A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection.This work was supported by the Australian Research Council (DP0771859) and the National Health and Medical Research Council (#459412, #635510)

Ligand coordination modulates reductive elimination from aluminium(III)

Oxidative addition to low-valent main-group centres is a major class of reactivity for these species. Here, we present a mechanistic study of the much rarer reverse process – reductive elimination – in Al(iii) systems, and unravel ligand effects in this process.</p

Structure of the Reduced Copper Active Site in Pre-Processed Galactose Oxidase: Ligand Tuning for One-Electron O2 Activation in Cofactor Biogenesis

Galactose oxidase (GO) is a copper-dependent enzyme that accomplishes 2e- substrate oxidation by pairing a single copper with an unusual cysteinylated tyrosine (Cys-Tyr) redox cofactor. Previous studies have demonstrated that the post-translational biogenesis of Cys-Tyr is copper- and O2-dependent, resulting in a self-processing enzyme system. To investigate the mechanism of cofactor biogenesis in GO, the active-site structure of Cu(I)-loaded GO was determined using X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopy, and density-functional theory (DFT) calculations were performed on this model. Our results show that the active-site tyrosine lowers the Cu potential to enable the thermodynamically unfavorable 1e- reduction of O2, and the resulting Cu(II)-O2¿- is activated toward H atom abstraction from cysteine. The final step of biogenesis is a concerted reaction involving coordinated Tyr ring deprotonation where Cu(II) coordination enables formation of the Cys-Tyr cross-link. These spectroscopic and computational results highlight the role of the Cu(I) in enabling O2 activation by 1e- and the role of the resulting Cu(II) in enabling substrate activation for biogenesis

Bis{(Z)-[(E)-2-(pyridin-2-ylmethylidene)hydrazin-1-ylidene][(pyridin-2-yl) methylsulfanyl]methanethiolato}nickel(II)

The title compound, [Ni(C13H11N4S 2)2], was obtained by the reaction of S-2- picolyldithiocarbazate and pyridine-2-carbaldehyde with nickel(II) acetate. The NiII atom is located on a twofold rotation axis and is bonded to four N atoms at distances of 2.037 (8) and 2.109 (9) Å, and to two S atoms at a distance of 2.406 (3) Å, leading to a distorted octahedral coordination. The angle between the mean planes of the coordinating moieties of the two symmetry-related tridentate ligands is 83.3 (2)°. In the crystal, complex molecules are linked by weak C - H⋯S hydrogen bonds, π-π interactions between the pyridine rings [centroid-centroid distance = 3.775 (9) Å] and C - H⋯π interactions. The hydrogen-bonding interactions lead to the formation of layers parallel to (010); π-π interactions link these layers into a three-dimensional network

'This is what democracy looks like' : New Labour's blind spot and peripheral vision

New Labour in government since 1997 has been roundly criticized for not possessing a clear, coherent and consistent democratic vision. The absence of such a grand vision has resulted, from this critical perspective, in an absence of 'joined-up' thinking about democracy in an evolving multi-level state. Tensions have been all too apparent between the government's desire to exert central direction - manifested in its most pathological form as 'control freakery' - and its democratising initiatives derived from 'third-way' obsessions with 'decentralising', 'empowering' and 'enabling'. The purpose of this article is to examine why New Labour displayed such apparently impaired democratic vision and why it appeared incapable of conceiving of democratic reform 'in the round'. This article seeks to explain these apparent paradoxes, however, through utilising the notion of 'macular degeneration'. In this analysis, the perceived democratic blind spot of New Labour at Westminster is connected to a democratic peripheral vision, which has envisaged innovative participatory and decentred initiatives in governance beyond Westminster

Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression

Repeated inoculation with messenger RNA (mRNA) vaccines elicits immunoglobulin G4 (IgG4) antibody production. Such an increase in the concentration of specific and non-specific IgG4 antibodies allows the growth of some types of cancer by blocking the activation of effector immune cells. This work proposes the hypothesis that cancer growth may be indirectly promoted by increased concentrations of non-specific IgG4 antibodies by the following mechanisms: 1) IgG4 antibodies can bind to anti-tumor IgG1 antibodies and block their interaction with receptors located on effector cells, thus preventing the destruction of cancer cells, 2) IgG4 can interact with fragment crystallizable gamma receptor IIb (FcγRIIB) inhibitory receptors, thus reducing effector functions of innate immune cells, and 3) targeting of specific epitopes by IgG4 could be oncogenic by inducing the production of a microenvironment that can promote cancer development. This article reviews the supporting literature and suggests several experimental protocols to evaluate this hypothesis in the context of repeated inoculation with mRNA vaccines. Additionally, this work proposes some management options aimed at reducing the unfavorable molecular consequences that could mediate cancer development when encountering high concentrations of IgG4 antibodies

The distribution of satellites around massive galaxies at 1<z<3 in ZFOURGE/CANDELS: dependence on star formation activity

We study the statistical distribution of satellites around star-forming and quiescent central galaxies at 1<z<3 using imaging from the FourStar Galaxy Evolution Survey (ZFOURGE) and the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). The deep near-IR data select satellites down to $\log(M/M_\odot)>9$ at z<3. The radial satellite distribution around centrals is consistent with a projected NFW profile. Massive quiescent centrals, $\log(M/M_\odot)>10.78$, have $\sim$2 times the number of satellites compared to star-forming centrals with a significance of 2.7$\sigma$ even after accounting for differences in the centrals' stellar-mass distributions. We find no statistical difference in the satellite distributions of intermediate-mass quiescent and star-forming centrals, $10.48<\log(M/M_\odot)<10.78$. Comparing to the Guo2011 semi-analytic model, the excess number of satellites indicates that quiescent centrals have halo masses 0.3 dex larger than star-forming centrals, even when the stellar-mass distributions are fixed. We use a simple toy model that relates halo mass and quenching, which roughly reproduces the observed quenched fractions and the differences in halo mass between star-forming and quenched galaxies only if galaxies have a quenching probability that increases with halo mass from $\sim$0 for $\log(M_h/M_\odot)\sim$11 to $\sim$1 for $\log(M_h/M_\odot)\sim$13.5. A single halo-mass quenching threshold is unable to reproduce the quiescent fraction and satellite distribution of centrals. Therefore, while halo quenching may be an important mechanism, it is unlikely to be the only factor driving quenching. It remains unclear why a high fraction of centrals remain star-forming even in relatively massive halos.Comment: 19 pages, 17 figures, accepted by ApJ. Information on ZFOURGE can be found at http://zfourge.tamu.ed

Repetition Count Concurrent Validity of Various Garmin Wrist Watches During Light Circuit Resistance Training

Wearable technology and strength training with free weights are two of the top 5 fitness trends worldwide. However, minimal physiological research has been conducted on the two together and none have measured the accuracy of devices measuring repetition counts across exercises. PURPOSE: The purpose of this study was to determine the concurrent validity of four wrist-worn Garmin devices, Instinct (x2), Fenix 6 Pro, and Vivoactive 3, to record repetition counts while performing 4 different exercises during circuit resistance training. METHODS: Twenty participants (n=10 female, n=10 male; age: 23.2 ± 7.7 years) completed this study. Participants completed 4 circuits of 4 exercises (front squat, reverse lunge, push-ups, and shoulder press) using dumbbells at a light intensity with 1 set of 10 repetitions per exercise and 30 seconds rest between exercises and 1-1.5 min rest between circuits. Mean absolute percent error (MAPE, ≤10%) and Lin’s Concordance Coefficient (CCC, ρ≥0.7) were used to validate the device’s repetitions counts in all exercises compared to the criterion reference manual count. Dependent T-tests determined differences (p≤0.05). RESULTS: No devices were considered valid (meeting both the threshold for MAPE and CCC) for measuring repetition counts during front squats (MAPE range: 3.0-18.5% and CCC range: 0.27-0.68, p value range: 0.00-0.94), reverse lunge (MAPE range: 44.5-67.0% and CCC range: 0.19-0.31, p value range: 0.00-0.28), push-ups (MAPE range: 12.5-67.5% and CCC range: 0.10-0.34, p value range: 0.07-0.83), and shoulder press (MAPE range: 18.0-51.0% and CCC range: 0.11-0.43, p value range: 0.00-0.79) exercises. CONCLUSION: The wearable wrist-worn devices were not considered accurate for repetition counts and thus manual counting should be utilized. People who strength train using free weights will need to wait for either improved repetition counting algorithms or increased sensitivity of devices before this measure can be obtained with confidence