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Mutations in nuclear genes regulating mitochondrial DNA (mtDNA) replication are associated with mtDNA depletion syndromes. Using whole-genome sequencing, we identified a heterozygous mutation (c.272G>A:p.Arg91Gln) in single-stranded DNA-binding protein 1 (SSBP1), a crucial protein involved in mtDNA replisome. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy. This mutation impeded multimer formation and DNA-binding affinity, leading to reduced efficiency of mtDNA replication, altered mitochondria dynamics, and compromised mitochondrial function. To correct this mutation, we tested two adenine base editor (ABE) variants on patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), showed higher editing efficacy (≤30%) and enhanced mitochondrial replication and function, despite off-target editing frequencies; however, risks from bystander editing were limited due to silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (≤10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. Taken together, base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated with SSBP1 mutations.
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Intravitreal injection of biodegradable implant drug carriers shows promise in reducing the injection frequency for neovascular retinal diseases. However, current intravitreal ocular devices have limitations in adjusting drug release rates for individual patients, thereby affecting treatment effectiveness. Accordingly, we developed mesoporous silica nanoparticles (MSNs) featuring a surface that reverse its charge in response to reactive oxygen species (ROS) for efficient delivery of humanin peptide (HN) to retinal epithelial cells (ARPE-19). The MSN core, designed with a pore size of 2.8 nm, ensures a high HN loading capacity 64.4% (w/w). We fine-tuned the external surface of the MSNs by incorporating 20% Acetyl-L-arginine (Ar) to create a partial positive charge, while 80% conjugated thioketal (TK) methoxy polyethylene glycol (mPEG) act as ROS gatekeeper. Ex vivo experiments using bovine eyes revealed the immobilization of Ar-MSNs-TK-PEG (mean zeta potential: 2 mV) in the negatively charged vitreous. However, oxidative stress reversed the surface charge to -25 mV by mPEG loss, facilitating the diffusion of the nanoparticles impeded with HN. In vitro studies showed that ARPE-19 cells effectively internalize HN-loaded Ar-MSNs-TK, subsequently releasing the peptide, which offered protection against oxidative stress-induced apoptosis, as evidenced by reduced TUNEL and caspase3 activation. The inhibition of retinal neovascularization was further validated in an in vivo oxygen-induced retinopathy (OIR) mouse model.
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BACKGROUND: A drug-eluting stent (DES) is a highly beneficial medical device used to widen or unblock narrowed blood vessels. However, the drugs released by the implantation of DES may hinder the re-endothelialization process, increasing the risk of late thrombosis. We have developed a tacrolimus-eluting stent (TES) that as acts as a potent antiproliferative and immunosuppressive agent, enhancing endothelial regeneration. In addition, we assessed the safety and efficacy of TES through both in vitro and in vivo tests. METHODS: Tacrolimus and Poly(lactic-co-glycolic acid) (PLGA) were applied to the metal stent using electrospinning equipment. The surface morphology of the stent was examined before and after coating using a scanning electron microscope (SEM) and energy dispersive X-rays (EDX). The drug release test was conducted through high-performance liquid chromatography (HPLC). Cell proliferation and migration assays were performed using smooth muscle cells (SMC). The stent was then inserted into the porcine coronary artery and monitored for a duration of 4 weeks. RESULTS: SEM analysis confirmed that the coating surface was uniform. Furthermore, EDX analysis showed that the surface was coated with both polymer and drug components. The HPCL analysis of TCL at a wavelength of 215 nm revealed that the drug was continuously released over a period of 4 weeks. Smooth muscle cell migration was significantly decreased in the tacrolimus group (54.1% ± 11.90%) compared to the non-treated group (90.1% ± 4.86%). In animal experiments, the stenosis rate was significantly reduced in the TES group (29.6% ± 7.93%) compared to the bare metal stent group (41.3% ± 10.18%). Additionally, the fibrin score was found to be lower in the TES group compared to the group treated with a sirolimus-eluting stent (SES). CONCLUSION: Similar to SES, TES reduces neointimal proliferation in a porcine coronary artery model, specifically decreasing the fibrins score. Therefore, tacrolimus could be considered a promising drug for reducing restenosis and thrombosis.
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Proliferação de Células , Vasos Coronários , Stents Farmacológicos , Tacrolimo , Animais , Tacrolimo/farmacologia , Vasos Coronários/efeitos dos fármacos , Suínos , Proliferação de Células/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/citologia , Movimento Celular/efeitos dos fármacosRESUMO
Recent advances in deep learning have led to a surge in computer vision research, including the recognition and classification of human behavior in video data. However, most studies have focused on recognizing individual behaviors, whereas recognizing crowd behavior remains a complex problem because of the large number of interactions and similar behaviors among individuals or crowds in video surveillance systems. To solve this problem, we propose a three-dimensional atrous inception module (3D-AIM) network, which is a crowd behavior classification model that uses atrous convolution to explore interactions between individuals or crowds. The 3D-AIM network is a 3D convolutional neural network that can use receptive fields of various sizes to effectively identify specific features that determine crowd behavior. To further improve the accuracy of the 3D-AIM network, we introduced a new loss function called the separation loss function. This loss function focuses the 3D-AIM network more on the features that distinguish one type of crowd behavior from another, thereby enabling a more precise classification. Finally, we demonstrate that the proposed model outperforms existing human behavior classification models in terms of accurately classifying crowd behaviors. These results suggest that the 3D-AIM network with a separation loss function can be valuable for understanding complex crowd behavior in video surveillance systems.
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Diabetic retinopathy (DR) is associated with ocular inflammation leading to retinal barrier breakdown, vascular leakage, macular edema, and vision loss. DR is not only a microvascular disease but also involves retinal neurodegeneration, demonstrating that pathological changes associated with neuroinflammation precede microvascular injury in early DR. Macrophage activation plays a central role in neuroinflammation. During DR, the inflammatory response depends on the polarization of retinal macrophages, triggering pro-inflammatory (M1) or anti-inflammatory (M2) activity. This study aimed to determine the role of macrophages in vascular leakage through the tight junction complexes of retinal pigment epithelium, which is the outer blood-retinal barrier (BRB). Furthermore, we aimed to assess whether interleukin-10 (IL-10), a representative M2-inducer, can decrease inflammatory macrophages and alleviate outer-BRB disruption. We found that modulation of macrophage polarization affects the structural and functional integrity of ARPE-19 cells in a co-culture system under high-glucose conditions. Furthermore, we demonstrated that intravitreal IL-10 injection induces an increase in the ratio of anti-inflammatory macrophages and effectively suppresses outer-BRB disruption and vascular leakage in a mouse model of early-stage streptozotocin-induced diabetes. Our results suggest that modulation of macrophage polarization by IL-10 administration during early-stage DR has a promising protective effect against outer-BRB disruption and vascular leakage. This finding provides valuable insights for early intervention in DR.
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Barreira Hematorretiniana , Diabetes Mellitus Experimental , Retinopatia Diabética , Interleucina-10 , Macrófagos , Animais , Humanos , Masculino , Camundongos , Barreira Hematorretiniana/metabolismo , Barreira Hematorretiniana/patologia , Polaridade Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Interleucina-10/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , EstreptozocinaRESUMO
The occurrence frequency of East Asia's extreme hot day in boreal spring has increased since 1979. Using observational data and a Linear baroclinic model experiment, our study suggests that the occurrence of hot day is mainly due to anomalous high pressure over East Asia associated with a horizontal stationary wave train originating from a positive phase of the North Atlantic Tripole (NAT) sea surface temperature (SST) in spring. The effect of a positive phase of the NAT SST is evident in the 2000s, apparently associated with the linear trend of the North Atlantic SST like a positive phase of the NAT SST. Before 2000s, in contrast, SST forcing in the Indian Ocean and eastern tropical Pacific, which is associated with a negative phase of the NAT SST, may contribute to induce the East Asian hot days through atmospheric teleconnections. This implies that the relationship between a positive phase of the NAT SST and the occurrence of hot days in East Asia has been changed during the 2000s.
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Aberrant neovascularization is the most common feature in retinopathy of prematurity (ROP), which leads to the retinal detachment and visual defects in neonates with a low gestational age eventually. Understanding the regulation of inappropriate angiogenic signaling benefits individuals at-risk. Recently, neural activity originating from the specific neural activity has been considered to contribute to retinal angiogenesis. Here, we explored the impact of cone cell dysfunction on oxygen-induced retinopathy (OIR), a mouse model commonly employed to understand retinal diseases associated with abnormal blood vessel growth, using the Gnat2cpfl3 (cone photoreceptor function loss-3) strain of mice (regardless of the sex), which is known for its inherent cone cell dysfunction. We found that the retinal avascular area, hypoxic area, and neovascular area were significantly attenuated in Gnat2cpfl3 OIR mice compared to those in C57BL/6 OIR mice. Moreover, the HIF-1α/VEGF axis was also reduced in Gnat2cpfl3 OIR mice. Collectively, our results indicated that cone cell dysfunction, as observed in Gnat2cpfl3 OIR mice, leads to attenuated retinal neovascularization. This finding suggests that retinal neural activity may precede and potentially influence the onset of pathological neovascularization.
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Oftalmopatias , Doenças Retinianas , Neovascularização Retiniana , Animais , Camundongos , Camundongos Endogâmicos C57BL , Células Fotorreceptoras Retinianas Cones , Oxigênio/toxicidade , Neovascularização Patológica , Modelos Animais de DoençasRESUMO
Severe PM10 (particulate matter with a diameter of <10 µm) events in South Korea are known to be caused by stable atmospheric circulation conditions related to high-pressure anomalies in the upper troposphere. However, research on why these atmospheric circulation patterns occur is unknown. In this study, we propose new large-scale teleconnection pathways that cause severe PM10 events during the midwinter in South Korea. This study investigated instances of extremely high (EH)-PM10 in South Korea during mid-winter and examined the corresponding atmospheric teleconnection patterns to identify the factors contributing to EH-PM10 events. K-means clustering analysis revealed that EH-PM10 instances were associated with two large-scale teleconnection patterns. Cluster 1 exhibited a wave train pattern originating in the North Atlantic that developed from Eurasia to the Korean Peninsula. Cluster 2 was associated with a wave-like teleconnection pattern from the Barents-Kara Sea to the Korean Peninsula. The Rossby waves, triggered by the North Atlantic and the Arctic, propagated and weakened the surface pressure system. This led to a high-pressure anomaly over the Korean Peninsula, reducing atmospheric ventilation and causing a rapid increase in PM10 concentration within a few days. Furthermore, an experiment involving a linear baroclinic model established that atmospheric forcing in upstream regions has the potential to induce large-scale atmospheric teleconnection patterns, resulting in EH-PM10 cases in South Korea. These findings emphasize the ventilation effect and transport of PM10 concentrations modulated by two large-scale teleconnection patterns originating from the Arctic and North Atlantic, leading to EH-PM10 events in South Korea. Understanding this combined phenomenon may assist in the implementation of emission reduction measures based on the results of short-term forecasts of severe PM10 events.
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Transplantation of mitochondria derived from mesenchymal stem cells (MSCs) has emerged as a new treatment method to improve mitochondrial dysfunction and alleviate cell impairment. Interest in using extrinsic mitochondrial transplantation as a therapeutic approach has been increasing because it has been confirmed to be effective in treating various diseases related to mitochondrial dysfunction, including ischemia, cardiovascular disease, and toxic damage. To support this application, we conducted an experiment to deliver external mitochondria to retinal pigment epithelial cells treated with oligomeric amyloid-beta (oAß). Externally delivered amyloid-beta internalizes into cells and interacts with mitochondria, resulting in mitochondrial dysfunction and intracellular damage, including increased reactive oxygen species and destruction of tight junction proteins. Externally delivered mitochondria were confirmed to alleviate mitochondrial dysfunction and tight junction protein disruption as well as improve internalized oAß clearance. These results were also confirmed in a mouse model in vivo. Overall, these findings indicate that the transfer of external mitochondria isolated from MSCs has potential as a new treatment method for age-related macular degeneration, which involves oAß-induced changes to the retinal pigment epithelium.
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Doenças Mitocondriais , Epitélio Pigmentado da Retina , Camundongos , Animais , Epitélio Pigmentado da Retina/metabolismo , Proteínas de Junções Íntimas/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismoRESUMO
When medical genetic syndromes are influenced by allelic hierarchies, mutant alleles have distinct effects on clinical phenotypes. Genotype-phenotype correlations for Usher syndrome type 2 (USH2) suggest that the USH2A gene exhibits an allelic hierarchy. Here, we analyzed the phenotypes and genotypes of 16 South Korean patients with USH2A biallelic variants to investigate an allelic hierarchy from audiological and ophthalmological perspectives. Using whole exome and genome sequencing, 18 mutant alleles, including 4 novel alleles, were identified and implicated in USH2A-related disorders. Truncated alleles were linked to earlier onset of subjective hearing loss and more severe thresholds; biallelic truncated alleles had more severe effects. Truncated alleles were also associated with retinal structure degeneration and severe functional deterioration. However, younger patients (aged < 16 years) did not exhibit overt retinitis pigmentosa even when they had biallelic truncated alleles, suggesting that USH2A-related USH2 can mimic nonsyndromic hearing loss. For truncated alleles, there was a clear correlation between mean hearing threshold and 30-Hz flicker electroretinography implicit time. This study provides the first evidence of an USH2A-related allelic hierarchy among South Korean patients; our data yield valuable insights concerning the natural courses of clinical phenotypes and how genotype-based therapies may be used.
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Síndromes de Usher , Humanos , Síndromes de Usher/genética , Alelos , Fenótipo , República da Coreia , Proteínas da Matriz Extracelular/genética , MutaçãoRESUMO
Accumulation of pathogenic amyloid-ß disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-ß, the autophagy-lysosome pathway plays the crucial role. In this context, mammalian target of rapamycin (mTOR) inhibits the process of autophagy and lysosomal degradation, acting as a potential therapeutic target for age-associated disorders. However, efficacy of targeting mTOR to treat age-related macular degeneration remains largely elusive. Here, we validated the therapeutic efficacy of the mTOR inhibitors, Torin and PP242, in clearing amyloid-ß by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-ß with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-ß oligomers induced autophagy-lysosome pathway impairment accompanied by the accumulation of p62 and decreased lysosomal activity in RPE cells. However, Torin and PP242 treatment restored the lysosomal activity via activation of LAMP2 and facilitated the clearance of amyloid-ß in vitro and in vivo. Furthermore, clearance of amyloid-ß by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration.
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Degeneração Macular , Epitélio Pigmentado da Retina , Camundongos , Animais , Epitélio Pigmentado da Retina/metabolismo , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Peptídeos beta-Amiloides/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Degeneração Macular/metabolismo , Lisossomos/metabolismo , Autofagia/fisiologia , MamíferosRESUMO
The common marmoset (Callithrix jacchus) is considered an ideal species for developing genetically modified nonhuman primates (NHP) models of human disease, particularly eye disease. They have been proposed as a suitable bridge between rodents and other NHP models due to their similar ophthalmological features to humans. Prenatal ultrasonography is an accurate and reliable diagnostic tool for monitoring fetal development and congenital malformation. We monitored fetal eye growth and development using noninvasive ultrasonography in 40 heads of clinically normal fetuses during pregnancy to establish the criteria for studying congenital eye anomalies in marmosets. The coronal, sagittal, and transverse planes were useful to identify the facial structures for any associated abnormalities. For orbital measurements, biorbital distance (BOD), ocular diameter (OD), interorbital distance (IOD), and total axial length (TAL) were measured in the transverse plane and carefully identified for intraorbital structures. As a result, high correlations were observed between delivery-based gestational age (GA) and biparietal diameter (BPD), BOD, OD, and TAL. The correlation assessments based on BOD provide more reliable results for monitoring eye growth and development in normal marmosets than any other parameters since BOD has the highest correlation coefficient according to both delivery-based GA and BPD among ocular measurements. In conclusion, orbital measurements by prenatal ultrasonography provide reliable indicators of marmoset eye growth, and it could offer early diagnostic criteria to facilitate the development of eye disease models and novel therapies such as genome editing technologies in marmosets.
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Marmosets have emerged as a valuable primate model in ophthalmic research due to their similarity to the human visual system and their potential for generating transgenic models to advance the development of therapies. In this study, we isolated and cultured primary retinal pigment epithelium (RPE) cells from marmosets to investigate the mechanisms underlying RPE dysfunction in aging and age-related macular degeneration (AMD). We confirmed that our culture conditions and materials supported the formation of RPE monolayers with functional tight junctions that closely resembled the in vivo RPE. Since serum has been shown to induce epithelial-mesenchymal transition (EMT) in RPE cells, we compared the effects of fetal bovine serum (FBS) with serum-free supplements B27 on transepithelial electrical resistance (TER), cell proliferation, and morphological characteristics. Additionally, we assessed the age-related morphological changes of in vivo and primary RPE cells. Our results indicate that primary marmoset RPE cells exhibit in vivo-like characteristics, while cells obtained from an older donor show evidence of aging, including a failure to form a polarized monolayer, low TER, and delayed cell cycle. In conclusion, our primary marmoset RPE cells provide a reliable in vitro model for developing novel therapeutics for visual-threatening disorders such as AMD, which can be used before animal experiments using marmosets.
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Callithrix , Degeneração Macular , Animais , Humanos , Epitélio Pigmentado da Retina/metabolismo , Células Cultivadas , Degeneração Macular/metabolismo , Células Epiteliais/metabolismo , Pigmentos da Retina/metabolismoRESUMO
Context: Circulating adipokines and ghrelin affect bone remodeling by regulating the activation and differentiation of osteoblasts and osteoclasts. Although the correlation between adipokines, ghrelin, and bone mineral density (BMD) has been studied over the decades, its correlations are still controversial. Accordingly, an updated meta-analysis with new findings is needed. Objective: This study aimed to explore the impact of serum adipokine and ghrelin levels on BMD and osteoporotic fractures through a meta-analysis. Data sources: Studies published till October 2020 in Medline, Embase, and the Cochrane Library were reviewed. Study selection: We included studies that measured at least one serum adipokine level and BMD or fracture risk in healthy individuals. We excluded studies with one or more of the following: patients less than 18 years old, patients with comorbidities, who had undergone metabolic treatment, obese patients, patients with high physical activities, and a study that did not distinguish sex or menopausal status. Data extraction: We extracted the data that include the correlation coefficient between adipokines (leptin, adiponectin, and resistin) and ghrelin and BMD, fracture risk by osteoporotic status from eligible studies. Data synthesis: A meta-analysis of the pooled correlations between adipokines and BMD was performed, demonstrating that the correlation between leptin and BMD was prominent in postmenopausal women. In most cases, adiponectin levels were inversely correlated with BMD. A meta-analysis was conducted by pooling the mean differences in adipokine levels according to the osteoporotic status. In postmenopausal women, significantly lower leptin (SMD = -0.88) and higher adiponectin (SMD = 0.94) levels were seen in the osteoporosis group than in the control group. By predicting fracture risk, higher leptin levels were associated with lower fracture risk (HR = 0.68), whereas higher adiponectin levels were associated with an increased fracture risk in men (HR = 1.94) and incident vertebral fracture in postmenopausal women (HR = 1.18). Conclusions: Serum adipokines levels can utilize to predict osteoporotic status and fracture risk of patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021224855, identifier CRD42021224855.
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Densidade Óssea , Fraturas por Osteoporose , Masculino , Humanos , Feminino , Adolescente , Densidade Óssea/fisiologia , Leptina , Adipocinas , Adiponectina , Grelina , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologiaRESUMO
Degenerative changes of the retinal pigment epithelium (RPE) triggered by transforming growth factor-ß2 (TGF-ß2) and oxidative stress play a critical role in the progression of age-related macular degeneration (AMD). The expression of α-klotho, an antiaging protein, declines with age, increasing the risk factors for age-related diseases. Here, we investigated the protective effects of soluble α-klotho on TGF-ß2-induced RPE degeneration. The morphological changes induced by TGF-ß2, including epithelial-mesenchymal transition (EMT), were attenuated in the mouse RPE by the intravitreal injection (IVT) of α-klotho. In ARPE19 cells, EMT and morphological alterations by TGF-ß2 were attenuated by co-incubation with α-klotho. TGF-ß2 decreased miR-200a accompanied by zinc finger e-box binding homeobox1 (ZEB1) upregulation and EMT, all of which were prevented by α-klotho co-treatment. Inhibitor of miR-200a mimicked TGF-ß2-induced morphological changes, which were recovered by ZEP1 silencing, but not by α-klotho, implying the upstream regulation of α-klotho on miR-200a-ZEP1-EMT axis. α-Klotho inhibited receptor binding of TGF-ß2, Smad2/3 phosphorylation, extracellular signal-regulated protein kinase 1/2 (ERK1/2)-a mechanistic target of rapamycin (mTOR) activation and oxidative stress via NADPH oxidase 4 (NOX4) upregulation. Furthermore, α-klotho recovered the TGF-ß2-induced mitochondrial activation and superoxide generation. Interestingly, TGF-ß2 upregulated α-klotho expression in the RPE cells, and genetic suppression of endogenous α-klotho aggravated TGF-ß2-induced oxidative stress and EMT. Lastly, α-klotho abrogated senescence-associated signaling molecules and phenotypes induced by long-term incubation with TGF-ß2. Hence, our findings indicate that the antiaging α-klotho plays a protective role against EMT and degeneration of the RPE, demonstrating the therapeutic potential for age-related retinal diseases, including the dry type of AMD.
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Proteínas Klotho , MicroRNAs , Epitélio Pigmentado da Retina , Animais , Camundongos , Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta2/metabolismo , Proteínas Klotho/metabolismoRESUMO
Phosphatidylinositol 3-phosphate (PI3P) is a signaling phospholipid that play a key role in endomembrane trafficking, specifically autophagy and endosomal trafficking. However, the mechanisms underlying the contribution of PI3P downstream effectors to plant autophagy remain unknown. Known PI3P effectors for autophagy in Arabidopsis thaliana include ATG18A (Autophagy-related 18A) and FYVE2 (Fab1p, YOTB, Vac1p, and EEA1 2), which are implicated in autophagosome biogenesis. Here, we report that FYVE3, a paralog of plant-specific FYVE2, plays a role in FYVE2-dependent autophagy. Using yeast two-hybrid and bimolecular fluorescence complementation assays, we determined that the FYVE3 protein was associated with autophagic machinery containing ATG18A and FYVE2, by interacting with ATG8 isoforms. The FYVE3 protein was transported to the vacuole, and the vacuolar delivery of FYVE3 relies on PI3P biosynthesis and the canonical autophagic machinery. Whereas the fyve3 mutation alone barely affects autophagic flux, it suppresses defective autophagy in fyve2 mutants. Based on the molecular genetics and cell biological data, we propose that FYVE3 specifically regulates FYVE2-dependent autophagy.
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BACKGROUND: Biodegradable poly (l-lactic acid) (PLLA), a bio safe polymer with a large elastic modulus, is widely used in biodegradable medical devices. However, because of its poor mechanical properties, a PLLA strut must be made twice as thick as a metal strut for adequate blood vessel support. Therefore, the mechanical properties of a drug-eluting metal-based stents (MBS) and a bioresorbable vascular scaffolds (BVS) were evaluated and their safety and efficacy were examined via a long-term rabbit iliac artery model. METHODS: The surface morphologies of the MBSs and BVSs were investigated via optical and scanning electron microscopy. An everolimus-eluting (EE) BVS or an EE-MBS was implanted into rabbit iliac arteries at a 1.1:1 stent-to-artery ratio. Twelve months afterward, stented iliac arteries from each group were analyzed via X-ray angiography, optical coherence tomography (OCT), and histopathologic evaluation. RESULTS: Surface morphology analysis of the EE coating on the MBS confirmed that it was uniform and very thin (4.7 µm). Comparison of the mechanical properties of the EE-MBS and EE-BVS showed that the latter outperformed the former in all aspects (radial force (2.75 vs. 0.162 N/mm), foreshortening (0.24% vs. 1.9%), flexibility (0.52 vs. 0.19 N), and recoil (3.2% vs. 6.3%). At all time points, the percent area restenosis was increased in the EE-BVS group compared to the EE-MBS group. The OCT and histopathological analyses indicate no significant changes in strut thickness. CONCLUSION: BVSs with thinner struts and shorter resorption times should be developed. A comparable long-term safety/efficacy evaluation after complete absorption of BVSs should be conducted.
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Stents Farmacológicos , Everolimo , Animais , Coelhos , Artéria Ilíaca , Implantes Absorvíveis , Angiografia Coronária/métodosRESUMO
The chemical industry releases various types of volatile organic compounds (VOCs) into the atmosphere, and the concentration of VOCs emitted from chimneys is regulated worldwide. However, some VOCs such as benzene are highly carcinogenic, while others such as ethylene and propylene may cause secondary air pollution, owing to their high ozone-generating ability. Accordingly, the US EPA(United State, Environment Protect Agency) introduced a fenceline monitoring system that regulates the concentration of VOCs at the boundary of a facility, away from the chimney source. This system was first introduced in the petroleum refining industry, which simultaneously emits benzene, affecting the local community because of its high carcinogenicity, and ethylene, propylene, xylene, and toluene, which have a high photochemical ozone creation potential (POCP). These emissions contribute to air pollution. In Korea, the concentration at the chimney is regulated; however, the concentration at the plant boundary is not considered. In accordance with the EPA regulations, Korea's petroleum refining industries were identified and the limitations of the Clean Air Conservation Act were studied. The average concentration of benzene at the research facility examined in this study was 8.53 µg/m3, which complied with the benzene action level of 9 µg/m3. However, this value was exceeded at some points along the fenceline, in proximity to the benzene-toluene-xylene (BTX) manufacturing process. The composition ratios of toluene and xylene were 27% and 16%, respectively, which were higher than those of ethylene or propylene. These results suggest that reduction measures in the BTX manufacturing process are necessary. This study shows that legal regulations should enforce reduction measures through continuous monitoring at the fenceline of petroleum refineries in Korea.Implications: Although volatile organic compounds(VOCs) are essential in various industrial sites, they adversely affect the health of people in the near community. Benzene is highly carcinogenic, so it is dangerous if exposed continuously. In addition, there are various types of VOCs, which combine with atmospheric ozone to generate smog. Globally, VOCs are managed as Total VOCs. However, through this study, VOCs have priority, and in the case of the petroleum refining industry, it is suggested that VOCs should be preemptively measured and analyzed to be regulated. In addition, it is necessary to minimize the impact on the local community by regulating the concentration at the fenceline beyond the chimney measurement.
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Poluentes Atmosféricos , Ozônio , Petróleo , Compostos Orgânicos Voláteis , Humanos , Poluentes Atmosféricos/análise , Compostos Orgânicos Voláteis/análise , Benzeno , Xilenos/análise , Conservação dos Recursos Naturais , Estudos de Viabilidade , Monitoramento Ambiental/métodos , Tolueno/análise , Etilenos , ChinaRESUMO
Flexible hydrogels are receiving significant attention for their application in wearable sensors. However, most hydrogel materials exhibit weak and one-time adhesion, low sensitivity, ice crystallization, water evaporation, and poor self-recovery, thereby limiting their application as sensors. These issues are only partly addressed in previous studies. Herein, a multiple-crosslinked poly(2-(methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide-co-acrylamide) (P(SBMA-co-AAm)) multifunctional hydrogel is prepared via a one-pot synthesis method to overcome the aforementioned limitations. Specifically, ions, glycerol, and 2-(methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide are incorporated to reduce the freezing point and improve the moisture retention ability. The proposed hydrogel is superior to existing hydrogels because it exhibits good stretchability (a strain of 2900%), self-healing properties, and transparency through effective energy dissipation in its dynamic crosslinked network. Further, 2-(methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide as a zwitterion monomer results in an excellent gauge factor of 43.4 at strains of 1300-1600% by improving the ion transportability and achieving a strong adhesion of 20.9 kPa owing to the dipole-dipole moment. The proposed hydrogel is promising for next-generation biomedical applications, such as soft robots, and health monitoring.