A Nanoscale Bistable Resistor for an Oscillatory Neural Network.

Coupled oscillators construct an oscillatory neural network (ONN) by mimicking the interactions among neurons in the human brain. This work demonstrates a fully CMOS-based oscillator consisting of a bistable resistor (biristor), which shares a structure identical with that of a metal-oxide-semiconductor field-effect transistor, except for the use of a gate electrode. The biristor-based oscillator (birillator) generates oscillating voltage signals in the form of spikes due to a single transistor latch phenomenon. When two birillators are connected with a coupling capacitor, they become synchronized with a phase difference of 180°. These coupled oscillation characteristics are experimentally investigated for an ONN. As practical applications of the ONN with coupled birillators, edge detection and vertex coloring are conducted by encoding information into phase differences between them. The proposed fully CMOS-based birillators are advantageous for low power consumption, high CMOS compatibility, and a compact footprint area.

Bio-Inspired Organic Synaptor with In Situ Ion-Doped Ultrathin Polyelectrolyte Containing Acetylcholine-Like Cation.

An ion-based synaptic transistor (synaptor) is designed to emulate a biological synapse using controlled ion movements. However, developing a solid-state electrolyte that can facilitate ion movement while achieving large-scale integration remains challenging. Here, a bio-inspired organic synaptor (BioSyn) with an in situ ion-doped polyelectrolyte (i-IDOPE) is demonstrated. At the molecular scale, a polyelectrolyte containing the tert-amine cation, inspired by the neurotransmitter acetylcholine is synthesized using initiated chemical vapor deposition (iCVD) with in situ doping, a one-step vapor-phase deposition used to fabricate solid-state electrolytes. This method results in an ultrathin, but highly uniform and conformal solid-state electrolyte layer compatible with large-scale integration, a form that is not previously attainable. At a synapse scale, synapse functionality is replicated, including short-term and long-term synaptic plasticity (STSP and LTSP), along with a transformation from STSP to LTSP regulated by pre-synaptic voltage spikes. On a system scale, a reflex in a peripheral nervous system is mimicked by mounting the BioSyns on various substrates such as rigid glass, flexible polyethylene naphthalate, and stretchable poly(styrene-ethylene-butylene-styrene) for a decentralized processing unit. Finally, a classification accuracy of 90.6% is achieved through semi-empirical simulations of MNIST pattern recognition, incorporating the measured LTSP characteristics from the BioSyns.

Neurologic Effects of SARS-CoV-2 Transmitted among Dogs.

SARS-CoV-2 induces illness and death in humans by causing systemic infections. Evidence suggests that SARS-CoV-2 can induce brain pathology in humans and other hosts. In this study, we used a canine transmission model to examine histopathologic changes in the brains of dogs infected with SARS-CoV-2. We observed substantial brain pathology in SARS-CoV-2-infected dogs, particularly involving blood-brain barrier damage resembling small vessel disease, including changes in tight junction proteins, reduced laminin levels, and decreased pericyte coverage. Furthermore, we detected phosphorylated tau, a marker of neurodegenerative disease, indicating a potential link between SARS-CoV-2-associated small vessel disease and neurodegeneration. Our findings of degenerative changes in the dog brain during SARS-CoV-2 infection emphasize the potential for transmission to other hosts and induction of similar signs and symptoms. The dynamic brain changes in dogs highlight that even asymptomatic individuals infected with SARS-CoV-2 may develop neuropathologic changes in the brain.

Establishment of multicenter COVID-19 therapeutics preclinical test system in Republic of Korea.

Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.

A Bioinspired Artificial Gustatory Neuron for a Neuromorphic Based Electronic Tongue.

A novel biomimicked neuromorphic sensor for an energy efficient and highly scalable electronic tongue (E-tongue) is demonstrated with a metal-oxide-semiconductor field-effect transistor (MOSFET). By mimicking a biological gustatory neuron, the proposed E-tongue can simultaneously detect ion concentrations of chemicals on an extended gate and encode spike signals on the MOSFET, which acts as an input neuron in a spiking neural network (SNN). Such in-sensor neuromorphic functioning can reduce the energy and area consumption of the conventional E-tongue hardware. pH-sensitive and sodium-sensitive artificial gustatory neurons are implemented by using two different sensing materials: Al2O3 for pH sensing and sodium ionophore X for sodium ion sensing. In addition, a sensitivity control function inspired by the biological sensory neuron is demonstrated. After the unit device characterization of the artificial gustatory neuron, a fully hardware-based E-tongue that can classify two distinct liquids is demonstrated to show a practical application of the artificial gustatory neurons.

Rag2 Deficiency Enhances Susceptibility to Systemic Mouse Adenovirus Type 1 Infection.

INTRODUCTION: Recombination-activating gene (Rag) 1 and Rag2, which are essential in V(D)J recombination, play a crucial role in B- and T-cell maturation. METHOD: We investigated the effects of Rag2 deficiency in clustered regularly interspaced short palindromic repeats/Cas9-mediated FVB-Rag2 knockout (KO) and wild-type (WT) mice infected with mouse adenovirus type 1 (MAV-1) via the intranasal route. RESULTS: MAV-1 infection caused more severe histopathological changes in FVB-Rag2 KO mice than in WT mice. FVB-Rag2 KO mice exhibited moderate to severe inflammation on day 4 and severe inflammation on day 8 post infection. In contrast, WT mice showed mild inflammation on day 4 and mild to severe inflammation on day 8 post infection, including interstitial pneumonia and inflammatory cell infiltration in the lungs and liver. Viral loads in the spleen and kidneys were significantly higher in FVB-Rag2 KO mice than in WT mice on day 8 post infection. Levels of cytokines and chemokines, including macrophage inflammatory protein-1α, induced protein 10, interferon (IFN)-α, IFN-γ, and tumor necrosis factor alpha, were upregulated in the spleens of FVB-Rag2 KO mice compared with those of WT mice. The upregulation of several cytokines occurred concurrently with the histopathological changes. MAV-1 infection induced more severe systemic infection in FVB-Rag2 KO mice than in WT mice. CONCLUSION: In mice, Rag2 deficiency induces inflammatory cell recruitment via the upregulation of cytokine and chemokine levels. The MAV-1 infection model can be utilized to assess the efficacy and safety of therapeutic agents for human adenoviral diseases.

A fusion of CD63-BCAR4 identified in lung adenocarcinoma promotes tumorigenicity and metastasis.

BACKGROUND: Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional characterisation of BCAR4 fusion has not been investigated. METHODS: Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63-BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63-BCAR4, in vitro and in vivo animal experiments were performed. RESULTS: In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63-BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63-BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63-BCAR4 overexpression in the in vitro and in vivo experiments. CONCLUSIONS: Taken together, our results suggest a newly identified fusion gene, CD63-BCAR4 as a potential novel oncogene in lung adenocarcinoma.

A Vertical Silicon Nanowire Based Single Transistor Neuron with Excitatory, Inhibitory, and Myelination Functions for Highly Scalable Neuromorphic Hardware.

A single transistor neuron (1T-neuron) is demonstrated by using a vertically protruded nanowire from an 8 in. silicon (Si) wafer. The 1T-neuron adopts a gate-all-around structure to completely surround the Si nanowire (Si-NW) to make a floating body and allow aggressive downscaling. The Si-NW is composed of an n+ drain at the top, n+ source at the bottom, and p-type floating body at the middle, which are self-aligned vertically. Thus, it occupies a small footprint area. The gate controls an excitatory/inhibitory function. In addition, myelination of a biological neuron that changes membrane capacitance is mimicked by an inherently asymmetric source/drain structure. Two spiking frequencies at the same input current are controlled by whether the neuron is myelinated or unmyelinated. Using the vertical 1T-neuron, pattern recognition is demonstrated with both measurements and semiempirical circuit simulations. Furthermore, handwritten numbers in the MNIST database are recognized with accuracy of 93% by software-based simulations. Applicability of the vertical 1T-neuron to various neural networks is verified, including a single-layer perceptron, multilayer perceptron, and spiking neural network.

Bioinspired Photoresponsive Single Transistor Neuron for a Neuromorphic Visual System.

Realizing a neuromorphic-based artificial visual system with low-cost hardware requires a neuromorphic device that can react to light stimuli. This study introduces a photoresponsive neuron device composed of a single transistor, developed by engineering an artificial neuron that responds to light, just like retinal neurons. Neuron firing is activated primarily by electrical stimuli such as current via a well-known single transistor latch phenomenon. Its firing characteristics, represented by spiking frequency and amplitude, are additionally modulated by optical stimuli such as photons. When light is illuminated onto the neuron transistor, electron-hole pairs are generated, and they allow the neuron transistor to fire at lower firing threshold voltage. Different photoresponsive properties can be modulated by the intensity and wavelength of the light, analogous to the behavior of retinal neurons. The artificial visual system can be miniaturized because a photoresponsive neuronal function is realized without bulky components such as image sensors and extra circuits.

Multilevel States of Nano-Electromechanical Switch for a PUF-Based Security Device.

A nano-electromechanical (NEM) switch using multilevel states based on the high security physical unclonable function (PUF) is proposed and experimentally demonstrated. Using the asymmetric random stiction of a silicon nanowire (SiNW), the conventional binary state is simply expanded to a quaternary-state encryption key without increasing chip area. The multiple states are determined by the asymmetrically bent direction and stiction of the SiNW. The experimental results show that the fabricated NEM-PUF with multistates retains unique, random, and robust characteristics, while the key capacity is doubled, even with the same array size footprint.

Interleukin-32θ inhibits tumor-promoting effects of macrophage-secreted CCL18 in breast cancer.

BACKGROUND: Tumor-associated macrophages can promote breast cancer metastasis by secreting cytokines and growth factors. Interleukin (IL)-32θ, a newly identified IL-32 isoform, was previously shown to down-regulate various proinflammatory factors of macrophages. Here, we report the presence of IL-32θ in breast cancer tissues and evaluate its effects on macrophage-regulated breast cancer metastasis. METHODS: RT-qPCR was used to analyze the mRNA expression of IL-32θ, Chemokine (C-C motif) ligand 18 (CCL18) in breast cancer tissues. In vitro cell-based experiments using IL-32θ-expressing MDA-MB-231 cells were conducted to examine the effects of IL-32θ on metastasis and its molecular signaling. In vivo xenograft, immunohistochemistry, and optical imaging models were generated to support in vitro and clinical findings. RESULTS: The clinical data displayed opposite expression patterns of CCL18 and IL-32θ mRNA in macrophage-infiltrated breast tumor tissues compared with those in the other tissues tested. In MDA-MB-231 cells, IL-32θ overexpression attenuated migration, invasion, tumor-promoting factors, and increased epithelial markers levels upon treatment with conditioned media from THP-1-derived macrophages. Additionally, IL-32θ expression in a xenograft model led to a remarkable decrease in tumor size and macrophage-stimulated tumor promotion. This inhibition was mediated through a direct interaction with protein kinase C-δ (PKCδ), subsequently eliminating the downstream factors STAT3 and NF-κB. Blocking CCL18 during co-culture of macrophages and breast cancer cells reduced the levels of breast cancer progression-related factors and PKCδ downstream signaling suggesting CCL18 as the main macrophage-secreted factors triggering the signaling pathway inhibited by IL-32θ. CONCLUSIONS: Our findings demonstrate a novel role of IL-32θ as an intracellular modulator to suppress macrophage-promoted breast cancer progression by targeting CCL18-dependent signaling.

Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma.

Fusion genes have been identified as oncogenes in several solid tumors including lung, colorectal, and stomach cancers. Here, we characterized the fusion gene, VAPA-Rab31, discovered from RNA-sequencing data of a patient with lung adenocarcinoma who did not harbor activating mutations in EGFR, KRAS and ALK. This fusion gene encodes a protein comprising the N-terminal region of vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) fused to the C-terminal region of Ras-related protein 31 (Rab31). Exogenous expression of VAPA-Rab31 in immortalized normal bronchial epithelial cells demonstrated the potential transforming effects of this fusion gene, including increased colony formation and cell proliferation in vitro. Also, enhanced tumorigenicity upon VAPA-Rab31 was confirmed in vivo using a mouse xenograft model. Metastatic tumors were also detected in the liver and lungs of xenografted mice. Overexpression of VAPA-Rab31 upregulated anti-apoptotic protein Bcl-2 and phosphorylated CREB both in cells and xenograft tumors. Reduced apoptosis and increased phosphorylation of CREB and Erk were observed in VAPA-Rab31-overexpressing cells after bortezomib treatment. Elevated Bcl-2 level via activated CREB contributed to the resistance to the bortezomib-induced apoptosis. Our data suggest the oncogenic function of the novel fusion gene VAPA-Rab31 via upregulated Bcl-2 and activated CREB in lung cancer.

Differences between immunodeficient mice generated by classical gene targeting and CRISPR/Cas9-mediated gene knockout.

Immunodeficient mice are widely used for pre-clinical studies to understand various human diseases. Here, we report the generation of four immunodeficient mouse models using CRISPR/Cas9 system without inserting any foreign gene sequences such as NeoR cassettes and their characterization. By eliminating any possible effects of adding a NeoR cassette, our mouse models may allow us to better elucidate the in vivo functions of each gene. Our FVB-Rag2-/-, B6-Rag2-/-, and BALB/c-Prkdc-/- mice showed phenotypes similar to those of the earlier immunodeficient mouse models, including a lack of mature B cells and T cells and an increase in the number of CD45+DX-5+ natural killer cells. However, B6-Il2rg-/- mice had a unique phenotype, with a lack of mature B cells, increased number of T cells, and decreased number of natural killer cells. Additionally, serum immunoglobulin levels in all four immunodeficient mouse models were significantly reduced when compared to those in wild-type mice with the exception of IgM in B6-Il2rg-/- mice. These results indicate that our immunodeficient mouse models are a robust tool for in vivo studies of the immune system and will provide new insights into the variation in phenotypic outcomes resulting from different gene-targeting methodologies.

Functional Circuitry on Commercial Fabric via Textile-Compatible Nanoscale Film Coating Process for Fibertronics.

Fabric-based electronic textiles (e-textiles) are the fundamental components of wearable electronic systems, which can provide convenient hand-free access to computer and electronics applications. However, e-textile technologies presently face significant technical challenges. These challenges include difficulties of fabrication due to the delicate nature of the materials, and limited operating time, a consequence of the conventional normally on computing architecture, with volatile power-hungry electronic components, and modest battery storage. Here, we report a novel poly(ethylene glycol dimethacrylate) (pEGDMA)-textile memristive nonvolatile logic-in-memory circuit, enabling normally off computing, that can overcome those challenges. To form the metal electrode and resistive switching layer, strands of cotton yarn were coated with aluminum (Al) using a solution dip coating method, and the pEGDMA was conformally applied using an initiated chemical vapor deposition process. The intersection of two Al/pEGDMA coated yarns becomes a unit memristor in the lattice structure. The pEGDMA-Textile Memristor (ETM), a form of crossbar array, was interwoven using a grid of Al/pEGDMA coated yarns and untreated yarns. The former were employed in the active memristor and the latter suppressed cell-to-cell disturbance. We experimentally demonstrated for the first time that the basic Boolean functions, including a half adder as well as NOT, NOR, OR, AND, and NAND logic gates, are successfully implemented with the ETM crossbar array on a fabric substrate. This research may represent a breakthrough development for practical wearable and smart fibertronics.

Highly stable 2D material (2DM) field-effect transistors (FETs) with wafer-scale multidyad encapsulation.

Field-effect transistors (FETs) composed of 2D materials (2DMs) such as transition-metal dichalcogenide (TMD) materials show unstable electrical characteristics in ambient air due to the high sensitivity of 2DMs to water adsorbates. In this work, in order to demonstrate the long-term retention of electrical characteristics of a TMD FET, a multidyad encapsulation method was applied to a MoS2 FET and thereby its durability was warranted for one month. It was well known that the multidyad encapsulation method was effective to mitigate high sensitivity to ambient air in light-emitting diodes (LEDs) composed of organic materials. However, there was no attempt to check the feasibility of such a multidyad encapsulation method for 2DM FETs. It is timely to investigate the water vapor transmission ratio (WVTR) required for long-term stability of 2DM FETs. The 2DM FETs were fabricated with MoS2 flakes by both an exfoliation method, that is desirable to attain high quality film, and a chemical vapor deposition (CVD) method, that is applicable to fabrication for a large-sized substrate. In order to eliminate other unwanted variables, the MoS2 FETs composed of exfoliated flakes were primarily investigated to assure the effectiveness of the encapsulation method. The encapsulation method uses multiple dyads comprised of a polymer layer by spin coating and an Al2O3 layer deposited by atomic layer deposition (ALD). The proposed method shows wafer-scale uniformity, high transparency, and protective barrier properties against adsorbates (WVTR of 8 × 10-6 g m-2 day-1) over one month.

Feasibility Study of Extended-Gate-Type Silicon Nanowire Field-Effect Transistors for Neural Recording.

In this research, a high performance silicon nanowire field-effect transistor (transconductance as high as 34 µS and sensitivity as 84 nS/mV) is extensively studied and directly compared with planar passive microelectrode arrays for neural recording application. Electrical and electrochemical characteristics are carefully characterized in a very well-controlled manner. We especially focused on the signal amplification capability and intrinsic noise of the transistors. A neural recording system using both silicon nanowire field-effect transistor-based active-type microelectrode array and platinum black microelectrode-based passive-type microelectrode array are implemented and compared. An artificial neural spike signal is supplied as input to both arrays through a buffer solution and recorded simultaneously. Recorded signal intensity by the silicon nanowire transistor was precisely determined by an electrical characteristic of the transistor, transconductance. Signal-to-noise ratio was found to be strongly dependent upon the intrinsic 1/f noise of the silicon nanowire transistor. We found how signal strength is determined and how intrinsic noise of the transistor determines signal-to-noise ratio of the recorded neural signals. This study provides in-depth understanding of the overall neural recording mechanism using silicon nanowire transistors and solid design guideline for further improvement and development.

Vertically Integrated Nanowire-Based Unified Memory.

A vertically integrated nanowire-based device for multifunctional unified memory that combine dynamic random access memory (DRAM) and flash memory in a single transistor is demonstrated for the first time. The device utilizes a gate-all-around (GAA) structure that completely surrounds the nanowire; the structure is built on a bulk silicon wafer. A vertically integrated unified memory (VIUM) device composed of five-story channels was fabricated via the one-route all-dry etching process (ORADEP) with reliable reproducibility, stiction-free stability, and high uniformity. In each DRAM and flash memory operation, the five-story VIUM showed a remarkably enhanced sensing current drivability compared with one-story unified memory (UM) characteristics. In addition to each independent memory mode, the switching endurance of the VIUM was evaluated in the unified mode, which alternatively activates two memory modes, resulting in an even higher sensing memory window than that of the UM. In addition to our previous work on a logic transistor joining high performance with good scalability, this work describes a novel memory hierarchy design with high functionality for system-on-chip (SoC) architectures, demonstrating the practicality and versatility of the vertically integrated nanowire configuration for use in various applications.

A Vertically Integrated Junctionless Nanowire Transistor.

A vertically integrated junctionless field-effect transistor (VJ-FET), which is composed of vertically stacked multiple silicon nanowires (SiNWs) with a gate-all-around (GAA) structure, is demonstrated on a bulk silicon wafer for the first time. The proposed VJ-FET mitigates the issues of variability and fabrication complexity that are encountered in the vertically integrated multi-NW FET (VM-FET) based on an identical structure in which the VM-FET, as recently reported, harnesses a source and drain (S/D) junction for its operation and is thus based on the inversion mode. Variability is alleviated by bulk conduction in a junctionless FET (JL-FET), where current flows through the core of the SiNW, whereas it is not mitigated by surface conduction in an inversion mode FET (IM-FET), where current flows via the surface of the SiNW. The fabrication complexity is reduced by the inherent JL structure of the JL-FET because S/D formation is not required. In contrast, it is very difficult to dope the S/D when it is positioned at each floor of a tall SiNW with greater uniformity and with less damage to the crystalline structure of the SiNW in a VM-FET. Moreover, when the proposed VJ-FET is used as nonvolatile flash memory, the endurance and retention characteristics are improved due to the above-mentioned bulk conduction.

Temperature measurement of Joule heated silicon micro/nanowires using selectively decorated quantum dots.

We developed a novel method to measure local temperature at micro/nano-scale regions using selective deposition of quantum dots (QDs) as a sensitive temperature probe and measured the temperature of Joule heated silicon microwires (SiMWs) and silicon nanowires (SiNWs) by this method. The QDs are selectively coated only on the surface of the SiMWs and SiNWs by a sequential process composed of selective opening of a polymethyl methacrylate layer via Joule heating, covalent bonding of QDs, and lift-off process. The temperatures of the Joule-heated SiMWs and SiNWs can be measured by characterizing the temperature-dependent shift of photoluminescence peak of the selectively deposited QDs even with far-field optics. The validity of the extracted temperature has been also confirmed by comparing with numerical simulation results. The proposed method can potentially provide micro/nanoscale measurement of localized temperatures for a wide range of electrical and optical devices.

Single Walled Carbon Nanotube-Based Electrical Biosensor for the Label-Free Detection of Pathogenic Bacteria.

We herein describe the development of a single-walled carbon nanotube (SWNT)-based electrical biosensor consisting of a two-terminal resistor, and report its use for the specific, label-free detection of pathogenic bacteria via changes in conductance. The ability of this biosensor to recognize different pathogenic bacteria was analyzed, and conditions were optimized with different probe concentrations. Using this system, the reference strains and clinical isolates of Staphylococcus aureus and Escherichia coli were successfully detected; in both cases, the sensor showed a detection limit of 10 CFU. This SWNT-based electrical biosensor will prove useful for the development of highly sensitive and specific handheld pathogen detectors.