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Controlling topological phases of light allows the observation of abundant topological phenomena and the development of robust photonic devices. The prospect of more sophisticated control with topological photonic devices for practical implementations requires high-level programmability. Here we demonstrate a fully programmable topological photonic chip with large-scale integration of silicon photonic nanocircuits and microresonators. Photonic artificial atoms and their interactions in our compound system can be individually addressed and controlled, allowing the arbitrary adjustment of structural parameters and geometrical configurations for the observation of dynamic topological phase transitions and diverse photonic topological insulators. Individual programming of artificial atoms on the generic chip enables the comprehensive statistical characterization of topological robustness against relatively weak disorders, and counterintuitive topological Anderson phase transitions induced by strong disorders. This generic topological photonic chip can be rapidly reprogrammed to implement multifunctionalities, providing a flexible and versatile platform for applications across fundamental science and topological technologies.
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Multiple myeloma is a heterogeneous hematological disease that originates from the bone marrow and is characterized by the monoclonal expansion of malignant plasma cells. Despite novel therapies, multiple myeloma remains clinically challenging. A common feature among patients with poor prognosis is the increased activity of the epigenetic silencer EZH2, which is the catalytic subunit of the PRC2. Interestingly, the recruitment of PRC2 lacks sequence specificity and, to date, the molecular mechanisms that define which genomic locations are destined for PRC2-mediated silencing remain unknown. The presence of a long non-coding RNA (lncRNA)-binding pocket on EZH2 suggests that lncRNA could potentially mediate PRC2 recruitment to specific genomic regions. Here, we coupled RNA immunoprecipitation sequencing, RNA-sequencing and chromatin immunoprecipitation-sequencing analysis of human multiple myeloma primary cells and cell lines to identify potential lncRNA partners to EZH2. We found that the lncRNA plasmacytoma variant translocation 1 (PVT1) directly interacts with EZH2 and is overexpressed in patients with a poor prognosis. Moreover, genes predicted to be targets of PVT1 exhibited H3K27me3 enrichment and were associated with pro-apoptotic and tumor suppressor functions. In fact, PVT1 inhibition independently promotes the expression of the PRC2 target genes ZBTB7C, RNF144A and CCDC136. Altogether, our work suggests that PVT1 is an interacting partner in PRC2-mediated silencing of tumor suppressor and pro-apoptotic genes in multiple myeloma, making it a highly interesting potential therapeutic target.
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Mieloma Múltiple , ARN Largo no Codificante , Humanos , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Proteína Potenciadora del Homólogo Zeste 2/genética , ARN Largo no Codificante/genética , Línea Celular Tumoral , Genómica , Péptidos y Proteínas de Señalización IntracelularRESUMEN
The non-neuronal cholinergic system, widely distributed in nature, is an ancient system that has not been well studied in insects. This study aims to investigate the key components of the cholinergic system and to identify the non-neuronal acetylcholine (ACh)-producing cells and the acting sites of ACh in the Malpighian tubules (MTs) of Mythimna separata. We found that non-neuronal ACh in MTs is synthesized by carnitine acetyltransferase (CarAT), rather than choline acetyltransferase (ChAT), as confirmed by using enzyme inhibitors and high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS). Fluorescence in situ hybridization revealed the presence of CarAT mRNA within MTs, specifically localized in the principal cells. Immunohistochemistry showed strong staining for A-mAChR, a muscarinic acetylcholine receptor, in the principal cells. Pharmacological analysis further demonstrated that ACh acts through A-mAChR in the principal cells to increase the intracellular Ca2+ concentration. These findings provide compelling evidence for the existence of a non-neuronal cholinergic system in the MTs of M. separata, and the principal cells play a crucial role in ACh synthesis via CarAT.
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Acetilcolina , Sistema Colinérgico no Neuronal , Animales , Acetilcolina/farmacología , Túbulos de Malpighi/metabolismo , Hibridación Fluorescente in Situ , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Clinical rehabilitation for brachial plexus injury is difficult in terms of chronic pain and dysfunction. Physiotherapy is considered a routine intervention for rehabilitation. Common physical therapy may require a variety of instruments. One approach that does not need instruments, but belongs to the field of complementary and alternative medicine, is naprapathy. Naprapathy, also called Tuina in China, has been applied in rehabilitation after brachial plexus injury for a long time. Naprapathy can relieve chronic neuropathic pain, promote local blood circulation, and improve body edema. Naprapathy can passively help improve motor functions in patients with peripheral nerve injury. However, the efficacy of naprapathy in improving rehabilitation after brachial plexus injury is unclear. OBJECTIVE: This study aims to evaluate the additional value of naprapathy when combined with conventional physical therapy for the treatment of brachial plexus injury. METHODS: This will be a single-center randomized controlled trial. A total of 116 eligible patients with brachial plexus injury will be randomly divided into an experimental group (naprapathy plus physical therapy group) or a control group (physical therapy group). The participants will be followed up for 4 weeks of treatment. Observation outcomes will include the visual analog scale score, upper limb index, electromyography findings, and adverse reactions, among others. The measuring points for outcomes will be the baseline and the completion of treatment. In addition, a quality control group independent from the research team will be set up to control the quality of the trial. Finally, the data will be analyzed using SPSS software (version 21.0; IBM Corp). RESULTS: The study is recruiting participants. The first participant was enrolled in September 2021. As of January 2023, a total of 100 participants have been enrolled. The trial is expected to be completed by September 2023. The study protocol was approved by the Ethics Review Committee of Yue Yang Hospital affiliated with the Shanghai University of Traditional Chinese Medicine (2021-012). CONCLUSIONS: One limitation of this trial is that we will be unable to achieve strict double-blinding because of the features of naprapathy. The trial aims to contribute reliable evidence for decision-making in naprapathy for treating brachial plexus injury. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100043515; http://www.chictr.org.cn/showproj.aspx?proj=122154. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46054.
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Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive component 2 is overexpressed in a variety of cancers and recognized as a therapeutic target molecule. However, EZH2 possesses immunomodulatory functions in the tumor microenvironment (TME). The impact of EZH2 on TME of hepatocellular carcinoma (HCC) using immunocompetent mouse model was evaluated in the present study. UNC1999, an EZH2 inhibitor, impaired growth of the murine HCC cells (H22 cells) and induced apoptosis in a dose-dependent manner. Although UNC1999 significantly inhibited the growth of H22 cells-derived and Hepa1-6 cells-derived tumors in nonobese diabetic/severe combined immunodeficiency mice, its antitumor effect was diminished in allogenic BALB/c and C57BL/6 mice. Flow cytometric analyses of TME cells in BALB/c mice demonstrated a significant decrease in the number of interferonγ+ CD8+ T cells and regulatory T cells and a significant increase in the number of myeloid-derived suppressor cells (MDSCs). Administration of Gr-1 neutralizing antibody concomitant with UNC1999 restored antitumor effect accompanied by an increase in the number of CD8+ T cells followed by a decrease in the number of MDSCs. Chemokine antibody array demonstrated an enhanced expression of chemokines responsible for MDSCs recruitment such as C5a, CCL8, and CCL9. In conclusion, the study results demonstrated that EZH2 inhibitor contributed to attenuation of tumor immunity caused by TME arrangement. Combination therapy with EZH2 inhibitors and agents that reduce MDSCs might represent a novel therapeutic strategy for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Carcinoma Hepatocelular/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Neoplasias Hepáticas/metabolismo , Linfocitos T CD8-positivos/metabolismo , Microambiente Tumoral , Ratones Endogámicos C57BL , Ratones Endogámicos , Inhibidores Enzimáticos/uso terapéutico , Línea Celular TumoralRESUMEN
Climate warming poses a great threat to ecosystems worldwide, which significantly affects the geographical distribution and suitable growth area of species. Taking Castanopsis hystrix Miq. as the research object, the potentially suitable cultivation regions under present and future climatic emission scenarios in China were predicted based on the MaxEnt model with 360 effective individual distributions and eight environmental variables. The min temperature of coldest month (bio6), precipitation of driest month (bio14), and precipitation of warmest quarter (bio18) are three leading factors affecting the geographical distribution area of C. hystrix Miq. The suitable cultivation regions of C. hystrix Miq. range from 18°-34° N, 89°-122° E in central and southern China and cover an area of 261.95 × 104 km2. The spatial pattern of C. hystrix Miq. will migrate to the southern region of low latitudes with a decreasing suitable area when in ssp1-2.6, and to the southwestern region of low latitudes or expand to the northeast region at high latitudes in ssp5-8.5, with an increasing suitable area; no significant change on the spatial pattern in ssp2-2.4. For ssp1-2.6 or ssp2-4.5 climate scenarios, the southern region of high latitudes will be appropriate for introducing and cultivating C. hystrix Miq., and the cultivation area will increase. For ssp5-8.5, its cultivation will increase and expand to the northeast of high-latitude areas slightly.
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Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation-related markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and simultaneous suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2's both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.
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Proteína Potenciadora del Homólogo Zeste 2 , Mieloma Múltiple , Humanos , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Histonas/metabolismo , Mieloma Múltiple/genética , Línea Celular Tumoral , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Carcinogénesis , Transformación Celular NeoplásicaRESUMEN
General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound 39 engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID. We also demonstrate the ability of compound 39 to alleviate MDSC-related T cell suppression and restore T cell proliferation, similar to the effect seen in MDSCs from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI) as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced by treatment with compound 39 demonstrating the complementarity of these two mechanisms.
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Células Supresoras de Origen Mieloide , eIF-2 Quinasa , Animales , Hemo , Ratones , Ratones Noqueados , Proteínas Serina-Treonina Quinasas , Linfocitos T/metabolismo , eIF-2 Quinasa/metabolismoRESUMEN
BACKGROUND: Acetylcholine (ACh), as a classical neurotransmitter, plays great roles in the nervous system. There is increasing evidence of its non-neuronal roles in regulating basic cell functions in vertebrates. However, knowledge about the non-neuronal cholinergic system in insects is scarce. RESULTS: A comparative transcriptome analysis was performed to investigate differences in the key molecular components of the cholinergic system between the head and ovary. The results showed that expression levels of most cholinergic system-related genes were higher in the head than in the ovary, and some cholinergic components were absent in the ovary. ACh contents ranged from 0.1 to 1.3 µg mg-1 of wet weight during the development of the ovary, and weak acetylcholinesterase activity was also detected. Moreover, the ovary has a capacity for ACh synthesis. Bromoacetylcarnitine (BrACar), a specific carnitine acetyltransferase (CarAT) inhibitor, greatly inhibits ACh synthesis by 83.83% in ovary homogenates, but bromoacetylcholine (BrACh), a specific choline acetyltransferase (ChAT) inhibitor, has no effect on ACh synthesis in the ovary. These findings indicate that non-neuronal ACh in the ovary is only catalyzed by CarAT. CONCLUSION: This study reveals the existence of the non-neuronal cholinergic system in the ovary of M. separata, whose synthesis and release mechanisms are different from those of the head. These results provide novel insights into the non-neuronal cholinergic system in insects, and will be valuable in the discovery of new target genes and the future development of green pest control. © 2022 Society of Chemical Industry.
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Mariposas Nocturnas , Sistema Colinérgico no Neuronal , Animales , Femenino , Spodoptera/metabolismo , Ovario/metabolismo , Acetilcolinesterasa/metabolismo , Acetilcolina/metabolismo , Acetilcolina/farmacología , Perfilación de la Expresión Génica , Colinérgicos/metabolismoRESUMEN
Enhancer of zeste homolog 2 (EZH2), a catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed in triple-negative breast cancer (TNBC), correlating with poor prognosis. However, EZH2 catalytic inhibitors are ineffective in suppressing the growth of TNBC cells that are dependent on EZH2. Knockdown of EZH2 inhibits the proliferation of these cells, suggesting that EZH2 protein overexpression but not its catalytic activity is critical for driving TNBC progression. Several proteolysis targeting chimera (PROTAC) degraders of EZH2, including the von Hippel-Lindau (VHL)-recruiting PROTAC YM281, have been reported. However, the effects of these EZH2 PROTACs in TNBC cells were not investigated. Here, we report the discovery and characterization of a novel, potent, and selective EZH2 PROTAC degrader, MS8815 (compound 16), which induced robust EZH2 degradation in a concentration-, time-, and proteasome-dependent manner in TNBC cells. Importantly, 16 effectively suppressed the cell growth in multiple TNBC cell lines and primary patient TNBC cells.
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Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Both canonical (EZH2-PRC2) and noncanonical (EZH2-TAD-cMyc-coactivators) activities of EZH2 promote oncogenesis, which explains the slow and ineffective antitumour effect of inhibitors of the catalytic function of EZH2. To suppress the multifaceted activities of EZH2, we used proteolysis-targeting chimera (PROTAC) to develop a degrader, MS177, which achieved effective, on-target depletion of EZH2 and interacting partners (that is, both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes). Compared with inhibitors of the enzymatic function of EZH2, MS177 is fast-acting and more potent in suppressing cancer growth. This study reveals noncanonical oncogenic roles of EZH2, reports a PROTAC for targeting the multifaceted tumorigenic functions of EZH2 and presents an attractive strategy for treating EZH2-dependent cancers.
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Proteína Potenciadora del Homólogo Zeste 2 , Neoplasias , Carcinogénesis/genética , Proteínas del Citoesqueleto/metabolismo , Proteína p300 Asociada a E1A , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Proteolisis , Activación TranscripcionalRESUMEN
Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2lowH3K27me3high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
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Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Carcinoma Hepatocelular/terapia , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Indazoles/uso terapéutico , Neoplasias Hepáticas/terapia , Piperazinas/uso terapéutico , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Piridonas/uso terapéutico , Sorafenib/uso terapéutico , Anciano , Animales , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Terapia Genética , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones SCID , Persona de Mediana Edad , Complejo Represivo Polycomb 2/genéticaRESUMEN
BACKGROUND: Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. RESULTS: Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. CONCLUSIONS: Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.
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Supervivencia Celular/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/administración & dosificación , Metiltransferasas/farmacología , Mieloma Múltiple/tratamiento farmacológico , Resistencia a Medicamentos/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/farmacología , Humanos , Metiltransferasas/administración & dosificación , Mieloma Múltiple/fisiopatologíaRESUMEN
During the process of vertebrate evolution, many thermogenic organs and mechanisms have appeared. Mammalian brown adipose tissue (BAT) generates heat through the uncoupling oxidative phosphorylation of mitochondria, acts as a natural defense against hypothermia and inhibits the development of obesity. Although the existence, cellular origin and molecular identity of BAT in humans have been well studied, the genetic and functional characteristics of BAT from lampreys remain unknown. Here, we identified and characterized a novel, naturally existing brown-like adipocytes at the lamprey brain periphery. Similar to human BAT, the lamprey brain periphery contains brown-like adipocytes that maintain the same morphology as human brown adipocytes, containing multilocular lipid droplets and high mitochondrion numbers. Furthermore, we found that brown-like adipocytes in the periphery of lamprey brains responded to thermogenic reagent treatment and cold exposure and that lamprey UCP2 promoted precursor adipocyte differentiation. Molecular mapping by RNA-sequencing showed that inflammation in brown-like adipocytes treated with LPS and 25HC was enhanced compared to controls. The results of this study provide new evidence for human BAT research and demonstrate the multilocular adipose cell functions of lampreys, including: (1) providing material energy and protecting structure, (2) generating additional heat and contributing to adaptation to low-temperature environments, and (3) resisting external pathogens.
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Commonly used fastener positioning methods include pixel statistics (PS) method and template matching (TM) method. For the PS method, it is difficult to judge the image segmentation threshold due to the complex background of the track. For the TM method, the search in both directions of the global is easily affected by complex background, as a result, the locating accuracy of fasteners is low. To solve the above problems, this paper combines the PS method with the TM method and proposes a new fastener positioning method called local unidirectional template matching (LUTM). First, the rail positioning is achieved by the PS method based on the gray-scale vertical projection. Then, based on the prior knowledge, the image of the rail and the surrounding area of the rail is obtained which is referred to as the 1-shaped rail image; then, the 1-shaped rail image and the produced offline symmetrical fastener template is pre-processed. Finally, the symmetrical fastener template image is searched from top to bottom along the rail and the correlation is calculated to realize the fastener positioning. Experiments have proved that the method in this paper can effectively realize the accurate locating of the fastener for ballastless track and ballasted track at the same time.
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Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are well-known viral RNA sensors in the cytoplasm. RIG-I-mediated antiviral signals are activated by interacting with the adapter protein mitochondrial antiviral signaling (MAVS), which triggers interferon (IFN) responses via a signaling cascade. Although the complete RIG-I receptor signaling pathway has been traced back to teleosts, definitive evidence of its presence in lampreys is lacking. Here, we identified 13 pivotal molecules in the RIG-I signaling pathway in lamprey, and demonstrated that the original RIG-I/MAVS signaling pathway was activated and mediated the expression of unique immunity factors such as RRP4, to inhibit viral proliferation after viral infection in vivo and in vitro. This study confirmed the conservation of the RIG-I pathway, and the uniqueness of the RRP4 effector molecule in lamprey, and further clarified the evolutionary process of the RIG-I antiviral signaling pathway, providing evidence on the origins of innate antiviral immunity in vertebrates.
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Antivirales , Lampreas , Animales , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/metabolismo , Genómica , Inmunidad Innata , Lampreas/genética , Lampreas/metabolismo , Transducción de SeñalRESUMEN
Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.
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Antineoplásicos/farmacología , Metilación de ADN/efectos de los fármacos , Resistencia a Antineoplásicos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Metaboloma , Metionina/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Piridonas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , TranscriptomaRESUMEN
BACKGROUND: This study was to explore the potential mechanism of naprapathy in treating neuropathic pain (NP) after brachial plexus injury (BPI). METHODS: Totally 72 rats were randomly divided into normal group, model control group, and naprapathy group (n=24 per group). A right upper-limb chronic NP model was established, and naprapathy was administered at C5-T1 Jiaji Points on 4th day after modeling. Naprapathy was performed for 15 min once daily with a frequency of 60 per minute. The treatment was applied for altogether 28 days. Cold pain threshold and mechanical pain threshold were measured 1 day before modeling, 3 days after modeling, and 7, 14, 21 and 28 days after naprapathy; 7, 14, 21 and 28 days after naprapathy, rats were killed and the ß-endorphin expression and γ-aminobutyric acid (GABA) content were detected in the thalamus. RESULTS: After 14-day treatment, there was significant difference of mechanical pain threshold between the naprapathy group and the normal group (P<0.05); after treatment for 21 and 28 days, there was no significant difference between the naprapathy group and the normal group (P>0.05); after 28-day naprapathy, there was significant difference of ß-EP expression between the normal group and the naprapathy group (P<0.05), while the difference between model control group and naprapathy group was statistically significant (P<0.05). After 14-day treatment, there was significant difference of GABA content between the model control group and the naprapathy group (P<0.05). After 28-day treatment, significant difference was also found between the model control group and the naprapathy group (P<0.05). CONCLUSIONS: After naprapathy, chronic NP is attenuated in rats with BPI, which might be ascribed to the upregulation of ß-endorphin and GABA.
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Plexo Braquial , Neuralgia , Animales , Plexo Braquial/lesiones , Neuralgia/tratamiento farmacológico , Umbral del Dolor , Ratas , Ratas Sprague-DawleyRESUMEN
The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.
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Antineoplásicos/química , Antineoplásicos/farmacología , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Piperazinas/farmacología , Piridinas/farmacología , Animales , Antineoplásicos/farmacocinética , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Técnicas de Inactivación de Genes , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Ratones Endogámicos BALB C , Terapia Molecular Dirigida , Proteolisis/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Complement factor I (CFI) is a serine protease which plays a key role in the modulation of complement system and the induced-fit factor responsible for controlling the complement-mediated processes. In this study, a CFI gene was cloned and characterized from Lampetra morii (designated as L-CFI) at molecular and cellular levels. The L-CFI protein included a factor I membrane attack complex domain (FIMAC), a scavenger receptor cysteine-rich domain (SRCR), a trypsin-like serine protease domain (Tryp_SPc) and 2 low-density lipoprotein receptor class A domains (LDLa) which would exhibit functional similarities to CFI superfamily proteins. Tissue expression profile analysis showed that L-CFI mRNA constitutively expressed in all tested tissues except erythrocytes, with the predominant expression in liver. The mRNA expression level of L-CFI increased significantly after Vibrio anguillarum and Staphylocccus aureus stimulation. It is demonstrated that L-CFI interacted with L-C3 protein and affected the deposition of L-C3 on the cell surface. Furthermore, lamprey serum after deplete L-CFI and L-C3 reduced the cytotoxic activity against HeLa cells. These findings suggest that L-CFI plays an important role in lamprey immunity and involved in the lamprey complement system.