Exciton-polariton topological insulator.

Topological insulators-materials that are insulating in the bulk but allow electrons to flow on their surface-are striking examples of materials in which topological invariants are manifested in robustness against perturbations such as defects and disorder1. Their most prominent feature is the emergence of edge states at the boundary between areas with different topological properties. The observable physical effect is unidirectional robust transport of these edge states. Topological insulators were originally observed in the integer quantum Hall effect2 (in which conductance is quantized in a strong magnetic field) and subsequently suggested3-5 and observed6 to exist without a magnetic field, by virtue of other effects such as strong spin-orbit interaction. These were systems of correlated electrons. During the past decade, the concepts of topological physics have been introduced into other fields, including microwaves7,8, photonic systems9,10, cold atoms11,12, acoustics13,14 and even mechanics15. Recently, topological insulators were suggested to be possible in exciton-polariton systems16-18 organized as honeycomb (graphene-like) lattices, under the influence of a magnetic field. Exciton-polaritons are part-light, part-matter quasiparticles that emerge from strong coupling of quantum-well excitons and cavity photons19. Accordingly, the predicted topological effects differ from all those demonstrated thus far. Here we demonstrate experimentally an exciton-polariton topological insulator. Our lattice of coupled semiconductor microcavities is excited non-resonantly by a laser, and an applied magnetic field leads to the unidirectional flow of a polariton wavepacket around the edge of the array. This chiral edge mode is populated by a polariton condensation mechanism. We use scanning imaging techniques in real space and Fourier space to measure photoluminescence and thus visualize the mode as it propagates. We demonstrate that the topological edge mode goes around defects, and that its propagation direction can be reversed by inverting the applied magnetic field. Our exciton-polariton topological insulator paves the way for topological phenomena that involve light-matter interaction, amplification and the interaction of exciton-polaritons as a nonlinear many-body system.

Propagative Oscillations in Codirectional Polariton Waveguide Couplers.

We report on novel exciton-polariton routing devices created to study and purposely guide light-matter particles in their condensate phase. In a codirectional coupling device, two waveguides are connected by a partially etched section that facilitates tunable coupling of the adjacent channels. This evanescent coupling of the two macroscopic wave functions in each waveguide reveals itself in real space oscillations of the condensate. This Josephson-like oscillation has only been observed in coupled polariton traps so far. Here, we report on a similar coupling behavior in a controllable, propagative waveguide-based design. By controlling the gap width, channel length, or propagation energy, the exit port of the polariton flow can be chosen. This codirectional polariton device is a passive and scalable coupler element that can serve in compact, next generation logic architectures.

Nanoscale Tipping Bucket Effect in a Quantum Dot Transistor-Based Counter.

Electronic circuits composed of one or more elements with inherent memory, that is, memristors, memcapacitors, and meminductors, offer lower circuit complexity and enhanced functionality for certain computational tasks. Networks of these elements are proposed for novel computational paradigms that rely on information processing and storage on the same physical platform. We show a nanoscaled memdevice able to act as an electronic analogue of tipping buckets that allows reducing the dimensionality and complexity of a sensing problem by transforming it into a counting problem. The device offers a well adjustable, tunable, and reliable periodic reset that is controlled by the amounts of transferred quantum dot charges per gate voltage sweep. When subjected to periodic voltage sweeps, the quantum dot (bucket) may require up to several sweeps before a rapid full discharge occurs thus displaying period doubling, period tripling, and so on between self-governing reset operations.

Half adder capabilities of a coupled quantum dot device.

In this paper we demonstrate two realizations of a half adder based on a voltage-rectifying mechanism involving two Coulomb-coupled quantum dots. First, we examine the ranges of operation of the half adder's individual elements, the AND and XOR gates, for a single rectifying device. It allows a switching between the two gates by a control voltage and thus enables a clocked half adder operation. The logic gates are shown to be reliably operative in a broad noise amplitude range with negligible error probabilities. Subsequently, we study the implementation of the half adder in a combined double-device consisting of two individually tunable rectifiers. We show that this double device allows a simultaneous operation of both relevant gates at once. The presented devices draw their power solely from electronic fluctuations and are therefore an advancement in the field of energy efficient and autonomous electronics.

Utilization of extended temporomandibular joint replacements in patients with hemifacial microsomia.

Hemifacial microsomia (HFM) patients may benefit from extended temporomandibular joint replacements (eTMJR) to improve function and quality of life. A cross-sectional survey was sent to surgeons who place alloplastic temporomandibular joints regarding their experience with and complications encountered when placing eTMJR in patients with HFM. Fifty-nine responded to the survey. Thirty-six (61.0%) reported treating patients with HFM and 30 (50.8%) of those reported placing an alloplastic temporomandibular joint (TMJ) prosthesis for patients with HFM. Twenty-three of the 30 surgeons (76.7%) placing alloplastic TMJ prostheses reported using an eTMJR in patients with HFM. The average maximum inter-incisal opening (MIO) after an eTMJR in HFM patients was repor ted as> 25 mm by 82.6% of the participants, and between 16 mm and 25 mm by 17.4%. No participants reported MIO < 15 mm. To avoid condylar sag and open bite changes postoperatively, over 70% reported using some form of modification to stabilize the occlusion. Respondents reported good functional outcomes for eTMJR in patients with HFM with relatively few complications. Therefore, eTMJR could be considered a viable option in the management of this patient population.

Irreversible dimerization/tetramerization and post-translational modifications inhibit proteolytic degradation of A beta peptides of Alzheimer's disease.

Experimental evidence increasingly implicates the beta-amyloid peptide in the pathogenesis of Alzheimer's disease. Beta-amyloid filaments dramatically accumulate in the neuritic plaques and vascular deposits as the result of the brain's inability to clear these structures. In this paper, we demonstrate that in addition to the intrinsic stability of A beta N-42, the time dependent generation of irreversibly associated A beta dimers and tetramers incorporated into A beta filaments are themselves resistant to proteolytic degradation. The presence of post-translational modifications such as isomerization of aspartyls 1 and 7, cyclization of glutamyl 3 to pyroglutamyl and oxidation of methionyl 35, further contribute to the insolubility and stability of A beta. All these factors promote the accumulation of neurotoxic amyloid in the brains of patients with Alzheimer's disease, and should be considered in therapeutic strategies directed towards the dissociation of the brain's A beta filaments.

The role of complement in Alzheimer's disease pathology.

Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review will examine the origins of complement in the brain and the role of beta-amyloid peptide (Abeta) in complement activation in Alzheimer's disease, an event that might serve as a nidus of chronic inflammation. Pharmacology therapies that may serve to inhibit Abeta-mediated complement activation will also be discussed.

Oligomerizaiton and fibril asssembly of the amyloid-beta protein.

In this chapter, we attempt to analyze the evolution of the amyloid-beta (Abeta) molecular structure from its inception as part of the Abeta precursor protein to its release by the secretases and its extrusion from membrane into an aqueous environment. Biophysical studies suggest that the Abeta peptide sustains a series of transitions from a molecule rich in alpha-helix to a molecule in which beta-strands prevail. It is proposed that initially the extended C-termini of two opposing Abeta dimers form an antiparallel beta-sheet and that the subsequent addition of dimers generates a helical Abeta protofilament. Two or more protofilaments create a strand in which the hydrophobic core of the beta-sheets is shielded from the aqueous environment by the N-terminal polar domains of the Abeta dimers. Once the nucleation has occurred, the Abeta filament grows in length by the addition of dimers or tetramers.

The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease.

Effective therapeutic intervention in Alzheimer disease (AD) will be most effective if it is directed at early events in the pathogenic sequence. The cholinergic deficit may be such an early event. In the present study, the brains of 26 subjects who had no history of cognitive loss and who were in early histopathologic stages of AD (average Braak stage less than II) were examined at autopsy to determine whether a cortical cholinergic decrement was associated with Abeta concentration or deposition. In the superior frontal and inferior temporal gyri, the choline acetyltransferase (ChAT) activity of plaque-containing cases was significantly decreased (p < 0.05, unpaired, two-tailed t-tests), measuring 70.9% and 79.5%, respectively, relative to plaque-free cases. In the inferior temporal gyrus, Spearman's rank correlation analysis showed that ChAT activity had a significant inverse correlation with Abeta concentration (p = 0.075; r = -0.3552). The results indicate that the cholinergic deficit is established at an early histopathologic stage of AD, before the onset of clinical symptoms.

Apolipoprotein E alters metabolism of AbetaPP in cells engaged in beta-amyloidosis.

Canine smooth muscle cells (SMCs), cultured from amyloid-affected brain blood vessels accumulate Alzheimer amyloid-beta peptide (Abeta) intracellularly, either spontaneously or after treatment with apolipoprotein E (apoE). ApoE is codeposited with Abeta, which suggests that apoE participates in Abeta accumulation. We tested the hypothesis that apoE-induced accumulation of Abeta in SMCs is caused by an increased production of amyloid-beta precursor protein (AbetaPP) and/or its altered metabolism. We found that 24 hours of treatment with apoE3 or apoE4 induced intracellular accumulation of Abeta-immunoreactive deposits in SMCs but did not influence AbetaPP production and processing. The treatment with apoE3 or E4 for 3 days resulted in the following: increased Abeta-accumulation; reduced levels of secreted Abeta; increased production and cellular retention of mature AbetaPP770; and reduced culture growth, cell proliferation, and viability. ApoE4, but not apoE3, increased cellular levels of mRNA AbetaPP 770 (the main form produced in SMCs) about ninefold. ApoE3 stimulated production and cellular retention of endogenous apoE. We hypothesize that Abeta accumulation is triggered by apoE, which may bind and immobilize soluble Abeta produced in SMCs. The newly formed Abeta deposits may further accelerate Abeta accumulation by altering metabolism of AbetaPP.

Inflammation and Alzheimer's disease pathogenesis.

Appreciation of the role that inflammatory mediators play in Alzheimer's disease (AD) pathogenesis continues to be hampered by two related misconceptions. The first is that to be pathogenically significant a neurodegenerative mechanism must be primary. The second is that inflammation merely occurs to clear the detritis of already existent pathology. The present review addresses these issues by showing that 1) inflammatory molecules and mechanisms are uniquely present or significantly elevated in the AD brain, 2) inflammation may be a necessary component of AD pathogenesis, 3) inflammation may be sufficient to cause AD neurodegeneration, and 4) retrospective and direct clinical trials suggest a therapeutic benefit of conventional antiinflammatory medications in slowing the progress or even delaying the onset of AD.

Inflammation and Alzheimer's disease.

Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

PD 142676 (CI 1002), a novel anticholinesterase and muscarinic antagonist.

Inhibition of brain acetylcholinesterase (AChE) can provide relief from the cognitive loss associated with Alzheimer's disease (AD). However, unwanted peripheral side effects often limit the usefulness of the available anticholinesterases. Recently, we identified a dihydroquinazoline compound, PD 142676 (CI 1002) that is a potent anticholinesterase and a functional muscarinic antagonist at higher concentrations. Peripherally, PD 142676, unlike other anticholinesterases, inhibits gastrointestinal motility in rats, an effect consistent with its muscarinic antagonist properties. Centrally, the compound acts as a cholinomimetic. In rats, PD 142676 decreases core body temperature. It also increases neocortical arousal, as measured by quantitative electroencephalography, and cortical acetylcholine levels, measured by in vivo microdialysis. The compound improves the performance of C57/B10j mice in a water maze task and of aged rhesus monkeys in a delayed match-to-sample task involving short-term memory. The combined effect of AChE inhibition and muscarinic antagonism distinguishes PD 142676 from other anticholinesterases, and may be useful in treating the cognitive dysfunction of AD and produce fewer peripheral side effects.

Interleukin-1 beta dissociates beta-amyloid precursor protein and beta-amyloid peptide secretion.

A heightened production of interleukin 1 beta (IL-1 beta) has been reported in microglial-associated amyloid deposits in Alzheimer's disease (AD) brains. These plaques are composed predominantly of beta/A4 peptide derived from beta-amyloid precursor protein (beta APP). We demonstrate that short-term (1 h) IL-1 beta-treatment increases beta APPs secretion and concomitantly decreases cell-associated beta APP in human H4 neuroglioma cells. Long-term (5 h) IL-1 beta treatment did not alter secreted or cell-associated beta APP content. In contrast, the secretion of beta/A4-containing epitope was not affected by short-term IL-1 beta stimulation; however, long-term IL-1 beta treatment decreased the amount of beta/A4-containing epitope secreted from the cells. These results show that IL-1 beta modifies the processing and secretion of beta APP to exacerbate perhaps the neuropathology of AD.

Identification of a 3-hydroxylated tacrine metabolite in rat and man: metabolic profiling implications and pharmacology.

Discrepancies in urinary metabolic profiles in rats administered tacrine (1) suggested the presence of an unidentified metabolite of 1. Chromatographic methods were developed that allowed isolation of a metabolite fraction containing both 1-hydroxytacrine (2) and an unknown metabolite from rat urine. Mass spectral analysis indicated this metabolite to be a monohydroxylated derivative, which upon two dimensional COSY NMR analysis could be assigned as 3-hydroxytacrine (4). This structural assignment was confirmed by independent synthesis of 4. Compound 4 was also identified as a human urinary metabolite of 1. Biologically, 4 was found to have in vitro human red blood cell acetylcholinesterase inhibitory activity similar to that of 2 and 4-hydroxytacrine (5) and approximately 8-fold less than that of 1. These results underscore the need to conduct rigorous structural identification studies, especially in cases where isomeric metabolites are possible, in assessing the accuracy of chromatographic profiling techniques.

2-amino-4H-3,1-benzoxazin-4-ones as inhibitors of C1r serine protease.

A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r. C1r is a serine protease at the beginning of the complement cascade, and complement activation by beta-amyloid may represent a major contributing pathway to the neuropathology of Alzheimer's disease. Compounds such as 7-chloro-2-[(2-iodophenyl)-amino]benz[d][1,3]oxazin-4-one (32) and 7-methyl-2-[(2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (37) show improved potency compared to the reference compound FUT-175. Many of these active compounds also possess increased selectivity for C1r compared to trypsin and enhanced hydrolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4-one (1).

Therapeutic intervention in dementia.

The search for novel therapeutics for human cognitive disorders has intensified. Neurotransmitter replacement therapies represent a short-term hope for treating cognitive dysfunction associated with Alzheimer's disease (AD). AD, however, is clearly a neurodegenerative disease and is characterized by a loss of synaptic elements. Ultimately, synaptic loss must be halted to alter the disease course. Agents mimicking or modulating the actions of neurotrophic factors may be useful. They may restore lost function and exert anabolic effects on existing neurons, making treated cells less susceptible to neurotoxic insult (i.e., excitotoxicity, oxidative stress, etc.). Intervening in the biogenesis of amyloid plaques and blunting local inflammatory responses may provide the ultimate treatment for AD. The success of any treatment, however, rests on early diagnosis. Early intervention in the neurodegenerative disease process will be required. Without early intervention, the risk of maintaining patients in a premorbid state is high. Therefore, it is likely that no single approach will provide optimal therapy for the AD patient and multifactorial treatment strategies may be required.

Molecular cloning of three cDNAs encoding aminopeptidases from the midgut of Helicoverpa punctigera, the Australian native budworm.

Three cDNAs encoding aminopeptidases HpAPN1, HpAPN2 and HpAPN3, were isolated from a 5th instar larval midgut cDNA library from Helicoverpa punctigera, the Australian native budworm. The sequences recovered contain open reading frames encoding proteins of 1011, 952, and 1013 amino acids, respectively. All three proteins share the consensus zinc binding/gluzincin motif HEXXHX(18)E and the sequence GAMEN common to gluzincin aminopeptidases. Furthermore, signal peptide sequences and C-terminal hydrophobic regions preceded by three small amino acids qualifying for cleavage and GPI anchor attachment are present in all three protein sequences. Northern blotting results indicate differences in the levels of expression and developmental regulation of all three aminopeptidases. HpAPN1, HpAPN2, and HpAPN3 are more closely related to APNs from other lepidopterans than they are to each other. This report of three different aminopeptidases N in Helicoverpa punctigera adds support to a recent suggestion that at least one gene duplication has taken place in ancestral lepidopterans. The full sequences of the aminopeptidases are available at GENBANK with the following accession numbers: HpAPN1: AF217248, HpAPN2: AF217249, HpAPN3: AF217250.

The role of arachidonic acid in the secretion of the amyloid precursor protein (APP).

We have studied the activation of human ml-muscarinic receptors in a genetically engineered Chinese hamster ovary cell line (CHO-ml) to determine which second messenger systems affect the secretion of APP via the non-amyloidogenic route. Carbachol activation of the signaling pathways in CHO-ml cells promotes APP secretion by activation of both protein kinase C (PKC)-dependent or Ca(++)-dependent second messenger pathways. Both pathways converge to increase the enzyme activity of phospholipase A2 (PLA2), the enzyme that releases arachidonic acid from cellular stores. Directly activating PLA2 with melittin, a peptide from bee venom, or by adding arachidonic acid directly to cultured cells increases the secretion of APP. Thus, our results indicate that arachidonic acid is yet another cellular second messenger involved in regulating the metabolism of APP in addition to PKC and cytoplasmic Ca++. Moreover, activation of PLA2 appears to be an obligatory event in increasing the secretion of APP from CHO-ml cells by the various methods of activation that we have tried thus far.

Traumatic brain injury elevates the Alzheimer's amyloid peptide A beta 42 in human CSF. A possible role for nerve cell injury.

The increased risk for Alzheimer's Disease (AD) associated with traumatic brain injury (TBI) suggests that environmental insults may influence the development of this age-related dementia. Recently, we have shown that the levels of the beta-amyloid peptide (A beta 1-42) increase in the cerebrospinal fluid (CSF) of patients after severe brain injury and remain elevated for some time after the initial event. The relationships of elevated A beta with markers of blood-brain barrier (BBB) disruption, inflammation, and nerve cell or axonal injury were evaluated in CSF samples taken daily from TBI patients. This analysis reveals that the rise in A beta 1-42 is best correlated with possible markers of neuronal or axonal injury, the cytoskeletal protein tau, neuron-specific enolase (NSE), and apolipoprotein E (ApoE). Similar or better correlations were observed between A beta 1-40 and the three aforementioned markers. These results imply that the degree of brain injury may play a decisive role in determining the levels of A beta 1-42 and A beta 1-40 in the CSF of TBI patients. Inflammation and alterations in BBB may play lesser, but nonetheless significant, roles in determining the A beta level in CSF after brain injury.