Uncoupling of osteoblast–osteoclast regulation in a chemical murine model of Gaucher disease

Gaucher disease (GD) is caused by mutations in the GBA gene that confer a deficient level of activity of glucocerebrosidase (GCase). This deficiency leads to accumulation of the glycolipid glucocerebroside in the lysosomes of cells of monocyte/macrophage system. Type I GD is the mildest form and is characterized by the absence of neuronopathic affection. Bone compromise in Gaucher disease patients is the most disabling aspect of the disease. However, pathophysiological aspects of skeletal alterations are still poorly understood.     

Dermatophyte–host relationship of a murine model of experimental invasive dermatophytosis

Recognizing the invasive potential of the dermatophytes and understanding the mechanisms involved in this process will help with disease diagnosis and with developing an appropriate treatment plan. In this report, we present the histopathological, microbiological and immunological features of a model of invasive dermatophytosis that is induced by subcutaneous infection of Trichophyton mentagrophytes in healthy adult Swiss mice. Using this model, we observed that the fungus rapidly spreads to the popliteal lymph nodes, spleen, liver and kidneys. Similar to the human disease, the lymph nodes were the most severely affected sites. The fungal infection evoked acute inflammation followed by a granulomatous reaction in the mice, which is similar to what is observed in patients. The mice were able to mount a Th1-polarized immune response and displayed IL-10-mediated immune regulation. We believe that the model described here will provide valuable information regarding the dermatophyte–host relationship and will yield new perspective for a better understanding of the immunological and pathological aspects of invasive dermatophytosis.     

Fluid–structure interaction in a fully coupled three-dimensional mitral–atrium–pulmonary model

This paper aims to investigate detailed mechanical interactions between the pulmonary haemodynamics and left heart function in pathophysiological situations (e.g. atrial fibrillation and acute mitral regurgitation). This is achieved by developing a complex computational framework for a coupled pulmonary circulation, left atrium and mitral valve model. The left atrium and mitral valve are modelled with physiologically realistic three-dimensional geometries, fibre-reinforced hyperelastic materials and fluid–structure interaction, and the pulmonary vessels are modelled as one-dimensional network ended with structured trees, with specified vessel geometries and wall material properties. This new coupled model reveals some interesting results which could be of diagnostic values. For example, the wave propagation through the pulmonary vasculature can lead to different arrival times for the second systolic flow wave (S2 wave) among the pulmonary veins, forming vortex rings inside the left atrium. In the case of acute mitral regurgitation, the left atrium experiences an increased energy dissipation and pressure elevation. The pulmonary veins can experience increased wave intensities, reversal flow during systole and increased early-diastolic flow wave (D wave), which in turn causes an additional flow wave across the mitral valve (L wave), as well as a reversal flow at the left atrial appendage orifice. In the case of atrial fibrillation, we show that the loss of active contraction is associated with a slower flow inside the left atrial appendage and disappearances of the late-diastole atrial reversal wave (AR wave) and the first systolic wave (S1 wave) in pulmonary veins. The haemodynamic changes along the pulmonary vessel trees on different scales from microscopic vessels to the main pulmonary artery can all be captured in this model. The work promises a potential in quantifying disease progression and medical treatments of various pulmonary diseases such as the pulmonary hypertension due to a left heart dysfunction.

     

Local therapy with CpG motifs in a murine model of allergic airway inflammation in IFN-β knock-out mice

Background

CpG oligodeoxynucleotides (CpG-ODN) are capable of inducing high amounts of type I IFNs with many immunomodulatory properties. Furthermore, type-I IFNs have been proposed to play a key role in mediating effects of CpG-ODN. The precise role of IFN-β in the immunomodulatory effects of CpG-ODN is not known.

Objective

Here, we aimed to elucidate the role of IFN-β in the anti-allergic effect of CpG motifs.

Methods

We assessed the immune response in OVA-primed/OVA-challenged IFN-β knockout (-/-) mice compared to wild type (WT) control, after intranasal and systemic treatment with synthetic CpG motifs.

Results

Vaccination with CpG-ODN reduced the number of cells in airways of OVA-sensitized WT but not IFN-β-/- mice. Although airway eosinophilia was reduced in both treated groups, they were significantly higher in IFN-β^-/- mice. Other inflammatory cells, such as lymphocytes and macrophages were enhanced in airways by CpG treatment in IFN-β-/- mice. The ratio of IFN-γ/IL-4 cytokines in airways was significantly skewed to a Th1 response in WT compared to IFN-β^-/- group. In contrast, IL-4 and IgE were reduced with no differences between groups. Ag-specific T-cell proliferation, Th1-cytokines such as IFN-γ, IL-2 and also IL-12 were significantly lower in IFN-β-/- mice. Surprisingly, we discovered that intranasal treatment of mice with CpG-ODN results in mild synovitis particularly in IFN-β-/- mice.

Conclusion

Our results indicate that induction of Th1 response by therapy with CpG-ODN is only slightly and partially dependent on IFN-β, while IFN-β is not an absolute requirement for suppression of airway eosinophilia and IgE. Furthermore, our finding of mild synovitis is a warning for possible negative effects of CpG-ODN vaccination.     

Biomarkers of pulmonary hypertension in patients with scleroderma: a case–control study

IntroductionSignificant pulmonary vascular disease is a leading cause of death in patients with scleroderma, and early detection and early medical intervention are important, as they may delay disease progression and improve survival and quality of life. Although several biomarkers have been proposed, there remains a need to define a reliable biomarker of early pulmonary vascular disease and subsequent development of pulmonary hypertension (PH). The purpose of this study was to define potential biomarkers for clinically significant pulmonary vascular disease in patients with scleroderma.MethodsThe circulating growth factors basic fibroblast growth factor, placental growth factor (PlGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor, and soluble VEGF receptor 1 (sFlt-1), as well as cytokines (interleukin [IL]-1β IL-2, IL-4, IL-5, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor-α, and interferon-γ), were quantified in patients with scleroderma with PH (n = 37) or without PH (n = 40). In non-parametric unadjusted analyses, we examined associations of growth factor and cytokine levels with PH. In a subset of each group, a second set of earlier samples, drawn 3.0±1.6 years earlier, were assessed to determine the changes over time.ResultssFlt-1 (p = 0.02) and PlGF (p = 0.02) were higher in the PH than in the non-PH group. sFlt-1 (ρ = 0.3245; p = 0.01) positively correlated with right ventricular systolic pressure. Both PlGF (p = 0.03) and sFlt-1 (p = 0.04) positively correlated with the ratio of forced vital capacity to diffusing capacity for carbon monoxide (DLCO), and both inversely correlated with DLCO (p = 0.01). Both PlGF and sFlt-1 levels were stable over time in the control population.ConclusionsOur study demonstrated clear associations between regulators of angiogenesis (sFlt-1 and PlGF) and measures of PH in scleroderma and that these growth factors are potential biomarkers for PH in patients with scleroderma. Larger longitudinal studies are required for validation of our results.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0712-4) contains supplementary material, which is available to authorized users.     

The role of noise in a predator–prey model with Allee effect

The existence and implications of alternative stable states in ecological systems have been investigated extensively within deterministic models. However, it is known that natural systems are undeniably subject to random fluctuations, arising from either environmental variability or internal effects. Thus, in this paper, we study the role of noise on the pattern formation of a spatial predator–prey model with Allee effect. The obtained results show that the spatially extended system exhibits rich dynamic behavior. More specifically, the stationary pattern can be induced to be a stable target wave when the noise intensity is small. As the noise intensity is increased, patchy invasion emerges. These results indicate that the dynamic behavior of predator–prey models may be partly due to stochastic factors instead of deterministic factors, which may also help us to understand the effects arising from the undeniable susceptibility to random fluctuations of real ecosystems.     

Chronic intranasal treatment with an anti-Aβ(30-42) scFv antibody ameliorates amyloid pathology in a transgenic mouse model of Alzheimer's disease

Amyloid-beta peptide (Aβ)-directed active and passive immunization therapeutic strategies reduce brain levels of Aβ, decrease the severity of beta-amyloid plaque pathology and reverse cognitive deficits in mouse models of Alzheimer's disease (AD). As an alternative approach to passive immunization with full IgG molecules, single-chain variable fragment (scFv) antibodies can modulate or neutralize Aβ-related neurotoxicity and inhibit its aggregation in vitro. In this study, we characterized a scFv derived from a full IgG antibody raised against the C-terminus of Aβ, and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce Aβ-related pathology. We found that the scFv entered the brain after intranasal application, and that it bound to beta-amyloid plaques in the cortex and hippocampus of APP transgenic mice. Moreover, the scFv inhibited Aβ fibril formation and Aβ-mediated neurotoxicity in vitro. In a preventative therapeutic approach chronic intranasal treatment with scFv reduced congophilic amyloid angiopathy (CAA) and beta-amyloid plaque numbers in the cortex of APPswe/PS1dE9 mice. This reduction of CAA and plaque pathology was associated with a redistribution of brain Aβ from the insoluble fraction to the soluble peptide pool. Due to their lack of the effector domain of full IgG, scFv may represent an alternative tool for the treatment of Aβ-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that Aβ-directed immunotherapy can reduce Aβ deposition in brain vessels in transgenic mice.     

Therapeutic effect of CHF5074, a new γ-secretase modulator,in a mouse model of scrapie

In transmissible spongiform encephalopathies (TSEs) and Alzheimer disease (AD) both misfolding and aggregation of specific proteins represent key features. Recently, it was observed that PrP^C is a mediator of a synaptic dysfunction induced by Aβ oligomers. We tested a novel γ-secretase modulator (CHF5074) in a murine model of prion disease. Groups of female mice were intracerebrally or intraperitoneally infected with the mouse-adapted Rocky Mountain Laboratory prions. Two weeks prior infection, the animals were provided with a CHF5074-medicated diet (375 ppm) or a standard diet (vehicle) until they showed neurological signs and eventually died. In intracerebrally infected mice, oral administration of CHF5074 did not prolong survival of the animals. In intraperitoneally-infected mice, CHF5074-treated animals showed a median survival time of 21 d longer than vehicle-treated mice (p < 0.001). In these animals, immunohistochemistry analyses showed that deposition of PrP^Sc in the cerebellum, hippocampus and parietal cortex in CHF5074-treated mice was significantly lower than in vehicle-treated animals. Immunostaining of glial fibrillary acidic protein (GFAP) in parietal cortex revealed a significantly higher reactive gliosis in CHF5074-treated mice compared with the control group of infected animals. Although the mechanism underlying the beneficial effects of CHF5074 in this murine model of human prion disease is unclear, it could be hypothesized that the drug counteracts PrP^Sc toxicity through astrocyte-mediated neuroprotection. CHF5074 shows a pharmacological potential in murine models of both AD and TSEs thus suggesting a link between these degenerative pathologies.Key words: TSE, prion, murine model, γ-secretase modulator, therapy     

Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer's disease

The mutant ubiquitin UBB(+1) is a substrate as well as an inhibitor of the ubiquitin-proteasome system (UPS) and accumulates in the neuropathological hallmarks of Alzheimer's disease (AD). A role for the UPS has been suggested in the generation of amyloid β (Aβ) plaques in AD. To investigate the effect of UBB(+1) expression on amyloid pathology in vivo, we crossed UBB(+1) transgenic mice with a transgenic line expressing AD-associated mutant amyloid precursor protein (APPSwe) and mutant presenilin 1 (PS1dE9), resulting in APPPS1/UBB(+1) triple transgenic mice. In these mice, we determined the Aβ levels at 3, 6, 9 and 11months of age. Surprisingly, we found a significant decrease in Aβ deposition in amyloid plaques and levels of soluble Aβ(42) in APPPS1/UBB(+1) transgenic mice compared to APPPS1 mice at 6months of age, without alterations in UBB(+1) protein levels or proteasomal chymotrypsin activity. These lowering effects of UBB(+1) on Aβ deposition were transient, as this relative decrease in plaque load was not significant in APPPS1/UBB(+1) mice at 9 and 11months of age. We also show that APPPS1/UBB(+1) mice exhibit astrogliosis, indicating that they may not be improved functionally compared to APPPS1 mice despite the Aβ reduction. The molecular mechanism underlying this decrease in Aβ deposition in APPPS1/UBB(+1) mice is more complex than previously assumed because UBB(+1) is also ubiquitinated at K63 opening the possibility of additional effects of UBB(+1) (e.g. kinase activation).     

The complex dynamics of a diffusive prey–predator model with an Allee effect in prey

This paper investigates complex dynamics of a predator–prey interaction model that incorporates: (a) an Allee effect in prey; (b) the Michaelis–Menten type functional response between prey and predator; and (c) diffusion in both prey and predator. We provide rigorous mathematical results of the proposed model including: (1) the stability of non-negative constant steady states; (2) sufficient conditions that lead to Hopf/Turing bifurcations; (3) a prior estimates of positive steady states; (4) the non-existence and existence of non-constant positive steady states when the model is under zero-flux boundary condition. We also perform completed analysis of the corresponding ODE model to obtain a better understanding on effects of diffusion on the stability. Our analytical results show that the small values of the ratio of the prey's diffusion rate to the predator's diffusion rate are more likely to destabilize the system, thus generate Hopf-bifurcation and Turing instability that can lead to different spatial patterns. Through numerical simulations, we observe that our model, with or without Allee effect, can exhibit extremely rich pattern formations that include but not limit to strips, spotted patterns, symmetric patterns. In addition, the strength of Allee effects also plays an important role in generating distinct spatial patterns.     

Initial reactions in the fungal degradation of guaiacylglycerol-β-coniferyl ether,a lignin substructure model

Fusarium solani M-13-1 was shake-cultured in a medium containing guaiacylglycerol-β-coniferyl ether (I), a model compound representing the arylglycerol-β-aryl ether linkage in lignin, as sole carbon source. From the culture filtrate guaiacylglycerol-β-coniferyl aldehyde ether (II) and guaiacylglycerol-β-ferulic acid ether (III) were isolated as metabolic products. Incubation with (III) resulted in formation of guaiacylglycerol-β-vanillin ether (IV), which was further metabolized to guaiacyglycerol-β-vanillic acid ether (V). The results indicate that the cinnamyl alcohol group of (I) is initially oxidized to an aldehyde group, which is further oxidized to a carboxyl group, yielding (II) and (III). Compound (III) is converted to (IV) by the release of a C₂ fragment, and the aldehyde group of (IV) is further oxidized to a carboxyl group, giving (V). In the pathway from (I) to (V), neither oxidation of the benzylic secondary alcohol to ketone nor cleavage of the arylglycerol-β-aryl ether linkage was observed. The fungus was found to attack both erythro and threo form without distinction.     

Tumor targeting in a murine tumor xenograft model with the (sFv′)2 divalent form of anti-c-erbB-2 single-chain Fv

This investigation has utilized novel forms of the single-chain Fv (sFv), wherein a cysteine-containing peptide has been fused to the sFv carboxyl terminus to facilitate disulfide bonding or specific crosslinking of this sFv′ to make divalent (sFv′)₂. The 741F8 anti-c-erbB-2 monoclonal antibody was used as the basis for construction of 741F8 sFv, from which the sFv′ and (sFv′)₂ derivatives were prepared. Recombinant c-erbB-2 extracellular domain (ECD) was prepared in CHO cells and the bivalency of 741F8 (sFv′)₂ demonstrated by its complex formation with ECD. The tumor binding properties of¹²⁵I-labeled anti-c-erbB-2 741F8 sFv, sFv′, and (sFv′)₂ were compared with radiolabeled antidigoxin 26-10 sFv′ and (sFv′)₂ controls. Following intravenous administration of radiolabeled species to severe combined immune-deficient (SCID) mice bearing SK-OV-3 tumors (which overexpress c-erbB-2), blood and organ samples were obtained as a function of time over 24 h. Comparative analysis of biodistribution and tumor-to-organ ratios demonstrated the 741F8 sFv, sFv′, and (sFv′)₂ had excellent specificity for tumors, which improved with time after injection. This contrasted with nonspecific interstitial pooling in tumors observed with the 26-10 sFv, sFv′, and (sFv′)₂, which decreased with time after administration. Tumor localization was significantly better for disulfide or peptide crosslinked 741F8 (sFv′)₂ having Gly₄Cys tails than for monovalent 741F8 sFv′ or Fab. The superior properties of the 741F8 (sFv′)₂ in targeting SK-OV-3 tumors in SCID mice suggests the importance of further investigations of divalent sFv analogs for immunotargeting.     

Fusing spatial resource heterogeneity with a competition–colonization trade-off in model communities

Two commonly cited mechanisms of multispecies coexistence in patchy environments are spatial heterogeneity in competitive abilities caused by variation in resources and a competition–colonization trade-off. In this paper, a model that fuses these mechanisms together is presented and analyzed. The model suggests that spatial variation in resource ratios can lead to multispecies coexistence, but this mechanism by itself is weak when the number of resources for which species compete is small. However, spatial resource heterogeneity is a powerful mechanism for multispecies coexistence when it acts synergistically with a competition–colonization trade-off. The model also shows how resource supply can control the competitive balance between species that are weak competitors but superior colonizers and strong competitors/inferior colonizers. This provides additional theoretical support for a possible explanation of empirically observed hump-shaped relationships between species diversity and ecological productivity.     

Structural sensitivity and resilience in a predator–prey model with density-dependent mortality

Numerous formulations with the same mathematical properties can be relevant to model a biological process. Different formulations can predict different model dynamics like equilibrium vs. oscillations even if they are quantitatively close (structural sensitivity). The question we address in this paper is: does the choice of a formulation affect predictions on the number of stable states? We focus on a predator–prey model with predator competition that exhibits multiple stable states. A bifurcation analysis is realized with respect to prey carrying capacity and species body mass ratio within range of values found in food web models. Bifurcation diagrams built for two type-II functional responses are different in two ways. First, the kind of stable state (equilibrium vs. oscillations) is different for 26.0–49.4% of the parameter values, depending on the parameter space investigated. Using generalized modelling, we highlight the role of functional response slope in this difference. Secondly, the number of stable states is higher with Ivlev's functional response for 0.1–14.3% of the parameter values. These two changes interact to create different model predictions if a parameter value or a state variable is altered. In these two examples of disturbance, Holling's disc equation predicts a higher system resilience. Indeed, Ivlev's functional response predicts that disturbance may trap the system into an alternative stable state that can be escaped from only by a larger alteration (hysteresis phenomena). Two questions arise from this work: (i) how much complex ecological models can be affected by this sensitivity to model formulation? and (ii) how to deal with these uncertainties in model predictions?     

Global behaviour of a predator–prey like model with piecewise constant arguments

The present study deals with the analysis of a predator–prey like model consisting of system of differential equations with piecewise constant arguments. A solution of the system with piecewise constant arguments leads to a system of difference equations which is examined to study boundedness, local and global asymptotic behaviour of the positive solutions. Using Schur–Cohn criterion and a Lyapunov function, we derive sufficient conditions under which the positive equilibrium point is local and global asymptotically stable. Moreover, we show numerically that periodic solutions arise as a consequence of Neimark-Sacker bifurcation of a limit cycle.     

Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue

Background We previously demonstrated that targeting lymphotoxin α (LTα) to the tumor evokes its immunological destruction in a syngeneic B16 melanoma model. Since treatment was associated with the induction of peritumoral tertiary lymphoid tissue, we speculated that the induced immune response was initiated at the tumor site. Methods and results In order to directly test this notion, we analyzed the efficacy of tumor targeted LTα in LTα knock-out (LTα^−/−) mice which lack peripheral lymph nodes. To this end, we demonstrate that tumor-targeted LTα mediates the induction of specific T-cell responses even in the absence of secondary lymphoid organs. In addition, this effect is accompanied by the initiation of tertiary lymphoid tissue at the tumor site in which B and T lymphocytes are compartmentalized in defined areas and which harbor expanded numbers of tumor specific T cells as demonstrated by in situ TRP-2/K^b tetramer staining. Mechanistically, targeted LTα therapy seems to induce changes at the tumor site which allows a coordinated interaction of immune competent cells triggering the induction of tertiary lymphoid tissue. Conclusion Thus, our data demonstrate that targeted LTα promotes an accelerated immune response by enabling the priming of T cells at the tumor site.     

Seidel–Herzel model of human baroreflex in cardiorespiratory system with stochastic delays

The stochastic versus deterministic solution of the Seidel–Herzel model describing the baroreceptor control loop (which regulates the short-time heart rate) are compared with the aim of exploring the heart rate variability. The deterministic model solutions are known to bifurcate from the stable to sustained oscillatory solutions if time delays in transfer of signals by sympathetic nervous system to the heart and vasculature are changed. Oscillations in the heart rate and blood pressure are physiologically crucial since they are recognized as Mayer waves. We test the role of delays of the sympathetic stimulation in reconstruction of the known features of the heart rate. It appears that realistic histograms and return plots are attainable if sympathetic time delays are stochastically perturbed, namely, we consider a perturbation by a white noise. Moreover, in the case of stochastic model the bifurcation points vanish and Mayer oscillations in heart period and blood pressure are observed for whole considered space of sympathetic time delays.