Phase-resolved measurement and control of ultrafast dynamics in terahertz electronic oscillators.

As a key component for next-generation wireless communications (6 G and beyond), terahertz (THz) electronic oscillators are being actively developed. Precise and dynamic phase control of ultrafast THz waveforms is essential for high-speed beam steering and high-capacity data transmission. However, measurement and control of such ultrafast dynamic process is beyond the scope of electronics due to the limited bandwidth of the electronic equipment. Here we surpass this limit by applying photonic technology. Using a femtosecond laser, we generate offset-free THz pulses to phase-lock the electronic oscillators based on resonant tunneling diode. This enables us to perform phase-resolved measurement of the emitted THz electric field waveform in time-domain with sub-cycle time resolution. Ultrafast dynamic response such as anti-phase locking behaviour is observed, which is distinct from in-phase stimulated emission observed in laser oscillators. We also show that the dynamics follows the universal synchronization theory for limit cycle oscillators. This provides a basic guideline for dynamic phase control of THz electronic oscillators, enabling many key performance indicators to be achieved in the new era of 6 G and beyond.

Potential of Lycii Radicis Cortex as an Ameliorative Agent for Skeletal Muscle Atrophy.

Lycii Radicis Cortex (LRC) is a traditional medicine in East Asia with various beneficial effects, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and anti-depressant properties. However, its potential effects on skeletal muscle atrophy have not been studied. In this study, the protective effects of LRC extract (LRCE) on dexamethasone (DEX)-induced muscle atrophy were investigated in C2C12 myotubes and mice. We evaluated the effect of LRCE on improving muscle atrophy using a variety of methods, including immunofluorescence staining, quantitative polymerase chain reaction (qPCR), Western blot, measurements of oxidative stress, apoptosis, ATP levels, and muscle tissue analysis. The results showed that LRCE improved myotube diameter, fusion index, superoxide dismutase (SOD) activity, mitochondrial content, ATP levels, expression of myogenin and myosin heavy chain (MHC), and reduced reactive oxygen species (ROS) production in dexamethasone-induced C2C12 myotubes. LRCE also enhanced protein synthesis and reduced protein degradation in the myotubes. In mice treated with DEX, LRCE restored calf thickness, decreased mRNA levels of muscle-specific RING finger protein 1 (MuRF1) and atrogin-1, and increased insulin-like growth factor 1 (IGF-1) mRNA level. Moreover, LRCE also repaired gastrocnemius muscle atrophy caused by DEX. Although human studies are not available, various preclinical studies have identified potential protective effects of LRCE against muscle atrophy, suggesting that it could be utilized in the prevention and treatment of muscle atrophy.

Where Does Hope Lie? The Dialectical Tensions Between Hopes and Expectations of Vocational Transition Planning from the Perspectives of Autistic Young Adults, Parents, and Practitioners.

The post-secondary transition for autistic youth is a complex process, with hopes and expectations serving as malleable mediators often overlooked in research and practice. Career awareness, exploration, and counseling services play a critical role in facilitating vocational transition, but the vocational hopes and expectations of autistic youth and their parents are often disregarded. This study aims to explore these aspirations and their impact on the vocational transition process, seeking to harmonize elements to better align with the needs of autistic youth and their families. This study used a focus group design involving group interviews with three participant groups: autistic transition-aged youth, parents, and practitioners. The findings reveal five key themes: 1) Accepting Disability or Constrained by Ableism: Resisting Marginalization, 2) Finding the Sweet Spot: Are Parents and Youth's Expectations Too High or Too Low, 3) Market Forces at Work-Finding a Meaningful Vocational Path in a Capitalist Society, 4) Despite Meticulous Planning, there is a Disconnect Between Needs and Resources, and 5) The Hills and Valleys of Finding Resilience. Navigating the multifaceted landscape of vocational transition planning for autistic youth necessitates a collaborative and flexible approach. Identified tensions serve as opportunities for growth and transformation. Recognizing and addressing system shortcomings is crucial for informed decision-making. Challenges extend beyond individual circumstances, reflecting broader systemic issues, and identifying these gaps allows for a comprehensive understanding of available resources, cultivating a basis of hope as uncertainties are addressed.

Development and Validation of a High-Performance Liquid Chromatography Method to Quantify Marker Compounds in Lysimachia vulgaris var. davurica and Its Effects in Diarrhea-Predominant Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS), a common gastrointestinal disorder worldwide, is characterized by chronic abdominal pain, bloating, and disordered defecation. IBS is associated with several factors, including visceral hypersensitivity, gut motility, and gut-brain interaction disorders. Because currently available pharmacological treatments cannot adequately improve symptoms and may cause adverse effects, the use of herbal therapies for managing IBS is increasing. Lysimachia vulgaris var. davurica (LV) is a medicinal plant used in traditional medicine to treat diarrhea. However, information on whether LV can effectively improve diarrhea-predominant IBS (IBS-D) remains limited. In this study, using an experimental mouse model of IBS-D, we elucidated the effects of the LV extract. The methanol extract of LV decreased fecal pellet output in the restraint stress- or 5-hydroxytryptamine (5-HT)-induced IBS mouse model and inhibited 5-HT-mediated [Ca2+]i increase in a dose-dependent manner. Furthermore, we developed and validated a high-performance liquid chromatography method using two marker compounds, namely, chlorogenic acid and rutin, for quality control analysis. Our study results suggest the feasibility of the methanol extract of LV for developing therapeutic agents to treat IBS-D by acting as a 5-HT3 receptor antagonist.

Ultra-compact and efficient photonic waveguide bends with different configurations designed by topology optimization.

Transporting light signals over the corners and sharp bends imposes high optical loss and distortion on the mode profiles. Usually, bends with larger radii are used in circuits to minimize the loss over transmission, resulting in a severe limitation in integration density. In this paper, we propose novel topology-optimized optimized L-bend and U-bend structures designed for a 220 nm silicon-on-insulator (SOI) platform. Optimized L-bends with footprints of 2.5 µm × 2.5 µm, 1.5 µm × 1.5 µm, and 1 µm × 1 µm show maximum insertion losses of only 0.07 dB, 0.26 dB, and 0.78 dB, respectively. For optimized U-bends with footprints of 3 µm × 3.6 µm, 2.5 µm × 2.5 µm, and 1.5 µm × 1.5 µm, the maximum insertion losses are 0.07 dB, 0.21 dB, and 3.16 dB. These optimized bends reduce the maximum insertion loss by over 50% compared to un-optimized arc-type bends across a broad wavelength range of 1450-1650 nm. Experimental verification of a meander line with 16 optimized U-bends (3 µm × 3.6 µm) demonstrates an averaged insertion loss of 1.23 dB in the wavelength range of 1520-1580 nm, agreeing with simulated results and indicating a high potential of loss reduction with optimized bends.

Intranasal immunization with the recombinant measles virus encoding the spike protein of SARS-CoV-2 confers protective immunity against COVID-19 in hamsters.

BACKGROUND: As the nasal mucosa is the initial site of infection for COVID-19, intranasal vaccines are more favorable than conventional vaccines. In recent clinical studies, intranasal immunization has been shown to generate higher neutralizing antibodies; however, there is a lack of evidence on sterilizing immunity in the upper airway. Previously, we developed a recombinant measles virus encoding the spike protein of SARS-CoV-2 (rMeV-S), eliciting humoral and cellular immune responses against SARS-CoV-2. OBJECTIVES: In this study, we aim to provide an experiment on nasal vaccines focusing on a measles virus platform as well as injection routes. STUDY DESIGN: Recombinant measles viruses expressing rMeV-S were prepared, and 5 × 105 PFUs of rMeV-S were administered to Syrian golden hamsters via intramuscular or intranasal injection. Subsequently, the hamsters were challenged with inoculations of 1 × 105 PFUs of SARS-CoV-2 and euthanized 4 days post-infection. Neutralizing antibodies and RBD-specific IgG in the serum and RBD-specific IgA in the bronchoalveolar lavage fluid (BALF) were measured, and SARS-CoV-2 clearance capacity was determined via quantitative reverse-transcription PCR (qRT-PCR) analysis and viral titer measurement in the upper respiratory tract and lungs. Immunohistochemistry and histopathological examinations of lung samples from experimental hamsters were conducted. RESULTS: The intranasal immunization of rMeV-S elicits protective immune responses and alleviates virus-induced pathophysiology, such as body weight reduction and lung weight increase in hamsters. Furthermore, lung immunohistochemistry demonstrated that intranasal rMeV-S immunization induces effective SARS-CoV-2 clearance that correlates with viral RNA content, as determined by qRT-PCR, in the lung and nasal wash samples, SARS-CoV-2 viral titers in lung, nasal wash, BALF samples, serum RBD-specific IgG concentration, and RBD-specific IgA concentration in the BALF. CONCLUSION: An intranasal vaccine based on the measles virus platform is a promising strategy owing to the typical route of infection of the virus, the ease of administration of the vaccine, and the strong immune response it elicits.

mRNA-HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV-mediated cancers via subcutaneous immunization.

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

Simultaneously enhancing the resolution and signal-to-background ratio in STED optical nanoscopy via differential depletion.

STED (stimulated emission depletion) far-field optical nanoscopy achieves resolution beyond the diffraction limit by depleting fluorescence at the periphery of excitation with a donut-shaped depletion laser. What is traded off with the superior resolution of STED nanoscopy is the unwanted elevation of structured background noise which hampers the quality of STED images. Here, we alleviate the background noise problem by adopting the differential stimulated emission depletion (diffSTED) approach. In diffSTED nanoscopy, signals obtained with different depletion strengths are compared and properly subtracted to remove two major background noise sources in STED nanoscopy. We show via simulations that by using diffSTED nanoscopy, background noise is significantly decreased, and the image contrast is improved. In addition, we show by simulation and analytical calculation that diffSTED improves resolution simultaneously. We assess the effect of different parameters, such as the STED beam intensity, depletion intensity ratio of two STED beams, and the subtraction factor, on the signal-to-background ratio (SBR) and the resolution of diffSTED nanoscopy. We introduce a logical algorithm to determine the optimal subtraction factor and the depletion intensity ratio. DiffSTED nanoscopy is a versatile technique that can be readily applied to any STED system without requiring any hardware modifications. We predict the wide applicability of diffSTED for its enhanced resolution, improved SBR, and easiness of implementation.

Deep neural network-based phase calibration in integrated optical phased arrays.

Calibrating the phase in integrated optical phased arrays (OPAs) is a crucial procedure for addressing phase errors and achieving the desired beamforming results. In this paper, we introduce a novel phase calibration methodology based on a deep neural network (DNN) architecture to enhance beamforming in integrated OPAs. Our methodology focuses on precise phase control, individually tailored to each of the 64 OPA channels, incorporating electro-optic phase shifters. To effectively handle the inherent complexity arising from the numerous voltage set combinations required for phase control across the 64 channels, we employ a tandem network architecture, further optimizing it through selective data sorting and hyperparameter tuning. To validate the effectiveness of the trained DNN model, we compared its performance with 20 reference beams obtained through the hill climbing algorithm. Despite an average intensity reduction of 0.84 dB in the peak values of the beams compared to the reference beams, our experimental results demonstrate substantial agreements between the DNN-predicted beams and the reference beams, accompanied by a slight decrease of 0.06 dB in the side-mode-suppression-ratio. These results underscore the practical effectiveness of the DNN model in OPA beamforming, highlighting its potential in scenarios that necessitate the intelligent and time-efficient calibration of multiple beams.

mRNA vaccine encoding Gn provides protection against severe fever with thrombocytopenia syndrome virus in mice.

We developed a promising mRNA vaccine against severe fever with thrombocytopenia syndrome (SFTS), an infectious disease caused by the SFTS virus that is primarily transmitted through tick bites. Administration of lipid nanoparticle-encapsulated mRNA-Gn successfully induced neutralizing antibodies and T-cell responses in mice. The vaccinated mice were protected against a lethal SFTS virus challenge, suggesting that this mRNA vaccine may be an effective and successful SFTS vaccine candidate.

The Antioxidant Activity of Undaria pinnatifida Sporophyll Extract Obtained Using Ultrasonication: A Focus on Crude Polysaccharide Extraction Using Ethanol Precipitation.

Undaria pinnatifida, a marine biological resource from which antioxidants such as polysaccharides can be obtained, is primarily distributed in the coastal areas of East Asia. Reactive oxygen species (ROS) are essential for physiological processes; however, excess ROS levels in the body result in cellular oxidative damage. Several extraction methods exist; however, factors such as long extraction times and high temperatures degrade polysaccharides. Therefore, this study aimed to increase the yield of U. pinnatifida sporophyll extract (UPE), a U. pinnatifida byproduct, using ultrasonication, an environmentally friendly extraction method, and identify UPE components with antioxidant activity. UPE_2, 4, 6, and 8 extracts were obtained at extraction times of 2, 4, 6, and 8 h, respectively. UPE_8 had the highest yield (31.91%) and polysaccharide (69.22%), polyphenol, (8.59 GAE µg/mg), and fucoxanthin contents (2.3 µg/g). UPE_8 showed the greatest protective and inhibitory effects on ROS generation in H2O2-damaged Vero cells. Ethanol precipitation of UPE_8 confirmed that UPE_8P (precipitate) had superior antioxidant activity in Vero cells compared to UPE_8S (supernatant). UPE_8P contained a large amount of polysaccharides, a major contributor to the antioxidant activity of UPE_8. This study shows that UPE_8 obtained using ultrasonication can be a functional food ingredient with excellent antioxidant activity.

Biocompatibility and Transplantation Efficacy of the C-Clear Artificial Cornea in a Rabbit Chemical Burn Model.

We investigated the bioavailability and stability of a C-Clear artificial cornea in a rabbit chemical burn model. Thirty-six rabbits were divided into a control group (n = 16) and a chemical burn group that used NaOH solution (n = 20). After lamellar dissection, the central posterior lamella was excised using a 3 mm diameter trephine, and an artificial cornea was transplanted into the lamellar pocket. After 2 weeks, the central anterior lamella was excised using a 3 mm diameter trephine to secure a clean visual axis. We examined the anterior segment of the eyes weekly for 12 weeks after transplantation. Successful subjects whose artificial corneas were maintained stably for 12 weeks were euthanized and underwent histologic examinations. Artificial corneas remained stable for up to 12 weeks in 62.5 and 50% of rabbits in the control and chemical burn groups, respectively. Two rabbits in the chemical burn group showed the formation of a retroprosthetic membrane, and one rabbit with visual axis blockage underwent membrane removal using a Nd:YAG laser. In histologic examinations, adhesion between artificial cornea and peripheral corneal stoma was observed. In conclusion, we confirmed structural stability and biocompatibility of the C-Clear artificial cornea for up to 12 weeks after implantation in control and chemical burn groups.

Analysis of the immunostimulatory effects of cytokine-expressing internal ribosome entry site-based RNA adjuvants and their applications.

Developing new adjuvants that can effectively induce both humoral and cellular immune responses while broadening the immune response is of great value. In this study, we aimed to develop GM-CSF- or IL-18-expressing single-stranded RNA (ssRNA) adjuvants based on the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) and tested their efficacy in combination with ovalbumin (OVA) or inactivated influenza vaccines. Notably, cytokine-expressing RNA adjuvants increased the expression of antigen-presenting cell activation markers. Specifically, GM-CSF-expressing RNA adjuvants increased CD4+T cell responses, while IL-18-expressing RNA adjuvants increased CD8+T cell responses in mice when combined with OVA. In addition, cytokine-expressing RNA adjuvants increased the frequency of polyclonal T cells in combination with the influenza vaccine and reduced the clinical illness scores and weight loss of mice after viral challenge. Collectively, our results suggest that cytokine-expressing RNA adjuvants can be applied to protein-based or inactivated vaccines to increase their efficacy.

Analysis of Phase Heterogeneity in Lipid Membranes Using Single-Molecule Tracking in Live Cells.

In live cells, the plasma membrane is composed of lipid domains separated by hundreds of nanometers in dynamic equilibrium. Lipid phase separation regulates the trafficking and spatiotemporal organization of membrane molecules that promote signal transduction. However, visualizing domains with adequate spatiotemporal accuracy remains challenging because of their subdiffraction limit size and highly dynamic properties. Here, we present a single lipid-molecular motion analysis pipeline (lipid-MAP) for analyzing the phase heterogeneity of lipid membranes by detecting the instantaneous velocity change of a single lipid molecule using the excellent optical properties of nanoparticles, high spatial localization accuracy of single-molecule localization microscopy, and separation capability of the diffusion state of the hidden Markov model algorithm. Using lipid-MAP, individual lipid molecules were found to be in dynamic equilibrium between two statistically distinguishable phases, leading to the formation of small (∼170 nm), viscous (2.5× more viscous than surrounding areas), and transient domains in live cells. Moreover, our findings provide an understanding of how membrane compositional changes, i.e., cholesterol and phospholipids, affect domain formation. This imaging method can contribute to an improved understanding of spatiotemporal-controlled membrane dynamics at the molecular level.

Mesenchymal Stem Cells and Exosomes: A Novel Therapeutic Approach for Corneal Diseases.

The cornea, with its delicate structure, is vulnerable to damage from physical, chemical, and genetic factors. Corneal transplantation, including penetrating and lamellar keratoplasties, can restore the functions of the cornea in cases of severe damage. However, the process of corneal transplantation presents considerable obstacles, including a shortage of available donors, the risk of severe graft rejection, and potentially life-threatening complications. Over the past few decades, mesenchymal stem cell (MSC) therapy has become a novel alternative approach to corneal regeneration. Numerous studies have demonstrated the potential of MSCs to differentiate into different corneal cell types, such as keratocytes, epithelial cells, and endothelial cells. MSCs are considered a suitable candidate for corneal regeneration because of their promising therapeutic perspective and beneficial properties. MSCs compromise unique immunomodulation, anti-angiogenesis, and anti-inflammatory properties and secrete various growth factors, thus promoting corneal reconstruction. These effects in corneal engineering are mediated by MSCs differentiating into different lineages and paracrine action via exosomes. Early studies have proven the roles of MSC-derived exosomes in corneal regeneration by reducing inflammation, inhibiting neovascularization, and angiogenesis, and by promoting cell proliferation. This review highlights the contribution of MSCs and MSC-derived exosomes, their current usage status to overcome corneal disease, and their potential to restore different corneal layers as novel therapeutic agents. It also discusses feasible future possibilities, applications, challenges, and opportunities for future research in this field.

Analyzing immune responses to varied mRNA and protein vaccine sequences.

In response to the COVID-19 pandemic, different types of vaccines, such as inactive, live-attenuated, messenger RNA (mRNA), and protein subunit, have been developed against SARS-CoV-2. This has unintentionally created a unique scenario where heterologous prime-boost vaccination against a single virus has been administered to a large human population. Here, we aimed to analyze whether the immunization order of vaccine types influences the efficacy of heterologous prime-boost vaccination, especially mRNA and protein-based vaccines. We developed a new mRNA vaccine encoding the hemagglutinin (HA) glycoprotein of the influenza virus using the 3'-UTR and 5'-UTR of muscle cells (mRNA-HA) and tested its efficacy by heterologous immunization with an HA protein vaccine (protein-HA). The results demonstrated higher IgG2a levels and hemagglutination inhibition titers in the mRNA-HA priming/protein-HA boosting (R-P) regimen than those induced by reverse immunization (protein-HA priming/mRNA-HA boosting, P-R). After the viral challenge, the R-P group showed lower virus loads and less inflammation in the lungs than the P-R group did. Transcriptome analysis revealed that the heterologous prime-boost groups had differentially activated immune response pathways, according to the order of immunization. In summary, our results demonstrate that the sequence of vaccination is critical to direct desired immune responses. This study demonstrates the potential of a heterologous vaccination strategy using mRNA and protein vaccine platforms against viral infection.

A MHz X-ray diffraction set-up for dynamic compression experiments in the diamond anvil cell.

An experimental platform for dynamic diamond anvil cell (dDAC) research has been developed at the High Energy Density (HED) Instrument at the European X-ray Free Electron Laser (European XFEL). Advantage was taken of the high repetition rate of the European XFEL (up to 4.5 MHz) to collect pulse-resolved MHz X-ray diffraction data from samples as they are dynamically compressed at intermediate strain rates (≤103 s-1), where up to 352 diffraction images can be collected from a single pulse train. The set-up employs piezo-driven dDACs capable of compressing samples in ≥340 µs, compatible with the maximum length of the pulse train (550 µs). Results from rapid compression experiments on a wide range of sample systems with different X-ray scattering powers are presented. A maximum compression rate of 87 TPa s-1 was observed during the fast compression of Au, while a strain rate of ∼1100 s-1 was achieved during the rapid compression of N2 at 23 TPa s-1.

Heterologous vaccination utilizing viral vector and protein platforms confers complete protection against SFTSV.

Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.

Demonstration of high-accuracy 3D imaging using a Si optical phased array with a tunable radiator.

Precise imaging in three-dimension (3D) is an essential technique for solid-state light detection and ranging (LiDAR). Among various solid-state LiDAR technologies, silicon (Si) optical phased array (OPA)-based LiDAR has the significant advantage of robust 3D imaging due to its high scanning speed, low power consumption, and compactness. Numerous techniques employing a Si OPA have utilized two-dimensional arrays or wavelength tuning for longitudinal scanning but the operation of those systems is restricted by additional requirements. Here, we demonstrate high-accuracy 3D imaging using a Si OPA with a tunable radiator. As we adapted a time-of-flight approach for distance measurement, we have developed an optical pulse modulator that allows a ranging accuracy of less than 2 cm. The implemented Si OPA is composed of an input grating coupler, multimode interferometers, electro-optic p-i-n phase shifters, and thermo-optic n-i-n tunable radiators. With this system, it is possible to attain a wide beam steering range of 45° in a transversal angle with a 0.7° divergence angle, and 10° in a longitudinal angle with a 0.6° divergence angle can be achieved using Si OPA. The character toy model was successfully imaged in three dimensions with a range resolution of 2 cm using the Si OPA. The further improvement of each component of the Si OPA will allow even more accurate 3D imaging over a longer distance.

Inverse design of an on-chip optical response predictor enabled by a deep neural network.

We proposed inverse-designed nanophotonic waveguide devices which have the desired optical responses in the wide band of 1450-1650 nm. The proposed devices have an ultra-compact size of just 1.5 µm × 3.0 µm and are designed on a silicon-on-insulator (SOI) waveguide platform. Individual nano-pixels with dimensions of 150 nm × 150 nm were made of either silicon or silicon dioxide, and the materials for the 200 total cells were determined using a trained deep neural network. While training the two networks, the hyperparameter optimization method was applied to make the training process efficient. We then fabricated the proposed devices using a CMOS-compatible fabrication process, and experimentally verified the fabricated device performance.