Biology subjects

Ke, C.

Publications and source records attributed to Ke, C..

15 recordsLinked to original sources

bioRxiv2026

Acetylation of NDUFA13 at K7 Senses OXPHOS Dysfunction to Disrupt Prohibitin Scaffolds and Drive Cristae Remodelling in Heart Failure

Mitochondrial cristae disintegration is a hallmark of heart failure, yet how oxidative phosphorylation (OXPHOS) dysfunction triggers this structural collapse remains unclear. Here we identify acetylation of the complex I subunit NDUFA13 at lysine 7 (K7) as a metabolic sensor coupling OXPHOS dysfunction to cristae remodelling. OXPHOS inhibition drove NDUFA13-K7 hyperacetylation, inducing conformational compaction and translocation to the intermembrane space. Acetylated NDUFA13 competitively engaged PHB2 through its coiled-coil domain, displacing PHB1 and disassembling prohibitin scaffolds. The acetylation-mimetic NDUFA13-K7Q induced cristae fragmentation in vitro, and cardiomyocyte-specific K7Q knock-in mice showed accelerated mortality and cristae loss under pressure overload, accompanied by impaired TCA cycle flux, defective fatty acid oxidation and selective depletion of polyunsaturated cardiolipins. These findings establish NDUFA13-K7 acetylation as a reversible switch converting bioenergetic failure into pathological cristae remodelling and metabolic reprogramming, highlighting therapeutic potential for targeted deacetylation.

cell biology↗

bioRxiv2026

Metagenomic insights into dose-dependent alterations in the tobacco rhizosphere microbiome by pyrroloquinoline quinone

Pyrroloquinoline quinone (PQQ) is known to promote plant growth, yet how the rhizosphere microbiome varies with PQQ concentration remains poorly understood. We applied metagenomic sequencing to characterize the taxonomic composition and functional potential of the tobacco rhizosphere microbiome across PQQ treatments at 0.5, 1 and 2 mol/L plus an untreated control. The rhizosphere microbiome was dominated by Pseudomonadota and Actinomycetota and differed among treatments in a concentration-associated, non-monotonic manner. The most pronounced differences were observed at 1 mol/L, where alpha diversity showed dimension-specific variation and beta-diversity analysis resolved the most distinct community profile. Taxonomic and functional profiles varied concurrently, with Streptomyces, Sphingomonas, Rhodanobacter and Lysobacter, together with functions related to biosynthesis, energy metabolism, colonization and environmental sensing, showing higher relative abundance at this concentration. No broad-spectrum antimicrobial effect was detected at the community level, and antibiotic resistance gene abundance showed no significant differences among treatments after correction for multiple testing. These findings provide a basis for further evaluation of PQQ in modulating the rhizosphere microbiome in continuous cropping systems.

microbiology↗

bioRxiv2025

A metadata managed FAIR end-to-end workflow for microbial community Omics data analysis

BackgroundMolecular profiling using high-throughput omics technologies has tremendously increased our ability to interrogate complex microbial communities at the molecular level. In the context of data reuse, the FAIRification of these extensive datasets is frequently perceived as a secondary administrative task, addressed only after data analysis has been completed. However, this approach overlooks the potential benefits of early metadata integration as the procedures for processing and analyzing raw data are primarily dictated by the underlying research design and experimental conditions. Gathering interoperable research metadata at the earliest stages creates a standardized basis for managing, processing, and analyzing data enabling more efficient and reproducible FAIR workflows. ResultsThe single containment principle was used to develop modular containerized reproducible workflows that support the FAIR principles for research software by systematically capturing standardized metadata for each data processing step along with the resulting data products. Using defined mock metagenomic datasets as an example, we show that interoperable research metadata can be used to drive such computational workflows. By processing raw data accordingly, machine-actionable provenance chains are created that enhance the reproducibility and reusability of the resulting data products. ConclusionsA seamless integration of wet lab experiments with computational investigations is essential for a FAIR end-to-end research process. Meta-data-managed workflows prevent the need for unnecessary data manipulation. Workflow provenance registration explicates the complex multi-step methods employed for data processing and analysis. Combining FAIR principles with data provenance registration enhances the reusability of omics datasets by promoting transparency and reproducibility. O_TEXTBOXKey PointsO_LIWe present the first metadata-managed FAIR end-to-end workflow for microbial community Omics data analysis. C_LIO_LIThe framework links experiment metadata with CWL workflows, enabling seamless metadata-driven execution from experiment to data product. C_LIO_LIComprehensive provenance tracking using RDF standards creates machine-actionable chains connecting wet-lab protocols to computational outputs, enhancing reproducibility and supporting automated workflow validation. C_LIO_LIBenchmarking with defined mock communities demonstrates workflow reliability across assembly methods while generating FAIR-compliant research objects suitable for community reuse and comparative studies. C_LI C_TEXTBOX

bioinformatics↗

bioRxiv2025

Gene expression profile dynamics of earthworms exposed to ZnO and ZnO:Mn nanomaterials

Zinc oxide containing nanomaterials may elicit toxic responses in environmental organisms such as earthworms. Although toxic responses in earthworms have been reported, few studies have attempted to understand the molecular mode of action dynamics explaining the observed toxicity at a transcriptional level. This study investigates the time-dependent gene expression response in earthworms exposed to ZnO nanomaterials and ZnO:Mn multicomponent nanomaterials. Earthworms were exposed to ZnO or ZnO:Mn for 7 days and to ZnO:Mn or MnCl2 for 14 days. Strong differential gene expression responses were observed after 4 days of exposure to ZnO nanomaterials and after 2 days of exposure to ZnO:Mn. Moderate differential gene expression responses were observed after 14 days of exposure to ZnO:Mn and MnCl2. Gene ontology (GO) enrichment analysis revealed that differentially expressed genes in earthworms exposed to ZnO were associated with terms such as actin, (striated) muscle cells, contractile fiber, myofibril, sarcomere and supramolecular cellular components. In addition, genes that were upregulated after 2 days of exposure to ZnO:Mn were linked to GO terms including cilium, microtubule, cell projection, axoneme and sperm flagellum cellular components. Downregulated genes were enriched to GO terms related to ribosomes, mitochondria, translation, peptide processes, respiration and oxidative phosphorylation. Finally, for earthworms exposed to ZnO:Mn and MnCl2 for 14 days, only a limited number of differentially expressed genes were involved in GO terms related to diverse biological implications. In summary, exposing earthworms to the ZnO and ZnO:Mn nanomaterials elicited a transient response in differential gene expression related to muscle biology and energy metabolism and translation that had largely disappeared by day 14 from the start of the exposure.

systems biology↗

bioRxiv2024

An Evaluation of the Tumor Microenvironment through CALR, IL1R1, IFNB1, and IFNG to Assess Prognosis and Immunotherapy Response in Bladder Cancer Patients

Immunogenic cell death (ICD) is a type of cell death sparking adaptive immune responses, can reshape the tumor microenvironment (TME). Exploring key ICD-related genes in bladder cancer (BLCA) could enhance personalized treatment. TCGA BLCA patients were divided into two ICD subtypes: ICD-high and ICD-low. High ICD expression linked to increased immune cell infiltration and longer survival, but with potentially suppressed immune function. The high ICD group responded better to PD1-targeted therapy. A risk-scoring model with four ICD-related genes (CALR, IL1R1, IFNB1, IFNG) was validated across TCGA, GEO datasets, and tissue samples, showing higher risk-score correlated with weaker anti-tumor immune function, more tumor-promoting elements, lower immunotherapy response rates, and shorter patient survival.This study connects ICD-related genes to BLCA prognosis and immune infiltration, offering a vital tool for personalized treatment guidance.

immunology↗

bioRxiv2023

Dendritic cell-derived lncRNA in patients with acute coronary syndrome

BackgroundLong non-coding RNA (lncRNA) and dendritic cells (DC) play an important role in the occurrence and development of acute coronary syndrome (ACS). However, the role and mechanism of DC-derived lncRNA in patients with ACS still remains understudied. ObjectiveTo investigate the expression difference and role of lncRNA in monocyte-derived DC(moDC) in patients with acute coronary syndrome(ACS). Methods and ResultsThe subjects were divided into 4 groups: (1) healthy control group (CON), (2) unstable angina group (UA), (3) non-ST elevation myocardial infarction group (NSEMI or NST) and (4) ST elevation myocardial infarction group (STEMI or ST). Peripheral blood was extracted and isolated to obtain mononuclear cells (PBMC). After induction into moDC, morphology was observed by electron microscope and identified by flow cytometry (FCM) (CD80, CD86, CD11c, CD14, HLA-DR), and morphological and functional differences were compared. The differentially expressed lncRNA were screened by gene sequencing, and the biological functions of which were predicted by GO and KEGG and the correlation between candidate lncRNA and target genes was analyzed. The expression levels of markers, signaling pathways, inflammatory factors and target gene were performed by FCM, RT-PCR, WB and ELISA after the candidate lncRNA were over-expressed or silenced. Electron microscope showed that the cells were suspended cells of dendritic pseudopodia. FCM showed that the expression levels of DC markers CD11c (99.02{+/-}0.12%) and HLA-DR (99.32{+/-}0.08%) were high, while the expression levels of CD80 (24.27{+/-}0.99%) and CD86 (32.38{+/-}0.59%) were low. The number of differentially expressed lncRNA screened by gene sequencing was as follows: CON vs UA, 3; CON vs. NST, 49; CON vs ST, 35; UA vs. NST, 115; UA vs ST, 113; ST vs NST, 4. The results of FCM, RT-PCR, WB and ELISA showed that the expression levels of markers (CD80, CD86, HLA-DR), signaling pathways (p-PI3K, p-AKT), inflammatory factors (IL-6 and IL-12p70) and target gene (CCL14) were increased after over-expression of CCL15-CCL14; On the contrary, its expression level was decreased. ConclusionsThere are differences in moDC morphology and function and lncRNA expression in different types of ACS patients, and the differentially expressed lncRNA (CCL15-CCL14) regulates the function of moDC.

immunology↗

bioRxiv2021

Single-shot rAAV5-based Vaccine Provides Long-term Protective Immunity against SARS-CoV-2 and Its Variants

The COVID-19 pandemic and the SARS-CoV-2 with its variants have posed unprecedented challenges worldwide. Existing vaccines have limited effectiveness against the SARS-CoV-2 variants. Therefore, novel vaccines to match current mutated viral lineages with long-term protective immunity are urgently in demand. In the current study, we for the first time designed a recombinant Adeno-Associated Virus 5 (rAAV5)-based vaccine named as rAAV-COVID-19 vaccine (Covacinplus) by using RBD-plus of spike protein with both the single-stranded and the self-complementary AAV5 delivering vectors (ssAAV5 and scAAAV5), which provides excellent protection from SARS-CoV-2 infection. A single dose vaccination induced the strong immune response against SARS-CoV-2. The induced neutralizing antibodies (NAs) titers were maintained at a high peak level of over 1:1024 even after more than one year of injection and accompanied with functional T-cells responses in mice. Importantly, both ssAAV- and scAAV-based RBD-plus vaccines exhibited high levels of serum NAs against current circulating variants including variants Alpha, Beta, Gamma and Delta. SARS-CoV-2 virus challenge test showed that ssAAV5-RBD-plus vaccine protected both young and old age mice from SARS-CoV-2 infection in the upper and the lower respiratory tracts. Moreover, whole genome sequencing demonstrated that AAV vector DNA sequences were not found in the genome of the vaccinated mice after one year vaccination, demonstrating excellent safety of the vaccine. Taken together, this study suggests that rAAV5-based vaccine is powerful against SARS-CoV-2 and its variants with long-term protective immunity and excellent safety, which has great potential for development into prophylactic vaccination in human to end this global pandemic.

immunology↗

bioRxiv2021

A tandem-repeat dimeric RBD protein-based COVID-19 vaccine ZF2001 protects mice and nonhuman primates

A safe, efficacious and deployable vaccine is urgently needed to control COVID-19 pandemic. We report here the preclinical development of a COVID-19 vaccine candidate, ZF2001, which contains tandem-repeat dimeric receptor-binding domain (RBD) protein with alum-based adjuvant. We assessed vaccine immunogenicity and efficacy in both mice and non-human primates (NHPs). ZF2001 induced high levels of RBD-binding and SARS-CoV-2 neutralizing antibody in both mice and NHPs, and also elicited balanced TH1/TH2 cellular responses in NHPs. Two doses of ZF2001 protected Ad-hACE2-transduced mice against SARS-CoV-2 infection, as detected by reduced viral RNA and relieved lung injuries. In NHPs, vaccination of either 25 g or 50 g ZF2001 prevented infection with SARS-CoV-2 in lung, trachea and bronchi, with milder lung lesions. No evidence of disease enhancement is observed in both models. ZF2001 is being evaluated in the ongoing international multi-center Phase 3 trials (NCT04646590) and has been approved for emergency use in Uzbekistan.

immunology↗

bioRxiv2020

Stanniocalcin 1a is a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca2+ uptake

The mechanisms governing cell quiescence-proliferation balance are poorly defined. Using a zebrafish model, here we report that Stc1a, a glycoprotein known as a hypocalcemic hormone, not only inhibits epithelial calcium uptake but also functions as a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance. Among the 4 stc genes, only the stc1a expression is [Ca2+]-dependent. Genetic deletion of stc1a, but not stc2b, resulted in elevated body Ca2+ contents, ectopic Ca2+ deposit, body swelling, and premature death. Reducing epithelial calcium channel Trpv6-mediated Ca2+ uptake alleviated these phenotypes. Loss of Stc1a also promoted quiescent epithelial cells to re-enter the cell cycle. This action was accompanied by local IGF signaling activation and increased expression in papp-aa, a zinc metalloproteinase degrading Igfbp5a. Genetic deletion of papp-aa or igfbp5a abolished the elevated epithelial cell reactivation in stc1a-/- mutants. Likewise, inhibition of IGF1 receptor, PI3 kinase, Akt, and Tor signaling abolished epithelial cell reactivation. These results reveal that Stc1a plays dual roles in regulating epithelial calcium uptake and cell quiescence-proliferation balance and implicate Trpv6 and Papp-aa-Igfbp5a-IGF signaling in these functions.

developmental biology↗

bioRxiv2020

Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro

Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.

molecular biology↗

bioRxiv2020

Comparison of SARS-CoV-2 infections among 3 species of non-human primates

COVID-19, caused by SARS-CoV-2 infection, has recently been announced as a pandemic all over the world. Plenty of diagnostic, preventive and therapeutic knowledges have been enriched from clinical studies since December 2019. However, animal models, particularly non-human primate models, are urgently needed for critical questions that could not be answered in clinical patients, evaluations of anti-viral drugs and vaccines. In this study, two families of non-human primates, Old world monkeys (12 Macaca mulatta, 6 Macaca fascicularis) and New world monkeys (6 Callithrix jacchus), were experimentally inoculated with SARS-CoV-2. Clinical signs were recorded. Samples were collected for analysis of viral shedding, viremia and histopathological examination. Increased body temperature was observed in 100% (12/12) M. mulatta, 33.3% (2/6) M. fascicularis and none (0/6) of C. jacchus post inoculation of SARS-CoV-2. All of M. mulatta and M. fascicularis showed chest radiographic abnormality. Viral genomes were detected in nasal swabs, throat swabs, anal swabs and blood from all 3 species of monkeys. Viral shedding from upper respiratory samples reached the peak between day 6 and day 8 post inoculation. From necropsied M. mulatta and M. fascicularis, the tissues showing virus positive were mainly lung, weasand, bronchus and spleen. No viral genome was seen in any of tissues from 2 necropsied C. jacchus. Severe gross lesions and histopathological changes were observed in lung, heart and stomach of SARS-CoV-2 infected animals. In summary, we have established a NHP model for COVID-19, which could be used to evaluate drugs and vaccines, and investigate viral pathogenesis. M. mulatta is the most susceptible to SARS-CoV-2 infection, followed by M. fascicularis and C. jacchus. One Sentence SummaryM. mulatta is the most susceptible to SARS-CoV-2 infection as compared to M. fascicularis and C. jacchus.

microbiology↗

bioRxiv2020

Identification of a common deletion in the spike protein of SARS-CoV-2

Two notable features have been identified in the SARS-CoV-2 genome: (1) the receptor binding domain of SARS-CoV-2; (2) a unique insertion of twelve nucleotide or four amino acids (PRRA) at the S1 and S2 boundary. For the first feature, the similar RBD identified in SARs-like virus from pangolin suggests the RBD in SARS-CoV-2 may already exist in animal host(s) before it transmitted into human. The left puzzle is the history and function of the insertion at S1/S2 boundary, which is uniquely identified in SARS-CoV-2. In this study, we identified two variants from the first Guangdong SARS-CoV-2 cell strain, with deletion mutations on polybasic cleavage site (PRRAR) and its flank sites. More extensive screening indicates the deletion at the flank sites of PRRAR could be detected in 3 of 68 clinical samples and half of 22 in vitro isolated viral strains. These data indicate (1) the deletion of QTQTN, at the flank of polybasic cleavage site, is likely benefit the SARS-CoV-2 replication or infection in vitro but under strong purification selection in vivo since it is rarely identified in clinical samples; (2) there could be a very efficient mechanism for deleting this region from viral genome as the variants losing 23585-23599 is commonly detected after two rounds of cell passage. The mechanistic explanation for this in vitro adaptation and in vivo purification processes (or reverse) that led to such genomic changes in SARS-CoV-2 requires further work. Nonetheless, this study has provided valuable clues to aid further investigation of spike protein function and virus evolution. The deletion mutation identified in vitro isolation should be also noted for current vaccine development.

genetics↗

bioRxiv2020

Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1

Selective-induction of regulated cell death is considered as a useful strategy for developing effective therapies against renal cell carcinoma (RCC). In this study, the role of nuclear factor-E2-related factor 2 (Nrf2) and its downstream genes in erastin-induced ferroptosis of renal carcinoma cells was investigated. Erastin induced endoplasmic reticulum (ER) stress and ferroptosis in renal carcinoma cells (786-0 and Caki-1), which was confirmed by morphological changes, increased lipid oxidation and ferroptosis inhibition. Data obtained from TCGA dataset showed that Nrf2 and heme oxygenase-1 (HO-1) were not only significantly differentially expressed between RCC and normal samples, but also associated with better survival in RCC patients. Moreover, the process of ferroptosis induced by erastin in renal carcinoma cells was accompanied by increased expression of Nrf2 and HO-1. Inhibition of Nrf2 or HO-1 expression enhanced lipid ROS accumulation and ferroptosis. Furthermore, pharmacological activation of HO-1 reversed ferroptosis-sensitizing effect of Nrf2 silencing, thereby clarifying the key role of Nrf2/HO-1 pathway in erastin-induced ferroptosis in renal carcinoma cells. In summary, we identified the role of Nrf2/HO-1 signaling pathway in the protection of renal carcinoma cells from ER stress-related ferroptosis, which indicated that targeting of Nrf2/HO-1 pathway as a viable treatment strategy for RCC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/977769v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1068dacorg.highwire.dtl.DTLVardef@13f388eorg.highwire.dtl.DTLVardef@199fd87org.highwire.dtl.DTLVardef@d3e03a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract (supplementary figure): Nrf2 protects against ER stress-related ferroptosis via HO-1 in renal cancer cells. Cystine/glutamate antiporter (SLC7A11) abbreviated as xCT. Mitochondria abbreviated as Mito. C_FIG

cancer biology↗

bioRxiv2019

The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

Human patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca2+]-dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca2+]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.

developmental biology↗

bioRxiv2017

Molecular evolution, diversity and adaptation of H7N9 influenza A viruses in China

A novel H7N9 avian influenza virus has caused five human epidemics in China since 2013. The substantial increase in prevalence and the emergence of antigenically divergent or highly pathogenic (HP) H7N9 strains during the current outbreak raises concerns about the epizootic-potential of these viruses. Here, we investigate the evolution and adaptation of H7N9 by combining publicly available data with newly generated virus sequences isolated in Guangdong between 2015-2017. Phylogenetic analyses show that currently-circulating H7N9 viruses belong to distinct lineages with differing spatial distributions. Using ancestral sequence reconstruction and structural modelling we have identified parallel amino-acid changes on multiple separate lineages. Furthermore, we infer mutations in HA primarily occur at sites involved in receptor-recognition and/or antigenicity. We also identify seven new HP strains, which likely emerged from viruses circulating in eastern Guangdong around March 2016 and is further associated with a high rate of adaptive molecular evolution.

evolutionary biology↗