1,825 research outputs found
Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods
A critical role for ATF2 transcription factor in the regulation of E-selectin expression in response to non-endotoxin components of Neisseria meningitidis
Vascular injury is a serious complication of sepsis due to the gram-negative bacterium Neisseria meningitidis. One of the critical early steps in initiating this injury is via the interaction of leucocytes, particularly neutrophils, with adhesion molecules expressed on inflamed endothelium. We have previously demonstrated that both lipopolysaccharide (LPS) and non-LPS components of meningococci can induce very high levels of expression of the vascular endothelial cell adhesion molecule E-selectin, which is critical for early tethering and capture of neutrophils onto endothelium under flow. Using an LPS-deficient strain of meningococcus, we showed that very high levels of expression can be induced in primary endothelial cells, even in the context of weak activation of the major host signal transduction factor [nuclear factor-κB (NF-κB)]. In this study, we show that the particular propensity for N. meningitidis to induce high levels of expression is regulated at a transcriptional level, and demonstrate a significant role for phosphorylation of the ATF2 transcription factor, likely via mitogen-activated protein (MAP) kinases, on the activity of the E-selectin promoter. Furthermore, inhibition of E-selectin expression in response to the lpxA- strain by a p38 inhibitor indicates a significant role of a p38-dependent MAPK signalling pathway in ATF2 activation. Collectively, these data highlight the role that LPS and other bacterial components have in modulating endothelial function and their involvement in the pathogenesis of meningococcal sepsis. Better understanding of these multiple mechanisms induced by complex stimuli such as bacteria, and the specific inflammatory pathways they activate, may lead to improved, focused interventions in both meningococcal and potentially bacterial sepsis more generally
Heterotic strings on G_2 orbifolds
We study compactification of heterotic strings to three dimensions on
orbifolds of G_2 holonomy. We consider the standard embedding and show that the
gauge group is broken from E_8 x E_8 or SO(32) to F_4 x E_8 or SO(25)
respectively. We also compute the spectrum of massless states and compare with
the results obtained from reduction of the 10-dimensional fields. Non-standard
embeddings are discussed briefly. For type II compactifications we verify that
IIB and IIA have equal massless spectrum.Comment: LaTex, 21 page
Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking
Rationale
GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine.
Objective
We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure.
Methods
α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg).
Results
No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not.
Conclusions
Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking
Towards Spinfoam Cosmology
We compute the transition amplitude between coherent quantum-states of
geometry peaked on homogeneous isotropic metrics. We use the holomorphic
representations of loop quantum gravity and the
Kaminski-Kisielowski-Lewandowski generalization of the new vertex, and work at
first order in the vertex expansion, second order in the graph (multipole)
expansion, and first order in 1/volume. We show that the resulting amplitude is
in the kernel of a differential operator whose classical limit is the canonical
hamiltonian of a Friedmann-Robertson-Walker cosmology. This result is an
indication that the dynamics of loop quantum gravity defined by the new vertex
yields the Friedmann equation in the appropriate limit.Comment: 8 page
Massive amplitudes on the Coulomb branch of N=4 SYM
We initiate a systematic study of amplitudes with massive external particles
on the Coulomb-branch of N=4 super Yang Mills theory: 1) We propose that
(multi-)soft-scalar limits of massless amplitudes at the origin of moduli space
can be used to determine Coulomb-branch amplitudes to leading order in the
mass. This is demonstrated in numerous examples. 2) We find compact explicit
expressions for several towers of tree-level amplitudes, including scattering
of two massive W-bosons with any number of positive helicity gluons, valid for
all values of the mass. 3) We present the general structure of superamplitudes
on the Coulomb branch. For example, the n-point "MHV-band" superamplitude is
proportional to a Grassmann polynomial of mixed degree 4 to 12, which is
uniquely determined by supersymmetry. We find explicit tree-level
superamplitudes for this MHV band and for other simple sectors of the theory.
4) Dual conformal generators are constructed, and we explore the dual conformal
properties of the simplest massive amplitudes. Our compact expressions for
amplitudes and superamplitudes should be of both theoretical and
phenomenological interest; in particular the tree-level results carry over to
truncations of the theory with less supersymmetry.Comment: 29 pages, 1 figur
Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats
The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats
Cross-sectional analysis of association between socioeconomic status and utilization of primary total hip joint replacements 2006-7 : Australian orthopaedic association national joint replacement registry
Background The utilization of total hip replacement (THR) surgery is rapidly increasing, however few data examine whether these procedures are associated with socioeconomic status (SES) within Australia. This study examined primary THR across SES for both genders for the Barwon Statistical Division (BSD) of Victoria, Australia.Methods Using the Australian Orthopaedic Association National Joint Replacement Registry data for 2006–7, primary THR with a diagnosis of osteoarthritis (OA) among residents of the BSD was ascertained. The Index of Relative Socioeconomic Disadvantage was used to measure SES; determined by matching residential addresses with Australian Bureau of Statistics census data. The data were categorised into quintiles; quintile 1 indicating the most disadvantaged. Age- and sex-specific rates of primary THR per 1,000 person years were reported for 10-year age bands using the total population at risk.Results Females accounted for 46.9% of the 642 primary THR performed during 2006–7. THR utilization per 1,000 person years was 1.9 for males and 1.5 for females. The highest utilization of primary THR was observed in those aged 70–79 years (males 6.1, and females 5.4 per 1,000 person years). Overall, the U-shaped pattern of THR across SES gave the appearance of bimodality for both males and females, whereby rates were greater for both the most disadvantaged and least disadvantaged groups.Conclusions Further work on a larger scale is required to determine whether relationships between SES and THR utilization for the diagnosis of OA is attributable to lifestyle factors related to SES, or alternatively reflects geographic and health system biases. Identifying contributing factors associated with SES may enhance resource planning and enable more effective and focussed preventive strategies for hip OA. <br /
Rapid short-duration hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular obstruction and myocardial infarct size
<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the combination of a rapid intravenous infusion of cold saline and endovascular hypothermia in a closed chest pig infarct model.</p> <p>Methods</p> <p>Pigs were randomized to pre-reperfusion hypothermia (n = 7), post-reperfusion hypothermia (n = 7) or normothermia (n = 5). A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min. Hypothermia was started after 25 min of ischemia or immediately after reperfusion by infusion of 1000 ml of 4°C saline and endovascular hypothermia. Area at risk was evaluated by in vivo SPECT. Infarct size was evaluated by ex vivo MRI.</p> <p>Results</p> <p>Pre-reperfusion hypothermia reduced infarct size/area at risk by 43% (46 ± 8%) compared to post-reperfusion hypothermia (80 ± 6%, p < 0.05) and by 39% compared to normothermia (75 ± 5%, p < 0.05). Pre-reperfusion hypothermia infarctions were patchier in appearance with scattered islands of viable myocardium. Pre-reperfusion hypothermia abolished (0%, p < 0.001), and post-reperfusion hypothermia significantly reduced microvascular obstruction (10.3 ± 5%; p < 0.05), compared to normothermia: (30.2 ± 5%).</p> <p>Conclusion</p> <p>Rapid hypothermia with cold saline and endovascular cooling before reperfusion reduces myocardial infarct size and microvascular obstruction. A novel finding is that hypothermia at the onset of reperfusion reduces microvascular obstruction without reducing myocardial infarct size. Intravenous administration of cold saline combined with endovascular hypothermia provides a method for a rapid induction of hypothermia suggesting a potential clinical application.</p
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