272 research outputs found
Phase diagram of mixtures of colloids and polymers in the thermal crossover from good to solvent
We determine the phase diagram of mixtures of spherical colloids and neutral
nonadsorbing polymers in the thermal crossover region between the
point and the good-solvent regime. We use the generalized free-volume theory
(GFVT), which turns out to be quite accurate as long as
( is the radius of gyration of the polymer and is the colloid
radius). Close to the point the phase diagram is not very sensitive to
solvent quality, while, close to the good-solvent region, changes of the
solvent quality modify significantly the position of the critical point and of
the binodals. We also analyze the phase behavior of aqueous solutions of
charged colloids and polymers, using the extension of GFVT proposed by Fortini
et al., J. Chem. Phys. 128, 024904 (2008)
Electric Field Controlled Columnar and Planar Patterning of Cholesteric Colloids
We study how dispersions of colloidal particles in a cholesteric liquid
crystal behave under a time-dependent electric field. By controlling the
amplitude and shape of the applied field wave, we show that the system can be
reproducibly driven out of equilibrium through different kinetic pathways and
navigated through a glassy-like free energy landscape encompassing many
competing metastable equilibria. Such states range from simple Saturn rings to
complex structures featuring amorphous defect networks, or stacks of
disclination loops. A non-equilibrium electric field can also trigger the
alignment of particles into columnar arrays, through defect-mediated force
impulses, or their repositioning within a plane. Our results are promising in
terms of providing new avenues towards controlled patterning and self-assembly
of soft colloid-liquid crystal composite materials.Comment: 5 pages, 4 figures. Phys. Rev. Lett., 2015, in pres
Migratory crustaceans as biomonitors of metal pollution in their nursery areas. The Lesina lagoon (SE Italy) as a case study
The Lesina lagoon is located on the
southern Adriatic coast of Italy; many marine species,
such as the shrimp M. kerathurus, use the Lesina
lagoon as a nursery, spending their initial growth
phase there. In order to assess the usefulness of
migratory species as biomonitors of the environmental
quality of this nursery area, we evaluated the metal
content of the M. kerathurus juveniles at the end of
their growth phase in the lagoon (October), when they
are assumed to have bioaccumulated the maximum
level of metals from the lagoon environment. The
concentrations of Cr, Cd, Pb, Zn, Mn and Cu were
measured in the muscle and exoskeleton of the
shrimp, and in the sediments and waters of three
areas of the Lesina Lagoon. Both the water and
sediment levels of the investigated metals tended to
fall within the ranges recorded for other lagoon
environments characterized by similar anthropic impact
and texturally similar sediment; the juveniles of
the shrimp M. kerathurus proved to be strong
bioaccumulators of heavy metals such as Zn and Cu
(biota-sediment accumulation factors – BSAFs – 6.01
and 25.0 respectively), which derive from agricultural
activities; therefore, at the end of their growing phase
in the lagoon they can be considered useful biomonitors
of metal contamination of agricultural origin in
their nursery area
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Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy
Background: Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. Methods: In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. Results: 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (−9% and −11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. Conclusions: This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant responses or durable disease control was seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy with PARP inhibition in EWS are actively ongoing. Trial registration ClinicalTrials.gov Identifier: NCT0158354
Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from the concentrated brain metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A is a key building block for lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of Canavan disease. Glyceryltriacetate (GTA) was administered orally to tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin lipids, and brain vacuolation were analyzed in GTA-treated and untreated tremor rats. Significant improvements were observed in motor performance and myelin galactocerebroside content in tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the acetyl coenzyme A synthesizing enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in tremor rats, with a return to near normal expression levels in GTA-treated tremor rats. These results confirm the critical role played by NAA-derived acetate in brain myelination and development, and demonstrate the potential usefulness of acetate therapy for the treatment of Canavan disease
A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin’s physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition
Hyperspectral leaf area index and chlorophyll retrieval over forest and row-structured vineyard canopies
As an unprecedented stream of decametric hyperspectral observations becomes available from recent and upcoming spaceborne missions, effective algorithms are required to retrieve vegetation biophysical and biochemical variables such as leaf area index (LAI) and canopy chlorophyll content (CCC). In the context of missions such as the Environmental Mapping and Analysis Program (EnMAP), Precursore Iperspettrale della Missione Applicativa (PRISMA), Copernicus Hyperspectral Imaging Mission for the Environment (CHIME), and Surface Biology Geology (SBG), several retrieval algorithms have been developed based upon the turbid medium Scattering by Arbitrarily Inclined Leaves (SAIL) radiative transfer model. Whilst well suited to cereal crops, SAIL is known to perform comparatively poorly over more heterogeneous canopies (including forests and row-structured crops). In this paper, we investigate the application of hybrid radiative transfer models, including a modified version of SAIL (rowSAIL) and the Invertible Forest Reflectance Model (INFORM), to such canopies. Unlike SAIL, which assumes a horizontally homogeneous canopy, such models partition the canopy into geometric objects, which are themselves treated as turbid media. By enabling crown transmittance, foliage clumping, and shadowing to be represented, they provide a more realistic representation of heterogeneous vegetation. Using airborne hyperspectral data to simulate EnMAP observations over vineyard and deciduous broadleaf forest sites, we demonstrate that SAIL-based algorithms provide moderate retrieval accuracy for LAI (RMSD = 0.92–2.15, NRMSD = 40–67%, bias = −0.64–0.96) and CCC (RMSD = 0.27–1.27 g m−2, NRMSD = 64–84%, bias = −0.17–0.89 g m−2). The use of hybrid radiative transfer models (rowSAIL and INFORM) reduces bias in LAI (RMSD = 0.88–1.64, NRMSD = 27–64%, bias = −0.78–−0.13) and CCC (RMSD = 0.30–0.87 g m−2, NRMSD = 52–73%, bias = 0.03–0.42 g m−2) retrievals. Based on our results, at the canopy level, we recommend that hybrid radiative transfer models such as rowSAIL and INFORM are further adopted for hyperspectral biophysical and biochemical variable retrieval over heterogeneous vegetation
Rab proteins and Rab-associated proteins: major actors in the mechanism of protein-trafficking disorders
Ras-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot–Marie–Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot–Marie–Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be ‘prenylated’—i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity. Conclusion: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents
Physical Links: Defining and detecting inter-chain entanglement
Fluctuating filaments, from densely-packed biopolymers to defect lines in structured fluids, are prone to become interlaced and form intricate architectures. Understanding the ensuing mechanical and relaxation properties depends critically on being able to capture such entanglement in quantitative terms. So far, this has been an elusive challenge. Here we introduce the first general characterization of non-ephemeral forms of entanglement in linear curves by introducing novel descriptors that extend topological measures of linking from close to open curves. We thus establish the concept of physical links. This general method is applied to diverse contexts: equilibrated ring polymers, mechanically-stretched links and concentrated solutions of linear chains. The abundance, complexity and space distribution of their physical links gives access to a whole new layer of understanding of such systems and open new perspectives for others, such as reconnection events and topological simplification in dissipative fields and defect lines
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