We study the use of the complex-Langevin equation (CLE) to simulate lattice QCD at a finite chemical potential (μ) for a quark-number, which has a complex fermion determinant that prevents the use of ...standard simulation methods based on importance sampling. Recent enhancements to the CLE specific to lattice QCD inhibit runaway solutions which had foiled earlier attempts to use it for such simulations. However, it is not guaranteed to produce correct results. Our goal is to determine under what conditions the CLE yields correct values for the observables of interest. Zero temperature simulations indicate that for moderate couplings, good agreement with expected results is obtained for small μ and for μ large enough to reach saturation, and that this agreement improves as we go to weaker coupling. For intermediate μ values these simulations do not produce the correct physics. We compare our results with those of the phase-quenched approximation. Since there are indications that correct results might be obtained if the CLE trajectories remain close to the SU(3) manifold, we study how the distance from this manifold depends on the quark mass and on the coupling. We find that this distance decreases with decreasing quark mass and as the coupling decreases, i.e., as the simulations approach the continuum limit.
The ferroelectric perovskite Na
0.5
Bi
0.5
TiO
3
, NBT, can exhibit three types of electrical behaviour,
i.e.
oxide-ion conduction (type I), mixed ionic-electronic conduction (type II) and ...insulating/dielectric (type III) based on various defect mechanisms. Here we review how to tune the electrical properties of NBT
via
several mechanisms, including A-site Na or Bi non-stoichiometry, isovalent substitution, and acceptor- and donor-doping. The diversity of the electrical behaviour in the NBT lattice is attributed to the high level of oxide-ion conductivity originating from highly mobile oxygen ions which can be fine-tuned to optimise or suppress ionic conduction. High oxide-ion conductivity can be obtained by manipulating the starting Na/Bi ≥1 and by acceptor-doping to make NBT a potential electrolyte material for intermediate temperature solid oxide fuel cells (IT-SOFCs). In contrast, the oxide-ion conduction can be partially or fully suppressed by having a starting (nominal) composition with Na/Bi <1, donor-doping, or utilising the trapping effect between oxygen vacancies and some B-site acceptor dopants. This significantly reduces the dielectric loss and makes NBT-based materials excellent candidates as high-temperature dielectrics for capacitor applications.
We review the diversity of the electrical behaviour of NBT induced by various defect mechanisms, including A-site Na or Bi non-stoichiometry, isovalent-substitution, and acceptor- and donor-doping.
The muscular dystrophies are rare orphan diseases, characterized by progressive muscle weakness: the most common and well known is Duchenne muscular dystrophy which affects young boys and progresses ...quickly during childhood. However, over 70 distinct variants have been identified to date, with different rates of progression, implications for morbidity, mortality, and quality of life. There are presently no curative therapies for these diseases, but a range of potential therapies are presently reaching the stage of multi-centre, multi-national first-in-man clinical trials. There is a need for sensitive, objective end-points to assess the efficacy of the proposed therapies. Present clinical measurements are often too dependent on patient effort or motivation, and lack sensitivity to small changes, or are invasive. Quantitative MRI to measure the fat replacement of skeletal muscle by either chemical shift imaging methods (Dixon or IDEAL) or spectroscopy has been demonstrated to provide such a sensitive, objective end-point in a number of studies. This review considers the importance of the outcome measures, discusses the considerations required to make robust measurements and appropriate quality assurance measures, and draws together the existing literature for cross-sectional and longitudinal cohort studies using these methods in muscular dystrophy.
The association between poor paternal diet, perturbed embryonic development, and adult offspring ill health represents a new focus for the Developmental Origins of Health and Disease hypothesis. ...However, our understanding of the underlying mechanisms remains ill-defined. We have developed a mouse paternal low-protein diet (LPD) model to determine its impact on semen quality, maternal uterine physiology, and adult offspring health. We observed that sperm from LPD-fed male mice displayed global hypomethylation associated with reduced testicular expression of DNA methylation and folate-cycle regulators compared with normal protein diet (NPD) fed males. Furthermore, females mated with LPD males display blunted preimplantation uterine immunological, cell signaling, and vascular remodeling responses compared to controls. These data indicate paternal diet impacts on offspring health through both sperm genomic (epigenetic) and seminal plasma (maternal uterine environment) mechanisms. Extending our model, we defined sperm- and seminal plasma-specific effects on offspring health by combining artificial insemination with vasectomized male mating of dietary-manipulated males. All offspring derived from LPD sperm and/or seminal plasma became heavier with increased adiposity, glucose intolerance, perturbed hepatic gene expression symptomatic of nonalcoholic fatty liver disease, and altered gut bacterial profiles. These data provide insight into programming mechanisms linking poor paternal diet with semen quality and offspring health.
BACKGROUND Most reproductive failures originate during the periconceptional period and are influenced by the age and the lifestyle of parents-to-be. We advance the hypothesis that these failures can ...arise as a partial consequence of derangements to one-carbon (1-C) metabolism (i.e. metabolic pathways that utilize substrates/cofactors such as methionine, vitamin B12, folate). 1-C metabolic pathways drive the synthesis of proteins, biogenic amines and lipids required for early growth, together with the synthesis and methylation of DNA and histones essential for the regulation of gene expression. We review how deficiencies in periconceptional 1-C metabolism affect fertility and development together with underlying mechanisms derived from animal studies. METHODS A literature search was performed using PubMed and bibliographies of all relevant original research articles and reviews. RESULTS We define 'periconception' as a 5-6-month period in women embracing oocyte growth, fertilization, conceptus formation and development to Week 10 of gestation (coinciding with the closure of the secondary palate in the embryo). During this period significant epigenetic modifications to chromatin occur that correspond with normal development. Subtle variations in 1-C metabolism genes and deficiencies in 1-C substrates/cofactors together with poor lifestyle, such as smoking and alcohol consumption, disturb 1-C metabolism and contribute to subfertility and early miscarriage and compromise offspring health. Procedures used in assisted reproduction can also disturb these metabolic pathways and contribute to poor pregnancy outcomes. CONCLUSIONS Evidence presented indicates that parental nutrition and other lifestyle factors during the periconceptional period can affect reproductive performance via 1-C metabolic pathways. This knowledge provides opportunities for treatment and prevention of reproductive failures and future non-communicable diseases.
Although the association between maternal periconceptional diet and adult offspring health is well characterised, our understanding of the impact of paternal nutrition at the time of conception on ...offspring phenotype remains poorly defined. Therefore, we determined the effect of a paternal preconception low protein diet (LPD) on adult offspring cardiovascular and metabolic health in mice. Male C57BL/6 mice were fed either normal protein diet (NPD; 18% casein) or LPD (9% casein) for 7 wk before mating. At birth, a reduced male-to-female ratio (P = 0.03) and increased male offspring weight (P = 0.009) were observed in litters from LPD compared with NPD stud males with no differences in mean litter size. LPD offspring were heavier than NPD offspring at 2 and 3 wk of age (P < 0.02). However, no subsequent differences in body weight were observed. Adult male offspring derived from LPD studs developed relative hypotension (decreased by 9.2 mmHg) and elevated heart rate (P < 0.05), whereas both male and female offspring displayed vascular dysfunction and impaired glucose tolerance relative to NPD offspring. At cull (24 wk), LPD males had elevated adiposity (P = 0.04), reduced heart-to-body weight ratio (P = 0.04), and elevated circulating TNF-α levels (P = 0.015) compared with NPD males. Transcript expression in offspring heart and liver tissue was reduced for genes involved in calcium signaling (Adcy, Plcb, Prkcb) and metabolism (Fto) in LPD offspring (P < 0.03). These novel data reveal the impact of suboptimal paternal nutrition on adult offspring cardiovascular and metabolic homeostasis, and provide some insight into the underlying regulatory mechanisms.
A nominal Bi-excess starting composition of sodium bismuth titanate, Na
0.5
Bi
0.51
TiO
3.015
(NB
0.51
T) produces dielectric ceramics that exhibit mixed n-type and oxide-ion conductivity with an ...ionic transport number of ∼0.1 at ≥600 °C. The bulk electrical conductivity,
σ
b
, of NB
0.51
T ceramics under a dc bias field of ≤100 V cm
−1
has been investigated by impedance spectroscopy. Over the temperature range ∼550 to 750 °C,
σ
b
increases by up to one order of magnitude under the dc bias and returns to its initial value on removal of the bias. The enhancement of conductivity is dependent on temperature, atmosphere, dc bias field and the electrode materials. A maximum conductivity enhancement of >2000% is achieved at 600 °C in nitrogen using Pt electrodes. This is in contrast to that observed for other n-type perovskite titanates and oxygen-deficient rutile where
σ
b
is suppressed under a dc bias. This 'unusual' non-ohmic behaviour is attributed mainly to the influence of highly mobile oxygen vacancies in NB
0.51
T. The field-enhanced
σ
b
is best described to be a consequence of increased pumping of oxygen from the cathode to the anode, in which the electrode reactions play an important role. In addition, dissociation of defect clusters may also contribute to the enhanced
σ
b
under a dc bias. The high, fast and reversible response to the dc bias voltage may expand the potential application of NBT-based materials to memory devices.
A maximum conductivity enhancement of >2000% is achieved in Na
0.5
Bi
0.51
TiO
3.015
under a small dc bias, in which the highly mobile oxygen ions and the electrode reactions play a critical role.
Summary Background A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional ...deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. Methods We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11·2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes—fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)—were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. Findings Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1·2%, 95% CI 0·5–1·9, p=0·002) but not thigh level (0·2%, −0·2 to 0·6, p=0·38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2·6%, 1·3–4·0, p=0·002) and thigh level (3·3%, 1·8–4·9, p=0·0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=–0·64, p=0·002) and the Charcot-Marie-Tooth examination score (ρ=0·63, p=0·003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4·0 ms SE 0·5, calf 3·5 ms 0·6; Charcot-Marie-Tooth 1A thigh 1·0 ms 0·3, calf 2·0 ms 0·3) and MTR reduced compared with controls (inclusion body myositis thigh −1·5 percentage units pu; 0·2, calf −1·1 pu 0·2; Charcot-Marie-Tooth 1A thigh −0·3 pu 0·1, calf −0·7 pu 0·1). Interpretation MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. Funding Medical Research Council UK.
•Sensory information needs to be filtered pre-attentively for the brain to function properly.•Autism spectrum disorder (ASD) and Fragile-X syndrome (FXS) are associated with hyper- and ...hyposensitivity indicating sensory filtering disruptions.•Different event-related potentials and behavioral measures can be used in humans and animal models to assess sensory filtering.•We here review evidence from clinical population and relevant animal models showing that sensory filtering disruptions are a robust feature of ASD and FXS.
Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics.
Tumors utilize aerobic glycolysis to support growth and invasion. However, the molecular mechanisms that link metabolism with invasion are not well understood. The nutrient sensor ...O-linked-β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) modifies intracellular proteins with N-acetylglucosamine. Cancers display elevated O-GlcNAcylation and suppression of O-GlcNAcylation inhibits cancer invasion and metastasis. Here, we show that the regulation of cancer invasion by OGT is dependent on the NAD
-dependent deacetylase SIRT1. Reducing O-GlcNAcylation elevates SIRT1 levels and activity in an AMPK (AMP-activated protein kinase α)-dependent manner. Reduced O-GlcNAcylation in cancer cells leads to SIRT1-mediated proteasomal degradation of oncogenic transcription factor FOXM1 in an MEK/ERK-dependent manner. SIRT1 is critical for OGT-mediated regulation of FOXM1 ubiquitination and reducing SIRT1 activity reverses OGT-mediated regulation of FOXM1. Moreover, we show that SIRT1 levels are required for OGT-mediated regulation of invasion and metastasis in breast cancer cells. Thus, O-GlcNAcylation is a central component linking metabolism to invasion and metastasis via an SIRT1/ERK/FOXM1 axis.
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