Impact of Incremental Perfusion Loss on Oxygen Transport in a Capillary Network Mathematical Model.

OBJECTIVES: To quantify how incremental capillary perfusion loss, such as that seen in experimental models of sepsis, affects tissue oxygenation using a computation model of oxygen transport. METHODS: A computational model was applied to capillary networks with dimensions 84x168x342 (NI) and 70x157x268 (NII) μm, reconstructed in vivo from rat skeletal muscle. Functional capillary density (FCD) loss was applied incrementally up to ~40% and combined with high tissue oxygen consumption to simulate severe sepsis. RESULTS: A loss of ~40% FCD loss decreased median tissue PO2 to 22.9 and 20.1 mmHg in NI and NII compared to 28.1 and 27.5 mmHg under resting conditions. Increasing red blood cell supply rate (SR) to baseline levels returned tissue PO2 to within 5% of baseline. High consumption combined with a 40% FCD loss, resulted in tissue anoxia in both network volumes and median tissue PO2 of 11.5 and 8.9 mmHg in NI and NII respectively; median tissue PO2 was recovered to baseline levels by increasing total SR 3 - 4 fold. CONCLUSIONS: These results suggest a substantial increase in total SR is required in order to compensate for impaired oxygen delivery as a result of loss of capillary perfusion and increased oxygen consumption during sepsis. This article is protected by copyright. All rights reserved

Extracellular Charge Adsorption Influences Intracellular Electrochemical Homeostasis in Amphibian Skeletal Muscle

The membrane potential measured by intracellular electrodes, Em, is the sum of the transmembrane potential difference (E1) between inner and outer cell membrane surfaces and a smaller potential difference (E2) between a volume containing fixed charges on or near the outer membrane surface and the bulk extracellular space. This study investigates the influence of E2 upon transmembrane ion fluxes, and hence cellular electrochemical homeostasis, using an integrative approach that combines computational and experimental methods. First, analytic equations were developed to calculate the influence of charges constrained within a three-dimensional glycocalyceal matrix enveloping the cell membrane outer surface upon local electrical potentials and ion concentrations. Electron microscopy confirmed predictions of these equations that extracellular charge adsorption influences glycocalyceal volume. Second, the novel analytic glycocalyx formulation was incorporated into the charge-difference cellular model of Fraser and Huang to simulate the influence of extracellular fixed charges upon intracellular ionic homeostasis. Experimental measurements of Em supported the resulting predictions that an increased magnitude of extracellular fixed charge increases net transmembrane ionic leak currents, resulting in either a compensatory increase in Na+/K+-ATPase activity, or, in cells with reduced Na+/K+-ATPase activity, a partial dissipation of transmembrane ionic gradients and depolarization of Em

Solid phase synthesis of a metronidazole oligonucleotide conjugate

Direct, solid phase synthesis of an oligonucleotide conjugate of the antibiotic drug metronidazole was accomplished by the phosphoramidite method. Removal of protecting groups and cleavage from the controlled pore glass (CPG) solid support was successful using mild conditions (20% EtN in pyridine, then conc. NH (aq) at rt for 30 min) whereas standard conditions (conc. NH (aq) at 55°C for 16 h) cleaved the drug

Managing Technical Debt in Software Engineering

Sustainable and scalable software systems require careful consideration over the force known as technical debt, i.e., the additional project cost connected to sub-optimal technical decisions. However, the friction that software systems can accumulate is not connected to technical decisions alone, but reflects also organizational, social, ontological and management decisions that refer to the social nature and any connected social debt of software – this nature is yet to be fully elaborated and understood. In a joint industry & academia panel, we refined our understanding of the emerging notion of social debt in pursuit of a crisper definition. We observed that social debt is not only a prime cause for technical debt but is also tightly knit to many of the dimensions that were observed so far concerning technical debt, for example software architectures and their reflection on organizations. Also we observed that social debt reflects and weighs heavily on the human process behind software engineering, since it is caused by circumstances such as cognitive distance, (lack of or too much of) communication, misaligned architectures and organizational structures.The goal for social debt in the next few years of research should be to reach a crisp definition that contains the essential traits of social debt which can be refined into practical operationalizations for use by software engineering professionals in need of knowing more about their organizational structure and the properties/cost trade-off that structure currently reflects.</p

Relationships between resting conductances, excitability, and t-system ionic homeostasis in skeletal muscle.

Activation of skeletal muscle fibers requires rapid sarcolemmal action potential (AP) conduction to ensure uniform excitation along the fiber length, as well as successful tubular excitation to initiate excitation-contraction coupling. In our companion paper in this issue, Pedersen et al. (2011. J. Gen. Physiol. doi:10.1085/jgp.201010510) quantify, for subthreshold stimuli, the influence upon both surface conduction velocity and tubular (t)-system excitation of the large changes in resting membrane conductance (G(M)) that occur during repetitive AP firing. The present work extends the analysis by developing a multi-compartment modification of the charge-difference model of Fraser and Huang to provide a quantitative description of the conduction velocity of actively propagated APs; the influence of voltage-gated ion channels within the t-system; the influence of t-system APs on ionic homeostasis within the t-system; the influence of t-system ion concentration changes on membrane potentials; and the influence of Phase I and Phase II G(M) changes on these relationships. Passive conduction properties of the novel model agreed with established linear circuit analysis and previous experimental results, while key simulations of AP firing were tested against focused experimental microelectrode measurements of membrane potential. This study thereby first quantified the effects of the t-system luminal resistance and voltage-gated Na(+) channel density on surface AP propagation and the resultant electrical response of the t-system. Second, it demonstrated the influence of G(M) changes during repetitive AP firing upon surface and t-system excitability. Third, it showed that significant K(+) accumulation occurs within the t-system during repetitive AP firing and produces a baseline depolarization of the surface membrane potential. Finally, it indicated that G(M) changes during repetitive AP firing significantly influence both t-system K(+) accumulation and its influence on the resting membrane potential. Thus, the present study emerges with a quantitative description of the changes in membrane potential, excitability, and t-system ionic homeostasis that occur during repetitive AP firing in skeletal muscle

Measure representation and multifractal analysis of complete genomes

This paper introduces the notion of measure representation of DNA sequences. Spectral analysis and multifractal analysis are then performed on the measure representations of a large number of complete genomes. The main aim of this paper is to discuss the multifractal property of the measure representation and the classification of bacteria. From the measure representations and the values of the $D_{q}$ spectra and related $C_{q}$ curves, it is concluded that these complete genomes are not random sequences. In fact, spectral analyses performed indicate that these measure representations considered as time series, exhibit strong long-range correlation. For substrings with length K=8, the $D_{q}$ spectra of all organisms studied are multifractal-like and sufficiently smooth for the $C_{q}$ curves to be meaningful. The $C_{q}$ curves of all bacteria resemble a classical phase transition at a critical point. But the 'analogous' phase transitions of chromosomes of non-bacteria organisms are different. Apart from Chromosome 1 of {\it C. elegans}, they exhibit the shape of double-peaked specific heat function.Comment: 12 pages with 9 figures and 1 tabl

The Primary Target Organ of Cryptococcus gattii Is Different from That of Cryptococcus neoformans in a Murine Model

Cryptococcosis is caused by the opportunistic pathogen Cryptococcus neoformans or by the primary pathogen Cryptococcus gattii. Epidemiological studies suggest that patients infected with C. gattii mainly present with pulmonary disease, while those infected with C. neoformans commonly manifest meningoencephalitis. We compared the pathogenesis of the two species using the C. neoformans H99 and C. gattii R265 strains in a murine inhalation model. C. neoformans grew faster in the brain and caused death by meningoencephalitis, while C. gattii grew faster in the lungs and caused death without producing fulminating meningoencephalitis. Despite the consistent failure to recover R265 cells from blood, a fraction of the R265 population was detected in the extrapulmonary organs, including the brain. Upon intravenous (i.v. ) inoculation of 104 cells via the tail vein, however, C. gattii produced severe meningoencephalitis, demonstrating that C. gattii cells can efficiently cross the blood-brain barrier. Interestingly, i.v. inoculation with five cells caused brain infection in only 10% of C. gattii-infected mice, compared to 60% of mice infected with C. neoformans. In mice that had been initially inoculated via the pulmonary route and subsequently challenged intravenously, a protective effect was observed only in mice infected with C. gattii. C. neoformans cells grew 10 to 100 times faster than C. gattii cells in blood or serum collected from naive mice. The paucity of meningoencephalitis upon inhalation of C. gattii, therefore, may be partly due to an unknown factor(s) in the host’s blood coupled with immune protection that reduces dissemination to the brain and fosters lung infection

Elvis’ Gospel music: Between the secular and the spiritual?

Do fans sanctify their heroes? In the past, I have argued that Elvis fandom is not a neo-religious practice but that attention to a modified version of Durkheim’s theory of religion can, nevertheless, help to explain it as a form of social interaction. I take that argument further here, first by revealing the ethical and analytical advantages of neo-Durkheimian theory, then by pitting this theory against three aspects of Elvis’ sincere engagement with gospel music. Elvis Presley won three Grammy awards for his gospel albums and was the musician who did most to bring the gospel quartet tradition to the mainstream. His eclectic personal ties to spirituality and religion have become a focus of debate within his fan culture. They offer a set of discursive resources through which to explain the emotional impact and social influence of his music. If star musicians are positioned as centres of attention, what happens when they use their privileged position in the spotlight to offer a “spiritual” message

Epidemiology of Cryptococcus gattii, British Columbia, Canada, 1999–2007

Incidence is high, but the predominant strain does not seem to cause greater illness or death than do other strains

Codon choice in genes depends on flanking sequence information—implications for theoretical reverse translation

Algorithms for theoretical reverse translation have direct applications in degenerate PCR. The conventional practice is to create several degenerate primers each of which variably encode the peptide region of interest. In the current work, for each codon we have analyzed the flanking residues in proteins and determined their influence on codon choice. From this, we created a method for theoretical reverse translation that includes information from flanking residues of the protein in question. Our method, named the neighbor correlation method (NCM) and its enhancement, the consensus-NCM (c-NCM) performed significantly better than the conventional codon-usage statistic method (CSM). Using the methods NCM and c-NCM, we were able to increase the average sequence identity from 77% up to 81%. Furthermore, we revealed a significant increase in coverage, at 80% identity, from < 20% (CSM) to > 75% (c-NCM). The algorithms, their applications and implications are discussed herein