Nanoparticles-cell association predicted by protein corona fingerprints

In a physiological environment (e.g., blood and interstitial fluids) nanoparticles (NPs) will bind proteins shaping a "protein corona" layer. The long-lived protein layer tightly bound to the NP surface is referred to as the hard corona (HC) and encodes information that controls NP bioactivity (e.g. cellular association, cellular signaling pathways, biodistribution, and toxicity). Decrypting this complex code has become a priority to predict the NP biological outcomes. Here, we use a library of 16 lipid NPs of varying size (Ø ≈ 100-250 nm) and surface chemistry (unmodified and PEGylated) to investigate the relationships between NP physicochemical properties (nanoparticle size, aggregation state and surface charge), protein corona fingerprints (PCFs), and NP-cell association. We found out that none of the NPs' physicochemical properties alone was exclusively able to account for association with human cervical cancer cell line (HeLa). For the entire library of NPs, a total of 436 distinct serum proteins were detected. We developed a predictive-validation modeling that provides a means of assessing the relative significance of the identified corona proteins. Interestingly, a minor fraction of the HC, which consists of only 8 PCFs were identified as main promoters of NP association with HeLa cells. Remarkably, identified PCFs have several receptors with high level of expression on the plasma membrane of HeLa cells

The Origanum Collection of Gaetano Savi (1769-1844) in the Herbarium Horti Pisani (PI)

The Origanum Collection of Gaetano Savi (1769-1844) in the Herbarium Horti Pisani (PI). The collection of exsiccata of the genus Origanum, studied by Gaetano Savi and kept in the Herbarium Horti Pisani (PI) represents a valuable document of Savi's work as a taxonomist. It provides useful news for researchers of systematics and history of botany. The collection is enriched by some original drawings and includes the lectotypes of Origanum confertum Savi and O. fortuitum Savi

Nanoparticles-cell association predicted by protein corona fingerprints

In a physiological environment (e.g., blood and interstitial fluids) nanoparticles (NPs) will bind proteins shaping a "protein corona" layer. The long-lived protein layer tightly bound to the NP surface is referred to as the hard corona (HC) and encodes information that controls NP bioactivity (e.g. cellular association, cellular signaling pathways, biodistribution, and toxicity). Decrypting this complex code has become a priority to predict the NP biological outcomes. Here, we use a library of 16 lipid NPs of varying size (Ø ≈ 100-250 nm) and surface chemistry (unmodified and PEGylated) to investigate the relationships between NP physicochemical properties (nanoparticle size, aggregation state and surface charge), protein corona fingerprints (PCFs), and NP-cell association. We found out that none of the NPs' physicochemical properties alone was exclusively able to account for association with human cervical cancer cell line (HeLa). For the entire library of NPs, a total of 436 distinct serum proteins were detected. We developed a predictive-validation modeling that provides a means of assessing the relative significance of the identified corona proteins. Interestingly, a minor fraction of the HC, which consists of only 8 PCFs were identified as main promoters of NP association with HeLa cells. Remarkably, identified PCFs have several receptors with high level of expression on the plasma membrane of HeLa cells

Finite element analysis applied to redesign of submerged entry nozzles for steelmaking

The production of steel by continuous casting is facilitated by the use of refractory hollow-ware components. A critical component in this process is the submerged entry nozzle (SEN). The normal operating conditions of the SEN are arduous, involving large temperature gradients and exposure to mechanical forces arising from the flow of molten steel; experimental development of the components is challenging in so hazardous an environment. The effects of the thermal stress conditions in relation to a well-tried design were therefore simulated using a finite element analysis approach. It was concluded from analyses that failures of the type being experienced are caused by the large temperature gradient within the nozzle. The analyses pointed towards a supported shoulder area of the nozzle being most vulnerable to failure and practical in-service experience confirmed this. As a direct consequence of the investigation, design modifications, incorporating changes to both the internal geometry and to the nature of the intermediate support material, were implemented, thereby substantially reducing the stresses within the Al2O3/graphite ceramic liner. Industrial trials of this modified design established that the component reliability would be significantly improved and the design has now been implemented in series production

Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer’s Disease in the 3xTg-AD mouse model

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10-15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models. Retina can be considered a simple model of the brain, as some pathological changes and therapeutic strategies from the brain may be observed or applicable to the retina. Here we propose new retinal biomarkers that could anticipate the AD diagnosis and help the beginning and the follow-up of possible future treatments. We analyzed retinal tissue of triple-transgenic AD mouse model (3xTg-AD) for the presence of pathological hallmarks during disease progression. We found the presence of amyloid beta plaques, tau tangles, neurodegeneration, and astrogliosis in the retinal ganglion cell layer of 3xTg-AD mice, already at pre-symptomatic stage. Moreover, retinal microglia in pre-symptomatic mice showed a ramified, anti-inflammatory phenotype which, during disease progression, switches to a pro-inflammatory, less ramified one, becoming neurotoxic. We hypothesize retina as a window through which monitor AD-related neurodegeneration process

Sensitivity plots for WIMP direct detection using the annual modulation signature

Annual modulation due to the Earth's motion around the Sun is a well known signature of the expected WIMP signal induced in a solid state underground detector. In the present letter we discuss the prospects of this technique on statistical grounds, introducing annual-modulation sensitivity plots for the WIMP-nucleon scalar cross section for different materials and experimental conditions. The highest sensitivity to modulation is found in the WIMP mass interval 10 GeV< m_W < 130 GeV, the actual upper limit depending from the choice of the astrophysical parameters, while the lowest values of the explorable WIMP-nucleon elastic cross-sections fall in most cases within one order of magnitude of the sensitivities of present direct detection WIMP searches.Comment: 24 pages, ReVTeX, 9 figures, submitted to Astroparticle Physic

Typicality vs. probability in trajectory-based formulations of quantum mechanics

Bohmian mechanics represents the universe as a set of paths with a probability measure defined on it. The way in which a mathematical model of this kind can explain the observed phenomena of the universe is examined in general. It is shown that the explanation does not make use of the full probability measure, but rather of a suitable set function deriving from it, which defines relative typicality between single-time cylinder sets. Such a set function can also be derived directly from the standard quantum formalism, without the need of an underlying probability measure. The key concept for this derivation is the {\it quantum typicality rule}, which can be considered as a generalization of the Born rule. The result is a new formulation of quantum mechanics, in which particles follow definite trajectories, but which is only based on the standard formalism of quantum mechanics.Comment: 24 pages, no figures. To appear in Foundation of Physic

Acetate intolerance is mediated by enhanced synthesis of nitric oxide by endothelial cells.

The clinical picture of acetate intolerance strictly mimics the nitric oxide (NO) effect, including smooth muscle relaxation and extreme vasodilation. Because acetate induces production of cAMP, which is a powerful stimulus of NO synthase (NOS), we evaluated the effect of different dialysate solutions with and without acetate on NOS activity in endothelial cells (EC). NOS activity of EC, evaluated as H3-citrulline produced from H3-arginine, was modulated by the dialysate composition (e.g., 38 mmol/L acetate produced an increase of 3.2 +/- 0.39-fold compared with basal values (P < 0.0005), and the small amount of acetate (4 mmol/L) in 35 mmol/L bicarbonate solution increased the NOS activity by 2 +/- 0.49-fold (P < 0.05). Conversely, the acetate-free solution produced no effect on NOS activity. The mRNA encoding for inducible NOS was highly expressed in EC incubated with acetate buffer and also with acetate in bicarbonate dialysis buffer. The EC proliferative index was depressed by acetate (P < 0.0005), and tumor necrosis factor synthesis was increased (P < 0.0005) compared with acetate-free buffer. This study suggests that dialytic "acetate intolerance" can be induced by the activation, through cAMP and tumor necrosis factor release, of NOS. The small amount of acetate in bicarbonate dialysate, although capable of inducing in vitro NOS activation, is likely to be rapidly metabolized, whereas the large amounts of this anion in acetate fluids overwhelm metabolism by the liver. Acetate-free dialysate is the only solution that provides an acceptable level of biocompatibility both in vivo and in vitro

Endotracheal tube-induced sore throat pain and inflammation is coupled to the release of mitochondrial DNA

In the absence of infection, the pathophysiology of endotracheal tube-induced sore throat pain is unclear. Activated neutrophils release elastase, reactive oxygen species, and inflammatory cytokines known to contribute to neuropathic pain. Sterile tissue injury can cause the release of damage-associated molecular patterns such as mitochondrial DNA that promote neutrophil activation. We hypothesized that endotracheal tube-induced sore throat pain is linked to mitochondrial DNA-mediated neutrophil inflammation. A nonrandomized prospective survey for sore throat pain was conducted in 31 patients who required short-term intubation and had no evidence of upper airway infection. Patterns of neutrophil abundance, activation, and mitochondrial DNA levels were analyzed in tracheal lavage fluid following intubation and prior to extubation. Thirteen of 31 patients reported sore throat pain. Sore throat patients had high neutrophilia with elevated adhesion molecule and TLR9 expression and constitutive reactive oxygen species generation. Tracheal lavage fluid from sore throat patients accumulated mitochondrial DNA and stimulated neutrophils to release mediators associated with pain in a TLR9- and DNAse-dependent fashion. Endotracheal tube-induced sore throat is linked to the release of mitochondrial DNA and can drive TLR9-mediated inflammatory responses by neutrophils reported to cause pain. Mitigating the effects of cell-free mitochondrial DNA may prove beneficial for the prevention of endotracheal tube-mediated sore throat pain