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Due to the small size and low speed of existing vibrating mechanical equipment, the vibrating bodies are often considered rigid, and structural vibrations are neglected. However, with the development of vibrating machinery towards large-scale and high-speed directions, it is difficult to avoid structural vibration. Despite this, there is a lack of investigation into the mechanism of the influence of structural vibration on vibrating machinery. This paper presents a study on the vibration performance and stability behavior of a thin rectangular plate vibration system under three vibrator excitations, considering self-synchronization and the Sommerfeld effect. The theoretical model used is a simple thin rectangular plate structure. Firstly, the modal shape and frequency equations of the thin rectangular plate are obtained using the semi-inverse method. Subsequently, the differential equations of the motion of the system are derived. Moreover, the conditions for synchronization and stability of the vibration system are determined using the average perturbation method. The theoretical results are then compared with simulation and experimental results to verify their correctness. Finally, the effects of unbalance masses and installation positions of vibrators on self-synchronization behavior, the Sommerfeld effect, and the dynamic response of the vibration system are discussed.

Fungal keratitis is challenging to diagnose and treat and remains a significant cause of blindness worldwide. The easiest and most common method of drug delivery for patients with fungal keratitis is eye drop administration. However, the therapeutic effect of traditional eye drops is unsatisfactory, largely due to the intrinsic nature of the ocular barriers, which limit drug absorption; the rapid decrease in the drug concentration caused by tears; and the side effects induced by the uncontrolled release of ocular drugs. Oxidative stress and inflammation are the main causes of corneal tissue necrosis in fungal keratitis, and reducing reactive oxygen species (ROS) and the inflammatory response are important goals in developing drugs for fungal keratitis. In the current study, we developed a ROS-responsive and controllable nanocarrier (GC-EB) that efficiently delivered a clinically used antifungal drug, voriconazole (VOR), to treat fungal keratitis. In vitro and in vivo results demonstrated that the developed GC-EB-VOR exhibited high penetration through corneal barriers, good retention in the cornea and controllable drug release under low concentrations of ROS. As a result, ROS were effectively depleted and the inflammatory response was inhibited; thus, GC-EB-VOR shows promising antifungal efficacy. This work may provide a new strategy for developing nanodrugs to improve the therapeutic effect of eye drop instillation on fungal keratitis and reduce the risk of blindness. We developed a ROS-responsive and controllable nanocarrier (GC-EB) that efficiently delivered a clinically used antifungal drug, voriconazole (VOR). GC-EB-VOR exhibited high penetration through corneal barriers, good retention in the cornea and controllable drug release under low concentrations of ROS. Mechanistically, the successful delivery and accumulation of GC-EB-VOR in the cornea followed by the inhibition of oxidative stress and of the inflammatory response contributed to the therapeutic effect of GC-EB-VOR against fungal keratitis.

ObjectivesWe recently identified microRNA-181a-5p (miR-181a-5p) as a critical mediator involved in the destruction of lumbar facet joint (FJ) cartilage. In this study, we tested if locked nucleic acid (LNA) miR-181a-5p antisense oligonucleotides (ASO) could be used as a therapeutic to limit articular cartilage degeneration.MethodsWe used a variety of experimental models consisting of both human samples and animal models of FJ and knee osteoarthritis (OA) to test the effects of LNA-miR-181a-5p ASO on articular cartilage degeneration. Histopathological analysis including immunohistochemistry and in situ hybridisation were used to detect key OA catabolic markers and microRNA, respectively. Apoptotic/cell death markers were evaluated by flow cytometry. qPCR and immunoblotting were applied to quantify gene and protein expression.ResultsmiR-181a-5p expression was increased in human FJ OA and knee OA cartilage as well as injury-induced FJ OA (rat) and trauma-induced knee OA (mouse) cartilage compared with control cartilage, correlating with classical OA catabolic markers in human, rat and mouse cartilage. We demonstrated that LNA-miR-181a-5p ASO in rat and mouse chondrocytes reduced the expression of cartilage catabolic and chondrocyte apoptotic/cell death markers in vitro. Treatment of OA-induced rat FJ or mouse knee joints with intra-articular injections of in vivo grade LNA-miR-181a-5p ASO attenuated cartilage destruction, and the expression of catabolic, hypertrophic, apoptotic/cell death and type II collagen breakdown markers. Finally, treatment of LNA-miR-181a-5p ASO in cultures of human knee OA chondrocytes (in vitro) and cartilage explants (ex vivo) further demonstrated its cartilage protective effects.ConclusionsOur data demonstrate, for the first time, that LNA-miR-181a-5p ASO exhibit cartilage-protective effects in FJ and knee OA.

The mechanisms regulating vascular smooth muscle cell (VSMC) phenotype switching and the critical signal modulation affecting the VSMCs remain controversial. Physical exercise acts as an effective drug in preventing elevated blood pressure and improving vascular function. This study was designed to explore the influence of aerobic exercise on the suppression of VSMC phenotype switching by balancing of the Akt, also known as PKB (protein kinase B) and mitogen-activated protein kinase (MAPK) signaling pathways. Spontaneously hypertensive rats (SHRs) and normotensive rats were subjected to exercise treatment before measuring the vascular morphological and structural performances. Exercise induced reverse expression of VSMC protein markers (α-SM-actin, calponin, and osteopontin (OPN)) in spontaneously hypertensive rats. It is noteworthy that the low expression of phosphorylated Akt significantly decreased the expression of VSMC contractile phenotype markers (α-SM-actin and calponin) and increased the expression of the VSMC synthetic phenotype marker (OPN). However, the MAPK signal pathway exerts an opposite effect. VSMCs and whole vessels were treated by inhibitors, namely the p-Akt inhibitor, p-ERK inhibitor, and p-p38 MAPK inhibitors. VSMC phenotype markers were reversed. It is important to note that a significant reverse regulatory relationship was observed between the expression levels of MAPK and the contractile markers in both normotensive and spontaneously hypertensive rats. We demonstrate that aerobic exercise regulates the VSMC phenotype switching by balancing the Akt and MAPK signaling pathways in SHRs.

The human DHRS4 gene cluster consists of DHRS4 and two immediately downstream homologous genes, DHRS4L2 and DHRS4L1 , generated by evolutionarily gene-duplication events. We previously demonstrated that a head-to-head natural antisense transcript (NAT) of DHRS4 , denoted DHRS4-AS1 , regulates all three genes of the DHRS4 gene cluster. However, it is puzzling that DHRS4L2 and DHRS4L1 did not evolve their own specific NATs to regulate themselves, as it seems both have retained sequences highly homologous to DHRS4-AS1 . In a search of the DHRS4-AS1 region for nearby enhancers, we identified an enhancer located 13.8 kb downstream of the DHRS4-AS1 transcriptional start site. We further showed, by using a chromosome conformation capture (3C) assay, that this enhancer is capable of physically interacting with the DHRS4-AS1 promoter through chromosomal looping. The enhancer produced an eRNA, termed AS1eRNA, that enhanced DHRS4-AS1 transcription by mediating the spatial interactions of the enhancer and DHRS4-AS1 promoter in cooperation with RNA polymerase II and p300/CBP. Moreover, the distributions of activating acetyl-H3 and H3K4me3 modifications were found to be greater at the DHRS4-AS1 promoter than at the homologous duplicated regions. We propose that AS1eRNA-driven DNA looping and activating histone modifications promote the expression of DHRS4-AS1 to economically control the DHRS4 gene cluster.

Immune rejection and side effects of long‐term administration of immunosuppressants are the two major obstacles to allograft acceptance and tolerance. The immunosuppressive extracellular vesicles (EVs)‐based approach has been proven to be effective in treating autoimmune/inflammatory disorders. Herein, the anti‐rejection advantage of exosomes (Rapa‐Exo) from rapamycin‐conditioned myeloid‐derived suppressor cells (MDSCs) over exosomes (Exo‐Nor) from the untreated MDSCs is shown. The exosomal small RNA sequencing and loss‐of‐function assays reveal that the anti‐rejection effect of Rapa‐Exo functionally relies on miR‐181d‐5p. Through target prediction and double‐luciferase reporter assay, Kruppel‐like factor (KLF) 6 is identified as a direct target of miR‐181d‐5p. Finally, KLF6 knockdown markedly resolves inflammation and prolongs the survival of corneal allografts. Taken together, these findings support that Rapa‐Exo executes an anti‐rejection effect, highlighting the immunosuppressive EVs‐based treatment as a promising approach in organ transplantation. This study has revealed that the exosome released from rapamycin‐conditioned MDSCs (Rapa‐Exo) significantly prolongs the survival of corneal allografts. Mechanistically, the identified exosomal miR‐181d‐5p directly targets KLF6, which then results in the lowered expression of proinflammatory cytokines, eventually contributing to the resolution of inflammation and the great improvement of corneal allograft rejection.

Accumulating evidence has shown that epigenetic regulation is involved in hypertension and aging. L-type voltage-gated Ca2+ channels (LTCCs), the dominant channels in vascular myocytes, greatly contribute to arteriole contraction and blood pressure (BP) control. We investigated the dynamic changes and epigenetic regulation of LTCC in the mesenteric arteries of aging hypertensive rats. LTCC function was evaluated by using microvascular rings and whole-cell patch-clamp in the mesenteric arteries of male Wistar-Kyoto rats and spontaneously hypertensive rats at established hypertension (3 month old) and an aging stage (16 month old), respectively. The expression of the LTCC α1C subunit was determined in the rat mesenteric microcirculation. The expression of miR-328, which targets α1C mRNA, and the DNA methylation status at the promoter region of the α1C gene (CACNA1C) were also determined. In vitro experiments were performed to assess α1C expression after transfection of the miR-328 mimic into cultured vascular smooth muscle cells (VSMCs). The results showed that hypertension superimposed with aging aggravated BP and vascular remodeling. Both LTCC function and expression were significantly increased in hypertensive arteries and downregulated with aging. miR-328 expression was inhibited in hypertension, but increased with aging. There was no significant difference in the mean DNA methylation of CACNA1C among groups, whereas methylation was enhanced in the hypertensive group at specific sites on a CpG island located upstream of the gene promoter. Overexpression of miR-328 inhibited the α1C level of cultured VSMCs within 48 h. The results of the present study indicate that the dysfunction of LTCCs may exert an epigenetic influence at both pre- and post-transcriptional levels during hypertension pathogenesis and aging progression. miR-328 negatively regulated LTCC expression in both aging and hypertension.

Background To investigate the short-term effects of blood donation on the morphology and blood flow of the retina and choroid in healthy people using optical coherence tomography angiography (OCTA). Methods Twenty-eight healthy blood donors (56 eyes) who participated in the 200 ml voluntary blood donation between March 2, 2021 and January 20, 2022 were included. The best corrected visual acuity (BCVA), systolic (SBP) and diastolic blood pressure (DBP), intraocular pressure (IOP), subfoveal choroid thickness (SFCT), retinal thickness (RT), retinal superficial vascular density (SVD), deep vascular density (DVD) and foveal avascular were a (FAZ) were measured and statistically analysed 10 min before, 30 min and 24 h after the blood donation. Results The 200 ml blood donation could cause significant IOP reduction at 24 h ( P  = 0.006), which was negatively correlated with SBP ( r = -0.268, P = 0.046), while SBP, DBP, or ocular perfusion pressure were not affected (> 0.05). Moreover, no significant difference existed in the OCT and OCTA indexes, including SFCT, RT, SVD, DVD, and FAZ, before and after the 200 ml blood donation ( P  > 0.05). The visual acuity was not affected either ( P  > 0.05). Conclusions The 200 ml blood donation was noted to be associated with statistically significant IOP reduction at 24 h, while SBP, DBP, or OPP was not affected. The blood flow of the retina and choroid or the visual acuity did not change significantly after the blood donation. Larger studies with different volumes of blood donation were needed to further analysis the effect of blood donation on ocular parameters.

The serotonin 5-HT 2 C receptor (5-HT 2 C R) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT 2 C R densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT 2 C R. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT 2 C R and high selectivity over 5-HT 2 A and 5-HT 2 B . [ 11 C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one ( 6 ) and [ 11 C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one ( 9 ) were synthesized in high radiochemical yield of 37–44% [ n = 10, decay corrected from end of ( 11 C)CH 3 I synthesis] with high radiochemical purity via O -methylation with [ 11 C]CH 3 I, respectively. MicroPET imaging studies in male rats with or without 5-HT 2 C antagonist SB-242084 showed that [ 11 C] 6 and [ 11 C] 9 display specific bindings to 5-HT 2 C R in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [ 11 C] 6 and [ 11 C] 9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [ 11 C] 6 , and 3.7 and 2.7, respectively, for [ 11 C] 9 , which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [ 11 C] 6 and [ 11 C] 9 for further study as radioligands for in vivo quantitation of 5-HT 2 C sites by PET.

This study was designed to investigate the effects of exogenous androgen and resistance exercise on skeletal muscle hypertrophy and the role of the mammalian target of rapamycin (mTOR) signalling during the process. A total of 24 male Sprague-Dawley rats were randomly assigned to sham operation and dihydrotestosterone (DHT) implantation groups with subgroups subjected to sedentary conditions or resistance exercise (SHAM+SED, SHAM+EX, DHT+SED, and DHT+EX). The experimental procedure lasted for 10 days. The mRNA expression of androgen receptor (AR) and insulin-like growth factor I (IGF-I), the expression of myosin heavy chain (MHC), as well as the phosphorylation statuses of AR, mTOR, p70 ribosomal S6 kinase (p70 ), and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) were determined in the white gastrocnemius muscle. The cross sectional area and wet mass of the muscle were also measured. The cross sectional area and MHC expression were significantly higher in SHAM+EX, DHT+SED, and DHT+EX than in SHAM+SED. There was no significant difference among groups in muscle mass. The mRNA expression of AR and IGF-I and the phosphorylation of mTOR, p70 , and 4EBP1 were significantly increased in DHT+SED and SHAM+EX and were significantly enhanced in DHT+EX compared with either DHT or exercise alone. These data show that DHT causes hypertrophy in skeletal muscle and that exercise has a synergistic effect on DHT-induced hypertrophy. Exercise enhances androgen-induced rapid anabolic action, which involves activation of the mTOR pathway.