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.     

Partitioning of predominant lipophilic bioactives (squalene, α-tocopherol and β-sitosterol) during olive oil processing

The partitioning of predominant lipophilic olive bioactives (squalene, β-sitosterol and α-tocopherol) in olive oil processing was studied for the first time using common integrated olive milling plant. 7% of the oil and 5% of the squalene present in the olives was lost in the last pomace. β-sitosterol and α-tocopherol, which are mainly concentrated in the seed of the olive fruit, was recovered in virgin olive oil to a lesser extent (66%, 67%) while 10% were lost in last pomace. Thus, the loss of β-sitosterol and α-tocopherol was higher than that of squalene and oil, due to nonrecovered bound forms. 19% of the α-tocopherol and 21% of the β-sitosterol loss was unaccounted for, which can be attributed to degradation of α-tocopherol and incomplete recovery of sterols from the olive and pomace matrices. This study provides a basis for process development studies.     

Quality Control for Scalable Media Processing Applications

Many media processing applications create a load that varies significantly over time. Hence, if such an application is assigned a lower processing-time budget than needed in its worst-case load situation, deadline misses are likely to occur. This problem can be dealt with by designing media processing applications in a scalable fashion. A scalable media processing application can run in multiple qualities, leading to correspondingly different resource demands. The problem we consider is to find an accompanying quality control strategy, which minimizes both the number of deadline misses and the number of quality changes, while maximizing the quality of processing. We present an initial approach to the above problem by modeling it as a Markov decision process (MDP). Our model is based on measuring relative progress at milestones. Solving the MDP results in a quality control strategy that can be applied during runtime with only little overhead. We evaluate our approach by means of a practical example, which concerns a scalable MPEG-2 decoder.     

Enoxaparin in the prevention of deep venous thrombosis after major surgery: multicentric study. The Italian Study Group

Four hundred forty-six patients with Tourette Syndrome (TS) and/or their parents completed a 52-item self-report survey about vocal and motor tics, and the frequency of associated co-morbid conditions of aggression, obsessions and compulsions, attentional problems, sleep disturbance, mood disturbance, anxiety, and self-mutilative behaviours which have been frequently reported in the literature on TS. Respondents also responded to an open-ended question regarding the most disabling aspects of TS. Results were analyzed within two age groups; under 18 years of age (N = 245) and 18 years of age or older (N = 177). Tics and associated conditions were the most frequently reported disabling aspect by both age groups. Subjects under age 18, however, reported significantly more frequent problems with hyperactivity, temper control, aggressive behaviours and sleepwalking than adults with TS.     

Nutritional status and delayed mortality following early exposure to measles

Community studies in Guinea-Bissau have found that exposure to measles prior to 6 months of age is associated with delayed mortality later in childhood. In an attempt to understand the underlying mechanism, we examined the role of pre-exposure nutritional status and the impact of exposure to measles on growth and subsequent mortality in these outbreaks. Though exposed children were lighter than controls, there was no association between pre-exposure weight-for-age and subsequent mortality adjusting for age. Although exposure was strongly associated with excess mortality, it did not have a negative impact on growth. Adjustment for state of nutrition did not alter the mortality ratio (MR) between 6 and 59 months of age for exposed children and controls; exposed children examined anthropometrically between 6-17 months had a MR of 3.70 compared with controls. This trend was the same for anthropometric measurements obtained at 18-59 months of age. Among the controls, there was a significant association between weight-for-age and subsequent mortality to the age of 5 years. However, for exposed children there was no association; the relation between weight-for-age and subsequent mortality was significantly different for exposed children compared with controls (tests for interaction between exposure and anthropometric measurements at 6-17 months: P = 0.05). Growth faltering as a consequence of early exposure to measles does not explain the marked excess mortality among these children. Further studies of the process underlying delayed mortality after early exposure to measles are warranted.     

Effects of magnesium sulfate and lidocaine in the treatment of ventricular arrhythmias in experimental amitriptyline poisoning in the rat

OBJECTIVES: Amitriptyline poisoning is associated with ventricular arrhythmias. Standard treatment is sodium bicarbonate but further intervention may be necessary. The present study compared the actions of lidocaine and magnesium sulfate on ventricular tachycardia induced by amitriptyline. DESIGN: Nonrandomized, controlled, intervention trial. SETTING: University laboratory. SUBJECTS: Thirty male Wistar rats anesthetized with pentobarbital and mechanically ventilated. INTERVENTIONS: After pretreatment with norepinephrine, the animals were subjected to a continuous infusion of amitriptyline. After the appearance of ventricular tachycardia, they were treated with magnesium sulfate (45 mg/kg + 15 mg/kg/min) or lidocaine (1 mg/kg + 0.5 mg/kg/min) or glucose infusion as a control. MEASUREMENTS AND MAIN RESULTS: In the group treated with magnesium sulfate, electrocardiogram tracings demonstrated that nine of ten animals converted from ventricular tachycardia to sinus rhythm compared with one of ten in both the lidocaine- and glucose-treated groups (p < .001). The animals treated with magnesium sulfate also had a significantly longer total time in sinus rhythm (10.0 +/- 1.6 mins) than those rats treated with lidocaine (1.7 +/- 1.5 mins) or glucose (1.5 +/- 1.5 mins). Magnesium sulfate significantly decreased blood pressure and heart rate, but no severe hemodynamic side effects were observed. CONCLUSIONS: Magnesium sulfate is effective in converting ventricular tachycardia in hyperadrenergic amitriptyline poisoning. In contrast, lidocaine had no effect on arrhythmias.     

Deconvolution of infrared spectra using various milk proteins as an example

The theory of deconvolution of infra-red spectra is presented and illustrated using milk protein spectra. The advantage of this method is impressively demonstrated and its relevance for dairy farming shown using a simple example, the cooling of milk.