Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: Effects of early-life stress

Background: Early-life stress (ELS) is a recognized risk factor for chronic pain disorders, and females appear to be more sensitive to the negative effects of stress. Moreover, estrous cycle-related fluctuations in estrogen levels have been linked with alternating pain sensitivity. Aberrant central circuitry involving both the anterior cingulate cortex (ACC) and the lumbosacral spinal cord has also been implicated in the modulation of visceral pain in clinical and preclinical studies. Here we further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS. Methods: We investigated visceral sensitivity in adult female Sprague-Dawley rats, which had undergone maternal separation (MS) in early life or remained non-separated (NS), by performing colorectal distension (CRD). We also assessed excitatory amino acid uptake through excitatory amino acid transporters (EAATs) in the lumbosacral spinal cord and ACC. Results: NS animals in proestrus and estrus exhibited reduced EAAT uptake and decreased threshold to CRD. Moreover, total pain behaviors were increased in these stages. MS rats exhibited lower pain thresholds and higher total pain behaviors to CRD across all stages of the estrous cycle. Interestingly, cortical EAAT function in MS rats was inhibited in the low estrogen state—an effect completely opposite to that seen in NS rats. Conclusions: This data confirms that estrous cycle and ELS are significant factors in visceral sensitivity and fluctuations in EAAT function may be a perpetuating factor mediating central sensitization

The Application of a Process Evaluation Form for Aphasic Individuals in a Small Group Setting

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A novel secreted protein, MYR1, is central to Toxoplasma’s manipulation of host cells

The intracellular protozoan Toxoplasma gondii dramatically reprograms the transcriptome of host cells it infects, including substantially up-regulating the host oncogene c-myc. By applying a flow cytometry-based selection to infected mouse cells expressing green fluorescent protein fused to c-Myc (c-Myc–GFP), we isolated mutant tachyzoites defective in this host c-Myc up-regulation. Whole-genome sequencing of three such mutants led to the identification of MYR1 (Myc regulation 1; TGGT1_254470) as essential for c-Myc induction. MYR1 is a secreted protein that requires TgASP5 to be cleaved into two stable portions, both of which are ultimately found within the parasitophorous vacuole and at the parasitophorous vacuole membrane. Deletion of MYR1 revealed that in addition to its requirement for c-Myc up-regulation, the MYR1 protein is needed for the ability of Toxoplasma tachyzoites to modulate several other important host pathways, including those mediated by the dense granule effectors GRA16 and GRA24. This result, combined with its location at the parasitophorous vacuole membrane, suggested that MYR1 might be a component of the machinery that translocates Toxoplasma effectors from the parasitophorous vacuole into the host cytosol. Support for this possibility was obtained by showing that transit of GRA24 to the host nucleus is indeed MYR1-dependent. As predicted by this pleiotropic phenotype, parasites deficient in MYR1 were found to be severely attenuated in a mouse model of infection. We conclude, therefore, that MYR1 is a novel protein that plays a critical role in how Toxoplasma delivers effector proteins to the infected host cell and that this is crucial to virulence

Dynamics and stability of the Godel universe

We use covariant techniques to describe the properties of the Godel universe and then consider its linear response to a variety of perturbations. Against matter aggregations, we find that the stability of the Godel model depends primarily upon the presence of gradients in the centrifugal energy, and secondarily on the equation of state of the fluid. The latter dictates the behaviour of the model when dealing with homogeneous perturbations. The vorticity of the perturbed Godel model is found to evolve as in almost-FRW spacetimes, with some additional directional effects due to shape distortions. We also consider gravitational-wave perturbations by investigating the evolution of the magnetic Weyl component. This tensor obeys a simple plane-wave equation, which argues for the neutral stability of the Godel model against linear gravity-wave distortions. The implications of the background rotation for scalar-field Godel cosmologies are also discussed.Comment: Revised version, to match paper published in Class. Quantum Gra

Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice

Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes

Three Small Planets Transiting a Hyades Star

We present the discovery of three small planets transiting K2-136 (LP 358 348, EPIC 247589423), a late K dwarf in the Hyades. The planets have orbital periods of $7.9757 \pm 0.0011$, $17.30681^{+0.00034}_{-0.00036}$, and $25.5715^{+0.0038}_{-0.0040}$ days, and radii of $1.05 \pm 0.16$, $3.14 \pm 0.36$, and $1.55^{+0.24}_{-0.21}$ $R_\oplus$, respectively. With an age of 600-800 Myr, these planets are some of the smallest and youngest transiting planets known. Due to the relatively bright (J=9.1) host star, the planets are compelling targets for future characterization via radial velocity mass measurements and transmission spectroscopy. As the first known star with multiple transiting planets in a cluster, the system should be helpful for testing theories of planet formation and migration.Comment: Accepted to The Astronomical Journa

The read-across hypothesis and environmental risk assessment of pharmaceuticals

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 American Chemical Society.Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.BBSRC Industrial Partnership Award BB/ I00646X/1 and BBSRC Industrial CASE Partnership Studentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme

Cosmology with inhomogeneous magnetic fields

We review spacetime dynamics in the presence of large-scale electromagnetic fields and then consider the effects of the magnetic component on perturbations to a spatially homogeneous and isotropic universe. Using covariant techniques, we refine and extend earlier work and provide the magnetohydrodynamic equations that describe inhomogeneous magnetic cosmologies in full general relativity. Specialising this system to perturbed Friedmann-Robertson-Walker models, we examine the effects of the field on the expansion dynamics and on the growth of density inhomogeneities, including non-adiabatic modes. We look at scalar perturbations and obtain analytic solutions for their linear evolution in the radiation, dust and inflationary eras. In the dust case we also calculate the magnetic analogue of the Jeans length. We then consider the evolution of vector perturbations and find that the magnetic presence generally reduces the decay rate of these distortions. Finally, we examine the implications of magnetic fields for the evolution of cosmological gravitational waves.Comment: Typos corrected. Version to appear in Physics Report