Comparative in silico analysis identifies bona fide MyoD binding sites within the Myocyte Stress 1 gene promoter

<p>Abstract</p> <p>Background</p> <p>Myocyte stress 1 (MS1) is a striated muscle actin binding protein required for the muscle specific activity of the evolutionary ancient myocardin related transcription factor (MRTF)/serum response factor (SRF) transcriptional pathway. To date, little is known about the molecular mechanisms that govern skeletal muscle specific expression of MS1. Such mechanisms are likely to play a major role in modulating SRF activity and therefore muscle determination, differentiation and regeneration. In this study we employed a comparative <it>in silico </it>analysis coupled with an experimental promoter characterisation to delineate these mechanisms.</p> <p>Results</p> <p>Analysis of MS1 expression in differentiating C2C12 muscle cells demonstrated a temporal differentiation dependent up-regulation in <it>ms1 </it>mRNA. An <it>in silico </it>comparative sequence analysis identified two conserved putative myogenic regulatory domains within the proximal 1.5 kbp of 5' upstream sequence. Co-transfecting C2C12 myoblasts with <it>ms1 </it>promoter/luciferase reporters and myogenic regulatory factor (MRF) over-expression plasmids revealed specific sensitivity of the <it>ms1 </it>promoter to MyoD. Subsequent mutagenesis and EMSA analysis demonstrated specific targeting of MyoD at two distinct E-Boxes (E1 and E2) within identified evolutionary conserved regions (ECRs, α and β). Chromatin immunoprecipitation (ChIP) analysis indicates that co-ordinated binding of MyoD at E-Boxes located within ECRs α and β correlates with the temporal induction in <it>ms1 </it>mRNA.</p> <p>Conclusion</p> <p>These findings suggest that the tissue specific and differentiation dependent up-regulation in <it>ms1 </it>mRNA is mediated by temporal binding of MyoD at distinct evolutionary conserved E-Boxes within the <it>ms1 </it>5' upstream sequence. We believe, through its activation of <it>ms1</it>, this is the first study to demonstrate a direct link between MyoD activity and SRF transcriptional signalling, with clear implications for the understanding of muscle determination, differentiation and regeneration.</p

The Phase Structure of Supersymmetric Sp(2N_c) Gauge Theories with an Adjoint

We study the phase structure of N = 1 supersymmetric Sp(2N_c) gauge theories with 2N_f fundamentals, an adjoint, and vanishing superpotential. Using a-maximization, we derive analytic expressions for the values of N_f below which the first several gauge-invariant operators in the chiral ring violate the unitarity bound and become free fields. In doing so we are able to explicitly check previous conjectures about the behavior of this theory made by Luty, Schmaltz, and Terning. We then compare this to an analysis of the first two 'deconfined' dual descriptions based on the gauge groups Sp(2N_f+2) x SO(2N_c+5) and Sp(2N_f+2) x SO(4N_f+4) x Sp(2N_c+2), finding precise agreement. In particular, we find no evidence for non-obvious accidental symmetries or the appearance of a mixed phase in which one of the dual gauge groups becomes free.Comment: 18 pages, 2 figures; v2: added references to match JHEP versio

The role of intracoronary imaging in translational research

Abstract: Atherosclerotic cardiovascular disease is a key public health concern worldwide and leading cause of morbidity, mortality and health economic costs. Understanding atherosclerotic plaque microstructure in relation to molecular mechanisms that underpin its initiation and progression is needed to provide the best chance of combating this disease. Evolving vessel wall-based, endovascular coronary imaging modalities, including intravascular ultrasound (IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS), used in isolation or as hybrid modalities, have been advanced to allow comprehensive visualization of the pathological substrate of coronary atherosclerosis and accurately measure temporal changes in both the vessel wall and plaque characteristics. This has helped further our appreciation of the natural history of coronary artery disease (CAD) and the risk for major adverse cardiovascular events (MACE), evaluate the responsiveness to conventional and experimental therapeutic interventions, and assist in guiding percutaneous coronary intervention (PCI). Here we review the use of different imaging modalities for these purposes and the lessons they have provided thus far.Nicholas J. Montarello, Adam J. Nelson, Johan Verjans, Stephen J. Nicholls, Peter J. Psalti

Integration of genetics into a systems model of electrocardiographic traits using humanCVD BeadChip

&lt;p&gt;Background—Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death.&lt;/p&gt; &lt;p&gt;Methods and Results—In this study, 3 population-based cohorts (n=10 526) genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits (PR interval, QRS axis, QRS duration, and QTc interval) were evaluated for single-nucleotide polymorphism associations. Six gene regions contained single nucleotide polymorphisms associated with these traits at P&#60;10−6, including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2, and KCNQ1 (QTc interval). Expression quantitative trait loci analyses of top associated single-nucleotide polymorphisms were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9, and CAV1 showed evidence of differential allelic expression. We modeled the effects of ion channel activity on electrocardiographic parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and expression quantitative trait loci data to a systems model of the ECG.&lt;/p&gt; &lt;p&gt;Conclusions—These association results replicate and refine the mapping of previous genome-wide association study findings for electrocardiographic traits, while the expression analysis and modeling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.&lt;/p&gt

Increasing prevalence of a fluoroquinolone resistance mutation amongst Campylobacter jejuni isolates from four human infectious intestinal disease studies in the United Kingdom

Background: Campylobacter jejuni is the most common bacterial cause of human infectious intestinal disease. Methods: We genome sequenced 601 human C. jejuni isolates, obtained from two large prospective studies of infectious intestinal disease (IID1 [isolates from 1993–1996; n = 293] and IID2 [isolates from 2008–2009; n = 93]), the INTEGRATE project [isolates from 2016–2017; n = 52] and the ENIGMA project [isolates from 2017; n = 163]. Results: There was a significant increase in the prevalence of the T86I mutation conferring resistance to fluoroquinolone between each of the three later studies (IID2, INTEGRATE and ENIGMA) and IID1. Although the distribution of major multilocus sequence types (STs) was similar between the studies, there were changes in both the abundance of minority STs associated with the T86I mutation, and the abundance of clones within single STs associated with the T86I mutation. Discussion: Four population-based studies of community diarrhoea over a 25 year period revealed an increase over time in the prevalence of the T86I amongst isolates of C. jejuni associated with human gastrointestinal disease in the UK. Although associated with many STs, much of the increase is due to the expansion of clones associated with the resistance mutation

The spectral action and cosmic topology

The spectral action functional, considered as a model of gravity coupled to matter, provides, in its non-perturbative form, a slow-roll potential for inflation, whose form and corresponding slow-roll parameters can be sensitive to the underlying cosmic topology. We explicitly compute the non-perturbative spectral action for some of the main candidates for cosmic topologies, namely the quaternionic space, the Poincare' dodecahedral space, and the flat tori. We compute the corresponding slow-roll parameters and see we check that the resulting inflation model behaves in the same way as for a simply-connected spherical topology in the case of the quaternionic space and the Poincare' homology sphere, while it behaves differently in the case of the flat tori. We add an appendix with a discussion of the case of lens spaces.Comment: 55 pages, LaTe

Radio Bursts Associated with Flare and Ejecta in the 13 July 2004 Event

We investigate coronal transients associated with a GOES M6.7 class flare and a coronal mass ejection (CME) on 13 July 2004. During the rising phase of the flare, a filament eruption, loop expansion, a Moreton wave, and an ejecta were observed. An EIT wave was detected later on. The main features in the radio dynamic spectrum were a frequency-drifting continuum and two type II bursts. Our analysis shows that if the first type II burst was formed in the low corona, the burst heights and speed are close to the projected distances and speed of the Moreton wave (a chromospheric shock wave signature). The frequency-drifting radio continuum, starting above 1 GHz, was formed almost two minutes prior to any shock features becoming visible, and a fast-expanding piston (visible as the continuum) could have launched another shock wave. A possible scenario is that a flare blast overtook the earlier transient, and ignited the first type II burst. The second type II burst may have been formed by the same shock, but only if the shock was propagating at a constant speed. This interpretation also requires that the shock-producing regions were located at different parts of the propagating structure, or that the shock was passing through regions with highly different atmospheric densities. This complex event, with a multitude of radio features and transients at other wavelengths, presents evidence for both blast-wave-related and CME-related radio emissions.Comment: 14 pages, 6 figures; Solar Physics Topical Issue, in pres

Structure Formation, Melting, and the Optical Properties of Gold/DNA Nanocomposites: Effects of Relaxation Time

We present a model for structure formation, melting, and optical properties of gold/DNA nanocomposites. These composites consist of a collection of gold nanoparticles (of radius 50 nm or less) which are bound together by links made up of DNA strands. In our structural model, the nanocomposite forms from a series of Monte Carlo steps, each involving reaction-limited cluster-cluster aggregation (RLCA) followed by dehybridization of the DNA links. These links form with a probability $p_{eff}$ which depends on temperature and particle radius $a$. The final structure depends on the number of monomers (i. e. gold nanoparticles) $N_m$, $T$, and the relaxation time. At low temperature, the model results in an RLCA cluster. But after a long enough relaxation time, the nanocomposite reduces to a compact, non-fractal cluster. We calculate the optical properties of the resulting aggregates using the Discrete Dipole Approximation. Despite the restructuring, the melting transition (as seen in the extinction coefficient at wavelength 520 nm) remains sharp, and the melting temperature $T_M$ increases with increasing $a$ as found in our previous percolation model. However, restructuring increases the corresponding link fraction at melting to a value well above the percolation threshold. Our calculated extinction cross section agrees qualitatively with experiments on gold/DNA composites. It also shows a characteristic ``rebound effect,'' resulting from incomplete relaxation, which has also been seen in some experiments. We discuss briefly how our results relate to a possible sol-gel transition in these aggregates.Comment: 12 pages, 10 figure

Evidence for osteocyte-mediated bone-matrix degradation associated with periprosthetic joint infection (PJI)

Osteomyelitis associated with periprosthetic joint infection (PJI) signals a chronic infection and the need for revision surgery. An osteomyelitic bone exhibits distinct morphological features, including evidence for osteolysis and an accelerated bone remodelling into poorly organised, poor-quality bone. In addition to immune cells, various bone cell-types have been implicated in the pathology. The present study sought to determine the types of bone-cell activities in human PJI bones. Acetabular biopsies from peri-implant bone from patients undergoing revision total hip replacement (THR) for chronic PJI (with several identified pathogens) as well as control bone from the same patients and from patients undergoing primary THR were analysed. Histological analysis confirmed that PJI bone presented increased osteoclastic activity compared to control bone. Analysis of osteocyte parameters showed no differences in osteocyte lacunar area between the acetabular bone taken from PJI patients or primary THR controls. Analysis of bone matrix composition using Masson's trichrome staining and second-harmonic generation microscopy revealed widespread lack of mature collagen, commonly surrounding osteocytes, in PJI bone. Increased expression of known collagenases, such as matrix metallopeptidase (MMP) 13, MMP1 and cathepsin K (CTSK), was measured in infected bone compared to non-infected bone. Human bone and cultured osteocyte-like cells experimentally exposed to Staphylococcus aureus exhibited strongly upregulated expression of MMP1, MMP3 and MMP13 compared to non-exposed controls. In conclusion, the study identified previously unrecognised bone-matrix changes in PJI caused by multiple organisms deriving from osteocytes. Histological examination of bone collagen composition may provide a useful adjunct diagnostic measure of PJI.R.T. Ormsby, A.R. Zelmer, D. Yang, N.J. Gunn, Y. Starczak, S.P. Kidd ... et al

Sediment routing and basin evolution in Proterozoic to Mesozoic east Gondwana: A case study from southern Australia

Sedimentary rocks along the southern margin of Australia host an important record of the break-up history of east Gondwana, as well as fragments of a deeper geological history, which collectively help inform the geological evolution of a vast and largely underexplored region. New drilling through Cenozoic cover has allowed examination of the Cretaceous rift-related Madura Shelf sequence (Bight Basin), and identification of two new stratigraphic units beneath the shelf; the possibly Proterozoic Shanes Dam Conglomerate and the interpreted Palaeozoic southern Officer Basin unit, the Decoration Sandstone. Recognition of these new units indicates an earlier basinal history than previously known. Lithostratigraphy of the new drillcore has been integrated with that published from onshore and offshore cores to present isopach maps of sedimentary cover on the Madura Shelf. New palynological data demonstrate progression from more localised freshwater-brackish fluvio-lacustrine clastics in the early Cretaceous (Foraminisporis wonthaggiensis – Valanginian to Barremian) to widespread topography-blanketing, fully marine, glauconitic mudrocks in the mid Cretaceous (Endoceratium ludbrookiae – Albian). Geochronology and Hf-isotope geochemistry show detrital zircon populations from the Madura Shelf are comparable to those from the southern Officer Basin, as well as Cenozoic shoreline and palaeovalley sediments in the region. The detrital zircon population from the Shanes Dam Conglomerate is defined by a unimodal ~1400 Ma peak, which correlates with directly underlying crystalline basement of the Madura Province. Peak ages of ~1150 Ma and ~1650 Ma dominate the age spectra of all other samples, indicating a stable sediment reservoir through much of the Phanerozoic, with sediments largely sourced from the Albany-Fraser Orogen and Musgrave Province (directly and via multiple recycling events). The Madura Shelf detrital zircon population differs from published data for the Upper CretaceousCeduna Delta to the east, indicating significant differences in sediment provenance and routing between the Ceduna Sub-basin and central Bight Basin