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Lu, F.

Publications and source records attributed to Lu, F..

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bioRxiv2021

Conserved T-cell epitopes predicted by bioinformatics in SARS-COV-2 variants

BackgroundFinding conservative T cell epitopes in the proteome of numerous variants of SARS-COV-2 is required to develop T cell activating SARS-COV-2 capable of inducing T cell responses against SARS-COV-2 variants. MethodsA computational workflow was performed to find HLA restricted CD8+ and CD4+ T cell epitopes among conserved amino acid sequences across the proteome of 474727 SARS-CoV-2 strains. ResultsA batch of covserved regions in the amino acid sequences were found in the proteome of the SARS-COV-2 strains. 2852 and 847 peptides were predicted to have high binding affinity to distint HLA class I and class II molecules. Among them, 1456 and 484 peptides are antigenic. 392 and 111 of the antigenic peptides were found in the conseved amino acid sequences. Among the antigenic-conserved peptides, 6 CD8+ T cell epitopes and 7 CD4+ T cell epitopes were identifed. The T cell epitopes could be presented to T cells by high-affinity HLA molecules which are encoded by the HLA alleles with high population coverage. ConclusionsThe T cell epitopes are conservative, antigenic and HLA presentable, and could be constructed into SARS-COV-2 vaccines for inducing protective T cell immunity against SARS-COV-2 and their variants.

immunology↗
bioRxiv2021

iRhom2 regulates ERBB signalling to promote KRAS-driven oncogenesis

Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer (1, 2). Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhoms, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17 (3, 4). Here we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 to induce ADAM17-dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancer-associated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing iRhom2 as a central component of a positive feedback loop in lung cancer cells. Overall, the cytoplasmic domain of iRhom2 is a critical component of KRAS-induced oncogenesis of lung cancer cells. Both ADAM17 and iRhom2 have also been implicated in a wide range of other cancers (5-10), so the mechanism we have revealed may also have wider oncogenic significance.

cancer biology↗
bioRxiv2021

mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

The retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mammals, zebrafish possess the ability to intrinsically regenerate a functional RPE layer after severe injury. The molecular underpinnings of this regenerative process remain largely unknown yet hold tremendous potential for developing treatment strategies to stimulate endogenous regeneration in the human eye. In this study, we demonstrate that the mTOR pathway is activated in RPE cells post-genetic ablation. Pharmacological and genetic inhibition of mTOR activity impaired RPE regeneration, while mTOR activation enhanced RPE recovery post-injury, demonstrating that mTOR activity is necessary and sufficient for RPE regeneration in zebrafish. RNA-seq of RPE isolated from mTOR-inhibited larvae identified a number of genes and pathways dependent on mTOR activity at early and late stages of regeneration; amongst these were components of the immune system, which is emerging as a key regulator of regenerative responses across various tissue and model systems. Our results identify crosstalk between macrophages/microglia and the RPE, wherein mTOR activity in the RPE is required for recruitment of macrophages/microglia to the injury site. In turn, these macrophages/microglia reinforce mTOR activity in regenerating RPE cells. Interestingly, the function of macrophages/microglia in maintaining mTOR activity in the RPE appeared to be inflammation-independent. Taken together, these data identify mTOR activity as a key regulator of RPE regeneration and link the mTOR pathway to immune responses in facilitating RPE regeneration. AUTHOR SUMMARYAge-related macular degeneration (AMD) is a leading cause of blindness world-wide, with incidences predicted to rise substantially over the next few decades. Cells of the retinal pigment epithelium (RPE) are affected in AMD and there are currently no effective therapies that slow RPE cell death or restore lost RPE cells in advanced-stage AMD. An exciting potential approach to treat many diseases of the eye, including AMD, is to stimulate endogenous regeneration to restore cells lost to disease. For this to become possible, we must first understand the molecular and cellular underpinnings of the regenerative response. In this study, we utilize zebrafish as a model system, which possess tremendous regenerative potential in multiple cell and tissue types, including the RPE. Our results identify the mTOR signaling pathway as a key regulator of RPE regeneration. We identify a link between mTOR signaling and immune responses, which are known to modulate regeneration of a variety of tissues and organs. Together, our results identify one of the first molecular mechanisms facilitating intrinsic RPE regeneration and these data could serve as a foundation for the development of new therapies aimed at stimulating the regeneration of RPE cells in the diseased eye.

developmental biology↗
bioRxiv2021

Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 64.3% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development.

immunology↗
bioRxiv2021

Identification of putative causal loci in whole-genome sequencing data via knockoff statistics

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimers Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

genetics↗
bioRxiv2021

Host protease activity on bacterial pathogens promotes complement- and antibiotic-directed killing

Our understanding of how the host immune system thwarts bacterial evasive mechanisms remains incomplete. Here, we show that host protease neutrophil elastase acts on Acinetobacter baumannii and Pseudomonas aeruginosa to destroy factors that prevent serum-associated, complement-directed killing. The protease activity also enhances bacterial susceptibility to antibiotics in sera. These findings implicate a new paradigm where host protease activity on bacteria acts synergistically with the host complement system and antibiotics to defeat bacterial pathogens.

microbiology↗
bioRxiv2021

Resurrection of human endogenous retroviruses during aging reinforces senescence

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process are largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. Activation of ERVs was also observed in organs of aged primates and mice, as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging. In briefLiu and colleagues uncover the ways in which de-repression of human endogenous retrovirus triggers cellular senescence and tissue aging; the findings provide fresh insights into therapeutic strategies for alleviating aging. HighlightsO_LIDerepression of the endogenous retrovirus contributes to programmed aging C_LIO_LIUpregulation of HERVK triggers the innate immune response and cellular senescence C_LIO_LIExtracellular HERVK retrovirus-like particles induce senescence in young cells C_LIO_LIEndogenous retrovirus serves as a potential target to alleviate agings C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/432260v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@31d384org.highwire.dtl.DTLVardef@13594c0org.highwire.dtl.DTLVardef@b8e070org.highwire.dtl.DTLVardef@196e5be_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗
bioRxiv2021

Molecular basis for Ras suppressor-1 recruitment to focal adhesions and stabilization of consensus adhesome complex

Ras suppressor-1 (Rsu-1) is a leucine-rich repeat (LRR)-containing protein that is crucial for regulating fundamental cell adhesion processes and tumor development. Rsu-1 interacts with a zinc-finger type multi LIM domain-containing adaptor protein PINCH-1 involved in the integrin-mediated consensus adhesome but not with highly homologous isoform PINCH-2. However, the structural basis for such specific interaction and regulatory mechanism remains unclear. Here, we determined the crystal structures of Rsu-1 and its complex with the PINCH-1 LIM4-5 domains. Rsu-1 displays an arc-shaped solenoid architecture with eight LRRs shielded by the N- and C-terminal capping modules. We show that a large conserved concave surface of the Rsu-1 LRR domain recognizes the PINCH-1 LIM5 domain, and that the C-terminal non-LIM region of PINCH-2 but not PINCH-1 sterically disfavors the Rsu-1 binding. We further show that Rsu-1 can be assembled, via PINCH-1-binding, into a tight hetero-pentamer complex comprising Rsu-1, PINCH-1, ILK, Parvin, and Kindlin-2 that constitute a major consensus integrin adhesome crucial for focal adhesion assembly. Consistently, our mutagenesis and cell biological data consolidate the significance of the Rsu-1/PINCH-1 interaction in focal adhesion assembly and cell spreading. Our results provide a crucial molecular insight into Rsu-1-mediated cell adhesion with implication on how it may regulate tumorigenic growth.

biochemistry↗
bioRxiv2020

Dynamic RNA 3' uridylation and guanylation during mitosis

ABSTRACTThe successful cell division involves highly regulated transcriptional and post-transcriptional control. Some of the cell cycle related genes are periodically expressed, while most of the genes show relatively stable steady state transcript level throughout the mitotic cell cycle (Bertoli et al., 2013; Park et al., 2016). Previous TAIL-seq analysis of S phase and M phase poly(A) tail information showed that less than 2% genes showed more than 2-fold change in their poly(A) tail length (Chang et al., 2014; Park et al., 2016). In addition, the changes in poly(A) tail length between these two stages showed minimal impact on the translation of the genes as long as the poly(A) tails were longer than 20 nt. Therefore, the significance of poly(A) tail dynamics during the cell cycle remains unknown. Here, by re-analyzing the S phase and M phase TAIL-seq data, we uncovered an interesting global dynamics of RNA poly(A) tails in terms of their terminal modifications, implying global RNA regulation between mitotic cell cycles through poly(A) tail terminal modifications.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗
bioRxiv2020

Convergence within divergence: insights of wheat adaptation from Triticum population sequencing

Bread wheat expanded its habitats from a small core area of the Fertile Crescent to global environments within [~]10,000 years. Genetic mechanisms of this remarkable evolutionary success are not well understood. By whole-genome sequencing of populations from 25 subspecies within genera Triticum and Aegilops, we identified composite introgression from these wild populations contributing 13%[~]36% of the bread wheat genome, which tremendously increased the genetic diversity of bread wheat and allowed its divergent adaptation. Meanwhile, convergent adaption to human selection showed 2- to 16-fold enrichment relative to random expectation in Triticum species despite their drastic differences in ploidy levels and growing zones, indicating the vital importance of adaptive constraints in the success of bread wheat. These results showed the genetic necessities of wheat as a global crop and provided new perspectives on leveraging adaptation success across species for crop improvement.

genetics↗
bioRxiv2019

Impacts of diets fed after weaning on gut microbiota and susceptibility to DSS-induced colitis in mice

BackgroundLiving in a sanitary environment and taking Western-style diet in early life are both risk factors for inflammatory bowel disease and important factors for shaping host gut microbiota. Here, we aimed to establish whether different dietary composition fed during the early period after weaning would associate the susceptibility to DSS-induced colitis with different gut microbiota shifts. MethodsEighty weaned Balb/c mice were fed with high sugar, fat, protein, fiber, and standard diet for 8weeks respectively. Inflammation was induced by administration of 2.5% (wt/vol) dextran sulfate sodium (DSS) in drinking water for 7 days, and the microbiota characterized by 16s rRNA based pyrosequencing. Analyzed the inflammatory factors and toll-like receptors by Real-time PCR ResultsThe high protein and high fiber+protein group exacerbated severity of DSS-induced colitis, the high fiber and high protein+fiber groups had the effect of reducing colitis, and the high sugar, fat and standard group show the similar disease phenotype of colitis. The diversity and richness of the microflora were significantly decreased in the high fiber group, while only decreased richness of flora was observed in the high protein group. The abundance of Firmicutes was decreased and the abundance of Bacteroides was increased in the high fat, high sugar, high protein and high fiber groups, especially in the high protein and high fiber group. The microbial community structure was slightly different at the species/genus level. The microbial community structure of high protein-fiber group and high fiber-protein group was still similar. ConclusionsMice were fed with different dietary compositions of high sugar, fat, protein and fiber diets since weaning, and similar gut microbiota of high-abundance Bacteroides and low-abundance Firmicutes are formed in adult mice. These microbiota do not cause colonic mucosal damage directly. Only high protein diet aggravated DSS-induced colitis, while high fiber diet alleviated the colitis.

microbiology↗
bioRxiv2019

Comparative Population Genomics of Bread Wheat (Triticum aestivum) Reveals Its Cultivation and Breeding History in China

The evolution of bread wheat (Triticum aestivum) is distinctive in that domestication, natural hybridization, and allopolyploid speciation have all had significant effects on the diversification of its genome. Wheat was spread around the world by humans and has been cultivated in China for ~4,600 years. Here, we report a comprehensive assessment of the evolution of wheat based on the genome-wide resequencing of 120 representative landraces and elite wheat accessions from China and other representative regions. We found substantially higher genetic diversity in the A and B subgenomes than in the D subgenome. Notably, the A and B subgenomes of the modern Chinese elite cultivars were mainly derived from European landraces, while Chinese landraces had a greater contribution to their D subgenomes. The duplicated copies of homoeologous genes from the A, B, and D subgenomes were commonly found to be under different levels of selection. Our genome-wide assessment of the genetic changes associated with wheat breeding in China provides new strategies and practical targets for future breeding.

plant biology↗
bioRxiv2018

Interplay between consensus and divergent RNA polymerase II C-terminal domain repeats in viability and targeting

The carboxy-terminal domain (CTD) of RNA polymerase II (Pol II) is composed of repeats of the consensus YSPTSPS, and is an essential binding scaffold for transcription-associated factors. Metazoan CTDs have well-conserved lengths and sequence compositions arising from the evolution of divergent motifs, features thought to be essential for development. To the contrary, we show that a truncated CTD composed solely of YSPTSPS repeats fully supports Drosophila viability, but a CTD with enough YSPTSPS repeats to match the length of the wild-type Drosophila CTD is defective. Furthermore, a fluorescently-tagged CTD lacking the rest of Pol II dynamically enters transcription compartments, indicating that the CTD functions as a signal sequence. However, CTDs with too many YSPTSPS repeats are more prone to localize to static nuclear foci independent of the chromosomes. We propose that the sequence complexity of the CTD offsets aberrant behavior caused by excessive repetitive sequences without compromising its targeting function.

molecular biology↗
bioRxiv2018

An \"inverse approach\" to the treatment of amblyopia

Recent laboratory finding suggest that short-term patching the amblyopic eye (i.e., inverse occlusion) results in a larger and more sustained improvement in the binocular balance compared with normal controls. In this study, we investigate the cumulative effects of the short-term inverse occlusion in adults and old children with amblyopia. A prospective cohort study of 18 amblyopes (10-35 years old; 3 with strabismus) who have been subjected to 2 hours/day of inverse occlusion for 2 months. Patients who required refractive correction or whose refractive correction needed updating were given a 2-month period of refractive adaptation. The primary outcome measure was the binocular balance which was measured using a phase combination task, the secondary outcome measures were the best corrected visual acuity which was measured with a Tumbling E acuity chart and convert to logMAR units and the stereo acuity which was measured with the Random-dot preschool stereotest. The averaged binocular gain was 0.11 in terms of the effective contrast ratio (z = -2.344, p = 0.019, 2-tailed Related samples Wilcoxon Signed Ranks Test). The average acuity gain was 0.14 logMAR equivalent (t(17) = 0.13, p < 0.001, 2-tailed paired samples t-test). The averaged stereo acuity gain was 253 arc seconds (z = -2.689, p = 0.007). Based on more recent research concerning adult ocular dominance plasticity, contrary to current practice, patching the amblyopic eye makes more sense; comparable acuity benefits, better compliance, better binocular outcome and applicable to adults as well as old children.

neuroscience↗
bioRxiv2018

Improved state-level influenza activity nowcasting in the United States leveraging Internet-based data sources and network approaches via ARGONet

In the presence of population-level health threats, precision public health approaches seek to provide the right intervention to the right population at the right time. Accurate real-time surveillance methodologies that can estimate infectious disease activity ahead of official healthcare-based reports, in relevant spatial resolutions, are critical to eventually achieve this goal. We introduce a novel methodological framework for this task which dynamically combines two distinct flu tracking techniques, using ensemble machine learning approaches, to achieve improved flu activity estimates at the state level in the US. The two predictive techniques behind the proposed ensemble methodology, named ARGONet, utilize (1) a dynamic and self-correcting statistical approach to combine flu-related Google search frequencies, information from electronic health records, and historical trends within a given state, as well as (2) a data-driven network-based approach that leverages spatial and temporal synchronicities observed in historical flu activity across states to improve state-level flu activity estimates. The proposed ensemble approach considerably outperforms each individual method and any previously proposed state-specific method for flu tracking, with higher correlations and lower prediction errors.

epidemiology↗
bioRxiv2017

Exchange protein directly activated by cAMP plays a critical role in regulation of vascular fibrinolysis

RationaleTo maintain vascular patency, endothelial cells (ECs) actively regulate hemostasis. Among the myriad of pathways by which they control both fibrin formation and fibrinolysis is EC expression of annexin A2 (ANXA2) in a heterotetrameric complex with S100A10 [(ANXA2-S100A10)2]. This complex is a well-recognized endothelial surface platform for the activation of plasminogen by tissue plasminogen activator. A noteworthy advance in this field came about when it was shown that the cAMP pathway is linked to the regulation of (ANXA2-S100A10)2 in ECs.\n\nObjectiveThese findings prompted us to determine whether a druggable target, namely the exchange protein directly activated by cAMP (EPAC) pathway, plays a role in vascular luminal fibrinolysis.\n\nMethods and ResultsTaking advantage of our Epac1-null mouse model, we found that depletion of Epac1 results in fibrin deposition, fibrinolytic dysfunction, and decreased endothelial surface ANXA2 in mice, which are similar to phenomena discovered in ANXA2-null and S100A10-null mice. We observed upregulation of EPAC1 and downregulation of fibrin in endocardial tissues beneath atrial mural thrombi in humans. Of note, our thrombosis model revealed that dysfunction of fibrinolysis in EPAC1-null mice can be ameliorated by recombinant ANXA2. Furthermore, we demonstrated that suppression of EPAC1 using a small-molecule inhibitor (ESI09) reduces the expression of ANXA2 in lipid rafts and impedes ANXA2 association with S100A10. Endothelial apical surface expression of both ANXA2 and S100A10 were markedly decreased in ESI09-treated ECs, which was corroborated by results from a nanoforce spectroscopy study. Moreover, inactivation of EPAC1 decreases tyrosine 23 phosphorylation of ANXA2 in the cell membrane compartment.\n\nConclusionsOur data reveal a novel role for EPAC1 in vascular fibrinolysis, by showing that EPAC1 is responsible for the translocation of ANXA2 to the EC surface. This process promotes conversion of plasminogen to plasmin, thereby enhancing local fibrinolytic activity.

cell biology↗