Stabilized four-node tetrahedron with nonlocal pressure for modeling hyperelastic materials

Non-linear hyperelastic response of reinforced elastomers is modeled using a novel three-dimensional mixed finite element method with a nonlocal pressure field. The element is unconditionally convergent and free of spurious pressure modes. Nonlocal pressure is obtained by an implicit gradient technique and obeys the Helmholtz equation. Physical motivation for this nonlocality is shown. An implicit finite element scheme with consistent linearization is presented. Finally, several hyperelastic examples are solved to demonstrate the computational algorithm including the inf–sup and verifications test

Teacher–Student Interaction in EFL Reading Comprehension Contexts at University Level: A Critical Thinking Perspective

SAGE Open, October-December, pp. 1–16In line with previous studies in English as a Foreign Language/English as a Second Language (EFL/ESL) contexts confirming the positive correlation between critical thinking and reading comprehension, this study was conducted to determine how frequently critical thinking is used in EFL reading comprehension contexts at the tertiary level in one Iranian university. To this end, all question types associated with general and Critical Reading Questions (CRQs), Vocabulary in Context (VIC), Literal Comprehension (LC), and Extended Reasoning (ER) were identified. The principal focus of the study was on ER questions leading to critical thinking. To classify the questions formulated by teachers and students for CRQs, Peterson’s model was used. To specify critical thinking question types, a framework proposed by Academic Skills Unit was used as another model. To collect the data, the researchers observed all reading comprehension courses in one of the universities in Isfahan Province. They recorded 30% of the total number of sessions using two mini-size MP4 wireless recorders during the second semester of the 2010-2011 academic year. The findings seem to suggest that teachers’ focus on each CRQ type strongly influences students’ attention when reading different passages. It was noted that students had serious problems with textually implicit information included in reading passages. Given this finding and the fact that the observations illustrated most teachers devote the bulk of their attention to other CRQs, this study highlights the need for raising teachers’ awareness of ER-based reading comprehension questions. Moreover, the findings have implications for researchers and teachers in EFL settings

Risk of neuropsychiatric adverse effects of lipid-lowering drugs: a Mendelian randomization study

Background: Recent studies have highlighted the possible risk of neuropsychiatric adverse effects during treatment with lipid-lowering medications. However, there are still controversies that require a novel genetic-based approach to verify whether the impact of lipid-lowering drug treatment results in neuropsychiatric troubles including insomnia, depression, and neuroticism. Thus, we applied Mendelian randomization to assess any potential neuropsychiatric adverse effects of conventional lipid-lowering drugs such as statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and ezetimibe. Methods: A 2-sample Mendelian randomization study was conducted based on summary statistics from genome-wide association studies for lipids, insomnia, depression, and neuroticism. Single-nucleotide polymorphisms located in or near drug target genes of HMGCR, PCSK9, and NPC1L1 were used as proxies for statins, PCSK9 inhibitors, and ezetimibe therapy, respectively. To assess the validity of the genetic risk score, their associations with coronary artery disease were used as a positive control. Results: The Mendelian randomization analysis showed a statistically significant (P <.004) increased risk of depression after correcting for multiple testing with both statins (odds ratio=1.15, 95% CI: 1.04–1.19) and PCSK9 inhibitor treatment (odds ratio =1.19, 95%CI: 1.1–1.29). The risk of neuroticism was slightly reduced with statin therapy (odds ratio=0.9, 95%CI: 0.83–0.97). No significant adverse effects were associated with ezetimibe treatment. As expected, the 3 medications significantly reduced the risk of coronary artery disease. Conclusion: Using a genetic-based approach, this study showed an increased risk of depression during statin and PCSK9 inhibitor therapy while their association with insomnia risk was not significant

Cheiradone: a vascular endothelial cell growth factor receptor antagonist

<p>Abstract</p> <p>Background</p> <p>Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing) and pathological conditions (tumour development). Vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) are the major angiogenic regulators. We have identified a natural product (cheiradone) isolated from a <it>Euphorbia </it>species which inhibited <it>in vivo </it>and <it>in vitro </it>VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in <it>in vitro </it>(proliferation, wound healing, invasion in Matrigel and tube formation) and <it>in vivo </it>(the chick chorioallantoic membrane) models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC₅₀) was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated.</p> <p>Results</p> <p>Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC₅₀values in the range 5.20–7.50 μM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC₅₀values of 2.9 and 0.61 μM respectively.</p> <p>Conclusion</p> <p>Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.</p

Hyaluronic acid of low molecular weight triggers the invasive “hummingbird” phenotype on gastric cancer cells

The overproduction and deposition of hyaluronic acid (HA) of different sizes in the tumor microenvironment is associated with cancer metastasis. Here, the development of layerâ byâ layer (LbL) constructs containing HA of different molecular weights (i.e., 5.6, 618, and 1450 kDa) that mimic the HAâ rich cancer extracellular matrix is described to study the effect of the HA's size on the behavior of gastric cancer cells (AGS). The results demonstrate that LbL constructs with short HA, i.e., 5.6 kDa, activate the cytoskeleton rearrangement leading to the â hummingbirdâ morphology, promote high cellular motility, and activate signaling pathways with increased expression of pâ ERK1/2 and pâ AKT. In addition, it is demonstrated that this malignant transformation involves an active participation of the HA coreceptor RHAMM in AGS cells.The authors acknowledge the financial support from the European Commission’s H2020 Programme, under grant agreements H2020-WIDESPREAD-2014-668983-FORECAST and H2020-MSCA-RISE-2019-872648-MEPHOS. S.A. acknowledge the Portuguese Foundation for Science and Technology (FCT) for the PhD grant (SFRH/BD/112075/2015). The authors also thank Ramon Novoa-Caballal for performing the GPC experiments and data analysis

Stimulatory Effects of Lycium shawii on Human Melanocyte Proliferation, Migration, and Melanogenesis: In Vitro and In Silico Studies

There is no first-line treatment for vitiligo, a skin disease characterized by a lack of melanin produced by the melanocytes, resulting in an urgent demand for new therapeutic drugs capable of stimulating melanocyte functions, including melanogenesis. In this study, traditional medicinal plant extracts were tested for cultured human melanocyte proliferation, migration, and melanogenesis using MTT, scratch wound-healing assays, transmission electron microscopy, immunofluorescence staining, and Western blot technology. Of the methanolic extracts, Lycium shawii L. (L. shawii) extract increased melanocyte proliferation at low concentrations and modulated melanocyte migration. At the lowest tested concentration (i.e., 7.8 μg/mL), the L. shawii methanolic extract promoted melanosome formation, maturation, and enhanced melanin production, which was associated with the upregulation of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2 melanogenesis-related proteins, and melanogenesis-related proteins. After the chemical analysis and L. shawii extract-derived metabolite identification, the in silico studies revealed the molecular interactions between Metabolite 5, identified as apigenin (4,5,6-trihydroxyflavone), and the copper active site of tyrosinase, predicting enhanced tyrosinase activity and subsequent melanin formation. In conclusion, L. shawii methanolic extract stimulates melanocyte functions, including melanin production, and its derivative Metabolite 5 enhances tyrosinase activity, suggesting further investigation of the L. shawii extract-derived Metabolite 5 as a potential natural drug for vitiligo treatment

Polyvinylpyrrolidone-coated gold nanoparticles inhibit endothelial cell viability, proliferation, and ERK1/2 phosphorylation and reduce the magnitude of endothelial-independent dilator responses in isolated aortic vessels

Background: Gold nanoparticles (AuNPs) demonstrate clinical potential for drug delivery and imaging diagnostics. As AuNPs aggregate in physiological fluids, polymer surface modifications are utilised to allow their stabilisation and enhance their retention time in blood. However, the impact of AuNPs on blood vessel function remains poorly understood. In the present study, we investigated the effects of AuNPs and their stabilisers on endothelial cell (EC) and vasodilator function. Methods: Citrate-stabilised AuNPs (12±3 nm) were synthesised and surface-modified using mercapto polyethylene glycol - (mPEG) and polyvinilpyrrolidine (PVP) polymers. Their uptake by isolated ECs and whole vessels was visualised using transmission electron microscopy (TEM) and quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Their biological effects on EC proliferation, viability, apoptosis and extracellular signal-regulated kinase (ERK) 1/2 signalling pathway were determined using the automated cell counter, flow cytometry, and western blotting, respectively. Endothelial-dependent and independent vasodilator functions were assessed using isolated murine aortic vessel rings, ex vivo. Results: AuNPs were located in endothelial endosomes within 30 min exposure, while their surface modification delayed this cellular uptake over time. After 24 hr exposure, all AuNPs (including polymer-modified AuNPs) induced apoptosis and decreased cell viability/proliferation. These inhibitory effects were lost after 48 hr exposure (except for the PVP-modified AuNPs). Furthermore, all AuNPs decreased acetylcholine (ACh)-induced phosphorylation of ERK1/2, a key signalling protein of cell function. mPEG-modified AuNPs had lower cytostatic effects than PVP-modified AuNPs. Citrate-stabilised AuNPs did not alter endothelial-dependent vasodilation induced by ACh but attenuated endothelial-independent responses induced by sodium nitroprusside (SNP). PVP-modified AuNPs attenuated ACh-induced dilation whereas mPEG-modified AuNPs did not, though this was dose-related. Conclusions: We demonstrate that mPEG-modified AuNPs, at a therapeutic dosage, show lower cytostatic effects and are less detrimental to vasodilator function than PVP-modified AuNPs, indicating greater potential as agents for diagnostic imaging and therapy

C-reactive protein exerts angiogenic effects on vascular endothelial cells and modulates associated signalling pathways and gene expression

Background: Formation of haemorrhagic neovessels in the intima of developing atherosclerotic plaques is thought to significantly contribute to plaque instability resulting in thrombosis. C-reactive protein (CRP) is an acute phase reactant whose expression in the vascular wall, in particular, in reactive plaque regions, and circulating levels increase in patients at high risk of cardiovascular events. Although CRP is known to induce a pro-inflammatory phenotype in endothelial cells (EC) a direct role on modulation of angiogenesis has not been established. Results: Here, we show that CRP is a powerful inducer of angiogenesis in bovine aortic EC (BAEC) and human coronary artery EC (HCAEC). CRP, at concentrations corresponding to moderate/high risk (1-5 mu g/ml), induced a significant increase in proliferation, migration and tube-like structure formation in vitro and stimulated blood vessel formation in the chick chorioallantoic membrane assay (CAM). CRP treated with detoxi-gel columns retained such effects. Western blotting showed that CRP increased activation of early response kinase-1/2 (ERK1/2), a key protein involved in EC mitogenesis. Furthermore, using TaqMan Low-density Arrays we identified key pro-angiogenic genes induced by CRP among them were vascular endothelial cell growth factor receptor-2 (VEGFR2/KDR), platelet-derived growth factor (PDGF-BB), notch family transcription factors (Notch1 and Notch3), cysteine-rich angiogenic inducer 61 (CYR61/CCN1) and inhibitor of DNA binding/differentiation-1 (ID1). Conclusion: This data suggests a role for CRP in direct stimulation of angiogenesis and therefore may be a mediator of neovessel formation in the intima of vulnerable plaques