The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation.

Exposure to a plethora of environmental challenges commonly triggers pathological type 2 cell-mediated inflammation. Here we report the pathological role of the Wnt antagonist Dickkopf-1 (Dkk-1) upon allergen challenge or non-healing parasitic infection. The increased circulating amounts of Dkk-1 polarized T cells to T helper 2 (Th2) cells, stimulating a marked simultaneous induction of the transcription factors c-Maf and Gata-3, mediated by the kinases p38 MAPK and SGK-1, resulting in Th2 cell cytokine production. Circulating Dkk-1 was primarily from platelets, and the increase of Dkk-1 resulted in formation of leukocyte-platelet aggregates (LPA) that facilitated leukocyte infiltration to the affected tissue. Functional inhibition of Dkk-1 impaired Th2 cell cytokine production and leukocyte infiltration, protecting mice from house dust mite (HDM)-induced asthma or Leishmania major infection. These results highlight that Dkk-1 from thrombocytes is an important regulator of leukocyte infiltration and polarization of immune responses in pathological type 2 cell-mediated inflammation.

Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells.

Regulatory T cells (Tregs) play an essential role in preventing autoimmunity. Mutations in the forkhead box protein 3 (FOXP3) gene, which encodes a transcription factor critical for Treg function, result in a severe autoimmune disorder and the production of various autoantibodies in mice and in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. However, it is unknown whether Tregs normally suppress autoreactive B cells. To investigate a role for Tregs in maintaining human B-cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells isolated from IPEX patients. Characteristics and reactivity of antibodies expressed by new emigrant/transitional B cells from IPEX patients were similar to those from healthy donors, demonstrating that defective Treg function does not impact central B-cell tolerance. In contrast, mature naive B cells from IPEX patients often expressed autoreactive antibodies, suggesting an important role for Tregs in maintaining peripheral B-cell tolerance. T cells displayed an activated phenotype in IPEX patients, including their Treg-like cells, and showed up-regulation of CD40L, PD-1, and inducibl T-cell costimulator (ICOS), which may favor the accumulation of autoreactive mature naive B cells in these patients. Hence, our data demonstrate an essential role for Tregs in the establishment and the maintenance of peripheral B-cell tolerance in humans.

Depth-of-Interaction Compensation Using a Focused-Cut Scintillator for a Pinhole Gamma Camera.

Preclinical SPECT offers a powerful means to understand the molecular pathways of drug interactions in animal models by discovering and testing new pharmaceuticals and therapies for potential clinical applications. A combination of high spatial resolution and sensitivity are required in order to map radiotracer uptake within small animals. Pinhole collimators have been investigated, as they offer high resolution by means of image magnification. One of the limitations of pinhole geometries is that increased magnification causes some rays to travel through the detection scintillator at steep angles, introducing parallax errors due to variable depth-of-interaction in scintillator material, especially towards the edges of the detector field of view. These parallax errors ultimately limit the resolution of pinhole preclinical SPECT systems, especially for higher energy isotopes that can easily penetrate through millimeters of scintillator material. A pixellated, focused-cut (FC) scintillator, with its pixels laser-cut so that they are collinear with incoming rays, can potentially compensate for these parallax errors and thus improve the system resolution. We performed the first experimental evaluation of a newly developed focused-cut scintillator. We scanned a Tc-99m source across the field of view of pinhole gamma camera with a continuous scintillator, a conventional "straight-cut" (SC) pixellated scintillator, and a focused-cut scintillator, each coupled to an electron-multiplying charge coupled device (EMCCD) detector by a fiber-optic taper, and compared the measured full-width half-maximum (FWHM) values. We show that the FWHMs of the focused-cut scintillator projections are comparable to the FWHMs of the thinner SC scintillator, indicating the effectiveness of the focused-cut scintillator in compensating parallax errors.

Multi-Material Decomposition using Low-Current X-Ray and a Photon-Counting CZT Detector.

We developed and evaluated an x-ray photon-counting imaging system using an energy-resolving cadmium zinc telluride (CZT) detector coupled with application specific integrated circuit (ASIC) readouts. This x-ray imaging system can be used to identify different materials inside the object. The CZT detector has a large active area (5×5 array of 25 CZT modules, each with 16×16 pixels, cover a total area of 200 mm × 200 mm), high stopping efficiency for x-ray photons (~ 100 % at 60 keV and 5 mm thickness). We explored the performance of this system by applying different energy windows around the absorption edges of target materials, silver and indium, in order to distinguish one material from another. The photon-counting CZT-based x-ray imaging system was able to distinguish between the materials, demonstrating its capability as a radiation-spectroscopic decomposition system.

Temperature dependent operation of PSAPD-based compact gamma camera for SPECT imaging.

We investigated the dependence of image quality on the temperature of a position sensitive avalanche photodiode (PSAPD)-based small animal single photon emission computed tomography (SPECT) gamma camera with a CsI:Tl scintillator. Currently, nitrogen gas cooling is preferred to operate PSAPDs in order to minimize the dark current shot noise. Being able to operate a PSAPD at a relatively high temperature (e.g., 5 °C) would allow a more compact and simple cooling system for the PSAPD. In our investigation, the temperature of the PSAPD was controlled by varying the flow of cold nitrogen gas through the PSAPD module and varied from -40 °C to 20 °C. Three experiments were performed to demonstrate the performance variation over this temperature range. The point spread function (PSF) of the gamma camera was measured at various temperatures, showing variation of full-width-half-maximum (FWHM) of the PSF. In addition, a 99mTc-pertechnetate (140 keV) flood source was imaged and the visibility of the scintillator segmentation (16×16 array, 8 mm × 8 mm area, 400 µm pixel size) at different temperatures was evaluated. Comparison of image quality was made at -25 °C and 5 °C using a mouse heart phantom filled with an aqueous solution of 99mTc-pertechnetate and imaged using a 0.5 mm pinhole collimator made of tungsten. The reconstructed image quality of the mouse heart phantom at 5 °C degraded in comparision to the reconstructed image quality at -25 °C. However, the defect and structure of the mouse heart phantom were clearly observed, showing the feasibility of operating PSAPDs for SPECT imaging at 5 °C, a temperature that would not need the nitrogen cooling. All PSAPD evaluations were conducted with an applied bias voltage that allowed the highest gain at a given temperature.

Phantom experiments on a PSAPD-based compact gamma camera with submillimeter spatial resolution for small animal SPECT.

We demonstrate a position sensitive avalanche photodiode (PSAPD) based compact gamma camera for the application of small animal single photon emission computed tomography (SPECT). The silicon PSAPD with a two-dimensional resistive layer and four readout channels is implemented as a gamma ray detector to record the energy and position of radiation events from a radionuclide source. A 2 mm thick monolithic CsI:Tl scintillator is optically coupled to a PSAPD with a 8mm×8mm active area, providing submillimeter intrinsic spatial resolution, high energy resolution (16% full-width half maximum at 140 keV) and high gain. A mouse heart phantom filled with an aqueous solution of 370 MBq (99m)Tc-pertechnetate (140 keV) was imaged using the PSAPD detector module and a tungsten knife-edge pinhole collimator with a 0.5 mm diameter aperture. The PSAPD detector module was cooled with cold nitrogen gas to suppress dark current shot noise. For each projection image of the mouse heart phantom, a rotated diagonal readout algorithm was used to calculate the position of radiation events and correct for pincushion distortion. The reconstructed image of the mouse heart phantom demonstrated reproducible image quality with submillimeter spatial resolution (0.7 mm), showing the feasibility of using the compact PSAPD-based gamma camera for a small animal SPECT system.

Extremely small multimode-interference coupled triangular resonator with sharp angle of incidence.

Novel triangular ring resonators combining extremely small multimode-interference (MMI) coupler, low loss total internal reflection (TIR) mirrors, and semiconductor optical amplifiers are reported for the first time. The MMI length of 90 microm is among the shortest reported. The incidence angle of the TIR mirror inside the resonator is 22 degrees. A free-spectral range of approximately 2 nm is observed near 1550 nm along with an on-off ratio of 17 dB. The triangular resonators with a sharp angle are very attractive components due to their promise of compact size and high levels of integration. Therefore, large numbers of resonators can be integrated on a chip to increase functionality in future optical wavelength division multiplexing system.

Doppler-free, multiwavelength acousto-optic deflector for two-photon addressing arrays of Rb atoms in a quantum information processor.

We demonstrate a dual wavelength acousto-optic deflector (AOD) designed to deflect two wavelengths to the same angles by driving with two RF frequencies. The AOD is designed as a beam scanner to address two-photon transitions in a two-dimensional array of trapped neutral Rb87 atoms in a quantum computer. Momentum space is used to design AODs that have the same diffraction angles for two wavelengths (780 and 480 nm) and have nonoverlapping Bragg-matched frequency response at these wavelengths, so that there will be no cross talk when proportional frequencies are applied to diffract the two wavelengths. The appropriate crystal orientation, crystal shape, transducer size, and transducer height are determined for an AOD made with a tellurium dioxide crystal (TeO(2)). The designed and fabricated AOD has more than 100 resolvable spots, widely separated band shapes for the two wavelengths within an overall octave bandwidth, spatially overlapping diffraction angles for both wavelengths (780 and 480 nm), and a 4 micros or less access time. Cascaded AODs in which the first device upshifts and the second downshifts allow Doppler-free scanning as required for addressing the narrow atomic resonance without detuning. We experimentally show the diffraction-limited Doppler-free scanning performance and spatial resolution of the designed AOD.

Loss-coupled distributed-feedback lasers with amplified optical feedback for optical microwave generation.

Multisection semiconductor lasers for optical microwave generation have been fabricated that consist of a loss-coupled distributed feedback (LC-DFB), a phase control, and an amplifier section. High-frequency self-pulsations are generated according to the concept of a single-mode laser with short optical feedback. The effect of the optical feedback via the phase control and the amplifier section on the self-pulsation is apparently shown as a result of the superior single-mode characteristic of the LC-DFB section. Continuous frequency tuning is achieved in the range of 17-35 GHz.