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Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons. Whether SOCs contribute to peripheral sensitization associated with chronic inflammatory pain is elusive. Here we report that global or conditional deletion of Orai1 attenuates Complete Freund's adjuvant (CFA)-induced pain hypersensitivity in both male and female mice. To further establish the role of Orai1 in inflammatory pain, we performed calcium imaging and patch-clamp recordings in wild-type (WT) and Orai1 knockout (KO) DRG neurons. We found that SOC function was significantly enhanced in WT but not in Orai1 KO DRG neurons from CFA- and carrageenan-injected mice. Interestingly, the Orai1 protein level in L3/4 DRGs was not altered under inflammatory conditions. To understand how Orai1 is modulated under inflammatory pain conditions, prostaglandin E2 (PGE2) was used to sensitize DRG neurons. PGE2-induced increase in neuronal excitability and pain hypersensitivity was significantly reduced in Orai1 KO mice. PGE2-induced potentiation of SOC entry (SOCE) was observed in WT, but not in Orai1 KO DRG neurons. This effect was attenuated by a PGE2 receptor 1 (EP1) antagonist and mimicked by an EP1 agonist. Inhibition of Gq/11, PKC, or ERK abolished PGE2-induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade. These findings demonstrate that Orai1 plays an important role in peripheral sensitization. Our study also provides new insight into molecular mechanisms underlying PGE2-induced modulation of inflammatory pain.Significance Statement Store-operated calcium channel (SOC) Orai1 is expressed and functional in dorsal root ganglion (DRG) neurons. Whether Orai1 contributes to peripheral sensitization is unclear. The present study demonstrates that Orai1-mediated SOC function is enhanced in DRG neurons under inflammatory conditions. Global and conditional deletion of Orai1 attenuates complete Freund's adjuvant (CFA)-induced pain hypersensitivity. We also demonstrate that prostaglandin E2 (PGE2) potentiates SOC function in DRG neurons through EP1-mediated signaling pathway. Importantly, we have found that Orai1 deficiency diminishes PGE2-induced SOC function increase and reduces PGE2-induced increase in neuronal excitability and pain hypersensitivity. These findings suggest that Orai1 plays an important role in peripheral sensitization associated with inflammatory pain. Our study reveals a novel mechanism underlying PGE2/EP1-induced peripheral sensitization. Orai1 may serve as a potential target for pathological pain.
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Cálcio , Dinoprostona , Animais , Feminino , Masculino , Camundongos , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Dinoprostona/farmacologia , Dinoprostona/metabolismo , Adjuvante de Freund/toxicidade , Adjuvante de Freund/metabolismo , Gânglios Espinais/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , DorRESUMO
BACKGROUND: Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to the genesis of neuropathic pain. SYNCRIP, an RNA-binding protein, is critical for the stabilisation of gene expression. Whether SYNCRIP participates in nerve injury-induced alterations in DRG gene expression and nociceptive hypersensitivity is unknown. METHODS: The expression and distribution of SYNCRIP in mouse DRG after chronic constriction injury (CCI) of the unilateral sciatic nerve were assessed. Effect of microinjection of Syncrip small interfering RNA into the ipsilateral L3 and L4 DRGs on the CCI-induced upregulation of chemokine (C-C motif) receptor 2 (CCR2) and nociceptive hypersensitivity were examined. Additionally, effects of microinjection of adeno-associated virus 5 expressing full length Syncrip mRNA (AAV5-Syncrip) on basal DRG CCR2 expression and nociceptive thresholds were observed. RESULTS: SYNCRIP is expressed predominantly in DRG neurones, where it co-exists with CCR2. Levels of Syncrip mRNA and SYNCRIP protein in injured DRG increased time-dependently on days 3-14 after CCI. Blocking this increase through microinjection of Syncrip small interfering RNA into injured DRG attenuated CCI-induced upregulation of DRG CCR2 and development and maintenance of nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of AAV5-Syncrip elevated CCR2 expression in microinjected DRGs, enhanced the responses to mechanical, heat, and cold stimuli, and induced ongoing pain in naive mice. Mechanistically, SYNCRIP bound to 3-UTR of Ccr2 mRNA and stabilised its expression in DRG neurones. CONCLUSIONS: SYNCRIP contributes to the induction and maintenance of neuropathic pain likely through stabilising expression of CCR2 in injured DRG. SYNCRIP may be a potential target for treating this disorder.
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Waste cooking oil's (WCO's) potential as a rejuvenator of aged asphalt has received attention in recent years, with the acid value of WCO affecting its rejuvenation effect. This study explored the rejuvenation effect of WCO with a high acid value on aged asphalt by using molecular dynamics simulation. First, the representative molecules of WCO with a high acid value and asphalt were determined. The rejuvenation effect of WCO on aged asphalt was analyzed by adding different contents of WCO to an aged asphalt model. The effect of WCO on the thermodynamic properties of the aged asphalt was analyzed. The results show that WCO can restore the thermodynamic properties of aged asphalt binder to a certain extent. Regarding the microstructure of rejuvenated asphalt, WCO molecules dispersed around asphaltenes weakened the latter's aggregation and improved the colloidal structure of the aged asphalt. In terms of interface adhesion properties, WCO can improve the adhesion properties between asphalt binder and SiO2, but it has limited influence on water sensitivity. The results allowed us to comprehensively evaluate the rejuvenation effect of WCO with a high acid value on aged asphalt and to explore its rejuvenation mechanism.
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OBJECTIVE: To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. METHODS: Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. RESULTS: The proband of pedigree 1 was a fetus at 23+5 weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. CONCLUSION: The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.
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Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Feminino , Humanos , Gravidez , Linhagem , Cerebelo/diagnóstico por imagem , Cerebelo/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/diagnóstico , Monoéster Fosfórico Hidrolases/genética , Retina/diagnóstico por imagem , Retina/anormalidades , População do Leste Asiático , MutaçãoRESUMO
Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) is an inherited disorder characterized by severe microcephaly and abnormal facial features. Kinesin family member 11 (KIF11) mutations have been reported closely related to microcephaly in different cases, while the pathogenicity was still unclear. Here, we report a de novo heterozygous mutation in exon 20 of the KIF11 (c.2922G>T; p.Pro974=) from a microcephaly patient through whole-exome sequencing. Further studies identified that this variant affected the normal splicing of KIF11 pre-mRNA, thus leading to the c.2815_2922 deletion of exon 20 through PBMC-derived pre-mRNA splicing assay and minigene experiment. Moreover, c.2815_2922 deletion would produce a shortened KIF11 protein, which may competitively bind to the normal KIF11 protein, suggesting a dominant negative effect mechanism in c.2922G>T mutation-induced MCLMR.
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Microcefalia , Displasia Retiniana , Humanos , Cinesinas/genética , Leucócitos Mononucleares , Microcefalia/genética , Linhagem , Splicing de RNA/genética , Displasia Retiniana/genéticaRESUMO
OBJECTIVE: To explore the genetic basis for a couple who had developed polyhydramnios during three pregnancies and given birth to two liveborns featuring limb contracture, dyspnea and neonatal death. METHODS: Whole-exome sequencing (WES) was carried out on fetal tissue and peripheral blood samples from the couple. Suspected variants were verified by Sanger sequencing. RESULTS: The fetus was found to harbor homozygous nonsense c.3718C>T (p.Arg1240Ter) variants of the CNTNAP1 gene, which were respectively inherited from its mother and father. The variant was unreported previously. According to the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PM2+PP4). CONCLUSION: The novel homozygous nonsense variants of the CNTNAP1 gene probably underlay the lethal congenital contracture syndrome type 7 (LCCS7) in this pedigree. Above finding has enabled genetic counseling and prenatal diagnosis for the family.
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Contratura , Moléculas de Adesão Celular Neuronais , China , Contratura/genética , Feminino , Humanos , Recém-Nascido , Mutação , Linhagem , Gravidez , Sequenciamento do ExomaRESUMO
Neuropathic pain (NP) is chronic, intractable, and typically not alleviated using analgesics. Ferroptosis is a new type of cell death characterized by mitochondrial damage, oxidative stress, and mitochondrial dysfunction, affecting specific types of synaptic plasticity in the spinal cord. Here, we evaluated the role of ferroptosis in NP using chronic contractile injury (CCI) in rats. The CCI and control groups were subjected to sciatic nerve ligation. The mechanical withdrawal threshold and thermal withdrawal reflex latency were used to detect changes in mechanical pain threshold and thermal pain threshold in rats, respectively. Notably, CCI caused mechanical and thermal stimulation of the injured hind paw, reduced levels of glutathione peroxidase 4 (GPX4), and increased acyl-CoA synthetase long-chain family member 4 (ACSL4). Treatment with the ferroptosis inhibitor ferrostatin-1 (10 mg/kg) 1 h after surgery upregulated GPX4 expression and downregulated ACSL4 expression, whereas the ferroptosis inducer, erastin (10 mg/kg), exerted opposite effects. Treatment with ferrostatin-1 upregulated NeuN expression and downregulated GPX4 expression, whereas erastin reversed these effects. CCI increased the number of damaged mitochondria and decreased the mean planar mitochondrial area, and treatment with erastin further exacerbated these effects. The iron ion content in the spinal cords of CCI-induced rats increased. Treatment with ferrostatin-1 decreased, whereas treatment with erastin increased iron ion content in the CCI-induced rat model. Taken together, our results showed that ferroptosis is involved in the development of NP in male rats by blocking neuron and astrocyte activation in the spinal dorsal horn.
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Ferroptose , Hiperalgesia/patologia , Neuralgia/patologia , Nervo Isquiático/patologia , Medula Espinal/patologia , Animais , Comportamento Animal , Hiperalgesia/etiologia , Masculino , Neuralgia/etiologia , Estresse Oxidativo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Extensive studies revealed that long non-coding RNAs (lncRNAs) could act as a regulator in tumors, including lung adenocarcinoma (LUAD). LncRNA FTX transcript, XIST regulator (FTX) has been reported to regulate the biological behaviors of some cancers. Nevertheless, its functional role and molecular mechanism remain obscure in LUAD. Our current study concentrates on exploring the biological function of FTX in LUAD. METHODS: RT-qPCR was used to test the expression of FTX, miR-335-5p or NUCB2 in LUAD cells. The effect of FTX on LUAD progression was investigated by colony formation, EdU, flow cytometry, TUNEL, transwell and western blot assays. The interaction between microRNA-335-5p (miR-335-5p) and FTX or nucleobindin 2 (NUCB2) was confirmed by luciferase reporter assay. RESULTS: RT-qPCR showed that FTX expression was up-regulated in LUAD cell lines. Loss-of-function assay indicated that FTX accelerated cell proliferation, migration and invasion, while inhibited cell apoptosis in LUAD. Besides, miR-335-5p, lowly expressed in LUAD cells, was discovered to be sponged by FTX. Subsequently, NUCB2 was identified as a target gene of miR-335-5p. Additionally, it was confirmed that NUCB2 functioned as an oncogene in LUAD. Rescue assays indicated that LUAD progression inhibited by FTX knockdown could be restored by NUCB2 up-regulation. CONCLUSION: FTX played an oncogenic role in LUAD and contributed to cancer development via targeting miR-335-5p/NUCB2 axis.
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OBJECTIVE: To explore the genetic basis for a child with supravalvular aortic stenosis. METHODS: The child and his parents were subjected to conventional G-banding karyotyping, array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: No karyotypic abnormality was detected in the child and his parents. aCGH has identified a de novo 278 kb deletion encompassing the ELN gene in 7q11.23, which overlapped with the critical region of Williams-Beuren syndrome (WBS). MLPA has confirmed above findings. CONCLUSION: The proband was diagnosed with atypical WBS. Deletion of the ELN gene may predispose to supravalvular aortic stenosis in the proband.
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Estenose Aórtica Supravalvular/genética , Deleção de Genes , Síndrome de Williams/genética , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 7/genética , Hibridização Genômica Comparativa , Testes Genéticos , Humanos , Síndrome de Williams/complicaçõesRESUMO
OBJECTIVE: To explore the molecular mechanism of a girl with developmental delay and intellectual disability. METHODS: Chromosomal karotypes of the child and her parents were analyzed with routine G-banding method. Their genomic DNA was also analyzed with array comparative genomic hybridization (aCGH) for chromosomal duplications/deletions. RESULTS: No karyotypic abnormality was detected in the child and her parents, while aCGH has identified a de novo 3.37 Mb deletion at 17p11.2 in the child. CONCLUSION: The child was diagnosed with Smith-Magenis syndrome, for which RAI1 may be the causative gene.
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Síndrome de Smith-Magenis/genética , Criança , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 17/genética , Hibridização Genômica Comparativa , Feminino , Humanos , CariotipagemRESUMO
OBJECTIVE: To explore the genetic basis for a pedigree affected with Bartter's syndrome (BS). METHODS: Panel-based next-generation sequencing (NGS) was carried out to detect mutation in BS-related genes SLC12A1, KCNJ1, BSND and CLCNKB. Sanger sequencing of MAGED2 gene and chromosomal microarray analysis (CMA) were also performed on the patient. Suspected mutation was validated in her family members. RESULTS: No pathogenic mutation was detected by NGS, while a 0.152 Mb microdeletion at Xp11.21 (54 834 585-54 986 301) was found in the male fetus, which removed the entire coding region of the MAGED2 gene. His mother was a heterozygous carrier of the deletion. His father and sister did not carry the same deletion. CONCLUSION: The loss of the MAGED2 gene may underlie the BS in this pedigree.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos de Neoplasias/genética , Síndrome de Bartter/genética , Deleção de Sequência , Feminino , Testes Genéticos , Heterozigoto , Humanos , Masculino , Mutação , LinhagemRESUMO
OBJECTIVE: To analyze the molecular mechanism and prognosis of a child with aortic stenosis and thumb aplasia. METHODS: The karotypes of the child and his parents were analyzed with routine G-banding. Their genomic DNA was also analyzed with array comparative genomic hybridization(aCGH) for chromosomal duplications/deletions. RESULTS: No karyotypic abnormality was detected at cytogenetic level for the child and his parents. aCGH identified a de novo 5.86 Mb deletion at 2q22.3-q23.3 in the child. CONCLUSION: The child was diagnosed with 2q23.1 microdeletion syndrome. MBD5 may be the key gene for the 2q23.1 microdeletion syndrome.
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Estenose da Valva Aórtica/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 2/genética , Polegar/anormalidades , Criança , Bandeamento Cromossômico , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Hibridização Genômica Comparativa , Proteínas de Ligação a DNA/genética , Humanos , MasculinoRESUMO
OBJECTIVE: To carry out genetic analysis on a child with developmental delay and multiple malformation. METHODS: The karotypes of the child and her parents were analyzed with routine chromosomal G-banding. Their genomic DNA was analyzed with array comparative genomic hybridization (aCGH). RESULTS: The karyotype of the proband was determined as 46,XX,del(6)(q22),inv(6)(p21.1q21), while no karyotypic abnormality was detected in her parents. aCGH has identified in the child a de novo 800 kb deletion encompassing the RUNX2 gene at 6p21.1 and a de novo 11.79 Mb deletion at 6q21-q22.31. CONCLUSION: Both of the de novo deletions are pathogenic. Deletion of the RUNX2 gene probably underlies the cleidocranial dysplasia in the patient, while the 6q21-q22.31 deletion may result in malformation of the brain.
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Deleção Cromossômica , Cromossomos Humanos Par 6 , Displasia Cleidocraniana/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Testes Genéticos , Pré-Escolar , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Feminino , Humanos , CariotipagemRESUMO
OBJECTIVE: To analyze a child with facial abnormalities with combined cytogenetic and molecular techniques and delineate its clinical phenotype. METHODS: Neuropsychological profile of the child was analyzed. Color Doppler, CT and MRI were used for detecting the nodules in the body. Conventional peripheral blood karyotypes of the child and his parents were analyzed with G-banding. Array-comparative genomic hybridization (aCGH) was performed to detect minor structural chromosomal abnormalities. RESULTS: The child had mental retardation, maxillofacial dysmorphism on the right side, and irregular solid nodules on the back. The karyotypes of the child and his parents were all normal, while aCGH has identified a de novo constitutive 1.2 Mb deletion at 17q11.2 in the child. The aCGH results of his parents were normal. CONCLUSION: The de novo 17q11.2 microdeletion probably underlies the facial abnormalities and neurofibromatosis in the patient.
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Síndrome de Smith-Magenis/genética , Pré-Escolar , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Hibridização Genômica Comparativa , Humanos , Deficiência Intelectual/genética , Cariotipagem , Masculino , Anormalidades Maxilofaciais/genética , FenótipoRESUMO
OBJECTIVE: To study the genetic polymorphisms and mutations of 20 frequently used autosomal microsatellites among ethnic Hans from Henan. METHODS: Peripheral blood samples of 2604 individuals were collected. DNA was amplified and genotyped using a PowerPlex(TM) 21 system. The frequencies, forensic parameters and mutation rates of the 20 short tandem repeat (STR) loci were analyzed. RESULTS: A total of 323 alleles were found in this population and the allelic frequencies have ranged from 0.0003 to 0.5144. Except for D3S1358, TH01 and TPOX, mutations have been found in all of the remaining 17 STR loci, which totaled 47, with mutation rates ranging from 0 to 3.46 × 10-3. CONCLUSION: The 20 STR loci selected by the PowerPlex(TM) 21 system are highly polymorphic among ethnic Hans from Henan, and may be of great value in forensic and human population studies. As no similar study has been carried out previously, above results may be of great value for individual discrimination and paternal testing.
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Povo Asiático/genética , Repetições de Microssatélites , Polimorfismo Genético , Adolescente , Adulto , Alelos , Povo Asiático/etnologia , Criança , Pré-Escolar , China/etnologia , Feminino , Genótipo , Humanos , Masculino , Mutação , Linhagem , Adulto JovemRESUMO
Glycogen synthase kinase-3 (GSK3) has either tumor-suppressive roles or pro-tumor roles in different types of human tumors. A number of GSK3 targets in diverse signaling pathways have been uncovered, such as tuberous sclerosis complex subunit 2 and ß-catenin. The O subfamily of forkhead/winged helix transcription factors (FOXO) is known as tumor suppressors that induce apoptosis. In this study, we find that FOXO binds to type I insulin-like growth factor receptor (IGF-IR) promoter and stimulates its transcription. GSK3 positively regulates the transactivation activity of FOXO and stimulates IGF-IR expression. Although kinase-dead GSK3ß cannot up-regulate IGF-IR, the constitutively active GSK3ß induces IGF-IR expression in a FOXO-dependent manner. Serum starvation or Akt inhibition leads to an increase in IGF-IR expression, which could be blunted by GSK3 inhibition. GSK3ß knockdown or GSK3 inhibitor suppresses IGF-I-induced IGF-IR, Akt, and ERK1/2 phosphorylation. Moreover, knockdown of GSK3ß or FOXO1/3/4 leads to a decrease in cellular proliferation and abrogates IGF-I-induced hepatoma cell proliferation. These results suggest that GSK3 and FOXO may positively regulate IGF-I signaling and hepatoma cell proliferation.
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Fatores de Transcrição Forkhead/genética , Quinase 3 da Glicogênio Sintase/genética , Receptor IGF Tipo 1/genética , Fatores de Transcrição/genética , Western Blotting , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína Forkhead Box O1 , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Modelos Genéticos , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Receptor IGF Tipo 1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
PURPOSE: Prostate cancer (PCa) is often considered as a "cold" tumor with low responsiveness to immunotherapy. Recent evidence suggests the activation of specific immune cells, such as tumor-associated macrophages (TAMs), could potentially influence the efficacy of immunotherapy in PCa. However, the relationship between TAMs and PD-L1, a significant regulator in immunotherapy, within PCa remains unexplored. METHODS: In this study, we assessed TAM infiltration and PD-L1 expression levels in a local cohort of 95 PCa tissue samples and two publicly available PCa datasets. We employed a combination of bioinformatics and experimental techniques, including gene set enrichment analysis, CIBERSORTx, tissue microarray, immunohistochemistry staining, and analysis of single-cell sequencing datasets, to provide a comprehensive understanding of the association between PD-L1 and TAMs in the PCa microenvironment. RESULTS: The study showed that CD68+ TAMs and CD163+ TAMs (M2-TAMs) were more abundant in the tumor microenvironment than in non-cancerous surrounding tissues. The infiltration of CD163+ TAMs was significantly associated with the Gleason score and risk stratification of PCa. Importantly, elevated PD-L1 expression correlated significantly with high infiltration of CD163+ TAMs. Furthermore, patients displaying high levels of CD163+ TAMs and PD-L1 expression exhibited shorter times to biochemical recurrence-free survival. CONCLUSION: Our study suggests that CD163+ TAMs are closely associated with PD-L1 expression and can act as a valuable prognostic indicator for PCa. The high infiltration of M2-TAMs, coupled with the overexpression of PD-L1, may contribute to immune escape mechanisms in PCa, thereby influencing disease prognosis.
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Neoplasias da Próstata , Macrófagos Associados a Tumor , Humanos , Masculino , Antígeno B7-H1/metabolismo , Imunoterapia , Macrófagos/metabolismo , Prognóstico , Neoplasias da Próstata/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismoRESUMO
Peripheral nerve injury-induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel subfamily N member 1 (KCNN1) mediates action potential afterhyperpolarization (AHP) and gates neuronal excitability. However, the specific contribution of DRG KCNN1 to neuropathic pain is not yet clear. We report that chronic constriction injury (CCI) of the unilateral sciatic nerve or unilateral ligation of the fourth lumbar nerve produced the downregulation of Kcnn1 mRNA and KCNN1 protein in the injured DRG. This downregulation was partially attributed to a decrease in DRG estrogen-related receptor gamma (ESRRG), a transcription factor, which led to reduced binding to the Kcnn1 promoter. Rescuing this downregulation prevented CCI-induced decreases in total potassium voltage currents and AHP currents, reduced excitability in the injured DRG neurons, and alleviated CCI-induced development and maintenance of nociceptive hypersensitivities, without affecting locomotor function and acute pain. Mimicking the CCI-induced DRG KCNN1 downregulation resulted in augmented responses to mechanical, heat, and cold stimuli in naive mice. Our findings indicate that ESRRG-controlled downregulation of DRG KCNN1 is likely essential for the development and maintenance of neuropathic pain. Thus, KCNN1 may serve as a potential target for managing this disorder.
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Regulação para Baixo , Gânglios Espinais , Neuralgia , Células Receptoras Sensoriais , Animais , Masculino , Camundongos , Potenciais de Ação , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Neuralgia/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/genética , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Células Receptoras Sensoriais/metabolismoRESUMO
The tooth surface structure of spiral bevel gear is complex and requires high machining accuracy. In order to reduce the tooth form deformation of heat treatment, this paper proposes a reverse adjustment correction model of tooth cutting for heat treatment tooth form deformation of spiral bevel gear. Based on the Levenberg-Marquardat method, a stable and accurate numerical solution for the reverse adjustment amount of the cutting parameters is solved. Firstly, a mathematical model of the tooth surface of spiral bevel gears was established based on the cutting parameters. Secondly, the effect law of each cutting parameter on tooth form was studied by using the method of small variable perturbation. Finally, based on the tooth form error sensitivity coefficient matrix, a reverse adjustment correction model of tooth cutting is established to compensate the heat treatment tooth form deformation by reserving the tooth cutting allowance in the tooth cutting stage. The effectiveness of the reverse adjustment correction model of tooth cutting was verified through experiments on reverse adjustment of tooth cutting processing. The experimental results show that the accumulative tooth form error of the spiral bevel gear after heat treatment is 199.8 µm, which is reduced by 67.71%, and the maximum tooth form error is 8.7 µm, which is reduced by 74.75%, after reverse adjustment of cutting parameters. This research can provide technical support and a theoretical reference for heat treatment tooth form deformation control and high-precision tooth cutting processing of spiral bevel gears.
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Huge synthetic chemicals and hydrocarbons have been released to inland waters and oceans, composing anthropogenic dissolved organic carbon (ADOC). They complement a large budget for CO2. Burial by inland and coastal marine sediments is crucial to reduce this budget. How ecological regime shifts influence the burial ability of ADOC by inland waters and coastal oceans, and what are the differences between them remain largely unknown. We collected sediment cores from an inland lake (Lake Qianhu) and the largest coastal lagoon (Lagoon Pinqing) in China, and chose 16 polycyclic aromatic hydrocarbons (PAHs) to address these issues. Burial ability of PAHs by sediments decreased by 55.1% - 98.5% in Lagoon Pinqing in the period from 1963 to 2018, and by 91.5% - 99.5% in Lake Qianhu in the period from 1970 to 2018. Burial ability and its decrease rate for most PAHs in Lagoon Pinqing were larger than those in Lake Qianhu in the same period. PAHs with higher hydrophobicity were more ready to be buried by both lake sediments and lagoon sediments. Burial ability of most PAHs in Lagoon Pinqing was negative correlated with total phosphorus concentration. In contrast, burial ability of most PAHs in Lake Qianhu was negative correlated with total nitrogen concentration. Regime shifted from phytoplankton to submerged macrophytes dominance in the year of 1976, and from submerged macrophytes to phytoplankton dominance in the year of 1999 in Lagoon Pinqing, driven by nitrogen. Regime shifted from vascular plants to phytoplankton dominance in Lake Qianhu in the year of 1991, driven by phosphorus. Different aromaticity and sources of organic matter related to regime shifts were responsible for the discrepancy of burial ability for PAHs by sediments of these two waters. Our study suggests that burial ability of ADOC by inland and coastal marine sediments will be reduced if eutrophication results in ecological regime shifts, which may undermine the efforts to mitigate global warming.