Dynamic phase measurement of fast liquid crystal phase modulators.

We present dynamic time-resolved measurements of a multi-pixel analog liquid crystal phase modulator driven at a 1 kHz frame rate. A heterodyne interferometer is used to interrogate two pixels independently and simultaneously, to deconvolve phase modulation with a wide bandwidth. The root mean squared optical phase error within a 30 Hz to 25 kHz bandwidth is <0.5° and the crosstalk rejection is 50 dB. Measurements are shown for a custom-built device with a flexoelectro-optic chiral nematic liquid crystal. However, the technique is applicable to many different types of optical phase modulators and spatial light modulators.

Single-mode sapphire fiber Bragg grating.

Sapphire optical fiber has the ability to withstand ultrahigh temperatures and high radiation, but it is multimoded which prevents its use in many sensing applications. Problematically, Bragg gratings in such fiber exhibit multiple reflection peaks with a fluctuating power distribution. In this work, we write single-mode waveguides with Bragg gratings in sapphire using a novel multi-layer depressed cladding design in the 1550 nm telecommunications waveband. The Bragg gratings have a narrow bandwidth (<0.5 nm) and have survived annealing at 1000°C. The structures are inscribed with femtosecond laser direct writing, using adaptive beam shaping with a non-immersion objective. A single-mode sapphire fiber Bragg grating is created by writing a waveguide with a Bragg grating within a 425 µm diameter sapphire optical fiber, providing significant potential for accurate remote sensing in ultra-extreme environments.

Accelerated aortic 4D flow MRI with wave-CAIPI.

PURPOSE: The aim of this study was to investigate the acceleration potential of wave-CAIPI (controlled aliasing in parallel imaging) for 4D flow MRI, provided that image quality and precision of flow parameters are maintained. METHODS: The 4D flow MRIs with acceleration factor R = 2 were performed on 10 healthy volunteers, using both wave-CAIPI and standard Cartesian/2D-CAIPI sampling for reference. In addition, 1 patient with known aortic valve stenosis was examined. The flow rate ( Q ), net flow ( Qnet ), peak velocity vmax , and net average through-plane velocity ( v¯âŠ¥ ) were calculated in eight analysis planes in the ascending and descending aorta. The acquisitions were retrospectively undersampled (R = 6), and deviations of flow parameters and hemodynamic flow patterns were evaluated. RESULTS: Flow parameters measured with an undersampled wave-CAIPI trajectory showed considerably smaller deviations to the references than the 2D-CAIPI images. For vmax , the mean absolute differences were 6.02±2.08 cm/s versus 14.36±5.68 cm/s; for Qnet , the mean absolute differences were 3.67±1.40 ml versus 5.87±1.91 ml for wave-CAIPI versus 2D-CAIPI, respectively. Noise calculations indicate that the 2D-CAIPI sampling exhibits a 43±38% higher average noise level than the wave-CAIPI technique. Qualitative discrepancies in hemodynamic flow patterns, visualized through streamlines, particle traces and flow velocity vectors, could be reduced by using the undersampled wave-CAIPI trajectory. CONCLUSION: Use of wave-CAIPI instead of 2D-CAIPI sampling in retrospectively 6-fold accelerated 4D flow MRI enhances the precision of flow parameters. The acquisition time of 4D flow measurements could be reduced by a factor of 3, with minimal differences in flow parameters.

Free-breathing self-gated 4D lung MRI using wave-CAIPI.

PURPOSE: The aim of this study was to compare the wave-CAIPI (controlled aliasing in parallel imaging) trajectory to the Cartesian sampling for accelerated free-breathing 4D lung MRI. METHODS: The wave-CAIPI k-space trajectory was implemented in a respiratory self-gated 3D spoiled gradient echo pulse sequence. Trajectory correction applying the gradient system transfer function was used, and images were reconstructed using an iterative conjugate gradient SENSE (CG SENSE) algorithm. Five healthy volunteers and one patient with squamous cell carcinoma in the lung were examined on a clinical 3T scanner, using both sampling schemes. For quantitative comparison of wave-CAIPI and standard Cartesian imaging, the normalized mutual information and the RMS error between retrospectively accelerated acquisitions and their respective references were calculated. The SNR ratios were investigated in a phantom study. RESULTS: The obtained normalized mutual information values indicate a lower information loss due to acceleration for the wave-CAIPI approach. Average normalized mutual information values of the wave-CAIPI acquisitions were 10% higher, compared with Cartesian sampling. Furthermore, the RMS error of the wave-CAIPI technique was lower by 19% and the SNR was higher by 14%. Especially for short acquisition times (down to 1 minute), the undersampled Cartesian images showed an increased artifact level, compared with wave-CAIPI. CONCLUSION: The application of the wave-CAIPI technique to 4D lung MRI reduces undersampling artifacts, in comparison to a Cartesian acquisition of the same scan time. The benefit of wave-CAIPI sampling can therefore be traded for shorter examinations, or enhancing image quality of undersampled 4D lung acquisitions, keeping the scan time constant.

Active Metamaterials with Negative Static Electric Susceptibility.

Although well-established textbook arguments suggest that static electric susceptibility χ(0) must be positive in "all bodies," it has been pointed out that materials that are not in thermodynamic equilibrium are not necessarily subject to this restriction. Media with inverted populations of atomic and molecular energy levels have been predicted theoretically to exhibit a χ(0) < 0 state, however the systems envisioned require reduced temperature, reduced pressure, and an external pump laser to maintain the population inversion. Further, the existence of χ(0) < 0 has never been confirmed experimentally. Here, a completely different approach is taken to the question of χ(0) < 0 and a design concept to achieve "true" χ(0) < 0 is proposed based on active metamaterials with internal power sources. Two active metamaterial structures are fabricated that, despite still having their power sources implemented externally for reasons of practical convenience, provide evidence in support of the general concept. Effective values are readily achieved at room temperature and pressure and are tunable throughout the range of stability -1 < χ(0) < 0, resulting in experimentally-determined magnitudes that are over one thousand times greater than those predicted previously. Since χ(0) < 0 is the missing electric analog of diamagnetism, this work opens the door to new technological capabilities such as stable electrostatic levitation.

Dynamic response of large tilt-angle flexoelectro-optic liquid crystal modulators.

We present here the first time-resolved tilt-angle and retardance measurements for large-tilt (>45°) flexoelectro-optic liquid crystal modulators. These devices have potential for next generation fast switching (>1 kHz), 0-2π analog phase spatial light modulators (SLMs), with applications in optical beamsteering, microscopy and micromachining. The chiral nematic device used consisted of a mixture of CBC7CB and the chiral dopant R5011 in a nominally 5 µm-thick cell, aligned in the uniform lying helix mode. As the device is dynamically switched over angles of ± 54°, retardance changes of up to 0.17λ are observed. Furthermore, the time-resolved measurements reveal an asymmetry in the tilt in the optic-axis depending on the polarity of the applied electric field. The change in the optic-axis exhibits a pattern dependence, whereby it is determined by both the pulse history and the applied field. This pattern dependence results in tilt-angle errors of up to 8.8°, which could manifest as phase errors as large as 35.2° in potential SLMs. These time domain measurements may allow correction of these deterministic errors, to realize practical devices.

Fast and low loss flexoelectro-optic liquid crystal phase modulator with a chiral nematic reflector.

In this paper, we demonstrate a flexoelectro-optic liquid crystal phase-only device that uses a chiral nematic reflector to achieve full 2π phase modulation. This configuration is found to be very tolerant to imperfections in the chiral nematic reflector provided that the flexoelectro-optic LC layer fulfils the half-wave condition. Encouragingly, the modulation in the phase, which operates at kHz frame rates, is also accompanied by low amplitude modulation. The configuration demonstrated herein is particularly promising for the development of next-generation liquid crystal on silicon spatial light modulators.

Femtosecond fiber Bragg grating fabrication with adaptive optics aberration compensation.

We present fiber Bragg gratings (FBGs) fabricated using adaptive optics aberration compensation for the first time to the best of our knowledge. The FBGs are fabricated with a femtosecond laser by the point-by-point method using an air-based objective lens, removing the requirement for immersion oil or ferrules. We demonstrate a general phase correction strategy that can be used for accurate fabrication at any point in the fiber cross-section. We also demonstrate a beam-shaping approach that nullifies the aberration when focused inside a central fiber core. Both strategies give results which are in excellent agreement with coupled-mode theory. An extremely low wavelength polarization sensitivity of 4 pm is reported.

Flexoelectro-optic liquid crystal analog phase-only modulator with a 2π range and 1 kHz switching.

We present a flexoelectro-optic liquid crystal (LC) analog phase modulator with >2π phase range at a 1 kHz switching frequency. The chiral nematic LC mixture consists of the bimesogen CBC7CB with chiral dopant R5011, aligned in the uniform lying helix mode. The mixture exhibits >±π/4 rotation of the optic axis for a drive voltage of ±21.5 V (E=±4.5 V µm-1). The rotation of the optic axis is converted into a phase modulation with the aid of a reflective device configuration incorporating a ∼5 µm LC cell, a polarizer, two quarter-wave plates, and a mirror. The residual amplitude modulation is found to be <23%. This flexoelectro-optic phase modulator combination has the potential to enable analog spatial light modulators with very fast frame rates suitable for a range of applications.

Two-dimensional Ising model on random lattices with constant coordination number.

We study the two-dimensional Ising model on networks with quenched topological (connectivity) disorder. In particular, we construct random lattices of constant coordination number and perform large-scale Monte Carlo simulations in order to obtain critical exponents using finite-size scaling relations. We find disorder-dependent effective critical exponents, similar to diluted models, showing thus no clear universal behavior. Considering the very recent results for the two-dimensional Ising model on proximity graphs and the coordination number correlation analysis suggested by Barghathi and Vojta [Phys. Rev. Lett. 113, 120602 (2014)PRLTAO0031-900710.1103/PhysRevLett.113.120602], our results indicate that the planarity and connectedness of the lattice play an important role on deciding whether the phase transition is stable against quenched topological disorder.

Time-resolved retardance and optic-axis angle measurement system for characterization of flexoelectro-optic liquid crystal and other birefringent devices.

A new polarimeter is presented which gives time-resolved measurements of both the optic-axis angle and the linear phase retardation for modulated birefringent optical devices. It is suitable for characterizing dynamic waveplate devices based on liquid crystal and other materials. It is fully automated and requires no angular alignment of the device under test. The system has an absolute angle error of < ± 0.3° and a retardance error of < ± 0.44°, with considerably better relative accuracy. The method has been tested with a chiral nematic liquid crystal device exhibiting flexoelectro-optic switching at 3 kHz in the uniform lying helix mode. These results represent the first time-resolved tilt-angle and phase retardation measurements for a liquid crystal device operating at fast switching frequencies.

Clinical, Biochemical, and Molecular Presentation in a Patient with the cblD-Homocystinuria Inborn Error of Cobalamin Metabolism.

Disorders of intracellular cobalamin (vitamin B12) metabolism result from deficient synthesis of the coenzymes derived from vitamin B12: adenosylcobalamin and methylcobalamin. Disturbances of cobalamin-cofactor synthesis result in elevated levels of homocysteine and/or methylmalonic acid. Nine defects of intracellular cobalamin metabolism have been defined. The most common of these disorders is cblC (combined methylmalonic aciduria and homocystinuria). The cblD disorder is rare with fewer than twenty cases reported in the literature. Some cblD patients have combined methylmalonic aciduria and homocystinuria (referred to as "cblD original," "cblD-combined," or herein "cblD-MMA/HC"); some have isolated homocystinuria (referred to as "cblD-variant 1" or herein "cblD-HC"); and others have isolated methylmalonic aciduria (called "cblD-variant 2" or herein "cblD-MMA"). Only six cases of cblD-HC have been defined thus far. We report the 7th case of cblD-HC. The clinical manifestations, biochemical profile, genetic mutation, and plausible ancestry are discussed.

Identification of protein biomarkers in human serum using iTRAQ and shotgun mass spectrometry.

Blood serum is one of the easiest accessible sources of biomarkers and its proteome presents a significant parcel of immune system proteins. These proteins can provide not only biological explanation but also diagnostic and drug response answers independently of the type of disease or condition in question. Shotgun mass spectrometry has profoundly contributed to proteome analysis and is presently considered as an indispensible tool in the field of biomarker discovery. In addition, the multiplexing potential of isotopic labeling techniques such as iTRAQ can increase statistical relevance and accuracy of proteomic data through the simultaneous analysis of different biological samples. Here, we describe a complete protocol using iTRAQ in a shotgun proteomics workflow along with data analysis steps, customized for the challenges associated with the serum proteome.

Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT.

OBJECTIVE: Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy. METHODS: We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy. RESULTS: Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1-1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients. CONCLUSIONS: The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.

Affinity depletion of plasma and serum for mass spectrometry-based proteome analysis.

Protein biomarker discovery in blood plasma and serum is severely hampered by the vast dynamic range of the proteome. With protein concentrations spanning 12 orders of magnitude, conventional mass spectrometric analysis allows for detection of only a few low-abundance proteins. Prior depletion of high-abundant proteins from the sample can increase analytical depth considerably and has become a widely used practice. We describe in detail an affinity depletion method that selectively removes 14 of the most abundant proteins in plasma and serum.

Protein phosphorylation patterns in serum from schizophrenia patients and healthy controls.

Most proteomic studies to date have attempted to identify changes in protein levels without considering the effects of post-translational modifications (PTM). However, characteristic changes of PTM such as phosphorylation could be biologically informative, as these can give insights into disease and drug mechanisms of action at the functional level. With this in mind, we have conducted a comparative proteomic and phosphoproteomic analysis of blood sera from 20 antipsychotic-naïve schizophrenia patients and 20 matched healthy controls. We used immobilised metal ion affinity chromatography (IMAC) for enrichment of phosphoproteins combined with label-free liquid chromatography-mass spectrometry (LC-MS(E)) for identification and measurement of protein and phosphoprotein levels. The LC-MS(E) analysis of both IMAC-fractions resulted in identification of 35 proteins with altered levels in schizophrenia. Analysis of the enriched fraction resulted in identification of 72 phosphoproteins with altered phosphorylation patterns. Of these, 59 showed changes in phosphorylation only, with no overall change in protein levels. This study provided evidence that schizophrenia patients feature serum abnormalities in phosphorylation of proteins involved in acute phase response and coagulation pathways. Further studies of such phosphorylation-specific changes could lead to a better understanding of the molecular aetiology of schizophrenia, and provide a means of biomarker identification for clinical studies. This article is part of a Special Issue entitled: Integrated omics.

Clinical use of phosphorylated proteins in blood serum analysed by immobilised metal ion affinity chromatography and mass spectrometry.

The process of protein phosphorylation in cells is well studied in the context of a wide range of biologic functions such as signalling, cell cycle, cell growth and differentiation, and others. In contrast, little progress has been made in the investigation of protein phosphorylation specifically in blood. Here, we focussed on the phosphoproteome in human blood serum to study its extent and characteristics, and to explore the potential clinical utility. Immobilised metal ion affinity chromatography (IMAC) for the enrichment of intact phosphorylated proteins and label-free liquid chromatography-mass spectrometry (LC-MS(E)) were used for the molecular analysis of a large number of serum samples. To obtain high-confidence results, phosphorylated peptides had to be detected in at least 2 out of 3 technical replicates per sample and in >70% of the serum samples drawn from 80 volunteers. Individual analysis of these 80 non-pooled samples resulted in the detection of 5825 unique phosphorylated peptides after filtering, which corresponded to 502 unique proteins. The results provided evidence that blood serum may be an untapped source of phosphoproteins suitable for potential use in understanding disease pathophysiology and for identification of disease and drug response biomarkers. This article is part of a Special Issue entitled: Integrated omics.

Multidimensional protein fractionation of blood proteins coupled to data-independent nanoLC-MS/MS analysis.

In order to exploit human blood as a source of protein disease biomarkers, robust analytical methods are needed to overcome the inherent molecular complexity of this bio-fluid. We present the coupling of label-free SAX chromatography and IMAC to a data-independent nanoLC-MS/MS (nanoLC-MS(E)) platform for analysis of blood plasma and serum proteins. The methods were evaluated using protein standards added at different concentrations to two groups of samples. The results demonstrate that both techniques enable accurate protein quantitation using low sample volumes and a minimal number of fractions. Combining both methods, 883 unique proteins were identified, of which 423 proteins showed high reproducibility. The two approaches resulted in identification of unique molecular signatures with an overlap of approximately 30%, thus providing complimentary information on sub-proteomes. These methods are potentially useful for systems biology, biomarker discovery, and investigation of phosphoproteins in blood.