103 research outputs found
The c.-292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective
Background: Reticulocyte-type 15-lipoxygenase-1 (ALOX15) has anti-inflammatory and inflammatory effects and is implicated in the development of asthma, arthritis and atherosclerosis. Previously, we screened the human ALOX15 gene for variations because genetic variability in ALOX15 might influence these diseases. We found a C>T substitution at position c.-292 in the ALOX15 promoter that created a novel binding site for the transcription factor SPI1 and increased ALOX15 mRNA levels in monocytes from c.-292CT heterozygous volunteers. Methods: To test whether the higher mRNA levels led to higher ALOX15 activity, we performed an activity assay and measured the arachidonic acid metabolite 15(S)-hydroxy-eicosatetraenoic acid [15(S)-HETE] by HPLC analysis. To test whether this polymorphism was associated with coronary artery disease (CAD), we investigated its association in a case-control study involving 498 Caucasians. Results: The c.-292C>T polymorphism was associated with higher enzyme activity in heterozygous carriers. Intriguingly, this polymorphism also showed a tendency to be protective against atherosclerosis. Conclusions: These results suggest that increased ALOX15 activity may attenuate inflammation, which could be caused by an increase in 15(S)-HETE and eventually by its metabolites, the lipoxins. Clin Chem Lab Med 2007;45:487-9
The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines
Bioprospecting contributes to the discovery of new molecules with anticancer properties. Compounds
with cytolytic activity and the ability to induce immunogenic cell death can be administered as
intratumoral injections with the aim to activate anti-tumor immune responses by causing the release
of tumor antigens as well as damage-associated molecular patterns (DAMPs) from dying cancer cells.
In the present study, we report the cytolytic and DAMP-releasing efects of a new natural product
mimic termed MPM-1 that was inspired by the marine Eusynstyelamides. We found that MPM-1 rapidly
killed cancer cells in vitro by inducing a necrosis-like death, which was accompanied by lysosomal
swelling and perturbation of autophagy in HSC-3 (human oral squamous cell carcinoma) cells.
MPM-1 also induced release of the DAMPs adenosine triphosphate (ATP) and high mobility group
box 1 (HMGB1) from Ramos (B-cell lymphoma) and HSC-3 cells, as well as cell surface expression of
calreticulin in HSC-3 cells. This indicates that MPM-1 has the ability to induce immunogenic cell death,
further suggesting that it may have potential as a novel anticancer compound
Erythromycin degradation by an esterase in enzymatic membrane reactors
1 Introduction
Pharmaceuticals products (PPs) and endocrine disrupting chemicals (EDCs) as well as their transformation products have been detected in almost all effluents from sewage facilities, in surface water, in groundwater, adsorbed on sediments and even in drinking water [1,2]. Ecotoxicity studies have demonstrated that pharmaceutical pollutants could affect the growth, reproduction and behavior of birds, fishes, invertebrates, plants and bacteria [3,4]. Some recently published studies report that the presence of low concentrations of antibiotics in the wastewaters may develop antibiotic resistance in the whole environment [5, 6]. As previously reported by Demarche et al. [7], the use of enzymes might be beneficial to enhance or complement conventional wastewater treatments. As far as enzymes are relatively expensive the reuse of the biocatalyst appears to be essential to ensure the economic and industrial viability of the process. Enzymatic membrane reactors appear to be an interesting alternative since they enable to couple reaction and separation [8]. In fact, in such enzymatic reactors, the substrate is continuously brought in contact with the biocatalyst, which is retained by the membrane, either freely circulating with the retentate or fixed on or within the membrane and the reaction products are recovered in the permeate.
This work describes the study of erythromycin degradation by an EreB esterase in free and immobilized forms. It focuses on the comparison between 3 different enzymatic membrane reactors for erythromycin degradation by esterase EreB. In the first configuration the free biocatalyst was confined in the reaction media by a ceramic membrane. In the two other cases, the enzyme was immobilized in the membrane either covalently grafted or adsorbed.
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\u3ci\u3eStaphylococcus aureus\u3c/i\u3e Metabolic Adaptations during the Transition from a Daptomycin Susceptibility Phenotype to a Daptomycin Nonsusceptibility Phenotype
Staphylococcus aureus is a major cause of nosocomial and community-acquired infections. The success of S. aureus as a pathogen is due in part to its many virulence determinants and resistance to antimicrobials. In particular, methicillin-resistant S. aureus has emerged as a major cause of infections and led to increased use of the antibiotics vancomycin and daptomycin, which has increased the isolation of vancomycin-intermediate S. aureus and daptomycin-nonsusceptible S. aureus strains. The most common mechanism by which S. aureus acquires intermediate resistance to antibiotics is by adapting its physiology and metabolism to permit growth in the presence of these antibiotics, a process known as adaptive resistance. To better understand the physiological and metabolic changes associated with adaptive resistance, six daptomycin-susceptible and -nonsusceptible isogenic strain pairs were examined for changes in growth, competitive fitness, and metabolic alterations. Interestingly, daptomycin nonsusceptibility coincides with a slightly delayed transition to the postexponential growth phase and alterations in metabolism. Specifically, daptomycin-nonsusceptible strains have decreased tricarboxylic acid cycle activity, which correlates with increased synthesis of pyrimidines and purines and increased carbon flow to pathways associated with wall teichoic acid and peptidoglycan biosynthesis. Importantly, these data provided an opportunity to alter the daptomycin nonsusceptibility phenotype by manipulating bacterial metabolism, a first step in developing compounds that target metabolic pathways that can be used in combination with daptomycin to reduce treatment failures
An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents
Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis.We analyzed gene expression profiles of non-tumor liver tissues from 392 patients with early-stage HCC (training set, n=167 and validation set, n=225) and liver tissue from patients with cirrhosis without HCC (n=216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of N-nitrosodiethylamine followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then given orally the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, given orally aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet.We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of non-tumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor beta signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% 1.21-4.80). Mice with chemically-induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel downregulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle.We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that associates with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and developed fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis
Cowpox Virus Transmission from Pet Rats to Humans, Germany
We describe a cluster of cowpox virus (CPXV) infections in humans that occurred near Munich, Germany, around the beginning of 2009. Previously, only sporadic reports of CPXV infections in humans after direct contact with various animals had been published. This outbreak involved pet rats from the same litter
A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards
BACKGROUND: Inflammation rapidly impairs mood and cognition and, when severe, can appear indistinguishable
from major depression. These sickness responses are characterized by an acute reorientation of motivational state;
pleasurable activities are avoided, and sensitivity to negative stimuli is enhanced. However, it remains unclear how
these rapid shifts in behavior are mediated within the brain.
METHODS: Here, we combined computational modeling of choice behavior, experimentally induced inflammation,
and functional brain imaging (functional magnetic resonance imaging) to describe these mechanisms. Using a
double-blind, randomized crossover study design, 24 healthy volunteers completed a probabilistic instrumental
learning task on two separate occasions, one 3 hours after typhoid vaccination and one 3 hours after saline (placebo)
injection. Participants learned to select high probability reward (win £1) and avoid high probability punishment (lose
£1) stimuli. An action-value learning algorithm was fit to the observed behavior, then used within functional magnetic
resonance imaging analyses to identify neural coding of prediction error signals driving motivational learning.
RESULTS: Inflammation acutely biased behavior, enhancing punishment compared with reward sensitivity, through
distinct actions on neural representations of reward and punishment prediction errors within the ventral striatum and
anterior insula. Consequently, choice options leading to potential rewards were less behaviorally attractive, and
those leading to punishments were more aversive.
CONCLUSIONS: Our findings demonstrate the neural mediation of a rapid, state-dependent reorientation of reward
versus punishment sensitivity during inflammation. This mechanism may aid the adaptive reallocation of metabolic
resources during acute sickness but might also account for
Sumoylation inhibits α-synuclein aggregation and toxicity
Sumoylation of α-synuclein decreases its rate of aggregation and its deleterious effects in vitro and in vivo
Upper limits on the strength of periodic gravitational waves from PSR J1939+2134
The first science run of the LIGO and GEO gravitational wave detectors
presented the opportunity to test methods of searching for gravitational waves
from known pulsars. Here we present new direct upper limits on the strength of
waves from the pulsar PSR J1939+2134 using two independent analysis methods,
one in the frequency domain using frequentist statistics and one in the time
domain using Bayesian inference. Both methods show that the strain amplitude at
Earth from this pulsar is less than a few times .Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo
Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July
200
Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers
We study frequency dependent (FD) input-output schemes for signal-recycling
interferometers, the baseline design of Advanced LIGO and the current
configuration of GEO 600. Complementary to a recent proposal by Harms et al. to
use FD input squeezing and ordinary homodyne detection, we explore a scheme
which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are
sub-optimal among all possible input-output schemes, provide a global noise
suppression by the power squeeze factor, while being realizable by using
detuned Fabry-Perot cavities as input/output filters. At high frequencies, the
two schemes are shown to be equivalent, while at low frequencies our scheme
gives better performance than that of Harms et al., and is nearly fully
optimal. We then study the sensitivity improvement achievable by these schemes
in Advanced LIGO era (with 30-m filter cavities and current estimates of
filter-mirror losses and thermal noise), for neutron star binary inspirals, and
for narrowband GW sources such as low-mass X-ray binaries and known radio
pulsars. Optical losses are shown to be a major obstacle for the actual
implementation of these techniques in Advanced LIGO. On time scales of
third-generation interferometers, like EURO/LIGO-III (~2012), with
kilometer-scale filter cavities, a signal-recycling interferometer with the FD
readout scheme explored in this paper can have performances comparable to
existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi
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