Irregular solution thermodynamics of wood pulp in the superbase ionic liquid [m-TBDH][AcO]

Knowledge of solution thermodynamics is fundamental for solution control and solvent selection processes. Herein, experimentally determined thermodynamic quantities for solutions of wood pulp (hardwood dissolving pulp, i.e. cellulose) in [m-TBDH][AcO] are presented. Model-free activities (a(i,j)) and associated mass fraction (w(i,j)) activity coefficients (omega(i,j)), are determined to quantify inherent solution non-ideality. Access to the Gibbs energy of mixing, G(mix), in combination with associated partial molar thermodynamic quantities, reveal strong enthalpically favourable (exothermic) interactions due to solvent-j and solute-i contact-encounters. Onset of an entropy driven phase instability appears at increased temperatures as excess entropic contributions dominate solvation character of the irregular solutions formed.Peer reviewe

Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors

4-Phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines were studied as prolyl oligopeptidase inhibitors. The compounds were more potent than expected from the assumption that the tetrazole would also here be a bioisostere of the carboxylic acid group and the corresponding carboxylic acids are at their best only weak inhibitors. The aminoacyl groups L-prolyl and L-alanyl gave potent inhibitors with IC50 values of 12 and 129 nM, respectively. This was in line with typical prolyl oligopeptidase inhibitors; however, we did observe a difference with N-methyl-L-alanyl, which gave potent inhibitors in typical prolyl oligopeptidase inhibitors but not in our novel compound series. Furthermore, all studied 4-phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines decreased alpha-synuclein dimerization at the concentration of 10 mu M, also when they were only weak inhibitors of the proteolytic activity of the enzyme with an IC50 value of 205 mu M. Molecular docking studies revealed that the compounds are likely to bind differently to the enzyme compared to typical prolyl oligopeptidase inhibitors represented in this study by 4-phenylbutanoyl-aminoacyl-2(S)-cyanopyrrolidines.Peer reviewe

Sustainability of cellulose dissolution and regeneration in 1,5-diazabicyclo[4.3.0]non-5-enium acetate : a batch simulation of the IONCELL-F process

The recyclability of 1,5-diazabicyclo[4.3.0] non-5-enium acetate ([DBNH][OAc]), as a direct dissolution solvent for cellulose, was evaluated during laboratory scale recycling trials. The main objective was to simulate the conditions of a spinning bath from a Lyocell-type air-gap spinning process, called the IONCELL-F process. The saline solution was then concentrated, recycled and reused as many times as possible before cellulose dissolution was no longer possible. The chemical compositions of the ionic liquid and pulp were recorded throughout the experiments. The results of the experiments showed that [DBNH][OAc] can be recycled from aqueous media with an average recovery rate of 95.6 wt% using basic laboratory equipment, without any further process intensification or optimisation. The recycling of the ionic liquid did not change the chemical composition or degree of polymerisation of the recovered pulp but the colour of the regenerated pulps gradually darkened as the recycling times increased. The ionic liquid was found to hydrolyse 6.0-13.6 mol% per cycle, under these conditions. The build-up of the hydrolysis product, 3-( aminopropyl)-2-pyrrolidonium acetate, killed the dissolution feature at between 30.6-45.6 wt% hydrolysis product. The enzymatic digestibility of the regenerated pulp samples was studied with both a monocomponent endoglucanase and a cellulase mixture. The amount of residual [DBNH][OAc] in the regenerated pulps was determined, by both NMR and capillary electrophoresis. Although hydrolysis of the ionic liquid occurs, this study clearly shows potential for industrial application, with appropriate process equipment and recycling conditions.Peer reviewe

Satisfiability of constraint specifications on XML documents

Jose Meseguer is one of the earliest contributors in the area of Algebraic Specification. In this paper, which we are happy to dedicate to him on the occasion of his 65th birthday, we use ideas and methods coming from that area with the aim of presenting an approach for the specification of the structure of classes of XML documents and for reasoning about them. More precisely, we specify the structure of documents using sets of constraints that are based on XPath and we present inference rules that are shown to define a sound and complete refutation procedure for checking satisfiability of a given specification using tableaux.Peer ReviewedPostprint (author's final draft

Level of Fatty Acid Binding Protein 5 (FABP5) Is Increased in Sputum of Allergic Asthmatics and Links to Airway Remodeling and Inflammation

FABP5 may contribute to the airway remodeling and inflammation in asthma by fine-tuning the levels of CysLTs, which induce VEGF production.</p

Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study

Recently, the rs6232 (N221D) and rs6235 (S690T) SNPs in the PCSK1 gene were associated with obesity in a meta-analysis comprising more than 13 000 individuals of European ancestry. Each additional minor allele of rs6232 or rs6235 was associated with a 1.34- or 1.22-fold increase in the risk of obesity, respectively. So far, only one relatively small study has aimed to replicate these findings, but could not confirm the association of the rs6235 SNP and did not study the rs6232 variant. In the present study, we examined the associations of the rs6232 and rs6235 SNPs with obesity in a population-based cohort consisting of 20 249 individuals of European descent from Norfolk, UK. Logistic regression and generalized linear models were used to test the associations of the risk alleles with obesity and related quantitative traits, respectively. Neither of the SNPs was significantly associated with obesity, BMI or waist circumference under the additive genetic model (P > 0.05). However, we observed an interaction between rs6232 and age on the level of BMI (P = 0.010) and risk of obesity (P = 0.020). The rs6232 SNP was associated with BMI (P = 0.021) and obesity (P = 0.022) in the younger individuals [less than median age (59 years)], but not among the older age group (P = 0.81 and P = 0.68 for BMI and obesity, respectively). In conclusion, our data suggest that the PCSK1 rs6232 and rs6235 SNPs are not major contributors to common obesity in the general population. However, the effect of rs6232 may be age-dependent

Randomized controlled trials in de-implementation research : a systematic scoping review

Background: Healthcare costs are rising, and a substantial proportion of medical care is of little value. De-implementation of low-value practices is important for improving overall health outcomes and reducing costs. We aimed to identify and synthesize randomized controlled trials (RCTs) on de-implementation interventions and to provide guidance to improve future research. Methods: MEDLINE and Scopus up to May 24, 2021, for individual and cluster RCTs comparing de-implementation interventions to usual care, another intervention, or placebo. We applied independent duplicate assessment of eligibility, study characteristics, outcomes, intervention categories, implementation theories, and risk of bias. Results: Of the 227 eligible trials, 145 (64%) were cluster randomized trials (median 24 clusters; median follow-up time 305 days), and 82 (36%) were individually randomized trials (median follow-up time 274 days). Of the trials, 118 (52%) were published after 2010, 149 (66%) were conducted in a primary care setting, 163 (72%) aimed to reduce the use of drug treatment, 194 (85%) measured the total volume of care, and 64 (28%) low-value care use as outcomes. Of the trials, 48 (21%) described a theoretical basis for the intervention, and 40 (18%) had the study tailored by context-specific factors. Of the de-implementation interventions, 193 (85%) were targeted at physicians, 115 (51%) tested educational sessions, and 152 (67%) multicomponent interventions. Missing data led to high risk of bias in 137 (60%) trials, followed by baseline imbalances in 99 (44%), and deficiencies in allocation concealment in 56 (25%). Conclusions: De-implementation trials were mainly conducted in primary care and typically aimed to reduce low-value drug treatments. Limitations of current de-implementation research may have led to unreliable effect estimates and decreased clinical applicability of studied de-implementation strategies. We identified potential research gaps, including de-implementation in secondary and tertiary care settings, and interventions targeted at other than physicians. Future trials could be improved by favoring simpler intervention designs, better control of potential confounders, larger number of clusters in cluster trials, considering context-specific factors when planning the intervention (tailoring), and using a theoretical basis in intervention design. Registration: OSF Open Science Framework hk4b2.Peer reviewe

Randomized controlled trials in de-implementation research : a systematic scoping review

Background: Healthcare costs are rising, and a substantial proportion of medical care is of little value. De-implementation of low-value practices is important for improving overall health outcomes and reducing costs. We aimed to identify and synthesize randomized controlled trials (RCTs) on de-implementation interventions and to provide guidance to improve future research. Methods: MEDLINE and Scopus up to May 24, 2021, for individual and cluster RCTs comparing de-implementation interventions to usual care, another intervention, or placebo. We applied independent duplicate assessment of eligibility, study characteristics, outcomes, intervention categories, implementation theories, and risk of bias. Results: Of the 227 eligible trials, 145 (64%) were cluster randomized trials (median 24 clusters; median follow-up time 305 days), and 82 (36%) were individually randomized trials (median follow-up time 274 days). Of the trials, 118 (52%) were published after 2010, 149 (66%) were conducted in a primary care setting, 163 (72%) aimed to reduce the use of drug treatment, 194 (85%) measured the total volume of care, and 64 (28%) low-value care use as outcomes. Of the trials, 48 (21%) described a theoretical basis for the intervention, and 40 (18%) had the study tailored by context-specific factors. Of the de-implementation interventions, 193 (85%) were targeted at physicians, 115 (51%) tested educational sessions, and 152 (67%) multicomponent interventions. Missing data led to high risk of bias in 137 (60%) trials, followed by baseline imbalances in 99 (44%), and deficiencies in allocation concealment in 56 (25%). Conclusions: De-implementation trials were mainly conducted in primary care and typically aimed to reduce low-value drug treatments. Limitations of current de-implementation research may have led to unreliable effect estimates and decreased clinical applicability of studied de-implementation strategies. We identified potential research gaps, including de-implementation in secondary and tertiary care settings, and interventions targeted at other than physicians. Future trials could be improved by favoring simpler intervention designs, better control of potential confounders, larger number of clusters in cluster trials, considering context-specific factors when planning the intervention (tailoring), and using a theoretical basis in intervention design. Registration: OSF Open Science Framework hk4b2.Peer reviewe