Elucidation of the Complete \u3ci\u3eAzorhizobium\u3c/i\u3e Nicotinate Catabolism Pathway

A complete pathway for Azorhizobium caulinodans nicotinate catabolism has been determined from mutant phenotype analyses, isolation of metabolic intermediates, and structural studies. Nicotinate serves as a respiratory electron donor to O2 via a membrane-bound hydroxylase and a specific c-type cytochrome oxidase. The resulting oxidized product, 6-hydroxynicotinate, is next reduced to 1,4,5,6-tetrahydro-6-oxonicotinate. Hydrolytic ring breakage follows, with release of pyridine N as ammonium. Decarboxylation then releases the nicotinate C-7 carboxyl group as CO2, and the remaining C skeleton is then oxidized to yield glutarate. Transthioesterification with succinyl coenzyme A (succinyl-CoA) yields glutaryl-CoA, which is then oxidatively decarboxylated to yield crotonyl-CoA. As with general acyl β oxidation, L-β-hydroxybutyryl-CoA, acetoacetyl-CoA, and finally two molecules of acetyl-CoA are produced. In sum, nicotinate is catabolized to yield two CO2 molecules, two acetyl-CoA molecules, and ammonium. Nicotinate catabolism stimulates Azorhizobium N2 fixation rates in culture. Nicotinate catabolism mutants still able to liberate pyridine N as ammonium retain this capability, whereas mutants so blocked do not. From, mutant analyses and additional physiological tests, N2 fixation stimulation is indirect. In N-limited culture, nicotinate catabolism augments anabolic N pools and, as a consequence, yields N2-fixing cells with higher dinitrogenase content

A biophysical model of atrial fibrillation to define the appropriate ablation pattern in modified maze

Objective: The surgical Maze III procedure remains the gold standard in treating atrial fibrillation (AF); however due to clinical difficulties and higher risks, less invasive ablation alternatives are clinically investigated. The present study aims to define more efficient ablation patterns of the modified maze procedure using a biophysical model of human atria with chronic AF. Methods: A three-dimensional model of human atria was developed using both MRI-imaging and a one-layer cellular model reproducing experimentally observed atrial cellular properties. Sustained AF could be induced by a burst-pacing protocol. Ablation lines were implemented in rendering the cardiac cells non-conductive, mimicking transmural lines. Lines were progressively implemented respectively around pulmonary veins (PV), left atrial appendage (LAA), left atrial isthmus (LAI), cavo-tricuspid isthmus (CTI), and intercaval lines (SIVC) in the computer model, defining the following patterns: P1=PV, P2=P1+LAA, P3=P2+LAI, P4=P3+CTI, P5=P3+SIVC, P6=P5+CTI. Forty simulations were done for each pattern and proportion of sinus rhythm (SR) conversion and time-to-AF termination (TAFT) were assessed. Results: The most efficient patterns are P5, P6, and Maze III with 100% success. The main difference is expressed in decreasing mean TAFT with a correlation coefficient R=−0.8. There is an inflexion point for 100% success rate at a 7.5s TAFT, meaning that no additional line is mandatory beyond pattern P5. Conclusions: Our biophysical model suggests that Maze III could be simplified in his right atrial pattern to a single line joining both vena cavae. This has to be confirmed in clinical setting

Use of a biophysical model of atrial fibrillation in the interpretation of the outcome of surgical ablation procedures

Objective: To determine the adequacy of ‘in silico' biophysical models of atrial fibrillation (AF) in the design of different ablation line patterns. Background: Permanent AF is a severe medical problem for which (surgical) ablation is a possible treatment. The ideal ablation pattern remains to be defined. Methods: Forty-six consecutive adult patients with symptomatic permanent drug refractory AF underwent mitral surgery combined with non-transmural, (n=20) and transmural (n=26) radiofrequency Minimaze. The fraction of ‘in vivo' conversions to sinus rhythm (SR) in both groups was compared with the performance of the fraction of ‘in silico' conversions observed in a biophysical model of permanent AF. The simulations allowed us to study the effectiveness of incomplete and complete ablation patterns. A simulated, complete, transmural Maze III ablation pattern was applied to 118 different episodes of simulated AF set-up in the model and its effectiveness was compared with the clinical results reported by Cox. Results: The fraction of conversions to SR was 92% ‘in vivo' and 88% ‘in silico' (p=ns) for transmural/complete ablations, 60% respectively 65% for non-transmural/incomplete Minimaze (p=ns) and 98% respectively 100% for Maze III ablations (p=ns). The fraction of conversions to SR ‘in silico' correlated with the rates ‘in vivo' (r2=0.973). Conclusions: The fraction of conversions to SR observed in the model closely corresponded to the conversion rate to SR post-surgery. This suggests that the model provides an additional, non-invasive tool for optimizing ablation line patterns for treating permanent A

All order I.R. finite expansion for short distance behavior of massless theories perturbed by a relevant operator

We consider here renormalizable theories without relevant couplings and present an I.R. consistent technique to study corrections to short distance behavior (Wilson O.P.E. coefficients) due to a relevant perturbation. Our method is the result of a complete reformulation of recent works on the field, and is characterized by a more orthodox treatment of U.V. divergences that allows for simpler formulae and consequently an explicit all order (regularization invariant) I.R. finitess proof. Underlying hypotheses are discussed in detail and found to be satisfied in conformal theories that constitute a natural field of application of this approach.Comment: 27 page

Schwinger-Keldysh Approach to Disordered and Interacting Electron Systems: Derivation of Finkelstein's Renormalization Group Equations

We develop a dynamical approach based on the Schwinger-Keldysh formalism to derive a field-theoretic description of disordered and interacting electron systems. We calculate within this formalism the perturbative RG equations for interacting electrons expanded around a diffusive Fermi liquid fixed point, as obtained originally by Finkelstein using replicas. The major simplifying feature of this approach, as compared to Finkelstein's is that instead of $N \to 0$ replicas, we only need to consider N=2 species. We compare the dynamical Schwinger-Keldysh approach and the replica methods, and we present a simple and pedagogical RG procedure to obtain Finkelstein's RG equations.Comment: 22 pages, 14 figure

Multipotent Embryonic Isl1+ Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification

SummaryCardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. We use genetic fate-mapping studies to document that isl1+ precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells, we clonally amplified a cellular hierarchy of isl1+ cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1+/Nkx2.5+/flk1+ defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1+ cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types

The Explication Defence of Arguments from Reference

In a number of influential papers, Machery, Mallon, Nichols and Stich have presented a powerful critique of so-called arguments from reference, arguments that assume that a particular theory of reference is correct in order to establish a substantive conclusion. The critique is that, due to cross-cultural variation in semantic intuitions supposedly undermining the standard methodology for theorising about reference, the assumption that a theory of reference is correct is unjustified. I argue that the many extant responses to Machery et al.’s critique do little for the proponent of an argument from reference, as they do not show how to justify the problematic assumption. I then argue that it can in principle be justified by an appeal to Carnapian explication. I show how to apply the explication defence to arguments from reference given by Andreasen (for the biological reality of race) and by Churchland (against the existence of beliefs and desires)

Composite bi-layered erodible films for potential ocular drug delivery

Bi-layered hydroxypropylmethylcellulose and Eudragit based films were formulated as potential ocular drug delivery systems using chloramphenicol as a model antibiotic. Films were plasticized with polyethylene glycol 400 present in the Eudragit layer or both Eudragit and hydroxypropylmethylcellulose layers, and loaded with chloramphenicol (0.5% w/v in solution) in the hydroxypropylmethylcellulose layer. The weight, thickness and folding endurance optimized formulations were measured and further characterized for transparency, tensile, mucoadhesive, swelling and in vitro drug dissolution properties. The physical form of chloramphenicol within the films was evaluated using differential scanning calorimetry (DSC), and X-ray diffraction (XRD), complimented with scanning electron microscopy and energy dispersive X-ray spectroscopy. Fourier transform infrared spectroscopy was used to assess the interactions between the drug and the film components and confirm chloramphenicol’s presence within the sample. Optimum films showed high transparency (≥ 80% transmittance), ease of peeling from Petri dish and folding endurance above 250. Average thickness was lower than contact lenses (0.4 - 1mm), confirming them as thin ocular films. The tensile properties showed a good balance between toughness and flexibility and mucoadhesivity showed that they could potentially adhere to the ocular surface for prolonged periods. The drug loaded films showed swelling capacity which was greater than 300% of their original weight. The physical form of chloramphenicol within the films was amorphous (DSC and XRD) whilst in vitro drug dissolution showed sustained drug release from the films for four hours, before complete erosion. The chloramphenicol loaded films represent a potential means of treating common eye infections