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.

Cryptographic transistor for true random number generator with low power consumption.

We design a cryptographic transistor (cryptoristor)-based true random number generator (tRNG) with low power consumption and small footprint. This is the first attempt to use irregular and unpredictable operation-induced randomness of a cryptoristor as an entropy source. To extract discrete random numbers with a binary code from the cryptoristor, we developed a noise-coupling analog-to-digital converter. This converter not only converts analog signals to digital random bits but also improves the randomness of the entropy source with low power consumption. The randomness of the cryptoristor is attributed to the random carrier multiplications with the creation and stochastic carrier escape as destruction, which occurs iteratively as long as the input current is fed. The cryptoristor-based tRNG passed 15 randomness test suites of NIST Special Publication 800-22. It is robust to iterative operational stresses and to ambient temperature changes, making it an attractive option for hardware-based security solutions in the Internet of Things due to its low power consumption and small size.

Self-Mixed Biphasic Liquid Metal Composite with Ultra-High Stretchability and Strain-Insensitivity for Neuromorphic Circuits.

Neuromorphic circuits that can function under extreme deformations are important for various data-driven wearable and robotic applications. Herein, biphasic liquid metal particle (BMP) with unprecedented stretchability and strain-insensitivity (ΔR/R0 = 1.4@ 1200% strain) is developed to realize a stretchable neuromorphic circuit that mimics a spike-based biologic sensory system. The BMP consists of liquid metal particles (LMPs) and rigid liquid metal particles (RLMPs), which are homogeneously mixed via spontaneous solutal-Marangoni mixing flow during coating. This permits facile single step patterning directly on various substrates at room temperature. BMP is highly conductive (2.3 × 106 S/m) without any post activation steps. BMP interconnects are utilized for a sensory system, which is capable of distinguishing variations of biaxial strains with a spiking neural network, thus demonstrating their potential for various sensing and signal processing applications.

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.

Cryptographic triboelectric random number generator with gentle breezes of an entropy source.

A wind-driven triboelectric nanogenerator (W-TENG) is a promising energy harvesting device due to its clean, ubiquitous and unexhausted properties. In addition, a W-TENG induces unpredictable chaotic outputs from wind flow that can serve as an entropy source for cryptography. This can be applied to a true random number generator (TRNG) for a secured system due to its inherent turbulent nature; thus, a W-TENG with a two-in-one structure can simultaneously generate both power and true random numbers. However, a previously reported W-TENG had one major drawback: a wind velocity of 10 m/s is required for stable energy harvesting by wind force. Thus, it is timely to demonstrate a W-TENG-based RNG whose operating condition is below 3 m/s, which is a gentle breeze similar to natural wind. In this study, we demonstrate a wind-driven cryptographic triboelectric random number generator (WCT-RNG) by using a W-TENG whose operating condition for wind speed is below 3 m/s by adopting a rear-fixed film structure instead of a conventional structure. The rear-fixed film refers to the fluttering film being freestanding on the front-side and fixed on the rear-side, where the front- and rear-sides are the wind inlet and outlet, respectively. The WCT-RNG enables the W-TENG to operate below a 3 m/s wind velocity. Because of this, the working time of the WCT-RNG is dramatically enhanced from only 8-42% at an average altitude above sea level. As the capability of operating at low wind speeds is significantly improved, a WCT-RNG becomes more useful and practical for generating both power and true random numbers in a single device. The device can thereby lead to the construction of a self-powered TRNG and secure communication for Internet of Things (IoT) devices in various environments, even under a gentle breeze. In this study, we explain the design of a WCT-RNG structure and also evaluate its randomness by using an NIST SP 800-22 B test suite with a reliability test.

Analyses of unpredictable properties of a wind-driven triboelectric random number generator.

Wind-driven triboelectric nanogenerators (W-TENGs) are a promising candidate for an energy harvester because wind itself possesses unexhausted, ubiquitous, and clean properties. W-TENG has also been used as a random number generator (RNG) due to the inherent chaotic properties of wind that is also an entropy source. Thus, a W-TENG which simultaneously generates both power and true random numbers with a two-in-one structure, is a wind-driven RNG (W-RNG) like the Janus. However, a root cause of W-RNG unpredictability has not been elucidated. In this work, the unpredictability, which is essential and critical for an RNG, is statistically and mathematically analyzed by auto-correlation, cross-correlation, joint entropy, and mutual information. Even though the overall shape of the total output analog signals from the W-RNG looks like a sinusoidal wave that is not obviously unpredictable, discretized digital signals from the continuous analog output become unpredictable. Furthermore, partial adoption of 4-bit data from 8-bit raw data, with the aid of analog-to-digital converter hardware, further boosts the unpredictability. The W-RNG, which functions as a W-TENG, can contribute to self-powering and self-securing outdoor electrical systems, such as drones, by harvesting energy and generating true random numbers.

Vertically Integrated CMOS Ternary Logic Device with Low Static Power Consumption and High Packing Density.

A ternary logic system to realize the simplest multivalued logic architecture can enhance energy efficiency compared to a binary logic system by reducing the number of transistors and interconnections. For the ternary logic system, a ternary logic device to harness three stable states is needed. In this study, a vertically integrated complementary metal-oxide-semiconductor ternary logic device is demonstrated by monolithically integrating a thin-film transistor (TFT) over a transistor-based threshold switch (TTS). Because the TFT and the TTS have their own source (S), drain (D), and gate (G), there are physically six electrodes. But the hybrid ternary logic device of the TFT over the TTS has only four electrodes: S, D, GTFT, and GTTS like a single MOSFET. It is because the D of the underlying TTS is electrically tied with the S of the superjacent TFT. By combining an on- and off-state of the TFT and the TTS, ternary logic values of low current ("0"-state), middle current ("1"-state), and high current ("2"-state) are realized. Particularly, static power consumption at the "1"-state is decreased by employing the TTS with low off-state leakage current compared to previously reported other ternary logic devices. In addition, a footprint of the ternary logic device with the vertically overlaying structure that has a framework of "one over the other" can be lowered by roughly twice compared to that with the laterally deployed structure that has an organization of "one alongside the other".

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.

3D Neuromorphic Hardware with Single Thin-Film Transistor Synapses Over Single Thin-Body Transistor Neurons by Monolithic Vertical Integration.

Neuromorphic hardware with a spiking neural network (SNN) can significantly enhance the energy efficiency for artificial intelligence (AI) functions owing to its event-driven and spatiotemporally sparse operations. However, an artificial neuron and synapse based on complex complementary metal-oxide-semiconductor (CMOS) circuits limit the scalability and energy efficiency of neuromorphic hardware. In this work, a neuromorphic module is demonstrated composed of synapses over neurons realized by monolithic vertical integration. The synapse at top is a single thin-film transistor (1TFT-synapse) made of poly-crystalline silicon film and the neuron at bottom is another single transistor (1T-neuron) made of single-crystalline silicon. Excimer laser annealing (ELA) is applied to activate dopants for the 1TFT-synapse at the top and rapid thermal annealing (RTA) is applied to do so for the 1T-neuron at the bottom. Internal electro-thermal annealing (ETA) via the generation of Joule heat is also used to enhance the endurance of the 1TFT-synapse without transferring heat to the 1T-neuron at the bottom. As neuromorphic vision sensing, classification of American Sign Language (ASL) is conducted with the fabricated neuromorphic module. Its classification accuracy on ASL is ≈92.3% even after 204 800 update pulses.

SARS-CoV-2 Omicron variant causes brain infection with lymphoid depletion in a mouse COVID-19 model.

BACKGROUND: The Omicron variant has become the most prevalent SARS-CoV-2 variant. Omicron is known to induce milder lesions compared to the original Wuhan strain. Fatal infection of the Wuhan strain into the brain has been well documented in COVID-19 mouse models and human COVID-19 cases, but apparent infections into the brain by Omicron have not been reported in human adult cases or animal models. In this study, we investigated whether Omicron could spread to the brain using K18-hACE2 mice susceptible to SARS-CoV-2 infection. RESULTS: K18-hACE2 mice were intranasally infected with 1 × 105 PFU of the original Wuhan strain and the Omicron variant of SARS-CoV-2. A follow-up was conducted 7 days post infection. All Wuhan-infected mice showed > 20% body weight loss, defined as the lethal condition, whereas two out of five Omicron-infected mice (40%) lost > 20% body weight. Histopathological analysis based on H&E staining revealed inflammatory responses in the brains of these two Omicron-infected mice. Immunostaining analysis of viral nucleocapsid protein revealed severe infection of neuron cells in the brains of these two Omicron-infected mice. Lymphoid depletion and apoptosis were observed in the spleen of Omicron-infected mice with brain infection. CONCLUSION: Lethal conditions, such as severe body weight loss and encephalopathy, can occur in Omicron-infected K18-hACE2 mice. Our study reports, for the first time, that Omicron can induce brain infection with lymphoid depletion in the mouse COVID-19 model.

Leaky FinFET for Reservoir Computing with Temporal Signal Processing.

Reservoir computing can greatly reduce the hardware and training costs of recurrent neural networks with temporal data processing. To implement reservoir computing in a hardware form, physical reservoirs transforming sequential inputs into a high-dimensional feature space are necessary. In this work, a physical reservoir with a leaky fin-shaped field-effect transistor (L-FinFET) is demonstrated by the positive use of a short-term memory property arising from the absence of an energy barrier to suppress the tunneling current. Nevertheless, the L-FinFET reservoir does not lose its multiple memory states. The L-FinFET reservoir consumes very low power when encoding temporal inputs because the gate serves as an enabler of the write operation, even in the off-state, due to its physical insulation from the channel. In addition, the small footprint area arising from the scalability of the FinFET due to its multiple-gate structure is advantageous for reducing the chip size. After the experimental proof of 4-bit reservoir operations with 16 states for temporal signal processing, handwritten digits in the Modified National Institute of Standards and Technology dataset are classified by reservoir computing.

COVID-19 spike polypeptide vaccine reduces the pathogenesis and viral infection in a mouse model of SARS-CoV-2.

The SARS-CoV-2 coronavirus, which causes a respiratory disease called COVID-19, has been declared a pandemic by the World Health Organization (WHO) and is still ongoing. Vaccination is the most important strategy to end the pandemic. Several vaccines have been approved, as evidenced by the ongoing global pandemic, but the pandemic is far from over and no fully effective vaccine is yet available. One of the most critical steps in vaccine development is the selection of appropriate antigens and their proper introduction into the immune system. Therefore, in this study, we developed and evaluated two proposed vaccines composed of single and multiple SARS-CoV-2 polypeptides derived from the spike protein, namely, vaccine A and vaccine B, respectively. The polypeptides were validated by the sera of COVID-19-vaccinated individuals and/or naturally infected COVID-19 patients to shortlist the starting pool of antigens followed by in vivo vaccination to hACE2 transgenic mice. The spike multiple polypeptide vaccine (vaccine B) was more potent to reduce the pathogenesis of organs, resulting in higher protection against the SARS-CoV-2 infection.

Short-term carcinogenicity study of N-methyl-N-nitrosourea in FVB-Trp53 heterozygous mice.

Carcinogenicity tests predict the tumorigenic potential of various substances in the human body by studying tumor induction in experimental animals. There is a need for studies that explore the use of FVB/N-Trp53em2Hwl/Korl (FVB-Trp53+/-) mice, created by TALEN-mediated gene targeting in Korea, in carcinogenicity tests. This study was performed to determine whether FVB-Trp53+/- mice are a suitable model for short-term carcinogenicity studies. To compare the carcinogenicity at different concentrations, 25, 50, and 75 mg/kg of N-methyl-N-nitrosourea (MNU), a known carcinogen, were administered intraperitoneally to FVB-Trp53+/- and wild-type male mice. After 26 weeks, the survival rate was significantly reduced in FVB-Trp53+/- mice compared to the wild-type mice in the 50 and 75 mg/kg groups. The incidence of thymic malignant lymphoma (TML) in the 50 and 75 mg/kg groups was 54.2 and 59.1% in FVB-Trp53+/- male mice, respectively. TML metastasized to the lungs, spleen, lymph nodes, liver, kidney, and heart in FVB-Trp53+/- male mice. Furthermore, the incidence of primary lung tumors, such as adenomas and adenocarcinomas, was 65.4, 62.5, and 45.4% in the FVB-Trp53+/- mice of the 25, 50, and 75 mg/kg groups, respectively. The main tumor types in FVB-Trp53+/- mice were TML and primary lung tumors, regardless of the dose of MNU administered. These results suggest that systemic tumors may result from malfunctions in the p53 gene and pathway, which is an important factor in the pathogenesis of human cancers. Therefore, FVB-Trp53 heterozygous mice are suitable for short-term carcinogenicity tests using positive carcinogens, and that the best result using MNU, a positive carcinogen, might have a single dose of 50 mg/kg.

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.

Artificial Multisensory Neuron with a Single Transistor for Multimodal Perception through Hybrid Visual and Thermal Sensing.

An artificial multisensory device applicable to in-sensor computing is demonstrated with a single-transistor neuron (1T-neuron) for multimodal perception. It simultaneously receives two sensing signals from visual and thermal stimuli. The 1T-neuron transforms these signals into electrical signals in the form of spiking and then fires them for a spiking neural network at the same time. This feature makes it feasible to realize input neurons for multimodal sensing. Visual and thermal sensing is achieved due to the inherent optical and thermal behaviors of the 1T-neuron. To demonstrate a neuromorphic multimodal sensing system with the artificial multisensory 1T-neuron, fingerprint recognition, widely used for biometric security, is implemented. Owing to the simultaneous sensing of heat as well as light, the proposed fingerprint recognition system composed of multisensory 1T-neurons not only identifies a genuine pattern but also judges whether or not it is forged.

Protective Role of the Toll-Like Receptor 5 Agonist KMRC011 against Murine Colitis Induced by Citrobacter rodentium and Dextran Sulfate Sodium.

This study aimed to identify the therapeutic ability of a novel toll-like receptor (TLR) 5 agonist, KMRC011, on ulcerative colitis induced by Citrobacter rodentium and dextran sulfate sodium in a C57BL/6N mouse model. Ulcerative colitis was induced in the mice by the oral administration of 1% dextran sulfate sodium in sterile drinking water for seven days ad libitum, followed by C. rodentium infection on the seventh day by intra-gastric administration (DSS-CT group). KMRC011 was administered intramuscularly at both 24 h and 15 min before (Treatment 1 group), and at both 15 min and 24 h after (Treatment 2 group) the C. rodentium infection. The length of the large intestine and histopathological counts were significantly greater and mucosal thickness was significantly thinner in the Treatment 1 group compared to the DSS-CT and Treatment 2 groups. Il-6 and Il-10 mRNA expression levels were upregulated, while Ifn-γ and Tnf-α mRNA expression levels were significantly downregulated in the Treatment 1 group, compared to the DSS-CT group. NF-κB p65 expression level was elevated due to ulcerative colitis in the DSS-CT group, but was significantly downregulated in the Treatment 1 group. Overall, KMRC011 showed protective effects against murine colitis by inhibiting NF-κB signaling.

Nonclinical safety evaluation of food colorant lac dye via systematic toxicity profiling with assessment of in vivo antigenic potential.

Lac dye is a natural colorant derived mainly from the insect Kerria lacca (Kerr) and has been used in food and beverage as a red-coloring additive. Despite its increasing use for human consumption as an alternative for allergy-associated cochineal, its toxicity profile remained incomplete to sufficiently assess its safety for the intended use. In this study, we evaluated systemic and genetic toxicity by performing acute and subacute oral toxicity studies in Sprague-Dawley (SD) rats using highly purified lac dye (LD) formulated in water and a battery of genotoxicity tests, respectively. To assess antigenic potentials, we carried out an in vivo passive cutaneous anaphylaxis test. A single dose of LD did not cause mortality at 5000 mg/kg body weight (BW), setting oral LD50 of >5000 mg/kg BW in SD rats. In the 90-day study, transient salivation without accompanying histopathological lesions in the salivary glands in 200 and 500 mg/kg BW groups and red-purple pigmentation on the surface of femora and skulls in 500 mg/kg groups were observed as nonadverse effects associated with LD, and no adverse effect was detected in all of the parameters examined, establishing a 500 mg/kg BW as no-observed-adverse-effect-level (NOAEL). Furthermore, LD was not mutagenic nor clastogenic in the genotoxicity tests. When tested for antigenicity, LD did not induce anaphylactic skin responses as opposed to the positive reaction by ovalbumin, suggesting a lack of antigenicity. Taken together, these findings provide extended toxicity information on LD with direct evidence supporting the lack of antigenicity, providing essential guidance for its safe use in humans.

The gate injection-based field-effect synapse transistor with linear conductance update for online training.

Neuromorphic computing, an alternative for von Neumann architecture, requires synapse devices where the data can be stored and computed in the same place. The three-terminal synapse device is attractive for neuromorphic computing due to its high stability and controllability. However, high nonlinearity on weight update, low dynamic range, and incompatibility with conventional CMOS systems have been reported as obstacles for large-scale crossbar arrays. Here, we propose the CMOS compatible gate injection-based field-effect transistor employing thermionic emission to enhance the linear conductance update. The dependence of the linearity on the conduction mechanism is examined by inserting an interfacial layer in the gate stack. To demonstrate the conduction mechanism, the gate current measurement is conducted under varying temperatures. The device based on thermionic emission achieves superior synaptic characteristics, leading to high performance on the artificial neural network simulation as 93.17% on the MNIST dataset.

Clinical evaluation of toll-like receptor-5 agonist for radiation-induced oral mucositis in beagle dogs.

This study aimed to evaluate the clinical safety and validate the radiomitigative effect of KMRC011, against radiation-induced oral mucositis in beagle dogs. Clinical safety was evaluated by assessing tolerability, complete blood tests, and plasma biochemistry after drug administration. The radiomitigative effect of KMRC011 was evaluated macropathologically and histopathologically after inducing oral mucositis iatrogenically using 20 Gy irradiation. The plasma concentration of interleukin-6 was measured via enzyme-linked immunosorbent assay, as a biomarker of KMRC011 bioreactivity. Decreased tolerability, increased neutrophil count, hepatic enzyme concentration, C-reactive protein concentration, and interleukin-6 concentration after the administration was observed and ceased within 24 h without additional treatment. Although all animals included in the present study developed severe mucositis in the late course of the study, animals administered KMRC011 showed less erythema, ulcer, inflammatory infiltration. These results suggest that KMRC011 may be used as an adjuvant for radiotherapy without severe adverse effects, especially during short-term radiotherapy, such as hypofractionated radiotherapy or stereotactic radiotherapy.

Cross-Species Transmission of Rabbit Hepatitis E Virus to Pigs and Evaluation of the Protection of a Virus-like Particle Vaccine against Rabbit Hepatitis E Virus Infection in Pigs.

We investigated the cross-species transmission of rabbit hepatitis E virus (rb HEV) to pigs and evaluated the cross-protection of a swine (sw) HEV-3 virus-like particle (VLP) vaccine against rb HEV infection in pigs. Twelve 4-week-old conventional pigs were divided into negative control (n = 3), positive control (rb HEV-infected, n = 4), and vaccinated (vaccinated and rb HEV-challenged, n = 5) groups. The vaccine was administered at weeks 0 and 2, and viral challenge was conducted at week 4. Serum HEV RNA, anti-HEV antibody, cytokine, and liver enzyme levels were determined. Histopathological lesions were examined in abdominal organs. Viral RNA was detected and increased anti-HEV antibody and alanine aminotransferase (ALT) levels were observed in positive control pigs; liver fibrosis, inflammatory cell infiltration in the lamina propria of the small intestine and shortened small intestine villi were also observed. In vaccinated pigs, anti-HEV antibody and Th1 cytokine level elevations were observed after the second vaccination; viral RNA was not detected, and ALT level elevations were not observed. The results verified the cross-species transmission of rb HEV to pigs and cross-protection of the sw HEV-3 VLP vaccine against rb HEV infection in pigs. This vaccine may be used for cross-protection against HEV infection in other species.