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"Shao, Xin"
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Uncovering an Organ’s Molecular Architecture at Single-Cell Resolution by Spatially Resolved Transcriptomics
Revealing fine-scale cellular heterogeneity among spatial context and the functional and structural foundations of tissue architecture is fundamental within biological research and pharmacology. Unlike traditional approaches involving single molecules or bulk omics, cutting-edge, spatially resolved transcriptomics techniques offer near-single-cell or even subcellular resolution within tissues. Massive information across higher dimensions along with position-coordinating labels can better map the whole 3D transcriptional landscape of tissues. In this review, we focus on developments and strategies in spatially resolved transcriptomics, compare the cell and gene throughput and spatial resolution in detail for existing methods, and highlight the enormous potential in biomedical research.
To accurately reflect organ architecture, spatially resolved transcriptomics aims to provide spatial and expression information at the single cellular level for higher-order reconstruction.In silico methods combine single-cell RNA sequencing (scRNA-seq), in situ hybridization, and prior knowledge to reconstruct spatial transcriptomes of tissues but cannot match coordinates and tend to simplify.Laser capture microdissection (LCM)-based approaches allow full gene single-cell profiling plus position information, but assay only a few cells.RNA imaging provides the expression landscape for millions of cells in situ but detects only targeted transcripts.In situ sequencing provides spatial whole genome-wide expression at the micron level by combining barcoding with NGS but fails to describe individual cells.
Journal Article
New avenues for systematically inferring cell-cell communication: through single-cell transcriptomics data
For multicellular organisms, cell-cell communication is essential to numerous biological processes. Drawing upon the latest development of single-cell RNA-sequencing (scRNA-seq), high-resolution transcriptomic data have deepened our understanding of cellular phenotype heterogeneity and composition of complex tissues, which enables systematic cell-cell communication studies at a single-cell level. We first summarize a common workflow of cell-cell communication study using scRNA-seq data, which often includes data preparation, construction of communication networks, and result validation. Two common strategies taken to uncover cell-cell communications are reviewed, e.g., physically vicinal structure-based and ligand-receptor interaction-based one. To conclude, challenges and current applications of cell-cell communication studies at a single-cell resolution are discussed in details and future perspectives are proposed.
Journal Article
Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases
Cardio-Cerebrovascular Disease is a collective term for cardiovascular disease and cerebrovascular disease, being a serious threat to human health. A growing number of studies have proved that the content of inflammatory factors or mediators determines the stability of vascular plaque and the incidence of cardio-cerebrovascular event, and involves in the process of Cardio-Cerebrovascular Diseases. Interleukin-6 is a widely used cytokine that causes inflammation and oxidative stress, which would further result in cardiac and cerebral injury. The increased expression of interleukin-6 is closely related to atherosclerosis, myocardial infarction, heart failure and ischemic stroke. It is a key risk factor for these diseases by triggering inflammatory reaction and inducing other molecules release. Therefore, interleukin-6 may become a potential target for Cardio-Cerebrovascular Diseases in the future. This paper is aimed to discuss the expression changes and pathological mechanisms of interleukin-6 in Cardio-Cerebrovascular Diseases, and to provide a novel strategy for the prevention and treatment of Cardio-Cerebrovascular Diseases.
Journal Article
FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway
Background
Long non-coding RNAs (lncRNAs) are extensively intricate in the tumorigenesis and metastasis of various cancer types. Nevertheless, the detailed molecular mechanisms of lncRNA in non-small cell lung cancer (NSCLC) still remain mainly undetermined.
Methods
qPCR was performed to verify LINC00301 expression in NSCLC clinical specimens or cell lines. Fluorescence in situ hybridization (FISH) was conducted to identify the localization of LINC00301 in NSCLC cells. Chromatin immunoprecipitation (ChIP) was subjected to validate the binding activity between FOXC1 and
LINC00301
promoters. RNA immunoprecipitation (RIP) was performed to explore the binding activity between LINC00301 and EZH2. RNA pull-down followed by dot-blot, protein domain mapping, and RNA electrophoresis mobility shift assay (EMSA) were conducted to identify the detailed binding regions between LINC00301 and EZH2. Alpha assay was conducted to quantitatively assess the interaction between LINC00301 and EZH2.
Results
LINC00301 is highly expressed in NSCLC and closely corelated to its prognosis by analyzing the relationship between differentially expressed lncRNAs and prognosis in NSCLC samples. in vitro and in vivo experiments revealed that LINC00301 facilitates cell proliferation, releases NSCLC cell cycle arrest, promotes cell migration and invasion, and suppresses cell apoptosis in NSCLC. In addition, LINC00301 increases regulatory T cell (Treg) while decreases CD8
+
T cell population in LA-4/SLN-205-derived tumors through targeting TGF-β. The transcription factor FOXC1 mediates LINC00301 expression in NSCLC. Bioinformatics prediction and in vitro experiments indicated that LINC00301 (83–123 nucleotide [nt]) can directly bind to the enhancer of zeste homolog 2 (EZH2) (612–727 amino acid [aa]) to promote H3K27me3 at the
ELL protein
-
associated factor 2
(
EAF2
) promoter. EAF2 directly binds and stabilizes von Hippel–Lindau protein (pVHL), so downregulated EAF2 augments hypoxia-inducible factor 1 α (HIF1α) expression by regulating pVHL in NSCLC cells. Moreover, we also found that LINC00301 could function as a competing endogenous RNA (ceRNA) against miR-1276 to expedite HIF1α expression in the cytoplasm of NSCLC cells.
Conclusions
In summary, our present research revealed the oncogenic roles of LINC00301 in clinical specimens as well as cellular and animal experiments, illustrating the potential roles and mechanisms of the FOXC1/LINC00301/EZH2/EAF2/pVHL/HIF1α and FOXC1/LINC00301/miR-1276/HIF1α pathways, which provides novel insights and potential theraputic targets to NSCLC.
Journal Article
Non-uniform model of relationship between surface strain and rust expansion force of reinforced concrete
When operating within the environments rich with sodium chloride, steel bars of reinforced concrete structures are often subject to corrosion caused by surrounding erosive materials, and the associated rust expansion force due to corrosion takes a critical role in determining the durability of relevant reinforced concrete structures. By investigating the corrosion course of steel reinforcement with theory of elasticity, a numerical rust expansion model is established for the moment of concrete surface rupture based on non-uniform sin function. Cuboid reinforced concrete specimen with squared cross sections is tested to analyze the rust expansion when concrete cracks due to corrosive forces. The utility of the established expansion model is validated by numerical simulation with Abaqus through the comparison between the associated outcomes. The impacts of steel bar diameter and concrete cover thickness on the magnitude of rust expansion force are discussed.
Journal Article
3D-printed aberration-free terahertz metalens for ultra-broadband achromatic super-resolution wide-angle imaging with high numerical aperture
Terahertz (THz) lens constitutes a vital component in the THz system. Metasurfaces-based THz metalenses and classical bulky lenses are severely constrained by chromatic/ spherical aberration and the diffraction limit. Consequently, achromatic super-resolution THz lenses are urgently needed. In this study, through translating the required phase distribution into a refractive index (RI) profile with a specific thickness, an innovative approach to designing THz metalenses is proposed and achieved by dielectric gradient metamaterials. The samples fabricated by 3D printing can realize achromatic super focusing with a numerical aperture (NA) of 0.555 from 0.2 to 0.9 THz. Submillimeter features separated by approximately 0.2 mm can be resolved with high precision, such as glass fabric patterns within FR4 panels and fibrous tissue on leaves, with a field of view (FOV) of 90°. Our approach offers a feasible and cost-effective means to implement THz super-resolution imaging, which holds great potential in non-destructive testing and biomedical imaging.
A 3D-printed terahertz metalens is designed and demonstrated with ultra-broadband achromatic super-resolution wide-angle capability, based on which super-resolution imaging on subwavelength microstructures is achieved with a spatial resolution of 0.2 mm with a 90
◦
FOV.
Journal Article
Copy number variation is highly correlated with differential gene expression: a pan-cancer study
Background
Cancer is a heterogeneous disease with many genetic variations. Lines of evidence have shown copy number variations (CNVs) of certain genes are involved in development and progression of many cancers through the alterations of their gene expression levels on individual or several cancer types. However, it is not quite clear whether the correlation will be a general phenomenon across multiple cancer types.
Methods
In this study we applied a bioinformatics approach integrating CNV and differential gene expression mathematically across 1025 cell lines and 9159 patient samples to detect their potential relationship.
Results
Our results showed there is a close correlation between CNV and differential gene expression and the copy number displayed a positive linear influence on gene expression for the majority of genes, indicating that genetic variation generated a direct effect on gene transcriptional level. Another independent dataset is utilized to revalidate the relationship between copy number and expression level. Further analysis show genes with general positive linear influence on gene expression are clustered in certain disease-related pathways, which suggests the involvement of CNV in pathophysiology of diseases.
Conclusions
This study shows the close correlation between CNV and differential gene expression revealing the qualitative relationship between genetic variation and its downstream effect, especially for oncogenes and tumor suppressor genes. It is of a critical importance to elucidate the relationship between copy number variation and gene expression for prevention, diagnosis and treatment of cancer.
Journal Article
The nonsmooth Newton’s method for the horizontal nonlinear complementarity problem
In this paper, we establish a modulus-based nonsmooth Newton’s method for solving a class of horizontal nonlinear complementarity problems and prove the nearly quadratic convergence of the method under certain assumptions. Based on the analysis of convergence, we give the selection strategy for the approximate iteration vector and propose the improved modulus-based nonsmooth Newton’s method. Finally, numerical experiments show that the new methods are superior to the modulus-based matrix iterative method regarding computational efficiency.
Journal Article
On the Size of Dominant Momentum Transporting Eddies in Stable Atmospheric Boundary Layers
The size of dominant momentum transporting eddies Lmt${L}_{mt}$in stable atmospheric boundary layers is poorly understood. This study demonstrates that the distance to the ground z is relevant in constraining Lmt${L}_{mt}$in weakly stable conditions (0<ζ<0.6$0< \\zeta < 0.6$ , where ζ$\\zeta $is the stability parameter) and less relevant in moderately stable conditions (0.6<ζ<2.0$0.6< \\zeta < 2.0$ ). The widely used Ozmidov scale, however, fails to represent Lmt${L}_{mt}$in moderately stable conditions. The low‐wavenumber ends of the −5/3 scaling law regions in the spanwise and vertical velocity spectra correlate better with a shear‐related length scale. Based on the characteristics of velocity spectra and the balance between kinetic energy and potential energy, a new length scale is proposed to indicate Lmt${L}_{mt}$for moderately stable conditions. Observational data show that this new length scale effectively characterizes Lmt${L}_{mt}$in moderately stable conditions. These findings can help develop better turbulence parameterization schemes for stable atmospheric boundary layers. Plain Language Summary The size of dominant momentum transporting eddies Lmt${L}_{mt}$in stable atmospheric boundary layers is poorly understood. This study proposes a new length scale to characterize Lmt${L}_{mt}$when the influence of the Earth's surface is negligible. These findings have significant implications for developing better turbulence parameterization schemes for stable atmospheric boundary layers. Key Points The size of dominant momentum transporting eddies scales with the distance to the ground z in weak stabilities The buoyancy influence on energy spectra differs among the three velocities in moderate stabilities A new scale different from the Ozmidov scale is proposed to indicate the size of dominant momentum transporting eddies in moderate stabilities
Journal Article