Plants-releasing exosome-like nanovesicles (PENs) contain miRNA, bioactive lipids, mRNAs, and proteins to exert antioxidant, anti-inflammatory, and regenerative activity. Substances extracted from ...yams have been reported to promote osteoblast growth in bone regeneration, which prevent weak and brittle bones in osteoporosis. Herein, we describe the beneficial effects of yam-derived exosome-like nanovesicles (YNVs) on promoting differentiation and mineralization of osteoblasts for bone regeneration in ovariectomized (OVX)-induced osteoporotic mice. YNVs were successfully isolated and characterized. YNVs stimulate the proliferation, differentiation, and mineralization of osteoblasts with increased bone differentiation markers (OPN, ALP, and COLI). Interestingly, YNVs do not contain saponins including diosgenin and dioscin known to mainly exert osteogenic activity of yams. Instead, the osteogenic activity of YNVs was revealed to be resulted from activation of the BMP-2/p-p38-dependent Runx2 pathway. As a result, YNVs promote longitudinal bone growth and mineral density of the tibia in the OVX-induced osteoporotic mice in vivo, and these results positively correlate the significant increases in osteoblast-related parameters. In addition, the orally administered YNVs were transported through the GI tract and absorbed through the small intestine. These results showed an excellent systemic biosafety determined by histological analysis and liver/kidney toxicity tests. Taken together, YNVs can serve as a safe and orally effective agent in the treatment of osteoporosis.
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•Isolation of PENs to prepare YNVs containing RNAs, proteins, and lipids is optimized.•Yam-derived exosome-like nanovesicles (YNVs) to promote differentiation and mineralization of osteoblasts•YNVs-mediated osteogenic differentiation is related to mechanism of BMP-2/p-p38-dependent Runx2 pathway.•YNVs promote longitudinal bone growth in the OVX-induced osteoporotic mice.
The distinguishing feature of a flexible electronic device is that it maintains its function even when the shape changes repeatedly. As the degree of integration of flexible devices increases, ...revealing failure mechanisms and extending the lifetime of the flexible devices are getting more difficult. One of the potential damage zones is the interface of heterogeneous material components, where strain can be localized due to the mismatch of mechanical properties. In this study, we investigate the mechanically reliable interconnect design of the flexible printed circuit board (FPCB) system in which the packaging chip is integrated. When the FPCB was bent, folding occurred at the edge of the packaging chip due to the high bending rigidity compared with the plastic substrate and resulted in high strain concentration. By introducing interconnect architecture that bypassed the strain concentration area around the packaging chip, mechanical damage of the interconnects was successfully reduced. Through finite element simulation, the strain applied to the interconnect crossing the strain-concentrated region was predicted to be 2 times larger than that bypassing the strain-concentrated region, from 8.32 to 4.64%. In addition, the strain gap of these two interconnects could be increased as the Young’s modulus mismatch between the packaging chip and the substrate increased. This study is expected to improve the design guidelines to mechanically reliable interconnects in highly integrated flexible electronics.
Graphical Abstract
Exosomes are small extracellular membrane vesicles released from endosomes of various cells and could be found in most body fluids. The main functions of exosomes have been recognized as important ...mediators of intercellular communication and as potential biomarkers of various disease states. This study investigated whether exogenous exosomes from mice with acetaminophen (APAP)-induced liver injury can damage the recipient hepatic cells or promote hepatotoxicity in mice. We observed that exogenous exosomes derived from APAP-exposed mice were internalized into the primary mouse hepatocytes or HepG2 hepatoma cells and significantly decreased the viability of these recipient cells. They also elevated mRNA transcripts and proteins associated with the cell death signaling pathways in primary hepatocytes or HepG2 cells via exosomes-to-cell communications. In addition, confocal microscopy of ex vivo liver section showed that exogenously added exosomes were accumulated in recipient hepatocytes. Furthermore, plasma reactive oxygen species and hepatic TNF-α/IL-1β production were elevated in APAP-exosomes recipient mice compared to control-exosomes recipient mice. The levels of apoptosis-related proteins such as phospho-JNK/JNK, Bax, and cleaved caspase-3 were increased in mouse liver received APAP-exosomes. These results demonstrate that exogenous exosomes from APAP-exposed mice with acute liver injury are functional and stimulate cell death or toxicity of the recipient hepatocytes and mice.
T cell‐derived small extracellular vesicles (sEVs) exhibit anti‐cancer effects. However, their anti‐cancer potential should be reinforced to enhance clinical applicability. Herein, we generated ...interleukin‐2‐tethered sEVs (IL2‐sEVs) from engineered Jurkat T cells expressing IL2 at the plasma membrane via a flexible linker to induce an autocrine effect. IL2‐sEVs increased the anti‐cancer ability of CD8+ T cells without affecting regulatory T (Treg) cells and down‐regulated cellular and exosomal PD‐L1 expression in melanoma cells, causing their increased sensitivity to CD8+ T cell‐mediated cytotoxicity. Its effect on CD8+ T and melanoma cells was mediated by several IL2‐sEV‐resident microRNAs (miRNAs), whose expressions were upregulated by the autocrine effects of IL2. Among the miRNAs, miR‐181a‐3p and miR‐223‐3p notably reduced the PD‐L1 protein levels in melanoma cells. Interestingly, miR‐181a‐3p increased the activity of CD8+ T cells while suppressing Treg cell activity. IL2‐sEVs inhibited tumour progression in melanoma‐bearing immunocompetent mice, but not in immunodeficient mice. The combination of IL2‐sEVs and existing anti‐cancer drugs significantly improved anti‐cancer efficacy by decreasing PD‐L1 expression in vivo. Thus, IL2‐sEVs are potential cancer immunotherapeutic agents that regulate both immune and cancer cells by reprogramming miRNA levels.
The evolution of damage due to mechanical fatigue in thin metal films on flexible substrates was investigated by in situ electrical resistance measurements. A tensile fatigue load was applied to the ...metal films by subjecting a single edge of the curved samples to repeated linear motion. The change in the resistance of the metal films was monitored in situ. Upon the nucleation of a fatigue-induced crack, the electrical resistance of the metal film began to increase. The resistance subsequently continued to increase with crack propagation. Therefore, in situ electrical resistance measurements can be used to identify the fatigue-induced crack nucleation cycle. The number of cycles required for crack nucleation decreased with the increase in the fatigue-stressed area of the samples. This behavior is attributed to an increase in the crack nucleation probability with increasing sample size. The amount of strain applied also modified the number of cycles required for crack nucleation according to the Coffin–Manson relationship. The increase in the electrical resistivity with respect to the number of fatigue cycles can be accurately predicted when the fatigue cycle is normalized by the nucleation cycle. This indicates that the fatigue lifetime is determined by crack nucleation and not by crack propagation.
To investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD).
A total of 190 women with NMOSD were enrolled from 7 referral hospitals in 4 countries. We ...reviewed medical records and used a structured questionnaire to investigate gravidity, parity, and the number of relapses during the 2 years before pregnancy, during each trimester of pregnancy, during the first and second trimesters after delivery, and for 6 months thereafter. The annualized relapse rate (ARR) was calculated for each period.
Of the 190 women with NMOSD, 40 patients experienced 54 informative pregnancies, and all of them were seropositive for aquaporin-4 antibody. Fourteen patients developed the first symptoms of NMOSD either during the pregnancy (3 patients) or within a year after delivery or abortion (8 and 3 patients, respectively). Twenty-six patients experienced 40 pregnancies after the onset of NMOSD (26 deliveries and 14 abortions 1 spontaneous and 13 elective). There was one preterm delivery with birth defects and no stillbirths. The ARR during pregnancy did not differ from that before pregnancy, but it increased significantly during the first and second trimesters after delivery (5.3 and 3.7 times, respectively). Moreover, 77% of the deliveries were associated with postpartum relapses.
The significantly increased relapse rate and numerous cases of NMOSD onset after pregnancy suggest that delivery adversely affects the course of NMOSD. Prospective studies are needed to confirm our findings.
Extracellular vesicles (EVs) have been implicated in the development and progression of hematological malignancies. We thus examined serum samples from patients with systemic mastocytosis (SM) and ...found EVs with a mast cell signature including the presence of tryptase, FcεRI, MRGX2, and KIT. The concentration of these EVs correlated with parameters of disease including levels of serum tryptase, IL-6, and alkaline phosphatase and physical findings including hepatosplenomegaly. Given reports that EVs from one cell type may influence another cell’s behavior, we asked whether SM-EVs might affect hepatic stellate cells (HSCs), based on the abnormal liver pathology associated with mastocytosis. We found that KIT was transferred from SM-EVs into an HSC line eliciting proliferation, cytokine production, and differentiation, processes that have been associated with liver pathology. These effects were reduced by KIT inhibition or neutralization and recapitulated by enforced expression of KIT or constitutively active D816V-KIT, a gain-of-function variant associated with SM. Furthermore, HSCs in liver from mice injected with SM-EVs had increased expression of α-SMA and human KIT, particularly around portal areas, compared with mice injected with EVs from normal individuals, suggesting that SM-EVs can also initiate HSC activation in vivo. Our data are thus consistent with the conclusion that SM-EVs have the potential to influence cells outside the hematological compartment and that therapeutic approaches for treatment of SM may be effective in part through inhibition of effects of EVs on target tissues, findings important both to understanding complex disease pathology and in developing interventional agents for the treatment of hematologic diseases.
This study reports the effects of post-annealing on the electrical reliability of a NiAl/SiO2 interconnect structure for potential use as post-Cu interconnect. Our materials characterization using ...transmission electron microscopy and secondary ion mass spectrometry discloses that annealing at elevated temperatures induced the diffusion of Al into SiO2: Al, for a 400 °C-annealed sample, diffused only to a few nanometers from the interface, forming a thin aluminum-rich oxide layer, while samples annealed at higher temperatures show an extensive Al diffusion and interfacial reactions. In a voltage ramp dielectric breakdown test, the 400 °C annealed sample shows the lowest breakdown voltage, possibly, due to the aluminum-rich oxide layer serving as a self-forming barrier while the samples annealed at higher temperatures display a drastic reliability degradation with the annealing temperature increasing. In addition, analyzing data acquired from time-dependent dielectric breakdown tests using the E-model helps us predict the lifetime of the 400 °C sample to be longer than 105 h at 1 MV/cm.
The authors used a micromirror under a microscope with an indocyanine green (ICG) imaging system to assess clipped aneurysms and the blood flow in hidden regions during aneurysm surgery. This study ...then investigated the usefulness of such mirroring with ICG angiography (MICGA).
A micromirror was used during aneurysm surgery on 25 patients, and MICGA was performed on 10 of these 25 patients to inspect the hidden region after clipping. The mirrored aneurysms were located at the posterior communicating artery (n = 4), anterior choroidal artery (n = 4), proximal A1 segment (n = 1), and middle cerebral artery (n = 1).
In all 10 cases, MICGA was successful in assessing the state of the clipped aneurysm and blood flow of the vessels in the hidden region after clipping. This led to clip repositioning in 3 patients (30.0%) because of incomplete clipping of a hidden aneurysm or occlusion of a hidden perforator. Complete occlusion of the aneurysm was achieved in 8 patients, and the other 2 patients showed near complete occlusion because of an intentional residual aneurysm to avoid a small vessel adherent to the posterior wall of the aneurysm base.
MICGA can provide useful and reliable information on the state of a clipped aneurysm and the blood flow of associated vessels and perforators in a hidden region after aneurysm clipping.
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