Surrogate-based uncertainty and sensitivity analysis for bacterial invasion in multi-species biofilm modeling

In this work, we present a probabilistic analysis of a detailed one-dimensional biofilm model that explicitly accounts for planktonic bacterial invasion in a multi-species biofilm. The objective is (1) to quantify and understand how the uncertainty in the parameters of the invasion submodel impacts the biofilm model predictions (here the microbial species volume fractions); and (2) to spot which parameters are the most important factors enhancing the biofilm model response. An emulator (or “surrogate”) of the biofilm model is trained using a limited experimental design of size N=216 and corresponding to a Halton’s low-discrepancy sequence in order to optimally cover the uncertain space of dimension d=3 (corresponding to the three scalar parameters newly introduced in the invasion submodel). A comparison of different types of emulator (generalized Polynomial Chaos expansion – gPC, Gaussian process model – GP) is carried out; results show that the best performance (measured in terms of the Q2 predictive coefficient) is obtained using a Least-Angle Regression (LAR) gPC-type expansion, where a sparse polynomial basis is constructed to reduce the problem size and where the basis coordinates are computed using a regularized least-square minimization. The resulting LAR gPC-expansion is found to capture the growth in complexity of the biofilm structure due to niche formation. Sobol’ sensitivity indices show the relative prevalence of the maximum colonization rate of autotrophic bacteria on biofilm composition in the invasion submodel. They provide guidelines for orienting future sensitivity analysis including more sources of variability, as well as further biofilm model developments.BERC 2014-2017 (Basque Government); BCAM Severo Ochoa accreditation SEV-2013-0323 (Spanish Ministry of Economy and Competitiveness MINECO); PhD Grant "La Caixa 2014" (La Caixa Foundation)

Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: Cannabinoid and non-cannabinoid receptor-mediated mechanisms

Background and purpose: Tetrazoles were recently developed as inhibitors of the cellular uptake of the endocannabinoid anandamide or of its hydrolysis by fatty acid amide hydrolase (FAAH), but were proposed to act also on non-endocannabinoid-related serine hydrolases. Experimental approach: We tested, in a model of inflammatory pain induced in mice by formalin, five chemically similar inhibitors: (i) OMDM119 and OMDM122, two potent carbamoyl tetrazole FAAH inhibitors with no effect on anandamide uptake; (ii) LY2183240, a carbamoyl tetrazole with activity as both FAAH and uptake inhibitor; (iii) OMDM132, a non-carbamoyl tetrazole with activity only as uptake inhibitor and iv) OMDM133, a non-carbamoyl tetrazole with no activity at either FAAH or uptake. Results: All compounds (2.5-10 mg kg -1, i.p.) inhibited the second phase of the nocifensive response induced by intraplantar injection of formalin. The effects of OMDM119, OMDM122 and OMDM133 were not antagonized by pretreatment with cannabinoid CB 1 receptor antagonists, such as rimonabant or AM251 (1-3 mg kg -1, i.p.). The effects of LY2183240 and OMDM132 were fully or partially antagonized by rimonabant, respectively, and the latter compound was also partly antagonized by the CB 2 receptor antagonist, AM630. Conclusions and implications: (i) non-FAAH hydrolases might be entirely responsible for the antinociceptive activity of some, but not all, tetrazole FAAH inhibitors, (ii) the presence of a carbamoylating group is neither necessary nor sufficient for such compounds to act through targets other than FAAH and (iii) inhibition of anandamide uptake is responsible for part of this antinociceptive activity, independently of effects on FAAH. © 2008 Macmillan Publishers Limited All rights reserved

Two-to-one resonant multi-modal dynamics of horizontal/inclined cables. Part I : theoretical formulation and model validation

This paper is first of the two papers dealingwith analytical investigation of resonant multimodal dynamics due to 2:1 internal resonances in the finite-amplitude free vibrations of horizontal/inclined cables. Part I deals with theoretical formulation and validation of the general cable model. Approximate nonlinear partial differential equations of 3-D coupled motion of small sagged cables - which account for both spatio-temporal variation of nonlinear dynamic tension and system asymmetry due to inclined sagged configurations - are presented. A multidimensional Galerkin expansion of the solution ofnonplanar/planar motion is performed, yielding a complete set of system quadratic/cubic coefficients. With the aim of parametrically studying the behavior of horizontal/inclined cables in Part II [25], a second-order asymptotic analysis under planar 2:1 resonance is accomplished by the method of multiple scales. On accounting for higher-order effectsof quadratic/cubic nonlinearities, approximate closed form solutions of nonlinear amplitudes, frequencies and dynamic configurations of resonant nonlinear normal modes reveal the dependence of cable response on resonant/nonresonant modal contributions. Depending on simplifying kinematic modeling and assigned system parameters, approximate horizontal/inclined cable models are thoroughly validated by numerically evaluating statics and non-planar/planar linear/non-linear dynamics against those of the exact model. Moreover, the modal coupling role and contribution of system longitudinal dynamics are discussed for horizontal cables, showing some meaningful effects due to kinematic condensation

Microbial colonization of anaerobic biofilms: a mathematical model

A 1-D mathematical model for analysis and prediction of microbial colonization of anaerobic multispecies biofilms for methane production is presented. The model combines the related processes of hydrolysis, acidogenesis, acetogenesis, methanogenesis and takes into account phenomena of substrate reaction and diffusion, biomass growth, detachment and, in particular, the colonization of new species from bulk liquid to biofilm. The colonization phenomenon is initiated by planktonic cells, present in the bulk liquid but not initially in the biofilm, which thanks to the characteristic porous structure of biofilm matrix, may enter the channels and establish where they find favorable growth conditions. The model consists of a free boundary value problem where the biofilm growth process is governed by nonlinear hyperbolic PDEs and substrate dynamics are dominated by semilinear parabolic PDEs. The transport of colonizing bacteria from the bulk liquid to the biofilm is modelled by using a diffusionreaction equation, where the reaction term represents the loss of planktonic bacteria due to their establishment within the biofilm. The method of characteristics is used for numerical purposes. The model is based on the biological framework of ADM1 and has been applied to simulate microbial competition and evaluate the influence of substrate diffusion on microbial stratification. Specific scenarios have been simulated describing the effect of colonization of motile bacteria into an established anaerobic biofilm

Scale-Free model for governing universe dynamics

We investigate the effects of scale-free model on cosmology, providing, in this way, a statistical background in the framework of general relativity. In order to discuss properties and time evolution of some relevant universe dynamical parameters (cosmographic parameters), such as $H(t)$ (Hubble parameter), $q(t)$ (deceleration parameter), $j(t)$ (jerk parameter) and $s(t)$ (snap parameter), which are well re-defined in the framework of scale-free model, we analyze a comparison between WMAP data. Hence the basic purpose of the work is to consider this statistical interpretation of mass distribution of universe, in order to have a mass density $\rho$ dynamics, not inferred from Friedmann equations, via scale factor $a(t)$. This model, indeed, has been used also to explain a possible origin and a viable explanation of cosmological constant, which assumes a statistical interpretation without the presence of extended theories of gravity; hence the problem of dark energy could be revisited in the context of a classical probability distribution of mass, which is, in particular, for the scale-free model, $P(k)\sim k^{-\gamma}$, with $2<\gamma<3$. The $\Lambda$CDM model becomes, with these considerations, a consequence of the particular statistics together with the use of general relativity.Comment: 7 pages, 4 figure

Variations in the Molecular and Physiological Characteristics and the Virulence of Monilinia fructicola, M. fructigena and M. laxa Isolates

Twenty-three Monilinia isolates of various origin were identified and compared by morphological means and by biomolecular protocols based on random amplified polymorphic DNA (RAPD) analysis, and on PCR detection by species-specific primer pairs. The identification of most Monilinia isolates by PCR and RAPD confirmed the identification by morphological criteria, although two isolates initially identified as M. fructigena by morphological means were attributed to M. fructicola by the biomolecular techniques. Monilinia isolates were also compared in terms of their in vitro pectolytic activity and isoenzyme patterns. All the isolates produced polygalacturonase and pectin methylesterase, but pectin lyase activity was found only in M. fructicola and M. fructigena, and not in most M. laxa isolates. The Monilinia isolates differed significantly in their isoenzyme patterns. Based on RAPD-PCR and PCR amplification and pectolytic isoenzymes, the isolates analysed clustered in three major groups, each corresponding to a Monilinia species. Artificial inoculations in peach and pear fruits revealed differences in virulence between the Monilinia species and within isolates. No correlation was found between the amount of pectolytic enzymes produced in vitro and virulence. Variations between and within the Monilinia species may depend at the physiological level on variations in the isoenzyme patterns of the pectolytic enzymes

Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C.

BACKGROUND AND AIMS: Chronic hepatitis C (CHC) and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age. We investigated the associations among menopause, sustained virologic response (SVR), and liver damage in patients with CHC. METHODS: We performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from CHC. Liver biopsy samples were analyzed (for fibrosis, inflammation, and steatosis) before patients received standard antiviral therapy. From women (n = 442), we collected data on the presence, type, and timing of menopause; associated hormone and metabolic features; serum levels of interleukin-6; and hepatic tumor necrosis factor (TNF)-α. RESULTS: Postmenopausal women achieved SVRs less frequently than women of reproductive age (46.0% vs 67.5%; P < .0001) but as frequently as men (51.1%; P = .283). By multivariate regression analysis, independent significant predictors for women to not achieve an SVR were early menopause (odds ratio [OR], 8.055; 95% confidence interval [CI], 1.834-25.350), levels of γ-glutamyl transpeptidase (OR, 2.165; 95% CI, 1.364-3.436), infection with hepatitis C virus genotype 1 or 4 (OR, 3.861; 95% CI, 2.433-6.134), and cholesterol levels (OR, 0.985; 95% CI, 0.971-0.998). Early menopause was the only independent factor that predicted lack of an SVR among women with genotype 1 hepatitis C virus infection (OR, 3.933; 95% CI, 1.274-12.142). Baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6 (P = .04), and hepatic TNF-α (P = .007) were significantly higher among postmenopausal women than women of reproductive age. CONCLUSIONS: Among women with CHC, early menopause was associated with a low likelihood of SVR, probably because of inflammatory factors that change at menopause