Direct observation of geometric-phase interference in dynamics around a conical intersection.

Conical intersections are ubiquitous in chemistry and physics, often governing processes such as light harvesting, vision, photocatalysis and chemical reactivity. They act as funnels between electronic states of molecules, allowing rapid and efficient relaxation during chemical dynamics. In addition, when a reaction path encircles a conical intersection, the molecular wavefunction experiences a geometric phase, which can affect the outcome of the reaction through quantum-mechanical interference. Past experiments have measured indirect signatures of geometric phases in scattering patterns and spectroscopic observables, but there has been no direct observation of the underlying wavepacket interference. Here we experimentally observe geometric-phase interference in the dynamics of a wavepacket travelling around an engineered conical intersection in a programmable trapped-ion quantum simulator. To achieve this, we develop a technique to reconstruct the two-dimensional wavepacket densities of a trapped ion. Experiments agree with the theoretical model, demonstrating the ability of analogue quantum simulators-such as those realized using trapped ions-to accurately describe nuclear quantum effects.

Assembly of Tight Junction Strands: Claudin-10b and Claudin-3 Form Homo-Tetrameric Building Blocks that Polymerise in a Channel-Independent Manner.

Tight junctions regulate paracellular permeability size and charge selectively. Models have been proposed for the molecular architecture of tight junction strands and paracellular channels. However, they are not fully consistent with experimental and structural data. Here, we analysed the architecture of claudin-based tight junction strands and channels by cellular reconstitution of strands, structure-guided mutagenesis, in silico protein docking and oligomer modelling. Prototypic channel- (Cldn10b) and barrier-forming (Cldn3) claudins were analysed. Förster resonance energy transfer (FRET) assays indicated multistep claudin polymerisation, starting with cis-oligomerization specific to the claudin subtype, followed by trans-interaction-triggered cis-polymerisation. Alternative protomer interfaces were modelled in silico and tested by cysteine-mediated crosslinking, confocal- and freeze fracture EM-based analysis of strand formation. The analysed claudin mutants included also mutations causing the HELIX syndrome. The results indicated that protomers in Cldn10b and Cldn3 strands form similar antiparallel double rows, as has been suggested for Cldn15. Mutually stabilising -hydrophilic and hydrophobic - cis- and trans-interfaces were identified that contained novel key residues of extracellular segments ECS1 and ECS2. Hydrophobic clustering of the flexible ECS1 ß1ß2 loops together with ECS2-ECS2 trans-interaction is suggested to be the driving force for conjunction of tetrameric building blocks into claudin polymers. Cldn10b and Cldn3 are indicated to share this polymerisation mechanism. However, in the paracellular centre of tetramers, electrostatic repulsion may lead to formation of pores (Cldn10b) and electrostatic attraction to barriers (Cldn3). Combining in vitro data and in silico modelling, this study improves mechanistic understanding of paracellular permeability regulation by elucidating claudin assembly and its pathologic alteration as in HELIX syndrome.

Direct Observation of Dynamical Quantum Phase Transitions in an Interacting Many-Body System.

The theory of phase transitions represents a central concept for the characterization of equilibrium matter. In this work we study experimentally an extension of this theory to the nonequilibrium dynamical regime termed dynamical quantum phase transitions (DQPTs). We investigate and measure DQPTs in a string of ions simulating interacting transverse-field Ising models. During the nonequilibrium dynamics induced by a quantum quench we show for strings of up to 10 ions the direct detection of DQPTs by revealing nonanalytic behavior in time. Moreover, we provide a link between DQPTs and the dynamics of other quantities such as the magnetization, and we establish a connection between DQPTs and entanglement production.

Swelling behavior of bisensitive interpenetrating polymer networks for microfluidic applications.

Bisensitive interpenetrating polymer network (IPN) hydrogels of temperature sensitive net-poly(N-isopropylacrylamide) and pH sensitive net-poly(acrylic acid-co-acrylamide) for microfluidic applications were prepared via a sequential synthesis using free radical polymerization. The IPN indicated a suitable reversible alteration of swelling in response to the change in pH and temperature. The adequate change of the hydrogel volume is a basic requirement for microfluidic applications. Using the introduced correction factor f, it is possible to determine the cooperative diffusion coefficient (Dcoop) of cylindrical samples at any aspect ratio. The determined cooperative diffusion coefficient allowed the evaluation of varying swelling processes of different network structures. The presence of the second sub-network of the IPN improved the swelling behaviour of the first sub-network compared to the individual networks.

Spectroscopy of Interacting Quasiparticles in Trapped Ions.

The static and dynamic properties of many-body quantum systems are often well described by collective excitations, known as quasiparticles. Engineered quantum systems offer the opportunity to study such emergent phenomena in a precisely controlled and otherwise inaccessible way. We present a spectroscopic technique to study artificial quantum matter and use it for characterizing quasiparticles in a many-body system of trapped atomic ions. Our approach is to excite combinations of the system's fundamental quasiparticle eigenmodes, given by delocalized spin waves. By observing the dynamical response to superpositions of such eigenmodes, we extract the system dispersion relation, magnetic order, and even detect signatures of quasiparticle interactions. Our technique is not limited to trapped ions, and it is suitable for verifying quantum simulators by tuning them into regimes where the collective excitations have a simple form.

Quasiparticle engineering and entanglement propagation in a quantum many-body system.

The key to explaining and controlling a range of quantum phenomena is to study how information propagates around many-body systems. Quantum dynamics can be described by particle-like carriers of information that emerge in the collective behaviour of the underlying system, the so-called quasiparticles. These elementary excitations are predicted to distribute quantum information in a fashion determined by the system's interactions. Here we report quasiparticle dynamics observed in a quantum many-body system of trapped atomic ions. First, we observe the entanglement distributed by quasiparticles as they trace out light-cone-like wavefronts. Second, using the ability to tune the interaction range in our system, we observe information propagation in an experimental regime where the effective-light-cone picture does not apply. Our results will enable experimental studies of a range of quantum phenomena, including transport, thermalization, localization and entanglement growth, and represent a first step towards a new quantum-optic regime of engineered quasiparticles with tunable nonlinear interactions.

Experimental violation of multipartite Bell inequalities with trapped ions.

We report on the experimental violation of multipartite Bell inequalities by entangled states of trapped ions. First, we consider resource states for measurement-based quantum computation of between 3 and 7 ions and show that all strongly violate a Bell-type inequality for graph states, where the criterion for violation is a sufficiently high fidelity. Second, we analyze Greenberger-Horne-Zeilinger states of up to 14 ions generated in a previous experiment using stronger Mermin-Klyshko inequalities, and show that in this case the violation of local realism increases exponentially with system size. These experiments represent a violation of multipartite Bell-type inequalities of deterministically prepared entangled states. In addition, the detection loophole is closed.

Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen.

Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by persisting mucoid biofilms in hypoxic endobronchial mucus. These biofilms are surrounded by numerous polymorphonuclear leucocytes (PMNs), which consume a major part of present molecular oxygen (O(2)) due to production of superoxide (O(2)(-)). In this study, we show that the PMNs also consume O(2) for production of nitric oxide (NO) by the nitric oxide synthases (NOS) in the infected endobronchial mucus. Fresh expectorated sputum samples (n = 28) from chronically infected CF patients (n = 22) were analysed by quantifying and visualizing the NO production. NO production was detected by optode measurements combined with fluorescence microscopy, flow cytometry and spectrophotometry. Inhibition of nitric oxide synthases (NOS) with N(G) -monomethyl-L-arginine (L-NMMA) resulted in reduced O(2) consumption (P < 0·0008, n = 8) and a lower fraction of cells with fluorescence from the NO-indicator 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM) (P < 0·002, n = 8). PMNs stained with DAF-FM and the superoxide indicator hydroethidine (HE) and host cells with inducible NOS (iNOS) were identified in the sputum. In addition, the production of the stable end-products of NO in CF sputum was correlated with the concentration of PMNs; NO(3)(-) (P < 0·04, r = 0·66, n = 10) and NO(2)(-) (P< 0·006, r = 0·78, n = 11). The present study suggests that besides consumption of O(2) for production of reactive oxygen species, the PMNs in CF sputum also consume O(2) for production of NO.

Measurement-based quantum computation with trapped ions.

Measurement-based quantum computation represents a powerful and flexible framework for quantum information processing, based on the notion of entangled quantum states as computational resources. The most prominent application is the one-way quantum computer, with the cluster state as its universal resource. Here we demonstrate the principles of measurement-based quantum computation using deterministically generated cluster states, in a system of trapped calcium ions. First we implement a universal set of operations for quantum computing. Second we demonstrate a family of measurement-based quantum error correction codes and show their improved performance as the code length is increased. The methods presented can be directly scaled up to generate graph states of several tens of qubits.

Experimental generation of quantum discord via noisy processes.

Quantum systems in mixed states can be unentangled and yet still nonclassically correlated. These correlations can be quantified by the quantum discord and might provide a resource for quantum information processing tasks. By precisely controlling the interaction of two ionic qubits with their environment, we investigate the capability of noise to generate discord. Firstly, we show that noise acting on only one quantum system can generate discord between two. States generated in this way are restricted in terms of the rank of their correlation matrix. Secondly, we show that classically correlated noise processes are capable of generating a much broader range of discordant states with correlation matrices of any rank. Our results show that noise processes prevalent in many physical systems can automatically generate nonclassical correlations and highlight fundamental differences between discord and entanglement.

Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors.

BACKGROUND AND PURPOSE: In mammalian cells, the anti-parasitic drug ivermectin is known as a positive allosteric modulator of the ATP-activated ion channel P2X4 and is used to discriminate between P2X4- and P2X7-mediated cellular responses. In this paper we provide evidence that the reported isoform selectivity of ivermectin is a species-specific phenomenon. EXPERIMENTAL APPROACH: Complementary electrophysiological and fluorometric methods were applied to evaluate the effect of ivermectin on recombinantly expressed and on native P2X7 receptors. A biophysical characterization of ionic currents and of the pore dilation properties is provided. KEY RESULTS: Unexpectedly, ivermectin potentiated currents in human monocyte-derived macrophages that endogenously express hP2X7 receptors. Likewise, currents and [Ca(2+) ](i) influx through recombinant human (hP2X7) receptors were potently enhanced by ivermectin at submaximal or saturating ATP concentrations. Since intracellular ivermectin did not mimic or prevent its activity when applied to the bath solution, the binding site of ivermectin on hP2X7 receptors appears to be accessible from the extracellular side. In contrast to currents through P2X4 receptors, ivermectin did not cause a delay in hP2X7 current decay upon ATP removal. Interestingly, NMDG(+) permeability and Yo-Pro-1 uptake were not affected by ivermectin. On rat or mouse P2X7 receptors, ivermectin was only poorly effective, suggesting a species-specific mode of action. CONCLUSIONS AND IMPLICATIONS: The data indicate a previously unrecognized species-specific modulation of human P2X7 receptors by ivermectin that should be considered when using this cell-biological tool in human cells and tissues.

Universal digital quantum simulation with trapped ions.

A digital quantum simulator is an envisioned quantum device that can be programmed to efficiently simulate any other local system. We demonstrate and investigate the digital approach to quantum simulation in a system of trapped ions. With sequences of up to 100 gates and 6 qubits, the full time dynamics of a range of spin systems are digitally simulated. Interactions beyond those naturally present in our simulator are accurately reproduced, and quantitative bounds are provided for the overall simulation quality. Our results demonstrate the key principles of digital quantum simulation and provide evidence that the level of control required for a full-scale device is within reach.

Quantum simulation of the Klein paradox with trapped ions.

We report on quantum simulations of relativistic scattering dynamics using trapped ions. The simulated state of a scattering particle is encoded in both the electronic and vibrational state of an ion, representing the discrete and continuous components of relativistic wave functions. Multiple laser fields and an auxiliary ion simulate the dynamics generated by the Dirac equation in the presence of a scattering potential. Measurement and reconstruction of the particle wave packet enables a frame-by-frame visualization of the scattering processes. By precisely engineering a range of external potentials we are able to simulate text book relativistic scattering experiments and study Klein tunneling in an analogue quantum simulator. We describe extensions to solve problems that are beyond current classical computing capabilities.

Ion imaging in a high-gradient magnetic guide.

We study a photoionization method to detect and image a narrow beam of cold atoms traveling along a high-gradient two-wire magnetic guide that is continuously on. Ions are accelerated in a compact acceleration region, directed through a drift region several centimeters in length, and detected using a position-sensitive ion detector. The potentials of several electrodes can be varied to adjust the imaging properties. Using ion trajectory simulations as well as experiments, we study the passage of the ions through the detection system, the magnification of the detection system, and the time-of-flight characteristics.

Image-guided surgery of the anterior skull base.

Minimally invasive surgical procedures have revolutionized surgery of the paranasal sinuses. The endonasal procedure has become standard practice due to a better understanding of pathological physiology. However, malformations, previous operations and bleeding can interfere greatly with intraoperative orientation. Together with microscopy and endoscopy, image-guided surgery has the potential to be of significant assistance to the surgeon. We evaluated the electromagnetic navigation system InstaTrak 2000 (Visualization Technologies Inc., Lawrence, MA) in 168 patients with various disorders of the paranasal sinuses who underwent endonasal surgery. The system consists of a headset attached to an electronic transmitter which is fitted on the dorsum of the nose and in the external auditory canal. With the aid of low-frequency magnetic fields the position of the instrument equipped with an electromagnetic receiver is calculated on the basis of the reaction of ferromagnetic components in the magnetic field; the location is displayed in orthogonal sections on a high resolution screen. The intraoperative accuracy of the system was estimated to be 1.2-2.8 mm. The preparation time amounted to < 10 min. No system failures were observed. The InstaTrak 2000 navigation system is only suitable for endonasal surgery. The placement of the electromagnetic transmitter and receiver allows flexible head positioning through the use of a headset. This system is a valuable aid for the surgeon under anatomically complex conditions. The technology also lends itself well to training purposes, as visualization in different sectional planes augments the understanding of anatomy and pathological anatomy.

Multiple forms of short-term plasticity at excitatory synapses in rat medial prefrontal cortex.

Short-term synaptic plasticity, in particular short-term depression and facilitation, strongly influences neuronal activity in cerebral cortical circuits. We investigated short-term plasticity at excitatory synapses onto layer V pyramidal cells in the rat medial prefrontal cortex, a region whose synaptic dynamic properties have not been systematically examined. Using intracellular and extracellular recordings of synaptic responses evoked by stimulation in layers II/III in vitro, we found that short-term depression and short-term facilitation are similar to those described previously in other regions of the cortex. In addition, synapses in the prefrontal cortex prominently express augmentation, a longer lasting form of short-term synaptic enhancement. This consists of a 40-60% enhancement of synaptic transmission which lasts seconds to minutes and which can be induced by stimulus trains of moderate duration and frequency. Synapses onto layer III neurons in the primary visual cortex express substantially less augmentation, indicating that this is a synapse-specific property. Intracellular recordings from connected pairs of layer V pyramidal cells in the prefrontal cortex suggest that augmentation is a property of individual synapses that does not require activation of multiple synaptic inputs or neuromodulatory fibers. We propose that synaptic augmentation could function to enhance the ability of a neuronal circuit to sustain persistent activity after a transient stimulus. This idea is explored using a computer simulation of a simplified recurrent cortical network.

The role of gemcitabine alone and in combination in the treatment of pancreatic cancer.

Pancreatic cancer, one of the most frequently reported gastrointestinal tumors, has a 5-year survival of less than 5%. Despite representing only 2-3% of the total cancer incidence, it is the fifth leading cause of cancer death. This is because it is commonly only diagnosed at an advanced stage. Until recently the traditional therapy for patients with advanced disease was palliative 5-fluorouracil (5-FU)-based chemotherapy. However, the novel antinucleoside gemcitabine (Gemzar) has demonstrated a survival benefit over 5-FU, and an improvement in disease-related symptoms and quality of life in patients with advanced disease. This review presents an overview of the clinical studies of gemcitabine, either alone or in combination, with other chemotherapeutic agents and/or radiation therapy, in the treatment of these patients. A comparison of these studies is made with those using alternative treatment regimens. The data suggest that gemcitabine in combination with biomodulated 5-FU should be considered the standard palliative treatment to which other new drug combinations or combined modality chemoradiation regimens should be compared.

Plasmid stability of recombinant Pseudomonas sp. B13 FR1 pFRC20P in continuous culture.

Plasmid stability of recombinant Pseudomonas sp. B13 FR1 pFRC20P, a strain capable of mineralizing 3- and 4-chlorobenzoate and 4-methylbenzoate, was investigated in continuous culture. The hybrid cosmid pFRC20P enables the strain to mineralize 4-methylbenzoate. Rapid plasmid loss was observed under nonselective conditions using 3-chlorobenzoate as the substrate. Plasmid stability decreased with increasing dilution rate. Despite the growth advantage of the generated plasmid free cells a total depletion of plasmid bearing cells was not observed. After approximately 50 generations the fraction of plasmid bearing cells reached a constant level of 10%, which was stably maintained during the next 25 generations. Cells from this stage were used to inoculate a new culture that resulted in a stable level of 50% plasmid bearing cells. By a temporary substrate change to selective conditions (4-methylbenzoate), this level could be further increased to 70%. Literature models on plasmid stability could not be applied to describe the experimental data. Therefore, a new but unstructured model was developed to describe the experimental results. The model is based on the existence of three subpopulations: a plasmid free one, an original plasmid bearing one with a growth disadvantage compared to plasmid free cells, and a second plasmid bearing subpopulation with increased stability that is generated from the original one and has a growth rate comparable to the plasmid free cells.

Spatio-temporal dynamics of cyclic AMP signals in an intact neural circuitm.

The functional properties of neuronal networks can be reconfigured by a variety of modulatory neurotransmitters, which may alter the excitable properties of neurons or the strengths of synaptic connections. Many of these neuromodulators act via the intracellular second messenger cyclic AMP, but their effects on the spatial distribution of cAMP concentration have never been examined in an intact neural circuit. We therefore used the cAMP-indicator dye FICRhR (refs 1, 2) to investigate the effect of several neuromodulators (octopamine, dopamine, acetylcholine, serotonin and proctolin) on cAMP distribution in identified neurons of the lobster stomatogastric ganglion (STG). When added to the bath solution, each of these neuromodulators produced a unique pattern of cAMP transients among the different neurons of the STG. Electrical stimulation of neurons innervating the STG causes synaptic release of endogenous modulators, leading within a few seconds to local increases of cAMP in fine neurite branches, the site where many modulators are thought to act. After prolonged stimulation, cAMP diffuses from the site of production to throughout the neuritic tree and eventually to the cell body. Diffusion of cAMP may explain how transient localized inputs to a neuron can produce long-range effects such as long-term changes in gene expression.

Axons and synapses mediating startle-like responses evoked by electrical stimulation of the reticular formation in rats: symmetric and asymmetric collision effects.

A new method for determining the locations, directions of transmission and transmission times of synapses mediating electrically evoked responses is proposed here. Electrical stimulation of pontine or medullary reticular formation with one 0.1-ms pulse evokes a short-latency startle-like response. Two pulses were delivered to single sites at various interpulse intervals and the currents required to evoke a criterion startle response were measured. The results suggest that the startle-evoking substrates have absolute refractory periods that range from 0.25-0.6 ms. When one pulse was delivered to a caudal pontine site and a second pulse was delivered to a an ipsilateral medulla site, decreases in required current were observed as interpulse interval increased from +0.4 to +0.8 ms or as interpulse interval decreased from -0.4 to -0.8 ms. These collision-like effects, being symmetric around an interpulse interval of 0, suggest that electrically evoked startle is mediated by fast axons that pass longitudinally through medulla. When one pulse was delivered to the rostral pons and a second pulse to the ipsilateral medulla, however, required currents decreased sharply as interpulse intervals increased from +0.4 to 1.0 ms and as interpulse intervals decreased from +0.2 to -0.2 ms. These asymmetric collision-like effects suggest that strong synapses in the caudal pons, transmitting from pons to medulla, mediate electrically evoked startle. The 0.3-ms asymmetry suggests that the transmission time (i.e., from presynaptic stimulus to postsynaptic action potential) averaged 0.3 ms via monosynaptic connections. The short duration of collision (0.7 ms) suggests that only one postsynaptic action potential was produced with high probability for each presynaptic action potential. From the localization of these effects and the short refractory periods, we estimate that < 60 giant cells on each side of the ventral pontine reticular formation mediate the startle reflex in the rat.