Parental origin of sequence variants associated with complex diseases

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldEffects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.info:eu-repo/grantAgreement/EC/FP7/21807

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Size Doesn't Matter: Towards a More Inclusive Philosophy of Biology

notes: As the primary author, O’Malley drafted the paper, and gathered and analysed data (scientific papers and talks). Conceptual analysis was conducted by both authors.publication-status: Publishedtypes: ArticlePhilosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Effect of Transition Metal Substitution on the Flexibility and Thermal Properties of MOF-Based Solid-Solid Phase Change Materials

A series of azobenzene-loaded metal-organic frameworks were synthesized with the general formula M2(BDC)2(DABCO)(AB)x (M = Zn, Co, Ni, and Cu; BDC = 1,4-benzenedicarboxylate; DABCO = 1,4-diazabicyclo[2.2.2]octane; and AB = azobenzene), herein named M-1ABx. Upon occlusion of AB, each framework undergoes guest-induced breathing, whereby the pores contract around the AB molecules forming a narrow-pore (np) framework. The loading level of the framework is found to be very sensitive to the synthetic protocol and although the stable loading level is close to M-1AB1.0, higher loading levels can be achieved for the Zn, Co, and Ni frameworks prior to vacuum treatment, with a maximum composition for the Zn framework of Zn-1AB1.3. The degree of pore contraction upon loading is modulated by the inherent flexibility of the metal-carboxylate paddlewheel unit in the framework, with the Zn-1AB1.0 showing the biggest contraction of 6.2% and the more rigid Cu-1AB1.0 contracting by only 1.7%. Upon heating, each composite shows a temperature-induced phase transition to an open-pore (op) framework, and the enthalpy and onset temperatures of the phase transition are affected by the framework flexibility. For all composites, UV irradiation causes trans → cis isomerization of the occluded AB molecules. The population of cis-AB at the photostationary state and the thermal stability of the occluded cis-AB molecules are also found to correlate with the flexibility of the framework. Over a full heating-cooling cycle between 0 and 200 °C, the energy stored within the metastable cis-AB molecules is released as heat, with a maximum energy density of 28.9 J g-1 for Zn-1AB1.0. These findings suggest that controlled confinement of photoswitches within flexible frameworks is a potential strategy for the development of solid-solid phase change materials for energy storage

Solid-state nuclear magnetic resonance study of polymorphism in tris(8-hydroxyquinolinate)aluminium

Tris(8-hydroxyquinolinate)aluminium (Alq3) is a metal–organic coordination complex, which is a widely used electroluminescent material in organic light-emitting diode technology. Crystalline Alq3 is known to occur in five polymorphic forms (denoted α, β, γ, δ, and ε), although the structures of some of these polymorphs have been the subject of considerable debate. In particular, the structure of α-Alq3, which is a model for the local structure in amorphous films used in devices, is highly complex and has never been conclusively solved. In this work, we use solid-state nuclear magnetic resonance (NMR) and density functional theory (DFT) calculations to investigate the local structure of four Alq3 samples. We find that the first structure proposed for α-Alq3 is inconsistent with all of the samples studied, and DFT calculations further suggest that this structure is energetically unfavourable. Instead, samples containing the meridional (mer) isomeric form are found to contain local structures consistent with ε-Alq3, and a sample containing the facial (fac) isomeric form is consistent with a mixture of γ-Alq3 and δ-Alq3. We also investigate the influence of different strategies for dispersion correction in DFT geometry optimisations. We find that a recently proposed modified semiempirical dispersion correction scheme gives good agreement with experiment. Furthermore, the DFT calculations also show that distinction between mer and fac isomers on the basis of ηQ that has been assumed in previous work is not always justified. © 2021 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd

Mathematical Modeling of Cathodic Protection Using the Boundary Element Method with a Nonlinear Polarization Curve

The distributions of potential and current density around a cathodically protected pipeline in seawater were determined using the boundary element technique. A nonlinear polarization curve for a low carbon steel in artificial sea water was obtained from dc-potentiodynamic measurements and was fitted for use as the boundary condition on the pipe. The program was used to evaluate cases in which one or two aluminum sacrificial anodes are used to protect a low carbon steel pipe in seawater. The results show that the number of anodes, the sizes of the anodes, and the distance between the anodes and the cathode are of importance for cathodic protection. © 1991, The Electrochemical Society, Inc. All rights reserved

Generalized collisional radiative model for light elements. Part B : data for the Be isonuclear sequence

A first-stage collision database is assembled which contains electron-impact excitation, ionization, and recombination rate coefficients for Be, Be+, Be2+, and Be3+. The first-stage database is constructed using the R-matrix with pseudo-states, time-dependent close-coupling, and perturbative, distorted-wave methods. A second-stage collision database is then assembled which contains generalized collisional-radiative and radiated power loss coefficients. The second-stage database is constructed by solution of collisional-radiative equations in the quasi-static equilibrium approximation using the first-stage database. Both collision database stages reside in electronic form at the ORNL Controlled Fusion Atomic Data Center and in the ADAS database, and are easily accessed over the worldwide internet

A structural investigation of organic battery anode materials by NMR crystallography

Conjugated alkali metal dicarboxylates have recently received attention for applications as organic anode materials in lithium- and sodium-ion batteries. In order to understand and optimise these materials, it is important to be able to characterise both the long-range and local aspects of the crystal structure, which may change during battery cycling. Furthermore, some materials can display polymorphism or hydration behaviour. NMR crystallography, which combines long-range crystallographic information from diffraction with local information from solid-state NMR via interpretation aided by DFT calculations, is one such approach, but this has not yet been widely applied to conjugated dicarboxylates. In this work, we evaluate the application of NMR crystallography for a set of model lithium and sodium dicarboxylate salts. We investigate the effect of different DFT geometry optimisation strategies and find that the calculated NMR parameters are not systematically affected by the choice of optimisation method, although the inclusion of dispersion correction schemes is important to accurately reproduce the experimental unit cell parameters. We also observe hydration behaviour for two of the sodium salts and provide insight into the structure of an as-yet uncharacterised structure of sodium naphthalenedicarboxylate. This highlights the importance of sample preparation and characterisation for organic sodium-ion battery anode materials in particular