Toll-like receptors （TLRs） are a group of highly conserved molecules which initiate the innate immune response to pathogens by recognizing structural motifs of microbes. Understanding the changes in chicken Toll-lik...Toll-like receptors （TLRs） are a group of highly conserved molecules which initiate the innate immune response to pathogens by recognizing structural motifs of microbes. Understanding the changes in chicken Toll-like receptors （ChTLRs） and signal adaptors expression that occur with Eimeria tenella infection will help to elucidate the molecular basis of immune control of coccidiosis caused by Eimeria. The present study detected the dynamic changes in the expression of ChTLRs and associated signal adaptors in the spleen and cecum ofE. tenella-infected chickens during the early stage of infection. The results showed that the expression peak for ChTLRs, MyD88 and TRIF occurred at 12 h post-infection （hpi）, ChTLR3, ChTLRI 5 and MyD88 mRNA expression in the spleen ofE. tenella infected chickens were significantly higher （P〈0.05） than that of negative control chickens, and there were similar tendencies of these molecules expression in the cecum and spleen of E. tenella-infected chickens. The expression of MyD88 was upregnlated at four time points in the cecum of E. tenella-infected chickens. The results of this study indicate that ChTLR3, ChTLR15 and MyD88 play a role in young chickens infected with E. tenella.展开更多
Amyloid precursor protein intracellular domain （AICD） is one of the potential candidates in deciphering the complexity of Alzheimer＇s disease. It plays important roles in determining cell fate and neurodegeneration...Amyloid precursor protein intracellular domain （AICD） is one of the potential candidates in deciphering the complexity of Alzheimer＇s disease. It plays important roles in determining cell fate and neurodegeneration through its interactions with several adaptors. The pres- ence or absence of phosphorylation at specific sites determines the choice of partners. In this study, we identified 20 novel AICD- interacting proteins by in vitro pull down experiments followed by 2D gel electrophoresis and MALDI-MS analysis. The identified proteins can be grouped into different functional classes including molecular chaperones, structural proteins, signaling and transport molecules, adaptors, motor proteins and apoptosis determinants. Interactions of nine proteins were further validated either by colocal- ization using confocal imaging or by co-immunoprecipitation followed by immunoblotting. The cellular functions of most of the proteins can be correlated with AD. Hence, illustration of their interactions with AICD may shed some light on the disease pathophysiology.展开更多
Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors(PRRs)to transduce signals to the hub of the innate immune signaling network-t...Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors(PRRs)to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1,where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/AP-1 and the signal transducer and activator of tran-scription 6(STAT6)to trigger the expression of typeІinterferons and inflammatory cytokines or the assem-bly of inflammasomes.Most pleiotropic cytokines are secreted and bind to specific receptors,activating the signaling pathways including JAK-STAT for the prolif-eration,differentiation and functional capacity of im-mune cells.This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.展开更多
Adaptor signature,a new primitive that alleviates the scalability issue of blockchain to some extent,has been widely adopted in the off-chain payment channel and atomic swap.As an extension of standard digital signatu...Adaptor signature,a new primitive that alleviates the scalability issue of blockchain to some extent,has been widely adopted in the off-chain payment channel and atomic swap.As an extension of standard digital signature,adaptor signature can bind the release of a complete digital signature with the exchange of a secret value.Existing constructions of adaptor signatures are mainly based on Schnorr or ECDSA signature algorithms,which suffer low signing efficiency and long signature length.In this paper,to address these issues,we propose a new construction of adaptor signature using randomized EdDSA,which has Schnorr-like structure with higher signing efficiency and shorter signature length.We prove the required security properties,including unforgeability,witness extractability and pre-signature adaptability,of the new adaptor signature scheme in the random oracle model.We conduct a comparative analysis with an ECDSA-based adaptor signature scheme to demonstrate the effectiveness and feasibility of our new proposal.展开更多
Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority.Our previous research demonstrated the efficacy of artesunate(ART)in alleviating liver fibrosis by elimi...Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority.Our previous research demonstrated the efficacy of artesunate(ART)in alleviating liver fibrosis by eliminating activated hepatic stellate cells(HSCs).However,the underlying mechanism remains unclear despite these findings.Notably,endocytic adaptor protein(NUMB)has significant implications for treating hepatic diseases,but current research primarily focuses on liver regeneration and hepatocellular carcinoma.The precise function of NUMB in liver fibrosis,particularly its ability to regulate HSCs,requires further investigation.This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs.We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs,exhibiting a negative correlation with the progression of liver fibrosis.Additionally,ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor(P53)axis.We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate.This research examines the specific target of ART in eliminating activated HSCs,providing both theoretical and experimental evidence for the treatment of liver fibrosis.展开更多
BACKGROUND Esophageal cancer(ESCA)is among the most prevalent and lethal tumors globally.While nitric oxide synthase 1(NOS1)is recognized for its important in-volvement in various cancers,its specific function in ESCA...BACKGROUND Esophageal cancer(ESCA)is among the most prevalent and lethal tumors globally.While nitric oxide synthase 1(NOS1)is recognized for its important in-volvement in various cancers,its specific function in ESCA remains unclear.AIM To explore the potential role and underlying mechanisms of NOS1 in ESCA.METHODS Survival rates were analyzed using GeneCards and Gene Expression Profiling Interactive Analysis.The effects and mechanisms of NOS1 on ESCA cells were evaluated via the Cell Counting Kit-8 assay,scratch assay,Transwell assay,flow cytometry,quantitative polymerase chain reaction,western blotting,and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining.The protein interaction network was used to screen the interacting proteins of NOS1 and validate these interactions through co-immuno-precipitation and dual luciferase assays.Additionally,a nude mouse xenograft model was established to evaluate the effect of NOS1 in vivo.RESULTS The survival rate of patients with ESCA with high NOS1 expression was higher than that of patients with low NOS1 expression.NOS1 expression in ESCA cell lines was lower than that in normal esophageal epithelial cells.Overexpression of NOS1(oe-NOS1)inhibited proliferation,invasion,and migration abilities in ESCA cell lines,resulting in decreased autophagy levels and increased apoptosis,pyroptosis,and ferroptosis.Protein interaction studies confirmed the interaction between NOS1 and NOS1 adaptor protein(NOS1AP).Following oe-NOS1 and the silencing of NOS1AP,levels of P62 and microtubule-associated protein 1 light chain 3 beta increased both in vitro and in vivo.Furthermore,the expression levels of E-cadherin,along with the activation of phosphatidylinositol 3-kinase(PI3K)and protein kinase B(AKT),were inhibited in ESCA cell lines.CONCLUSION NOS1 and NOS1 proteins interact to suppress autophagy,activate the PI3K/AKT pathway,and exert anti-cancer effects in ESCA.展开更多
OBJECTIVE: To investigate the effect of electroacupuncture(EA) on irritable bowel syndrome(IBS) in mice through regulating nucleotide-binding oligomerization domain protein-like receptor family pyrin domain containing...OBJECTIVE: To investigate the effect of electroacupuncture(EA) on irritable bowel syndrome(IBS) in mice through regulating nucleotide-binding oligomerization domain protein-like receptor family pyrin domain containing 6(NLRP6).METHODS: Water-avoidance stress(WAS) mice model was used to investigate the effects and the mechanism of EA. Abdominal withdrawal reflex test, open field test, and intestinal motility test were used to evaluate visceral sensitivity, anxiety,and intestinal motility in mice. The expressions of NLRP6, Mucin-2(MUC2) and E-cadherin were determined using immunofluorescence and Western blotting assays.RESULTS: EA significantly upregulated the expression of NLRP6 in the intestine of mice. Moreover, EA increased the expressions of MUC2 and E-cadherin in WAS mice.CONCLUSION: Our study found that the relief of IBS symptoms by EA may involve the increase in the expression of NLRP6 in WAS mice.展开更多
OBJECTIVE:To examine the efficacy of Qinghuayin(清化饮,QHY)in rat chronic atrophic gastritis(CAG)models and explored the molecular mechanism of QHY in treating CAG.METHODS:In total,65 Wistar rats were randomly divided...OBJECTIVE:To examine the efficacy of Qinghuayin(清化饮,QHY)in rat chronic atrophic gastritis(CAG)models and explored the molecular mechanism of QHY in treating CAG.METHODS:In total,65 Wistar rats were randomly divided into the control(n=10)and CAG groups(n=55).CAG model rats were further divided into five groups:model(n=10),vitacoenzyme(n=10),low-dose QHY(n=10),medium-dose QHY(n=10),and high-dose QHY groups(n=10).We analyzed histopathological changes using hematoxylin and eosin staining and measured interleukin(IL)-6 and IL-8 levels in serum using enzyme-linked immunosorbent assay(ELISA)(Boster Bio,Pleasanton,USA).In addition,gastrin(GAS),pepsinogen I(PGI),and PGII expressions were evaluated using ELISA.The protein and m RNA expression of toll-like receptor 4(TLR4)and toll or interleukin-1 receptor domaincontaining adaptor inducing interferon-β(TRIF)was detected by Western blotting and quantitative reverse transcription-polymerase chain reaction,respectively.RESULTS:Our results revealed that histopathological changes in CAG model rates could be restored by low-,medium-,and high-dose QHY.The changes in GAS and PGI/II expression demonstrated that QHY improved CAG.Serum IL-6 and IL-levels were decreased by QHY administration.TLR4 and TRIF were upregulated at the m RNA and protein levels in the model group but downregulated by QHY administration.CONCLUSION:We concluded that QHY could effectively improve the histopathological changes of the gastric mucosa induced by CAG in rats.The therapeutic mechanism of QHY may be related to inhibition of the inflammatory factors IL-6 and IL-8 and suppression of TLR4/TRIF m RNA and protein expression.展开更多
Toll-like receptor 4(TLR4) and protease-activated receptor 2(PAR2) play pivotal roles in the mammalian innate immune response.Notably,in addition to their involvement in detection of invading pathogens,PAR2 and TLR4 m...Toll-like receptor 4(TLR4) and protease-activated receptor 2(PAR2) play pivotal roles in the mammalian innate immune response.Notably,in addition to their involvement in detection of invading pathogens,PAR2 and TLR4 modulate the levels of cell death-induced sterile inflammation by activating pro-or anti-inflammatory downstream signaling cascades.Within the central nervous system,there is emerging evidence that both receptors are involved in synaptic transmission and brain plasticity.Furthermore,due to their prominent role in mediating neuroinflammation,PAR2 and TLR4 are associated with development and progression of neurodegenerative disorders including but not limited to Alzheimer's disease,Parkinson's disease and multiple sclerosis.In this article,we summarise the current knowledge on the cooperation between PAR2 and TLR4,discuss the potential cross-talk levels and highlight the impact of the cross-coupling on neuroinflammation.展开更多
BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recu...BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1 immunostaining was significantly increased in hippocampus,thalamus(intralaminar nuclei),hypothalamus,and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors,pancreatic fibrosis,and brain microglial changes.ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.展开更多
The neuroprotective effect against spinal cord ischemia/reperfusion injury in rats exerted by delayed xenon post-conditioning is stronger than that produced by immediate xenon post-conditioning. However, the mechanism...The neuroprotective effect against spinal cord ischemia/reperfusion injury in rats exerted by delayed xenon post-conditioning is stronger than that produced by immediate xenon post-conditioning. However, the mechanisms underlying this process remain unclear. Activated microglia are the main inflammatory cell type in the nervous system. The release of pro-inflammatory factors following microglial activation can lead to spinal cord damage, and inhibition of microglial activation can relieve spinal cord ischemia/reperfusion injury. To investigate how xenon regulates microglial activation and the release of inflammatory factors, a rabbit model of spinal cord ischemia/reperfusion injury was induced by balloon occlusion of the infrarenal aorta. After establishment of the model, two interventions were given： （1） immediate xenon post-conditioning—after reperfusion, inhalation of 50% xenon for 1 hour, 50% N2/50%O2 for 2 hours; （2） delayed xenon post-conditioning—after reperfusion, inhalation of 50% N2/50%O2 for 2 hours, 50% xenon for 1 hour. At 4, 8, 24, 48 and 72 hours after reperfusion, hindlimb locomotor function was scored using the Jacobs locomotor scale. At 72 hours after reperfusion, interleukin 6 and interleukin 10 levels in the spinal cord of each group were measured using western blot assays. Iba1 levels were determined using immunohistochemistry and a western blot assay. The number of normal neurons at the injury site was quantified using hematoxylin-eosin staining. At 72 hours after reperfusion, delayed xenon post-conditioning remarkably enhanced hindlimb motor function, increased the number of normal neurons at the injury site, decreased Iba1 levels, and inhibited interleukin-6 and interleukin-10 levels in the spinal cord.Immediate xenon post-conditioning did not noticeably affect the above-mentioned indexes. These findings indicate that delayed xenon post-conditioning after spinal cord injury improves the recovery of neurological function by reducing microglial activation and the release of interleukin-6 and interleukin-10.展开更多
Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury(SCI) to such comorbidities. Here, we interrogated the expression of astrocyte-and microglial-specific markers ...Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury(SCI) to such comorbidities. Here, we interrogated the expression of astrocyte-and microglial-specific markers glial fibrillary acidic protein(GFAP) and ionized calcium binding adaptor molecule 1(Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy;half of the rats received a mild contusion injury at the level of the T10 vertebral body(SCI group), the other half did not(Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus(dorsal and ventral) in rats were collected. GFAP and Iba1 m RNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP m RNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee(UTS ACEC13-0069).展开更多
AIM:To examine the expression of downstream of tyrosine kinase(DOK)1-6 genes in normal and breast cancer tissue and correlated this with several clinicopathological and prognostic factors.METHODS:DOK1-6 m RNA extracti...AIM:To examine the expression of downstream of tyrosine kinase(DOK)1-6 genes in normal and breast cancer tissue and correlated this with several clinicopathological and prognostic factors.METHODS:DOK1-6 m RNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples(n = 112) and normal background breast tissue(n = 31). Tissues were collected between 1991 and 1996 at two centres and all patients underwent mastectomy and ipsilateral axillary node dissection. All tissues were randomly numbered and the details were only made known after all analyses were completed. Transcript levels of expression were determined using real-time polymerase chain reaction and analyzed against TNM stage, tumour grade and clinical outcome over a 10-year follow-up period.RESULTS:DOK-2 and DOK-6 expression decreased with increasing TNM stage. DOK-6 expression decreased with increasing Nottingham Prognostic Index(NPI) [NPI-1 vs NPI-3(mean copy number 15.4 vs 0.22, 95%CI:2.7-27.6, P = 0.018) and NPI-2 vs NPI-3(mean copy number 7.6 vs 0.22, 95%CI:0.1-14.6, P = 0.048)]. After a median follow up period of 10 years, higherlevels of DOK-2 expression were found among patients who remained disease-free compared to those who developed local or distant recurrence(mean copy number 3.94 vs 0.0000096, 95%CI:1.0-6.85, P = 0.0091), and distant recurrence(mean copy number 3.94 vs 0.0025, 95%CI:1.0-6.84, P = 0.0092). Patients who remained disease-free had higher levels of DOK-6 expression compared to those who died from breast cancer.CONCLUSION:Decreasing expression levels of DOK-2 and DOK-6 with increased breast tumour progression supports the notion that DOK-2 and DOK-6 behave as tumour suppressors in human breast cancer.展开更多
Most of the existing approaches focus on identifying mismatches and synthesizing adaptors at design-time or recently at run-time. However, few works have been proposed to support adaptor reconfiguration when services ...Most of the existing approaches focus on identifying mismatches and synthesizing adaptors at design-time or recently at run-time. However, few works have been proposed to support adaptor reconfiguration when services in the composition evolve due to changes in business needs. To address the deficiencies, the problem of adaptor reconfiguration is targeted in the context of service composition. Firstly, the formal models for describing services and adaptors are presented. Then, under this formalization,the notion of reconfiguration compliance is proposed to determine the validity of an adaptor instance with respect to its history executions and future executions. Based on the notion,the algorithm for reconfiguration analysis of adaptors is presented and it can be used for determining the migratability of an adaptor instance and the corresponding target state of reconfiguration if migratable.Finally,feasibility of the proposed approach is validated on a realistic case study. The proposed approach improves the flexibility of adaptor-based service composition by equipping adaptors with reconfiguration capabilities.展开更多
Signal transduction pathways activated by receptor tyrosine kinases （RTK） play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signalin...Signal transduction pathways activated by receptor tyrosine kinases （RTK） play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we locus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes. CRKL. GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.展开更多
基金the Fundamental Research Funds for the Central Universities,China(XDJK2010C099)the Science Fundation for Young Scientists of Southwest University,China(QNRC200804)the Scientific Research Fund of Veterinary Medicine Department of Southwest University,China
文摘Toll-like receptors （TLRs） are a group of highly conserved molecules which initiate the innate immune response to pathogens by recognizing structural motifs of microbes. Understanding the changes in chicken Toll-like receptors （ChTLRs） and signal adaptors expression that occur with Eimeria tenella infection will help to elucidate the molecular basis of immune control of coccidiosis caused by Eimeria. The present study detected the dynamic changes in the expression of ChTLRs and associated signal adaptors in the spleen and cecum ofE. tenella-infected chickens during the early stage of infection. The results showed that the expression peak for ChTLRs, MyD88 and TRIF occurred at 12 h post-infection （hpi）, ChTLR3, ChTLRI 5 and MyD88 mRNA expression in the spleen ofE. tenella infected chickens were significantly higher （P〈0.05） than that of negative control chickens, and there were similar tendencies of these molecules expression in the cecum and spleen of E. tenella-infected chickens. The expression of MyD88 was upregnlated at four time points in the cecum of E. tenella-infected chickens. The results of this study indicate that ChTLR3, ChTLR15 and MyD88 play a role in young chickens infected with E. tenella.
基金supported by the Structural Proteomics and Genomics of Human Genetic Disorders Project of Department of Atomic Energy
文摘Amyloid precursor protein intracellular domain （AICD） is one of the potential candidates in deciphering the complexity of Alzheimer＇s disease. It plays important roles in determining cell fate and neurodegeneration through its interactions with several adaptors. The pres- ence or absence of phosphorylation at specific sites determines the choice of partners. In this study, we identified 20 novel AICD- interacting proteins by in vitro pull down experiments followed by 2D gel electrophoresis and MALDI-MS analysis. The identified proteins can be grouped into different functional classes including molecular chaperones, structural proteins, signaling and transport molecules, adaptors, motor proteins and apoptosis determinants. Interactions of nine proteins were further validated either by colocal- ization using confocal imaging or by co-immunoprecipitation followed by immunoblotting. The cellular functions of most of the proteins can be correlated with AD. Hence, illustration of their interactions with AICD may shed some light on the disease pathophysiology.
文摘Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors(PRRs)to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1,where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/AP-1 and the signal transducer and activator of tran-scription 6(STAT6)to trigger the expression of typeІinterferons and inflammatory cytokines or the assem-bly of inflammasomes.Most pleiotropic cytokines are secreted and bind to specific receptors,activating the signaling pathways including JAK-STAT for the prolif-eration,differentiation and functional capacity of im-mune cells.This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.
基金supported by the National Key R&D Program of China(2022YFB2701500)the National Natural Science Foundation of China(62272385,62311540156)+2 种基金Shaanxi Distinguished Youth Project(2022JC-47)the Key Research and Development Program of Shaanxi(2021ZDLGY06-04)Major Program of Shandong Provincial Natural Science Foundation for the Fundamental Research(ZR2022ZD03).
文摘Adaptor signature,a new primitive that alleviates the scalability issue of blockchain to some extent,has been widely adopted in the off-chain payment channel and atomic swap.As an extension of standard digital signature,adaptor signature can bind the release of a complete digital signature with the exchange of a secret value.Existing constructions of adaptor signatures are mainly based on Schnorr or ECDSA signature algorithms,which suffer low signing efficiency and long signature length.In this paper,to address these issues,we propose a new construction of adaptor signature using randomized EdDSA,which has Schnorr-like structure with higher signing efficiency and shorter signature length.We prove the required security properties,including unforgeability,witness extractability and pre-signature adaptability,of the new adaptor signature scheme in the random oracle model.We conduct a comparative analysis with an ECDSA-based adaptor signature scheme to demonstrate the effectiveness and feasibility of our new proposal.
基金supported by the National Natural Science Foundation of China(Nos.82474164,82374124,82073914,82173874,82274185,82305046 and 82304902)the Natural Science Foundation of Jiangsu Province(Nos.BK20230458 and BK20220467)+1 种基金the General Project of the Natural Science Research of Jiangsu Higher Education Institutions(No.23KJB310017)Young Elite Scientists Sponsorship Program by CACM(No.2022-QNRC2-B15).
文摘Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority.Our previous research demonstrated the efficacy of artesunate(ART)in alleviating liver fibrosis by eliminating activated hepatic stellate cells(HSCs).However,the underlying mechanism remains unclear despite these findings.Notably,endocytic adaptor protein(NUMB)has significant implications for treating hepatic diseases,but current research primarily focuses on liver regeneration and hepatocellular carcinoma.The precise function of NUMB in liver fibrosis,particularly its ability to regulate HSCs,requires further investigation.This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs.We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs,exhibiting a negative correlation with the progression of liver fibrosis.Additionally,ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor(P53)axis.We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate.This research examines the specific target of ART in eliminating activated HSCs,providing both theoretical and experimental evidence for the treatment of liver fibrosis.
基金Supported by the National Natural Science Foundation of China,No.81000201.
文摘BACKGROUND Esophageal cancer(ESCA)is among the most prevalent and lethal tumors globally.While nitric oxide synthase 1(NOS1)is recognized for its important in-volvement in various cancers,its specific function in ESCA remains unclear.AIM To explore the potential role and underlying mechanisms of NOS1 in ESCA.METHODS Survival rates were analyzed using GeneCards and Gene Expression Profiling Interactive Analysis.The effects and mechanisms of NOS1 on ESCA cells were evaluated via the Cell Counting Kit-8 assay,scratch assay,Transwell assay,flow cytometry,quantitative polymerase chain reaction,western blotting,and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining.The protein interaction network was used to screen the interacting proteins of NOS1 and validate these interactions through co-immuno-precipitation and dual luciferase assays.Additionally,a nude mouse xenograft model was established to evaluate the effect of NOS1 in vivo.RESULTS The survival rate of patients with ESCA with high NOS1 expression was higher than that of patients with low NOS1 expression.NOS1 expression in ESCA cell lines was lower than that in normal esophageal epithelial cells.Overexpression of NOS1(oe-NOS1)inhibited proliferation,invasion,and migration abilities in ESCA cell lines,resulting in decreased autophagy levels and increased apoptosis,pyroptosis,and ferroptosis.Protein interaction studies confirmed the interaction between NOS1 and NOS1 adaptor protein(NOS1AP).Following oe-NOS1 and the silencing of NOS1AP,levels of P62 and microtubule-associated protein 1 light chain 3 beta increased both in vitro and in vivo.Furthermore,the expression levels of E-cadherin,along with the activation of phosphatidylinositol 3-kinase(PI3K)and protein kinase B(AKT),were inhibited in ESCA cell lines.CONCLUSION NOS1 and NOS1 proteins interact to suppress autophagy,activate the PI3K/AKT pathway,and exert anti-cancer effects in ESCA.
基金Supported by the National Natural Science Fund(No.81473748,81804193)the Youth Natural Foundation of the Science and Technology Department of Jiangsu Province(No.BK20161083)+3 种基金a Grant from Clinical Medicine Center of Digestive Diseases of Traditional Chinese Medicine in Jiangsu(No.BL2014100-4)the Leading Talents Project from Jiangsu Provincial Administration of TCM(SLJ0206)the Science and Technology Project of Jiangsu Provincial Administration of TCM(No.JD201506)the peak talent project of Jiangsu Province Hospital of TCM(No.y2018rc05)。
文摘OBJECTIVE: To investigate the effect of electroacupuncture(EA) on irritable bowel syndrome(IBS) in mice through regulating nucleotide-binding oligomerization domain protein-like receptor family pyrin domain containing 6(NLRP6).METHODS: Water-avoidance stress(WAS) mice model was used to investigate the effects and the mechanism of EA. Abdominal withdrawal reflex test, open field test, and intestinal motility test were used to evaluate visceral sensitivity, anxiety,and intestinal motility in mice. The expressions of NLRP6, Mucin-2(MUC2) and E-cadherin were determined using immunofluorescence and Western blotting assays.RESULTS: EA significantly upregulated the expression of NLRP6 in the intestine of mice. Moreover, EA increased the expressions of MUC2 and E-cadherin in WAS mice.CONCLUSION: Our study found that the relief of IBS symptoms by EA may involve the increase in the expression of NLRP6 in WAS mice.
基金Supported by Natural Science Foundation of Fujian Province(Based on NLRP3 Inflammatory Body/Caspase-1-mediated Gastric Epithelial Cell Death to Explore the Molecular Mechanism of Qinghua Decoction in the Treatment of Chronic Atrophic Gastritis,No.2020J01253)。
文摘OBJECTIVE:To examine the efficacy of Qinghuayin(清化饮,QHY)in rat chronic atrophic gastritis(CAG)models and explored the molecular mechanism of QHY in treating CAG.METHODS:In total,65 Wistar rats were randomly divided into the control(n=10)and CAG groups(n=55).CAG model rats were further divided into five groups:model(n=10),vitacoenzyme(n=10),low-dose QHY(n=10),medium-dose QHY(n=10),and high-dose QHY groups(n=10).We analyzed histopathological changes using hematoxylin and eosin staining and measured interleukin(IL)-6 and IL-8 levels in serum using enzyme-linked immunosorbent assay(ELISA)(Boster Bio,Pleasanton,USA).In addition,gastrin(GAS),pepsinogen I(PGI),and PGII expressions were evaluated using ELISA.The protein and m RNA expression of toll-like receptor 4(TLR4)and toll or interleukin-1 receptor domaincontaining adaptor inducing interferon-β(TRIF)was detected by Western blotting and quantitative reverse transcription-polymerase chain reaction,respectively.RESULTS:Our results revealed that histopathological changes in CAG model rates could be restored by low-,medium-,and high-dose QHY.The changes in GAS and PGI/II expression demonstrated that QHY improved CAG.Serum IL-6 and IL-levels were decreased by QHY administration.TLR4 and TRIF were upregulated at the m RNA and protein levels in the model group but downregulated by QHY administration.CONCLUSION:We concluded that QHY could effectively improve the histopathological changes of the gastric mucosa induced by CAG in rats.The therapeutic mechanism of QHY may be related to inhibition of the inflammatory factors IL-6 and IL-8 and suppression of TLR4/TRIF m RNA and protein expression.
文摘Toll-like receptor 4(TLR4) and protease-activated receptor 2(PAR2) play pivotal roles in the mammalian innate immune response.Notably,in addition to their involvement in detection of invading pathogens,PAR2 and TLR4 modulate the levels of cell death-induced sterile inflammation by activating pro-or anti-inflammatory downstream signaling cascades.Within the central nervous system,there is emerging evidence that both receptors are involved in synaptic transmission and brain plasticity.Furthermore,due to their prominent role in mediating neuroinflammation,PAR2 and TLR4 are associated with development and progression of neurodegenerative disorders including but not limited to Alzheimer's disease,Parkinson's disease and multiple sclerosis.In this article,we summarise the current knowledge on the cooperation between PAR2 and TLR4,discuss the potential cross-talk levels and highlight the impact of the cross-coupling on neuroinflammation.
基金United States Department of Veterans Affairs,VA Merit Grant,No.BX002695United States National Institute of Health,No.R01AG055359,No.R01GM126181 and No.R01NS39041-15.
文摘BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1 immunostaining was significantly increased in hippocampus,thalamus(intralaminar nuclei),hypothalamus,and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors,pancreatic fibrosis,and brain microglial changes.ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.
基金supported by the National Natural Science Foundation of China,No.81271387the Research Special Fund of Public Welfare and Health Department of China,No.201402009a grant form the National Key Technology R&D Program in China,No.Z141107002514031
文摘The neuroprotective effect against spinal cord ischemia/reperfusion injury in rats exerted by delayed xenon post-conditioning is stronger than that produced by immediate xenon post-conditioning. However, the mechanisms underlying this process remain unclear. Activated microglia are the main inflammatory cell type in the nervous system. The release of pro-inflammatory factors following microglial activation can lead to spinal cord damage, and inhibition of microglial activation can relieve spinal cord ischemia/reperfusion injury. To investigate how xenon regulates microglial activation and the release of inflammatory factors, a rabbit model of spinal cord ischemia/reperfusion injury was induced by balloon occlusion of the infrarenal aorta. After establishment of the model, two interventions were given： （1） immediate xenon post-conditioning—after reperfusion, inhalation of 50% xenon for 1 hour, 50% N2/50%O2 for 2 hours; （2） delayed xenon post-conditioning—after reperfusion, inhalation of 50% N2/50%O2 for 2 hours, 50% xenon for 1 hour. At 4, 8, 24, 48 and 72 hours after reperfusion, hindlimb locomotor function was scored using the Jacobs locomotor scale. At 72 hours after reperfusion, interleukin 6 and interleukin 10 levels in the spinal cord of each group were measured using western blot assays. Iba1 levels were determined using immunohistochemistry and a western blot assay. The number of normal neurons at the injury site was quantified using hematoxylin-eosin staining. At 72 hours after reperfusion, delayed xenon post-conditioning remarkably enhanced hindlimb motor function, increased the number of normal neurons at the injury site, decreased Iba1 levels, and inhibited interleukin-6 and interleukin-10 levels in the spinal cord.Immediate xenon post-conditioning did not noticeably affect the above-mentioned indexes. These findings indicate that delayed xenon post-conditioning after spinal cord injury improves the recovery of neurological function by reducing microglial activation and the release of interleukin-6 and interleukin-10.
基金The University of Technology Sydney(UTS)Start-up Research Grant 2018 funded this study(to AC)。
文摘Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury(SCI) to such comorbidities. Here, we interrogated the expression of astrocyte-and microglial-specific markers glial fibrillary acidic protein(GFAP) and ionized calcium binding adaptor molecule 1(Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy;half of the rats received a mild contusion injury at the level of the T10 vertebral body(SCI group), the other half did not(Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus(dorsal and ventral) in rats were collected. GFAP and Iba1 m RNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP m RNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee(UTS ACEC13-0069).
文摘AIM:To examine the expression of downstream of tyrosine kinase(DOK)1-6 genes in normal and breast cancer tissue and correlated this with several clinicopathological and prognostic factors.METHODS:DOK1-6 m RNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples(n = 112) and normal background breast tissue(n = 31). Tissues were collected between 1991 and 1996 at two centres and all patients underwent mastectomy and ipsilateral axillary node dissection. All tissues were randomly numbered and the details were only made known after all analyses were completed. Transcript levels of expression were determined using real-time polymerase chain reaction and analyzed against TNM stage, tumour grade and clinical outcome over a 10-year follow-up period.RESULTS:DOK-2 and DOK-6 expression decreased with increasing TNM stage. DOK-6 expression decreased with increasing Nottingham Prognostic Index(NPI) [NPI-1 vs NPI-3(mean copy number 15.4 vs 0.22, 95%CI:2.7-27.6, P = 0.018) and NPI-2 vs NPI-3(mean copy number 7.6 vs 0.22, 95%CI:0.1-14.6, P = 0.048)]. After a median follow up period of 10 years, higherlevels of DOK-2 expression were found among patients who remained disease-free compared to those who developed local or distant recurrence(mean copy number 3.94 vs 0.0000096, 95%CI:1.0-6.85, P = 0.0091), and distant recurrence(mean copy number 3.94 vs 0.0025, 95%CI:1.0-6.84, P = 0.0092). Patients who remained disease-free had higher levels of DOK-6 expression compared to those who died from breast cancer.CONCLUSION:Decreasing expression levels of DOK-2 and DOK-6 with increased breast tumour progression supports the notion that DOK-2 and DOK-6 behave as tumour suppressors in human breast cancer.
基金National Natural Science Foundations of China(Nos.61272083,61262002,61170043)China Postdoctoral Science Foundation(Nos.20110491411,2014M562177)The Science Foundations of Nanjing Institute of Technology,China(Nos.QKJB201304,YKJ201420)
文摘Most of the existing approaches focus on identifying mismatches and synthesizing adaptors at design-time or recently at run-time. However, few works have been proposed to support adaptor reconfiguration when services in the composition evolve due to changes in business needs. To address the deficiencies, the problem of adaptor reconfiguration is targeted in the context of service composition. Firstly, the formal models for describing services and adaptors are presented. Then, under this formalization,the notion of reconfiguration compliance is proposed to determine the validity of an adaptor instance with respect to its history executions and future executions. Based on the notion,the algorithm for reconfiguration analysis of adaptors is presented and it can be used for determining the migratability of an adaptor instance and the corresponding target state of reconfiguration if migratable.Finally,feasibility of the proposed approach is validated on a realistic case study. The proposed approach improves the flexibility of adaptor-based service composition by equipping adaptors with reconfiguration capabilities.
基金supported in part by grants from the U.S. NIH (U01 CA176058)the H.L. Snyder Medical Research Foundation and a HHMI Medical Student Fellowship
文摘Signal transduction pathways activated by receptor tyrosine kinases （RTK） play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we locus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes. CRKL. GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.
