A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy.

Nanomedicine has attracted increasing attention in recent years, because it offers great promise to provide personalized diagnostics and therapy with improved treatment efficacy and specificity. In this study, we developed a gold nanostar (GNS) probe for multi-modality theranostics including surface-enhanced Raman scattering (SERS) detection, x-ray computed tomography (CT), two-photon luminescence (TPL) imaging, and photothermal therapy (PTT). We performed radiolabeling, as well as CT and optical imaging, to investigate the GNS probe's biodistribution and intratumoral uptake at both macroscopic and microscopic scales. We also characterized the performance of the GNS nanoprobe for in vitro photothermal heating and in vivo photothermal ablation of primary sarcomas in mice. The results showed that 30-nm GNS have higher tumor uptake, as well as deeper penetration into tumor interstitial space compared to 60-nm GNS. In addition, we found that a higher injection dose of GNS can increase the percentage of tumor uptake. We also demonstrated the GNS probe's superior photothermal conversion efficiency with a highly concentrated heating effect due to a tip-enhanced plasmonic effect. In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS. This multifunctional GNS probe has the potential to be used for in vivo biosensing, preoperative CT imaging, intraoperative detection with optical methods (SERS and TPL), as well as image-guided photothermal therapy.

High-Resolution CT for Small-Animal Imaging Research

Preclinical imaging has a critical role in phenotyping, in drug discovery, and in providing a basic understanding of mechanisms of disease. Translating imaging methods from humans to small animals is not an easy task. The purpose of this work is to review high-resolution computed tomography (CT) also known as micro-CT for small-animal imaging. We present the principles, the technologies, the image quality parameters, and the types of applications. We show that micro-CT can be used to provide not only morphological but also functional information such as cardiac function or vascular permeability. Another way in which micro-CT can be used in the study of both function and anatomy is by combining it with other imaging modalities, such as positron emission tomography or single-photon emission tomography. Compared to other modalities, micro-CT imaging is usually regarded as being able to provide higher throughput at lower cost and higher resolution. The limitations are usually associated with the relatively poor contrast mechanisms and the radiation damage, although the use of novel nanoparticle-based contrast agents and careful design of studies can address these limitations.

Investigation and Development of a Fully 3D Tilt Capable Hybrid SPECT - CT System for Dedicated Breast Imaging

X-ray mammography has been the gold standard for breast imaging for decades, despite the significant limitations posed by the two dimensional (2D) image acquisitions. Difficulty in diagnosing lesions close to the chest wall and axilla, high amount of structural overlap and patient discomfort due to compression are only some of these limitations. To overcome these drawbacks, three dimensional (3D) breast imaging modalities have been developed including dual modality single photon emission computed tomography (SPECT) and computed tomography (CT) systems. This thesis focuses on the development and integration of the next generation of such a device for dedicated breast imaging. The goals of this dissertation work are to: [1] understand and characterize any effects of fully 3-D trajectories on reconstructed image scatter correction, absorbed dose and Hounsifeld Unit accuracy, and [2] design, develop and implement the fully flexible, third generation hybrid SPECT-CT system capable of traversing complex 3D orbits about a pendant breast volume, without interference from the other. Such a system would overcome artifacts resulting from incompletely sampled divergent cone beam imaging schemes and allow imaging closer to the chest wall, which other systems currently under research and development elsewhere cannot achieve.

The dependence of x-ray scatter radiation on object shape, size, material composition and the CT acquisition trajectory, was investigated with a well-established beam stop array (BSA) scatter correction method. While the 2D scatter to primary ratio (SPR) was the main metric used to characterize total system scatter, a new metric called ‘normalized scatter contribution’ was developed to compare the results of scatter correction on 3D reconstructed volumes. Scatter estimation studies were undertaken with a sinusoidal saddle (±15° polar tilt) orbit and a traditional circular (AZOR) orbit. Clinical studies to acquire data for scatter correction were used to evaluate the 2D SPR on a small set of patients scanned with the AZOR orbit. Clinical SPR results showed clear dependence of scatter on breast composition and glandular tissue distribution, otherwise consistent with the overall phantom-based size and density measurements. Additionally, SPR dependence was also observed on the acquisition trajectory where 2D scatter increased with an increase in the polar tilt angle of the system.

The dose delivered by any imaging system is of primary importance from the patient’s point of view, and therefore trajectory related differences in the dose distribution in a target volume were evaluated. Monte Carlo simulations as well as physical measurements using radiochromic film were undertaken using saddle and AZOR orbits. Results illustrated that both orbits deliver comparable dose to the target volume, and only slightly differ in distribution within the volume. Simulations and measurements showed similar results, and all measured dose values were within the standard screening mammography-specific, 6 mGy dose limit, which is used as a benchmark for dose comparisons.

Hounsfield Units (HU) are used clinically in differentiating tissue types in a reconstructed CT image, and therefore the HU accuracy of a system is very important, especially when using non-traditional trajectories. Uniform phantoms filled with various uniform density fluids were used to investigate differences in HU accuracy between saddle and AZOR orbits. Results illustrate the considerably better performance of the saddle orbit, especially close to the chest and nipple region of what would clinically be a pedant breast volume. The AZOR orbit causes shading artifacts near the nipple, due to insufficient sampling, rendering a major portion of the scanned phantom unusable, whereas the saddle orbit performs exceptionally well and provides a tighter distribution of HU values in reconstructed volumes.

Finally, the third generation, fully-suspended SPECT-CT system was designed in and developed in our lab. A novel mechanical method using a linear motor was developed for tilting the CT system. A new x-ray source and a custom made 40 x 30 cm2 detector were integrated on to this system. The SPECT system was nested, in the center of the gantry, orthogonal to the CT source-detector pair. The SPECT system tilts on a goniometer, and the newly developed CT tilting mechanism allows ±15° maximum polar tilting of the CT system. The entire gantry is mounted on a rotation stage, allowing complex arbitrary trajectories for each system, without interference from the other, while having a common field of view. This hybrid system shows potential to be used clinically as a diagnostic tool for dedicated breast imaging.

The Superresolution Problem in Doppler Difference Laser Anemometry

info:eu-repo/semantics/published

Regularized iterative and non-iterative procedures for object restoration from experimental data

A regularized algorithm for the recovery of band-limited signals from noisy data is described. The regularization is characterized by a single parameter. Iterative and non-iterative implementations of the algorithm are shown to have useful properties, the former offering the advantage of flexibility and the latter a potential for rapid data processing. Comparative results, using experimental data obtained in laser anemometry studies with a photon correlator, are presented both with and without regularization. © 1983 Taylor & Francis Ltd.

Numerical Simulations and Coherence Properties of Supercontinuum Generation in Photonic Crystal and Tapered Optical Fibers

Numerical simulations have been used to study broad-band supercontinuum generation in optical fibers with dispersion and nonlinearity characteristics typical and photonic crystal or tapered fibers structures. The simulations include optical shock and Raman nonlinearity terms, with quantum noise taken into account phenomenologically by including in the input field a noise seed of one photon per mode with random phase. For input pulses of 150-fs duration injected in the anomalous dispersion regime, the effect of modulational instability is shown to lead to severe temporal jitter in the output, and associated fluctuations in the spectral amplitude and phase across the generated supercontinuum. The spectral phase fluctuations are quantified by performing multiple simulations and calculating both the standard deviation of the phase and, more rigorously, the degree of first-order coherence as a function of wavelength across the spectrum. By performing simulations over a range of input pulse durations and wavelengths, we can identify the conditions under which coherent supercontinua with a well-defined spectral phase are generated.

CONTRIBUTION OF A SPERM PROTEIN, PAWP, TO THE SIGNAL TRANSDUCT PATHWAY DURING VERTEBRATE FERTILIZATION

PAWP, postacrosomal sheath WW domain binding protein, is a novel sperm protein identified as a candidate sperm borne, oocyte-activating factor (SOAF). PAWP induces both early and later egg activation events including meiotic resumption, pronuclear formation and egg cleavage. Based on the fact that calcium increase is universally accepted as the sole requirement for egg activation, we hypothesized that PAWP is an upstream regulator of the calcium signaling pathway during fertilization. Intracellular calcium increase was detected by two-photon laser scanning fluorescence microscopy following microinjection of recombinant PAWP into Xenopus oocytes, bolstering our hypothesis and suggesting the involvement of a novel PAWP-mediated signaling pathway during fertilization. The N-terminal of PAWP shares a high homology to WW domain binding protein while the C-terminal half contains a functional PPXY motif, which allows it to interact with group I WW domain proteins. These structural considerations together with published data indicating that PPXY synthetic peptide derived from PAWP inhibits ICSI-induced fertilization led to the hypothesis that PAWP triggers egg activation by binding to a group I WW domain protein in the oocyte. By far-Western analysis of oocyte cytoplasmic fraction, PAWP was found to bind to a 52 kDa protein. The competitive inhibition studies with PPXY synthetic peptide, WW domain constructs, and their point mutants demonstrated that the interaction between PAWP and its binding partner is specifically via the PPXY-WW domain module. The 52 kDa protein band crossreacted with antibodies against group I WW domain protein YAP in Western blot assay, indicating that this 52 kDa PAWP binding partner is either YAP or a YAP-related protein. In addition, the far-Western competitive inhibition studies with recombinant GST fusion protein YAP and another WW domain-containing protein, TAZ, demonstrated that the binding of PAWP to its binding partner was significantly reduced by TAZ, providing evidence that TAZ could be the 52 kDa protein candidate. Mass spectrometry was employed to identify this PAWP binding partner candidate. However, due to the low abundance of the candidate protein and the complexity of the sample, several strategies are still needed to enrich this protein. This study correlates PAWP induced meiotic resumption and calcium efflux at fertilization and uncovers a 52 kDa candidate WW domain protein in the oocyte cytoplasm that most likely interacts with PAWP to trigger egg activation.

Developing Single-Laser Sources for Multimodal Coherent Anti-Stokes Raman Scattering Microscopy

Coherent anti-Stokes Raman scattering (CARS) microscopy has developed rapidly and is opening the door to new types of experiments. This work describes the development of new laser sources for CARS microscopy and their use for different applications. It is specifically focused on multimodal nonlinear optical microscopy—the simultaneous combination of different imaging techniques. This allows us to address a diverse range of applications, such as the study of biomaterials, fluid inclusions, atherosclerosis, hepatitis C infection in cells, and ice formation in cells. For these applications new laser sources are developed that allow for practical multimodal imaging. For example, it is shown that using a single Ti:sapphire oscillator with a photonic crystal fiber, it is possible to develop a versatile multimodal imaging system using optimally chirped laser pulses. This system can perform simultaneous two photon excited fluorescence, second harmonic generation, and CARS microscopy. The versatility of the system is further demonstrated by showing that it is possible to probe different Raman modes using CARS microscopy simply by changing a time delay between the excitation beams. Using optimally chirped pulses also enables further simplification of the laser system required by using a single fiber laser combined with nonlinear optical fibers to perform effective multimodal imaging. While these sources are useful for practical multimodal imaging, it is believed that for further improvements in CARS microscopy sensitivity, new excitation schemes are necessary. This has led to the design of a new, high power, extended cavity oscillator that should be capable of implementing new excitation schemes for CARS microscopy as well as other techniques. Our interest in multimodal imaging has led us to other areas of research as well. For example, a fiber-coupling scheme for signal collection in the forward direction is demonstrated that allows for fluorescence lifetime imaging without significant temporal distortion. Also highlighted is an imaging artifact that is unique to CARS microscopy that can alter image interpretation, especially when using multimodal imaging. By combining expertise in nonlinear optics, laser development, fiber optics, and microscopy, we have developed systems and techniques that will be of benefit for multimodal CARS microscopy.

Higher brain neurons succumb to acute stroke-like insult while lower brain neurons strongly resist

Pyramidal neurons (PyNs) in ‘higher’ brain are highly susceptible to acute stroke injury yet ‘lower’ brain regions better survive global ischemia, presumably because of better residual blood flow. Here we show that projection neurons in ‘lower’ brain regions of hypothalamus and brainstem intrinsically resist acute stroke-like injury independent of blood flow in the brain slice. In contrast `higher` projection neurons in neocortex, hippocampus, striatum and thalamus are highly susceptible. In live brain slices from rat deprived of oxygen and glucose (OGD), we imaged anoxic depolarization (AD) as it propagates through these regions. AD, the initial electrophysiological event of stroke, is a depolarizing front that drains residual energy in compromised gray matter. The extent of AD reliably determines ensuing damage in higher brain, but using whole-cell recordings we found that all CNS neurons do not generate a robust AD. Higher neurons generate strong AD and show no functional recovery in contrast to neurons in hypothalamus and brainstem that generate a weak and gradual AD. Most dramatically, lower neurons recover their membrane potential, input resistance and spike amplitude when oxygen and glucose is restored, while higher neurons do not. Following OGD, new recordings could be acquired in all lower (but not higher) brain regions, with some neurons even withstanding multiple OGD exposure. Two-photon laser scanning microscopy confirmed neuroprotection in lower, but not higher gray matter. Specifically pyramidal neurons swell and lose their dendritic spines post-OGD, whereas neurons in hypothalamus and brainstem display no such injury. Exposure to the Na+/K+ ATPase inhibitor ouabain (100 μM), induces depolarization similar to OGD in all cell types tested. Moreover, elevated [K+]o evokes spreading depression (SD), a milder version of AD, in higher brain but not hypothalamus or brainstem so weak AD correlates with the inability to generate SD. In summary, overriding the Na+/K+ pump using OGD, ouabain or elevated [K+]o evokes steep and robust depolarization of higher gray matter. We show that this important regional difference can be largely accounted for by the intrinsic properties of the resident neurons and that Na+/K+ ATPase pump efficiency is a major determining factor generating strong or weak spreading depolarizations.

Multiwavelength observations of the M15 intermediate-velocity cloud

We present Westerbork Synthesis Radio Telescope HI images, Lovell telescope multibeam H I wide-field mapping, William Herschel Telescope long-slit echelle Ca II observations, Wisconsin Halpha Mapper (WHAM) facility images, and IRAS ISSA 60- and 100-mum co-added images towards the intermediate- velocity cloud (IVC) at + 70 km s(-1), located in the general direction of the M15 globular cluster. When combined with previously published Arecibo data, the H I gas in the IVC is found to be clumpy, with a peak H I column density of similar to1.5 x 10(20) cm(-2), inferred volume density (assuming spherical symmetry) of similar to24 cm(-3)/D (kpc) and a maximum brightness temperature at a resolution of 81 x 14 arcsec(2) of 14 K. The major axis of this part of the IVC lies approximately parallel to the Galactic plane, as does the low- velocity H I gas and IRAS emission. The H I gas in the cloud is warm, with a minimum value of the full width at half-maximum velocity width of 5 km s(-1) corresponding to a kinetic temperature, in the absence of turbulence, of similar to540 K. From the H I data, there are indications of two-component velocity structure. Similarly, the Ca II spectra, of resolution 7 km s(-1), also show tentative evidence of velocity structure, perhaps indicative of cloudlets. Assuming that there are no unresolved narrow-velocity components, the mean values of log(10)[N(Ca II K) cm(2)] similar to 12.0 and Ca II/H I similar to2 5 x 10(-8) are typical of observations of high Galactic latitude clouds. This compares with a value of Ca II/H I>10(-6) for IVC absorption towards HD 203664, a halo star of distance 3 kpc, some 3.degrees1 from the main M15 IVC condensation. The main IVC condensation is detected by WHAM in Halpha with central local-standard-of-rest velocities of similar to60-70 km s(-1), and intensities uncorrected for Galactic extinction of up to 1.3 R, indicating that the gas is partially ionized. The FWHM values of the Halpha IVC component, at a resolution of 1degrees, exceed 30 km s(-1). This is some 10 km s(-1) larger than the corresponding H I value at a similar resolution, and indicates that the two components may not be mixed. However, the spatial and velocity coincidence of the Halpha and H I peaks in emission towards the main IVC component is qualitatively good. If the Halpha emission is caused solely by photoionization, the Lyman continuum flux towards the main IVC condensation is similar to2.7 x 10(6) photon cm(-2) s(-1). There is not a corresponding IVC Halpha detection towards the halo star HD 203664 at velocities exceeding similar to60 km s(- 1). Finally, both the 60- and 100-mum IRAS images show spatial coincidence, over a 0.675 x 0 625 deg(2) field, with both low- and intermediate-velocity H I gas (previously observed with the Arecibo telescope), indicating that the IVC may contain dust. Both the Halpha and tentative IRAS detections discriminate this IVC from high-velocity clouds, although the H I properties do not. When combined with the H I and optical results, these data point to a Galactic origin for at least parts of this IVC.

Simulation of quantum random walks using the interference of a classical field

We suggest a theoretical scheme for the simulation of quantum random walks on a line using beam splitters, phase shifters, and photodetectors. Our model enables us to simulate a quantum random walk using of the wave nature of classical light fields. Furthermore, the proposed setup allows the analysis of the effects of decoherence. The transition from a pure mean-photon-number distribution to a classical one is studied varying the decoherence parameters.

Quantum nonlocality test for continuous-variable states with dichotomic observables

There have been theoretical and experimental studies on quantum nonlocality for continuous variables, based on dichotomic observables. In particular, we are interested in two cases of dichotomic observables for the light field of continuous variables: One case is even and odd numbers of photons and the other case is no photon and the presence of photons. We analyze various observables to give the maximum violation of Bell's inequalities for continuous-variable states. We discuss an observable which gives the violation of Bell's inequality for any entangled pure continuous-variable state. However, it does not have to be a maximally entangled state to give the maximal violation of Bell's inequality. This is attributed to a generic problem of testing the quantum nonlocality of an infinite- dimensional state using a dichotomic observable.

Quantum homogenization for continuous variables: Realization with linear optical elements

Recently Ziman et al. [Phys. Rev. A 65, 042105 (2002)] have introduced a concept of a universal quantum homogenizer which is a quantum machine that takes as input a given (system) qubit initially in an arbitrary state rho and a set of N reservoir qubits initially prepared in the state xi. The homogenizer realizes, in the limit sense, the transformation such that at the output each qubit is in an arbitrarily small neighborhood of the state xi irrespective of the initial states of the system and the reservoir qubits. In this paper we generalize the concept of quantum homogenization for qudits, that is, for d-dimensional quantum systems. We prove that the partial-swap operation induces a contractive map with the fixed point which is the original state of the reservoir. We propose an optical realization of the quantum homogenization for Gaussian states. We prove that an incoming state of a photon field is homogenized in an array of beam splitters. Using Simon's criterion, we study entanglement between outgoing beams from beam splitters. We derive an inseparability condition for a pair of output beams as a function of the degree of squeezing in input beams.

Perspectives for quantum state engineering via high nonlinearity in a double-EIT regime

We analyse the possibilities for quantum state engineering offered by a model for Kerr-type nonlinearity enhanced by electromagnetically induced transparency (EIT), which was recently proposed by Petrosyan and Kurizki [2002, Phys. Rev. A, 65, 33833]. We go beyond the semiclassical treatment and derive a quantum version of the model with both a full Hamiltonian approach and an analysis in terms of dressed states. The preparation of an entangled coherent state via a cross-phase modulation effect is demonstrated. We briefly show that the violation of locality for such an entangled coherent state is robust against low detection efficiency. Finally, we investigate the possibility of a bi-chromatic photon blockade realized via the interaction of a low density beam of atoms with a bi-modal electromagnetic cavity which is externally driven. We show the effectiveness of the blockade effect even when more than a single atom is inside the cavity. The possibility to control two different cavity modes allows some insights into the generation of an entangled state of cavity modes.