Accurate Nonstandard Path Integral Models for Arbitrary Dielectric Boundaries in 2-D NS-FDTD Domains.

An efficient path integral (PI) model for the accurate analysis of curved dielectric structures on coarse grids via the two-dimensional nonstandard finite-difference time-domain (NS-FDTD) technique is introduced in this paper. In contrast to previous PI implementations of the perfectly electric conductor case, which accommodates orthogonal cells in the vicinity of curved surfaces, the novel PI model employs the occupation ratio of dielectrics in the necessary cells, providing thus a straightforward and instructive means to treat an assortment of practical applications. For its verification, the reflection from a flat plate and the scattering from a cylinder using the PI model are investigated. Results indicate that the featured methodology can enable the reliable and precise modeling of arbitrarily shaped dielectrics in the NS-FDTD algorithm on coarse grids.

Challenges for Field-Effect-Transistor-Based Graphene Biosensors.

Owing to its outstanding physical properties, graphene has attracted attention as a promising biosensor material. Field-effect-transistor (FET)-based biosensors are particularly promising because of their high sensitivity that is achieved through the high carrier mobility of graphene. However, graphene-FET biosensors have not yet reached widespread practical applications owing to several problems. In this review, the authors focus on graphene-FET biosensors and discuss their advantages, the challenges to their development, and the solutions to the challenges. The problem of Debye screening, in which the surface charges of the detection target are shielded and undetectable, can be solved by using small-molecule receptors and their deformations and by using enzyme reaction products. To address the complexity of sample components and the detection mechanisms of graphene-FET biosensors, the authors outline measures against nonspecific adsorption and the remaining problems related to the detection mechanism itself. The authors also introduce a solution with which the molecular species that can reach the sensor surfaces are limited. Finally, the authors present multifaceted approaches to the sensor surfaces that provide much information to corroborate the results of electrical measurements. The measures and solutions introduced bring us closer to the practical realization of stable biosensors utilizing the superior characteristics of graphene.

Biosensing with Surface-Charge-Modulated Graphene Field-Effect Transistors beyond Nonlinear Electrolytic Screening.

In field-effect transistor (FET) biosensors, charge screening in electrolyte solutions limits the sensitivity, thereby restricting the applicability of FET sensors. This is particularly pronounced in graphene FET (GFET) biosensors, where the bare graphene surface possesses a strongly negative charge, which impedes the high sensitivity of GFETs owing to nonlinear electrolytic screening at the interfaces between graphene and liquid. In this study, we counteracted the negative surface charge of graphene by decorating positively charged compounds and demonstrated the sensing of C-reactive protein (CRP) with surface-charge-modulated GFETs (SCM-GFETs). We integrated multiple SCM-GFETs with anti-CRP antibodies and nonfunctionalized GFETs into a chip and measured differentials to eliminate background changes to improve measurement reliability. The FET response corresponded to the fluorescence images, which visualized the specific adsorption of CRP. The estimated dissociation constant was consistent with previously reported values; this supports the conclusion that the results are attributed to specific adsorption. Conversely, the signal in GFETs without decoration was obscured by noise because of nonlinear electrolytic screening, further emphasizing the significance of surface-charge modulation. The limit of detection of the system was determined to be 2.9 nM. This value has the potential to be improved through further optimization of the surface charges to align with specific applications. Our devices effectively circumvent nonlinear electrolytic screening, opening the door for further advancements in GFET biosensor technology.

Ionic strength-sensitive and pH-insensitive interactions between C-reactive protein (CRP) and an anti-CRP antibody.

C-reactive protein (CRP) is an important biomarker of infection and inflammation, as CRP is one of the most prominent acute-phase proteins. CRP is usually detected using anti-CRP antibodies (Abs), where the intermolecular interactions between CRP and the anti-CRP Ab are largely affected by the pH and ionic strength of environmental solutions. Therefore, it is important to understand the environmental effects of CRP-anti-CRP Ab interactions when designing highly sensitive biosensors. Here, we investigated the efficiency of fluorescently labeled CRP-anti-CRP monoclonal antibody (mAb) interactions at different pHs and ionic strengths. Our results indicate that the affinity was insensitive to pH changes in the range of 5.9 to 8.1, while it was significantly sensitive to ionic strength changes. The binding affinity decreased by 55% at an ionic strength of 1.6 mM, when compared to that under a physiological condition (~150 mM). Based on the isoelectric focusing results, both the labeled CRP and anti-CRP mAb were negatively charged in the studied pH range, which rendered the system insensitive to pH changes, but sensitive to ionic strength changes. The decreased ionic strength led to a significant enhancement of the repulsive force between CRP and the anti-CRP mAb. Although the versality of the findings is not fully studied yet, the results provide insights into designing highly sensitive CRP sensors, especially field-effect transistor-based sensors.

Drift Suppression of Solution-Gated Graphene Field-Effect Transistors by Cation Doping for Sensing Platforms.

Solution-gated graphene field-effect transistors (SG-GFETs) provide an ideal platform for sensing biomolecules owing to their high electron/hole mobilities and 2D nature. However, the transfer curve often drifts in an electrolyte solution during measurements, making it difficult to accurately estimate the analyte concentration. One possible reason for this drift is that p-doping of GFETs is gradually countered by cations in the solution, because the cations can permeate into the polymer residue and/or between graphene and SiO2 substrates. Therefore, we propose doping sufficient cations to counter p-doping of GFETs prior to the measurements. For the pre-treatment, GFETs were immersed in a 15 mM sodium chloride aqueous solution for 25 h. The pretreated GFETs showed that the charge neutrality point (CNP) drifted by less than 3 mV during 1 h of measurement in a phosphate buffer, while the non-treated GFETs showed that the CNP was severely drifted by approximately 50 mV, demonstrating a 96% reduction of the drift by the pre-treatment. X-ray photoelectron spectroscopy analysis revealed the accumulation of sodium ions in the GFETs through pre-treatment. Our method is useful for suppressing drift, thus allowing accurate estimation of the target analyte concentration.

Graphene Field Effect Transistor-Based Immunosensor for Ultrasensitive Noncompetitive Detection of Small Antigens.

Due to its high carrier mobility, graphene is considered a suitable material for use in field-effect transistors. However, its application to immunosensing of small molecules is still elusive. To investigate the potential of graphene field effect transistors (G-FET) as a sensor for small molecules with small or no charge, we applied the open-sandwich immunoassay (OS-IA), which detects low-molecular-weight antigens noncompetitively, to G-FET. Using an antibody variable fragment VL immobilized on graphene and a hyperacidic region of amyloid precursor protein fused to the other variable fragment VH, we successfully detected a small antigen peptide consisting of 7 amino acids (BGP-C7), with a more than 100-fold increase in sensitivity compared with that measured by enzyme-linked OS-IA. Furthermore, we succeeded in detecting BGP-C7 in the presence of human serum with similar sensitivity, suggesting its potential application in clinical diagnostics.

Low dark current and high-responsivity graphene mid-infrared photodetectors using amplification of injected photo-carriers by photo-gating.

Low dark current, high-responsivity middle-wavelength infrared (IR) graphene photodetectors using photo-gating amplification of injected photo-carriers are demonstrated. A graphene/p-indium antimonide (InSb) heterojunction and graphene/insulator region were formed. The injected photo-carriers from InSb to graphene were amplified by photo-gating induced in the graphene/tetraethyl orthosilicate (TEOS) region, resulting in the high responsivity and low dark current performance. A responsivity of 14.9 A/W and an ON/OFF ratio of 2.66×104 were achieved. The photoresponse is shown to be determined by the cross-sectional area between the graphene and the TEOS-SiO2, in which the injected photo-carriers into graphene were modulated and amplified by the photo-gating effect. Our results indicate that high-performance IR photodetectors based on the developed graphene photodetectors can be realized.

Electrical Biosensing at Physiological Ionic Strength Using Graphene Field-Effect Transistor in Femtoliter Microdroplet.

Graphene has strong potential for electrical biosensing owing to its two-dimensional nature and high carrier mobility which transduce the direct contact of a detection target with a graphene channel to a large conductivity change in a graphene field-effect transistor (G-FET). However, the measurable range from the graphene surface is highly restricted by Debye screening, whose characteristic length is less than 1 nm at physiological ionic strength. Here, we demonstrated electrical biosensing utilizing the enzymatic products of the target. We achieved quantitative measurements of a target based on the site-binding model and real-time measurement of the enzyme kinetics in femtoliter microdroplets. The combination of a G-FET and microfluidics, named a "lab-on-a-graphene-FET", detected the enzyme urease with high sensitivity in the zeptomole range in 100 mM sodium phosphate buffer. Also, the lab-on-a-graphene-FET detected the gastric cancer pathogen Helicobacter pylori captured at a distance greater than the Debye screening length from the G-FET.

Single-electron charge sensing in self-assembled quantum dots.

Measuring single-electron charge is one of the most fundamental quantum technologies. Charge sensing, which is an ingredient for the measurement of single spins or single photons, has been already developed for semiconductor gate-defined quantum dots, leading to intensive studies on the physics and the applications of single-electron charge, single-electron spin and photon-electron quantum interface. However, the technology has not yet been realized for self-assembled quantum dots despite their fascinating transport phenomena and outstanding optical functionalities. In this paper, we report charge sensing experiments in self-assembled quantum dots. We choose two adjacent dots, and fabricate source and drain electrodes on each dot, in which either dot works as a charge sensor for the other target dot. The sensor dot current significantly changes when the number of electrons in the target dot changes by one, demonstrating single-electron charge sensing. We have also demonstrated real-time detection of single-electron tunnelling events. This charge sensing technique will be an important step towards combining efficient electrical readout of single-electron with intriguing quantum transport physics or advanced optical and photonic technologies developed for self-assembled quantum dots.

Graphene as an Imaging Platform of Charged Molecules.

Graphene, a single atom layer of carbon atoms, provides a two-dimensional platform with an extremely high sensitivity to charges due to its unique band structure and high surface-to-volume ratio. Graphene field-effect transistor (G-FET) biosensors have, indeed, demonstrated a detection limit of subnanomolar or even subpicomolar. However, in G-FET, signal is averaged throughout the whole channel, so there remains a need to visualize the spatial distribution of target molecules on a single G-FET, to provide further insight into target molecules and/or biological functions. Here, we made use of graphene as an imaging platform of charged molecules via Raman microscopy. Positively (or negatively) charged microbeads with a diameter of 1 µm were dispersed in a buffer solution and were attached on graphene. We found out that Raman peaks of graphene, where positively (or negatively) charged beads contacted, were up-shifted (or down-shifted) significantly, indicating that the carrier density in the graphene was locally modulated by the charged beads and the charge state of the beads was represented by the peak-shift direction. From the peak shift, the change in the carrier density was calculated to be +1.4 × 1012 cm-2 (or -1.0 × 1012 cm-2). By taking Raman peak-shift images, we visualized distribution of charged molecules on graphene with a spatial resolution below 1 µm. The technique described here overcomes the limitation of spatial resolution of G-FET and provides a new route to graphene-based chemical and biosensors.

N-glycan structures of human alveoli provide insight into influenza A virus infection and pathogenesis.

The rapidly evolvable influenza A virus has caused pandemics linked to millions of deaths in the past century. Influenza A viruses are categorized by H (hemagglutinin; HA) and N (neuraminidase; NA) proteins expressed on the viral envelope surface. Analyses of past pandemics suggest that the HA gene segment comes from a nonhuman virus, which is then introduced into an immunologically naïve human population with potentially devastating consequences. As a prerequisite for infection, the nonhuman HA molecules of H1-H16 viruses must be able to bind to specific sialyl receptors on the host cell surface along the human respiratory tract. Thus, additional insight into the structures of host cell glycans and how different HAs interact with different glycans might provide new insight into the mechanisms underlying sustained infection and transmission in humans. In this work, we identified the sialyl N-glycans found in normal human alveoli and characterized the influenza viruses that preferentially bound to these different structures. We also determined the amino acid changes in HA that were linked to a switch of receptor-binding preference from nonhuman to pandemic, as well as pandemic to seasonal. Our data provide insight into why seasonal viruses are associated with reduced alveolar infection and damage and suggest new considerations for designing anti-HA vaccines and drugs. The results provide a better understanding of viral tropism and pathogenesis in humans that will be important for prediction and surveillance of zoonotic, pandemic, and epidemic influenza outbreaks. DATABASE: The novel hemagglutinin nucleotide sequences reported here were deposited in GISAID under the accession numbers of EPI685738 for A/Yamaguchi/20/2006(H1N1) and EPI685740 for A/Kitakyushu/10/2006(H1N1).

Graphene Surface Acoustic Wave Sensor for Simultaneous Detection of Charge and Mass.

We have combined a graphene field-effect transistor (GFET) and a surface acoustic wave (SAW) sensor on a LiTaO3 substrate to create a graphene surface acoustic wave (GSAW) sensor. When a SAW propagates in graphene, an acoustoelectric current (IA) flows between two attached electrodes. This current has unique electrical characteristics, having both positive and negative peak values with respect to the electrolyte-gate voltage (VEg) in solution. We found that IA is controlled by VEg and the amplitude of the SAW. It was also confirmed that the GSAW sensor detects changes of electrical charge in solution like conventional GFET sensors. Furthermore, the detection of amino-group-modified microbeads was performed by employing a GSAW sensor in a phthalate buffer solution at pH 4.1. The hole current peak shifted to the lower left in the IA-VEg characteristics. The left shift was caused by charge detection by the GFET and can be explained by an increase of amino groups that have positive charges at pH 4.1. In contrast, the downward shift is thought to be due to a reduction in the amplitude of the propagating SAW because of an increase in the mass loading of microbeads. This mass loading was detected by the SAW sensor. Thus, we have demonstrated that the GSAW sensor is a transducer capable of the simultaneous detection of charge and mass, which indicates that it is an attractive platform for highly sensitive and multifunctional solution sensing.

Planar Hall effect from the surface of topological insulators.

A prominent feature of topological insulators (TIs) is the surface states comprising of spin-nondegenerate massless Dirac fermions. Recent technical advances have made it possible to address the surface transport properties of TI thin films by tuning the Fermi levels of both top and bottom surfaces. Here we report our discovery of a novel planar Hall effect (PHE) from the TI surface, which results from a hitherto-unknown resistivity anisotropy induced by an in-plane magnetic field. This effect is observed in dual-gated devices of bulk-insulating Bi2-x Sb x Te3 thin films, where the field-induced anisotropy presents a strong dependence on the gate voltage with a characteristic two-peak structure near the Dirac point. The origin of PHE is the peculiar time-reversal-breaking effect of an in-plane magnetic field, which anisotropically lifts the protection of surface Dirac fermions from backscattering. The observed PHE provides a useful tool to analyze and manipulate the topological protection of the TI surface.

Room-temperature discrete-charge-fluctuation dynamics of a single molecule adsorbed on a carbon nanotube.

Detection and use of physical noise fluctuations in a signal provides significant advantages in the development of bio- and neuro-sensing and functional mimicking devices. Low-dimensional carbon nanomaterials are a good candidate for use in noise generation due to the high surface sensitivity of these materials, which may themselves serve as the main building blocks of these devices. Here, we demonstrate that the addition of a molecule with high redox activity to a carbon nanotube (CNT) field-effect transistor provides tunable current fluctuation noise. A unique charge-trap state in the vicinity of the CNT surface due to the presence of the single molecule is the origin of the noise, which generates a prominent and unique slow discrete random telegraph signal in the device current. The power spectral density reveals the peculiar frequency limit of the fluctuation for different types of molecules depending on their redox activity and adsorption configuration. These results indicate that the detected noise will provide new opportunities to obtain electronic information for a single molecule combined with a nanotube surface, and that controllability of the noise may contribute to the expansion of noise utilization in future bio-inspired devices.

In vitro and in vivo metabolism of a novel chymase inhibitor, SUN13834, and the predictability of human metabolism using mice with humanized liver.

1. A novel oral chymase inhibitor, SUN13834, is under clinical development for the treatment of atopic dermatitis (AD). In this study, in vitro and in vivo metabolic profiles of SUN13834 were compared between severe combined immunodeficiency (SCID) mice, chimeric mice with humanized liver and humans. 2. In in vitro experiments using liver microsomes, predominant metabolites of SUN13834 were glucuronide (MG-1) in SCID mice and hydroxylated metabolite (M-3) in chimeric mice and humans. 3. After a single oral dose of [(14)C]SUN13834 to SCID and chimeric mice, glucuronidation was the major metabolic pathway in SCID mice, while the parent compound, ring opening form (M-5), O-demethylated form of M-5 (M-6) and glucuronidation of M-6 (M-6G) were detected at higher levels in chimeric mice compared to SCID mice. 4. When AD patients were orally treated using SUN13834 for 28 days, the parent compound had the highest concentration in plasma, and M-6, M-6G, M-5 and MG-1 were identified as major metabolites. 5. This is the first report of SUN13834 metabolic information in human. In addition, based on similarities in metabolic profiles between chimeric mice and humans, it was concluded that chimeric mice are useful for predicting SUN13834 metabolism in humans during early stages of drug development.

Electromagnetic analysis of an RF rectangular resonant cavity applicator for hyperthermic treatment using whole-body voxel human model of Japanese adult male.

The numerical whole-body voxel human model (numerical model) developed by National Institute of Information and Communications Technology (NICT) was assumed and hyperthemic treatment using radio-frequency wave was investigated. We assumed 51 different human tissues and organs with 2-mm spatial resolution in the numerical model, inserted it into the resonant cavity applicator, and Maxwell's equations were solved by FDTD method with variable mesh. We obtained the realistic energy patterns for a deep-seated tumor as compared to those obtained in our previous studies.

Electromagnetic-thermal analysis of an RF rectangular resonant cavity applicator for hyperthermia targeting deep-seated tumors using a human model with blood flow and fat layer.

Maxwell's and heat transfer equations were coupled and solved to determine the heating characteristics of an RF rectangular resonant cavity applicator for hyperthermia before the clinical stage. A simple human model with blood flow and a fat layer was constructed. The region unaffected by tumor was shielded from electromagnetic fields by using conductive caps. The surface of the human model that was exposed to the electromagnetic fields was cooled with pure water bolus. Calculated results show that this applicator can heat a deep-seated tumor.

Discussion based on numerical and experimental studies on heating characteristics of an RF rectangular resonant cavity applicator for hyperthermia targeting deep-seated tumors.

The heating characteristics of an RF rectangular cavity applicator for hyperthermic treatment that targets deep-seated tumors were investigated numerically and experimentally. In the numerical study, Maxwell's equations and heat transfer equations were solved for a dielectric phantom with and without blood flow. Conductive caps attached to the dielectric phantom to shield the non-tumor regions. The experimental study showed the validity and possibility of heating deep-seated tumors. Thus, the rectangular resonant cavity applicator with an L-type antenna can heat deep-seated tumors.

Heating characteristics of a RF hyperthermia for deep-seated regions.

Electromagnetic and heat-transfer equations were solved to investigate a radio frequency (RF) rectangular resonant cavity applicator. The possibility of heating a deep-seated tumor was demonstrated. A torso-shaped dielectric phantom was made. It has electrical constants resembling those of human muscle. Several L-type antennas were made and placed at appropriate locations to heat a deep region. Measured results agreed with the calculated results. Results show that the rectangular resonant cavity applicator with the L-type antennas can heat deep-seated tumors.

Central actions of neuromedin U via corticotropin-releasing hormone.

Neuromedin U (NMU), a hypothalamic peptide, has been known to be involved in feeding behavior as a catabolic signaling molecule. However, little is known about the participation of NMU in the neuronal network. One NMU receptor, NMU2R, is abundantly expressed in the hypothalamic paraventricular nucleus, where corticotrophin-releasing hormone (CRH) is synthesized. The functions of CRH, regulation of stress response and feeding behavior, are comparable with those of NMU. Here, we have investigated the functional relationships between NMU and CRH using CRH knockout (KO) mice. Intracerebroventricular administration of NMU suppressed dark-phase food intake and fasting-induced feeding in wild-type mice. In contrast, these suppressions were not observed in CRH KO mice. NMU-induced increases in oxygen consumption and body temperature were attenuated in CRH KO mice. These results suggest that NMU plays a role in feeding behavior and catabolic functions via CRH. This study demonstrates a novel hypothalamic pathway that links NMU and CRH in the regulation of feeding behavior and energy homeostasis.