Biomedical subjects

N R Cooper

Publications and source records attributed to N R Cooper.

At least 19 recordsLinked to original sources

PubMed2005

Vortex lattices in rotating atomic bose gases with dipolar interactions.

We show that dipolar interactions have dramatic effects on the ground states of rotating atomic Bose gases in the weak-interaction limit. With increasing dipolar interaction (relative to the net contact interaction), the mean field, or high filling factor, ground state undergoes a series of transitions between vortex lattices of different symmetries: triangular, square, "stripe," and "bubble" phases. We also study the effects of dipolar interactions on the quantum fluids at low filling factors. We show that the incompressible Laughlin state at filling factor nu = 1/2 is replaced by compressible stripe and bubble phases.

Journal Article↗

PubMed2005

Incompressible liquid state of rapidly rotating bosons at filling factor 3/2.

Bosons in the lowest Landau level, such as rapidly rotating cold trapped atoms, are investigated numerically in the specially interesting case in which the filling factor (ratio of particle number to vortex number) is 3/2. When a moderate amount of a longer-range (e.g., dipolar) interaction is included, we find clear evidence that the ground state is in a phase constructed earlier by two of us, in which excitations possess non-Abelian statistics.

Journal Article↗

PubMed2004

Exact ground states of rotating Bose gases close to a Feshbach resonance.

We study the ground states of rotating Bose gases when interactions are affected by a nearby Feshbach resonance. We show that exact ground states at high angular momentum can be found analytically for a general model for the resonant interactions. We identify parameter regimes where the exact ground states are exotic fractional quantum Hall states, the excitations of which obey nonabelian exchange statistics.

Journal Article↗

PubMed2003

Interaction effects at crossings of spin-polarized one-dimensional subbands.

We report conductance measurements of ballistic one-dimensional (1D) wires defined in GaAs/AlGaAs heterostructures in an in-plane magnetic field, B. When the Zeeman energy is equal to the 1D subband energy spacing, the spin-split subband N upward arrow intersects (N+1) downward arrow, where N is the index of the spin-degenerate 1D subband. At the crossing of N=1 upward arrow and N=2 downward arrow subbands, there is a spontaneous splitting giving rise to an additional conductance structure evolving from the 1.5(2e(2)/h) plateau. With further increase in B, the structure develops into a plateau and lowers to 2e(2)/h. With increasing temperature and magnetic field the structure shows characteristics of the 0.7 structure. Our results suggest that at low densities a spontaneous spin splitting occurs whenever two 1D subbands of opposite spins cross.

Journal Article↗

PubMed2002

Stable skyrmions in two-component Bose-Einstein condensates.

We show that stable Skyrmions exist in two-component atomic Bose-Einstein condensates, in the regime of phase separation. Using full three-dimensional simulations we find the stable Skyrmions with topological charges Q = 1 and 2, and compute their properties. With reference to these computations we suggest the salient features of an experimental setup in which they might realized.

Journal Article↗

PubMed2001

Quantum phases of vortices in rotating Bose-Einstein condensates.

We investigate the ground states of weakly interacting bosons in a rotating trap as a function of the number of bosons, N, and the average number of vortices, N(V). We identify the filling fraction nu identical with N/N(V) as the parameter controlling the nature of these states. We present results indicating that, as a function of nu, there is a zero temperature phase transition between a triangular vortex lattice phase, and strongly correlated vortex liquid phases. The vortex liquid phases appear to be the Read-Rezayi parafermion states.

Journal Article↗

PubMed2001

Complement activation by neurofibrillary tangles in Alzheimer's disease.

Brain inflammation is widely documented to occur in Alzheimer's disease (AD), but its sources are still incompletely understood. Here, we present in vitro and in situ evidence that, like amyloid beta peptide (Abeta), tau, the major protein constituent of the neurofibrillary tangle, is a potent, antibody-independent activator of the classical complement pathway. Complement activation, in turn, is known to drive numerous inflammatory responses, including scavenger cell activation and cytokine production. Because Abeta deposits and extracellular tangles are present from early preclinical to terminal stages of AD, their ability to activate complement provides a ready mechanism for initiating and sustaining chronic, low-level inflammatory responses that may cumulate over the disease course.

Alzheimer Disease↗

PubMed2001

Characterization of a novel proapoptotic caspase-2- and caspase-9-binding protein.

Caspases play important roles in regulating apoptotic signaling pathways. Here we report the cloning, by the yeast two hybrid system with dominant negative caspase-2 as "bait," of a proapoptotic molecule named proapoptotic caspase adaptor protein (PACAP), encoded by a 372-base pair open reading frame. Binding of this novel protein to caspase-2 (casp-2) was confirmed in yeast two hybrid, in vitro, and in vivo assays. The deduced amino acid sequence revealed homology to functional motifs, including ATP and cytochrome c binding sites. PACAP mRNA was widely expressed in most human tissues; in transfected cells, PACAP was diffusely expressed in the cytoplasm. Bindings studies with the PACAP recombinant protein demonstrated specific binding to casp-2 and casp-9 but not to casp-3, -4, -7, or -8 in cell extracts. Cotransfection experiments showed that PACAP binds to casp-2 and -9 in 293T cells. In addition, studies with truncated PACAP demonstrated a requirement for residues 39-72 of PACAP for specific binding to casp-2 and -9. Transient transfection of PACAP into 293T human kidney cells and rat-1 fibroblasts triggered apoptosis at 24 h, which was at least in part prevented by an inhibitor of casp-3-like enzymes. Transfection of PACAP into human B cell lines using a retroviral system also triggered apoptotic cell death. In addition, transcription of PACAP in primary human B cells was dramatically down-regulated early after cellular activation by CD40L and Staphylococcus aureus and markedly up-regulated as the cells apoptose. These findings identify a novel proapoptotic caspase adaptor protein.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Neuronal expression of a functional receptor for the C5a complement activation fragment.

The present studies were undertaken to determine whether neuronal subsets in normal brains constitutively express functionally competent C5a receptors. In situ hybridization studies coupled with immunohistochemical approaches revealed that most neurons in the hippocampal formation, many pyramidal cortical neurons, and cerebellar Purkinje neurons in normal human and murine brains constitutively express C5a receptors. Neuronal C5a receptors bound C5a-coated fluorescent microspheres, and primary rodent hippocampal neurons responded to C5a with increased calcium fluxes via a pertussis-sensitive, presumably Gi-coupled protein. Additional studies with human neuroblastoma cells conducted to address the functional role of C5a receptors revealed that C5a triggered rapid activation of protein kinase C and activation and nuclear translocation of the NF-kappa B transcription factor. In addition, C5a was found to be mitogenic for undifferentiated human neuroblastoma cells, a novel action for the C5aR. In contrast, C5a protected terminally differentiated human neuroblastoma cells from toxicity mediated by the amyloid A beta peptide. Thus, normal rodent hippocampal neurons as well as undifferentiated and differentiated human neuroblastoma cells express functional C5a receptors. These results have implications for understanding the role of neuronal C5aR receptors in normal neuronal development, neuronal homeostasis, and neuroinflammatory conditions such as Alzheimer's disease.

Aged↗

PubMed2000

The C5a complement activation peptide increases IL-1beta and IL-6 release from amyloid-beta primed human monocytes: implications for Alzheimer's disease.

Alzheimer's disease (AD) brains contain large numbers of amyloid-beta peptide (Abeta) deposits associated with activated microglia, astrocytes and dystrophic neurites. Activated complement components and pro-inflammatory cytokines are also present, indicative of focal inflammation. However, neither Abeta, nor the chemokine-like mediator, C5a, which is generated by Abeta-mediated complement activation, significantly activates microglia, as assessed by pro-inflammatory cytokine release. We evaluated the possibility that both together would co-stimulate such release using the THP-1 human monocytic cell line as a microglial surrogate, and found this to be the case. These studies support the hypothesis that Abeta and C5a induce a chronic microglia-mediated focal inflammatory response in AD.

Alzheimer Disease↗

PubMed2000

Molecular cloning of the C6A form cDNA of the mouse sixth complement component: functional integrity despite the absence of factor I modules.

The sixth complement component (C6) is an essential component of the biologically active C5b-9 membrane attack complex of the complement system. The multimolecular C5b-9 complex is an important mediator of the biological effects of the activated complement system through its prominent cell signaling and cytolytic functions. To begin to provide essential information and reagents needed to analyze the functions of the complement system in mouse models of human diseases, the cDNA of the A form of mouse C6, which is present in all mouse strains, was cloned and characterized structurally and functionally. Although strikingly homologous in deduced amino acid sequence and modular structure to human C6 (75% identity), mouse C6 is substantially smaller due to the absence of the two carboxyl-terminal factor I modules (FIMs) found in human C6. Various approaches, including studies with antibody generated to recombinant mouse C6, failed to reveal evidence for FIMs in this form of mouse C6. Despite the absence of these modules in C6A, reported to be important for interactions with C5 in the human system, mouse C6A is functionally active and is readily incorporated into the mouse C5b-9 complex.

Amino Acid Sequence↗

PubMed2000

beta1 integrin antagonism on adherent, differentiated human neuroblastoma cells triggers an apoptotic signaling pathway.

Integrin receptors mediate several functions including prevention of matrix detachment-induced apoptosis (anoikis) of several adherent cell types. We report here that antagonists of beta1 integrins trigger an apoptotic signaling pathway in adherent differentiated LAN-5 human neuroblastoma cells, a cell line which represents a model system for the study of human neurons. The pathway is characterized by cytochrome c release into the cytoplasm, and activation of caspase-9 and caspase-3, 4-6h after treatment; cleavage products of caspase-8 and caspase-2 were not detectable in the cells. Coordinate inactivation of cell survival pathways, including cleavage of focal adhesion kinase, decreased expression of protein kinase B, and reduced phosphorylation of the pro-apoptotic protein, Bad, also characterized the signaling pathway. These events occurred in adherent cells; DNA fragmentation and detachment followed as late events 18-24h after addition of beta1 integrin antagonists. zDEVD-fmk, an irreversible inhibitor of caspase-3-like enzymes, and cytochalasin D, an actin depolymerizing agent, blocked caspase-3 cleavage and delayed cell death. In contrast to these results, undifferentiated, adherent and dividing LAN-5 cells did not die in response to beta1 integrin antagonists. These studies identify a distinct apoptotic pathway which is triggered by antagonists of beta1 integrins on differentiated adherent neuronal cells.

Antibodies, Monoclonal↗

PubMed2000

Focal inflammation in the brain: role in Alzheimer's disease.

We hypothesize that amyloid (Abeta) peptide-containing neuritic plaques in the brains of patients with Alzheimer's disease represent chronic inflammatory foci mediated by the actions of the complement system and proinflammatory cytokines. In support of this, in vitro studies show that the (Abeta) peptide is a potent complement activator and that such complement activation leads to the formation of covalent (Abeta)-C3 activation fragment complexes, the generation of the chemokine-like C5a complement activation peptide, and the formation of the proinflammatory C5b-9 complex in functionally active form able to insert into neuronal cell membranes. Other studies show that C5a, together with (Abeta), synergistically augments the release of proinflammatory cytokines from human monocytes. These studies, which provide in vitro support for the hypothesis, are being pursued in an animal model of Alzheimer's disease.

Alzheimer Disease↗

PubMed1999

B cell apoptosis triggered by antigen receptor ligation proceeds via a novel caspase-dependent pathway.

In contrast to positive signaling leading to proliferation, the mechanisms involved in negative signaling culminating in apoptosis after B cell Ag receptor (BCR) ligation have received little study. We find that apoptosis induced by BCR cross-linking on EBV-negative mature and immature human B cell lines involves the following sequential, required events: a cyclosporin A-inhibitable, likely calcineurin-mediated step; and activation of caspase-2, -3, and -9. Caspase-2 is activated early and plays a major role in the apoptotic pathway, while caspase-9 is activated later in the apoptotic pathway and most likely functions to amplify the apoptotic signal. Caspase-8 and -1, which are activated by ligation of the CD95 and TNF-R1 death receptors, are not involved. Apoptosis induced by BCR ligation thus proceeds via a previously unreported intracellular signaling pathway.

Animals↗

PubMed1998

Levels of p53 in Epstein-Barr virus-infected cells determine cell fate: apoptosis, cell cycle arrest at the G1/S boundary without apoptosis, cell cycle arrest at the G2/M boundary without apoptosis, or unrestricted proliferation.

The marked increases in p53 and p21/WAF1 levels that occur during Epstein-Barr virus (EBV) infection and the generation of immortal B lymphoblastoid cell lines (LCL) do not lead to growth arrest or apoptosis, although increasing wild-type (wt) p53 levels in EBV-infected cells by transfection or DNA damage induce these effects. We hypothesized that the concentration of p53 relative to that of LMP1 determines whether EBV-infected B cells undergo growth arrest and apoptosis. Cell cycle arrest and apoptosis were evaluated in LCL expressing varying p53 levels achieved by treating the cells with increasing concentrations of cisplatin, and we supplemented this approach with experiments in EBV-infected Burkitt's lymphoma (BL) cells transfected with a temperature-sensitive (ts) mutant human p53 and studies in LCL infected with recombinant adenoviruses expressing wt and ts mutant p53. Small increases in p53 and p21/WAF1 led to cell cycle arrest at the G2/M boundary, but not to apoptosis; moderate increases resulted in growth arrest at the G1/S boundary, also without apoptosis; and large increases also induced apoptosis. These results confirm the hypothesis and reveal unanticipated complexities in cell cycle regulation by p53.

Apoptosis↗

PubMed1998

Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide.

Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the beta-amyloid peptide (Abeta), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Abeta deposits in NP. We report that Abeta peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Abeta with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.

Alzheimer Disease↗

PubMed1998

Activation of a ras-MAPK-dependent pathway by Epstein-Barr virus latent membrane protein 1 is essential for cellular transformation.

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is the only EBV protein which possesses the properties of an oncogene. In studies initiated to evaluate the mechanisms involved in EBV-induced malignant transformation, the extracellular response kinase (ERK) 1/2 were found to be activated 2 days after EBV infection of purified resting human B cells. Transfection studies in Rat-1 fibroblasts, an established rodent cell line, showed that LMP1 mediates ERK 1/2 activation. Cotransfection experiments with a dominant negative ras mutant demonstrated that such MAPK activation occurs via a ras-dependent pathway. Finally, cotransfection studies showed that ras activation is required for LMP-1-mediated malignant transformation of Rat-1 cells.

Animals↗

PubMed1997

Epstein-Barr virus binding to CD21 activates the initial viral promoter via NF-kappaB induction.

Epstein-Barr virus (EBV), an oncogenic human herpesvirus, binds to and infects normal human B lymphocytes via CD21, the CR2 complement receptor. Studies of the mechanisms that enable EBV to infect nonactivated, noncycling B cells provide compelling evidence for a sequence of events in which EBV binding to CD21 on purified resting human B cells rapidly activates the NF-kappaB transcription factor, which, in turn, binds to and mediates transcriptional activation of Wp, the initial viral latent gene promoter. Thus, EBV binding to its cellular receptor on resting B cells triggers an NF-kappaB-dependent intracellular signaling pathway which is required for infection.

Aspirin↗