Investigations into the Synthesis of InherentlyChiral Calix[4]arenes

The design and synthesis of highly functionalised calix[4]arenes are of great interest for research. The modification of the upper-rim of calix[4]arene allows the lower-rim to act as a potential molecular binding site. Our objective is to develop methodologies and synthetic routes that allow us to generate a range of tetra-substituted, upper-rim functionalised calix[4]arenes in an AABC and ABCD pattern. We started by the selective functionalisation of calix[4]arenes by iodination at the upper-rim in the presence of aldehyde moieties. The Cannizzaro method has been developed within the Bew group, utilising a simple pestle and mortar, which has proved to be an extremely efficient method of grinding both the base and the calix[4]arene with a few drops of solvent. Protection of the Cannizzaro compound made the next step easier as acid compounds tend to streak during purification via column chromatography. We were able to obtain AABC compounds via Sonogashira cross-coupling. For the ABCD compounds, the first step of the synthesis begins via a Suzuki-Miyuara coupling of the bis-1,3-aldehyde-bis-2,4-iodo calix[4]arene with a variety of boronic acids affording mono-aryl and di-aryl compounds, followed by the Cannizzaro and alkylation to the benzyl esters. This procedure is an amenable tool for the synthesis of ‘inherently chiral’ calix[4]arenes in an AABC and ABCD pattern

Caffeine intake helps maintain 3-km cycling performance the morning following sleep restriction

Abstract Introduction: Although a full understanding of the role of sleep is debated, it is widely accepted that sleep is important for recovery from heavy exercise. Recent research suggests that sleep restriction (SR) may negatively impact recovery and subsequent performance. It is unknown if caffeine supplementation mitigates this performance decrement. Our objective was to investigate the effect of caffeine supplementation on exercise performance following one night of SR in trained cyclists. Methods: Subjects (n=10) completed a 3-km time trial (TT) and an exhaustive bout of exercise in the evening (EX1), then returned to repeat the TT the following morning (EX2). Exercise trials were separated by a full night of sleep (FULL) or a night of restricted sleep (SR). Perceived fatigue was also assessed prior to EX2. Caffeine (CAF) or placebo (PLA) treatments were given before the start of EX2. A randomly counterbalanced, double blind, placebo controlled design was used to compare the effects of four different treatment conditions: FULL/PLA, SR/PLA, FULL/CAF, SR/CAF. Results: Data were analyzed using magnitude-based inferences to compare differences in EX2 performances only. Power output was ‘possibly’ greater (0.9 ± 3.6%) following SR/PLA compared to FULL/PLA. Power output was ‘likely’ higher (5.5 ± 4.8%) following SR/CAF compared with SR/PLA. Perceived fatigue was rank ordered as 1) SR/PLA, 2) SR/CAF, 3) FULL/PLA, 4) FULL/CAF. Specifically, CAF ‘very likely’ reduced perceived fatigue following SR compared to SR PLA, but remained ‘likely’ higher than FULL/CAF. Conclusion: These data show that caffeine has the ability to mitigate performance decrements resulting from a single night of SR following heavy exercise. Caffeine also prevented increases in perceived fatigue following SR

Performance Impairment Following Sleep Restriction - Is Caffeine the Antidote?

The purpose of this project was to test the hypothesis that caffeine supplementation can lessen the negative effects that sleep restriction (i.e. shortened sleep duration) has on next day performance. Recent work done in our lab showed that sleep restriction has a negative effect on 3-km cycling time trial performance. Thus, it is important to investigate potential ways to lessen the negative effects sleep restriction may have on performance, since it is commonly seen in athletes. In this study, participants completed a battery of performance testing and then a heavy exercise session. This was followed by either a full night of sleep (~7.5 hours) or a night of sleep restriction (~3.5 hours). The following morning, they were given either caffeine or a placebo treatment, then completed the follow-up performance testing. Each subject completed four experimental trials including a full night of sleep with caffeine, a full night of sleep with placebo, a night of sleep restriction with caffeine, and a night of sleep restriction with placebo

Cataloging and organizing p73 interactions in cell cycle arrest and apoptosis

We have compiled the p73-mediated cell cycle arrest and apoptosis pathways. p73 is a member of the p53 family, consisting of p53, p63 and p73. p73 exists in several isoforms, presenting different domain structures. p73 functions not only as a tumor suppressor in apoptosis but also as differentiator in embryo development. p53 mutations are responsible for half of the human cancers; p73 can partially substitute mutant p53 as tumor suppressor. The pathways we assembled create a p73-centered network consisting of 53 proteins and 176 interactions. We clustered our network into five functional categories: Upregulation, Activation, Suppression, Transcriptional Activity and Degradation. Our literature searches led to discovering proteins (c-Jun and pRb) with apparent opposing functional effects; these indicate either currently missing proteins and interactions or experimental misidentification or functional annotation. For convenience, here we present the p73 network using the molecular interaction map (MIM) notation. The p73 MIM is unique amongst MIMs, since it further implements detailed domain features. We highlight shared pathways between p53 and p73. We expect that the compiled and organized network would be useful to p53 family-based studies

Total factor productivity in the states of the European Union

Diplomová práce na základě odborné literatury identifikuje základní determinanty souhrnné produktivity faktorů (TFP). Pomocí metody vícenásobné lineární regrese a průřezových dat se snaží vysvětlit vliv vybraných indikátorů: výdaje na vědu a výzkum, patenty, otevřenost ekonomiky, přímé zahraniční investice, výdaje na infrastrukturu, index finančního rozvoje trhu, vládní výdaje na vzdělání a Giniho koeficient na změnu TFP v rámci států EU-28, v letech 1996-2017. Ze zmíněných regresní model vyhodnotil jako statisticky významné indikátory: index rozvoje finančního trhu a otevřenost ekonomiky. Vlivy ostatních indikátorů byli vyhodnoceny na hladině významnosti 5 % jako nevýznamné. Jejich nepřímý vliv na TFP však není možné vyloučit, jelikož indikátory navzájem poukazují na významnou lineární závislost. Práce se také věnuje vývoji TFP ve vybraných zemích EU-28 v před a pokrizovém období r. 2007 a dává ji do kontextu s vývojem ukazatele HDP na obyvatele.Diploma thesis based on the review of scientific literature identifies fundamental determinants of total factor productivity (TFP). By using of multiple regression method and cross-sectional data it attempts to explain the influence of selected indicators: research and development, patents, economy openness, foreign direct investments, infrastructure expenditures, financial development index, government expenditures on education and Gini coefficient on the variance of TFP in the states of EU-28 in years 1996 – 2017. According to the regression model, there are two statistically significant indicators: financial development index and economy openness. The influence of the remaining factors was found statistically insignificant on the 5% level of significance. However, their indirect influence on TFP cannot be excluded as indicators prove significant mutual linear dependence. Paper also focuses on the development of TFP in selected states of EU-28 before and after the world crisis in 2007 and discusses it in the context of GDP per capita development

Inteligentní řízení pro chytrá prostředí

The aim of this thesis is to design and implement a smart home control system using ROS. The work includes the implementation of smart home control software and explores the possibilities of efficient storage of sensor data. The implementation includes communication and data transfer between the systems using MQTT protocol. The thesis explores the possibilities of using multi-agent systems in smart environments

Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines

Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant p53 with small molecules a promising strategy for the development of novel anticancer therapeutics. The oncogenic p53 mutation Y220C, which accounts for approximately 100,000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain, which destabilizes p53 and causes denaturation and aggregation. Here, we describe the structure-guided design of a novel class of small-molecule Y220Cstabilizers and the challenging synthetic routes developed in the process. The synthesized chemical probe MB710, an aminobenzothiazole derivative, binds tightly to the Y220C pocket and stabilizes p53- Y220C in vitro. MB725, an ethylamide analogue of MB710, induced selective viability reduction inseveral p53-Y220C cancer cell lines while being well tolerated in control cell lines. Reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediatedtranscriptional activation of the Y220C mutant. Our data provide a framework for the development of a class of potent, non-toxic compounds for reactivating the Y220C mutant in anticancer therapy<br/

Pancreatic cancer in Europe: Ki-ras gene mutation pattern shows geographical differences

Seventy-seven pancreatic adenocarcinomas (60 Spanish and 17 Italian) were tested for Ki-ras gene mutations by analysis of polymerase chain reaction amplified sequences. Mutations involving codon 12 (GGT; gly) were detected in 16 Italian and 46 Spanish cases (80.5% in total). All Italian mutations involved the second base and were G to A transitions (GAT; asp) in 8 cases and G to T transversions (GTT; val) in the remaining 8. Forty-two Spanish mutations were characterized. Thirty-eight were at the second and 4 at the first base: asp in 24 cancers, val in 14, arg (CGT) in 2 and cys (TGT) in 2. Previous European studies and our present data show that 149 of the 186 pancreatic cancers harbored a codon 12 Ki-ras mutation (80%), the large majority affecting the second base (73%), with a transitions/transversions ratio of 1.3:1. However, the mutational pattern of cancers of the different European countries shows remarkable differences, both in the site of the mutation (first or second base) and in the ratio of transitions over transversions. Moreover, a significant subgroup of pancreatic carcinomas do not harbor Ki-ras mutations. The classification of pancreatic cancers, according to the presence or absence, and type of Ki-ras mutation, may be of importance in epidemiological studies. A critical reappraisal of existing epidemiological data, through a retrospective genotypic study using paraffin-embedded cancer samples, may reveal significant correlations with specific genotoxic agents

Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines

Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant p53 with small molecules a promising strategy for the development of novel anticancer therapeutics. The oncogenic p53 mutation Y220C, which accounts for approximately 100,000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain, which destabilizes p53 and causes denaturation and aggregation. Here, we describe the structure-guided design of a novel class of small-molecule Y220Cstabilizers and the challenging synthetic routes developed in the process. The synthesized chemical probe MB710, an aminobenzothiazole derivative, binds tightly to the Y220C pocket and stabilizes p53- Y220C in vitro. MB725, an ethylamide analogue of MB710, induced selective viability reduction inseveral p53-Y220C cancer cell lines while being well tolerated in control cell lines. Reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediatedtranscriptional activation of the Y220C mutant. Our data provide a framework for the development of a class of potent, non-toxic compounds for reactivating the Y220C mutant in anticancer therapy<br/