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Recombinant insulin is a life-saving therapeutic for millions of patients affected by diabetes mellitus. Standard mutagenesis has led to insulin variants with improved control of blood glucose; for instance, the fast-acting insulin lispro contains two point mutations that suppress dimer formation and expedite absorption. However, insulins undergo irreversible denaturation, a process accelerated for the insulin monomer. Here we replace ProB29 of insulin lispro with 4R-fluoroproline, 4S-fluoroproline, and 4,4-difluoroproline. All three fluorinated lispro variants reduce blood glucose in diabetic mice, exhibit similar secondary structure as measured by CD, and rapidly dissociate from the zinc- and resorcinol-bound hexamer upon dilution. Notably, however, we find that 4S-fluorination of ProB29 delays the formation of undesired insulin fibrils that can accumulate at the injection site in vivo and can complicate insulin production and storage. These results demonstrate how subtle molecular changes achieved through non-canonical amino acid mutagenesis can improve the stability of protein therapeutics. [ABSTRACT FROM AUTHOR]

Comparison of railway trough bridges for decision making in the planning stages 2–4 Bridges with a small to medium span width are of great importance for the German railway network. Because of their high number it is necessary to find bridge solutions for the future rehabilitation and renewal actions which are economically advantageous and lead to low negative impacts from the railway operation. Thickplate‐trough bridges with a span width up to 20 m show many benefits which manifest in very high levels of prefabrication and result in short erection periods. Next to economic aspects the understanding of the load‐bearing behavior of trough bridges is important. Fatigue tests of large‐scale and small‐scale experiments combined with numeric analyses allow to gain a deeper insight in the load‐bearing behavior and help consultants to design economic and durable constructions. [ABSTRACT FROM AUTHOR]

Abstract: Development of a DASt‐guideline for high frequency mechanical impact treatments – conclusion of investigations and proposal of DASt‐guideline‐draft. Numerous research work in recent years has proven an increase in fatigue strength by using high frequency mechanical impact (HFMI) treatment on welded steel joints. Regardless of the profound research activities in the field of HFMI‐methods at national and international level, the increase in fatigue strength that can be achieved by these methods may not be taken into account for the design of welded structures in Germany until now. Previous use of HFMI‐methods for structural applications is limited to projects in which a technical approval has been obtained for particular cases (ZiE). A DASt‐guideline, which regulates the design of HFMI‐treated structures, will make a decisive contribution regarding structural applications of these methods in future. This paper presents the results of a research project with the objective of developing a design concept for HFMI‐treated welds. This design proposal forms the basis for the forthcoming DASt‐guideline and regulates the classification of fatigue strength for HFMI‐treated welds depending on the stress ratio and the material yield strength according to Eurocode 3, specifying suitable application limits. The developed concept also takes into account the increasing effectiveness of these methods with increasing material strength. [ABSTRACT FROM AUTHOR]

Abstract: Modern railway bridges as thick‐plate trough bridges – Optimization of fatigue design and life‐cycle analyses. Innovative improved design solutions of bridge constructions increasingly aim at maintenance reduced structures where the utilization and surrounding traffic routes are affected only in minor extent by rehabilitation and maintenance works. As part of the FOSTA‐AiF‐research project „Holistic Assessment of steel‐ and composite railway bridges according to criteria of sustainability” (P978) specific investigations were carried out in order to optimize different railway bridge types by improving single structural details and construction variants types. To assess the benefits of these optimized constructions within the life‐cycle of the bridge, the conventional and improved constructions were compared with each other by applying sustainability analyses. This paper deals with the evaluation of the trough bridges with thick track plates which was especially developed for rail traffic constructions and which is also known as thick‐plate trough bridges. It focusses on questions related to the fatigue design, uses large scale tests for verifications and provides recommendations for the construction and design. [ABSTRACT FROM AUTHOR]

Holistic analysis on steel- and composite railway bridges - Innovative solutions for strengthening durability and reducing construction times (Part 1). Investigations on sustainability on infrastructure projects differ from comparable investigations on building constructions through their longer life-cycle of the objects. Questions regarding sustainability are thus accompanied by questions of durability and simple, mostly undisturbed maintenance through the whole life-cycle. By the application of innovative railway bridges with steel and composite constructions blocking times induced by the construction time and maintenance actions within the usage phase, can be effectively reduced. Additionally the optimization of restrictive fatigue-details can affect the whole life-cycle of a bridge-construction. In the frame of the FOSTA-AiF-research project 'Holistic Assessment of steel- and composite railway bridges according to criteria of sustainability' different innovative railway bridge types have been compared to their corresponding conventional bridge types and evaluated over their whole life-cycle to quantify their advantageousness. While this article shows the investigated innovative bridge-variants in constructive regards and optimization proposals and design approaches are explained, the second article is about the holistic approach and the results of the sustainability assessment of the investigated steel-and composite railway bridge. [ABSTRACT FROM AUTHOR]

1,2,4-Triazoles and 1,3,4-oxadiazoles are prevalent moieties in pharmaceutical agents, yet fused [1,2,4]triazolo[3,4- b ][1,3,4]oxadiazoles are surprisingly under-represented for both synthesis and biological application. We report a rapid, two-step synthesis of [1,2,4]triazolo[3,4- b ][1,3,4]oxadiazoles from commercial 4-amino-1,2,4-triazoles that is highlighted by a microwave accelerated intramolecular cyclization to generate the fused ring system. Our efforts to optimize reaction conditions and elucidate reaction mechanism are also described. [ABSTRACT FROM AUTHOR]

Innovations are often initiated by bridge design. In this paper out of the large variety of new solutions and developments in bridge design, the focus is on three different subjects: Especially composite constructions made of structural steel and reinforced concrete adapt very easily to the most diverse situations and lead to efficient and beautiful bridges. The requirement of time effectiveness has driven solutions with prefabrication. First, a newly developed composite section with a trapezoidal steel web and horizontally lying studs is presented. Secondly, slender structures of thin plates are usually designed according to EN 1993-1-5. In order to adapt to an optimized overall curved shape in longitudinal direction the development of new buckling rules for non-rectangular steel panels is addressed. As a third point fatigue design, which is most relevant for the bridge dimensions, is addressed. Improvements by HFMI-treatment have been verified so that advantage can now be taken especially for high strength steels that allow a more slender design. The influence of the terms of application of HFMI-treatment on the quality has been investigated in a recent project. These different developments can lead to more slender, more efficient long living steel and composite bridges that satisfy future demands of increased sustainability. • New developments in steel and composite bridges • Composite Girders with horizontally lying studs and corrugated steel web • Buckling verification of non-rectangular panels • Effect of varying qualities of HFMI-treatment [ABSTRACT FROM AUTHOR]