Let M_(n,p)=(X_(i,k))_(n×p)be an n×p random matrix whose p columns X^((1)),...,X^((p))are an n-dimensional i.i.d.random sample of size p from 1-dependent Gaussian populations.Instead of investigating the spe...Let M_(n,p)=(X_(i,k))_(n×p)be an n×p random matrix whose p columns X^((1)),...,X^((p))are an n-dimensional i.i.d.random sample of size p from 1-dependent Gaussian populations.Instead of investigating the special case where p and n are comparable,we consider a much more general case in which log n=o(p^(1/3)).We prove that the maximum interpoint distance Mn=max{|X_(i)-X_(j)|;1≤i<j≤n}converges to an extreme-value distribution,where X_(i)and X_(j)denote the i-th and j-th row of M_(n,p),respectively.The proofs are completed by using the Chen-Stein Poisson approximation method and the moderation deviation principle.展开更多
Small RNAs(sRNAs)are essential for regulating plant growth and development,and they possess the notable ability to travel long distances within organisms to regulate target gene expression.Our study examined the dcl2 ...Small RNAs(sRNAs)are essential for regulating plant growth and development,and they possess the notable ability to travel long distances within organisms to regulate target gene expression.Our study examined the dcl2 mutant,a key enzyme in s RNA biogenesis,to determine the role of the DCL2 protein in s RNA synthesis and to identify mobile s RNAs under DCL2 regulation.Through grafting experiments between dcl2 mutants and wild-type soybean plants,coupled with s RNA sequencing,we identified14,105 s RNAs significantly affected by DCL2 and discovered 375 mobile s RNAs under its regulation.Degradome analysis provided deeper insights into the regulatory effects of these mobile s RNAs on their target genes,enabling us to understand their potential influences on plant development and stress responses.Leveraging the systemic movement of s RNAs from roots to shoots,we propose a novel strategy for manipulating gene expression in aboveground tissues.Overall,our research findings not only deepen our understanding of the complex regulatory networks involving mobile s RNAs regulated by DCL2,but also provide a new strategy for gene regulation,which could have a positive impact on agricultural biotechnology.展开更多
In this study,we mainly discuss some spectral properties of the Dirac operator with eigenparameter-dependent boundary condition.Initially,we reformulate the spectral problem into linear operator eigenparameter problem...In this study,we mainly discuss some spectral properties of the Dirac operator with eigenparameter-dependent boundary condition.Initially,we reformulate the spectral problem into linear operator eigenparameter problem in a suitable Hilbert space,and obtain some pivotal properties of self-adjoint operator.Subsequently,by establishing the boundary condition space and constructing the embedded mapping,we show that the simple eigenvalue branch of this system is not only continuous,but also smooth.We then obtain the differential expressions of the eigenvalue branch in the sense of Frechet derivative.展开更多
BACKGROUND Growth arrest-specific gene 2(GAS2)plays a role in modulating in reversible growth arrest cell cycle,apoptosis,and cell survival.GAS2 protein is universally expressed in most normal tissues,particularly in ...BACKGROUND Growth arrest-specific gene 2(GAS2)plays a role in modulating in reversible growth arrest cell cycle,apoptosis,and cell survival.GAS2 protein is universally expressed in most normal tissues,particularly in the liver,but is depleted in some tumor tissues.However,the functional mechanisms of GAS2 in hepatocellular carcinoma(HCC)are not fully defined.AIM To investigate the function and mechanism of GAS2 in HCC.METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting.Cell proliferation was analyzed by counting,MTS,and colony formation assays.Cell cycle analysis was performed by flow cytometry.Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting.RESULTS GAS2 protein expression was lower in HCC than in normal tissues.Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53,while knockdown of GAS2 promoted the proliferation of hepatocytes(P<0.05).Furthermore,GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells,particularly the elevation of sub G1(P<0.01).Apoptosis induced by GAS2 was dependent on p53,which was increased by etoposide addition.The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated,but became diminished upon downregulation of GAS2.In the clinic specimen,GAS2 was downregulated in more than 60%of HCCs.The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues(P<0.05).CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis,possibly by regulating the cell cycle and p53-dependent apoptosis pathway.展开更多
Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is...Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time,the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2-/-mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment.Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction,ameliorate local inflammation for more predictable periodontitis.展开更多
Excessive activation of G-protein coupled receptor (GPCR) and receptor tyrosine kinase (RTK) pathways has been linked to prostate cancer metastasis. Rac activation
The study aims to confirm the neuroregenerative effects of bacterial melanin （BM） on central nervous system injury using a special staining method based on the detection of Ca^2＋-dependent acid phosphatase activity...The study aims to confirm the neuroregenerative effects of bacterial melanin （BM） on central nervous system injury using a special staining method based on the detection of Ca^2＋-dependent acid phosphatase activity. Twenty-four rats were randomly assigned to undergo either unilateral destruction of sensorimotor cortex （group I; n = 12） or unilateral rubrospinal tract transection at the cervical level （C3-4） （group II; n = 12）. In each group, six rats were randomly selected after surgery to undergo intramuscular injection of BM solution （BM subgroup） and the remaining six rats were intramuscularly in）ected with saline （saline subgroup）. Neurological testing confirmed that BM accelerated the recovery of motor function in rats from both BM and saline subgroups. Two months after surgery, Ca^2＋-dependent acid phosphatase activity detection in combination with Chilingarian＇s calcium adenoside triphosphate method revealed that BM stimulated the sprouting of fibers and dilated the capillaries in the brain and spinal cord. These results suggest that BM can promote the recovery of motor function of rats with central nervous system injury; and detection of Ca^2＋-dependent acid phosphatase activity is a fast and easy method used to study the regeneration-promoting effects of BM on the injured central nervous system.展开更多
Background and Objective The morbidity of lower extremity atherosclerotic disease(LEAD)has increased year by year.Chronic stress attenuates the ability of angiogenesis and deteriorates the prognosis of LEAD.Chronic st...Background and Objective The morbidity of lower extremity atherosclerotic disease(LEAD)has increased year by year.Chronic stress attenuates the ability of angiogenesis and deteriorates the prognosis of LEAD.Chronic stress increases plasma and tissue DPP-4 activities in mice.DPP-4 plays an important role in angiogenesis.Therefore,we hypothesized that chronic stress exerted its cardiovascular effects by increasing DPP-4 activation.We investigated the role of DPP-4/GLP-1 axis in ischemiainduced neovascularization in mice under restraint stress.展开更多
Let Y_i=M(X_i)+ei, where M(x)=E(Y|X=x) is an unknown realfunction on B(? R), {(X_1,Y_i)} is a stationary and m(n)-dependent sample from(X, Y), the residuals {e_i} are independent of {X_i} and have unknown common densi...Let Y_i=M(X_i)+ei, where M(x)=E(Y|X=x) is an unknown realfunction on B(? R), {(X_1,Y_i)} is a stationary and m(n)-dependent sample from(X, Y), the residuals {e_i} are independent of {X_i} and have unknown common densityf(x). In [2] a nonparametric estimate f_n(x) for f(x) has been proposed on the basisof the residuals estimates. In this paper, we further obtain the asymptotic normalityand the law of the iterated logarithm of f_n(x) under some suitable conditions. Theseresults together with those in [2] bring the asymptotic theory for the residuals densityestimate in nonparametric regression under m(n)-dependent sample to completion.展开更多
Objective The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation.Autophagy is a catabolic process responsible for maintaining cellular homeos...Objective The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation.Autophagy is a catabolic process responsible for maintaining cellular homeostasis.In recent years,autophagy has been demonstrated to play an important role in neuroinflammation.Resolvin D1(RvD1)is a promising therapeutic mediator that has been shown to exert substantial anti-inflammatory and proresolving activities.However,whether RvD1-mediated resolution of inflammation in microglia is related to autophagy regulation needs further investigation.The present study aimed to explore the effect of RvD1 on microglial autophagy and its corresponding pathways.Methods Mouse microglial cells(BV-2)were cultured,treated with RvD1,and examined by Western blotting,confocal immunofluorescence microscopy,transmission electron microscopy,and flow cytometry.Results RvD1 promoted autophagy in both BV-2 cells and mouse primary microglia by favoring the maturation of autophagosomes and their fusion with lysosomes.Importantly,RvD1 had no significant effect on the activation of mammalian target of rapamycin(mTOR)signaling.Furthermore,RvD1-induced mTOR-independent autophagy was confirmed by observing reduced cytoplasmic calcium levels and suppressed calcium/calmodulin-dependent protein kinase II(CaMK II)activation.Moreover,by downregulating ATG5,the increased phagocytic activity induced by RvD1 was demonstrated to be tightly controlled by ATG5-dependent autophagy.Conclusion The present work identified a previously unreported mechanism responsible for the role of RvD1 in microglial autophagy,highlighting its therapeutic potential against neuroinflammation.展开更多
Secondary xylem development has long been recognized as a typical case of programmed cell death （PCD） in plants. During PCD, the degradation of genomic DNA is catalyzed by endonucleases. However, to date, no endonuc...Secondary xylem development has long been recognized as a typical case of programmed cell death （PCD） in plants. During PCD, the degradation of genomic DNA is catalyzed by endonucleases. However, to date, no endonuclease has been shown to participate in secondary xylem development. Two novel Ca^2＋-dependent DNase genes, EuCaN1 and EuCaN2, were identified from the differentiating secondary xylem of the tree Eucommia ulmoides Oliv., their functions were studied by DNase activity assay, in situ hybridization, protein immunolocalization and virus-induced gene silencing experiments. Full-length cDNAs of EuCaN1 and EuCaN2 contained an open reading frame of 987 bp, encoding two proteins of 328 amino acids with SNase-like functional domains. The genomic DNA sequence for EuCaN1 had no introns, while EuCaN2 had 8 introns. EuCaN1 and EuCaN2 digested ssDNA and dsDNA with Ca^2＋-dependence at neutral pH. Their expression was confined to differentiating secondary xylem cells and the proteins were localized in the nucleus. Their activity dynamics was closely correlated with secondary xylem development. Secondary xylem cell differentiation is influenced by RNAi of endonuclease genes. The results provide evidence that the Ca^2＋-dependent DNases are involved in secondary xylem development.展开更多
Mechanisms on cancer cell migration and invasion have been major topics of cancer research and anti-cancer therapy development. Among the multiple cell signaling pathways involved in cell migration, those elicited by ...Mechanisms on cancer cell migration and invasion have been major topics of cancer research and anti-cancer therapy development. Among the multiple cell signaling pathways involved in cell migration, those elicited by transforming growth factorβ（TGF-β） have attracted tremendous attention. The TGF-βpolypeptide cytokines include four isoforms：TGF-β1, TGF-β2, TGF-β3, and TGF-β4, which are secreted mainly from cells of white blood cell lineage, such as macrophages, T cells and platelets.展开更多
The conjugation of SUMO （small ubiquitin-like modifier） to protein substrates is a reversible process （SUMOylation/deSUMOylation） that regulates plant devel- opment and stress responses. The essential metal copper...The conjugation of SUMO （small ubiquitin-like modifier） to protein substrates is a reversible process （SUMOylation/deSUMOylation） that regulates plant devel- opment and stress responses. The essential metal copper （Cu） is required for normal plant growth, but excess amounts are toxic. The SUMO E3 ligase, SIZI, and SIZ1- mediated SUMOylation function in plant tolerance to excess Cu. It is unknown whether deSUMOylation also contributes to Cu tolerance in plants. Here, we report that OTSI, a protease that cleaves SUMO from its substrate proteins, participates in Cu tolerance in Arabidopsis thaliana （Arabi- dopsis）. OTS1 loss-of-function mutants （otsl-2 and otsl-3） displayed increased sensitivity to excess Cu. Redox homeostasis and the balance between SUMOylation and deSUMOylation were disrupted in the otsl-3 mutant under excess Cu conditions, The otsl-3 mutant accumulated higher levels of Cu in both shoots and roots compared to wild type. Specific Cu-related metal transporter genes were upregu- lated due to the loss-of-function of OTS% which might explain the high Cu levels in otsl-3. These results suggest that the SUMOylation/deSUMOylation machinery is acti- vated in response to excess Cu, and modulates Cu homeostasis and tolerance by regulating both Cu uptake and detoxification. Together, our findings provide insight into the biological function and regulatory role of SUMOylation/deSUMOylation in plant tolerance to Cu.展开更多
Tumor microenvironment(TME),as the“soil”of tumor growth and metastasis,exhibits significant differences from normal physiological conditions.However,how to manipulate the distinctions to achieve the accurate therapy...Tumor microenvironment(TME),as the“soil”of tumor growth and metastasis,exhibits significant differences from normal physiological conditions.However,how to manipulate the distinctions to achieve the accurate therapy of primary and metastatic tumors is still a challenge.Herein,an innovative nanoreactor(AH@MBTF)is developed to utilize the apparent differences(copper concentration and H_(2)O_(2)level)between tumor cells and normal cells to eliminate primary tumor based on H_(2)O_(2)-dependent photothermal-chemodynamic therapy and suppress metastatic tumor through copper complexation.This nanoreactor is constructed using functionalized MSN incorporating benzoyl thiourea(BTU),triphenylphosphine(TPP),and folic acid(FA),while being co-loaded with horseradish peroxidase(HRP)and its substrate ABTS.During therapy,the BTU moieties on AH@MBTF could capture excessive copper(highly correlated with tumor metastasis),presenting exceptional anti-metastasis activity.Simultaneously,the complexation between BTU and copper triggers the formation of cuprous ions,which further react with H_(2)O_(2)to generate cytotoxic hydroxyl radical(•OH),inhibiting tumor growth via che-modynamic therapy.Additionally,the stepwise targeting of FA and TPP guides AH@MBTF to accurately accu-mulate in tumor mitochondria,containing abnormally high levels of H_(2)O_(2).As a catalyst,HRP mediates the oxidation reaction between ABTS and H_(2)O_(2)to yield activated ABTS•^(+).Upon 808 nm laser irradiation,the activated ABTS•^(+)performs tumor-specific photothermal therapy,achieving the ablation of primary tumor by raising the tissue temperature.Collectively,this intelligent nanoreactor possesses profound potential in inhib-iting tumor progression and metastasis.展开更多
By means of the nuclear parton distribution studied only with lepton deep-inelastic scattering experimental data, the J/ψ ＂normal nuclear absorption＂ and energy loss effects are studied in a GIauber formalism at HE...By means of the nuclear parton distribution studied only with lepton deep-inelastic scattering experimental data, the J/ψ ＂normal nuclear absorption＂ and energy loss effects are studied in a GIauber formalism at HERA and RHIC energies. Assuming that the absorption cross section σabs increases with the charmonium-nucleon center of mass energy, the results reveal a significant dependence of the aabs on rapidity g at RHIC energies. The initial-state energy loss effect, which is found important only at HERA energies, is also considered, and its influence should be eliminated when we studied the absorption effect at low collision energies. Finally, we also present the theoretical prediction for LHC.展开更多
Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangle...Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the brain.The NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and aggregation.Because NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines.Here,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau phosphorylation.Using biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons.In primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis present.In the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical neurons.Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses.We also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced responses.These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in neurons.Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.展开更多
Biocatalysis with nicotinamide adenine dinucleotide phosphate(NADP)-dependent oxidoreductases faces a challenge in improving the efficiency of the costly cofactor utilization.Although enzyme fusion can offer cofactor ...Biocatalysis with nicotinamide adenine dinucleotide phosphate(NADP)-dependent oxidoreductases faces a challenge in improving the efficiency of the costly cofactor utilization.Although enzyme fusion can offer cofactor regeneration,the high-volume input and limited cofactor recyclability still make the enzymatic processes unsustainable.Therefore,it is of great significance to reduce cofactor input in a fusion enzyme(FuE)system,but no successful practice has been reported.Herein,we design a decapeptide bridge,RRRQRRRARR(R10),with high affinity for NADPH to construct fusion oxidoreductases(phenylacetone monooxygenase and phosphite dehydrogenase)for ester synthesis and NADP recycling.The peptide bridge enables electrostatic cofactor channeling that transports NADPH/NADP^(+)across the peptide between the enzymes’NADP-binding pockets,so the fusion enzyme(FuE-R10)presents 2.1-folds and 2.0-folds higher conversions than mixed free enzymes and a flexible linker(GGGGSGGGGS)-fused enzyme,respectively,at NADPH/FuE of 0.1.The fusion enzyme,FuE-R5,bridged by a half-shortened linker,is proved more effective in facilitating cofactor channeling;compared to the mixed free enzymes,FuE-R5 exhibits two orders of magnitude reduction of NADPH input in ester synthesis.The work has thus demonstrated the potential of the cofactor bridging strategy in the development of sustainable cofactor-dependent cascade biocatalysis.展开更多
The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte ...The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We've previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca^(2+) ) dynamics. Here, by simultaneously monitoring Ca^(2+) and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca^(2+) transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles(EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1(LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca^(2+) signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to vehicle.Micro-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca^(2+) -dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca^(2+) signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca^(2+) -mediated signaling in bone adaptation.展开更多
基金Supported by the National Natural Science Foundation of China(Grant Nos.1177117812171198)+2 种基金the Science and Technology Development Program of Jilin Province(Grant No.20210101467JC)the Technology Program of Jilin Educational Department During the“14th Five-Year”Plan Period(Grant No.JJKH20241239KJ)the Fundamental Research Funds for the Central Universities.
文摘Let M_(n,p)=(X_(i,k))_(n×p)be an n×p random matrix whose p columns X^((1)),...,X^((p))are an n-dimensional i.i.d.random sample of size p from 1-dependent Gaussian populations.Instead of investigating the special case where p and n are comparable,we consider a much more general case in which log n=o(p^(1/3)).We prove that the maximum interpoint distance Mn=max{|X_(i)-X_(j)|;1≤i<j≤n}converges to an extreme-value distribution,where X_(i)and X_(j)denote the i-th and j-th row of M_(n,p),respectively.The proofs are completed by using the Chen-Stein Poisson approximation method and the moderation deviation principle.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA24010205)the CAS Project for Young Scientists in Basic Research(YSBR-011)+1 种基金National Natural Science Foundation of China(32272101)the Agricultural Science and Technology Innovation Program of CAAS。
文摘Small RNAs(sRNAs)are essential for regulating plant growth and development,and they possess the notable ability to travel long distances within organisms to regulate target gene expression.Our study examined the dcl2 mutant,a key enzyme in s RNA biogenesis,to determine the role of the DCL2 protein in s RNA synthesis and to identify mobile s RNAs under DCL2 regulation.Through grafting experiments between dcl2 mutants and wild-type soybean plants,coupled with s RNA sequencing,we identified14,105 s RNAs significantly affected by DCL2 and discovered 375 mobile s RNAs under its regulation.Degradome analysis provided deeper insights into the regulatory effects of these mobile s RNAs on their target genes,enabling us to understand their potential influences on plant development and stress responses.Leveraging the systemic movement of s RNAs from roots to shoots,we propose a novel strategy for manipulating gene expression in aboveground tissues.Overall,our research findings not only deepen our understanding of the complex regulatory networks involving mobile s RNAs regulated by DCL2,but also provide a new strategy for gene regulation,which could have a positive impact on agricultural biotechnology.
基金Supported by the National Natural Science Foundation of China(12461039)Excellent Graduate Innovation Star Scientific Research Project of Gansu Province of China(2025CXZX-273)。
文摘In this study,we mainly discuss some spectral properties of the Dirac operator with eigenparameter-dependent boundary condition.Initially,we reformulate the spectral problem into linear operator eigenparameter problem in a suitable Hilbert space,and obtain some pivotal properties of self-adjoint operator.Subsequently,by establishing the boundary condition space and constructing the embedded mapping,we show that the simple eigenvalue branch of this system is not only continuous,but also smooth.We then obtain the differential expressions of the eigenvalue branch in the sense of Frechet derivative.
基金Supported by the National Natural Science Foundation of China,No.81702777Natural Science Foundation of Guangdong Province,No.2015A030310053
文摘BACKGROUND Growth arrest-specific gene 2(GAS2)plays a role in modulating in reversible growth arrest cell cycle,apoptosis,and cell survival.GAS2 protein is universally expressed in most normal tissues,particularly in the liver,but is depleted in some tumor tissues.However,the functional mechanisms of GAS2 in hepatocellular carcinoma(HCC)are not fully defined.AIM To investigate the function and mechanism of GAS2 in HCC.METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting.Cell proliferation was analyzed by counting,MTS,and colony formation assays.Cell cycle analysis was performed by flow cytometry.Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting.RESULTS GAS2 protein expression was lower in HCC than in normal tissues.Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53,while knockdown of GAS2 promoted the proliferation of hepatocytes(P<0.05).Furthermore,GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells,particularly the elevation of sub G1(P<0.01).Apoptosis induced by GAS2 was dependent on p53,which was increased by etoposide addition.The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated,but became diminished upon downregulation of GAS2.In the clinic specimen,GAS2 was downregulated in more than 60%of HCCs.The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues(P<0.05).CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis,possibly by regulating the cell cycle and p53-dependent apoptosis pathway.
基金supported by the National Natural Science Foundation of China (31971282 and 32071362)2019 Chongqing Graduate Tutor Team Construction Project (dstd201903)Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN201900415)。
文摘Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time,the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2-/-mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment.Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction,ameliorate local inflammation for more predictable periodontitis.
文摘Excessive activation of G-protein coupled receptor (GPCR) and receptor tyrosine kinase (RTK) pathways has been linked to prostate cancer metastasis. Rac activation
基金supported by the Armenian National Science and Education Fund for Project in New York,USA(No.ANSEF biotech-4241)
文摘The study aims to confirm the neuroregenerative effects of bacterial melanin （BM） on central nervous system injury using a special staining method based on the detection of Ca^2＋-dependent acid phosphatase activity. Twenty-four rats were randomly assigned to undergo either unilateral destruction of sensorimotor cortex （group I; n = 12） or unilateral rubrospinal tract transection at the cervical level （C3-4） （group II; n = 12）. In each group, six rats were randomly selected after surgery to undergo intramuscular injection of BM solution （BM subgroup） and the remaining six rats were intramuscularly in）ected with saline （saline subgroup）. Neurological testing confirmed that BM accelerated the recovery of motor function in rats from both BM and saline subgroups. Two months after surgery, Ca^2＋-dependent acid phosphatase activity detection in combination with Chilingarian＇s calcium adenoside triphosphate method revealed that BM stimulated the sprouting of fibers and dilated the capillaries in the brain and spinal cord. These results suggest that BM can promote the recovery of motor function of rats with central nervous system injury; and detection of Ca^2＋-dependent acid phosphatase activity is a fast and easy method used to study the regeneration-promoting effects of BM on the injured central nervous system.
文摘Background and Objective The morbidity of lower extremity atherosclerotic disease(LEAD)has increased year by year.Chronic stress attenuates the ability of angiogenesis and deteriorates the prognosis of LEAD.Chronic stress increases plasma and tissue DPP-4 activities in mice.DPP-4 plays an important role in angiogenesis.Therefore,we hypothesized that chronic stress exerted its cardiovascular effects by increasing DPP-4 activation.We investigated the role of DPP-4/GLP-1 axis in ischemiainduced neovascularization in mice under restraint stress.
基金Project Supported by National Natural Science Foundation of China.
文摘Let Y_i=M(X_i)+ei, where M(x)=E(Y|X=x) is an unknown realfunction on B(? R), {(X_1,Y_i)} is a stationary and m(n)-dependent sample from(X, Y), the residuals {e_i} are independent of {X_i} and have unknown common densityf(x). In [2] a nonparametric estimate f_n(x) for f(x) has been proposed on the basisof the residuals estimates. In this paper, we further obtain the asymptotic normalityand the law of the iterated logarithm of f_n(x) under some suitable conditions. Theseresults together with those in [2] bring the asymptotic theory for the residuals densityestimate in nonparametric regression under m(n)-dependent sample to completion.
基金the National Natural Science Foundation of China(No.81902016).
文摘Objective The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation.Autophagy is a catabolic process responsible for maintaining cellular homeostasis.In recent years,autophagy has been demonstrated to play an important role in neuroinflammation.Resolvin D1(RvD1)is a promising therapeutic mediator that has been shown to exert substantial anti-inflammatory and proresolving activities.However,whether RvD1-mediated resolution of inflammation in microglia is related to autophagy regulation needs further investigation.The present study aimed to explore the effect of RvD1 on microglial autophagy and its corresponding pathways.Methods Mouse microglial cells(BV-2)were cultured,treated with RvD1,and examined by Western blotting,confocal immunofluorescence microscopy,transmission electron microscopy,and flow cytometry.Results RvD1 promoted autophagy in both BV-2 cells and mouse primary microglia by favoring the maturation of autophagosomes and their fusion with lysosomes.Importantly,RvD1 had no significant effect on the activation of mammalian target of rapamycin(mTOR)signaling.Furthermore,RvD1-induced mTOR-independent autophagy was confirmed by observing reduced cytoplasmic calcium levels and suppressed calcium/calmodulin-dependent protein kinase II(CaMK II)activation.Moreover,by downregulating ATG5,the increased phagocytic activity induced by RvD1 was demonstrated to be tightly controlled by ATG5-dependent autophagy.Conclusion The present work identified a previously unreported mechanism responsible for the role of RvD1 in microglial autophagy,highlighting its therapeutic potential against neuroinflammation.
基金supported by the National Basic Research Program of China (2012CB114500)the National Natural Science Foundation of China (31070156)
文摘Secondary xylem development has long been recognized as a typical case of programmed cell death （PCD） in plants. During PCD, the degradation of genomic DNA is catalyzed by endonucleases. However, to date, no endonuclease has been shown to participate in secondary xylem development. Two novel Ca^2＋-dependent DNase genes, EuCaN1 and EuCaN2, were identified from the differentiating secondary xylem of the tree Eucommia ulmoides Oliv., their functions were studied by DNase activity assay, in situ hybridization, protein immunolocalization and virus-induced gene silencing experiments. Full-length cDNAs of EuCaN1 and EuCaN2 contained an open reading frame of 987 bp, encoding two proteins of 328 amino acids with SNase-like functional domains. The genomic DNA sequence for EuCaN1 had no introns, while EuCaN2 had 8 introns. EuCaN1 and EuCaN2 digested ssDNA and dsDNA with Ca^2＋-dependence at neutral pH. Their expression was confined to differentiating secondary xylem cells and the proteins were localized in the nucleus. Their activity dynamics was closely correlated with secondary xylem development. Secondary xylem cell differentiation is influenced by RNAi of endonuclease genes. The results provide evidence that the Ca^2＋-dependent DNases are involved in secondary xylem development.
文摘Mechanisms on cancer cell migration and invasion have been major topics of cancer research and anti-cancer therapy development. Among the multiple cell signaling pathways involved in cell migration, those elicited by transforming growth factorβ（TGF-β） have attracted tremendous attention. The TGF-βpolypeptide cytokines include four isoforms：TGF-β1, TGF-β2, TGF-β3, and TGF-β4, which are secreted mainly from cells of white blood cell lineage, such as macrophages, T cells and platelets.
基金supported by the National Transgenic Major Project of China (2016ZX08009-003-002 to H.L.)the National Natural Science Foundation of China (31600201 to H.Z+1 种基金 31470342 and 31670235 to H.L.)the National Basic Research Program of China (2015CB150100 to H.L)
文摘The conjugation of SUMO （small ubiquitin-like modifier） to protein substrates is a reversible process （SUMOylation/deSUMOylation） that regulates plant devel- opment and stress responses. The essential metal copper （Cu） is required for normal plant growth, but excess amounts are toxic. The SUMO E3 ligase, SIZI, and SIZ1- mediated SUMOylation function in plant tolerance to excess Cu. It is unknown whether deSUMOylation also contributes to Cu tolerance in plants. Here, we report that OTSI, a protease that cleaves SUMO from its substrate proteins, participates in Cu tolerance in Arabidopsis thaliana （Arabi- dopsis）. OTS1 loss-of-function mutants （otsl-2 and otsl-3） displayed increased sensitivity to excess Cu. Redox homeostasis and the balance between SUMOylation and deSUMOylation were disrupted in the otsl-3 mutant under excess Cu conditions, The otsl-3 mutant accumulated higher levels of Cu in both shoots and roots compared to wild type. Specific Cu-related metal transporter genes were upregu- lated due to the loss-of-function of OTS% which might explain the high Cu levels in otsl-3. These results suggest that the SUMOylation/deSUMOylation machinery is acti- vated in response to excess Cu, and modulates Cu homeostasis and tolerance by regulating both Cu uptake and detoxification. Together, our findings provide insight into the biological function and regulatory role of SUMOylation/deSUMOylation in plant tolerance to Cu.
基金supported by the National High Level Talents Special Support Plan(X.C.)the National Natural Science Foundation of China(82272141 to X.C.)+4 种基金the“Young Talent Support Plan”of Xi’an Jiaotong University(X.C.)the Shaanxi Innovative Research Team of Science and Technology(S2023-ZC-TD-0152)the Natural Science Foundation of Shaanxi Province(2022JZ-48 to X.C.)the National Key Research and Development Program of China(2023YFC2509104 to X.C.)the Postdoctoral Science Foundation of China(2023M732812 to T.L.).
文摘Tumor microenvironment(TME),as the“soil”of tumor growth and metastasis,exhibits significant differences from normal physiological conditions.However,how to manipulate the distinctions to achieve the accurate therapy of primary and metastatic tumors is still a challenge.Herein,an innovative nanoreactor(AH@MBTF)is developed to utilize the apparent differences(copper concentration and H_(2)O_(2)level)between tumor cells and normal cells to eliminate primary tumor based on H_(2)O_(2)-dependent photothermal-chemodynamic therapy and suppress metastatic tumor through copper complexation.This nanoreactor is constructed using functionalized MSN incorporating benzoyl thiourea(BTU),triphenylphosphine(TPP),and folic acid(FA),while being co-loaded with horseradish peroxidase(HRP)and its substrate ABTS.During therapy,the BTU moieties on AH@MBTF could capture excessive copper(highly correlated with tumor metastasis),presenting exceptional anti-metastasis activity.Simultaneously,the complexation between BTU and copper triggers the formation of cuprous ions,which further react with H_(2)O_(2)to generate cytotoxic hydroxyl radical(•OH),inhibiting tumor growth via che-modynamic therapy.Additionally,the stepwise targeting of FA and TPP guides AH@MBTF to accurately accu-mulate in tumor mitochondria,containing abnormally high levels of H_(2)O_(2).As a catalyst,HRP mediates the oxidation reaction between ABTS and H_(2)O_(2)to yield activated ABTS•^(+).Upon 808 nm laser irradiation,the activated ABTS•^(+)performs tumor-specific photothermal therapy,achieving the ablation of primary tumor by raising the tissue temperature.Collectively,this intelligent nanoreactor possesses profound potential in inhib-iting tumor progression and metastasis.
文摘By means of the nuclear parton distribution studied only with lepton deep-inelastic scattering experimental data, the J/ψ ＂normal nuclear absorption＂ and energy loss effects are studied in a GIauber formalism at HERA and RHIC energies. Assuming that the absorption cross section σabs increases with the charmonium-nucleon center of mass energy, the results reveal a significant dependence of the aabs on rapidity g at RHIC energies. The initial-state energy loss effect, which is found important only at HERA energies, is also considered, and its influence should be eliminated when we studied the absorption effect at low collision energies. Finally, we also present the theoretical prediction for LHC.
基金supported by a grant from Key Laboratory of Alzheimer's Disease of Zhejiang Province,Institute of Aging,Wenzhou Medical University,No.ZJAD-2021002(to ZW)。
文摘Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the brain.The NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and aggregation.Because NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines.Here,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau phosphorylation.Using biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons.In primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis present.In the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical neurons.Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses.We also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced responses.These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in neurons.Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.
文摘Biocatalysis with nicotinamide adenine dinucleotide phosphate(NADP)-dependent oxidoreductases faces a challenge in improving the efficiency of the costly cofactor utilization.Although enzyme fusion can offer cofactor regeneration,the high-volume input and limited cofactor recyclability still make the enzymatic processes unsustainable.Therefore,it is of great significance to reduce cofactor input in a fusion enzyme(FuE)system,but no successful practice has been reported.Herein,we design a decapeptide bridge,RRRQRRRARR(R10),with high affinity for NADPH to construct fusion oxidoreductases(phenylacetone monooxygenase and phosphite dehydrogenase)for ester synthesis and NADP recycling.The peptide bridge enables electrostatic cofactor channeling that transports NADPH/NADP^(+)across the peptide between the enzymes’NADP-binding pockets,so the fusion enzyme(FuE-R10)presents 2.1-folds and 2.0-folds higher conversions than mixed free enzymes and a flexible linker(GGGGSGGGGS)-fused enzyme,respectively,at NADPH/FuE of 0.1.The fusion enzyme,FuE-R5,bridged by a half-shortened linker,is proved more effective in facilitating cofactor channeling;compared to the mixed free enzymes,FuE-R5 exhibits two orders of magnitude reduction of NADPH input in ester synthesis.The work has thus demonstrated the potential of the cofactor bridging strategy in the development of sustainable cofactor-dependent cascade biocatalysis.
基金supported by NIH R01 AR052461 and NIH R01 AR069148supported by a NSF Graduate Research Fellowship. A. E. M.supported by training grant T32 AR059038
文摘The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin(OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We've previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca^(2+) ) dynamics. Here, by simultaneously monitoring Ca^(2+) and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca^(2+) transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles(EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1(LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca^(2+) signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to vehicle.Micro-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca^(2+) -dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca^(2+) signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca^(2+) -mediated signaling in bone adaptation.
