scholarly journals Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yadi Zhou ◽  
Jielin Xu ◽  
Yuan Hou ◽  
James B. Leverenz ◽  
Asha Kallianpur ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Marker Genes ◽  
Antiviral Defense ◽  
Neurological Manifestations ◽  
Cell Nuclei ◽  
Defense Genes ◽  
Aberrant Expression ◽  
Microvascular Injury

Abstract Background Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. Methods In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. Results We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. Conclusion Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.

scholarly journals Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

2021 ◽  
Author(s):  
Yadi Zhou ◽  
Jielin Xu ◽  
Yuan Hou ◽  
James B. Leverenz ◽  
Asha Kallianpur ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cell Types ◽  
Marker Genes ◽  
Antiviral Defense ◽  
Neurological Manifestations ◽  
Cell Nuclei ◽  
Defense Genes ◽  
Aberrant Expression ◽  
Microvascular Injury ◽  
Underlying Mechanisms

AbstractBackgroundDementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions.MethodsIn this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.ResultsWe found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals.ConclusionOur results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.

scholarly journals Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

2020 ◽  
Author(s):  
K. Blake Chancellor ◽  
Sarah E. Chancellor ◽  
Joseph E. Duke-Cohan ◽  
Bertrand R. Huber ◽  
Thor D. Stein ◽  
...  
Keyword(s):  
White Matter ◽  
Chronic Traumatic Encephalopathy ◽  
Cell Types ◽  
Cellular Stress Response ◽  
Therapeutic Interventions ◽  
Cell Nuclei ◽  
Head Impacts ◽  
Starting Point ◽  
Cell Groups ◽  
And Control

Abstract Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts (RHI)1–6. White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level2,7,8. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. Astrocyte alterations were more nuanced; total astrocyte number was indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups as compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and may provide a starting point for the development of diagnostics and therapeutic interventions.

scholarly journals Decontamination of ambient RNA in single-cell RNA-seq with DecontX

2019 ◽  
Author(s):  
Shiyi Yang ◽  
Sean E. Corbett ◽  
Yusuke Koga ◽  
Zhe Wang ◽  
W. Evan Johnson ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Marker Genes ◽  
Specific Marker ◽  
Aberrant Expression ◽  
Cell Type Specific ◽  
Hierarchical Bayesian Method ◽  
Assess Quality

ABSTRACTDroplet-based microfluidic devices have become widely used to perform single-cell RNA sequencing (scRNA-seq) and discover novel cellular heterogeneity in complex biological systems. However, ambient RNA present in the cell suspension can be incorporated into these droplets and aberrantly counted along with a cell’s native mRNA. This results in cross-contamination of transcripts between different cell populations and can potentially decrease the precision of downstream analyses. We developed a novel hierarchical Bayesian method called DecontX to estimate and remove contamination in individual cells from scRNA-seq data. DecontX accurately predicted the proportion of contaminated counts in a mixture of mouse and human cells. Decontamination of PBMC datasets removed aberrant expression of cell type specific marker genes from other cell types and improved overall separation of cell clusters. In general, DecontX can be incorporated into scRNA-seq workflows to assess quality of dissociation protocols and improve downstream analyses.

scholarly journals Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

2020 ◽  
Author(s):  
K. Blake Chancellor ◽  
Sarah E. Chancellor ◽  
Joseph E. Duke-Cohan ◽  
Bertrand R. Huber ◽  
Thor D. Stein ◽  
...  
Keyword(s):  
White Matter ◽  
Chronic Traumatic Encephalopathy ◽  
Cell Types ◽  
Cellular Level ◽  
Cellular Stress Response ◽  
Therapeutic Interventions ◽  
Cell Nuclei ◽  
Starting Point ◽  
Cell Groups ◽  
And Control

SUMMARYChronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts (RHI)1–6. White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level2,7,8. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. Astrocyte alterations were more nuanced; total astrocyte number was indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups as compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and may provide a starting point for the development of diagnostics and therapeutic interventions.

scholarly journals scSorter: assigning cells to known cell types according to marker genes

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hongyu Guo ◽  
Jun Li
Keyword(s):  
Real Data ◽  
Cell Types ◽  
Exact Expression ◽  
Marker Genes ◽  
Specific Marker ◽  
Sequencing Data ◽  
Reference Dataset ◽  
Over Expression ◽  
Higher Power ◽  
Cell Type Specific

AbstractOn single-cell RNA-sequencing data, we consider the problem of assigning cells to known cell types, assuming that the identities of cell-type-specific marker genes are given but their exact expression levels are unavailable, that is, without using a reference dataset. Based on an observation that the expected over-expression of marker genes is often absent in a nonnegligible proportion of cells, we develop a method called scSorter. scSorter allows marker genes to express at a low level and borrows information from the expression of non-marker genes. On both simulated and real data, scSorter shows much higher power compared to existing methods.

scholarly journals Diving into the Pleural Fluid: Liquid Biopsy for Metastatic Malignant Pleural Effusions

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2798
Author(s):  
Maria Alba Sorolla ◽  
Anabel Sorolla ◽  
Eva Parisi ◽  
Antonieta Salud ◽  
José M. Porcel
Keyword(s):  
Pleural Fluid ◽  
Liquid Biopsy ◽  
Cell Types ◽  
Circulating Tumor Dna ◽  
Therapeutic Interventions ◽  
Driver Mutations ◽  
Pleural Effusions ◽  
Malignant Pleural Effusions ◽  
Micro Rnas ◽  
Low Sensitivity

Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE.

scholarly journals Molecular characteristics and spatial distribution of adult human corneal cell subtypes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ann J. Ligocki ◽  
Wen Fury ◽  
Christian Gutierrez ◽  
Christina Adler ◽  
Tao Yang ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Cross Sections ◽  
Cell Types ◽  
Marker Genes ◽  
Molecular Characteristics ◽  
Transcriptional Level ◽  
Human Cornea ◽  
Adult Human ◽  
And Migration

AbstractBulk RNA sequencing of a tissue captures the gene expression profile from all cell types combined. Single-cell RNA sequencing identifies discrete cell-signatures based on transcriptomic identities. Six adult human corneas were processed for single-cell RNAseq and 16 cell clusters were bioinformatically identified. Based on their transcriptomic signatures and RNAscope results using representative cluster marker genes on human cornea cross-sections, these clusters were confirmed to be stromal keratocytes, endothelium, several subtypes of corneal epithelium, conjunctival epithelium, and supportive cells in the limbal stem cell niche. The complexity of the epithelial cell layer was captured by eight distinct corneal clusters and three conjunctival clusters. These were further characterized by enriched biological pathways and molecular characteristics which revealed novel groupings related to development, function, and location within the epithelial layer. Moreover, epithelial subtypes were found to reflect their initial generation in the limbal region, differentiation, and migration through to mature epithelial cells. The single-cell map of the human cornea deepens the knowledge of the cellular subsets of the cornea on a whole genome transcriptional level. This information can be applied to better understand normal corneal biology, serve as a reference to understand corneal disease pathology, and provide potential insights into therapeutic approaches.

scholarly journals Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

2021 ◽  
Vol 22 (6) ◽  
pp. 3007
Author(s):  
Isabel Lastres-Becker ◽  
Gracia Porras ◽  
Marina Arribas-Blázquez ◽  
Inés Maestro ◽  
Daniel Borrego-Hernández ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Metabolic Disturbances ◽  
Molecular Alterations ◽  
Healthy Donors ◽  
Inflammatory Profile ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

scholarly journals Expression of SOX2 and OCT4 in odontogenic cysts and tumors

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Ekarat Phattarataratip ◽  
Tarit Panitkul ◽  
Watunyoo Khodkaew ◽  
Pattarapong Anupuntanun ◽  
Jirapat Jaroonvechatam ◽  
...  
Keyword(s):  
Cell Types ◽  
Odontogenic Cysts ◽  
Positive Staining ◽  
Stem Cell Markers ◽  
Aberrant Expression ◽  
Future Studies ◽  
Sox2 Expression ◽  
Cells Of Origin ◽  
Dentigerous Cysts ◽  
Patient Prognosis

Abstract Background Aberrant expression of stem cell markers has been observed in several types of neoplasms. This trait attributes to the acquired stem-like property of tumor cells and can impact patient prognosis. The objective of this study was to comparatively analyze the expression and significance of SOX2 and OCT4 in various types of odontogenic cysts and tumors. Methods Fifty-five cases of odontogenic cysts and tumors, including 15 ameloblastomas (AM), 5 adenomatoid odontogenic tumors (AOT), 5 ameloblastic fibromas (AF), 5 calcifying odontogenic cysts (COC), 10 dentigerous cysts (DC) and 15 odontogenic keratocysts (OKC) were investigated for the expression of SOX2 and OCT4 immunohistochemically. Results Most OKCs (86.7 %) and all AFs expressed SOX2 in more than 50 % of epithelial cells. Its immunoreactivity was moderate-to-strong in all epithelial cell types in both lesions. In contrast, SOX2 expression was undetectable in AOTs and limited to the ameloblast-like cells in a minority of AM and COC cases. Most DCs showed positive staining in less than 25 % of cystic epithelium. Significantly greater SOX2 expression was noted in OKC compared with DC or AM, and in AF compared with COC or AOT. OCT4 rarely expressed in odontogenic lesions with the immunoreactivity being mild and present exclusively in OKCs. Conclusions SOX2 is differentially expressed in odontogenic cysts and tumors. This could be related to their diverse cells of origin or stages of histogenesis. The overexpression of SOX2 and OCT4 in OKC indicates the acquired stem-like property. Future studies should investigate whether the overexpression of OCT4 and SOX2 contributes to the aggressive behaviors of the tumors.

scholarly journals Divergent functions of endotrophin on different cell populations in adipose tissue

2016 ◽  
Vol 311 (6) ◽  
pp. E952-E963 ◽  
Author(s):  
Yueshui Zhao ◽  
Xue Gu ◽  
Ningyan Zhang ◽  
Mikhail G. Kolonin ◽  
Zhiqiang An ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Accumulation ◽  
Lysyl Oxidase ◽  
Stromal Vascular Fraction ◽  
Cell Types ◽  
Marker Genes ◽  
New Perspective ◽  
Collagen Genes ◽  
Different Cell Types

Endotrophin is a cleavage product of collagen 6 (Col6) in adipose tissue (AT). Previously, we demonstrated that endotrophin serves as a costimulator to trigger fibrosis and inflammation within the unhealthy AT milieu. However, how endotrophin affects lipid storage and breakdown in AT and how different cell types in AT respond to endotrophin stimulation remain unknown. In the current study, by using a doxycycline-inducible mouse model, we observed significant upregulation of adipogenic genes in the white AT (WAT) of endotrophin transgenic mice. We further showed that the mice exhibited inhibited lipolysis and accelerated hypertrophy and hyperplasia in WAT. To investigate the effects of endotrophin in vitro, we incubated different cell types from AT with conditioned medium from endotrophin-overexpressing 293T cells. We found that endotrophin activated multiple pathological pathways in different cell types. Particularly in 3T3-L1 adipocytes, endotrophin triggered a fibrotic program by upregulating collagen genes and promoted abnormal lipid accumulation by downregulating hormone-sensitive lipolysis gene and decreasing HSL phosphorylation levels. In macrophages isolated from WAT, endotrophin stimulated higher expression of the collagen-linking enzyme lysyl oxidase and M1 proinflammatory marker genes. In the stromal vascular fraction isolated from WAT, endotrophin induced upregulation of both profibrotic and proinflammatory genes. In conclusion, our study provides a new perspective on the effect of endotrophin in abnormal lipid accumulation and a mechanistic insight into the roles played by adipocytes and a variety of other cell types in AT in shaping the unhealthy microenvironment upon endotrophin treatment.

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