Glucose-Coated Superparamagnetic Iron Oxide Nanoparticles Prepared by Metal Vapour Synthesis Are Electively Internalized in a Pancreatic Adenocarcinoma Cell Line Expressing GLUT1 Transporter

Iron oxide nanoparticles (IONP) can have a variety of biomedical applications due to their visualization properties through Magnetic Resonance Imaging (MRI) and heating with radio frequency or alternating magnetic fields. In the oncological field, coating IONP with organic compounds to provide specific features and to achieve the ability of binding specific molecular targets appears to be very promising. To take advantage of the high avidity of tumor cells for glucose, we report the development of very small glucose-coated IONP (glc-IONP) by employing an innovative technique, Metal Vapor Synthesis (MVS). Moreover, we tested the internalization of our gl-IONP on a tumor line, BxPC3, over-expressing GLUT 1 transporter. Both glc-IONP and polyvinylpyrrolidone-IONP (PVP-IONP), as control, were prepared with MVS and were tested on BxPC3 at various concentrations. To evaluate the role of GLUT-1 transporter, we also investigated the effect of adding a polyclonal anti-GLUT1 antibody. After proper treatment, the iron value was assessed by atomic absorption spectrometer, reported in mcg/L and expressed in mg of protein. Our IONP prepared with MVS were very small and homogeneously distributed in a narrow range (1.75-3.75 nm) with an average size of 2.7 nm and were super-paramagnetic. Glc-IONP were internalized by BxPC3 cells in a larger amount than PVP-IONP. After 6h of treatment with 50 mcg/mL of IONPs, the content of Fe was 1.5 times higher in glc-IONP-treated cells compared with PVP-IONP-treated cells. After 1h pre-treatment with anti-GLUT1, a reduction of 41% cellular accumulation of glc-IONP was observed. Conversely, the uptake of PVP-IONPs was reduced only by 14% with antibody pretreatment. In conclusion, MVS allowed us to prepare small, homogeneous, super-paramagnetic glc-IONP, which are electively internalized by a tumor line over-expressing GLUT1. Our glc-IONP appear to have many requisites for in vivo use

Simulation of Channel Segregation During Directional Solidification of In—75 wt pct Ga. Qualitative Comparison with In Situ Observations

International audienceFreckles are common defects in industrial casting. They result from thermosolutal convection due to buoyancy forces generated from density variations in the liquid. The present paper proposes a numerical analysis for the formation of channel segregation using the three-dimensional (3D) cellular automaton (CA)—finite element (FE) model. The model integrates kinetics laws for the nucleation and growth of a microstructure with the solution of the conservation equations for the casting, while introducing an intermediate modeling scale for a direct representation of the envelope of the dendritic grains. Directional solidification of a cuboid cell is studied. Its geometry, the alloy chosen as well as the process parameters are inspired from experimental observations recently reported in the literature. Snapshots of the convective pattern, the solute distribution, and the morphology of the growth front are qualitatively compared. Similitudes are found when considering the coupled 3D CAFE simulations. Limitations of the model to reach direct simulation of the experiments are discussed

Phase-field approach to polycrystalline solidification including heterogeneous and homogeneous nucleation

Advanced phase-field techniques have been applied to address various aspects of polycrystalline solidification including different modes of crystal nucleation. The height of the nucleation barrier has been determined by solving the appropriate Euler-Lagrange equations. The examples shown include the comparison of various models of homogeneous crystal nucleation with atomistic simulations for the single component hard-sphere fluid. Extending previous work for pure systems (Gránásy L, Pusztai T, Saylor D and Warren J A 2007 Phys. Rev. Lett. 98 art no 035703), heterogeneous nucleation in unary and binary systems is described via introducing boundary conditions that realize the desired contact angle. A quaternion representation of crystallographic orientation of the individual particles (outlined in Pusztai T, Bortel G and Gránásy L 2005 Europhys. Lett. 71 131) has been applied for modeling a broad variety of polycrystalline structures including crystal sheaves, spherulites and those built of crystals with dendritic, cubic, rhombododecahedral, truncated octahedral growth morphologies. Finally, we present illustrative results for dendritic polycrystalline solidification obtained using an atomistic phase-field model

Liver fibrosis score, physical frailty, and the risk of dementia in older adults: The Italian longitudinal study on aging

Introduction: Liver fibrosis increases progressively with aging and has been associated with poorer cognitive performance in middle-aged and older adults. We investigated the relationships between a non-invasive score for advanced liver fibrosis (non-alcoholic fatty liver disease [NAFLD] fibrosis score [NFS]) and dementia risk. We also assessed physical frailty, a common geriatric condition which is associated to dementia. We tested the joint effects of physical frailty and fibrosis on dementia incidence. Methods: A total of 1061 older adults (65 to 84 years), from the Italian Longitudinal Study on Aging, were prospectively evaluated for the risk of dementia in a period between 1992 and 2001. Liver fibrosis was defined according to the NFS. Physical frailty was assessed according to the Fried's criteria. Cox proportional hazards models were used to estimate the short- and long-term risk of overall dementia, associated to the NFS, testing the effect modifier of physical frailty status. Results: Older adults with only high NFS (F3-F4) did not exhibit a significant increased risk of overall dementia. Over 8 years of follow-up, frail older adults with high NFS had an increased risk of overall dementia (hazard ratio [HR]: 4.23; 95% confidence interval [CI]: 1.22 to 14.70, P = .023). Finally, physically frail older adults with low albumin serum levels (albumin < 4.3 g/dL) and with advanced liver fibrosis (F3-F4 NFS) compared to those with lower liver fibrosis score (F0-F2 NFS) were more likely to have a higher risk of overall dementia in a long term-period (HR: 16.42; 95% CI: 1.44 to 187.67, P = .024). Discussion: Advanced liver fibrosis (F3-F4 NFS) could be a long-term predictor for overall dementia in people with physical frailty. These findings should encourage a typical geriatric, multidisciplinary assessment which accounts also for the possible co-presence of frail condition in older adults with chronic liver disease and liver fibrosis

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

Associations between cardiac arrhythmia, incident disability in activities of daily living and physical performance: the ILSA study

Background: Cardiac arrhythmias are common conditions in older people. Unfortunately, there is limited literature on associations between cardiac arrhythmias and physical performance or disability. We therefore aimed to prospectively investigate associations between cardiac arrhythmias and changes in disability and physical performance during 8 years of follow-up, using data from the Italian Longitudinal Study on Aging (ILSA). Methods: Cardiac arrhythmias diagnosis was posed through a screening phase, confirmed by a physician. The onset of disability in activities of daily living (ADL) and the changes in several physical performance tests during follow-up were considered as outcomes. Fully-adjusted and propensity-score Cox Proportional Hazard models and mixed models were used for exploring associations between cardiac arrhythmia and the outcomes of interest. Results: The prevalence of cardiac arrhythmia at baseline was 23.3%. People reporting cardiac arrhythmia at the baseline were significantly older, more frequently male, smokers and reported a higher presence of all medical conditions investigated (hypertension, heart failure, angina, myocardial infarction, diabetes, stroke), but no difference in dementia, Parkinsonism, cognitive or mood disorder. Cardiac arrhythmia at baseline was significantly associated with the incidence of disability in ADL (HR = 1.23; 95%: CI: 1.01–1.50; P = 0.0478 in propensity score analyses; HR = 1.28; 95% CI: 1.01–1.61; P = 0.0401 in fully adjusted models). Cardiac arrhythmia at baseline was also associated with a significant worsening in balance test (P = 0.0436). Conclusions: The presence of cardiac arrhythmia at baseline was associated with a significant higher risk of disability and of worsening in some physical performance tests, particularly those relating to balance. Screening and frequently assessing physical performance in older people affected by cardiac arrhythmia can be important to prevent a loss of physical performance, with further, potential, complications of medical management

SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy

Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.ope

Generation of ribosome imprinted polymers for sensitive detection of translational responses

Whilst the profiling of the transcriptome and proteome even of single-cells becomes feasible, the analysis of the translatome, which refers to all messenger RNAs (mRNAs) engaged with ribosomes for protein synthesis, is still an elaborate procedure requiring millions of cells. Herein, we report the generation and use of “smart materials”, namely molecularly imprinted polymers (MIPs) to facilitate the isolation of ribosomes and translated mRNAs from merely 1,000 cells. In particular, we show that a hydrogel-based ribosome imprinted polymer could recover ribosomes and associated mRNAs from human, simian and mice cellular extracts, but did not selectively enrich yeast ribosomes, thereby demonstrating selectivity. Furthermore, ribosome imprinted polymers enabled the sensitive measurement of an mRNA translational regulatory event, requiring 1,000-fold less cells than current methodologies. These results provide first evidence for the suitability of MIPs to selectively recover ribonucleoprotein complexes such as ribosomes, founding a novel means for sensitive detection of gene regulation