Quadruple ultrasound, photoacoustic, optical coherence, and fluorescence fusion imaging with a transparent ultrasound transducer.

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats' eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.

Commensurate Assembly of C60 on Black Phosphorus for Mixed-Dimensional van der Waals Transistors.

2D crystals can serve as templates for the realization of new van der Waals (vdW) heterostructures via controlled assembly of low-dimensional functional components. Among available 2D crystals, black phosphorus (BP) is unique due to its puckered atomic surface topography, which may lead to strong epitaxial phenomena through guided vdW assembly. Here, it is demonstrated that a BP template can induce highly oriented assembly of C60 molecular crystals. Transmission electron microscopy and theoretical analysis of the C60 /BP vdW heterostructure clearly confirm that the BP template results in oriented C60 assembly with higher-order commensurism. Lateral and vertical devices with C60 /BP junctions are fabricated via a lithography-free clean process, which allows one to investigate the ideal electrical properties of pristine C60 /BP junctions. Effective tuning of the C60 /BP junction barrier from 0.2 to 0.5 eV and maximum on-current density higher than 104  mA cm-2 are achieved with graphite/C60 /BP vertical vdW transistors. Due to the formation of high-quality C60 film and the semitransparent graphite top-electrode, the vertical transistors show high photoresponsivities up to ≈100 A W-1 as well as a fast response time under visible light illumination.

Bi-modal near-infrared fluorescence and ultrasound imaging via a transparent ultrasound transducer for sentinel lymph node localization.

Sentinel lymph node biopsy with an indocyanine green-based near-infrared fluorescence imaging system avoids the shortcomings of using a radioisotope or a combination of a blue dye and a radioactive tracer. To improve surgical precision, recent research has provided a depth profile of the sentinel lymph node by fusing fluorescence and ultrasound imaging. Here, we present a combined near-infrared fluorescence and ultrasound imaging system based on a transparent ultrasound transducer. The transparent ultrasound transducer enables seamless coaxial alignment of the fluorescence and ultrasound beam paths, allowing bi-modal observation of a single region of interest. Further, we demonstrate that the sentinel lymph node of mice injected with indocyanine green can be successfully localized and dissected based on information from the bi-modal imaging system.

Bi-modal near-infrared fluorescence and ultrasound imaging via a transparent ultrasound transducer for sentinel lymph node localization: publisher's note.

This publisher's note contains a correction to Opt. Lett.47, 393 (2022)10.1364/OL.446041.

Optimal Implementation Parameters of a Nonlinear Electrical Impedance Tomography Method Using the Complete Electrode Model.

This study discusses a nonlinear electrical impedance tomography (EIT) technique under different analysis conditions to propose its optimal implementation parameters. The forward problem for calculating electric potential is defined by the complete electrode model. The inverse problem for reconstructing the target electrical conductivity profile is presented based on a partial-differential-equation-constrained optimization approach. The electrical conductivity profile is iteratively updated by solving the Karush-Kuhn-Tucker optimality conditions and using the conjugate gradient method with an inexact line search. Various analysis conditions such as regularization scheme, number of electrodes, current input patterns, and electrode arrangement were set differently, and the corresponding results were compared. It was found from this study that the proposed EIT method yielded appropriate inversion results with various parameter settings, and the optimal implementation parameters of the EIT method are presented. This study is expected to expand the utility and applicability of EIT for the non-destructive evaluation of structures.

Low-Dose Radiation Affects Cardiovascular Disease Risk in Human Aortic Endothelial Cells by Altering Gene Expression under Normal and Diabetic Conditions.

High doses of ionizing radiation can cause cardiovascular diseases (CVDs); however, the effects of <100 mGy radiation on CVD remain underreported. Endothelial cells (ECs) play major roles in cardiovascular health and disease, and their function is reduced by stimuli such as chronic disease, metabolic disorders, and smoking. However, whether exposure to low-dose radiation results in the disruption of similar molecular mechanisms in ECs under diabetic and non-diabetic states remains largely unknown; we aimed to address this gap in knowledge through the molecular and functional characterization of primary human aortic endothelial cells (HAECs) derived from patients with type 2 diabetes (T2D-HAECs) and normal HAECs in response to low-dose radiation. To address these limitations, we performed RNA sequencing on HAECs and T2D-HAECs following exposure to 100 mGy of ionizing radiation and examined the transcriptome changes associated with the low-dose radiation. Compared with that in the non-irradiation group, low-dose irradiation induced 243 differentially expressed genes (DEGs) (133 down-regulated and 110 up-regulated) in HAECs and 378 DEGs (195 down-regulated and 183 up-regulated) in T2D-HAECs. We also discovered a significant association between the DEGs and the interferon (IFN)-I signaling pathway, which is associated with CVD by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein−protein network analysis, and module analysis. Our findings demonstrate the potential impact of low-dose radiation on EC functions that are related to the risk of CVD.

Verbenalin Reduces Amyloid-Beta Peptide Generation in Cellular and Animal Models of Alzheimer's Disease.

Verbenalin, among the major constituents of Verbena officinalis, has been reported to exhibit sleep-promoting and antioxidant activities. This study demonstrates the effects of verbenalin on amyloid-beta (Aß) peptide generation in Swedish mutant amyloid precursor protein (APP)-overexpressing Neuro2a cells (SweAPP/N2a) and in Alzheimer's disease (AD) animal models. We further performed molecular biological analyses of these in vitro and in vivo models of AD. The effects of verbenalin were assessed based on the expression of factors related to Aß peptide production using Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry (IHC). The intracellular expression and release of APP protein were both decreased by verbenalin treatment in SweAPP/N2a cells. Thus, the production of Aß peptides was decreased. Compared to those in AD transgenic (Tg) mice, IHC revealed that verbenalin-treated animals showed decreased Aß and tau expression levels in the hippocampus. In addition, verbenalin restored the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of AD animal models. These findings suggest that verbenalin may decrease Aß formation both in vitro and in vivo. Verbenalin may also help improve the pathological hallmarks of AD.

Thermal Ablation and High-Resolution Imaging Using a Back-to-Back (BTB) Dual-Mode Ultrasonic Transducer: In Vivo Results.

We present a back-to-back (BTB) structured, dual-mode ultrasonic device that incorporates a single-element 5.3 MHz transducer for high-intensity focused ultrasound (HIFU) treatment and a single-element 20.0 MHz transducer for high-resolution ultrasound imaging. Ultrasound image-guided surgical systems have been developed for lesion monitoring to ensure that ultrasonic treatment is correctly administered at the right locations. In this study, we developed a dual-element transducer composed of two elements that share the same housing but work independently with a BTB structure, enabling a mode change between therapy and imaging via 180-degree mechanical rotation. The optic fibers were embedded in the HIFU focal region of ex vivo chicken breasts and the temperature change was measured. Images were obtained in vivo mice before and after treatment and compared to identify the treated region. We successfully acquired B-mode and C-scan images that display the hyperechoic region indicating coagulation necrosis in the HIFU-treated volume up to a depth of 10 mm. The compact BTB dual-mode ultrasonic transducer may be used for subcutaneous thermal ablation and monitoring, minimally invasive surgery, and other clinical applications, all with ultrasound only.

Molecularly Controlled Stark Effect Induces Significant Rectification in Polycyclic-Aromatic-Hydrocarbon-Terminated n-Alkanethiolates.

The variation of the electronic structure of individual molecules as a function of the applied bias matters for the performance of molecular and organic electronic devices. Understanding the structure-electric-field relationship, however, remains a challenge because of the lack of in-operando spectroscopic technique and complexity arising from the ill-defined on-surface structure of molecules and organic-electrode interfaces within devices. We report that a reliable and reproducible molecular diode can be achieved by control of the conjugation length in polycyclic-aromatic-hydrocarbon (PAH)-terminated n-alkanethiolate (denoted as SC11PAH), incorporated into liquid-metal-based large-area tunnel junctions in the form of a self-assembled monolayer. By taking advantage of the structural simplicity and tunability of SC11PAH and the high-yielding feature of the junction technique, we demonstrate that the increase in the conjugation length of the PAH terminal group leads to a significant rectification ratio up to ∼1.7 × 102 at ±740 mV. Further study suggests that the Stark shift of the molecular energy resonance of the PAH breaks the symmetry of the energy topography across the junction and induces rectification in a temperature-independent charge-transport regime.

Involvement of G-Protein-Coupled Receptor 40 in the Inhibitory Effects of Docosahexaenoic Acid on SREBP1-Mediated Lipogenic Enzyme Expression in Primary Hepatocytes.

Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride levels. Various physiological activities of omega-3 fatty acids are due to their agonistic actions on G-protein-coupled receptor 40 (GPR40) and GPR120. Lipid droplets (LD) accumulation in hepatocytes confirmed that DHA treatment reduced the number of larger ( >10 µm2) LDs, as well as the total area of LDs. Moreover, DHA lowered protein and mRNA expression levels of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase and stearoyl-CoA desaturase-1 (SCD-1) in primary hepatocytes incubated with liver X receptor (LXR) agonist T0901317 or high glucose and insulin. DHA also decreased protein expression of nuclear and precursor sterol response-element binding protein (SREBP)-1, a key lipogenesis transcription factor. We further found that exposure of murine primary hepatocytes to DHA for 12 h increased GPR40 and GPR120 mRNA levels. Specific agonists (Compound A for GPR120 and AMG-1638 for GPR40), hepatocytes from GPR120 knock-out mice and GPR40 selective antagonist (GW1100) were used to assess whether DHA's antilipogenic effects are mediated through GPR120 or GPR40. Compound A did not decrease SREBP-1 and FAS protein expression in hepatocytes exposed to T0901317 or high glucose with insulin. Moreover, DHA downregulated lipogenesis enzyme expression in GPR120-null hepatocytes. In contrast, AMG-1638 lowered SREBP-1 and SCD-1 protein levels. Additionally, GW1100, a GPR40 antagonist, reversed the antilipogenic effects of DHA. Collectively, our data demonstrate that DHA downregulates the expression SREBP-1-mediated lipogenic enzymes via GPR40 in primary hepatocytes.

CK2 downregulation induces senescence-associated heterochromatic foci formation through activating SUV39h1 and inactivating G9a.

Cellular senescence is an irreversible form of cell cycle arrest and senescent cells have a unique gene expression profile that is frequently accompanied by senescence-associated heterochromatic foci (SAHF). Here, we present evidence that CK2 downregulation induces trimethylation of histone H3 Lys 9 (H3K9me3), selective binding of HP1γ to H3K9me3, formation of SAHF, and reduction of cyclin D1 expression in HCT116 and MCF-7 cells. CK2 downregulation-mediated H3K9me3 is associated with induction of H3K9 trimethylase SUV39h1 as well as reduction of H3K9 dimethylase G9a and GLP in cells. In addition, Pharmacological inhibition of SUV39h1 and G9a overexpression significantly attenuated induction of senescence-associated ß-galactosidase (SA-ß-gal) activity, H3K9me3 and SAHF formation in CK2-downregulated cells. Moreover, CK2 downregulation induced H3K9me3 in nematodes. Taken together, these results demonstrate that CK2 downregulation leads to H3K9me3 and SAHF formation by increasing SUV39h1 and decreasing G9a.

Protein kinase C downregulation induces senescence via FoxO3a inhibition in HCT116 and HEK293 cells.

We investigated the impact of protein kinase C (PKC) on cellular senescence. The PKC activity and expression of conventional PKC (cPKC) and atypical PKC (aPKC) isoforms decreased during replicative senescence in IMR-90 cells. Forced inhibition of cPKC or aPKC induced the activation of senescence markers, including senescence-associated ß-galactosidase activity and reactive oxygen species (ROS)-p53-p21Cip1/WAF1 axis in HCT116 and HEK293 cells. PKC inhibition triggered the nuclear exportation of FoxO3a via stimulation of AKT-mediated phosphorylation of FoxO3a, and thereby decreased the transcription of FoxO3a target genes. Conversely, ectopic expression of the PKC isoforms led to stimulation of the nuclear import of FoxO3a and expression of the FoxO3a target genes. Ectopic FoxO3a expression attenuated ROS accumulation and senescent phenotypes induced by PKC inhibition. Therefore, this study suggests for the first time that downregulation of PKC induces senescence through the AKT-FoxO3a-ROS-p53-p21Cip1/WAF1 pathway in HCT116 and HEK293 cells.

Equilibrium, Kinetics, and Spectroscopic Studies of SF6 Hydrate in NaCl Electrolyte Solution.

Many studies have focused on desalination via hydrate formation; however, for their potential application, knowledge pertaining to thermodynamic stability, formation kinetics, and guest occupation behavior in clathrate hydrates needs to be determined. Herein, the phase equilibria of SF6 hydrates in the presence of NaCl solutions (0, 2, 4, and 10 wt %) were monitored in the temperature range of 277-286 K and under pressures of up to 1.4 MPa. The formation kinetics of SF6 hydrates in the presence of NaCl solutions (0, 2, and 4 wt %) was also investigated. Gas consumption curves of SF6 hydrates showed that a pure SF6 hydrate system allowed fast hydrate growth as well as high conversion yield, whereas SF6 hydrate in the presence of NaCl solutions showed retarded hydrate growth rate as well as low conversion yield. In addition, structural identification of SF6 hydrates with and without NaCl solutions was performed using spectroscopic tools such as Raman spectroscopy and X-ray diffraction. The Raman spectrometer was also used to evaluate the temperature-dependent release behavior of guest molecules in SF6 and SF6 + 4 wt % NaCl hydrates. The results indicate that whereas SF6 hydrate starts to decompose at around 240 K, the escape of SF6 molecules in SF6 + 4 wt % NaCl hydrate is initiated rapidly at around 205 K. The results of this study can provide a better understanding of guest-host interaction in electrolyte-containing systems.

Enhancement of light-extraction efficiency of organic light-emitting diodes using silica nanoparticles embedded in TiO2 matrices.

We investigate two types of internal light-extraction layer structures for organic light-emitting diodes (OLEDs) that consist of silica nanoparticles (NPs) embedded in high-refractive-index TiO2 matrices. The composite of silica NPs and TiO2 matrices was coated on the glass substrate and fabricated with and without a SiO2 planarization layer. An increase in the optical out-coupling efficiency by a factor of 2.0 was obtained at a high luminance of 3,000 cd/m² from OLEDs containing the silica NPs embedded in TiO2 matrices between glass substrates and Zn-doped In2O3 (IZO) electrodes after additional planarization processes. This is consistent with the analytical result using the finite-difference time-domain (FDTD) method. Randomly distributed silica NPs acting as scattering centers could reduce the optical loss when extracting light. By using additional planarization processes with a PECVD-derived SiO2 layer, one can assure that smoother surfaces provide higher out-coupling efficiency, which attain 100% and 97% enhancements in power (lm/W) and current (cd/A) efficiencies, respectively.

Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.

Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ) are the main effectors of the Hippo pathway and their dysregulation contributes to diseases in tissues including the liver. Although mitochondria are capable of transmitting signals to change transcriptomic landscape of diseased hepatocytes, such retrograde signaling and the related nuclear machinery are largely unknown. Here, we show that increased YAP activity is associated with mitochondrial stress during liver injury; and this is required for secondary inflammation, promoting hepatocyte death. Mitochondrial stress inducers robustly promoted YAP/TAZ dephosphorylation, nuclear accumulation, and target gene transcription. RNA sequencing revealed that the majority of mitochondrial stress transcripts required YAP/TAZ. Mechanistically, direct oxidation of RhoA by mitochondrial superoxide was responsible for PP2A-mediated YAP/TAZ dephosphorylation providing a novel physiological input for the Hippo pathway. Hepatocyte-specific Yap/Taz ablation suppressed acetaminophen-induced liver injury and blunted transcriptomic changes associated with the pathology. Our observations uncover unappreciated pathway of mitochondrial stress signaling and reveal YAP/TAZ activation as the mechanistic basis for liver injury progression.

An ultrasensitive and broadband transparent ultrasound transducer for ultrasound and photoacoustic imaging in-vivo.

Transparent ultrasound transducers (TUTs) can seamlessly integrate optical and ultrasound components, but acoustic impedance mismatch prohibits existing TUTs from being practical substitutes for conventional opaque ultrasound transducers. Here, we propose a transparent adhesive based on a silicon dioxide-epoxy composite to fabricate matching and backing layers with acoustic impedances of 7.5 and 4-6 MRayl, respectively. By employing these layers, we develop an ultrasensitive, broadband TUT with 63% bandwidth at a single resonance frequency and high optical transparency ( > 80%), comparable to conventional opaque ultrasound transducers. Our TUT maximises both acoustic power and transfer efficiency with maximal spectrum flatness while minimising ringdowns. This enables high contrast and high-definition dual-modal ultrasound and photoacoustic imaging in live animals and humans. Both modalities reach an imaging depth of > 15 mm, with depth-to-resolution ratios exceeding 500 and 370, respectively. This development sets a new standard for TUTs, advancing the possibilities of sensor fusion.

Effect of chitooligosaccharide on the binding domain of the SARS-COV-2 receptor.

The receptor-binding domain (RBD) is crucial for understanding how severe acute respiratory syndrome coronavirus (SARS-CoV-2) recognizes and infects host cells. Chitooligosaccharide (CS) exhibits diverse antiviral activities, with its derivatives showing remarkable efficacy in blocking SARS-CoV-2 infection. Thus, this study employed spectroscopy, virus-infected cell experiments, and molecular simulation to investigate the molecular interactions between CS and SARS-CoV-2 RBD, as well as their mechanisms. In spectroscopic experiments, all four CS variants with different molecular weights formed interactions with the RBD. These variants increased the resistance of HEK293ACE2 cells to SARS-CoV-2 invasion. Molecular docking revealed that the four CS variants could bind to the RBD through hydrogen bonding or salt-bridge interactions, forming stable complexes. Chitotetraose provided stronger protection to HEK293ACE2 cells compared to other CS variants and displayed higher molecular docking scores. Further investigation into the optimal docking conformation of chitotetraose was conducted through molecular dynamics simulation methods. This study lays a solid theoretical foundation and provides a scientific basis for the development of targeted RBD inhibitors, as well as drug screening and application against novel coronaviruses.

Overexpression of developmentally regulated GTP-binding protein-2 increases bone loss.

The developmentally regulated GTP-binding protein-2 (DRG2) is a novel subclass of GTP-binding proteins. Many functional characteristics of osteoclasts (OC) are associated with small GTPases. We hypothesized that DRG2 affects bone mass via modulating OC activity. Using DRG2 transgenic mice, we investigated the role of DRG2 in bone remodeling. DRG2 overexpression caused a decrease in bone mass and an increase in the number and activity of OC in vivo. DRG2 overexpression increased fusion, spreading, survival, and resorption activity of OC in vitro. Downregulation of DRG2 by siRNA decreased fusion, spreading, and survival of OC, supporting the observations found in DRG2 transgenic OC. Transgenic mature OCs were larger, with actin rings and higher ERK, Akt, Rac1 and Rho activities than wild-type OCs. Inhibition of these proteins abolished the effects of DRG2 on formation of large OCs with actin rings, implying that DRG2 affects cytoskeleton reorganization in a Rac1/Rho/ERK/Akt-dependent manner. In summary, DRG2 is associated with survival and cytoskeleton organization of OC under influence of macrophage colony-stimulating factor, and its overexpression leads to elevated bone resorptive activity of OC, resulting in bone loss.

InGaAs Schottky barrier diode array detector for a real-time compact terahertz line scanner.

We present a terahertz (THz) broadband antenna-integrated 1 × 20 InGaAs Schottky barrier diode (SBD) array detector with an average responsivity of 98.5 V/W at a frequency of 250 GHz, which is measured without attaching external amplifiers and Si lenses, and an average noise equivalent power (NEP) of 106.6 pW/√Hz. The 3-dB bandwidth of the SBD detector is also investigated at approximately 180 GHz. For implementing an array-type SBD detector by a simple fabrication process to achieve a high yield, a structure comprising an SiN(x) layer instead of an air bridge between the anode and the cathode is designed. THz line beam imaging using a Gunn diode emitter with a center frequency of 250 GHz and a 1 × 20 SBD array detector is successfully demonstrated.

Low-temperature-grown InGaAs terahertz photomixer embedded in InP thermal spreading layer regrown by metalorganic chemical vapor deposition.

A novel buried photomixer for integrated photonic terahertz devices is proposed. The active region of the mesa-structure InGaAs photomixer is buried in an InP layer grown by metalorganic chemical vapor deposition (MOCVD) to improve heat dissipation, which is an important problem for terahertz photomixers. The proposed photomixer shows good thermal properties compared to a conventional planar-type photomixer. The MOCVD regrowth process indicates the possibility for THz photomixers to be integrated monolithically with conventional photonic devices.