Non-Markovian data-driven modeling of single-cell motility

Trajectories of human breast cancer cells moving on one-dimensional circular tracks are modeled by thenon-Markovian version of the Langevin equation that includes an arbitrary memory function. When averagedover cells, the velocity distribution exhibits spurious non-Gaussian behavior, while single cells are characterizedby Gaussian velocity distributions. Accordingly, the data are described by a linear memory model whichincludes different random walk models that were previously used to account for various aspects of cell motilitysuch as migratory persistence, non-Markovian effects, colored noise, and anomalous diffusion. The memoryfunction is extracted from the trajectory data without restrictions or assumptions, thus making our approachtruly data driven, and is used for unbiased single-cell comparison. The cell memory displays time-delayedsingle-exponential negative friction, which clearly distinguishes cell motion from the simple persistent randomwalk model and suggests a regulatory feedback mechanism that controls cell migration. Based on the extractedmemory function we formulate a generalized exactly solvable cell migration model which indicates thatnegative friction generates cell persistence over long timescales. The nonequilibrium character of cell motionis investigated by mapping the non-Markovian Langevin equation with memory onto a Markovian model thatinvolves a hidden degree of freedom and is equivalent to the underdamped active Ornstein-Uhlenbeck process

Application of system dynamics for holistic product-service system development

In order to develop Product Service Systems (PSS), a holistic view on the system and a coequal development of service and product parts is necessary. Particularly for the beginning of the development of PSS, existing approaches show lacks and start with vague defined initial phases. This leads to inadequate methodological support for the consistent design of the overall system and simultaneous elaboration of the requirements down to the parameters of individual components. Therefore, a procedure is required that completely maps the PSS and enables detailed development for relevant individual areas, taking into account existing constraints. At the beginning of the development a model is necessary, which first defines the system boundaries of the PSS and maps the performance and control flows of the system. In addition, the integration of further actors into the PSS must be made possible. This paper presents an approach that uses System Dynamics (SD) to design a PSS. With this approach, the representation of the system is initially possible at a high level of abstraction, whereby the representation can be further refined and detailed. Parallel to this, a preliminary design for planning and controlling media flows can be carried out from the first system representation and further detailed parallel to the system representation. An essential advantage is that the detailing can also only be carried out for individual areas, which can be displayed in sub-models, but can also be reintegrated into the overall representation. The sub-models can be implemented function-specifically on the basis of resources and competencies of individual actors. For system-relevant areas, planning and design can be concretized in the sub-models (which can be realized by products as well as services) down to the lowest hierarchy level. This can take place up to the definition of individual physical component parameters and has thus up to the phase of the elaboration effects on the development of the parts. In return, the effects of changes in system-relevant parameters on the overall system can also be examined. For the PSS, a model is built in which system-determining functions and principles are represented and developed. The model is constructed in such a way that non-system-determining functions and principles are defined as variables or black boxes. Requirements and parameters are derived from this system development. These are used for the further development steps in the development process. Depending on whether it concerns system-relevant areas or not, the entry into the development process takes place later in the elaboration phase (e.g. in the area of detailed design) or partly earlier in the concept phase (e.g. function development). It is also possible to enter an early phase in the development process of the individual parts, accompanied by already defined functions, sub-functions or parameters that must not be changed in the course of development. With this approach a holistic development of the system with all product and service parts as well as their connections and dependencies is possible

Oberammergau Pilot Action Region: Mountain Forest Initiative (BWO)

Natural hazards caused by climate change pose a permanent threat to the inhabitants of the Alpine Space. In addition to technical protection measures, forests are very often the key to permanent and cost-effective protection against these hazards. In the Mountain Forest initiative (BWO) of the Bavarian state government, launched more than 10 years ago, suitable measures for the preservation of protective forest are discussed and, if possible, decided by consensus in on-site round tables with all involved interest groups. Only a functioning interaction between the different actors in the Alpine Space will contribute towards the set objective of integrating forests and ecosystem services in risk governance and balancing the numerous interests, demands and costs. Using the example of the Oberammergau Pilot Action Region (PAR), the process and implementation of the BWO is presented against a background of more than 10 years of experience. At the beginning, the identification of stakeholders and the overall goal and expectations of the participatory process (technical issues, trust and community building) is clarified. After a detailed actor analysis, the moderated participatory process is described

Functional characterization of two novel 5' untranslated exons reveals a complex regulation of NOD2 protein expression

<p>Abstract</p> <p>Background</p> <p>NOD2 is an innate immune receptor for the bacterial cell wall component muramyl-dipeptide. Mutations in the leucine-rich repeat region of NOD2, which lead to an impaired recognition of muramyl-dipeptide, have been associated with Crohn disease, a human chronic inflammatory bowel disease. Tissue specific constitutive and inducible expression patterns of NOD2 have been described that result from complex regulatory events for which the molecular mechanisms are not yet fully understood.</p> <p>Results</p> <p>We have identified two novel exons of the <it>NOD2 </it>gene (designated exon 1a and 1b), which are spliced to the canonical exon 2 and constitute the 5' untranslated region of two alternative transcript isoforms (i.e. exon 1a/1b/2 and exon 1a/2). The two novel transcripts are abundantly expressed and seem to comprise the majority of NOD2 transcripts under physiological conditions. We confirm the expression of the previously known canonical first exon (designated exon 1c) of the gene in unstimulated mononuclear cells. The inclusion of the second alternative exon 1b, which harbours three short upstream open reading frames (uORFs), is downregulated upon stimulation with TNF-α or under pro-inflammatory conditions in the inflamed intestinal mucosa <it>in vivo</it>. Using the different 5' UTR splice forms fused to a firefly luciferase (LUC) reporter we demonstrate a rapamycin-sensitive inhibitory effect of the uORFs on translation efficacy.</p> <p>Conclusion</p> <p>The differential usage of two alternative promoters in the <it>NOD2 </it>gene leads to tissue-specific and context-dependent <it>NOD2 </it>transcript isoform patterns. We demonstrate for the first time that context-dependent alternative splicing is linked to uORF-mediated translational repression. The results suggest complex parallel control mechanisms that independently regulate NOD2 expression in the context of inflammatory signaling.</p

Generation of nonclassical biphoton states through cascaded quantum walks on a nonlinear chip

We demonstrate a nonlinear optical chip that generates photons with reconfigurable nonclassical spatial correlations. We employ a quadratic nonlinear waveguide array, where photon pairs are generated through spontaneous parametric down-conversion and simultaneously spread through quantum walks between the waveguides. Because of the quantum interference of these cascaded quantum walks, the emerging photons can become entangled over multiple waveguide positions. We experimentally observe highly nonclassical photon-pair correlations, confirming the high fidelity of on-chip quantum interference. Furthermore, we demonstrate biphoton-state tunability by spatial shaping and frequency tuning of the classical pump beam

Novel Binding Mode of a Potent and Selective Tankyrase Inhibitor

Tankyrases (TNKS1 and TNKS2) are key regulators of cellular processes such as telomere pathway and Wnt signaling. IWRs (inhibitors of Wnt response) have recently been identified as potent and selective inhibitors of tankyrases. However, it is not clear how these IWRs interact with tankyrases. Here we report the crystal structure of the catalytic domain of human TNKS1 in complex with IWR2, which reveals a novel binding site for tankyrase inhibitors. The TNKS1/IWR2 complex provides a molecular basis for their strong and specific interactions and suggests clues for further development of tankyrase inhibitors

Protein cluster formation in aqueous solution in the presence of multivalent metal ions -a light scattering study

The formation of protein clusters as precursors for crystallization and phase separation is of fundamental and practical interest in protein science. Using multivalent ions, the strengths of both long-range Coulomb repulsion and short-range attraction can be tuned in protein solutions, representing a wellcontrolled model system to study static and dynamic properties of clustering during the transition from a charge-stabilized to an aggregate regime. Here, we study compressibility, diffusion, and size of solutes by means of static (SLS) and dynamic light scattering (DLS) in solutions of bovine serum albumin (BSA) and YCl 3 . For this and comparable systems, an increasing screening and ultimately inversion of the protein surface charge induce a rich phase behavior including reentrant condensation, liquid-liquid phase separation and crystallization, which puts the cluster formation in the context of precursor formation and nucleation of liquid and crystalline phases. We find that, approaching the turbid aggregate regime with increasing salt concentration c s , the diffusion coefficients decrease and the scattered intensity increases by orders of magnitude, evidencing increasing correlation lengths likely associated with clustering. The combination of static and dynamic observations suggests the formation of BSA clusters with a size on the order of 100 nm. The global thermodynamic state seems to be stable over at least several hours. Surprisingly, results on collective diffusion and inverse compressibility from different protein concentrations can be rescaled into master curves as a function of c s /c*, where c* is the critical salt concentration of the transition to the turbid aggregate regime