Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

Oxidative flavour deterioration of fish oil enriched milk

The oxidative deterioration of milk emulsions supplemented with 1.5 wt‐% fish oil was investigated by sensory evaluation and by determining the peroxide value and volatile oxidation products after cold storage. Two types of milk emulsions were produced, one with a highly unsaturated tuna oil (38 wt‐% of n‐3 fatty acids) and one with cod liver oil (26 wt‐% of n‐3 fatty acids). The effect of added calcium disodium ethylenediaminetetraacetate (EDTA) on oxidation was also investigated. Emulsions based on cod liver oil with a slightly elevated peroxide value (1.5 meq/kg) oxidised significantly faster than the tuna oil emulsions, having a lower initial peroxide value (0.1 meq/kg). In the tuna oil emulsions the fishy off‐flavour could not be detected throughout the storage period. Addition of 5—50 ppm EDTA significantly reduced the development of volatile oxidation products in the cod liver oil emulsions, indicating that metal chelation with EDTA could inhibit the decomposition of lipid hydroperoxides in these emulsions. This study showed that an oxidatively stable milk emulsion containing highly polyunsaturated tuna fish oil could be prepared without significant fishy off‐flavour development upon storage, provided that the initial peroxide value was sufficiently low.     

Gaming Prediction Markets: Equilibrium Strategies with a Market Maker

We study the equilibrium behavior of informed traders interacting with market scoring rule (MSR) market makers. One attractive feature of MSR is that it is myopically incentive compatible: it is optimal for traders to report their true beliefs about the likelihood of an event outcome provided that they ignore the impact of their reports on the profit they might garner from future trades. In this paper, we analyze non-myopic strategies and examine what information structures lead to truthful betting by traders. Specifically, we analyze the behavior of risk-neutral traders with incomplete information playing in a dynamic game. We consider finite-stage and infinite-stage game models. For each model, we study the logarithmic market scoring rule (LMSR) with two different information structures: conditionally independent signals and (unconditionally) independent signals. In the finite-stage model, when signals of traders are independent conditional on the state of the world, truthful betting is a Perfect Bayesian Equilibrium (PBE). Moreover, it is the unique Weak Perfect Bayesian Equilibrium (WPBE) of the game. In contrast, when signals of traders are unconditionally independent, truthful betting is not a WPBE. In the infinite-stage model with unconditionally independent signals, there does not exist an equilibrium in which all information is revealed in a finite amount of time. We propose a simple discounted market scoring rule that reduces the opportunity for bluffing strategies. We show that in any WPBE for the infinite-stage market with discounting, the market price converges to the fully-revealing price, and the rate of convergence can be bounded in terms of the discounting parameter. When signals are conditionally independent, truthful betting is the unique WPBE for the infinite-stage market with and without discounting.     

Parameter inference in a computational model of haemodynamics in pulmonary hypertension

Pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg, is characterized by increased pulmonary vascular resistance and decreased pulmonary arterial compliance. There are few measurable biomarkers of PH progression, but a conclusive diagnosis of the disease requires invasive right heart catheterization (RHC). Patient-specific cardiovascular systems-level computational models provide a potential non-invasive tool for determining additional indicators of disease severity. Using computational modelling, this study quantifies physiological parameters indicative of disease severity in nine PH patients. The model includes all four heart chambers, the pulmonary and systemic circulations. We consider two sets of calibration data: static (systolic and diastolic values) RHC data and a combination of static and continuous, time-series waveform data. We determine a subset of identifiable parameters for model calibration using sensitivity analyses and multi-start inference and perform posterior uncertainty quantification. Results show that additional waveform data enables accurate calibration of the right atrial reservoir and pump function across the PH cohort. Model outcomes, including stroke work and pulmonary resistance-compliance relations, reflect typical right heart dynamics in PH phenotypes. Lastly, we show that estimated parameters agree with previous, non-modelling studies, supporting this type of analysis in translational PH research.     

Shot-noise limited,supercontinuum-based optical coherence tomography

We present the first demonstration of shot-noise limited supercontinuum-based spectral domain optical coherence tomography (SD-OCT) with an axial resolution of ...     

Flow induced particle migration in fresh concrete: Theoretical frame,numerical simulations and experimental results on model fluids

In this paper, we describe and compare the various physical phenomena which potentially lead to flow induced particle migration in concrete. We show that, in the case of industrial casting of concrete, gravity induced particle migration dominates all other potential sources of heterogeneities induced by flow. We then show, from comparisons between experiments using model materials, dimensional analysis and numerical simulations, that, from a quantitative point of view, the viscous drag force, which prevents particles from migrating during a casting process, shall neither be computed from the apparent viscosity nor from the plastic viscosity of the suspending phase but from its tangential viscosity. Finally, the transfer of this type of numerical prediction tool to real concrete is discussed.     

Active packaging of cheese with allyl isothiocyanate, an alternative to modified atmosphere packaging

The natural antimicrobial compound allyl isothiocyanate (AITC), found in mustard oil, is effective against cheese-related fungi both on laboratory media and cheese. Penicillium commune, Penicillium roqueforti, and Aspergillus flavus were more sensitive to AITC when it was added just after the spores had completed 100% germination and branching had started on Czapek yeast extract agar than were spores in the dormant phase. The use of 1 AITC label (Wasaouro interior labels, LD30D, 20 by 20 mm) in combination with atmospheric air in the packaging extended the shelf life of Danish Danbo cheese from 4 1/2 to 13 weeks. Two AITC labels extended the shelf life from 4 1/2 to 28 weeks. Both 1 and 2 labels in combination with modified atmosphere packaging extended the shelf life of the cheese from 18 to 28 weeks. This study showed that AITC was absorbed in the cheese, but it was not possible to detect any volatile breakdown products from AITC in the cheese. Cheese stored for up to 12 weeks with an AITC label had an unacceptable mustard flavor. The mustard flavor decreased to an acceptable level between weeks 12 and 28. Cheese stored in atmospheric air had a fresher taste without a CO2 off-flavor than did cheese stored in modified atmosphere packaging. AITC may be a good alternative to modified atmosphere packaging for cheese. The extended shelf life of cheese in the package is very desirable: the cheese can be transported longer distances, and the packaging can be used for the final maturing of the cheese. Furthermore, AITC can address problems such as pinholes and leaking seals in cheese packaging.     

A longitudinal observational study of the dynamics of Mycoplasma bovis antibodies in naturally exposed and diseased dairy cows

Mycoplasma bovis is an important pathogen causing disease and substantial economic losses in cattle. However, knowledge of the dynamics of antibody responses in individual cows in the face of an outbreak is currently extremely limited. The use of commercial antibody tests to support clinical decision-making and for surveillance purposes is therefore challenging. Our objective was to describe the dynamics of M. bovis antibody responses in 4 Danish dairy herds experiencing an acute outbreak of M. bovis-associated disease, and to compare the antibody dynamics between dairy cows with different disease manifestations. A total of 120 cows were examined using a standardized clinical protocol and categorized into 4 disease groups: “mastitis,” “systemic,” “nonspecific,” and “none.” Paired blood and milk samples were collected and tested using a commercial M. bovis antibody–detecting ELISA. Plots of raw data and generalized additive mixed models with cow and herd as random effects were used to describe serum and milk antibody dynamics relative to the estimated time of onset of clinical disease. Cows with mastitis had high optical density measurement (ODC%) of antibodies in both milk and serum at disease onset. The estimated mean ODC% in milk was below the manufacturer's cut-off for the other groups for the entire study period. The estimated mean serum ODC% in the “systemic” group was high at onset of disease and stayed above the cut-off until 65 d after disease onset. However, the lower 95% confidence interval (CI) for the mean ODC% was only above the manufacturer's cut-off between 7 and 17 d after onset of disease. The CI of the “systemic” and “none” groups did not overlap at any time between the day of disease onset and 65 d after disease onset, and the estimated mean ODC% for both the “nonspecific” and “none” groups were generally below the cut-off for the majority of the study period. In conclusion, the serum antibody responses were highly dynamic and showed a high level of variation between individual cows. This strongly suggests that serology is unlikely to be useful for individual diagnosis of M. bovis-associated disease in dairy cows. However, it might still be useful for herd- or group-level diagnosis. Antibodies in milk were only increased in cows with M. bovis mastitis, indicating that milk antibody measurements only have diagnostic utility for cows with mastitis.