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PRCIS: Hypobaric hypoxia, the major environmental factor at high altitudes, has been observed to induce pupil miosis and widening of the anterior chamber angle. This environment may be safe for individuals with narrow angle and deserves further study. PURPOSE: This study aimed to quantify anterior chamber biometric parameters before and after acute short-term, effortless exposure to hypobaric hypoxia (HH) in healthy lowlanders using swept-source anterior segment optical coherence tomography (SS AS-OCT). METHODS: This prospective study included 25 healthy young lowlanders (50 eyes) who underwent SS AS-OCT measurements and intraocular pressure (IOP) assessments under baseline sea-level conditions (T1).They were then passively exposed to simulated 4000 m above sea level for 3 hours and underwent Acute mountain sickness (AMS) symptoms evaluation and IOP measurement after 2-hours exposure to HH (T2).Repeat SS AS-OCT measurements and IOP assessments were taken within 15 minutes after leaving the hypobaric chamber (T3). Anterior segment parameters including anterior chamber depth (ACD),lens vault (LV),angle opening distance (AOD500), trabecular-iris space area (TISA500), angle recess area (ARA500) at 500 µm from the scleral spur, iris curvature (IC), iris volume (IV), pupil diameter (PD), and central corneal thickness (CCT) were obtained through SS AS-OCT. These repeated measurements were compared using linear mixed model analysis. RESULTS: In comparison to sea level, both IOP (16.4±3.4 vs. 14.9±2.4 mm Hg, P=0.029) and PD (5.36±0.77 vs. 4.78±0.89 mm, P=0.001) significantly decreased after exposure to HH. Significant post-HH changes (Mean difference (95% CI)) were observed in AOD500 (0.129 (0.006, 0.252), P=0.04), TISA500 (0.059 (0.008, 0.11), P=0.025), ARA500 (0.074 (0.008, 0.141), P=0.029), IV (1.623 (0.092, 3.154), P=0.038), and IC (-0.073 (-0.146, 0.001), P=0.047), while CCT, ACD, and LV remained stable. After adjusting for age, post-HH variations in AOD500 (Beta=0.553, 95% CI: 0.001, 1.105, P=0.048) and TISA500 (Beta=0.256, 95% CI: 0.02, 0.492, P=0.034) were associated with decreased IC but were not related to lowered arterial oxygen pressure or IV increase per millimeter of pupil miosis (IV/PD). These differences in anterior segment parameters were neither correlated with differences in IOP nor AMS. CONCLUSION: After short-term, effortless exposure to hypobaric hypoxia, pupil miosis occurred with widening of the anterior chamber angle and decreased IC. These changes in anterior chamber angle parameters were associated with decreased IC but did not correlate with the post-hypobaric variations in IV/PD, IOP, or AMS.
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BACKGROUND: Patients with glioblastoma (GBM) have a poor prognosis and limited treatment options. The mRNA decapping enzyme scavenger (DCPS) is a cap-hydrolyzing enzyme. The DCPS inhibitor RG3039 exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of RG3039 in various preclinical models of GBM. METHODS: DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of RG3039 was determined using GBM cell lines, patient-derived organoids, and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored. RESULTS: DCPS is overexpressed in GBM and is associated with poor survival of patients with GBM. The DCPS inhibitor RG3039 exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, RG3039 downregulated STAT5B expression, thereby suppressing proliferation, survival and colony formation of GBM cells. CONCLUSIONS: DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy.
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Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Animais , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Endorribonucleases/metabolismo , Endorribonucleases/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Feminino , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Camundongos Nus , Camundongos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Pessoa de Meia-IdadeRESUMO
Rabies is a fatal neurological infectious disease caused by rabies virus (RABV), which invades the central nervous system (CNS). RABV with varying virulence regulates chemokine expression, and the mechanisms of signaling pathway activation remains to be elucidated. The relationship between Toll-like receptors (TLRs) and immune response induced by RABV has not been fully clarified. Here, we investigated the role of TLR7 in the immune response induced by RABV, and one-way analysis of variance (ANOVA) was employed to evaluate the data. We found that different RABV strains (SC16, HN10, CVS-11) significantly increased CCL2, CXCL10 and IL-6 production. Blocking assays indicated that the TLR7 inhibitor reduced the expression of CCL2, CXCL10 and IL-6 (p < 0.01). The activation of the Myd88 pathway in BV-2 cells stimulated by RABV was TLR7-dependent, whereas the inhibition of Myd88 activity reduced the expression of CCL2, CXCL10 and IL-6 (p < 0.01). Meanwhile, the RABV stimulation of BV-2 cells resulted in TRL7-mediated activation of NF-κB and induced the nuclear translocation of NF-κB p65. CCL2, CXCL10 and IL-6 release was attenuated by the specific NF-κB inhibitor used (p < 0.01). The findings above demonstrate that RABV-induced expression of CCL2, CXCL10 and IL-6 involves Myd88 and NF-κB pathways via the TLR7 signal.
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Fator 88 de Diferenciação Mieloide , NF-kappa B , Vírus da Raiva , Transdução de Sinais , Receptor 7 Toll-Like , Receptor 7 Toll-Like/metabolismo , Animais , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Vírus da Raiva/patogenicidade , Vírus da Raiva/imunologia , Camundongos , NF-kappa B/metabolismo , Linhagem Celular , Interleucina-6/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Raiva/virologia , Raiva/metabolismo , Raiva/imunologia , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Inflamação/metabolismoRESUMO
Rabies is a highly lethal infectious disease with no existing treatment available, thus investigating effective antiviral compounds to control rabies virus (RABV) infection is of utmost importance. Resveratrol is a natural phenolic compound that, as a phytoalexin, exhibits several biological activities, including antiviral activity. In this study, we evaluated the inhibitory effect of resveratrol on RABV infection and investigated its molecular antiviral mechanism. We found that resveratrol significantly inhibited RABV infection, including the phases of adsorption, replication, and release, and also directly inactivated RABV and inhibited its infectivity. However, resveratrol had no significant effect on RABV internalization. Resveratrol also reduced RABV-induced oxidative stress, specifically reactive oxygen species and malondialdehyde levels. Western blotting analysis revealed that resveratrol enhanced antioxidant signaling via the SIRT1/Nrf2/HO-1 pathway and inhibited viral replication. Viral infection was enhanced after SIRT1 knockdown, which inhibited the SIRT1/Nrf2/HO-1 antioxidant signaling pathway, suggesting that this pathway plays an important role in RABV replication. Overall, resveratrol prevented the adsorption, replication, and release of RABV and directly inactivated RABV, but failed to inhibit RABV internalization. Furthermore, resveratrol activated the SIRT1/Nrf2/HO-1 pathway to inhibit RABV replication and suppressed RABV-induced oxidative stress. These findings highlight the therapeutic potential of resveratrol for fighting RABV infections.
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Helicobacter pylori (H. pylori) is one of the most common bacterial infections in the world, and its key virulence component CagA is the leading cause of gastric cancer. Mitophagy is a form of selective autophagy that eliminates damaged mitochondria and is essential for some viruses and bacteria to evade the immune system. However, the mechanisms by which CagA mediates H. pylori-induced mitophagy and NLRP3 inflammasome activation remain elusive. In this study, we reported that H. pylori primarily uses its CagA to induce mitochondrial oxidative damage, mitochondrial dysfunction, dynamic imbalance, and to block autophagic flux. Inhibition of mitophagy led to an increase in NLRP3 inflammasome activation and apoptosis and a decrease in the viability of H. pylori-infected cells. Our findings suggested that H. pylori induces mitochondrial dysfunction and mitophagy primarily via CagA. It reduces NLRP3 inflammasome activation to evade host immune surveillance and increases the survival and viability of infected cells, potentially leading to gastric cancer initiation and development. Our findings provide new insights into the pathogenesis of H. pylori-induced gastric cancer, and inhibition of mitophagy may be one of the novel techniques for the prevention and treatment of this disease.
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Antígenos de Bactérias , Proteínas de Bactérias , Helicobacter pylori , Inflamassomos , Mitocôndrias , Mitofagia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Inflamassomos/metabolismo , Helicobacter pylori/patogenicidade , Helicobacter pylori/fisiologia , Humanos , Mitocôndrias/metabolismo , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/imunologia , Sobrevivência Celular , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , ApoptoseRESUMO
Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 3 on p. 1510, the western blot images selected to portray the caspase 7 and PARP/cleaved PARP experiments were remarkably similar. After having referred to their original data, the authors realized that the PARP/cleaved PARP blots had been inadvertently duplicated in the figure. The revised version of Fig. 3, showing the correct data for the caspase7 experiment, is shown below. The authors confirm that the errors made during the assembly of Fig. 3 did not adversely affect the major conclusions presented in this paper, and are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a corrigendum. They also apologize to the readership for any inconvenience caused. [International Journal of Oncology 46: 15071515, 2015; DOI: 10.3892/ijo.2015.2869].
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The blood-brain barrier (BBB) serves as a crucial vascular specialization, shielding and nourishing brain neurons and glia while impeding drug delivery. Here, we conducted single-cell mRNA sequencing of human cerebrovascular cells from 13 surgically resected glioma samples and adjacent normal brain tissue. The transcriptomes of 103,230 cells were mapped, including 57,324 endothelial cells (ECs) and 27,703 mural cells (MCs). Both EC and MC transcriptomes originating from lower-grade glioma were indistinguishable from those of normal brain tissue, whereas transcriptomes from glioblastoma (GBM) displayed a range of abnormalities. Among these, we identified LOXL2-dependent collagen modification as a common GBM-dependent trait and demonstrated that inhibiting LOXL2 enhanced chemotherapy efficacy in both murine and human patient-derived xenograft (PDX) GBM models. Our comprehensive single-cell RNA sequencing-based molecular atlas of the human BBB, coupled with insights into its perturbations in GBM, holds promise for guiding future investigations into brain health, pathology, and therapeutic strategies.
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Barreira Hematoencefálica , Neoplasias Encefálicas , Glioma , Análise de Célula Única , Humanos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Camundongos , Animais , Glioma/metabolismo , Glioma/patologia , Células Endoteliais/metabolismo , Transcriptoma , Aminoácido Oxirredutases/metabolismo , Aminoácido Oxirredutases/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/genética , Masculino , FemininoRESUMO
BACKGROUND: Immune-related characteristics can serve as reliable prognostic biomarkers in various cancers. Herein, we aimed to construct an individualized immune prognostic signature in nasopharyngeal carcinoma (NPC). METHODS: This study retrospectively included 455 NPC samples and 39 normal healthy nasopharyngeal tissue specimens. Samples from Gene Expression Omnibus (GEO) were obtained as discovery cohort to screen candidate prognostic immune-related gene pairs based on relative expression ordering of the genes. Quantitative real-time reverse transcription-PCR was used to detect the selected genes to construct an immune-related gene pair signature in training cohort, which comprised 118 clinical samples, and was then validated in validation cohort 1, comprising 92 clinical samples, and validation cohort 2, comprising 88 samples from GEO. RESULTS: We identified 26 immune-related gene pairs as prognostic candidates in discovery cohort. A prognostic immune signature comprising 11 immune gene pairs was constructed in training cohort. In validation cohort 1, the immune signature could significantly distinguish patients with high or low risk in terms of progression-free survival (PFS) (hazard ratio [HR] 2.66, 95 % confidence interval (CI) 1.17-6.02, P=0.015) and could serve as an independent prognostic factor for PFS in multivariate analysis (HR 2.66, 95 % CI 1.17-6.02, P=0.019). Similar results were obtained using validation cohort 2, in which PFS was significantly worse in high risk group than in low risk group (HR 3.02, 95 % CI 1.12-8.18, P=0.022). CONCLUSIONS: The constructed immune signature showed promise for estimating prognosis in NPC. It has potential for translation into clinical practice after prospective validation.
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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/mortalidade , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Adulto , Idoso , Regulação Neoplásica da Expressão GênicaRESUMO
Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
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Aminoácidos de Cadeia Ramificada , Carcinogênese , Proliferação de Células , Colesterol , Neoplasias Colorretais , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Colesterol/metabolismo , Animais , Humanos , Camundongos , Aminoácidos de Cadeia Ramificada/metabolismo , Clostridium/metabolismo , Clostridium/genética , Transdução de Sinais , Proteínas Hedgehog/metabolismo , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Masculino , FemininoRESUMO
Fluxes in human copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate. We herein apply an unbiased temporal evaluation of the signaling and whole genome transcriptional activities modulated by copper level fluctuations to identify potential copper sensor proteins responsible for driving these activities. We find that fluctuations in physiologically relevant copper levels modulate EGFR signal transduction and activation of the transcription factor CREB. Both intracellular and extracellular assays support Cu1+ inhibition of the EGFR phosphatase PTPN2 (and potentially PTPN1)-via ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism. We additionally show i) copper supplementation drives weak transcriptional repression of the copper importer CTR1 and ii) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper stimulated EGFR/CREB signaling and CTR1 expression.
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Transportador de Cobre 1 , Cobre , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Receptores ErbB , Proteína Tirosina Fosfatase não Receptora Tipo 2 , Transdução de Sinais , Receptores ErbB/metabolismo , Receptores ErbB/genética , Cobre/metabolismo , Humanos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Transportador de Cobre 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Transcrição Gênica/efeitos dos fármacosRESUMO
Combining LiDAR points and images for robust semantic segmentation has shown great potential. However, the heterogeneity between the two modalities (e.g. the density, the field of view) poses challenges in establishing a bijective mapping between each point and pixel. This modality alignment problem introduces new challenges in network design and data processing for cross-modal methods. Specifically, 1) points that are projected outside the image planes; 2) the complexity of maintaining geometric consistency limits the deployment of many data augmentation techniques. To address these challenges, we propose a cross-modal knowledge imputation and transition approach. First, we introduce a bidirectional feature fusion strategy that imputes missing image features and performs cross-modal fusion simultaneously. This allows us to generate reliable predictions even when images are missing. Second, we propose a Uni-to-Multi modal Knowledge Distillation (U2MKD) framework, leveraging the transfer of informative features from a single-modality teacher to a cross-modality student. This overcomes the issues of augmentation misalignment and enables us to train the student effectively. Extensive experiments on the nuScenes, Waymo, and SemanticKITTI datasets demonstrate the effectiveness of our approach. Notably, our method achieves an 8.3 mIoU gain over the LiDAR-only baseline on the nuScenes validation set and achieves state-of-the-art performance on the three datasets.
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Objective: Epilepsy-related stigma is a global problem, yet there has been an inadequate focus on children and adolescents. The purpose of this study was to determine the status quo of stigma and its determinants among children and adolescents with epilepsy in China. Methods: A multicenter cross-sectional study was conducted across nine hospitals in eight cities within six provinces in China from 10 October 2023 to 15 June 2024. Participants included patients aged 8 to 18 years with epilepsy and their caregivers. Felt stigma was assessed with the Kilifi Stigma Scale for Epilepsy (KSSE). Social support and self-efficacy were collected through the Social Support Rating Scale (SSRS) and the Generalized Self-Efficacy Scale (GSES). The data were analyzed using t-tests, analysis of variance (ANOVA), Spearman correlation analysis, and multiple linear regression analysis. Results: The study enrolled 281 children and adolescents, with a mean age of 12.25 years (SD = 2.56), including 46.6% females. A total of 35.6% participants had self-reported felt stigma. The mean KSSE score is 9.58 (SD = 7.11). Meanwhile, stigma scores correlated strongly with reduced social support (r = -0.55, p < 0.01) and self-efficacy (r = -0.43, p < 0.01). Place of residence (rural vs. non-rural), academic performance (average and above vs. fair or poor), region (western region vs. non-western region), duration of epilepsy (≤5 years vs. >5 years), drug-resistant epilepsy (yes vs. no), comorbidities (yes vs. no), social support and self-efficacy are major influencing factors among the complex factors influencing the felt stigma among children and adolescents. Conclusion: Medical staff should be more aware of stigma among children and adolescents with epilepsy, especially those who live in rural and western areas, have poor academic performance, have epilepsy duration of more than 5 years, have drug-resistant epilepsy, and have comorbidities, who are at higher risk of stigma. It is recommended that effective measures be taken to alleviate stigma by improving children and adolescents' self-efficacy and providing more social support for them and their families.
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Vault is a massive ribonucleoprotein complex found across Eukaryota. The major vault protein (MVP) oligomerizes into an ovular cage, which contains several minor vault components (MVCs) and is thought to transport transiently bound "cargo" molecules. Vertebrate vaults house a poly (ADP-ribose) polymerase (known as PARP4 in humans), which is the only MVC with known enzymatic activity. Despite being discovered decades ago, the molecular basis for PARP4's interaction with MVP remains unclear. In this study, we determined the structure of the human vault cage in complex with PARP4 and its enzymatic substrate NAD + . The structures reveal atomic-level details of the protein-binding interface, as well as unexpected NAD + -binding pockets within the interior of the vault cage. In addition, proteomics data show that human vaults purified from wild-type and PARP4-depleted cells interact with distinct subsets of proteins. Our results thereby support a model in which PARP4's specific incorporation into the vault cage helps to regulate vault's selection of cargo and its subcellular localization. Further, PARP4's proximity to MVP's NAD + -binding sites could support its enzymatic function within the vault.
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Underwater acoustic target recognition has emerged as a prominent research area within the field of underwater acoustics. However, the current availability of authentic underwater acoustic signal recordings remains limited, which hinders data-driven acoustic recognition models from learning robust patterns of targets from a limited set of intricate underwater signals, thereby compromising their stability in practical applications. To overcome these limitations, this study proposes a recognition framework called M3 (multitask, multi-gate, multi-expert) to enhance the model's ability to capture robust patterns by making it aware of the inherent properties of targets. In this framework, an auxiliary task that focuses on target properties, such as estimating target size, is designed. The auxiliary task then shares parameters with the recognition task to realize multitask learning. This paradigm allows the model to concentrate on shared information across tasks and identify robust patterns of targets in a regularized manner, thus, enhancing the model's generalization ability. Moreover, M3 incorporates multi-expert and multi-gate mechanisms, allowing for the allocation of distinct parameter spaces to various underwater signals. This enables the model to process intricate signal patterns in a fine-grained and differentiated manner. To evaluate the effectiveness of M3, extensive experiments were implemented on the ShipsEar underwater ship-radiated noise dataset. The results substantiate that M3 has the ability to outperform the most advanced single-task recognition models, thereby achieving the state-of-the-art performance.
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Hyperthermia therapy is considered an effective anticancer strategy. However, high temperature can trigger an excessive inflammatory response, leading to tumor self-protection, immunosuppression, metastasis, and recurrence. To address this issue, we reported a multifunctional photothermal nanoplatform to achieve mild hyperthermia photothermal therapy (mild PTT) based on cisplatin (DDP) and a ferrocene metal-organic framework (MOF-Fc) nanocomposite, which can specifically enhance ferroptosis-triggered oxidative stress levels and synchronously amplify mild hyperthermia PTT-mediated anticancer responses. Both in vitro and in vivo antineoplastic results verify the superiority of mild PTT with DDP/MOF-Fc@HA. The combination of DDP and MOF-Fc exhibits Fenton catalytic activity and glutathione depletion capacity, magnifying mild hyperthermia effects via the radical oxygen species (ROS)-adenosine triphosphate (ATP)-HSP silencing pathway, with important implications for clinical hyperthermia therapy.
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Background: Though considerable studies suggesting connections between micronutrients and pregnancy complications, current evidence remains inconsistent and lacks causative confirmation. Our study aimed to explore the causal links between them with a two-sample Mendelian randomization (MR) analysis. Methods: Genome-wide association studies (GWAS) data for circulating micronutrients were sourced from GWAS Catalog consortium and PubMed, while data for pregnancy outcomes, including gestational diabetes mellitus (GDM), gestational hypertension (GH), spontaneous abortion (SA), preterm birth (PTB), and stillbirth (SB), were retrieved from the UK Biobank and FinnGen consortia. Causal effects were appraised using inverse variance weighted (IVW), weighted median (WM), and MR-Egger, followed by sensitivity analyses and meta-analysis for validation. Results: Genetically predicted higher vitamin E (OR = 0.993, 95% CI 0.987-0.998; p = 0.005) levels were inversely associated with SA risk. Consistent results were obtained in meta-analysis (OR = 0.99, 95% CI 0.99-1.00; p = 0.005). Besides, a potential positive causality between genetic predisposition to vitamin B12 and SB was identified in both IVW (OR = 0.974, 95% CI 0.953-0.996; p = 0.018) and WM analysis (OR = 0.965, 95% CI 0.939-0.993; p = 0.013). However, no causal relationships were observed between other analyzed circulating micronutrients and pregnancy complications. Conclusion: This study offers compelling evidence of causal associations between circulating levels of vitamins E, B12 and the risk of SA and SB, respectively. These findings are pivotal for pregnancy complications screening and prevention, potentially guiding clinical practice and public health policies toward targeted nutritional interventions.
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ABSTRACT: Platelet-rich plasma (PRP) shows promise as a regenerative modality for mild-to-moderate erectile dysfunction (ED). However, its efficacy in treating severe ED remains unknown. Blood samples from 8-week-old male rats were used to prepare PRP through a two-step centrifugation procedure, followed by chitosan activation and freezeâthaw cycle. A hyperhomocysteinemia (HHcy)-related ED model was established using a methionine-enriched diet, and an apomorphine (APO) test was conducted during the 4 th week. APO-negative rats were divided into two groups and were injected with PRP or saline every 2 weeks. Erectile function and histological analyses of the corpus cavernosum were performed during the 16 th week. The results revealed that erectile function was significantly impaired in rats with HHcy-related ED compared to that in age-matched rats but was improved by repeated PRP injections. Immunofluorescence staining revealed a reduction in reactive oxygen species and additional benefits on the recovery of structures within the corpus cavernosum in rats that received PRP treatment compared to those in the saline-injected control group. Therefore, PRP could enhance functional and structural recovery in a severe HHcy-related ED model. A notable strength of the present study lies in the use of a repeated intracavernous injection method, mirroring protocols used in human studies, which offers more reliable results for translating the findings to humans.
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Underwater acoustic target recognition based on passive sonar faces numerous challenges in practical maritime applications. One of the main challenges lies in the susceptibility of signal characteristics to diverse environmental conditions and data acquisition configurations, which can lead to instability in recognition systems. While significant efforts have been dedicated to addressing these influential factors in other domains of underwater acoustics, they are often neglected in the field of underwater acoustic target recognition. To overcome this limitation, this study designs auxiliary tasks that model influential factors (e.g., source range, water column depth, or wind speed) based on available annotations and adopts a multi-task framework to connect these factors to the recognition task. Furthermore, we integrate an adversarial learning mechanism into the multi-task framework to prompt the model to extract representations that are robust against influential factors. Through extensive experiments and analyses on the ShipsEar dataset, our proposed adversarial multi-task model demonstrates its capacity to effectively model the influential factors and achieve state-of-the-art performance on the 12-class recognition task.
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A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 µM and potent iron-chelating ability (pFe3+ = 18.79) comparable to that of deferiprone (pFe3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.
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Doença de Alzheimer , Cromonas , Deferiprona , Quelantes de Ferro , Inibidores da Monoaminoxidase , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/química , Quelantes de Ferro/síntese química , Deferiprona/farmacologia , Deferiprona/química , Monoaminoxidase/metabolismo , Humanos , Cromonas/química , Cromonas/farmacologia , Cromonas/síntese química , Relação Estrutura-Atividade , Animais , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Ferroptose/efeitos dos fármacos , Estrutura Molecular , Simulação de Acoplamento Molecular , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Relação Dose-Resposta a DrogaRESUMO
In this research, a series of K+-intercalated quasi-1D vanadium-based nano-ribbons (KxV2O5 NRs) were synthesized via a facile solvothermal method. The solvation and reductive effects of vanadium oxide precursors (V2O5 powder) on the crystallization and growth of KxV2O5 NRs were studied. Besides, post-heat treatment was performed to improve the crystallinity of KxV2O5 NRs. These KxV2O5 NRs were adopted as active cathodes for potassium-ion batteries (PIBs), whose K+ storage properties were systematically evaluated using various electrochemical methods. The relationship among the morphology, crystallinity, working voltage window and electrochemical reversible K+ storage performance of KxV2O5 NRs was studied and established. Results reveal that KxV2O5-HG, which was prepared via a solvothermal reaction involving a solvation process (using H2O2) and a proper reducing condition (proper dose of glucose) with V2O5 powder as the raw material, would be more beneficial for the reversible storage of K+ when used as the cathode for PIBs compared to other contrast samples. In addition, the enhanced crystallinity and slightly broadened working voltage window of KxV2O5-HG could hinder its long-term cycling stability upon repeated K+ insertions/extractions.