A 2-dimensional computational model to analyze the effects of cellular heterogeinity on cardiac pacemaking

The mechanical action of the heart is made possible in response to electrical events that involve the cardiac cells, a property that classifies the heart tissue between the excitable tissues. At the cellular level, the electrical event is the signal that triggers the mechanical contraction, inducing a transient increase in intracellular calcium which, in turn, carries the message of contraction to the contractile proteins of the cell. The primary goal of my project was to implement in CUDA (Compute Unified Device Architecture, an hardware architecture for parallel processing created by NVIDIA) a tissue model of the rabbit sinoatrial node to evaluate the heterogeneity of its structure and how that variability influences the behavior of the cells. In particular, each cell has an intrinsic discharge frequency, thus different from that of every other cell of the tissue and it is interesting to study the process of synchronization of the cells and look at the value of the last discharge frequency if they synchronized.

Efficiency limits for silicon/perovskite tandem solar cells: a theoretical model

The primary goal of this work is related to the extension of an analytic electro-optical model. It will be used to describe single-junction crystalline silicon solar cells and a silicon/perovskite tandem solar cell in the presence of light-trapping in order to calculate efficiency limits for such a device. In particular, our tandem system is composed by crystalline silicon and a perovskite structure material: metilammoniumleadtriiodide (MALI). Perovskite are among the most convenient materials for photovoltaics thanks to their reduced cost and increasing efficiencies. Solar cell efficiencies of devices using these materials increased from 3.8% in 2009 to a certified 20.1% in 2014 making this the fastest-advancing solar technology to date. Moreover, texturization increases the amount of light which can be absorbed through an active layer. Using Green’s formalism it is possible to calculate the photogeneration rate of a single-layer structure with Lambertian light trapping analytically. In this work we go further: we study the optical coupling between the two cells in our tandem system in order to calculate the photogeneration rate of the whole structure. We also model the electronic part of such a device by considering the perovskite top cell as an ideal diode and solving the drift-diffusion equation with appropriate boundary conditions for the silicon bottom cell. We have a four terminal structure, so our tandem system is totally unconstrained. Then we calculate the efficiency limits of our tandem including several recombination mechanisms such as Auger, SRH and surface recombination. We focus also on the dependence of the results on the band gap of the perovskite and we calculare an optimal band gap to optimize the tandem efficiency. The whole work has been continuously supported by a numerical validation of out analytic model against Silvaco ATLAS which solves drift-diffusion equations using a finite elements method. Our goal is to develop a simpler and cheaper, but accurate model to study such devices.

Tumor necrosis factor sensitizes primary murine hepatocytes to Fas/CD95-induced apoptosis in a Bim- and Bid-dependent manner

Fas/CD95 is a critical mediator of cell death in many chronic and acute liver diseases and induces apoptosis in primary hepatocytes in vitro. In contrast, the proinflammatory cytokine tumor necrosis factor α (TNFα) fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Here we report that TNFα sensitizes primary murine hepatocytes cultured on collagen to Fas ligand (FasL)-induced apoptosis. This synergism is time-dependent and is specifically mediated by TNFα. Fas itself is essential for the sensitization, but neither Fas up-regulation nor endogenous FasL is responsible for this effect. Although FasL is shown to induce Bid-independent apoptosis in hepatocytes cultured on collagen, the sensitizing effect of TNFα is clearly dependent on Bid. Moreover, both c-Jun N-terminal kinase activation and Bim, another B cell lymphoma 2 homology domain 3 (BH3)-only protein, are crucial mediators of TNFα-induced apoptosis sensitization. Bim and Bid activate the mitochondrial amplification loop and induce cytochrome c release, a hallmark of type II apoptosis. The mechanism of TNFα-induced sensitization is supported by a mathematical model that correctly reproduces the biological findings. Finally, our results are physiologically relevant because TNFα also induces sensitivity to agonistic anti-Fas-induced liver damage. CONCLUSION: Our data suggest that TNFα can cooperate with FasL to induce hepatocyte apoptosis by activating the BH3-only proteins Bim and Bid.

Physical coronary arteriogenesis: a human "model" of collateral growth promotion

In patients with coronary artery disease, the size of myocardial infarction mainly determines the subsequent clinical outcome. Accordingly, it is the primary strategy to decrease cardiovascular mortality by minimizing infarct size. Promotion of collateral artery growth (arteriogenesis) is an appealing option of reducing infarct size. It has been demonstrated in experimental models that tangential fluid shear stress is the major trigger of arterial remodeling and, thus, of collateral growth. Lower-leg, high-pressure external counterpulsation triggered to occur during diastole induces a flow velocity signal and thus tangential endothelial shear stress in addition to the flow signal caused by cardiac stroke volume. We here present two cases of cardiac transplant recipients as human "models" of physical coronary arteriogenesis, providing an example of progressing and regressing clinical arteriogenesis, and review available evidence from clinical studies on other feasible forms of physical arteriogenesis.

Projected 21st century decrease in marine productivity: a multi-model analysis

Changes in marine net primary productivity (PP) and export of particulate organic carbon (EP) are projected over the 21st century with four global coupled carbon cycle-climate models. These include representations of marine ecosystems and the carbon cycle of different structure and complexity. All four models show a decrease in global mean PP and EP between 2 and 20% by 2100 relative to preindustrial conditions, for the SRES A2 emission scenario. Two different regimes for productivity changes are consistently identified in all models. The first chain of mechanisms is dominant in the low- and mid-latitude ocean and in the North Atlantic: reduced input of macro-nutrients into the euphotic zone related to enhanced stratification, reduced mixed layer depth, and slowed circulation causes a decrease in macro-nutrient concentrations and in PP and EP. The second regime is projected for parts of the Southern Ocean: an alleviation of light and/or temperature limitation leads to an increase in PP and EP as productivity is fueled by a sustained nutrient input. A region of disagreement among the models is the Arctic, where three models project an increase in PP while one model projects a decrease. Projected changes in seasonal and interannual variability are modest in most regions. Regional model skill metrics are proposed to generate multi-model mean fields that show an improved skill in representing observation-based estimates compared to a simple multi-model average. Model results are compared to recent productivity projections with three different algorithms, usually applied to infer net primary production from satellite observations.

Experimental acute type B aortic dissection: different sites of primary entry tears cause different ways of propagation

Many dissections seem to also have a retrograde component. The aim of the study was to evaluate different sites of primary entry tears and the propagation of the dissecting membrane, antegrade and retrograde, in an experimental model of acute type B aortic dissection.

A Model to Predict Percolation Threshold and Effective Conductivity of Infiltrated Electrodes for Solid Oxide Fuel Cells

We present a mechanistic modeling methodology to predict both the percolation threshold and effective conductivity of infiltrated Solid Oxide Fuel Cell (SOFC) electrodes. The model has been developed to mirror each step of the experimental fabrication process. The primary model output is the infiltrated electrode effective conductivity which provides results over a range of infiltrate loadings that are independent of the chosen electronically conducting material. The percolation threshold is utilized as a valuable output data point directly related to the effective conductivity to compare a wide range of input value choices. The predictive capability of the model is demonstrated by favorable comparison to two separate published experimental studies, one using strontium molybdate and one using La0.8Sr0.2FeO3-δ as infiltrate materials. Effective conductivities and percolation thresholds are shown for varied infiltrate particle size, pore size, and porosity with the infiltrate particle size having the largest impact on the results.

A Model to Predict Percolation Threshold and Effective Conductivity of Infiltrated Electrodes for Solid Oxide Fuel Cells

We present a mechanistic modeling methodology to predict both the percolation threshold and effective conductivity of infiltrated Solid Oxide Fuel Cell (SOFC) electrodes. The model has been developed to mirror each step of the experimental fabrication process. The primary model output is the infiltrated electrode effective conductivity which provides results over a range of infiltrate loadings that are independent of the chosen electronically conducting material. The percolation threshold is utilized as a valuable output data point directly related to the effective conductivity to compare a wide range of input value choices. The predictive capability of the model is demonstrated by favorable comparison to two separate published experimental studies, one using strontium molybdate and one using La0.8Sr0.2FeO3-delta as infiltrate materials. Effective conductivities and percolation thresholds are shown for varied infiltrate particle size, pore size, and porosity with the infiltrate particle size having the largest impact on the results. (C) 2013 The Electrochemical Society. All rights reserved.

Primary bovine synoviocyte cultures: a useful tool for in vitro drug testing?

The aim of the study was to evaluate bovine synoviocyte culture as an in vitro model to test new intra-articular drugs. The inflammatory reaction pattern of synoviocytes as compared to fibroblasts was studied over nine passages. Expression of pro-inflammatory cytokines was assessed after stimulation with lipopolysaccharide. Immunohistochemical markers were used to identify synoviocyte populations. Primary synoviocytes expressed markedly higher amounts of interleukin-1beta mRNA and tumour necrosis factor-alpha mRNA than fibroblasts after stimulation. This difference was lost over two passages. CD68-positive macrophage-like synoviocytes diminished over three passages, which may explain the reduced pro-inflammatory cytokine response. Primary bovine synoviocytes appear to be an appropriate and optimised model for testing novel drugs for cattle, because their response may more closely reflect in vivo tissue responses compared to cultured cell lines.

Predictors of sickness absence in patients with a new episode of low back pain in primary care

This study examines predictors of sickness absence in patients presenting to a health practitioner with acute/ subacute low back pain (LBP). Aims of this study were to identify baseline-variables that detect patients with a new LBP episode at risk of sickness absence and to identify prognostic models for sickness absence at different time points after initial presentation. Prospective cohort study investigating 310 patients presenting to a health practitioner with a new episode of LBP at baseline, three-, six-, twelve-week and six-month follow-up, addressing work-related, psychological and biomedical factors. Multivariate logistic regression analysis was performed to identify baseline-predictors of sickness absence at different time points. Prognostic models comprised 'job control', 'depression' and 'functional limitation' as predictive baseline-factors of sickness absence at three and six-week follow-up with 'job control' being the best single predictor (OR 0.47; 95%CI 0.26-0.87). The six-week model explained 47% of variance of sickness absence at six-week follow-up (p<0.001). The prediction of sickness absence beyond six-weeks is limited, and health practitioners should re-assess patients at six weeks, especially if they have previously been identified as at risk of sickness absence. This would allow timely intervention with measures designed to reduce the likelihood of prolonged sickness absence.

Surfactant protein D modulates allergen particle uptake and inflammatory response in a human epithelial airway model

Background Allergen-containing subpollen particles (SPP) are released from whole plant pollen upon contact with water or even high humidity. Because of their size SPP can preferentially reach the lower airways where they come into contact with surfactant protein (SP)-D. The aim of the present study was to investigate the influence of SP-D in a complex three-dimensional human epithelial airway model, which simulates the most important barrier functions of the epithelial airway. The uptake of SPP as well as the secretion of pro-inflammatory cytokines was investigated. Methods SPP were isolated from timothy grass and subsequently fluorescently labeled. A human epithelial airway model was built by using human Type II-pneumocyte like cells (A549 cells), human monocyte derived macrophages as well as human monocyte derived dendritic cells. The epithelial cell model was incubated with SPP in the presence and absence of surfactant protein D. Particle uptake was evaluated by confocal microscopy and advanced computer-controlled analysis. Finally, human primary CD4+ T-Cells were added to the epithelial airway model and soluble mediators were measured by enzyme linked immunosorbent assay or bead array. Results SPP were taken up by epithelial cells, macrophages, and dendritic cells. This uptake coincided with secretion of pro-inflammatory cytokines and chemokines. SP-D modulated the uptake of SPP in a cell type specific way (e.g. increased number of macrophages and epithelial cells, which participated in allergen particle uptake) and led to a decreased secretion of pro-inflammatory cytokines. Conclusion These results display a possible mechanism of how SP-D can modulate the inflammatory response to inhaled allergen.

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

Imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (TKs) and is effective in the treatment of malignancies characterized by constitutive activation of these TKs such as chronic myeloid leukemia and gastrointestinal stromal tumors. TKs also play an important role in T-cell receptor (TCR) signal transduction. Inhibitory as well as stimulating effects of imatinib on T cells and dendritic cells have been described. Here, we analyzed the effects of imatinib treatment on antiviral immune responses in vivo. Primary cytotoxic T-cell (CTL) responses were not impaired in imatinib-treated mice after infection with lymphocytic choriomeningitis virus (LCMV) or after immunization with a tumor cell line expressing LCMV glycoprotein (LCMV-GP). Similarly, neutralizing antibody responses to vesicular stomatitis virus (VSV) were not affected. In contrast, secondary expansion of LCMV-specific memory CTLs was reduced in vitro and in vivo, resulting in impaired protection against reinfection. In addition, imatinib treatment delayed the onset of diabetes in a CTL-induced diabetes model. In summary, imatinib treatment in vivo selectively inhibits the expansion of antigen-experienced memory CTLs without affecting primary T- or B-cell responses. Therefore, imatinib may be efficacious in the suppression of CTL-mediated immunopathology in autoimmune diseases without the risk of acquiring viral infections.

Significance of primary stability for osseointegration of dental implants

AIM: To investigate the significance of the initial stability of dental implants for the establishment of osseointegration in an experimental capsule model for bone augmentation. MATERIAL AND METHODS: Sixteen male rats were used in the study. In each rat, muscle-periosteal flaps were elevated on the lateral aspect of the mandibular ramus on both sides, resulting in exposure of the bone surface. Small perforations were then produced in the ramus. A rigid, hemispherical Teflon capsule with a diameter of 6 mm and a height of 4 mm and with a hole in its middle portion, prepared to fit the circumference of an ITI HC titanium implant of 2.8 mm in diameter, was fixed to the ramus using 4 mini-screws. On one side of the jaw, the implant was placed through the hole in such a way that its apex did not make contact with the mandibular ramus (test). This placement of the implant did not ensure primary stability. On the other side of the jaw, a similar implant was placed through the hole of the capsule in such a way that contact was made between the implant and the surface of the ramus (control). This provided primary stability of the implant. After placement of the implants, the soft tissues were repositioned over the capsules and sutured. After 1, 3, 6 and 9 months, four animals were sacrificed and subjected to histometric analysis. RESULTS: The mean height of direct bone-to-implant contact of implants with primary stability was 38.8%, 52.9%, 64.6% and 81.3% of the implant length at 1, 3, 6 and 9 months, respectively. Of the bone adjacent to the implant surface, 28.1%, 28.9%, 52.6% and 69.6%, respectively, consisted of mineralized bone. At the test implants, no bone-to-implant contact was observed at any observation time or in any of these non-stabilized specimens. CONCLUSION: The findings of the present study indicate that primary implant stability is a prerequisite for successful osseointegration, and that implant instability results in fibrous encapsulation, thus confirming previously made clinical observations.

Canine distemper virus infection of primary hippocampal cells induces increase in extracellular glutamate and neurodegeneration

The canine distemper virus (CDV) belongs to the Morbillivirus genus which includes important human pathogens like the closely related measles virus. CDV infection can reach the nervous system where it causes serious malfunctions. Although this pathology is well described, the molecular events in brain infection are still poorly understood. Here we studied infection in vitro by CDV using a model of dissociated cell cultures from newborn rat hippocampus. We used a recombinant CDV closely related to the neurovirulent A75/17 which also expresses the enhanced green fluorescent protein. We found that infected neurons and astrocytes could be clearly detected, and that infection spreads only slowly to neighboring cells. Interestingly, this infection causes a massive cell death of neurons, which includes also non-infected neurons. Antagonists of NMDA-type or alpha-amino-3-hydroxy-5-methylisoxazole-4-propinate (AMPA)-type glutamate receptors could slow down this neuron loss, indicating an involvement of the glutamatergic system in the induction of cell death in infected and non-infected cells. Finally, we show that, following CDV infection, there is a steady increase in extracellular glutamate in infected cultures. These results indicate that CDV infection induces excitotoxic insults on neurons via glutamatergic signaling.

Granulocyte colony-stimulating factor supports liver regeneration in a small-for-size liver remnant mouse model

Experimental partial hepatectomy of more than 80% of the liver weight bears an increased mortality in rodents, due to impaired hepatic regeneration in small-for-size liver remnants. Granulocyte colony-stimulating factor (G-CSF) promotes progenitor cell expansion and mobilization and also has immunomodulatory properties. The aim of this study was to determine the effect of systemically administered G-CSF on liver regeneration and animal survival in a small-for-size liver remnant mouse model. Mice were preconditioned daily for 5 days with subcutaneous injections of 5 microg G-CSF or aqua ad injectabile. Subsequently, 83% partial hepatectomy was performed by resecting the median, the left, the caudate, and the right inferior hepatic lobes in all animals. Daily sham or G-CSF injection was continued. Survival was significantly better in G-CSF-treated animals (P < 0.0001). At 36 and 48 h after microsurgical hepatic resection, markers of hepatic proliferation (Ki67, BrdU) were elevated in G-CSF-treated mice compared to sham injected control animals (P < 0.0001) and dry liver weight was increased (P < 0.05). G-CSF conditioning might prove to be useful in patients with small-for-size liver remnants after extended hepatic resections due to primary or secondary liver tumors or in the setting of split liver transplantation.