Dynamic optimal experimental design yields marginal improvement over steady‐state results for computational maximisation of regulatory T‐cell induction in ex vivo culture

The isolation of T cells, followed by differentiation into Regulatory T cells (Tregs), and re‐transplantation into the body has been proposed as a therapeutic option for inflammatory bowel disease. A key requirement for making this a viable therapeutic option is the generation of a large population of Tregs. However, cytokines in the local microenvironment can impact the yield of Tregs during differentiation. As such, experimental design is an essential part of evaluating the importance of different cytokine concentrations for Treg differentiation. However, currently only single, constant concentrations of the cytokines have been investigated. This work addresses this point by performing experimental design in silico which seeks to maximize the predicted induction of Tregs relative to Th17 cells, by selecting an optimal input function for the concentrations of TGF‐β, IL‐2, IL‐6, and IL‐23. While this approach sounds promising, the results show that only marginal improvements in the concentration of Tregs can be achieved for dynamic cytokine profiles as compared to optimal constant concentrations. Since constant concentrations are easier to implement in experiments, it is recommended for this particular system to keep the concentrations constant where IL‐6 should be kept low and high concentrations of TGF‐β, IL‐2, and IL‐23 should be used.Inspec keywords: patient treatment, molecular biophysics, proteins, cellular biophysics, diseasesOther keywords: Tregs relative, optimal input function, dynamic cytokine profiles, optimal constant concentrations, IL‐23, computational maximisation, regulatory T‐cell induction, inflammatory bowel disease, viable therapeutic option, local microenvironment, Treg differentiation, single concentrations, predicted induction, dynamic optimal experimental design, interleukin‐2, IL‐6, transforming growth factor‐β     

Microalgae-Based Biohybrid Microrobot for Accelerated Diabetic Wound Healing

A variety of wound healing platforms have been proposed to alleviate the hypoxic condition and/or to modulate the immune responses for the treatment of chronic wounds in diabetes. However, these platforms with the passive diffusion of therapeutic agents through the blood clot result in the relatively low delivery efficiency into the deep wound site. Here, a microalgae-based biohybrid microrobot for accelerated diabetic wound healing is developed. The biohybrid microrobot autonomously moves at velocity of 33.3 µm s⁻¹ and generates oxygen for the alleviation of hypoxic condition. In addition, the microrobot efficiently bound with inflammatory chemokines of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) for modulating the immune responses. The enhanced penetration of microrobot is corroborated by measuring fibrin clots in biomimetic wound using microfluidic devices and the enhanced retention of microrobot is confirmed in the real wounded mouse skin tissue. After deposition on the chronic wound in diabetic mice without wound dressing, the wounds treated with microrobots are completely healed after 9 days with the significant decrease of inflammatory cytokines below 31% of the control level and the upregulated angiogenesis above 20 times of CD31⁺ cells. These results confirm the feasibility of microrobots as a next-generation platform for diabetic wound healing.     

Wavelet transforms for detecting microcalcifications in mammograms

Clusters of fine, granular microcalcifications in mammograms may be an early sign of disease. Individual grains are difficult to detect and segment due to size and shape variability and because the background mammogram texture is typically inhomogeneous. The authors develop a 2-stage method based on wavelet transforms for detecting and segmenting calcifications. The first stage is based on an undecimated wavelet transform, which is simply the conventional filter bank implementation without downsampling, so that the low-low (LL), low-high (LH), high-low (HL), and high-high (HH) sub-bands remain at full size. Detection takes place in HH and the combination LH+HL. Four octaves are computed with 2 inter-octave voices for finer scale resolution. By appropriate selection of the wavelet basis the detection of microcalcifications in the relevant size range can be nearly optimized. In fact, the filters which transform the input image into HH and LH+HL are closely related to prewhitening matched filters for detecting Gaussian objects (idealized microcalcifications) in 2 common forms of Markov (background) noise. The second stage is designed to overcome the limitations of the simplistic Gaussian assumption and provides an accurate segmentation of calcification boundaries. Detected pixel sites in HH and LH+HL are dilated then weighted before computing the inverse wavelet transform. Individual microcalcifications are greatly enhanced in the output image, to the point where straightforward thresholding can be applied to segment them. FROG curves are computed from tests using a freely distributed database of digitized mammograms.     

Nutritional regulation of the activities of lipogenic enzymes of rat liver and brown adipose tissue

Nutrition-induced effects on the activity of enzymes of lipogenesis, fatty acid synthase (FAS: EC 2.3.1.85), ATP citrate lyase (ACL: EC 4.1.3.8), malic enzyme (ME; EC 1.1.1.40), glucose-6-phosphate dehydrogenase (G6PDH: EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (PGDH; EC 1.1.1.44) were investigated in liver and interscapular brown adipose tissue (BAT) of rats. The lipogenic enzymes could be grouped into two categories according to their response to dietary manipulations: FAS and ACL, both key enzymes of lipogenesis, responded fast and strongly to dietary manipulations. ME, G6PDH and PGDH, enzymes which also contribute to metabolic pathways other than lipogenesis, responded in a more sustained and less pronounced fashion. Feed deprivation caused the specific activities of lipogenic enzymes to decline several-fold. Refeeding of previously fasted (up to 3 days) animals increased the activities dramatically (10-to 25-fold) to far above pre-fasting levels ("overshoot"). Repetition of the fasting/refeeding regimen increasingly impaired the ability of both tissues to synthesize overshooting enzyme activities in the subsequent refeeding period. The fasting-induced decline of the activities was prevented when sugars were provided to the animals via drinking water. The sugars displayed different effectivities: sucrose = glucose > fructose > maltose > > lactose. Sugars as the sole nutrient after fasting were also able to induce overshooting enzyme activities. Again, activities of FAS and ACL responded in a more pronounced fashion than the other three enzymes. Transition from feeding one diet to feeding a new diet of different composition led to adaptation of the lipogenic enzyme activities to levels characteristic for the new diet. Replacing a low-carbohydrate with a high-carbohydrate diet proceeded with major alterations of enzyme activities. This process of attaining a new level took up to 20 days and involved pronounced oscillations of the specific activities. In contrast, when a high-carbohydrate diet was replaced with another diet. particular one high in fat, transition to new enzyme activities was completed within 2-3 days and proceeded without oscillations. All dietary manipulations caused more pronounced responses in young (35d-old) than in adult (180d-old) animals.     

GPU-based real-time approximation of the ablation zone for radiofrequency ablation

Percutaneous radiofrequency ablation (RFA) is becoming a standard minimally invasive clinical procedure for the treatment of liver tumors. However, planning the applicator placement such that the malignant tissue is completely destroyed, is a demanding task that requires considerable experience. In this work, we present a fast GPU-based real-time approximation of the ablation zone incorporating the cooling effect of liver vessels. Weighted distance fields of varying RF applicator types are derived from complex numerical simulations to allow a fast estimation of the ablation zone. Furthermore, the heat-sink effect of the cooling blood flow close to the applicator's electrode is estimated by means of a preprocessed thermal equilibrium representation of the liver parenchyma and blood vessels. Utilizing the graphics card, the weighted distance field incorporating the cooling blood flow is calculated using a modular shader framework, which facilitates the real-time visualization of the ablation zone in projected slice views and in volume rendering. The proposed methods are integrated in our software assistant prototype for planning RFA therapy. The software allows the physician to interactively place virtual RF applicator models. The real-time visualization of the corresponding approximated ablation zone facilitates interactive evaluation of the tumor coverage in order to optimize the applicator's placement such that all cancer cells are destroyed by the ablation.     

Characterization of terrestrial water dynamics in the Congo Basin using GRACE and satellite radar altimetry

The Congo Basin is the world's third largest in size (~ 3.7 million km²), and second only to the Amazon River in discharge (~ 40,200 m³ s^− 1 annual average). However, the hydrological dynamics of seasonally flooded wetlands and floodplains remains poorly quantified. Here, we separate the Congo wetland into four 3° × 3° regions, and use remote sensing measurements (i.e., GRACE, satellite radar altimeter, GPCP, JERS-1, SRTM, and MODIS) to estimate the amounts of water filling and draining from the Congo wetland, and to determine the source of the water. We find that the amount of water annually filling and draining the Congo wetlands is 111 km³, which is about one-third the size of the water volumes found on the mainstem Amazon floodplain. Based on amplitude comparisons among the water volume changes and timing comparisons among their fluxes, we conclude that the local upland runoff is the main source of the Congo wetland water, not the fluvial process of river-floodplain water exchange as in the Amazon. Our hydraulic analysis using altimeter measurements also supports our conclusion by demonstrating that water surface elevations in the wetlands are consistently higher than the adjacent river water levels. Our research highlights differences in the hydrology and hydrodynamics between the Congo wetland and the mainstem Amazon floodplain.     

A lumped-parameter model to investigate the effect of plantar pressure on arterial blood flow in a diabetic foot

This paper presents a lumped-parameter model for the big-toe region that investigates the effect of plantar pressure on the diameter of the blood vessels, specifically the arteries, in the presence of arterial and/or tissue changes. The model developed in this paper uses a multi-domain energy system approach to develop the lumped-parameter differential equations. Blood flow is modelled as fluidic flow through compliant pipes that have inertia, stiffness, and damping. The tissue material is treated as a soft compliant material that transmits the external force to the blood vessels. Conclusions have been drawn to show the effect of plantar pressure, tissue damage, and their combination on the diameter of the blood vessels. The principles used here can be used to model the entire foot and the model used to investigate the effect of plantar pressure, tissue damage, and arterial changes on different parts of the foot. The work presented here may also have applications in other vascular diseases.     

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Electrical reflection coefficient and velocity shift for groove gratings

The electrical reflection coefficient r(e) and velocity shift (Deltanu/nu)(e) for grooves has never been formulated. All previous calculations for r(e) and (Deltanu/nu)(e) have used formulas valid for the reflection of a surface acoustic wave (SAW) from an array of conducting strips. However, the discontinuity in electrical boundary conditions leading to these formulas does not exist in groove gratings. A new expression for the electrical reflection coefficient and velocity shift for some material overlays is derived from both the variational principle and perturbation theory. The results for various substrates are compared to show the agreement between the two approaches. The implications of this new formulation for the design of grooved arrays on various materials are discussed, effectively resolving the discrepancy between theory and experiment.