Selective Enhancer Dependencies in MYC -Intact and MYC -Rearranged Germinal Center B-cell Diffuse Large B-cell Lymphoma.

High expression of MYC and its target genes define a subset of germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) associated with poor outcomes. Half of these high-grade cases show chromosomal rearrangements between the MYC locus and heterologous enhancer-bearing loci, while focal deletions of the adjacent non-coding gene PVT1 are enriched in MYC -intact cases. To identify genomic drivers of MYC activation, we used high-throughput CRISPR-interference (CRISPRi) profiling of candidate enhancers in the MYC locus and rearrangement partner loci in GCB-DLBCL cell lines and mantle cell lymphoma (MCL) comparators that lacked common rearrangements between MYC and immunoglobulin (Ig) loci. Rearrangements between MYC and non-Ig loci were associated with unique dependencies on specific enhancer subunits within those partner loci. Notably, fitness dependency on enhancer modules within the BCL6 super-enhancer ( BCL6 -SE) cluster regulated by a transcription factor complex of MEF2B, POU2F2, and POU2AF1 was higher in cell lines bearing a recurrent MYC::BCL6 -SE rearrangement. In contrast, GCB-DLBCL cell lines without MYC rearrangement were highly dependent on a previously uncharacterized 3' enhancer within the MYC locus itself (GCBME-1), that is regulated in part by the same triad of factors. GCBME-1 is evolutionarily conserved and active in normal germinal center B cells in humans and mice, suggesting a key role in normal germinal center B cell biology. Finally, we show that the PVT1 promoter limits MYC activation by either native or heterologous enhancers and demonstrate that this limitation is bypassed by 3' rearrangements that remove PVT1 from its position in cis with the rearranged MYC gene. Key points: CRISPR-interference screens identify a conserved germinal center B cell MYC enhancer that is essential for GCB-DLBCL lacking MYC rearrangements. Functional profiling of MYC partner loci reveals principles of MYC enhancer-hijacking activation by non-immunoglobulin rearrangements.

ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia.

Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+/- like B-ALL "signature" genes, including the likely leukemogenic driver EPOR. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of repeat enhancer-activated genes. Together, our findings reveal an epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene-expression program of ETV6-RUNX1+/- like B-ALL. SIGNIFICANCE: We find a unifying mechanism underlying a leukemia subtype-defining gene-expression signature that relies on repetitive elements with poor conservation between humans and rodents. The ability of ETV6 to antagonize promiscuous, nonphysiologic ERG activity may shed light on other roles of these key regulators in hematolymphoid development and human disease. See related commentary by Mercher, p. 2. This article is highlighted in the In This Issue feature, p. 1.

Complex 10-nm resolution nanogap and nanowire geometries for plasmonic metasurface miniaturization.

Emerging electromagnetic inverse design methods have pushed nanofabrication methods to their limits to extract maximum performance from plasmonic aperture-based metasurfaces. Using plasmonic metamaterial-lined apertures as an example, we demonstrate the importance of fine nanowire and nanogap features for achieving strong miniaturization of plasmonic nanoapertures. Metamaterial-lined nanoapertures are miniaturized over bowtie nanoapertures with identical minimum feature sizes by a factor of 25% without loss of field enhancement. We show that features as small as 10 nm can be reliably patterned over the wide areas required of metasurfaces using the helium focused ion beam microscope. Under imperfect fabrication conditions, we achieve 11-nm-wide nanogaps and 12-nm-wide nanowires over an area of 13 µm2, and successfully validate our results with optical characterization and comparable full-wave simulations.

The Preclinical Evaluation of a Second-Generation Antivenom for Treating Snake Envenoming in India.

Snake envenoming afflicts the Indian subcontinent with the highest rates of mortality (47,000) and morbidity globally. The only effective treatment for snakebites is the administration of antivenom, which is produced by the hyperimmunisation of equines. Commercial Indian antivenoms, however, have been shown to exhibit a poor preclinical performance in neutralising venom, as a result of inter- and intrapopulation snake venom variation. Additionally, their poor dose effectiveness necessitates the administration of larger volumes of antivenom for treatment, leading to several harmful side effects in snakebite victims, including serum sickness and fatal anaphylaxis. In this study, we employed chromatographic purification to enhance the dose efficacy of commercial Indian antivenoms. The efficacy of this 'second-generation' antivenom was comparatively evaluated against six other marketed antivenoms using a number of in vitro and in vivo preclinical assays, which revealed its superior venom recognition capability. Enhanced purity also resulted in significant improvements in dose effectiveness, as the 'second-generation' antivenom exhibited a 3 to 4.5 times increased venom neutralisation potential. Furthermore, preclinical assays revealed the increased effectiveness of the 'second-generation' antivenom in countering morbid effects inflicted by the 'big four' Indian snakes. Thus, we demonstrate the role of simpler purification steps in significantly enhancing the effectiveness of snakebite therapy in regions that are most affected by snakebites.

Ultrasound Echogenicity as an Indicator of Muscle Fatigue during Functional Electrical Stimulation.

Functional electrical stimulation (FES) is a potential neurorehabilitative intervention to enable functional movements in persons with neurological conditions that cause mobility impairments. However, the quick onset of muscle fatigue during FES is a significant challenge for sustaining the desired functional movements for more extended periods. Therefore, a considerable interest still exists in the development of sensing techniques that reliably measure FES-induced muscle fatigue. This study proposes to use ultrasound (US) imaging-derived echogenicity signal as an indicator of FES-induced muscle fatigue. We hypothesized that the US-derived echogenicity signal is sensitive to FES-induced muscle fatigue under isometric and dynamic muscle contraction conditions. Eight non-disabled participants participated in the experiments, where FES electrodes were applied on their tibialis anterior (TA) muscles. During a fatigue protocol under either isometric and dynamic ankle dorsiflexion conditions, we synchronously collected the isometric dorsiflexion torque or dynamic dorsiflexion angle on the ankle joint, US echogenicity signals from TA muscle, and the applied stimulation intensity. The experimental results showed an exponential reduction in the US echogenicity relative change (ERC) as the fatigue progressed under the isometric (R2=0.891±0.081) and dynamic (R2=0.858±0.065) conditions. The experimental results also implied a strong linear relationship between US ERC and TA muscle fatigue benchmark (dorsiflexion torque or angle amplitude), with R2 values of 0.840±0.054 and 0.794±0.065 under isometric and dynamic conditions, respectively. The findings in this study indicate that the US echogenicity signal is a computationally efficient signal that strongly represents FES-induced muscle fatigue. Its potential real-time implementation to detect fatigue can facilitate an FES closed-loop controller design that considers the FES-induced muscle fatigue.

Wireless Capacitive Liquid-Level Detection Sensor Based on Zero-Power RFID-Sensing Architecture.

In this paper, a new method for the wireless detection of liquid level is proposed by integrating a capacitive IDC-sensing element with a passive three-port RFID-sensing architecture. The sensing element transduces changes in the liquid level to corresponding fringe-capacitance variations, which alters the phase of the RFID backscattered signal. Variation in capacitance also changes the resonance magnitude of the sensing element, which is associated with a high phase transition. This change in the reactive phase is used as a sensing parameter by the RFID architecture for liquid-level detection. Practical measurements were conducted in a real-world scenario by placing the sensor at a distance of approximately 2 m (with a maximum range of about 7 m) from the RFID reader. The results show that the sensor node offers a high sensitivity of 2.15°/mm to the liquid-level variation. Additionally, the sensor can be used within or outside the container for the accurate measurement of conductive- or non-conductive-type liquids due to the use of polyethylene coating on the sensitive element. The proposed sensor increases the reliability of the current level sensors by eliminating the internal power source as well as complex signal-processing circuits, and it offers real-time response, linearity, high sensitivity, and excellent repeatability, which are suitable for widespread deployment of sensor node applications.

Ultrasound Echogenicity-based Assessment of Muscle Fatigue During Functional Electrical Stimulation.

The rapid onset of muscle fatigue during functional electrical stimulation (FES) is a major challenge when attempting to perform long-term periodic tasks such as walking. Surface electromyography (sEMG) is frequently used to detect muscle fatigue for both volitional and FES-evoked muscle contraction. However, sEMG contamination from both FES stimulation artifacts and residual M-wave signals requires sophisticated processing to get clean signals and evaluate the muscle fatigue level. The objective of this paper is to investigate the feasibility of computationally efficient ultrasound (US) echogenicity as a candidate indicator of FES-induced muscle fatigue. We conducted isometric and dynamic ankle dorsiflexion experiments with electrically stimulated tibialis anterior (TA) muscle on three human participants. During a fatigue protocol, we synchronously recorded isometric dorsiflexion force, dynamic dorsiflexion angle, US images, and stimulation intensity. The temporal US echogenicity from US images was calculated based on a gray-scaled analysis to assess the decrease in dorsiflexion force or motion range due to FES-induced TA muscle fatigue. The results showed a monotonic reduction in US echogenicity change along with the fatigue progression for both isometric (R2 =0.870±0.026) and dynamic (R2 =0.803±0.048) ankle dorsiflexion. These results implied a strong linear relationship between US echogenicity and TA muscle fatigue level. The findings indicate that US echogenicity may be a promising computationally efficient indicator for assessing FES-induced muscle fatigue and may aid in the design of muscle-in-the-loop FES controllers that consider the onset of muscle fatigue.

Surface-enhanced mid-infrared absorption spectroscopy using miniaturized-disc metasurface.

Surface-enhanced infrared spectroscopy is an important technique for improving the signal-to-noise ratio of spectroscopic material identification measurements in the mid-infrared fingerprinting region. However, the lower bound of the fingerprinting region receives much less attention due to a scarcity of transparent materials, more expensive sources, and weaker plasmonic effects. In this paper, we present a miniaturized metasurface unit cell for surface-enhanced infrared spectroscopy of the 15-[Formula: see text]m vibrational band of CO[Formula: see text]. The unit cell consists of a gold disc, patterned along the edge with fine gaps/wires to create a resonant metamaterial liner. In simulation, our plasmonic metamaterial-lined disc achieves greater than [Formula: see text] the average field intensity enhancement of a comparable dipole array and a miniaturized size of [Formula: see text] using complex, 100-nm features that are patterned using 100-kV electron-beam lithography. In a simple experiment, the metamaterial-lined disc metasurface shows a high tolerance to fabrication imperfections and enhances the absorption of CO[Formula: see text] at 15 [Formula: see text]m. The resonant wavelength and reflection magnitude can be tuned over a wide range by adjusting the liner feature sizes and the metasurface array pitch to target other vibrational bands. This work is a step toward low-cost, more compact on-chip integrated gas sensors.

Venomics of the Enigmatic Andaman Cobra (Naja sagittifera) and the Preclinical Failure of Indian Antivenoms in Andaman and Nicobar Islands.

The Andaman and Nicobar Islands are an abode to a diversity of flora and fauna, including the many endemic species of snakes, such as the elusive Andaman cobra (Naja sagittifera). However, the ecology and evolution of venomous snakes inhabiting these islands have remained entirely uninvestigated. This study aims to bridge this knowledge gap by investigating the evolutionary history of N. sagittifera and its venom proteomic, biochemical and toxicity profile. Phylogenetic reconstructions confirmed the close relationship between N. sagittifera and the Southeast Asian monocellate cobra (N. kaouthia). Overlooking this evolutionary history, a polyvalent antivenom manufactured using the venom of the spectacled cobra (N. naja) from mainland India is used for treating N. sagittifera envenomations. Comparative evaluation of venoms of these congeners revealed significant differences in their composition, functions and potencies. Given the close phylogenetic relatedness between N. sagittifera and N. kaouthia, we further assessed the cross-neutralising efficacy of Thai monovalent N. kaouthia antivenom against N. sagittifera venoms. Our findings revealed the inadequate preclinical performance of the Indian polyvalent and Thai monovalent antivenoms in neutralising N. sagittifera venoms. Moreover, the poor efficacy of the polyvalent antivenom against N. naja venom from southern India further revealed the critical need to manufacture region-specific Indian antivenoms.

Patterning of Complex, Nanometer-Scale Features in Wide-Area Gold Nanoplasmonic Structures Using Helium Focused Ion Beam Milling.

Meeting the evolving demands of plasmonics research requires increasingly precise control over surface plasmon properties, which necessitates extremely fine nanopatterning, complex geometries, and/or long-range order. Nanoplasmonic metasurfaces are representative of a modern research area requiring intricate, high-fidelity features reproduced over areas of several free-space wavelengths, making them one of the most challenging fabrication problems in the field today. This work presents a systematic study of the helium focused ion beam milling of gold for nanoplasmonic metasurface applications, using as its example a nanoplasmonic metasurface based on an array of nanometer-scale plasmonic-wire-loaded subwavelength apertures in a gold film. At each step, the pattern variations are compared to simulation to predict the experimental outcome. Our results show that even in a practical fabrication environment, helium ion beam milling can be used to reliably pattern 10 nm features into gold with 1:5 aspect ratio in complex geometries over a wide area.

A Survey on Battery-Less RFID-Based Wireless Sensors.

We present a survey on battery-less Radio Frequency Identification (RFID-based wireless sensors that have emerged in the past several years. We discuss the evolution of RFID turning into wireless sensors. Moreover, we talk about different components of these battery-less RFID-based wireless sensors, five main topologies that transform a simple RFID chip into a battery-less wireless sensor, and state-of-the-art implementations of these topologies. In battery-less wireless sensors, the read range is of key importance. Hence, we discuss how each component of the sensor plays its role in determining the read range and how each topology exploits these components to optimize read range, complexity, and/or cost. Additionally, we discuss potential future directions that can help provide improvements in RFID-based wireless sensor technology.

A Dual-Modal Approach Using Electromyography and Sonomyography Improves Prediction of Dynamic Ankle Movement: A Case Study.

For decades, surface electromyography (sEMG) has been a popular non-invasive bio-sensing technology for predicting human joint motion. However, cross-talk, interference from adjacent muscles, and its inability to measure deeply located muscles limit its performance in predicting joint motion. Recently, ultrasound (US) imaging has been proposed as an alternative non-invasive technology to predict joint movement due to its high signal-to-noise ratio, direct visualization of targeted tissue, and ability to access deep-seated muscles. This paper proposes a dual-modal approach that combines US imaging and sEMG for predicting volitional dynamic ankle dorsiflexion movement. Three feature sets: 1) a uni-modal set with four sEMG features, 2) a uni-modal set with four US imaging features, and 3) a dual-modal set with four dominant sEMG and US imaging features, together with measured ankle dorsiflexion angles, were used to train multiple machine learning regression models. The experimental results from a seated posture and five walking trials at different speeds, ranging from 0.50 m/s to 1.50 m/s, showed that the dual-modal set significantly reduced the prediction root mean square errors (RMSEs). Compared to the uni-modal sEMG feature set, the dual-modal set reduced RMSEs by up to 47.84% for the seated posture and up to 77.72% for the walking trials. Similarly, when compared to the US imaging feature set, the dual-modal set reduced RMSEs by up to 53.95% for the seated posture and up to 58.39% for the walking trials. The findings show that potentially the dual-modal sensing approach can be used as a superior sensing modality to predict human intent of a continuous motion and implemented for volitional control of clinical rehabilitative and assistive devices.

Biogeographic venom variation in Russell's viper (Daboia russelii) and the preclinical inefficacy of antivenom therapy in snakebite hotspots.

BACKGROUND: Snakebite in India results in over 58,000 fatalities and a vast number of morbidities annually. The majority of these clinically severe envenomings are attributed to Russell's viper (Daboia russelii), which has a near pan-India distribution. Unfortunately, despite its medical significance, the influence of biogeography on the composition and potency of venom from disparate D. russelii populations, and the repercussions of venom variation on the neutralisation efficacy of marketed Indian antivenoms, remain elusive. METHODS: Here, we employ an integrative approach comprising proteomic characterisation, biochemical analyses, pharmacological assessment, and venom toxicity profiling to elucidate the influence of varying ecology and environment on the pan-Indian populations of D. russelii. We then conducted in vitro venom recognition experiments and in vivo neutralisation assays to evaluate the efficacy of the commercial Indian antivenoms against the geographically disparate D. russelii populations. FINDINGS: We reveal significant intraspecific variation in the composition, biochemical and pharmacological activities and potencies of D. russelii venoms sourced from five distinct biogeographic zones across India. Contrary to our understanding of the consequences of venom variation on the effectiveness of snakebite therapy, commercial antivenom exhibited surprisingly similar neutralisation potencies against the majority of the investigated populations, with the exception of low preclinical efficacy against the semi-arid population from northern India. However, the ability of Indian antivenoms to counter the severe morbid effects of Daboia envenoming remains to be evaluated. CONCLUSION: The concerning lack of antivenom efficacy against the north Indian population of D. russelii, as well as against two other 'big four' snake species in nearby locations, underscores the pressing need to develop pan-India effective antivenoms with improved efficacy in high snakebite burden locales.

Evolution Bites - Timeworn Inefficacious Snakebite Therapy in the Era of Recombinant Vaccines.

Snakebite is a neglected tropical disease that inflicts severe socioeconomic burden on developing countries by primarily affecting their rural agrarian populations. India is a major snakebite hotspot in the world, as it accounts for more than 58,000 annual snakebite mortalities and over three times that number of morbidities. The only available treatment for snakebite is a commercially marketed polyvalent antivenom, which is manufactured exclusively against the 'big four' Indian snakes. In this review, we highlight the influence of ecology and evolution in driving inter- and intra-specific venom variations in snakes. We describe the repercussions of this molecular variation on the effectiveness of the current generation Indian antivenoms in mitigating snakebite pathologies. We highlight the disturbing deficiencies of the conventional animal-derived antivenoms, and review next-generation recombinant antivenoms and other promising therapies for the efficacious treatment of this disease.

Evaluation of Non-Invasive Ankle Joint Effort Prediction Methods for Use in Neurorehabilitation Using Electromyography and Ultrasound Imaging.

OBJECTIVE: Reliable measurement of voluntary human effort is essential for effective and safe interaction between the wearer and an assistive robot. Existing voluntary effort prediction methods that use surface electromyography (sEMG) are susceptible to prediction inaccuracies due to non-selectivity in measuring muscle responses. This technical challenge motivates an investigation into alternative non-invasive effort prediction methods that directly visualize the muscle response and improve effort prediction accuracy. The paper is a comparative study of ultrasound imaging (US)-derived neuromuscular signals and sEMG signals for their use in predicting isometric ankle dorsiflexion moment. Furthermore, the study evaluates the prediction accuracy of model-based and model-free voluntary effort prediction approaches that use these signals. METHODS: The study evaluates sEMG signals and three US imaging-derived signals: pennation angle, muscle fascicle length, and echogenicity and three voluntary effort prediction methods: linear regression (LR), feedforward neural network (FFNN), and Hill-type neuromuscular model (HNM). RESULTS: In all the prediction methods, pennation angle and fascicle length significantly improve the prediction accuracy of dorsiflexion moment, when compared to echogenicity. Also, compared to LR, both FFNN and HNM improve dorsiflexion moment prediction accuracy. CONCLUSION: The findings indicate FFNN or HNM approach and using pennation angle or fascicle length predict human ankle movement intent with higher accuracy. SIGNIFICANCE: The accurate ankle effort prediction will pave the path to safe and reliable robotic assistance in patients with drop foot.

Targeting Phospholipase D4 Attenuates Kidney Fibrosis.

Phospholipase D4 (PLD4), a single-pass transmembrane glycoprotein, is among the most highly upregulated genes in murine kidneys subjected to chronic progressive fibrosis, but the function of PLD4 in this process is unknown. Here, we found PLD4 to be overexpressed in the proximal and distal tubular epithelial cells of murine and human kidneys after fibrosis. Genetic silencing of PLD4, either globally or conditionally in proximal tubular epithelial cells, protected mice from the development of fibrosis. Mechanistically, global knockout of PLD4 modulated innate and adaptive immune responses and attenuated the upregulation of the TGF-ß signaling pathway and α1-antitrypsin protein (a serine protease inhibitor) expression and downregulation of neutrophil elastase (NE) expression induced by obstructive injury. In vitro, treatment with NE attenuated TGF-ß-induced accumulation of fibrotic markers. Furthermore, therapeutic targeting of PLD4 using specific siRNA protected mice from folic acid-induced kidney fibrosis and inhibited the increase in TGF-ß signaling, decrease in NE expression, and upregulation of mitogen-activated protein kinase signaling. Immunoprecipitation/mass spectrometry and coimmunoprecipitation experiments confirmed that PLD4 binds three proteins that interact with neurotrophic receptor tyrosine kinase 1, a receptor also known as TrkA that upregulates mitogen-activated protein kinase. PLD4 inhibition also prevented the folic acid-induced upregulation of this receptor in mouse kidneys. These results suggest inhibition of PLD4 as a novel therapeutic strategy to activate protease-mediated degradation of extracellular matrix and reverse fibrosis.

Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation.

Secreted modular calcium-binding protein 2 (SMOC2) belongs to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins whose members are known to modulate cell-matrix interactions. We report that SMOC2 is upregulated in the kidney tubular epithelial cells of mice and humans following fibrosis. Using genetically manipulated mice with SMOC2 overexpression or knockdown, we show that SMOC2 is critically involved in the progression of kidney fibrosis. Mechanistically, we found that SMOC2 activates a fibroblast-to-myofibroblast transition (FMT) to stimulate stress fiber formation, proliferation, migration, and extracellular matrix production. Furthermore, we demonstrate that targeting SMOC2 by siRNA results in attenuation of TGFß1-mediated FMT in vitro and an amelioration of kidney fibrosis in mice. These findings implicate that SMOC2 is a key signaling molecule in the pathological secretome of a damaged kidney and targeting SMOC2 offers a therapeutic strategy for inhibiting FMT-mediated kidney fibrosis - an unmet medical need.

New approach for extraordinary transmission through an array of subwavelength apertures using thin ENNZ metamaterial liners.

Extraordinary transmission (ET) through a periodic array of subwavelength apertures on a perfect metallic screen has been studied extensively in recent years, and has largely been attributed to diffraction effects, for which the periodicity of the apertures, rather than their dimensions, dominates the response. The transmission properties of the apertures at resonance, on the other hand, are not typically considered 'extraordinary' because they may be explained using more conventional aperture-theoretical mechanisms. This work describes a novel approach for achieving ET in which subwavelength apertures are made to resonate by lining them using thin, epsilon-negative and near-zero (ENNZ) metamaterials. The use of ENNZ metamaterials has recently proven successful in miniaturizing circular waveguides by strongly reducing their natural cutoff frequencies, and the theory is adapted here for the design of subwavelength apertures in a metallic screen. We present simulations and proof-of-concept measurements at microwave frequencies that demonstrate ET for apertures measuring one-quarter of a wavelength in diameter and suggest the potential for even more dramatic miniaturization simply by engineering the ENNZ metamaterial dispersion. The results exhibit a fano-like profile whose frequency varies with the properties of the metamaterial liner, but is independent of period. It is suggested that similar behaviour can be obtained at optical frequencies, where ENNZ metamaterials may be realized using appropriately arranged chains of plasmonic nanoparticles.

Anisotropic metamaterial optical fibers.

Internal physical structure can drastically modify the properties of waveguides: photonic crystal fibers are able to confine light inside a hollow air core by Bragg scattering from a periodic array of holes, while metamaterial loaded waveguides for microwaves can support propagation at frequencies well below cutoff. Anisotropic metamaterials assembled into cylindrically symmetric geometries constitute light-guiding structures that support new kinds of exotic modes. A microtube of anodized nanoporous alumina, with nanopores radially emanating from the inner wall to the outer surface, is a manifestation of such an anisotropic metamaterial optical fiber. The nanopores, when filled with a plasmonic metal such as silver or gold, greatly increase the electromagnetic anisotropy. The modal solutions in such anisotropic circular waveguides can be uncommon Bessel functions with imaginary orders.

Experimental and theoretical verification of focusing in a large, periodically loaded transmission line negative refractive index metamaterial.

We have previously shown that a new class of Negative Refractive Index (NRI) metamaterials can be constructed by periodically loading a host transmission line medium with inductors and capacitors in a dual (high-pass) configuration. A small planar NRI lens interfaced with a Positive Refractive Index (PRI) parallel-plate waveguide recently succeeded in demonstrating focusing of cylindrical waves. In this paper, we present theoretical and experimental data describing the focusing and dispersion characteristics of a significantly improved device that exhibits minimal edge effects, a larger NRI region permitting precise extraction of dispersion data, and a PRI region consisting of a microstrip grid, over which the fields may be observed. The experimentally obtained dispersion data exhibits excellent agreement with the theory predicted by periodic analysis, and depicts an extremely broadband region from 960MHz to 2.5GHz over which the refractive index remains negative. At the frequency at which the theory predicts a relative refractive index of -1, the measured field distribution shows a focal spot with a maximum beam width under one-half of a guide wavelength. These results are compared with field distributions obtained through mathematical simulations based on the plane-wave expansion technique, and exhibit a qualitative correspondence. The success of this experiment attests to the repeatability of the original experiment and affirms the viability of the transmission line approach to the design of NRI metamaterials.