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Sensitive magnetic nucleic acid (NA) detection via frequency mixing magnetic detection (FMMD) requires amplified NA samples for which a reliable temperature control is necessary. The feasibility of recombinase polymerase amplification (RPA) was studied within a newly integrated temperature-controlled sensor unit of a mobile FMMD based setup. It has been demonstrated that the inherently generated heat of the low frequency (LF) excitation signal of FMMD can be utilized and controlled by means of pulse width modulation (PWM). To test control performance in a point of care (PoC) setting with changing ambient conditions, a steady state and dynamic response model for the thermal behavior at the sample position of the sensor were developed. We confirmed that in the sensor unit of the FMMD device, RPA performs similar as in a temperature-controlled water bath. For narrow steady state temperature regions, a linear extrapolation suffices for estimation of the sample position temperature, based on the temperature feedback sensor for PWM control. For any other ambient conditions, we identified and validated a lumped parameter model (LPM) performing with high estimation accuracy. We expect that the method can be used for NA amplification and magnetic detection using FMMD in resource-limited settings.

Magnetic nanoparticles (MNPs), particularly iron oxide nanoparticles (IONPs), play a pivotal role in biomedical applications ranging from magnetic resonance imaging (MRI) enhancement and cancer hyperthermia treatments to biosensing. This study focuses on the synthesis, characterization, and application of IONPs with two different size distributions for frequency mixing magnetic detection (FMMD), a technique that leverages the nonlinear magnetization properties of MNPs for sensitive biosensing. IONPs are synthesized through thermal decomposition and subsequent growth steps. Our findings highlight the critical influence of IONP size on the FMMD signal, demonstrating that larger particles contribute dominantly to the FMMD signal. This research advances our understanding of IONP behavior, underscoring the importance of size in their application in advanced diagnostic tools.

We present two magnetic particle imaging (MPI) systems with bore sizes of 75 mm and 100 mm, respectively, using three-dimensionally arranged permanent magnets for excitation and frequency mixing magnetic detection (FMMD) coils for detection. A rotational and a translational stage were combined to move the field free line (FFL) and acquire the MPI signal, thereby enabling simultaneous overall translation and rotational movement. With this concept, the complex coil system used in many MPI systems, with its high energy consumption to generate the drive field, can be replaced. The characteristic signal of superparamagnetic iron oxide (SPIO) nanoparticles was generated via movement of the FFL and acquired using the FMMD coil. The positions of the stages and the occurrence of the f 1 + 2 f 2 harmonics were mapped to reconstruct the spatial location of the SPIO. Image reconstruction was performed using Radon and inverse Radon transformations. As a result, the presented method based on mechanical movement of permanent magnets can be used to measure the MPI, even for samples as large as 100 mm. Our research could pave the way for further technological developments to make the equipment human size, which is one of the ultimate goals of MPI.

Frequency mixing magnetic detection (FMMD) is a sensitive and selective technique to detect magnetic nanoparticles (MNPs) serving as probes for binding biological targets. Its principle relies on the nonlinear magnetic relaxation dynamics of a particle ensemble interacting with a dual frequency external magnetic field. In order to increase its sensitivity, lower its limit of detection and overall improve its applicability in biosensing, matching combinations of external field parameters and internal particle properties are being sought to advance FMMD. In this study, we systematically probe the aforementioned interaction with coupled Néel-Brownian dynamic relaxation simulations to examine how key MNP properties as well as applied field parameters affect the frequency mixing signal generation. It is found that the core size of MNPs dominates their nonlinear magnetic response, with the strongest contributions from the largest particles. The drive field amplitude dominates the shape of the field-dependent response, whereas effective anisotropy and hydrodynamic size of the particles only weakly influence the signal generation in FMMD. For tailoring the MNP properties and parameters of the setup towards optimal FMMD signal generation, our findings suggest choosing large particles of core sizes dC>25 nm with narrow size distributions (σ<0.1) to minimize the required drive field amplitude. This allows potential improvements of FMMD as a stand-alone application, as well as advances in magnetic particle imaging, hyperthermia and magnetic immunoassays.

In this study, we propose an efficient field-free line (FFL) generator for mechanically driven FFL magnetic particle imaging (MPI) applications. The novel FFL generator comprises pairs of Halbach arrays and bar magnets. The proposed design generates high-gradient FFLs with low-mass permanent magnets, realizing fine spatial resolutions in MPI. We investigate the magnetic field generated using simulations and experiments. Our results show that the FFL generator yields a high gradient of 4.76 T/m at a cylindrical field of view of 30 mm diameter and a 70 mm open bore. A spatial resolution of less than 3.5 mm was obtained in the mechanically driven FFL-MPI.

Due to the limitations of conventional Brucella detection methods, including safety concerns, long incubation times, and limited specificity, the development of a rapid, selective, and accurate technique for the early detection of Brucella in livestock animals is crucial to prevent the spread of the associated disease. In the present study, we introduce a magnetic nanoparticle marker-based biosensor using frequency mixing magnetic detection for point-of-care testing and quantification of Brucella DNA. Superparamagnetic nanoparticles were used as magnetically measured markers to selectively detect the target DNA hybridized with its complementary capture probes immobilized on a porous polyethylene filter. Experimental conditions like density and length of the probes, hybridization time and temperature, and magnetic binding specificity, sensitivity, and detection limit were investigated and optimized. Our sensor demonstrated a relatively fast detection time of approximately 10 min, with a detection limit of 55 copies (0.09 fM) when tested using DNA amplified from Brucella genetic material. In addition, the detection specificity was examined using gDNA from Brucella and other zoonotic bacteria that may coexist in the same niche, confirming the method's selectivity for Brucella DNA. Our proposed biosensor has the potential to be used for the early detection of Brucella bacteria in the field and can contribute to disease control measures.

Frequency mixing magnetic detection (FMMD) has been explored for its applications in fields of magnetic biosensing, multiplex detection of magnetic nanoparticles (MNP) and the determination of core size distribution of MNP samples. Such applications rely on the application of a static offset magnetic field, which is generated traditionally with an electromagnet. Such a setup requires a current source, as well as passive or active cooling strategies, which directly sets a limitation based on the portability aspect that is desired for point of care (POC) monitoring applications. In this work, a measurement head is introduced that involves the utilization of two ring-shaped permanent magnets to generate a static offset magnetic field. A steel cylinder in the ring bores homogenizes the field. By variation of the distance between the ring magnets and of the thickness of the steel cylinder, the magnitude of the magnetic field at the sample position can be adjusted. Furthermore, the measurement setup is compared to the electromagnet offset module based on measured signals and temperature behavior.

Epithelial cells of human breast glands are exposed to various mechanical ECM stresses that regulate tissue development and homeostasis. Mechanoadaptation of breast gland tissue to ECM-transmitted shear stress remained poorly investigated due to the lack of valid experimental approaches. Therefore, we created a magnetic shear strain device that enabled, for the first time, to analyze the instant shear strain response of human breast gland cells. MCF10A-derived breast acini with basement membranes (BM) of defined maturation state and basoapical polarization were used to resemble breast gland morphogenesis in vitro . The novel biophysical tool was used to apply cyclic shear strain with defined amplitudes (≤15%, 0.2 Hz) over 22 h on living spheroids embedded in an ultrasoft matrix (<60 Pa). We demonstrated that breast spheroids gain resistance to shear strain, which increased with BM maturation and basoapical polarization. Most intriguingly, poorly developed spheroids were prone to cyclic strain-induced extrusion of apoptotic cells from the spheroid body. In contrast, matured spheroids were insensitive to this mechanoresponse-indicating changing mechanosensing or mechanotransduction mechanisms during breast tissue morphogenesis. Together, we introduced a versatile tool to study cyclic shear stress responses of 3D cell culture models. It can be used to strain, in principle, all kinds of cell clusters, even those that grow only in ultrasoft hydrogels. We believe that this approach opens new doors to gain new insights into dynamic shear strain-induced mechanobiological regulation circuits between cells and their ECM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Friedland, Babu, Springer, Konrad, Herfs, Gerlach, Gehlen, Krause, De Laporte, Merkel and Noetzel.)

Magnetic immunoassays employing Frequency Mixing Magnetic Detection (FMMD) have recently become increasingly popular for quantitative detection of various analytes. Simultaneous analysis of a sample for two or more targets is desirable in order to reduce the sample amount, save consumables, and save time. We show that different types of magnetic beads can be distinguished according to their frequency mixing response to a two-frequency magnetic excitation at different static magnetic offset fields. We recorded the offset field dependent FMMD response of two different particle types at frequencies f 1 + n ⋅ f 2 , n = 1, 2, 3, 4 with f 1 = 30.8 kHz and f 2 = 63 Hz. Their signals were clearly distinguishable by the locations of the extremes and zeros of their responses. Binary mixtures of the two particle types were prepared with different mixing ratios. The mixture samples were analyzed by determining the best linear combination of the two pure constituents that best resembled the measured signals of the mixtures. Using a quadratic programming algorithm, the mixing ratios could be determined with an accuracy of greater than 14%. If each particle type is functionalized with a different antibody, multiplex detection of two different analytes becomes feasible.

The rapid and sensitive diagnosis of the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the crucial issues at the outbreak of the ongoing global pandemic that has no valid cure. Here, we propose a SARS-CoV-2 antibody conjugated magnetic graphene quantum dots (GQDs)-based magnetic relaxation switch (MRSw) that specifically recognizes the SARS-CoV-2. The probe of MRSw can be directly mixed with the test sample in a fully sealed vial without sample pretreatment, which largely reduces the testers' risk of infection during the operation. The closed-tube one-step strategy to detect SARS-CoV-2 is developed with home-made ultra-low field nuclear magnetic resonance (ULF NMR) relaxometry working at 118 μT. The magnetic GQDs-based probe shows ultra-high sensitivity in the detection of SARS-CoV-2 due to its high magnetic relaxivity, and the limit of detection is optimized to 248 Particles mL ‒1 . Meanwhile, the detection time in ULF NMR system is only 2 min, which can significantly improve the efficiency of detection. In short, the magnetic GQDs-based MRSw coupled with ULF NMR can realize a rapid, safe, and sensitive detection of SARS-CoV-2., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Elsevier B.V. All rights reserved.)

Dual frequency magnetic excitation of magnetic nanoparticles (MNP) enables enhanced biosensing applications. This was studied from an experimental and theoretical perspective: nonlinear sum-frequency components of MNP exposed to dual-frequency magnetic excitation were measured as a function of static magnetic offset field. The Langevin model in thermodynamic equilibrium was fitted to the experimental data to derive parameters of the lognormal core size distribution. These parameters were subsequently used as inputs for micromagnetic Monte-Carlo (MC)-simulations. From the hysteresis loops obtained from MC-simulations, sum-frequency components were numerically demodulated and compared with both experiment and Langevin model predictions. From the latter, we derived that approximately 90% of the frequency mixing magnetic response signal is generated by the largest 10% of MNP. We therefore suggest that small particles do not contribute to the frequency mixing signal, which is supported by MC-simulation results. Both theoretical approaches describe the experimental signal shapes well, but with notable differences between experiment and micromagnetic simulations. These deviations could result from Brownian relaxations which are, albeit experimentally inhibited, included in MC-simulation, or (yet unconsidered) cluster-effects of MNP, or inaccurately derived input for MC-simulations, because the largest particles dominate the experimental signal but concurrently do not fulfill the precondition of thermodynamic equilibrium required by Langevin theory.

A novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in China in December 2019, causing an ongoing, rapidly spreading global pandemic. Worldwide, vaccination is now expected to provide containment of the novel virus, resulting in an antibody-mediated immunity. To verify this, serological antibody assays qualitatively as well as quantitatively depicting the amount of generated antibodies are of great importance. Currently available test methods are either laboratory based or do not have the ability to indicate an estimation about the immune response. To overcome this, a novel and rapid serological magnetic immunodetection (MID) point-of-care (PoC) assay was developed, with sensitivity and specificity comparable to laboratory-based DiaSorin Liaison SARS-CoV-2 S1/S2 IgG assay. To specifically enrich human antibodies against SARS-CoV-2 in immunofiltration columns (IFCs) from patient sera, a SARS-CoV-2 S1 antigen was transiently produced in plants, purified and immobilized on the IFC. Then, an IgG-specific secondary antibody could bind to the retained antibodies, which was finally labeled using superparamagnetic nanoparticles. Based on frequency magnetic mixing technology (FMMD), the magnetic particles enriched in IFC were detected using a portable FMMD device. The obtained measurement signal correlates with the amount of SARS-CoV-2-specific antibodies in the sera, which could be demonstrated by titer determination. In this study, a MID-based assay could be developed, giving qualitative as well as semiquantitative results of SARS-CoV-2-specific antibody levels in patient's sera within 21 min of assay time with a sensitivity of 97% and a specificity of 92%, based on the analysis of 170 sera from hospitalized patients that were tested using an Food and Drug Administration (FDA)-certified chemiluminescence assay., Competing Interests: TS was employed by the company Cape Biologix Technologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pietschmann, Voepel, Voß, Rasche, Schubert, Kleines, Krause, Shaw, Spiegel and Schroeper.)

The misuse of antibiotics as well as incorrect dosage or insufficient time for detoxification can result in the presence of pharmacologically active molecules in fresh milk. Hence, in many countries, commercially available milk has to be tested with immunological, chromatographic or microbiological analytical methods to avoid consumption of antibiotic residues. Here a novel, sensitive and portable assay setup for the detection and quantification of penicillin and kanamycin in whole fat milk (WFM) based on competitive magnetic immunodetection (cMID) is described and assay accuracy determined. For this, penicillin G and kanamycin-conjugates were generated and coated onto a matrix of immunofiltration columns (IFC). Biotinylated penicillin G or kanamycin-specific antibodies were pre-incubated with antibiotics-containing samples and subsequently applied onto IFC to determine the concentration of antibiotics through the competition of antibody-binding to the antibiotic-conjugate molecules. Bound antibodies were labeled with streptavidin-coated magnetic particles and quantified using frequency magnetic mixing technology. Based on calibration measurements in WFM with detection limits of 1.33 ng·mL -1 for penicillin G and 1.0 ng·mL -1 for kanamycin, spiked WFM samples were analyzed, revealing highly accurate recovery rates and assay precision. Our results demonstrate the suitability of cMID-based competition assay for reliable and easy on-site testing of milk.

The magnetic particle imaging (MPI) is a technology that can image the concentrations of the superparamagnetic iron oxide nanoparticles (SPIONs) which can be used in biomedical diagnostics and therapeutics as non-radioactive tracers. We proposed a point-of-care testing MPI system (PoCT-MPI) that can be used for preclinical use for imaging small rodents (mice) injected with SPIONs not only in laboratories, but also at emergency sites far from laboratories. In particular, we applied a frequency mixing magnetic detection method to the PoCT-MPI, and proposed a hybrid field free line generator to reduce the power consumption, size and weight of the system. The PoCT-MPI is [Formula: see text] in size and weighs less than 100 kg. It can image a three-dimensional distribution of SPIONs injected into a biosample with less than 120 Wh of power consumption. Its detection limit is [Formula: see text], 10 mg/mL, [Formula: see text] (Fe).

Food and crop contaminations with mycotoxins are a severe health risk for consumers and cause high economic losses worldwide. Currently, different chromatographic- and immuno-based methods are used to detect mycotoxins within different sample matrices. There is a need for novel, highly sensitive detection technologies that avoid time-consuming procedures and expensive laboratory equipment but still provide sufficient sensitivity to achieve the mandated detection limit for mycotoxin content. Here we describe a novel, highly sensitive, and portable aflatoxin B1 detection approach using competitive magnetic immunodetection (cMID). As a reference method, a competitive ELISA optimized by checkerboard titration was established. For the novel cMID procedure, immunofiltration columns, coated with aflatoxin B1-BSA conjugate were used for competitive enrichment of biotinylated aflatoxin B1-specific antibodies. Subsequently, magnetic particles functionalized with streptavidin can be applied to magnetically label retained antibodies. By means of frequency mixing technology, particles were detected and quantified corresponding to the aflatoxin content in the sample. After the optimization of assay conditions, we successfully demonstrated the new competitive magnetic detection approach with a comparable detection limit of 1.1 ng aflatoxin B1 per ml sample to the cELISA reference method. Our results indicate that the cMID is a promising method reducing the risks of processing contaminated commodities., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Occlusion of the major cerebral artery usually results in brain hypoxic-ischemic injury, which evokes neuroinflammation and microglial activation. Activated microglia are considered a source of multiple neurotoxic factors, such as reactive oxygen species (ROS), in the central nervous system (CNS). We herein present a 3D-rendering brain imaging technique in an experimental rodent model of cerebral ischemia based on 2D magnetic images of superparamagnetic iron oxide nanoparticles (SPIONs) using the planar frequency mixing magnetic detection (p-FMMD) technique. A rat model of cerebral ischemia was established by unilateral middle cerebral artery occlusion with reperfusion (MCAO/R) injury. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was performed to demonstrate the irreversibly damaged ischemic brain tissues, and double immunofluorescent labeling of OX6 (activated microglial marker) and ethidium (ROS marker) was conducted to confirm ROS generation in the activated microglia in the infarcted brain region. The ischemic brain sections treated with OX6-conjugated SPIONs were scanned using our p-FMMD system, yielding 2D images on the basis of the nonlinear magnetic characteristics inherent in SPIONs. The p-FMMD signal images representing microglia activation show an infarct ratio of 44.6 ± 7.1% compared to the contralateral counterpart, which is smaller than observed by TTC (60.9 ± 4.9%) or magnetic resonance imaging (MRI, 65.7 ± 2.7%). Furthermore, we developed a 3D-rendering brain imaging process based on the 2D p-FMMD signal images. The 3D reconstructed model showed a decreased ratio of coincidence of the ischemic regions compared with MRI models. In this study, we successfully conducted a feasibility test on whether our p-FMMD technology, a technique for signaling and imaging based on the nonlinearity of SPIONs, can be used to visualize the ischemic brain region in real time by detecting activated microglia in an MCAO/R animal model. Therefore, our method might allow for a different approach to analyze the pathophysiology of ischemic stroke through molecular imaging. Furthermore, we propose that this magnetic particle imaging (MPI) technique that detects the nonlinear magnetization properties of SPIONs could be applied not only to a stroke model but also to various types of pathophysiological studies as a new bioimaging tool.

Low field (LF) nuclear magnetic resonance (NMR) shows potential advantages to study pure heteronuclear J-coupling and observe the fine structure of matter. Power-line harmonics interferences and fixed-frequency noise peaks might introduce discrete noise peaks into the LF-NMR spectrum in an open environment or in a conductively shielded room, which might disturb J-coupling spectra of matter recorded at LF. In this paper, we describe a multi-channel sensor configuration of superconducting quantum interference devices, and measure the multiple peaks of the 2,2,2-trifluoroethanol J-coupling spectrum. For the case of low signal to noise ratio (SNR) < 1, we suggest two noise suppression algorithms using discrete wavelet analysis (DWA), combined with either least squares method (LSM) or gradient descent (GD). The de-noising methods are based on spatial correlation of the interferences among the superconducting sensors, and are experimentally demonstrated. The DWA-LSM algorithm shows a significant effect in the noise reduction and recovers SNR > 1 for most of the signal peaks. The DWA-GD algorithm improves the SNR further, but takes more computational time. Depending on whether the accuracy or the speed of the de-noising process is more important in LF-NMR applications, the choice of algorithm should be made.

Cholera is a life-threatening disease caused by the cholera toxin (CT) as produced by some Vibrio cholerae serogroups. In this research we present a method which directly detects the toxin's B subunit (CTB) in drinking water. For this purpose we performed a magnetic sandwich immunoassay inside a 3D immunofiltration column. We used two different commercially available antibodies to capture CTB and for binding to superparamagnetic beads. ELISA experiments were performed to select the antibody combination. The beads act as labels for the magnetic frequency mixing detection technique. We show that the limit of detection depends on the type of magnetic beads. A nonlinear Hill curve was fitted to the calibration measurements by means of a custom-written python software. We achieved a sensitive and rapid detection of CTB within a broad concentration range from 0.2 ng/ml to more than 700 ng/ml., Competing Interests: The authors have declared that no competing interests exist.

In modern bioanalytical methods, it is often desired to detect several targets in one sample within one measurement. Immunological methods including those that use superparamagnetic beads are an important group of techniques for these applications. The goal of this work is to investigate the feasibility of simultaneously detecting different superparamagnetic beads acting as markers using the magnetic frequency mixing technique. The frequency of the magnetic excitation field is scanned while the lower driving frequency is kept constant. Due to the particles' nonlinear magnetization, mixing frequencies are generated. To record their amplitude and phase information, a direct digitization of the pickup-coil's signal with subsequent Fast Fourier Transformation is performed. By synchronizing both magnetic fields, a stable phase information is gained. In this research, it is shown that the amplitude of the dominant mixing component is proportional to the amount of superparamagnetic beads inside a sample. Additionally, it is shown that the phase does not show this behaviour. Excitation frequency scans of different bead types were performed, showing different phases, without correlation to their diverse amplitudes. Two commercially available beads were selected and a determination of their amount in a mixture is performed as a demonstration for multiplex measurements.

For performing point-of-care molecular diagnostics, magnetic immunoassays constitute a promising alternative to established enzyme-linked immunosorbent assays (ELISA) because they are fast, robust and sensitive. Simultaneous detection of multiple biomolecular targets from one body fluid sample is desired. The aim of this work is to show that multiplex magnetic immunodetection based on magnetic frequency mixing by means of modular immunofiltration columns prepared for different targets is feasible. By calculations of the magnetic response signal, the required spacing between the modules was determined. Immunofiltration columns were manufactured by 3D printing and antibody immobilization was performed in a batch approach. It was shown experimentally that two different target molecules in a sample solution could be individually detected in a single assaying step with magnetic measurements of the corresponding immobilization filters. The arrangement order of the filters and of a negative control did not influence the results. Thus, a simple and reliable approach to multi-target magnetic immunodetection was demonstrated.

In recent years, NMR with hyperpolarized (HP) xenon inside functionalized host structures (e.g., cryptophanes) have become a potential candidate for the direct observation of metabolic processes (i.e., molecular imaging). A critical issue for real applications is the dissolution of the HP-gas in the liquid which contains the host. In this work, we present recent developments for an improved and controlled dissolution of HP-Xe in liquids using hollow fiber membranes and different compressor systems. The designed apparatus consists of a compressor and a membrane unit. The compressor provides HP- 129 Xe continuously at small adjustable pressures and in a polarization-preserving way. The membrane unit enables a molecular solution of the HP-gas in aqueous liquids, avoiding the formation of bubbles or even foams. Two different types of compressors were tested in terms of function and useful materials. Special emphasis was put on a systematic reduction of transfer losses in the gas and liquid phase. In order to optimize the system parameters, several physical models were developed to describe the transport and the losses of nuclear polarization. Finally, the successful implementation was demonstrated in several experiments. HP-Xe was dissolved in an aqueous cryptophane-A-(OCH 2 COOH) 6 solution, and stable Xe signals could be measured over 35 min, only limited by the size of the gas reservoir. Such long and stable experimental conditions enabled the study of chemical exchange of xenon between cryptophane and water environments even for a time-consuming 2D NMR experiment. The good signal stability over the measurement time allowed an exact determination of the residence time of the Xe atom inside the cryptophane, resulting in an average residence time of 44.5 ± 2.7 ms.

A magnetic frequency mixing technique with a set of miniaturized planar coils was investigated for use with a completely integrated Lab-on-Chip (LoC) pathogen sensing system. The system allows the detection and quantification of superparamagnetic beads. Additionally, in terms of magnetic nanoparticle characterization ability, the system can be used for immunoassays using the beads as markers. Analytical calculations and simulations for both excitation and pick-up coils are presented; the goal was to investigate the miniaturization of simple and cost-effective planar spiral coils. Following these calculations, a Printed Circuit Board (PCB) prototype was designed, manufactured, and tested for limit of detection, linear response, and validation of theoretical concepts. Using the magnetic frequency mixing technique, a limit of detection of 15 µg/mL of 20 nm core-sized nanoparticles was achieved without any shielding.

Power-line harmonic interference and fixed-frequency noise peaks may cause stripe-artifacts in ultra-low field (ULF) magnetic resonance imaging (MRI) in an unshielded environment and in a conductively shielded room. In this paper we describe an adaptive suppression method to eliminate these artifacts in MRI images. This technique utilizes spatial correlation of the interference from different positions, and is realized by subtracting the outputs of the reference channel(s) from those of the signal channel(s) using wavelet analysis and the least squares method. The adaptive suppression method is first implemented to remove the image artifacts in simulation. We then experimentally demonstrate the feasibility of this technique by adding three orthogonal superconducting quantum interference device (SQUID) magnetometers as reference channels to compensate the output of one 2nd-order gradiometer. The experimental results show great improvement in the imaging quality in both 1D and 2D MRI images at two common imaging frequencies, 1.3 kHz and 4.8 kHz. At both frequencies, the effective compensation bandwidth is as high as 2 kHz. Furthermore, we examine the longitudinal relaxation times of the same sample before and after compensation, and show that the MRI properties of the sample did not change after applying adaptive suppression. This technique can effectively increase the imaging bandwidth and be applied to ULF MRI detected by either SQUIDs or Faraday coil in both an unshielded environment and a conductively shielded room., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Over the past decade, the richness of electronic properties of graphene has attracted enormous interest for electrically detecting chemical and biological species using this two-dimensional material. However, the creation of practical graphene electronic sensors greatly depends on our ability to understand and maintain a low level of electronic noise, the fundamental reason limiting the sensor resolution. Conventionally, to reach the largest sensing response, graphene transistors are operated at the point of maximum transconductance, where 1/ f noise is found to be unfavorably high and poses a major limitation in any attempt to further improve the device sensitivity. We show that operating a graphene transistor in an ambipolar mode near its neutrality point can markedly reduce the 1/ f noise in graphene. Remarkably, our data reveal that this reduction in the electronic noise is achieved with uncompromised sensing response of the graphene chips and thus significantly improving the signal-to-noise ratio-compared to that of a conventionally operated graphene transistor for conductance measurement. As a proof-of-concept demonstration of the usage of the aforementioned new sensing scheme to a broader range of biochemical sensing applications, we selected an HIV-related DNA hybridization as the test bed and achieved detections at picomolar concentrations.

Emerging miniaturization technologies for biological and bioengineering applications require precise control over position and actuation of microparticles. While many of these applications call for high-throughput approaches, common tools for particle manipulation, such as magnetic or optical tweezers, suffer from low parallelizability. To address this issue, we introduce a chip-based platform that enables flexible three-dimensional control over individual magnetic microparticles. Our system relies on microwire crossbar arrays for simultaneous generation of magnetic and dielectric forces, which actuate the particles along highly localized traps. We demonstrate the precise spatiotemporal control of individual particles by tracing complex trajectories in three dimensions and investigate the forces that can be generated along different axes. Furthermore, we show that our approach for particle actuation can be parallelized by simultaneously controlling the position and movement of 16 particles in parallel.

There is increasing evidence that mechanical issues play a vital role in neuron growth and brain development. The importance of this grows as novel devices, whose material properties differ from cells, are increasingly implanted in the body. In this work, we studied the mechanical properties of rat brain cells over time and on different materials by using a high throughput magnetic tweezers system. It was found that the elastic moduli of both neurite and soma in networked neurons increased with growth. However, neurites at DIV4 exhibited a relatively high stiffness, which could be ascribed to the high outgrowth tension. The power-law exponents (viscoelasticity) of both neurites and somas of neurons decreased with culture time. On the other hand, the stiffness of glial cells also increased with maturity. Furthermore, both neurites and glia become softer when cultured on compliant substrates. Especially, the glial cells cultured on a soft substrate obviously showed a less dense and more porous actin and GFAP mesh. In addition, the viscoelasticity of both neurites and glia did not show a significant dependence on the substrates' stiffness., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We represent the experimental results of our planar-frequency mixing magnetic detection (p-FMMD) technique to obtain 2D superparamagnetic images for magnetic immunoassay purpose. The imaging of magnetic beads is based on the nonlinear magnetic characteristics inherent in superparamagnetic materials. The p-FMMD records the sum-frequency components originating from both a high and a low frequency magnetic field incident on the magnetically nonlinear nanoparticles. In this study, we apply the p-FMMD technique to 2D scanning imaging of superparamagnetic iron oxide nanoparticles (SPIONs) in a microfluidic platform. Our p-FMMD system enables to acquire planar images of SPIONs filled in a microchannel as narrow as 30µm in width. The minimum detectable amount is ~1.0×10(8) beads of 100nm size. The system shows a spatial resolution enabling to distinguish between two distinct channels even 2mm apart from each other. Our p-FMMD system as a magnetic immunoassaying system has permitted the detection of amyloid beta 42 (Aβ42), a promising biomarker of Alzheimer's disease, at the minimum concentration of 23.8pg/ml. This may enable the identification of the Aβ42 levels for the early-stage of Alzheimer's disease with the assistance of the MPI using p-FMMD technique. The results show that the deployment of the p-FMMD can be an alternative to conventional biosensing analytical methods, and can be used as a fast and portable screening method., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We observe a deuteron beam polarization lifetime near 1000 s in the horizontal plane of a magnetic storage ring (COSY). This long spin coherence time is maintained through a combination of beam bunching, electron cooling, sextupole field corrections, and the suppression of collective effects through beam current limits. This record lifetime is required for a storage ring search for an intrinsic electric dipole moment on the deuteron at a statistical sensitivity level approaching 10^{-29}  e cm.

Functionalized magnetic nanoparticles (MNPs) can serve as magnetic relaxation sensors (MRSs) to detect different biological targets, because the clustering of magnetic particle may cause the spin-spin relaxation time (T2) decrease of the surrounding water protons. However, the application of MNPs in clinical NMR systems faces the challenge of poor stability at magnetic field strengths in the order of tesla. The recently developed ultra-low field (ULF) NMR technique working at microtesla (μT) range then becomes a candidate. Herein, we incorporated superconducting quantum interference device (SQUID) as the detector in the ultra-low field system to enhance the sensitivity. We functionalized the Fe3O4 nanoparticles with the gama-aminobutyrate type A receptor-associated proteins (GABARAP), which specifically interact with calreticulin (CRT). As a result of the interaction between GABARAP and CRT, the clustering of the functionalized MNPs generates local magnetic fields, which accelerate the dephasing of the water protons in the vicinity. We analyzed the relation between T2 values and the CRT concentrations at 211μT and the low detection limit for CRT is 10 pg/ml, which is superior to the immunoblot system. The high sensitivity of the ULF NMR system for protein-protein interaction detection demonstrates the potential to use this inexpensive, portable system for quick biochemical and clinical assays., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The setup of a planar Frequency Mixing Magnetic Detection (p-FMMD) scanner for performing Magnetic Particles Imaging (MPI) of flat samples is presented. It consists of two magnetic measurement heads on both sides of the sample mounted on the legs of a u-shaped support. The sample is locally exposed to a magnetic excitation field consisting of two distinct frequencies, a stronger component at about 77 kHz and a weaker field at 61 Hz. The nonlinear magnetization characteristics of superparamagnetic particles give rise to the generation of intermodulation products. A selected sum-frequency component of the high and low frequency magnetic field incident on the magnetically nonlinear particles is recorded by a demodulation electronics. In contrast to a conventional MPI scanner, p-FMMD does not require the application of a strong magnetic field to the whole sample because mixing of the two frequencies occurs locally. Thus, the lateral dimensions of the sample are just limited by the scanning range and the supports. However, the sample height determines the spatial resolution. In the current setup it is limited to 2 mm. As examples, we present two 20 mm × 25 mm p-FMMD images acquired from samples with 1 µm diameter maghemite particles in silanol matrix and with 50 nm magnetite particles in aminosilane matrix. The results show that the novel MPI scanner can be applied for analysis of thin biological samples and for medical diagnostic purposes.

We implemented a novel 2D magnetic twisting cytometry (MTC) based on a previously reported multi-pole high permeability electromagnet, in which both the strength and direction of the twisting field can be controlled. Thanks to the high performance twisting electromagnet and the heterodyning technology, the measurement frequency has been extended to the 1 kHz range. In order to obtain high remanence of the ferromagnetic beads, a separate electromagnet with feedback control was adopted for the high magnetic field polarization. Our setup constitutes the first instrument which can be operated both in MTC mode and in magnetic tweezers (MT) mode. In this work, the mechanical properties of HL-1 cardiomyocytes were characterized in MTC mode. Both anisotropy and log-normal distribution of cell stiffness were observed, which agree with our previous results measured in MT mode. The response from these living cells at different frequencies can be fitted very well by the soft glassy rheology model.

In this Letter, the ambipolar properties of an electrolyte-gated graphene field-effect transistor (GFET) have been explored to fabricate frequency-doubling biochemical sensor devices. By biasing the ambipolar GFETs in a common-source configuration, an input sinusoidal voltage at frequency f applied to the electrolyte gate can be rectified to a sinusoidal wave at frequency 2f at the drain electrode. The extraordinary high carrier mobility of graphene and the strong electrolyte gate coupling provide the graphene ambipolar frequency doubler an unprecedented unity gain, as well as a detection limit of ∼4 pM for 11-mer single strand DNA molecules in 1 mM PBS buffer solution. Combined with an improved drift characteristics and an enhanced low-frequency 1/f noise performance by sampling at doubled frequency, this good detection limit suggests the graphene ambipolar frequency doubler a highly promising biochemical sensing platform.

Recently the spin-lattice relaxation time T1 of hyperpolarized (HP)-(129)Xe was significantly improved by using uncoated and Rb-free storage vessels of GE180 glass. For these cells, a simple procedure was established to obtain reproducible wall relaxation times of about 18 h. Then the limiting relaxation mechanism in pure Xe is due to the coupling between the nuclear spins and the angular momentum of the Xe-Xe van-der-Waals-molecules. This mechanism can be significantly reduced by using different buffer gases of which CO2 was discovered to be the most efficient so far. From these values, it was estimated that for a 1:1 mixture of HP-Xe with CO2 a longitudinal relaxation time of about 7 h can be expected, sufficient to transport HP-Xe from a production to a remote application site. This prediction was verified for such a mixture at a total pressure of about 1 bar in a 10 cm glass cell showing a storage time of T1≈9 h (for T1(wall)=(34±9) h) which was transported inside a magnetic box over a distance of about 200 km by car., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A new method to determine the spin tune is described and tested. In an ideal planar magnetic ring, the spin tune-defined as the number of spin precessions per turn-is given by ν(s)=γG (γ is the Lorentz factor, G the gyromagnetic anomaly). At 970  MeV/c, the deuteron spins coherently precess at a frequency of ≈120  kHz in the Cooler Synchrotron COSY. The spin tune is deduced from the up-down asymmetry of deuteron-carbon scattering. In a time interval of 2.6 s, the spin tune was determined with a precision of the order 10^{-8}, and to 1×10^{-10} for a continuous 100 s accelerator cycle. This renders the presented method a new precision tool for accelerator physics; controlling the spin motion of particles to high precision is mandatory, in particular, for the measurement of electric dipole moments of charged particles in a storage ring.

Magnetic field fluctuations in our unshielded urban laboratory can reach hundreds of nT in the noisy daytime and is only a few nT in the quiet midnight. The field fluctuation causes the Larmor frequency fL to drift randomly for several Hz during the unshielded ultra-low field (ULF) nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) measurements, thus seriously spoiling the averaging effect and causing imaging artifacts. By using an active compensation (AC) technique based on the spatial correlation of the low-frequency magnetic field fluctuation, the field fluctuation can be suppressed to tens of nT, which is a moderate situation between the noisy daytime and the quiet midnight. In this paper, the effect of the field fluctuation on ULF MRI measurements was investigated. The 1D and 2D MRI signals of a water phantom were measured using a second-order low-Tc superconducting quantum interference device (SQUID) in three fluctuation cases: severe fluctuation (noisy daytime), moderate fluctuation (daytime with AC) and minute fluctuation (quiet midnight) when different gradient fields were applied. When the active compensation is applied or when the frequency encoding gradient field Gx reaches a sufficiently strong value in our measurements, the image artifacts become invisible in all three fluctuation cases. Therefore it is feasible to perform ULF-MRI measurements in unshielded urban environment without imaging artifacts originating from magnetic fluctuations by using the active compensation technique and/or strong gradient fields., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Plant pathogens cause major economic losses in the agricultural industry because late detection delays the implementation of measures that can prevent their dissemination. Sensitive and robust procedures for the rapid detection of plant pathogens are therefore required to reduce yield losses and the use of expensive, environmentally damaging chemicals. Here we describe a simple and portable system for the rapid detection of viral pathogens in infected plants based on immunofiltration, subsequent magnetic detection, and the quantification of magnetically labeled virus particles. Grapevine fanleaf virus (GFLV) was chosen as a model pathogen. Monoclonal antibodies recognizing the GFLV capsid protein were immobilized onto immunofiltration columns, and the same antibodies were linked to magnetic nanoparticles. GFLV was quantified by immunofiltration with magnetic labeling in a double-antibody sandwich configuration. A magnetic frequency mixing technique, in which a two-frequency magnetic excitation field was used to induce a sum frequency signal in the resonant detection coil, corresponding to the virus concentration within the immunofiltration column, was used for high-sensitivity quantification. We were able to measure GFLV concentrations in the range of 6 ng/ml to 20 μg/ml in less than 30 min. The magnetic immunoassay could also be adapted to detect other plant viruses, including Potato virus X and Tobacco mosaic virus, with detection limits of 2 to 60 ng/ml., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

As a powerful and versatile scientific instrument, magnetic tweezers have been widely used in biophysical research areas, such as mechanical cell properties and single molecule manipulation. If one wants to steer bead position, the nonlinearity of magnetic properties and the strong position dependence of the magnetic field in most magnetic tweezers lead to quite a challenge in their control. In this article, we report multi-pole electromagnetic tweezers with high permeability cores yielding high force output, good maneuverability, and flexible design. For modeling, we adopted a piece-wise linear dependence of magnetization on field to characterize the magnetic beads. We implemented a bi-linear interpolation of magnetic field in the work space, based on a lookup table obtained from finite element simulation. The electronics and software were custom-made to achieve high performance. In addition, the effects of dimension and defect on structure of magnetic tips also were inspected. In a workspace with size of 0.1 × 0.1 mm(2), a force of up to 400 pN can be applied on a 2.8 μm superparamagnetic bead in any direction within the plane. Because the magnetic particle is always pulled towards a tip, the pulling forces from the pole tips have to be well balanced in order to achieve control of the particle's position. Active video tracking based feedback control is implemented, which is able to work at a speed of up to 1 kHz, yielding good maneuverability of the magnetic beads.

In several low-field Nuclear Magnetic Resonance (LF-NMR) and surface nuclear magnetic resonance applications, i.e., in the frequency range of kHz, high sensitivity magnetic field detectors are needed. Usually, low-Tc superconducting quantum interference devices (SQUIDs) with a high field sensitivity of about 1 fT/Hz(1/2) are employed as detectors. Considering the flux trapping and operational difficulties associated with low-Tc SQUIDs, we designed and fabricated liquid-nitrogen-cooled Cu coils for NMR detection in the kHz range. A cooled coil system consisting of a 9-cm diameter Cu coil and a low noise preamplifier was systematically investigated and reached a sensitivity of 2 fT/Hz(1/2) at 77 K, which is 3 times better compared to the sensitivity at 300 K. A Q-switch circuit as an essential element for damping the ringing effects of the pickup coil was developed to acquire free induction decay signals of a water sample with minimum loss of signal. Our studies demonstrate that cooled Cu coils, if designed properly, can provide a comparable sensitivity to low-Tc SQUIDs.

We investigated and optimized the low-frequency noise characteristics of a preamplifier used for readout of direct current superconducting quantum interference devices (SQUIDs). When the SQUID output was detected directly using a room-temperature low-voltage-noise preamplifier, the low-frequency noise of a SQUID system was found to be dominated by the input current noise of the preamplifiers in case of a large dynamic resistance of the SQUID. To reduce the current noise of the preamplifier in the low-frequency range, we investigated the dependence of total preamplifier noise on the collector current and source resistance. When the collector current was decreased from 8.4 mA to 3 mA in the preamplifier made of 3 parallel SSM2220 transistor pairs, the low-frequency total voltage noise of the preamplifier (at 0.1 Hz) decreased by about 3 times for a source resistance of 30 Ω whereas the white noise level remained nearly unchanged. Since the relative contribution of preamplifier's input voltage and current noise is different depending on the dynamic resistance or flux-to-voltage transfer of the SQUID, the results showed that the total noise of a SQUID system at low-frequency range can be improved significantly by optimizing the preamplifier circuit parameters, mainly the collector current in case of low-noise bipolar transistor pairs.

Frequency mixing magnetic detection (FMMD) was used to detect superoxide from hypoxanthine and xanthine reaction and to detect hydroxyl radical from the Fenton reaction. FMMD was also applied to measure the reactive oxygen species (ROS) level released from microglial cells. We could assess the formation and extinction of the free radicals without a spin trap reagent. The FMMD signal amplitude scaled with the concentration of the radicals. It was verified that no signals are obtained from the substrates and reagents. Based on the observations and on previous research, we suggest that the FMMD signals originate from superoxide and hydroxyl radicals, indicating that FMMD can be used to detect O-centered radicals. Subsequent analysis of free radicals generated from living microglial cells showed that there were significant differences between the activated microglial cells and resting ones. The results of this research are promising regarding the applications of FMMD for in situ measurement of free radicals from various sources, including the cell., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We present the first experimental results of our planar-Frequency Mixing Magnetic Detection (p-FMMD) technique to obtain Magnetic Particles Imaging (MPI). The p-FMMD scanner consists of two magnetic measurement heads with intermediate space for the analysis of the sample. The magnetic signal originates from the nonlinear magnetization characteristics of superparamagnetic particles as in case of the usual MPI scanner. However, the detection principle is different. Standard MPI records the higher order harmonic response of particles at a field-free point or line. By contrast, FMMD records a sum-frequency component generated from both a high and a low frequency magnetic field incident on the magnetically nonlinear particles. As compared to conventional MPI scanner, there is no limit on the lateral dimensions of the sample; just the sample height is limited to 2 mm. In addition, the technique does not require a strong magnetic field or gradient because of the mixing of the two different frequencies. In this study, we acquired an 18 mm × 18 mm image of a string sample decorated with 100 nm diameter magnetic particles, using the p-FMMD technique. The results showed that it is feasible to use this novel MPI scanner for biological analysis and medical diagnostic purposes.

An integrated detection circuitry based on a lock-in amplifier was designed for contactless conductivity determination of heavy metals. Combined with a simple-structure electrophoresis microchip, the detection system is successfully utilized for the separation and determination of various heavy metals. The influences of the running buffer and detection conditions on the response of the detector have been investigated. Six millimole 2-morpholinoethanesulfonic acid + histidine were selected as buffer for its stable baseline and high sensitivity. The best signals were recorded with a frequency of 38 kHz and 20 V(pp). The results showed that Mn(2+), Cd(2+), Co(2+), and Cu(2+) can be successfully separated and detected within 100 s by our system. The detection limits for five heavy metals (Mn(2+), Pb(2+), Cd(2+), Co(2+), and Cu(2+)) were determined to range from about 0.7 to 5.4 μM. This microchip system performs a crucial step toward the realization of a simple, inexpensive, and portable analytical device for metal analysis., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) have attracted attention because of their current and potential usefulness as contrast agents for magnetic resonance imaging (MRI) and nuclear magnetic resonance (NMR). USPIOs are usually used for their significant capacity to produce predominant proton relaxation effects, which result in signal reduction. However, most previous studies that utilized USPIOs have been focused on the relaxation behavior at commonly used magnetic fields of clinical MRI systems (typically 1-3 T). In this paper, magnetic relaxation processes of protons in water surrounding the USPIOs are studied at ultralow (≤10 mT) and ultrahigh magnetic fields (14.1 T). USPIOs used in our experiments were synthesized with a core size of 6 nm, and transferred from organic to water by ligand exchange. The proton spin-lattice relaxation time (T(1)) and spin-spin relaxation time (T(2)) were investigated at ultralow (212 μT for T(2) and 10 mT for T(1)) and at 14.1 T with different iron concentrations. At all of the fields, there is a linear relationship between the inverse of relaxation times and the iron concentration. The spin-spin relaxivity (r(2)) at 14.1 T is much larger than that value of the ultralow field. At ultralow field, however, the spin-lattice relaxivity (r(1)) is larger than the r(1) at ultrahigh field. The results provide a perspective on potential in vivo and in vitro applications of USPIOs in ultralow and ultrahigh field NMR and MRI.

In most applications of biotechnology and downstream processing proteins are exposed to fluid stresses in various flow configurations which often lead to the formation of unwanted protein aggregates. In this paper we present physical degradation experiments for proteins under well-defined flow conditions in a four-roll apparatus. The flow field was characterized numerically by computational fluid dynamics (CFD) and experimentally by particle image velocimetry (PIV). The local shear strain rate as well as the local shear and elongation rate was used to characterize the hydrodynamic stress environment acting on the proteins. Lysozyme was used as a model protein and subjected to well-defined fluid stresses in high and low stress environment. By using in situ turbidity measurements during stressing the aggregate formation was monitored directly in the fluid flow. An increase in absorbance at 350 nm was attributed to a higher content of visible particles (>1 µm). In addition to lysozyme, the formation of aggregates was confirmed for two larger proteins (bovine serum albumin and alcohol dehydrogenase). Thus, the presented experimental setup is a helpful tool to monitor flow-induced protein aggregation with high reproducibility. For instance, screening experiments for formulation development of biopharmaceuticals for fill and finish operations can be performed in the lab-scale in a short time-period if the stress distributions in the application are transferred and applied in the four-roll mill., (Copyright © 2011 Wiley Periodicals, Inc.)

A contactless conductivity detector integrated into a poly(dimethylsiloxane) microchip for electrophoresis is presented. It adopted the simplest configuration of electrodes commonly used in this detection mode for capillary electrophoresis microchips. Although the chip is based on a simple and effective design, it is able to obtain low detection levels due to the low noise of the detection circuit. A circuit based on a lock-in amplifier was designed on printed circuit boards to read out the signal. The property of the detection cell was studied by applying excitation signals of different frequencies and different amplitudes. It was found that the best detection limit could be achieved with a frequency of 50 kHz and amplitude of 20 V. The performance of the detector was demonstrated by successfully separating and detecting several inorganic ions and also a mixture of heavy metal ions. An average detection limit of 0.4 μM was obtained for inorganic cations. This value is significantly improved compared to similar microchip-based detectors. The presented detector could be promising for mass production due to its properties, such as simple construction, high degree of integration, high performance and low cost., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Here we describe a new analytical method for the detection of two influenza A viruses by nitrocellulose membrane and magnetic sensors that employ a special frequency mixing technique. The combination of the nitrocellulose membrane and magnetic bead detection permits a rapid assay procedure and excludes two steps (the development of color and the stop reaction) required for usual immunochemical detection methods such as ELISA. Quantitative virus detection was performed using magnetic beads conjugated with secondary antibody. The results were compared with conventional assay methods and with a dot-blot assay with fluorescence compound (FITC). Under optimum conditions, our new assay procedure is capable of detecting picograms of virus per well. This new method combining the nitrocellulose membrane and magnetic bead detection reduces analytical time and allows stable and repeatable analyses of samples in point-of-care applications., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Concern around the lack of monitoring of proteinaceous subvisible particulates in the 0.1-10 microm range has been heightened (Carpenter et al., 2009, J Pharm Sci 98: 1202-1205), primarily due to uncertainty around the potential immunogenicity risk from these particles. This article, representing the opinions of a number of industry scientists, aims to further the discussion by developing a common understanding around the technical capabilities, limitations, as well as utility of monitoring this size range; reiterating that the link between aggregation and clinical immunogenicity has not been unequivocally established; and emphasizing that such particles are present in marketed products which remain safe and efficacious despite the lack of monitoring. Measurement of subvisible particulates in the <10 microm size range has value as an aid in product development and characterization. Limitations in measurement technologies, variability from container/closure, concentration, viscosity, history, and inherent batch heterogeneity, make these measurements unsuitable as specification for release and stability or for comparability, at the present time. Such particles constitute microgram levels of protein with currently monitored sizes >or=10 microm representing the largest fraction. These levels are well below what is detected or reported for other product quality attributes. Subvisible particles remain a product quality attribute that is also qualified in clinical trials., ((c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association)

Non-invasive and rapid determination of plant biomass would be beneficial for a number of research aims. Here, we present a novel device to non-invasively determine plant water content as a proxy for plant biomass. It is based on changes of dielectric properties inside a microwave cavity resonator induced by inserted plant material. The water content of inserted shoots leads to a discrete shift in the centre frequency of the resonator. Calibration measurements with pure water showed good spatial homogeneity in the detection volume of the microwave resonators and clear correlations between water content and centre frequency shift. For cut tomato and tobacco shoots, linear correlations between fresh weight and centre frequency shift were established. These correlations were used to continuously monitor diel growth patterns of intact plants and to determine biomass increase over several days. Interferences from soil and root water were excluded by shielding pots with copper. The presented proof of principle shows that microwave resonators are promising tools to quantitatively detect the water content of plants and to determine plant biomass. As the method is non-invasive, integrative and fast, it provides the opportunity for detailed, dynamic analyses of plant growth, water status and phenotype.

In reported low-field nuclear magnetic resonance (NMR) measurements using Superconducting Quantum Interference Device (SQUID) detection, the pre-polarizing magnetic field has been usually oriented orthogonal to the measuring field, B(p) perpendicular B(m). Melton et al. systematically analyzed the consequences of B(p) decay in time after turnoff and showed that this decay should be nonadiabatic. We evaluated our measuring procedure in the light of that analysis, and found good quantitative agreement. It was showed that, when the decay time constant is comparable to the precession period of the magnetization of the sample, M, the optimum procedure is to orient B(p) parallel to B(m) and to apply a pi/2 pulse to flip M, similar as in the case of conventional NMR.

Certain applications of superconducting quantum interference devices (SQUIDs) require a magnetic field measurement only in a very narrow frequency range. In order to selectively improve the alternating-current (ac) magnetic field sensitivity of a high-temperature superconductor SQUID for a distinct frequency, a single-coil LC resonant circuit has been used. Within the liquid nitrogen bath, the coil surrounds the SQUID and couples to it inductively. Copper coils with different numbers of windings were used to cover the frequency range from <1 to nearly 100 kHz. A superconducting coil made of YBa(2)Cu(3)O(7-delta) tape conductor was also tested. With the LC circuit, the signal-to-noise ratio of measurements could be improved typically by one order of magnitude or more in a narrow frequency band around the resonance frequency exceeding a few kilohertz. The best attained equivalent magnetic field resolution was 2.5 fT/radicalHz at 88 kHz. The experimental findings are in good agreement with mathematical analysis of the circuit with copper coil.