Trisubstituted pyrazolopyrimidines as novel angiogenesis inhibitors.

Current inhibitors of angiogenesis comprise either therapeutic antibodies (e.g. bevacicumab binding to VEGF-A) or small molecular inhibitors of receptor tyrosin kinases like e.g. sunitinib, which inhibits PDGFR and VEGFR. We have recently identified cyclin-dependent kinase 5 (Cdk5) as novel alternative and pharmacologically accessible target in the context of angiogenesis. In the present work we demonstrate that trisubstituted pyrazolo[4,3-d]pyrimidines constitute a novel class of compounds which potently inhibit angiogenesis. All seven tested compounds inhibited endothelial cell proliferation with IC(50) values between 1 and 18 µM. Interestingly, this seems not to be due to cytotoxicity, since none of them showed acute cytotoxic effects on endothelial cells at a concentration of 10 µM,. The three most potent compounds (LGR1404, LGR1406 and LGR1407) also inhibited cell migration (by 27, 51 and 31%, resp.), chemotaxis (by 50, 70 and 60% in accumulative distance, resp.), and tube formation (by 25, 60 and 30% of total tube length, resp.) at the non-toxic concentration of 10 µM. Furthermore, angiogenesis was reduced in vivo in the CAM assay by these three compounds. A kinase selectivity profiling revealed that the compounds prevalently inhibit Cdk2, Cdk5 and Cdk9. The phenotype of the migrating cells (reduced formation of lamellipodia, loss of Rac-1 translocation to the membrane) resembles the previously described effects of silencing of Cdk5 in endothelial cells. We conclude that especially LGR1406 and LGR1407 are highly attractive anti-angiogenic compounds, whose effects seem to largely depend on their Cdk5 inhibiting properties

IN-SITU COMPRESSION TEST OF ARTIFICIAL BONE FOAMS IN CONTROLLED ENVIRONMENT USING X-RAY MICRO-COMPUTED TOMOGRAPHY

In this study, we investigated specimens of artificial bone foams, developed by the research group for surgical simulators at the UAS Linz, which are used to mimic the haptic feedback of physiologic and pathologic bone for more realistic surgery training. Specimens with two kinds of mineral filler material as well as different amounts of foaming agent were tested in an environmental in-situ loading stage developed by the ITAM CAS and scanned via X-ray micro-computed tomography. In this in-situ stage, specimens can be immersed in liquid and tested under temperature-controlled conditions. Consequently, a total amount of 12 specimens was subjected to compression loading; half of them immersed in water at 36.5◦C and half in dry condition. Results showed that there is no significant influence of liquid immersion to the compression outcome. However, foams with less amount of foaming agent appeared to have smaller pores resulting in higher compression strength

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Globalization and The United States

Hlavním tématem bakalářské práce je slábnoucí globální vliv USA a vzestup ostatních zemí. Výchozím bodem teoretické části, která předkládá různé teorie globalizace, je vymezení disproporcí světových regionů a kulturních paradigmat. K tomuto účelu jsou použité teorie komunikace, konfliktu civilizací a multikulturalismu, komparace lokálního a globálního, ale také konzumního kapitalismu. Následuje vymezení pojmu Západ a jeho silná adaptace kapitalistického systému, který se v pojetí liberálního modelu a pomocí globalizace rozšiřuje do jiných zemí. Představitelem tohoto procesu jsou USA s vymezením referenční země globalizace. Poslední část textu analyzuje vzestup USA v globalizačním procesu a zároveň omezení samotného vlivu. K tomu dochází prostřednictvím vzestupu ostatních zemí, což Fareed Zakaria nazývá ?postamerickým světem?. Analýza probíhá také zároveň pomocí ekonomických ukazatelů. Práce se snaží ukázat, že globální procesy, které učinily z USA světového hegemona, začínají zároveň tuto globální suverenitu ohrožovat a mění postavení světové moci.Katedra politologie a mezinárodních vztahůObhájenoThe main theme of the bachelor?s thesis is weakening global U.S. influence and rise of other countries. Starting point of the theoretical portion, which assumes various theories of globalization, is a definition of disproportions of the world regions and cultural paradigms. For this purpose are used communication theories, civilization and multicultural conflicts, comparison of local and global, but also consumer capitalism. Followed by the definition of the West and its powerful adaptation of the capitalist system that is spreading into other countries under the interpretation of the liberal model. Representative of this process are United States with the demarcation as the referential country of globalization. Last part of the thesis simultaneously analyzes the rise of U.S. in the globalization process with the limit itself influence. This occurs through the rise of other countries, which Fareed Zakaria calls "post-American world?. Analysis is also carried out simultaneously using economic indicators. The thesis is trying to proof that global processes, which made United States the world?s hegemon, are also starting to threaten its global sovereignty and change the position of the world power

Ways of education of first aid in driving schools

The thesis "Ways of education of first aid in driving schools," focuses on the teaching system of medical training in driving schools. According to the statistics, on our roads there are approximately 250 traffic accidents every day. Many of them then request injury or the death. At that moment, the immediate help after the accident is crucial for the survival. This help shall be provided by other road users. Each driver should attend the first aid training as part of the course at a driving school and should be ready for this situation. In the thesis, there was applied mixed research, set one goal and three research questions. Data collection method for the qualitative part were the interviews with the owners of some selected driving schools, which were completed with the anonymous questionnaires filled by alumnuses and students of driving schools in the quantitative part. The research results show that teaching in various driving schools can differ, both in the form of training, as well as in the thematic content topics and qualifying education of instructors. The research has also found out that training in some driving schools do not meet the legal requirements, especially in respecting the amount of hours, and the ratio of theoretical to practical teaching. For the practice, this research shows, that there should be a change in the current system in order to proceed the teaching of medical training well and according to the applicable legislation. The research has also found oud the view and reservations about the current system of teaching the first aid in driving schools, both from the owners of driving schools, as well as the students

Software for simulation of fat deacidification by single contact extraction

P(7D09004), P(ED2.1.00/03.0089), Z(MSM7088352102

Possibility of using tannery waste for biodiesel production

Odpadní tuk produkovaný koželužnami během procesů, při nichž se surová kůže mění na useň, představuje velmi důležitou vstupní surovinu pro produkci bionafty. V laboratorních a poloprovozních podmínkách byly připraveny vzorky bionafty z odpadních koželužských tuků a byly provedeny příslušné analýzy. Proces výroby bionafty má tři fáze: 1) zonální rafinační tavení vstupní suroviny (separace tuku od nežádoucích komponent), 2) methanolýza katalyzovaná organickou bází a 3) separace glycerinové vrstvy. V prezentovaném příspěvku je představen matematický model zonálního rafinačního tavení a rovněž výsledky analýz produktů zonálního tavení a methanolýzy. Inovačním přístupem je použití organických bází (tetramethylammonium hydroxid, n-butylamin, cyklohexylamin apod.). Jejich použití umožňuje, kromě značných úspor výrobních nákladů, produkovat vysoce kvalitní bionaftu a glycerin s prakticky nulovým obsahem popela. Dále výsledná směs methylesterů obsahuje zbytkové aminy, které fungují jako stabilizátory,a po methanolýze mohou být tyto aminy částečně recyklovány.Waste fat produced by tanneries during the processes in which raw hide is transformed into leather represents a very important raw material for biodiesel production. Under laboratory and pilot-scale conditions, biodiesel samples were prepared from waste tannery fat and required analyses were carried out. The process of biodiesel production has three stages: 1) refining melting of the raw material (separation of fats from other undesirable components), 2) organic base-catalyzed methanolysis and 3) separation of glycerin layer. The mathematical model of zonal refining melting is presented in this paper as well as the results of the refining and methanolysis product analyses. The use of organic bases (tetramethylammonium hydroxide, n-butylamine, cyclohexylamine, etc.) is innovative. It enables us, in addition to considerable financial benefits, to produce a high quality biodiesel and glycerin containing practically no ash. Further, it contains a residual amine that works as a stabilizer, and after methanolysis the amine can be partially recycled

Mathematical Simulation of Calcimine Deliming in the Production of Gelatin

Článek představuje matematický model pohybu acido-bazického rozhraní při chemickém odvápňování klihovky. Model může posloužit k optimisaci chemického odvápňování.Calcimine is a valuable by-product originating during the processing of cured hide into leather. It is used as raw material in the production of gelatin and biodegradable sheets. For further usage, it is necessary to remove calcium hydroxide from calcimine by chemical deliming, which is, from the environmental protection point of view, the most important stage of the entire deliming process. In this article, a mathematical description of chemical deliming is proposed, based on the unreacted nucleus approach. Numerical solution of the model is found, concentration fields of the reacting chemicals described, and the evolution of the acido-basic boundary inside calcimine shown. The model is used to justify a simplified way to determine the effective diffusion coefficient of the deliming agent. The model can also be used as a basis for optimization of the deliming process

Sharkovskii's theorem, differential inclusions, and beyond

We explain why the Poincaré translation operators along the trajectories of upper-Carathéodory differential inclusions do not satisfy the exceptional cases, described in our earlier counter-examples, for upper semicontinuous maps. Such a discussion was stimulated by a recent paper of F. Obersnel and P. Omari, where they show that, for Carathéodory scalar differential equations, the existence of just one subharmonic solution (e.g of order $2$) implies the existence of subharmonics of all orders. We reprove this result alternatively just via a multivalued Poincaré translation operator approach. We also establish its randomized version on the basis of a universal randomization scheme developed recently by the first author