Publications

Coffee's long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = -0.0007, 95% C.I. -0.009 to 0.008, P = 0.87; β = -0.001, 95% C.I. -0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (Pheterogeneity > 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.

Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.

This Account describes a strategy for fabricating multicomponent microsystems in which the structures of essentially all of the components are formed in a single step of micromolding. This strategy, which we call "cofabrication", is an alternative to multilayer microfabrication, in which multiple layers of components are sequentially aligned ("registered") and deposited on a substrate by photolithography. Cofabrication has several characteristics that make it an especially useful approach for building multicomponent microsystems. It rapidly and inexpensively generates correctly aligned components (for example, wires, heaters, magnetic field generators, optical waveguides, and microfluidic channels) over very large surface areas. By avoiding registration, the technique does not impose on substrates the size limitations of common registrations tools, such as steppers and contact aligners. We have demonstrated multicomponent microsystems with surface areas exceeding 100 cm2, but in principle, device size is only limited by the requirements of generating the original master. In addition, cofabrication can serve as a low-cost strategy for building microsystems. The technique is amenable to a variety of laboratory settings and uses fabrication tools that are less expensive than those used for multistep microfabrication. Moreover, the process requires only small amounts of solvent and photoresist, a costly chemical required for photolithography; in cofabrication, photoresist is applied and developed only once to produce a master, which is then used to produce multiple copies of molds containing the microfluidic channels. From a broad perspective, cofabrication represents a new processing paradigm in which the exterior (or shell) of the desired structures are produced before the interior (or core). This approach, generating the insulation or packaging structure first and injecting materials that provide function in channels in liquid phase, makes it possible to design and build microsystems with component materials that cannot be easily manipulated conventionally (such as solid materials with low melting points, liquid metals, liquid crystals, fused salts, foams, emulsions, gases, polymers, biomaterials, and fragile organics). Moreover, materials can be altered, removed, or replaced after the manufacturing stage. For example, cofabrication allows one to build devices in which a liquid flows through the device during use, or is replaced after use. Metal wires can be melted and reset by heating (in principle, repairing a break). This method leads to certain kinds of structures, such as integrated metallic wires with large cross-sectional areas or optical waveguides aligned in the same plane as microfluidic channels, that would be difficult or impossible to make with techniques such as sputter deposition or evaporation. This Account outlines the strategy of cofabrication and describes several applications. Specifically, we highlight cofabricated systems that combine microfluidics with (i) electrical wires for microheaters, electromagnets, and organic electrodes, (ii) fluidic optical components, such as optical waveguides, lenses, and light sources, (iii) gels for biological cell cultures, and (iv) droplets for compartmentalized chemical reactions, such as protein crystallization.

This paper reports rates of charge tunneling across self-assembled monolayers (SAMs) of compounds containing oligophenyl groups, supported on gold and silver, using Ga2O3/EGaIn as the top electrode. It compares the attenuation constant, β, and the pre-exponential parameter, J0, of the simplified Simmons equation across oligophenyl groups (R = Phn; n = 1, 2, 3) with three different anchoring groups (thiol, HSR; methanethiol, HSCH2R; and acetylene, HC≡CR) that attach R to the template-stripped gold or silver substrate. The results demonstrate that the structure of the molecular linker between the anchoring group (−S– or −C≡C−) and the oligophenyl moiety significantly influences the rate of charge transport. SAMs of SPhn and C≡CPhn on gold show similar values of β and log |J0| (β = 0.28 ± 0.03 Å–1 and log |J0| = 2.7 ± 0.1 for Au/SPhn; β = 0.30 ± 0.02 Å–1 and log |J0| = 3.0 ± 0.1 for Au/C≡CPhn). The introduction of a single intervening methylene (CH2) group between the anchoring sulfur atom and the aromatic units generates SAMs of SCH2Phn and increases β to ca. 0.66 ± 0.06 Å–1 on both gold and silver substrates. (For n-alkanethiolates on gold, the corresponding values are β = 0.76 ± 0.03 Å–1 and log |J0| = 4.2 ± 0.2). Density functional theory calculations indicate that the highest occupied molecular orbitals (HOMOs) of both SPhn and C≡CPhn extend beyond the anchoring group and onto the phenyl rings; SAMs composed of these two groups of molecules result in indistinguishable rates of charge transport. The introduction of the CH2 group, to generate SCH2Phn, disrupts the delocalization of the orbitals, localizes the HOMO on the anchoring sulfur atom, and results in the experimentally observed increase in β to a value closer to that of a SAM of n-alkylthiolate molecules.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

This paper demonstrates the use of aqueous multiphase systems (MuPSs) as media for rate-zonal centrifugation to separate nanoparticles of different shapes and sizes. The properties of MuPSs do not change with time or during centrifugation; this stability facilitates sample collection after separation. A three-phase system demonstrates the separation of the reaction products (nanorods, nanospheres, and large particles) of a synthesis of gold nanorods, and enriches the nanorods from 48 to 99% in less than ten minutes using a benchtop centrifuge.

<b>Background:</b> Mutations in the <i>SERPINA1</i> gene can lead to alpha-1 antitrypsin (AAT) deficiency and subsequently emphysema. Differential <i>SERPINA1</i> methylation was associated with COPD, FEV1/FVC and FEV1 in a family-based study of predominantly smoking adults without severe AAT deficiency. This study is the first to assess if <i>SERPINA1</i> methylation is cross-sectionally and longitudinally associated with lung function (FEV1/FVC, FEV1, FVC) in a population-based study of smokers. <b>Methods:</b> Novel SAPALDIA data from 1121 participants collected at baseline and 10 years later were analyzed. Associations of methylation beta values with lung function adjusted for potential confounders (except for smoking, neutrophils and BMI) and corrected for principal components of technical covariates were assessed in ever smokers using repeat cross-sectional and longitudinal models. In the <i>SERPINA1</i> gene region (<i>PPP4R4-SERPINA13P</i>), 108 CpGs were investigated for association. <b>Results:</b> Several differentially methylated CpGs in <i>SERPINA1</i> gene were significantly associated with lung function in cross-sectional and longitudinal models. One of the top two <i>SERPINA1</i> signals from the family-based study was replicated in SAPALDIA; yet as expected in a population-based study, with a lower significance level. Lastly, the most strongly associated CpG with change in FEV1/FVC was the smoking-related cg08257009. This result was replicated in the ECRHS cohort. While nominally significant, none of the results reached a Bonferroni-corrected significance level. <b>Conclusion:</b> SAPALDIA findings suggest that methylation in <i>SERPINA1</i> may not be a relevant predictor of lung function. Replication in the ECRHS and NFBC cohorts is ongoing.

Higher dietary intakes of major SFAs are associated with an increased risk of coronary heart disease. Owing to similar associations and high correlations among individual SFAs, dietary recommendations for the prevention of coronary heart disease should continue to focus on replacing total saturated fat with more healthy sources of energy.