Detoxifying enzymes such as flavin-containing monooxygenases deal with a huge array of highly diverse xenobiotics and toxic compounds. In addition to being of high physiological relevance, these ...drug-metabolizing enzymes are useful catalysts for synthetic chemistry. Despite the wealth of studies, the molecular basis of their relaxed substrate selectivity remains an open question. Here, we addressed this issue by applying a cumulative alanine mutagenesis approach to cyclohexanone monooxygenase from Thermocrispum municipale, a flavin-dependent Baeyer–Villiger monooxygenase which we chose as a model system because of its pronounced thermostability and substrate promiscuity. Simultaneous removal of up to eight noncatalytic active-site side chains including four phenylalanines had no effect on protein folding, thermostability, and cofactor loading. We observed a linear decrease in activity, rather than a selectivity switch, and attributed this to a less efficient catalytic environment in the enlarged active-site space. Time-resolved kinetic studies confirmed this interpretation. We also determined the crystal structure of the enzyme in complex with a mimic of the reaction intermediate that shows an unaltered overall protein conformation. These findings led us to propose that this cyclohexanone monooxygenase may lack a distinct substrate selection mechanism altogether. We speculate that the main or exclusive function of the protein shell in promiscuous enzymes might be the stabilization and accessibility of their very reactive catalytic intermediates.
Oxidative stress and inflammation induced by abundant consumption of high-energy foods and caloric overload are implicated in the dysfunction of the blood‒brain barrier (BBB), cognitive impairment, ...and overactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These enzymes hydrolyse acetylcholine, affecting anti-inflammatory cholinergic signalling. Our aim was to evaluate whether nicotinamide (NAM) attenuates the impairment of the BBB and cognitive function, improving cholinergic signalling. Forty male rats were distributed into five groups: one group was fed a standard diet, and the remaining groups were fed a high-fat diet and a beverage with 40% sucrose (HFS; high-fat sucrose). In three of the HFS groups, the carbohydrate was replaced by drinking water containing different concentrations of NAM for 5 h every morning for 12 weeks. The biochemical profile, levels of stress and inflammation markers, cholinesterase activities, BBB permeability, and cognitive capacity were evaluated. The results showed that the HFS diet disturbed the metabolism of carbohydrates and lipids, causing insulin resistance. Simultaneously, AChE and BChE activities, levels of proinflammatory cytokines, oxidation of proteins and lipoperoxidation increased along with decreased antioxidant capacity in serum. In the hippocampus, increased activity of cholinesterases, protein carbonylation and lipoperoxidation were associated with decreased antioxidant capacity. Systemic and hippocampal changes were reflected in increased BBB permeability and cognitive impairment. In contrast, NAM attenuated the above changes by reducing oxidative stress and inflammation through decreasing cholinesterase activities, especially by uncompetitive inhibition. NAM may be a potential systemic and neuroprotective agent to mitigate cognitive damage due to hypercaloric diets.
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•A 3D transient model for the simulation of fixed bed biomass combustion was developed.•The thermal conversion of solid wood was modelled by solving transport equations of several variables.•A ...compaction model was introduced to account for the local shrinkage of the bed.•The model predictions was compared with experimental data.
CFD codes are well equipped in the resolution of the gas phase combustion, however the solid phase modelling still needs to be developed. The aim of this work is to implement several submodels of thermal conversion of solid fuels and the interaction with the gas phase in a commercial CFD code. For this, a set of submodels taken from literature is proposed for simulating the combustion of solid biomass in packed beds. The modelling method implements several variables that represent the main parameters of the solid mass in the framework of a commercial CFD code. The transport equations of the solid phase are used to predict the transient evolution of the bed and the interaction with the gas phase within the bed and the area surrounding it. The radiative heat transfer is modelled by modifying the standard Discrete Ordinates model to consider the temperature difference between the solid and gas phases and the high absorptivity of the medium. A compaction model is introduced to account for the local shrinkage of the bed due to the collapse of regions weakened by their combustion. The results of the model are presented and discussed by the contrast of the model through the simulation of an experimental burner whose ignition rates, maximum temperatures, and drying, devolatilisation, and char thicknesses are known. The model shows a reasonably accuracy in the predictions of some variables as ignition rates, maximum temperatures and the bed height transient evolution. The comparison of the drying, devolatilisation, and char thicknesses for different air mass fluxes shows reasonably good tendencies even thought the values are excessively high. Compared with previous works done by the authors and by others, it can be seen that the introduction of a bed compaction submodel, as the one presented here, can help in the realistic estimation of the processes involved in packed be combustion of biomass and point to particle shrinkage and bed’s mechanics as an important process to be considered.
Laminar heterostructures composed by materials with different ferroic properties have been proposed for the control of magnetism with an applied voltage. We present here a study of the structural and ...magnetic properties of chemically disordered FePt ferromagnetic films of different thicknesses that have been sputter-deposited on ferroelectric PMN-PT (011) single crystals.
By means of static and dynamic magnetic measurements we have found that it is possible to switch the magnetization easy axis by 90° if an electric field is applied in a direction perpendicular to the film plane. Using ferromagnetic resonance techniques we have estimated the strain induced magnetoelectric coupling of the FePt/PMN-PT heterostructure, obtaining ME=477(15) Oe m/MV for FePt thicknesses greater than 26 nm, which corresponds to an average magnetoelastic constant B=−13.2(1.1) MJ/m3. The associated saturation magnetostriction was estimated in λs∼90 ppm. Films thinner than 26 nm present corresponding values that are smaller by approximately 20%. A possible explanation for this difference is the well known transition from planar to stripe-like magnetic domains that occurs in FePt around this film thickness. However, this thickness dependence of ME is relatively smaller than that found in other ferromagnets such as Fe or FeGa, which makes FePt a potential candidate for thin film applications in magnetoelectronic devices.
•Magnetoelectricity of FePt films deposited on ferroelectric PMN-PT (011) crystals.•Dependence of the magnetoelastic constant B of FePt alloy films on film thickness.•B changes when stripe domains are formed for thicknesses larger than ∼ 26 nm.
Pt and Au are not miscible within a whole range of concentrations. To obtain PtAu alloys, severe thermal treatments are required that to provide aggregation phenomena. However, it is possible to ...synthesize bimetallic PtAu nanoparticles provided the proper synthesis route is employed. When they are prepared from water-in-oil microemulsions or with the impregnation technique, it is possible to obtain nanosized bimetallic PtAu particles. In contrast, other colloidal routes have been seen to be adequate for the synthesis of other bimetallic Pt-based particles, affording segregated samples with Pt- or Au-enriched zones. When alloyed, bimetallic PtAu nanoparticles display unique physicochemical properties that are different from those of monometallic and nonalloyed solids. Thus, the performance of alloyed PtAu samples as electrocatalysts for the oxygen reduction reaction is superior to that of the PtAu-segregated samples. In fact, the ability of carbon-supported bimetallic PtAu samples in the oxygen reduction reactions equals or even surpasses that of archetypal Pt/C electrocatalysts.
Background
There are few data on the prevalence of obesity in the general psoriasis population and on the real impact of obesity on the management of psoriasis patients in the clinical setting.
...Objectives
To evaluate the prevalence of overweight and obesity in patients with moderate‐to‐severe psoriasis compared to the general population and to assess the relationship between Body Mass Index (BMI) and the risk of discontinuing treatment.
Methods
Patients registered on Biobadaderm, a prospective registry, were grouped according the different categories of BMI and compared to the general Spanish population. Drug survival was analysed considering only drug withdrawal due to lack of effectiveness, remission and adverse events.
Results
A total of 1162 moderate‐to‐severe psoriasis patients on systemic conventional or biological treatment were recruited. The prevalence of obesity was found to be significantly higher in psoriasis patients than in the general Spanish population (P < 0.001). In multivariate analysis a 5‐unit increase in BMI, similar to a change in BMI category from normal weight to overweight and from overweight to obesity, was associated with a 12% increased risk of discontinuing therapy due to lack of effectiveness (HR 1.12, 95% CI: 1.01–1.24) and with a 17% increased risk of having an adverse event (HR 1.17, 95% CI: 1.02–1.36), both independently of the drug used.
Conclusions
Patients with moderate‐to‐severe psoriasis had a higher prevalence of obesity than the general population. Increased BMI was associated with an increased risk of treatment discontinuation due to lack of effectiveness and a higher risk of adverse events.
Aliment Pharmacol Ther 2012; 35: 275–283
Summary
Background Ciclosporin has proven to be effective in patients with corticosteroid‐refractory ulcerative colitis (UC). When therapy with this drug ...fails, infliximab can be considered to avoid colectomy. The efficacy and safety of this sequential approach remain unknown.
Aim To assess the efficacy and safety profile of treatment with infliximab after failure of ciclosporin in patients with a corticosteroid‐refractory flare of UC.
Methods Retrospective review of medical records of patients with a corticosteroid‐refractory flare of UC who did not respond to ciclosporin and received salvage therapy with infliximab within a month of discontinuing ciclosporin. The severity of the flare and response to the treatment were graded using the Lichtiger index. Cumulative rates of colectomy were calculated using Kaplan–Meier analysis. Cox regression analysis was performed to identify predictors of colectomy. To evaluate the safety profile of this treatment strategy, any adverse event occurring after the first infusion of infliximab was considered.
Results The study population comprised 47 patients with corticosteroid‐refractory UC treated with infliximab after failure of ciclosporin. The median baseline Lichtiger index was 13. The mean time from the last ciclosporin dose to the first infliximab infusion was 6 days. After the first infliximab infusion, 13% of patients achieved remission, and 74% partial response. Of the 35 patients who received the third infliximab infusion, 60% achieved remission, and 37% partial response. Fourteen patients (30%) underwent colectomy. The rate of adverse events was 23%. One death occurred in a 40‐year‐old man who failed ciclosporin and infliximab and underwent surgery 10 days after the first infliximab infusion; he died of nosocomial pneumonia.
Conclusions Treatment with infliximab makes it possible to avoid colectomy in two‐thirds of corticosteroid‐refractory UC patients in whom ciclosporin fails. However, the rates of adverse events and mortality mean that the decision to administer sequential therapy (ciclosporin–infliximab) should be taken on an individual basis.
This paper challenges the prevalent notion that family-owned firms are more risk averse than publicly owned firms. Using behavioral theory, we argue that for family firms, the primary reference point ...is the loss of their socioemotional wealth, and to avoid those losses, family firms are willing to accept a significant risk to their performance; yet at the same time, they avoid risky business decisions that might aggravate that risk. Thus, we propose that the predictions of behavioral theory differ depending on family ownership. We confirm our hypotheses using a population of 1,237 family-owned olive oil mills in Southern Spain who faced the choice during a 54-year period of becoming a member of a cooperative, a decision associated with loss of family control but lower business risk, or remaining independent, which preserves the family's socioemotional wealth but greatly increases its performance hazard. As shown in this study, family firms may be risk willing and risk averse at the same time.
Chlorophenols, commonly found in the wastewaters of numerous industries, are widely considered as priority pollutants and their persistence may cause severe environmental problems. Among the methods ...described for their removal, pressure-driven membrane processes are considered as a reliable alternative. In this paper we study the influence of different operational variables (applied pressure, feed concentration and pH) on the removal of 4-chlorophenol from synthetic aqueous solutions by nanofiltration using three different polyamide membranes (NF-97, NF-99 and RO98pHt). The Spiegler–Kedem–Kachalsky model was applied to predict the nanofiltration removal process. Model constants for the three membranes were obtained and there was good agreement between the experimental and model rejection data.
► Chlorophenols are listed as priority pollutants that cause environmental problems. ► Nanofiltration with different polyamide membranes has been applied to 4-chlorophenol. ► Spiegler–Kedem–Kachalsky model was successfully applied to predict process behavior.
Objective
To assess the efficacy of tocilizumab (TCZ) for the treatment of juvenile idiopathic arthritis (JIA)–associated uveitis.
Methods
We conducted a multicenter study of patients with ...JIA‐associated uveitis that was refractory to conventional immunosuppressive drugs and anti–tumor necrosis factor (anti‐TNF) agents.
Results
We assessed 25 patients (21 female; 47 affected eyes) with a mean ± SD age of 18.5 ± 8.3 years. Uveitis was bilateral in 22 patients. Cystoid macular edema was present in 9 patients. Ocular sequelae found at initiation of TCZ included cataracts (n = 13), glaucoma (n = 7), synechiae (n = 10), band keratopathy (n = 12), maculopathy (n = 9), and amblyopia (n = 5). Before TCZ, patients had received corticosteroids, conventional immunosuppressive drugs, and biologic agents (median 2 range 1–5), including adalimumab (n = 24), etanercept (n = 8), infliximab (n = 7), abatacept (n = 6), rituximab (n = 2), anakinra (n = 1), and golimumab (n = 1). Patients received 8 mg/kg TCZ intravenously every 4 weeks in most cases. TCZ yielded rapid and maintained improvement in all ocular parameters. After 6 months of therapy, 79.2% of patients showed improvement in anterior chamber cell numbers, and 88.2% showed improvement after 1 year. Central macular thickness measured by optical coherence tomography in patients with cystoid macular edema decreased from a mean ± SD of 401.7 ± 86.8 μm to 259.1 ± 39.5 μm after 6 months of TCZ (P = 0.012). The best‐corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (P < 0.01). After a median follow‐up of 12 months, visual improvement persisted, and complete remission of uveitis was observed in 19 of 25 patients. Significant reduction in the prednisone dosage was also achieved. The main adverse effects were severe autoimmune thrombocytopenia in 1 patient, pneumonia and then autoimmune anemia and thrombocytopenia in 1 patient, and viral conjunctivitis and bullous impetigo in 1 patient.
Conclusion
TCZ appears to be a useful therapy for severe refractory JIA‐associated uveitis.
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