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Biomedical subjects

S Sachdev

Publications and source records attributed to S Sachdev.

At least 19 recordsLinked to original sources

PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies.

The Wnt-responsive transcription factor LEF1 can activate transcription in association with beta-catenin and repress transcription in association with Groucho. In search of additional regulatory mechanisms of LEF1 function, we identified the protein inhibitor of activated STAT, PIASy, as a novel interaction partner of LEF1. Coexpression of PIASy with LEF1 results in potent repression of LEF1 activity and in covalent modification of LEF1 with SUMO. PIASy markedly stimulates the sumoylation of LEF1 and multiple other proteins in vivo and functions as a SUMO E3 ligase for LEF1 in a reconstituted system in vitro. Moreover, PIASy binds to nuclear matrix-associated DNA sequences and targets LEF1 to nuclear bodies, suggesting that PIASy-mediated subnuclear sequestration accounts for the repression of LEF1 activity.

Animals↗

Spin-ordering quantum transitions of superconductors in a magnetic field.

We argue that recent neutron scattering measurements by Lake et al. [Science 291, 1759 (2001)] of the spin excitation spectrum of La(2-delta)Sr(delta)CuO4 in a magnetic field can be understood in terms of proximity to a phase with co-existing superconductivity and spin density wave order. We present a general theory for such quantum transitions, and argue that their low energy spin fluctuations are controlled by a singular correction from the superflow kinetic energy, acting in the region outside the vortex cores. We propose numerous experimental tests of our theory.

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Spin orthogonality catastrophe in two-dimensional antiferromagnets and superconductors.

We compute the spectral function of a spin S hole injected into a two-dimensional antiferromagnet or superconductor in the vicinity of a magnetic quantum critical point. We show that, near Van Hove singularities, the problem maps onto that of a static vacancy carrying excess spin S. The hole creation operator is characterized by a new boundary anomalous dimension and a vanishing quasiparticle residue at the critical point. We discuss possible relevance to photoemission spectra of cuprate superconductors near the antinodal points.

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Impurity in a d-wave superconductor: Kondo effect and STM spectra.

We present a theory for recent STM studies of Zn impurities in the superconductor Bi2Sr2CaCu2O8+delta, using insights from NMR experiments which show that there is a net S = 1/2 moment on the Cu ions near the Zn. We argue that the Kondo spin dynamics of this moment is the origin of the low bias peak in the differential conductance, rather than a resonance in a purely potential scattering model. The spatial and energy dependence of the STM spectra of our model can also fit the experiments.

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Quantum phase transitions in d-wave superconductors

Motivated by the strong, low temperature damping of nodal quasiparticles observed in some cuprate superconductors, we study quantum phase transitions in d(x(2)-y(2)) superconductors with a spin-singlet, zero momentum, fermion bilinear order parameter. We present a complete, group-theoretic classification of such transitions into seven distinct cases (including cases with nematic order) and analyze fluctuations by the renormalization group. We find that only two, the transitions to d(x(2)-y(2))+is and d(x(2)-y(2))+id(xy) pairing, possess stable fixed points with universal damping of nodal quasiparticles; the latter leaves the gapped quasiparticles along (1,0), (0,1) essentially undamped.

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Mean field theory of a quantum heisenberg spin glass

A full mean-field solution of a quantum Heisenberg spin-glass model is presented in a large- N limit. A spin-glass transition is found for all values of the spin S. The quantum critical regime associated with the quantum transition at S = 0 and the various regimes in the spin-glass phase at high spin are analyzed. The specific heat is shown to vanish linearly with temperature. In the spin-glass phase, intriguing connections between the equilibrium properties of the quantum problem and the out-of-equilibrium dynamics of classical models are pointed out.

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Thermally fluctuating superconductors in two dimensions

In many two-dimensional superconducting systems, such as Josephson-junction arrays, granular superconducting films, and the high-temperature superconductors, it appears that the electrons bind into Cooper pairs below a pairing temperature (T(P)) that is well above the Kosterlitz-Thouless temperature (T(KT)) the temperature below which there is long-range superconducting order). The electron dynamics at temperatures between T(KT) and T(P) involve a complex interplay of thermal and quantum fluctuations, for which no quantitative theory exists. Here we report numerical results for this region, by exploiting its proximity to a T = 0 superconductor-insulator quantum phase transition. This quantum critical point need not be experimentally accessible for our results to apply. We characterize the static, thermodynamic properties by a single dimensionless parameter, gamma(T). Quantitative and universal results are obtained for the frequency dependence of the conductivity, which are dependent only upon gamma(T) and fundamental constants of nature.

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Quantum criticality: competing ground states in low dimensions

Small changes in an external parameter can often lead to dramatic qualitative changes in the lowest energy quantum mechanical ground state of a correlated electron system. In anisotropic crystals, such as the high-temperature superconductors where electron motion occurs primarily on a two-dimensional square lattice, the quantum critical point between two such lowest energy states has nontrivial emergent excitations that control the physics over a significant portion of the phase diagram. Nonzero temperature dynamic properties near quantum critical points are described, using simple theoretical models. Possible quantum phases and transitions in the two-dimensional electron gas on a square lattice are discussed.

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Nuclear import of IkappaBalpha is accomplished by a ran-independent transport pathway.

The inhibitor of kappa B alpha (IkappaBalpha) protein is able to shuttle between the cytoplasm and the nucleus. We have utilized a combination of in vivo and in vitro approaches to provide mechanistic insight into nucleocytoplasmic shuttling by IkappaBalpha. IkappaBalpha contains multiple functional domains that contribute to shuttling of IkappaBalpha between the cytoplasm and the nucleus. Nuclear import of IkappaBalpha is mediated by the central ankyrin repeat domain. Similar to previously described nuclear import pathways, nuclear import of IkappaBalpha is temperature and ATP dependent and is blocked by a dominant-negative mutant of importin beta. However, in contrast to classical nuclear import pathways, nuclear import of IkappaBalpha is independent of soluble cytosolic factors and is not blocked by the dominant-negative RanQ69L protein. Nuclear export of IkappaBalpha is mediated by an N-terminal nuclear export sequence. Nuclear export of IkappaBalpha requires the CRM1 nuclear export receptor and is blocked by the dominant-negative RanQ69L protein. Our results are consistent with a model in which nuclear import of IkappaBalpha is mediated through direct interactions with components of the nuclear pore complex, while nuclear export of IkappaBalpha is mediated via a CRM1-dependent pathway.

Biological Transport↗

Quantum impurity in a nearly critical two-dimensional antiferromagnet

The spin dynamics of an arbitrary localized impurity in an insulating two-dimensional antiferromagnet, across the host transition from a paramagnet with a spin gap to a Neel state, is described. The impurity spin susceptibility has a Curie-like divergence at the quantum-critical coupling, but with a universal effective spin that is neither an integer nor a half-odd integer. In the Neel state, the transverse impurity susceptibility is a universal number divided by the host spin stiffness (which determines the energy cost to slow twists in the orientation of the Neel order). These and numerous other results for the thermodynamics, Knight shift, and magnon damping have important applications in experiments on layered transition metal oxides.

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Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences.

The ability of the IkappaB alpha protein to sequester dimeric NF-kappaB/Rel proteins in the cytoplasm provides an effective mechanism for regulating the potent transcriptional activation properties of NF-kappaB/Rel family members. IkappaB alpha can also act in the nucleus as a postinduction repressor of NF-kappaB/Rel proteins. The mechanism by which IkappaB alpha enters the nucleus is not known, as IkappaB alpha lacks a discernible classical nuclear localization sequence (NLS). We now report that nuclear localization of IkappaB alpha is mediated by a novel nuclear import sequence within the second ankyrin repeat. Deletion of the second ankyrin repeat or alanine substitution of hydrophobic residues within the second ankyrin repeat disrupts nuclear localization of IkappaB alpha. Furthermore, a region encompassing the second ankyrin repeat of IkappaB alpha is able to function as a discrete nuclear import sequence. The presence of a discrete nuclear import sequence in IkappaB alpha suggests that cytoplasmic sequestration of the NF-kappaB/Rel-IkappaB alpha complex is a consequence of the mutual masking of the NLS within NF-kappaB/Rel proteins and the import sequence within IkappaB alpha. Nuclear import may be a conserved property of ankyrin repeat domains (ARDs), as the ARDs from two other ARD-containing proteins, 53BP2 and GABPbeta, are also able to function as nuclear import sequences. We propose that the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences.

Ankyrins↗

Loss of IkappaB alpha-mediated control over nuclear import and DNA binding enables oncogenic activation of c-Rel.

The IkappaB alpha protein is able both to inhibit nuclear import of Rel/NF-kappaB proteins and to mediate the export of Rel/NF-kappaB proteins from the nucleus. We now demonstrate that the c-Rel-IkappaB alpha complex is stably retained in the cytoplasm in the presence of leptomycin B, a specific inhibitor of Crm1-mediated nuclear export. In contrast, leptomycin B treatment results in the rapid and complete relocalization of the v-Rel-IkappaB alpha complex from the cytoplasm to the nucleus. IkappaB alpha also mediates the rapid nuclear shuttling of v-Rel in an interspecies heterokaryon assay. Thus, continuous nuclear export is required for cytoplasmic retention of the v-Rel-IkappaB alpha complex. Furthermore, although IkappaB alpha is able to mask the c-Rel-derived nuclear localization sequence (NLS), IkappaB alpha is unable to mask the v-Rel-derived NLS in the context of the v-Rel-IkappaB alpha complex. Taken together, our results demonstrate that IkappaB alpha is unable to inhibit nuclear import of v-Rel. We have identified two amino acid differences between c-Rel and v-Rel (Y286S and L302P) which link the failure of IkappaB alpha to inhibit nuclear import and DNA binding of a mutant c-Rel protein to oncogenesis. Our results support a model in which loss of IkappaB alpha-mediated control over c-Rel leads to oncogenic activation of c-Rel.

Amino Acid Sequence↗

A threshold nuclear level of the v-Rel oncoprotein is required for transformation of avian lymphocytes.

The net distribution of eukaryotic transcription factors between the cytoplasm and the nucleus provides an effective mechanism for controlling gene expression. We have utilized cis-acting signals for both nuclear import and nuclear export to experimentally manipulate the distribution of the v-Rel oncoprotein between the nucleus and the cytoplasm. The respective abilities of the v-Rel oncoprotein to localize to the nucleus in chicken embryo fibroblasts, to activate kappaB-dependent transcription in yeast, and to transform avian lymphoid cells were each markedly reduced by the fusion of a cis-acting nuclear export signal onto v-Rel. Our results demonstrate that a threshold nuclear function of v-Rel is required for manifestation of its oncogenic properties. In contrast, while increased expression of the avian IkappaB-alpha protein was able to prevent nuclear localization of v-Rel in chicken embryo fibroblasts, coexpression of IkappaB-alpha with v-Rel in the target cell for v-Rel mediated transformation did not reduce the ability of v-Rel to transform avian lymphoid cells or alter the distribution of v-Rel between the nucleus and the cytoplasm in v-Rel-transformed cells. Our results suggest that the ability of IkappaB-alpha to inhibit nuclear localization of v-Rel is affected by cell-type specific differences between fibroblasts and lymphoid cells.

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