Acidosis slows electrical conduction through the atrio-ventricular node

Acidosis affects the mechanical and electrical activity of mammalian hearts but comparatively little is known about its effects on the function of the atrio-ventricular node (AVN). In this study, the electrical activity of the epicardial surface of the left ventricle of isolated Langendorff-perfused rabbit hearts was examined using optical methods. Perfusion with hypercapnic Tyrode's solution (20% CO2, pH 6.7) increased the time of earliest activation (Tact) from 100.5 ± 7.9 to 166.1 ± 7.2 ms (n = 8) at a pacing cycle length (PCL) of 300 ms (37°C). Tact increased at shorter PCL, and the hypercapnic solution prolonged Tact further: at 150 ms PCL, Tact was prolonged from 131.0 ± 5.2 to 174.9 ± 16.3 ms. 2:1 AVN block was common at shorter cycle lengths. Atrial and ventricular conduction times were not significantly affected by the hypercapnic solution suggesting that the increased delay originated in the AVN. Isolated right atrial preparations were superfused with Tyrode's solutions at pH 7.4 (control), 6.8 and 6.3. Low pH prolonged the atrial-Hisian (AH) interval, the AVN effective and functional refractory periods and Wenckebach cycle length significantly. Complete AVN block occurred in 6 out of 9 preparations. Optical imaging of conduction at the AV junction revealed increased conduction delay in the region of the AVN, with less marked effects in atrial and ventricular tissue. Thus acidosis can dramatically prolong the AVN delay, and in combination with short cycle lengths, this can cause partial or complete AVN block and is therefore implicated in the development of brady-arrhythmias in conditions of local or systemic acidosis

Simulated Galaxy Interactions as Probes of Merger Spectral Energy Distributions

We present the first systematic comparison of ultraviolet-millimeter spectral energy distributions (SEDs) of observed and simulated interacting galaxies. Our sample is drawn from the Spitzer Interacting Galaxy Survey, and probes a range of galaxy interaction parameters. We use 31 galaxies in 14 systems which have been observed with Herschel, Spitzer, GALEX, and 2MASS. We create a suite of GADGET-3 hydrodynamic simulations of isolated and interacting galaxies with stellar masses comparable to those in our sample of interacting galaxies. Photometry for the simulated systems is then calculated with the SUNRISE radiative transfer code for comparison with the observed systems. For most of the observed systems, one or more of the simulated SEDs match reasonably well. The best matches recover the infrared luminosity and the star formation rate of the observed systems, and the more massive systems preferentially match SEDs from simulations of more massive galaxies. The most morphologically distorted systems in our sample are best matched to simulated SEDs close to coalescence, while less evolved systems match well with SEDs over a wide range of interaction stages, suggesting that an SED alone is insufficient to identify interaction stage except during the most active phases in strongly interacting systems. This result is supported by our finding that the SEDs calculated for simulated systems vary little over the interaction sequence.Comment: 24 pages, 16 figures, 2 tables, accepted for publication in ApJ. Animations of the evolution of the simulated SEDs can be found at http://www.cfa.harvard.edu/~llanz/sigs_sim.htm

IL-21 receptor expression in human tendinopathy

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward and early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly up regulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy

Model-Independent 3D Descriptors of Vertebral Cancellous Bone Architecture

High-resolution micro computed tomography has enabled measurement of bone architecture derived from 3D representations of cancellous bone. Twenty-eight vertebral bodies were obtained from four embalmed male cadavers. From 3D anaglyphs, trabecular rod thickness and length were measured and the trabecular rod Buckling index was calculated. From 3D voxel-based datasets, bone volume density, trabecular thickness, and trabecular separation were measured. Also, trabecular bone pattern factor, structural model index, connectivity density, and degree of anisotropy were calculated. Bone volume density alone explains 59% of the variability in trabecular rod Buckling index. The addition of connectivity density, trabecular separation, and structural model index, in a multiple regression statistical model, improves the explanatory power to 77%. The relationships between measures of cancellous bone architecture and a derived measure of trabecular rod strength were investigated. Morphological descriptors of cancellous bone provide a composite explanatory model of trabecular rod strength

Origin of ferroelectricity in the multiferroic barium fluorides BaMF4

We present a first principles study of the series of multiferroic barium fluorides with the composition BaMF4, where M is Mn, Fe, Co, or Ni. We discuss trends in the structural, electronic, and magnetic properties, and we show that the ferroelectricity in these systems results from the "freezing in" of a single unstable polar phonon mode. In contrast to the case of the standard perovskite ferroelectrics, this structural distortion is not accompanied by charge transfer between cations and anions. Thus, the ferroelectric instability in the multiferroic barium fluorides arises solely due to size effects and the special geometrical constraints of the underlying crystal structure.Comment: 8 pages, 6 figures, 3 table

Analysis of a family 6 carbohydrate-binding module and three family 69 hyaluronidases

To investigate the interactions between a family 6 carbohydrate-binding module (CBM) from Clostridium thermocellum Xynl 1A (CtCBM6) and its target ligands and to identify the location of the ligand binding site(s) through a mutagenesis strategy, the protein was expressed in Escherichia coli and purified to homogeneity. CtCBM6 was shown previously to interact with xylan (Fernandes et al., 1999) and, informed by the crystal structure, it was found that CtCBM6 was unusual, as it contained two potential ligand-binding clefts (Clefts A and B). Qualitative ligand specificity studies through affinity gel electrophoresis (AGE) demonstrated that CtCBM6 bound preferentially to xylans, interacts weakly with 13-glucan and some soluble substituted forms of cellulose. Quantitative analysis of ligand binding by isothermal titration calorimetry showed that CtCBM6 bound xylooligosaccharides from xylobiose to xylohexaose, with affinity increasing with chain length. The affinity of CtCBM6 for soluble xylan of varying degrees of substitution was judged to be similar. NMR spectroscopy (Dr M. Czjzek at CNRS, Marseille) indicated that xylohexaose interacts with the two solvent exposed aromatic amino acids (Tyr-34 and Trp-92) and a polar amino acid (namely Asn-120) in cleft A of CtCBM6. Site-directed mutagenesis revealed that hydrophobic stacking interactions and hydrogen bonds potentiate the binding of CtCBM6 to xylan. Surface aromatic residues Tyr-34 and Trp-92 of CtCBM6 are pivotal in the interaction between this module and its ligand, as substitution of these amino acids with alanine and methionine resulted in an 8-fold and 50-fold respective decrease in affinity of CtCBM6 for oat spelt xylan, as judged by quantitative AGE. Hydrogen-bonding interactions also made pivotal contributions to the overall binding in CtCBM6. Asn-120 was critical to ligand binding, as the mutant N120A showed —130-fold loss of binding affinity. This suggests that this residue directly participates in ligand binding via hydrogen bonds. Collectively, mutagenesis and NMR studies showed that cleft A can accommodate xylooligosaccharides and xylan, while cleft B was unable to interact with target ligands. Three hyaluronidases (Hy1P1, HylP2 and HylP3) of glycoside hydrolase family 69 (GH69) were cloned from the genome sequenced organism Streptococcus pyogenes SF370, expressed in E. coli and purified to homogeneity. Characterisation of the N-terminally tagged HylP1 (38.4 kDa), Hy1P2 (42.0 kDa) and Hy1133 (41.8 kDa) revealed activity against sodium hyaluronate with a KM for Hy1P1, HylP2 and Hy1P3 of 0.90, 2.07 and 4.35 ml mg 1, and a kcat of 1390.90, 742.01 and 1253.04 s-1, respectively. HylP1, HylP2 and Hy1P3 displayed an optimum pH of 6.5, 6.0 and 5.5, respectively, and an optimum activity at 37 °C. Moreover, PAGE analysis showed each enzyme was endo-cleaving. All three enzymes have been crystallised and sufficient quality diffraction data obtained for Hy1P1 and HylP3 (data collection and processing was performed by Dr Edward Taylor). The 3D structure of HylP1 has been solved at a resolution of 1.8 A and is composed of three monomeric strands that are intertwined to form a trimer.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Vaccinia Virus Gene B7R Encodes an 18-kDa Protein That is Resident in the Endoplasmic Reticulum and Affects Virus Virulence

AbstractThis paper presents a characterisation of vaccinia virus (VV) gene B7R that was predicted to encode a polypeptide of 182 amino acids with an N-terminal signal peptide. In vitro transcription and translation analysis showed the B7R gene product was a 21-kDa protein that, in the presence of microsomes, was processed into an 18-kDa mature form. The 18-kDa form associated with the microsomal membranes and was within the lumen of the vesicle where it was inaccessible to exogenous protease or an antibody raised against the B7R C terminus. Within VV-infected cells, the 18-kDa form of B7R was detected late during infection in the endoplasmic reticulum where it colocalised with protein disulphide isomerase. The B7R protein was detected neither in the culture supernatant nor associated with virus particles. A virus deletion mutant lacking the B7R gene and a revertant virus were constructed. Compared to wild-type and revertant viruses, the deletion mutant replicated normally in cell culture and had unaltered virulence in a murine intranasal model of infection. However, the deletion mutant was attenuated in a murine intradermal model where it induced a smaller lesion than the control viruses

Hydrogen bonding and coordination in normal and supercritical water from X-ray inelastic scattering

A direct measure of hydrogen bonding in water under conditions ranging from the normal state to the supercritical regime is derived from the Compton scattering of inelastically-scattered X-rays. First, we show that a measure of the number of electrons $n_e$ involved in hydrogen bonding at varying thermodynamic conditions can be directly obtained from Compton profile differences. Then, we use first-principles simulations to provide a connection between $n_e$ and the number of hydrogen bonds $n_{HB}$. Our study shows that over the broad range studied the relationship between $n_e$ and $n_{HB}$ is linear, allowing for a direct experimental measure of bonding and coordination in water. In particular, the transition to supercritical state is characterized by a sharp increase in the number of water monomers, but also displays a significant number of residual dimers and trimers.Comment: 14 pages, 5 figures, 1 tabl

Assessing the impact of a national clinical guideline for the management of chronic pain on opioid prescribing rates:a controlled interrupted time series analysis

Background: Opioids can be effective analgesics, but long-term use may be associated with harms. In 2013, the first national, comprehensive, evidence-based pain management guideline was published, from the Scottish Intercollegiate Guideline Network (SIGN 136: Management of Chronic Pain) with key recommendations on analgesic prescribing. This study aimed to examine the potential impact on national opioid prescribing rates in Scotland. Methods: Trends in national and regional community opioid prescribing data for Scotland were analysed from quarter one (Q1) 2005 to Q2 2020. Interrupted time series regression examined the association of SIGN 136 publication with prescribing rates for opioid-containing drugs. Gabapentinoid prescribing was used as a comparison drug. Results: After a positive prescribing trend pre-publication, the timing of SIGN 136 publication was associated with a negative change in the trend of opioid prescribing rates (−2.82 items per 1000 population per quarter [PTPPQ]; P < 0.01). By Q2 2020, the relative reduction in the opioid prescribing rate was −20.67% (95% CI: −23.61, −17.76). This persisted after correcting for gabapentinoid prescribing and was mainly driven by the reduction in weak opioids, whereas strong opioid prescribing rates continued to rise. Gabapentinoid prescribing showed a significant rise in level (8.00 items per 1000 population; P = 0.01) and trend (0.27 items PTPPQ; P = 0.01) following SIGN 136 publication. Conclusions: The publication of SIGN 136 was associated with a reduction in opioid prescribing rates. This suggests that changes in clinical policy through evidence-based national clinical guidelines may affect community opioid prescribing, though this may be partially replaced by gabapentinoids, and other factors may also contribute

Testing refinements by refining tests

One of the potential benefits of formal methods is that they offer the possibility of reducing the costs of testing. A specification acts as both the benchmark against which any implementation is tested, and also as the means by which tests are generated. There has therefore been interest in developing test generation techniques from formal specifications, and a number of different methods have been derived for state based languages such as Z, B and VDM. However, in addition to deriving tests from a formal specification, we might wish to refine the specification further before its implementation. The purpose of this paper is to explore the relationship between testing and refinement. As our model for test generation we use a DNF partition analysis for operations written in Z, which produces a number of disjoint test cases for each operation. In this paper we discuss how the partition analysis of an operation alters upon refinement, and we develop techniques that allow us to refine abstract tests in order to generate test cases for a refinement. To do so we use (and extend existing) methods for calculating the weakest data refinement of a specification