3,133 research outputs found
The Role of the SWI/SNF Component INI1 in Mammalian Development and Tumorigenesis: a Dissertation
In vivo DNA is compacted tightly, via its association with histones and non-histone proteins, into higher-order chromatin structure. In this state, the DNA is refractory to the cellular factors that require access to DNA. The repressive nature of chromatin is alleviated in part by the action enzymes that modify chromatin structure. There are two major groups of chromatin modifying enzymes: those that post-translationally modify histones by the addition of small chemical moieties and those that utilize the energy derived from ATP hydrolysis to physically disrupt chromatin structure. The SWI/SNF enzyme belongs to this latter group.
The SWI/SNF complex was identified originally in yeast. Several of its subunits are required for the expression of a subset of inducible genes. The ATPase activity is provided by the SWI2/SNF2 protein. In mammals, there are two biochemically separable SWI/SNF complexes that contain either BRG1 or BRM, both homologs of yeast SWI2/SNF2. The yeast and mammalian SWI/SNF complexes are able to disrupt the Dnase I digestion pattern of in vitro assembled mononucleosomes and arrays, as well as facilitate the accessibility of restriction nucleases and transcription factors. The mechanism by which SWI/SNF functions has yet to be elucidated.
SNF5 is a component of the yeast SWI/SNF complex. It is required for sucrose fermentation and mating type switching. The mammalian homolog of Snf5 is SNF5/INI1. SNF5/INI1 was identified simultaneously by two groups as a protein that shares homology with Snf5 and via a yeast two hybrid assay as a protein that interacts with HIV integrase (INtegrase Interactor). INI1 is a component of all mammalian SWI/SNF complexes purified to date.
In humans, mutations and/or deletions in INI1 are associated with a variety of cancers, including malignant rhabdoid tumors, choroid plexus carcinomas, medullablastomas, primitive neuralectodermal tumors, and some cases of leukemia. Furthermore, constitutional mutations within INI1in individuals presenting with these tumors support the role of INI1 as a tumor suppressor.
In this thesis, we show that Ini1 also functions as a tumor suppressor in mice. Approximately 20% of mice heterozygous for Ini1 present with tumors. Most of these tumors are undifferentiated or poorly differentiated sarcomas with variable rhabdoid features. All tumors examined to date show loss of heterozygosity at the Ini1 locus. We also show that Ini1 is essential for embryonic development. Mice homozygous-null for Ini1die between days 4 and 5.5 post-fertilization due to an inability to adhere to their substratum, form trophectoderm, and expand their inner cell mass.
We further characterize the function of Ini1 in tumor suppression by generating mice heterozygous for both Ini1 and either Rb or p53. While heterozygosity at the Ini1 locus appears to have no effect on the rate of tumorigenesis in Rb-heterozygous mice, many of the tumors arising in compound heterozygous mice present with an altered morphology. This finding suggests that Ini1 may contribute to tumor progression due to loss of Rb. In contrast, mice compound heterozygous for Ini1 and p53 show a marked reduction in the rate of tumorigenesis compared to p53-heterozygous mice. Furthermore, the tumor spectrum is altered in these compound heterozygous mice. These findings suggest that Ini1 may function normally to repress p53 activity.
Lastly, we show that expression of the Ini1 tumor suppressor itself is regulated tightly. Tissues and cells heterozygous for Ini1 express roughly equivalent levels of Ini1 protein and mRNA as their wild-type counterparts. We further show that this compensation is mediated by an increase in the rate of transcription from the wild-type Ini1 allele. Moreover, when exogenous Ini1 is introduced into Ini1-heterozygous cells, expression from the Ini1 promoter is reduced. These data indicate that a compensatory mechanism exists to ensure that the steady-state levels of Ini1 are constant.
In summary, research detailed in this thesis has contributed to our understanding of the regulation of Ini1 as well as the role this protein plays in mammalian development and tumor suppression
Quasiparticle Breakdown and Spin Hamiltonian of the Frustrated Quantum Pyrochlore YbTiO in Magnetic Field
The frustrated pyrochlore magnet YbTiO has the remarkable
property that it orders magnetically, but has no propagating magnons over wide
regions of the Brillouin zone. Here we use inelastic neutron scattering to
follow how the spectrum evolves in cubic-axis magnetic fields. At high fields
we observe in addition to dispersive magnons also a two-magnon continuum, which
grows in intensity upon reducing the field and overlaps with the one-magnon
states at intermediate fields leading to strong renormalization of the
dispersion relations, and magnon decays. Using heat capacity measurements we
find that the low and high field regions are smoothly connected with no sharp
phase transition, with the spin gap increasing monotonically in field. Through
fits to an extensive data set we re-evaluate the spin Hamiltonian finding
dominant quantum exchange terms, which we propose are responsible for the
anomalously strong fluctuations and quasiparticle breakdown effects observed at
low fields.Comment: 5 pages main text + 19 pages supplemental materia
Excitations in the quantum paramagnetic phase of the quasi-one-dimensional Ising magnet CoNbO in a transverse field: Geometric frustration and quantum renormalization effects
The quasi-one-dimensional (1D) Ising ferromagnet CoNbO has recently
been driven via applied transverse magnetic fields through a continuous quantum
phase transition from spontaneous magnetic order to a quantum paramagnet, and
dramatic changes were observed in the spin dynamics, characteristic of weakly
perturbed 1D Ising quantum criticality. We report here extensive single-crystal
inelastic neutron scattering measurements of the magnetic excitations
throughout the three-dimensional (3D) Brillouin zone in the quantum
paramagnetic phase just above the critical field to characterize the effects of
the finite interchain couplings. In this phase, we observe that excitations
have a sharp, resolution-limited line shape at low energies and over most of
the dispersion bandwidth, as expected for spin-flip quasiparticles. We map the
full bandwidth along the strongly dispersive chain direction and resolve clear
modulations of the dispersions in the plane normal to the chains,
characteristic of frustrated interchain couplings in an antiferromagnetic
isosceles triangular lattice. The dispersions can be well parametrized using a
linear spin-wave model that includes interchain couplings and further neighbor
exchanges. The observed dispersion bandwidth along the chain direction is
smaller than that predicted by a linear spin-wave model using exchange values
determined at zero field, and this effect is attributed to quantum
renormalization of the dispersion beyond the spin-wave approximation in fields
slightly above the critical field, where quantum fluctuations are still
significant.Comment: 11 pages, 6 figures. Updated references. Minor changes to text and
figure
The Psychosomatic Practice.
There is increasing awareness of the limitations of the disease-oriented approach in medical care. The primary goal of psychosomatic medicine is to correct this inadequacy by incorporation of innovative operational strategies into clinical practice. Psychosomatic practice can be recognized by 2 distinctive features: the holistic approach to patient management (encompassing psychosocial factors) and the clinical model of reasoning (which reflects a multifactorial frame of reference). A basic psychosomatic assumption is the consideration of patients as partners in managing disease. The partnership paradigm includes collaborative care (a patient-physician relationship in which physicians and patients make health decisions together) and implementation of self-management (a plan that provides patients with problem-solving skills to enhance their self-efficacy). Pointing to strategies that focus on individual needs may improve patient quality of life and final outcomes
Exotic magnetism on the quasi-FCC lattices of the double perovskites LaNaBO (B Ru, Os)
We find evidence for long-range and short-range ( 70 \AA~at 4 K)
incommensurate magnetic order on the quasi-face-centered-cubic (FCC) lattices
of the monoclinic double perovskites LaNaRuO and LaNaOsO
respectively. Incommensurate magnetic order on the FCC lattice has not been
predicted by mean field theory, but may arise via a delicate balance of
inequivalent nearest neighbour and next nearest neighbour exchange
interactions. In the Ru system with long-range order, inelastic neutron
scattering also reveals a spin gap 2.75 meV. Magnetic
anisotropy is generally minimized in the more familiar octahedrally-coordinated
systems, so the large gap observed for LaNaRuO may result from
the significantly enhanced value of spin-orbit coupling in this
material.Comment: 5 pages, 4 figure
Effect of Mn substitution by Ga on the optical properties of a metallic manganite
In a metallic manganite like La(2/3)Sr(1/3)MnO(3), the substitution of Mn(+3)
by Ga(+3) dilutes the ferromagnetic order and locally cancels the Jahn-Teller
distortion, without heavily affecting the crystal structure. One can thus
follow the changes in the charge dynamics induced by Ga, until the
ferro-metallic manganite is turned into an insulator. Here this phenomenon is
studied in detail through the infrared reflectivity of five samples of
La(2/3)Sr(1/3)Mn(1-x)Ga(x)O(3), with x increasing from 0 to 0.30 and for 50 < T
< 320 K. A simple model which links the measured optical parameters to the
magnetization M(x, T) well describes the behavior of the plasma frequency, the
scattering rate, and the mid-infrared absorption along the metal-to-insulator
transition.Comment: 8 pages including 7 figure
Observation of charge-density-wave excitations in manganites
In the optical conductivity of four different manganites with commensurate
charge order (CO), strong peaks appear in the meV range below the ordering
temperature T_{CO}. They are similar to those reported for one-dimensional
charge density waves (CDW) and are assigned to pinned phasons. The peaks and
their overtones allow one to obtain, for La{1-n/8}Ca{n/8}$MnO{3} with n = 5, 6,
the electron-phonon coupling, the effective mass of the CO system, and its
contribution to the dielectric constant. These results support a description of
the CO in La-Ca manganites in terms of moderately weak-coupling and of the CDW
theory.Comment: To be published on Phys. Rev. Let
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