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The polymer liner of the hydrogen storage cylinder was studied to investigate better hydrogen storage capacity in Type-IV cylinders. Molecular dynamics methods were used to simulate the adsorption and diffusion processes of hydrogen in a graphene-filled polyamide 6 (PA6) system. The solubility and diffusion characteristics of hydrogen in PA6 systems filled with different filler ratios (3 wt%, 4 wt%, 5 wt%, 6 wt%, and 7 wt%) were studied under working pressures (0.1 MPa, 35 MPa, 52 MPa, and 70 MPa). The effects of filler ratio, temperature, and pressure on hydrogen diffusion were analyzed. The results show that at atmospheric pressure when the graphene content reaches 5 wt%, its permeability coefficient is as low as 2.44 × 10-13 cm3·cm/(cm2·s·Pa), which is a 54.6% reduction compared to PA6. At 358 K and 70 MPa, the diffusion coefficient of the 5 wt% graphene/PA6 composite system is 138% higher than that at 298 K and 70 MPa. With increasing pressure, the diffusion coefficients of all materials generally decrease linearly. Among them, pure PA6 has the largest diffusion coefficient, while the 4 wt% graphene/PA6 composite system has the smallest diffusion coefficient. Additionally, the impact of FFV (free volume fraction) on the barrier properties of the material was studied, and the movement trajectory of H2 in the composite system was analyzed.
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Light-harvesting is of vital importance for many events, such as photosynthesis. To efficiently gather and transfer solar energy, delicate antenna is needed, which has been achieved by algae and plants. However, construction of efficient light-harvesting systems using multiple, artificial building blocks is still challenging. Here, blue-emitting organosilicone capsules containing carbon dots (denoted as CDs-Si) in ethanol are prepared, which can effectively transfer energy to green-emitting (silicone-functionalized bodipy, Si-BODIPY) or red-emitting (rhodamine b, RhB) dyes. In ternary system, sequential Förster resonance energy transfer from CDs-Si to Si-BODIPY and further to RhB is realized, which is accompanied with a less pronounced, parallel FRET directly from CDs-Si to RhB. The overall efficiency of energy transfer reaches ≈86%. By introducing a photoswitch (1,2-bis(2,4-dimethyl-5-phenyl-3-thienyl)-3,3,4,4,5,5-hexafluoro-1-cyclopentene, DAE) to the system, the emission becomes switchable under alternative illumination with UV and visible light, leading to the formation of smart artificial light-harvesting systems.
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Objective: This study focuses on enhancing the precision of epidemic time series data prediction by integrating Gated Recurrent Unit (GRU) into a Graph Neural Network (GNN), forming the GRGNN. The accuracy of the GNN (Graph Neural Network) network with introduced GRU (Gated Recurrent Units) is validated by comparing it with seven commonly used prediction methods. Method: The GRGNN methodology involves multivariate time series prediction using a GNN (Graph Neural Network) network improved by the integration of GRU (Gated Recurrent Units). Additionally, Graphical Fourier Transform (GFT) and Discrete Fourier Transform (DFT) are introduced. GFT captures inter-sequence correlations in the spectral domain, while DFT transforms data from the time domain to the frequency domain, revealing temporal node correlations. Following GFT and DFT, outbreak data are predicted through one-dimensional convolution and gated linear regression in the frequency domain, graph convolution in the spectral domain, and GRU (Gated Recurrent Units) in the time domain. The inverse transformation of GFT and DFT is employed, and final predictions are obtained after passing through a fully connected layer. Evaluation is conducted on three datasets: the COVID-19 datasets of 38 African countries and 42 European countries from worldometers, and the chickenpox dataset of 20 Hungarian regions from Kaggle. Metrics include Average Root Mean Square Error (ARMSE) and Average Mean Absolute Error (AMAE). Result: For African COVID-19 dataset and Hungarian Chickenpox dataset, GRGNN consistently outperforms other methods in ARMSE and AMAE across various prediction step lengths. Optimal results are achieved even at extended prediction steps, highlighting the model's robustness. Conclusion: GRGNN proves effective in predicting epidemic time series data with high accuracy, demonstrating its potential in epidemic surveillance and early warning applications. However, further discussions and studies are warranted to refine its application and judgment methods, emphasizing the ongoing need for exploration and research in this domain.
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Redes Neurales de la Computación , Humanos , COVID-19/epidemiología , Enfermedades Transmisibles/epidemiología , Análisis de Fourier , Brotes de EnfermedadesRESUMEN
Advancements in long-read transcriptome sequencing (long-RNA-seq) technology have revolutionized the study of isoform diversity. These full-length transcripts enhance the detection of various transcriptome structural variations, including novel isoforms, alternative splicing events, and fusion transcripts. By shifting the open reading frame or altering gene expressions, studies have proved that these transcript alterations can serve as crucial biomarkers for disease diagnosis and therapeutic targets. In this project, we proposed IFDlong, a bioinformatics and biostatistics tool to detect isoform and fusion transcripts using bulk or single-cell long-RNA-seq data. Specifically, the software performed gene and isoform annotation for each long-read, defined novel isoforms, quantified isoform expression by a novel expectation-maximization algorithm, and profiled the fusion transcripts. For evaluation, IFDlong pipeline achieved overall the best performance when compared with several existing tools in large-scale simulation studies. In both isoform and fusion transcript quantification, IFDlong is able to reach more than 0.8 Spearman's correlation with the truth, and more than 0.9 cosine similarity when distinguishing multiple alternative splicing events. In novel isoform simulation, IFDlong can successfully balance the sensitivity (higher than 90%) and specificity (higher than 90%). Furthermore, IFDlong has proved its accuracy and robustness in diverse in-house and public datasets on healthy tissues, cell lines and multiple types of diseases. Besides bulk long-RNA-seq, IFDlong pipeline has proved its compatibility to single-cell long-RNA-seq data. This new software may hold promise for significant impact on long-read transcriptome analysis. The IFDlong software is available at https://github.com/wenjiaking/IFDlong.
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Bi-Sb-Te-based thermoelectric materials have the best room-temperature thermoelectric properties, but their inherent brittleness and rigidity limit their application in the wearable field. In this study, W-doped p-type Bi0.5Sb1.5Te3 (W-BST) thin films were prepared using magnetron sputtering on polyimide substrates to create thermoelectric generators (TEGs). Bending tests showed that the thin film has excellent flexibility and mechanical durability, meeting the flexible requirements of wearable devices. W doping can significantly increase the carrier concentration, Seebeck coefficient, and electrical conductivity of BST thin films. At 300 K, the power factor of the W-BST film is 2.25 times higher than that of the undoped film, reaching 13.75 µW cm-1 K-2. First-principles calculations showed that W doping introduces significant impurity peaks in the bandgap, in which W d electrons remarkably hybridize with the Sb and Te p electrons, leading to an improved electrical conductivity of BST films. Furthermore, W doping significantly reduces the work function of BST films, thereby improving the carrier mobility. A TEG module fabricated from four layers of W-BST thin films achieved a maximum output power density of 6.91 mW cm-2 at a temperature difference of 60 K. Application tests showed that the flexible TEG module could power a portable clock using the temperature difference between body temperature and room temperature. At a medium temperature of 439 K, the assembled TEG module can provide a stable output voltage of 1.51 V to power a LED. This study demonstrates the feasibility of combining inorganic thermoelectric materials with flexible substrates to create high-performance flexible TEGs.
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Accurate identification and rapid analysis of PM2.5 sources and formation mechanisms are essential to mitigate PM2.5 pollution. However, studies were limited in developing a method to apportion sources to the total PM2.5 mass in real-time. In this study, we developed a real-time source apportionment method based on chemical mass balance (CMB) modeling and a mass-closure PM2.5 composition online monitoring system in Shenzhen, China. Results showed that secondary sulfate, secondary organic aerosol (SOA), vehicle emissions and secondary nitrate were the four major PM2.5 sources during autumn 2019 in Shenzhen, together contributed 76 % of PM2.5 mass. The novel method was verified by comparing with other source apportionment methods, including offline filter analysis, aerosol mass spectrometry, and carbon isotopic analysis. The comparison of these methods showed that the new real-time method obtained results generally consistent with the others, and the differences were interpretable and implicative. SOA and vehicle emissions were the major PM2.5 and OA contributors by all methods. Further investigation on the OA sources indicated that vehicle emissions were not only the main source of primary organic aerosol (POA), but also the main contributor to SOA by rapid aging of the exhaust in the atmosphere. Our results demonstrated the great potential of the new real-time source apportionment method for aerosol pollution control and deep understandings on emission sources.
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Metal nanoclusters (NCs) with atomic precision are growing into a fascinating class of building blocks for supramolecular chemistry. What makes it more interesting is the enhanced optical properties of the ordered structures, including aggregation-induced emission (AIE). However, algorithm dictating the self-assembly of metal NCs in multicomponent environment remains largely unknown, and effective means to manipulate the self-assembly is still lacking, especially under kinetic control. Herein, nanofibers which contain sub-1 nm nanowires and exhibit circularly polarized phosphorescence (CPP) are obtained from crystallization-induced self-assembly (CISA) of water-soluble, negatively charged silver NCs (Ag9 -NCs) in the presence of glutamic acid (Glu). By the introduction of a positively-charged additive (choline chloride, CC), the structure of the nanowires is modulated and the lateral interaction between adjacent nanofibers is adjusted, leading to simultaneous improvement of the phosphorescence and chirality which finally enhances CPP. Importantly, changing the time at which CC is introduced altered the kinetic pathway of the CISA, which enables to effectively manipulate both the final structures of the self-assembled Ag9 -NCs and the output of the optical signals.
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Objective To evaluate the clinical efficacy of oral use of Jiawei Puji Xiaodu Granules(mainly composed of Lonicerae Japonicae Flos,Forsythiae Fructus,Taraxaci Herba,Violae Herba,Schizonepetae Herba,Arctii Fructus,Gleditsiae Spina,Paeoniae Radix Rubra,Moutan Cortex,and Phragmitis Rhizoma)combined with external application of Xiaozhong Sanjie Ointment(mainly composed of Scutellariae Radix,Coptidis Rhizoma,Phellodendri Chinensis Cortex,and Gleditsiae Spina,etc.)in the treatment of acute tonsillitis in children,and to observe their effects on the immune function and related inflammatory indexes of the patients.Methods A total of 116 children with acute tonsillitis of heat stagnation in the lung and stomach type were randomly divided into the control group and the observation group,with 58 cases in each group.The control group was treated with Cefixime Dispersible Tablets,while the observation group was treated with Jiawei Puji Xiaodu Granules for oral use and Xiaozhong Sanjie Ointment for external application.Both groups were treated for 14 days and then were followed-up for a period of 6 months.The changes of traditional Chinese medicine(TCM)syndrome scores,white blood cell(WBC)count,T lymphocyte subset CD3+,CD4+,CD8+ and CD4+/CD8+ levels,and serum levels of tumor necrosis factor α(TNF-α),interleukin 1β(IL-1β),interleukin 6(IL-6)and C-reactive protein(CRP)in the two groups were observed before and after the treatment.Moreover,the clinical efficacy and time for the disappearance of clinical symptoms were compared between the two groups,and the occurrence of adverse reactions and the recurrence of tonsillitis in the two groups were monitored at the same time.Results(1)During the trial,there were 8 cases falling off in the control group but none case falling off in the observation group,and eventually 50 cases in the control group and 58 cases in the observation group completed the full course of treatment.(2)After 14 days of treatment,the total effective rate of the observation group was 98.28%(57/58),while that of the control group was 90.00%(45/50).The intergroup(tested by rank sum test)showed that the clinical efficacy of the observation group was significantly superior to that of the control group(P<0.05).(3)After treatment,the time for the disappearance of sore throat,time for the disappearance of purulent spots,time for subsiding fever and time for the tonsils recovering to normal in the observation group were all significantly shorter than those in the control group(P<0.05).(4)After treatment,the scores of primary and secondary symptoms and the overall symptom scores in the two groups were significantly lower than those before treatment(P<0.05),and the reduction of the scores in the observation group was significantly superior to that in the control group(P<0.05).(5)After treatment,the levels of T lymphocyte subset CD3+,CD4+ and CD4+/CD8+ in the two groups were significantly higher(P<0.05)while the level of CD8 + was significantly lower(P<0.05)than those before treatment,and the increase in the levels of CD3+,CD4+ and CD4+/CD8+ and the reduction of the CD8+ level of the observation group were significantly superior to those of the control group(P<0.05).(6)After treatment,the levels of WBC,TNF-α,IL-1β,IL-6 and CRP in the two groups were significantly lower than those before treatment(P<0.05),and the reduction in the observation group was significantly superior to that in the control group(P<0.05).(7)During the treatment period,no skin allergy,nausea,vomiting or other gastrointestinal adverse reactions occurred in the two groups,which showed a high degree of safety.(8)The 6-month follow-up showed that the recurrence rate of tonsillitis in the observation group was 5.17%(3/58),which was significantly lower than that of 24.00%(12/50)in the control group,and the difference was statistically significant(χ2 = 8.330,P<0.05).Conclusion The efficacy of Jiawei Puji Xiaodu Granules combined with Xiaozhong Sanjie Ointment exert notable curative effect for children with acute tonsillitis of heat stagnation in the lung and stomach type.The combined therapy can significantly shorten the duration of the disease,improve the clinical symptoms of the children and effectively reduce the recurrence rate of tonsillitis.The therapeutic mechanism may be related to the enhancement of the immune function and the inhibition of inflammatory response.
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Eight compounds were isolated from ethyl acetate fraction of 80% ethanol extract of the hulls of Garcinia mangostana by silica gel, Sephadex LH-20 column chromatography, as well as prep-HPLC methods. By HR-ESI-MS, MS, 1D and 2D NMR spectral analyses, the structures of the eight compounds were identified as 16-en mangostenone E(1), α-mangostin(2), 1,7-dihydroxy-2-(3-methy-lbut-2-enyl)-3-methoxyxanthone(3), cratoxyxanthone(4), 2,6-dimethoxy-para-benzoquinone(5), methyl orselinate(6), ficusol(7), and 4-(4-carboxy-2-methoxyphenoxy)-3,5-dimethoxybenzoic acid(8). Compound 1 was a new xanthone, and compound 4 was a xanthone dimer, compound 5 was a naphthoquinone. All compounds were isolated from this plant for the first time except compounds 2 and 3. Cytotoxic bioassay suggested that compounds 1, 2 and 4 possessed moderate cytotoxicity, suppressing HeLa cell line with IC_(50) va-lues of 24.3, 35.5 and 17.1 µmol·L~(-1), respectively. Compound 4 also could suppress K562 cells with an IC_(50) value of 39.8 µmol·L~(-1).
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Antineoplásicos , Garcinia mangostana , Garcinia , Xantonas , Humanos , Garcinia mangostana/química , Células HeLa , Espectroscopía de Resonancia Magnética , Xantonas/farmacología , Garcinia/química , Extractos Vegetales/química , Estructura MolecularRESUMEN
The conventional star-shaped honeycomb (CSSH) structure is inherently rich in mechanical properties. Based on the CSSH structure, the Poisson's ratio and Young's modulus can be improved by adding the tip re-entrant angle (ISSH). In this paper, a new concave four-arc honeycomb (CFAH) structure is proposed by designing the straight rod as a curved rod and retaining the tip re-entrant angle from the ISSH structure. The Young's modulus, specific stiffness and Poisson's ratio of CFAH structures are derived from Castigliano's second theorem and Moore's theorem. The theoretical results show good agreement with the numerical and experimental results. The results show that the normalized effective specific stiffness and normalized effective Young's modulus of the CFAH structure are further improved by about 12.95% and 16.86%, respectively, compared with the ISSH structure, and more significant auxiliary effects are obtained. CFAH structures show good promise in aerospace, construction and other applications due to their enhanced mechanical property. Meanwhile, the present work provides guidance for the study of concave four-arc honeycomb structures.
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BACKGROUND: McCune-Albright syndrome (MAS) is extremely rare clinically. We here report a case of MAS with severe symptoms that have not been reported previously. CASE SUMMARY: A 10-year-old boy attended our outpatient clinic due to craniofacial malformations found two years ago. He underwent temporal bone computed tomography and digital radiography photography. Based on a literature review combined with the patient's medical history and imaging examination findings, he was diagnosed with multiple fibrous dysplasia of bone. As the clinical symptoms related to MAS in this patient were not obvious, he was only followed up and not given any special treatment. CONCLUSION: The unique clinical manifestations in this MAS patient may be related to mutations in the GNAS gene.
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Over the past few decades, research on the benefits of beneficial microorganisms on skin health has expanded and attracted a lot of attention. Today, a wide range of probiotic products are becoming available. With their extensive component profiles and varied physiological effects, probiotics, as well as extracts of them, have a significant impact on cosmetics. However, the present boom in consumer interest in alternatives has broadened the probiotic industry's research and development frontiers. Considering the foregoing, it should come as no surprise that probiotics are highly valued for their proven anti-aging, skin whitening, anti-inflammatory, and photoprotective effects. This review aims to compile information on probiotics' properties, their extracts, and preparations used in cosmetics. It also further summarizes research and applications on probiotic fermentation to promote the use of probiotic fermentation products in cosmetics. Notably, this review also adds information on particular properties and mechanisms of action of probiotics, which fills a gap in the research and application of probiotics in skin treatment and care. Their antioxidant and anti-aging qualities have received particular consideration. This review provides a new basis for the broad application of probiotics in cosmetics.
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Cosméticos , Probióticos , Antioxidantes/farmacología , FermentaciónRESUMEN
Introduction: Human Papillomavirus (HPV) infection is a risk factor for cervical cancer, the fourth most common cancer among women globally. Its burden is the highest in sub-Saharan Africa, with over 90% mortality. Interventions may fail without evidence-based data on stratified prevalence and risk factors among most at-risk women across Nigeria. Methods: A cross-sectional comparative study, with participants recruited from the Nigerian Institute of Medical Research's Clinics, NGO outreaches, a cancer screening centre and a university teaching hospital. Questionnaires were self-administered. Trained medics performed sampling at healthcare facilities, and self-sampling was used at outreaches. Results: Nine hundred eighty-five study participants were recruited. About 37% and 27% of the women knew about HPV and its vaccines, respectively, but only 6% confirmed vaccination with HPV vaccines. HPV prevalence was highest among women with unknown marital status (35.9%), single women (33.8%), widowed/divorced/separated women (30.3%), and married/cohabiting women (19.6%). HPV infection was significantly higher among women who take alcohol (odds=1.7 [95% CI: 1.2-2.4]) and women who smoke (odds=2.6 [95% CI: 1.4 - 4.6]. HPV strains detected included HPV16 (1.3%), HPV18 (1.5%), Low Risk (0.2%) and Other High-Risk groups (19.7%). Conclusion: The inverse relationship between prevalence and education suggests interventions improving awareness and prevention would be impactful. Such interventions could also target HIV-positive women, women presenting with sexually-transmitted infections, who smoke and frequently drink alcohol.
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The suppressor of variegation enhancer of zeste-trithorax (SET) domain methyltransferases have been reported to function as key regulators in multiple tumor types by catalyzing histone lysine methylation. Nevertheless, our understanding on the role of these lysine methyltransferases, including SETD4, in prostate cancer (PCa) remains limited. Hence, the specific role of SETD4 in PCa was investigated in this study. The expression of SETD4 in PCa cells and tissue samples was downregulated in PCa cells and tissue specimens, and decreased SETD4 expression led to inferior clinicopathological characteristics in patients with PCa. knockdown of SETD4 facilitated the proliferation of PCa cells and accelerated cell cycle progression. Mechanistically, SETD4 repressed NUPR1 transcription by methylating H3K27 to generate H3K27me3, subsequently inactivated Akt pathway and impeded the tumorigenesis of PCa. Our results highlight that SETD4 prevents the development of PCa by catalyzing the methylation of H3K27 and suppressing NUPR1 transcription, subsequently inactivating the Akt signaling pathway. The findings suggest the potential application of SETD4 in PCa prognosis and therapeutics.
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Histonas , Neoplasias de la Próstata , Humanos , Masculino , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Histonas/genética , Histonas/metabolismo , Lisina/metabolismo , Metiltransferasas/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Small RNAs (sRNAs) within 15-30 nt such as miRNA, tsRNA, srRNA with 3'-OH have been identified. However, whether these sRNAs are the major 15-30 nt sRNAs is still unknown. Here we show about 90% mammalian sRNAs within 15-30 nt end with 2',3'-cyclic phosphate (3'-cP). TANT-seq was developed to simultaneously profile sRNAs with 3'-cP (sRNA-cPs) and sRNA-OHs, and huge amount of sRNA-cPs were detected. Surprisingly, sRNA-cPs and sRNA-OHs usually have distinct sequences. The data from TANT-seq were validated by a novel method termed TE-qPCR, and Northern blot. Furthermore, we found that Angiogenin and RNase 4 contribute to the biogenesis of sRNA-cPs. Moreover, much more sRNA-cPs than sRNA-OHs bind to Ago2, and can regulate gene expression. Particularly, snR-2-cP regulates Bcl2 by targeting to its 3'UTR dependent on Ago2, and subsequently regulates apoptosis. In addition, sRNA-cPs can guide the cleavage of target RNAs in Ago2 complex as miRNAs without the requirement of 3'-cP. Our discovery greatly expands the repertoire of mammalian sRNAs, and provides strategies and powerful tools towards further investigation of sRNA-cPs.
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MicroARNs , Animales , MicroARNs/genética , Regiones no Traducidas 3' , Apoptosis/genética , Northern Blotting , Mamíferos/genéticaRESUMEN
Metal-organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual-stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe-based MOFs with pH/glutathione (GSH)-sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo-chemodynamic-starvation synergistic therapy. H+ and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn2+/4+ /Fe2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H2 O2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H2 O2 . Then H2 O2 is catalyzed by Mn2+ /Fe2+ to generate highly toxic â¢OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.
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Nanopartículas del Metal , Estructuras Metalorgánicas , Nanopartículas , Neoplasias , Humanos , Oro , Glutatión , Microambiente Tumoral , Nanotecnología , Concentración de Iones de Hidrógeno , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Peróxido de HidrógenoRESUMEN
BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate bloodâbrain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. FINDINGS: In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = - 0.401, p = 0.031). CONCLUSION: Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Barrera Hematoencefálica , Humanos , Metaloproteinasa 9 de la Matriz , Microglía , BiomarcadoresRESUMEN
General control of amino acid synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodynamic stress is largely unknown. Here, we show that cardiomyocyte-specific GCN5L1 knockout mice (cGCN5L1 KO) display exacerbated heart failure progression following transaortic constriction (TAC). Mitochondrial DNA and protein levels were decreased in cGCN5L1 KO hearts after TAC, and isolated neonatal cardiomyocytes with reduced GCN5L1 expression had lower bioenergetic output in response to hypertrophic stress. Loss of GCN5L1 expression led to a decrease in the acetylation status of mitochondrial transcription factor A (TFAM) after TAC in vivo, which was linked to a reduction in mtDNA levels in vitro. Together, these data suggest that GCN5L1 may protect from hemodynamic stress by maintaining mitochondrial bioenergetic output.
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Obesity and diabetes are risk factors for hepatocellular carcinoma (HCC); however, the underlying mechanisms are yet to be elucidated. Adeno-associated virus (AAV) frequently infects humans and has been widely used in gene therapy, but the risk of AAV infection such as HCC should be further evaluated. Here, we show that recombinant AAV injection caused liver injury, hepatic necroptosis, and HCC in db/db or high-fat diet-induced hyperglycemic and obese mice, but not in mice with only hyperglycemia or obesity. Prednisone administration or knockdown of Pebp1, highly expressed in db/db mice, alleviated hepatic injury and necroptosis induced by recombinant AAV in mice with diabetes and obesity. Inhibition of Pebp1 pathway also attenuated inflammation and necroptosis in vitro. Our findings show that AAV infection is a critical risk factor for HCC in patients with diabetes and obesity, and AAV gene therapy for these patients should be carefully evaluated. Both prednisone treatment and targeting Pebp1 pathway are promising strategies to alleviate inflammation and necroptosis that occurred in AAV gene therapy or related diseases.