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The inducement of compressive residual stress by means of deep rolling (also known as ball or roller burnishing) has been widely investigated over the last decades; however, the influence of cyclic loading on stress relaxation of rolled components has not received the same attention. Therefore, the principal aim of this work is to study the behaviour of macro- and microresidual stresses (the latter assessed in terms of the full width at half maximum, FWHM) on the surface of AISI 1060 steel specimens under rotating bending tests. For this purpose, samples with three distinct heat treatments (subcritical annealing, full annealing and hardening by quenching and tempering) were deep rolled at various combinations of rolling pressure and number of passes. The results indicate that the tensile residual stress obtained after turning shifted to compressive stress after deep rolling. The FWHM decreased after deep rolling at the lowest pressure, thus suggesting that deep rolling promoted a better distribution of the dislocations induced by previous turning; however, the further elevation of rolling pressure and number of passes caused the elevation of the FWHM. The macro- and microresidual stress values were not drastically altered after rotating bending testing with an applied stress corresponding to 50 % of the yield strength. Nevertheless, residual stress relaxation was observed with an applied stress of 80 % of the yield strength, though the FWHM did not provide evidence of microresidual stress relaxation. Finally, the analysis of the fractured cross-sections of hardened specimens indicated that the location of the crack initiation site deepens with the elevation of rolling pressure.

This article presents a technical concept and machining possibilities for milling of micro structures with a fast tool servo (FTS). The tool is capable of tool tip displacements with a variable frequency up to 4000Hz and an amplitude up to 30μm. The control system of the actuator is linked to the angular spindle position, allowing to freely manipulate the excitation signal. Combining this tool system with a single tooth face milling head, micro structures on flat surfaces can be generated on conventional milling centers. Selected micro structures are machined and evaluated in terms of precision and surface quality.Video abstract

Milling of hardened steels is a challenging task for mould and die manufacturing due to the high material strength. One major drawback is the tool wear, which is a result of the high thermo-mechanical stress on the tool. The wear rate can generally be influenced by the tool geometry, coatings and substrates. A further approach is to modify the flank face of the tool, which leads to geometrical limitation of the flank wear. The challenge of this approach is to design flank face modifications, which offer process reliability and increased performance. Against this backdrop a finite element simulation has been constructed to analyze tool stresses. Therefore, different material and friction models were investigated. Based on this simulation a regression model has been developed. Due to the regression model the flank face modifications have been designed and manufactured by laser machining. In cutting tests the potential of the flank face modifications compared to conventional hard milling tools was investigated. The flank face modifications enable the increase of tool life time and the production of workpieces with reduced tensile residual stresses.

Natural healing is based on highly orchestrated processes, in which the extracellular matrix plays a key role. To resemble the native cell environment, we introduce an artificial extracellular matrix (aECM) with the capability to template hierarchical and anisotropic structures in situ, allowing a minimally-invasive application via injection. Synthetic, magnetically responsive, rod-shaped microgels are locally aligned and fixed by a biocompatible surrounding hydrogel, creating a hybrid anisotropic hydrogel (Anisogel), of which the physical, mechanical, and chemical properties can be tailored. The microgels are rendered cell-adhesive with GRGDS and incorporated either inside a cell-adhesive fibrin or bioinert poly(ethylene glycol) hydrogel to strongly interact with fibroblasts. GRGDS-modified microgels inside a fibrin-based Anisogel enhance fibroblast alignment and lead to a reduction in fibronectin production, indicating successful replacement of structural proteins. In addition, YAP-translocation to the nucleus increases with the concentration of microgels, indicating cellular sensing of the overall anisotropic mechanical properties of the Anisogel. For bioinert surrounding PEG hydrogels, GRGDS-microgels are required to support cell proliferation and fibronectin production. In contrast to fibroblasts, primary nerve growth is not significantly affected by the biomodification of the microgels. In conclusion, this approach opens new opportunities towards advanced and complex aECMs for tissue regeneration.

The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD¹⁵⁴Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers. The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.

This work addresses the influence of distinct microstructures and deep rolling parameters on the behaviour of AISI 1060 steel. For this purpose, the work material was initially subjected to subcritical and full annealing as well as to hardening through quenching and tempering. The specimens were subsequently deep rolled under different rolling pressures and numbers of passes. The findings indicate that plastic deformation increases with rolling pressure and number of passes due to more intense cold working and that under identical deep rolling conditions the fully annealed material presents more severe deformation than the subcritically annealed samples. Moreover, the ability of deep rolling to increase surface hardness decreases with the elevation of the hardness of the original material. The values of the yield and ultimate tensile strength were affected in different manners by deep rolling depending on work material condition and the tensile residual stresses observed after turning were converted into compressive values by deep rolling. Finally, the elevation of rolling pressure and number of passes presented distinct effects on the microhardness distribution beneath the surface depending on the work material condition.

The load carrying capacity of the tooth root mainly depends on its fillet geometry and subsurface integrity, which are affected by the hard finish processes. This paper analyzes the contact conditions in continuous generating grinding and aims to fill the knowledge gap concerning the elementary effects during penetration of tool tip and gear tooth root fillet. In order to obtain fundamental understanding of this process, the three-dimensional removal simulation software CutS® was used. The gained results show that the simulated data correlate to experimental results concerning tool wear and thermal load on gear subsurface. Thereby, the reasonable use of vitrified bond corundum-tools is severely restricted by grinding burn and macro-geometrical wear, which can be described by the tool surface normal feed rate v fn.max . An analytical approach to the calculation of v fn.max is presented, which can be applied on a practical scale.

In order to increase tool life and improve workpiece quality, cutting processes with geometrically defined cutters demand inserts with a prepared cutting edge. Chamfers are widely used in many processes, since they can provide edge strengthening without damaging the chip flow. In order to achieve a stable and reliable cutting process, uniform chamfer geometry along the insert and high edge quality are necessary. For this, proper grinding strategies for chamfer manufacturing must be taken into account. With the objective of getting knowledge about the chamfer manufacturing process, strategies for grinding of chamfers are investigated in this paper. Chamfers were ground on PCBN, mixed ceramic and cemented carbide cutting inserts with a vitrified bond diamond grinding wheel. A single grain chip thickness model is used to characterize the process and different grinding strategies are analyzed in terms of reduction of chamfer geometry deviation. It was found that high insert rotational speeds increase the edge chipping and that the cutting insert material has a considerable influence on the chamfer geometry deviation.

The use of cemented tungsten carbide inserts in hard machining requires proper coatings and edge micro-geometries. A suitable choice of these factors enables the reduction of cutting forces, the increase of tool life and the improvement of workpiece surface quality. However, the effects of the edge preparation method and coating process on the substrate properties influence the performance of the insert during cutting. In this context, the influence of two different edge preparation methods (plunge-face grinding and brushing) on the performance of TiAlN-coated cemented tungsten carbide inserts during hard turning is investigated. In general, higher values of surface roughness (Rz ≅ 0.3 μm) and edge chipping (Rk ≅ 4.5 μm) were observed for brushed inserts in comparison to the ground tools (Rz ≅ 0.2 μm, Rk ≅ 3.7 μm). Moreover, higher compressive residual stresses are induced by brushing in comparison to grinding (≅ 500 MPa against ≅ 400 MPa). In turning tests, cutting forces for the ground inserts are approximately 10% higher than for the brushed inserts. However, higher wear values are better related to lower compressive residual stresses in the substrate than to higher cutting forces.

In various tumours PET/CT with [(18)F]FDG is widely accepted as the diagnostic standard of care. The purpose of this study was to compare a dedicated [(18)F]FDG PET/MRI protocol with [(18)F]FDG PET/CT for TNM staging in a cohort of oncological patients.A dedicated [(18)F]FDG PET/MRI protocol was performed in 73 consecutive patients (mean age of 59 years, range 21 - 85 years) with different histologically confirmed solid primary malignant tumours after a routine clinical FDG PET/CT scan (60 min after injection of 295 ± 45 MBq [(18)F]FDG). TNM staging according to the 7th edition of the AJCC Cancer Staging Manual was performed by two readers in separate sessions for PET/CT and PET/MRI images. Assessment of the primary tumour and nodal and distant metastases with FDG PET/CT and FDG PET/MRI was based on qualitative and quantitative analyses. Histopathology, and radiological and clinical follow-up served as the standards of reference. A McNemar test was performed to evaluate the differences in diagnostic performance between the imaging procedures.From FDG PET/CT and FDG PET/MRI T stage was correctly determined in 22 (82 %) and 20 (74 %) of 27 patients, N stage in 55 (82 %) and 56 (84 %) of 67 patients, and M stage in 32 (76 %) and 35 (83 %) of 42 patients, respectively. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for lymph node metastases were 65 %, 94 %, 79 %, 89 % and 87 % for PET/CT, and 63 %, 94 %, 80 %, 87 % and 85 % for PET/MRI. The respective values for the detection of distant metastases were 50 %, 82 %, 40 %, 88 % and 76 % for PET/CT, and 50 %, 91 %, 57 %, 89 % and 83 % for PET/MRI. Differences between the two imaging modalities were not statistically significant (P 0.05).According to our results, FDG PET/CT and FDG PET/MRI are of equal diagnostic accuracy for TNM staging in patients with solid tumours.

The effectiveness of gas turbines can be improved significantly by decreasing the friction losses. Compared to smooth surfaces riblet-structures have been proven to reduce skin friction in turbulent flow up to 10 %. For the technical application on compressor blades in turbo machines, micro riblet-structures with a riblet width between 20 μm and 120 μm and a depth of the half width are required. Furthermore, the application on compressor blades needs ideal riblet-geometries with an aspect ratio of 0.5, trapezoid groove geometry and a shape accuracy of the compressor blade about 10 μm. This paper presents the relevant influencing factors on the overall shape accuracy as well as the riblet geometry in five axes grinding of riblet-structures on double curved compressor blades. The results show, that the shape accuracy is affected by the CAD data and the macro-geometry of the grinding wheel. Therefore, specialized requirements on the CAD data were defined in order to increase the shape accuracy. To decrease the influence of the grinding wheel geometry on the overall shape geometry, a method adjusting the grinding wheel geometry on double curved surfaces was developed. Furthermore, the effect of the 5 axes kinematic on the aspect ratio and the profile wear was examined.

Therapeutic decisions in non-small cell lung cancer (NSCLC) patients depend on the tumor stage. PET/CT with (18)F-FDG is widely accepted as the diagnostic standard of care. The purpose of this study was to compare a dedicated pulmonary (18)F-FDG PET/MR imaging protocol with (18)F-FDG PET/CT for primary and locoregional lymph node staging in NSCLC patients using histopathology as the reference.Twenty-two patients (12 men, 10 women; mean age ± SD, 65.1 ± 9.1 y) with histopathologically confirmed NSCLC underwent (18)F-FDG PET/CT, followed by (18)F-FDG PET/MR imaging, including a dedicated pulmonary MR imaging protocol. T and N staging according to the seventh edition of the American Joint Committee on Cancer staging manual was performed by 2 readers in separate sessions for (18)F-FDG PET/CT and PET/MR imaging, respectively. Results from histopathology were used as the standard of reference. The mean and maximum standardized uptake value (SUV(mean) and SUV(max), respectively) and maximum diameter of the primary tumor was measured and compared in (18)F-FDG PET/CT and PET/MR imaging.PET/MR imaging and (18)F-FDG PET/CT agreed on T stages in 16 of 16 of patients (100%). All patients were correctly staged by (18)F-FDG PET/CT and PET/MR (100%), compared with histopathology. There was no statistically significant difference between (18)F-FDG PET/CT and (18)F-FDG PET/MR imaging for lymph node metastases detection (P = 0.48). For definition of thoracic N stages, PET/MR imaging and (18)F-FDG PET/CT were concordant in 20 of 22 patients (91%). PET/MR imaging determined the N stage correctly in 20 of 22 patients (91%). (18)F-FDG PET/CT determined the N stage correctly in 18 of 22 patients (82%). The mean differences for SUV(mean) and SUV(max) of NSCLC in (18)F-FDG PET/MR imaging and (18)F-FDG PET/CT were 0.21 and -5.06. These differences were not statistically significant (P0.05). The SUV(mean) and SUV(max) measurements derived from (18)F-FDG PET/CT and (18)F-FDG PET/MR imaging exhibited a high correlation (R = 0.74 and 0.86, respectively; P0.0001). Size measurements showed an excellent correlation between (18)F-FDG PET/MR imaging and (18)F-FDG PET/CT (R = 0.99; P0.0001). The lower and upper limits of agreement between (18)F-FDG PET/CT and (18)F-FDG PET/MR imaging using Bland-Altman analysis were -2.34 to 3.89 for SUV(mean), -7.42 to 4.40 for SUV(max), and -0.59 to 0.83 for the tumor size, respectively.(18)F-FDG PET/MR imaging using a dedicated pulmonary MR imaging protocol, compared with (18)F-FDG PET/CT, does not provide advantages in thoracic staging in NSCLC patients.

Plunge-face grinding is commonly used to finish PCBN cutting inserts. In order to reach an adequate process design, an investigation of the influence of the grinding parameters on the quality of high content PCBN inserts is carried out in this work. For this, the inserts are ground with different grinding wheels (including a variation of grain size and bonding), dressing feed rates, feed and cutting speeds and the edge chipping and flank face roughness are measured. It was found that a reduction of the abrasive grain size as well as an increase of the dressing feed rate lead to an improvement of the insert edge and surface quality. Moreover, a variation of the cutting and feed speeds has only a small influence on the PCBN insert quality.

The aim of this work is to study the influence of selected deep rolling parameters (rolling pressure and number of passes) on the surface integrity of fully annealed AISI 1060 high carbon steel. In addition to the mechanical properties, a comprehensive investigation on surface integrity is carried out. The findings indicate that despite the increase in surface hardness and ultimate tensile stress, deep rolling can negatively affect the yield strength. The amplitude and functional roughness parameters show a considerable reduction after deep rolling, however, increasing rolling pressure and number of passes leads to poorer surface finish. Finally, the tensile residual stress generated by turning shifts to compressive values after deep rolling and the microhardness and microstructure analyses indicate that the depth of the layer affected by deep rolling depends on both the rolling pressure and number of passes. DFG/CRC/653 CAPES Foundation, Ministry of Education of Brazil

The major step of the process chain for regeneration of damaged components is the removal of excess weld material, called re-contouring. This material removal process influences the surface integrity and therefore the functional performance of components. But today the surface integrity, e.g. residual stresses, cannot be predicted to a satisfying degree due to the complex physical effects during the cutting process. This paper investigates the fundamental influence of cutting conditions, tool geometry and weld characteristics on the residual stress formation after 5-axis ball nose end milling of Ti-6Al-4V. It is shown experimentally, that the cutting edge radius is the most influencing factor on residual stresses. Furthermore it is shown, that the thermal effects during cutting have a minor influence on the residual stresses due to the properties of titanium and the ball nose end milling process. Finally a basic physical approach is given to explain the effects by considering only the uncut chip volume, which is generating the final surface.

PCBN cutting inserts have been more often used in order to attend to the demands of an economically viable process and to lead to a proper workpiece surface quality. A proper application of this cutting material requires its adequate processing. Plunge-face grinding is used for finishing the inserts after sintering. To choose a suitable grinding tool and process parameters, the properties of the ground cutting inserts must be taken into account. Therefore, the influence of PCBN grain size and composition on the insert cutting edge and surface quality has to be investigated. This work aims to give an overview of material removal mechanisms, process forces and abrasive grain wear during grinding different PCBN inserts. It was found that the insert quality depends mainly on the material removal mechanism, which in the studied case is defined by the PCBN grain size.

Residual stresses can cause part distortion especially in the case of large components such as structural parts in aerospace industry. Therefore, this paper investigates the machining induced residual stresses for milling of a workpiece material with increasing usage in industry, the β-annealed titanium alloy Ti6Al4V. This thermal treatment results in a large grained material structure. For this reason X-ray diffraction, the standard residual stress measurement method, cannot be used for stress determination. In this paper an adopted indirect measurement method, the layer removal method is discussed. With respect to the material removal, two different methods are investigated, electrochemical material removal and laser ablation. Finally, the influence of the tool wear on the residual stress state after face milling is analyzed. Lower Saxony Ministry for Economics, Labour and Transport Premium Aerotec GmbH, Varel

In order to optimize the cutting performance of end mills, the geometry of such cutters is optimized by toolmakers constantly. As a result of geometric changes, process forces can be reduced, i.e. by serrated end mills. Tools with unequal helix angles can lead to an increase of process stability. In this paper, a method to calculate the process forces of end mills with complex geometries is presented. The method for calculating the process forces is designed for the application for stability analysis of end mill cutters with complex geometries. A basic introduction of the method for the stability prediction of such tools is given. Cutting forces of end mills are analyzed at incremental axial depth of cuts to show the influence of the tool geometry on the process forces. The comparison with experimental data verifies this method and shows the influence of further effects on the process forces. Furthermore, stability charts obtained with the Semi-Discretization Method are presented to show the potential of end mills with complex geometries regarding stability improvement. Ministry for Science and Culture of Lower Saxony (MWK)

Purpose To assess the feasibility of non-Gaussian DWI as part of a FDG-PET/MRI protocol in patients with histologically proven non-small cell lung cancer. Material and methods 15 consecutive patients with histologically proven NSCLC (mean age 61 ± 11 years) were included in this study and underwent whole-body FDG-PET/MRI following whole-body FDG-PET/CT. As part of the whole-body FDG-PET/MRI protocol, an EPI-sequence with 5 b-values (0, 100, 500, 1000 and 2000 s/mm2) was acquired for DWI of the thorax during free-breathing. Volume of interest (VOI) measurements were performed to determine the maximum and mean standardized uptake value (SUVmax; SUVmean). A region of interest (ROI) was manually drawn around the tumor on b = 0 images and then transferred to the corresponding parameter maps to assess ADCmono, Dapp and Kapp. To assess the goodness of the mathematical fit R2 was calculated for monoexponential and non-Gaussian analysis. Spearman's correlation coefficients were calculated to compare SUV values and diffusion coefficients. A Student's t-test was performed to compare the monoexponential and non-Gaussian diffusion fitting (R2). Results T staging was equal between FDG-PET/CT and FDG-PET/MRI in 12 of 15 patients. For NSCLC, mean ADCmono was 2.11 ± 1.24 × 10−3 mm2/s, Dapp was 2.46 ± 1.29 × 10−3 mm2/s and mean Kapp was 0.70 ± 0.21. The non-Gaussian diffusion analysis (R2 = 0.98) provided a significantly better mathematical fitting to the DWI signal decay than the monoexponetial analysis (R2 = 0.96) (p Conclusion Simultaneous PET and non-Gaussian diffusion acquisitions are feasible. Non-Gaussian diffusion parameters show a good correlation with SUV and might provide additional information beyond monoexponential ADC, especially as non-Gaussian diffusion exhibits better mathematical fitting to the decay of the diffusion signal than monoexponential DWI.

The enantiomers of the potent σ1 ligand fluspidine (1) were prepared by using chiral preparative HPLC. Synthesis of racemic tosylate 2 and subsequent separation of enantiomers yielded (R)-2 and (S)-2 in excellent enantiomeric purities. The fluspidine enantiomers (R)-1 and (S)-1 were synthesized from (R)-2 and (S)-2 by nucleophilic substitution with tetra-n-butyl-ammonium fluoride, affording (R)-1 with 99.6% ee and (S)-1 with 96.4% ee. Tosylates (R)-2 and (S)-2 can also serve as precursors for the radiosynthesis of enantiomerically pure radiotracers [18F](R)-1 and [18F](S)-1. The absolute configuration of the pure enantiomers was elucidated by comparison of their CD spectra with a calculated CD spectrum of a simplified model compound. In receptor binding studies, both enantiomers displayed very high σ1 receptor affiniy and selectivity against the σ2 receptor. (R)-Fluspidine ((R)-1) is the eutomer, with a K1 value of 0.57 nM and a eudysmic ratio of 4. Incubation of (R)-1 and (S)-1 with rat liver microsomes led to the identification of seven and eight metaboites, respectively. Although the S-configured enantiomer formed additional metabolite (S)-1-3, it ist metabolically more stable than (R)-1.

In order to increase tool life and workpiece surface quality, cutting processes with geometrically defined cutting edges demand inserts with a targeted prepared edge. For example, chamfers are largely used in many processes to provide edge strengthening without damaging the chip flow. In order to achieve a stable and reliable cutting process, small and uniform chamfers are necessary. In this context, the influence of grinding parameters on the edge quality and on the chamfer width deviations is investigated. It was found that larger abrasive grains increase edge chipping and that elastic deformation during chamfer grinding at insert corner radius is the main responsible for chamfer width deviation.

The presented approach evaluates the application of the surface integrity of machined components as load sensors. Residual stress relaxation due to mechanical load is utilized to retrieve information on the load history of a component. The critical load stress, the sensitivity and the relaxation gradient are quantified and analyzed for AISI 1060 steel. More specifically, the influence of heat treatment and therefore of the materials ultimate strength has been evaluated. The results show that the knowledge on the error determining the residual stress is crucial for the accuracy of the approach. Furthermore, a sufficient relaxation gradient has to be provided by low residual stress sensitivity and high initial residual stress magnitude. Both properties can be influenced by heat treatment and machining.

Due to their low load resistance, sharp ground cutting edges are generally considered disadvantageous to high performance cutting processes. Consequently, providing additional cutting edge preparation in order to enhance tool-lifetime and – performance has become increasingly important. In this context, the following paper presents a novel method for generating customized cutting edges by means of grinding. An approximation of general round edges by applying several chamfers has been proposed and a geometric model for designing these special edges has been suggested. Grinding tests have been carried out to verify the reliability of the new method. The relative errors caused by the limited precision of the machine tool have also been taken into account. Furthermore, an improvement of the edge quality based on the implementation of the micro geometry has been demonstrated.

In contrast to the established role of epidermal growth factor receptor (EGFR) inhibitors for the first-line treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR blockade and of EGFR molecular testing in the second-line treatment remains less clear. The irreversible pan-ErbB family inhibitor afatinib (Gi(l)otrif®) was recently FDA- and EMA-approved for the second-line treatment of NSCLC with squamous cell histology irrespective of the EGFR mutational status (LUX-Lung 8). Contrariwise, results from the TAILOR and DELTA trials among retrospective biomarker analyses show the predictive value of the EGFR mutational status for efficacy of reversible EGFR inhibitors also as a second-line therapy. This mini review critically summarizes the current role of EGFR-targeting strategies in the second-line treatment of NSCLC with special respect to afatinib in light of emerging T790M-specific EGFR and immune check point inhibitors. The review also emphasizes the urgent need for reliable biomarkers to guide therapeutic decision-making and outlines prospective changes to the second-line landscape with some of the current second-line treatment concepts likely to be moved to the first-line.

In diesem Kapitel werden wir die in den vorherigen Kapiteln ausgefuhrte Basis komplexer Systeme mittels Modellen zu Sozialtechniken ausgestalten. Wir beginnen damit, Fuhrung in komplexen sozialen Systemen mit Hilfe der Dilts Pyramide zu beschreiben und am Beispiel einer werteorientierten Fuhrung zu konkretisieren.

Advanced driver assistance systems (ADAS) offer compelling benefits for vehicle drivers. However, they also require a deep integration with safety critical vehicle functions such as steering, acceleration, and breaking. This fact makes it relevant to review ADAS not only with regard to safety, but also with regard to security. It constitutes a serious impact on the safety of passengers if an attacker gets in the position to manipulate ADAS components.

Nachdem wir in den vorherigen Kapiteln wesentliche Eigenschaften komplexer Systeme kennengelernt haben, wollen wir uns in diesem Kapitel der Regulation von Komplexitat in Projekten weiter nahern. Dies tun wir, indem wir auf die grundlegenden Moglichkeiten der Regulation eingehen. Diese benotigen wir als Voraussetzung, um die in den folgenden Kapiteln aufgefuhrten Theorien und Modelle sowie Beispiele einordnen, verstehen und anwenden zu konnen.

Nano letters 17(6), 3782-3791 (2017). doi:10.1021/acs.nanolett.7b01123, Published by ACS Publ., Washington, DC

In diesem Kapitel spannen wir einen Bogen von unseren Grundannahmen und Glaubensatzen, uber das „Grose Bild“, mit dem wir Projektmanagement betreiben, hin zu unserem Verstandnis von Komplexitat und damit verbundenen Konsequenzen.

Im vorherigen Kapitel haben wir verschiedene Modelle zu Sozialtechniken vorgestellt und diese Modelle mit Anwendungsbeispielen verdeutlicht. In diesem Kapitel wollen wir einige der Modelle auf bestehende Managementsysteme anwenden, um besser zu verstehen, was sie bewirken konnen und was nicht. Auserdem werfen wir mittels „fluider Organisationen“ ein neues Licht auf die „klassischen“ Dilemmata Projekt-Linie und virtuelles Team. Hierbei haben wir nicht den Anspruch, diese Themen mit Hilfe der obigen Modelle erschopfend zu behandeln, was auch sicherlich nicht gelingen durfte. Jedoch haben wir den Anspruch, mittels der ausgewahlten Modelle und deren Anwendung im jeweiligen Thema eine neue Perspektive zu offnen.

Applying bioceramics for complex-shaped endoprostheses promises to improve the implant durability significantly. High precision grinding and polishing processes for free-formed ceramic surfaces are therefore essential. The contact conditions for grinding with toric pins are focused to ensure a constant material removal along the tool path. Based on the geometrical intersection, it is possible to calculate the roughness. Furthermore, the grinding layer topography and the grinding kinematics are taken into account to predict the resulting roughness, which is verified by grinding experiments. The wear of machined ceramic pairings is therefore reduced by a factor of 30 compared to conventional cobalt-chrome–polyethylene pairings.

Since the 1930s iron-aluminides are investigated due to their excellent corrosion resistance, low density and high specific strength. However, little work has been carried out on the machining of these alloys since then. This paper deals with grinding of Fe-26Al- 4Cr (at.%) with corundum grinding wheels and shows that the material can be machined in a ductile way, regardless of the material grain size. Material removal rates below Q w = 0.75 mm3/mms and open grinding wheel topographies lead to low grinding temperatures and an advantageous chip removal. Thus, high process reliability regarding workpiece quality and tool wear can be reached.

In this paper the performance of a magnesium based implant system is analyzed. A special emphasis is placed on the impact of stress on the corrosion behavior of the magnesium alloy. An implant system containing a plate and 4 corresponding screws is machined from Mg LAE442. Its corrosion behavior is tested in-vivo in New Zealand White Rabbits for 6 and 12 weeks of implantation. The plate is monocortically fixated on the medial tibia. At the interface between screw and plate increased corrosion is observed. This phenomenon is stronger on the caudal side of the screw. Parallel to the in-vivo test the influence of stress load on the corrosion rate is analyzed for LAE442 in in-vitro tests. Compressive load is applied on cylindrical specimens in axial direction and the corrosion rate is measured in 0.9 wt% NaCl solution by eudiometry and mass loss. Additionally rectangular samples are bent to apply tensile stress on the surface. A drop of 5 wt% NaCl is deposited on the surface and the corrosion is evaluated by microscopic images. It is shown that stress essentially influences the corrosion rate. While tensile stress decreases the corrosion, compressive stress leads to higher corrosion rates.

The mass reduction of components is one of the most effective ways to reduce fuel consumption and emissions in the automotive and aircraft industry. A lightweight strategy used for highly loaded components is the combination of different materials to workpiece compounds. In that way components can be designed depending on the local load using the most qualified material. For the production of high-performance workpiece compounds high quality requirements concerning the accuracy of dimension and shape as well as surface roughness must be fulfilled. However, machining of workpiece compounds leads to unfavorable changes of the workpiece quality in comparison to machining of the single materials. Significant shape deviations occur when different materials are machined alternately in one cutting operation. This is due to unequal material properties, cutting characteristics, chip formation mechanisms as well as characteristic interactions between the single components. This paper describes the causes of the three main criteria material height deviation, transition deviation and surface roughness deviation that significantly influence the surface quality in parallel machining. The focus is on the process understanding as well as modeling of the surface defects. The approaches and results show that the characteristic shape deviations can be predicted. With the knowledge of the causes that lead to the surface defects in parallel machining it is possible to optimize the process setup for a surface quality oriented machining process of a workpiece compound.

Since grinding is used to finish flank faces, a cutting edge preparation by means of this same process offers the possibility of finishing an insert in one clamping. On the other hand, cutting edge preparation in the region of insert corner radius demands a new method as a result of machine kinematic limitations. This work presents an investigation of cutting edge preparation of PCBN inserts by grinding and the verification of their applicability in hard turning. Results showed that the used method to prepare edge micro geometries is adequate and asymmetric roundings can increase tool life and compressive residual stresses.

We synthesized and investigated the NMDA and σ₁ receptor affinity of enantiomerically pure 2-(2-phenyl-1,3-dioxan-4-yl)ethanamines 17-26. The primary amines (R,R)-18-20 with an axially oriented phenyl moiety in position 2 interacted with high enantioselectivity (eudismic ratios 70-130) and high affinity (K(i)((R,R)-19) = 13 nM) with the PCP binding site of the NMDA receptor. Introduction of an N-benzyl moiety led to potent σ₁ ligands including compound (S,R)-22 (K(i) = 6 nM) with an equatorially oriented phenyl moiety in position 2.

A new strategy for the synthesis of tetrahydro-3-benzazepinones 6 by reductive amination of keto acid 3 and subsequent carbonyl diimidazole (CDI) mediated cyclization was developed. Use of enantiomerically pure (R)-1-phenylethylamine led to the formation of diastereomeric lactams (Rα-R)-6d and (Rα-S)-6e in a 80:20 ratio. Diastereoselective alkylation of (Rα-R)-6d, BH3-mediated reduction and exchange of the N-phenylethyl substituent provided enantiomerically pure tetrahydro-3-benzazepines with various substituents in the 1-, 3-, and 4-positions. High σ1 affinity was achieved with a benzyl, cyclohexylmethyl, or 1-phenylethyl moiety at the N-atom. Whereas (R)-configuration of the N-substituent is crucial for high σ1 affinity, the configuration of the 3-benzazepine ring system does not influence the σ1 affinity considerably. Introduction of additional substituents in the 1-position led to almost complete loss of σ1 affinity. Potent σ1 ligands show high selectivity against the σ2 subtype and the NMDA receptor.

Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are effective cancer therapeutics, but tumors harboring RAS mutations are resistant. To functionally dissect RAS-mediated resistance, we have studied clinically approved anti-EGFR antibodies, cetuximab and panitumumab, in cancer models. Both antibodies were equally cytotoxic in vitro. However, cetuximab, which also triggers antibody-dependent cellular cytotoxicity (ADCC), was more effective than panitumumab in vivo. Oncogenic RAS neutralized the activity of both antibodies in vivo. Mechanistically, RAS upregulated BCL-XL in cancer cell lines and in primary colorectal cancers. Suppression of BCL-XL by short hairpin RNA or treatment with a BH3 mimetic overcame RAS-mediated antibody resistance. In conclusion, RAS-mutant tumors escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacological targeting of RAS effectors can restore sensitivity to antibody therapy.

The enantioselective desymmetrization of a prochiral 3-O-silyl protected pentane-1,3,5-triol derivative was achieved by lipase-catalysed hydrolysis. The lipase from B. cepacia led to 95.4% enantiomeric excess (ee)of the (R)-configured compound (R)-4 at a theoretical yield of 79% and was isolated with 98.2% ee and 27% yield. Furthermore, it was found that the ee switched from an excess of (R)-4 to an excess of (S)-4 during the course of the reaction using crude lipase from C. rugosa under the same conditions. This finding was investigated in detail and compared to the change of substrate selectivity known for the lipase from M. miehei. It is supposed that both phenomena may result from a movement of the lid.

Shine a light: a circular dichroism effect in the ±10 % regime on randomly oriented chiral molecules in the gas phase is demonstrated. The signal is derived from images of photoelectron angular distributions produced by resonance-enhanced multiphoton ionization and allows the enantiomers to be distinguished. To date, this effect could only be generated with a synchrotron source. The new tabletop laser-based approach will make this approach far more accessible.

The design of the cutting tool microgeometry influences the thermo-mechanical load profile on the wedge. Applying the appropriate hone design stabilizes the cutting edge, leads to improved wear behavior and higher tool life. Higher process forces and temperature, induced by larger hone, can be described as a side effect of cutting edge preparation, which should also be observed. This paper presents the quality oriented cutting edge preparation via abrasive brushing. The influence of the hone design on process forces, wear behavior and tool life of coated inserts will be analyzed within a wide range of cutting edge microgeometries and process parameters.

Residual stresses can cause part distortion especially in the case of large components such as structural parts in aerospace industry. Therefore, this paper investigates the machining induced residual stresses for milling of a workpiece material with increasing usage in industry, titanium. For stress determination a practical modification of an indirect measuring method, the layer removal method, is applied, as it can offer advantages compared to X-ray-measurements. It is robust against material properties such as grain size or texture which can complicate the X-ray-method. Afterwards two typical machining processes, face milling and peripheral milling are investigated regarding residual stress. A correlation between process forces and value and depth of the induced stresses is identified by a variation of feed per tooth and the tool geometry by means of usage of a worn tool. Increasing cutting speed leads to increased penetration depth in case of face milling and did not exhibit strong influence on the end milled subsurface. Lower Saxony Ministry for Economics, Labour and Transport/QualiTi WB3-80121829