A global disorder of imprinting in the human female germ line

Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment

A Pycellerator Tutorial.

We present a tutorial on using Pycellerator for biomolecular simulations. Models are described in human readable (and editable) text files (UTF8 or ASCII) containing collections of reactions, assignments, initial conditions, function definitions, and rate constants. These models are then converted into a Python program that can optionally solve the system, e.g., as a system of differential equations using ODEINT, or be run by another program. The input language implements an extended version of the Cellerator arrow notation, including mass action, Hill functions, S-Systems, MWC, and reactions with user-defined kinetic laws. Simple flux balance analysis is also implemented. We will demonstrate the implementation and analysis of progressively more complex models, starting from simple mass action through indexed cascades. Pycellerator can be used as a library that is integrated into other programs, run as a command line program, or in iPython notebooks. It is implemented in Python 2.7 and available under an open source GPL license

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Perturbations of nuclear C*-algebras

Kadison and Kastler introduced a natural metric on the collection of all C*-subalgebras of the bounded operators on a separable Hilbert space. They conjectured that sufficiently close algebras are unitarily conjugate. We establish this conjecture when one algebra is separable and nuclear. We also consider one-sided versions of these notions, and we obtain embeddings from certain near inclusions involving separable nuclear C*-algebras. At the end of the paper we demonstrate how our methods lead to improved characterisations of some of the types of algebras that are of current interest in the classification programme.Comment: 45 page

Nanoclusters and nanolines: the effect of molybdenum oxide substrate stoichiometry on iron self-assembly

The growth of Fe nanostructures on the stoichiometric MoO₂/Mo(110) and oxygen-rich MoO₂+x /Mo(110) surfaces has been studied using low-temperature scanning tunnelling microscopy (STM) and density functional theory calculations. STM results indicate that at low coverage Fe nucleates on the MoO₂/Mo(110) surface, forming small, well-ordered nanoclusters of uniform size, each consisting of five Fe atoms. These five-atom clusters can agglomerate into larger nanostructures reflecting the substrate geometry, but they retain their individual character within the structure. Linear Fe nanocluster arrays are formed on the MoO₂/Mo(110) surface at room temperature when the surface coverage is greater than 0.6 monolayers. These nanocluster arrays follow the direction of the oxide rows of the strained MoO₂/Mo(110) surface. Slightly altering the preparation procedure of MoO₂/Mo(110) leads to the presence of oxygen adatoms on this surface. Fe deposition onto the oxygen-rich MoO₂+x /Mo(110) surface results in elongated nanostructures that reach up to 24 nm in length. These nanolines have a zigzag shape and are likely composed of partially oxidised Fe formed upon reaction with the oxygen-rich surface

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

Requirement for Abasic Endonuclease Gene Homologues in Arabidopsis Seed Development

Arabidopsis thaliana has three genes, Ape1L, Ape2, and Arp, that show homology to abasic (apurinic/apyrimidinic) endonuclease genes of bacterial, yeast, or animal cells. In bacteria, yeast, and animals, abasic endonucleases function in base excision repair of oxidized and other modified DNA bases. Here we report that plants with knock-out mutations in any one of Ape1L, Ape2, or Arp show no apparent differences from wild type in growth rate, growth habit, and fertility. However, coincident knock-out mutations in Ape1L and Ape2 are lethal and lead to abortion of developing embryos. Mutations of Arp are not deleterious, even in combination with one of the other two mutations. The results are consistent with the interpretation that the process of base excision repair, involving at least one intact copy of Ape1L or Ape2, is required in the process of embryogenesis

Deep Neural Networks for Automatic Classification of Anesthetic-Induced Unconsciousness

Despite the common use of anesthetics to modulate consciousness in the clinic, brain-based monitoring of consciousness is uncommon. We com-bined electroencephalographic measurement of brain activity with deep neural networks to automatically discriminate anesthetic states induced by propofol. Our results with leave-one-participant-out-cross-validation show that convolutional neural networks significantly outperform multilayer perceptrons in discrimination accuracy when working with raw time series. Perceptrons achieved comparable accuracy when provided with power spec-tral densities. These findings highlight the potential of deep convolutional networks for completely automatic extraction of useful spatio-temporo-spectral features from human EEG

MRC ORACLE Children Study. Long term outcomes following prescription of antibiotics to pregnant women with either spontaneous preterm labour or preterm rupture of the membranes

BACKGROUND: The Medical Research Council (MRC) ORACLE trial evaluated the use of co-amoxiclav 375 mg and/or erythromycin 250 mg in women presenting with preterm rupture of membranes (PROM) ORACLE I or in spontaneous preterm labour (SPL) ORACLE II using a factorial design. The results showed that for women with a singleton baby with PROM the prescription of erythromycin is associated with improvements in short term neonatal outcomes, although co-amoxiclav is associated with prolongation of pregnancy, a significantly higher rate of neonatal necrotising enterocolitis was found in these babies. Prescription of erythromycin is now established practice for women with PROM. For women with SPL antibiotics demonstrated no improvements in short term neonatal outcomes and are not recommended treatment. There is evidence that both these conditions are associated with subclinical infection so perinatal antibiotic administration may reduce the risk of later disabilities, including cerebral palsy, although the risk may be increased through exposure to inflammatory cytokines, so assessment of longer term functional and educational outcomes is appropriate. METHODS: The MRC ORACLE Children's Study will follow up UK children at age 7 years born to 4809 women with PROM and the 4266 women with SPL enrolled in the earlier ORACLE trials. We will use a parental questionnaire including validated tools to assess disability and behaviour. We will collect the frequency of specific medical conditions: cerebral palsy, epilepsy, respiratory illness including asthma, diabetes, admission to hospital in last year and other diseases, as reported by parents. National standard test results will be collected to assess educational attainment at Key Stage 1 for children in England. DISCUSSION: This study is designed to investigate whether or not peripartum antibiotics improve health and disability for children at 7 years of age. TRIAL REGISTRATION: The ORACLE Trial and Children Study is registered in the Current Controlled Trials registry. ISCRTN 52995660

Bench-to-bedside review : targeting antioxidants to mitochondria in sepsis

Peer reviewedPublisher PD