Design and Layout Appearance of Brewery in Zahrádky Near Česká Lípa

The Renaissance chateau brewery no. 55 in Zahrádky near Česká Lípa is changing in the ruins for several decades and a part of the buildings have completely been torn down. Nevertheless, till today its relics belong to the unique examples of building design, where many structures had been carved into the sandstone bedrock. This paper summarizes the earlier findings from no more existing parts of the building and new the landscaping findings in confrontation with preserved building plans. The preserved core of the malt-house, the vestibule and home torso of the brewer provably come from the year 1609. Noteworthy is also the evidence of substantially continuous reconstruction of the brewery at the end of the 17th century, documenting unusual amount of datings on a rocky massif, architectural elements or plasters. The attempt to modernize the operation was ended up at the end of the 19th century and has never been realized, apparently not even on the level of a project preparation of the malt kiln reconstruction to the so-called English type of vertical kiln. Intensive building activity had been registered especially in the thirties and the fifties to the seventies of the 19th century. A massive use of sandstone bedrock at the edge of the valley slope is for the North Bohemia very typical issue, which is common for other breweries in the region as well

Proportioning spur planetary gear of special motor vehicle

Diplomová práce se zabývá návrhem planetové kolové redukce speciálního motorového vozidla. Podle požadavků na vozidlo bylo spočítáno, zda je nutné použití redukce. Dále byl zvolen druh redukce a výpočtem z přenášených momentů určeny její rozměry.Katedra dopravních prostředkůDokončená práce s úspěšnou obhajobo

Technological equipment, survey and restoration of the paper mill no. 5 in Hamr na Jezeře

Die Studie ist der komplexen bauhistorischen Auswertung des Frühbarockobjektes der Papierfabrik in Hammer gewidmet. Der bestehende Kern des Gebäudes wurde in den 1680er Jahren auf dem Gebiet der ehemaligen älteren, 1655 gegründeten Papierfabrik gebaut. Grundlegend wurden dann die Umbauten im Hochbarockstil mit verzierter Fassade und die klassizistischen baulichen Veränderungen in den 1820er und 1830er Jahren. Die älteste Etappe mit gemauertem Souterrain und Erdgeschoss und mit dem Fachwerkgeschoss wird aufgrund der neuesten Erkenntnissen und der Identifizierung einer ganzen Reihe an Bauten aus dem Bauhorizont des 17. Jahrhundert in den Kontext der Entwicklung der technischen und dörflichen Bauten eingereiht. Besondere Aufmerksamkeit wird dem als Unikat erhaltenen Torso der technologischen Papierfabrik-Anlage und dem Betriebsumbau in bestimmten zeitabschnitten gewidmet. An den Beispielen der Auswertung der Fundsituationen im Innenraum und besonders an der Fassade werden die Möglichkeiten der durchlaufend durchgeführten Untersuchungsarbeiten und ihre Notwendigkeit für die qualifizierte Erneuerung der Bauten dargestellt. Die meiste Aufmerksamkeit konzentriert sich auf die Untersuchung und folgende Erneuerung der Fassade der Papierfabrik, die in der verzierten Form des Hochbarockstils präsentiert wurde und die dank ihrer hochwertigen Ausführung zu den gelungensten Denkmalerneuerungen wenigstens in Nordböhmen gehört.The study is devoted to the historical building survey of the Early Baroque paper mill in Hamr na Jezeře. On the examples of evaluation of finding situations at the facade are presented possibilities of exploratory works and their necessity for qualified reconstruction of buildings. The facade was presented in a decorative Baroque style. Close attention is paid to the preserved torsion of the paper mill‘s technological equipment. Findings from the fieldwork are confronted with data from archival research and analogies from the industrial field. The paper mill was established in 1655, but the existing building core dates from the 1680´s. The appearance of the building was modified by the Baroque rebuilding and Classicistic adaptations in the second and third decades of the 19th century. The oldest stage with a brick basement and a ground floor and a half-timbered floor coincides with the development of village buildings in Northern Bohemia during the 17th century. In regard to the technological facilities, it was possible to reconstruct the operation of the company in individual time periods.Studium jest poświęcone komplek- sowemu budowlano-historycznemu obiektowi wczesnobarokowej papierni w miejscowości Hamr na Jezeře. Na przykładach ocenienia sytuacji znaleziska przede wszystkim przy fasadzie są zaprezento- wane możliwości stopniowo wykonywanych prac badawczych i nie- zbędności kwalifikowanego wznowienia budowli. Obserwowana jest również rekonstrukcja fasady papierni, która była prezentowana w okresie szczytowego ozdabianego baroku i dzięki dobremu wykonaniu należy do najlepiej wykonanej rekonstrukcji zabytków co najmniej w czechach Północnych. Szczegółowa uwaga jest również poświęcona unikatowo przetrwałemu niedokończonemu urządzeniu technicznemu papierni. Punkt ciężkości pracy polega na badaniu źródła materiałowego, tj. samej budowli papierni i tor- su historycznego urządzenia maszynowego. Stwierdzenia z prac terenowych są konfrontowane z danymi archiwalnymi i analogiami z odpowiedniej dziedziny budowlanej. Papiernia została założona do roku 1655, ale obecny rdzeń budowy był bezpiecznie datowany do lat 70-tych XVII wieku. zasadnicze były również barokowe prze- budowy z ozdabianymi fasadami i klasycystyczne przepracowania w drugim i trzecim dziesięcioleciu XIX wieku. Najstarszy etap z mu- rowaną suteryną i parterem jest umieszczony w kontekście rozwoju budowli technicznych i wiejskich w czechach Północnych na pod- stawie najnowszej wiedzy i identyfikacji całego szeregu budowli z horyzontu budowlanego XVII wieku. w przypadku urządzenia technologicznego udało się wiarogodnie rekonstruować eksploata- cję obiektu w poszczególnych okresach czasu

Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7

Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 Å resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors

Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors

Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo