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1.
J Zhejiang Univ Sci B ; 22(10): 805-817, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34636185

RESUMO

Atrial fibrillation (AF) is one of the most common arrhythmias, associated with high morbidity, mortality, and healthcare costs, and it places a significant burden on both individuals and society. Anti-arrhythmic drugs are the most commonly used strategy for treating AF. However, drug therapy faces challenges because of its limited efficacy and potential side effects. Catheter ablation is widely used as an alternative treatment for AF. Nevertheless, because the mechanism of AF is not fully understood, the recurrence rate after ablation remains high. In addition, the outcomes of ablation can vary significantly between medical institutions and patients, especially for persistent AF. Therefore, the issue of which ablation strategy is optimal is still far from settled. Computational modeling has the advantages of repeatable operation, low cost, freedom from risk, and complete control, and is a useful tool for not only predicting the results of different ablation strategies on the same model but also finding optimal personalized ablation targets for clinical reference and even guidance. This review summarizes three-dimensional computational modeling simulations of catheter ablation for AF, from the early-stage attempts such as Maze III or circumferential pulmonary vein isolation to the latest advances based on personalized substrate-guided ablation. Finally, we summarize current developments and challenges and provide our perspectives and suggestions for future directions.

2.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120321, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34481257

RESUMO

Zn1-xMnxAl2O4:0.1 mol% Cr3+ (0.04≤x≤0.16) phosphors with single spinel phase were synthesized by using sol-gel method and the structure, optical and temperature sensing performances were reported herein. The results of X-ray photoelectron spectra indicate that the inversion defects related to octahedral Zn are reduced and the crystal field surrounding Al changes with Mn2+ doping in ZnAl2O4 lattices. Mn2+/Cr3+ co-doped ZnAl2O4 nanophosphors reveal a green emission band assigned to Mn2+ and a series of red emission peaks assigned to Cr3+, respectively. With the concentration of Mn2+ increasing, the intensity of zero phonon line (R line) assigned to Cr3+ increases, reaching the maximum at the optimal Mn2+ concentration of x=0.14. The energy transfer from Mn2+ to Cr3+ is confirmed with the energy transfer efficiency of 83%. The separation between 2E(eg) and 2E(tg) of Cr3+ is enlarged due to Mn2+ dopants giving rise to a change of crystal field. The luminous intensity ratio between two separated emission peaks at 685 nm (R3) and 689 nm (R2) reveals an obvious temperature dependence. The relative sensitivity changes from 3.7 %K-1 to 0.25 %K-1 with the temperature increasing from 80 K to 310 K, which is much larger than that of ZnAl2O4:Cr3+ nanophosphors without Mn2+, indicating its good application prospect in optical thermometry.

3.
Nat Commun ; 12(1): 5642, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561459

RESUMO

Magmatic and tectonic processes can contribute to discontinuous crustal accretion and play an important role in hydrothermal circulation at ultraslow-spreading ridges, however, it is difficult to accurately describe the processes without an age framework to constrain crustal evolution. Here we report on a multi-scale magnetic survey that provides constraints on the fine-scale evolution of a detachment faulting system that hosts hydrothermal activity at 49.7°E on the Southwest Indian Ridge. Reconstruction of the multi-stage detachment faulting history shows a previous episode of detachment faulting took place 0.76~1.48 My BP, while the present fault has been active for the past ~0.33 My and is just in the prime of life. This fault sustains hydrothermal circulation that has the potential for developing a large sulfide deposit. High resolution multiscale magnetics allows us to constrain the relative balance between periods of detachment faulting and magmatism to better describe accretionary processes on an ultraslow spreading ridge.

4.
Stem Cell Rev Rep ; 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34510361

RESUMO

Autologous stem cell transplantation (ASCT) is a potentially curative therapy but requires collection of sufficient blood stem cells (PBSC). Up to 40 % of patients with multiple myeloma (MM) fail to collect an optimum number of PBSC using filgrastim only and often require costly plerixafor rescue. The nonsteroidal anti-inflammatory drug meloxicam mobilizes PBSC in mice, nonhuman primates and normal volunteers, and has the potential to attenuate mobilization-induced oxidative stress on stem cells. In a single-center study, we evaluated whether a meloxicam regimen prior to filgrastim increases collection and/or homeostasis of CD34+ cells in MM patients undergoing ASCT. Mobilization was not significantly different with meloxicam in this study; a median of 2.4 × 106 CD34+ cells/kg were collected in the first apheresis and 9.2 × 106 CD34+ cells/kg were collected overall for patients mobilized with meloxicam-filgrastim, versus 4.1 × 106 in first apheresis and 7.2 × 106/kg overall for patients mobilized with filgrastim alone. CXCR4 expression was reduced on CD34+ cells and a higher CD4+/CD8+ T-cell ratio was observed after mobilization with meloxicam-filgrastim. All patients treated with meloxicam-filgrastim underwent ASCT, with neutrophil and platelet engraftment similar to filgrastim alone. RNA sequencing of purified CD34+ cells from 22 MM patients mobilized with meloxicam-filgrastim and 10 patients mobilized with filgrastim only identified > 4,800 differentially expressed genes (FDR < 0.05). Enrichment analysis indicated significant attenuation of oxidative phosphorylation and translational activity, possibly mediated by SIRT1, suggesting meloxicam may counteract oxidative stress during PBSC collection. Our results indicate that meloxicam was a safe, low-cost supplement to filgrastim mobilization, which appeared to mitigate HSPC oxidative stress, and may represent a simple means to lessen stem cell exhaustion and enhance graft quality.

5.
Oncogene ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504297

RESUMO

Neoantigen peptides arising from genetic alterations may serve as targets for personalized cancer vaccines and as positive predictors of response to immune checkpoint therapy. Mutations in genes regulating RNA splicing are common in hematological malignancies leading to dysregulated splicing and intron retention (IR). In this study, we investigated IR as a potential source of tumor neoantigens in multiple myeloma (MM) patients and the relationship of IR-induced neoantigens (IR-neoAg) with clinical outcomes. MM-specific IR events were identified in RNA-sequencing data from the Multiple Myeloma Research Foundation CoMMpass study after removing IR events that also occurred in normal plasma cells. We quantified the IR-neoAg load by assessing IR-induced novel peptides that were predicted to bind to major histocompatibility complex (MHC) molecules. We found that high IR-neoAg load was associated with poor overall survival in both newly diagnosed and relapsed MM patients. Further analyses revealed that poor outcome in MM patients with high IR-neoAg load was associated with high expression levels of T-cell co-inhibitory molecules and elevated interferon signaling activity. We also found that MM cells exhibiting high IR levels had lower MHC-II protein abundance and treatment of MM cells with a spliceosome inhibitor resulted in increased MHC-I protein abundance. Our findings suggest that IR-neoAg may represent a novel biomarker of MM patient clinical outcome and further that targeting RNA splicing may serve as a potential therapeutic strategy to prevent MM immune escape and promote response to checkpoint blockade.

6.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445339

RESUMO

Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.


Assuntos
Dermatite/genética , Epiderme/metabolismo , PPAR gama/fisiologia , Fenômenos Fisiológicos da Pele/genética , Animais , Células Cultivadas , Dermatite/metabolismo , Dermatite/patologia , Dermatite/fisiopatologia , Epiderme/fisiologia , Homeostase/genética , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos/genética , PPAR gama/genética , PPAR gama/metabolismo
7.
Nat Commun ; 12(1): 5071, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417470

RESUMO

Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.


Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Doenças Neurodegenerativas/genética , Encéfalo/metabolismo , Epigênese Genética , Feto/metabolismo , Redes Reguladoras de Genes , Loci Gênicos , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação/genética , Análise da Randomização Mendeliana , Mapeamento Físico do Cromossomo , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética
8.
Drug Alcohol Depend ; 227: 108914, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364194

RESUMO

Background While many studies have described the impact of prenatal opioid exposure on development, possible mechanisms for how opioids exert developmental impairments remain elusive. Emerging evidence indicates disruptions in the maternal gut microbiome can alter offspring development; however, no studies to date have examined the impact of maternal opioid treatment on maternal-offspring microbiome dysbiosis. Methods A mouse model of prenatal methadone exposure (PME) was employed to assess the impact of maternal opioid treatment on the microbiome of methadone-treated dams (MD) and their offspring. Fecal samples were collected from dams (n = 8 per treatment), one male and one female offspring per dam (n = 8 offspring per sex per treatment) for 16S rRNA sequencing. Results Methadone treatment significantly increased the microbial diversity and led to an expansion in family level bacterial abundance. Correlational analysis revealed significant positive associations between dam and offspring measures of diversity indicating methadone-induced shifts in the microbial communities are shared between dam and offspring. Sixteen features in dams and 10 features in offspring were significantly differentially abundant between treatment groups with many features corresponding to the Lachnospiraceae NK4A136 genus. Of the six features identified as differentially abundant in both MD and PME offspring, all were assigned to the Lachnospiraceae NK4A136 group, and the abundances demonstrated strong positive correlations between dam and offspring. Conclusions These preliminary findings indicate that maternal opioid treatment during pregnancy alters the composition of the maternal microbiome, and this opioid-induced shift is similarly observed in offspring which could contribute to the impaired developmental phenotypes previously described.

9.
Theranostics ; 11(17): 8517-8534, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373756

RESUMO

Rationale: The progression of cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option. We previously created tumor-suppressive secretomes by activating Wnt signaling in MSCs. Here, we examined whether the anti-tumor secretomes can be produced from tumor cells. Methods: Wnt signaling was activated in tumor cells by overexpressing ß-catenin or administering BML284, a Wnt activator. Their conditioned medium (CM) was applied to cancer cells or tissues, and the effects of CM were evaluated. Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through µCT imaging and histology. Whole-genome proteomics analysis was conducted to determine and characterize novel tumor-suppressing proteins, which were enriched in CM. Results: The overexpression of ß-catenin or the administration of BML284 generated tumor-suppressive secretomes from breast, prostate and pancreatic cancer cells. In the mouse model, ß-catenin-overexpressing CM reduced tumor growth and tumor-driven bone destruction. This inhibition was also observed with BML284-treated CM. Besides p53 and Trail, proteomics analysis revealed that CM was enriched with enolase 1 (Eno1) and ubiquitin C (Ubc) that presented notable tumor-suppressing actions. Importantly, Eno1 immunoprecipitated CD44, a cell-surface adhesion receptor, and its silencing suppressed Eno1-driven tumor inhibition. A pan-cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes (p < 0.00001). CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator. Conclusions: The tumor-suppressive secretome can be generated from tumor cells, in which ß-catenin presented two opposing roles, as an intracellular tumor promoter in tumor cells and a generator of extracellular tumor suppressor in CM. Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-tumor action. Besides presenting a potential option for treating primary cancers and metastases, the result indicates that aggressive tumors may inhibit the growth of less aggressive tumors via tumor-suppressive secretomes.

10.
Biotechniques ; 71(2): 431-438, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34374302

RESUMO

The ability to study the bone microenvironment of failed fracture healing may lead to biomarkers for fracture nonunion. Herein the authors describe a technique for isolating individual cells suitable for single-cell RNA sequencing analyses from intramedullary canal tissue collected by reaming during surgery. The purpose was to detail challenges and solutions inherent to the collection and processing of intramedullary canal tissue samples. The authors then examined single-cell RNA sequencing data from fresh and reanimated samples to demonstrate the feasibility of this approach for prospective studies.

11.
Cells ; 10(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34440898

RESUMO

BACKGROUND & AIMS: Liver fibrosis is a pathological healing process resulting from hepatic stellate cell (HSC) activation and the generation of myofibroblasts from activated HSCs. The precise underlying mechanisms of liver fibrogenesis are still largely vague due to lack of understanding the functional heterogeneity of activated HSCs during liver injury. Approach and Results: In this study, to define the mechanism of HSC activation, we performed the transcriptomic analysis at single-cell resolution (scRNA-seq) on HSCs in mice treated with carbon tetrachloride (CCl4). By employing LRAT-Cre:Rosa26mT/mG mice, we were able to isolate an activated GFP-positive HSC lineage derived cell population by fluorescence-activated cell sorter (FACS). A total of 8 HSC subpopulations were identified based on an unsupervised analysis. Each HSC cluster displayed a unique transcriptomic profile, despite all clusters expressing common mouse HSC marker genes. We demonstrated that one of the HSC subpopulations expressed high levels of mitosis regulatory genes, velocity, and monocle analysis indicated that these HSCs are at transitioning and proliferating phases at the beginning of HSCs activation and will eventually give rise to several other HSC subtypes. We also demonstrated cell clusters representing HSC-derived mature myofibroblast populations that express myofibroblasts hallmark genes with unique contractile properties. Most importantly, we found a novel HSC cluster that is likely to be critical in liver regeneration, immune reaction, and vascular remodeling, in which the unique profiles of genes such as Rgs5, Angptl6, and Meg3 are highly expressed. Lastly, we demonstrated that the heterogeneity of HSCs in the injured mouse livers is closely similar to that of cirrhotic human livers. CONCLUSIONS: Collectively, our scRNA-seq data provided insight into the landscape of activated HSC populations and the dynamic transitional pathway from HSC to myofibroblasts in response to liver injury.

12.
Clin Pharmacol Ther ; 110(4): 1106-1118, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34314509

RESUMO

MiRNAs regulate the expression of hepatic genes involved in pharmacokinetics and pharmacodynamics. Genetic variants affecting miRNA binding (mirSNPs) have been associated with altered drug response, but previously used methods to identify miRNA binding sites and functional mirSNPs in pharmacogenes are indirect and limited by low throughput. We utilized the high-throughput chimeric-eCLIP assay to directly map thousands of miRNA-mRNA interactions and define the miRNA binding sites in primary hepatocytes. We then used the high-throughput PASSPORT-seq assay to functionally test 262 potential mirSNPs with coordinates overlapping the identified miRNA binding sites. Using chimeric-eCLIP, we identified a network of 448 miRNAs that collectively target 11,263 unique genes in primary hepatocytes pooled from 100 donors. Our data provide an extensive map of miRNA binding of each gene, including pharmacogenes, expressed in primary hepatocytes. For example, we identified the hsa-mir-27b-DPYD interaction at a previously validated binding site. A second example is our identification of 19 unique miRNAs that bind to CYP2B6 across 20 putative binding sites on the transcript. Using PASSPORT-seq, we then identified 24 mirSNPs that functionally impacted reporter mRNA levels. To our knowledge, this is the most comprehensive identification of miRNA binding sites in pharmacogenes. Combining chimeric-eCLIP with PASSPORT-seq successfully identified functional mirSNPs in pharmacogenes that may affect transcript levels through altered miRNA binding. These results provide additional insights into potential mechanisms contributing to interindividual variability in drug response.


Assuntos
Hepatócitos/metabolismo , MicroRNAs/metabolismo , Variantes Farmacogenômicos/genética , RNA Mensageiro/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação , Citocromo P-450 CYP2B6/genética , Di-Hidrouracila Desidrogenase (NADP)/genética , Humanos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA-Seq
13.
Mol Immunol ; 137: 145-154, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34247100

RESUMO

Previous studies have found that the expression level of Megalobrama amblycephala intelectin (MaINTL) increased significantly post Aeromonas hydrophila infection, and recombinant MaINTL (rMaINTL) protein could activate macrophages and enhance the phagocytosis and killing activity of macrophages. In order to reveal the immune regulatory mechanisms of MaINTL, primary M. amblycephala macrophages were treated with endotoxin-removed rMaINTL and GST-tag proteins, then total RNA were extracted and used for comparative Digital Gene Expression Profiling (DGE). 1247 differentially expressed genes were identified by comparing rMaINTL and GST-tag treated macrophage groups, including 482 up-regulated unigenes and 765 down-regulated unigenes. In addition, eleven randomly selected differentially expressed genes were verified by qRT-PCR, and most of them shared the similar expression patterns as that of DGE results. GO enrichment revealed that the differentially expressed genes were mainly concentrated in the membrane part and cytoskeleton of cellular component, the binding and signal transducer activity of molecular function, the cellular process, regulation of biological process, signaling and localization of biological process, most of which might related with the phagocytosis and killing activity of macrophages. KEGG analysis revealed the activation and involvement of differentially expressed genes in immune related pathways, such as Tumor necrosis factor (TNF) signaling pathway, Interleukin 17 (IL-17) signaling pathway, Toll-like receptor signaling pathway, and NOD like receptor signaling pathway, etc. In these pathways, TNF-ɑ, Activator protein-1 (AP-1), Myeloid differentiation primary response protein MyD88 (MyD88), NF-kappa-B inhibitor alpha (ikBɑ) and other key signaling factors were significantly up-regulated. These results will be helpful to clarify the immune regulatory mechanisms of fish intelectin on macrophages, thus providing a theoretical basis for the prevention and control of fish bacterial diseases.


Assuntos
Aeromonas hydrophila/imunologia , Cyprinidae/imunologia , Cyprinidae/microbiologia , Infecções por Bactérias Gram-Negativas/imunologia , Macrófagos/imunologia , Fagocitose/imunologia , Animais , Regulação para Baixo/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/métodos , Infecções por Bactérias Gram-Negativas/microbiologia , Fatores Imunológicos/imunologia , Macrófagos/microbiologia , Transdução de Sinais/imunologia , Transcriptoma/imunologia , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima/imunologia
14.
Int J Biol Macromol ; 187: 880-891, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34329666

RESUMO

Water pollution is one of the most serious threats facing mankind today and has obtained widespread attention. Significant advances have been made in the past decades to apply porous materials in wastewater treatment, due to their large specific surface areas (SBET) for interaction with the aimed ions or molecules. However, the majority of porous materials are prepared from fossil-based resources and still possess some drawbacks, such as high cost and non-degradability, which inevitably cause secondary pollution to the environment from their production to disposal. Lignin is the most abundant and the only scalable renewable aromatic resource on earth. Due to its unique physicochemical properties including high carbon content, plentiful functional groups and environmental friendliness, the lignin-based porous materials (LPMs) have shown promising prospects in efficient removal of soluble pollutants from wastewater. In this review, we firstly described the structural and chemical basis of LPMs, following presented the recent progress in the decontamination of heavy metal ions, organic dyes, antibiotics, anions and radionuclides from aqueous systems. Additionally, the outlook was provided to promote more practical implementation of LPMs in the near future.

15.
Anal Chem ; 93(27): 9593-9601, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34191475

RESUMO

DNA walkers have shown superior performance in biosensing due to their programmability to design molecular walking behaviors with specific responses to different biological targets. However, it is still challenging to make DNA walkers capable of distinguishing DNA targets with single-base differences, so that DNA walkers that can be used for circulating tumor DNA sensing are rarely reported. Herein, a flap endonuclease 1 (FEN 1)-assisted DNA walker has been proposed to achieve mutant biosensing. The target DNA is captured on a gold nanoparticle (AuNP) as a walking strand to walk by hybridizing to the track strands on the surface of the AuNP. FEN 1 is employed to report the walking events by cleaving the track strands that must form a three-base overlapping structure recognized by FEN 1 after hybridizing with the captured target DNA. Owing to the high specificity of FEN 1 for structure recognition, the one-base mutant DNA target can be discriminated from wild-type DNA. By constructing a sensitivity-enhanced DNA walker system, as low as 1 fM DNA targets and 0.1% mutation abundance can be sensed, and the theoretical detection limits for detecting the DNA target and mutation abundance achieve 0.22 fM and 0.01%, respectively. The results of epidermal growth factor receptor (EGFR) L858R mutation detection on cell-free DNA samples from 15 patients with nonsmall cell lung cancer were completely consistent with that of next-generation sequencing, indicating that our DNA walker has potential for liquid biopsy.


Assuntos
Técnicas Biossensoriais , Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante/análise , Neoplasias Pulmonares , Nanopartículas Metálicas , Endonucleases Flap , Ouro , Humanos
16.
Immunohorizons ; 5(6): 395-409, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103370

RESUMO

Clinical use of various forms of immunotherapeutic drugs in glioblastoma (GBM), has highlighted severe T cell dysfunction such as exhaustion in GBM patients. However, reversing T cell exhaustion using immune checkpoint inhibitors in GBM clinical trials has not shown significant overall survival benefit. Phenotypically, CD8+ T cells with downregulated CD28 coreceptors, low CD27 expression, increased CD57 expression, and telomere shortening are classified as senescent T cells. These senescent T cells are normally seen as part of aging and also in many forms of solid cancers. Absence of CD28 on T cells leads to several functional irregularities including reduced TCR diversity, incomplete activation of T cells, and defects in Ag-induced proliferation. In the context of GBM, presence and/or function of these CD8+CD28- T cells is unknown. In this clinical correlative study, we investigated the effect of aging as well as tumor microenvironment on CD8+ T cell phenotype as an indicator of its function in GBM patients. We systematically analyzed and describe a large population of CD8+CD28- T cells in both the blood and tumor-infiltrating lymphocytes of GBM patients. We found that phenotypically these CD8+CD28- T cells represent a distinct population compared with exhausted T cells. Comparative transcriptomic and pathway analysis of CD8+CD28- T cell populations in GBM patients revealed that tumor microenvironment might be influencing several immune related pathways and thus further exaggerating the age associated immune dysfunction in this patient population.

17.
Alzheimers Res Ther ; 13(1): 110, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108016

RESUMO

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.


Assuntos
Doença de Alzheimer , COVID-19 , Disfunção Cognitiva , Doença de Alzheimer/genética , Encéfalo , Células Endoteliais , Humanos , Proteínas de Membrana , Proteínas de Ligação a RNA , SARS-CoV-2
18.
Stem Cell Rev Rep ; 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33974233

RESUMO

Aging of hematopoiesis is associated with increased frequency and clonality of hematopoietic stem cells (HSCs), along with functional compromise and myeloid bias, with donor age being a significant variable in survival after HSC transplantation. No clinical methods currently exist to enhance aged HSC function, and little is known regarding how aging affects molecular responses of HSCs to biological stimuli. Exposure of HSCs from young fish, mice, nonhuman primates, and humans to 16,16-dimethyl prostaglandin E2 (dmPGE2) enhances transplantation, but the effect of dmPGE2 on aged HSCs is unknown. Here we show that ex vivo pulse of bone marrow cells from young adult (3 mo) and aged (25 mo) mice with dmPGE2 prior to serial competitive transplantation significantly enhanced long-term repopulation from aged grafts in primary and secondary transplantation (27 % increase in chimerism) to a similar degree as young grafts (21 % increase in chimerism; both p < 0.05). RNA sequencing of phenotypically-isolated HSCs indicated that the molecular responses to dmPGE2 are similar in young and old, including CREB1 activation and increased cell survival and homeostasis. Common genes within these pathways identified likely key mediators of HSC enhancement by dmPGE2 and age-related signaling differences. HSC expression of the PGE2 receptor EP4, implicated in HSC function, increased with age in both mRNA and surface protein. This work suggests that aging does not alter the major dmPGE2 response pathways in HSCs which mediate enhancement of both young and old HSC function, with significant implications for expanding the therapeutic potential of elderly HSC transplantation.

19.
Ying Yong Sheng Tai Xue Bao ; 32(5): 1761-1767, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34042371

RESUMO

To explore the effects of arbuscular mycorrhizal fungi (AMF) on the growth of legume crop, pot and field experiments with soybean were conducted. Treatments of inoculation (+AMF) and non-inoculation with AMF (-AMF) were set up for the pot experiment, and AMF mycelium non-limited and limited for the field experiment. Results of the pot experiment showed that inoculation with AMF significantly increased soybean aboveground biomass (16.5%) and root nodules number (131.4%), above-ground plant phosphorus and nitrogen concentrations and uptakes. In the field trial, the above-ground and root biomasses and root nodules number under AMF mycelium non-limited were significantly increased by 123.6%, 61.5%, and 212.5% compared with those under the limited condition, respectively. Plant phosphorus uptake, nitrogen concentration and uptake, and soil available nitrogen and phosphorus concentrations were significantly higher under AMF mycelium non-limited than the limited both in both shoot and root. Our findings provide theoretical reference for further understanding the relationship between legume crop and AMF, as well as the efficient utilization of phosphorus fertilizer.


Assuntos
Fabaceae , Micorrizas , Nitrogênio , Fósforo , Raízes de Plantas
20.
Brief Bioinform ; 2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34021560

RESUMO

Understanding the functional consequence of noncoding variants is of great interest. Though genome-wide association studies or quantitative trait locus analyses have identified variants associated with traits or molecular phenotypes, most of them are located in the noncoding regions, making the identification of causal variants a particular challenge. Existing computational approaches developed for prioritizing noncoding variants produce inconsistent and even conflicting results. To address these challenges, we propose a novel statistical learning framework, which directly integrates the precomputed functional scores from representative scoring methods. It will maximize the usage of integrated methods by automatically learning the relative contribution of each method and produce an ensemble score as the final prediction. The framework consists of two modes. The first 'context-free' mode is trained using curated causal regulatory variants from a wide range of context and is applicable to predict regulatory variants of unknown and diverse context. The second 'context-dependent' mode further improves the prediction when the training and testing variants are from the same context. By evaluating the framework via both simulation and empirical studies, we demonstrate that it outperforms integrated scoring methods and the ensemble score successfully prioritizes experimentally validated regulatory variants in multiple risk loci.

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