Rheumatoid arthritis(RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A b...Rheumatoid arthritis(RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages:(i) triggering,(ii) maturation,(iii) targeting, and(iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies(including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.展开更多
Objective:Lynch syndrome(LS)predisposes patients to early onset endometrioid endometrial cancer(EEC).However,little is known about LS-related EEC in the Chinese population.The aim of this study was to investigate the ...Objective:Lynch syndrome(LS)predisposes patients to early onset endometrioid endometrial cancer(EEC).However,little is known about LS-related EEC in the Chinese population.The aim of this study was to investigate the prevalence of LS and to identify the specific variants of LS in Chinese patients with EEC.Methods:We applied universal immunohistochemistry screening to detect the expression of mismatch repair(MMR)proteins,which was followed by MLH1 methylation analysis to identify suspected LS cases,next-generation sequencing(NGS)to confirm LS,and microsatellite instability(MSI)analysis to verify LS.Results:We collected 211 samples with EEC.Twenty-seven(27/211,12.8%)EEC cases had a loss of MMR protein expression.After MLH1 methylation analysis,16 EEC cases were suggested to be associated with LS.Finally,through NGS and MSI analysis,we determined that 10 EEC(10/209,4.78%)cases were associated with LS.Among those cases,3 unreported mutations(1 frameshift and 2 nonsense)were identified.M SH6 c.597_597delC,found in 4 patients,is likely to be a founder mutation in China.Conclusions:We demonstrated the feasibility of a process for LS screening in Chinese patients with EEC,by using universal immunohistochemistry screening followed by MLH1 methylation analysis and confirmation through NGS and MSI analysis.The novel mutations identified in this study expand knowledge of LS.展开更多
Amyotrophic lateral syndrome(ALS)is a progressive degenerative disorder characterized by motor neuron death and axon degeneration.Mitochondrial dysfunction plays a key role in the pathogenesis of ALS,the mechanism of ...Amyotrophic lateral syndrome(ALS)is a progressive degenerative disorder characterized by motor neuron death and axon degeneration.Mitochondrial dysfunction plays a key role in the pathogenesis of ALS,the mechanism of which remains poorly understood.The B-cell lymphoma-2(Bcl-2)family of proteins that control and mediate mitochondrial function and apoptosis,including the pro-apoptotic members Bcl2-Associated X(Bax),are involved in ALS development.The death receptor 6(DR6)regulates motor neuron death in ALS,and DR6 antibodies can prevent axon degeneration and motor neuron damage by blocking DR6.Previous studies demonstrated that PSAP localized to mitochondria and was required for DR6-induced apoptosis.In this study,SOD1^(G93A) was transfected into the motor neuron cell line NSC-34 to serve as an ALS cell model in vitro.The data assessed the role of PSAP in SOD1^(G93A)induced apoptosis and demonstrated that the overexpression of SOD1^(G93A),but not wtSOD1,induced PARP cleavage,caspase-3 activation,cytochrome c release,and Bax translocation.PSAP,Bax,and Bak were necessary for SOD1^(G93A)induced apoptosis,as silencing PSAP inhibited SOD1^(G93A)-mediated cell death that was dependent on Bax-Bak interaction.展开更多
In the published Figure 11,errors appeared in Figure 1B on page 69.In Figure 1B,bands for p-Akt S473,Akt,and Actin in H1355 cells were mistakenly placed.Here,we have updated Figure 1B to correct the mistake above.The ...In the published Figure 11,errors appeared in Figure 1B on page 69.In Figure 1B,bands for p-Akt S473,Akt,and Actin in H1355 cells were mistakenly placed.Here,we have updated Figure 1B to correct the mistake above.The errors do not impact the conclusions of this article.We apologize for the errors and for any confusion it may have caused.展开更多
Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer(NSCLC).However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI...Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer(NSCLC).However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown.Methods: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo.Results: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation.Conclusions: Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRASmutated NSCLC.展开更多
Transfer alignment is used to initialize SINS(Strapdown Inertial Navigation System)in motion.Lever-arm effect compensation is studied existing in an AUV(Autonomous Underwater Vehicle)before launched from the mother sh...Transfer alignment is used to initialize SINS(Strapdown Inertial Navigation System)in motion.Lever-arm effect compensation is studied existing in an AUV(Autonomous Underwater Vehicle)before launched from the mother ship.The AUV is equipped with SINS,Doppler Velocity Log,depth sensor and other navigation sensors.The lever arm will cause large error on the transfer alignment between master inertial navigation system and slave inertial navigation system,especially in big ship situations.This paper presents a novel method that can effectively estimate and compensate the flexural lever arm between the main inertial navigation system mounted on the mother ship and the slave inertial navigation system equipped on the AUV.The nonlinear measurement equation of angular rate is derived based on three successive rotations of the body frame of the master inertial navigation system.Nonlinear filter is utilized as the nonlinear estimator for its capability of non-linear approximation.Observability analysis was conducted on the SINS state vector based on singular value decomposition method.State equation of SINS was adopted as the system state equation.Simulation experiments were conducted and results showed that the proposed method can estimate the flexural lever arm more accurately,the precision of transfer alignment was improved and alignment time was shortened accordingly.展开更多
In the field of data mining and machine learning,clustering is a typical issue which has been widely studied by many researchers,and lots of effective algorithms have been proposed,including K-means,fuzzy c-means(FCM)...In the field of data mining and machine learning,clustering is a typical issue which has been widely studied by many researchers,and lots of effective algorithms have been proposed,including K-means,fuzzy c-means(FCM)and DBSCAN.However,the traditional clustering methods are easily trapped into local optimum.Thus,many evolutionary-based clustering methods have been investigated.Considering the effectiveness of brain storm optimization(BSO)in increasing the diversity while the diversity optimization is performed,in this paper,we propose a new clustering model based on BSO to use the global ability of BSO.In our experiment,we apply the novel binary model to solve the problem.During the period of processing data,BSO was mainly utilized for iteration.Also,in the process of K-means,we set the more appropriate parameters selected to match it greatly.Four datasets were used in our experiment.In our model,BSO was first introduced in solving the clustering problem.With the algorithm running on each dataset repeatedly,our experimental results have obtained good convergence and diversity.In addition,by comparing the results with other clustering models,the BSO clustering model also guarantees high accuracy.Therefore,from many aspects,the simulation results show that the model of this paper has good performance.展开更多
Water fluoride pollution has caused non-negligible harm to the environment and humans,and thus it is crucial to find a suitable treatment technology.In this study,La-Fe@PTA adsorbent was synthesized for the defluorida...Water fluoride pollution has caused non-negligible harm to the environment and humans,and thus it is crucial to find a suitable treatment technology.In this study,La-Fe@PTA adsorbent was synthesized for the defluoridation of mine water.The results showed that the optimum conditions for defluoridation by La-Fe@PTA were p H close to 7.0,the initial F-concentration of 10 mg/L,the dosage of 0.5 g/L and the adsorption time of 240 min.Compared with SO_4^(2-),Cl^(-),NO_(3)^(-),Ca^(2+)and Mg^(2+),CO_(3)^(2-)and HCO_(3)^(-)presented severer inhibition on fluoride uptake by La-Fe@PTA.The adsorption process fits well with the pseudo-second-order kinetic model and Freundlich model,and the maximum adsorption capacity of Langmuir model was 95 mg/g.Fixed-bed adsorption results indicated that fluoride in practical fluorinated mine water could be effectively removed from 3.6 mg/L to less than 1.5 mg/L within130 bed volume(BV)by using 1.5 g La-Fe@PTA.Furthermore,the adsorbent still had good adsorption capacity after regeneration,which confirms the great application potential of La-Fe@PTA as a fluoride ion adsorbent.The mechanism analysis showed that La-Fe@PTA adsorption of fluorine ions is a physicochemical reaction driven by electrostatic attraction and ion exchange.展开更多
Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment,significantly curtailing the efficacy of these treatments and,in some cases,resulting in fatal conse-quences.Despite identifying i...Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment,significantly curtailing the efficacy of these treatments and,in some cases,resulting in fatal conse-quences.Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis,the paucity of effective treatments for such damage is evident.In our study,we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells,thereby fortifying the integrity of the intestinal mucus barrier.This enhanced barrier function serves to resist microbial invasion and sub-sequently reduces the inflammatory response.Importantly,this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs.Mechanistically,E.copr up-regulates the expression of AUF1,leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells.An espe-cially significant finding is that E.copr activates the AhR pathway,thereby promoting the expression of AUF1.In summary,our results strongly indicate that E.copr enhances the intestinal mucus barrier,effec-tively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUFl pathway,consequently enhancing Muc2 mRNA stability.展开更多
EuCd_(2)As_(2)was theoretically predicted to be a minimal model of Weyl semimetals with a single pair of Weyl points in the ferromagnet state.However,the heavily p-doped Eu Cd_(2)As_(2)crystals in previous experiments...EuCd_(2)As_(2)was theoretically predicted to be a minimal model of Weyl semimetals with a single pair of Weyl points in the ferromagnet state.However,the heavily p-doped Eu Cd_(2)As_(2)crystals in previous experiments prevent direct identification of the semimetal hypothesis.Here,we present a comprehensive magneto-transport study of high-quality Eu Cd_(2)As_(2)crystals with ultralow bulk carrier density(10^(13)cm^(-3)).In contrast to the general expectation of a Weyl semimetal phase,Eu Cd_(2)As_(2)shows insulating behavior in both antiferromagnetic and ferromagnetic states as well as surface-dominated conduction from band bending.Moreover,the application of a dc bias current can dramatically modulate the resistance by over one order of magnitude,and induce a periodic resistance oscillation due to the geometric resonance.Such nonlinear transport results from the high nonequilibrium state induced by an electrical field near the band edge.Our results suggest an insulating phase in Eu Cd_(2)As_(2)and put a strong constraint on the underlying mechanism of anomalous transport properties in this system.展开更多
In this study,Al–4Cu alloy specimens with spherical grains and liquid flms were obtained by isothermal reheating treatment.The hot cracking of the solidifcation process was determined using a modifed constrained rod ...In this study,Al–4Cu alloy specimens with spherical grains and liquid flms were obtained by isothermal reheating treatment.The hot cracking of the solidifcation process was determined using a modifed constrained rod casting experimental apparatus,and the efect of liquid flm characteristics at the end of solidifcation on hot cracking initiation of Al–4Cu alloys was systematically investigated by combining molecular dynamics simulations and other methods.With the extension of soaking time,the liquid fraction(liquid flm fraction at the end of solidifcation)and grain shape factor increased with higher isothermal reheating temperatures.Additionally,the widened flling channel decreased the hot cracking initiation temperature and the critical hot cracking shrinkage stress was found to increase,thus reducing the hot cracking severity in Al–4Cu alloys.Molecular dynamics simulations revealed that with the extension of soaking time,the composition of the liquid flm changed at diferent isothermal reheating temperatures,but the short-range structure and atomic ordering of the liquid flm remained the same.The activity of the liquid flm increased in equilibrium,leading to a decrease in viscosity and an increase in fuidity,which contributed to the flling behaviour.After isothermal reheating at 640℃for 60 min,the liquid fraction reached the maximum,and the viscosity of the liquid flm was the minimum.In addition,almost no hot cracks were found.展开更多
Background:Congenital scoliosis(CS)is a complex spinal malformation of unknown etiology with abnormal bone metabolism.Fibroblast growth factor 23(FGF23),secreted by osteoblasts and osteocytes,can inhibit bone formatio...Background:Congenital scoliosis(CS)is a complex spinal malformation of unknown etiology with abnormal bone metabolism.Fibroblast growth factor 23(FGF23),secreted by osteoblasts and osteocytes,can inhibit bone formation and mineralization.This research aims to investigate the relationship between CS and FGF23.Methods:We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region.FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured.Receiver operator characteristic(ROC)curve analyses were conducted to evaluate the specificity and sensitivity of FGF23.The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3(FGFr3)/tissue non-specific alkaline phosphatase(TNAP)/osteopontin(OPN)in primary osteoblasts from CS patients(CS-Ob)and controls(CT-Ob)were detected.In addition,the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined.Results:DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins,accompanied by increased mRNA levels.CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography(CT)values compared with controls.The FGF23 mRNA levels were negatively correlated with the CT value of the spine,and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS.Additionally,significantly increased levels of FGF23,FGFr3,OPN,impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob.Moreover,FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels,while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob.Mineralization of CS-Ob was rescued after FGF23 knockdown.Conclusions:Our results suggested increased peripheral blood FGF23 levels,decreased bone mineral density in CS patients,and a good predictive ability of CS by peripheral blood FGF23 levels.FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP/OPN pathway.展开更多
Background:Osteopenia has been well documented in adolescent idiopathic scoliosis(AIS).Bone marrow stem cells(BMSCs)are a crucial regulator of bone homeostasis.Our previous study revealed a decreased osteogenic abilit...Background:Osteopenia has been well documented in adolescent idiopathic scoliosis(AIS).Bone marrow stem cells(BMSCs)are a crucial regulator of bone homeostasis.Our previous study revealed a decreased osteogenic ability of BMSCs in AIS-related osteopenia,but the underlying mechanism of this phenomenon remains unclear.Methods:A total of 22 AIS patients and 18 age-matched controls were recruited for this study.Anthropometry and bone mass were measured in all participants.Bone marrow blood was collected for BMSC isolation and culture.Osteogenic and adipogenic induction were performed to observe the differences in the differentiation of BMSCs between the AIS-related osteopenia group and the control group.Furthermore,a total RNA was extracted from isolated BMSCs to perform RNA sequencing and subsequent analysis.Results:A lower osteogenic capacity and increased adipogenic capacity of BMSCs in AIS-related osteopenia were revealed.Differences in mRNA expression levels between the AIS-related osteopenia group and the control group were identified,including differences in the expression of LRRC17,DCLK1,PCDH7,TSPAN5,NHSL2,and CPT1B.Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed several biological processes involved in the regulation of autophagy and mitophagy.The Western blotting results of autophagy markers in BMSCs suggested impaired autophagic activity in BMSCs in the AIS-related osteopenia group.Conclusion:Our study revealed that BMSCs from AIS-related osteopenia patients have lower autophagic activity,which may be related to the lower osteogenic capacity and higher adipogenic capacity of BMSCs and consequently lead to the lower bone mass in AIS patients.展开更多
Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monito...Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.展开更多
Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis.Esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC)are two major subtypes of eso...Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis.Esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC)are two major subtypes of esophageal cancer.ESCC predominantly affects African and Asian populations,which is closely related to chronic smoking and alcohol consumption.EAC typically arises in Barrett’s esophagus with a predilection for Western countries.While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer,molecularly targeted therapy is still at the early stages.With the development of large-scale next-generation sequencing,various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied.Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer.In this review,we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer.Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.展开更多
Cap-like α-Fe2O3 films are fabricated and deposited onto quartz fabric by using radio frequency magnetron sputtering and annealing.The treated fabric sample in this study shows highly sensitive surface-enhanced Raman...Cap-like α-Fe2O3 films are fabricated and deposited onto quartz fabric by using radio frequency magnetron sputtering and annealing.The treated fabric sample in this study shows highly sensitive surface-enhanced Raman scattering (SERS) and excellent flexibility,reproducibility and stability.In addition,the sample can be recovered after a washing process with an organic solvent and repeatedly used.The sensitive SERS performance is attributed to chemical enhancement through a charge transfer process.Moreover,the SERS performance is also found to be dependent on the light coupling effect.When the light absorbance rate of the α-Fe2O3 films increases at a wavelength near that of laser light,the film shows excellent sensitivity due to light coupling effect.展开更多
Event temporal relation extraction is an important part of natural language processing.Many models are being used in this task with the development of deep learning.However,most of the existing methods cannot accurate...Event temporal relation extraction is an important part of natural language processing.Many models are being used in this task with the development of deep learning.However,most of the existing methods cannot accurately obtain the degree of association between different tokens and events,and event-related information cannot be effectively integrated.In this paper,we propose an event information integration model that integrates event information through multilayer bidirectional long short-term memory(Bi-LSTM)and attention mechanism.Although the above scheme can improve the extraction performance,it can still be further optimized.To further improve the performance of the previous scheme,we propose a novel relational graph attention network that incorporates edge attributes.In this approach,we first build a semantic dependency graph through dependency parsing,model a semantic graph that considers the edges’attributes by using top-k attention mechanisms to learn hidden semantic contextual representations,and finally predict event temporal relations.We evaluate proposed models on the TimeBank-Dense dataset.Compared to previous baselines,the Micro-F1 scores obtained by our models improve by 3.9%and 14.5%,respectively.展开更多
基金supported in part by the Australian National Health and Medical Research Council (NHMRC, No. 1107828)Arthritis foundation of Australiathe University of Western Australia Research Collaboration Awards
文摘Rheumatoid arthritis(RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages:(i) triggering,(ii) maturation,(iii) targeting, and(iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies(including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.
基金grants from the National Key Research and Development Program of China to CL(grant No.2018 YFC1004002)National Natural Science Foundation of China(grant Nos.81730071,81472734 and 81321003 to HZ and 81402388 to CR)+3 种基金Natural Science Foundation of Beijing Municipality(grant No.7162102 to YW and 7171005 to HZ)Ministry of Science and Technology of China(grant No.2016 YFC 1302103 to HZ)Leading Academic Discipline Project of Beijing Education Bureau(grant No.BMU 20110254 to CR)the 111 Project of the Ministry of Education,Peking University(grant No.BMU 2018 JC004 to HZ and BMU 20150492 to CR).
文摘Objective:Lynch syndrome(LS)predisposes patients to early onset endometrioid endometrial cancer(EEC).However,little is known about LS-related EEC in the Chinese population.The aim of this study was to investigate the prevalence of LS and to identify the specific variants of LS in Chinese patients with EEC.Methods:We applied universal immunohistochemistry screening to detect the expression of mismatch repair(MMR)proteins,which was followed by MLH1 methylation analysis to identify suspected LS cases,next-generation sequencing(NGS)to confirm LS,and microsatellite instability(MSI)analysis to verify LS.Results:We collected 211 samples with EEC.Twenty-seven(27/211,12.8%)EEC cases had a loss of MMR protein expression.After MLH1 methylation analysis,16 EEC cases were suggested to be associated with LS.Finally,through NGS and MSI analysis,we determined that 10 EEC(10/209,4.78%)cases were associated with LS.Among those cases,3 unreported mutations(1 frameshift and 2 nonsense)were identified.M SH6 c.597_597delC,found in 4 patients,is likely to be a founder mutation in China.Conclusions:We demonstrated the feasibility of a process for LS screening in Chinese patients with EEC,by using universal immunohistochemistry screening followed by MLH1 methylation analysis and confirmation through NGS and MSI analysis.The novel mutations identified in this study expand knowledge of LS.
基金supported by grants from the National Natural Science Foundation of China[Grant No.81701076,Linlin Zeng]the Science and Technology Department of Jilin Province[Grant No.20190701037GH,Fuqiang Zhang+2 种基金Grant No.20190701036GH,Linlin Zengand Grant No.20200201386JC,Guodong Li]the Education Department of Jilin Province[Grant No.JJKH20200948KJ,Linlin Zeng]。
文摘Amyotrophic lateral syndrome(ALS)is a progressive degenerative disorder characterized by motor neuron death and axon degeneration.Mitochondrial dysfunction plays a key role in the pathogenesis of ALS,the mechanism of which remains poorly understood.The B-cell lymphoma-2(Bcl-2)family of proteins that control and mediate mitochondrial function and apoptosis,including the pro-apoptotic members Bcl2-Associated X(Bax),are involved in ALS development.The death receptor 6(DR6)regulates motor neuron death in ALS,and DR6 antibodies can prevent axon degeneration and motor neuron damage by blocking DR6.Previous studies demonstrated that PSAP localized to mitochondria and was required for DR6-induced apoptosis.In this study,SOD1^(G93A) was transfected into the motor neuron cell line NSC-34 to serve as an ALS cell model in vitro.The data assessed the role of PSAP in SOD1^(G93A)induced apoptosis and demonstrated that the overexpression of SOD1^(G93A),but not wtSOD1,induced PARP cleavage,caspase-3 activation,cytochrome c release,and Bax translocation.PSAP,Bax,and Bak were necessary for SOD1^(G93A)induced apoptosis,as silencing PSAP inhibited SOD1^(G93A)-mediated cell death that was dependent on Bax-Bak interaction.
文摘In the published Figure 11,errors appeared in Figure 1B on page 69.In Figure 1B,bands for p-Akt S473,Akt,and Actin in H1355 cells were mistakenly placed.Here,we have updated Figure 1B to correct the mistake above.The errors do not impact the conclusions of this article.We apologize for the errors and for any confusion it may have caused.
基金supported by grants from "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDA12020218 & XDA12020111)National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" (Grant No. 2018ZX09711002-011-014)+1 种基金National Natural Science Foundation of China (Grant No. 81773760)partially supported by FudanSIMM Joint Research Program (Grant No. FUSIMM20172005)
文摘Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer(NSCLC).However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown.Methods: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo.Results: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation.Conclusions: Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRASmutated NSCLC.
基金This work is funded by Natural Science Foundation of Jiangsu Province under Grant BK20160955a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Science Research Foundation of Nanjing University of Information Science and Technology under Grant 20110430+1 种基金Open Foundation of Jiangsu Key Laboratory of Meteorological Observation and Information Processing(KDXS1304)Open Foundation of Jiangsu Key Laboratory of Ocean Dynamic Remote Sensing and Acoustics(KHYS1405).
文摘Transfer alignment is used to initialize SINS(Strapdown Inertial Navigation System)in motion.Lever-arm effect compensation is studied existing in an AUV(Autonomous Underwater Vehicle)before launched from the mother ship.The AUV is equipped with SINS,Doppler Velocity Log,depth sensor and other navigation sensors.The lever arm will cause large error on the transfer alignment between master inertial navigation system and slave inertial navigation system,especially in big ship situations.This paper presents a novel method that can effectively estimate and compensate the flexural lever arm between the main inertial navigation system mounted on the mother ship and the slave inertial navigation system equipped on the AUV.The nonlinear measurement equation of angular rate is derived based on three successive rotations of the body frame of the master inertial navigation system.Nonlinear filter is utilized as the nonlinear estimator for its capability of non-linear approximation.Observability analysis was conducted on the SINS state vector based on singular value decomposition method.State equation of SINS was adopted as the system state equation.Simulation experiments were conducted and results showed that the proposed method can estimate the flexural lever arm more accurately,the precision of transfer alignment was improved and alignment time was shortened accordingly.
基金supported by Natural Science Foundation of Jiangsu Province(Grant No.BK20141005)by Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.14KJB520025).
文摘In the field of data mining and machine learning,clustering is a typical issue which has been widely studied by many researchers,and lots of effective algorithms have been proposed,including K-means,fuzzy c-means(FCM)and DBSCAN.However,the traditional clustering methods are easily trapped into local optimum.Thus,many evolutionary-based clustering methods have been investigated.Considering the effectiveness of brain storm optimization(BSO)in increasing the diversity while the diversity optimization is performed,in this paper,we propose a new clustering model based on BSO to use the global ability of BSO.In our experiment,we apply the novel binary model to solve the problem.During the period of processing data,BSO was mainly utilized for iteration.Also,in the process of K-means,we set the more appropriate parameters selected to match it greatly.Four datasets were used in our experiment.In our model,BSO was first introduced in solving the clustering problem.With the algorithm running on each dataset repeatedly,our experimental results have obtained good convergence and diversity.In addition,by comparing the results with other clustering models,the BSO clustering model also guarantees high accuracy.Therefore,from many aspects,the simulation results show that the model of this paper has good performance.
基金supported by the National Natural Science Foundation of China(No.51978658)。
文摘Water fluoride pollution has caused non-negligible harm to the environment and humans,and thus it is crucial to find a suitable treatment technology.In this study,La-Fe@PTA adsorbent was synthesized for the defluoridation of mine water.The results showed that the optimum conditions for defluoridation by La-Fe@PTA were p H close to 7.0,the initial F-concentration of 10 mg/L,the dosage of 0.5 g/L and the adsorption time of 240 min.Compared with SO_4^(2-),Cl^(-),NO_(3)^(-),Ca^(2+)and Mg^(2+),CO_(3)^(2-)and HCO_(3)^(-)presented severer inhibition on fluoride uptake by La-Fe@PTA.The adsorption process fits well with the pseudo-second-order kinetic model and Freundlich model,and the maximum adsorption capacity of Langmuir model was 95 mg/g.Fixed-bed adsorption results indicated that fluoride in practical fluorinated mine water could be effectively removed from 3.6 mg/L to less than 1.5 mg/L within130 bed volume(BV)by using 1.5 g La-Fe@PTA.Furthermore,the adsorbent still had good adsorption capacity after regeneration,which confirms the great application potential of La-Fe@PTA as a fluoride ion adsorbent.The mechanism analysis showed that La-Fe@PTA adsorption of fluorine ions is a physicochemical reaction driven by electrostatic attraction and ion exchange.
基金This work was supported by the National Natural Science Foundation of China(No.82373910,82204409)The“Double First-Class”University Project(CPU2022QZ20,China)。
文摘Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment,significantly curtailing the efficacy of these treatments and,in some cases,resulting in fatal conse-quences.Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis,the paucity of effective treatments for such damage is evident.In our study,we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells,thereby fortifying the integrity of the intestinal mucus barrier.This enhanced barrier function serves to resist microbial invasion and sub-sequently reduces the inflammatory response.Importantly,this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs.Mechanistically,E.copr up-regulates the expression of AUF1,leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells.An espe-cially significant finding is that E.copr activates the AhR pathway,thereby promoting the expression of AUF1.In summary,our results strongly indicate that E.copr enhances the intestinal mucus barrier,effec-tively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUFl pathway,consequently enhancing Muc2 mRNA stability.
基金sponsored by the National Key R&D Program of China(Grant No.2022YFA1405700)the National Natural Science Foundation of China(Grant Nos.12174069,and 92365104)+6 种基金the Shuguang Program supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commissionsupported by the Double First-Class Initiative Fund of Shanghai Tech Universitythe open project from Beijing National Laboratory for Condensed Matter Physicssupported by the National Key R&D Program of China(Grant No.2022YFA1602603)the National Natural Science Foundation of China(Grant No.12122411)supported by the National Natural Science Foundation of China(Grant No.12274090)the Natural Science Foundation of Shanghai(Grant No.22ZR1406300)。
文摘EuCd_(2)As_(2)was theoretically predicted to be a minimal model of Weyl semimetals with a single pair of Weyl points in the ferromagnet state.However,the heavily p-doped Eu Cd_(2)As_(2)crystals in previous experiments prevent direct identification of the semimetal hypothesis.Here,we present a comprehensive magneto-transport study of high-quality Eu Cd_(2)As_(2)crystals with ultralow bulk carrier density(10^(13)cm^(-3)).In contrast to the general expectation of a Weyl semimetal phase,Eu Cd_(2)As_(2)shows insulating behavior in both antiferromagnetic and ferromagnetic states as well as surface-dominated conduction from band bending.Moreover,the application of a dc bias current can dramatically modulate the resistance by over one order of magnitude,and induce a periodic resistance oscillation due to the geometric resonance.Such nonlinear transport results from the high nonequilibrium state induced by an electrical field near the band edge.Our results suggest an insulating phase in Eu Cd_(2)As_(2)and put a strong constraint on the underlying mechanism of anomalous transport properties in this system.
基金supported by the National Natural Science Foundation of China(No.51875365).
文摘In this study,Al–4Cu alloy specimens with spherical grains and liquid flms were obtained by isothermal reheating treatment.The hot cracking of the solidifcation process was determined using a modifed constrained rod casting experimental apparatus,and the efect of liquid flm characteristics at the end of solidifcation on hot cracking initiation of Al–4Cu alloys was systematically investigated by combining molecular dynamics simulations and other methods.With the extension of soaking time,the liquid fraction(liquid flm fraction at the end of solidifcation)and grain shape factor increased with higher isothermal reheating temperatures.Additionally,the widened flling channel decreased the hot cracking initiation temperature and the critical hot cracking shrinkage stress was found to increase,thus reducing the hot cracking severity in Al–4Cu alloys.Molecular dynamics simulations revealed that with the extension of soaking time,the composition of the liquid flm changed at diferent isothermal reheating temperatures,but the short-range structure and atomic ordering of the liquid flm remained the same.The activity of the liquid flm increased in equilibrium,leading to a decrease in viscosity and an increase in fuidity,which contributed to the flling behaviour.After isothermal reheating at 640℃for 60 min,the liquid fraction reached the maximum,and the viscosity of the liquid flm was the minimum.In addition,almost no hot cracks were found.
基金National Natural Science Foundation of China(No.82072390)Natural Science Foundation of Hunan,China(No.2020JJ4873)
文摘Background:Congenital scoliosis(CS)is a complex spinal malformation of unknown etiology with abnormal bone metabolism.Fibroblast growth factor 23(FGF23),secreted by osteoblasts and osteocytes,can inhibit bone formation and mineralization.This research aims to investigate the relationship between CS and FGF23.Methods:We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region.FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured.Receiver operator characteristic(ROC)curve analyses were conducted to evaluate the specificity and sensitivity of FGF23.The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3(FGFr3)/tissue non-specific alkaline phosphatase(TNAP)/osteopontin(OPN)in primary osteoblasts from CS patients(CS-Ob)and controls(CT-Ob)were detected.In addition,the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined.Results:DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins,accompanied by increased mRNA levels.CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography(CT)values compared with controls.The FGF23 mRNA levels were negatively correlated with the CT value of the spine,and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS.Additionally,significantly increased levels of FGF23,FGFr3,OPN,impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob.Moreover,FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels,while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob.Mineralization of CS-Ob was rescued after FGF23 knockdown.Conclusions:Our results suggested increased peripheral blood FGF23 levels,decreased bone mineral density in CS patients,and a good predictive ability of CS by peripheral blood FGF23 levels.FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP/OPN pathway.
基金National Natural Science Foundation of China(No.82072390)Natural Science Foundation of Hunan,China(No.2020JJ4873)
文摘Background:Osteopenia has been well documented in adolescent idiopathic scoliosis(AIS).Bone marrow stem cells(BMSCs)are a crucial regulator of bone homeostasis.Our previous study revealed a decreased osteogenic ability of BMSCs in AIS-related osteopenia,but the underlying mechanism of this phenomenon remains unclear.Methods:A total of 22 AIS patients and 18 age-matched controls were recruited for this study.Anthropometry and bone mass were measured in all participants.Bone marrow blood was collected for BMSC isolation and culture.Osteogenic and adipogenic induction were performed to observe the differences in the differentiation of BMSCs between the AIS-related osteopenia group and the control group.Furthermore,a total RNA was extracted from isolated BMSCs to perform RNA sequencing and subsequent analysis.Results:A lower osteogenic capacity and increased adipogenic capacity of BMSCs in AIS-related osteopenia were revealed.Differences in mRNA expression levels between the AIS-related osteopenia group and the control group were identified,including differences in the expression of LRRC17,DCLK1,PCDH7,TSPAN5,NHSL2,and CPT1B.Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed several biological processes involved in the regulation of autophagy and mitophagy.The Western blotting results of autophagy markers in BMSCs suggested impaired autophagic activity in BMSCs in the AIS-related osteopenia group.Conclusion:Our study revealed that BMSCs from AIS-related osteopenia patients have lower autophagic activity,which may be related to the lower osteogenic capacity and higher adipogenic capacity of BMSCs and consequently lead to the lower bone mass in AIS patients.
基金supported by the Lingang Laboratory (LG202103-02-03)National Natural Science Foundation of China (82173832,81973345 and 82104199)+2 种基金the State Key Laboratory of Drug Research (SIMM2205KF-05)Science and Technology Commission of Shanghai Municipality (22ZR1474400)“Personalized Medicines-Molecular Signature-based Drug Discovery and Development”,Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020111).
文摘Phosphatidylinositol 3-kinase alpha(PI3Kα)inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma(ESCC).It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kαinhibitors in an aim to improve the clinical responsive rate in ESCC.Here,ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33,a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC.Elevated level of cyclin D1,p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells.CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase,which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2.Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1,which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21.Moreover,CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33.These findings provided mechanistic rationale to evaluate PI3Kαinhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.
基金supported by National Natural Science Foundation of China(81973345 and 82173832)"Personalized MedicinesMolecular Signature-based Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020111,China)。
文摘Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis.Esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC)are two major subtypes of esophageal cancer.ESCC predominantly affects African and Asian populations,which is closely related to chronic smoking and alcohol consumption.EAC typically arises in Barrett’s esophagus with a predilection for Western countries.While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer,molecularly targeted therapy is still at the early stages.With the development of large-scale next-generation sequencing,various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied.Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer.In this review,we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer.Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.
文摘Cap-like α-Fe2O3 films are fabricated and deposited onto quartz fabric by using radio frequency magnetron sputtering and annealing.The treated fabric sample in this study shows highly sensitive surface-enhanced Raman scattering (SERS) and excellent flexibility,reproducibility and stability.In addition,the sample can be recovered after a washing process with an organic solvent and repeatedly used.The sensitive SERS performance is attributed to chemical enhancement through a charge transfer process.Moreover,the SERS performance is also found to be dependent on the light coupling effect.When the light absorbance rate of the α-Fe2O3 films increases at a wavelength near that of laser light,the film shows excellent sensitivity due to light coupling effect.
基金supported by the National key Research&Development Program of China(No.2017YFC0820503)the National Natural Science Foundation of China(No.62072149)+2 种基金the National Social Science Foundation of China(No.19ZDA348)the Primary Research&Development Plan of Zhejiang(No.2021C03156)the Public Welfare Research Program of Zhejiang(No.LGG19F020017)。
文摘Event temporal relation extraction is an important part of natural language processing.Many models are being used in this task with the development of deep learning.However,most of the existing methods cannot accurately obtain the degree of association between different tokens and events,and event-related information cannot be effectively integrated.In this paper,we propose an event information integration model that integrates event information through multilayer bidirectional long short-term memory(Bi-LSTM)and attention mechanism.Although the above scheme can improve the extraction performance,it can still be further optimized.To further improve the performance of the previous scheme,we propose a novel relational graph attention network that incorporates edge attributes.In this approach,we first build a semantic dependency graph through dependency parsing,model a semantic graph that considers the edges’attributes by using top-k attention mechanisms to learn hidden semantic contextual representations,and finally predict event temporal relations.We evaluate proposed models on the TimeBank-Dense dataset.Compared to previous baselines,the Micro-F1 scores obtained by our models improve by 3.9%and 14.5%,respectively.
