Cationic ≠3-allylmetal complexes, 13a) electrical properties of new poly(phenylacetylene) obtained from nickel catalysts

Monometallic complexes of Nickel have been successfully, tested in reaction with olefinic and acetylenic compounds. This paper is devoted to one of the resulting products, a polyphenylacetylene which presents interesting properties. It is readily obtained avoiding the step of a polymer precursor; it is soluble in several solvents, stable in air up to 200° C and may possess a rather high conductivity, depending on polymerization conditions. This is a noticeable difference versus previously reported polyphenylacetylenes which were insulating materials.     

Estimation of the effects of an intensive solar intervention in the historical centre of jaén (Spain)

This paper is directed at evaluating the theoretical potential of an intensive solar intervention in the historical centre of the city of Jaén (Spain). Using the outputs of a solar intervention proposal comprising biomass, photovoltaics and solar thermal domestic hot water (DHW) over a 50-building sample (in which those suitable for solar measures have been selected by evaluating each one over a collection of parameters), energy savings, environmental benefits and economic aspects of the envisaged actions are extrapolated over the entire historical centre. A saving of about 70% of conventional source energy annual consumption and a decrease of some 70% and 73% of CO₂ and SO_x annual releases, respectively, could be reached with respect to the present situation. Besides, an amount of conventionally generated electricity equivalent to the yearly photovoltaic-generated electricity would require 131500 m³ of water a year, which is a rather significant feature for a dry climate like that of the city. the unitary cost of energy in the new scenario would be 60.7 pta kWh-¹ for photovoltaics, 329.9 pta m-³ for DHW using solar thermal installations and 4.6 Pta kWh-¹ for biomass heating (1 US$ = 132.7 pta; 1 ECU = 160.9 pta).     

Blends of natural and synthetic polymers: A new route to novel biomaterials

Blends of natural and synthetic polymers were studied for potential applications in the biomedical field. Collagen and hyaluronic acid were mixed in aqueous solution with poly(vinyl alcohol) and poly(acrylic acid). The properties of the blends were studied by differential scanning calorimetry and dynamic mechanical thermal analysis. Some methods were also investigated to enhance the miscibility of the polymers in these blends.     

Large-scale production of polypropylenimine dendrimers

The synthesis and characterization of a new series of polypropylenimine dendrimers is reported. Using a repetition of the sequence of a Michael addition to a primary amine, followed by a heterogeneously catalyzed hydrogenation, ultra-pure polypropylenimine macromolecules with molecular weights up to 6912 are synthesized. The reaction sequence allows the preparation of these dendrimers at very large scales, whilst the availability of a simple purification in the sequence affords ultra-pure samples. The polypropylenimine dendrimers are fully characterized; apart from the first 0.5 generation they are all oils, possess a Tg in the range from −90 to −40 °C, are unexpectedly stable, and their intrinsic viscosity drops after generation 4.     

Hindered interdiffusion in asymmetric polymer-polymer junctions

We discuss theoretically the diffuse interface formed when a long (L) polymer is put into contact with shorter chains (S) of the same material (all chains being entangled). At time t shorter than the reptation time T_L of the long chains, the L chains behave like a gel swollen by the S chains. The “penetration factor” ψ (i.e. the volume fraction of S near the gel surface) is controled by a balance between the osmotic pressure of the swollen L chains, and the elastic tension ψ due to swelling. If t is larger than T_S (the reptation time of the short chains), ψ is of order N_e/N_S (where N_e is the number of monomers between entanglement points, and N_S is the degree of polymerisation of the short chains). On the other hand, if t < T_S, N_S must be replaced by the average number s (t) of monomers of an S chain which have entered the L region, and ψ ∼ N_e/ s (t) ∼t^−1/2. The width of the mixed region e(t) increases like s ^1/2(t) at T_S, and like (D_St)^1/2 (where D_S is the reptation diffusion constant of the S chains) at t>T_S.     

Development and Validation of a Reliable UHPLC-MS/MS Method for Simultaneous Quantification of Macrocyclic Lactones in Bovine Plasma

A fast, accurate and reliable ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method was developed for simultaneous quantification of ivermectin (IVER), doramectin (DORA), and moxidectin (MOXI) in bovine plasma. A priority for sample preparation was the eradication of possible infectious diseases to avoid travel restrictions. The sample preparation was based on protein precipitation using 1% formic acid in acetonitrile, followed by Ostro^® 96-well plate pass-through sample clean-up. The simple and straightforward procedure, along with the short analysis time, makes the current method unique and suitable for a large set of sample analyses per day for PK studies. Chromatographic separation was performed using an Acquity UPLC HSS-T3 column, with 0.01% acetic acid in water and methanol, on an Acquity H-Class ultra-high performance liquid chromatograph (UHPLC) system. The MS/MS instrument was a Xevo TQ-S^® mass spectrometer, operating in the positive electrospray ionization mode and two multiple reaction monitoring (MRM) transitions were monitored per component. The MRM transitions of m/z 897.50 > 753.4 for IVER, m/z 921.70 > 777.40 for DORA and m/z 640.40 > 123.10 for MOXI were used for quantification. The method validation was performed using matrix-matched calibration curves in a concentration range of 1 to 500 ng/mL. Calibration curves fitted a quadratic regression model with 1/x2 weighting (r ≥ 0.998 and GoF ≤ 4.85%). Limits of quantification (LOQ) values of 1 ng/mL were obtained for all the analytes, while the limits of detection (LOD) were 0.02 ng/mL for IVER, 0.03 ng/mL for DORA, and 0.58 ng/mL for MOXI. The results of within-day (RSD < 6.50%) and between-day (RSD < 8.10%) precision and accuracies fell within acceptance ranges. No carry-over and no peak were detected in the UHPLC-MS/MS chromatogram of blank samples showing good specificity of the method. The applicability of the developed method was proved by an analysis of the field PK samples.     

Monthly Increase in Vitamin D Levels upon Supplementation with 2000 IU/Day in Healthy Volunteers: Result from “Integriamoci”, a Pilot Pharmacokinetic Study

Vitamin D (VD) is a calcium- and phosphate-controlling hormone used to treat bone disorders; yet, several other effects are progressively emerging. VD deficiency is highly prevalent worldwide, with suboptimal exposure to sunlight listed among the leading causes: oral supplementation with either cholecalciferol or calcitriol is used. However, there is a scarcity of clinical studies investigating how quickly VD concentrations can increase after supplementation. In this pilot study, the commercial supplement ImmuD3 (by Erboristeria Magentina^®) was chosen as the source of VD and 2000 IU/day was administered for one month to 21 healthy volunteers that had not taken any other VD supplements in the previous 30 days. Plasma VD levels were measured through liquid chromatography coupled to tandem mass spectrometry after 7, 14, and 28 days of supplementation. We found that 95% of the participants had insufficient VD levels at baseline (<30 ng/mL; median 23.72 ng/mL; IQR 18.10–26.15), but after 28 days of supplementation, this percentage dropped to 62% (median 28.35 ng/mL; IQR 25.78–35.20). The median increase in VD level was 3.09 ng/mL (IQR 1.60–5.68) after 7 days and 8.85 ng/mL (IQR 2.85–13.97F) after 28 days. This study suggests the need for continuing VD supplementation and for measuring target level attainment.     

How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP,TP2 and ONEG?

Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to a greater knowledge of, and potential treatments for, a broad range of diseases. To determine whether molecular simulation is able to generate accurate conformational ensembles of IDPs, we explore the structural landscape of the PLP peptide (an intrinsically disordered region of the proteolipid membrane protein) in aqueous and membrane-mimicking solvents, using replica exchange with solute scaling (REST2), and examine the ability of four force fields (ff14SB, ff14IDPSFF, CHARMM36 and CHARMM36m) to reproduce literature circular dichroism (CD) data. Results from variable temperature (VT) ¹H and Rotating frame Overhauser Effect SpectroscopY (ROESY) nuclear magnetic resonance (NMR) experiments are also presented and are consistent with the structural observations obtained from the simulations and CD. We also apply the optimum simulation protocol to TP2 and ONEG (a cell-penetrating peptide (CPP) and a negative control peptide, respectively) to gain insight into the structural differences that may account for the observed difference in their membrane-penetrating abilities. Of the tested force fields, we find that CHARMM36 and CHARMM36m are best suited to the study of IDPs, and accurately predict a disordered to helical conformational transition of the PLP peptide accompanying the change from aqueous to membrane-mimicking solvents. We also identify an α-helical structure of TP2 in the membrane-mimicking solvents and provide a discussion of the mechanistic implications of this observation with reference to the previous literature on the peptide. From these results, we recommend the use of CHARMM36m with the REST2 protocol for the study of environment-specific IDP conformations. We believe that the simulation protocol will allow the study of a broad range of IDPs that undergo conformational transitions in different biological environments.

A protocol for simulating intrinsically disordered peptides in aqueous and hydrophobic solvents is proposed. Results from four force fields are compared with experiment. CHARMM36m performs the best for the simulated IDPs in all environments.     

PLA Nanofibers for Microenvironmental-Responsive Quercetin Release in Local Periodontal Treatment

The management of periodontitis remains a vital clinical challenge due to the interplay between the microorganisms of the dental biofilm and the host inflammatory response leading to a degenerative process in the surrounding tissues. Quercetin (QUE), a natural flavonol found in many foods, including apples, onions and tea, has exhibited prolonged and strong antibiofilm and anti-inflammatory effects both in vitro and in vivo. However, its clinical application is limited by its poor stability and water solubility, as well as its low bioavailability. Thus, in the present study, electrospun polylactic acid (PLA) nanofibers loaded with different amounts (5–10% w/w) of QUE were produced to rapidly respond to the acidic microenvironment typical of periodontal pockets during periodontal disease. This strategy demonstrated that PLA-QUE membranes can act as a drug reservoir releasing high QUE concentrations in the presence of oral bacterial infection (pH < 5.5), and thus limiting Pseudomonas aeruginosa PAO1 and Streptococcus mutans biofilm maturation. In addition, released QUE exerts antioxidant and anti-inflammatory effects on P. gingivalis Lipopolysaccharide (LPS)-stimulated human gingival fibroblast (HGFs). The reported results confirmed that PLA-QUE membranes could inhibit subgingival biofilm maturation while reducing interleukin release, thereby limiting host inflammatory response. Overall, this study provided an effective pH-sensitive drug delivery system as a promising strategy for treating periodontitis.     

Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety

Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC₅₀ values of 3.4–37.8 µM. Compound 8 with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC₅₀ value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (−7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11.