Spatio-Trajectorial Optical Flow for Higher-Order Deformation Analysis in Solid Experimental Mechanics.

Material models are required to solve continuum mechanical problems. These models contain parameters that are usually determined by application-specific test setups. In general, the theoretically developed models and, thus, the parameters to be determined become increasingly complex, e.g., incorporating higher-order motion derivatives, such as the strain or strain rate. Therefore, the strain rate behaviour needs to be extracted from experimental data. Using image data, the most-common way in solid experimental mechanics to do so is digital image correlation. Alternatively, optical flow methods, which allow an adaption to the underlying motion estimation problem, can be applied. In order to robustly estimate the strain rate fields, an optical flow approach implementing higher-order spatial and trajectorial regularisation is proposed. Compared to using a purely spatial variational approach of higher order, the proposed approach is capable of calculating more accurate displacement and strain rate fields. The procedure is finally demonstrated on experimental data of a shear cutting experiment, which exhibited complex deformation patterns under difficult optical conditions.

Where's the Noise? Key Features of Spontaneous Activity and Neural Variability Arise through Learning in a Deterministic Network.

Even in the absence of sensory stimulation the brain is spontaneously active. This background "noise" seems to be the dominant cause of the notoriously high trial-to-trial variability of neural recordings. Recent experimental observations have extended our knowledge of trial-to-trial variability and spontaneous activity in several directions: 1. Trial-to-trial variability systematically decreases following the onset of a sensory stimulus or the start of a motor act. 2. Spontaneous activity states in sensory cortex outline the region of evoked sensory responses. 3. Across development, spontaneous activity aligns itself with typical evoked activity patterns. 4. The spontaneous brain activity prior to the presentation of an ambiguous stimulus predicts how the stimulus will be interpreted. At present it is unclear how these observations relate to each other and how they arise in cortical circuits. Here we demonstrate that all of these phenomena can be accounted for by a deterministic self-organizing recurrent neural network model (SORN), which learns a predictive model of its sensory environment. The SORN comprises recurrently coupled populations of excitatory and inhibitory threshold units and learns via a combination of spike-timing dependent plasticity (STDP) and homeostatic plasticity mechanisms. Similar to balanced network architectures, units in the network show irregular activity and variable responses to inputs. Additionally, however, the SORN exhibits sequence learning abilities matching recent findings from visual cortex and the network's spontaneous activity reproduces the experimental findings mentioned above. Intriguingly, the network's behaviour is reminiscent of sampling-based probabilistic inference, suggesting that correlates of sampling-based inference can develop from the interaction of STDP and homeostasis in deterministic networks. We conclude that key observations on spontaneous brain activity and the variability of neural responses can be accounted for by a simple deterministic recurrent neural network which learns a predictive model of its sensory environment via a combination of generic neural plasticity mechanisms.

Plasticity-Induced Heating: Revisiting the Energy-Based Variational Model.

Temperature evolution during plastic deformation is of great importance for the design of manufacturing processes, as well as for the analysis and prediction of tool wear. However, the results from experimental- and numerical-type research are still often contradictory. In this paper, we analyze methods for estimating plasticity-induced heating directly from displacement fields that can be recorded during experiments or extracted from simulation results. In terms of computational methodology, the thermodynamically motivated energy-based variational formulation of the coupled thermo-mechanical boundary-value problem is adapted to the problem at hand. Since an analysis of this variational formulation exhibits challenges and distinct inconsistencies with respect to the problem at hand, an alternative approach is proposed. This alternative approach is essentially a purely thermal finite element simulation, and it is conducted using a heat source term that is empirically based on the fraction of irreversible deformation work converted to heat. Our approach estimates plasticity-induced heating based on the strain and strain rate data derived from displacement fields. We therefore incorporate thermo-visco-plastic constitutive behavior (Johnson-Cook) with a thermodynamically motivated model that specifies the fraction of plastic work converted to heat (the Taylor-Quinney coefficient).

Peptidomimetic escape mechanisms arise via genetic diversity in the ligand-binding site of the hepatitis C virus NS3/4A serine protease.

BACKGROUND & AIMS: It is a challenge to develop direct-acting antiviral agents that target the nonstructural protein 3/4A protease of hepatitis C virus because resistant variants develop. Ketoamide compounds, designed to mimic the natural protease substrate, have been developed as inhibitors. However, clinical trials have revealed rapid selection of resistant mutants, most of which are considered to be pre-existing variants. METHODS: We identified residues near the ketoamide-binding site in x-ray structures of the genotype 1a protease, co-crystallized with boceprevir or a telaprevir-like ligand, and then identified variants at these positions in 219 genotype-1 sequences from a public database. We used side-chain modeling to assess the potential effects of these variants on the interaction between ketoamide and the protease, and compared these results with the phenotypic effects on ketoamide resistance, RNA replication capacity, and infectious virus yields in a cell culture model of infection. RESULTS: Thirteen natural binding-site variants with potential for ketoamide resistance were identified at 10 residues in the protease, near the ketoamide binding site. Rotamer analysis of amino acid side-chain conformations indicated that 2 variants (R155K and D168G) could affect binding of telaprevir more than boceprevir. Measurements of antiviral susceptibility in cell-culture studies were consistent with this observation. Four variants (ie, Q41H, I132V, R155K, and D168G) caused low-to-moderate levels of ketoamide resistance; 3 of these were highly fit (Q41H, I132V, and R155K). CONCLUSIONS: Using a comprehensive sequence and structure-based analysis, we showed how natural variation in the hepatitis C virus protease nonstructural protein 3/4A sequences might affect susceptibility to first-generation direct-acting antiviral agents. These findings increase our understanding of the molecular basis of ketoamide resistance among naturally existing viral variants.

Brain derived neurotrophic factor inhibits apoptosis in enteric glia during gut inflammation.

BACKGROUND: Enteric glia cells (EGCs) are essential for the integrity of the bowel. A loss of EGCs leads to a severe inflammation of the intestines. As a diminished EGC network is postulated in Crohn's disease (CD), we aimed to investigate if EGCs could be a target of apoptosis during inflammation in CD, which can be influenced by Brain derived neurotrophic factor (BDNF). MATERIAL/METHODS: GFAP, BDNF and cCaspase-3 were detected in the gut of patients with CD. Primary EGC cultures were established and cultivated. Tyrosine receptor kinase (TrkB) receptors on these cells were investigated by western blot and immunofluorescence. Rate of apoptosis was induced by tumor necrosis factor (TNF-alpha) and interferon (IFN-gamma). Apoptosis was determined by a fluorometric caspase 3/7 activation assay after preincubation of these cells with BDNF or neutralizing anti-BDNF antibodies. RESULTS: Mucosal GFAP-positive EGCs undergo apoptosis revealed by cCaspase-3 in the gut of patients with CD expressing BDNF highly. The combination of TNF-alpha and IFN-gamma was able to induce apoptosis in primary EGCs, whereas these factors alone did not. Brain derived neurotrophic factor (BDNF) attenuate glia cell apoptosis to a small extent, but neutralizing antibodies against BDNF dramatically increased apoptosis. CONCLUSIONS: Mucosal EGC apoptosis is an important finding in the gut of patients with CD. Proinflammatory cytokines, which are highly increased in CD, induce EGC apoptosis, whereas the neurotrophin BDNF might be protective for EGC. Since EGCs are implicated in the maintenance of the enteric mucosal integrity, EGC apoptosis may contribute to the pathophysiological changes in CD.

Application of Fractal Image Analysis by Scale-Space Filtering in Experimental Mechanics.

Increasingly complex numerical analyses require more and more precise, accurate and varied input parameters in order to achieve results that are as realistic and reliable as possible. Therefore, experimental analyses for material parameter identification are of high importance and a driving force for further developments. In this work, opportunities by applying fractal analysis to optical measurement data of a shear cutting process are investigated. The fractal analysis is based on a modification of the concept of scale-space filtering. Scale exponent fields are calculated for the image sequences of the shear cutting process that are taken by a mobile microscope. A least-square approximation is used for the automated evaluation of the local scale exponent values. In order to determine the change of the scale exponent of individual material points, a digital image correlation is applied.

Removal of Stair-Step Effects in Binder Jetting Additive Manufacturing Using Grayscale and Dithering-Based Droplet Distribution.

Binder jetting is a layer-based additive manufacturing process for three-dimensional parts in which a print head selectively deposits binder onto a thin layer of powder. After the deposition of the binder, a new layer of powder is applied. This process repeats to create three-dimensional parts. The binder jetting principle can be adapted to many different materials. Its advantages are the high productivity and the high degree of freedom of design without the need for support structures. In this work, the combination of binder jetting and casting is utilized to fabricate metal parts. However, the achieved properties of binder jetting parts limit the potential of this technology, specifically regarding surface quality. The most apparent surface phenomenon is the so-called stair-step effect. It is considered an inherent feature of the process and only treatable by post-processing. This paper presents a method to remove the stair-step effect entirely in a binder jetting process. The result is achieved by controlling the binder saturation of the individual voxel volumes by either over or underfilling them. The saturation is controlled by droplet size variation as well as dithering, creating a controlled migration of the binder between powder particles. This work applies the approach to silica sand particle material with an organic binder for casting molds and cores. The results prove the effectiveness of this approach and outline a field of research not identified previously.

Distribution of enteric glia and GDNF during gut inflammation.

BACKGROUND: The enteric glia network may be involved in the pathogenesis of inflammatory bowel disease (IBD). Enteric glia cells (EGCs) are the major source of glial-derived neurotrophic factor (GDNF), which regulates apoptosis of enterocytes. The aim of the study was to determine the distribution of EGCs and GDNF during gut inflammation and to elucidate a possible diminished enteric glia network in IBD. METHODS: The expression of glial fibrillary acidic protein (GFAP) in colonic biopsies of patients with IBD, controls and patients with infectious colitis was detected by immunohistochemistry and Western blot. Tissue GDNF levels were measured by ELISA. RESULTS: The expression of GFAP and GDNF in the mucosal plexus is highly increased in the inflamed colon of patients with ulcerative colitis (UC) and infectious colitis. Although the GDNF and GFAP content are increased in Crohn's disease (CD), it is significantly less. Additionally the non-inflamed colon of CD patients showed a reduced GFAP and no GDNF expression compared to controls and the non-inflamed colon of UC patients. CONCLUSIONS: GFAP and GDNF as signs of activated EGCs are increased in the inflamed mucosa of patients with UC and infectious colitis, which underline an unspecific role of EGC in the regulation of intestinal inflammation. The reduced GFAP and GDNF content in the colon of CD patients suggest a diminished EGC network in this disease. This might be a part of the pathophysiological puzzle of CD.

A Plane Stress Failure Criterion for Inorganically-Bound Core Materials.

Inorganically-bound core materials are used in foundries in high quantities. However, there is no validated mechanical failure criterion, which allows performing finite-element calculations on the core geometries, yet. With finite-element simulations, the cores could be optimised for various production processes from robotic core handling to the decoring process after the casting. To identify a failure criterion, we propose testing methods, that enable us to investigate the fracture behaviour of inorganically-bound core materials. These novel testing methods induce multiple bi-axial stress states into the specimens and are developed for cohesive frictional materials in general and for sand cores in particular. This allows validating failure criteria in principal stress space. We found that a Mohr-Coulomb model describes the fracture of inorganic core materials in a plane stress state quite accurately and adapted it to a failure criterion, which combines the Mohr-Coulomb model with the Weakest-Link theory in one consistent mechanical material model. This novel material model has been successfully utilised to predict the fracture force of a Brazilian test. This prediction is based on the stress fields of a finite element method (FEM) calculation.

Food Oral Processing-An Industry Perspective.

We illustrate how scientific understanding of Food Oral Processing enables food product development with specific benefits for several target populations. in vivo, in vitro, and in silico approaches are discussed in the context of their ability to quantify oral processing from the molecular to the macroscopic scale. Based on this understanding, food structures with enhanced performance in terms of hedonic and nutritional properties as well as appropriateness for age and certain medical conditions can be developed. We also discuss current gaps and highlight development opportunities from an industry perspective.

Combining Structural Optimization and Process Assurance in Implicit Modelling for Casting Parts.

The structural optimization of manufacturable casting parts is still a challenging and time-consuming task. Today, topology optimization is followed by a manual reconstruction of the design proposal and a process assurance simulation to endorse the design proposal. Consequently, this process is iteratively repeated until it reaches a satisfying compromise. This article shows a method to combine structural optimization and process assurance results to generate automatically structure- and process-optimized die casting parts using implicit geometry modeling. Therefore, evaluation criteria are developed to evaluate the current design proposal and qualitatively measure the improvement of manufacturability between two iterations. For testing the proposed method, we use a cantilever beam as an example of proof. The combined iterative method is compared to manual designed parts and a direct optimization approach and evaluated for mechanical performance and manufacturability. The combination of topology optimization (TO) and process assurance (PA) results is automated and shows a significant enhancement to the manual reconstruction of the design proposals. Further, the improvement of manufacturability is better or equivalent to previous work in the field while using less computational effort, which emphasizes the need for suitable metamodels to significantly reduce the effort for process assurance and enable much shorter iteration times.

Grain Size Influence on the Magnetic Property Deterioration of Blanked Non-Oriented Electrical Steels.

Non-oriented electrical steel sheets are applied as a core material in rotors and stators of electric machines in order to guide and magnify their magnetic flux density. Their contouring is often realized in a blanking process step, which results in plastic deformation of the cut edges and thus deteriorates the magnetic properties of the base material. This work evaluates the influence of the material's grain size on its iron losses after the blanking process. Samples for the single sheet test were blanked at different cutting clearances (15 µm-70 µm) from sheets with identical chemical composition (3.2 wt.% Si) but varying average grain size (28 µm-210 µm) and thickness (0.25 mm and 0.5 mm). Additionally, in situ measurements of blanking force and punch travel were carried out. Results show that blanking-related iron losses either increase for 0.25 mm thick sheets or decrease for 0.5 mm thick sheets with increasing grain size. Although this is partly in contradiction to previous research, it can be explained by the interplay of dislocation annihilation and transgranular fracturing. The paper thus contributes to a deeper understanding of the blanking process of coarse-grained, thin electrical steel sheets.

The endothelin axis influences enteric glia cell functions.

BACKGROUND: The biologic effects of endothelin-1 (ET-1) are not limited to its vasoconstricting activity. A new and highly interesting role of the endothelin axis is its involvement in immune functions. As ET-1 is highly increased during gut inflammation, the aim of this study was to see if the endothelin axis influences enteric glia cell (EGC) functions, and through them, the immune response, during gut inflammation. MATERIAL/METHODS: Cultured EGCs were treated with interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNFalpha), IL-4, interferon-gamma, and ET-1. Secretion of ET-1 was detected by ELISA. Cultured EGCs were labeled with anti-glial fibrillary acidic protein (GFAP), endothelin-A (ETA), and endothelin-B (ETB), antibodies. The expression of ETA and ETB receptors was evaluated using reverse transcription PCR. Glial fibrillary acidic protein expression was determined by Western blot. RESULTS: ET-1 secretion of EGCs could be stimulated by IL-1 beta and TNFalpha in a time and dose-dependent manner, whereas IL-4 and interferon-gamma showed no effect on ET-1 production. Cultured EGCs expressed ETA and ETB-receptors. Endothelin B mRNA expression was increased after incubation with IL-1 beta. Incubation of cells with IL-1 beta, TNFalpha, and ET-1 led to a significant increase of GFAP in EGCs. CONCLUSIONS: Enteric glia cells express functional ETA and ETB receptors and produce huge amounts of ET-1 during gut inflammation, which increase GFAP expression in EGCs. These ET-1/ET receptors autocrine or paracrine loops might provide a new means to modulate EGC function, such as change in gut motility, cytokine production, and regulating gut homeostasis.

Frequent mitotic activity in banal melanocytic nevi uncovered by immunohistochemical analysis.

The presence and distribution of mitotic figures is an important discriminatory parameter in the assessment of melanocytic lesions. We evaluated the number and distribution of mitotic figures in 353 randomly collected melanocytic nevi of various subtypes by hematoxylin and eosin (H&E) staining and immunohistochemically with the 2 mitotic markers Phospho-Histone H3 Ser28 (PHH3) and MPM2. At least 1 mitotic figure was present in 19.5%, 31.3%, and 42.8% of H&E-, PHH3-, and MPM2-stained lesions, respectively. In common compound nevi, the mean number of dermal mitoses amounted to 0.024/mm dermal surface area in the H&E staining (PHH3: 0.061; MPM2: 0.087) and to 0.175/mm in Spitz nevi (PHH3: 0.325; MPM2: 0.45). Nevi exhibiting mitotic figures were significantly more frequent in the youngest age group (0-20 years) than in patients older than 50 years (P < 0.0001). In the upper half of the dermis, mitotic activity was roughly 3 times as frequent as compared with the lower half. Clusters of mitotic figures within the dermis were not observed. Mitotic activity in obviously benign melanocytic nevi is not rare even in the deep dermal part. More than 2 mitotic figures per lesion can usually be explained either by the nevus subtype, young patient age, traumatization, or inflammation. PHH3 and MPM2 are a valuable diagnostic adjunct in the evaluation of melanocytic tumors allowing more sensitive and faster recognition of mitotic figures and their distribution.

Acoustical and Optical Determination of Mechanical Properties of Inorganically-Bound Foundry Core Materials.

Inorganically-bound sand cores are used in many light-metal foundries to form cavities in the cast part, which cannot be realised by the mould itself. To enable FEM simulations with core materials, their mechanical properties have to be measured. In this article, we adapt methods to determine the Young's and shear modulus, the Poisson ratio and the fracture strain of sand cores. This allows us to fully parametrise an ideal brittle FEM model. We found that the Young's and shear modulus can be obtained acoustically via the impulse excitation technique. The fracture strain was measured with a high-speed camera and a digital image correlation algorithm.

Measurement of molten chocolate friction under simulated tongue-palate kinematics: Effect of cocoa solids content and aeration.

The perception of some food attributes is related to mechanical stimulation and friction experienced in the tongue-palate contact during mastication. This paper reports a new bench test to measure friction in the simulated tongue-palate contact. The test consists of a flat PDMS disk, representing the tongue loaded and reciprocating against a stationary lower glass surface representing the palate. The test was applied to molten chocolate samples with and without artificial saliva. Friction was measured over the first few rubbing cycles, simulating mechanical degradation of chocolate in the tongue-palate region. The effects of chocolate composition (cocoa solids content ranging between 28 â€‹wt% and 85 â€‹wt%) and structure (micro-aeration/non-aeration 0-15 â€‹vol%) were studied. The bench test clearly differentiates between the various chocolate samples. The coefficient of friction increases with cocoa solids percentage and decreases with increasing micro-aeration level. The presence of artificial saliva in the contact reduced the friction for all chocolate samples, however the relative ranking remained the same.

PLAC1 is essential for FGF7/FGFRIIIb-induced Akt-mediated cancer cell proliferation.

PLAC1 (placenta enriched 1) is a mammalian trophoblast-specific protein. Aberrant expression of PLAC1 is observed in various human cancers, where it is involved in the motility, migration, and invasion of tumor cells, which are associated with the phosphoinositide 3-kinase (PI3K)/AKT pathway. We previously demonstrated that AKT activation mediates the downstream effects of PLAC1; however, the molecular mechanisms of PLAC1-induced AKT-mediated tumor-related processes are unclear. We studied human choriocarcinoma and breast cancer cell lines to explore the localization and receptor-ligand interactions, as well as the downstream effects of PLAC1. We show secretion and adherence of PLAC1 to the extracellular matrix, where it forms a trimeric complex with fibroblast growth factor 7 (FGF7) and its receptor, FGF receptor 2 IIIb (FGFR2IIIb). We further show that PLAC1 signaling via FGFR2IIIb activates AKT phosphorylation in cancer cell lines. As the FGF pathway is of major interest in anticancer therapeutic strategies, these data further promote PLAC1 as a promising anticancer drug target.

Docking and scoring with alternative side-chain conformations.

We describe a scoring and modeling procedure for docking ligands into protein models that have either modeled or flexible side-chain conformations. Our methodical contribution comprises a procedure for generating new potentials of mean force for the ROTA scoring function which we have introduced previously for optimizing side-chain conformations with the tool IRECS. The ROTA potentials are specially trained to tolerate small-scale positional errors of atoms that are characteristic of (i) side-chain conformations that are modeled using a sparse rotamer library and (ii) ligand conformations that are generated using a docking program. We generated both rigid and flexible protein models with our side-chain prediction tool IRECS and docked ligands to proteins using the scoring function ROTA and the docking programs FlexX (for rigid side chains) and FlexE (for flexible side chains). We validated our approach on the forty screening targets of the DUD database. The validation shows that the ROTA potentials are especially well suited for estimating the binding affinity of ligands to proteins. The results also show that our procedure can compensate for the performance decrease in screening that occurs when using protein models with side chains modeled with a rotamer library instead of using X-ray structures. The average runtime per ligand of our method is 168 seconds on an Opteron V20z, which is fast enough to allow virtual screening of compound libraries for drug candidates.

TIMP-3: a novel target for glucocorticoid signaling at the blood-brain barrier.

Glucocorticoids (GCs) are used in the treatment of neuroinflammatory diseases such as multiple sclerosis. Several studies have demonstrated the beneficial effect of GCs on the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors, the TIMPs (tissue inhibitors of metalloproteinases). We could demonstrate that all four known TIMPs are present at the blood-brain barrier (BBB) endothelium. Hydrocortisone (HC) selectively upregulates TIMP-3 while TIMP-1, TIMP-2 and TIMP-4 were downregulated on the mRNA-level. This effect could be completely reversed by the glucocorticoid receptor inhibitor mifepristone (Mife). On the protein-level all TIMPs could be detected in the apical supernatants whereas in the isolated extracellular matrix (ECM) only TIMP-3 was found. The application of HC led to a strong enrichment of TIMP-3 in the ECM. Our findings demonstrate that HC directly targets TIMP-3 at the BBB assuming a protective role against matrix disruption and thus to guarantee the barrier integrity.

Perception of oral food breakdown. The concept of sensory trajectory.

Texture perceived in mouth largely depends on the behaviour of the food when it is broken down and transformed by the mouth elements. Texture results from a dynamic process in which texture attributes are continuously analysed by the oral sensory systems during mastication. However, the particular sequence of perceptual events that occur during oral food breakdown remains unknown. The aim of the present study is to describe the succession of perceptual events that happen in mouth during mastication and to show that for each food a texture pathway can be built. This for, we used a sensory method enabling to evaluate the dynamics of texture perceptions during food consumption: the Temporal Dominance of Sensation. On different breakfast cereals, we measured the sensation dominating at each point of the mastication process. We showed that the dynamics of appearance and disappearance of each texture sensation experienced in mouth during the eating process differed among cereals. However, some common features in this sensory trajectory were also observed for the category of products studied. Hardness, crackliness and crispness were rather perceived at the beginning of the mastication period, brittleness and lightness in the middle and stickiness at the end.