The kinetics of the metal-free hydrogen transfer from amine–borane Me2NH·BH3 to aminoborane iPr2NBH2, yielding iPr2NH·BH3 and cyclodiborazane Me2N-BH22 via transient Me2NBH2, have been investigated ...in detail, with further information derived from isotopic labeling and DFT computations. The approach of the system toward equilibrium was monitored in both directions by 11B{1H} NMR spectroscopy in a range of solvents and at variable temperatures in THF. Simulation of the resulting temporal–concentration data according to a simple two-stage hydrogen transfer/dimerization process yielded the rate constants and thermodynamic parameters attending both equilibria. At ambient temperature, the bimolecular hydrogen transfer is slightly endergonic in the forward direction (ΔG 1°(295) = 10 ± 7 kJ·mol–1; ΔG 1 ⧧ (295) = 91 ± 5 kJ·mol–1), with the overall equilibrium being driven forward by the subsequent exergonic dimerization of the aminoborane Me2NBH2 (ΔG 2°(295) = −28 ± 14 kJ·mol–1). Systematic deuterium labeling of the NH and BH moieties in Me2NH·BH3 and iPr2NBH2 allowed the kinetic isotope effects (KIEs) attending the hydrogen transfer to be determined. A small inverse KIE at boron (k H/k D = 0.9 ± 0.2) and a large normal KIE at nitrogen (k H/k D = 6.7 ± 0.9) are consistent with either a pre-equilibrium involving a B-to-B hydrogen transfer or a concerted but asynchronous hydrogen transfer via a cyclic six-membered transition state in which the B-to-B hydrogen transfer is highly advanced. DFT calculations are fully consistent with a concerted but asynchronous process.
The potential for wetland emissions to feedback on climate change has been previously hypothesised Houghton et al., 2001. We assess this hypothesis using an interactive wetlands scheme radiatively ...coupled to an integrated climate change effects model. The scheme predicts wetland area and methane (CH4) emissions from soil temperature and water table depth, and is constrained by optimising its ability to reproduce the observed inter‐annual variability in atmospheric CH4. In transient climate change simulations the wetland response amplifies the total anthropogenic radiative forcing at 2100 by about 3.5–5%. The modelled increase in global CH4 flux from wetland is comparable to the projected increase in anthropogenic CH4 emissions over the 21st century under the IS92a scenario.
The application of extracellular vesicles (EVs) as natural delivery vehicles capable of enhancing tissue regeneration could represent an exciting new phase in medicine. We sought to define the ...capacity of EVs derived from mineralising osteoblasts (MO-EVs) to induce mineralisation in mesenchymal stem cell (MSC) cultures and delineate the underlying biochemical mechanisms involved. Strikingly, we show that the addition of MO-EVs to MSC cultures significantly (P < 0.05) enhanced the expression of alkaline phosphatase, as well as the rate and volume of mineralisation beyond the current gold-standard, BMP-2. Intriguingly, these effects were only observed in the presence of an exogenous phosphate source. EVs derived from non-mineralising osteoblasts (NMO-EVs) were not found to enhance mineralisation beyond the control. Comparative label-free LC-MS/MS profiling of EVs indicated that enhanced mineralisation could be attributed to the delivery of bridging collagens, primarily associated with osteoblast communication, and other non-collagenous proteins to the developing extracellular matrix. In particular, EV-associated annexin calcium channelling proteins, which form a nucleational core with the phospholipid-rich membrane and support the formation of a pre-apatitic mineral phase, which was identified using infrared spectroscopy. These findings support the role of EVs as early sites of mineral nucleation and demonstrate their value for promoting hard tissue regeneration.
Sedentary behaviour is a public health concern that requires surveillance and epidemiological research. For such large scale studies, self-report tools are a pragmatic measurement solution. A large ...number of self-report tools are currently in use, but few have been validated against an objective measure of sedentary time and there is no comparative information between tools to guide choice or to enable comparison between studies. The aim of this study was to provide a systematic comparison, generalisable to all tools, of the validity of self-report measures of sedentary time against a gold standard sedentary time objective monitor.
Cross sectional data from three cohorts (N = 700) were used in this validation study. Eighteen self-report measures of sedentary time, based on the TAxonomy of Self-report SB Tools (TASST) framework, were compared against an objective measure of postural sitting (activPAL) to provide information, generalizable to all existing tools, on agreement and precision using Bland-Altman statistics, on criterion validity using Pearson correlation, and on data loss.
All self-report measures showed poor accuracy compared with the objective measure of sedentary time, with very wide limits of agreement and poor precision (random error > 2.5 h). Most tools under-reported total sedentary time and demonstrated low correlations with objective data. The type of assessment used by the tool, whether direct, proxy, or a composite measure, influenced the measurement characteristics. Proxy measures (TV time) and single item direct measures using a visual analogue scale to assess the proportion of the day spent sitting, showed the best combination of precision and data loss. The recall period (e.g. previous week) had little influence on measurement characteristics.
Self-report measures of sedentary time result in large bias, poor precision and low correlation with an objective measure of sedentary time. Choice of tool depends on the research context, design and question. Choice can be guided by this systematic comparative validation and, in the case of population surveillance, it recommends to use a visual analog scale and a 7 day recall period. Comparison between studies and improving population estimates of average sedentary time, is possible with the comparative correction factors provided.
Aims/hypothesis
We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in ...Mexican-Americans from Starr County, TX, USA.
Method
Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico.
Result
The top signals (unadjusted
p
value <1 × 10
−5
) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (
PER3
,
PARD3B
,
EPHA4
,
TOMM7
,
PTPRD
,
HNT
also known as
RREB1
,
LOC729993
and
IL34
) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene
PER3
, a system recently implicated in diabetes. We also report a second signal (minimum
p
value 1.52 × 10
−6
) within
PTPRD
, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions
HNF1A
and
KCNQ1
. Annotation of top association signals in both studies revealed a marked excess of
trans
-acting eQTL in both adipose and muscle tissues.
Conclusions/Interpretation
In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues.
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview Alexander, Stephen PH; Kelly, Eamonn; Marrion, Neil V ...
British journal of pharmacology,
December 2017, Letnik:
174, Številka:
S1
Journal Article, Web Resource
Recenzirano
Odprti dostop
The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an ...emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13882/full. In addition to this overview, in which are identified ‘Other protein targets’ which fall outside of the subsequent categorisation, there are eight areas of focus: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The formation of oligomeric molecules, an important step in secondary organic aerosol production, is reported. Aerosols were produced by the reaction of α-pinene and ozone in the presence of acid ...seed aerosol and characterized by exact mass measurements and tandem mass spectrometry. Oligomeric products between 200 and 900 u were detected with both electrospray ionization and matrix-assisted laser desorption ionization. The exact masses and dissociation products of these ions were consistent with various combinations of the known primary products of this reaction (“monomers”) with and/or without the expected acid-catalyzed decomposition products of the monomers. Oligomers as large as tetramers were detected. Both aldol condensations and gem-diol reactions are suggested as possible pathways for oligomer formation. Exact mass measurements also revealed reaction products that cannot be explained by simple oligomerization of monomers and monomer decomposition products, suggesting the existence of complex reaction channels. Chemical reactions leading to oligomer formation provide a reasonable answer to a difficult problem associated with secondary organic aerosol production in the atmosphere. It is unlikely that monomers alone play an important role in the formation and growth of nuclei in the atmosphere as their Kelvin vapor pressures are too high for them to significantly partition into the particle phase. Polymerization provides a mechanism by which partitioning to the particle phase becomes favored.
Many studies have shown that correlation between clinical asthma status and asthma-specific quality of life is only weak to moderate. However, this relationship has never been explored to determine ...whether the weakness is due to noise of measurement or whether quality of life is a distinct component of asthma health status. With a database from three clinical trials (n = 763), factor analysis was used to explore the relationships between quality of life, measured by the Asthma Quality of Life Questionnaire (AQLQ), and conventional measures of asthma clinical status (symptoms, airway calibre and rescue beta2-agonist use). The analysis revealed that although patients with severe, poorly controlled asthma tend to have worse quality of life than milder, well-controlled patients, overall asthma health status has four components (factors): asthma-specific quality of life; airway calibre; daytime symptoms and daytime beta2-agonist use, and night-time symptoms and night-time beta2-agonist use. The clean loading of all 21 outcomes onto four distinct and clinically identifiable factors suggests that, although some weakness of correlation between clinical indices and quality of life may be due to noise of measurement, it is mainly attributable to asthma health status being composed of distinct components.
To assess effects of the CARE4Carer blended care intervention on caregiver mastery and psychosocial functioning compared with usual care in partners of patients with acquired brain injury (ABI).
...Multicenter randomized controlled trial.
Nine sites for rehabilitation medicine.
120 partners of outpatients with ABI were randomly allocated to blended care (N=59) or usual care (N=61).
The blended care intervention (20 weeks) was aimed at improving caregiving skills and consisted of 9 online sessions, combined with 2 face-to-face consultations with a social worker.
Mastery was assessed with the Caregiver Mastery Scale, secondary outcome measures were caregiver strain (Caregiver Strain Index), family functioning (Family Assessment Device), anxiety and depression (Hospital Anxiety and Depression Scale), burden (self-rated), and quality of life (CarerQol). Assessments were performed at baseline, 24, and 40 weeks.
The adjusted mean difference in caregiver mastery between intervention and control group at week 24 was 1.31 (SD3.48, 95% confidence interval (CI) -0.12 to 2.74, P=.072) and at week 40 was 1.31 (SD3.69, 95% CI -0.26 to 2.88, P=.100). In the per protocol analysis, the adjusted mean difference in caregiver mastery at week 24 was 1.53 (SD3.38, 95% CI 0.10 to 2.96, P=.036) and at week 40 was 1.57 (SD3.63, 95% CI 0.01 to 3.14, P=.049). Regarding secondary outcomes, caregiver strain was lower in the intervention group in the per protocol analysis at week 40. Family functioning was higher in the intervention group in week 24, whereas anxiety was lower at both timepoints.
In the subset of participants who were able to complete the intervention, caregiver mastery and psychosocial functioning improved. Future work should focus on improving adherence as this will optimize beneficial effects of blended care.
The early history of island Southeast Asia is often characterized as the story of two major population dispersals: the initial Paleolithic colonization of Sahul approximately 45 ka ago and the much ...later Neolithic expansion of Austronesian-speaking farmers approximately 4 ka ago. Here, in the largest survey of Indonesian Y chromosomes to date, we present evidence for multiple genetic strata that likely arose through a series of distinct migratory processes. We genotype an extensive battery of Y chromosome markers, including 85 single-nucleotide polymorphisms/indels and 12 short tandem repeats, in a sample of 1,917 men from 32 communities located across Indonesia. We find that the paternal gene pool is sharply subdivided between western and eastern locations, with a boundary running between the islands of Bali and Flores. Analysis of molecular variance reveals one of the highest levels of between-group variance yet reported for human Y chromosome data (e.g., Phi(ST) = 0.47). Eastern Y chromosome haplogroups are closely related to Melanesian lineages (i.e., within the C, M, and S subclades) and likely reflect the initial wave of colonization of the region, whereas the majority of western Y chromosomes (i.e., O-M119*, O-P203, and O-M95*) are related to haplogroups that may have entered Indonesia during the Paleolithic from mainland Asia. In addition, two novel markers (P201 and P203) provide significantly enhanced phylogenetic resolution of two key haplogroups (O-M122 and O-M119) that are often associated with the Austronesian expansion. This more refined picture leads us to put forward a four-phase colonization model in which Paleolithic migrations of hunter-gatherers shape the primary structure of current Indonesian Y chromosome diversity, and Neolithic incursions make only a minor impact on the paternal gene pool, despite the large cultural impact of the Austronesian expansion.
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