Maternal Protein Restriction Elevates Cholesterol in Adult Rat Offspring Due to Repressive Changes in Histone Modifications at the Cholesterol 7α-Hydroxylase Promoter

Adverse events in utero, such as intrauterine growth restriction (IUGR), can permanently alter epigenetic mechanisms leading to the metabolic syndrome, which encompasses a variety of symptoms including augmented cholesterol. The major site for cholesterol homeostasis occurs via the actions of hepatic cholesterol 7α-hydroxylase (Cyp7a1), which catabolizes cholesterol to bile acids. To determine whether posttranslational histone modifications influence the long-term expression of Cyp7a1 in IUGR, we used a protein restriction model in rats. This diet during pregnancy and lactation led to IUGR offspring with decreased liver to body weight ratios, followed by increased circulating and hepatic cholesterol levels in both sexes at d 21 and exclusively in the male offspring at d 130. The augmented cholesterol was associated with decreases in the expression of Cyp7a1. Chromatin immunoprecipitation revealed that this was concomitant with diminished acetylation and enhanced methylation of histone H3 lysine 9 [K9,14], markers of chromatin silencing, surrounding the promoter region of Cyp7a1. These epigenetic modifications originate in part due to dietary-induced decreases in fetal hepatic Jmjd2a expression, a histone H3 [K9] demethylase. Collectively, these findings suggest that the augmented cholesterol observed in low-protein diet-derived offspring is due to permanent repressive posttranslational histone modifications at the promoter of Cyp7a1. Moreover, this is the first study to demonstrate that maternal undernutrition leads to long-term cholesterol dysregulation in the offspring via epigenetic mechanisms. (Molecular Endocrinology 25: 785–798, 2011

Maternal taurine supplementation in rats partially prevents the adverse effects of early-life protein deprivation on β-cell function and insulin sensitivity

Dietary protein restriction during pregnancy and lactation in rats impairs β-cell function and mass in neonates and leads to glucose intolerance in adult offspring. Maternal taurine (Tau) supplementation during pregnancy in rats restores β-cell function and mass in neonates, but its long-term effects are unclear. The prevention of postnatal catch-up growth has been suggested to improve glucose tolerance in adult offspring of low-protein (LP)-fed mothers. The objective of this study was to examine the relative contribution of β-cell dysfunction and insulin resistance to impaired glucose tolerance in 130-day-old rat offspring of LP-fed mothers and the effects of maternal Tau supplementation on β-cell function and insulin resistance in these offspring. Pregnant rats were fed i) control, ii) LP, and iii) LP+Tau diets during gestation and lactation. Offspring were given a control diet following weaning. A fourth group consisting of offspring of LP-fed mothers, maintained on a LP diet following weaning, was also studied (LP-all life). Insulin sensitivity in the offspring of LP-fed mothers was reduced in females but not in males. In both genders, LP exposure decreased β-cell function. Tau supplementation improved insulin sensitivity in females and β-cell function in males. The LP-all life diet improved β-cell function in males. We conclude that i) maternal Tau supplementation has persistent effects on improving glucose metabolism (β-cell function and insulin sensitivity) in adult rat offspring of LP-fed mothers and ii) increasing the amount of protein in the diet of offspring adapted to a LP diet after weaning may impair glucose metabolism (β-cell function) in a gender-specific manner. © 2013 Society for Reproduction and Fertility

WAVE2 is regulated by multiple phosphorylation events within its VCA domain.

addresses: Department of Biochemistry, Faculty of Medical and Veterinary Sciences, University of Bristol, Bristol, United Kingdom.notes: PMCID: PMC2798068OnlineOpen Article. This is a copy of an article published in Cell Motility and the Cytoskeleton. This journal is available online at: http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1949-3592The definitive version is available at www3.interscience.wiley.comThe (Wiskott-Aldrich Syndrome Protein)-family verprolin homologous protein (WAVE) family of proteins occupies a pivotal position in the cell, converting extracellular signals into the formation of branched filamentous (F) actin structures. WAVE proteins contain a verprolin central acidic (VCA) domain at their C-terminus, responsible for binding to and activating the Arp2/3 complex, which in-turn nucleates the formation of new actin filaments. Here we identify five Casein Kinase 2 (CK2) phosphorylation sites within the VCA domain of WAVE2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the Arp2/3 complex. Phosphorylation of ser 482 and 484 specifically inhibits the activation of the Arp2/3 complex by the WAVE2 VCA domain, but has no effect on the affinity for the Arp2/3 complex when the other phosphorylation sites are occupied. We demonstrate phosphorylation of all five sites on endogenous WAVE2 and show that their mutation to non-phosphorylatable alanine residues inhibits WAVE2 function in vivo, inhibiting cell ruffling and disrupting the integrity of the leading edge of migrating cells

Pragmatic randomised controlled trial to evaluate the effectiveness and cost effectiveness of a multi-component intervention to reduce substance use and risk-taking behaviour in adolescents involved in the criminal justice system: A trial protocol (RISKIT-CJS)

Background: Adolescence is a critical developmental stage when young people make lifestyle choices that have the potential to impact on their current and future health and social wellbeing. The relationship between substance use and criminal activity is complex but there is clear evidence that the prevalence of problematic substance use is far higher among adolescent offenders than the general adolescent population. Adolescent offenders are a marginalized and vulnerable population who are significantly more likely to experience health and social inequalities in later life than their non-offending peers. There is a paucity of evidence on effective interventions to address substance use and risk-taking behaviours in adolescent offender populations but it is clear that preventative or abstinence orientated interventions are not effective. RISKIT-CJS is an intervention developed in collaboration with young people taking account of the current best evidence. Feasibility and pilot studies have found the intervention addresses the needs of adolescents, is acceptable and has demonstrated potential in reducing substance use and risk-taking behavior. Methods: The study is a mixed method, two-armed, prospective, pragmatic randomized controlled trial with individual randomisation to either treatment as usual alone or the RISKIT-CJS intervention in addition to treatment as usual. Adolescents, aged 13 to 17 years inclusive, engaged with the criminal justice system who are identified as having problematic substance use are eligible to participate. The study will be conducted across three geographical areas; South and South East England, London and North East England between March 2017 and February 2019. Discussion: The study represents an ambitious programme of work to address an area of need for a marginalized and vulnerable population

Substance misuse and community supervision: A systematic review of the literature

A narrative systematic review was undertaken of the literature concerning the health of people on probation or parole (community supervision). In this paper, we provide an up-to-date summary of what is known about substance misuse in this context. This includes estimates of the prevalence and complexity of substance misuse in those under community supervision, and studies of the effectiveness of approaches to treating substance misuse and engaging and retaining this population in treatment. A total of 5125 papers were identified in the initial electronic searches, and after careful double-blind review only 31 papers related to this topic met our criteria. In addition, a further 15 background papers were identified which are reported. We conclude that internationally there is a high prevalence and complexity of substance misuse amongst people under community supervision. Despite clear benefits to individuals and the wider society through improved health, and reduced re-offending; it is still difficult to identify the most effective ways of improving health outcomes for this group in relation to substance misuse from the research literature. Further research and investment is needed to support evidence-based commissioning by providing a detailed and up-to-date profile of needs and the most effective ways of addressing them, and sufficient funds to ensure that appropriate treatment is available and its impact can be continually measured. Without this, it will be impossible to truly establish effective referral and treatment pathways providing continuity of care for individuals as they progress through, and exit, the criminal justice pathway

Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice

Hard probes of short-range nucleon-nucleon correlations

One of the primary goals of nuclear physics is providing a complete description of the structure of atomic nuclei. While mean-field calculations provide detailed information on the nuclear shell structure for a wide range of nuclei, they do not capture the complete structure of nuclei, in particular the impact of small, dense structures in nuclei. The strong, short-range component of the nucleon-nucleon potential yields hard interactions between nucleons which are close together, generating a high-momentum tail to the nucleon momentum distribution, with momenta well in excess of the Fermi momentum. This high-momentum component of the nuclear wave-function is one of the most poorly understood parts of nuclear structure. Utilizing high-energy probes, we can isolate scattering from high-momentum nucleons, and use these measurements to examine the structure and impact of short-range nucleon-nucleon correlations. Over the last decade we have moved from looking for evidence of such short-range structures to mapping out their strength in nuclei and examining their isospin structure. This has been made possible by high-luminosity and high-energy accelerators, coupled with an improved understanding of the reaction mechanism issues involved in studying these structures. We review the general issues related to short-range correlations, survey recent experiments aimed at probing these short-range structures, and lay out future possibilities to further these studies.Comment: Review article to appear in Prog.Part.Nucl.Phys. 77 pages, 33 figure

Virtual Compton Scattering and Neutral Pion Electroproduction in the Resonance Region up to the Deep Inelastic Region at Backward Angles

We have made the first measurements of the virtual Compton scattering (VCS) process via the H$(e,e'p)\gamma$ exclusive reaction in the nucleon resonance region, at backward angles. Results are presented for the $W$-dependence at fixed $Q^2=1$ GeV$^2$, and for the $Q^2$-dependence at fixed $W$ near 1.5 GeV. The VCS data show resonant structures in the first and second resonance regions. The observed $Q^2$-dependence is smooth. The measured ratio of H$(e,e'p)\gamma$ to H$(e,e'p)\pi^0$ cross sections emphasizes the different sensitivity of these two reactions to the various nucleon resonances. Finally, when compared to Real Compton Scattering (RCS) at high energy and large angles, our VCS data at the highest $W$ (1.8-1.9 GeV) show a striking $Q^2$- independence, which may suggest a transition to a perturbative scattering mechanism at the quark level.Comment: 20 pages, 8 figures. To appear in Phys.Rev.

Virtual Compton Scattering and the Generalized Polarizabilities of the Proton at Q^2=0.92 and 1.76 GeV^2

Virtual Compton Scattering (VCS) on the proton has been studied at Jefferson Lab using the exclusive photon electroproduction reaction (e p --> e p gamma). This paper gives a detailed account of the analysis which has led to the determination of the structure functions P_LL-P_TT/epsilon and P_LT, and the electric and magnetic generalized polarizabilities (GPs) alpha_E(Q^2) and beta_M(Q^2) at values of the four-momentum transfer squared Q^2= 0.92 and 1.76 GeV^2. These data, together with the results of VCS experiments at lower momenta, help building a coherent picture of the electric and magnetic GPs of the proton over the full measured Q^2-range, and point to their non-trivial behavior.Comment: version 2: modified according to PRC Editor's and Referee's recommendations. Archival paper for the E93-050 experiment at JLab Hall A. 28 pages, 23 figures, 5 cross-section tables. To be submitted to Phys.Rev.

A new set of relativistic screening constants for the screened hydrogenic model

AnewRelativisticScreenedHydrogenicModel has been developed to calculate atomic data needed to compute the optical and thermodynamic properties of high energy density plasmas. The model is based on anewset of universal screeningconstants, including nlj-splitting that has been obtained by fitting to a large database of ionization potentials and excitation energies. This database was built with energies compiled from the National Institute of Standards and Technology (NIST) database of experimental atomic energy levels, and energies calculated with the Flexible Atomic Code (FAC). The screeningconstants have been computed up to the 5p3/2 subshell using a Genetic Algorithm technique with an objective function designed to minimize both the relative error and the maximum error. To select the best set of screeningconstants some additional physical criteria has been applied, which are based on the reproduction of the filling order of the shells and on obtaining the best ground state configuration. A statistical error analysis has been performed to test the model, which indicated that approximately 88% of the data lie within a ±10% error interval. We validate the model by comparing the results with ionization energies, transition energies, and wave functions computed using sophisticated self-consistent codes and experimental data