Cell surface RNAs control neutrophil recruitment.

RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions.

Infiltrating macrophages amplify doxorubicin-induced cardiac damage: role of catecholamines.

BACKGROUND: The functional contribution of non-myocyte cardiac cells, such as inflammatory cells, in the setup of heart failure in response to doxorubicin (Dox) is recently becoming of growing interest. OBJECTIVES: The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment. METHODS: C57BL/6 mice were treated with one intraperitoneal injection of Dox (20 mg/kg) and followed up for 5 days by cardiac ultrasounds (CUS), histological, and flow cytometry evaluations. We also tested the impact of Dox in macrophage-depleted mice. Rat cardiomyoblasts were directly treated with Dox (D-Dox) or with a conditioned medium from cultured murine macrophages treated with Dox (M-Dox). RESULTS: In response to Dox, macrophage infiltration preceded cardiac damage. Macrophage depletion prevents Dox-induced damage, suggesting a key role of these cells in promoting cardiotoxicity. To evaluate the crosstalk between macrophages and cardiac cells in response to DOX, we compared the effects of D-Dox and M-Dox in vitro. Cell vitality was lower in cardiomyoblasts and apoptosis was higher in response to M-Dox compared with D-Dox. These events were linked to p53-induced mitochondria morphology, function, and autophagy alterations. We identify a mechanistic role of catecholamines released by Dox-activated macrophages that lead to mitochondrial apoptosis of cardiac cells through ß-AR stimulation. CONCLUSIONS: Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox.

Exosomal miR-145 and miR-885 Regulate Thrombosis in COVID-19.

We hypothesized that exosomal microRNAs could be implied in the pathogenesis of thromboembolic complications in coronavirus disease 2019 (COVID-19). We isolated circulating exosomes from patients with COVID-19, and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for the internalization of the "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), including angiotensin converting enzyme 2, transmembrane protease serine 2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared with cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. SIGNIFICANCE STATEMENT: This work demonstrates for the first time that two specific microRNAs (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. These findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long COVID.

Ten-Eleven-Translocation Genes in Cancer.

The Ten-Eleven-Translocation (TET) family of genes, including TET1, TET2, and TET3, play critical roles in the oxidation of 5-methylcytosine marks in both DNA and RNA, thereby regulating the epigenome and epitranscriptome in cells. These genes are frequently mutated in both hematopoietic malignancies and in solid cancers. TET2, in particular, is one of the most frequently mutated genes in clonal hematopoiesis in the general population, which impacts both the transformation of hematopoietic malignancies and the immune responses in solid tumors. While much has been learned in the 14 years since the discovery of TETs' biochemical function and mutations, many important questions remain. This review covers several aspects of TET-related biology to discuss key yet unanswered questions. What are the functions of different forms of TET mutations found in human cancers? How does TET2 mutation enable pre-malignant hematopoietic expansion? How does TET2 mutation cooperate with partner lesions to cause transformation? And how do TET mutations affect immune responses in solid cancers.

Reference Genes Screening and Gene Expression Patterns Analysis Involved in Gelsenicine Biosynthesis under Different Hormone Treatments in Gelsemium elegans.

Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an accurate method for quantifying gene expression levels. Choosing appropriate reference genes to normalize the data is essential for reducing errors. Gelsemium elegans is a highly poisonous but important medicinal plant used for analgesic and anti-swelling purposes. Gelsenicine is one of the vital active ingredients, and its biosynthesis pathway remains to be determined. In this study, G. elegans leaf tissue with and without the application of one of four hormones (SA, MeJA, ETH, and ABA) known to affect gelsenicine synthesis, was analyzed using ten candidate reference genes. The gene stability was evaluated using GeNorm, NormFinder, BestKeeper, ∆CT, and RefFinder. The results showed that the optimal stable reference genes varied among the different treatments and that at least two reference genes were required for accurate quantification. The expression patterns of 15 genes related to the gelsenicine upstream biosynthesis pathway was determined by RT-qPCR using the relevant reference genes identified. Three genes 8-HGO, LAMT, and STR, were found to have a strong correlation with the amount of gelsenicine measured in the different samples. This research is the first study to examine the reference genes of G. elegans under different hormone treatments and will be useful for future molecular analyses of this medically important plant species.

Eliminating Edge Electronic and Phonon States of Phosphorene Nanoribbon by Unique Edge Reconstruction.

Edge termination plays a vital role in determining the properties of 2D materials. By performing compelling ab initio simulations, a lowest-energy U-edge [ZZ(U)] reconstruction is revealed in the bilayer phosphorene. Such reconstruction reduces 60% edge energy compared with the pristine one and occurs almost without an energy barrier, implying it should be the dominating edge in reality. The electronic band structure of phosphorene nanoribbon with such reconstruction resembles that of an intrinsic 2D layer, exhibiting nearly edgeless band characteristics. Although ZZ(U) changes the topology of phosphorene nanoribbons, simulated transmission electron microscope, scanning transmission electron microscope and scanning tunneling microscope images indicate it is very hard to be identified. One possible identified method is infrared/Raman analyses because the ZZ(U) edge alters vibrational modes dramatically. In addition, it also increases the thermal conductivity of PNR 1.4 and 2.3 times than the pristine and Klein edges.

Phosphorene grain boundary effect on phonon transport and phononic applications.

Grain boundaries (GBs) widely exist in black phosphorene (BP), which plays a vital role in determining the properties of 2D materials. Significant GB effect on the thermal boundary resistance in BP structures is found by using molecular dynamics calculations and lattice dynamic analysis. A remarkably high interface thermal resistance is observed. By analyzing the strain distribution and phonon vibrational spectra, we reveal this high thermal resistance originates from phonon localization and strong phonon boundary scattering induced by the local stress at the GB area. Particularly, it is interesting to find that the partial phonon modes display weak localization when GBs present. The fraction of atoms participating in a particular phonon vibrational mode has been quantified through the calculation of phonon participation ratio. In addition, the thermal boundary resistance is found size-dependent, which further induces interesting thermal rectification effect in the BP structures. A high rectification ratio is obtained by adjusting the structural length and temperature bias. These findings provide a through insight into the GB effects on individual phonon mode transmission across the GBs, and highlight that the GB effect is an important factor and should be taken into account for the applications of BP-based phononic devices.

A Retinoic Acid Receptor ß 2 Agonist Improves Cardiac Function in a Heart Failure Model.

We previously demonstrated that the selective retinoic acid receptor (RAR) ß 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. We hypothesized that by decreasing oxidative stress and consequent fibrogenesis, AC261066 could attenuate the development of contractile dysfunction in post-ischemic heart failure (HF). We tested this hypothesis in vivo using an established murine model of myocardial infarction (MI), obtained by permanent occlusion of the left anterior descending coronary artery. Treating mice with AC261066 in drinking water significantly attenuated the post-MI deterioration of echocardiographic indices of cardiac function, diminished remodeling, and reduced oxidative stress, as evidenced by a decrease in malondialdehyde level and p38 mitogen-activated protein kinase expression in cardiomyocytes. The effects of AC261066 were also associated with a decrease in interstitial fibrosis, as shown by a marked reduction in collagen deposition and α-smooth muscle actin expression. In cardiac murine fibroblasts subjected to hypoxia, AC261066 reversed hypoxia-induced decreases in superoxide dismutase 2 and angiopoietin-like 4 transcriptional levels as well as the increase in NADPH oxidase 2 mRNA, demonstrating that the post-MI cardioprotective effects of AC261066 are associated with an action at the fibroblast level. Thus, AC261066 alleviates post-MI cardiac dysfunction by modulating a set of genes involved in the oxidant/antioxidant balance. These AC261066 responsive genes diminish interstitial fibrogenesis and remodeling. Since MI is a recognized major cause of HF, our data identify RARß 2 as a potential pharmacological target in the treatment of HF. SIGNIFICANCE STATEMENT: A previous report showed that the selective retinoic acid receptor (RAR) ß 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. This study shows that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF) by modulating a set of genes involved in oxidant/antioxidant balance. Since myocardial infarction is a recognized major cause of HF, these data identify RARß 2 as a potential pharmacological target in the treatment of HF.

Multi-omics facilitated variable selection in Cox-regression model for cancer prognosis prediction.

MOTIVATION: New developments in high-throughput genomic technologies have enabled the measurement of diverse types of omics biomarkers in a cost-efficient and clinically-feasible manner. Developing computational methods and tools for analysis and translation of such genomic data into clinically-relevant information is an ongoing and active area of investigation. For example, several studies have utilized an unsupervised learning framework to cluster patients by integrating omics data. Despite such recent advances, predicting cancer prognosis using integrated omics biomarkers remains a challenge. There is also a shortage of computational tools for predicting cancer prognosis by using supervised learning methods. The current standard approach is to fit a Cox regression model by concatenating the different types of omics data in a linear manner, while penalty could be added for feature selection. A more powerful approach, however, would be to incorporate data by considering relationships among omics datatypes. METHODS: Here we developed two methods: a SKI-Cox method and a wLASSO-Cox method to incorporate the association among different types of omics data. Both methods fit the Cox proportional hazards model and predict a risk score based on mRNA expression profiles. SKI-Cox borrows the information generated by these additional types of omics data to guide variable selection, while wLASSO-Cox incorporates this information as a penalty factor during model fitting. RESULTS: We show that SKI-Cox and wLASSO-Cox models select more true variables than a LASSO-Cox model in simulation studies. We assess the performance of SKI-Cox and wLASSO-Cox using TCGA glioblastoma multiforme and lung adenocarcinoma data. In each case, mRNA expression, methylation, and copy number variation data are integrated to predict the overall survival time of cancer patients. Our methods achieve better performance in predicting patients' survival in glioblastoma and lung adenocarcinoma.

Relation Between Crystal Structure and Electrochemical Performance of LiNi1/3ZnxCo1/3-xMn1/3O2 (0.000 ≤ x ≤ 0.133).

LiNi1/3ZnxCo1/3-xMn1/3O2 (0.000 ≤ x ≤ 0.133) hollow microspheres are synthesized using MnO2 hollow microspheres both as a self-template and Mn source. These hollow microspheres, ~4 µm in diameter, are composed of approximately 300 nm basic nanoparticles. The XRD patterns of LiNi1/3ZnxCo1/3-xMn1/3O2 were analyzed by the RIETAN-FP program, and the obtained samples have a layered α-NaFeO2 structure. Electrochemical performances of the samples were carried out between 2.5 V and 4.5 V. The behavior of the lattice parameters is consistent with Cycling performance and rate performance change with increase of x. Compared with the others, the sample of x = 0.133 exhibits a relatively superior electrochemical performance. The specific capacity of x = 0.133 was increased by 10.7% than no-doped. In addition, the cyclic voltammograms curves of the second cycle show no significant alteration compared with the first cycle and the electrochemical impedance of zinc doping sample showed smaller transfer resistance than the no-doping sample.

NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition.

Metastasis is the major cause for high mortality of lung cancer with the underlying mechanisms poorly understood. The scaffolding protein neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) has been identified as a pro-metastasis gene in several types of cancers including melanoma and breast cancer. However, the exact role and related mechanism of NEDD9 in regulating lung cancer metastasis still remain largely unknown. Here, we demonstrate that NEDD9 knockdown significantly inhibits migration, invasion and metastasis of lung cancer cells in vitro and in vivo. The pro-metastasis role of Nedd9 in lung cancer is further supported by studies in mice models of spontaneous cancer metastasis. Moreover, we find that NEDD9 promotes lung cancer cell migration and invasion through the induction of epithelial-mesenchymal transition (EMT) potentially via focal adhesion kinase activation. More importantly, NEDD9 expression inversely correlates with E-cadherin expression in human lung cancer specimens, consistent with the findings from in vitro studies. Taken together, this study highlights that NEDD9 is an important mediator promotes lung cancer metastasis via EMT.

Integrative analysis of gene and miRNA expression profiles with transcription factor-miRNA feed-forward loops identifies regulators in human cancers.

We describe here a novel method for integrating gene and miRNA expression profiles in cancer using feed-forward loops (FFLs) consisting of transcription factors (TFs), miRNAs and their common target genes. The dChip-GemiNI (Gene and miRNA Network-based Integration) method statistically ranks computationally predicted FFLs by their explanatory power to account for differential gene and miRNA expression between two biological conditions such as normal and cancer. GemiNI integrates not only gene and miRNA expression data but also computationally derived information about TF-target gene and miRNA-mRNA interactions. Literature validation shows that the integrated modeling of expression data and FFLs better identifies cancer-related TFs and miRNAs compared to existing approaches. We have utilized GemiNI for analyzing six data sets of solid cancers (liver, kidney, prostate, lung and germ cell) and found that top-ranked FFLs account for ∼20% of transcriptome changes between normal and cancer. We have identified common FFL regulators across multiple cancer types, such as known FFLs consisting of MYC and miR-15/miR-17 families, and novel FFLs consisting of ARNT, CREB1 and their miRNA partners. The results and analysis web server are available at http://www.canevolve.org/dChip-GemiNi.

The complete chloroplast genome sequence of Calanthe sieboldii (orchidaceae).

Calanthe sieboldii Decne. ex Regel is a terrestrial orchid with high ornamental and commercial value. In the present study, the chloroplast genome of C. sieboldii was characterized using Illumina technology. The chloroplast genome is 158,345 bp in length with a total AT content of 63.28%. There are 127 genes, comprising 37 tRNA genes, 82 protein-coding genes, and 8 rRNA genes. Phylogenetic relationship analysis was performed using common protein-coding genes extracted from 13 chloroplast genomes of Orchidaceae. It was revealed that C. sieboldi was sister to C. hancockii and closely clustered with C. aristulifera and C. henryi. These findings provide valuable genomic resources that are helpful for further phylogenetic and evolutionary studies of Calanthe.

Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.

Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.

The shaping and functional consequences of the dosage effect landscape in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a malignant proliferation of plasma B cells. Based on recurrent aneuploidy such as copy number alterations (CNAs), myeloma is divided into two subtypes with different CNA patterns and patient survival outcomes. How aneuploidy events arise, and whether they contribute to cancer cell evolution are actively studied. The large amount of transcriptomic changes resultant of CNAs (dosage effect) pose big challenges for identifying functional consequences of CNAs in myeloma in terms of specific driver genes and pathways. In this study, we hypothesize that gene-wise dosage effect varies as a result from complex regulatory networks that translate the impact of CNAs to gene expression, and studying this variation can provide insights into functional effects of CNAs. RESULTS: We propose gene-wise dosage effect score and genome-wide karyotype plot as tools to measure and visualize concordant copy number and expression changes across cancer samples. We find that dosage effect in myeloma is widespread yet variable, and it is correlated with gene expression level and CNA frequencies in different chromosomes. Our analysis suggests that despite the enrichment of differentially expressed genes between hyperdiploid MM and non-hyperdiploid MM in the trisomy chromosomes, the chromosomal proportion of dosage sensitive genes is higher in the non-trisomy chromosomes. Dosage-sensitive genes are enriched by genes with protein translation and localization functions, and dosage resistant genes are enriched by apoptosis genes. These results point to future studies on differential dosage sensitivity and resistance of pro- and anti-proliferation pathways and their variation across patients as therapeutic targets and prognosis markers. CONCLUSIONS: Our findings support the hypothesis that recurrent CNAs in myeloma are selected by their functional consequences. The novel dosage effect score defined in this work will facilitate integration of copy number and expression data for identifying driver genes in cancer genomics studies. The accompanying R code is available at http://www.canevolve.org/dosageEffect/.

CaSNP: a database for interrogating copy number alterations of cancer genome from SNP array data.

Cancer is known to have abundant copy number alterations (CNAs) that greatly contribute to its pathogenesis and progression. Investigation of CNA regions could potentially help identify oncogenes and tumor suppressor genes and infer cancer mechanisms. Although single-nucleotide polymorphism (SNP) arrays have strengthened our ability to identify CNAs with unprecedented resolution, a comprehensive collection of CNA information from SNP array data is still lacking. We developed a web-based CaSNP (http://cistrome.dfci.harvard.edu/CaSNP/) database for storing and interrogating quantitative CNA data, which curated ∼11,500 SNP arrays on 34 different cancer types in 104 studies. With a user input of region or gene of interest, CaSNP will return the CNA information summarizing the frequencies of gain/loss and averaged copy number for each study, and provide links to download the data or visualize it in UCSC Genome Browser. CaSNP also displays the heatmap showing copy numbers estimated at each SNP marker around the query region across all studies for a more comprehensive visualization. Finally, we used CaSNP to study the CNA of protein-coding genes as well as LincRNA genes across all cancer SNP arrays, and found putative regions harboring novel oncogenes and tumor suppressors. In summary, CaSNP is a useful tool for cancer CNA association studies, with the potential to facilitate both basic science and translational research on cancer.

Transition metal-doped germanium oxide nanozyme with enhanced enzyme-like activity for rapid detection of pesticide residues in water samples.

Designing highly active nanozymes for bioanalysis and environmental sensing remains a challenge. In this study, transition metal, palladium (Pd) and iron (Fe), doped germanium oxide (GeO2) nanozyme was designed and optimized. Compared with the pristine GeO2 nanozyme, the transition metal doped GeO2 nanozyme have lower Michaelis-Menten constants and higher catalytic activity, indicating that the Pd and Fe doped GeO2 nanozyme not only enhance their affinity for the substrate but also improve its catalytic activity. In addition, a colorimetric sensor based on the GeO2@Pd-H2O2-TMB system was constructed for the visual detection of simazine in water samples due to the good affinity between TMB and simazine. This sensor has good selectivity and sensitivity with a detection limit of 6.21 µM because of the highest catalytic performance of GeO2@Pd nanozyme. This study broadens the application of nanozymes in environmental field and other nanozymes can also be enhanced in activity by simple transition metal doping.

Efficient and recyclable degradation of organic dye pollutants by CeO2@ZIF-8 nanozyme-based non-photocatalytic system.

Advanced oxidation processes-based catalysis system as the most typical pollutant degradation technology always suffer from poor durability and photo-dependent. Inspired by the fact that some nanomaterials exhibit catalytic properties closer to natural enzymes, a high peroxidase-like activity and stability CeO2@ZIF-8 nanozyme was synthesized in this study for non-photodegradation of dyes pollution. Multiple characterization techniques were applied to prove the successful synthesis of the nanozyme. The influence of different parameters on the catalytic degradation of organic dye by nanozyme was investigated. This nanozyme achieved a maximum degradation efficiency of 99.81% for methyl orange and maintained its catalytic performance in repeated experiments. Possible degradation intermediates and pathways for methyl orange were then proposed. In addition, the CeO2@ZIF-8 loaded starch/agarose films were prepared for the portable and recyclable remediation of real dye wastewater, which maintained more than 80% degradation efficiency after 5 successive cycles. These results suggested that nanozyme based non-photocatalytic system is a potential catalyst for dye degradation and it opens a new avenue to develop high-performance and recyclable catalysts for pollutant remediation.

COVID-19 Causes Ferroptosis and Oxidative Stress in Human Endothelial Cells.

Oxidative stress and endothelial dysfunction have been shown to play crucial roles in the pathophysiology of COVID-19 (coronavirus disease 2019). On these grounds, we sought to investigate the impact of COVID-19 on lipid peroxidation and ferroptosis in human endothelial cells. We hypothesized that oxidative stress and lipid peroxidation induced by COVID-19 in endothelial cells could be linked to the disease outcome. Thus, we collected serum from COVID-19 patients on hospital admission, and we incubated these sera with human endothelial cells, comparing the effects on the generation of reactive oxygen species (ROS) and lipid peroxidation between patients who survived and patients who did not survive. We found that the serum from non-survivors significantly increased lipid peroxidation. Moreover, serum from non-survivors markedly regulated the expression levels of the main markers of ferroptosis, including GPX4, SLC7A11, FTH1, and SAT1, a response that was rescued by silencing TNFR1 on endothelial cells. Taken together, our data indicate that serum from patients who did not survive COVID-19 triggers lipid peroxidation in human endothelial cells.

Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.

Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with ß-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies.