Heterogeneous Diffusion and Nonlinear Advection in a One-Dimensional Fisher-KPP Problem.

The goal of this study is to provide an analysis of a Fisher-KPP non-linear reaction problem with a higher-order diffusion and a non-linear advection. We study the existence and uniqueness of solutions together with asymptotic solutions and positivity conditions. We show the existence of instabilities based on a shooting method approach. Afterwards, we study the existence and uniqueness of solutions as an abstract evolution of a bounded continuous single parametric (t) semigroup. Asymptotic solutions based on a Hamilton-Jacobi equation are then analyzed. Finally, the conditions required to ensure a comparison principle are explored supported by the existence of a positive maximal kernel.

MARTINI coarse-grained model for crystalline cellulose microfibers.

Commercial-scale biofuel production requires a deep understanding of the structure and dynamics of its principal target: cellulose. However, an accurate description and modeling of this carbohydrate structure at the mesoscale remains elusive, particularly because of its overwhelming length scale and configurational complexity. We have derived a set of MARTINI coarse-grained force field parameters for the simulation of crystalline cellulose fibers. The model is adapted to reproduce different physicochemical and mechanical properties of native cellulose Iß. The model is able not only to handle a transition from cellulose Iß to another cellulose allomorph, cellulose IIII, but also to capture the physical response to temperature and mechanical bending of longer cellulose nanofibers. By developing the MARTINI model of a solid cellulose crystalline fiber from the building blocks of a soluble cellobiose coarse-grained model, we have provided a systematic way to build MARTINI models for other crystalline biopolymers.

Structural determination of Streptococcus pneumoniae repeat units in serotype 41A and 41F capsular polysaccharides to probe gene functions in the corresponding capsular biosynthetic loci.

We report the repeating unit structures of the native capsular polysaccharides of Streptococcus pneumoniae serotypes 41A and 41F. Structural determinations yielded six carbohydrate units in the doubly branched repeating unit to give the following structure for serotype 41A: The structure determinations were motivated (1) by an ambition to help close the remaining gaps in S. pneumoniae capsular polysaccharide structures, and (2) by the attempt to derive functional annotations of carbohydrate active enzymes in the biosynthesis of bacterial polysaccharides from the determined structures. An activity present in 41F but not 41A is identified as an acetyltransferase acting on the rhamnopyranosyl sidechain E. The genes encoding the formation of the six glycosidic bonds in serogroup 41 were determined from the capsular polysaccharide structures of serotype 41A, 41F, and genetically related serotypes, in conjunction with corresponding genomic information and computational homology searches. In combination with complementary information, NMR spectroscopy considerably simplifies the functional annotation of carbohydrate active enzymes in the biosynthesis of bacterial polysaccharides.

Determination of native capsular polysaccharide structures of Streptococcus pneumoniae serotypes 39, 42, and 47F and comparison to genetically or serologically related strains.

The diversity of capsular polysaccharides of the bacterial pathogen Streptococcus pneumoniae leads to at least 91 different serotypes. While the genetic loci for capsular biosynthesis have been characterized for all serotypes, the determination of resultant polysaccharide structures remains incomplete. Here, we report the chemical structures of the capsular polysaccharides of serotypes 39, 42, and 47F from the genetic cluster 4, and discuss the structures in the context of structures from serologically and genetically related serotypes. Antigenic determinants can be approximated in this manner. The structure of the serotype 39 capsular polysaccharide is [formula: see text] and has identical composition to the capsular polysaccharide 10A, but two different linkages. The serotype 42 structure [formula: see text] closely resembles the genetically related serotype 35A, which does not contain residue A. The structure of the serotype 47F capsular polysaccharide [formula: see text] is somewhat different from a recently determined structure from the same serogroup, while containing a structural motif that is reflected in serotype 35A and 42 capsular polysaccharide structures, thus explaining the cross-reactivity of serotype 47F with the typing serum 35a.

Structural elucidation of the capsular polysaccharide from Streptococcus pneumoniae serotype 47A by NMR spectroscopy.

The structure of the serotype 47A (Danish nomenclature system) capsular polysaccharide from Streptococcus pneumoniae was elucidated by NMR spectroscopy. The following structure of the repeating heptasaccharide was deduced: [structure: see text]. The serotype 47A capsular polysaccharide is one of 91 structurally and serologically distinct capsular polysaccharides that have been recognized in S. pneumoniae, a significant human pathogenic bacterium and model system in medical microbiology. Structure and NMR spectra are compared to previously solved capsular polysaccharide structures of other serotypes.

Lanreotide autogel-induced acute pancreatitis in a patient with acromegaly.

Somatostatin and somatostatin analogues are considered very useful for the treatment of hormone producing tumors and acute variceal bleeding. They have also been proposed for the treatment of acute pancreatitis and for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis although clinical trials have failed to show any efficacy. The authors report the case of a 45-year-old man, recently diagnosed of acromegaly, which developed an acute pancreatitis shortly after his first injection of lanreotide autogel. The patient developed a severe dilatation of his hypocontractile gallbladder with distension of the intra and extrahepatic biliary ducts, the choledochus and the main pancreatic duct, without lithiasis or other abnormalities at the papilla, which resolved spontaneously in a month. We consider that lanreotide most likely induced a functional spasm of the Sphincter of Oddi, with impairment of the biliary-pancreatic outflow, leading to an acute pancreatitis, and review the literature concerning this drug related pancreatitis.

A coarse-grained model for synergistic action of multiple enzymes on cellulose.

BACKGROUND: Degradation of cellulose to glucose requires the cooperative action of three classes of enzymes, collectively known as cellulases. Endoglucanases randomly bind to cellulose surfaces and generate new chain ends by hydrolyzing ß-1,4-D-glycosidic bonds. Exoglucanases bind to free chain ends and hydrolyze glycosidic bonds in a processive manner releasing cellobiose units. Then, ß-glucosidases hydrolyze soluble cellobiose to glucose. Optimal synergistic action of these enzymes is essential for efficient digestion of cellulose. Experiments show that as hydrolysis proceeds and the cellulose substrate becomes more heterogeneous, the overall degradation slows down. As catalysis occurs on the surface of crystalline cellulose, several factors affect the overall hydrolysis. Therefore, spatial models of cellulose degradation must capture effects such as enzyme crowding and surface heterogeneity, which have been shown to lead to a reduction in hydrolysis rates. RESULTS: We present a coarse-grained stochastic model for capturing the key events associated with the enzymatic degradation of cellulose at the mesoscopic level. This functional model accounts for the mobility and action of a single cellulase enzyme as well as the synergy of multiple endo- and exo-cellulases on a cellulose surface. The quantitative description of cellulose degradation is calculated on a spatial model by including free and bound states of both endo- and exo-cellulases with explicit reactive surface terms (e.g., hydrogen bond breaking, covalent bond cleavages) and corresponding reaction rates. The dynamical evolution of the system is simulated by including physical interactions between cellulases and cellulose. CONCLUSIONS: Our coarse-grained model reproduces the qualitative behavior of endoglucanases and exoglucanases by accounting for the spatial heterogeneity of the cellulose surface as well as other spatial factors such as enzyme crowding. Importantly, it captures the endo-exo synergism of cellulase enzyme cocktails. This model constitutes a critical step towards testing hypotheses and understanding approaches for maximizing synergy and substrate properties with a goal of cost effective enzymatic hydrolysis.

Coarse-grained model for the interconversion between native and liquid ammonia-treated crystalline cellulose.

We present the results of Langevin dynamics simulations on a coarse-grained model for a structural transition in crystalline cellulose pertinent to the cellulose degradation problem. We analyze two different cellulose crystalline forms: cellulose Iß (the natural form of cellulose) and cellulose III(I) (obtained after cellulose Iß is treated with anhydrous liquid ammonia). Cellulose III(I) has been the focus of wide interest in the field of cellulosic biofuels, as it can be efficiently hydrolyzed to readily fermentable glucose (its enzymatic degradation rates are up to 5-fold higher than those of cellulose Iß). The coarse-grained model presented in this study is based on a simplified geometry and on an effective potential mimicking the changes in both intracrystalline hydrogen bonds and stacking interactions during the transition from cellulose Iß to cellulose III(I). The model reproduces both structural and thermomechanical properties of cellulose Iß and III(I). The work presented herein describes the structural transition from cellulose Iß to cellulose III(I) as driven by the change in the equilibrium state of two degrees of freedom in the cellulose chains. The structural transition from cellulose Iß to cellulose III(I) is essentially reduced to a search for optimal spatial arrangement of the cellulose chains.

Quantum chemical study of carbohydrate-phospholipid interactions.

Carbohydrates on host membranes are fundamental to many important biological processes. Here, we seek a basic understanding of the nature of the interactions between carbohydrates and phospholipids to dissect their roles in molecular recognition. A hybrid quantum mechanics/quantum mechanics (QM/QM) scheme with two different levels of treatment was used to explore the conformations and energetics of carbohydrate-phospholipid complexes. We investigate the interactions of two phospholipids (POPC and DOPC) with mannose using density functional theory. Carbohydrate-phospholipid interactions are probed with respect to competing interactions with water. Our hybrid QM/QM approach demonstrates that mannose interactions with phospholipids can result in alterations in charge distributions and conformations of phospholipids. The results clearly reveal the interplay between conventional and nonconventional hydrogen bonding; moreover, nonpolar interactions are shown to be crucial in the recognition and further stabilization of carbohydrate-phospholipid complexes. The influence of the acyl chain on phospholipid headgroup orientation is clearly evident in our investigation. The significance of the conventional OH···O and nonconventional CH···O and CH···C interactions in the stabilization of the intermolecular complexes is deduced from the molecular electron density topology using Bader's atoms-in-molecules theory. Finally, we have compared the QM energies with molecular mechanics energies for the same interactions to aid in the refinement of the all-atom lipid-carbohydrate force fields.

In silico studies of crystalline cellulose and its degradation by enzymes.

In this report, the current state of computational studies on crystalline cellulose is reviewed. The discussion is focused on fully atomistic molecular-dynamics simulations as well as on other computational approaches which are relevant in the context of enzymatic degradation of cellulose. Finally, possible directions and necessary improvements for future computational studies in this challenging research field are summarized.

Disjoining pressure for nonuniform thin films.

The effect of the attractive forces originating from van der Waals interactions on the dynamics of thin films (

Coarse-grained rigid blob model for soft matter simulations.

We have developed a coarse-grained multiscale molecular simulation method for soft matter systems that directly incorporates stereochemical information. We divide the material into disjoint groups of atoms or particles that move as separate rigid bodies; we call these groups "rigid blobs," hence the name coarse-grained rigid blob model. The method is enabled by the construction of transferable interblob potentials that approximate the net intermolecular interactions, as obtained from ab initio electronic structure calculations, other all-atom empirical potentials, experimental data, or any combination of the above. We utilize a multipolar expansion to obtain the interblob potential-energy functions. The series, which contains controllable approximations that allow us to estimate the errors, approaches the original intermolecular potential as the number of terms increases. Using a novel numerical algorithm, we can calculate the interblob potentials very efficiently in terms of a few interaction moment tensors. This reduces the labor well beyond what is required in standard molecular-dynamics calculations and allows large-scale simulations for temporal scales commensurate with characteristic times of nano- and mesoscale systems. A detailed derivation of the formulas is presented, followed by illustrative applications to several systems showing that the method can effectively capture realistic microscopic details and can easily extend to large-scale simulations.

Capacitance-derived dielectric constants demonstrate differential preinitiation complexes in TBP-independent and TBP-dependent transcription.

The electronic properties of proteins and DNA may change dramatically upon complex formation, yet there are not many experimental methods which can be used to measure these properties. It has been previously shown that measuring the capacitance of a solution containing interacting DNA and protein species can yield information about changing dipole moments. The measured dielectric constant relates directly to the dipole moment of the complexes in solution. Here, we apply this method to partial transcription initiation complexes in order to investigate the changing electronic properties in the transcriptional preinitiation complex. These experiments are the first reported observations relating to the overall dipole moment and its changes in preinitiation complex formation. Comparing results from TBP-independent and TBP-dependent transcriptional systems shows a divergence in the electronic properties of built-up transcription complexes, suggesting that they initiate transcription by significantly different electronic and structural pathways.

An alternative multipolar expansion for intermolecular potential functions.

We have derived a new multipolar expansion for intermolecular potential-energy functions with applications in molecular physics, theoretical chemistry, and mathematical physics. The new formulation employs a separation of radial and angular terms with a simple index structure that leads to computational efficiency and ease of physical interpretation. For the case of the Coulomb interaction, we compare the present formulation with two conventional multipole expansions: the Cartesian tensor and the irreducible spherical tensor expansions. The new formalism leads to efficient numerical algorithms that are useful for general applications beyond intermolecular potentials. In addition to the electrostatic Coulomb interaction, we illustrate the formalism with applications to special function theory and a bipolar expansion involved in potential theory.

Investigation of early events in Fc epsilon RI-mediated signaling using a detailed mathematical model.

Aggregation of Fc epsilon RI on mast cells and basophils leads to autophosphorylation and increased activity of the cytosolic protein tyrosine kinase Syk. We investigated the roles of the Src kinase Lyn, the immunoreceptor tyrosine-based activation motifs (ITAMs) on the beta and gamma subunits of Fc epsilon RI, and Syk itself in the activation of Syk. Our approach was to build a detailed mathematical model of reactions involving Fc epsilon RI, Lyn, Syk, and a bivalent ligand that aggregates Fc(epsilon)RI. We applied the model to experiments in which covalently cross-linked IgE dimers stimulate rat basophilic leukemia cells. The model makes it possible to test the consistency of mechanistic assumptions with data that alone provide limited mechanistic insight. For example, the model helps sort out mechanisms that jointly control dephosphorylation of receptor subunits. In addition, interpreted in the context of the model, experimentally observed differences between the beta- and gamma-chains with respect to levels of phosphorylation and rates of dephosphorylation indicate that most cellular Syk, but only a small fraction of Lyn, is available to interact with receptors. We also show that although the beta ITAM acts to amplify signaling in experimental systems where its role has been investigated, there are conditions under which the beta ITAM will act as an inhibitor.

Kinetic proofreading in receptor-mediated transduction of cellular signals: receptor aggregation, partially activated receptors, and cytosolic messengers.

Signaling by the T cell receptor (TCR), and the related immunoreceptor Fc epsilon RI, is sensitive to ligand-receptor binding kinetics. Differences in the rate at which a ligand dissociates from a receptor cause disproportionate differences in signaling events and cellular responses to ligand-receptor engagement. Analysis of a simple mathematical model, developed by McKeithan (1995, Proc. Natl. Acad. Sci. USA, 92, 5042-5046), has indicated that such sensitivity to binding kinetics is expected if a bound receptor must complete a cascade of modifications before generating a productive signal. However, recent experiments show that some cellular responses mediated by immunoreceptors escape from the control of kinetic proofreading, in the sense that these responses do not exhibit the expected sensitivity to the lifetime of a ligand-receptor bond. Here, we use an extended form of the McKeithan model to investigate possible explanations for such exceptions to the kinetic proofreading rule. We examine cellular responses triggered by cytosolic messengers, which are activated by modified receptors, and responses triggered by receptors in intermediate states of modification, i.e., receptors that have not progressed through the full series of potential modifications. Receptor aggregation is also considered. We find that the expected relationship between ligand-receptor binding kinetics and cellular responses can change significantly when signal transduction depends on a messenger or a partially modified receptor. In particular, cellular responses triggered by a messenger, such as a transcription factor that translocates from the membrane to the nucleus after receptor-mediated activation, can be sensitive or insensitive to a change in the lifetime of a ligand-receptor bond, depending on the parameters that govern the activation and decay of a messenger.

Modeling the early signaling events mediated by FcepsilonRI.

We present a detailed mathematical model of the phosphorylation and dephosphorylation events that occur upon ligand-induced receptor aggregation, for a transfectant expressing FcepsilonRI, Lyn, Syk and endogenous phosphatases that dephosphorylate exposed phosphotyrosines on FcepsilonRI and Syk. Through model simulations we show how changing the ligand concentration, and consequently the concentration of receptor aggregates, can change the nature of a cellular response as well as its amplitude. We illustrate the value of the model in analyzing experimental data by using it to show that the intrinsic rate of dephosphorylation of the FcepsilonRI gamma immunoreceptor tyrosine-based activation motif (ITAM) in rat basophilic leukemia (RBL) cells is much faster than the observed rate, provided that all of the cytosolic Syk is available to receptors.

Utilización del reservorio continente de indiana en la patología del tracto urinario inferior

El presente artículo revisa los resultados de la aplicación de la Técnica Quirúrgica de Indiana, en 4 pacientes con daño total o parcial en la vejiga causados: por cáncer vesical, 1 por parto distósico y 1 posthistectomía total. Las dos pacientes con fístulas uretrovesicales, cloaca, consultaron por salida permanente de orina por genitales externos. Su edad media fue de 22 años. La prueba del colorante fue positiva en ambas y la cistoscopia confirmó la presencia de fístula uretrovesicovaginal extensa con gran pérdida de tejido vaginal y vesical. La técnica aplicada fue la de Bolsa Continente de Indiana. La morbilidad en postoperatorio inmediato y tardío fue poco significativa y se resolvió satisfactoriamente. La mortalidad(1 caso) no fue inherente a la cirugía(Invasión tumoral de Ca. de vejiga)