A stochastic collocation method for uncertainty quantification and propagation in cardiovascular simulations

Simulations of blood flow in both healthy and diseased vascular models can be used to compute a range of hemodynamic parameters including velocities, time varying wall shear stress, pressure drops, and energy losses. The confidence in the data output from cardiovascular simulations depends directly on our level of certainty in simulation input parameters. In this work, we develop a general set of tools to evaluate the sensitivity of output parameters to input uncertainties in cardiovascular simulations. Uncertainties can arise from boundary conditions, geometrical parameters, or clinical data. These uncertainties result in a range of possible outputs which are quantified using probability density functions (PDFs). The objective is to systemically model the input uncertainties and quantify the confidence in the output of hemodynamic simulations. Input uncertainties are quantified and mapped to the stochastic space using the stochastic collocation technique. We develop an adaptive collocation algorithm for Gauss-Lobatto-Chebyshev grid points that significantly reduces computational cost. This analysis is performed on two idealized problems--an abdominal aortic aneurysm and a carotid artery bifurcation, and one patient specific problem--a Fontan procedure for congenital heart defects. In each case, relevant hemodynamic features are extracted and their uncertainty is quantified. Uncertainty quantification of the hemodynamic simulations is done using (a) stochastic space representations, (b) PDFs, and (c) the confidence intervals for a specified level of confidence in each problem.     

Thiol oxidation in signaling and response to stress: detection and quantification of physiological and pathophysiological thiol modifications

Cysteine thiol modifications are increasingly recognized to occur under both physiological and pathophysiological conditions, making their accurate detection, identification, and quantification of growing importance. Among free cysteines, the bulk of modifications occurs on a subset of cysteines that are more reactive. These exist as thiolate anions at physiological pH because of their surrounding electrostatic environment. Reagents with iodoacetamide-active groups can be used to selectively label these reactive thiols with a high degree of selectivity. Thiol adducts can be detected by the failure to label with iodoacetamide or other reagents; restoration of labeling by specific reducing agents (e.g., ascorbate or glutaredoxin) can be used to detect reversible S-nitroso and S-glutathione adducts. These adducts also may be detected with radiolabels and antibodies. S-Glutathiolation in response to physiological stimuli may be detected in cells and tissues with glutathione ester labeled with biotin. Mass spectrometry can identify thiol modifications with precision, and with isotope-coded affinity tags, used to quantify modification of specific thiols. Combinations of these methods increase sensitivity and specificity, and enable quantification and precise identification of thiol modifications that occur under physiological and pathological conditions.     

A three-stage kinetic model of amyloid fibrillation

Amyloid fibrillation has been intensively studied because of its association with various neurological disorders. While extensive time-dependent fibrillation experimental data are available and appear similar, few mechanistic models have been developed to unify those results. The aim of this work was to interpret these experimental results via a rigorous mathematical model that incorporates the physical chemistry of nucleation and fibril growth dynamics. A three-stage mechanism consisting of protein misfolding, nucleation, and fibril elongation is proposed and supported by the features of homogeneous fibrillation responses. Estimated by nonlinear least-squares algorithms, the rate constants for nucleation were approximately 10,000,000 times smaller than those for fibril growth. These results, coupled with the positive feedback characteristics of the elongation process, account for the typical sigmoidal behavior during fibrillation. In addition, experiments with different proteins, various initial concentrations, seeding versus nonseeding, and several agitation rates were analyzed with respect to fibrillation using our new model. The wide applicability of the model confirms that fibrillation kinetics may be fairly similar among amyloid proteins and for different environmental factors. Recommendations on further experiments and on the possible use of molecular simulations to determine the desired properties of potential fibrillation inhibitors are offered.     

Evaluation of chitosan nanoformulations as potent anti-HIV therapeutic systems

Background

Antiretroviral Therapy (ART) is currently the major therapeutic intervention in the treatment of AIDS. ART, however, is severely limited due to poor availability, high cytotoxicity, and enhanced metabolism and clearance of the drug molecules by the renal system. The use of nanocarriers encapsulating the anti-retroviral drugs may provide a solution to the aforementioned problems. Importantly, the application of mildly immunogenic polymeric carrier confers the advantage of making the nanoparticles more visible to the immune system leading to their efficient uptake by the phagocytes.

Methods

The saquinavir-loaded chitosan nanoparticles were characterized by transmission electron microscopy and differential scanning calorimetry and analyzed for the encapsulation efficiency, swelling characteristics, particle size properties, and the zeta potential. Furthermore, cellular uptake of the chitosan nanocarriers was evaluated using confocal microscopy and Flow cytometry. The antiviral efficacy was quantified using viral infection of the target cells.

Results

Using novel chitosan carriers loaded with saquinavir, a protease inhibitor, we demonstrate a drug encapsulation efficiency of 75% and cell targeting efficiency greater than 92%. As compared to the soluble drug control, the saquinavir-loaded chitosan carriers caused superior control of the viral proliferation as measured by using two different viral strains, NL4-3 and Indie-C1, and two different target T-cells, Jurkat and CEM-CCR5.

Conclusion

Chitosan nanoparticles loaded with saquinavir were characterized and they demonstrated superior drug loading potential with greater cell targeting efficiency leading to efficient control of the viral proliferation in target T-cells.

General significance

Our data ascertain the potential of chitosan nanocarriers as novel vehicles for HIV-1 therapeutics.     

Hydrogel based injectable scaffolds for cardiac tissue regeneration

Tissue engineering promises to be an effective strategy that can overcome the lacuna existing in the current pharmacological and interventional therapies and heart transplantation. Heart failure continues to be a major contributor to the morbidity and mortality across the globe. This may be attributed to the limited regeneration capacity after the adult cardiomyocytes are terminally differentiated or injured. Various strategies involving acellular scaffolds, stem cells, and combinations of stem cells, scaffolds and growth factors have been investigated for effective cardiac tissue regeneration. Recently, injectable hydrogels have emerged as a potential candidate among various categories of biomaterials for cardiac tissue regeneration due to improved patient compliance and facile administration via minimal invasive mode that treats complex infarction. This review discusses in detail on the advances made in the field of injectable materials for cardiac tissue engineering highlighting their merits over their preformed counterparts.     

Identification of group I introns within the SSU rDNA gene in species of Ceratocystiopsis and related taxa

During a recent phylogenetic study, group I introns were noted that interrupt the nuclear small subunit ribosomal RNA (SSU rDNA) gene in species of Ceratocystiopsis. Group I introns were found to be inserted at the following rDNA positions: S943, S989, and S1199. The introns have been characterized and phylogenetic analysis of the host gene and the corresponding intron data suggest that for S943 vertical transfer and frequent loss appear to be the most parsimonious explanation for the distribution of nuclear SSU rDNA introns among species of Ceratocystiopsis. The SSU rDNA data do suggest that a recent proposal of segregating the genus Ophiostoma sensu lato into Ophiostoma sensu stricto, Grosmannia, and Ceratocystiopsis has some merit but may need further amendments, as the SSU rDNA suggests that Ophiostoma s. str. may now represent a paraphyletic grouping.     

Studies on the removal of dyes from a synthetic textile effluent using barley husk in static-batch mode and in a continuous flow,packed-bed,reactor

Yarrowia lipolytica LGAM S(7)1 presented remarkable growth on industrial glycerol used as sole carbon substrate. Nitrogen-limited flask cultures were accompanied by restricted synthesis of reserve lipid, whilst amounts of citric acid were produced extracellularly. On the contrary, high amounts of reserve lipid (up to 3.5 g/l, 43% w/w of lipids in dry biomass) were produced in highly aerated continuous cultures. Lipid production was favoured at low specific dilution rates whilst fat-free material yield increased over the whole range of D (h(-1)). The maximum volumetric productivity obtained was 0.12 g lipid/1 h. Storage lipid composition did not present remarkable changes in the specific dilution rates tested. Oleate and linoleate were the dominant cellular fatty acids.