Niclosamide modulates phenotypic switch and inflammatory responses in human pulmonary arterial smooth muscle cells.

Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) represent key steps of pulmonary vascular remodeling, leading to the development of pulmonary arterial hypertension (PAH) and right ventricular failure. Niclosamide (NCL), an FDA-approved anthelmintic, has been shown to regulate cell proliferation, migration, invasion, and apoptosis through a variety of signaling pathways. However, its role on modulating the phenotypic switch and inflammatory responses in PASMCs remains unclear. In this study, cell proliferation assay showed that NCL inhibited PDGF-BB induced proliferation of human PASMCs in a dose-dependent manner. Western blot analysis further confirmed a notable reduction in the expression of cyclin D1 and PCNA proteins. Subsequently, flow cytometry analysis demonstrated that NCL induced an increased percentage of cells in the G1 phase while promoting apoptosis in PASMCs. Moreover, both scratch wound assay and transwell assay confirmed that NCL decreased PDGF-BB-induced migration of PASMCs. Mechanistically, western blot revealed that pretreatment of PASMCs with NCL markedly restored the protein levels of SMA, SM22, and calponin, while reducing phosphorylation of P38/STAT3 signaling in the presence of PDGF-BB. Interestingly, macrophages adhesion assay showed that NCL markedly reduced recruitment of Calcein-AM labeled RAW264.7 by TNFα-stimulated PASMCs. Western blot revealed that NCL suppressed TNFα-induced expression of both of VCAM-1 and ICAM-1 proteins. Furthermore, pretreatment of PASMCs with NCL significantly inhibited NLRP3 inflammasome activity through reducing NLRP3, AIM2, mature interleukin-1ß (IL-ß), and cleaved Caspase-1 proteins expression. Together, these results suggested versatile effects of NCL on controlling of proliferation, migration, and inflammatory responses in PASMCs through modulating different pathways, indicating that repurposing of NCL may emerge as a highly effective drug for PAH treatment.

Bioinspired Plasmo-virus for Point-of-Care SARS-CoV-2 Detection.

Directly identifying the presence of the virus in infected hosts with an appropriate speed and sensitivity permits early epidemic management even during the presymptomatic incubation period of infection. Here, we synthesize a bioinspired plasmo-virus (BPV) particle for rapid and sensitive point-of-care (POC) detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via a self-assembled plasmonic nanoprobe array on spike proteins. The BPV enables strong near-infrared (NIR) extinction peaks caused by plasmonic nanogaps. We quantify SARS-CoV-2 in viral transport medium (VTM) at low titers within 10 min with a limit of detection (LOD) of 1.4 × 101 pfu/mL, which is 103 times more sensitive than the current gold-standard method. The high-sensitivity and high-speed POC detection may be widely used for the timely, individualized diagnosis of infectious agents in low-resource settings.

An Integrated Plasmo-Photoelectronic Nanostructure Biosensor Detects an Infection Biomarker Accompanying Cell Death in Neutrophils.

Bacterial infections leading to sepsis are a major cause of deaths in the intensive care unit. Unfortunately, no effective methods are available to capture the early onset of infectious sepsis near the patient with both speed and sensitivity required for timely clinical treatment. To fill the gap, the authors develop a highly miniaturized (2.5 × 2.5 µm2 ) plasmo-photoelectronic nanostructure device that detected citrullinated histone H3 (CitH3), a biomarker released to the blood circulatory system by neutrophils. Rapidly detecting CitH3 with high sensitivity has the great potential to prevent infections from developing life-threatening septic shock. To this end, the author's device incorporates structurally engineered arrayed hemispherical gold nanoparticles that are functionalized with high-affinity antibodies. A nanoplasmonic resonance shift induces a photoconduction increase in a few-layer molybdenum disulfide (MoS2 ) channel, and it provides the sensor signal. The device achieves label-free detection of serum CitH3 with a 5-log dynamic range from 10-4 to 101 ng mL and a sample-to-answer time <20 min. Using this biosensor, the authors longitudinally measure the dynamic CitH3 profiles of individual living mice in a sepsis model at high resolution over 12 hours. The developed biosensor may be poised for future translation to personalized management of systemic bacterial infections.

Ionic modulation and ionic coupling effects in MoS2 devices for neuromorphic computing.

Coupled ionic-electronic effects present intriguing opportunities for device and circuit development. In particular, layered two-dimensional materials such as MoS2 offer highly anisotropic ionic transport properties, facilitating controlled ion migration and efficient ionic coupling among devices. Here, we report reversible modulation of MoS2 films that is consistent with local 2H-1T' phase transitions by controlling the migration of Li+ ions with an electric field, where an increase/decrease in the local Li+ ion concentration leads to the transition between the 2H (semiconductor) and 1T' (metal) phases. The resulting devices show excellent memristive behaviour and can be directly coupled with each other through local ionic exchange, naturally leading to synaptic competition and synaptic cooperation effects observed in biology. These results demonstrate the potential of direct modulation of two-dimensional materials through field-driven ionic processes, and can lead to future electronic and energy devices based on coupled ionic-electronic effects and biorealistic implementation of artificial neural networks.

Integrated on-site collection and detection of airborne microparticles for smartphone-based micro-climate quality control.

The rapid emergence of air-mediated diseases in a micro-climate demands on-site monitoring of airborne microparticles. The on-site detection of airborne microparticles becomes more challenging as the particles are highly localized and change dynamically over time. However, most existing monitoring systems rely on time-consuming sample collection and centralized off-site analysis. Here, we report a smartphone-based integrated microsystem for on-site collection and detection that enables real-time detection of indoor airborne microparticles with high sensitivity. The collection device, inspired by the Venturi effect, was designed to collect airborne microparticles without requiring an additional power supply. Our systematic analysis showed that the collection device was able to collect microparticles with consistent negative pressure, regardless of the particle concentration in the air sample. By incorporating a microfluidic-biochip based on inertial force to trap particles and an optoelectronic photodetector into a miniaturized device with a smartphone, we demonstrate real-time and sensitive detection of the collected airborne microparticles, such as Escherichia coli, Bacillus subtilis, Micrococcus luteus, and Staphylococcus with a particle-density dynamic range of 103-108 CFU mL-1. Because of its capabilities of minimal-power sample collection, high sensitivity, and rapid detection of airborne microparticles, this integrated platform can be readily adopted by the government and industrial sectors to monitor indoor air contamination and improve human healthcare.

Resolution-enhanced imaging through scattering media by high-order correlation.

Super-resolution optical imaging is a rapidly emerging technology enabling many applications. Recently, correlation imaging has shown its capability in imaging beyond the diffraction limit, relying on quantum and statistical properties of light. High-order correlation imaging can further enhance resolution, however, at the expense of complicated algorithms. Here, we experimentally demonstrate a resolution-enhanced method of imaging through scattering media by exploiting high-order correlation of fluorescence light. Based on this method, individual fluorophores' temporal fluctuations are recorded and computed for their distinguished high-order correlations that enable super-resolution. Special designed time sequences are chosen to reduce computation time and memory. Such high-order correlation imaging exhibits reliable performance through scattering media with significant resolution enhancement and background noise reduction. This efficient imaging method paves the way for new biomedical applications.

Assessment of the Behaviors of an In Vitro Brain Model On-Chip under Shockwave Impacts.

Herein we report the assessment of the effects of shockwave (SW) impacts on adult rat hippocampal progenitor cell (AHPC) neurospheres (NSs), which are used as in vitro brain models, for enhancing our understanding of the mechanisms of traumatic brain injury (TBI). The assessment has been achieved by using culture dishes and a new microchip. The microchip allows the chemicals released from the brain models cultured inside the cell culture chamber under SW impacts to diffuse to the nanosensors in adjacent sensor chambers through built-in diffusion barriers, which are used to prevent the cells from entering the sensor chambers, thereby mitigating the biofouling issues of the sensor surface. Experiments showed the negative impact of the SW on the viability, proliferation, and differentiation of the cells within the NSs. A qPCR gene expression analysis was performed and appeared to confirm some of the immunocytochemistry (ICC) results. Finally, we demonstrated that the microchip can be used to monitor lactate dehydrogenase (LDH) released from the AHPC-NSs subjected to SW impacts. As expected, LDH levels changed when AHPC-NSs were injured by SW impacts, verifying this chip can be used for assessing the degrees of injuries to AHPC-NSs by monitoring LDH levels. Taken together, these results suggest the feasibility of using the chip to better understand the interactions between SW impacts and in vitro brain models, paving the way for potentially establishing in vitro TBI models on a chip.

Hot phonon dynamics in graphene.

The dynamics of hot phonons in supported, suspended, and gated monolayer graphene was studied by using time-resolved anti-Stokes Raman spectroscopy. We found that the hot phonon relaxation is dominated by phonon-phonon interaction in graphene, and strongly affected by the interaction between graphene and the substrate. Relaxation via carrier-phonon coupling, known as Landau damping, is ineffective for hot phonons which are in thermal equilibrium with excited carriers. Our findings provide a basis for better management of energy dissipation in graphene devices.

Nanoscale negative-tone quantized patterning by novel selective electrochemical etching of a nanoimprinted sub-200 nm bimetallic tile array.

Quantum lithography (QL) is a revolutionary approach to significantly increase the throughput and lower the cost of electron beam lithography in writing large-area masks with nanoscale features. A major challenge in QL is that its principle can be readily applied to positive- but not negative-tone QL. In fact, negative-tone QL, which is as indispensable as positive-tone QL in practical usage, has not been achieved. Here we propose a new method to overcome the obstacle, and report the first experimental demonstration of negative-tone QL. The new method uses a new type of nanoimprinted blank with the nanoscale tiles made of an aluminum/chromium bi-layer of metals, and a novel electrochemical process that removes only non-tagged quantized tiles of the new blank while keeping tagged ones. The demonstrated negative-tone QL has a 200 nm pitch and 30 nm gap and can be further scaled down to even smaller pitch sizes.

Formation of bandgap and subbands in graphene nanomeshes with sub-10 nm ribbon width fabricated via nanoimprint lithography.

We fabricated hexagonal graphene nanomeshes (GNMs) with sub-10 nm ribbon width. The fabrication combines nanoimprint lithography, block-copolymer self-assembly for high-resolution nanoimprint template patterning, and electrostatic printing of graphene. Graphene field-effect transistors (GFETs) made from GNMs exhibit very different electronic characteristics in comparison with unpatterned GFETs even at room temperature. We observed multiplateaus in the drain current-gate voltage dependence as well as an enhancement of ON/OFF current ratio with reduction of the average ribbon width of GNMs. These effects are attributed to the formation of electronic subbands and a bandgap in GNMs. Such mesoscopic graphene structures and the nanofabrication methods could be employed to construct future electronic devices based on graphene superlattices.

Extreme-Pressure Imprint Lithography for Heat and Ultraviolet-Free Direct Patterning of Rigid Nanoscale Features.

Nanoimprint lithography (NIL) is typically performed by filling up of molds by heated polymers or UV-curable liquid resists, inevitably requiring subsequent pattern-transfer processes. Although direct NIL techniques have been suggested alternatively, they usually require precursors or ink-type resists containing undesired organic components. Here, we demonstrate extreme-pressure imprint lithography (EPIL) that effectively produces well-defined multiscale structures with a wide range from 10 nm to 10 mm on diverse surfaces even including pure or alloy metals without using any precursors, heating, UV exposure, or pattern transfer. In particular, EPIL is accomplished through precise control of room-temperature plastic deformation in nanoscale volumes, which is elucidated by finite element analyses and molecular dynamics simulations. In addition to scalability to macroscopic areas, we confirm the outstanding versatility of EPIL via its successful applications to Ni, Cu, steel, and organics. We expect that the state-of-the-art EPIL process combined with other emerging nanopatterning technologies will be extendable to the future large-area nanofabrication of various devices.

Few-Layer MoS2 Photodetector Arrays for Ultrasensitive On-Chip Enzymatic Colorimetric Analysis.

Enzymatic colorimetric analysis of metabolites provides signatures of energy conversion and biosynthesis associated with disease onsets and progressions. Miniaturized photodetectors based on emerging two-dimensional transition metal dichalcogenides (TMDCs) promise to advance point-of-care diagnosis employing highly sensitive enzymatic colorimetric detection. Reducing diagnosis costs requires a batched multisample assay. The construction of few-layer TMDC photodetector arrays with consistent performance is imperative to realize optical signal detection for a miniature batched multisample enzymatic colorimetric assay. However, few studies have promoted an optical reader with TMDC photodetector arrays for on-chip operation. Here, we constructed 4 × 4 pixel arrays of miniaturized molybdenum disulfide (MoS2) photodetectors and integrated them with microfluidic enzyme reaction chambers to create an optoelectronic biosensor chip device. The fabricated device allowed us to achieve arrayed on-chip enzymatic colorimetric detection of d-lactate, a blood biomarker signifying the bacterial translocation from the intestine, with a limit of detection that is 1000-fold smaller than the clinical baseline, a 10 min assay time, high selectivity, and reasonably small variability across the entire arrays. The enzyme (Ez)/MoS2 optoelectronic biosensor unit consistently detected d-lactate in clinically important biofluids, such as saliva, urine, plasma, and serum of swine and humans with a wide detection range (10-3-103 µg/mL). Furthermore, the biosensor enabled us to show that high serum d-lactate levels are associated with the symptoms of systemic infection and inflammation. The lensless, optical waveguide-free device architecture should readily facilitate development of a monolithically integrated hand-held module for timely, cost-effective diagnosis of metabolic disorders in near-patient settings.

Inkjet-defined site-selective (IDSS) growth for controllable production of in-plane and out-of-plane MoS2 device arrays.

Along with the increasing interest in MoS2 as a promising electronic material, there is also an increasing demand for nanofabrication technologies that are compatible with this material and other relevant layered materials. In addition, the development of scalable nanofabrication approaches capable of directly producing MoS2 device arrays is an imperative task to speed up the design and commercialize various functional MoS2-based devices. The desired fabrication methods need to meet two critical requirements. First, they should minimize the involvement of resist-based lithography and plasma etching processes, which introduce unremovable contaminations to MoS2 structures. Second, they should be able to produce MoS2 structures with in-plane or out-of-plane edges in a controlled way, which is key to increase the usability of MoS2 for various device applications. Here, we introduce an inkjet-defined site-selective (IDSS) method that meets these requirements. IDSS includes two main steps: (i) inkjet printing of microscale liquid droplets that define the designated sites for MoS2 growth, and (ii) site-selective growth of MoS2 at droplet-defined sites. Moreover, IDSS is capable of generating MoS2 with different structures. Specifically, an IDSS process using deionized (DI) water droplets mainly produces in-plane MoS2 features, whereas the processes using graphene ink droplets mainly produce out-of-plane MoS2 features rich in exposed edges. Using out-of-plane MoS2 structures, we have demonstrated the fabrication of miniaturized on-chip lithium ion batteries, which exhibit reversible lithiation/delithiation capacity. This IDSS method could be further expanded as a scalable and reliable nanomanufacturing method for generating miniaturized on-chip energy storage devices.

A novel method for fabricating sub-16 nm footprint T-gate nanoimprint molds.

A novel method for fabricating nanoimprint lithography (NIL) molds for T-shaped gates (T-gates) for high speed transistors is proposed and demonstrated. This method uses NIL, low pressure chemical vapor deposition and reactive ion etching processes, and avoids costly electron beam lithography and high accuracy alignment technology. Using the T-gate nanoimprint molds fabricated by this novel method, T-gates with a footprint as small as sub-16 nm were achieved. This method can be extended to fabricate a broad range of 3D nanostructures.

Quantized patterning using nanoimprinted blanks.

Quantum lithography (QL) is a revolutionary approach, increasing the throughput and lowering the cost of scanning electron beam lithography (EBL). But it has not been pursued since its inception 17 years ago, due to the lack of a viable method for making the blanks needed. Here we propose and demonstrate a new general viable approach to QL blank fabrication, that is based on (a) nanoimprinting and (b) a new wafer-scale nanoimprint mold fabrication that uses not EBL but a unique combination of interference lithography, self-perfection, multiple nanoimprinting, and other novel nanopatterning. We fabricated QL blanks (a 2D Cr square tile array of 200 nm pitch, 9 nm gap, and sub-10 nm corners, corresponding to a 50 nm node 4 x photomask) and demonstrated that QL can greatly relax the requirements for the EBL tool, increase the throughput and reduce the cost of EBL by orders of magnitude, and is scalable to the 22 nm node.

All-optical tunable plasmonic nano-aggregations for surface-enhanced Raman scattering.

Interparticle forces play a crucial role in nanoparticle-based nanoscience and nanoengineering for synthesizing new materials, manipulating nanoscale structures, understanding biological processes and ultrasensitive sensing. Complicated by the fluid-dynamical and chemical nature of the liquid environment of nanoparticles, previous attempts are limited to electromagnetic and chemical methods. Alternatively, optically induced forces provide a convenient and fabrication-free route to manipulate nanoparticles at the nanoscale. Here we demonstrate a new double laser trapping scheme for metallic nano-aggregation by inducing strong near-field optical interparticle forces without any chemical agents or complicated fabrication processes. These induced optical forces arising from strong localized plasmon resonance strongly depend on the interparticle separation well beyond the diffraction limit and the polarization of the incident laser field. We examine such sub-resolved interparticle separation in trapped nanoaggregates by measuring surface-enhanced Raman scattering, and further demonstrate the single-molecule sensitivity by implementing such nanostructures. This new technique opens a new avenue for all-optical manipulation of nanomaterials as well as ultra-sensitive bio-chemical sensing applications.

Rubbing-Induced Site-Selective Growth of MoS2 Device Patterns.

The superior electronic and mechanical properties of two-dimensional layered transition-metal dichalcogenides could be exploited to make a broad range of devices with attractive functionalities. However, the nanofabrication of such layered material-based devices still needs resist-based lithography and plasma etching processes for patterning layered materials into functional device features. Such patterning processes lead to unavoidable contaminations, to which the transport characteristics of atomically thin-layered materials are very sensitive. More seriously, such lithography-introduced contaminants cannot be safely eliminated by conventional semiconductor cleaning approaches. This challenge seriously retards the manufacturing of large arrays of layered material-based devices with consistent characteristics. Toward addressing this challenge, we introduce a rubbing-induced site-selective growth method capable of directly generating few-layer MoS2 device patterns without the need of any additional patterning processes. This method consists of two critical steps: (i) a damage-free mechanical rubbing process for generating microscale triboelectric charge patterns on a dielectric surface and (ii) site-selective deposition of MoS2 within rubbing-induced charge patterns. Our microscopy characterizations in combination with finite element analysis indicate that the field magnitude distribution within triboelectric charge patterns determines the morphologies of grown MoS2 patterns. In addition, the MoS2 line patterns produced by the presented method have been implemented for making arrays of working transistors and memristors. These devices exhibit a high yield and good uniformity in their electronic properties over large areas. The presented method could be further developed into a cost-efficient nanomanufacturing approach for producing functional device patterns based on various layered materials.

MoS2 Memristors Exhibiting Variable Switching Characteristics toward Biorealistic Synaptic Emulation.

Memristors based on 2D layered materials could provide biorealistic ionic interactions and potentially enable construction of energy-efficient artificial neural networks capable of faithfully emulating neuronal interconnections in human brains. To build reliable 2D-material-based memristors suitable for constructing working neural networks, the memristive switching mechanisms in such memristors need to be systematically analyzed. Here, we present a study on the switching characteristics of the few-layer MoS2 memristors made by mechanical printing. First, two types of dc-programmed switching characteristics, termed rectification-mediated and conductance-mediated behaviors, are observed among different MoS2 memristors, which are attributed to the modulation of MoS2/metal Schottky barriers and redistribution of vacancies, respectively. We also found that an as-fabricated MoS2 memristor initially exhibits an analog pulse-programmed switching behavior, but it can be converted to a quasi-binary memristor with an abrupt switching behavior through an electrical stress process. Such a transition of switching characteristics is attributed to field-induced agglomeration of vacancies at MoS2/metal interfaces. The additional Kelvin probe force microscopy, Auger electron spectroscopy analysis, and electronic characterization results support this hypothesis. Finally, we fabricated a testing device consisting of two adjacent MoS2 memristors and demonstrated that these two memristors can be ionically coupled to each other. This device interconnection scheme could be exploited to build neural networks for emulating ionic interactions among neurons. This work advances the device physics for understanding the memristive properties of 2D-material-based memristors and serves as a critical foundation for building biorealistic neuromorphic computing systems based on such memristors.