Effect of the cation structure on the properties of homobaric imidazolium ionic liquids

In this work we investigate the structure-property relationships in a series of alkylimidazolium ionic liquids with almost identical molecular weight. Using a combination of theoretical calculations and experimental measurements, we have shown that re-arranging the alkyl side chain or adding functional groups results in quite distinct features in the resultant ILs. The synthesised ILs, although structurally very similar, cover a wide spectrum of properties ranging from highly fluid, glass forming liquids to high melting point crystalline salts. Theoretical ab initio calculations provide insight on minimum energy orientations for the cations, which then are compared to experimental X-ray crystallography measurements to extract information on hydrogen bonding and to verify our understanding of the studied structures. Molecular dynamics simulations of the simplest (core) ionic liquids are used in order to help us interpret our experimental results and understand better why methylation of C^{2} position of the imidazolium ring results in ILs with such different properties compared to their non-methylated analogues

Pancreas-derived mesenchymal stromal cells share immune response-modulating and angiogenic potential with bone marrow mesenchymal stromal cells and can be grown to therapeutic scale under GMP conditions

Background aims: Mesenchymal stromal cells (MSCs) isolated from various tissues are under investigation as cellular therapeutics in a wide range of diseases. It is appreciated that the basic biological functions of MSCs vary depending on tissue source. However, in-depth comparative analyses between MSCs isolated from different tissue sources under Good Manufacturing Practice (GMP) conditions are lacking. Human clinical-grade low-purity islet (LPI) fractions are generated as a byproduct of islet isolation for transplantation. MSC isolates were derived from LPI fractions with the aim of performing a systematic, standardized comparative analysis of these cells with clinically relevant bone marrow-derived MSCs (BM MSCs). Methods: MSC isolates were derived from LPI fractions and expanded in platelet lysate-supplemented medium or in commercially available xenogeneic-free medium. Doubling rate, phenotype, differentiation potential, gene expression, protein production and immunomodulatory capacity of LPIs were compared with those of BM MSCs. Results: MSCs can be readily derived in vitro from non-transplanted fractions resulting from islet cell processing (i.e., LPI MSCs). LPI MSCs grow stably in serum-free or platelet lysate-supplemented media and demonstrate in vitro self-renewal, as measured by colony-forming unit assay. LPI MSCs express patterns of chemokines and pro-regenerative factors similar to those of BM MSCs and, importantly, are equally able to attract immune cells in vitro and in vivo and suppress T-cell proliferation in vitro. Additionally, LPI MSCs can be expanded to therapeutically relevant doses at low passage under GMP conditions. Conclusions: LPI MSCs represent an alternative source of GMP MSCs with functions comparable to BM MSCs

Geological relationships and laser ablation ICP-MS U-Pb geochronology of the Saint George Batholith, southwestern New Brunswick, Canada: implications for its tectonomagmatic evolution

  The Late Silurian to Late Devonian Saint George Batholith in southwestern New Brunswick is a large composite intrusion (2000 km2) emplaced into the continental margin of the peri-Gondwanan microcontinent of Ganderia. The batholith includes: (1) Bocabec Gabbro; (2) equigranular Utopia and Wellington Lake biotite granites; (3) Welsford, Jake Lee Mountain, and Parks Brook peralkaline granites; (4) two-mica John Lee Brook Granite; (6) Jimmy Hill and Magaguadavic megacrystic granites; and (6) rapakivi Mount Douglas Granite. New LA ICP-MS in situ analyses of six samples from the Saint George Batholith are as follows: (1) U-Pb monazite crystallization age of 425.5 ± 2.1 Ma for the Utopia Granite in the western part of the batholith (2) U-Pb zircon crystallization ages of 420.4 ± 2.4 Ma and 420.0 ± 3.5 Ma for two samples of the Utopia Granite from the central part of the batholith; (3) U-Pb zircon crystallization age of 418.0 ± 2.3 Ma for the Jake Lee Mountain Granite; (4) U-Pb zircon crystallization age of 415.5 ± 2.1 Ma for the Wellington Lake Granite; and (5) U-Pb monazite crystallization age of 413.3 ± 2.1 Ma for the John Lee Brook Granite. The new geochronological together with new and existing geochemical data suggest that the protracted magmatic evolution of the Late Silurian to Early Devonian plutonic rocks is related to the transition of the Silurian Kingston arc-Mascarene backarc system from an extensional to compressional tectonic environment during collision of the Avalonian microcontinent with Laurentia followed by slab break-off.

Role of the C-terminal domain in the structure and function of tetrameric sodium channels.

Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 Å resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil

Role of the C-terminal domain in the structure and function of tetrameric sodium channels

Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 Å resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil

Real-world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice

An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behavior

Serpins are important regulators of proteolytic pathways with an antiprotease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an intermolecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of many pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-Antitrypsin (α1-AT) polymerisation in cells. Here, we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39 and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A - on the opposite face of the molecule - more liable to adopt an 'open' state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of a preformed serpin-enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the 'open' state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for a rational design of ligands that is able to dynamically influence α1-AT polymerisation

A list of reptiles and amphibians from Box Gum Grassy Woodlands in south-eastern Australia

A large-scale biodiversity monitoring program examining the response of herpetofauna to the Australian Government’s Environmental Stewardship Program is taking place in south-eastern Australia within the critically endangered Box Gum Grassy Woodland vegetation community. Field surveys involve counting reptiles in areas under Environmental Stewardship management. These “Stewardship” areas have been matched with areas managed for primary production (domestic livestock grazing). We list reptiles recorded during surveys conducted between 2010 and 2012. We recorded sixty-nine species from ten families. The list will be useful for workers interested in the zoogeographical distribution of reptiles and amphibians in fragmented agricultural woodland ecosystems

An economic evaluation of the healthcare cost of tinnitus management in the UK

Background: There is no standard treatment pathway for tinnitus patients in the UK. Possible therapies include education and reassurance, cognitive behavioural therapies, modified tinnitus retraining therapy (education and sound enrichment), or amplification of external sound using hearing aids. However, the effectiveness of most therapies is somewhat controversial. As health services come under economic pressure to deploy resources more effectively there is an increasing need to demonstrate the value of tinnitus therapies, and how value may be continuously enhanced. The objective of this project was to map out existing clinical practice, estimate the NHS costs associated with the management approaches used, and obtain initial indicative estimates of cost-effectiveness.Methods: Current treatment pathways, costs and health outcomes were determined from the tinnitus literature, national statistics, a patient survey, and expert opinion. These were used to create an Excel-based economic model of therapy options for tinnitus patients. The probabilities associated with the likelihood of an individual patient receiving a particular combination of therapies was used to calculate the average cost of treatment per patient, average health outcome per patient measured in QALYs gained, and cost-effectiveness, measured by the average cost per QALY gained.Results: The average cost of tinnitus treatment per patient per year is GB£717, equating to an NHS healthcare bill of GB£750 million per year. Across all pathways, tinnitus therapy costs £10,600 per QALY gained. Results were relatively insensitive to restrictions on access to cognitive behaviour therapy, and a subsequent reliance on other therapies.Conclusions: NHS provisions for tinnitus are cost-effective against the National Institute for Health and Care Excellence cost-effective threshold. Most interventions help, but education alone offers very small QALY gains. The most cost-effective therapies in the model were delivered within audiology

Nanopore metagenomics enables rapid clinical diagnosis of bacterial lower respiratory infection

The gold standard for clinical diagnosis of bacterial lower respiratory infections (LRIs) is culture, which has poor sensitivity and is too slow to guide early, targeted antimicrobial therapy. Metagenomic sequencing could identify LRI pathogens much faster than culture, but methods are needed to remove the large amount of human DNA present in these samples for this approach to be feasible. We developed a metagenomics method for bacterial LRI diagnosis that features efficient saponin-based host DNA depletion and nanopore sequencing. Our pilot method was tested on 40 samples, then optimized and tested on a further 41 samples. Our optimized method (6 h from sample to result) was 96.6% sensitive and 41.7% specific for pathogen detection compared with culture and we could accurately detect antibiotic resistance genes. After confirmatory quantitative PCR and pathobiont-specific gene analyses, specificity and sensitivity increased to 100%. Nanopore metagenomics can rapidly and accurately characterize bacterial LRIs and might contribute to a reduction in broad-spectrum antibiotic use