Biology subjects

Zhang, Q.

Publications and source records attributed to Zhang, Q..

At least 469 records · Page 26Linked to original sources

bioRxiv2022

SARS-CoV-2 infected cells sprout actin-rich filopodia that facilitate viral invasion

Emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a great threat to human health and economics. Although SARS-CoV-2 entry mechanism has been explored, little is known about how SARS-CoV-2 regulates the host cell remodeling to facilitate virus invasion process. Here we unveil that SARS-CoV-2 boosts and repurposes filopodia for entry to the target cells. Using SARS-CoV-2 virus-like particle (VLP), real-time live-cell imaging and simulation of active gel model, we reveal that VLP-induced Cdc42 activation leads to the formation of filopodia, which reinforce the viral entry to host cells. By single-particle tracking and sparse deconvolution algorithm, we uncover that VLP particles utilize filopodia to reach the entry site in two patterns, surfing and grabbing, which are more efficient and faster than entry via flat plasma membrane regions. Furthermore, the entry process via filopodia is dependent on the actin cytoskeleton and actin-associated proteins fascin, formin, and Arp2/3. Importantly, either inhibition the actin cross-linking protein fascin or the active level of Cdc42 could significantly hinders both the VLP and the authentic SARS-CoV-2 entry. Together, our results highlight that the spatial-temporal regulation of the actin cytoskeleton by SARS-CoV-2 infection makes filopodia as a highway for virus entry, which emerges as an antiviral target. Significance StatementRevealing the mechanism of SARS-CoV-2 invasion is of great significance to explain its high pathogenic and rapid transmission in the world. We discovered a previously unknown route of SARS-CoV-2 entry. SARS-CoV-2 virus-like particles boost cellular filopodia formation by activating Cdc42. Using state-of-art-technology, we spatial-temporally described how virus utilize filopodia to enter the target cell in two modes: surfing and grabbing. Filopodia can directly transport the virus to endocytic hot spots to avoid the virus from disorderly searching on the plasma membrane. Our study complements current knowledge of SARS-CoV-2 that filopodia and its components not only play an important role in virus release and cell-cell transmission, but also in the entry process, and provides several potential therapeutic targets for SARS-CoV-2. HighlightsO_LISARS-CoV-2 VLP infection promotes filopodia formation by activating Cdc42 C_LIO_LISARS-CoV-2 VLP utilizes filopodia to enter target cell via two modes, surfing and grabbing C_LIO_LIFilopodia disruption compromises the invasion of both VLP and authentic SARS-CoV-2 C_LI

cell biology↗

bioRxiv2022

A marmoset brain cell census reveals persistent influence of developmental origin on neurons

The mammalian brain is composed of many brain structures, each with its own ontogenetic and developmental history. Transcriptionally-based cell type taxonomies reveal cell type composition and similarity relationships within and across brain structures. We sampled over 2.4 million brain cells across 18 locations in the common marmoset, a New World monkey primed for genetic engineering, and used single-nucleus RNA sequencing to examine global gene expression patterns of cell types within and across brain structures. Our results indicate that there is generally a high degree of transcriptional similarity between GABAergic and glutamatergic neurons found in the same brain structure, and there are generally few shared molecular features between neurons that utilize the same neurotransmitter but reside in different brain structures. We also show that in many cases the transcriptional identities of cells are intrinsically retained from their birthplaces, even when they migrate beyond their cephalic compartments. Thus, the adult transcriptomic identity of most neuronal types appears to be shaped much more by their developmental identity than by their primary neurotransmitter signaling repertoire. Using quantitative mapping of single molecule FISH (smFISH) for markers for GABAergic interneurons, we found that the similar types (e.g. PVALB+ interneurons) have distinct biodistributions in the striatum and neocortex. Interneuron types follow medio-lateral gradients in striatum but form complex distributions across the neocortex that are not described by simple gradients. Lateral prefrontal areas in marmoset are distinguished by high relative proportions of VIP+ neurons. We further used cell-type-specific enhancer driven AAV-GFP to visualize the morphology of molecularly-resolved interneuron classes in neocortex and striatum, including the previously discovered novel primate-specific TAC3+ striatal interneurons. Our comprehensive analyses highlight how lineage and functional class contribute to the transcriptional identity and biodistribution of primate brain cell types. One-Sentence SummaryAdult primate neurons are imprinted by their region of origin, more so than by their functional identity.

neuroscience↗

bioRxiv2022

Born with intronless ERF transcriptional factors: C4 photosynthesis inherits a legacy dating back 450 million years

The genus Flaveria, containing species at different evolutionary stages of the progression from C3 to C4 photosynthesis, is used as a model system to study the evolution of C4 photosynthesis. Here, we report chromosome-scale genome sequences for five Flaveria species, including C3, C4, and intermediate species. Our analyses revealed that both acquiring additional gene copies and recruiting ethylene responsive factor (ERF) cis-regulatory elements (CREs) contributed to the emergence of C4 photosynthesis. ERF transcriptional factors (TFs), especially intronless ERF TFs, were co-opted in dicotyledonous C4 species and monocotyledonous C4 species in parallel. These C4 species co-opted intronless ERF TFs originated from the Late Ordovician mass extinction that occurred [~]450 million years ago in coping with environmental stress. Therefore, this study demonstrated that intronless ERF TFs were acquired during the early evolution of plants and provided the molecular toolbox facilitating multiple subsequent independent evolutions of C4 photosynthesis.

evolutionary biology↗

bioRxiv2022

Proteomic profiling reveals lysosomal heterogeneity in association with longevity

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with different longevity mechanisms. We further discovered the lysosomal recruitment of AMPK and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we discovered lysosomal heterogeneity across tissues as well as the specific enrichment of the Ragulator complex on Cystinosin positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity at different levels and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk and organism longevity.

cell biology↗

bioRxiv2022

LINC01184 is highly expressed and functions as a tumor-promotive factor in hepatocellular carcinoma

The expression and function of LINC01184 in hepatocellular carcinoma are unknown. We analyzed the changes in LINC01184 expression in hepatocellular carcinoma using public data, and also analyzed the relationship between LINC01184 and patient prognosis. In vitro, we investigated the effect of LINC01184 on HCC cell growth using cell activity analysis, clone formation analysis, and regulatory death analysis. We also explored the effect of LINC01184 on HCC cell migration using transwell analysis and scratch assay. We found that LINC01184 was significantly highly expressed in hepatocellular carcinoma tissues. Patients with high LINC01184 levels had poorer overall survival and disease-free survival. knockdown of LINC01184 in HUH7 and PLC/PRF/5 cells inhibited cell proliferation and induced regulatory death. Down-regulation of LINC01184 also leads to a reduction in the migratory capacity of cells. In conclusion, LINC01184 may become a biomarker or a new therapeutic target for HCC.

cancer biology↗

bioRxiv2022

LINC02428, a liver-specific long noncoding RNA suppresses hepatocellular carcinoma progression

There is growing evidence that lncRNAs play an important role in the progression of HCC, especially liver-specific expression of lncRNAs. LINC02428 is a liver-specific labeled lncRNA, but its role in HCC is unclear. We investigated the expression characteristics of LINC02428 in hepatocellular carcinoma tissues and analyzed its function in HCC. Using TCGA public data we found that the expression level of LINC02428 was significantly reduced in hepatocellular carcinoma tissues, compared to normal tissues. LINC02428 was also significantly reduced in hepatocellular carcinoma tissues in our cDNA microarray data from HCC patients. Survival analysis suggests that HCC patients with lower LINC02428 have a lower overall survival rate. In an in vitro analysis, overexpression of LINC02428 inhibited HCC cell proliferation, migration, and induced apoptosis. In conclusion, we report for the first time the expression profile of a liver-specific lncRNA, LINC02428, in HCC and confirmed its ability to inhibit the progression of HCC. LINC02428 may become a new target for the diagnosis and treatment of HCC.

cancer biology↗

bioRxiv2022

MedDiC: high dimensional mediation analysis via difference in coefficients

High dimensional mediation analysis has been receiving increasing popularity, largely motivated by the scientific problems in genomics and biomedical imaging. Previous literature has primarily focused on mediator selection for high dimensional mediators. In this paper, we aim at the estimation and inference of overall indirect effect for high dimensional exposures and high dimensional mediators. We propose MedDiC, a novel debiased estimator of the high dimensional overall indirect effect based on difference-in-coefficients approach. We evaluate the proposed method using intensive simulations and find that MedDiC provides valid inference and offers higher power and shorter computing time than the competitors for both low dimensional and high dimensional exposures. We also apply MedDiC to a mouse f2 dataset for diabetes study and a dataset composed of diverse maize inbred lines for flowering time, and show that MedDiC yields more biologically meaningful gene lists, and the results are reproduciable across analyses using different measures of identical biological signal or related phenotype as the outcome. Upon the acceptance of the paper, the code will be available on GitHub (https://github.com/QiZhangStat/MedDiC).

genetics↗

bioRxiv2022

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants following an order of BA.1>BA.2>BA.4/5. In naive animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccines targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection across all VOCs. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine- primed populations.

molecular biology↗

bioRxiv2022

CIRKO: A chemical-induced reversible gene knockout system for studying gene function in situ

Conditional loss and restoration of function are becoming important approaches for investigating gene function. Given that reversible conditional gene knockouts in cells required complicated manipulation, conditional inactivation and reactivation of a gene in primary somatic cells with limited proliferative capacity and in animal models remain difficult to achieve. Here, we first developed a reportable and reversible conditional intronic cassette (ReCOIN), wherein inactivation and reactivation of the gene are mediated via sequential expression of Cre and Flp recombinases, respectively. The expression pattern of the target gene can be monitored by direct visualization. To simply and tightly control temporal expression of the recombinases, on the basis of ReCOIN, we further presented a dual chemical-induced reversible gene knockout system (CIRKO) by insertion of reverse tetracycline transcriptional activator (rtTA) and tetracycline response element (TRE)-controlled Cre and FlpoERT2 recombinases cassettes into Rosa26 and Hipp11 loci of cells, respectively, in which transcription termination of the target gene can be induced at a specific stage in the presence of doxycycline, while gene restoration is achieved in the presence of doxycycline and tamoxifen simultaneously. This system provides a simple, rapid, and flexible gene switch for studying gene function in situ both in vitro and in vivo. Impact statementA novel chemical-induced reversible gene knockout system provides a simple, rapid, and flexible gene switch to facilitate the study of gene function in primary somatic cells in vitro, embryos in vitro or in vivo, and animals in vivo.

genetics↗

bioRxiv2022

A Neural Index Reflecting the Amount of Cognitive Resources Available during Memory Encoding: A Model-based Approach

Humans have a limited amount of cognitive resources to process various cognitive operations at a given moment. The Source of Activation Confusion (SAC) model of episodic memory proposes that resources are consumed during each processing and once depleted they need time to recover gradually. This has been supported by a series of behavioral findings in the past. However, the neural substrate of the resources is not known. In the present study, over an existing EEG dataset of a free recall task (Kahana et al., 2022), we provided a neural index reflecting the amount of cognitive resources available for forming new memory traces. Unique to our approach, we obtained the neural index not through correlating neural patterns with behavior outcomes or experimental conditions, but by demonstrating its alignment with a latent quantity of cognitive resources inferred from the SAC model. In addition, we showed that the identified neural index can be used to propose novel hypothesis regarding other long-term memory phenomena. Specifically, we found that according to the neural index, neural encoding patterns for subsequently recalled items correspond to greater available cognitive resources compared with that for subsequently unrecalled items. This provides a mechanistic account for the long-established subsequent memory effects (SMEs, i.e. differential neural encoding patterns between subsequently recalled versus subsequently unrecalled items), which has been previously associated with attention, fatigue and properties of the stimuli.

neuroscience↗

bioRxiv2022

Dynamics, signals and influencing factors of CD4 T cell activation revealed by single cell RNA-seq

T cell activation is a key event in adaptive immunity. However, factors affecting T cell activation have not been systematically analyzed. Here, we analyzed stimulated CD4 T cells with anti-CD3/CD28 under several conditions to explore the factors affecting T cell activation. We defined stimulated T overlapped with resting T on UMAP as inert T. Inert T expressed activated T specific genes and cytokines, indicating it is a special functional state. Stimulated T derived from peripheral CD4 T has higher fraction of effector T (TEFF) while stimulated T derived from CD4 TN has higher fraction of proliferation T and interferon highly expressed T (IFNhi T). CD4 T was more likely to differentiate into TEFF and less likely to differentiate into heat shock protein specific T (HSPhi T) and IFNhi T in the presence of CD8 T. Interestingly, CXCR4low T responded to stimulation more efficiently than CXCR4hi T. These information facilitates we design stimulation to obtain ideal activated T.

immunology↗

bioRxiv2022

Plasticity and lineage commitment of individual Th1 cells are determined by stable T-bet expression quantities

T helper 1 (Th1) cell identity is defined by the expression of the lineage-defining transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated Th1 cells based on their quantitative expression of T-bet and interferon-{gamma}. Heterogeneous T-bet expression states were regulated by virus-induced type-I interferons and were stably maintained even after secondary viral infection. Exposed to Th2-polarizing conditions, the sorted subpopulations exhibited graded levels of plasticity: T-bet quantities were inversely correlated with the ability to express the Th2 lineage-specifying transcription factor GATA-3 and Th2 cytokines. Reprogramed Th1 cells acquired graded, but stable mixed Th1+2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated Th1 cells was essential to ensure Th1 cell stability. Thus, innate cytokine signals regulate Th1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges. HIGHLIGHTSO_LIType-I interferons triggered by infection determine T-bet expression states in Th1 cells C_LIO_LIT-bet and IFN-{gamma} expression states indicate the plasticity of individual Th1 cells C_LIO_LIIndividual T-bet expression states and plasticity persist after secondary infection C_LIO_LIReprogramming yields stable Th1+2 phenotypes and a mixed epigenetic landscape C_LI

immunology↗

bioRxiv2022

TIST: Transcriptome and Histopathological Image Integrative Analysis for Spatial Transcriptomics

Sequencing-based spatial transcriptomics (ST) is an emerging technique to study in situ gene expression patterns at the whole-genome scale. In addition to transcriptomic data, the technique usually generates matched histopathological images for the same tissue sample. ST data analysis is complicated by severe technical noise; matched histopathological images with high spatial continuity and resolution introduce complementary cellular phenotypical information and provide a chance to mitigate the noise in ST data. Hence, we propose a novel ST data analysis method called transcriptome and histopathological image integrative analysis for spatial transcriptomics (TIST), which integrates the information from sequencing-based ST data and histopathological images. TIST uses a Markov random field (MRF) model to learn the macroscopic cellular features from histopathological images and devises a random-walk-based strategy to integrate the extracted image features, the transcriptomic features and the location information for spatial cluster (SC) identification and gene expression enhancement. We tested TIST both on simulated datasets and on 33 real datasets; we found that TIST achieved superior performance on multiple tasks, which illustrates the utility of this method in facilitating the discovery of biological insights from sequencing-based ST data.

bioinformatics↗

bioRxiv2022

Bioinformatics analysis of immune-related prognostic genes and immunotherapy in renal clear cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor and investigating the immunorelated genes is of great significance. To investigate the immunoprognostic genes of ccRCC, we analyzed the data assimilated from a public database (The Cancer Genome Atlas (TCGA) database and the gene expression omnibus (GEO) database) using bioinformatics. Then, a immunoprognosis model was constructed to identify 4 hub genes with moderate predictive values for the prognosis of ccRCC patients. Interestingly, these 4 genes were associated with the prognosis of ccRCC patients based on Oncomine and Gena Expression Profiling Interactive Analysis (GEPIA) databases. The correlation analysis between the immune infiltrate, immune checkpoints, and immunotherapy and this immunoprognosis model showed that immune infiltrate and could predict the immunotherapy effects. We also conducted a quantitative real-time polymerase chain reaction analysis and found that the expressions of 3 hub genes were associated with tumor progression (P<0.1). In conclusion, 4 genes that may serve as potential biomarkers in ccRCC were identified with respect to prognosis.

cancer biology↗

bioRxiv2022

Novel methods to identify TCM constitution of hyperlipidemic patients and predict atherosclerotic diseases

Hyperlipidemia can accelerate the progression of atherosclerosis, ultimately leading to cardiovascular disease. TCM constitution has been widely used as an indicator of health status and susceptibility to diseases. However, there still lack of objective, credible ways to identify TCM constitution of hyperlipidemic patients, and the connection between TCM constitution and atherosclerotic diseases in individuals with hyperlipidemia is unknown. This study aims to identify differentially expressed microRNAs (DEMs) as biomarkers of the TCM constitution of hyperlipidemic patients and explore the potential connection between TCM constitution and atherosclerotic diseases. In the study, we randomly recruited 10 hyperlipidemic patients with asthenic constitution (HAC), 10 hyperlipidemic patients with strong constitution (HSC), and 10 hyperlipidemic patients with normal constitution (HNC) and collected serum miRNA. After analyzing the miRNA expression profiles, we found that hsa-miR-338-3p may be a potential blood biomarker for the identification of the TCM constitution of hyperlipidemic patients. Moreover, the HSC classification is likely a cardiocerebrovascular disease predisposition and is closely related to the inflammatory process and glucose and lipid metabolism, which contribute to the development of atherosclerotic diseases.

bioinformatics↗

bioRxiv2022

Characteristics of circadian rhythm-related genes and establishment of a prognostic scoring system (CRscore) for lung adenocarcinoma with experimental verification

BackgroundNon-small-cell lung cancer (NSCLC) is one of the most common malignant tumors worldwide. Lung adenocarcinoma (LUAD), which is the m ain subtype of NSCLC, has a poor prognosis. In recent years, circadian rhythm (CR)-related genes (CRRGs) have demonstrated associations with tumor occurrence and development, but the relationship between CRRGs and LUAD is not clear. MethodsBased on data from The Cancer Genome Atlas and Gene Expression Omnibus databases, we explored the biological function and immune cell infiltration of LUAD in different CR clusters and quantified CR genes using principal component analysis. Then, we built a CR scoring system (CRscore) to explore the relationship between CRRGs and LUAD prognosis. ResultsPatients were divided into three clusters (A, B, and C). Biological characteristics, such as survival, immune cell infiltration, and gene enrichment, were significantly different among the three clusters. We then established the usefulness of the CR score, which could effectively predict the prognosis of LUAD. Specifically, patients with a high CR score had a better prognosis and were more sensitive to chemotherapy than patients with a low CR score. ConclusionCRRGs can be used to assess the prognosis of patients with LUAD. Quantification of CR using the CRscore tool in patients with LUAD could help to guide personalized cancer immunotherapy strategies in the future. Thus, the CRscore may be a powerful prognostic tool for LUAD.

genomics↗

bioRxiv2022

Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation

Osteoporosis is a highly prevalent disorder with a strong genetic component. Recent studies identify PLS3 as a novel bone regulator of bone metabolism and PLS3 mutations lead to a rare monogenic early-onset osteoporosis. However, the mechanism of PLS3 mutation leading to osteoporosis is unknown with no animal models carrying patient-derived PLS3 mutations generated. The effective treatment strategies for PLS3-related have not been established. Here we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation of PLS3 (PLS3E10-16del/0) that recapitulate the osteoporotic phenotypes with obviously thinner cortical thickness, significant decreases in yield load, maximum load, and breaking load of femora at 3, 6, 9 months compared to WT rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3E10-16del/0rats. Treatment with alendronate (ALN, 1.0 ug/kg per day) or teriparatide (TPTD, 40ug/kg five times weekly) for 8 weeks significantly improved bone mass and bone microarchitecture, and bone strength was significantly increased after TPTD treatment (P < 0.05). Thus, our results indicate the roles of PLS3 in the regulation of bone microstructure and bone strength, providing a novel animal model for the study of early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by PLS3 mutation.

genetics↗

bioRxiv2022

Ancient midbrain inhibitory neurons control selective spatial attention

To behave adaptively in complex environments, animals must selectively process the most important information in space while ignoring distractors. Contrary to the dominant cortico-centric view, we report that an evolutionarily old group of inhibitory neurons in the brainstem, called PLTi, is critical for this function of selective spatial attention. In freely behaving mice performing a human-like spatial attention task, we found that bilateral silencing of PLTi severely disrupted target selection without causing perceptual or motor impairments. PLTis effects depended necessarily on goal-relevant, rather than just physical salience-based signals, together revealing it as a dedicated brain site for priority-driven attentional target selection. PLTis core computational function is its explicit implementation of the abstract cognitive decision boundary separating target from distracters: it controlled the accuracy and categorical precision of this decision boundary, doing so by shaping neural representations of competing stimuli in the superior colliculus, a major sensorimotor hub. PLTi may, therefore, be a conserved brainstem engine across vertebrates for winner-take-all-like spatial decisions in goal-driven behavior.

neuroscience↗