the majority of the thousands of caste-associated genes are plastically-expressed, rapidly evolving, and relatively evolutionarily young. These results emphasize that the recruitment of both highly conserved and lineage-specific genes underlie the convergent evolution of novel traits such as eusociality.

evolutionary biology↗

bioRxiv2018

Molecular characterization of the viral structural gene of the first dengue virus type 1 outbreak in Xishuangbanna, a border area of China, Burma and Laos

In the context of recent arbovirus epidemics, dengue fever is becoming a greater concern around the world. In August 2017, Xishuangbanna, which is a border city of China, Burma and Laos, had its first major dengue outbreak. A total of 156 serum samples from febrile patients were collected; 97 DENV positive serum samples were screened out, and viral RNAs were successfully and directly extracted, including 77 cases from China and 20 cases from Myanmar. Phylogenetic analysis revealed that all of the strains were classified as DENV-1. There are eight epidemic dengue strains from Myanmar and 74 from Jinghong, Xishuangbanna, that were classified as cluster 1, which are the most similar to the strain of China Guangzhou 2011. There are three epidemic strains from Xishuangbanna Mengla that were classified as cluster 2, which have the closest relationship to the strain of China Hubei 2014. However, there are 12 epidemic strains from Myanmar that were classified as cluster 3, which have the closest relationship to the strain of Laos from 2008, which shows that there is a recycling epidemic trend of DENV in China. There were 236 mutations in the base, which caused 31 nonsynonymous mutations in the DENV structural protein C/prM/E genes when the strain of Xishuangbanna and Myanmar were compared with the DENV-1SS. There is no clear homologous recombination signal among these stains. Homology modeling possibly predicted a three-dimensional structure of the structural protein of these strains and revealed that they had the same three-dimensional structure and all had five predicted protein binding sites, but there are differences in binding site 434 (DENV-1SS: Thr434, DV-Jinghong: Ser434, DV-Myanmar: Ser434, DV-Mengla: Ser434). The results of the molecular clock phylogenetic and demographic reconstruction analysis show that DENV-1 became highly diversified in 1972 followed by a slightly decreased period until 2017. In conclusion, our study lays the foundation for studying the global evolution and prevalence of DENV.\n\nAuthor SummaryDengue fever (DF) is a mosquito-borne illness caused by a flavivirus. Human infections with Dengue virus (DENV) could cause fever, cutaneous rash and malaise. Xishuangbanna, which is located in the southwestern Yunnan Province and is a border city with China, Burma and Laos, was reported to have outbreak of DENV in 2013 and 2015 with different types. However, there was a large outburst of dengue in May 2017. To understand the genetic characterization, potential source and evolution of the virus, 156 serum samples were analyzed. We focused on: (i) Phylogenetic analysis of the structural protein genes sequences; (ii) Mutation, recombination analysis and predicted protein binding sites of the structural protein genes; (iii) Molecular clock and demographic reconstruction of global dengue virus serotype 1(DENV-1). Our results indicated that this is the first outbreak of DENV-1 in Xishuangbanna, dengue epidemic strains on the Burma border of China show diversification, we found a virulence site changed from I to T(amino acid position: 440), which may lead to weakened virulence of the epidemic strains. We found that the evolution of DENV-1 is dominated by regional evolution. Whats more, DENV-1 became highly diversified in 1972 followed by a slightly decreased period until 2017.

epidemiology↗

bioRxiv2018

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

Liver-specific knockout of Nrf1 in mice leads to non-alcoholic steatohepatitis with dyslipidemia, and its deterioration results in spontaneous hepatoma, but the underlying mechanism remains elusive. A similar pathological model is herein reconstructed by using human Nrf1-specific knockout cell lines. We demonstrated that a marked increase of the inflammation marker COX2 in Nrf1-/- cells. Loss of Nrf1 leads to hyperactivation of Nrf2, which results from substantial decreases in both Keap1 and PTEN in Nrf1-/- cells. Further investigation of xenograft mice showed that malignant growth of Nrf1-/--derived tumor is almost abolished by silencing Nrf2, while Nrf1+/+-tumor is markedly repressed by inactive Nrf2-/-{Delta}TA, but unaffected by a priori constitutive activator of caNrf2{Delta}N. Mechanistic studies unraveled there exist opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2. Collectively, Nrf1 manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity, while Nrf2 can directly activate the transcriptional expression of Nrf1 to form a negative feedback loop.\n\nHIGHLIGHTSO_LIOpposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2\nC_LIO_LIMalignant growth of Nrf1-/--derived tumor is prevented by silencing Nrf2\nC_LIO_LIHyper-activation of Nrf2 by Nrf1-/- results from decreased Keap1 and PTEN\nC_LIO_LINrf1+/+-tumor is repressed by Nrf2-/-{Delta}TA, but unaltered by its active caNrf2{Delta}N\nC_LI

molecular biology↗

bioRxiv2018

Penton-dodecahedron of fowl adenovirus serotype 4 as a vaccine candidate for the control of related diseases

In some serotypes of adenovirus (Ad), the penton base protein and attached trimeric fiber assemble into dodecameric virus-like particles called penton-dodecahedron (Pt-Dd), which can internalize into cells and can be used to deliver the vaccine antigen and drugs. Fowl adenovirus serotype 4 (FAdV-4) is an important poultry pathogens and causing seriously economic lost to poultry industry in China and several other counties. The produce of Pt-Dd in FAdV-4 infected cells as well as in those infected with the recombinant human Ad expressing fiber-1, fiber-2, and penton base was determine by Transmission electron microscopy (TEM). For the First time, we proved that FAdV-4 produced Pt-Dd in infected cells, which can also be assembled by the overexpressed recombinant proteins fiber-1, fiber-2, and penton base. Pt-Dd, as well as the recombinant proteins fiber-1, fiber-2, and penton base, were then used to immunize chickens. The humoral immune response, cell mediate immune response (CMI), and challenge results were used to evaluate the immune efficacy of the vaccine candidates. Pt-Dd induced the highest level of enzyme-linked immunosorbent assay antibodies and high levels of CMI, showing a significantly (p < 0.05) high level of interferon {gamma}, interleukin-4, and major histocompatibility complex II expressions in peripheral blood mononuclear cells at 48 h post-infection. The challenge results showed that Pt-Dd, inactivated FAdV-4 vaccine, as well as fiber-1 induced the best protection (100%), followed by fiber-2 (80%) and penton (67%). The present study showed that FAdV-4-Pt-Dd and recombinant fiber-1 are good FAdV-4 vaccine candidates and could be used to replace the tissue-sourced inactivated FAdV-4 vaccine.\n\nImportanceFAdV-4-Pt-Dds were discovered in FAdV-4 infected cells, and which were also assembled in cells transduced with recombinant human adenovirus expressing fiber-1, fiber-2, and penton base. FAdV-4-Pt-Dds internalize into cells with high efficiency, so that it can be used for delivery vaccine antigen or drugs. Immunization chickens with Pt-Dd and fiber-1 obtained by transduction HEK-293T cells induced significant high level humoral and cellular mediated immune responses, and also 100% challenge protection in chickens indicating that they are good FAdV-4 vaccine candidates. What more, the Pt-Dd obtained by transduction HEK-293T cell would have no DNA and adenovirus contamination as adenovirus could not package in HEK-293T cells.

immunology↗

bioRxiv2018

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

Under hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.\n\nSignificanceTumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.

biochemistry↗

bioRxiv2018

Distinct isoforms of Nrf1 diversely regulate different subsets of its cognate target genes

The single Nrf1 gene has capability to be differentially transcripted alongside with alternative mRNA-splicing and subsequent translation through different initiation signals so as to yield distinct lengths of polypeptide isoforms. Amongst them, three of the most representatives are Nrf1, Nrf1{beta} and Nrf1{gamma}, but the putative specific contribution of each isoform to regulating ARE-driven target genes remains unknown. To address this, we have here established three cell lines on the base of the Flp-In T-REx system, which are allowed for tetracycline-inducibly stable expression of Nrf1, Nrf1{beta} and Nrf1{gamma}. The RNA-Sequencing results have demonstrated that a vast majority of differentially expressed genes (i.e. >90% DEGs detected) were dominantly up-regulated by Nrf1 and/or Nrf1{beta} following induction by tetracycline. By contrast, other DEGs regulated by Nrf1{gamma} were far less than those regulated by Nrf1/{beta} (i.e. ~11% of Nrf1 and 7% of Nrf1{beta}). Further transcriptomic analysis revealed that tetracycline-induced expression of Nrf1{gamma} significantly increased the percentage of down-regulated genes in total DEGs. These statistical data were further validated by quantitative real-time PCR. The experimental results indicate that distinct Nrf1 isoforms make diverse and even opposing contributions to regulating different subsets of target genes, such as those encoding 26S proteasomal subunits and others involved in various biological processes and functions. Collectively, Nrf1{gamma} acts as a major dominant-negative competitor against Nrf1/{beta} activity, such that a number of DEGs regulated by Nrf1/{beta} are counteracted by Nrf1{gamma}.

molecular biology↗

bioRxiv2018

Nrf1D is the first candidate secretory transcription factor in the blood plasma, with its precursor existing as a unique redox-sensitive transmembrane CNC-bZIP protein in somatic tissues

Amongst multiple distinct isoforms, Nrf1D is synthesized from translation of an alternatively-spliced transcript of Nrf1 mRNA, with a naturally-occurring deletion of its stop codon-flanking 1466 nucleotides. This molecular event leads to the reading frameshift mutation, which results in a constitutive substitution of the intact Nrf1s C-terminal 72 amino acids (aa, covering the second half of the leucine zipper motif to C-terminal Neh3L domain) by an additional extended 80-aa stretch to generate a unique variant Nrf1D. The C-terminal extra 80-aa region of Nrf1D was identified to fold into a redox-sensitive transmembrane domain that enables it to be tightly integrated within the endoplasmic reticulum (ER) membranes. Notably, the salient feature of Nrf1D confers it to be distinguishable from prototypic Nrf1, such that Nrf1D is endowed with only a less ability than wild-type Nrf1 at mediating target gene expression. Further evidence has been presented revealing that both mRNA and protein levels of Nrf1D were detected to varying extents in somatic tissues. Surprisingly, we also found the existence of Nrf1D-derived isoforms in the blood plasma, implying that it is a candidate secretory transcription factor, although its precursor acts as an integral transmembrane-bound CNC-bZIP protein that entails dynamic topologies, before being unleashed from the ER to enter the blood plasma.

cell biology↗

bioRxiv2018

The Doublesex sex determination pathway regulates reproductive division of labor in honey bees

Eusociality, the ultimate level of social organization, requires reproductive division of labor, and a sophisticated system of communication to maintain societal homeostasis. Reproductive division of labor is maintained by physiological differences between reproductive and sterile castes, typically dictated by pheromonal queen fertility signals that suppress worker reproduction. Intriguingly, reproduction and pheromonal signalling share regulatory machinery across insects.The gene Doublesex (Dsx) controls somatic sex determination and differentiation, including the development of ovaries and secondary sexual characteristics, such as pheromonal signalling. We hypothesized that this regulatory network was co-opted during eusocial evolution to regulate reproductive division of labor. Taking advantage of the breakdown in reproductive division of labor that occurs in honey bees when workers commence to lay eggs in the absence of a queen, we knocked down Dsx to observe effects on ovary development and fertility signal production. As expected, treated workers had lower levels of egg yolk protein, for which Dsx is a cis-regulatory enhancer in other insects, and greatly reduced ovary development. Also as expected, while control workers increased their levels of pheromonal fertility signals, treated workers did not, confirming the role of Dsx in regulating pheromone biosynthesis. We further found that Dsx is part of a large network enriched for regulatory proteins, which is also involved during early larval development, and upregulated in queen-destined larvae. Thus, the ancient developmental framework controlling sex specification and reproduction in solitary insects has been exapted for eusociality, forming the basis for reproductive division of labor and pheromonal signalling pathways.\n\nSignificance statementComplex social insect societies rely on division of reproductive labor among their members. Reproductive individuals ( queens) suppress worker reproduction using pheromonal fertility signalling. We show that an ancient regulatory network that controls specification of sex and secondary sexual characteristics in solitary insects, has been co-opted for both both pheromonal signalling and ovary inactivation in honey bees. In addition, this network is also active during caste specification that takes place during the first few days of larval life. These results show that pheromonal signalling and ovary development share a common regulatory framework, potentially explaining why fertility signalling is honest. Furthermore, they show that higher levels of biological complexity can arise by rewiring and elaborating ancestral gene regulatory networks.

genetics↗

bioRxiv2018

Molecular mechanisms controlling the multistage post-translational processing of endogenous Nrf1α/TCF11 proteins to yield distinct proteoforms within the coupled positive and negative feedback circuits

In an attempt to terminate the chaotic state of the literature on Nrf1/TCF11 with various confused molecular masses, we herein establish a generally acceptable criterion required for identification of its endogenous full-length proteins and derivative isoforms expressed differentially in distinct experimental cell lines. Further work has been focused on the molecular mechanisms that dictate the successive multistate post-translational modifications (i.e. glycosylation by OST, deglycosylation by NGLY, and ubiquitination by Hrd1) of this CNC-bZIP protein and its proteolytic processing to yield multiple isoforms. Several lines of experimental evidence have demonstrated that the nascent Nrf1/TCF11 polypeptide (non-glycosylated) is transiently translocated into the endoplasmic reticulum (ER), in which it becomes an inactive glycoprotein-A, and also folded in a proper topology within and around membranes. Thereafter, dynamic repositioning of the ER-resident domains in Nrf1 glycoprotein is driven by p97-fueled retrotranslocation into extra-ER compartments. Therein, glycoprotein of Nrf1 is allowed for digestion into a deglycoprotein-B and then its progressive proteolytic processing by cytosolic DDI-1/2 and proteasomes to yield distinct proteoforms (i.e. protein-C/D). The processing is accompanied by removal of a major N-terminal ~12.5-kDa polypeptide from Nrf1. Interestingly, our present study has further unraveled that coupled positive and negative feedback circuits exist between Nrf1 and its cognate target genes, including those encoding its regulators p97, Hrd1, DDI-1 and proteasomes. These key players are differentially or even oppositely involved in diverse cellular signalling responses to distinct extents of ER-derived proteotoxic and oxidative stresses induced by different concentrations of proteasomal inhibitors.

biochemistry↗

bioRxiv2018

Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor

The topobiological behaviour of Nrf1 dictates its post-translational modification and its ability to transactivate target genes. Here, we have elucidated that topovectorial mechanisms control the juxtamembrane processing of Nrf1 on the cyto/nucleoplasmic side of endoplasmic reticulum (ER), whereupon it is cleaved and degraded to remove various lengths of its N-terminal domain (NTD, also refold into a UBL module) and acidic domain-1 (AD1) to yield multiple isoforms. Notably, an N-terminal [~]12.5-kDa polypeptide of Nrf1 arises from selective cleavage at an NHB2-adjoining region within NTD, whilst other longer UBL-containing isoforms may arise from proteolytic processing of the protein within AD1 around PEST1 and Neh2L degrons. The susceptibility of Nrf1 to proteolysis is determined by dynamic repositioning of potential UBL-adjacent degrons and cleavage sites from the ER lumen through p97-driven retrotranslocation and -independent pathways into the cyto/nucleoplasm. These repositioned degrons and cleavage sites within NTD and AD1 of Nrf1 are coming into their bona fide functionality, thereby enabling it to be selectively processed by cytosolic DDI-1/2 proteases and also degraded via 26S proteasomes. The resultant proteolytic processing of Nrf1 gives rise to a mature [~]85-kDa CNC-bZIP transcription factor, which regulates transcriptional expression of cognate target genes. Furthermore, putative ubiquitination of Nrf1 is not a prerequisite necessary for involvement of p97 in the client processing. Overall, the regulated juxtamembrane proteolysis (RJP) of Nrf1, though occurring in close proximity to the ER, is distinctive from the mechanism that regulates the intramembrane proteolytic (RIP) processing of ATF6 and SREBP1.

biochemistry↗

bioRxiv2018

A naturally-occurring dominant-negative competitor of Keap1 against its inhibition of Nrf2

Transcription factor Nrf2 is a master regulator of antioxidant and/or electrophile response elements (AREs/EpREs)driven genes involved in homeostasis, detoxification and adaptation to various stresses. The cytoprotective activity of Nrf2, though being oppositely involved in both cancer prevention and progression, is critically controlled by Keap1 (Kelch-like ECH-associated protein 1) as an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, that is a key sensor for oxidative and electrophilic stresses. Now, we first report a novel naturally-occurring mutant of Keap1, designated Keap1{Delta}C, which lacks most of its C-terminal Nrf2-interacting domain essential for inhibition of the CNC-bZIP factor. This mutant Keap1{Delta}C is yielded by translation from an alternatively mRNA-spliced variant lacking the fourth and fifth exons, but their coding sequences are retained in the wild-type Keap1 locus (with no genomic deletions). Although this variant was found primarily in the human highly-metastatic hepatoma (MHCC97H) cells, it was widely expressed at very lower levels in all other cell lines examined. No matter whether Keap1{Delta}C retains less or no ability to inhibit Nrf2, it functions as a dominant-negative competitor of Keap1 against its inhibition of Nrf2-target genes. This is due to its antagonist effect on Keap1-mediated turnover of Nrf2 protein.

molecular biology↗

bioRxiv2018

Nach is a novel ancestral subfamily of the CNC-bZIP transcription factors selected during evolution from the marine bacteria to human

All living organisms have undergone the evolutionary selection under the changing natural environments to survive as diverse life forms. All life processes including normal homeostatic development and growth into organismic bodies with distinct cellular identifications, as well as their adaptive responses to various intracellular and environmental stresses, are tightly controlled by signaling of transcriptional networks towards regulation of cognate genes by many different transcription factors. Amongst them, one of the most conserved is the basic-region leucine zipper (bZIP) family. They play vital roles essential for cell proliferation, differentiation and maintenance in complex multicellular organisms. Notably, an unresolved divergence on the evolution of bZIP proteins is addressed here. By a combination of bioinformatics with genomics and molecular biology, we have demonstrated that two of the most ancestral family members classified into BATF and Jun subgroups are originated from viruses, albeit expansion and diversification of the bZIP superfamily occur in different vertebrates. Interestingly, a specific ancestral subfamily of bZIP proteins is identified and also designated Nach (Nrf and CNC homology) on account of their highly conservativity with NF-E2 p45 subunit-related factors Nrf1/2. Further experimental evidence reveals that Nach1/2 from the marine bacteria exerts distinctive functions from Nrf1/2 in the transcriptional ability to regulate antioxidant response element (ARE)-driven cytoprotective genes. Collectively, an insight into Nach/CNC-bZIP proteins provides a better understanding of distinct biological functions between these factors selected during evolution from the marine bacteria to human.\n\nSignificanceWe identified the novel ancestral subfamily (i.e. Nach) of CNC-bZIP transcription factors with highly conservativity from marine bacteria to human. Combination of bioinformatics with genomics and molecular biology demonstrated that two of the most ancestral family members classified into BATF and Jun subgroups are originated from viruses. The Jun and CNC subfamilies also share a common origin of these bZIP proteins. Further experimental evidence reveals that Nach1/2 from the marine bacteria exerts nuance functions from human Nrf1/2 in the transcriptional ability to regulate antioxidant response element (ARE)-driven genes, responsible for the host cytoprotection against inflammation and cancer. Overall, this study is of multidisciplinary interests to provide a better understanding of distinct biological functions between Nach/CNC-bZIPs selected during evolution.

ecology↗

bioRxiv2017

The Neural System of Metacognition Accompanying Decision-Making in The Prefrontal Cortex

Decision-making is usually accompanied by metacognition, through which a decision maker monitors the decision uncertainty and consequently revises the decision, even prior to feedback. However, the neural mechanisms of metacognition remain controversial: one theory proposes that metacognition coincides the decision-making process; and another addresses that it entails an independent neural system in the prefrontal cortex (PFC). Here we devised a novel paradigm of \"decision-redecision\" to investigate the metacognition process in redecision, in comparison with the decision process. We here found that the anterior PFC, including dorsal anterior cingulate cortex (dACC) and lateral frontopolar cortex (lFPC), were exclusively activated after the initial decisions. dACC was involved in decision uncertainty monitoring, whereas lFPC was involved in decision adjustment controlling, subject to control demands of the tasks. Our findings support that the PFC is essentially involved in metacognition and further suggest that functions of the PFC in metacognition are dissociable.

neuroscience↗