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JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/ß-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury-induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.
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The colonic peristaltic pressure signal is helpful for the diagnosis of intestinal diseases, but it is difficult to reflect the real situation of colonic peristalsis due to the interference of various factors. To solve this problem, an improved wavelet threshold denoising method based on discrete wavelet transform is proposed in this paper. This algorithm can effectively extract colonic peristaltic pressure signals and filter out noise. Firstly, a threshold function with three shape adjustment factors is constructed to give the function continuity and better flexibility. Then, a threshold calculation method based on different decomposition levels is designed. By adjusting the three preset shape factors, an appropriate threshold function is determined, and denoising of colonic pressure signals is achieved through hierarchical thresholding. In addition, the experimental analysis of bumps signal verifies that the proposed denoising method has good reliability and stability when dealing with non-stationary signals. Finally, the denoising performance of the proposed method was validated using colonic pressure signals. The experimental results indicate that, compared to other methods, this approach performs better in denoising and extracting colonic peristaltic pressure signals, aiding in further identification and treatment of colonic peristalsis disorders.
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Parrotia subaequalis is of great ornamental value due to its unique bark, featuring interesting textures and colors, and its large, striking galls. These characteristics make it a popular choice for bonsai cultivation. (Yan et al. 2022) . In July 2023, an outbreak of leaf blight was observed on 40, six-month-old P. subaequalis seedlings in Anqing, Anhui, China, with an incidence rate of 80%. In the early stages of infection, small brown spots appear on the leaf surface, which gradually become round or irregular and darken to a deep brown color. As the disease progresses, the affected areas expand from the leaf margins towards the center, causing the leaf surface to become concave, wilt, and necrotize. This resulted in restricted plant growth, and in severe cases, partial or complete plant death. For isolation, 30 tissue slices (5 × 5 mm) were taken from the leaves of 10 symptomatic seedlings and surface sterilized with 75% ethanol for 5 seconds, followed by five rinses with sterilized distilled water. After two days of dark incubation at 28°C, hyphal tips of fungi were transferred onto new potato dextrose agar (PDA) plates and incubated until conidia production. Six unidentified isolates with similar morphological characteristics were obtained. The colonies, initially white, darken to black after 7 to 10 days of incubation. They produced colorless, aseptate conidia that were oblong or fusiform, measuring 18-26 µm in length and 5-8 µm in width (n=50). The morphological characteristics of the isolates resembled those of Botryosphaeria (Udayanga et al. 2015) . Isolate IS2116-1 was further confirmed through molecular methods. The rDNA internal transcribed spacer (ITS) region, translation elongation factor 1-α (TEF1-α), and beta-tubulin (TUB2) genes were amplified and sequenced using the primers ITS1/ITS4 (White et al., 1990), EF1-728F/EF1-986R, and Bt2a/Bt2b (Ferreira et al., 2021; Carbone et al., 1999), respectively. BLAST analysis revealed that the ITS (OR958722) sequence was 100% similar to the B. dothidea isolate HZ5(MH329650.1), TEF1-a (PP214058) sequence was 100% similar to the B. dothidea strain JZB310220(ON890458.1), and strain TUB2 (PP214057) sequence was 99.78% similar to the B. dothidea strain L14 (KR260833.1). Maximum likelihood analyses were performed for the combined ITSãTUB2ãTEF datasets using PhyloSuite v1.2.2, the resulting phylogenetic tree indicated that isolate IS2116-1 clustered together with Botryosphaeria dothidea in a clade with 97% bootstrap support(Zheng et al. 2020) . Pathogenicity tests were conducted on 3-6 month-old P. subaequalis seedlings (n = 5) grown in a greenhouse. A conidial suspension (106 spores/ml) collected from the isolates was sprayed onto P. subaequalis seedlings, while the control was treated with distilled water. All plants were maintained in a growth chamber at 28°C with a 12-h photoperiod. The experiment was conducted twice independently . After 20 days of inoculation, brownish lesions similar to those observed in the field appeared on the treated plants, while the noninoculated control plants remained symptomless. The pathogen was reisolated from the leaves of the obviously diseased seedlings and confirmed as B. dothidea through morphological and sequence analysis. No isolates were obtained from uninoculated control plants, thus fulfilling Koch's hypothesis. This report marks the first record of B. dothidea causing leaf blight in P. subaequalis. In light of the rarity of natural P. subaequalis populations, it is imperative to assess both the extent of disease spread and its economic impact. These insights are crucial for devising strategies to protect this endangered species from disease threats and to preserve its ecological significance.
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The Lateral Organ Boundaries Domain (LBD) proteins, an exclusive family of transcription factors (TFs) found solely in plants, play pivotal roles in lateral organogenesis, stress adaptation, secondary growth, and hormonal signaling responses. In this study, a total of 55 PtLBD TFs from Populus trichocarpa were identified and systematically classified into two subfamilies, designated as subfamily-I and subfamily-II with seven distinct groups based on phylogenetic analysis. Gene structure detection indicated that the difference of phase numbers linking adjacent exons contribute to the variations in splicing patterns among different PtLBD groups. Numerous transcription factor binding sites and cis-elements pertinent to hormone signaling pathways and stress response mechanisms were identified within the upstream promoter regions of the PtLBD genes. Thirty-five PtLBDs were found to be engaged in either tandem or segmental duplications, and genomic collinearity analysis revealed a stronger alignment between PtLBD genes and eudicots plants compared to their relationship with monocots. GO enrichment and temporal-spatio expression patterns showed that PtLBD7 from subfamily-I and PtLBD20 from subfamily-II, along with other 13 PtLBDs, were involved in plant growth and development biological processes. The multilayered hierarchical gene networks (ML-hGRN) mediated by PtLBD7 and PtLBD20 indicated that PtLBDs were mainly function in poplar growth and stress tolerance through a multifaceted and intricate regulatory machinery. This study lays a solid groundwork for delving deeper into the roles and underlying mechanisms of LBD transcription factors in poplar, specifically those related to plant hormones and stress tolerance.
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Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Genoma de Planta , Filogenia , Proteínas de Plantas , Populus , Fatores de Transcrição , Populus/genética , Populus/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiões Promotoras Genéticas , Perfilação da Expressão GênicaRESUMO
Rationale: Understanding the immune mechanisms associated with liver transplantation (LT), particularly the involvement of tissue-resident memory T cells (TRMs), represents a significant challenge. Methods: This study employs a multi-omics approach to analyse liver transplant samples from both human (n = 17) and mouse (n = 16), utilizing single-cell RNA sequencing, bulk RNA sequencing, and immunological techniques. Results: Our findings reveal a comprehensive T cell-centric landscape in LT across human and mouse species, involving 235,116 cells. Notably, we found a substantial increase in CD8+ TRMs within rejected grafts compared to stable ones. The elevated presence of CD8+ TRMs is characterised by a distinct expression profile, featuring upregulation of tissue-residency markers (CD69, CXCR6, CD49A and CD103+/-,), immune checkpoints (PD1, CTLA4, and TIGIT), cytotoxic markers (GZMB and IFNG) and proliferative markers (PCNA and TOP2A) during rejection. Furthermore, there is a high expression of transcription factors such as EOMES and RUNX3. Functional assays and analyses of cellular communication underscore the active role of CD8+ TRMs in interacting with other tissue-resident cells, particularly Kupffer cells, especially during rejection episodes. Conclusions: These insights into the distinctive activation and interaction patterns of CD8+ TRMs suggest their potential utility as biomarkers for graft rejection, paving the way for novel therapeutic strategies aimed at enhancing graft tolerance and improving overall transplant outcomes.
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Linfócitos T CD8-Positivos , Rejeição de Enxerto , Transplante de Fígado , Células T de Memória , Análise de Célula Única , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Rejeição de Enxerto/imunologia , Animais , Camundongos , Células T de Memória/imunologia , Células T de Memória/metabolismo , Análise de Célula Única/métodos , Análise de Sequência de RNA/métodos , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Memória Imunológica , Masculino , Camundongos Endogâmicos C57BL , Antígenos CD/metabolismo , Antígenos CD/genética , Feminino , Pessoa de Meia-Idade , Proteínas com Domínio TRESUMO
BACKGROUND: Protein-protein interactions are the primary means through which proteins carry out their functions. These interactions thus have crucial roles in life activities. The wide availability of fully sequenced animal and plant genomes has facilitated establishment of relatively complete global protein interaction networks for some model species. The genomes of cultivated and wild peanut (Arachis hypogaea L.) have also been sequenced, but the functions of most of the encoded proteins remain unclear. RESULTS: We here used homologous mapping of validated protein interaction data from model species to generate complete peanut protein interaction networks for A. hypogaea cv. 'Tifrunner' (282,619 pairs), A. hypogaea cv. 'Shitouqi' (256,441 pairs), A. monticola (440,470 pairs), A. duranensis (136,363 pairs), and A. ipaensis (172,813 pairs). A detailed analysis was conducted for a putative disease-resistance subnetwork in the Tifrunner network to identify candidate genes and validate functional interactions. The network suggested that DX2UEH and its interacting partners may participate in peanut resistance to bacterial wilt; this was preliminarily validated with overexpression experiments in peanut. CONCLUSION: Our results provide valuable new information for future analyses of gene and protein functions and regulatory networks in peanut.
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Arachis , Proteínas de Plantas , Mapas de Interação de Proteínas , Arachis/genética , Arachis/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Mapeamento de Interação de Proteínas , Resistência à Doença/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/genéticaRESUMO
ß-Ionone, sustainably derived from Petunia hybrida as a natural bioresource, was identified as a lead compound for integrated aphid management. A series of ß-ionone derivatives containing ester groups were designed and synthesized for the purpose of discovering renewable botanical-based products. The odorant-binding protein (OBP) binding test indicated that ß-ionone and its derivatives displayed binding affinities with Acyrthosiphon pisum OBP9 (ApisOBP9) and Harmonia axyridis OBP15 (HaxyOBP15). Bioactivity assays revealed that most ß-ionone derivatives exhibited a higher repellent activity than that of ß-ionone. ß-Ionone and derivatives 4g and 4l displayed attractiveness to H. axyridis. Specifically, 4g was a highly promising derivative, possessing good repellent activity against A. pisum and attractiveness to H. axyridis. Molecular dynamics simulations revealed that integrating the hydrophobic ester group into the ß-ionone framework strengthened the van der Waals interactions of 4g with ApisOBP9/HaxyOBP15, improving the binding affinity with OBPs and producing higher push-pull activity than ß-ionone; 4g also had low toxicity toward nontarget organisms. Thus, 4g is a potential ecofriendly, botanical-based option for aphid management.
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Binary layered double hydroxides (LDHs) are an emerging class of materials for supercapacitors owing to their tunable topological structure and excellent theoretical energy storage capacity. However, aggregation and restacking cause a decrease in the interlayer distance of LDHs, resulting in a considerable drop in real specific capacitance. To address this, large-sized anions are intercalated into the interlayer space. Herein, we constructed 3D top-tangled NiCo-LDH nanobranches in situ on a biomass micro-sized carbon plate (CP). By varying the amount of benzene-1,4-dicarboxylic acid (BDC), we prepared a BDC-intercalated CP/NiCo-LDH composite material with adjustable interlayer spacing. Remarkably, the CP/NiCo-LDH-BDC(0.03) composite exhibited excellent electrochemical properties (1530 F g-1/212.5 mAh/g at 1 A/g). It retained 88.36 % capacity after 5000 charge-discharge cycles. The constructed CP/NiCo-LDH-BDC(0.03)//CP asymmetric supercapacitor showed excellent gravimetric capacitance (123 F g-1/54.7 mAh/g at 1 A/g) and energy density (43.7 Wh kg-1 at 800 W kg-1). Furthermore, two asymmetric capacitors connected in series powered a small lightbulb for 2 min, even in a bent state. These findings show that the fabricated CP and CP/NiCo-LDH-BDC(0.03) electrode materials can be applied in flexible and wearable energy storage systems.
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INTRODUCTION: Computational fluid dynamic (CFD) modeling has previously indicated that distorted nasal airflow patterns may contribute to empty nose syndrome (ENS); however, no data show that aggressive turbinate surgery always leads to ENS. We aim to use virtual surgery planning (VSP) to investigate how a total inferior turbinectomy affects airflow parameters compared with ENS patients. METHODS: We retrospectively recruited six nasal obstruction patients who underwent turbinate reduction surgery. We virtually performed total inferior turbinectomy on these patients to compare CFD modeling results to patients' actual surgical outcomes and to that of a previously collected ENS patient cohort (n = 27). RESULTS: Patients' actual surgery outcomes were excellent, with Nasal-Obstruction Symptom Evaluation (NOSE) score (pre: 72.5 ± 13.2 vs post-surgery: 10.8 ± 9.8, p < 0.001) and unilateral visual analog scale (VAS) scores of nasal obstruction (pre: 6 ± 2.56 vs post-surgery: 1.2 ± 1, p < 0.001) improved and was statistically significant. The virtual turbinectomy does not create the same distorted nasal airflow patterns as seen in ENS patients, with no statistically significant difference in nasal resistance as compared with post-actual surgery (virtual turbinectomy: 0.10 ± 0.03 Pa/mL*s; actual surgery: 0.12 ± 0.04 Pa/mL*s; ENS: 0.11 ± 0.04, p > 0.05) nor in regional wall shear force distribution, an important indicator of air/mucosa stimulation (inferior turbinate WSF%: virtual 47.3% ± 11.3% vs actual 51.5% ± 15.1%, p > 0.05); however, both are statistically significant higher than that of ENS patients (WSF: 32.2% ± 12.5%, p < 0.001), despite ENS cohort having wider inferior airway cross-sectional area (CSA) than actual surgeries. CONCLUSION: Empty nose syndrome is likely a multifactorial disease process that cannot be solely attributed to aggressive turbinate reduction surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.
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PURPOSE: This study aimed to establish suitable threshold values for biochemical indicators in low-risk pregnant women who underwent second trimester screening and design strategies for consecutive prenatal testing to increase trisomy 21 detection. METHODS: This study examined singleton pregnant women who underwent double, triple, or quadruple screening in the second trimester over six years. To obtain adequate detection efficiency for low-risk pregnancies, threshold values for serum biochemical indicators were established, and a cost-effectiveness assessment of the improved contingent screening strategy was conducted. RESULTS: Participants were included in serum double- (n = 88,550), triple- (n = 29,991), and quadruple-screening (n = 15,004) groups. Threshold values were defined as having a free beta subunit of human chorionic gonadotropin (free ß-hCG) multiple of the median (MoM) ≥ 2.50, alpha-fetoprotein (AFP) MoM ≤ 0.50, or unconjugated estriol (uE3) MoM ≤ 0.70 for low risk. Low-risk pregnancies, comprising 1.35% (988/73,183), 4.45% (1,171/26,286), and 11.91% (1,559/13,085) of the double-, triple-, and quadruple-screening groups, respectively, underwent further non-invasive prenatal screening. In the double-, triple-, and quadruple-screening groups, we detected 11.76% (2/17), 40.00% (2/5), and 66.67% (2/3) of trisomy 21 cases with false negative results, respectively, with the overall detection rates of 85.00% (85/100), 90.63% (29/32), and 95.24% (20/21), respectively, and decreased ratio of overall costs of 5.26%, 16.63%, and 24.36%, respectively. CONCLUSION: Utilizing threshold values of AFP, free ß-hCG, and uE3 to trigger further non-invasive prenatal screening may increase trisomy 21 detection in pregnancies deemed low risk in the second trimester while reducing the overall costs of screening strategies.
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Rose is an important ornamental crop cultivated globally for perfume production. However, our understanding of the mechanisms underlying scent production and molecular breeding for fragrance is hindered by the lack of a reference genome for tea roses. We present the first complete telomere-to-telomere (T2T) genome of Rosa gigantea, with high quality (QV > 60), including detailed characterization of the structural features of repetitive regions. The expansion of genes associated with phenylpropanoid biosynthesis may account for the unique tea scent. We uncover the release rhythm of aromatic volatile organic compounds and their gene regulatory networks through comparative genomics and time-ordered gene co-expression networks. Analyzes of eugenol homologs demonstrate how plants attract pollinators using specialized phenylpropanoids in specific tissues. This study highlights the conservation and utilization of genetic diversity from wild endangered species through multi-omics approaches, providing a scientific foundation for enhancing rose fragrance via de novo domestication.
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Regulação da Expressão Gênica de Plantas , Genoma de Planta , Odorantes , Rosa , Compostos Orgânicos Voláteis , Rosa/genética , Rosa/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Odorantes/análise , Redes Reguladoras de Genes , Genômica/métodos , Eugenol/análogos & derivados , Eugenol/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Polinização , MultiômicaRESUMO
Solar-blind ultraviolet (UV) detection plays a critical role in imaging and communication due to its low-noise background, high signal-to-noise ratio, and strong anti-interference capabilities. Detecting the polarization state of UV light can enhance image information and expand the communication dimension. Although polarization detection is explored in visible and infrared light, and applied in fields such as astrophysics and submarine seismic wave detection, solar-blind UV polarization detection remains largely unreported. This is primarily due to the challenge of creating UV polarizers with high transmittance, high extinction ratio, and strong resistance to UV radiation. In this study, it is discovered that the space symmetry breaking of the ß-Ga2O3's b-c plane results in a significant optical absorption dichroic ratio. Leveraging ß-Ga2O3's high solar-blind UV response, a lensless solar-blind UV polarization-sensitive photodetector, circumventing the challenges associated with solar-blind UV polarizers is designed. This photodetector exhibits an exceptionally high intrinsic polarization ratio under 254 nm linearly polarized light, approximately two orders of magnitude higher than other reported nanomaterial-based polarization-sensitive photodetectors. Additionally, it demonstrates significant advantages in solar-blind UV imaging and light communication. This work introduces a novel strategy for solar-blind ultraviolet polarization detection and offers a promising approach for solar-blind light communication.
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BACKGROUND: Jasminum sambac, a widely recognized ornamental plant prized for its aromatic blossoms, exhibits three flora phenotypes: single-petal ("SP"), double-petal ("DP"), and multi-petal ("MP"). The lack of detailed characterization and comparison of J. sambac mitochondrial genomes (mitogenomes) hinders the exploration of the genetic and structural diversity underlying the varying floral phenotypes in jasmine accessions. RESULTS: Here, we de novo assembled three mitogenomes of typical phenotypes of J. sambac, "SP", "DP", and "MP-hutou" ("HT"), with PacBio reads and the "HT" chloroplast (cp) genome with Illumina reads, and verified them with read mapping and fluorescence in situ hybridization (FISH). The three mitogenomes present divergent sub-genomic conformations, with two, two, and four autonomous circular chromosomes ranging in size from 35.7 kb to 405.3 kb. Each mitogenome contained 58 unique genes. Ribosome binding sites with conserved AAGAAx/AxAAAG motifs were detected upstream of uncanonical start codons TTG, CTG and GTG. The three mitogenomes were similar in genomic content but divergent in structure. The structural variations were mainly attributed to recombination mediated by a large (~ 5 kb) forward repeat pair and several short repeats. The three jasmine cp. genomes showed a well-conserved structure, apart from a 19.9 kb inversion in "HT". We identified a 14.3 kb "HT"-specific insertion on Chr7 of the "HT" nuclear genome, consisting of two 7 kb chloroplast-derived fragments with two intact ndhH and rps15 genes, further validated by polymerase chain reaction (PCR). The well-resolved phylogeny suggests faster mitogenome evolution in J. sambac compared to other Oleaceae species and outlines the mitogenome evolutionary trajectories within Lamiales. All evidence supports that "DP" and "HT" evolved from "SP", with "HT" being the most recent derivative of "DP". CONCLUSION: The comprehensive characterization of jasmine organelle genomes has added to our knowledge of the structural diversity and evolutionary trajectories behind varying jasmine traits, paving the way for in-depth exploration of mechanisms and targeted genetic research.
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Genoma Mitocondrial , Genoma de Planta , Jasminum , Jasminum/genética , Genoma de Cloroplastos , Cloroplastos/genética , Hibridização in Situ FluorescenteRESUMO
Superoxide dismutase (SOD) is widely present in plants and plays a crucial role in defending against oxidative stress and preventing tissue damage. This study discovered that the PagSOD2a gene in 84K poplar (Populus alba × P. glandulosa) exhibits a distinct capacity to be induced in response to salt stress. To delve into the pivotal role of PagSOD2a in conferring salt tolerance, the entire PagSOD2a fragment was successfully cloned from 84K poplar and the potential function of PagSOD2a was explored using bioinformatics and subcellular localization. PagSOD2a was found to encode a CuZn-SOD protein localized in chloroplasts. Furthermore, six CuZn-SOD family members were identified in poplar, with closely related members displaying similar gene structures, indicating evolutionary conservation. Morphological and physiological indexes of transgenic 84K poplar overexpressing PagSOD2a (OE) were compared with non-transgenic wild-type (WT) plants under salt stress. The OE lines (OE1 and OE3) showed improved growth performance, characterized by increased plant height and fresh weight, along with reduced malondialdehyde (MDA) content and electrolyte leakage rate under salt stress. Meanwhile, overexpression of PagSOD2a significantly augmented CuZn-SOD and total SOD enzyme activities, leading to a reduction in superoxide anion accumulation and an enhancement of salt tolerance. Additionally, co-expression and multilayered hierarchical gene regulatory network (ML-hGRN) mediated by PagSOD2a constructed using transcriptome data revealed that PagSOD2a gene may be directly regulated by SPL13, NGA1b and FRS5, as well as indirectly regulated by MYB102 and WRKY6, in response to salt stress. These findings provide a theoretical and material foundation for further elucidating the function of PagSOD2a under salt stress and for developing salt-tolerant poplar varieties.
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BACKGROUND: Glioblastoma (GBM) is the most common and lethal primary brain tumor with low effectiveness of available treatments. The tumor heterogeneity and therapeutic resistance are largely due to the presence of glioma stem cells (GSCs). Therefore, eliminating GSCs can overcome the progression, relapse, and resistance of GBM. Previous studies have shown that gambogic acid (GA), a natural active ingredient, has anti-glioma properties. Nonetheless, it is still unclear whether it has an inhibitory effect on GSCs and what its target might be. This study aimed to investigate the anti-tumor effects of GA on GSCs. In addition, this study found the target of GA in GSCs and elucidated the potential specific mechanisms by conducting both in vitro and in vivo experiments. B-cell-specific Moloney leukemia virus insert site 1 (BMI1) is a key stem cell factor of the polycomb group (PcG) family with important effects on the development, recurrence, and chemoresistance of several cancers. In both normal and cancer stem cells, BMI1 maintains stem cell self-renewal by regulating the cell cycle, cellular immortalization, and senescence. Its high expression in a variety of cancers correlates with poor clinical prognosis and chemoresistance. These mechanisms of BMI1 make it a potential therapeutic target for cancer therapy, and future studies may further reveal the specific roles of BMI1 mechanism and provide a basis for the development of new cancer therapeutic strategies. PURPOSE: This study investigated the in vitro and in vivo effects of GA in inducing apoptosis in GSCs and inhibiting GSCs self-renewal, as well as its underlying mechanisms. METHODS: This study synthesized biotinylated gambogic acid for the first time and angled for the target of gambogic acid using LC-MS/MS analysis, which has not been reported previously. Human-derived glioma stem cells GSC123 and GSC111 were used for in vitro studies, analyzing functions and mechanisms via microscale thermophoresis (MST), Annexin V/PI staining, Western blotting, immunofluorescence, and co-immunoprecipitation. The orthotopic glioma mouse model was used to assess the anti-tumor effects of GA in vivo. RESULTS: This study demonstrated that GA is a specific inhibitor of BMI1, a key regulator controlling stem cell growth and self-renewal. GA binds to BMI1's RING domain, accelerating K51-dependent degradation and suppressing H2A ubiquitination. Importantly, GA induces apoptosis, and inhibits GSC self-renewal, but minimally impacts neural progenitor cells (NPCs). GA can also be combined effectively with temozolomide and radiotherapy to increase their sensitivities in resistant cells. Furthermore, exogenous induction of BMI1 expression significantly hinders the disruption of GSCs by GA. In vivo, GA inhibits tumorigenicity, enhances the effect of temozolomide, and reduces BMI1 expression. CONCLUSION: These findings suggest that GA is a potential candidate for targeting GSCs and therefore be used to treat GBM.
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Recognition of the translocation of NLRP3 to various organelles has provided new insights for understanding how the NLRP3 inflammasome is activated by different stimuli. Mitochondria have already been demonstrated to be the site of NLRP3 inflammasome activation, and the latest research suggests that NLRP3 is first recruited to mitochondria, then disassociated, and subsequently recruited to the Golgi network. Although some mitochondrial factors have been found to contribute to the recruitment of NLRP3 to mitochondria, the detailed process of NLRP3 mitochondrial translocation remains unclear. Here, we identify a previously unknown role for Signal transducer and activator of transcription-3 (STAT3) in facilitating the translocation of NLRP3 to mitochondria. STAT3 interacts with NLRP3 and undergoes phosphorylation at Ser727 in response to several NLRP3 agonists, enabling the translocation of STAT3 and thus the bound NLRP3 to mitochondria. Disruption of the interaction between STAT3 and NLRP3 impairs the mitochondrial localization of NLRP3, specifically suppressing NLRP3 inflammasome activation both in vitro and in vivo. In summary, we demonstrate that STAT3 acts as a transporter for mitochondrial translocation of NLRP3 and provide new insight into the spatial regulation of NLRP3.
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Inflamassomos , Mitocôndrias , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transporte Proteico , Fator de Transcrição STAT3 , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Transcrição STAT3/metabolismo , Mitocôndrias/metabolismo , Inflamassomos/metabolismo , Animais , Humanos , Camundongos , Fosforilação , Ligação Proteica , Camundongos Endogâmicos C57BL , Células HEK293RESUMO
Dielectrophoresis (DEP) is an advanced microfluidic manipulation technique that is based on the interaction of polarized particles with the spatial gradient of a non-uniform electric field to achieve non-contact and highly selective manipulation of particles. In recent years, DEP has made remarkable progress in the field of microfluidics, and it has gradually transitioned from laboratory-scale research to high-throughput manipulation in practical applications. This paper reviews the recent advances in dielectric manipulation and separation of microparticles and biological cells and discusses in detail the design of chip structures for the two main methods, direct current dielectrophoresis (DC-DEP) and alternating current dielectrophoresis (AC-DEP). The working principles, technical implementation details, and other improved designs of electrode-based and insulator-based chips are summarized. Functional customization of DEP systems with specific capabilities, including separation, capture, purification, aggregation, and assembly of particles and cells, is then performed. The aim of this paper is to provide new ideas for the design of novel DEP micro/nano platforms with the desired high throughput for further development in practical applications.
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Separação Celular , Eletroforese , Separação Celular/métodos , Humanos , Técnicas Analíticas Microfluídicas , MicrofluídicaRESUMO
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measures microvascular perfusion by capturing the temporal changes of an MRI contrast agent in a target tissue, and it provides valuable information for the diagnosis and prognosis of a wide range of tumors. Quantitative DCE-MRI analysis commonly relies on the nonlinear least square (NLLS) fitting of a pharmacokinetic (PK) model to concentration curves. However, the voxel-wise application of such nonlinear curve fitting is highly time-consuming. The arterial input function (AIF) needs to be utilized in quantitative DCE-MRI analysis. and in practice, a population-based arterial AIF is often used in PK modeling. The contribution of intravascular dispersion to the measured signal enhancement is assumed to be negligible. The MR dispersion imaging (MRDI) model was recently proposed to account for intravascular dispersion, enabling more accurate PK modeling. However, the complexity of the MRDI hinders its practical usability and makes quantitative PK modeling even more time-consuming. In this paper, we propose fast MR dispersion imaging (fMRDI) to effectively represent the intravascular dispersion and highly accelerated PK parameter estimation. We also propose a deep learning-based, two-stage framework to accelerate PK parameter estimation. We used a deep neural network (NN) to estimate PK parameters directly from enhancement curves. The estimation from NN was further refined using several steps of NLLS, which is significantly faster than performing NLLS from random initializations. A data synthesis module is proposed to generate synthetic training data for the NN. Two data-processing modules were introduced to improve the model's stability against noise and variations. Experiments on our in-house clinical prostate MRI dataset demonstrated that our method significantly reduces the processing time, produces a better distinction between normal and clinically significant prostate cancer (csPCa) lesions, and is more robust against noise than conventional DCE-MRI analysis methods.
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Exploring efficient and easily implementable prenatal screening strategies aims at birth defect prevention and control. However, there have been limited economic evaluations of non-invasive prenatal screening (NIPS) strategies in China. Furthermore, these studies were predominantly confined to local or geographically proximate provinces and lacked universality and representativeness. This study assesses the health economics of current prenatal screening strategies and NIPS as first-line screening programs, analyzing their efficacy to determine an optimal strategy. From the perspective of health economics, cost-effectiveness, cost-benefit, and single-factor sensitivity were conducted for five different screening strategies using a decision tree model. Among pregnant women aged < 35 years who underwent only one screening for foetal Down syndrome (DS), the detection rate, false positive rate and positive predictive value of NIPS for foetuses with DS were superior to those of the other four serological screening methods. Although applying NIPS as first-line screening method yields the highest efficacy and benefits, it currently lacks cost-effectiveness when compared to serological screening and sequential NIPS screening strategies.