Panton-Valentine leukocidin (PVL) is a cytotoxin that causes leukocyte destruction and tissue necrosis. It is produced by fewer than 5% of Staphylococcus aureus strains. A collection of 172 S. aureus ...strains were screened for PVL genes by polymerase chain reaction amplification. PVL genes were detected in 93% of strains associated with furunculosis and in 85% of those associated with severe necrotic hemorrhagic pneumonia (all community-acquired). They were detected in 55% of cellulitis strains, 50% of cutaneous abscess strains, 23% of osteomyelitis strains, and 13% of finger-pulp-infection strains. PVL genes were not detected in strains responsible for other infections, such as infective endocarditis, mediastinitis, hospital-acquired pneumonia, urinary tract infection, and enterocolitis, or in those associated with toxic-shock syndrome. It thus appears that PVL is mainly associated with necrotic lesions involving the skin or mucosa.
Highlights • Both μ-opioid receptor and TLR4 can be activated by opioids or their metabolites. • Cell based assays can be used to quantify receptor agonism in biological samples. • Morphine ...administration results in circulating MOR and TLR4 agonism. • IP injections of morphine to mice every 12 h lead to intermittent MOR activation. • This mode of morphine administration results in TLR4-independent NF-κB activation.
In addition to their well-defined roles in replenishing depleted endoplasmic reticulum (ER) Ca(2+) reserves, molecular components of the store-operated Ca(2+) entry pathway regulate breast cancer ...metastasis. A process implicated in cancer metastasis that describes the conversion to a more invasive phenotype is epithelial-mesenchymal transition (EMT). In this study we show that EGF-induced EMT in MDA-MB-468 breast cancer cells is associated with a reduction in agonist-stimulated and store-operated Ca(2+) influx, and that MDA-MB-468 cells prior to EMT induction have a high level of non-stimulated Ca(2+) influx. The potential roles for specific Ca(2+) channels in these pathways were assessed by siRNA-mediated silencing of ORAI1 and transient receptor potential canonical type 1 (TRPC1) channels in MDA-MB-468 breast cancer cells. Non-stimulated, agonist-stimulated and store-operated Ca(2+) influx were significantly inhibited with ORAI1 silencing. TRPC1 knockdown attenuated non-stimulated Ca(2+) influx in a manner dependent on Ca(2+) influx via ORAI1. TRPC1 silencing was also associated with reduced ERK1/2 phosphorylation and changes in the rate of Ca(2+) release from the ER associated with the inhibition of the sarco/endoplasmic reticulum Ca(2+)-ATPase (time to peak Ca(2+)(CYT) = 188.7 ± 34.6 s (TRPC1 siRNA) versus 124.0 ± 9.5 s (non-targeting siRNA); P<0.05). These studies indicate that EMT in MDA-MB-468 breast cancer cells is associated with a pronounced remodeling of Ca(2+) influx, which may be due to altered ORAI1 and/or TRPC1 channel function. Our findings also suggest that TRPC1 channels in MDA-MB-468 cells contribute to ORAI1-mediated Ca(2+) influx in non-stimulated cells.
Abstract
Background and hypothesis
Around 20% of people at clinical high risk (CHR) for psychosis later develop a psychotic disorder, but it is difficult to predict who this will be. We assessed the ...incidence of hearing speech (termed speech illusions SIs) in noise in CHR participants and examined whether this was associated with adverse clinical outcomes.
Study design
At baseline, 344 CHR participants and 67 healthy controls were presented with a computerized white noise task and asked whether they heard speech, and whether speech was neutral, affective, or whether they were uncertain about its valence. After 2 years, we assessed whether participants transitioned to psychosis, or remitted from the CHR state, and their functioning.
Study results
CHR participants had a lower sensitivity to the task. Logistic regression revealed that a bias towards hearing targets in stimuli was associated with remission status (OR = 0.21, P = 042). Conversely, hearing SIs with uncertain valence at baseline was associated with reduced likelihood of remission (OR = 7.72. P = .007). When we assessed only participants who did not take antipsychotic medication at baseline, the association between hearing SIs with uncertain valence at baseline and remission likelihood remained (OR = 7.61, P = .043) and this variable was additionally associated with a greater likelihood of transition to psychosis (OR = 5.34, P = .029).
Conclusions
In CHR individuals, a tendency to hear speech in noise, and uncertainty about the affective valence of this speech, is associated with adverse outcomes. This task could be used in a battery of cognitive markers to stratify CHR participants according to subsequent outcomes.
Although N storage determines early spring growth in trees, the usefulness of autumn N supply remains unclear as N uptake decreases in autumn, but could be restored earlier in spring to compensate ...for low N cycling. We intended here to evaluate the effects of autumn N supply on N uptake, storage and cycling, and spring growth. Four levels of N fertilisation were applied to 1-year-old peach trees, between the end of shoot growth and leaf fall. In spring, N supply was
15
N labelled. Organ dry weights and concentrations of
14
N,
15
N, starch and soluble sugars were evaluated after the first growth flush. Bud development had previously been described in the same trees by Jordan et al. (Trees-Struct Func 23:235–245,
2009
). Fertilisation promoted autumn N uptake, spring N uptake and growth up to a threshold level, since no differences were evidenced between the three highest N treatments. The variability in tree
14
N contents was related to the number of phytomers per tree in autumn, i.e. to tree size. In spring, the depletion of the perennial structures was independent of treatment, indicating a complete mobilisation of the N stores. Spring growth was related to the amounts of cycling N, and spring N uptake was in turn proportioned to shoot and fruit growth. The lower N uptake of the N limited trees was not due to a C shortage since these trees displayed the highest starch concentrations. We conclude that a moderate autumn fertilisation improved spring growth and fruit production (Jordan et al. in Trees-Struct Func 23:235–245,
2009
) and that a deficit of N storage could not be compensated for by an increase in spring N uptake.
To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline ...compliance.
This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation).
We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with “timely long-term prophylaxis” as compared with “delayed long-term prophylaxis”: hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with “long-term prophylaxis guideline compliance” vs “long-term prophylaxis anticipation.”
This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.
Monocyte to macrophage differentiation is an essential step in atherogenesis. The structure protein of caveolae, caveolin-1, is increased in primary monocytes after its adhesion to endothelium. We ...explore the hypothesis that caveolin-1 plays a role in monocyte differentiation to macrophages.
Both phorbol myristate acetate-induced THP-1 and colony-stimulating factor-induced primary monocyte differentiation was associated with an increase in cellular caveolin-1 expression. Overexpression of caveolin-1 by transfection increased macrophage surface markers and inflammatory genes, whereas caveolin-1 knockdown by small interfering RNA or knockout reduced these. Also, caveolin-1 knockdown inhibited the differentiation-induced nuclear translocation of early growth response 1 (EGR-1) through extracellular signal-regulated kinase phosphorylation, further decreased the binding of EGR-1 to CD115 promoter, thus decreasing EGR-1 transcriptional activity. In functional assays, caveolin-1 inhibited transmigration but promoted phagocytosis in the monocyte-macrophage lineage. Decreasing caveolin-1 inhibited the uptake of modified low-density lipoprotein and reduced cellular lipid content. Finally, we showed that caveolin-1 knockout mice displayed less monocyte differentiation than wild-type mice and that EGR-1 transcription activity was also decreased in these mice because of the inhibition of extracellular signal-regulated kinase phosphorylation.
Caveolin-1 promotes monocyte to macrophage differentiation through the regulation of EGR-1 transcriptional activity, suggesting that phagocytic caveolin-1 may be critical for atherogenesis.
Purpose
Mitral valve computational models are widely studied in the literature. They can be used for preoperative planning or anatomical understanding. Manual extraction of the valve geometry on ...medical images is tedious and requires special training, while automatic segmentation is still an open problem.
Methods
We propose here a fully automatic pipeline to extract the valve chordae architecture compatible with a computational model. First, an initial segmentation is obtained by sub-mesh topology analysis and RANSAC-like model-fitting procedure. Then, the chordal structure is optimized with respect to objective functions based on mechanical, anatomical, and image-based considerations.
Results
The approach has been validated on 5 micro-CT scans with a graph-based metric and has shown an
87.5
%
accuracy rate. The method has also been tested within a structural simulation of the mitral valve closed state.
Conclusion
Our results show that the chordae architecture resulting from our algorithm can give results similar to experienced users while providing an equivalent biomechanical simulation.
Two-partner secretion (TPS) is widespread in the bacterial world. The pore-forming TPS toxin ExlA of Pseudomonas aeruginosa is conserved in pathogenic and environmental Pseudomonas. While ...P. chlororaphis and P. entomophila displayed ExlA-dependent killing, P. putida did not cause damage to eukaryotic cells. ExlA proteins interacted with epithelial cell membranes; however, only ExlAPch induced the cleavage of the adhesive molecule E-cadherin. ExlA proteins participated in insecticidal activity toward the larvae of Galleria mellonella and the fly Drosophila melanogaster. Evolutionary analyses demonstrated that the differences in the C-terminal domains are partly due to horizontal movements of the operon within the genus Pseudomonas. Reconstruction of the evolutionary history revealed the complex horizontal acquisitions. Together, our results provide evidence that conserved TPS toxins in environmental Pseudomonas play a role in bacteria-insect interactions and discrete differences in CTDs may determine their specificity and mode of action toward eukaryotic cells.
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•ExlA is a two-partner secreted toxin conserved across Pseudomonas spp.•Environmental Pseudomonas strains encode ExlA with different cytotoxic activities•ExlA of environmental Pseudomonas strains play a role in bacteria-insect interactions•ExlBA operon shows a complex evolutionary history of horizontal gene transfer
Genetics; Microbiology
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