Structural Analysis of Spiro β-Lactone Proteasome Inhibitors

Spiro β-lactone-based proteasome inhibitors were discovered in the context of an asymmetric catalytic total synthesis of the natural product (+)-lactacystin (1). Lactone 4 was found to be a potent inhibitor of the 26S proteasome, while its C-6 epimer (5) displayed weak activity. Crystallographic studies of the two analogues covalently bound to the 20S proteasome permitted characterization of the important stabilizing interactions between each inhibitor and the proteasome’s key catalytic N-terminal threonine residue. This structural data support the hypothesis that the discrepancy in potency between 4 and 5 may be due to differences in the hydrolytic stabilities of the resulting acyl enzyme complexes.Chemistry and Chemical Biolog

Капитальный ремонт магистрального газопровода «НГПЗ – Парабель» на участке 227-254 км

Объектом исследования является магистральный газопровод Ду 1000 протяженностью 26,267км. Цель работы – выбор эффективного способа выполнения работ по капитальному ремонту магистрального газопровода. Проведены расчеты толщины стенки трубы, трубопровод на прочность и устойчивость. Рассмотрена разработка траншеи, сварочно-монтажные работы, прокладка, ликвидации разрывов, проведение испытания, мероприятия по охране труда и безопасности строительства, охране окружающей среды, технико-экономическая часть. Было предложено выполнять укладку нового трубопровода параллельно существующему, силами КТП. На основании выполненных расчетов на прочность было рекомендовано увеличения толщины стенки.The object of study is (are) the main gas pipeline DN 1000 with a length of 26,267 km. Purpose – the choice of effective method of execution of works on capital repair of the trunk gas pipeline. The calculations of wall thickness, tubing for strength and stability. Describes the development of a trench, welding and installation works, laying, bridging the gaps, running the test, measures on labor protection and building safety, environmental, technical and economic part. It was proposed to carry out laying a new pipeline parallel to the existing, by the CTU. On the basis of the calculations for strength, it was recommended that increasing the thickness of the wall

Drivers and prediction of organic search engine ctr - the effects of serp features and their business implications

33% of web traffic in the $5.7 trillion e-commerce industry originates from organic search engine results. Thus, website providers benefit from a holistic understanding of the drivers of click-through rates (CTR) on organic searches to increase traffic. However, providers face a knowledge gap, as existing literature focuses on position as the primary CTR influence, disregarding other result page characteristics. To solve this problem, we use an extensive dataset comprising organic Google result page information. We conduct an elaborate data analysis highlighting the impact of four categories of result page characteristics before determining suitable CTR prediction modeling techniques. We discover novel patterns impacting CTR for each category and find tree-based models to outperform state-of-the-art deep-learning models. Furthermore, we reveal particular SERP feature effects on CTR and highlight their possible business implications

The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain

The plant cytotoxin ricin enters mammalian cells by receptor-mediated endocytosis, undergoing retrograde transport to the endoplasmic reticulum (ER) where its catalytic A chain (RTA) is reductively separated from the holotoxin to enter the cytosol and inactivate ribosomes. The currently accepted model is that the bulk of ER-dislocated RTA is degraded by proteasomes. We show here that the proteasome has a more complex role in ricin intoxication than previously recognised, that the previously reported increase in sensitivity of mammalian cells to ricin in the presence of proteasome inhibitors simply reflects toxicity of the inhibitors themselves, and that RTA is a very poor substrate for proteasomal degradation. Denatured RTA and casein compete for a binding site on the regulatory particle of the 26S proteasome, but their fates differ. Casein is degraded, but the mammalian 26S proteasome AAA-ATPase subunit RPT5 acts as a chaperone that prevents aggregation of denatured RTA and stimulates recovery of catalytic RTA activity in vitro. Furthermore, in vivo, the ATPase activity of Rpt5p is required for maximal toxicity of RTA dislocated from the Saccharomyces cerevisiae ER. Our results implicate RPT5/Rpt5p in the triage of substrates in which either activation (folding) or inactivation (degradation) pathways may be initiated

Dust storms, dust transfer and depositions in the southern Aral Sea region

Land surfaces poor in vegetation coverage and dried out soils are accelerating factors of sand and dust transport. Dust transport also has considerable impact on the human society if highly populated regions are on the transport pathway or sink areas as dust transport can bring pollutants into residence areas. The quantitative prediction of dust storms is impossible unless the entire dust cycle, consisting of dust emission, transport and deposition, can be correctly assessed. In recent years, dust emission schemes have been developed that account reasonably well for the impacts of atmospheric forcing and land-surface properties on dust emission. The Aral Sea disaster has been caused by the overexploitation of the water and land resources and is related to problems of polluted surface and ground water bodies, the loss of agricultural productivity and biodiversity, the regional climate change and also the human health, especially within the disaster zone. Major consequences of the Aral Sea shrinkage, apart from the decrease of its water volume and area, an increase of the water salinity and a modification of the salinity pattern is the formation of a vast saline desert with the area of almost 3.6 mln ha on the exposed seabed. The main factors of dust storm occurrences are the frequency of strong winds and availability of source material in dust emission sites. During the last decades the total area of dust emission sites in the Aral Sea region increased significantly because of the shrinking of the Aral Sea and consequent drying of its exposed bottom and deltaic areas of Amudarya and Syrdarya Rivers

Ecological, socio-economic and demographic analyses as prerequisites for sewage treatment problem solutions in rural areas. The case study of Dirlammen, Vogelsberg, Germany

The municipal sewage treatment in Germany is traditionally centralized and allows for a high disposal security. The implementation of the EU Water Framework Directive (EU-WFD) showed that the central target, the so-called ‘good ecological state’ has not yet been reached in 90% of all surface water bodies. A common and widespread measure to reach said target is the improvement of sewage treatment plants (STP). A large part of the expenses for that has to be shouldered by local communities. But many rural communities already have to manage high costs caused by the modernization of the sewage pipe system. And as the size of the rural population decreases continuously, the per capita burden increases. This raises the question whether the construction of a new sewage treatment plant is the most efficient way to improve the water quality in rural areas. A comprehensive approach has been developed for answering this question, consisting of 1) biological and physico-chemical wastewater analyses, 2) a modified eco-balance for the construction of a new STP and 3) socio-economic and demographic population analyses. The results show that the water quality of the studied creek is good with exception of the sewage disposal point. The eco-balance for the construction, the operation, and the environmental side effects show that the continued operation of the existing STP is more effective than the construction of a modern facility. This conclusion is supported by the aging and general decrease of the rural population. The diminishing potential to shoulder additional costs is in contrast to the reduced future demand for a modern STP

Beziehungen zwischen der Gewässermorphologie und dem Makrozoobenthos an renaturierten Abschnitten der Lahn

Die europäischen Fließgewässer unterliegen seit Jahrhunderten einem starken anthropogenen Nutzungsdruck, welcher den morphologischen und faunistischen Charakter der Gewässer nachhaltig verändert hat. In den vergangenen Jahrzehnten rückten die Defizite der Fließgewässer zunehmend in das Blickfeld der Öffentlichkeit und erste Bestrebungen der Zustandsverbesserung durch die Renaturierung von Gewässerabschnitten wurden unternommen. Maßgeblich vorangetrieben wird dieser Prozess durch die EU-Wasserrahmenrichtlinie. Um die Ziele der Wasserrahmenrichtlinie sowohl fristgerecht als auch kosteneffizient erreichen zu können, bedarf es genauer Kenntnisse über die Wirksamkeit konkreter Maßnahmen, die durch die detaillierte Evaluation bereits umgesetzter Maßnahmen gewonnen werden könnten. In der Praxis erfolgt eine wissenschaftliche Auseinandersetzung mit renaturierten Gewässerabschnitten jedoch ausgesprochen selten oder oberflächlich und auch die Monitoringprogramme der EU-Wasserrahmenrichtlinie können die bestehenden Wissenslücken nicht füllen. Speziell für das Makrozoobenthos als einer der vier Qualitätskomponenten für die Bewertung der Fließgewässer kann die zentrale Frage „Welche morphologischen Prozesse und Strukturen können gefördert werden, um einen guten ökologischen Zustand zu erreichen?“ trotz mehr als 100-jähriger limnologischer Forschung noch immer nicht befriedigend beantwortet werden. Zwar existieren zahlreiche Untersuchungen, die die Abhängigkeit des Makrozoobenthos’ von verschiedenen Umweltfaktoren auf der Makro- und Mesoskala analysieren. Die als Hauptlebensraum relevante Ebene der Mikrohabitate (Choriotope) jedoch ist diesbezüglich kaum untersucht, was zumindest teilweise darin begründet liegt, dass bislang kaum Verfahren existierten, welche die Strukturen des Gewässerbetts in der erforderlichen räumlichen Auflösung erfassen können. In diesem Spannungsfeld zwischen angewandter Wissenschaft und Grundlagenforschung wurden von 2006 bis 2008 intensive Untersuchungen am Mittelauf der Lahn (Fließgewässertyp 9.2) durchgeführt. In drei Untersuchungsgebieten (zwei davon durch eigendynamische Entwicklungsmaßnahmen renaturiert) erfolgten hochaufgelöste Kartierungen der Gewässersohle unter Verwendung des TRiSHa-Verfahrens („Typology of Riverbed Structures and Habitats“) sowie detaillierte Aufnahmen des Makrozoobenthos’ nach dem PERLODES-Verfahren. Analysiert wurde neben der räumlichen Verteilung der Strukturparameter in den renaturierten und nicht renaturierten Untersuchungsabschnitte auch deren zeitliche Dynamik unter besonderer Berücksichtung eines HQ50. Die Zusammenhänge zwischen der Mikrostruktur der Gewässersohle und der Besiedelung durch das Makrozoobenthos wurden statistisch ausgewertet und eine Bewertung der Renaturierungsmaßnahmen wurde durchgeführt. Hierbei konnten unter anderem Lücken in der Fließgewässertypologie und dem PERLODES-Verfahren aufgezeigt werden, die einer breiteren wissenschaftlichen Diskussion bedürfen