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Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (α-syn) in the form of Lewy bodies. LBD pathologies are characterized by α-syn deposition in association with other proteins such as Amyloid ß (Aß), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) C. elegans strains (α-synA53T;Taupro-agg (OE) and α-synA53T;Aß1-42;Taupro-agg (OE)) and compared them with previously established Parkinson's, Alzheimer's, and Lewy Body Dementia disease models. The LBD models presented here demonstrate impairments including uncoordinated movement, egg-laying deficits, altered serotonergic and cholinergic signaling, memory and posture deficits, as well as dopaminergic neuron damage and loss. Expression levels of total and prone to aggregation α-syn protein were increased in α-synA53T;Aß1-42 but decreased in α-synA53T;Taupro-agg animals when compared to α-synA53T animals suggesting protein interactions. These alterations were also observed at the mRNA level suggesting a pre-transcriptional mechanism. miRNA-seq revealed that cel-miR-1018 was upregulated in LBD models α-synA53T, α-synA53T;Aß1-42, and α-synA53T;Taupro-agg compared with WT. cel-miR-58c was upregulated in α-synA53T;Taupro-agg but downregulated in α-synA53T and α-synA53T;Aß1-42 compared with WT. cel-miR-41-3p and cel-miR-355-5p were significantly downregulated in 3 LBD models. Our results obtained in a model organism provide evidence of interactions between different pathological proteins and alterations in specific miRNAs that may further exacerbate or ameliorate LBD pathology.
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Peptídeos beta-Amiloides , Animais Geneticamente Modificados , Caenorhabditis elegans , Modelos Animais de Doenças , Doença por Corpos de Lewy , MicroRNAs , alfa-Sinucleína , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Humanos , Proteínas tau/metabolismo , Proteínas tau/genética , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologiaRESUMO
PIWI-interacting RNAs (piRNAs) are short 21-35 nucleotide molecules that comprise the largest class of non-coding RNAs and found in a large diversity of species including yeast, worms, flies, plants and mammals including humans. The most well-understood function of piRNAs is to monitor and protect the genome from transposons particularly in germline cells. Recent data suggest that piRNAs may have additional functions in somatic cells although they are expressed there in far lower abundance. Compared with microRNAs (miRNAs), piRNAs have more limited bioinformatics resources available. This review collates 39 piRNA specific and non-specific databases and bioinformatics resources, describes and compares their utility and attributes and provides an overview of their place in the field. In addition, we review 33 computational models based upon function: piRNA prediction, transposon element and mRNA-related piRNA prediction, cluster prediction, signature detection, target prediction and disease association. Based on the collection of databases and computational models, we identify trends and potential gaps in tool development. We further analyze the breadth and depth of piRNA data available in public sources, their contribution to specific human diseases, particularly in cancer and neurodegenerative conditions, and highlight a few specific piRNAs that appear to be associated with these diseases. This briefing presents the most recent and comprehensive mapping of piRNA bioinformatics resources including databases, models and tools for disease associations to date. Such a mapping should facilitate and stimulate further research on piRNAs.
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Proteínas Argonautas , Células Germinativas , Animais , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Simulação por Computador , Elementos de DNA Transponíveis , Células Germinativas/metabolismo , Humanos , Mamíferos/genética , Mamíferos/metabolismo , RNA Interferente Pequeno/genéticaRESUMO
OBJECTIVE: To investigate whether compression therapy after thermal ablation of varicose veins can improve the prognosis of patients. METHODS: Systematic research were applied for Chinese and English electronic databases(PubMed, Web of Science, Cochrane Library, CNKI, Wanfang, VIP Databases). Eligible prospective studies that comparing the efficacy of compression therapy and non-compression therapy on patients after thermal ablation of varicose veins were included. The interest outcome such as pain, quality of life (QOL), venous clinical severity score (VCSS), time to return to work and complications were analyzed. RESULTS: 10 studies were of high quality, and randomized controlled trials involving 1,545 patients met the inclusion criteria for this study. At the same time, the meta-analysis showed that the application of compression therapy improved pain (SMD: -0.51, 95% CI: -0.95, -0.07) but exhibited no statistically significant effect on QOL (SMD: 0.04, 95% CI: -0.08, 0.16), VCSS (MD: -0.05, 95% CI: -1.19, 1.09), time to return to work (MD: -0.43, 95% CI: -0.90, 0.03), total complications (RR: 0.54, 95% CI: 0.27, 1.09), and thrombosis (RR: 0.71, 95% CI: 0.31, 1.62). CONCLUSION: Compression therapy after thermal ablation of varicose veins can slightly relieve pain, but it has not been found to be associated with improvement in other outcomes.
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Varizes , Humanos , Bandagens Compressivas , Qualidade de Vida , Retorno ao Trabalho/estatística & dados numéricos , Meias de Compressão , Resultado do Tratamento , Varizes/cirurgia , Varizes/terapiaRESUMO
Object detection is one of the core technologies for autonomous driving. Current road object detection mainly relies on visible light, which is prone to missed detections and false alarms in rainy, night-time, and foggy scenes. Multispectral object detection based on the fusion of RGB and infrared images can effectively address the challenges of complex and changing road scenes, improving the detection performance of current algorithms in complex scenarios. However, previous multispectral detection algorithms suffer from issues such as poor fusion of dual-mode information, poor detection performance for multi-scale objects, and inadequate utilization of semantic information. To address these challenges and enhance the detection performance in complex road scenes, this paper proposes a novel multispectral object detection algorithm called MRD-YOLO. In MRD-YOLO, we utilize interaction-based feature extraction to effectively fuse information and introduce the BIC-Fusion module with attention guidance to fuse different modal information. We also incorporate the SAConv module to improve the model's detection performance for multi-scale objects and utilize the AIFI structure to enhance the utilization of semantic information. Finally, we conduct experiments on two major public datasets, FLIR_Aligned and M3FD. The experimental results demonstrate that compared to other algorithms, the proposed algorithm achieves superior detection performance in complex road scenes.
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BACKGROUND: Neisseria gonorrhoeae antimicrobial resistance (AMR) is an urgent public health threat. With dissemination of FC428-related clones, the efficacy of ceftriaxone has become controversial. METHODS: Agar dilution and whole genome sequencing were used to analyze AMR. RESULTS: High resistance to penicillin (75.2%), tetracycline (87.9%), ciprofloxacin (98.3%), ceftriaxone (8.9%), cefixime (14.3%), and azithromycin (8.6%) was observed among 463 isolates first collected in China in 2021. All penA-60.001 clones exhibited resistance to ceftriaxone or cefixime, and 1 of the 12 cases was resistant to azithromycin. ngMAST and ngSTAR of penA-60.001 isolates showed that single-nucleotide polymorphisms in the porB, tbpB, ponA, gyrA, and parC genes were the major causes of different sequence types. MLST-7365 (n = 5) and MLST-1903 (n = 3) were main genotypes, and the other 4 strains featured MLST-10314, MLST-13871, MLST-7827 and MLST-1600. Furthermore, resistance markers (eg, penA, blaTEM-1, blaTEM-135) and virus factors were detected. Most penA-60.001 strains were fully mixed with global FC428-related clones; 2021-A2 and F89 had the same origin; and 2021-A1 exhibited a unique evolutionary trajectory. CONCLUSIONS: Results provide the first demonstration of extremely severe AMR rates of N gonorrhoeae in China in 2021, particularly strains with ceftriaxone decreased susceptibility. The sustained transmission of penA-60.001 subclones might further threaten treatment effectiveness.
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Antibacterianos , Gonorreia , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Neisseria gonorrhoeae , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Cefixima/farmacologia , Cefixima/uso terapêutico , Azitromicina/uso terapêutico , Tipagem de Sequências Multilocus , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade Microbiana , Gonorreia/epidemiologia , Gonorreia/tratamento farmacológicoRESUMO
Herpetic-related neuralgia (HN) caused by varicella-zoster virus (VZV) infection is one of the most typical and common neuropathic pain in the clinic. However, the potential mechanisms and therapeutic approaches for the prevention and treatment of HN are still unclear. This study aims to provide a comprehensive understanding of the molecular mechanisms and potential therapeutic targets of HN. We used an HSV-1 infection-induced HN mouse model and screened the differentially expressed genes (DEGs) in the DRG and spinal cord using an RNAseq technique. Moreover, bioinformatics methods were used to figure out the signaling pathways and expression regulation patterns of the DEGs enriched. In addition, quantitative real-time RT-PCR and western blot were carried out to further confirm the expression of DEGs. HSV-1 inoculation in mice resulted in mechanical allodynia, thermal hyperalgesia, and cold allodynia, following the infection of HSV-1 in both DRG and spinal cord. Besides, HSV-1 inoculation induced an up-regulation of ATF3, CGRP, and GAL in DRG and activation of astrocytes and microglia in the spinal cord. Moreover, 639 genes were upregulated, 249 genes were downregulated in DRG, whereas 534 genes were upregulated and 12 genes were downregulated in the spinal cord of mice 7 days after HSV-1 inoculation. GO and KEGG enrichment analysis suggested that immune responses and cytokine-cytokine receptor interaction are involved in DRG and spinal cord neurons in mice after HSV-1 infection. In addition, CCL5 and its receptor CCR5 were significantly upregulated in DRG and spinal cord upon HSV-1 infection in mice. And blockade of CCR5 exhibited a significant analgesic effect and suppressed the upregulation of inflammatory cytokines in DRG and spinal cord induced by HSV-1 infection in mice. HSV-1 infection-induced allodynia and hyperalgesia in mice through dysregulation of immune response and cytokine-cytokine receptor interaction mechanism. Blockade of CCR5 alleviated allodynia and hyperalgesia probably through the suppression of inflammatory cytokines. Therefore, CCR5 could be a therapeutic target for the alleviation of HSV-1 infection-induced HN.
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Herpes Simples , Herpesvirus Humano 1 , Neuralgia , Animais , Camundongos , Citocinas , Modelos Animais de Doenças , Herpes Simples/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Inflamação/metabolismo , Neuralgia/metabolismo , Quimiocina CCL5/metabolismo , Receptores CCR5/metabolismoRESUMO
Perfluorononanoic acid (PFNA), commonly used as an alternative polyfluorinated compound (PFC) of perfluorooctanoic acid (PFOA), has been widely detected in the aquatic environment. Previous ecotoxicological and epidemiological results suggested that some neurobehavioral effects were associated with PFC exposure; however, the ecological impacts and underlying neurotoxicity mechanisms remain unclear, particularly in aquatic organisms during sensitive, early developmental stages. In this study, zebrafish embryos were exposed to environmentally relevant concentrations of PFNA for 120 h, and the neurological effects of PFNA were comprehensively assessed using transcriptional, biochemical, morphological, and behavioral assays. RNA sequencing and advanced bioinformatics analyses predicted and characterized the key biological processes and pathways affected by PFNA exposure, which included the synaptogenesis signaling pathway, neurotransmitter synapse, and CREB signaling in neurons. Neurotransmitter levels (acetylcholine, glutamate, 5-hydroxytryptamine, γ-aminobutyric acid, dopamine, and noradrenaline) were significantly decreased in zebrafish larvae, and the Tg(gad67:GFP) transgenic line revealed a decreased number of GABAergic neurons in PFNA-treated larvae. Moreover, the swimming distance, rotation frequency, and activity degree were also significantly affected by PFNA, linking molecular-level changes to behavioral consequences.
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Poluentes Químicos da Água , Peixe-Zebra , Animais , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Larva , Poluentes Químicos da Água/toxicidade , Embrião não MamíferoRESUMO
Due to the challenges of small detection targets, dense target distribution, and complex backgrounds in aerial images, existing object detection algorithms perform poorly in aerial image detection tasks. To address these issues, this paper proposes an improved algorithm called YOLOv5s-DSD based on YOLOv5s. Specifically, the SPDA-C3 structure is proposed and used to reduce information loss while focusing on useful features, effectively tackling the challenges of small detection targets and complex backgrounds. The novel decoupled head structure, Res-DHead, is introduced, along with an additional small object detection head, further improving the network's performance in detecting small objects. The original NMS is replaced by Soft-NMS-CIOU to address the issue of neighboring box suppression caused by dense object distribution. Finally, extensive ablation experiments and comparative tests are conducted on the VisDrone2019 dataset, and the results demonstrate that YOLOv5s-DSD outperforms current state-of-the-art object detection models in aerial image detection tasks. The proposed improved algorithm achieves a significant improvement compared with the original algorithm, with an increase of 17.4% in mAP@0.5 and 16.4% in mAP@0.5:0.95, validating the superiority of the proposed improvements.
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This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.
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Quimiorradioterapia/métodos , Terapia Neoadjuvante/métodos , Neoplasias Retais/cirurgia , Neoplasias Retais/terapia , Reto/cirurgia , Adulto , Idoso , Antígenos Glicosídicos Associados a Tumores/sangue , Antígeno Carcinoembrionário/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Retais/sangue , Neoplasias Retais/patologia , Reto/patologia , Estudos Retrospectivos , Medição de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Ubiquitin-conjugating enzyme E2W (UBE2W) is a protein-coding gene that has an important role in ubiquitination and may be vital in the repair of DNA damage. However, studies on the prognostic value of UBE2W and its correlation with tumor-infiltrating immune cells in multiple cancers have not been addressed. METHODS: We investigated UBE2W expression in the Oncomine database, the Tumor Immune Estimation Resource (TIMER), TNMplot database. Then, the clinical prognostic value of UBE2W was analyzed via online public databases. Meanwhile, we explored the correlation between UBE2W and DNA repair associate genes expression and DNA methyltransferase expression by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). By using the same method, the correlation between UBE2W and tumor-infiltrating immune cells was explored. Genomic Profiles of UBE2W in breast cancer (BRCA) were accessed in cBioPortal (v3.5.0). Functional proteins associated network was analyzed by STRING database (v11.0). RESULTS: UBE2W was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels, DNA methyltransferase, and BRCA1/2 expression in breast cancer. High expression of UBE2W may promote the tumor immunosuppression and metastasis, induce endocrine therapy resistance and deteriorate outcomes of patients with breast cancer. These findings suggest that UBE2W could be a potential biomarker of prognosis and tumor-infiltrating immune cells. Besides, RBX1 may be a new E3 that was regulated by UBE2W. CONCLUSIONS: Ubiquitin E2 UBE2W is a potential prognostic biomarker and is correlated with immune infiltration in BRCA.
Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Linfócitos do Interstício Tumoral , Enzimas de Conjugação de Ubiquitina/metabolismo , Neoplasias da Mama/mortalidade , Bases de Dados Factuais , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genes BRCA1 , Genes BRCA2 , Humanos , Metiltransferases/metabolismo , Mutação , Neoplasias/metabolismo , Prognóstico , Microambiente Tumoral/imunologia , Enzimas de Conjugação de Ubiquitina/genética , UbiquitinaçãoRESUMO
BACKGROUND: The optimal treatment of stage IV rectal cancer remains controversial. The purpose of this study was to assess the treatment outcomes and toxicity of neoadjuvant chemotherapy and radiotherapy followed by local treatment of all tumor sites and subsequent adjuvant chemotherapy in stage IV rectal cancer patients with potentially resectable metastases. METHODS: Adult patients diagnosed with locally advanced rectal adenocarcinoma with potentially resectable metastases, who received neoadjuvant chemotherapy and radiotherapy from July 2013 and September 2019 at Sun Yat-sen University cancer center, were included. Completion of the whole treatment schedule, pathological response, treatment-related toxicity and survival were evaluated. RESULTS: A total of 228 patients were analyzed with a median follow-up of 33 (range 3.3 to 93.4) months. Eventually, 112 (49.1%) patients finished the whole treatment schedule, of which complete response of all tumor sites and pathological downstaging of the rectal tumor were observed in three (2.7%) and 90 (80.4%) patients. The three-year overall survival (OS) and progression-free survival (PFS) of all patients were 56.6% (50.2 to 63.9%) and 38.6% (95% CI 32.5 to 45.8%), respectively. For patients who finished the treatment schedule, 3-year OS (74.4% vs 39.2%, P < 0.001) and 3-year PFS (45.5% vs 30.5%, P = 0.004) were significantly improved compared those who did not finish the treatment. Grade 3-4 chem-radiotherapy treatment toxicities were observed in 51 (22.4%) of all patients and surgical complications occurred in 22 (9.6%) of 142 patients who underwent surgery, respectively. CONCLUSIONS: Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation and subsequent adjuvant chemotherapy offered chances of long-term survival with tolerable toxicities for selected patients with potentially resectable stage IV rectal cancer, and could be considered as an option in clinical practice.
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Técnicas de Ablação/mortalidade , Adenocarcinoma/terapia , Terapia Neoadjuvante/mortalidade , Protectomia/mortalidade , Neoplasias Retais/terapia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos Antineoplásicos , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/mortalidade , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Radioterapia Adjuvante/métodos , Radioterapia Adjuvante/mortalidade , Neoplasias Retais/mortalidade , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a common symptom, but prophylactic measures cannot still be carried out effectively. In addition, the efficacy of vitamin E in preventing peripheral neurotoxicity caused by chemotherapy is inconclusive. Therefore, we collected the relevant randomized controlled trials (RCTs) and performed a meta-analysis to examine whether the vitamin E has a positive effect in CIPN. METHODS: We searched PubMed, EMBASE, Cochrane, and other databases in December 2019 for eligible trials. Two reviewers conducted the analysis independently when studies were homogeneous enough. RESULTS: Eight RCTs, involving 488 patients, were identified. Upon pooling these RCTs, patients who received vitamin E supplementation of 600 mg/day had a lower incidence of CIPN (risk ratio [RR] 0.31; 95% confidence interval [CI] 0.14-0.65; p = 0.002) than the placebo group. Vitamin E played a key role in decreasing the incidence of peripheral neuropathy in the cisplatin chemotherapy group (RR 0.28; 95% CI 0.14-0.54; p = 0.0001). Moreover, vitamin E supplementation significantly decreased patients' sural amplitude after 3 rounds of chemotherapy (RR -2.66; 95% CI -5.09 to -0.24; p = 0.03) in contrast with that of placebo supplementation, while no significant difference was observed when patients were treated with vitamin E after 6 rounds of chemotherapy. In addition, the vitamin E-supplemented group had better improvement in the neurotoxicity score and lower incidence of reflexes and distal paraesthesias than the control group. CONCLUSION: Available data in this meta-analysis showed that vitamin E supplementation can confer modest improvement in the prevention of CIPN.
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Doenças do Sistema Nervoso Periférico , Antineoplásicos/efeitos adversos , Cisplatino , Humanos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina E/uso terapêuticoRESUMO
Aberrant over-expressions of FGF9 in gastric cancer (GC) and its high-affinity receptor FGFR3c in bladder cancer (BC) provide possibilities for the treatment of GC and BC via targeting FGF9. In this study, we isolated a novel FGF9-binding peptide (P4) by screening a phage display random heptapeptide library. Sequence comparison showed that P4 shared high homology with the conserved motif in the immunoglobulin-like (Ig-like) domain IIâ¼III (D2-D3) linker of the FGF9 high-affinity receptor (FGFR3c). The interaction between P4 and FGF9 was confirmed by the surface plasmon resonance (SPR) assay. Functional analysis indicated that P4 counteracted FGF9-induced aggressive phenotype, including cell proliferation, migration, and invasion in vitro, as well as suppressed tumor growth in vivovia down-regulation of the MAPKs and Akt cascades. More importantly, we found that FGF9 served as an underlying mechanism of the chemoresistance in GC and BC cells, and P4 could increase the sensitivity to the chemical agent via antagonizing the suppression effects of FGF9 on cell apoptosis. Taken together, our study identified a novel binding peptide for FGF9, which may serve as a potential therapeutic agent for malignant tumors featured by abnormally up-regulation of FGF9.
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Fator 9 de Crescimento de Fibroblastos/antagonistas & inibidores , Peptídeos/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Biblioteca de Peptídeos , Peptídeos/farmacologia , Neoplasias Gástricas/patologia , Carga Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologiaRESUMO
Previous studies suggest that specific binding to the complex consisting of fibroblast growth factor receptor-1 (FGFR1) and the coreceptor beta-Klotho (KLB) is the premise for human FGF19 and FGF21 activating the downstream signaling cascades, and regulating the metabolic homeostasis. However, it was found that human FGF21 loses its ability to bind to FGFR1-KLB after iodination with Na125 I and chloramine T, whereas human FGF19 retained its affinity for FGFR1-KLB even after iodination. The molecular mechanisms underlying these differences remained elusive. In this study, we first demonstrated that an intramolecular disulfide bond was formed between cysteine-102 and cysteine-121 in FGF21, implying that the oxidation of the cysteine to cysteic acid, which may interfere with the active conformation of FGF21, did not occur during the iodination procedures, and thus ruled out the possibility of the two conserved cysteine residues mediating the loss of FGF21 binding affinity to FGFR1-KLB upon iodination. Site-directed mutagenesis and molecular modeling were further applied to determine the residue(s) responsible for the loss of FGFR1-KLB affinity. The results showed that mutation of a single tyrosine-207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1-KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1-KLB, but decreased the receptor binding ability of the iodinated protein, suggesting that tyrosine-207 is the crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.
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Fatores de Crescimento de Fibroblastos/genética , Proteínas de Membrana/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Aminoácidos/efeitos dos fármacos , Aminoácidos/genética , Linhagem Celular , Cloraminas/farmacologia , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Halogenação , Homeostase/genética , Humanos , Proteínas Klotho , Oxirredução/efeitos dos fármacos , Fenilalanina/genética , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Iodeto de Sódio/farmacologia , Compostos de Tosil/farmacologia , Tirosina/efeitos dos fármacosRESUMO
Fibroblast growth factor-2 (FGF2) is a protein ligand, which exerts essential roles in development, angiogenesis, and tumor progression via activation of the downstream signaling cascades. Accumulating evidence has demonstrated that FGF2 is involved in the progression of ovarian cancer, providing a novel potential target for ovarian cancer therapy. In this study, we showed that FGF2 is significantly increased in ovarian tumors, and is negatively associated with the overall survival of ovarian cancer by database analysis. A short peptide obtained from a heptapeptide phage display library suppressed FGF2-induced proliferation, migration, and invasion of the p53-null epithelial ovarian cancer (EOC) cells. Further investigations revealed that the short peptide antagonized the effects of FGF2 on G0/G1 to S cell phase promotion, cyclin D1 expression, and MAPK and Akt signaling activation, which might contribute to the mechanism underlying the inhibitory effects of the short peptide on the aggressive phenotype of the ovarian cancer cells triggered by FGF2. Moreover, the short peptide might have the potentials of reversing FGF2-induced resistance to the doxorubicin via downregulation of the antiapoptotic proteins and counteracting of the antiapoptotic effects of FGF2 on p53-null EOC cells. Taken together, the short peptide targeting FGF2 may provide a novel strategy for improving the therapeutic efficiency in a subset of EOC.
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Carcinoma Epitelial do Ovário/tratamento farmacológico , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Peptídeos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Biblioteca de Peptídeos , Fase S/efeitos dos fármacos , Proteína Supressora de Tumor p53/genéticaRESUMO
Objective: To study the potential of using glucose as carbon source to produce microalgae biomass and biochemical components, such as photosynthetic pigments, lipids, carbohydrates and proteins by tropical marine microalgae Chloralla sp. HN08. Methods: We compared the growth characteristics of Chloralla sp. HN08 cells under photoautotrophic and mixotrophic (10 g/L glucose was added into the medium) conditions. The photosynthesis, specific growth rates, cell densities, and the content of cell's major components including lipids, starch, soluble sugar, and soluble protein were determined and compared. Results: Glucose (10 g/L in medium) could promote Chlorella growth and increase the final cell density under light condition. However, cells declined gradually under heterotrophic condition. Under mixotrophic condition, the specific growth rate and the final cell density were 6.8 and 1.3 times as that of cells under photoautotrophic condition, respectively. The content of soluble sugar, starch, and lipids in mixotrophic cells was also significantly higher (P<0.05) than that in photoautotrophic cells. However, the content of soluble protein and photosynthetic pigments of mixotrophic cells was significantly lower (P<0.05) than that of autotrophic cells. Algae culture with glucose addition showed a higher light saturation as well as respiration rate. No significant difference in net photosynthesis rate was found between autotrophic and mixotrophic cultures (P>0.05). Conclusion: Under light condition, glucose as a carbon source can promote lipids and starch accumulation, as well as biomass production.
Assuntos
Chlorella/crescimento & desenvolvimento , Chlorella/metabolismo , Glucose/metabolismo , Fotossíntese , Processos Autotróficos , Biomassa , Metabolismo dos Carboidratos , Processos Heterotróficos , Metabolismo dos Lipídeos , Microalgas/crescimento & desenvolvimento , Microalgas/metabolismo , Proteínas/metabolismoRESUMO
An ultra-thin, planar, broadband metalens composed of L-shaped gap antennas on a thin gold film has been designed, which is suitable for both circular and X/Y linear polarizations focusing simultaneously. The phase discontinuity of the cross-polarized transmisson light can be manipulated by the length and width of the L-shaped gap antenna accurately. The designed planar metalens posses a strong focusing ability over a large wavelength range, and the size of the focus spot is in sub-wavelength scale. The focal lengths change from 13 to 7 um with incident wavelength from 750 to 1300 nm, and the cause of dispersion is explained and analyzed in detail. The designed metalens can work very well at a wide incident angles of 0~45°. Most importantly, its unique focusing ability that is independent of the incident polarizations will greatly promotes the practical applications and developments of the metasurfaces.
RESUMO
A miniature, simplified and planar plasmonic lens based on the circular array of nano-pinholes for on-axis beaming has been proposed and investigated systematically in the visible spectrum. Focusing properties of the designed plasmonic lens illuminated under circular polarized (CP) light for different radius of circular ring, filled with different dielectrics, with different numbers of pinholes have been investigated and analyzed in detail by finite element method (FEM). Our simulated results demonstrate such a miniature single-turn structure can also generate a totally centrosymmetric focusing spot under the CP illumination. Besides, by properly manipulating the filled dielectric and incident wavelengths, enhanced transmission, elongated depth of focus have also be realized, which can be used to modulate the transmitting fields effectively. Such a miniature and simplified plasmonic focusing lens can open up a vital path toward fiber-end planar photonic devices for biosensing and imaging.
RESUMO
We propose an ultra-thin metasurface of the metal rectangular split-ring resonators (MRSRR) array which can modulate and analyze the wavefront of circularly polarized light efficiently. An incident circularly polarized light could be converted into the corresponding cross-polarized light which would be bent to ± 23° at a wavelength of 808 nm for the normal incidence. And a linearly polarized light would be decomposed into two lights of left and right-handed circular polarizations in the directions of ∓23° respectively. These phenomena have also been observed at 1200 nm with different geometric parameters. And these results depend on controlling the optical-axis profile of the resonators in a subwavelength scale by precisely modulating two degrees of freedom in our nanostructures.
Assuntos
Simulação por Computador , Luz , Metais/química , Nanoestruturas/química , Refratometria/instrumentação , Espalhamento de RadiaçãoRESUMO
As a building block of knowledge acquisition, knowledge graph completion (KGC) aims at inferring missing facts in knowledge graphs (KGs) automatically. Previous studies mainly focus on graph convolutional network (GCN)-based KG embedding (KGE) to determine the representations of entities and relations, accordingly predicting missing triplets. However, most existing KGE methods suffer from limitations in predicting tail entities that are far away or even unreachable in KGs. This limitation can be attributed to the related high-order information being largely ignored. In this work, we focus on learning the information from the related high-order neighbors in KGs to improve the performance of prediction. Specifically, we first introduce a set of new nodes called pedal nodes to augment the KGs for facilitating message passing between related high-order entities, effectively injecting the information of high-order neighbors into entity representation. Additionally, we propose strength-guided graph neural networks to aggregate neighboring entity representations. To address the issue of transmitting irrelevant higher order information to entities through pedal nodes, which can potentially hurt entity representation, we further propose to dynamically integrate the aggregated representation of each node with its corresponding self-representation. Extensive experiments have been conducted on three benchmark datasets and the results demonstrate the superiority of our method compared to strong baseline models.