A hierarchical mesh refinement technique for global 3-D spherical mantle convection modelling

A method for incorporating multi-resolution capabilities within pre-existing global 3-D spherical mantle convection codes is presented. The method, which we term "geometric multigrid refinement", is based upon the application of a multigrid solver on non

A hierarchical mesh refinement technique for global 3-D spherical mantle convection modelling

A method for incorporating multi-resolution capabilities within pre-existing global 3-D spherical mantle convection codes is presented. The method, which we term "geometric multigrid refinement", is based upon the application of a multigrid solver on non-uniform, structured grids and allows for the incorporation of local high-resolution grids within global models. Validation tests demonstrate that the method is accurate and robust, with highly efficient solutions to large-scale non-uniform problems obtained. Significantly, the scheme is conceptually simple and straightforward to implement, negating the need to reformulate and restructure large sections of code. Consequently, although more advanced techniques are under development at the frontiers of mesh refinement and solver technology research, the technique presented is capable of extending the lifetime and applicability of pre-existing global mantle convection codes

Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland

Despite the well-recognized role of loss-of-function mutations of the aryl hydrocarbon receptor interacting protein gene (AIP) predisposing to pituitary adenomas, the pituitary-speci c function of this tumor suppressor remains an enigma. To determine the repertoire of interacting partners for the AIP protein in somatotroph cells, wild-type and variant AIP proteins were used for pull-down/quantitative mass spectrometry experiments against lysates of rat somatotropinoma-derived cells; relevant ndings were validated by co-immunoprecipitation and co-localization. Global gene expression was studied in AIP mutation positive and negative pituitary adenomas via RNA microarrays. Direct interaction with AIP was con rmed for three known and six novel partner proteins. Novel interactions with HSPA5 and HSPA9, together with known interactions with HSP90AA1, HSP90AB1 and HSPA8, indicate that the function/ stability of multiple chaperone client proteins could be perturbed by a de cient AIP co-chaperone function. Interactions with TUBB, TUBB2A, NME1 and SOD1 were also identi ed. The AIP variants p.R304* and p.R304Q showed impaired interactions with HSPA8, HSP90AB1, NME1 and SOD1; p.R304* also displayed reduced binding to TUBB and TUBB2A, and AIP-mutated tumors showed reduced TUBB2A expression. Our ndings suggest that cytoskeletal organization, cell motility/adhesion, as well as oxidative stress responses, are functions that are likely to be involved in the tumor suppressor activity of AIP

Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes

Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR domain-containing complexes such as Cpr6-(Hsp90)2-Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR domain proteins. Dimerization also explains how other monomeric TPR-domain proteins are excluded from forming inappropriate mixed co-chaperone complexes

Rapid microwave-assisted polyol synthesis of TiO2-supported ruthenium catalysts for levulinic acid hydrogenation

One wt% Ru/TiO2 catalysts prepared by a one-pot microwave-assisted polyol method have been shown to be highly active for Levulinic acid hydrogenation to γ-Valerolactone. Preparation temperature, microwave irradiation time and choice of Ru precursor were found to have a significant effect on catalyst activity. In the case of Ru(acac)3-derived catalysts, increasing temperature and longer irradiation times increased catalyst activity to a maximum LA conversion of 69%. Conversely, for catalysts prepared using RuCl3, shorter preparation times and lower temperatures yielded more active catalysts, with a maximum LA conversion of 67%. Catalysts prepared using either precursor were found to contain highly dispersed nanoparticles <3 nm in diameter. XPS analysis of the most and least active catalysts shows that the catalyst surface is covered in a layer of insoluble carbon with surface concentrations exceeding 40% in some cases. This can be attributed to the formation of large condensation oligomers from the reaction between the solvent, ethylene glycol and its oxidation products, as evidenced by the presence of C-O and C = O functionality on the catalyst surfac

Investigations into the applicability of adaptive finite element methods to two-dimensional infinite Prandtl number thermal and thermochemical convection

An adaptive finite element procedure is presented for improving the quality of solutions to convection-dominated problems in geodynamics. The method adapts the mesh automatically around regions of high solution gradient, yielding enhanced resolution of the associated flow features. The approach requires the coupling of an automatic mesh generator, a finite element flow solver, and an error estimator. In this study, the procedure is implemented in conjunction with the well-known geodynamical finite element code ConMan. An unstructured quadrilateral mesh generator is utilized, with mesh adaptation accomplished through regeneration. This regeneration employs information provided by an interpolation-based local error estimator, obtained from the computed solution on an existing mesh. The technique is validated by solving thermal and thermochemical problems with well-established benchmark solutions. In a purely thermal context, results illustrate that the method is highly successful, improving solution accuracy while increasing computational efficiency. For thermochemical simulations the same conclusions can be drawn. However, results also demonstrate that the grid-based methods employed for simulating the compositional field are not competitive with the other methods (tracer particle and marker chain) currently employed in this field, even at the higher spatial resolutions allowed by the adaptive grid strategies

Rapid proteasomal degradation of mutant proteins is the primary mechanism leading to tumorigenesis in patients with missense AIP mutations

CONTEXT The pathogenic effect of AIP mutations (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts. OBJECTIVE To analyze the mechanism/speed of protein turnover of wild-type (WT) and missense AIP variants, correlating protein half-life with clinical parameters. DESIGN Half-life and protein-protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed. SETTING Clinical academic research institution. PATIENTS Data was obtained from our cohort of pituitary adenoma patients and literature-reported cases. INTERVENTIONS Protein turnover of endogenous AIP in two cell lines and fifteen AIP variants overexpressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. GST pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by co-immunoprecipitation and gene knockdown. Relevant clinical data was collected. MAIN OUTCOME MEASURES Half-life of WT and mutant AIP proteins and its correlation with clinical parameters. RESULTS Endogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7h). AIP variants were divided in stable proteins (median 77.7h [IQR 60.7-92.9]), and those with short (27h [21.6-28.7]) or very short (7.7h [5.6-10.5]) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r=0.411, P=0.002). The FBXO3-containing SCF complex was identified as the E3 ubiquitin-ligase recognizing AIP. CONCLUSIONS AIP is a stable protein, driven to ubiquitination by the SCF complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype

GenoChemetic strategy for derivatization of the violacein natural product scaffold

H.E.L. was supported by an Imperial College President’s Ph.D. Scholarship. We thank UKRI EPSRC (EP/K038648/1, EP/L011573/1 to P.S.F.) and the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC grant agreement no. 614779 GenoChemetics to R.J.M.G.) for funding. A.M.C.O. receives funding from EPSRC CRITICAT, EP/L016419/1.Natural products and their analogues are often challenging to synthesize due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds, which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, six halogenated analogues of violacein or deoxyviolacein were generated, demonstrating the promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via the Suzuki–Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein we demonstrate a flexible and rapid approach to access a diverse chemical space that can be applied to a wide range of natural product scaffolds.Publisher PDFPeer reviewe

Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition

PMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Health impact, and economic value, of meeting housing quality standards: a retrospective longitudinal data linkage study

Background Poor-quality housing adversely affects residents’ health but there is a paucity of high-quality evidence to support this. Objective This research investigated the health impact of bringing housing to a national quality standard. Design A natural experiment of improvements to housing quality analysed using repeated measures of health-care utilisation and economic outcomes at an individual person level. Setting Carmarthenshire, UK. Participants A total of 32,009 residents registered for a minimum of 60 days at 8558 social homes that received housing improvements between January 2005 and March 2015. Interventions Multiple internal and external housing improvements, including wall and loft insulation, windows and doors, heating system upgrades, new kitchens and bathrooms, garden path safety improvements and electrical system upgrades (adding power sockets, and extractor fans in kitchens and bathrooms). Main outcome measures Emergency hospital admissions for cardiorespiratory conditions and injuries. Primary health-care utilisation for respiratory and common mental health disorders, emergency department injury attendances and health-care utilisation costs. Data sources Carmarthenshire County Council home address and intervention records were anonymously linked within the Secure Anonymous Information Linkage databank to demographic information from the Welsh Demographic Service data set; hospital admission data from the Patient Episode Dataset for Wales; primary care contacts and prescribed medications from general practice data; emergency department attendances from the Emergency Department Data Set; and deaths from the Office for National Statistics mortality register. Methods The study used a longitudinal panel design to examine changes in standard of eight housing cointervention from intervention records, and linked to individuals registered at intervention homes. Health outcomes were obtained retrospectively for each individual in a dynamic cohort and were captured for up to 123 consecutive months. An additional local authority region could not be utilised as a comparator owing to different reporting pressures resulting in the recording of a different intervention. The exposure group for each cointervention was compared with an internal reference group of people living in homes that did not receive the cointervention during their tenancy. A multilevel modelling approach was used to account for repeated observations for individuals living in intervention homes. Counts of health outcomes were analysed using negative binomial regression models to determine the effect of each cointervention that reached housing quality standards during an individual’s period of tenancy, compared with those living in properties that did not. We adjusted for potential confounding factors and for background trends in the regional general population. A cost–consequences analysis was conducted as part of the health economic evaluation. Results Residents aged ≥ 60 years living in homes in which electrical systems were upgraded were associated with 39% fewer admissions than those living in homes in which they were not [incidence rate ratio (IRR) 0.61, 95% confidence interval (CI) 0.53 to 0.72; p < 0.01]. Reduced admissions were also associated with windows and doors (IRR 0.71, 95% CI 0.63 to 0.81; p < 0.01), wall insulation (IRR 0.75, 95% CI 0.67 to 0.84; p < 0.01) and gardens and estates (IRR 0.73, 95% CI 0.64 to 0.83; p < 0.01) for those living in homes in which these cointervention were upgraded. There were no associations of change in emergency admissions with upgrading heating (IRR 0.91, 95% CI 0.82 to 1.01; p = 0.072), loft insulation (IRR 0.98, 95% CI 0.86 to 1.11; p = 0.695), kitchens (IRR 0.98, 95% CI 0.83 to 1.17; p = 0.843) or bathrooms (IRR 0.93, 95% CI 0.81 to 1.06; p = 0.287). Limitations There was no randomisation, there were incomplete data on the scale of the intervention for individual households and there were no estimates for the impact of the whole programme. Conclusions This complex interdisciplinary study found that hospital admissions could be avoided through improving housing quality standards