Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

<p>Abstract</p> <p>Background</p> <p>Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA.</p> <p>Methods</p> <p>Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later.</p> <p>Results</p> <p>Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning.</p> <p>Conclusions</p> <p>These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA.</p

Recruitment of cognitive control regions during effortful self-control is associated with altered brain activity in control and reward systems in dieters during subsequent exposure to food commercials

Engaging in effortful self-control can sometimes impair people’s ability to resist subsequent temptations. Existing research has shown that when chronic dieters’ self-regulatory capacity is challenged by prior exertion of effort, they demonstrate disinhibited eating and altered patterns of brain activity when exposed to food cues. However, the relationship between brain activity during self-control exertion and subsequent food cue exposure remains unclear. In the present study, we investigated whether individual differences in recruitment of cognitive control regions during a difficult response inhibition task are associated with a failure to regulate neural responses to rewarding food cues in a subsequent task in a cohort of 27 female dieters. During self-control exertion, participants recruited regions commonly associated with inhibitory control, including dorsolateral prefrontal cortex (DLPFC). Those dieters with higher DLPFC activity during the initial self-control task showed an altered balance of food cue elicited activity in regions associated with reward and self-control, namely: greater reward-related activity and less recruitment of the frontoparietal control network. These findings suggest that some dieters may be more susceptible to the effects of self-control exertion than others and, whether due to limited capacity or changes in motivation, these dieters subsequently fail to engage control regions that may otherwise modulate activity associated with craving and reward

The paradox of verbal autopsy in cause of death assignment: symptom question unreliability but predictive accuracy

Background: We believe that it is important that governments understand the reliability of the mortality data which they have at their disposable to guide policy debates. In many instances, verbal autopsy (VA) will be the only source of mortality data for populations, yet little is known about how the accuracy of VA diagnoses is affected by the reliability of the symptom responses. We previously described the effect of the duration of time between death and VA administration on VA validity. In this paper, using the same dataset, we assess the relationship between the reliability and completeness of symptom responses and the reliability and accuracy of cause of death (COD) prediction. Methods: The study was based on VAs in the Population Health Metrics Research Consortium (PHMRC) VA Validation Dataset from study sites in Bohol and Manila, Philippines and Andhra Pradesh, India. The initial interview was repeated within 3-52 months of death. Question responses were assessed for reliability and completeness between the two survey rounds. COD was predicted by Tariff Method. Results: A sample of 4226 VAs was collected for 2113 decedents, including 1394 adults, 349 children, and 370 neonates. Mean question reliability was unexpectedly low (kappa = 0.447): 42.5 % of responses positive at the first interview were negative at the second, and 47.9 % of responses positive at the second had been negative at the first. Question reliability was greater for the short form of the PHMRC instrument (kappa = 0.497) and when analyzed at the level of the individual decedent (kappa = 0.610). Reliability at the level of the individual decedent was associated with COD predictive reliability and predictive accuracy. Conclusions: Families give coherent accounts of events leading to death but the details vary from interview to interview for the same case. Accounts are accurate but inconsistent; different subsets of symptoms are identified on each occasion. However, there are sufficient accurate and consistent subsets of symptoms to enable the Tariff Method to assign a COD. Questions which contributed most to COD prediction were also the most reliable and consistent across repeat interviews; these have been included in the short form VA questionnaire. Accuracy and reliability of diagnosis for an individual death depend on the quality of interview. This has considerable implications for the progressive roll out of VAs into civil registration and vital statistics (CRVS) systems

THP-1 macrophage cholesterol efflux is impaired by palmitoleate through Akt activation.

Lipoprotein lipase (LPL) is upregulated in atherosclerotic lesions and it may promote the progression of atherosclerosis, but the mechanisms behind this process are not completely understood. We previously showed that the phosphorylation of Akt within THP-1 macrophages is increased in response to the lipid hydrolysis products generated by LPL from total lipoproteins. Notably, the free fatty acid (FFA) component was responsible for this effect. In the present study, we aimed to reveal more detail as to how the FFA component may affect Akt signalling. We show that the phosphorylation of Akt within THP-1 macrophages increases with total FFA concentration and that phosphorylation is elevated up to 18 hours. We further show that specifically the palmitoleate component of the total FFA affects Akt phosphorylation. This is tied with changes to the levels of select molecular species of phosphoinositides. We further show that the total FFA component, and specifically palmitoleate, reduces apolipoprotein A-I-mediated cholesterol efflux, and that the reduction can be reversed in the presence of the Akt inhibitor MK-2206. Overall, our data support a negative role for the FFA component of lipoprotein hydrolysis products generated by LPL, by impairing macrophage cholesterol efflux via Akt activation

A database of microRNA expression patterns in Xenopus laevis

MicroRNAs (miRNAs) are short, non-coding RNAs around 22 nucleotides long. They inhibit gene expression either by translational repression or by causing the degradation of the mRNAs they bind to. Many are highly conserved amongst diverse organisms and have restricted spatio-temporal expression patterns during embryonic development where they are thought to be involved in generating accuracy of developmental timing and in supporting cell fate decisions and tissue identity. We determined the expression patterns of 180 miRNAs in Xenopus laevis embryos using LNA oligonucleotides. In addition we carried out small RNA-seq on different stages of early Xenopus development, identified 44 miRNAs belonging to 29 new families and characterized the expression of 5 of these. Our analyses identified miRNA expression in many organs of the developing embryo. In particular a large number were expressed in neural tissue and in the somites. Surprisingly none of the miRNAs we have looked at show expression in the heart. Our results have been made freely available as a resource in both XenMARK and Xenbase

Elliptic and hyperelliptic magnetohydrodynamic equilibria

The present study is a continuation of a previous one on "hyperelliptic" axisymmetric equilibria started in [Tasso and Throumoulopoulos, Phys. Plasmas 5, 2378 (1998)]. Specifically, some equilibria with incompressible flow nonaligned with the magnetic field and restricted by appropriate side conditions like "isothermal" magnetic surfaces, "isodynamicity" or P + B^2/2 constant on magnetic surfaces are found to be reducible to elliptic integrals. The third class recovers recent equilibria found in [Schief, Phys. Plasmas 10, 2677 (2003)]. In contrast to field aligned flows, all solutions found here have nonzero toroidal magnetic field on and elliptic surfaces near the magnetic axis.Comment: 9 page

The short term debt vs. long term debt puzzle: a model for the optimal mix

This paper argues that the existing finance literature is inadequate with respect to its coverage of capital structure of small and medium sized enterprises (SMEs). In particular it is argued that the cost of equity (being both conceptually ill defined and empirically non quantifiable) is not applicable to the capital structure decisions for a large proportion of SMEs and the optimal capital structure depends only on the mix of short and long term debt. The paper then presents a model, developed by practitioners for optimising the debt mix and demonstrates its practical application using an Italian firm's debt structure as a case study

Kepler-68: Three Planets, One With a Density Between That of Earth and Ice Giants

NASA's Kepler Mission has revealed two transiting planets orbiting Kepler-68. Follow-up Doppler measurements have established the mass of the innermost planet and revealed a third jovian-mass planet orbiting beyond the two transiting planets. Kepler-68b, in a 5.4 day orbit has mass 8.3 +/- 2.3 Earth, radius 2.31 +/- 0.07 Earth radii, and a density of 3.32 +/- 0.92 (cgs), giving Kepler-68b a density intermediate between that of the ice giants and Earth. Kepler-68c is Earth-sized with a radius of 0.953 Earth and transits on a 9.6 day orbit; validation of Kepler-68c posed unique challenges. Kepler-68d has an orbital period of 580 +/- 15 days and minimum mass of Msin(i) = 0.947 Jupiter. Power spectra of the Kepler photometry at 1-minute cadence exhibit a rich and strong set of asteroseismic pulsation modes enabling detailed analysis of the stellar interior. Spectroscopy of the star coupled with asteroseismic modeling of the multiple pulsation modes yield precise measurements of stellar properties, notably Teff = 5793 +/- 74 K, M = 1.079 +/- 0.051 Msun, R = 1.243 +/- 0.019 Rsun, and density 0.7903 +/- 0.0054 (cgs), all measured with fractional uncertainties of only a few percent. Models of Kepler-68b suggest it is likely composed of rock and water, or has a H and He envelope to yield its density of about 3 (cgs).Comment: 32 pages, 13 figures, Accepted to Ap

Epidemic processes with immunization

We study a model of directed percolation (DP) with immunization, i.e. with different probabilities for the first infection and subsequent infections. The immunization effect leads to an additional non-Markovian term in the corresponding field theoretical action. We consider immunization as a small perturbation around the DP fixed point in d<6, where the non-Markovian term is relevant. The immunization causes the system to be driven away from the neighbourhood of the DP critical point. In order to investigate the dynamical critical behaviour of the model, we consider the limits of low and high first infection rate, while the second infection rate remains constant at the DP critical value. Scaling arguments are applied to obtain an expression for the survival probability in both limits. The corresponding exponents are written in terms of the critical exponents for ordinary DP and DP with a wall. We find that the survival probability does not obey a power law behaviour, decaying instead as a stretched exponential in the low first infection probability limit and to a constant in the high first infection probability limit. The theoretical predictions are confirmed by optimized numerical simulations in 1+1 dimensions.Comment: 12 pages, 11 figures. v.2: minor correction