Estimating flow and transport parameters in the unsaturated zone with pore water stable isotopes

The first author was funded by the DFG Research Group: From Catchments as Organised Systems to Models based on Functional Units (FOR 1598). The second author was funded by the DFG project Coupled soil-plant water dynamics – Environmental drivers and species effects (contract numbers: GE 1090/10-1 and WE 4598/2-1). The isotope data in the precipitation for Roodt were provided by FNR/CORE/SOWAT, project of the Luxembourg Institute of Science and Technology – LIST. Sampling of the isotope profiles was made possible by the support of the CAOS Team and Begona Lorente Sistiaga, Benjamin Gralher, Andre Böker, Marvin Reich and Andrea Popp. Special thanks to Britta Kattenstroth and Jean Francois Iffly for their technical support in the field and Barbara Herbstritt for her support in the laboratory. For Roodt, soil texture and hydraulic parameter information were provided by Conrad Jackisch and Christoph Messer (KIT, Karlsruhe, Germany) and hydraulic conductivity data were provided by Christophe Hissler and Jérôme Juilleret (LIST). Pore water isotope and soil moisture data for Hartheim were provided by Steffen Holzkämper and Paul Königer. Temperature and precipitation data for Hartheim were provided by the Chair of Meteorology and Climatology, University of Freiburg.Peer reviewedPublisher PD

Real-time single cell analysis of Smac/DIABLO release during apoptosis

We examined the temporal and causal relationship between Smac/DIABLO release, cytochrome c (cyt-c) release, and caspase activation at the single cell level during apoptosis. Cells treated with the broad-spectrum caspase inhibitor z-VAD-fmk, caspase-3 (Casp-3)–deficient MCF-7 cells, as well as Bax-deficient DU-145 cells released Smac/DIABLO and cyt-c in response to proapoptotic agents. Real-time confocal imaging of MCF-7 cells stably expressing Smac/DIABLO-yellow fluorescent protein (YFP) revealed that the average duration of Smac/DIABLO-YFP release was greater than that of cyt-c-green fluorescent protein (GFP). However, there was no significant difference in the time to the onset of release, and both cyt-c-GFP and Smac/DIABLO-YFP release coincided with mitochondrial membrane potential depolarization. We also observed no significant differences in the Smac/DIABLO-YFP release kinetics when z-VAD-fmk–sensitive caspases were inhibited or Casp-3 was reintroduced. Simultaneous measurement of DEVDase activation and Smac/DIABLO-YFP release demonstrated that DEVDase activation occurred within 10 min of release, even in the absence of Casp-3

The Influence of the Degree of Heterogeneity on the Elastic Properties of Random Sphere Packings

The macroscopic mechanical properties of colloidal particle gels strongly depend on the local arrangement of the powder particles. Experiments have shown that more heterogeneous microstructures exhibit up to one order of magnitude higher elastic properties than their more homogeneous counterparts at equal volume fraction. In this paper, packings of spherical particles are used as model structures to computationally investigate the elastic properties of coagulated particle gels as a function of their degree of heterogeneity. The discrete element model comprises a linear elastic contact law, particle bonding and damping. The simulation parameters were calibrated using a homogeneous and a heterogeneous microstructure originating from earlier Brownian dynamics simulations. A systematic study of the elastic properties as a function of the degree of heterogeneity was performed using two sets of microstructures obtained from Brownian dynamics simulation and from the void expansion method. Both sets cover a broad and to a large extent overlapping range of degrees of heterogeneity. The simulations have shown that the elastic properties as a function of the degree of heterogeneity are independent of the structure generation algorithm and that the relation between the shear modulus and the degree of heterogeneity can be well described by a power law. This suggests the presence of a critical degree of heterogeneity and, therefore, a phase transition between a phase with finite and one with zero elastic properties.Comment: 8 pages, 6 figures; Granular Matter (published online: 11. February 2012

ALISSA: an automated live-cell imaging system for signal transduction analyses

Probe photobleaching and a specimen’s sensitivity to phototoxicity severely limit the number of possible excitation cycles in time-lapse fluorescent microscopy experiments. Consequently, when a study of cellular processes requires measurements over hours or days, temporal resolution is limited, and spontaneous or rapid events may be missed, thus limiting conclusions about transduction events. We have developed ALISSA, a design framework and reference implementation for an automated live-cell imaging system for signal transduction analysis. It allows an adaptation of image modalities and laser resources tailored to the biological process, and thereby extends temporal resolution from minutes to seconds. The system employs online image analysis to detect cellular events that are then used to exercise microscope control. It consists of a reusable image analysis software for cell segmentation, tracking, and time series extraction, and a measurement-specific process control software that can be easily adapted to various biological settings. We have applied the ALISSA framework to the analysis of apoptosis as a demonstration case for slow onset and rapid execution signaling. The demonstration provides a clear proof-of-concept for ALISSA, and offers guidelines for its application in a broad spectrum of signal transduction studies

A machine learning platform to optimize the translation of personalized network models to the clinic

PURPOSE Dynamic network models predict clinical prognosis and inform therapeutic intervention by elucidating disease-driven aberrations at the systems level. However, the personalization of model predictions requires the profiling of multiple model inputs, which hampers clinical translation. PATIENTS AND METHODS We applied APOPTO-CELL, a prognostic model of apoptosis signaling, to showcase the establishment of computational platforms that require a reduced set of inputs. We designed two distinct and complementary pipelines: a probabilistic approach to exploit a consistent subpanel of inputs across the whole cohort (Ensemble) and a machine learning approach to identify a reduced protein set tailored for individual patients (Tree). Development was performed on a virtual cohort of 3,200,000 patients, with inputs estimated from clinically relevant protein profiles. Validation was carried out in an in-house stage III colorectal cancer cohort, with inputs profiled in surgical resections by reverse phase protein array (n = 120) and/or immunohistochemistry (n = 117). RESULTS Ensemble and Tree reproduced APOPTO-CELL predictions in the virtual patient cohort with 92% and 99% accuracy while decreasing the number of inputs to a consistent subset of three proteins (40% reduction) or a personalized subset of 2.7 proteins on average (46% reduction), respectively. Ensemble and Tree retained prognostic utility in the in-house colorectal cancer cohort. The association between the Ensemble accuracy and prognostic value (Spearman ρ = 0.43; P = .02) provided a rationale to optimize the input composition for specific clinical settings. Comparison between profiling by reverse phase protein array (gold standard) and immunohistochemistry (clinical routine) revealed that the latter is a suitable technology to quantify model inputs. CONCLUSION This study provides a generalizable framework to optimize the development of network-based prognostic assays and, ultimately, to facilitate their integration in the routine clinical workflow

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44⁺ Natural Killer Cells in Ulcerative Colitis

Background &amp; Aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.</p

Observations on the changing language of accounting

The meaning of words can change over time. In addition, new words may enter a language, sometimes replacing other words. This article extends prior literature on language change in accounting by drawing to a larger extent on theories from linguistics, and by placing greater emphasis on mechanisms of and motivations for change. Particular emphasis is placed on the need to verbalize new concepts, and sociocultural change. The latter is illustrated with examples from the development of accounting as an occupational interest group, and the adoption of Anglo-American accounting terminology and culture. The article concludes that language change in accounting, including transmission between languages and cultures, can inform accounting historians about the transfer of technical developments, as well as about socio-economic, political or ideological processes, power relationships, and the importance of terminology in jurisdictional disputes

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44⁺ Natural Killer Cells in Ulcerative Colitis

Background &amp; Aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.</p