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Misfolded proteins associated with various neurodegenerative diseases often accumulate in tissues or circulate in biological fluids years before the clinical onset, thus representing ideal diagnostic targets. Real-time quaking-induced conversion (RT-QuIC), a protein-based seeded-amplification assay, holds great potential for early disease detection, yet challenges remain for routine diagnostic application. Chronic Wasting Disease (CWD), associated with misfolded prion proteins of cervids, serves as an ideal model for evaluating new RT-QuIC methodologies. In this study, we investigate the previously untested hypothesis that incorporating nanoparticles into RT-QuIC assays can enhance their speed and sensitivity when applied to biological samples. We show that adding 50 nm silica nanoparticles to RT-QuIC experiments (termed Nano-QuIC) for CWD diagnostics greatly improves the performance by reducing detection times 2.5-fold and increasing sensitivity 10-fold by overcoming the effect of inhibitors in complex tissue samples. Crucially, no false positives were observed with these 50 nm silica nanoparticles, demonstrating the enhanced reliability and potential for diagnostic application of Nano-QuIC in detecting misfolded proteins.

Subwavelength terahertz (THz) imaging methods are highly desirable for biochemical sensing as well as materials sciences, yet sensitive spectral fingerprinting is still challenging in the frequency domain due to weak light–matter interactions. Here, we demonstrate subwavelength THz resonance imaging (STRING) that overcomes this limitation to achieve ultrasensitive molecular fingerprinting. STRING combines individual ring-shaped coaxial single resonators with near-field spectroscopy, yielding considerable sensitivity gains from both local field enhancement and the near-field effect. As an initial demonstration, we obtained spectral fingerprints from isomers of α-lactose and maltose monohydrates, achieving sensitivity that was enhanced by up to 10 orders of magnitude compared to far-field THz measurements with pelletized samples. Our results show that the STRING platform could enable the development of THz spectroscopy as a practical and sensitive tool for the fingerprinting and spectral imaging of molecules and nanoparticles.

Cellular retinoic acid-binding protein 1 (CRABP1) binds retinoic acid (RA) specifically in the cytoplasm with unclear functions. CRABP1 is highly and specifically expressed in spinal motor neurons (MNs). Clinical and pre-clinical data reveal a potential link between CRABP1 and MN diseases, including the amyotrophic lateral sclerosis (ALS). We established a sequenced MN-muscle co-differentiation system to engineer an in vitro functional 3D NMJ model for molecular studies and demonstrated that CRABP1 in MNs contributes to NMJ formation and maintenance. Consistently, Crabp1knockout (CKO) mice exhibited an adult-onset ALS-like phenotype with progressively deteriorated NMJs, characterized with behavioral, EchoMRI, electrophysiological, histological, and immunohistochemical studies at 2–20-months old. Mechanistically, CRABP1 suppresses CaMKII activation to regulate neural Agrnexpression and downstream muscle LRP4-MuSK signaling, thereby maintaining NMJ. A proof-of-concept was provided by specific re-expression of CRABP1 to rescue Agrnexpression and the phenotype. This study identifies CRABP1-CaMKII-Agrnsignaling as a physiological pre-synaptic regulator in the NMJ. This study also highlights a potential protective role of CRABP1 in the progression of NMJ deficits in MN diseases.

Detection of terahertz (THz) radiation has many potential applications, but presently available detectors are limited in many aspects of their performance, including sensitivity, speed, bandwidth and operating temperature. Most do not allow the characterization of THz polarization states. Recent observation of THz-driven luminescence in quantum dots offers a possible detection mechanism via field-driven interdot charge transfer. We demonstrate a room-temperature complementary metal–oxide–semiconductor THz camera and polarimeter based on quantum-dot-enhanced THz-to-visible upconversion mechanism with optimized luminophore geometries and fabrication designs. Besides broadband and fast responses, the nanoslit-based sensor can detect THz pulses with peak fields as low as 10 kV cm–1. A related coaxial nanoaperture-type device shows a to-date-unexplored capability to simultaneously record the THz polarization state and field strength with similar sensitivity.

Nanophotonic devices, which control light in subwavelength volumes and enhance light–matter interactions, have opened up exciting prospects for biosensing. Numerous nanophotonic biosensors have emerged to address the limitations of the current bioanalytical methods in terms of sensitivity, throughput, ease-of-use and miniaturization. In this Review, we provide an overview of the recent developments of label-free nanophotonic biosensors using evanescent-field-based sensing with plasmon resonances in metals and Mie resonances in dielectrics. We highlight the prospects of achieving an improved sensor performance and added functionalities by leveraging nanostructures and on-chip and optoelectronic integration, as well as microfluidics, biochemistry and data science toolkits. We also discuss open challenges in nanophotonic biosensing, such as reducing the overall cost and handling of complex biological samples, and provide an outlook for future opportunities to improve these technologies and thereby increase their impact in terms of improving health and safety.

On-chip integration of plasmonics and electronics can benefit a broad range of applications in biosensing, signal processing, and optoelectronics. A key requirement is a chip-scale manufacturing method. Here, we demonstrate a split-trench resonator platform that combines a high-quality-factor resonant plasmonic biosensor with radio frequency (RF) nanogap tweezers. The split-trench resonator can simultaneously serve as a dielectrophoretic trap and a nanoplasmonic sensor. Trapping is accomplished by applying an RF electrical bias across a 10 nm gap, thereby either attracting or repelling analytes. Trapped analytes are detected in a label-free manner using refractive-index sensing, enabled by interference between surface-plasmon standing waves in the trench and light transmitted through the gap. This active sample concentration mechanism enables detection of nanoparticles and proteins at a concentration as low as 10 pM. We can manufacture centimeter-long split-trench cavity resonators with high throughput viaphotolithography and atomic layer deposition, toward practical applications in biosensing, spectroscopy, and optoelectronics.

Two-dimensional (2D) materials are promising candidates for building ultrashort-channel devices because their thickness can be reduced down to a single atomic layer. Here, we demonstrate an ultraflat nanogap platform based on atomic layer deposition (ALD) and utilize the structure to fabricate 2D material-based optical and electronic devices. In our method, ultraflat metal surfaces, template-stripped from a Si wafer mold, are separated by an Al2O3ALD layer down to a gap width of 10 nm. Surfaces of both electrodes are vertically aligned without a height difference, and each electrode is ultraflat with a measured root-mean-square roughness as low as 0.315 nm, smaller than the thickness of monolayer graphene. Simply by placing 2D material flakes on top of the platform, short-channel field-effect transistors based on black phosphorus and MoS2are fabricated, exhibiting their typical transistor characteristics. Furthermore, we use the same platform to demonstrate photodetectors with a nanoscale photosensitive channel, exhibiting higher photosensitivity compared to microscale gap channels. Our wafer-scale atomic layer lithography method can benefit a diverse range of 2D optical and electronic applications.

Although van der Waals-layered transition metal dichalcogenides from transient absorption spectroscopy have successfully demonstrated an ideal carrier multiplication (CM) performance with an onset of nearly 2Eg, interpretation of the CM effect from the optical approach remains unresolved owing to the complexity of many-body electron–hole pairs. We demonstrate the escalated photocurrent with excitation photon energy by fabricating the dual-gate p–n junction of a MoTe2film on a transparent substrate. Electrons and holes were efficiently extracted by eliminating the Schottky barriers in the metal contact and minimizing multiple reflections. The photocurrent was elevated proportionately to the excitation photon energy. The boosted quantum efficiency confirms the multiple electron–hole pair generation of >2Eg, consistent with CM results from an optical approach, pushing the solar cell efficiency beyond the Shockley–Queisser limit.

With strong light–matter interaction in their atomically thin layered structures, two-dimensional (2D) materials have been widely investigated for optoelectronic applications such as photodetectors and photovoltaic devices. Depending on the aim of optoelectronic applications, different device structures have been employed. Lateral phototransistor structures have been employed for high optical gain, while vertical photodiode structures have been employed for fast response and low power operation. Herein, we demonstrate a multimodal photodetector platform based on 2D materials, combining both a phototransistor and a photodiode and taking the corresponding desirable characteristics from each structure within a single device. In this platform, a multilayered transition-metal dichalcogenide flake is transferred on top of metal electrodes, and a transparent gate electrode is employed. The channel region of the flake between electrodes operates as a phototransistor providing a high gain mode, while the electrode region in the same flake operates as a vertical Schottky photodiode providing a fast response mode. These modes can be dynamically selected by controlling the drain voltage and gate voltage.

Vibrational ultrastrong coupling, where the light–matter coupling strength is comparable to the vibrational frequency of molecules, presents new opportunities to probe the interactions between molecules and zero-point fluctuations, harness cavity-modified chemical reactions and develop novel devices in the mid-infrared spectral range. Here we use epsilon-near-zero nanocavities filled with a model polar medium (SiO2) to demonstrate ultrastrong coupling between phonons and gap plasmons. We present classical and quantum-mechanical models to quantitatively describe the observed plasmon–phonon ultrastrong coupling phenomena and demonstrate a modal splitting of up to 50% of the resonant frequency (normalized coupling strength ?> 0.25). Our wafer-scale nanocavity platform will enable a broad range of vibrational transitions to be harnessed for ultrastrong coupling applications.

Tuning the properties of optical metamaterials in real time is one of the grand challenges of photonics. Being able to do so will enable a class of adaptive photonic materials for use in applications such as surface enhanced Raman spectroscopy and reflectors/absorbers. One strategy to achieving this goal is based on the electrovariable self-assembly and disassembly of two-dimensional nanoparticle arrays at a metal | liquid interface. As expected, the structure results in plasmonic coupling between NPs in the array but perhaps as importantly between the array and the metal surface. In such a system, the density of the nanoparticle array can be reversibly controlled by the variation of electrode potential. Theory suggests that due to a collective plasmon-coupling effect  less than 1 V variation of electrode potential can give rise to a dramatic simultaneous change in optical reflectivity from ∼93% to ∼1% and the amplification of the SERS signal by up to 5 orders of magnitude. This is experimentally demonstrated using a platform based on the voltage-controlled assembly of 40 nm Au-nanoparticle arrays at a TiN/Ag electrode in contact with an aqueous electrolyte. We show that all the physics underpinning the behavior of this platform works precisely as suggested by the proposed theory, setting the electrochemical nanoplasmonics as a promising direction in photonics research.

One of the fundamental hurdles in plasmonics is the trade-off between electromagnetic field confinement and the coupling efficiency with free-space light, a consequence of the large momentum mismatch between the excitation source and plasmonic modes. Acoustic plasmons in graphene, in particular, have an extreme level of field confinement, as well as an extreme momentum mismatch. Here, we show that this fundamental compromise can be overcome and demonstrate a graphene acoustic plasmon resonator with nearly perfect absorption (94%) of incident mid-infrared light. This high efficiency is achieved by utilizing a two-stage coupling scheme: free-space light coupled to conventional graphene plasmons, which then couple to ultraconfined acoustic plasmons. To realize this scheme, we transfer unpatterned large-area graphene onto template-stripped ultraflat metal ribbons. A monolithically integrated optical spacer and a reflector further boost the enhancement. We show that graphene acoustic plasmons allow ultrasensitive measurements of absorption bands and surface phonon modes in ångström-thick protein and SiO2layers, respectively. Our acoustic plasmon resonator platform is scalable and can harness the ultimate level of light–matter interactions for potential applications including spectroscopy, sensing, metasurfaces and optoelectronics.

Much of the functionality of multicellular systems arises from the spatial organization and dynamic behaviours within and between cells. Current single-cell genomic methods only provide a transcriptional ‘snapshot’ of individual cells. The real-time analysis and perturbation of living cells would generate a step change in single-cell analysis. Here we describe minimally invasive nanotweezers that can be spatially controlled to extract samples from living cells with single-molecule precision. They consist of two closely spaced electrodes with gaps as small as 10–20 nm, which can be used for the dielectrophoretic trapping of DNA and proteins. Aside from trapping single molecules, we also extract nucleic acids for gene expression analysis from living cells without affecting their viability. Finally, we report on the trapping and extraction of a single mitochondrion. This work bridges the gap between single-molecule/organelle manipulation and cell biology and can ultimately enable a better understanding of living cells.

The integration of nanoplasmonic devices with a silicon photonic platform affords a new approach for efficient light delivery by combining the high field enhancement of plasmonics and the ultralow propagation loss of dielectric waveguides. Such a hybrid integration obviates the need for a bulky free-space optics setup and can lead to fully integrated, on-chip optical sensing systems. Here, we demonstrate ultracompact plasmonic resonators directly patterned atop a silicon waveguide for mid-infrared spectroscopic chemical sensing. The footprint of the plasmonic nanorod resonators is as small as 2 μm2, yet they can couple with the mid-infrared waveguide mode efficiently. The plasmonic resonance is directly measured through the transmission spectrum of the waveguide with a coupling efficiency greater than 70% and a field intensity enhancement factor of over 3600 relative to the evanescent waveguide field intensity. Using this hybrid device and a tunable mid-infrared laser source, surface-enhanced infrared absorption spectroscopy of both a thin poly(methyl methacrylate) film and an octadecanethiol monolayer is successfully demonstrated.

rHIgM22 is a recombinant human monoclonal IgM designed to promote remyelination, and it is currently in Phase I clinical trials in patients with multiple sclerosis (MS). In animal models of demyelination, a single low dose of rHIgM22 stimulates oligodendrocyte maturation, induces remyelination, preserves axons, and slows the decline of locomotor deficits. Natural autoantibodies like rHIgM22 typically bind to multiple antigens with weak affinity. rHIgM22 binds to oligodendrocytes and myelin. Because the antigens for rHIgM22 is prevalent within and exclusive to central nervous system (CNS) myelin, we used CNS myelin particles in combination with surface plasmon resonance to determine the kinetic and affinity constants for the interaction of rHIgM22 to myelin. We found that both the serum and recombinant forms of the antibody bind to myelin with very small dissociation constants in the 100 pM range, which is highly unusual for natural autoantibodies. The extraordinary affinity between rHIgM22 and myelin may explain why such a low effective dose can stimulate CNS repair in animal models of demyelination and underlie the accumulation of rHIgM22 in the CSF in treated MS patients by targeting myelin.

A rapid, label-free, and broadly applicable chemical analysis platform for nanovesicles and subcellular components is highly desirable for diagnostic assays. We demonstrate an integrated nanogap plasmonic sensing platform that combines subvolt dielectrophoresis (DEP) trapping, gold nanoparticles (AuNPs), and a lineated illumination scheme for real-time, surface-enhanced Raman spectroscopy (SERS) imaging of biological nanoparticles. Our system is capable of isolating suspended sub-100 nm vesicles and imaging the Raman spectra of their cargo within seconds, 100 times faster than conventional point-scan Raman systems. Bare AuNPs are spiked into solution and simultaneously trapped with the nanovesicles along the gap to boost local optical fields. In addition, our platform offers simultaneous and delay-free spatial and temporal multiplexing functionality. These nanogap devices can be mass-produced via atomic layer lithography and provide a practical platform for high-speed SERS analysis of biological nanoparticles.

Metal nanoparticles that can couple light into tightly confined surface plasmons bridge the size mismatch between the wavelength of light and nanostructures are one of the smallest building blocks of nano-optics. However, plasmonic nanoparticles have been primarily studied to concentrate or scatter incident light as an ultrasmall antenna, while studies of their intrinsic plasmonic light emission properties have been limited. Although light emission from plasmonic structures can be achieved by inelastic electron tunneling, this strategy cannot easily be applied to isolated single nanoparticles due to the difficulty in making electrical connections without disrupting the particle plasmon mode. Here, we solve this problem by placing gold nanoparticles on a graphene tunnel junction. The monolayer graphene provides a transparent counter electrode for tunneling while preserving the ultrasmall footprint and plasmonic mode of nanoparticle. The tunneling electrons excite the plasmonic mode, followed by radiative decay of the plasmon. We also demonstrate that a dielectric overlayer atop the graphene tunnel junction can be used to tune the light emission. We show the simplicity and scalability of this approach by achieving electroluminescence from single nanoparticles without bulky contacts as well as millimeter-sized arrays of nanoparticles.

This paper is concerned with electromagnetic wave scattering of an annular nanogap in the terahertz regime. We present an efficient vertical mode expansion method (VMEM) to solve the scattering problem, and study the extraordinary optical transmission and field enhancement for the nanostructure with various configurations. The VMEM expands the electromagnetic field in and outside the nanogap along the invariant direction by the one-dimensional modes, where the expansion coefficients satisfy scalar two-dimensional Helmholtz equations on the cross-sectional plane. The continuity conditions of electromagnetic fields on the vertical boundaries of neighboring regions are then employed to establish the linear system for the unknown coefficients. Based on the numerical simulations, we investigate the field enhancement in the nanogap. In particular, we investigate the nanostructure with a series of gap sizes and push the gap width limit to 1 nm in the numerical simulation. The normal and oblique incidence cases and the transverse electric (TE) and transverse magnetic (TM) polarization cases are considered.

A high spatial resolution, cyclical thinning method for realizing black phosphorus (BP) heterostructures is reported. This process utilizes a cyclic technique involving BP surface oxidation and vacuum annealing to create BP flakes as thin as 1.6 nm. The process also utilizes a spatially patternable mask created by evaporating Al that oxidizes to form Al2O3, which stabilizes the unetched BP regions and enables the formation of lateral heterostructures with spatial resolution as small as 150 nm. This thinning/patterning technique has also been used to create the first-ever lateral heterostructure BP metal oxide semiconductor field-effect transistor (MOSFET), in which half of a BP flake was thinned in order to increase its band gap. This heterostructure MOSFET showed an ON/OFF current ratio improvement of 1000× compared to homojunction MOSFETs.

We present a new technique to engineer metallic interfaces to produce sharp tips with smooth curved surfaces and variable tip angles, as well as ridges with arbitrary contour shapes, all of which can be integrated with grating couplers for applications in plasmonics and nanophotonics. We combine template stripping, a nanofabrication scheme, with atomic layer deposition (ALD) to produce the ultrasharp nanoscale tips and wedges using only conventional photolithography. Conformal ALD coating of insulators over silicon trench molds of various shapes reduces their widths to make nanoscale features without high-resolution lithography. Along with a metal deposition and template stripping, this size-reduction scheme can mass-produce narrow and ultrasharp (<10 nm radius of curvature) metallic wedges and tips over an entire 4 in. wafer. This size-reduction scheme can create metallic tips out of arbitrary trench patterns that have smooth curved surfaces to facilitate efficient adiabatic nanofocusing which will benefit applications in near-field optical spectroscopy, plasmonic waveguides, particle trapping, hot-electron plasmonics, and nonlinear optics.

ABSTRACTIntroduction: Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients.Areas Covered: Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans. Availability of improved antibody production technologies resulted in a paradigm shift in MS treatment strategies. In this review, an overview of immunotherapies for MS that use conventional monoclonal antibodies reactive to immune system and their properties and mechanisms of action will be discussed, including recent advances in MS therapeutics and highlight natural autoantibodies (NAbs) that directly target CNS cells.Expert Opinion: Recent challenges for MS therapy are the identification of relevant molecular and cellular targets, time frame of treatment, and antibody toxicity profiles to identify safe treatment options for MS patients. The application of monoclonal antibody therapies with better biological efficacy associated with minimum side effects possesses huge clinical potential. Advances in monoclonal antibody technologies that directly target cells of nervous system may promote the CNS regeneration field from bench to bedside.

We present large-scale reproducible fabrication of multifunctional ultrasharp metallic structures on planar substrates with capabilities including magnetic field nanofocusing and plasmonic sensing. Objects with sharp tips such as wedges and pyramids made with noble metals have been extensively used for enhancing local electric fields via the lightning-rod effect or plasmonic nanofocusing. However, analogous nanofocusing of magnetic fields using sharp tips made with magnetic materials has not been widely realized. Reproducible fabrication of sharp tips with magnetic as well as noble metal layers on planar substrates can enable straightforward application of their material and shape-derived functionalities. We use a template-stripping method to produce plasmonic-shell-coated nickel wedge and pyramid arrays at the wafer-scale with tip radius of curvature close to 10 nm. We further explore the magnetic nanofocusing capabilities of these ultrasharp substrates, deriving analytical formulas and comparing the results with computer simulations. These structures exhibit nanoscale spatial control over the trapping of magnetic microbeads and nanoparticles in solution. Additionally, enhanced optical sensing of analytes by these plasmonic-shell-coated substrates is demonstrated using surface-enhanced Raman spectroscopy. These methods can guide the design and fabrication of novel devices with applications including nanoparticle manipulation, biosensing, and magnetoplasmonics.

The scattering of electromagnetic waves by periodic layered media plays a crucial role in many applications in optics and photonics, in particular in nanoplasmonics for topics as diverse as extraordinary optical transmission, photonic crystals, metamaterials, and surface plasmon resonance biosensing. With these applications in mind, we focus on surface plasmon resonances excited in the context of insulator–metal structures with a periodic, corrugated interface. The object of this contribution is to study the geometric limits required to generate these fundamentally important phenomena. For this we use the robust, rapid, and highly accurate field expansions method to investigate these delicate phenomena and demonstrate how very small perturbations (e.g., a 5 nm deviation on a 530 nm period grating) can generate strong (in this instance 20%) plasmonic absorption, and vanishingly small perturbations (e.g., a 1 nm deviation on a 530 nm period grating) can generate nontrivial (in this instance 1%) plasmonic absorption.

The effect of thickness, temperature, and source–drain bias voltage, VDS, on the subthreshold slope, SS, and off-state properties of black phosphorus (BP) field-effect transistors is reported. Locally back-gated p-MOSFETs with thin HfO2gate dielectrics were analyzed using exfoliated BP layers ranging in thickness from ∼4 to 14 nm. SS was found to degrade with increasing VDSand to a greater extent in thicker flakes. In one of the thinnest devices, SS values as low as 126 mV/decade were achieved at VDS= −0.1 V, and the devices displayed record performance at VDS= −1.0 V with SS = 161 mV/decade and on-to-off current ratio of 2.84 × 103within a 1 V gate bias window. A one-dimensional transport model has been utilized to extract the band gap, interface state density, and the work function of the metal contacts. The model shows that SS degradation in BP MOSFETs occurs due to the ambipolar turn on of the carriers injected at the drain before the onset of purely thermionic-limited transport at the source. The model is further utilized to provide design guidelines for achieving ideal SS and meet off-state leakage targets, and it is found that band edge work functions and thin flakes are required for ideal operation at high VDS. This work represents a comprehensive analysis of the fundamental performance limitations of Schottky-contacted BP MOSFETs under realistic operating conditions.

We use template stripping to integrate metallic nanostructures onto flexible, stretchable, and rollable substrates. Using this approach, high-quality patterned metals that are replicated from reusable silicon templates can be directly transferred to polydimethylsiloxane (PDMS) substrates. First we produce stretchable gold nanohole arrays and show that their optical transmission spectra can be modulated by mechanical stretching. Next we fabricate stretchable arrays of gold pyramids and demonstrate a modulation of the wavelength of light resonantly scattered from the tip of the pyramid by stretching the underlying PDMS film. The use of a flexible transfer layer also enables template stripping using a cylindrical roller as a substrate. As an example, we demonstrate roller template stripping of metallic nanoholes, nanodisks, wires, and pyramids onto the cylindrical surface of a glass rod lens. These nonplanar metallic structures produced viatemplate stripping with flexible and stretchable films can facilitate many applications in sensing, display, plasmonics, metasurfaces, and roll-to-roll fabrication.

IMPORTANCE: Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases. OBJECTIVE: To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders. EVIDENCE REVIEW: Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. FINDINGS: Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis. CONCLUSIONS AND RELEVANCE: Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurological disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 µg intraperitoneal dose of rHIgM12 increases survival in two independent genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurological deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to the complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases α-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurological function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurological disease, we propose that the IgM might act late in the cascade of neuronal stress and/or death by a broad mechanism.

The scattering of time-harmonic linear waves by periodic media arises in a wide array of applications from materials science and nondestructive testing to remote sensing and oceanography. In this work we have in mind applications in optics, more specifically plasmonics, and the surface plasmon polaritons that are at the heart of remarkable phenomena such as extraordinary optical transmission, surface-enhanced Raman scattering, and surface plasmon resonance biosensing. In this paper we develop robust, highly accurate, and extremely rapid numerical solvers for approximating solutions to grating scattering problems in the frequency regime where these are commonly used. For piecewise-constant dielectric constants, which are commonplace in these applications, surface formulations are clearly advantaged as they posit unknowns supported solely at the material interfaces. The algorithms we develop here are high-order perturbation of surfaces methods and generalize previous approaches to take advantage of the fact that these algorithms can be significantly accelerated when some or all of the interfaces are trivial (flat). More specifically, for configurations with one nontrivial interface (and one trivial interface) we describe an algorithm that has the same computational complexity as a two-layer solver. With numerical simulations and comparisons with experimental data, we demonstrate the speed, accuracy, and applicability of our new algorithms.

In this paper we demonstrate that rigorous high-order perturbation of surfaces (HOPS) methods coupled with analytic continuation mechanisms are particularly well-suited for the assessment and design of nanoscale devices (e.g., biosensors) that operate based on surface plasmon resonances generated through the interaction of light with a periodic (metallic) grating. In this connection we explain that the characteristics of the latter are perfectly aligned with the optimal domain of applicability of HOPS schemes, as these procedures can be shown to be the methods of choice for low to moderate wavelengths of radiation and grating roughness that is representable by a few (e.g., tens of) Fourier coefficients. We argue that, in this context, the method can, for instance, produce full and precise reflectivity maps in computational times that are orders of magnitude faster than those of alternative numerical schemes (e.g., the popular “C-method,” finite differences, integral equations or finite elements). In this initial study we concentrate on the description of the basic principles that underlie the solution scheme, including those that relate to analytic continuation procedures. Within this framework, we explain how, in spite of conventional wisdom to the contrary, the resulting perturbative techniques can provide a most valuable tool for practical investigations in plasmonics. We demonstrate this with some examples that have been previously discussed in the literature (including treatments of the reflectivity and band gap structure of some simple geometries) and extend this to demonstrate the wider applicability of the proposed approach.

The template-stripping method can yield smooth patterned films without surface contamination. However, the process is typically limited to coinage metals such as silver and gold because other materials cannot be readily stripped from silicon templates due to strong adhesion. Herein, we report a more general template-stripping method that is applicable to a larger variety of materials, including refractory metals, semiconductors, and oxides. To address the adhesion issue, we introduce a thin gold layer between the template and the deposited materials. After peeling off the combined film from the template, the gold layer can be selectively removed via wet etching to reveal a smooth patterned structure of the desired material. Further, we demonstrate template-stripped multilayer structures that have potential applications for photovoltaics and solar absorbers. An entire patterned device, which can include a transparent conductor, semiconductor absorber, and back contact, can be fabricated. Since our approach can also produce many copies of the patterned structure with high fidelity by reusing the template, a low-cost and high-throughput process in micro- and nanofabrication is provided that is useful for electronics, plasmonics, and nanophotonics.

There are many potential sensing applications for Au nanorods due to a tunable localized surface plasmon resonance (LSPR) frequency that changes with aspect ratio. However, their application at high temperatures is limited due to a shape change that can take place well below the melting point of bulk Au, driven by a reduction in surface energy. A method of stabilizing Au nanorods is provided here by encapsulating them with a 15 nm capping layer of yttria stabilized zirconia (YSZ). After annealing rods with nominal dimensions of 100 × 44 nm to a temperature of 600 °C, small reductions in length were observed, but the rods remained stable for all subsequent sensing tests at 500 °C, which amounted to 80 h. It was shown with a separate sample that the rod geometry can be preserved even up to 800 °C over a 12 h annealing period, although a significant shortening of the rod length occurred, leaving a void space in the YSZ. The sensing response of both the transverse and the longitudinal LSPR peaks was monitored for H2, CO, and NO2exposures in an air background at 500 °C. In all cases, the longitudinal LSPR peak shows a larger shift upon gas exposure than does the transverse peak.

Optical biosensors based on surface plasmon resonance (SPR) in metallic thin films are currently standard tools for measuring molecular binding kinetics and affinities – an important task for biophysical studies and pharmaceutical development. Motivated by recent progress in the design and fabrication of metallic nanostructures, such as nanoparticles or nanoholes of various shapes, researchers have been pursuing a new generation of biosensors harnessing tailored plasmonic effects in these engineered nanostructures. Nanoplasmonic devices, while demanding nanofabrication, offer tunability with respect to sensor dimension and physical properties, thereby enabling novel biological interfacing opportunities and extreme miniaturization. Here we provide an integrated overview of refractometric biosensing with nanoplasmonic devices and highlight some recent examples of nanoplasmonic sensors capable of unique functions that are difficult to accomplish with conventional SPR. For example, since the local field strength and spatial distribution can be readily tuned by varying the shape and arrangement of nanostructures, biomolecular interactions can be controlled to occur in regions of high field strength. This may improve signal-to-noise and also enable sensing a small number of molecules. Furthermore, the nanoscale plasmonic sensor elements may, in combination with nanofabrication and materials-selective surface-modifications, make it possible to merge affinity biosensing with nanofluidic liquid handling.

The experimental observation of unusually sharp plasmon resonance peaks in periodic Ag nanohole arrays made using template stripping is reported. The extraordinary optical transmission (EOT) peak associated with the surface plasmon polaritons at the smooth Ag‐water interface shows a well‐defined Fano‐type profile with a linewidth below 10 nm at a wavelength of around 700 nm. Notably, this sharp and intense radiant peak (Q factor of 71) is obtained at visible frequencies in water and at normally incident illumination. This is accomplished by obtaining high‐quality Ag surfaces with a roughness below 1 nm, which reduces the imaginary component of the Ag dielectric function that is associated with material damping, as well as shrinking the nanohole radius to decrease radiative damping of plasmons. The localized spectral response of the radiant plasmon peak is characterized using the nanohole array in water in a layer‐by‐layer fashion via sequential atomic layer deposition of Al2O3. Because the ultrasharp EOT peak is obtained with excellent uniformity over a centimeter‐sized area from the metallic nanohole array in water, these template‐stripped nanohole arrays will benefit many practical applications based on EOT.

With a template-stripping fabrication technique, we demonstrate the mass fabrication of high-quality, uniform, ultrasharp (10 nm) metallic probes suitable for single-molecule fluorescence imaging, tip-enhanced Raman spectroscopy (TERS), and other near-field imaging techniques. We achieve reproducible single-molecule imaging with sub-20-nm spatial resolution and an enhancement in the detected fluorescence signal of up to 200. Similar results are obtained for TERS imaging of carbon nanotubes. We show that the large apex angle (70.5°) of our pyramidal tip is well suited to scatter the near-field optical signal into the far-field, leading to larger emission enhancement and hence to a larger quantum yield. Each gold or silver pyramidal probe is used on-demand, one at a time, and the unused tips can be stored for extended times without degradation or contamination. The high yield (>95%), reproducibility, durability, and massively parallel fabrication (1.5 million identical probes over a wafer) of the probes hold promise for reliable optical sensing and detection and for cementing near-field optical imaging and spectroscopy as a routine characterization technique.

We present a detailed study of the inter-nanohole distance that governs the self-imaging phenomenon created by the three-dimensional propagation of light through periodic nanohole arrays on plasmonic substrates. We used scanning near-field optical microscopy (SNOM) to map the light intensity distributions at various heights above 10 × 10 nanohole arrays of varying pitch sizes on silver films. Our results suggest the interhole spacing has to be greater than the wavelength of the incident light to create the self-imaging phenomenon. We also present finite-difference time-domain (FDTD) calculations which show qualitative corroboration of our experimental results. Both our experimental and FDTD results show that the self-imaging phenomenon is more pronounced for structures with larger pitch sizes. We believe this self-imaging phenomenon is related to the Talbot imaging effect that has also been modified by a plasmonic component and can potentially be used to provide the basis for a new class of optical microscopes.

Microarray technology has facilitated many powerful high-throughput studies in the fields of genetics and proteomics, among others. However, preparation of microarrays composed of cell-derived membranes with embedded receptors has proven difficult. Here we describe a new method for forming microarrays composed of synthetic lipid vesicles and natural cell membranes. The method is based upon assembly of vesicles and natural membranes into recessed micro- and nanowells and using a polydimethylsiloxane (PDMS) block as a “squeegee.” This method is used to assemble phospholipid vesicles into arrays with micrometer and nanoscale dimensions. Native myelin and neuronal lipid raft arrays are also formed in 30 min or less. We show the natural membrane arrays can be used for sensing lipid–protein interactions by detecting cholera toxin binding to ganglioside GM1 in neuronal lipid rafts. In multicomponent arrays myelin can be distinguished from neuronal rafts by antibody binding to cell-specific surface antigens. Finally, myelin arrays formed in gold nanowells are used for surface plasmon resonance sensing. This assembly approach is simple, broadly applicable, and opens up new avenues of research not easily accomplished with standard microarray technology.

Inexpensive, reproducible, and high-throughput fabrication of nanometric apertures in metallic films can benefit many applications in plasmonics, sensing, spectroscopy, lithography, and imaging. Here we use template-stripping to pattern periodic nanohole arrays in optically thick, smooth Ag films with a silicon template made viananoimprint lithography. Ag is a low-cost material with good optical properties, but it suffers from poor chemical stability and biocompatibility. However, a thin silica shell encapsulating our template-stripped Ag nanoholes facilitates biosensing applications by protecting the Ag from oxidation as well as providing a robust surface that can be readily modified with a variety of biomolecules using well-established silane chemistry. The thickness of the conformal silica shell can be precisely tuned by atomic layer deposition, and a 15 nm thick silica shell can effectively prevent fluorophore quenching. The Ag nanohole arrays with silica shells can also be bonded to polydimethylsiloxane (PDMS) microfluidic channels for fluorescence imaging, formation of supported lipid bilayers, and real-time, label-free SPR sensing. Additionally, the smooth surfaces of the template-stripped Ag films enhance refractive index sensitivity compared with as-deposited, rough Ag films. Because nearly centimeter-sized nanohole arrays can be produced inexpensively without using any additional lithography, etching, or lift-off, this method can facilitate widespread applications of metallic nanohole arrays for plasmonics and biosensing.

Abstract: In anomaly intrusion detection, modeling the normal behavior of activities performed by a user is an important issue. To extract normal behavior from the activities of a user, conventional data mining techniques are widely applied to a finite audit data set. However, these approaches model only the static behavior of a user in the audit data set. This drawback can be overcome by viewing a user’s continuous activities as an audit data stream. This paper proposes an anomaly intrusion detection method that continuously models the normal behavior of a user over the audit data stream. A set of features is used to represent the characteristics of an activity. For each feature, clusters of feature values corresponding to activities observed thus far in an audit data stream are identified by a statistical grid-based clustering algorithm for a data stream. Each cluster represents the frequency range of the activities with respect to the feature. As a result, without the physical maintenance of any historical activity of the user, the user’s new activities can be continuously reflected in the ongoing results. At the same time, various statistics of activities related to the identified clusters are also modeled to improve the performance of anomaly detection. The proposed algorithm is illustrated by a series of experiments to identify various characteristics. [Copyright &y& Elsevier]

Several sulfur-containing acrylate polymers were developed for a high refractive index with high transparency and good processing performance for thin films. A series of poly(methacrylate)s were synthesized by radical polymerization, in which thin films are coated on a quartz substrate for optical characterization. One, two and three sulfur atoms were bound into acrylate monomers and thermally copolymerized with methyl methacrylate. An alicyclic structure was used to achieve a dense molecular volume of the sulfur-containing monomer. Refractive index was measured under visible light. The index linearly increased with the sulfur-containing monomer content of the copolymer. Each homopolymer was predicted by an extrapolation method, resulting in a high refractive index of 1.624–1.725 at 589?nm. An Abbe's number of ~30 was recorded for most sulfur polymers, indicating low wavelength dispersion of the index. A polymer with dipolar functionality displayed an Abbe's number of 40.9. High optical transparency of films was observed at the wavelengths of the index measurement. All polymers were thermally stable up to ~250?°C and exhibited glass transition around 100?°C.

Fabricating plasmonic nanostructures with robust optical and chemical properties remains a challenging task, especially with silver, which has superior optical properties but poor environmental stability. In this work, conformal atomic layer deposition (ALD) of thin alumina overlayers is used to precisely tune the optical transmission properties of periodic nanohole arrays made in gold and silver films. Experiments and computer simulations confirm that ALD overlayers with optimized thicknesses tune and enhance the transmitted intensity due to refractive index matching effects and by modifying the dielectric properties of each nanohole. Furthermore, encapsulating silver nanohole arrays with thin alumina overlayers protects the patterned surfaces against unwanted oxidation and contamination. The ability to precisely tune the optical properties while simultaneously providing robust chemical stability can benefit a broad range of applications, including biosensing and fluorescence imaging.

Protein microarray technology, in which a large number of capture ligands are spatially arrayed at a high density, presents an attractive method for high-throughput proteomic analysis. Toward this end, we demonstrate the first cell-based protein detection in a microsystem, wherein Escherichia colicells are genetically engineered to express the desired capture proteins on the membrane surface and are spatially arrayed as sensing elements in a microfluidic device. An E. coliclone expressing peptide ligands with high affinity and high specificity for target molecules was isolated a priori. Then these cells were electrokinetically immobilized on gold electrodes using dielectrophoresis, thus allowing each sensor element to be electrically addressable. Flow cytometry and subsequent fluorescence analysis verified the highly specific capture and detection of target molecules by the bacteria. Finally, through the coexpression of peptide-based capture ligands on the cell surface and fluorescent protein in the cytoplasm, we demonstrate an effective means of directly linking the fluorescence intensity to the density of capture ligands.

Free-space-based channelized dynamic spectral equalizers are theoretically investigated by solving the temporal-frequency-dependent power-coupling integral for commonly used active device technologies: liquid-crystal modulators, tilting micromirror arrays, and deformable gratings. Channel-filter characteristics, such as bandwidth and interchannel transition, are found to depend on the different attenuation mechanisms provided by the active devices. Such information is required for choosing the proper device parameters in designing channel equalizers and similar free-space spatially dispersed subsystems.

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Current methods for pathogen detection require days before a result is available, while biosensors offer the advantage of quick, on the spot results. In this project we present the proof of concept of a biosensor that uses giant magnetoresistance (GMR) sensors and a microfluidic system. The bioprobe consists of a 30 bp oligonucleotide, 5′ functionalized with a thiol group (T-DNA30) immobilized on a gold surface. Hybridization was tested with a 5′-biotinylated oligonucleotide complementary to T-DNA30 to which Streptavidin-R-Phycoerythrin was attached later. The difference in fluorescence between the target sample and control samples was observed using a scanning laser confocal fluorescence microscope. The GMR device consists of an Ir0.8Mn0.2/Co0.9Fe0.1/Cu/Co0.9Fe0.1/Ni0.82Fe0.12 multilayer structure. Magnetic nanoparticles were deposited directly on the surface of the GMR sensors. An external magnetic field was employed to polarize the nanoparticles, which can then be detected by comparing the resistance change loops of the GMR sensors before and after their deposition. A transparent elastomer, polydimethylsiloxane (PDMS), was used for the microfluidic system. The system comprises two microfluidic channels separated by a 200 μm PDMS wall. The channel width is 200 μm and its height 100 μm. The PDMS channel was permanently bonded to the SiO2 surface of the GMR sensor. The integrated biosensor will immobilize thiolated DNA on the gold surface below which the GMR device is located. For hybridization, biotinylated DNA will be used. Finally, magnetic nanoparticles, coated with streptavidin will be attached to the hybridized DNA and detected by the GMR device.