Epigenetic modulation of intestinal homeostasis and tumorigenesis by Brm SWI/SNF chromatin remodelling factor

SWI/SNF chromatin remodelling complexes are one of the well-characterized cellular machineries capable of regulation of gene expression. Numerous lines of evidence indicate that SWI/SNF complexes are involved in a wide range of cellular processes and the maintenance of homeostasis whereas aberrant expression of those proteins contributes towards cancer development. Colorectal cancer remains one of the most clinically significant cancers due to its high incidence in developed countries and previous studies have demonstrated that SWI/SNF complexes are aberrantly regulated in a significant proportion of patients with this disease. However, whilst the sequence of molecular events leading to CRC has been well-established, the role of SWI/SNF chromatin remodelling complex ATPase subunits Brm and its paralogue Brg1 in the colorectal tumorigenesis remains elusive. The chromatin remodelling catalytic subunit Brm has been found to interact with the Notch pathway effectors ICD-22 and CBF-1 and also to be necessary for expression of the Wnt target gene CD44 and for Rb-mediated cell cycle arrest. In this PhD thesis, the potential of Brm to modulate Wnt-driven intestinal tumorigenesis was addressed. Initially, a murine model carrying constitutively deleted Brm was used to assess the consequences of this loss on homeostasis of the small intestinal and colonic epithelia. The effects of Brm deficiency were also examined in the context of Wnt-activated epithelium via conditional loss of Apc. Additionally, the effect of concomitant loss of Brm and Brg1 was addressed in the contexts of both normal homeostasis and aberrant Wnt signalling. The results presented here demonstrate that Brm plays an important role in the small intestine by regulating the distribution of proliferating cells and cell fate decisions mediated through Notch pathway effectors. Furthermore, Brm deficiency was found to modulate intestinal phenotype of Wnt activation through the attenuation of the Wnt transcriptional programme and the suppressed expression of the intestinal stem cell marker Olfm4. Thus while Brg1 has been widely characterized as a bone fide tumour suppressor, the function of Brm continues to remain elusive especially in the light of contrasting effects co-mediated by Brm on proliferation, differentiation and gene expression. Taken together, these results elucidate the tissue-specific role of Brm, the catalytic subunit of SWI/SNF chromatin remodelling complex, on both normal intestinal homeostasis and acute activation of Wnt pathway while the extent of these Brm-dependent effects depend upon the gradient of Wnt signalling throughout the epithelium of small and large intestine

Influence of environment exposures on the frequency of contact allergies in children and adolescents

Contact allergy is detected in every second child with the symptoms of chronic or recurrent eczema, and in every third child the final diagnosis is allergic contact dermatitis. Haptens responsible for the majority of contact sensitizations in children are substances ubiquitous in our environment, e.g. metals, preservatives, fragrances, propolis, and balsam of Peru. Much concern is provoked by the higher rates of sensitization to fragrances in younger children, compared to adolescents, which may be attributed to the higher exposure nowadays of infants and children to fragrant products. On the other hand, a limitation of exposure to the preservatives thimerosal and Kathon CG has resulted in decreased rates of sensitization to these haptens. Altogether, these observations demonstrate that the rates of contact sensitizations in children reflect changes in their environment, and limitations imposed on the use of haptens with strong sensitizing properties, may be an effective tool in the prevention of contact allergy

Hydrogen spillover in tungsten oxide bronzes as observed by broadband neutron spectroscopy

Funding: This research was funded by the UK Science and Technology Facilities Council via direct access proposal (RB1920033, VESUVIO).Hydrogen spillover is an elusive process, and its characterization, using experimental probes and ab initio modeling, poses a serious challenge. In this work, the nuclear quantum dynamics of hydrogen in a palladium-decorated cubic polymorph of tungsten oxide, Pd/cWO3, are characterized by the technique of neutron Compton scattering augmented by ab initio harmonic lattice modeling. The deeply penetrating nature of the neutron scattering process, the lack of spectroscopic selection rules, the inherent high sensitivity to hydrogen, the high energy and momentum resolution for hydrogen, and the mass selectivity of the technique render the neutron Compton scattering a very potent and unique tool for investigating the local dynamics of hydrogen species in bulk matrices. The total neutron Compton scattering response of hydrogen is described in terms of the hydrogen momentum distribution. The distribution is deconvoluted under the assumption of three pools of hydrogen with distinctly different nuclear quantum dynamical behavior: (i) hydrogen-terminated beta-palladium hydride, (ii) hydrogen in acid centers (OH+ groups) on the surface of the cubic phase of tungsten oxide, and (iii) quasi-free atomic hydrogen inside the saturated hydrogen bronze resulting from the spillover process. The ab initio modeling of lattice dynamics yields theoretical predictions for the values of the widths of proton momentum distributions in the first two hydrogen pools, which allows for obtaining the contribution and the width of the momentum distribution of the quasi-free atomic hydrogen resulting from the hydrogen spillover process. The analysis reveals that the local binding strength of the quasi-free hydrogen is characterized by the values of nuclear momentum distribution width, nuclear kinetic energy, and force constant of the underlying potential of the mean force close to those of free, unconstrained hydrogen atomic species in a gas of non-interacting particles described by the Maxwell–Boltzmann distribution. Moreover, this picture of the local dynamics of the quasi-free hydrogen is consistent with the proton polaron model of hydrogen-induced coloration of bulk hydrogenated WO3.Publisher PDFPeer reviewe

Molecular structure refinement by direct fitting of atomic coordinates to experimental ESR spectra

An attempt is made to bypass spectral analysis and fit internal coordinates of radicals directly to experimental liquid- and solid-state electron spin resonance (ESR) spectra. We take advantage of the recently introduced large-scale spin dynamics simulation algorithms and of the fact that the accuracy of quantum mechanical calculations of ESR parameters has improved to the point of quantitative correctness. Partial solutions are offered to the local minimum problem in spectral fitting and to the problem of spin interaction parameters (hyperfine couplings, chemical shifts, etc.) being very sensitive to distortions in molecular geometry.Comment: Submitted for publicatio

Investigation of the Dynamic Behaviour of H2 and D2 in a Kinetic Quantum Sieving System

Porous organic cages (POCs) are nanoporous materials composed of discrete molecular units that have uniformly distributed functional pores. The intrinsic porosity of these structures can be tuned accurately at the nanoscale by altering the size of the porous molecules, particularly to an optimal size of 3.6 Å, to harness the kinetic quantum sieving effect. Previous research on POCs for isotope separation has predominantly centered on differences in the quantities of adsorbed isotopes. However, nuclear quantum effects also contribute significantly to the dynamics of the sorption process, offering additional opportunities for separating H2 and D2 at practical operational temperatures. In this study, our investigations into H2 and D2 sorption on POC samples revealed a higher uptake of D2 compared to that of H2 under identical conditions. We employed quasi-elastic neutron scattering to study the diffusion processes of D2 and H2 in the POCs across various temperature and pressure ranges. Additionally, neutron Compton scattering was utilized to measure the values of the nuclear zero-point energy of individual isotopic species in D2 and H2. The results indicate that the diffusion coefficient of D2 is approximately one-sixth that of H2 in the POC due to the nuclear quantum effect. Furthermore, the results reveal that at 77 K, D2 has longer residence times compared to H2 when moving from pore to pore. Consequently, using the kinetic difference of H2 and D2 in a porous POC system enables hydrogen isotope separation using a temperature or pressure swing system at around liquid nitrogen temperatures

Translational and rotational mobility of methanol-d(4) molecules in NaX and NaY zeolite cages: A deuteron NMR investigation

Nuclear magnetic resonance (NMR) provides means to investigate molecular dynamics at every state of matter. Features characteristic for the gas phase, liquid-like layers and immobilized methanol-d(4) molecules in NaX and NaY zeolites were observed in the temperature range from 300 K down to 20 K. The NMR spectra at low temperature are consistent with the model in which molecules are bonded at two positions: horizontal (methanol oxygen bonded to sodium cation) and vertical (hydrogen bonding of hydroxyl deuteron to zeolite framework oxygen). Narrow lines were observed at high temperature indicating an isotropic reorientation of a fraction of molecules. Deuteron spin-lattice relaxation gives evidence for the formation of trimers, based on observation of different relaxation rates for methyl and hydroxyl deuterons undergoing isotropic reorientation. Internal rotation of methyl groups and fixed positions of hydrogen bonded hydroxyl deuterons in methyl trimers provide relaxation rates observed experimentally. A change in the slope of the temperature dependence of both relaxation rates indicates a transition from the relaxation dominated by translational motion to prevailing contribution of reorientation. Trimers undergoing isotropic reorientation disintegrate and separate molecules become localized on adsorption centers at 166.7 K and 153.8 K for NaX and NaY, respectively, as indicated by extreme broadening of deuteron NMR spectra. Molecules at vertical position remain localized up to high temperatures. That indicates the dominating role of the hydrogen bonding. Mobility of single molecules was observed for lower loading (86 molecules/uc) in NaX. A direct transition from translation to localization was observed at 190 K. (C) 2012 Elsevier Inc. All rights reserved

Pollution related effects on immune function and stress in a free-living population of pied flycatcher Ficedula hypoleuca

We investigated whether exposure to heavy metal pollution affected the immune function of individuals in a free living population of a small insectivorous passerine bird, the pied flycatcher Ficedula hypoleuca. We measured humoral immune responses in two study areas: a polluted area in the vicinity of a copper smelter and a control area far from the smelter. Plasma corticosterone level and blood heterophil/lymphocyte ratio (H/L) were used as more general physiological measures of stress. The immune response of F hypoleuca was not suppressed by pollution stress. In contrast, we found that F hypoleuca males showed stronger Immoral immune responses to a novel antigen (tetanus toxoid) in the polluted environment than in the unpolluted one. After the immunization of males, numbers of lymphocytes rose significantly more in the polluted area, leading to a smaller H/L ratio than in males from the control area. Females showed no pollution related effects on their immune responses. Corticosterone levels of males and nestlings were not related to pollution levels. Nestlings showed somewhat higher H/L ratios and lower fledging success in the polluted area, both factors indicating increased stress levels in a polluted area. Our results suggest that Immoral immune response of male F hypoleuca may be enhanced under moderate levels of heavy metal Pollution. Enhanced immune function may, however, also be costly for birds and the higher humoral immune responses in polluted areas may thus have negative effects on the birds' breeding performance and survival

Gamma background characterization on VESUVIO: before and after the moderator upgrade

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