Dually sensitive dextran-based micelles for methotrexate delivery

Temperature-sensitive polymeric micelles were prepared from dextran grafted with poly(N-isopropylacrylamide) (PNIPAAm) or polyethylene glycol methyl ether (PEGMA) via controlled radical polymerization and evaluated as delivery systems of the anticancer drug methotrexate (MTX). Polymer-grafting was carried out after introduction of initiating groups onto the polysaccharide backbone, without the need for protection of hydroxyl groups and avoiding the use of toxic solvents. Temperature-responsive dextran-based copolymers were designed to exhibit self-aggregation behaviour, affinity for MTX and high cellular internalization. In addition, some grafted polymers incorporated 2-aminoethyl methacrylate to reinforce MTX encapsulation in the micelles by means of ionic interactions. Dextran-based micelles were cytocompatible and had an appropriate size to be used as drug carriers. MTX release was dependent on the pH and temperature. The combination of poly(2-aminoethylmethacrylate) and PNIPAAm with the dextran backbone permitted the complete release of MTX at normal physiological temperature. Co-polymer micelles were highly internalized by tumour cells (CHO-K1) and, when loaded with MTX, led to enhanced cytotoxicity compared to the free drug

Small-angle neutron scattering and Molecular Dynamics structural study of gelling DNA nanostars

DNA oligomers with properly designed sequences self-assemble into well defined constructs. Here, we exploit this methodology to produce bulk quantities of tetravalent DNA nanostars (each one composed by 196 nucleotides) and to explore the structural signatures of their aggregation process. We report small-angle neutron scattering experiments focused on the evaluation of both the form factor and the temperature evolution of the scattered intensity at a nano star concentration where the system forms a tetravalent equilibrium gel. We also perform molecular dynamics simulations of one isolated tetramer to evaluate the form factor theoretically, without resorting to any approximate shape. The numerical form factor is found to be in very good agreement with the experimental one. Simulations predict an essentially temperature independent form factor, offering the possibility to extract the effective structure factor and its evolution during the equilibrium gelation.Comment: 9 pages, 5 figure

Synthesis of temperature-responsive Dextran-MA/PNIPAAm particles for controlled drug delivery using superhydrophobic surfaces

Purpose: To implement a bioinspired methodology using superhydrophobic surfaces suitable for producing smart hydro- gel beads in which the bioactive substance is introduced in the particles during their formation. Methods: Several superhydrophobic surfaces, including polystyrene, aluminum and copper, were prepared. Polymeric solutions composed by photo-crosslinked dextran-methacrylated and thermal responsive poly(N-isopropylacrylamide) mixed with a protein (insulin or albumin) were dropped on the superhydrophobic surfaces, and the obtained millimetric spheres were hardened in a dry environment under UV light. Results: Spherical and non-sticky hydrogels particles were formed in few minutes on the superhydrophobic surfaces. The proteins included in the liquid formulation were homogeneously distributed in the particle network. The particles exhibited temperature-sensitive swelling, porosity and protein release rate, with the responsiveness tunable by the dextran-MA/PNIPAAm weight ratio.Conclusions: The proposed method permitted the preparation of smart hydrogel particles in one step with almost 100% encapsulation yield. The temperature-sensitive release profiles suggest that the obtained spherical-shaped biomaterials are suitable as protein carriers. These stimuli-responsive beads could have potential to be used in pharmaceutical or other biomedical applications, including tissue engineering and regenerative medicine.The authors acknowledge funding from the project: PTDC/QUI/68804/2006 (FCT), IBEROMARE-Procept, FEDER and MICINN (SAF2008-01679). The research leading to these results has also received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement #NMP4-SL-2009-229292. The authors are grateful to project DISC REGENERATION, Collaborative Project-Large-scale integrating project, NMP3-LA-2008-213904 for the use of the UV lamp

Effects of temperature and nutrient supply on resource allocation, photosynthetic strategy, and metabolic rates of Synechococcus sp.

Temperature and nutrient supply are key factors that control phytoplankton ecophysiology, but their role is commonly investigated in isolation. Their combined effect on resource allocation, photosynthetic strategy, and metabolism remains poorly understood. To characterize the photosynthetic strategy and resource allocation under different conditions, we analyzed the responses of a marine cyanobacterium ( Synechococcus PCC 7002) to multiple combinations of temperature and nutrient supply. We measured the abundance of proteins involved in the dark (RuBis CO , rbc L) and light (Photosystem II , psbA) photosynthetic reactions, the content of chlorophyll a , carbon and nitrogen, and the rates of photosynthesis, respiration, and growth. We found that rbc L and psbA abundance increased with nutrient supply, whereas a temperature‐induced increase in psbA occurred only in nutrient‐replete treatments. Low temperature and abundant nutrients caused increased RuBis CO abundance, a pattern we observed also in natural phytoplankton assemblages across a wide latitudinal range. Photosynthesis and respiration increased with temperature only under nutrient‐sufficient conditions. These results suggest that nutrient supply exerts a stronger effect than temperature upon both photosynthetic protein abundance and metabolic rates in Synechococcus sp. and that the temperature effect on photosynthetic physiology and metabolism is nutrient dependent. The preferential resource allocation into the light instead of the dark reactions of photosynthesis as temperature rises is likely related to the different temperature dependence of dark‐reaction enzymatic rates versus photochemistry. These findings contribute to our understanding of the strategies for photosynthetic energy allocation in phytoplankton inhabiting contrasting environments.Agencia Estatal de Investigación | Ref. PGC2018‐094553‐B‐I00National Science Foundation (USA) | Ref. ANT‐0944254National Environmental Research Council (UK) | Ref. NE/F019254/1National Environmental Research Council (UK) | Ref. NE/G009155/1Xunta de Galici

Communication: Studies of the Lennard-Jones fluid in 2, 3, and 4 dimensions highlight the need for a liquid-state 1/d expansion

The recent theoretical prediction by Maimbourg and Kurchan [arXiv:1603.05023] that for regular pair-potential systems the virial potential-energy correlation coefficient increases towards unity as the dimension $d$ goes to infinity is investigated for the standard 12-6 Lennard-Jones fluid. This is done by computer simulations for $d=2,3,4$ going from the critical point along the critical isotherm/isochore to higher density/temperature. In all cases the virial potential-energy correlation coefficient increases significantly. For a given density and temperature relative to the critical point, with increasing number of dimension the Lennard-Jones system conforms better to the hidden-scale-invariance property characterized by high virial potential-energy correlations (a property that leads to the existence of isomorphs in the thermodynamic phase diagram, implying that it becomes effectively one-dimensional in regard to structure and dynamics). The present paper also gives the first numerical demonstration of isomorph invariance of structure and dynamics in four dimensions. Our findings emphasize the need for a universally applicable $1/d$ expansion in liquid-state theory; we conjecture that the systems known to obey hidden scale invariance in three dimensions are those for which the yet-to-be-developed $1/d$ expansion converges rapidly

Critical Behavior of Three-Dimensional Disordered Potts Models with Many States

We study the 3D Disordered Potts Model with p=5 and p=6. Our numerical simulations (that severely slow down for increasing p) detect a very clear spin glass phase transition. We evaluate the critical exponents and the critical value of the temperature, and we use known results at lower $p$ values to discuss how they evolve for increasing p. We do not find any sign of the presence of a transition to a ferromagnetic regime.Comment: 9 pages and 9 Postscript figures. Final version published in J. Stat. Mec

Comparison between thermophysical and tribological properties of two engine lubricant additives: electrochemically exfoliated graphene and molybdenum disulfide nanoplatelets.

Recently graphene and other 2D materials were suggested as nano additives to enhance the performance of nanolubricants and reducing friction and wear-related failures in moving mechanical parts. Nevertheless, to our knowledge there are no previous studies on electrochemical exfoliated nanomaterials as lubricant additives. In this work, engine oil-based nanolubricants were developed via two-steps method using two different 2D nanomaterials: a carbon-based nano additive, graphene nanoplatelets (GNP) and a sulphide nanomaterial, molybdenum disulfide (MoS2) nanoplatelets (MSNP). The influence of these nano additives on the thermophysical properties of the nanolubricants, such as viscosity index, density and wettability, was investigated. The unique features of the electrochemical exfoliated GNP and MSNP allow the formulation of nanolubricant with unusual thermophysical properties. Both the viscosity and density of the nanolubricants decreased by increasing the nanoplatelets loading. The effect of the nano additives loading and temperature on the tribological properties of nanolubricants was investigated using two different test configurations: reciprocating ball-on-plate and rotational ball-on-three-pins. The tribological specimens were analysed by scanning electron microscopy (SEM) and 3D profiler in order to evaluate the wear. The results showed significant improvement in the antifriction and anti-wear properties, for the 2D-materials-based nanolubricants as compared with the engine oil, using different contact conditions. For the reciprocal friction tests, maximum friction and worn area reductions of 20% and 22% were achieved for the concentrations of 0.10 wt% and 0.20 wt% GNP, respectively. Besides, the best anti-wear performance was found for the nanolubricant containing 0.05 wt% MSNP in rotational configuration test, with reductions of 42% and 60% in the scar width and depth, respectively, with respect to the engine oil

PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity

Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population

Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction

Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization

Inhibition in spinal nociceptive pathways is weaker and more labile in lamina I —where thermal input is primarily processed— than in lamina II that encodes predominantly high threshold mechanical input. This explains why noxious thermal input makes spinal circuits prone to catastrophic sensitization