QSAR analysis as a tool in search for new BGT-1 transporter inhibitors

We wstępie niniejszej pracy magisterskiej scharakteryzowano metody racjonalnego poszukiwania leków ze szczególnym naciskiem na komputerowo wspomagane projektowanie leków. Opisano modelowanie oparte o znajomość struktury celu, modelowanie oparte o fragmenty, a także modelowanie oparte o znajomość liganda. Poszczególne metody zostały wzbogacone o przykłady.Część eksperymentalna zawiera analizę QSAR inhibitorów transportera BGT1, należącego do rodziny białek SLC6. Transportery te odpowiadają za wychwyt zwrotny GABA, a hamowanie transportera BGT1 zostało powiązane z aktywnością przeciwdrgawkową i przeciwbólową. W literaturze znaleziono bazę związków o znanej aktywności wobec zadanego transportera. Równania QSAR generowano przy użyciu programu Scigress, który umożliwia wygenerowanie równań Quick QSAR, Complete Topological QSAR, Quick Quantum QSAR i Complete Quantum QSAR dwoma różnymi algorytmami. Z 24 otrzymanych równań wyłoniono 2 o najwyższych współczynnikach determinacji i ulepszono je, eliminując z danych wsadowych związki charakteryzujące się najwyższym błędem predykcji. Na podstawie najlepszych równań zaproponowano struktury nowych inhibitorów BGT1 w oparciu o strukturę GABA i równaniami przewidziano ich aktywność. Zaproponowane związki charakteryzowały się niską masą cząsteczkową, zawierały układy mono- lub bicykliczne, a ich przewidywana aktywność była wysoka. Wyniki były jednak ekstrapolowane.Otrzymane równania QSAR mogą stanowić pomocne narzędzie do wstępnego przewidywania aktywności związków pod kątem hamowania transportera BGT1, a uwzględnione w nich deskryptory mogą stanowić wskazówkę jakie właściwości cząsteczka projektowana de novo powinna posiadać, by wykazywać wysoką aktywność.In the introduction to this master’s thesis rational drug design methods were characterized, with particular emphasis on computer aided drug design. Structure based design, fragment based design and ligand based design were described. Particular drug design methods were supplemented with examples.Experimental section contains the QSAR analysis of inhibitors of BGT1 transporter, which belongs to the SLC6 transporter family. These transporters are responsible for reuptake of GABA, and the inhibition of BGT1 transporter was related to anticonvulsant and antiallodynic activity. Databases were searched to find a collection of BGT1 inhibitors with known activity. QSAR equations were generated with Scigress, which allows generation of four types of equations: Quick QSAR, Complete Topological QSAR, Quick Quantum QSAR and Complete Quantum QSAR with two different algorithms. Two best equations were selected from all generated based on the determination coefficient and were improved by removing compounds characterized by the largest error. Improved equations were used to design new GABA-based BGT1 inhibitors and predict their activity. The designed compounds had low molecular mass, they contained mono- or bicyclic scaffolds. Their predicted activity was high; however the results were extrapolated. Generated QSAR equations can be a helpful tool to initially predict the activity of new compounds, and the included descriptors can indicate what properties a new compound designed de novo should possess to have high activity

Political and social moods in Cracow during martial law in Poland

13 grudnia 1981 r. komunistyczna władza z generałem Jaruzelskim na czele wprowadziła w Polsce stan wojenny. Decyzja ta wywołała w społeczeństwie skrajne emocje: od pełnej akceptacji do nieskrywanej krytyki. We wszystkich kręgach społecznych wytworzyły się podziały, które przetrwały niekiedy aż do dziś. Tematem niniejszej pracy są nastroje społeczno-polityczne w Krakowie w latach 1981-1983. W pierwszym rozdziale omówiona została atmosfera panująca wśród członków Polskiej Zjednoczonej Partii Robotniczej. Następnie przedstawiony jest klimat „wojennego” świata artystycznego i dziennikarskiego. Trzeci rozdział dotyczy grup szkolnych i uniwersyteckich: uczniów, studentów oraz nauczycieli. Ostatnia cześć pracy porusza natomiast wątek krakowskiego środowiska robotniczego.Communist authorities, led by general Jaruzelski, established marital law in Poland on 13th December 1981. That period lasted to 22nd July 1983. Announcement of the marital law sparked various and extreme emotions in the polish society. Part of the polish utterly accepted Jaruzelski’s decision, but the other ones strongly criticized his decision. The society become divided. Results of some of those divisions are visible even nowadays. The thesis is about political and social moods in Cracow in 1981-1983. The first chapter describes atmosphere among members of The Polish United Workers' Party. The next one shows artistic and journalistic world during those years in Poland. The third chapter tells about school and academic groups of the society: pupils, students and teachers. The last part of the thesis is committed to the labourers’ situation in Cracow during marital law in Poland

Chemometric and environmental assessment of arsenic, antimony, and chromium speciation form occurrence in a water reservoir subjected to thermal anthropopressure

<div>In the study, arsenic, antimony, and chromium concentrations and selected physicochemical parameters in water and sediment samples from the thermal anthroporessure subjected Rybnik Reservoir (Poland) were determined. As(III), As(V), Sb(III), and Sb(V) ions were successfully separated on Dionex IonPac AS7 column, and Cr(III) and Cr(VI) on Dionex IonPac AG7 column. The obtained limits of detection were 0.18, 0.22, 0.009, 0.012, 0.11, and 0.17 μg/L, respectively. Water and bottom sediment samples were collected monthly at three-point transect between January and November 2013. The As(III) and Sb(III) speciation forms dominated in the bottom water, and Cr(VI) concentration in the bottom water was twice as high as the value measured for the surface water. The oxidized arsenic, antimony, and chromium forms</div><div>dominated in the bottom sediments in the heated water discharge zone of the Rybnik Power Plant. The location of sampling point had a significant influence on the observed transformations and contents of the analyzed speciation forms. The chemometric analysis coupled with the dissimilarity analysis and principal component analysis helped to visualize the variability in the concentrations of the element speciation forms within the researched period and analyzing correlations.</div

Physical, Psychological and Social Frailty Are Predictive of Heart Failure: A Cross-Sectional Study

Abstract: Background: Little is known about frailty among patients hospitalized with heart failure (HF). To date, the limited information on frailty in HF is based on a unidimensional view of frailty, in which only physical aspects are considered when determining frailty. The aims of this study were to study different dimensions of frailty (physical, psychological and social) in patients with HF and the effect of different dimensions of frailty on the incidence of heart failure. Methods: The study used a cross-sectional design and included 965 patients hospitalized for heart failure and 164 healthy controls. HF was defined according to the ESC guidelines. The Tilburg Frailty Indicator (TFI) was used to assess frailty. Probit regression analyses and chi-square statistics were used to examine associations between the occurrence of heart failure and TFI domains of frailty. Results: Patients diagnosed with frailty were 15.3% more likely to develop HF compared to those not diagnosed with frailty (p < 0.001). An increase in physical, psychological and social frailty corresponded to an increased risk of HF of 2.9% (p < 0.001), 4.4% (p < 0.001) and 6.6% (p < 0.001), respectively. Conclusions: We found evidence of the association between different dimensions of frailty and incidence of HF