Atherosclerosis is one of the most common vascular disorders. Endothelial cell (EC) dysfunction and vascular smooth muscle cell (VSMC) proliferation contributes to the development of atherosclerosis. ...Long non-coding RNAs (lncRNAs) have been implicated in several biological processes and human diseases. Here we show that lncRNA-RNCR3 is expressed in ECs and VSMCs. RNCR3 expression is significantly upregulated in mouse and human aortic atherosclerotic lesions, and cultured ECs and VSMCs upon ox-LDL treatment in vitro. RNCR3 knockdown accelerates the development of atherosclerosis, aggravates hypercholesterolemia and inflammatory factor releases, and decreases EC and VSMC proliferation in vivo. RNCR3 knockdown also reduces the proliferation and migration, and accelerates apoptosis development of EC and VSMC in vitro. RNCR3 acts as a ceRNA, and forms a feedback loop with Kruppel-like factor 2 and miR-185-5p to regulate cell function. This study reveals that RNCR3 has an atheroprotective role in atherosclerosis, and its intervention is a promising strategy for treating atherosclerosis-related vascular dysfunction.
Liquid photoresists are abundant in the field of light‐based additive manufacturing (AM). However, printing unsupported directly into a vat of material in emerging volumetric AM ...technologies―typically a benefit due to fewer geometric constraints and less material waste―can be a limitation when printing low‐viscosity liquid monomers and multimaterial constructs due to part drift or sedimentation. With ethyl cellulose (EC), a thermoplastic soluble in organic liquids, a simple three‐component transparent thermoreversible gel photoresist with melting temperature of ≈64 °C is formulated. The physically crosslinked network of the gel leads to storage moduli in the range of 0.1−10 kPa and maximum yield stress of 2.7 kPa for a 10 wt% EC gel photoresist. Nonzero yield stress enables sedimentation‐free tomographic volumetric patterning in low‐viscosity monomer without additional hardware or modification of apparatus. In addition, objects inserted into the print container can be suspended in the gel material which enables overprinting of multimaterial devices without anchors connecting the object to the printing container. Flexural strength is also improved by 100% compared to the neat monomer for a formulation with 7 wt% EC.
Thermoreversible organogel photoresist enables tomographic volumetric additive manufacturing with low‐viscosity monomers and overprinting of multimaterial devices. The ethyl cellulose gelator is soluble in several common monomers used in light‐based additive manufacturing. Organogel photoresist made with a simple formulation can create thick freestanding films and bulk bodies. After selective volumetric photopolymerization, nonpolymerized gel can be liquefied to develop the printed object.
Herpes simplex virus type-1 (HSV-1) can cause severe ocular infection and blindness. We have previously shown that the HSV-1 VC2 vaccine strain is protective in mice and guinea pigs against genital ...herpes infection following vaginal challenge with HSV-1 or HSV-2. In this study, we evaluated the efficacy of VC2 intramuscular vaccination in mice against herpetic keratitis following ocular challenge with lethal human clinical strain HSV-1(McKrae). VC2 vaccination in mice produced superior protection and morbidity control in comparison to its parental strain HSV-1(F). Specifically, after HSV-1(McKrae) ocular challenge, all VC2 vaccinated- mice survived, while 30% of the HSV-1(F)- vaccinated and 100% of the mock-vaccinated mice died post challenge. VC2-vaccinated mice did not exhibit any symptoms of ocular infection and completely recovered from initial conjunctivitis. In contrast, HSV-1(F)-vaccinated mice developed time-dependent progressive keratitis characterized by corneal opacification, while mock-vaccinated animals exhibited more severe stromal keratitis characterized by immune cell infiltration and neovascularization in corneal stroma with corneal opacification. Cornea in VC2-immunized mice exhibited significantly increased infiltration of CD3+ T lymphocytes and decreased infiltration of Iba1+ macrophages in comparison to mock- or HSV-1(F)-vaccinated groups. VC2 immunization produced higher virus neutralization titers than HSV-1(F) post challenge. Furthermore, VC-vaccination significantly increased the CD4 T central memory (TCM) subsets and CD8 T effector memory (TEM) subsets in the draining lymph nodes following ocular HSV-1 (McKrae) challenge, then mock- or HSV-1(F)-vaccination. These results indicate that VC2 vaccination produces a protective immune response at the site of challenge to protect against HSV-1-induced ocular pathogenesis.
STAT3 is well corroborated preclinically as a cancer therapeutic target, but tractable translational strategies for its blockade by small molecule inhibitors have remained elusive. In this study, we ...report the development of a novel class of bifunctional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (-NOH) group, which exhibits minimal toxicity against normal cells and good oral bioavailability. Molecular modeling studies of this class suggested direct interaction with the STAT3 DNA binding domain. In particular, the DAP compound HO-3867 selectively inhibited STAT3 phosphorylation, transcription, and DNA binding without affecting the expression of other active STATs. HO-3867 exhibited minimal toxicity toward noncancerous cells and tissues but induced apoptosis in ovarian cancer cells. Pharmacologic analysis revealed greater bioabsorption and bioavailability of the active (cytotoxic) metabolites in cancer cells compared with normal cells. The selective cytotoxicity of HO-3867 seemed to be multifaceted, eliciting differential activation of the Akt pathway in normal versus cancer cells. RNAi attenuation experiments confirmed the requirement of STAT3 for HO-3867-mediated apoptosis in ovarian cancer cells. In vivo testing showed that HO-3867 could block xenograft tumor growth without toxic side effects. Furthermore, in primary human ovarian cancer cells isolated from patient ascites, HO-3867 inhibited cell migration/invasion and survival. Our results offer preclinical proof-of-concept for HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely upregulated.
Pulsed laser deposition (PLD) technique is used to deposit pure and Al-doped ZnO thin films at different temperatures on glass substrates. From the transmission data from optical spectroscopy the ...band gap energy E
g of the films is derived. The dependences of E
g on the deposition temperatures of the pure and Al-doped ZnO films are different. The band gap energy of the pure ZnO increases and saturates with temperature. However, E
g of Al-doped ZnO shows an exponential decrease. Refractive indices of 1.9–2.1 in the VIS are determined by the spectroscopic ellipsometry (SE). Photoluminescence (PL) data reveal the strong near band emission by increasing the deposition temperature.
The objective of this work was to use transcriptional profiling to assess the biological activity of structurally related chemicals to define their biological similarity and with that, substantiate ...the validity of a read-across approach usable in risk assessment. Two case studies are presented, one with 4 short alkyl chain parabens: methyl (MP), ethyl (EP), butyl (BP), and propylparaben (PP), as well as their main metabolite, p-hydroxybenzoic acid (pHBA) with the assumption that propylparaben was the target chemical; and a second one with caffeine and its main metabolites theophylline, theobromine and paraxanthine where CA was the target chemical. The comprehensive transcriptional response of MCF7, HepG2, A549 and ICell cardiomyocytes was evaluated (TempO-Seq) after exposure to vehicle-control, each paraben or pHBA, CA or its metabolites, at 3 non-cytotoxic concentrations, for 6 h. Differentially expressed genes (FDR ≥0.05, and fold change ±1.2≥) were identified for each chemical, at each concentration, and used to determine similarities. Each of the chemicals is able to elicit changes in the expression of a number of genes, as compared to controls. Importantly, the transcriptional profile elicited by each of the parabens shares a high degree of similarity across the group. The highest number of genes commonly affected was between butylparaben and PP. The transcriptional profile of the parabens is similar to the one elicited by estrogen receptor agonists, with BP being the closest structural and biological analogue for PP. In the CA case, the transcriptional profile elicited of all four methylxanthines had a high degree of similarity across the cell types, with CA and theophylline being the most active. The most robust response was obtained in the cardiomyocytes with the highest transcriptional profile similarity between CA and TP. The transcriptional profile of the methylxanthines is similar to the one elicited by inhibitors of phosphatidylinositol 3-kinase as well as other kinase inhibitors. Overall, our results support the approach of incorporating transcriptional profiling in well-designed
tests as one robust stream of data to support biological similarity driven read-across procedures and strengthening the traditional structure-based approaches useful in risk assessment.
Coevolution of tumor cells and adjacent stromal elements is a key feature during tumor progression; however, the precise regulatory mechanisms during this process remain unknown. Here, we show ...stromal p53 loss enhances oncogenic KrasG12D, but not ErbB2, driven tumorigenesis in murine mammary epithelia. Stroma-specific p53 deletion increases both epithelial and fibroblast proliferation in mammary glands bearing the KrasG12D oncogene in epithelia, while concurrently increasing DNA damage and/or DNA replication stress and decreasing apoptosis in the tumor cells proper. Normal epithelia was not affected by stromal p53 deletion. Tumors with p53-null stroma had a significant decrease in total, cytotoxic, and regulatory T cells; however, there was a significant increase in myeloid-derived suppressor cells, total macrophages, and M2-polarized tumor-associated macrophages, with no impact on angiogenesis or connective tissue deposition. Stroma-specific p53 deletion reprogrammed gene expression in both fibroblasts and adjacent epithelium, with p53 targets and chemokine receptors/chemokine signaling pathways in fibroblasts and DNA replication, DNA damage repair, and apoptosis in epithelia being the most significantly impacted biological processes. A gene cluster in p53-deficient mouse fibroblasts was negatively associated with patient survival when compared with two independent datasets. In summary, stroma-specific p53 loss promotes mammary tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately impacts patient survival.
Expression of the p53 tumor suppressor in breast cancer tumor stroma regulates tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately impacts patient survival.
To develop a pretest probability model of obstructive coronary artery disease with machine learning based on multi-site Chinese population data.
Chinese regiStry in early deTection and Risk ...strAtificaTion of coronary plaques (C-Strat) study is a prospective multi-center cohort study, in which consecutive patients with suspected obstructive coronary artery disease and ≥64 detector row coronary computed tomography angioplasty (CCTA) evaluation were included. Data from the patients were randomly split into a training set (70%) and a test set (30%). More than 50% of coronary artery stenosis by CCTA was defined as positive outcome. A boosted ensemble algorithm (XGBoost), 10-fold cross-validation and Bayesian optimization were used to establish a new prediction model-CARDIACS(pretest probability model from Chinese registry in eARly Detection and rIsk stratificAtion of Coronary plaques Study), and a logistic regression was used to establish a model-LOGISTIC in training set. The test set was used for validation and c
ZnO thin films are prepared on the glass, GaAs (100), Si(111), and Si(100) substrates at different temperatures by the pulsed laser deposition (PLD) method. X-ray diffraction (XRD) measurements ...indicate that the substrate temperatures of 200–500, 200–500, 300–500, and 300–500 °C are the optimized conditions of crystalline for the glass, GaAs (100), Si (111), and Si (100) substrates, respectively. In spite of the films deposited on the different substrates, the films always show (002) orientation at the optimized conditions. Photoluminescence (PL) results indicate that the thin films fabricated at the optimized conditions show the intense near band PL emissions. The optimized conditions for PL are 500, 500, 400–500, and 500 °C for glass, GaAs (100), Si (111), and Si (100) substrates, respectively.
ZnO thin films were deposited on the glass substrates at different temperatures (room temperature, 100, 200, 300, 400, and 500
°C) in the pulsed laser deposition (PLD) system. The crystal structure ...of the thin film was found to be
c-axis preferred orientation. The crystal quality of the thin film was confirmed by the
ω
scan (rocking curve) by measuring the (0
0
2) orientation. The full-width at half-maximum (FWHM) value of the thin film deposited at 400
°C was as small as 0.52°. The band gap energies of the thin films were determined by a linear fit of the transmittance spectra. It was found that, with increasing growth temperature, the band gap energy increases and saturates at 3.28
eV. By the fitting of ellipsometry angles (
Ψ
and
Δ
) the optical constants and the thicknesses of the thin films were calculated. The refractive indices of the thin films show normal dispersion behavior and are in the reasonable range compared with ZnO single crystal (2.008 at
6328
Å
). Luminescent measurements were also carried out by spectrometer. There existed two emission peaks in all thin films; one is the near band edge (NBE) emission at about 379
nm; the other is the wide deep level (DL) emission at about 500
nm. With increasing growth temperature, NBE emission enhanced and DL emission quenched. By measuring the photoluminescence (PL) of the samples at different date after deposition, the aging effects were observed. Micro-Raman was used to investigate the vibrational properties of the thin films. E
2 modes at 101 and 438
cm
−1 were observed to locate at 92.1 and 437.6
cm
−1, respectively. This shift was believed to be from the stress in the thin films. Hall measurement indicates that the resistivity decreases and the Hall mobility increases with increasing growth temperature.
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