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Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) can show variable histological growth patterns and present remarkable overlap with T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL). Previous studies suggest that NLPHL histological variants represent progression forms of NLPHL and THRLBCL transformation in aggressive disease. Since molecular studies of both lymphomas are limited due to the low number of tumor cells, the present study aimed to learn if a better understanding of these lymphomas is possible via detailed measurements of nuclear and cell size features in 2D and 3D sections. Whereas no significant differences were visible in 2D analyses, a slightly increased nuclear volume and a significantly enlarged cell size were noted in 3D measurements of the tumor cells of THRLBCL in comparison to typical NLPHL cases. Interestingly, not only was the size of the tumor cells increased in THRLBCL but also the nuclear volume of concomitant T cells in the reactive infiltrate when compared with typical NLPHL. Particularly CD8+ T cells had frequent contacts to tumor cells of THRLBCL. However, the nuclear volume of B cells was comparable in all cases. These results clearly demonstrate that 3D tissue analyses are superior to conventional 2D analyses of histological sections. Furthermore, the results point to a strong activation of T cells in THRLBCL, representing a cytotoxic response against the tumor cells with unclear effectiveness, resulting in enhanced swelling of the tumor cell bodies and limiting proliferative potential. Further molecular studies combining 3D tissue analyses and molecular data will help to gain profound insight into these ill-defined cellular processes.
We derive a shape derivative formula for the family of principal Dirichlet eigenvalues λs(Ω) of the fractional Laplacian (−Δ)s associated with bounded open sets Ω⊂RN of class C1,1. This extends, with a help of a new approach, a result in Dalibard and Gérard-Varet (Calc. Var. 19(4):976–1013, 2013) which was restricted to the case s=12. As an application, we consider the maximization problem for λs(Ω) among annular-shaped domains of fixed volume of the type B∖B¯¯¯¯′, where B is a fixed ball and B′ is ball whose position is varied within B. We prove that λs(B∖B¯¯¯¯′) is maximal when the two balls are concentric. Our approach also allows to derive similar results for the fractional torsional rigidity. More generally, we will characterize one-sided shape derivatives for best constants of a family of subcritical fractional Sobolev embeddings.
We provide a Hopf boundary lemma for the regional fractional Laplacian (−Δ)sΩ, with Ω ⊂ RN a bounded open set. More precisely, given u a pointwise or weak super-solution of the equation (−Δ)s u = c(x)u in Ω, we show that the ratio u(x)∕(dist(x, 𝜕Ω))2s−1 is strictly Ω positive as x approaches the boundary 𝜕Ω of Ω. We also prove a strong maximum principle for distributional super-solutions.
The development of epilepsy (epileptogenesis) involves a complex interplay of neuronal and immune processes. Here, we present a first-of-its-kind mathematical model to better understand the relationships among these processes. Our model describes the interaction between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model reproduces the available data from three animal models. The model successfully describes characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries or the existence of qualitatively different outcomes for varying injury intensity. In line with the concept of degeneracy, our simulations reveal multiple routes toward epilepsy with neuronal loss as a sufficient but non-necessary component. Finally, we show that our model allows for in silico predictions of therapeutic strategies, revealing injury-specific therapeutic targets and optimal time windows for intervention.
We consider a linear ill-posed equation in the Hilbert space setting. Multiple independent unbiased measurements of the right-hand side are available. A natural approach is to take the average of the measurements as an approximation of the right-hand side and to estimate the data error as the inverse of the square root of the number of measurements. We calculate the optimal convergence rate (as the number of measurements tends to infinity) under classical source conditions and introduce a modified discrepancy principle, which asymptotically attains this rate.
We show how nonlocal boundary conditions of Robin type can be encoded in the pointwise expression of the fractional operator. Notably, the fractional Laplacian of functions satisfying homogeneous nonlocal Neumann conditions can be expressed as a regional operator with a kernel having logarithmic behaviour at the boundary.
In this survey paper, we present a multiscale post-processing method in exploration. Based on a physically relevant mollifier technique involving the elasto-oscillatory Cauchy–Navier equation, we mathematically describe the extractable information within 3D geological models obtained by migration as is commonly used for geophysical exploration purposes. More explicitly, the developed multiscale approach extracts and visualizes structural features inherently available in signature bands of certain geological formations such as aquifers, salt domes etc. by specifying suitable wavelet bands.
Adaptive, synchronous, and mobile online education: developing the ASYMPTOTE learning environment
(2022)
The COVID-19-induced distance education was perceived as highly challenging by teachers and students. A cross-national comparison of five European countries identified several challenges occurred during the distance learning period. On this basis, the article aims to develop a theoretical framework and design requirements for distance and online learning tools. As one example for online learning in mathematics education, the ASYMPTOTE system is introduced. It will be freely available by May 2022. ASYMPTOTE is aimed at the adaptive and synchronous delivery of online education by taking a mobile learning approach. Its core is the so-called digital classroom, which not only allows students to interact with each other or with the teacher but also enables teachers to monitor their students’ work progress in real time. With respect to the theoretical framework, this article analyses to what extent the ASYMPTOTE system meets the requirements of online learning. Overall, the digital classroom can be seen as a promising tool for teachers to carry out appropriate formative assessment and—partly—to maintain personal and content-related interaction at a distance. Moreover, we highlight the availability of this tool. Due to its mobile learning approach, almost all students will be able to participate in lessons conducted with ASYMPTOTE.
We show the existence of additive kinematic formulas for general flag area measures, which generalizes a recent result by Wannerer. Building on previous work by the second named author, we introduce an algebraic framework to compute these formulas explicitly. This is carried out in detail in the case of the incomplete flag manifold consisting of all (p+1)-planes containing a unit vector.
Biological ageing is a degenerative and irreversible process, ultimately leading to death of the organism. The process is complex and under the control of genetic, environmental and stochastic traits. Although many theories have been established during the last decades, none of these are able to fully describe the complex mechanisms, which lead to ageing. Generally, biological processes and environmental factors lead to molecular damage and an accumulation of impaired cellular components. In contrast, counteracting surveillance systems are effective, including repair, remodelling and degradation of damaged or impaired components, respectively. Nevertheless, at some point these systems are no longer effective, either because the increasing amount of molecular damages can not longer be removed efficiently or because the repairing and removing mechanisms themselves become affected by impairing effects. The organism finally declines and dies. To investigate and to understand these counteracting mechanisms and the complex interplay of decline and maintenance, holistic and systems biological investigations are required. Hence, the processes which lead to ageing in the fungal model organism Podospora anserina, had been analysed using different advanced bioinformatics methods. In contrast to many other ageing models, P. anserina exhibits a short lifespan, a less biochemical complexity and it provides a good accessibility for genetic manipulations.
To achieve a general overview on the different biochemical processes, which are affected during ageing in P. anserina, an initial comprehensive investigation was applied, which aimed to reveal genes significantly regulated and expressed in an age-dependent manner. This investigation was based on an age-dependent transcriptome analysis. Sophisticated and comprehensive analyses revealed different age-related pathways and indicated that especially autophagy may play a crucial role during ageing. For example, it was found that the expression of autophagy-associated genes increases in the course of ageing.
Subsequently, to investigate and to characterise the autophagy pathway, its associated single components and their interactions, Path2PPI, a new bioinformatics approach, was developed. Path2PPI enables the prediction of protein-protein interaction networks of particular pathways by means of a homology comparison approach and was applied to construct the protein-protein interaction network of autophagy in P. anserina.
The predicted network was extended by experimental data, comprising the transcriptome data as well as newly generated protein-protein interaction data achieved from a yeast two-hybrid analysis. Using different mathematical and statistical methods the topological properties of the constructed network had been compared with those of randomly generated networks to approve its biological significance. In addition, based on this topological and functional analysis, the most important proteins were determined and functional modules were identified, which correspond to the different sub-pathways of autophagy. Due to the integrated transcriptome data the autophagy network could be linked to the ageing process. For example, different proteins had been identified, which genes are continuously up- or down-regulated during ageing and it was shown for the first time that autophagy-associated genes are significantly often co-expressed during ageing.
The presented biological network provides a systems biological view on autophagy and enables further studies, which aim to analyse the relationship of autophagy and ageing. Furthermore, it allows the investigation of potential methods for intervention into the ageing process and to extend the healthy lifespan of P. anserina as well as of other eukaryotic organisms, in particular humans.