Survival and proliferation of human pathogenic Candida species within phagocytes

The opportunistic Candida species, C. albicans and C. glabrata, can colonize multiple organs during systemic infection and face different defense activities of the host. Immune cells, like macrophages, ingest fungal cells into phagosomes facing a hostile environment with low nutrient levels. C. albicans and C. glabrata cells adapt to this limitation inside the phagosome by adjusting their central metabolic pathways. The prerequisite for vitamins cannot be bypassed as these are cofactors, like biotin for which both Candida species are auxotrophic. This thesis aimed to gain new insights into the relevance of fungal biotin acquisition on fungal proliferation in specific host niches, such as the phagosome of macrophages, and virulence. The identified biotin transporter gene VHT1 in C. albicans and C. glabrata contributed to biotin-dependent growth and VHT1 transcription was shown to be regulated by biotin availability and the transcription factor Vhr1. The impact of Vht1-mediated biotin acquisition for intraphagosomal proliferation together with the increased VHR1 and VHT1 expression in phagocytosed fungal cells suggested a limited biotin access in Candida-containing phagosomes. The efficient colonization of C. glabrata and C. albicans in distinct organs and for virulence of C. albicans during systemic candidiasis were dependent on Vht1-mediated biotin acquisition. Overall, these results propose that both species experience biotin limitation in certain host niches and that Vht1-dependent biotin import is a mechanism to overcome this limitation. The evolutionary adaptation of pathogenic Candida species may have originated from ancient interactions with environmental amoebae. Peroxiredoxin-mediated redox homeostasis was essential for survival of C. parapsilosis in amoebae and macrophages. These data showed the importance of micronutrient and redox homeostasis as counterstrategies of pathogenic Candida species to survive phagocytosis and pivotal virulence determinants

Synthesizing Strategies for Needle Steering in Gelatin Phantoms

In medicine, needles are frequently used to deliver treatments to subsurface targets or to take tissue samples from the inside of an organ. Current clinical practice is to insert needles under image guidance or haptic feedback, although that may involve reinsertions and adjustments since the needle and its interaction with the tissue during insertion cannot be completely controlled. (Automated) needle steering could in theory improve the accuracy with which a target is reached and thus reduce surgical traumata especially for minimally invasive procedures, e.g., brachytherapy or biopsy. Yet, flexible needles and needle-tissue interaction are both complex and expensive to model and can often be computed approximatively only. In this paper we propose to employ timed games to navigate flexible needles with a bevel tip to reach a fixed target in tissue. We use a simple non-holonomic model of needle-tissue interaction, which abstracts in particular from the various physical forces involved and appears to be simplistic compared to related models from medical robotics. Based on the model, we synthesize strategies from which we can derive sufficiently precise motion plans to steer the needle in soft tissue. However, applying those strategies in practice, one is faced with the problem of an unpredictable behavior of the needle at the initial insertion point. Our proposal is to implement a preprocessing step to initialize the model based on data from the real system, once the needle is inserted. Taking into account the actual needle tip angle and position, we generate strategies to reach the desired target. We have implemented the model in Uppaal Stratego and evaluated it on steering a flexible needle in gelatin phantoms; gelatin phantoms are commonly used in medical technology to simulate the behavior of soft tissue. The experiments show that strategies can be synthesized for both generated and measured needle motions with a maximum deviation of 1.84mm.Comment: In Proceedings MARS 2020, arXiv:2004.1240

Development of a phantom to modulate the maternal and fetal pulse curve for pulse oximetry measurements

For getting reliable information about the state of health from the fetus and the mother during labor and delivery, a fetal pulse oximeter is being developed. This paper describes the development of a special phantom to verify the algorithms for separating the weak fetal from the dominant maternal optical signal. To reach a realistic behavior it is necessary for two circulations to be controlled independently. Inspired by the natural blood circulation behavior, a RC-System with fixed resistance and capacity was created. Pumping a liquid with a roller pump into the tubes widens them. The digital signal processor (DSP) controls the expansion of the tube diameter by modifying the rotation velocity of the pump for active regulation. Therefore a soft and good enlargeable material was used. The measured values of the pressure sensor enabled active feedback for motor control The determined system characteristics are used to adapt the given pulse curve to the real system behavior. Via a LabView interface it is possible to change curve parameters like amplitude and frequency. The goal was to replicate the pulsation of the blood vessels like in the abdomen of a pregnant woman. Changing the parameters influences the modulation of the signal under consideration of the transfer function. With this phantom it is possible to simulate different scenarios, for example different states of pregnancy or pathogen indications

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

The pathophysiology of sepsis involves activation of acid sphingomyelinase (SMPD1) with subsequent generation of the bioactive mediator ceramide. We herein evaluate the hypothesis that the enzyme exerts biological effects in endothelial stress response. Plasma-secreted sphingomyelinase activity, ceramide generation and lipid raft formation were measured in human microcirculatory endothelial cells (HMEC-1) stimulated with serum obtained from sepsis patients. Clustering of receptors relevant for signal transduction was studied by immunostaining. The role of SMPD1 for macrodomain formation was tested by pharmacological inhibition. To confirm the involvement of the stress enzyme, direct inhibitors (amino bisphosphonates) and specific downregulation of the gene was tested with respect to ADAMTS13 expression and cytotoxicity. Plasma activity and amount of SMPD1 were increased in septic patients dependent on clinical severity. Increased breakdown of sphingomyelin to ceramide in HMECs was observed following stimulation with serum from sepsis patients in vitro. Hydrolysis of sphingomyelin, clustering of receptor complexes, such as the CD95L/Fas-receptor, as well as formation of ceramide enriched macrodomains were abrogated using functional inhibitors (desipramine and NB6). Strikingly, the stimulation of HMECs with serum obtained from sepsis patients or mixture of proinflammatory cytokines resulted in cytotoxicity and ADAMTS13 downregulation which was abrogated using desipramine, amino bisphosphonates and genetic inhibitors. SMPD1 is involved in the dysregulation of ceramide metabolism in endothelial cells leading to macrodomain formation, cytotoxicity and downregulation of ADAMTS13 expression. Functional inhibitors, such as desipramine, are capable of improving endothelial stress response during sepsis and might be considered as a pharmacological treatment strategy to obtain a favorable outcome

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Systematic analysis of volumetric ultrasound parameters for markerless 4D motion tracking

Objectives: Motion compensation is an interesting approach to improve treatments of moving structures. For example, target motion can substantially affect dose delivery in radiation therapy, where methods to detect and mitigate the motion are widely used. Recent advances in fast, volumetric ultrasound have rekindled the interest in ultrasound for motion tracking. We present a setup to evaluate ultrasound based motion tracking and we study the effect of imaging rate and motion artifacts on its performance. Methods: We describe an experimental setup to acquire markerless 4D ultrasound data with precise ground truth from a robot and evaluate different real-world trajectories and system settings toward accurate motion estimation. We analyze motion artifacts in continuously acquired data by comparing to data recorded in a step-and-shoot fashion. Furthermore, we investigate the trade-off between the imaging frequency and resolution. Results: The mean tracking errors show that continuously acquired data leads to similar results as data acquired in a step-and-shoot fashion. We report mean tracking errors up to 2.01 mm and 1.36 mm on the continuous data for the lower and higher resolution, respectively, while step-and-shoot data leads to mean tracking errors of 2.52 mm and 0.98 mm. Conclusions: We perform a quantitative analysis of different system settings for motion tracking with 4D ultrasound. We can show that precise tracking is feasible and additional motion in continuously acquired data does not impair the tracking. Moreover, the analysis of the frequency resolution trade-off shows that a high imaging resolution is beneficial in ultrasound tracking

Smart Objects und Smart Finance für das Supply Chain Management

Logistic transport processes are highly distributed and often subject to disturbances, as they are embedded in dynamic environments that prohibit tight control, as many third-party actors and influences exist. Classical approaches for planning and controlling supply chains based on centralized architectures often encounter their limits managing processes at runtime, due to inherent latencies. Decentralized approaches promise a more robust and timely control. The project SOFiA strives to elevate the machines and objects themselves to smart objects, equipped with an understanding of processes and capable of independent decision-making, rather than a centralized server-based system. This paper discusses the project’s decentralized control architecture and the integration of semantic process models with event-discrete simulations as well as smart payment technology to provide an integrated solution for planning, controlling, monitoring and accounting of logistic processes.Planungs- und Steuerungsprozesse in Supply Chain sind stark verteilt und oft Störungen durch die involvierten Stakeholder und externen Einflussfaktoren ausgesetzt. Die klassischen Ansätze zur Planung und Steuerung bauen auf einer zentralisierten IT-Architektur auf und sind für das Management von kurzfristigen Störungen aufgrund der inhärenten Latenzzeit bei der Übermittlung von Zustandsinformationen zu schwerfällig. In diesem Artikel wird die hierfür entwickelte Lösung des SOFiA-Projekts vorgestellt. Die Lösung besteht aus einer dezentralen Architektur, dem Einsatz von Smart Objects und der ereignis-diskreten Simulation sowie Blockchain-basierte Verfahren für das Smart Contracting und das Smart Payment in Supply Chains

RNA-mediated control of cell shape modulates antibiotic resistance in Vibrio cholerae

Vibrio cholerae, the cause of cholera disease, exhibits a characteristic curved rod morphology, which promotes infectivity and motility in dense hydrogels. Periplasmic protein CrvA determines cell curvature in V. cholerae, yet the regulatory factors controlling CrvA are unknown. Here, we discover the VadR small RNA (sRNA) as a post-transcriptional inhibitor of the crvA mRNA. Mutation of vadR increases cell curvature, whereas overexpression has the inverse effect. We show that vadR transcription is activated by the VxrAB two-component system and triggered by cell-wall-targeting antibiotics. V. cholerae cells failing to repress crvA by VadR display decreased survival upon challenge with penicillin G indicating that cell shape maintenance by the sRNA is critical for antibiotic resistance. VadR also blocks the expression of various key biofilm genes and thereby inhibits biofilm formation in V. cholerae. Thus, VadR is an important regulator for synchronizing peptidoglycan integrity, cell shape, and biofilm formation in V. cholerae

Ultrasound Shear Wave Elasticity Imaging with Spatio-Temporal Deep Learning

Ultrasound shear wave elasticity imaging is a valuable tool for quantifying the elastic properties of tissue. Typically, the shear wave velocity is derived and mapped to an elasticity value, which neglects information such as the shape of the propagating shear wave or push sequence characteristics. We present 3D spatio-temporal CNNs for fast local elasticity estimation from ultrasound data. This approach is based on retrieving elastic properties from shear wave propagation within small local regions. A large training data set is acquired with a robot from homogeneous gelatin phantoms ranging from 17.42 kPa to 126.05 kPa with various push locations. The results show that our approach can estimate elastic properties on a pixelwise basis with a mean absolute error of 5.01+-4.37 kPa. Furthermore, we estimate local elasticity independent of the push location and can even perform accurate estimates inside the push region. For phantoms with embedded inclusions, we report a 53.93% lower MAE (7.50 kPa) and on the background of 85.24% (1.64 kPa) compared to a conventional shear wave method. Overall, our method offers fast local estimations of elastic properties with small spatio-temporal window sizes