A series of heteroleptic monoamido‐monohydrido‐dialkylaluminate complexes of general formula iBu2AlTMPHLi⋅donor were synthesized and characterised in solution and in the solid state. Applying these ...complexes in catalytic hydroboration reactions with representative aldehydes and ketones reveals that all are competent, however a definite donor substituent effect is discernible. The bifunctional nature of the complexes is also probed by assessing their performance in metallation of a triazole and phenylacetylene and addition across pyrazine. These results lead to an example of phenylacetylene hydroboration, which likely proceeds via deprotonation, rather than insertion as observed with the aldehydes and ketones. Collectively, the results emphasise that reactivity is strongly influenced by both the mixed‐metal constitution and mixed‐ligand constitution of the new aluminates.
Its Al in the design: Access to the lithium centre appears to be a key factor in the efficiency of donor‐supported aluminates in catalytic hydroborations of carbonyl substrates with pinacolborane, while inclusion of a TMP ligand in their design facilitates multifunctional behaviour in the form of metallation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims and objectives
This study investigated nurses' roles and their perspectives on the factors that influence interdisciplinary teamwork within Canadian primary care setting.
Background
...Interdisciplinary teams have shown to lead to better system‐ and patient‐level outcomes and, accordingly, have became important aspects of healthcare systems especially within primary care settings. Nurses play a key role in these primary care teams, particularly with respect to chronic disease management.
Design
A focused ethnography design using semi‐structured individual interviews was conducted.
Methods
Interviews were conducted with 20 primary care nurses between July 2010–May 2011. Interviews were recorded, transcribed, and content and thematic analysis was performed.
Results
Nurses experienced increasing scope of practice and professional responsibility as they transitioned into the primary care setting. Nine major roles of primary care nurses were identified. Several factors that facilitate or hinder teamwork were identified and categorised under four theme areas: (1) organisation/leadership (e.g. having common goals and mandate, unclear descriptions of team members' roles); (2) team relationships (e.g. closed loop of communication, trust, respect); (3) process/support (e.g. unclear referral process and reporting structure, large patient panels); and (4) physical environment (e.g. decentralised model of care).
Conclusions
Nurses' roles within primary care setting appear to be focused mainly on case management. Minimal orientation and lack of preparation of nurses for their roles, vagueness of these roles among the interdisciplinary primary care team members and lack of communication appeared to be among the most important factors that influence teamwork and nurses' functioning within these teams.
Relevance to clinical practice
Given that nurses play a key role in interdisciplinary primary care teams, particularly in managing chronic disease patients, approaches to improve chronic disease management and care of these patients should incorporate strategies to ensure effective preparation of these nurses for their roles within these teams and settings.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Abstract
Summary
Data integration and visualization help geneticists make sense of large amounts of data. To help facilitate interpretation of genetic association data we developed Toppar, a ...customizable visualization tool that stores results from association studies and enables browsing over multiple results, by combining features from existing tools and linking to appropriate external databases.
Availability and implementation
Detailed information on Toppar's features and functionality are on our website http://mccarthy.well.ox.ac.uk/toppar/docs along with instructions on how to download, install and run Toppar. Our online version of Toppar is accessible from the website and can be test-driven using Firefox, Safari or Chrome on sub-sets of publicly available genome-wide association study anthropometric waist and body mass index data (Locke et al., 2015; Shungin et al., 2015) from the Genetic Investigation of ANthropometric Traits consortium.
Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene ...(SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-misfolded forms of SOD1. We raised this antibody to an epitope that is normally buried in the SOD1 native homodimer interface. The SOD1 exposed dimer interface (SEDI) antibody recognizes only those SOD1 conformations in which the native dimer is disrupted or misfolded and thereby exposes the hydrophobic dimer interface. Using the SEDI antibody, we established the presence of monomer-misfolded SOD1 in three ALS mouse models, with G37R, G85R and G93A SOD1 mutations, and in a human individual with an A4V SOD1 mutation. Despite ubiquitous expression, misfolded SOD1 was found primarily within degenerating motor neurons. Misfolded SOD1 appeared before the onset of symptoms and decreased at the end stage of the disease, concomitant with motor neuron loss.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons leading to paralysis. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are the ...second most common cause of familial ALS, and considerable evidence suggests that these mutations result in an increase in toxicity due to protein misfolding. We previously demonstrated in the SOD1G93A rat model that misfolded SOD1 exists as distinct conformers and forms deposits on mitochondrial subpopulations. Here, using SOD1G93A rats and conformation-restricted antibodies specific for misfolded SOD1 (B8H10 and AMF7-63), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding proteins that uniquely interacted with either AMF7-63 or B8H10-reactive SOD1 conformers as well as a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor–associated factor 6 (TRAF6) as a SOD1 interactor, and we determined that exposure of the SOD1 functional loops facilitates this interaction. Of note, this conformational change was not universally fulfilled by all SOD1 variants and differentiated TRAF6 interacting from TRAF6 noninteracting SOD1 variants. Functionally, TRAF6 stimulated polyubiquitination and aggregation of the interacting SOD1 variants. TRAF6 E3 ubiquitin ligase activity was required for the former but was dispensable for the latter, indicating that TRAF6-mediated polyubiquitination and aggregation of the SOD1 variants are independent events. We propose that the interaction between misfolded SOD1 and TRAF6 may be relevant to the etiology of ALS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical ...trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future.
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•High circulating leptin and high BMI correlate with VEGFRi benefit in mCRC•Tumors with greater response have a glycolytic/hypoxic/angiogenic phenotype•Glycolytic/hypoxic/angiogenic phenotype influences preclinical VEGFRi sensitivity•Leptin exposure induces a metabolic/angiogenic phenotype in cancer
Response to VEGF signaling inhibitors is poorly understood. Pommier et al. revealed circulating leptin, BMI, and a tumor glycolytic/angiogenic/hypoxia profile associated with clinical response to VEGFR inhibition. Tumor cell metabolic profile also influenced sensitivity in pre-clinical models. The findings suggest that patient physiology and tumor cell phenotype may influence response to VEGFRi.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in ...the contexts of diabetes and smoking status.
We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status.
We identified 5 genome-wide significant (
≤5×10
) associations with PAD in 449 548 (N
=12 086) individuals of European ancestry near
) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the
) locus was associated with PAD (odds ratio 95% CI, 1.51 1.32-1.74,
=2.5×10
,
=5.3×10
). Furthermore, in smokers, rs12910984 at the
locus was associated with PAD (odds ratio 95% CI, 1.15 1.11-1.19,
=9.3×10
,
=3.9×10
).
Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) ...extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are ...mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.
Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) ...is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies.
We identified 235 independent single nucleotide polymorphisms (SNPs) associated at
<5×10
with estimated heel bone mineral density (eBMD) in 116,501 individuals from the UK Biobank study, accounting for 13.9% of eBMD variance. For each eBMD-associated SNP, we extracted effect estimates from the largest available GWAS studies for T2D (DIAGRAM: n=26,676 T2D cases and 132,532 controls) and CHD (CARDIoGRAMplusC4D: n=60,801 CHD cases and 123,504 controls). A two-sample design using several Mendelian randomization approaches was used to investigate the causal relevance of eBMD for risk of T2D and CHD. In addition, we explored the relationship of eBMD, instrumented by the 235 SNPs, on 12 cardiovascular and metabolic risk factors. Finally, we conducted Mendelian randomization analysis in the reverse direction to investigate reverse causality.
Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm
) was associated with an 8% higher risk of T2D (odds ratio OR 1.08; 95% confidence interval CI: 1.02 to 1.14;
=0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10;
=0.034). Consistent results were obtained in sensitivity analyses using several different Mendelian randomization approaches. Equivalent increases in eBMD were also associated with lower plasma levels of HDL-cholesterol and increased insulin resistance. Mendelian randomization in the reverse direction using 94 T2D SNPs or 52 CHD SNPs showed no evidence of reverse causality with eBMD.
These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.
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