Discovery of novel inhibitors to investigate diacylglycerol lipases and α/β hydrolase domain 16A

  This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several structure- and ligand-based drug discovery methodologies were employed, such as in silico screening and high throughput screening, in combination with activity-based protein profiling (ABPP). The glycine sulfonamides reported in this Thesis, such as LEI106, are important peripherally restricted inhibitors that can be used to evaluate the contribution of perturbing DAGL activity in the potential treatment of metabolic syndrome, diabetes and pheriphiral obesity. The α-keto heterocycles in this Thesis, such as LEI107, could be important inhibitors to evaluate if a therapeutic window can be established for (central) DAGL inhibitors in the potential treatment of addiction, obesity and neuroinflammation. Lastly, 1,2,4-triazole urea sulfonamides that are reported in this Thesis can be used as novel tool compounds to evaluate DAGL and ABHD16A function in both health and disease.  Molecular Physiolog

Сократівсько-платонівські версії мужності як спроба знайдення засобу синхронізації індивідуальної та колективної суверенності

У статті аналізується соціально-політична цінність мужності в її сократівсько-платонівській версії, що забезпечує синхронізацію індивідуальної та колективної суверенності та є ключовою чеснотою ефективного існування публічного простору.В статье анализируется социально-политическая ценность мужества в ее сократовско-платоновской версии, которая обеспечивает синхронизацию индивидуальной и коллективной суверенности и является ключевой добродетелью существования публичного пространства.In the article the socio-political value of courage is analysed in its sokrat-plato version which provides synchronization of individual and collective sovereignty and is the key virtue of existence of public space

Random Resistor-Diode Networks and the Crossover from Isotropic to Directed Percolation

By employing the methods of renormalized field theory we show that the percolation behavior of random resistor-diode networks near the multicritical line belongs to the universality class of isotropic percolation. We construct a mesoscopic model from the general epidemic process by including a relevant isotropy-breaking perturbation. We present a two-loop calculation of the crossover exponent $\phi$. Upon blending the $\epsilon$-expansion result with the exact value $\phi =1$ for one dimension by a rational approximation, we obtain for two dimensions $\phi = 1.29\pm 0.05$. This value is in agreement with the recent simulations of a two-dimensional random diode network by Inui, Kakuno, Tretyakov, Komatsu, and Kameoka, who found an order parameter exponent $\beta$ different from those of isotropic and directed percolation. Furthermore, we reconsider the theory of the full crossover from isotropic to directed percolation by Frey, T\"{a}uber, and Schwabl and clear up some minor shortcomings.Comment: 24 pages, 2 figure

Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders

2-Arachidonoylglycerol (2-AG) is an endocannabinoid that activates the cannabinoid receptors type 1 and 2. It also serves as an important lipid precursor for the eicosanoid signaling pathway. Consequently, 2-AG is involved in many physiological functions, including anxiety, food intake, inflammation, memory, pain sensation and neurotransmission. Diacylglycerol lipases (DAGLs) are the main biosynthetic enzymes for 2-AG and their role in several pathophysiological conditions is currently under investigation. In this Digest we review all DAGL inhibitors reported to date and their effects in preclinical models of neurodegeneration and metabolic disorders.Molecular Physiolog

Scaling Analysis of Fluctuating Strength Function

We propose a new method to analyze fluctuations in the strength function phenomena in highly excited nuclei. Extending the method of multifractal analysis to the cases where the strength fluctuations do not obey power scaling laws, we introduce a new measure of fluctuation, called the local scaling dimension, which characterizes scaling behavior of the strength fluctuation as a function of energy bin width subdividing the strength function. We discuss properties of the new measure by applying it to a model system which simulates the doorway damping mechanism of giant resonances. It is found that the local scaling dimension characterizes well fluctuations and their energy scales of fine structures in the strength function associated with the damped collective motions.Comment: 22 pages with 9 figures; submitted to Phys. Rev.

A high tumour-stroma ratio (TSR) in colon tumours and its metastatic lymph nodes predicts poor cancer-free survival and chemo resistance

Purpose Despite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance. Methods Two independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 mu m haematoxylin and eosin (H&E) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low ( 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan-Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I-II, TNM-stage III and patients with an indication for chemotherapy separately. Results We found that high TSR was associated with poor cancer-free survival in TNM-stage I-II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II-III colon tumour. Conclusion In colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance