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Glutarimide-containing polyketides usually exhibit anti-fungi activity, which was well exampled by cycloheximide. In our work, three new polyketide structures, 12-amidestreptimidone (1), 12-carboxylstreptimidone (2) and 3-(5S,8R)-(2-amino-2-oxoethyl-2'-methoxy-2'-oxoethyl)-8,10-dimethyl-7-oxododeca-5-hydroxy-9E,11-diolefin (3) were isolated from Streptomyces sp. JCM 4793. 3 without the glutarimide moiety is not active against fungi as expected, while 1 bearing the amide moiety is much more active than its carboxylic form 2. Here we report the isolation, structural elucidation, antifungal activity, and proposed biosynthesis pathway of 1-3.
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KEY MESSAGE: A total of 416 InDels and 112 SNPs were significantly associated with soybean photosynthesis-related traits. GmIWS1 and GmCDC48 might be related to chlorophyll fluorescence and gas-exchange parameters, respectively. Photosynthesis is one of the main factors determining crop yield. A better understanding of the genetic architecture for photosynthesis is of great significance for soybean yield improvement. Our previous studies identified 5,410,112 single nucleotide polymorphisms (SNPs) from the resequencing data of 219 natural soybean accessions. Here, we identified 634,106 insertions and deletions (InDels) from these 219 accessions and used these InDel variations to perform principal component and linkage disequilibrium analysis of this population. The genome-wide association study (GWAS) were conducted on six chlorophyll fluorescence parameters (chlorophyll content, light energy absorbed per reaction center, quantum yield for electron transport, probability that a trapped exciton moves an electron into the electron transport chain beyond primary quinone acceptor, maximum quantum yield of photosystem II primary photochemistry in the dark-adapted state, performance index on absorption basis) and four gas-exchange parameters (intercellular carbon dioxide concentration, stomatal conductance, net photosynthesis rate, transpiration rate) and revealed 416 significant InDels and 112 significant SNPs. Based on GWAS results, GmIWS1 (encoding a transcription elongation factor) and GmCDC48 (encoding a cell division cycle protein) with the highest expression in the mapping region were determined as the candidate genes responsible for chlorophyll fluorescence and gas-exchange parameters, respectively. Further identification of favorable haplotypes with higher photosynthesis, seed weight and seed yield were carried out for GmIWS1 and GmCDC48. Overall, this study revealed the natural variations and candidate genes underlying the photosynthesis-related traits based on abundant phenotypic and genetic data, providing valuable insights into the genetic mechanisms controlling photosynthesis and yield in soybean.
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Estudio de Asociación del Genoma Completo , Glycine max , Glycine max/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Fotosíntesis/genética , Clorofila/metabolismoRESUMEN
Retinitis pigmentosa (RP) is one of the most common forms of hereditary neurodegeneration. It is caused by one or more of at least 3,100 mutations in over 80 genes that are primarily expressed in rod photoreceptors. In RP, the primary rod-death phase is followed by cone death, regardless of the underlying gene mutation that drove the initial rod degeneration. Dampening the oxidation of glycolytic end products in rod mitochondria enhances cone survival in divergent etiological disease models independent of the underlying rod-specific gene mutations. Therapeutic editing of the prolyl hydroxylase domain-containing protein gene (PHD2, also known as Egln1) in rod photoreceptors led to the sustained survival of both diseased rods and cones in both preclinical autosomal-recessive and dominant RP models. Adeno-associated virus-mediated CRISPR-based therapeutic reprogramming of the aerobic glycolysis node may serve as a gene-agnostic treatment for patients with various forms of RP.
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Células Fotorreceptoras Retinianas Bastones , Retinitis Pigmentosa , Animales , Humanos , Células Fotorreceptoras Retinianas Bastones/metabolismo , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/terapia , Células Fotorreceptoras Retinianas Conos/metabolismo , Modelos Animales de EnfermedadRESUMEN
When employing the open stope mining method for extracting materials in underground mines, it is necessary for personnel and equipment to operate within a specified range of the goaf area, thus, adoption of appropriate mining parameters in the mining field is crucial for promoting safe production practices. In this study, the Harazi iron mine is taken as the research subject, with theoretical analysis combined with numerical simulation that enables the authors to simulate and analyze the width parameter of the mining field. Theoretical analysis utilizing the Matthew stability chart method confirms that the width of the mining field in Harazi iron mine should not exceed 9 m. Based on this finding, the mechanical response characteristics accompanying the mining process at different widths within the mining field limits are analyzed via the Flac3D numerical analysis software. As a result of this analysis, the optimal width of the mining field in Harazi iron mine is determined to be 8 m. The method utilized in this article provides a rational approach to determining structural parameters of the mining field and can effectively aid in promoting mine safety practices.
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PURPOSE: Traditional flow diverters (FDs) for treating aneurysms at the fetal posterior communicating artery are unsatisfactory. Surpass Streamline is a novel FD with different mesh characteristics; however, the outcomes for such aneurysms remain unclear. This study aimed to compare hemodynamic alterations induced by Surpass Streamline, Pipeline Flex, and Tubridge devices and explore possible strategies for aneurysms at the fetal posterior communicating artery. METHODS: Two simulated aneurysms (Case 1, Case 2) were constructed from digital subtraction angiography (DSA). The three FDs were virtually deployed, and hemodynamic analysis based on computational fluid dynamics was performed. Hemodynamic parameters, including the sac-averaged velocity magnitude (Velocity), high-flow volume (HFV), and wall shear stress (WSS), were compared between each FD and the untreated model (control). Surpass Streamline was performed in real life for two aneurysms and the clinical outcomes were collected for analysis. RESULTS: Compared to the control, the Surpass resulted in the most significant reduction in flow. In Case 1, the Velocity, HFV, and WSS were reduced by 51.6%, 78.1%, and 64.3%, respectively. In Case 2, the Velocity, HFV, and WSS were reduced by 48.0%, 81.1%, and 65.3%, respectively. Tubridge showed slightly larger changes in hemodynamic parameters than Pipeline. In addition, our analysis suggested that metal coverage was correlated with the WSS, Velocity, and HFV. The postoperative DSA showed that the aneurysm was nearly occluded in Case 1 and decreased in Case 2. CONCLUSION: Compared to that with the Pipeline and Tubridge, the Surpass resulted in the greatest reduction in hemodynamic parameters and might be effective for aneurysms at the fetal posterior communicating artery. Virtual FD deployment and computational fluid dynamics analysis may be used to predict the treatment outcomes.
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Aneurisma Intracraneal , Humanos , Aneurisma Intracraneal/terapia , Aneurisma Intracraneal/cirugía , Hemodinámica , Resultado del Tratamiento , Hidrodinámica , ArteriasRESUMEN
Prediction-for-perception theories suggest that the brain predicts incoming stimuli to facilitate their categorization.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 However, it remains unknown what the information contents of these predictions are, which hinders mechanistic explanations. This is because typical approaches cast predictions as an underconstrained contrast between two categories18,19,20,21,22,23,24-e.g., faces versus cars, which could lead to predictions of features specific to faces or cars, or features from both categories. Here, to pinpoint the information contents of predictions and thus their mechanistic processing in the brain, we identified the features that enable two different categorical perceptions of the same stimuli. We then trained multivariate classifiers to discern, from dynamic MEG brain responses, the features tied to each perception. With an auditory cueing design, we reveal where, when, and how the brain reactivates visual category features (versus the typical category contrast) before the stimulus is shown. We demonstrate that the predictions of category features have a more direct influence (bias) on subsequent decision behavior in participants than the typical category contrast. Specifically, these predictions are more precisely localized in the brain (lateralized), are more specifically driven by the auditory cues, and their reactivation strength before a stimulus presentation exerts a greater bias on how the individual participant later categorizes this stimulus. By characterizing the specific information contents that the brain predicts and then processes, our findings provide new insights into the brain's mechanisms of prediction for perception.
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Encéfalo , Señales (Psicología) , Humanos , Encéfalo/fisiología , Mapeo Encefálico , Estimulación LuminosaRESUMEN
Due to their weak intrinsic spin-orbit coupling and a distinct bandgap of 3.06 eV, 2D carbon nitride (CN) flakes are promising materials for next-generation spintronic devices. However, achieving strong room-temperature (RT) and ambient-stable ferromagnetism (FM) remains a huge challenge. Here, we demonstrate that the strong RT FM with a high Curie temperature (TC) up to â¼400 K and saturation magnetization (Ms) of 2.91 emu/g can be achieved. Besides, the RT FM exhibits excellent air stability, with Ms remaining stable for over 6 months. Through the magneto-optic Kerr effect, Hall device, X-ray magnetic circular dichroism, and magnetic force microscopy measurements, we acquired clear evidence of magnetic behavior and magnetic domain evolutions at room temperature. Electrical and optical measurements confirm that the Co-doped CN retains its semiconductor properties. Detailed structural characterizations confirm that the single-atom Co coordination and nitrogen defects as well as C-C covalent bonds are simultaneously introduced into CN. Density functional theory calculations reveal that introducing C-C bonds causes carrier spin polarization, and spin-polarized carrier-mediated magnetic exchange between adjacent Co atoms leads to long-range magnetic ordering in CN. We believe that our findings provide a strong experimental foundation for the enormous potential of 2D wide bandgap semiconductor spintronic devices.
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The microecology of endophytic fungi in special habitats, such as the interior of different tissues from a medicinal plant, and its effects on the formation of metabolites with different biological activities are of great importance. However, the factors affecting fungal community formation are unclear. This study is the first to utilize "mini-community" remodeling to understand the above phenomena. First, high-throughput sequencing technology was applied to explore the community composition and diversity of endophytic fungi in the above-ground tissues (Ea) and below-ground tissues (Eb) of Ephedra sinica. Second, fungi were obtained through culture-dependent technology and used for "mini-community" remodeling in vitro. Then, the effects of environmental factors, partner fungi, and plant tissue fluid (internal environment) on endophytic fungal community formation were discussed. Results showed that environmental factors played a decisive role in the selection of endophytic fungi, that is, in Ea and Eb, 93.8% and 25.3% of endophytic fungi were halophilic, respectively, and 10.6% and 60.2% fungi were sensitive to high temperature (33 °C), respectively. Meanwhile, pH had little effect on fungal communities. The internal environment of the plant host further promoted the formation of endophytic fungal communities.
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Ephedra sinica , Micobioma , Biodiversidad , Endófitos/genética , Ecosistema , Hongos/genética , Plantas/microbiologíaRESUMEN
Background: Amnestic mild cognitive impairment (aMCI) is an early stage of Alzheimer's disease (AD). Regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) are employed to explore spontaneous brain function in patients with aMCI. This study applied ALFF and ReHo indicators to analyze the neural mechanism of aMCI by resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Twenty-six patients with aMCI were included and assigned to the aMCI group. The other 26 healthy subjects were included as a healthy control (HC) group. Rs-fMRI was performed for all participants in both groups. Between-group comparisons of demographic data and neuropsychological scores were analyzed using SPSS 25.0. Functional imaging data were analyzed using DPARSF and SPM12 software based on MATLAB 2017a. Gender, age, and years of education were used as covariates to obtain ALFF and ReHo indices. Results: Compared with HC group, ALFF decreased in the left fusiform gyrus, left superior temporal gyrus, and increased in the left cerebellum 8, left inferior temporal gyrus, left superior frontal gyrus (BA11), and right inferior temporal gyrus (BA20) in the aMCI group (p < 0.05, FWE correction). In addition, ReHo decreased in the right middle temporal gyrus and right anterior cuneiform lobe, while it increased in the left middle temporal gyrus, left inferior temporal gyrus, cerebellar vermis, right parahippocampal gyrus, left caudate nucleus, right thalamus, and left superior frontal gyrus (BA6) (p < 0.05, FWE correction). In the aMCI group, the ALFF of the left superior frontal gyrus was negatively correlated with Montreal Cognitive Assessment (MoCA) score (r = -0.437, p = 0.026), and the ALFF of the left superior temporal gyrus was positively correlated with the MoCA score (r = 0.550, p = 0.004). The ReHo of the right hippocampus was negatively correlated with the Mini-Mental State Examination (MMSE) score (r = -0.434, p = 0.027), and the ReHo of the right middle temporal gyrus was positively correlated with MMSE score (r = 0.392, p = 0.048). Conclusion: Functional changes in multiple brain regions rather than in a single brain region have been observed in patients with aMCI. The abnormal activity of multiple specific brain regions may be a manifestation of impaired central function in patients with aMCI.
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BACKGROUND: Hepatocellular carcinoma (HCC) is a highly lethal cancer characterized by dominant driver mutations, including p53. Consequently, there is an urgent need to search for novel therapeutic agents to treat HCC. Andrographolide (Andro), a clinically available anti-inflammatory phytochemical agent, has shown inhibitory effects against various types of cancer, including HCC. However, the underlying molecular mechanisms of its action remain poorly understood. PURPOSE: This study aims to investigate the molecular mechanisms by which p53 and p62 collectively affect Andro-induced HCC cell death, using both in vitro and in vivo models. METHODS: In vitro cellular experiments were conducted to examine the effects of Andro on cell viability and elucidate its mechanisms of action. In vivo xenograft experiments further validated the anti-cancer effects of Andro. RESULTS: Andro induced dose- and time-dependent HCC cell death while sparing normal HL-7702 hepatocytes. Furthermore, Andro caused DNA damage through the generation of reactive oxygen species (ROS), a critical event leading to cell death. Notably, HCC cells expressing p53 exhibited greater resistance to Andro-induced cell death compared to p53-deficient cells, likely due to the ability of p53 to induce G2/M cell cycle arrest. Additionally, Andro-induced p62 aggregation led to the proteasomal degradation of RAD51 and 53BP1, two key proteins involved in DNA damage repair. Consequently, silencing or knocking out p62 facilitated DNA damage repair and protected HCC cells. Importantly, disruption of either p53 or p62 did not affect the expression of the other protein. These findings were further supported by the observation that xenograft tumors formed by p62-knockout HCC cells displayed increased resistance to Andro treatment. CONCLUSION: This study elucidates the mechanistic basis of Andro-induced HCC cell death. It provides valuable insights for repurposing Andro for the treatment of HCC, regardless of the presence of functional p53.
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Carcinoma Hepatocelular , Diterpenos , Neoplasias Hepáticas , Humanos , Apoptosis , Carcinoma Hepatocelular/tratamiento farmacológico , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Muerte Celular , Diterpenos/farmacología , Diterpenos/uso terapéutico , Línea Celular Tumoral , Antiinflamatorios/farmacología , Daño del ADNRESUMEN
This study aimed to investigate the research hotspots and global trends of acupuncture in the treatment of headaches from 1974 to 2022. The Web of Science core collection database and literature related to acupuncture for headache treatment were retrieved. The CiteSpace (version 5.1.R8) and VOSviewer (version 1.6.19) software perform collaborative network analysis on the information of countries, academic institutions, authors, and co-occurrence network analysis on keywords, co-cited journals, and references. A total of 841 studies were included. Overall, the number of publications has increased over the past 5 decades. We identified and analyzed the countries, institutions, authors, and journals that were most active in the domain of acupuncture treatment for headaches. The most productive countries were the United States and China. Chengdu University of Traditional Chinese Medicine was the most productive institution and Linde Klaus was the most productive author. Cephalalgia was the most productive and co-cited journal, whereas Lancet had the highest impact factor. The research hotspots mainly focus on headache, migraine, tension headache, electroacupuncture, and acupuncture. Research trends have mainly focused on acupuncture therapy and its curative effects, migraine without aura, paroxysmal migraine, and the mechanism of acupuncture treatment. The main research hotspots and frontier trends were the therapeutic effect and mechanism of acupuncture for headaches. The mechanism of acupuncture in the treatment of headache mainly focused on the neural mechanism by multimodal MRI.
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Terapia por Acupuntura , Trastornos Migrañosos , Cefalea de Tipo Tensional , Humanos , Bibliometría , Cefalea/terapiaRESUMEN
Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in ß-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.
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Adipocitos Marrones , Ácido Succínico , Ácido Succínico/metabolismo , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Ácidos Grasos/metabolismo , Termogénesis/fisiologíaRESUMEN
Seed germination is a vital developmental transition for the production of progeny by sexual reproduction in spermatophytes. The seed-to-seedling transition is predominately driven by hypocotyl cell elongation. However, the mechanism that underlies hypocotyl growth remains largely unknown. In this study, we characterized the actin array reorganization in embryonic hypocotyl epidermal cells. Live-cell imaging revealed a basally organized actin array formed during hypocotyl cell elongation. This polarized actin assembly is a barrel-shaped network, which comprises a backbone of longitudinally aligned actin cables and a fine actin cap linking these cables. We provide genetic evidence that the basal actin array formation requires formin-mediated actin polymerization and directional movement of actin filaments powered by myosin XIs. In fh1-1 and xi3ko mutants, actin filaments failed to reorganize into the basal actin array, and the hypocotyl cell elongation was inhibited compared with wild-type plants. Collectively, our work uncovers the molecular mechanisms for basal actin array assembly and demonstrates the connection between actin polarization and hypocotyl elongation during seed-to-seedling transition.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Plantones , Hipocótilo , Actinas , Proteínas de Arabidopsis/genética , SemillasRESUMEN
The aim of this study was to generate a polygenic risk score (PRS) for type 2 diabetes (T2D) and test whether it could be used in identifying high-risk individuals for lifestyle intervention in a Chinese cohort. We genotyped 80 genetic variants among 5024 participants without non-communicable diseases at baseline in the Wuxi Non-Communicable Diseases cohort (Wuxi NCDs cohort). During the follow-up period of 14 years, 440 cases of T2D were newly diagnosed. Using Cox regression, we found that the PRS of 46 SNPs identified by the East Asians was relevant to the future T2D. Participants with a high PRS (top quintile) had a two-fold higher risk of T2D than the bottom quintile (hazard ratio: 2.06, 95% confidence interval: 1.42-2.97). Lifestyle factors were considered, including cigarette smoking, alcohol consumption, physical exercise, diet, body mass index (BMI), and waist circumference (WC). Among high-PRS individuals, the 10-year incidence of T2D slumped from 6.77% to 3.28% for participants having ideal lifestyles (4-6 healthy lifestyle factors) compared with poor lifestyles (0-2 healthy lifestyle factors). When integrating the high PRS, the 10-year T2D risk of low-clinical-risk individuals exceeded that of high-clinical-risk individuals with a low PRS (3.34% vs. 2.91%). These findings suggest that the PRS of 46 SNPs could be used in identifying high-risk individuals and improve the risk stratification defined by traditional clinical risk factors for T2D. Healthy lifestyles can reduce the risk of a high PRS, which indicates the potential utility in early screening and precise prevention.
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Diabetes Mellitus Tipo 2 , Enfermedades no Transmisibles , Humanos , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Pueblos del Este de Asia , Estilo de Vida , Estudios Prospectivos , Factores de Riesgo , Herencia MultifactorialRESUMEN
Retinal gene therapies have shown tremendous progress in the past decade, but the sheer number of disease-causing mutations makes their applicability challenging. In this study we test our hypothesis that retinitis pigmentosa-associated retinal degeneration can be prevented through AMP-activated protein kinase (AMPK)-associated metabolic pathway reprogramming using a gene-independent model of degeneration and rescue. We show that recue of photoreceptor structure and function is not achieved through our model of metabolic reprogramming. These results suggest that RP may not be treatable through AMPK pathway modulation-based therapies.
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Metformina , Retinitis Pigmentosa , Humanos , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Células Fotorreceptoras Retinianas Bastones/metabolismo , Retina/metabolismoRESUMEN
Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion-deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 (ARMS2) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 (HTRA1) promoter. The fourth variant is Y402H complement factor H (CFH), which directs CFH signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.
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Células Madre Pluripotentes Inducidas , Degeneración Macular , Humanos , Serina Peptidasa A1 que Requiere Temperaturas Altas/genética , Células Madre Pluripotentes Inducidas/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Proteínas/metabolismo , Serina Endopeptidasas/genética , Estudio de Asociación del Genoma Completo , Degeneración Macular/genética , Estrés Oxidativo , Polimorfismo de Nucleótido Simple , Factor H de Complemento/genética , GenotipoRESUMEN
The advent of big data era has put forward higher requirements for electronic nanodevices that have low energy consumption for their application in analog computing with memory and logic circuit to address attendant energy efficiency issues. Here, a miniaturized diode with a reversible switching state based on N-n MoS2 homojunction used a bandgap renormalization effect through the band alignment type regulated by both dielectric and polarization, controllably switched between type-I and type-II, which can be simulated as artificial synapse for sensing memory processing because of its rectification, nonvolatile characteristic and high optical responsiveness. The device demonstrates a rectification ratio of 103 . When served as memory retention time, it can attain at least 7000 s. For the synapse simulation, it has an ultralow-level energy consumption because of the pA-level operation current with 5 pJ for long-term potentiation and 7.8 fJ for long-term depression. Furthermore, the paired pulse facilitation index reaches up to 230%, and it realizes the function of optical storage that can be applied to simulate visual cells.
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Five new toosendanin limonoids with highly oxidative furan ring walsurobustones A-D (1-4), and one new furan ring degraded limonoid walsurobustone E (5) together with one known compound toonapubesic acid B (6) were isolated from the leaves of Walsura robusta. Their structures were elucidated by NMR and MS data. Especially, the absolute configuration of toonapubesic acid B (6) was confirmed by X-ray diffraction study. Compounds 1-6 exhibited good cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480.
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Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.
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Quelantes del Hierro , Enfermedades de la Retina , Humanos , Quelantes del Hierro/efectos adversos , Muerte Celular , Atrofia/inducido químicamenteRESUMEN
Fundus autofluorescence (FAF) imaging is a noninvasive retinal imaging methodology that allows mapping of lipofuscin distribution in the retinal pigment epithelium cell (RPE). Excessive accumulation of lipofuscin granules in the lysosomal compartment of RPE cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases, including age-related macular degeneration. The clinical applications of FAF coupled with its ease of use, and the noninvasive nature of characterizing retinal diseases, are increasingly valuable to the field of ophthalmology and in assessing the progression of retinitis pigmentosa (RP). Quantitative AF (qAF) enhances the understanding of retinal disease processes, serves as a diagnostic aid, and allows for the monitoring of the effects of therapeutic interventions. This chapter introduces basic principles of FAF and general protocols of FAF evaluating retinal disease progression in rodents.