Bi-directional Mendelian randomization analysis provides evidence for the causal involvement of dysregulation of CXCL9, CCL11 and CASP8 in the pathogenesis of ulcerative colitis

Background and Aims Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. Methods We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk. Results Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 x 10(-10)]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 x 10(-19)] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. Conclusion Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC

Solid contact ion selective electrodes: from potentiometric application to voltammetric investigation

The solid contact ion selective electrodes are different from the liquid contact ion selective electrodes by replacing the inner filling solution with solid-state ion-to-electron transducers. In this thesis, two different types of ion-to-electron transducers are introduced. The first is the multi-walled carbon nanotubes modified with alkyl group for fabrication of solid contact electrodes for on-line and in-situ potentiometric detection of environmental anions (e.g., chloride, carbonate, nitrate). The second utilizes the electropolymerized poly (3-octylthiophene) for voltammetric study of ion transfer process between membrane and solution interface. By proper experimental design, the voltammetry experiment could be a useful technique for probing the ion-ionophore interactions inside the membrane. In addition to the research of solid contact ion selective electrodes, robust boundary element calculations in the computer simulations of ion exchange process for ion selective membrane are also described

Overcoming Pitfalls in Boundary Elements Calculations with Computer Simulations of Ion Selective Membrane Electrodes

Finite difference analysis of ion-selective membranes is a valuable tool for understanding a range of time dependent phenomena such as response times, long and medium term potential drifts, determination of selectivity, and (re)­conditioning kinetics. It is here shown that an established approach based on the diffusion layer model applied to an ion-exchange membrane fails to use mass transport to account for concentration changes at the membrane side of the phase boundary. Instead, such concentrations are imposed by the ion-exchange equilibrium condition, without taking into account the source of these ions. The limitation is illustrated with a super-Nernstian potential jump, where a membrane initially void of analyte ion is exposed to incremental concentrations of analyte in the sample. To overcome this limitation, the two boundary elements, one at either side of the sample–membrane interface, are treated here as a combined entity and its total concentration change is dictated by diffusional fluxes into and out of the interface. For each time step, the concentration distribution between the two boundary elements is then computed by ion-exchange theory. The resulting finite difference simulation is much more robust than the earlier model and gives a good correlation to experiments

Separating boundary potential changes at thin solid contact ion transfer voltammetric membrane electrodes

Thin ion-selective membrane films deposited on solid electrode substrate are useful tools to study ion transfer processes. This is because the experimental conditions may be chosen such that diffusion processes within the membrane and contacting aqueous solution are not rate limiting. In an ideal case, therefore, equilibrium considerations may be used to describe the resulting ion transfer voltammograms. For example, the electrochemical oxidation of an electrically neutral redox molecule in the membrane results in a cationic oxidized form. To preserve electroneutrality, a cation is transferred out of the membrane into solution, freeing the cation-exchanger of the membrane to become the counterion of the oxidized redox molecule. This work describes a model system that agrees well with thermodynamic theory, using the lipophilic (1-dodecyl-1H-1,2,3-triazol-4-yl)ferrocene as redox molecule and a monovalent reference cation for ion transfer. The full peak width at half maximum was found as 0.110 V, in agreement with theory, and with peak current proportional to scan rate supporting thin layer behavior. The charge passed during the voltammetric scan was related to ion-exchanger concentration available for ion extraction as a function of potential. Subtraction of the ion transfer potential using the reference ion from the experimental one for each charge increment gave the potential change for the electrochemical ion-to-electron transducer. In one application, the potential change of the polymeric transducing layer poly(3-octylthiophene) (POT) film upon electrochemical oxidation within the membrane was characterized. A non-linear potential–charge curve was observed, in contrast to earlier assumptions

Influence of grain discharge rate on the normal force of arch

The arch stress of grain particles during the discharge of the silo is very important to the safety of the silo. At present, most silos adopt the standard discharge port size. To improve the discharge efficiency, it is generally achieved by changing the angle of the discharge port. In this article, an improved silo model is used to study the discharge experiments in the silo with five inclination angles of the discharge port, and analyze the normal force distribution of the wheat grains at the arch, comparing the normal force distribution under five different discharge rates. From the results given, when the angle of the discharge port is 45°, the area where the normal force among particles is larger is wider. At other flow rates, increasing the flow rate can shorten the arching period. During the arching cycle, the normal force among particles in the center area of the silo at the same height is smaller than at the silo wall and is negatively correlated with the discharge rate. In addition, the normal force on the silo wall gradually decreases with the increase in the discharge rate

Paper-supported thin-layer ion transfer voltammetry for ion detection

We report here on paper-supported thin sample layer voltammetry for the determination of ions. To achieve this goal, a simple setup for the coupling of a commercially available electrode to a silver rod electrode was designed and evaluated for paper-supported thin-layer voltammetry. Linear scan ion transfer voltammetry was explored here for ion-selective membranes doped with an ionophore. The ion-transfer processes and electrochemical behaviors of the system are here evaluated and confirmed by numerical simulation. In the proof-of-concept experiments described, the ions tetrabutylammonium chloride (TBA+) and potassium (K+) were studied as model analytes at membranes without and with ionophore, respectively. A linear relationship from 0.1mM to 1.0mM K+ was obtained between the charge and ion concentration. The coexistence of background sodium ions did not give appreciable interference, but the background wave was not completely isolated from the analyte wave, as also confirmed by the model. The methodology was successfully demonstrated for determination of K+ in mineral water. It is anticipated that this paper-supported thin-layer detection approach may provide an attractive readout protocol for disposable paper-based analytical devices as the methodology does not place strict demands on reference electrode performance

Voltammetric thin-layer ionophore-based films : Part 1. Experimental evidence and numerical simulations

Voltammetric thin layer (~200 nm) ionophore-based polymeric films have recently emerged as a promising approach to acquire multi-ion information about the sample, in analogy to performing multiple potentiometric measurements with individual membranes. They behave under two different regimes that depend on the ion concentration. A thin layer control (no mass transport limitation of the polymer film or solution) is identified for ion concentrations higher than 10 µM in which case the peak potential serves as the readout signal in analogy to a potentiometric sensor. On the other hand, ion transfer at lower concentrations is chiefly controlled by diffusional mass transport from the solution to the sensing film, resulting in an increase of peak current with ion concentration. This concentration range is suitable for electrochemical ion transfer stripping analysis. The transition between the two mentioned scenarios is here explored experimentally using a silver selective membrane as a highly selective proof-of-concept under different conditions (variation of ion concentration in the sample from 0.1 µM to 1 mM, scan rate from 25 to 200 mV s-1, and angular frequency from 100 to 6400 rpm). Apart from experimental evidence, a numerical simulation is developed that considers an idealized conducting polymer behavior and permits one to predict experimental behavior under diffusion or thin layer control

Voltammetric thin-layer ionophore-based films : Part 2. Semi-empirical treatment

This work reports on a semiempirical treatment that allows one to rationalize and predict experimental conditions for thin-layer ionophore-based films with cationexchange capacity read out with cyclic voltammetry. The transition between diffusional mass transport and thin-layer regime is described with a parameter (α), which depends on membrane composition, diffusion coefficient, scan rate, and electrode rotating speed. Once the thin-layer regime is fulfilled (α = 1), the membrane behaves in some analogy to a potentiometric sensor with a second discrimination variable (the applied potential) that allows one to operate such electrodes in a multianalyte detection mode owing to the variable applied ion-transfer potentials. The limit of detection of this regime is defined with a second parameter (β = 2) and is chosen in analogy to the definition of the detection limit for potentiometric sensors provided by the IUPAC. The analytical equations were validated through the simulation of the respective cyclic voltammograms under the same experimental conditions. While simulations of high complexity and better accuracy satisfactorily reproduced the experimental voltammograms during the forward and backward potential sweeps (companion paper 1), the semiempirical treatment here, while less accurate, is of low complexity and allows one to quite easily predict relevant experimental conditions for this emergent methodology