Circulating miRNA-4701-3p as a predictive biomarker of cardiovascular disease which induces angiogenesis by inhibition of TOB2.

Angiogenesis is mainly regulated by the delivery of VEGF-dependent signaling to cells. However, the angiogenesis mechanism regulated by VEGF-induced miRNA is still not understood. After VEGF treatment in HUVECs, we screened the changed miRNAs through small-RNA sequencing and found VEGF-induced miR-4701-3p. Furthermore, the GFP reporter gene was used to reveal that TOB2 expression was regulated by miR-4701-3p, and it was found that TOB2 and miR-4701-3p modulation could cause angiogenesis in an in-vitro angiogenic assay. Through the luciferase assay, it was confirmed that the activation of the angiogenic transcription factor MEF2 was regulated by the suppression and overexpression of TOB2 and miR-4701-3p. As a result, MEF2 downstream gene mRNAs that induce angiogenic function were regulated. We used the NCBI GEO datasets to reveal that the expression of TOB2 and MEF2 was significantly changed in cardiovascular disease. Finally, it was confirmed that the expression of circulating miR-4701-3p in the blood of myocardial infarction patients was remarkably increased. In patients with myocardial infarction, circulating miR-4701-3p was increased regardless of age, BMI, and sex, and showed high AUC levels in specificity and sensitivity analysis (AUROC) (AUC = 0.8451, 95 % CI 0.78-0.90). Our data showed TOB2-mediated modulation of MEF2 and its angiogenesis by VEGF-induced miR-4701-3p in vascular endothelial cells. In addition, through bioinformatics analysis using GEO data, changes in TOB2 and MEF2 were revealed in cardiovascular disease. We suggest that circulating miR-4701-3p has high potential as a biomarker for myocardial infarction.

MiR-29 and MiR-140 regulate TRAIL-induced drug tolerance in lung cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.

Yeast-derived particulate beta-glucan induced angiogenesis via regulating PI3K/Src and ERK1/2 signaling pathway.

The importance of ß-glucan from S. cerevisiae in angiogenesis has not been well studied. We investigated whether ß-glucan induces angiogenesis through PI3K/Src and ERK1/2 signaling pathway in HUVECs. We identified that ß-glucan induced phosphorylation of PI3K, Src, Akt, eNOS, and ERK1/2. Subsequently, we found that this phosphorylation increased the viability of HUVECs. We also observed that stimulation of ß-glucan promoted the activity of MEF2 and MEF2-dependent pro-angiogenic genes, including EGR2, EGR3, KLF2, and KLF4. Additionally, the role of ß-glucan in angiogenesis was confirmed using in vitro and ex vivo experiments including cell migration, capillary-like tube formation and mouse aorta ring assays. To determine the effect of ß-glucan on the PI3K/Akt/eNOS and ERK1/2 signaling pathway, PI3K inhibitor wortmannin and ERK1/2 inhibitor SCH772984 were used. Through the Matrigel plug assay, we confirmed that ß-glucan significantly increased angiogenesis in vivo. Taken together, our study demonstrates that ß-glucan promotes angiogenesis via through PI3K and ERK1/2 signaling pathway.

Dual-wavelength metalens enables Epi-fluorescence detection from single molecules.

Single molecule fluorescence spectroscopy is at the heart of molecular biophysics research and the most sensitive biosensing assays. The growing demand for precision medicine and environmental monitoring requires the creation of miniaturized and portable sensing platforms. However, the need for highly sophisticated objective lenses has precluded the development of single molecule detection systems for truly portable devices. Here, we propose a dielectric metalens device of submicrometer thickness to excite and collect light from fluorescent molecules instead of an objective lens. The high numerical aperture, high focusing efficiency, and dual-wavelength operation of the metalens enable the implementation of fluorescence correlation spectroscopy with a single Alexa 647 molecule in the focal volume. Moreover, the metalens enables real-time monitoring of individual fluorescent nanoparticle transitions and identification of hydrodynamic diameters ranging from a few to hundreds of nanometers. This advancement in sensitivity extends the application of the metalens technology to ultracompact single-molecule sensors.

Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease.

X-linked inhibitor of apoptosis protein (XIAP) deficiency causes refractory inflammatory bowel disease. The XIAP protein plays a pivotal role in the pro-inflammatory response through the nucleotide-binding oligomerization domain-containing signaling pathway that is important in mucosal homeostasis. We analyzed the molecular mechanism of non-synonymous pathogenic variants (PVs) of XIAP BIR2 domain. We generated N-terminally green fluorescent protein-tagged XIAP constructs of representative non-synonymous PVs. Co-immunoprecipitation and fluorescence cross-correlation spectroscopy showed that wild-type XIAP and RIP2 preferentially interacted in live cells, whereas all non-synonymous PV XIAPs failed to interact properly with RIP2. Structural analysis showed that various structural changes by mutations, such as hydrophobic core collapse, Zn-finger loss, and spatial rearrangement, destabilized the two loop structures (174-182 and 205-215) that critically interact with RIP2. Subsequently, it caused a failure of RIP2 ubiquitination and loss of protein deficiency by the auto-ubiquitination of all XIAP mutants. These findings could enhance our understanding of the role of XIAP mutations in XIAP-deficient inflammatory bowel disease and may benefit future therapeutic strategies.

HDAC5-mediated exosomal Maspin and miR-151a-3p as biomarkers for enhancing radiation treatment sensitivity in hepatocellular carcinoma.

BACKGROUND: Tumor-derived exosomes are critical elements of the cell-cell communication response to various stimuli. This study aims to reveal that the histone deacetylase 5 (HDAC5) and p53 interaction upon radiation in hepatocellular carcinoma intricately regulates the secretion and composition of exosomes. METHODS: We observed that HDAC5 and p53 expression were significantly increased by 2 Gy and 4 Gy radiation exposure in HCC. Normal- and radiation-derived exosomes released by HepG2 were purified to investigate the exosomal components. RESULTS: We found that in the radiation-derived exosome, exosomal Maspin was notably increased. Maspin is known as an anti-angiogenic gene. The expression of Maspin was regulated at the cellular level by HDAC5, and it was elaborately regulated and released in the exosome. Radiation-derived exosome treatment caused significant inhibition of angiogenesis in HUVECs and mouse aortic tissues. Meanwhile, we confirmed that miR-151a-3p was significantly reduced in the radiation-derived exosome through exosomal miRNA sequencing, and three HCC-specific exosomal miRNAs were also decreased. In particular, miR-151a-3p induced an anti-apoptotic response by inhibiting p53, and it was shown to induce EMT and promote tumor growth by regulating p53-related tumor progression genes. In the HCC xenograft model, radiation-induced exosome injection significantly reduced angiogenesis and tumor size. CONCLUSIONS: Our present findings demonstrated HDAC5 is a vital gene of the p53-mediated release of exosomes resulting in tumor suppression through anti-cancer exosomal components in response to radiation. Finally, we highlight the important role of exosomal Maspin and mi-151a-3p as a biomarker in enhancing radiation treatment sensitivity. Therapeutic potential of HDAC5 through p53-mediated exosome modulation in radiation treatment of hepatocellular carcinoma.

Dual-wavelength UV-visible metalens for multispectral photoacoustic microscopy: A simulation study.

Photoacoustic microscopy is advancing with research on utilizing ultraviolet and visible light. Dual-wavelength approaches are sought for observing DNA/RNA- and vascular-related disorders. However, the availability of high numerical aperture lenses covering both ultraviolet and visible wavelengths is severely limited due to challenges such as chromatic aberration in the optics. Herein, we present a groundbreaking proposal as a pioneering simulation study for incorporating multilayer metalenses into ultraviolet-visible photoacoustic microscopy. The proposed metalens has a thickness of 1.4 µm and high numerical aperture of 0.8. By arranging cylindrical hafnium oxide nanopillars, we design an achromatic transmissive lens for 266 and 532 nm wavelengths. The metalens achieves a diffraction-limited focal spot, surpassing commercially available objective lenses. Through three-dimensional photoacoustic simulation, we demonstrate high-resolution imaging with superior endogenous contrast of targets with ultraviolet and visible optical absorption bands. This metalens will open new possibilities for downsized multispectral photoacoustic microscopy in clinical and preclinical applications.

Vibrational circular dichroism unveils hidden clues.

Infrared chiral plasmonic metamaterials based on perpendicularly positioned nanorods enable surface-enhanced vibrational circular dichroism for more selective and sensitive identification of protein fingerprints and enantioselective sensing, which creates a new pathway for chemical or biomedical applications.

Bright-Field and Edge-Enhanced Imaging Using an Electrically Tunable Dual-Mode Metalens.

The imaging of microscopic biological samples faces numerous difficulties due to their small feature sizes and low-amplitude contrast. Metalenses have shown great promise in bioimaging as they have access to the complete complex information, which, alongside their extremely small and compact footprint and potential to integrate multiple functionalities into a single device, allow for miniaturized microscopy with exceptional features. Here, we design and experimentally realize a dual-mode metalens integrated with a liquid crystal cell that can be electrically switched between bright-field and edge-enhanced imaging on the millisecond scale. We combine the concepts of geometric and propagation phase to design the dual-mode metalens and physically encode the required phase profiles using hydrogenated amorphous silicon for operation at visible wavelengths. The two distinct metalens phase profiles include (1) a conventional hyperbolic metalens for bright-field imaging and (2) a spiral metalens with a topological charge of +1 for edge-enhanced imaging. We demonstrate the focusing and vortex generation ability of the metalens under different states of circular polarization and prove its use for biological imaging. This work proves a method for in vivo observation and monitoring of the cell response and drug screening within a compact form factor.

Recent Advances in Metaphotonic Biosensors.

Metaphotonic devices, which enable light manipulation at a subwavelength scale and enhance light-matter interactions, have been emerging as a critical pillar in biosensing. Researchers have been attracted to metaphotonic biosensors, as they solve the limitations of the existing bioanalytical techniques, including the sensitivity, selectivity, and detection limit. Here, we briefly introduce types of metasurfaces utilized in various metaphotonic biomolecular sensing domains such as refractometry, surface-enhanced fluorescence, vibrational spectroscopy, and chiral sensing. Further, we list the prevalent working mechanisms of those metaphotonic bio-detection schemes. Furthermore, we summarize the recent progress in chip integration for metaphotonic biosensing to enable innovative point-of-care devices in healthcare. Finally, we discuss the impediments in metaphotonic biosensing, such as its cost effectiveness and treatment for intricate biospecimens, and present a prospect for potential directions for materializing these device strategies, significantly influencing clinical diagnostics in health and safety.

A new cyclin-dependent kinase-9 inhibitor A09-003 induces apoptosis in acute myeloid leukemia cells with reduction of myeloid cell leukemia sequence-1 protein.

Acute myeloid leukemia (AML) is the most common type of hematological disease in adults, and has a very poor outcome [1]. Based on its wide range of efficacy in AML models, a small-molecule inhibitor of the anti-apoptotic protein BCL-2, venetoclax (ABT-199/GDC-0199), was developed for clinical trials. However, venetoclax showed limited monotherapy activity [2]. The overexpression of myeloid cell leukemia sequence-1 protein (Mcl-1)-due to mutations in Fms-like tyrosine kinase 3 internal tandem duplication (FLT-3 ITD)-was considered to be the main reason for low efficacy of venetoclax in clinical trials [3-5]. To achieve venetoclax sensitization in AML, targeting CDK-9 with venetoclax is a promising therapeutic strategy. In this study, we developed A09-003 as a potent inhibitor of CDK-9, with an IC50 value of 16 nM. A09-003 inhibited cell proliferation in various leukemia cell lines. In particular, the proliferation inhibitory effect of A09-003 was most potent in MV4-11 and Molm-14 cells, harboring the FLT-3 ITD mutation with a high expression profile of Mcl-1. Marker analysis revealed that A09-003 reduced CDK-9 phosphorylation and reduced RNA polymerase II activity with decreased Mcl-1 expression. Finally, combining A09-003 with venetoclax induced apoptotic cell death in a synergistic manner. In summary, this study shows the potential of A09-003 in AML therapy.

Subwavelength control of light transport at the exceptional point by non-Hermitian metagratings.

The concept of non-Hermitian physics, originally developed in the context of quantum field theory, has been investigated on distinct photonic platforms and created a plethora of counterintuitive phenomena. Interfacing non-Hermitian photonics and nanoplasmonics, here, we demonstrate unidirectional excitation and reflection of surface plasmon polaritons by elaborately designing the permittivity profile of non-Hermitian metagratings, in which the eigenstates of the system can coalesce at an exceptional point. Continuous tuning of the excitation or reflection ratios is also possible through altering the geometry of the metagrating. The controllable directionality and robust performance are attributed to the phase transition near the exceptional point, which is fully confirmed by the theoretic calculation, numerical simulation, and experimental characterization. Our work pushes non-Hermitian photonics to the nanoscale regime and paves the way toward high-performance plasmonic devices with superior controllability, performance, and robustness by using the topological effect associated with non-Hermitian systems.

Hyperlens for capturing sub-diffraction nanoscale single molecule dynamics.

Hyperlenses offer an appealing opportunity to unlock bioimaging beyond the diffraction limit with conventional optics. Mapping hidden nanoscale spatiotemporal heterogeneities of lipid interactions in live cell membrane structures has been accessible only using optical super-resolution techniques. Here, we employ a spherical gold/silicon multilayered hyperlens that enables sub-diffraction fluorescence correlation spectroscopy at 635 nm excitation wavelength. The proposed hyperlens enables nanoscale focusing of a Gaussian diffraction-limited beam below 40 nm. Despite the pronounced propagation losses, we quantify energy localization in the hyperlens inner surface to determine fluorescence correlation spectroscopy (FCS) feasibility depending on hyperlens resolution and sub-diffraction field of view. We simulate the diffusion FCS correlation function and demonstrate the reduction of diffusion time of fluorescent molecules up to nearly 2 orders of magnitude as compared to free space excitation. We show that the hyperlens can effectively distinguish nanoscale transient trapping sites in simulated 2D lipid diffusion in cell membranes. Altogether, versatile and fabricable hyperlens platforms display pertinent applicability for the enhanced spatiotemporal resolution to reveal nanoscale biological dynamics of single molecules.

Metasurfaces-Driven Hyperspectral Imaging via Multiplexed Plasmonic Resonance Energy Transfer.

Obtaining single-molecular-level fingerprints of biomolecules and electron-transfer dynamic imaging in living cells are critically demanded in postgenomic life sciences and medicine. However, the possible solution called plasmonic resonance energy transfer (PRET) spectroscopy remains challenging due to the fixed scattering spectrum of a plasmonic nanoparticle and limited multiplexing. Here, multiplexed metasurfaces-driven PRET hyperspectral imaging, to probe biological light-matter interactions, is reported. Pixelated metasurfaces with engineered scattering spectra are first designed over the entire visible range by the precision nanoengineering of gap plasmon and grating effects of metasurface clusters. Pixelated metasurfaces are created and their full dark-field coloration is optically characterized with visible color palettes and high-resolution color printings of the art pieces. Furthermore, three different biomolecules (i.e., chlorophyll a, chlorophyll b, and cytochrome c) are applied on metasurfaces for color palettes to obtain selective molecular fingerprint imaging due to the unique biological light-matter interactions with application-specific biomedical metasurfaces. This metasurface-driven PRET hyperspectral imaging will open up a new path for multiplexed real-time molecular sensing and imaging methods.

Gravitational Acceleration Test Results by Lifestyle and Physical Fitness of Air Force Cadets.

BACKGROUND: The purpose of this study was to analyze G test results according to the Three-Factor Eating Questionnaire (TFEQ), body composition, and physical fitness of fourth-grade air force cadets. This was done to identify the relationship between the TFEQ, body composition, and G resistance, in order to provide basic data for pilots and air force cadets to strengthen G tolerance.METHODS: From the Republic of Korea Air Force Academy (ROKAFA), 138 fourth-year cadets were assessed using the TFEQ and for body composition and physical fitness. Based on these measurement results, a G test result analysis and a correlation analysis were conducted.RESULT: The TFEQ showed statistically significant differences in several areas when comparing the G test pass group (GP group) to the G test fail group (GF group). Three-km running time was significantly faster in the GP group than in the GF group. Physical activity levels were higher in the GP group compared to the GF group.CONCLUSION: The TFEQ demonstrated utility in predicting whether cadets will pass or fail G-LOC testing. G test success for any cadet will require improvement in continuous eating behavior and physical fitness management. If variables affecting the G test are analyzed and applied to physical education and training through continuous research over the next two to three years, it is expected to have a greater effect on the success of the G test for every cadet.Sung J-Y, Kim I-K, Jeong D-H. Gravitational acceleration test results by lifestyle and physical fitness of air force cadets. Aerosp Med Hum Perform. 2023; 94(5):384-388.

Angiogenic adipokine C1q-TNF-related protein 9 ameliorates myocardial infarction via histone deacetylase 7-mediated MEF2 activation.

C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine and has high potential as a therapeutic target. However, the role of CTRP9 in cardiovascular disease pathogenesis remains unclear. We found CTRP9 to induce HDAC7 and p38 MAPK phosphorylation via tight regulation of AMPK in vascular endothelial cells, leading to angiogenesis through increased MEF2 activity. The expression of CTRP9 and atheroprotective MEF2 was decreased in plaque tissue of atherosclerotic patients and the ventricle of post-infarction mice. CTRP9 treatment inhibited the formation of atherosclerotic plaques in ApoE KO and CTRP9 KO mice. In addition, CTRP9 induced significant ischemic injury prevention in the post-MI mice. Clinically, serum CTRP9 levels were reduced in patients with MI compared with healthy controls. In summary, CTRP9 induces a vasoprotective response via the AMPK/HDAC7/p38 MAPK pathway in vascular endothelial cells, whereas its absence can contribute to atherosclerosis and MI. Hence, CTRP9 may represent a valuable therapeutic target and biomarker in cardiovascular diseases.

High-sensitivity waveguide-integrated bolometer based on free-carrier absorption for Si photonic sensors.

Conventional photon detectors necessarily face critical challenges regarding strong wavelength-selective response and narrow spectral bandwidth, which are undesirable for spectroscopic applications requiring a wide spectral range. With this perspective, herein, we overcome these challenges through a free-carrier absorption-based waveguide-integrated bolometer for infrared spectroscopic sensors on a silicon-on-insulator (SOI) platform featuring a spectrally flat response at near-infrared (NIR) range (1520-1620 nm). An in-depth thermal analysis was conducted with a systematic investigation of geometry dependence on the detectors. We achieved great performances: temperature coefficient of resistance (TCR) of -3.786%/K and sensitivity of -26.75%/mW with a low wavelength dependency, which are record-high values among reported waveguide bolometers so far, to our knowledge. In addition, a clear on-off response with the rise/fall time of 24.2/29.2 µs and a 3-dB roll-off frequency of ∼22 kHz were obtained, sufficient for a wide range of sensing applications. Together with the possibility of expanding an operation range to the mid-infrared (MIR) band, as well as simplicity in the detector architecture, our work here presents a novel strategy for integrated photodetectors covering NIR to MIR at room temperature for the development of the future silicon photonic sensors with ultrawide spectral bandwidth.

Metasurface-driven full-space structured light for three-dimensional imaging.

Structured light (SL)-based depth-sensing technology illuminates the objects with an array of dots, and backscattered light is monitored to extract three-dimensional information. Conventionally, diffractive optical elements have been used to form laser dot array, however, the field-of-view (FOV) and diffraction efficiency are limited due to their micron-scale pixel size. Here, we propose a metasurface-enhanced SL-based depth-sensing platform that scatters high-density ~10 K dot array over the 180° FOV by manipulating light at subwavelength-scale. As a proof-of-concept, we place face masks one on the beam axis and the other 50° apart from axis within distance of 1 m and estimate the depth information using a stereo matching algorithm. Furthermore, we demonstrate the replication of the metasurface using the nanoparticle-embedded-resin (nano-PER) imprinting method which enables high-throughput manufacturing of the metasurfaces on any arbitrary substrates. Such a full-space diffractive metasurface may afford ultra-compact depth perception platform for face recognition and automotive robot vision applications.

Broad-Band Polarization-Insensitive Metasurface Holography with a Single-Phase Map.

The remarkable potential of metasurface holography promises revolutionary advancements for imaging, chip-integrated augmented/virtual reality (AR/VR) technology, and flat optical displays. The choice of constituent element geometry constrains many potential applications purveyed through polarization-independent optical response. The limited capabilities and degree of freedoms in commonly used meta-atoms restrict the design flexibility to break the conventional trade-off between polarization-insensitivity and bandwidth. Here, we propose a geometric phase-enabled novel design strategy to break this conventional trade-off. The proposed strategy ensures the realization of broad-band polarization-insensitivity through a simplified design procedure. An identical output wavefront manipulation is achieved by adjusting the phase delay freedom of geometric phase engineering under different incident polarization conditions. For proof of concept, a metahologram device is fabricated by an optimized complementary metal-oxide-semiconductor (CMOS)-compatible material of hydrogenated amorphous silicon (a-Si:H). This metahologram device reproduces the required hologram with high image fidelity and efficiency under different polarization scenarios of white light incidence. Due to the simple design strategy, low computational cost, and easy fabrication, the proposed technique can be an excellent candidate for realizing polarization-insensitive metahologram devices.

Single-Step Fabricable Flexible Metadisplays for Sensitive Chemical/Biomedical Packaging Security and Beyond.

Secure packaging and transportation of light-sensitive chemical and biomedical test tubes are crucial for environmental protection and public health. Benefiting from the compact form factor and high efficiency of optical metasurfaces, we propose a broad-band polarization-insensitive flexible metasurface for the security of sensitive packages in the transport industry. We employ both the propagation and the geometric phase of novel TiO2 resin-based anisotropic nanoresonators to demonstrate a flexible and broad-band polarization-insensitive metasurface in the visible domain. The ultraviolet nanoimprint lithographic technique (UV-NIL) is used to fabricate high-index TiO2 nanoparticle-embedded-resin (nano-PER) structures that are patterned on a flexible substrate. This novel approach provides swift single-step fabrication without secondary fabrication steps such as deposition and etching. Moreover, replicating and transforming patterns over flexible substrates make the proposed technique highly suitable for large-throughput commercial manufacturing. As the proposed metahologram manifests high transmission efficiency in the visible domain, such flexible metaholographic platforms could find several exciting applications in bendable/curved displays, wearable devices, and holographic labeling for interactive displays.