403 research outputs found
The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer's Disease
Alzheimer's disease (AD) is associated with progressive endogenous neurotoxicity and hampered inflammatory regulation. The kynurenine (Kyn) pathway, which is controlled by tryptophan 2,3-dioxygenase (TDO), produces neuroactive and anti-inflammatory metabolites. Age-related Kyn pathway activation might contribute to AD pathology in humans, and inhibition of TDO was found to reduce AD-related cellular toxicity and behavioral deficits in animal models. To further explore the effect of aging on the Kyn pathway in the context of AD, we analyzed Kyn metabolite profiles in serum and brain tissue of the APP23 amyloidosis mouse model. We found that aging had genotype-independent effects on Kyn metabolite profiles in serum, cortex, hippocampus and cerebellum, whereas serum concentrations of many Kyn metabolites were reduced in APP23 mice. Next, to further establish the role of TDO in AD-related behavioral deficits, we investigated the effect of long-term pharmacological TDO inhibition on cognitive performance in APP23 mice. Our results indicated that TDO inhibition reversed recognition memory deficits without producing measurable changes in cerebral Kyn metabolites. TDO inhibition did not affect spatial learning and memory or anxiety-related behavior. These data indicate that age-related Kyn pathway activation is not specific for humans and could represent a cross-species phenotype of aging. These data warrant further investigation on the role of peripheral Kyn pathway disturbances and cerebral TDO activity in AD pathophysiology
Shortening the lipid A acyl chains of Bordetella pertussis enables depletion of lipopolysaccharide endotoxic activity
Whooping cough, or pertussis, is an acute respiratory infectious disease caused by the Gram-negative bacterium Bordetella pertussis. Whole-cell vaccines, which were introduced in the fifties of the previous century and proved to be effective, showed considerable reactogenicity and were replaced by subunit vaccines around the turn of the century. However, there is a considerable increase in the number of cases in industrialized countries. A possible strategy to improve vaccine-induced protection is the development of new, non-toxic, whole-cell pertussis vaccines. The reactogenicity of whole-cell pertussis vaccines is, to a large extent, derived from the lipid A moiety of the lipopolysaccharides (LPS) of the bacteria. Here, we engineered B. pertussis strains with altered lipid A structures by expressing genes for the acyltransferases LpxA, LpxD, and LpxL from other bacteria resulting in altered acyl-chain length at various positions. Whole cells and extracted LPS from the strains with shorter acyl chains showed reduced or no activation of the human Toll-like receptor 4 in HEK-Blue reporter cells, whilst a longer acyl chain increased activation. Pyrogenicity studies in rabbits confirmed the in vitro assays. These findings pave the way for the development of a new generation of whole-cell pertussis vaccines with acceptable side effects
Age- and Disease-Specific Changes of the Kynurenine Pathway in Parkinson's and Alzheimer's Disease
The Kynurenine (Kyn) pathway, which regulates neuroinflammation and n-methyl-d-aspartate (NMDA) receptor activation, is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). Age-related changes in Kyn metabolism and altered cerebral Kyn uptake along large-neutral amino acid (LNAA) transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter-mediated uptake in the brain. Kyn metabolites and LNAAs were retrospectively measured in serum and cerebrospinal fluid (CSF) of clinically well-characterized PD patients (n=33), AD patients (n=33) and age-matched controls (n=39) using solid-phase extraction-liquid chromatographic-tandem mass spectrometry. Aging was disease-independently associated with increased Kyn, kynurenic acid and quinolinic acid in serum and CSF. Concentrations of kynurenic acid were reduced in CSF of PD and AD patients (p=.001; p=.002) but estimations of Kyn brain uptake did not differ between diseased and controls. Furthermore, serum Kyn and quinolinic acid levels strongly correlated with their respective content in CSF and Kyn in serum negatively correlated with AD disease severity (p=.002). Kyn metabolites accumulated with aging in serum and CSF similarly in PD patients, AD patients and control subjects. In contrast, kynurenic acid was strongly reduced in CSF of PD and AD patients. Differential transporter-mediated Kyn uptake is unlikely to majorly contribute to these cerebral Kyn pathway disturbances. We hypothesize that the combination of age- and disease-specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease. This article is protected by copyright. All rights reserved
Detecting the direction of a signal on high-dimensional spheres: Non-null and Le Cam optimality results
We consider one of the most important problems in directional statistics,
namely the problem of testing the null hypothesis that the spike direction
of a Fisher-von Mises-Langevin distribution on the -dimensional
unit hypersphere is equal to a given direction . After a reduction
through invariance arguments, we derive local asymptotic normality (LAN)
results in a general high-dimensional framework where the dimension goes
to infinity at an arbitrary rate with the sample size , and where the
concentration behaves in a completely free way with , which
offers a spectrum of problems ranging from arbitrarily easy to arbitrarily
challenging ones. We identify various asymptotic regimes, depending on the
convergence/divergence properties of , that yield different
contiguity rates and different limiting experiments. In each regime, we derive
Le Cam optimal tests under specified and we compute, from the Le Cam
third lemma, asymptotic powers of the classical Watson test under contiguous
alternatives. We further establish LAN results with respect to both spike
direction and concentration, which allows us to discuss optimality also under
unspecified . To investigate the non-null behavior of the Watson test
outside the parametric framework above, we derive its local asymptotic powers
through martingale CLTs in the broader, semiparametric, model of rotationally
symmetric distributions. A Monte Carlo study shows that the finite-sample
behaviors of the various tests remarkably agree with our asymptotic results.Comment: 47 pages, 4 figure
Generation of entangled states of two atoms inside a leaky cavity
An in-depth theoretical study is carried out to examine the
quasi-deterministic entanglement of two atoms inside a leaky cavity. Two
-type three-level atoms, initially in their ground states, may become
maximally entangled through the interaction with a single photon. By working
out an exact analytic solution, we show that the probability of success depends
crucially on the spectral function of the injected photon. With a cavity
photon, one can generate a maximally entangled state with a certain probability
that is always less than 50%. However, for an injected photon with a narrower
spectral width, this probability can be significantly increased. In particular,
we discover situations in which entanglement can be achieved in a single trial
with an almost unit probability
Variation in the Neisseria lactamica porin, and its relationship to meningococcal PorB
One potential vaccine strategy in the fight against meningococcal disease involves the exploitation of outer-membrane components of Neisseria lactamica, a commensal bacterium closely related to the meningococcus, Neisseria meningitidis. Although N. lactamica shares many surface structures with the meningococcus, little is known about the antigenic diversity of this commensal bacterium or the antigenic relationships between N. lactamica and N. meningitidis. Here, the N. lactamica porin protein (Por) was examined and compared to the related PorB antigens of N. meningitidis, to investigate potential involvement in anti-meningococcal immunity. Relationships among porin sequences were determined using distance-based methods and FST, and maximum-likelihood analyses were used to compare the selection pressures acting on the encoded proteins. These analyses demonstrated that the N. lactamica porin was less diverse than meningococcal PorB and although it was subject to positive selection, this was not as strong as the positive selection pressures acting on the meningococcal porin. In addition, the N. lactamica porin gene sequences and the protein sequences of the loop regions predicted to be exposed to the human immune system were dissimilar to the corresponding sequences in the meningococcus. This suggests that N. lactamica Por, contrary to previous suggestions, may have limited involvement in the development of natural immunity to meningococcal disease and might not be effective as a meningococcal vaccine component
Full capacitance-matrix effects in driven Josephson-junction arrays
We study the dynamic response to external currents of periodic arrays of
Josephson junctions, in a resistively capacitively shunted junction (RCSJ)
model, including full capacitance-matrix effects}. We define and study three
different models of the capacitance matrix : Model A
includes only mutual capacitances; Model B includes mutual and self
capacitances, leading to exponential screening of the electrostatic fields;
Model C includes a dense matrix that is constructed
approximately from superposition of an exact analytic solution for the
capacitance between two disks of finite radius and thickness. In the latter
case the electrostatic fields decay algebraically. For comparison, we have also
evaluated the full capacitance matrix using the MIT fastcap algorithm, good for
small lattices, as well as a corresponding continuum effective-medium analytic
evaluation of a finite voltage disk inside a zero-potential plane. In all cases
the effective decays algebraically with distance, with
different powers. We have then calculated current voltage characteristics for
DC+AC currents for all models. We find that there are novel giant capacitive
fractional steps in the I-V's for Models B and C, strongly dependent on the
amount of screening involved. We find that these fractional steps are quantized
in units inversely proportional to the lattice sizes and depend on the
properties of . We also show that the capacitive steps
are not related to vortex oscillations but to localized screened phase-locking
of a few rows in the lattice. The possible experimental relevance of these
results is also discussed.Comment: 12 pages 18 Postscript figures, REVTEX style. Paper to appear in July
1, Vol. 58, Phys. Rev. B 1998 All PS figures include
Genetic and Microbial Associations to Plasma and Fecal Bile Acids in Obesity Relate to Plasma Lipids and Liver Fat Content
Bile acids (BAs) have been implicated in obesity-related conditions such as NAFLD and hyperlipidemia. Different human BAs exert variable biological activities. Chen et al. define genetic and microbial associations to plasma and fecal BA concentrations and composition in persons with obesity and establish their relationships with liver fat and lipid phenotypes
LPS unmasking of Shigella flexneri reveals preferential localisation of tagged outer membrane protease IcsP to septa and new poles
The Shigella flexneri outer membrane (OM) protease IcsP (SopA) is a member of the enterobacterial Omptin family of proteases which cleaves the polarly localised OM protein IcsA that is essential for Shigella virulence. Unlike IcsA however, the specific localisation of IcsP on the cell surface is unknown. To determine the distribution of IcsP, a haemagglutinin (HA) epitope was inserted into the non-essential IcsP OM loop 5 using Splicing by Overlap Extension (SOE) PCR, and IcsP(HA) was characterised. Quantum Dot (QD) immunofluorescence (IF) surface labelling of IcsP(HA) was then undertaken. Quantitative fluorescence analysis of S. flexneri 2a 2457T treated with and without tunicaymcin to deplete lipopolysaccharide (LPS) O antigen (Oag) showed that IcsP(HA) was asymmetrically distributed on the surface of septating and non-septating cells, and that this distribution was masked by LPS Oag in untreated cells. Double QD IF labelling of IcsP(HA) and IcsA showed that IcsP(HA) preferentially localised to the new pole of non-septating cells and to the septum of septating cells. The localisation of IcsP(HA) in a rough LPS S. flexneri 2457T strain (with no Oag) was also investigated and a similar distribution of IcsP(HA) was observed. Complementation of the rough LPS strain with rmlD resulted in restored LPS Oag chain expression and loss of IcsP(HA) detection, providing further support for LPS Oag masking of surface proteins. Our data presents for the first time the distribution for the Omptin OM protease IcsP, relative to IcsA, and the effect of LPS Oag masking on its detection.Elizabeth Ngoc Hoa Tran, Matthew Thomas Doyle, Renato Moron
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