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Modulating the inflammatory microenvironment to reconstruct the fibrocartilaginous layer while promoting tendon repair is crucial for enhancing tendon-to-bone healing in rotator cuff repair (RCR), a persistent challenge in orthopedics. Small extracellular vesicles (sEVs) hold significant potential to modulate inflammation, yet the efficient production of highly bioactive sEVs remains a substantial barrier to their clinical application. Moreover, achieving minimally invasive local delivery of sEVs to the tendon-to-bone interface presents significant technical difficulties. Herein, the circadian rhythm of adipose-derived stem cells is modulated to increase the yield and enhance the inflammatory regulatory capacity of sEVs. Circadian rhythm-regulated sEVs (CR-sEVs) enhance the cyclic adenosine monophosphate signaling pathway in macrophage (Mφ) via platelet factor 4 delivery, thereby inhibiting Mφ M1 polarization. Subsequently, a triphasic microneedle (MN) scaffold with a tip, stem, and base is designed for the local delivery of CR-sEVs (CR-sEVs/MN) at the tendon-to-bone junction, incorporating tendon-derived decellularized extracellular matrix in the base to facilitate tendon repair. CR-sEVs/MN mitigates inflammation, promotes fibrocartilage regeneration, and enhances tendon healing, thereby improving biomechanical strength and shoulder joint function in a rat RCR model. Combining CR-sEVs with this triphasic microneedle delivery system presents a promising strategy for enhancing tendon-to-bone healing in clinical settings.
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Ritmo Circadiano , Vesículas Extracelulares , Agulhas , Tendões , Cicatrização , Animais , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/química , Ratos , Ritmo Circadiano/fisiologia , Tendões/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Lesões do Manguito Rotador/metabolismo , Lesões do Manguito Rotador/terapia , Osso e Ossos/metabolismo , Ratos Sprague-Dawley , Humanos , Alicerces Teciduais/química , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Macrófagos/metabolismoRESUMO
Injectable hydrogels find extensive application in the treatment of diabetic wound healing. However, traditional bulk hydrogels are significantly limited due to their nano-porous structure, which obstructs cell migration and tissue infiltration. Moreover, regulating inflammation and matrix metalloproteinase -9 (MMP-9) expression in diabetic wounds is crucial for enhancing wound healing. This study marks the first instance of introducing an efficient, scalable, and simple method for producing microfiber-gel granules encapsulating bioceramics powders. Utilizing this method, an injectable microporous granular microgel-fiber hydrogel (MFgel) is successfully developed by assembling microgel-fibers made from hyaluronic acid (HA) and sodium alginate (SA) loaded with small interfering RNA (siRNA) and bioglass (BG) particles. Compared to traditional hydrogels (Tgel), MFgel possesses a highly interconnected network with micron-sized pores, demonstrating favorable properties for cell adhesion and penetration in in vitro experiments. Additionally, MFgel exhibits a higher compressive modulus and superior mechanical stability. When implanted subcutaneously in mice, MFgel promotes cellular and tissue infiltration, facilitating cell proliferation. Furthermore, when applied to skin defects in diabetic rats, MFgel not only effectively regulates inflammation and suppresses MMP-9 expression but also enhances angiogenesis and collagen deposition, thereby significantly accelerating diabetic wound healing. Taken together, this hydrogel possesses great potential in diabetic wound healing applications.
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Osteoporotic tendon-to-bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose-derived stem cells (sEVs) (MHA-sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA-sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA-sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA-sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell-hydrogel interaction studies reveal that the alignment of microfiber gels in MHA-sEVs induces tenogenic differentiation of tendon-derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor-kappaB (NF-κb) signaling pathway. Taken together, MHA-sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.
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Vesículas Extracelulares , Hidrogéis , Ratos , Animais , Hidrogéis/química , Ratos Sprague-Dawley , Tendões , Vesículas Extracelulares/metabolismo , Inflamação/metabolismoRESUMO
Human epidermal growth factor receptor 2-targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance. In the current study, we found that upregulation of dolichyl-phosphate N-acetylglucosaminyltransferase (DPAGT1) sustained high-level HER2 shedding to confer trastuzumab resistance, which was associated with poor clinical outcomes. Upon trastuzumab treatment, the membrane-bound DPAGT1 protein was endocytosed via the caveolae pathway and retrogradely transported to the ER, where DPAGT1 induced N-glycosylation of the sheddase - ADAM metallopeptidase domain 10 (ADAM10) - to ensure its expression, maturation, and activation. N-glycosylation of ADAM10 at N267 protected itself from ER-associated protein degradation and was essential for DPAGT1-mediated HER2 shedding and trastuzumab resistance. Importantly, inhibition of DPAGT1 with tunicamycin acted synergistically with trastuzumab treatment to block HER2 signaling and reverse resistance. These findings reveal a prominent mechanism for HER2 shedding and suggest that targeting DPAGT1 might be a promising strategy against trastuzumab-resistant breast cancer.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais , Proteínas de Membrana/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Antineoplásicos/farmacologiaRESUMO
Rationale: Chemoresistance is a major challenge in the clinical management of patients with breast cancer. Mutant p53 proteins tend to form aggregates that promote tumorigenesis in cancers. We here aimed to explore the mechanism for the generation of mutant p53 aggregates in breast cancer and assess its role in inducing chemoresistance. Methods: Expression of BCL2-associated athanogene 2 (BAG2) was evaluated by qRT-PCR, western blotting, and immunohistochemistry in breast cancer patient specimens. The significance of BAG2 expression in prognosis was assessed by Kaplan-Meier survival analysis and the Cox regression model. The roles of BAG2 in facilitating the formation of mutant p53 aggregates were analyzed by co-immunoprecipitation, immunofluorescence, and semi-denaturing detergent-agarose gel electrophoresis assays. The effects of BAG2 on the chemoresistance of breast cancer were demonstrated by cell function assays and mice tumor models. Results: In the present study, we found that BAG2 was significantly upregulated in relapse breast cancer patient tissues and high BAG2 was associated with a worse prognosis. BAG2 localized in mutant p53 aggregates and interacted with misfolded p53 mutants. BAG2 exacerbated the formation of the aggregates and recruited HSP90 to promote the propagation and maintenance of the aggregates. Consequently, BAG2-mediated mutant p53 aggregation inhibited the mitochondrial apoptosis pathway, leading to chemoresistance in breast cancer. Importantly, silencing of BAG2 or pharmacological targeting of HSP90 substantially reduced the aggregates and increased the sensitivity of chemotherapy in breast cancer. Conclusion: These findings reveal a significant role of BAG2 in the chemoresistance of breast cancer via exacerbating mutant p53 aggregates and suggest that BAG2 may serve as a potential therapeutic target for breast cancer patients with drug resistance.
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Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Chaperonas Moleculares , Proteína Supressora de Tumor p53 , Animais , Camundongos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Choque Térmico HSP90/metabolismo , Recidiva Local de Neoplasia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neoplasias da Mama/genética , Humanos , FemininoRESUMO
Macropinocytosis is an effective strategy to mitigate nutrient starvation. It can fuel cancer cell growth in nutrient-limited conditions. However, whether and how macropinocytosis contributes to the rapid proliferation of hepatocellular carcinoma cells, which frequently experience an inadequate nutrient supply, remains unclear. Here, we demonstrated that nutrient starvation strongly induced macropinocytosis in some hepatocellular carcinoma cells. It allowed the cells to acquire extracellular nutrients and supported their energy supply to maintain rapid proliferation. Furthermore, we found that the phospholipid flippase ATP9A was critical for regulating macropinocytosis in hepatocellular carcinoma cells and that high ATP9A levels predicted a poor outcome for patients with hepatocellular carcinoma. ATP9A interacted with ATP6V1A and facilitated its transport to the plasma membrane, which promoted plasma membrane cholesterol accumulation and drove RAC1-dependent macropinocytosis. Macropinocytosis inhibitors significantly suppressed the energy supply and proliferation of hepatocellular carcinoma cells characterised by high ATP9A expression under nutrient-limited conditions. These results have revealed a novel mechanism that overcomes nutrient starvation in hepatocellular carcinoma cells and have identified the key regulator of macropinocytosis in hepatocellular carcinoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Membrana Celular , Neoplasias Hepáticas/metabolismo , Nutrientes , Fosfolipídeos/metabolismoRESUMO
The adult brain can efficiently track both lower-level (i.e., syllable) and higher-level (i.e., phrase) linguistic structures to comprehend speech. When children actively or passively listened to speech, we found robust neural tracking of syllabic structure but marginally significant tracking of phrasal structure.
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Percepção da Fala , Fala , Adulto , Humanos , Criança , Magnetoencefalografia , Linguística , EncéfaloRESUMO
Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)-mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3'UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC. SIGNIFICANCE: This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.
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Carcinoma Hepatocelular , Janus Quinase 2 , Neoplasias Hepáticas , Estabilidade de RNA , Proteínas de Ligação a RNA , Fator de Transcrição STAT3 , Proteína 3 Supressora da Sinalização de Citocinas , Humanos , Carcinoma Hepatocelular/patologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Neoplasias Hepáticas/patologia , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genéticaRESUMO
Subjective tinnitus patients experience more hearing difficulties than normal peers in complex hearing environments, even though most of these patients have normal pure-tone hearing thresholds. Using speech recognition tasks under different masking conditions can provide insight into whether the effects of tinnitus are lateralized and the mechanisms behind the effects. By simulating sound field recordings, we obtain a target speech sentence that can be perceived as presented on one side and noise or speech masking with or without spatial separation from it. Our study used the virtual sound field technique to investigate the difference in speech recognition ability between chronic subjective tinnitus patients and a normal-hearing control group under the four masking conditions (speech-spectrum noise masking or two-talker speech masking, with or without perceived spatial separation). Experiment 1 showed no differences for target speech perceived location (left or right), which rules out a lateralization of the effect of tinnitus patients. Experiment 2 further found that although tinnitus patients had weaker performance than normal people in very complex auditory scenarios, when the spatial cue of the target speech exists, they can make good use of this cue to make up for the original processing disadvantage and achieve a similar performance as the normal-hearing group. In addition, the current study distinguished the effects of informational masking and energetic masking on speech recognition in patients with tinnitus and normal hearing. The results suggest that the impact of tinnitus on speech recognition in patients is more likely to occur in the auditory center rather than the periphery.
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BACKGROUND: Distant metastasis is the prominent factor for cancer-induced death of gastric cancer in which peritoneum is one of the dominating targets of gastric cancer metastasis. However, there is still a lack of effective predictive indicators and treatment methods for gastric cancer patients with peritoneal metastasis. METHODS: A clustering assay was used to investigate the cell aggregates formation ability. While the soft agar assay and anoikis assay were performed to detect the anchorage-independent growth and anoikis-resistant ability respectively. Luciferase activity assay, western blotting and immunofluorescence were used to explore the effect of HMMR on AKT signaling activity. The peritoneal implantation model was examined to explore the role of HMMR in vivo. RESULTS: Silencing of HMMR expression markedly reduced the peritoneal metastasis of gastric cancer cells through reducing cell-cell interactions. Mechanistically, HA-HMMR could activate Akt signaling, thus succeeding in distant colonization and metastatic outgrowth. Importantly, inducible depletion of HMMR significantly abrogates peritoneal implantation of gastric cancer in vitro and in vivo. CONCLUSION: Our study highlights that HMMR promotes peritoneal implantation of gastric cancer. A better understanding of HMMR's functions and mechanism might provide a novel therapeutic target and prognostic marker for metastatic gastric cancer.
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Since December 2019, the novel coronavirus disease (COVID-19) caused by the syndrome coronavirus 2 (SARS-CoV-2) strain has spread widely around the world and has become a serious global public health problem. For this high-speed infectious disease, the application of X-ray to chest diagnosis plays a key role. In this study, we propose a chest X-ray image classification method based on feature fusion of a dense convolutional network (DenseNet) and a visual geometry group network (VGG16). This paper adds an attention mechanism (global attention machine block and category attention block) to the model to extract deep features. A residual network (ResNet) is used to segment effective image information to quickly achieve accurate classification. The average accuracy of our model in detecting binary classification can reach 98.0%. The average accuracy for three category classification can reach 97.3%. The experimental results show that the proposed model has good results in this work. Therefore, the use of deep learning and feature fusion technology in the classification of chest X-ray images can become an auxiliary tool for clinicians and radiologists.
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Triple-negative breast cancer (TNBC) is fast-growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3ß) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3ß inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p-PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3ß phosphorylation at high levels. Furthermore, p-PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non-phosphorylated GSK3ß. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3ß inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.
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Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias de Mama Triplo Negativas/genética , Progressão da Doença , Feminino , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos adversos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
In the continuous variable measurement-device-independent quantum key distribution (CV-MDI-QKD) protocol, both Alice and Bob send quantum states to an untrusted third party, Charlie, for detection through the quantum channel. In this paper, we mainly study the performance of the CV-MDI-QKD system using the noiseless linear amplifier (NLA). The NLA is added to the output of the detector at Charlie's side. The research results show that NLA can increase the communication distance and secret key rate of the CV-MDI-QKD protocol. Moreover, we find that the more powerful the improvement of the performance with the longer gain of NLA and the optimum gain is given under different conditions.
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Nicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer's poor prognosis; however, nicotine's role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-'UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis, suggesting that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer.
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Regulação para Baixo/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Metástase Linfática , Nicotina/farmacologia , Estabilidade de RNA/fisiologia , Proteases Específicas de Ubiquitina/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Indutores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/metabolismo , Tristetraprolina/metabolismo , Proteases Específicas de Ubiquitina/genética , Fator C de Crescimento do Endotélio Vascular/genéticaRESUMO
Pneumonia remains the leading infectious cause of death in children under the age of five, killing about 700,000 children each year and affecting 7% of the world's population. X-ray images of lung become the key to the diagnosis of this disease, skilled doctors in the diagnosis of a certain degree of subjectivity, if the use of computer-aided medical diagnosis to automatically detect lung abnormalities, will improve the accuracy of diagnosis. This research aims to introduce a deep learning technology based on the combination of Xception neural network and long-term short-term memory (LSTM), which can realize automatic diagnosis of patients with pneumonia in X-ray images. First, the model uses the Xception network to extract the deep features of the data, passes the extracted features to the LSTM, and then the LSTM detects the extracted features, and finally selects the most needed features. Secondly, in the training set samples, the traditional cross-entropy loss cannot more balance the mismatch between categories. Therefore, this research combines Pearson's feature selection ideas, fusion of the correlation between the two loss functions, and optimizes the problem. The experimental results show that the accuracy rate of this paper is 96%, the receiver operator characteristic curve accuracy rate is 99%, the precision rate is 98%, the recall rate is 91%, and the F1 score accuracy rate is 94%. Compared with the existing technical methods, the research has achieved expected results on the currently available datasets. And assist doctors to provide higher reliability in the classification task of childhood pneumonia.
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Diagnóstico por Computador , Pulmão/diagnóstico por imagem , Pneumonia/diagnóstico , Tórax/diagnóstico por imagem , Aprendizado Profundo , Humanos , Pulmão/fisiopatologia , Redes Neurais de Computação , Pneumonia/diagnóstico por imagem , Pneumonia/fisiopatologia , Tórax/fisiopatologiaRESUMO
Detection of transient changes in interaural correlation is based on the temporal precision of the central representations of acoustic signals. Whether schizophrenia impairs the temporal precision in the interaural correlation process is not clear. In both participants with schizophrenia and matched healthy-control participants, this study examined the detection of a break in interaural correlation (BIC, a change in interaural correlation from 1 to 0 and back to 1), including the longest interaural delay at which a BIC was just audible, representing the temporal extent of the primitive auditory memory (PAM). Moreover, BIC-induced electroencephalograms (EEGs) and the relationships between the early binaural psychoacoustic processing and higher cognitive functions, which were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), were examined. The results showed that compared to healthy controls, participants with schizophrenia exhibited poorer BIC detection, PAM and RBANS score. Both the BIC-detection accuracy and the PAM extent were correlated with the RBANS score. Moreover, participants with schizophrenia showed weaker BIC-induced N1-P2 amplitude which was correlated with both theta-band power and inter-trial phase coherence. These results suggested that schizophrenia impairs the temporal precision of the central representations of acoustic signals, affecting both interaural correlation processing and higher-order cognitions.
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Esquizofrenia , Estimulação Acústica , Percepção Auditiva , Eletroencefalografia , Potenciais Evocados Auditivos do Tronco Encefálico , Humanos , PsicoacústicaRESUMO
This study was to investigate whether human listeners are able to detect a binaurally uncorrelated arbitrary-noise fragment embedded in binaurally identical arbitrary-noise markers [a break in correlation, break in interaural correlation (BIAC)] in either frequency-constant (frequency-steady) or frequency-varied (unidirectionally frequency gliding) noise. Ten participants with normal hearing were tested in Experiment 1 for up-gliding, down-gliding, and frequency-steady noises. Twenty-one participants with normal hearing were tested in Experiment 2a for both up-gliding and frequency-steady noises. Another nineteen participants with normal hearing were tested in Experiment 2b for both down-gliding and frequency-steady noises. Listeners were able to detect a BIAC in the frequency-steady noise (center frequency = 400 Hz) and two types of frequency-gliding noises (center frequency: between 100 and 1,600 Hz). The duration threshold for detecting the BIAC in frequency-gliding noises was significantly longer than that in the frequency-steady noise (Experiment 1), and the longest interaural delay at which a duration-fixed BIAC (200 ms) in frequency-gliding noises could be detected was significantly shorter than that in the frequency-steady noise (Experiment 2). Although human listeners can detect a BIAC in frequency-gliding noises, their sensitivity to a BIAC in frequency-gliding noises is much lower than that in frequency-steady noise.
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BACKGROUND: Frozen shoulders (FS) is a major clinical concern, where chronic synovial inflammation, abnormal angiogenesis, and fibrosis represent the critical pathologies in the glenohumeral capsule. However, no pharmacotherapy has been introduced to treat this pathology. Tetrandrine (TET) has been proposed as a treatment for many diseases due to its strong anti-inflammatory, anti-angiogenic, and anti-fibrotic effects. PURPOSE: To study the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of TET on FS, and identify whether TET can prevent the development of FS in rats. STUDY DESIGN: A controlled laboratory study. METHODS: Forty-eight male Sprague-Dawley (SD) rats were randomly divided into control, TET, and FS groups. The TET group was intraperitoneally injected with TET every 2 days. TET and saline treatment were started on the day of FS surgery. After 8 weeks, the animals were sacrificed, and samples were collected for X-ray examination, glenohumeral range of motion (ROM) evaluation, histology and immunohistochemistry analysis, transmission electron microscopy (TEM) observation, and profibrogenic factors as well as proinflammatory cytokines measurements. RESULTS: No significant difference in shoulder ROM was observed between the TET and control groups, but a significant difference was noted between these groups and the FS group (P < 0.01). Immunohistochemical staining showed no abnormal angiogenesis or fibrosis in the TET group or the control group. However, significant angiogenesis, collagen remodeling, and fibrosis were observed in the FS group, and the expression and proportion of type I and type III collagen in the FS group were significantly higher than those in the TET group or the control group (P < 0.01). TEM observation showed that TET protected the ultrastructure of collagen fibrous reticular arrangement of the articular capsule and prevented the formation of scar-like fibrotic structures, which are unique to FS. The significantly increased expression of Smad7 and the suppressed expression of Smad 2 in the TET group compared with that of the FS group indicated that TET also significantly inhibited the TGF-ß1 intracellular signal pathway. The expression of profibrogenic factors and proinflammatory cytokines in the TET group and the control group was significantly lower than that in the TET group (P < 0.01). CONCLUSION: The results demonstrated that TET protected the normal reticular structure of the capsule during the freezing period and prevented the development of FS by inhibiting inflammation, angiogenesis, and fibrosis in a rat FS model. CLINICAL RELEVANCE: TET may be a safe and effective clinical medication for preventing and treating FS.
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Inibidores da Angiogênese/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzilisoquinolinas/uso terapêutico , Bursite/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Benzilisoquinolinas/farmacologia , Bursite/metabolismo , Bursite/patologia , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Fibrose , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/metabolismo , Cápsula Articular/patologia , Cápsula Articular/ultraestrutura , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
Balancing mRNA nuclear export kinetics with its nuclear decay is critical for mRNA homeostasis control. How this equilibrium is aberrantly disrupted in esophageal cancer to acquire cancer stem cell properties remains unclear. Here we find that the RNA-binding protein interleukin enhancer binding factor 2 (ILF2) is robustly upregulated by nicotine, a major chemical component of tobacco smoke, via activation of JAK2/STAT3 signaling and significantly correlates with poor prognosis in heavy-smoking patients with esophageal cancer. ILF2 bound the THO complex protein THOC4 as a regulatory cofactor to induce selective interactions with pluripotency transcription factor mRNAs to promote their assembly into export-competent messenger ribonucleoprotein complexes. ILF2 facilitated nuclear mRNA export and inhibited hMTR4-mediated exosomal degradation to promote stabilization and expression of SOX2, NANOG, and SALL4, resulting in enhanced stemness and tumor-initiating capacity of esophageal cancer cells. Importantly, inducible depletion of ILF2 significantly increased the therapeutic efficiency of cisplatin and abrogated nicotine-induced chemoresistance in vitro and in vivo. These findings reveal a novel role of ILF2 in nuclear mRNA export and maintenance of cancer stem cells and open new avenues to overcome smoking-mediated chemoresistance in esophageal cancer. SIGNIFICANCE: This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer.
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Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Nicotina/farmacologia , Proteína do Fator Nuclear 45/metabolismo , RNA Mensageiro/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Agonistas Nicotínicos/farmacologia , Proteína do Fator Nuclear 45/genética , Prognóstico , RNA Mensageiro/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Taxa de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chemoresistance is a major obstacle to the treatment of triple-negative breast cancer (TNBC), which has a poor prognosis. Increasing evidence has demonstrated the essential role of cancer stem cells (CSCs) in the process of TNBC chemoresistance. However, the underlying mechanism remains unclear. In the present study, we report that block of proliferation 1 (BOP1) serves as a key regulator of chemoresistance in TNBC. BOP1 expression was significantly upregulated in chemoresistant TNBC tissues, and high expression of BOP1 correlated with shorter overall survival and relapse-free survival in patients with TNBC. BOP1 overexpression promoted, while BOP1 downregulation inhibited the drug resistance and CSC-like phenotype of TNBC cells in vitro and in vivo. Moreover, BOP1 activated Wnt/ß-catenin signaling by increasing the recruitment of cyclic AMP response element-binding protein (CBP) to ß-catenin, enhancing CBP-mediated acetylation of ß-catenin, and increasing the transcription of downstream stemness-related genes CD133 and ALDH1A1. Notably, treating with the ß-catenin/CBP inhibitor PRI-724 induced an enhancement of chemotherapeutic response of paclitaxel in BOP1-overexpressing TNBC cells. These findings indicate that BOP1 is involved in chemoresistance development and might serve as a prognostic marker and therapeutic target in TNBC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.