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Gene therapy in its current design is an irreversible process. It cannot be stopped in case of unwanted side effects, nor can expression levels of therapeutics be adjusted to individual patient’s needs. Thus, the Gene-Switch (GS) system for pharmacologically regulable neurotrophic factor expression was established for treatment of parkinsonian patients. Mifepristone, the synthetic steroid used to control transgene expression of the GS vector, is an approved clinical drug. However, pharmacokinetics and -dynamics of mifepristone vary considerably between different experimental animal species and depend on age and gender. In humans, but not in any other species, mifepristone binds to a high-affinity plasma carrier protein. We now demonstrate that the formulation of mifepristone can have robust impact on its ability to activate the GS system. Furthermore, we show that a pharmacological booster, ritonavir (Rtv), robustly enhances the pharmacological effect of mifepristone, and allows it to overcome gender- and species-specific pharmacokinetic and -dynamic issues. Most importantly, we demonstrate that the GS vector can be efficiently controlled by mifepristone in the presence of its human plasma carrier protein, α1-acid glycoprotein, in a “humanized” rat model. Thus, we have substantially improved the applicability of the GS vector toward therapeutic use in patients., Graphical abstract, Regulable gene therapy may enable personalized genetic medicines. We demonstrate optimized pharmacological control over expression of the neurotrophic factor GDNF from an AAV-Gene-Switch vector. This work substantially advances our understanding of how to gain external control over a regulable vector for treatment of Parkinson’s disease.

Purpose (1) to improve the comprehension of the topographical position of the talar dome beneath the inferior articular surface of the tibia and, (2) to illustrate the changes of possible access to the articular surface of the talar dome during arthroscopic treatment of talar osteochondral defects in an anatomical model. Methods Twenty matched pairs (n = 40) of anatomical ankle specimen were used. All specimens were mounted in a standardized fashion, 3-dimensional radiography was performed in 4 defined positions (maximum dorsiflexion, neutral position, noninvasive distraction, and maximum plantarflexion). All radiographs were analyzed and statistically compared. Results Anterior accessibility was highest in maximum plantarflexion (medial: 49.20 ± 9.86%, lateral: 48.19 ± 8.85%), followed by non-invasive distraction (medial: 33.60 ± 7.96%, lateral: 31.98 ± 8.30%). Neutral position (medial: 19.34 ± 6.90%, lateral: 17.54 ± 6.63%) and dorsiflexion (medial: 15.36 ± 5.03%, lateral: 13.88 ± 4.33%) were not able to significantly increase accessibility. Posterior accessibility was greatest in maximum dorsiflexion (medial: 56.69 ± 9.65%, lateral: 46.82 ± 8.36%), followed by neutral position of the ankle joint (medial: 40.95 ± 8.28%, lateral: 31.06 ± 6.92%). Noninvasive distraction (medial: 31.41 ± 8.18%, lateral: 22.99 ± 7.63%) was still significantly better than plantarflexion (medial: 14.54 ± 5.10%, lateral: 13.89 ± 3.14%) and slightly increased accessibility to the talar dome. Medially, a central area of 5.89 ± 9.76% was accessible by maximum plantarflexion and maximum dorsiflexion from anterior and posterior, respectively, laterally a central blind spot of 4.99 ± 8.61% was detected. Conclusions From an anatomical point of view, maximum joint positions of the ankle (i.e., plantarflexion and dorsiflexion) allow for better access to the talar dome in anterior and posterior ankle arthroscopy. Noninvasive distraction may increase accessibility in anterior approaches, but has no benefit from posterior. Clinical Relevance This study provides insight into the morphology of the ankle joint in a standardized laboratory setup and illustrates the influence of different surgically relevant ankle joint positions. The presented data allow for better preoperative planning for the arthroscopic treatment of talar osteochondral defects.

Purpose: Accurate estimation of the position and orientation (pose) of surgical instruments is crucial for delicate minimally invasive temporal bone surgery. Current techniques lack in accuracy and/or line-of-sight constraints (conventional tracking systems) or expose the patient to prohibitive ionizing radiation (intra-operative CT). A possible solution is to capture the instrument with a c-arm at irregular intervals and recover the pose from the image. Methods: i3PosNet infers the position and orientation of instruments from images using a pose estimation network. Said framework considers localized patches and outputs pseudo-landmarks. The pose is reconstructed from pseudo-landmarks by geometric considerations. Results: We show i3PosNet reaches errors less than 0.05mm. It outperforms conventional image registration-based approaches reducing average and maximum errors by at least two thirds. i3PosNet trained on synthetic images generalizes to real x-rays without any further adaptation. Conclusion: The translation of Deep Learning based methods to surgical applications is difficult, because large representative datasets for training and testing are not available. This work empirically shows sub-millimeter pose estimation trained solely based on synthetic training data., Accepted at International journal of computer assisted radiology and surgery pending publication

Soundscapes offer rich descriptions of composite acoustic environments. Characterizing marine soundscapes simply through sound levels results in incomplete descriptions, limits the understanding of unique features, and impedes meaningful comparisons. Sources that contribute to sound level metrics shift in time and space with changes in biological patterns, physical forces, and human activity. The presence of a constant or chronic source is often interwoven with episodic sounds. Further, the presence and intensity of sources can influence other sources, calling for a more integrated approach to characterizing soundscapes. Here, we illustrate this complexity using data from a national-scale effort, the Sanctuary Soundscape Monitoring Project (SanctSound), an initiative designed to support collection of biological, environmental, and human use data to compliment the interpretation of sound level measurements. Using nine examples from this diverse dataset we demonstrate the benefit of integrating source identification and site features to interpret sound levels across a diversity of shallow water marine soundscapes (

Zusammenfassung. Theoretischer Hintergrund: Misshandlung, Missbrauch und Vernachlässigung (MMV) in der Kindheit stehen mit einem erhöhten Risiko für schizophrene Spektrumsstörungen sowie einem schlechten Verlauf in Zusammenhang. Fragestellung: 1.) Wie verteilen sich die Schweregrade von MMV bei Patient_innen im Vergleich zu Gesunden? 2.) Ist MMV mit höherer Erkrankungsschwere zu Behandlungsbeginn sowie 3.) einem schlechteren Verlauf einer akuten Psychose assoziiert? Methode: MMV wurde bei Patient_innen mit schizophrenen Spektrumsstörungen ( n = 101) und Gesunden ( n = 50) erhoben. Die Patient_innen wurden bei der stationären Aufnahme (t1), Entlassung (t2) und sechs Monate später (t3) untersucht. Ergebnisse: 1.) Gegenüber Kontrollpersonen zeigte sich ein ansteigender Anteil von Patient_innen mit mittleren und hohen MMV-Schweregraden. MMV-Erfahrungen waren zudem 2.) mit häufigerer psychiatrischer Komorbidität sowie 3.) mit höherer Depressivität, störungsunspezifischer Symptomatik und geringerer Lebenszufriedenheit im Verlauf assoziiert. Schlussfolgerungen: MMV-Erfahrungen sind für Erkrankungschwere und akuten Verlauf von schizophrenen Spektrumsstörungen bedeutsam.

Data-driven technologies have found their way into all areas of engineering. In product development they can accelerate the customization to individualized requirements. Therefore, they need a database that exceeds common product data management systems. The creation of this database proves to be challenging because in addition to explicit standards and regulations the product design contains implicit knowledge of product developers. Hence, this paper presents an approach for the semantic integration of the engineering design (SeED). The goal is an automated design of an ontology, which represents the product design in detail.SeED fulfils two tasks. First, the ontology provides a machine-processable representation of the products design, which enables all kind of data-driven technologies. Among other representations, the ontology contains formal logics and semantics. Accordingly, it is a more comprehensible solution for product developers and knowledge engineers. Second, the detailed representation enables discovering of intrinsic knowledge, e.g. design patterns in product generations. Consequently, SeED is a novel approach for efficient semantic integration of the product design.

Vast amounts of information and knowledge is produced and stored within product design projects. Especially for reuse and adaptation there exists no suitable method for product designers to handle this information overload. Due to this, the selection of relevant information in a specific development situation is time-consuming and inefficient. To tackle this issue, the novel approach Intentional Forgetting (IF) is applied for product design, which aims to support reuse and adaptation by reducing the vast amount of information to the relevant. Within this contribution an IF-operator called Cascading Forgetting is introduced and evaluated, which was implemented for forgetting related information elements in ontology knowledge bases. For the evaluation the development process of a test-rig for studying friction and wear behaviour of the cam/tappet contact in combustion engines is analysed. Due to the interdisciplinary task of the evaluation and the characteristics of semantic model, challenges are discussed. In conclusion, the focus of the evaluation is to consider how reliable the Cascading Forgetting works and how intuitive ontology-based representations appear to engineers.

Software of automatic flight control systems requires thorough verification and validation. Traditionally, this is achieved with elaborate development processes following pertinent industry standards. To reduce the development effort, however, new methods have emerged: a model-based software development process is used at the Institute of Flight System Dynamics of the Technical University of Munich for the design of auto-flight systems with MATLAB/Simulink. Besides, the model-based safety assessment (MBSA) framework ExCuSe has been developed, which implements methods for fault modeling and automatic cut-set extraction using the Simulink Design Verifier. This paper proposes an application of MBSA techniques for the efficient requirements and design validation of decision logic in auto-flight-system software. With ExCuSe, software design models of an investigated decision logic are supplemented by models for off-nominal inputs (e.g., a sensor fault) and for the design requirements. With the analysis, either a formal proof is obtained that the investigated decision logic fulfills the requirements under any circumstances (guaranteed properties), or a counterexample illustrates a requirement violation. The functional principle and applicability of the method are demonstrated by the analysis of decision logic of the autoland system of the SAGITTA Demonstrator UAV. ExCuSe is used to prove that the logic guarantees a timely flare initiation so that a safe touchdown sink rate is achieved despite altitude-measurement inaccuracy and closed-loop flare dynamics uncertainty. As virtually all auto-flight systems feature decision logic, this initial demonstration of the technique opens up many opportunities for further applications in future work.

Recent publications describe profiled single trace side-channel attacks (SCAs) against the DES key-schedule of a “commercially available security controller”. They report a significant reduction of the average remaining entropy of cryptographic keys after the attack, with surprisingly large, key-dependent variations of attack results, and individual cases with remaining key entropies as low as a few bits. Unfortunately, they leave important questions unanswered: Are the reported wide distributions of results plausible - can this be explained? Are the results device-specific or more generally applicable to other devices? What is the actual impact on the security of 3-key triple DES? We systematically answer those and several other questions by analyzing two commercial security controllers and a general purpose microcontroller. We observe a significant overall reduction and, importantly, also observe a large key-dependent variation in single DES key security levels, i.e. 49.4 bit mean and 0.9 % of keys < 40 bit (first investigated security controller; other results similar). We also observe a small fraction of keys with exceptionally low security levels that can be called weak keys. It is unclear, whether a device’s side-channel security should be assessed based on such rare weak key outliers. We generalize results to other leakage models by attacking the hardware DES accelerator of a general purpose microcontroller exhibiting a different leakage model. A highly simplified leakage simulation also confirms the wide distribution and shows that security levels are predictable to some extent. Through extensive investigations we find that the actual weakness of keys mainly stems from the specific switching noise they cause. Based on our investigations we expect that widely distributed results and weak outliers should be expected for all profiled attacks against (insufficiently protected) key-schedules, regardless of the algorithm and specific implementation. Finally, we describe a sound approach to estimate actual 3-key triple-DES security levels from empirical single DES results and find that the impact on the security of 3-key triple-DES is limited, i.e. 96.1 bit mean and 0.24 % of key-triples < 80 bit for the same security controller., IACR Transactions on Cryptographic Hardware and Embedded Systems, Volume 2020, Issue 3

Numerical simulation techniques such as Finite Element Analyses are essential in today's engineering design practices. However, comprehensive knowledge is required for the setup of reliable simulations to verify strength and further product properties. Due to limited capacities, design-accompanying simulations are performed too rarely by experienced simulation engineers. Therefore, product models are not sufficiently verified or the simulations lead to wrong design decisions, if they are applied by less experienced users. This results in belated redesigns of already detailed product models and to highly cost- and time-intensive iterations in product development. Thus, in order to support less experienced simulation users in setting up reliable Finite Element Analyses, a novel ontology-based approach is presented. The knowledge management tools developed on the basis of this approach allow an automated acquisition and target-oriented provision of necessary simulation knowledge. This knowledge is acquired from existing simulation models and text-based documentations from previous product developments by Text and Data Mining. By offering support to less experienced simulation users, the presented approach may finally lead to a more efficient and extensive application of reliable FEA in product development.

Gene therapy is currently an irreversible approach, without possibilities to fine-tune or halt the expression of a therapeutic gene product. Especially when expressing neurotrophic factors to treat neurodegenerative disorders, options to regulate transgene expression levels might be beneficial. We thus developed an advanced single-genome inducible AAV vector for expression of GDNF, under control of the approved small molecule drug mifepristone. In the rat brain, GDNF expression can be induced over a wide range up to three hundred-fold over endogenous background, and completely returns to baseline within 3-4 weeks. When applied with appropriate serotype and titre, the vector is absolutely free of any non-induced background expression. In the BACHD model of Huntington's disease we demonstrate that the vector can be kept in a continuous ON-state for extended periods of time. In a model of Parkinson's disease we demonstrate that repeated short-term expression of GDNF restores motor capabilities in 6-OHDA-lesioned rats. We also report on sex-dependent pharmacodynamics of mifepristone in the rodent brain. Taken together, we show that wide-range and high-level induction, background-free, fully reversible and therapeutically active GDNF expression can be achieved under tight pharmacological control by this novel AAV - "Gene Switch" vector.

Mass customization aims to meet individual requirements and, therefore, is one way to attract and retain customers—a key challenge in the design industry. The increase in design automation has offered new opportunities to design customized products at high speed in a way that is cost equivalent to mass production. Design automation is built upon the reuse of product and process knowledge. Ontologies have proven to be a feasible, highly aggregated knowledge representation in engineering design. While product and process knowledge from other lifecycle phases are represented in multiple approaches, the design process of the product as well as the adaption process of product variants is missing, causing breakpoints or additional iterations in design automation. Therefore, suitable knowledge representation tailored to design automation is still missing. Accordingly, this contribution proposes a novel knowledge representation approach to enable design automation for mass customization. Methodically, this novel approach uses semantic enrichment of CAD environments to automatically deduce information about a design task, design rationale, and design process represented by a formal ontology. The integration of the design process significantly differentiates the approach from previous ones. The feasibility of the approach is demonstrated by a bike crank customization process.

Despite recent successes, the advances in Deep Learning have not yet been fully translated to Computer Assisted Intervention (CAI) problems such as pose estimation of surgical instruments. Currently, neural architectures for classification and segmentation tasks are adopted ignoring significant discrepancies between CAI and these tasks. We propose an automatic framework (AutoSNAP) for instrument pose estimation problems, which discovers and learns architectures for neural networks. We introduce 1) an efficient testing environment for pose estimation, 2) a powerful architecture representation based on novel Symbolic Neural Architecture Patterns (SNAPs), and 3) an optimization of the architecture using an efficient search scheme. Using AutoSNAP, we discover an improved architecture (SNAPNet) which outperforms both the hand-engineered i3PosNet and the state-of-the-art architecture search method DARTS.

Collisions between birds and aircraft pose a severe threat to aviation and avian safety. To understand and prevent these bird strikes, knowledge about the factors leading to these bird strikes is vital. However, even though it is a global issue, data availability strongly varies and is difficult to put into a global picture. This paper aims to close this gap by providing an in-depth review of studies and statistics to obtain a concise overview of the bird strike problem in commercial aviation on an international level. The paper illustrates the factors contributing to the occurrence and the potential consequences in terms of effect on flight and damage. This is followed by a presentation of the risk-reducing measures currently in place as well as their limitations. The paper closes with an insight into current research investigating novel methods to prevent bird strikes.

“Simply, people can no longer remember passwords good enough to reliably defend against dictionary attacks, and are much more secure if they choose a password too complicated to remember and then write it down. We’re all good at securing small pieces of paper. I recommend that people write their passwords down on a small piece of paper, and keep it with their other valuable small pieces of paper: in their wallet.”

The infrastructure of instrument landing systems or ground-based augmentation for global navigation satellite systems is often not available at smaller private and general-aviation airfields. This restricts operation there to less accurate approach procedures with lower integrity. Yet, advanced flight guidance and control technology becomes available to smaller aircraft, which promises safety improvements and facilitates increased automation. In this context, a novel vision-augmented automatic landing system for general aviation aircraft has been developed within the German-national funded research project `C2Land.' The system is independent of ground infrastructure and facilitates fully-automatic approach and landing with high accuracy and a high-integrity self-monitoring capability. In this paper, the integration of the prototype of the vision-augmented navigation system into the general aviation fly-by-wire demonstrator aircraft OE-FSD is presented, a highly modified Diamond Aircraft DA42 MNG. The concept for testing and validation of vision-aided automatic landing are discussed and results of simulation, system integration, and flight testing are shown and the capabilities of the C2Land system are demonstrated.

Recombinant adeno-associated viral (rAAV) vectors are a promising tool for therapeutic gene delivery to the brain. However, the delivery of rAAVs across the blood-brain barrier (BBB) and entry into the brain remains a major challenge for rAAV-based gene therapy. To circumvent this limitation, transcranial MRI-guided focused ultrasound (MRIgFUS) combined with intravenously injected microbubbles has been used to transiently and reversibly increase BBB permeability in targeted brain regions. Systemic administration of rAAVs at the time of sonication with focused ultrasound (FUS) facilitates the passage of rAAVs through the BBB and into the brain parenchyma. We and others have demonstrated that FUS-mediated rAAV delivery to the brain results in efficient transduction and transgene expression in vivo. Using this approach, the dose of intravenously injected rAAV variants that can cross the BBB can be reduced by 100 times, achieving significant transgene expression in the brain parenchyma with reduced peripheral transduction. Moreover, this strategy can be used to deliver rAAV variants that do not cross the BBB from the blood to selected brain regions. Here, we provide a detailed protocol for FUS-induced BBB permeability for targeted rAAV delivery to the brain of adult mice and rats.

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein β-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of β-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, β-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of β-synuclein in provoking T-cell-mediated pathology of the central nervous system. In a rat model of multiple sclerosis, β-synuclein-specific T cells induce inflammation and pathological changes in the grey matter of the central nervous system; these cells were also found in higher numbers in patients with multiple sclerosis, particularly those with a chronic progressive course.

This paper examines phonological phrasing in the Kwa language Akan. Regressive [+ATR] vowel harmony between words (RVH) serves as a hitherto unreported diagnostic of phonological phrasing. In this paper I discuss VP-internal and NP-internal structures, as well as SVO(O) and serial verb constructions. RVH is a general process in Akan grammar, although it is blocked in certain contexts. The analysis of phonological phrasing relies on universal syntax–phonology mapping constraints whereby lexically headed syntactic phrases are mapped onto phonological phrases. Blocking contexts call for a domain-sensitive analysis of RVH assuming recursive prosodic structure which makes reference to maximal and non-maximal phonological phrases. It is proposed (i) that phonological phrase structure is isomorphic to syntactic structure in Akan, and (ii) that the process of RVH is blocked at the edge of a maximal phonological phrase; this is formulated in terms of a domain-sensitive CrispEdgeconstraint.

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival and regeneration-promoting factor for dopaminergic neurons in cell and animal models of Parkinson disease (PD). GDNF is currently tested in clinical trials on PD patients with so far inconclusive results. The receptor tyrosine kinase Ret is the canonical GDNF receptor, but several alternative GDNF receptors have been proposed, raising the question of which signaling receptor mediates here the beneficial GDNF effects. To address this question we overexpressed GDNF in the striatum of mice deficient for Ret in dopaminergic neurons and subsequently challenged these mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Strikingly, in this established PD mouse model, the absence of Ret completely abolished GDNF's neuroprotective and regenerative effect on the midbrain dopaminergic system. This establishes Ret signaling as absolutely required for GDNF's effects to prevent and compensate dopaminergic system degeneration and suggests Ret activation as the primary target of GDNF therapy in PD.

Resumen del trabajo presentado al 5th Symposium on Biomedical Research: "Advances and Perspectives In Pharmacology, Drug Toxicity and Pharmacogenetics", celebrado en Madrid del 15 al 16 de marzo de 2018., [Introduction]: TAU protein aggregation is the main characteristic of a group of age-related neurodegenerative diseases called tauopathies. One of the key hallmarks associated with neurodegeneration is the presence of low-grade chronic inflammation, indicating a crosstalk between damaged neuron and glial cells. Previously we have shown that TAUP301L overexpressing neurons released CX3CL1 that activates anti-inflammatory NRF2 signalling in microglial cells in vitro and in vivo. However, the potential role of CX3CR1 in the context of TAU pathology and its implication neuroinflammation are poorly described., [Material and Methods]: Pro-inflammatory markers in immortalized microglia cells (IMG) treated with CX3CL1 were analysed. We also studied mRNA expression levels of NF-ƘB, anti-inflammatory Nrf2 signalling and TAM receptors (TYRO3, AXL and MER) in CX3CR1-deficient primary microglia cells. Finally, the effect of sulforaphane (SFN), a NRF2 inducer, was examined on neuroinflammation in Cx3cr1+/+ and Cx3cr1-/- mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with SFN (50mg/kg, i.p) during three weeks., [Results]: In this study we show that CX3CL1 treatment induced NF-ƘB-p65 and pro-inflammatory cytokines expression. On the other hand, CX3CR1-deficient primary microglia cells present impaired NF-ƘB mRNA expression levels and decreased anti-inflammatory NRF2 signalling, suggesting a dual role of CX3CL1/CX3CR1 axis in neuroinflammation. Lack of CX3CR1 microglia exhibit decreased mRNA expression levels of TAM receptors (TYRO3, AXL and MER) that functionally results in a deficiency in phagocytosis. SFN treatment reverses astrogliosis in Cx3cr1+/+ and Cx3cr1-/-, whereas at microglial level we did not see any improvement in the Cx3cr1-/- mice., [Conclusions]: These findings suggest that CX3CR1-NRF2 axis activation is essential in the modulation of microglial activation associated with tauopathy, and that the associated polymorphisms of CX3CR1 must be taken into account in the design of pharmacological strategies for the treatment of taupathies.

Advanced unmanned aerial vehicles (UAV) become increasingly popular inter alia as low-risk demonstration platforms for new aircraft-design concepts and technologies in aviation industry and research. Due to the experimental nature and complexity of such systems, flight tests regularly require the support of design engineers who monitor and assess the behavior and performance of the aircraft and its subsystems while it is in flight. At the Institute of Flight System Dynamics of the Technical University of Munich (TUM-FSD), the flight guidance and control system for the novel ‘SAGITTA Demonstrator’ UAV has been developed. It enables fully-automatic operation of the aircraft, which has been successfully demonstrated during the maiden flight campaign in July 2017. This paper presents the challenges of real-time monitoring of a fully-automatic UAV and explains how they were solved within the maiden-flight test campaign of the SAGITTA Demonstrator. The ground station setup and displays that were applied to supervise the flight guidance and control system are presented. Experiences gained during the flight tests are gathered and recommendations derived.

Clinical outcome of several Minimally Invasive Surgeries (MIS) heavily depend on the accuracy of intraoperative pose estimation of the surgical instrument from intraoperative x-rays. The estimation consists of finding the tool in a given set of x-rays and extracting the necessary data to recreate the tool’s pose for further navigation - resulting in severe consequences of incorrect estimation. Though state-of-the-art MIS literature has exploited image registration as a tool for instrument pose estimation, lack of practical considerations in previous study design render their conclusion ineffective from a clinical standpoint. One major issue of such a study is the lack of Ground Truth in clinical data -as there are no direct ways of measuring the ground truth pose and indirect estimation accumulates error. A systematic way to overcome this problem is to generate Digitally Reconstructed Radiographs (DRR), however, such procedure generates data which are free from measuring errors (e.g. noise, number of projections), resulting claims of registration performance inconclusive. Generalization of registration performance across different instruments with different Degrees of Freedom (DoF) has not been studied as well. By marrying a rigorous study design involving several clinical scenarios with, for example, several optimizers, metrics and others parameters for image registration, this paper bridges this gap effectively. Although the pose estimation error scales inversely with instrument size, we show image registration generalizes well for different instruments and DoF. In particular, it is shown that increasing the number of x-ray projections can reduce the pose estimation error significantly across instruments - which might lead to the acquisition of several x-rays for pose estimation in a clinical workflow.

Failure cases of black-box deep learning, e.g. adversarial examples, might have severe consequences in healthcare. Yet such failures are mostly studied in the context of real-world images with calibrated attacks. To demystify the adversarial examples, rigorous studies need to be designed. Unfortunately, complexity of the medical images hinders such study design directly from the medical images. We hypothesize that adversarial examples might result from the incorrect mapping of image space to the low dimensional generation manifold by deep networks. To test the hypothesis, we simplify a complex medical problem namely pose estimation of surgical tools into its barest form. An analytical decision boundary and exhaustive search of the one-pixel attack across multiple image dimensions let us localize the regions of frequent successful one-pixel attacks at the image space.

When reusing product knowledge in design processes, developers have to decide which knowledge elements are relevant for a task. Thus, mechanisms of knowledge removal are vital for a successful reuse, but are not yet assisted by procedure models. This contribution introduces Intentional Forgetting as a methodology of intelligent removal processes in ontological knowledge bases. The aim is to support developers by providing relevant contents for reuse systematically. The development process of a test-rig, that is highly based on knowledge reuse, is considered as use case.

The ontology modeling practice of engineering metaproperties of concepts is a well-known technique. Some metaproperties of concepts describe the dynamics of concept instances, i.e. how instances can and cannot be altered. We investigate how deletions in an ontology-based knowledge base interact with the metaproperties rigidity and dependence. A particularly useful effect are delete cascades. We evaluate how rigidity and dependence may guide delete cascades in an engineering application. A case study in the area of product development shows that beyond explicitly defined deletions, our approach achieves further automated and desirable deletions of facts with high precision and good recall.

In comparison to the pilot aboard a manned aircraft, the flight operator of an unmanned aerial vehicle (UAV) has less possibilities to supervise its automatic flight guidance and control system and intervene if necessary. This is especially critical during automatic take-off and landing (ATOL), as these phases of flight demand low reaction time and tolerate little error. This paper presents an online self-monitoring algorithm for the ATOL system of a fixed-wing UAV. It assesses systems, controllers, and flight-performance during the maneuvers and enables automatic decision to alter or abort. The algorithm has been successfully implemented in the flight control system of the SAGITTA Demonstrator UAV, the functional software of which has been developed at the Institute of Flight System Dynamics of the Technical University of Munich. Simulation results and ground testing of the SAGITTA Demonstrator have proven the concept of the self-monitoring algorithm and give an outlook to its applicability in flight.

The ability to conduct an automatic landing maneuver is a key requirement for many unmanned aerial vehicles. By the example of the novel SAGITTA Demonstrator UAV, an autoland algorithm is presented as a modular extension to an automatic flight guidance and control system. At the Institute of Flight System Dynamics of the Technical University of Munich, a procedural definition of the automatic landing has been elaborated and implemented as a finite state machine. Based on this, existing guidance and control modules of the auto flight system are utilized to perform the landing maneuver. Particular attention has been paid to the design of transition conditions of the state machine, as these guide the temporal sequence of the maneuver and must reflect the high uncertainties that prevail concerning the performance of a novel aircraft configuration and its systems. Simulation testing and verification results in combination with ground testing of SAGITTA present a proof of concept of the design and give an outlook to its application during SAGITTA's maiden flight.

BACKGROUND: Adeno-associated virus (AAV) vectors are used to deliver potentially therapeutic genes in clinical trials in Parkinson's disease (PD). Pre-existing immunity to AAV and a local neuroinflammatory response might negatively affect the efficacy of such AAV-mediated gene delivery. METHODS: We pre-immunized rats with wild-type AAV-2. Three months later, we created PD-like lesions by intrastriatal injections of 6-hydroxydopamine (6-OHDA) in 50% of the animals. One month later, we injected AAV2 vector expressing enhanced green fluorescent protein (eGFP) in the striatum. Using immunohistochemistry, we assessed eGFP expression, microglia activation and CD8 T cell infiltration. We also measured AAV-2 specific neutralizing antibody titers in the serum. RESULTS: The number of striatal cells transduced with AAV2 vector expressing eGFP was reduced by 71% in rats pre-immunized with wild-type AAV2 compared to non-immunized animals. We detected elevated numbers of OX6(+) activated microglia in the striatum and circulating AAV2-specific neutralizing antibodies in pre-immunized rats. We also observed that the intrastriatal 6-OHDA injection promoted CD8(+) T cell infiltration and enhanced microglia activation. Nevertheless, the 6-OHDA lesion did not alter AAV2-mediated expression of eGFP in either pre-immunized or non-immunized rats. CONCLUSIONS: Our findings indicate that intracerebral AAV2-based gene therapy is compromised in rats with pre-existing immunity to AAV2. By contrast, a local neuroinflammatory response, caused by intrastriatal a 6-OHDA injection, does not affect viral vector-mediated transgene expression. Our results emphasize the importance of monitoring circulating AAV-specific neutralizing antibodies in patients undergoing intracerebral gene therapy using AAV vectors. Copyright © 2014 John Wiley & Sons, Ltd. peerReviewed

To test different types of noise abatement approach procedures the Institute of Flight Guidance and the Institute of Aerodynamics and Flow Technology performed flight tests on 6 September 2010 with a Boeing 737-700. In total, 13 approaches to the research airport in Brunswick, Germany (EDVE) were flown while the approach area of the airport was equipped with six noise measurement microphones. Brunswick airport is equipped with an experimental ground based augmentation system which allows the implementation of 49 instrument landing system (ILS) look-alike precision approach procedures with different approach angles simultaneously.

Companies are increasingly adopting social software to support collaboration and networking. Although increasing their employees’ connectedness is a major driver for organizations to deploy enterprise social software (ESS), the social connectedness concept itself is still not sufficiently defined and conceptualized. The study therefore provides a richer perspective on social connectedness’s role in an ESS context. The authors thus investigate (1) social connectedness’s antecedents and (2) its impact on employees’ individual performance. With a survey-based investigation among 174 employees of an international business software provider headquartered in Germany, the authors show that both reputation and a critical mass significantly influence employees’ social connectedness. The authors further find that reputation’s effect is significantly stronger than critical mass’s effect and that social connectedness influences employees’ individual performance positively. The findings are discussed in the light of psychological studies and deduce implications for theory and practice.

The SAGITTA Demonstrator is a novel UAV with a digital flight control system being developed by the Institute of Flight System Dynamics of the Technical University of Munich. This paper presents the implementation of an automatic take-off algorithm as a system automation module of the auto flight system. Based on a phase-breakdown of take-off, the implementation features a state machine that covers the procedure of the maneuver and the transition conditions from one phase to another. Through this state machine, the automatic take-off algorithm enables controller modules of the auto flight system and provides corresponding commands for the conduct of take-off. The design of the automatic take-off algorithm focuses on maximizing safety and robustness against uncertainties and disturbances. Presented simulation results prove the concept of the algorithm as well as its robustness to simulated reality effects.

At the Institute of Flight System Dynamics of the Technische Universitat Munchen, a digital flight control system is developed for highly-automated operation of the novel fixed-wing UAV ‘SAGITTA Demonstrator.’ It features an automatic take-off and landing (ATOL) system, for which safety and reliability of operation are crucial, especially with respect to unforeseen interferences, errors or malfunctions. Therefore, functional monitoring and fault detection algorithms are employed to observe aircraft and flight control system performance. Building on these, this paper presents the extension of the ATOL system by an aircraft-condition-based availability algorithm in combination with automated contingency procedures. Depending on the availability status, the conduct of a nominal automatic take-off or landing is automatically aborted with a corresponding contingency maneuver, or continued with an altered procedure at reduced performance. The ATOL contingency procedures for all relevant cases have been designed for SAGITTA and evaluated in simulation. Corresponding results are presented in this paper. Future work includes further testing of the ATOL system in a hardware-in-the-loop environment in preparation for the maiden flight of SAGITTA.

The BlueSky Open Air Traffic Simulator developed by the Control \& Simulation section of TU Delft aims at supporting research for analysing Air Traffic Management concepts by providing an open source simulation platform. The goal of this study was to complement BlueSky with aircraft performance models in order to enable performance-related Air Traffic Management studies. The aircraft performance model developed within this work consists of a kinetic Flight Dynamics Model, which stores the required performance characteristics in a database with type-specific aircraft and engine coefficients. Currently, sixteen commercial turbofan and turboprop aircraft from different range and weight categories are represented. To evaluate the quality of the aircraft performance model, its outputs were compared to results from literature as well as from real flights. It was found that the applied methodologies for the determination of aircraft performance accurately model high-speed drag polars as well as fuel consumption for cruising and taxiing aircraft. The fuel consumption model of climbing and descending aircraft, however, leaves room for improvement. Possible strategies for obtaining a more precise estimation of fuel burn over the entire flight are recommended based on the results of this study. With this work, the BlueSky Open Air Traffic Simulator considers individual aircraft performance. This is an important step in the creation of an open simulation platform for Air Traffic Management research.

Several microorganisms are known to produce a wide variety of surface-active substances, which are referred to as biosurfactants. Interesting examples for biosurfactants are rhamnolipids, glycolipids mainly known from Pseudomonas aeruginosa produced during cultivation on different substrates like vegetable oils, sugars, glycerol or hydrocarbons. However, besides costs for downstream processing of rhamnolipids, relatively high raw-material prices and low productivities currently inhibit potential economical production of rhamnolipids on an industrial scale. This review focuses on cost-effective and sustainable production of rhamnolipids by introducing new possibilities and strategies regarding renewable substrates. Additionally, past and recent production strategies using alternative substrates such as agro-industrial byproducts or wastes are summarized. Requirements and concepts for next-generation rhamnolipid producing strains are discussed and potential targets for strain-engineering are presented. The discussion of potential new strategies is supported by an analysis of the metabolism of different Pseudomonas species. According to calculations of theoretical substrate-to-product conversion yields and current world-market price analysis, different renewable substrates are compared and discussed from an economical point of view. A next-generation rhamnolipid producing strain, as proposed within this review, may be engineered towards reduced formation of byproducts, increased metabolic spectrum, broadened substrate spectrum and controlled regulation for the induction of rhamnolipid synthesis.

European beef consumption has been gradually declining during the past decades, while consumers' concerns about beef safety have increased. This paper explores consumer perceptions of and interest in beef safety and beef safety information, and their role in beef safety assessment and the beef consumption decision making process. Eight focus group discussions were performed with a total of 65 beef consumers in four European countries. Content analysis revealed that European consumers experienced difficulties in the assessment of the safety of beef and beef products and adopted diverging uncertainty reduction strategies. These include the use of colour, labels, brands and indications of origin as cues signalling beef safety. In general, consumer trust in beef safety was relatively high, despite distrust in particular actors. European beef consumption has been gradually declining during the past decades, while consumers' concerns about beef safety have increased. This paper explores consumer perceptions of and interest in beef safety and beef safety information, and their role in beef safety assessment and the beef consumption decision making process. Eight focus group discussions were performed with a total of 65 beef consumers in four European countries. Content analysis revealed that European consumers experienced difficulties in the assessment of the safety of beef and beef products and adopted diverging uncertainty reduction strategies. These include the use of colour, labels, brands and indications of origin as cues signalling beef safety. In general, consumer trust in beef safety was relatively high, despite distrust in particular actors.

Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. Both hallmarks are inseparable and remain diagnostic as described by Alois Alzheimer more than a century ago. Nevertheless, these pathological features are largely abandoned as being the actual pathogenic or neurotoxic factors. The previous, almost exclusive experimental attention on amyloid has shifted over the last 10 years in two directions. Firstly, from the "concrete" deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. A second shift in research focus is from amyloid to tauopathy, and to their mutual relation. The role of Tau in the pathogenesis and disease progression is appreciated as leading to synaptic and neuronal loss, causing cognitive deficits and dementia. Both trends are incorporated in a modified amyloid cascade hypothesis, briefly discussed in this paper that is mainly concerned with the second aspect, that is, protein Tau and its associated fundamental questions. ispartof: International journal of Alzheimer's disease vol:2010 pages:573138- ispartof: location:United States status: published

The objective of the study is to map citizen attitudes towards pigmeat production systems, and to investigate whether these attitudes associate with pork and pork product consumption. A conjoint experimentwas carried out with empirical data collected from 1931 individuals in four European countries with higher-than-average per capita meat consumption (Belgium, Denmark, Poland and Germany). The experiment was based on the following pig farming characteristics: herd size, housing and floor type, efforts to reduce the impact of the production system on the environment, animal feed designed for producing pork with specific fat content, and finally the preferred quality characteristics of the pork end-product. The results of the conjoint analysis were used for a subsequent cluster analysis in order to identify European citizen clusters. Respondents' socio-demographic profile, attitudes towards issues that are expected to influence the way people evaluate pig meat production systems, and consumption frequency of various pork products are used as background information to identify segment profiles. Pork appears to play a substantial role as a part of the diet for most respondents in the four countries of this study. The results of the conjoint experiment at the sample level show that people assigned most importance to animal and environmental well-being as criteria to discriminate between "good" and "bad" pig production practices, despite the fact that their attitudes towards environmental protection, animal welfare and industrial food production were only moderately strong. Moreover, the results of the cluster analysis allowed small-sized, clear-cut clusters of citizens to appear, which pay attention to specific pig farming attributes. In conclusion, attitudes towards environment and nature, animal welfare and the need for an environment-friendly food production were indeed related to citizens' specific attitudes towards pig farming at the cluster level. However, the relationship between citizenship and consumption behaviour was found to be weak. What people think in their role as citizens related to pig production did not appear to significantly influence their pork consumption choices. The objective of the study is to map citizen attitudes towards pigmeat production systems, and to investigate whether these attitudes associate with pork and pork product consumption. A conjoint experimentwas carried out with empirical data collected from 1931 individuals in four European countries with higher-than-average per capita meat consumption (Belgium, Denmark, Poland and Germany). The experiment was based on the following pig farming characteristics: herd size, housing and floor type, efforts to reduce the impact of the production system on the environment, animal feed designed for producing pork with specific fat content, and finally the preferred quality characteristics of the pork end-product. The results of the conjoint analysis were used for a subsequent cluster analysis in order to identify European citizen clusters. Respondents' socio-demographic profile, attitudes towards issues that are expected to influence the way people evaluate pig meat production systems, and consumption frequency of various pork products are used as background information to identify segment profiles. Pork appears to play a substantial role as a part of the diet for most respondents in the four countries of this study. The results of the conjoint experiment at the sample level show that people assigned most importance to animal and environmental well-being as criteria to discriminate between "good" and "bad" pig production practices, despite the fact that their attitudes towards environmental protection, animal welfare and industrial food production were only moderately strong. Moreover, the results of the cluster analysis allowed small-sized, clear-cut clusters of citizens to appear, which pay attention to specific pig farming attributes. In conclusion, attitudes towards environment and nature, animal welfare and the need for an environment-friendly food production were indeed related to citizens' specific attitudes towards pig farming at the cluster level. However, the relationship between citizenship and consumption behaviour was found to be weak. What people think in their role as citizens related to pig production did not appear to significantly influence their pork consumption choices.

[Aims]: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. [Results]: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. [Innovation]: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. [Conclusion]: DMF is ready for clinical validation in PD., This work was supported by grants from Biogen, SAF2013-143271-R and ‘‘Fundación Salud 2000.’’ ILB was recipient of a Ramón y Cajal contract (MICINN-RYC).