Transformation properties and microstructure of sputter-deposited Ni-Ti shape memory alloy thin films

The influence of annealing parameters on the martensitic phase transformation in sputter-deposited Ti rich Ni-Ti films is systematically studied by differential scanning calorimetry and by transmission electron microscopy. The annealing temperature range extends from the crystallization temperature of the films up to 900°C. For increasing temperature, multiple phase transformations, transformations via an R-phase or direct martensite/austenite transformations are observed. A similar behavior is found for increasing annealing time. Related changes of the film microstructure, such as the strongly varying distribution of round Ti2Ni precipitates in the grains, are analyzed. Transformation temperatures could be shifted over a wide range by adjusting the film composition from 48 to 54 at.% Ti. The corresponding transformation curves, grain structure as well as nature and amount of precipitates were investigated. No subsequent annealing process is required for films deposited on substrates heated above about 500°C. In this case, the as-deposited films have a very fine-grained and homogeneous microstructur

The Foreign Direct Investment Location Decision: A Contingency Model of the Foreign Direct Investment Location Decision-Making Process

Despite considerable prior research into foreign direct investment (FDI) location decisions, our understanding of the processes underlying such decisions is still limited. Findings from work based in the economics and behavioral theories of the multinational enterprise (MNE) both acknowledge that FDI is not a point-of-time decision but a gradual process that yields important changes over its duration. However, these competing traditions both fall short when attempting to portray the actual process by which FDI location decisions are made by managers in MNEs. This gap has been recently attributed to two interrelated limitations. Firstly, level of analysis concerns have artificially separated managerial decision-making processes from the organizational and environmental structures within which they are made. Secondly, because of the complexity inherent in the FDI location decision environment, the study of these decisions has not taken contextual factors into consideration. This study addresses three important questions in order to build our understanding of the FDI location decision-making processes: (1) What are the decision-making processes that lead to FDI location choice? (2) What is the impact of contextual variables on FDI location decision-making processes at different levels of analysis, and are there any patterns of variation in decision processes under different decision conditions? (3) What factors drive final FDI location choice, and can a useful framework or theory be developed that links FDI location decision-making processes and context to drivers of FDI location choice? In order to address level of analysis concerns, the study places the manager at the center of the FDI location decision in modeling and in research, a strategy recommended by an emerging stream of behavioral-focused international business research (Aharoni, 2010; Buckley et al., 2007; Devinney, 2011). By examining FDI location decisions from the perspective of the managers who implement them, it is possible to clarify the nature of processes that lead to FDI location choice, and identify the impact of different elements of decision maker, firm and environmental context on such processes. The conceptual framework builds on Aharoni’s (1966) pivotal research while incorporating findings from broader behavioral managerial decision models and international business research. The framework is based on the assumption that FDI location decision-making processes and final choice are contingent upon interactions between the environmental, firm and decision maker context under which the decision is made. The research was undertaken in three phases. Phase 1 included a literature review that covered research on the MNE, internationalization, and decision making. The findings of the review identified key aspects of FDI location decision context and led to the development of an initial contingency framework of strategic decision making. Phase 2 consisted of an exploratory case study of twenty four FDI location decisions. The initial contingency framework developed during the literature review was used during this stage to identify the relationship between decision-making processes and contextual variables at the case decisions. By drawing on results from the exploratory research, an initial conceptual model and a set of propositions were developed. In Phase 3, twenty case studies were theoretically sampled from a pool of MNEs of varying size and parent-country nationality within the knowledge-based industries. The data collection and analysis followed a process, event-driven approach to case study research involving the mapping of key sequences of events as well as within- and cross-case analysis. The results identify the key elements of the decision process that explain FDI location behavior and develop a framework that links them together and makes them sensible. The four key elements of the FDI location decision that comprise the framework include: (i) the process, (ii) the context, (iii) patterns, and (iv) location. Research findings show the FDI location decision process as comprising of five broad stages, the content of each driven by a dynamic and evolving interpretation of maximum subjective expected utility. Utility preferences are identified as the consequence of shifting and opaque goals, founded upon imperfect information, operating in an environment marked by uncertainty. Five variations in the overall orientation of utility at case decisions, classified in the study as ‘decision rules,’ proved to be more useful predictors of decision-making behavior than traditional notions of bounded rationality seeking rent extraction and profitability. Decision processes were found to vary in five prototypical patterns, according to clusters of contextual variables that together moderated the level of decision-maker autonomy, hierarchical centralization, rule formalization, commitment to strategy, and politicization of the decision. Patterns are described as FDI location decision-making models, and proposed as an initial step towards the development of a taxonomy of FDI location decision-making processes. Because of the dynamic and staged nature of the process, findings showed that factors that were important at one stage of the decision were not as important at the next. As such, the task of identifying universal drivers of FDI location was deemed an unfeasible one. In place of universal drivers, the initiating force of the investment, the purpose of investment and information sources and networks are identified as the key context-specific determinants of location in FDI decisions. Bounded by uncertainty, chance, the dynamics of the process and decision-maker effects, each of these aspects of the decision served to limit the possible consideration set for investment, and formed the value basis and measures from which to select the most attractive location choice. Despite the contextual differences in these drivers, however, the study revealed a strong pattern that showed that the importance of specific location considerations differed in much the same way across case decisions. During the first stage of case decisions primarily strategic aspects of locations were considered; during the second, considerations relating to the system; operational concerns in the third; implementation concerns in the fourth; and added value factors in the final choice. How each of these concerns was interpreted to reach final location choice differed according to the drivers mentioned previously, although the patterns were the same. This study develops a contingency framework for examining the FDI location decision-making processes of MNEs under different operating conditions. By identifying the four key components of the FDI location decision, their interrelationships and many sources of variance, this thesis shows that despite its complexity, the FDI location decision is amenable to useful conceptual structuring. From an academic standpoint, the framework answers Aharoni’s most recent call to action in ‘Behavioral Elements in Foreign Direct Investment’ (2010) by developing a replicable structure within which to think about incorporating managerial decision models and context into the theory of the MNE. These findings enhance understandings of decision making at MNEs, reconcile a number of inconsistencies between opposing perspectives of MNE theory, and thereby update extant theory so that it has greater relevance in today’s diverse international business environment. From a managerial standpoint, the thesis helps managers to recognize the opportunities and limitations posed by different aspects of decision context so that they are able to tailor their FDI location decision strategies to best suit their needs. Finally, from the perspective of policy markers, research findings provide great support for the use of investment attraction schemes through the use of targeted location marketing and investment incentives.

Temperature controlled martensitic phase transformations in a model NiAl alloy

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The cell adhesion protein CAR is a negative regulator of synaptic transmission

The Coxsackievirus and adenovirus receptor (CAR) is essential for normal electrical conductance in the heart, but its role in the postnatal brain is largely unknown. Using brain specific CAR knockout mice (KO), we discovered an unexpected role of CAR in neuronal communication. This includes increased basic synaptic transmission at hippocampal Schaffer collaterals, resistance to fatigue, and enhanced long-term potentiation. Spontaneous neurotransmitter release and speed of endocytosis are increased in KOs, accompanied by increased expression of the exocytosis associated calcium sensor synaptotagmin 2. Using proximity proteomics and binding studies, we link CAR to the exocytosis machinery as it associates with syntenin and synaptobrevin/VAMP2 at the synapse. Increased synaptic function does not cause adverse effects in KO mice, as behavior and learning are unaffected. Thus, unlike the connexin-dependent suppression of atrioventricular conduction in the cardiac knockout, communication in the CAR deficient brain is improved, suggesting a role for CAR in presynaptic processes

Computational redesign of thioredoxin is hypersensitive towards minor conformational changes in the backbone template

Despite the development of powerful computational tools, the full-sequence design of proteins still remains a challenging task. To investigate the limits and capabilities of computational tools, we conducted a study of the ability of the program Rosetta to predict sequences that recreate the authentic fold of thioredoxin. Focusing on the influence of conformational details in the template structures, we based our study on 8 experimentally determined template structures and generated 120 designs from each. For experimental evaluation, we chose six sequences from each of the eight templates by objective criteria. The 48 selected sequences were evaluated based on their progressive ability to (1) produce soluble protein in Escherichia coli and (2) yield stable monomeric protein, and (3) on the ability of the stable, soluble proteins to adopt the target fold. Of the 48 designs, we were able to synthesize 32, 20 of which resulted in soluble protein. Of these, only two were sufficiently stable to be purified. An X-ray crystal structure was solved for one of the designs, revealing a close resemblance to the target structure. We found a significant difference among the eight template structures to realize the above three criteria despite their high structural similarity. Thus, in order to improve the success rate of computational full-sequence design methods, we recommend that multiple template structures are used. Furthermore, this study shows that special care should be taken when optimizing the geometry of a structure prior to computational design when using a method that is based on rigid conformations

Towards standardization of absolute SPECT/CT quantification: a multi-center and multi-vendor phantom study

Abstract: Absolute quantification of radiotracer distribution using SPECT/CT imaging is of great importance for dosimetry aimed at personalized radionuclide precision treatment. However, its accuracy depends on many factors. Using phantom measurements, this multi-vendor and multi-center study evaluates the quantitative accuracy and inter-system variability of various SPECT/CT systems as well as the effect of patient size, processing software and reconstruction algorithms on recovery coefficients (RC). Methods: Five SPECT/CT systems were included: Discovery™ NM/CT 670 Pro (GE Healthcare), Precedence™ 6 (Philips Healthcare), Symbia Intevo™, and Symbia™ T16 (twice) (Siemens Healthineers). Three phantoms were used based on the NEMA IEC body phantom without lung insert simulating body mass indexes (BMI) of 25, 28, and 47 kg/m2. Six spheres (0.5–26.5 mL) and background were filled with 0.1 and 0.01 MBq/mL 99mTc-pertechnetate, respectively. Volumes of interest (VOI) of spheres were obtained by a region growing technique using a 50% threshold of the maximum voxel value corrected for background activity. RC, defined as imaged activity concentration divided by actual activity concentration, were determined for maximum (RCmax) and mean voxel value (RCmean) in the VOI for each sphere diameter. Inter-system variability was expressed as median absolute deviation (MAD) of RC. Acquisition settings were standardized. Images were reconstructed using vendor-specific 3D iterative reconstruction algorithms with institute-specific settings used in clinical practice and processed using a standardized, in-house developed processing tool based on the SimpleITK framework. Additionally, all data were reconstructed with a vendor-neutral reconstruction algorithm (Hybrid Recon™; Hermes Medical Solutions). Results: RC decreased with decreasing sphere diameter for each system. Inter-system variability (MAD) was 16 and 17% for RCmean and RCmax, respectively. Standardized reconstruction decreased this variability to 4 and 5%. High BMI hampers quantification of small lesions (< 10 ml). Conclusion: Absolute SPECT quantification in a multi-center and multi-vendor setting is feasible, especially when reconstruction protocols are standardized, paving the way for a standard for absolute quantitative SPECT

Albumin-derived peptides efficiently reduce renal uptake of radiolabelled peptides

Contains fulltext : 88022.pdf (publisher's version ) (Closed access)PURPOSE: In peptide-receptor radionuclide therapy (PRRT), the maximum activity dose that can safely be administered is limited by high renal uptake and retention of radiolabelled peptides. The kidney radiation dose can be reduced by coinfusion of agents that competitively inhibit the reabsorption of radiolabelled peptides, such as positively charged amino acids, Gelofusine, or trypsinised albumin. The aim of this study was to identify more specific and potent inhibitors of the kidney reabsorption of radiolabelled peptides, based on albumin. METHODS: Albumin was fragmented using cyanogen bromide and six albumin-derived peptides with different numbers of electric charges were selected and synthesised. The effect of albumin fragments (FRALB-C) and selected albumin-derived peptides on the internalisation of (111)In-albumin, (111)In-minigastrin, (111)In-exendin and (111)In-octreotide by megalin-expressing cells was assessed. In rats, the effect of Gelofusine and albumin-derived peptides on the renal uptake and biodistribution of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide was determined. RESULTS: FRALB-C significantly reduced the uptake of all radiolabelled peptides in vitro. The albumin-derived peptides showed different potencies in reducing the uptake of (111)In-albumin, (111)In-exendin and (111)In-minigastrin in vitro. The most efficient albumin-derived peptide (peptide #6), was selected for in vivo testing. In rats, 5 mg of peptide #6 very efficiently inhibited the renal uptake of (111)In-minigastrin, by 88%. Uptake of (111)In-exendin and (111)In-octreotide was reduced by 26 and 33%, respectively. CONCLUSIONS: The albumin-derived peptide #6 efficiently inhibited the renal reabsorption of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide and is a promising candidate for kidney protection in PRRT.1 februari 201

Variability in lutetium-177 SPECT quantification between different state-of-the-art SPECT/CT systems

Background: Quantitative SPECT imaging in targeted radionuclide therapy with lutetium-177 holds great potential for individualized treatment based on dose assessment. The establishment of dose-effect relations requires a standardized method for SPECT quantification. The purpose of this multi-center study is to evaluate quantitative accuracy and inter-system variations of different SPECT/CT systems with corresponding commercially available quantitative reconstruction algorithms. This is an important step towards a vendor-independent standard for quantitative lutetium-177 SPECT. Methods: Four state-of-the-art SPECT/CT systems were included: Discovery™ NM/CT 670Pro (GE Healthcare), Symbia Intevo™, and two Symbia™ T16 (Siemens Healthineers). Quantitative accuracy and inter-system variations were evaluated by repeatedly scanning a cylindrical phantom with 6 spherical inserts (0.5 – 113 ml). A sphere-to-background activity concentration ratio of 10:1 was used. Acquisition settings were standardized: medium energy collimator, body contour trajectory, photon energy window of 208 keV (± 10%), adjacent 20% lower scatter window, 2 × 64 projections, 128 × 128 matrix size, and 40 s projection time. Reconstructions were performed using GE Evolution with Q.Metrix™, Siemens xSPECT Quant™, Siemens Broad Quantification™ or Siemens Flash3D™ algorithms using vendor recommended settings. In addition, projection data were reconstructed using Hermes SUV SPECT™ with standardized reconstruction settings to obtain a vendor-neutral quantitative reconstruction for all systems. Volumes of interest (VOI) for the spheres were obtained by applying a 50% threshold of the sphere maximum voxel value corrected for background activity. For each sphere, the mean and maximum recovery coefficient (RCmean and RCmax) of three repeated measurements was calculated, defined as the imaged activity concentration divided by the actual activity concentration. Inter-system variations were defined as the range of RC over all systems. Re

Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Contains fulltext : 98302.pdf (publisher's version ) (Closed access)PURPOSE: Radiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of (111)In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated. METHODS: Groups of kidney-specific megalin-deficient mice and wild-type mice were injected with (111)In-labelled somatostatin, exendin, neurotensin or minigastrin analogues. Single photon emission computed tomographic (SPECT) images of the kidneys were acquired and analysed quantitatively, or the animals were killed 3 h after injection and the activity concentration in the kidneys was measured. RESULTS: Megalin-deficient mice showed significantly lower uptake of all studied radiolabelled peptides in the kidneys, ranging from 22% ((111)In-octreotide) to 65% ((111)In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation. CONCLUSION: Megalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin. This knowledge may help in the design of strategies to reduce this reabsorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy. Small-animal SPECT is an accurate tool, allowing in vivo quantification of renal uptake and serial measurements in individual mice

CAR links hypoxia signaling to improved survival after myocardial infarction

The coxsackievirus and adenovirus receptor (CAR) mediates homo- and heterotopic interactions between neighboring cardiomyocytes at the intercalated disc. CAR is upregulated in the hypoxic areas surrounding myocardial infarction (MI). To elucidate whether CAR contributes to hypoxia signaling and MI pathology, we used a gain- and loss-of-function approach in transfected HEK293 cells, H9c2 cardiomyocytes and CAR knockout mice. CAR overexpression increased RhoA activity, HIF-1α expression and cell death in response to chemical and physical hypoxia. In vivo, we subjected cardiomyocyte-specific CAR knockout (KO) and wild-type mice (WT) to coronary artery ligation. Survival was drastically improved in KO mice with largely preserved cardiac function as determined by echocardiography. Histological analysis revealed a less fibrotic, more compact lesion. Thirty days after MI, there was no compensatory hypertrophy or reduced cardiac output in hearts from CAR KO mice, in contrast to control mice with increased heart weight and reduced ejection fraction as signs of the underlying pathology. Based on these findings, we suggest CAR as a therapeutic target for the improved future treatment or prevention of myocardial infarction