In order to improve the catalytic performance of the nitrobenzene hydrogenation rearrangement to prepare p-aminophenol,a bimetallic Pt-Ni/C(PNC)catalyst was synthesized.Taking advantage of the synergistic effect of Ni...In order to improve the catalytic performance of the nitrobenzene hydrogenation rearrangement to prepare p-aminophenol,a bimetallic Pt-Ni/C(PNC)catalyst was synthesized.Taking advantage of the synergistic effect of Ni and Pt to enhance product selectivity and catalytic performance stability,the electrons in Ni are moved to Pt by the electron effect,which affects the catalyst’s ability to activate H_(2)as well as the amount of hydrogen activated.Furthermore,due to the strong Pt(5d)-Ni(3d)coupling effect,Ni can effectively maintain Pt stability in the acidic system and reduce Pt dissolution.The stability of the PNC can be found to be greatly enhanced compared to the Pt/C(PC)catalyst,and p-aminophenol selectivity is greatly enhanced,showing excellent catalytic performance.展开更多
Magneto-dielectric properties of Co_(2)Z ferrite materials are tuned via Gd doping for applications in high-frequency antennas and filters in the present work.Ba_(3)Co_(2)Fe_(24-x)Gd_(x)O_(41)(x=0.00,0.05,0.10,0.15,an...Magneto-dielectric properties of Co_(2)Z ferrite materials are tuned via Gd doping for applications in high-frequency antennas and filters in the present work.Ba_(3)Co_(2)Fe_(24-x)Gd_(x)O_(41)(x=0.00,0.05,0.10,0.15,and 0.20)materials are successfully prepared by using solid-state method at 925℃for 4 h with 2.5-wt%Bi_(2)O_(3)sintering aids.The content of Gd^(3+)ion can affect micromorphology,grain size,bulk density,and magneto-dielectric properties of the ferrite.With Gd^(3+)ion content increasing,saturation magnetization(Ms)first increases and then decreases.The maximum value of Ms is 44.86 emu/g at x=0.15.Additionally,sites occupied by Gd^(3+)ions can change magnetic anisotropy constant of the ferrite.Magnetocrystalline anisotropy constant(K_1)is derived from initial magnetization curve,and found to be related to spin-orbit coupling and intersublattice interactions between metal ions.The real part of magnetic permeability(μ′)and real part of dielectric permittivity(ε′)are measured in a frequency range of 10 MHz-1 GHz.When x=0.15,material has excellent magneto-dielectric properties(μ′≈12.2 andε′≈17.61),low magnetic loss(tanδμ≈0.03 at 500 MHz),and dielectric loss(tanδε≈0.04 at 500 MHz).The results show that Gd-doped Co_(2)Z ferrite has broad application prospects in multilayer filters and high-frequency antennas.展开更多
Background:The expression of pyruvate kinase muscle 2(PKM2)is augmented in macrophages of patients with atherosclerotic coronary artery disease.The role of PKM2 in atherosclerosis is to be determined.Methods:Global an...Background:The expression of pyruvate kinase muscle 2(PKM2)is augmented in macrophages of patients with atherosclerotic coronary artery disease.The role of PKM2 in atherosclerosis is to be determined.Methods:Global and myeloid cell-specific PKM2 knock-in mice with ApoE^(-/-)background(ApoE^(-/-),PKM2^(KI/KI)and Lyz2-cre,ApoE^(-/-),and PKM2^(flox/flox))were produced to evaluate the clinical significance of PKM2 in atherosclerosis development.Wild-type and PKM2 knock-in macrophages were isolated to assess the function of PKM2 in macrophage phagocytosis.Atherosclerotic mice were treated with PKM2 inhibitor shikonin(SKN)to evaluate the therapeutic potential of PKM2 suppression in atherosclerosis.Results:Oxidized low-density lipoprotein(oxLDL)upregulated PKM2 in macrophages.PKM2 in return promoted the uptake of oxLDL by macrophages.Overexpressed PKM2 accelerated atherosclerosis in mice.SKN blocked the progress of mouse atherosclerosis.Conclusions:PKM2 accelerates macrophage phagocytosis and atherosclerosis.Targeting PKM2 is a potential therapy for atherosclerosis.展开更多
Our previous studies have revealed that amyloidβ(Aβ)-binding alcohol dehydrogenase (ABAD) decoy peptide antagonizes Aβ42-induced neurotoxicity. However, whether it improves oxidative stress injury remains uncle...Our previous studies have revealed that amyloidβ(Aβ)-binding alcohol dehydrogenase (ABAD) decoy peptide antagonizes Aβ42-induced neurotoxicity. However, whether it improves oxidative stress injury remains unclear. In this study, a recombinant adenovirus constitutively secreting and expressing Aβ-ABAD decoy peptide (rAAV/ABAD-DP-6His) was successfully constructed. Our results showed that rAAV/ABAD-DP-6His increased superoxide dismutase activity in hydro-gen peroxide-induced oxidative stress-mediated injury of PC12 cells. Moreover, rAAV/ABAD-DP-6His decreased malondialdehyde content, intracellular Ca2+concentration, and the level of reactive oxygen species. rAAV/ABAD-DP-6His maintained the stability of the mitochondrial membrane potential. In addition, the ATP level remained constant, and apoptosis was reduced. Overall, the results indicate that rAAV/ABAD-DP-6His generates the fusion peptide, Aβ-ABAD decoy peptide, which effectively protects PC12 cells from oxidative stress injury induced by hy-drogen peroxide, thus exerting neuroprotective effects.展开更多
Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransfera...Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C(CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene m RNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.展开更多
Nanomaterial-based drug sustainable release systems have been tentatively applied to bone regeneration.They,however,still face disadvantages of high toxicity,low biocompatibility,and low drug-load capacity.In view of ...Nanomaterial-based drug sustainable release systems have been tentatively applied to bone regeneration.They,however,still face disadvantages of high toxicity,low biocompatibility,and low drug-load capacity.In view of the low toxicity and high biocompatibility of polymer nanomaterials and the excellent load capacity of hollow nanomaterials with high specific surface area,we evaluated the hollow polydopamine nanoparticles(HPDA NPs),in order to find an optimal system to effectively deliver the osteogenic drugs to improve treatment of bone defect.Data demonstrated that the HPDA NPs synthesized herein could efficiently load four types of osteogenic drugs and the drugs can effectively release from the HPDA NPs for a relatively longer time in vitro and in vivo with low toxicity and high biocompatibility.Results of qRT-PCR,ALP,and alizarin red S staining showed that drugs released from the HPDA NPs could promote osteogenic differentiation and proliferation of rat bone marrow mesenchymal stem cells(rBMSCs)in vitro.Image data from micro-CT and H&E staining showed that all four osteogenic drugs released from the HPDA NPs effectively promoted bone regeneration in the defect of tooth extraction fossa in vivo,especially tacrolimus.These results suggest that the HPDA NPs,the biodegradable hollow polymer nanoparticles with high drug load rate and sustainable release ability,have good prospect to treat the bone defect in future clinical practice.展开更多
<div style="text-align:justify;"> In this paper, we study the error estimates for direct discontinuous Galerkin methods based on the upwind-biased fluxes. We use a newly global projection to obtain the...<div style="text-align:justify;"> In this paper, we study the error estimates for direct discontinuous Galerkin methods based on the upwind-biased fluxes. We use a newly global projection to obtain the optimal error estimates. The numerical experiments imply that <em>L</em><sup>2 </sup>norms error estimates can reach to order <em>k</em> + 1 by using time discretization methods. </div>展开更多
The combined effects of Sm^(3+)substitution together with the addition of 3 wt%Bi_(2)O_(3)endow Mg Cd ferrites with excellent magnetic permeability and dielectric permittivity.Various concentrations of Sm^(3+)(x=0,0.0...The combined effects of Sm^(3+)substitution together with the addition of 3 wt%Bi_(2)O_(3)endow Mg Cd ferrites with excellent magnetic permeability and dielectric permittivity.Various concentrations of Sm^(3+)(x=0,0.03,0.06,0.09,0.12and 0.15)were employed to modify the permeability(μ)and permittivity(ε)of the Mg Cd ferrites.X-ray diffraction,scanning electron microscopy(SEM),vibrating sample magnetometry and vector network analysis techniques were used to characterize the samples.The measurement results reveal that the ferrites processed a saturation magnetization of up to 36.8 emu/g and coercivity of up to 29.2 Oe via the conventional solid-state reaction method.The surface morphology SEM confirms that with increasing Sm^(3+)concentration,the grain shape changes from a polygon to a circle.Moreover,the dielectric permittivity can reach a value of 23.The excellent properties obtained in Sm^(3+)-substituted Mg ferrites suggest that they could be promising candidates for modern high-frequency antenna substrates or multilayer devices.展开更多
The capacity is impacted badly by pedestrians' violation behavior at signal intersections. In order to quantify the impact,the time-headway and the vehicular speed from start-up to reach the stable saturation flow...The capacity is impacted badly by pedestrians' violation behavior at signal intersections. In order to quantify the impact,the time-headway and the vehicular speed from start-up to reach the stable saturation flow with and without pedestrian traffic are used as the direct measurements. Using the statistical analysis,the timeheadway of saturation flow is mainly affected by the position of pedestrians and the degree of pedestrians 'influence is classified into four levels. Then the speed-time profile for the vehicular acceleration at each level is fitted by Curve Fitting Software. Based on the effect to the time-headway and acceleration time,the model of capacity influenced by pedestrians is established and the influence is quantified, which enriches the fundamental theory of traffic engineering. The result shows that the vehicular capacity can be decreased by 14%at the worst case( level I). The conclusions obtained in this paper are valuable for better management of the signal intersection.展开更多
Heavily congested intersections in metropolitan areas in China are facing unique problems due to high travel demand and a high degree of traffic law violations. Based on a study conducted by the authors of this paper,...Heavily congested intersections in metropolitan areas in China are facing unique problems due to high travel demand and a high degree of traffic law violations. Based on a study conducted by the authors of this paper, 93% of left-turn vehicles turning left in these areas were slowed in order to avoid conflict with pedestrians. Intertwined pedestrian and vehicular flows can significantly reduce the capacity of exclusive left-turn lane group through reducing saturation flow rate, which increases the congestion at intersections. This paper investigates how the saturation flow rate of exclusive left-turn lane group is affected by the characteristics of pedestrian flow. By analyzing the imagery data collected by video cameras installed at intersections, the research team is able to obtain the characteristics of both vehicular and pedestrian flows, such as speed and spatial locations. The average operating speed at the saturation flow rate with and without pedestrian traffic is used as a direct measurement to evaluate the effect of pedestrians. Based on the statistical analysis, the paper concludes that saturation flow rate is mainly affected by the position of pedestrian in the crosswalk (inside or outside of left-turn vehicle’s trajectory), and the distance between the vehicle and pedestrians. In general, when the distance is less than four meters, the smaller the distance between vehicle and pedestrians, the larger the impact. However, there is no significant impact when the distance is larger than four meters. To accurately quantify the effect, the degree of pedestrian-vehicle impact is defined in four levels. The results show that the difference in the saturation flow rate between the best and the worst level could be 15.7%, which clearly indicates how important it is to enforce pedestrian crossing behavior.展开更多
Speed-flow relationship is the fundamental for the traffic simulation and traffic volume forecast. Traditional quadratic polynomial model can’t reflect the saturate flow at signal intersections. In order to determine...Speed-flow relationship is the fundamental for the traffic simulation and traffic volume forecast. Traditional quadratic polynomial model can’t reflect the saturate flow at signal intersections. In order to determine the speed-flow relationship at signal intersections, the speed and time-headway of vehicles at two signal intersections were investigated and the accuracy of software used to get the speed was tested. After vehicle starting-up from queuing, the time-headway reduces gradually with the increase of speed. The relationship of power exponential function between speed and time-headway is formulated. Traffic volume can be calculated by the vehicle time-headway. Then the speed-flow relationship was developed and an S-shaped curve model was built in this paper. In the S-shaped curve model, traffic flow approaches to the saturate when the speed doesn’t increase. Thus, S-shaped curve model is better to describe the speed-flow relationship at signal intersection. The results can provide a reference to determine the parameters in traffic simulation and for the study of level of service of intersections.展开更多
During the development of therapeutic microRNAs(miRNAs or miRs),it is essential to define their pharmacological actions.Rather,miRNA research and therapy mainly use miRNA mimics synthesized in vitro.After experimental...During the development of therapeutic microRNAs(miRNAs or miRs),it is essential to define their pharmacological actions.Rather,miRNA research and therapy mainly use miRNA mimics synthesized in vitro.After experimental screening of unique recombinant miRNAs produced in vivo,three lead antiproliferative miRNAs against human NSCLC cells,miR-22-3p,miR-9-5p,and miR-218-5p,were revealed to target folate metabolism by bioinformatic analyses.Recombinant miR-22-3p,miR-9-5p,and miR-218-5p were shown to regulate key folate metabolic enzymes to inhibit folate metabolism and subsequently alter amino acid metabolome in NSCLC A549 and H1975 cells.Isotope tracing studies further confirmed the disruption of one-carbon transfer from serine to folate metabolites by all three miRNAs,inhibition of glucose uptake by miR-22-3p,and reduction of serine biosynthesis from glucose by miR-9-5p and-218-5p in NSCLC cells.With greater activities to interrupt NSCLC cell respiration,glycolysis,and colony formation than miR-9-5p and-218-5p,recombinant miR-22-3p was effective to reduce tumor growth in two NSCLC patient-derived xenograft mouse models without causing any toxicity.These results establish a common antifolate mechanism and differential actions on glucose uptake and metabolism for three lead anticancer miRNAs as well as antitumor efficacy for miR-22-3p nanomedicine,which shall provide insight into developing antimetabolite RNA therapies.展开更多
The onset of Quaternary glaciations is a critical event in the climate and tectonic history of the Tibetan Plateau.The Shishapangma Glaciation,defined based on the till deposit from the northern slopes of Mt.Shishapan...The onset of Quaternary glaciations is a critical event in the climate and tectonic history of the Tibetan Plateau.The Shishapangma Glaciation,defined based on the till deposit from the northern slopes of Mt.Shishapangma,has been identified as the oldest glaciation on the Tibetan Plateau.However,the timing of this glaciation has not been constrained.We measured^(10)Be and^(26)Al concentrations of a set of boulders on top of this till and simulated their complex exposure-burial histories.The simulated results indicate that the formation age of this till is likely around 835.2±241.0 ka,representing the minimum timing of glacial onset on the Tibetan Plateau.The Shishapangma Glaciation is apparently much younger than the glacial onset in many other areas of the world,such as Europe and North America,and was likely driven by the coupled effect between tectonic uplift and climate cooling during the early–middle Pleistocene transition.展开更多
Acetaminophen(APAP)overdose is the leading cause of drug-induced liver injury,and its prognosis depends on the balance between hepatocyte death and regeneration.Sirtuin 6(SIRT6)has been reported to protect against oxi...Acetaminophen(APAP)overdose is the leading cause of drug-induced liver injury,and its prognosis depends on the balance between hepatocyte death and regeneration.Sirtuin 6(SIRT6)has been reported to protect against oxidative stress-associated DNA damage.But whether SIRT6 regulates APAPinduced hepatotoxicity remains unclear.In this study,the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment,respectively.Sirt6 knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress,inhibited cell viability and proliferation,and downregulated CCNA1,CCND1 and CKD4 protein levels.Sirt6 knockdown signifi-cantly prevented APAP-induced NRF2 activation,reduced the transcriptional activities of GSTm andNQO1 and the m RNA levels of Nrf2,Ho-1,Gsta and Gstm.Furthermore,SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation(Co-IP)assay.Additionally,the protective effect of P53 against APAP-induced hepatocytes injury was Sirt6-dependent.The Sirt6 m RNA was significantly down-regulated in P53à/àmice.P53 activated the transcriptional activity of SIRT6 and exerted interaction with SIRT6.Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation,and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.展开更多
Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness.To experimentally demonstrate the epidemiological results,we performed animal studies to infect male and female...Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness.To experimentally demonstrate the epidemiological results,we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2.Remarkably,high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss,weakness,piloerection,hunched back and abdominal respiration,as well as severe pneumonia,pulmonary edema,consolidation,and fibrosis.In contrast with the males,the female hamsters showed much lower shedding viral titers,moderate symptoms,and relatively mild lung pathogenesis.The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.展开更多
A main focus of machine learning research has been improving the generalization accuracy and efficiency of prediction models. However, what emerges as missing in many applications is actionability, i.e., the ability t...A main focus of machine learning research has been improving the generalization accuracy and efficiency of prediction models. However, what emerges as missing in many applications is actionability, i.e., the ability to turn prediction results into actions. Existing effort in deriving such actionable knowledge is few and limited to simple action models while in many real applications those models are often more complex and harder to extract an optimal solution. In this paper, we propose a novel approach that achieves actionability by combining learning with planning, two core areas of AI. In particular, we propose a framework to extract actionable knowledge from random forest, one of the most widely used and best off-the-shelf classifiers. We formulate the actionability problem to a sub-optimal action planning (SOAP) problem, which is to find a plan to alter certain features of a given input so that the random forest would yield a desirable output, while minimizing the total costs of actions. Technically, the SOAP problem is formulated in the SAS+ planning formalism, and solved using a Max-SAT based ap- proach. Our experimental results demonstrate the effectiveness and efficiency of the proposed approach on a personal credit dataset and other benchmarks. Our work represents a new application of automated planning on an emerging and challenging machine learning paradigm.展开更多
基金funded by the National Natural Science Foundation of China(U20A20119,22078292 and 22008212)。
文摘In order to improve the catalytic performance of the nitrobenzene hydrogenation rearrangement to prepare p-aminophenol,a bimetallic Pt-Ni/C(PNC)catalyst was synthesized.Taking advantage of the synergistic effect of Ni and Pt to enhance product selectivity and catalytic performance stability,the electrons in Ni are moved to Pt by the electron effect,which affects the catalyst’s ability to activate H_(2)as well as the amount of hydrogen activated.Furthermore,due to the strong Pt(5d)-Ni(3d)coupling effect,Ni can effectively maintain Pt stability in the acidic system and reduce Pt dissolution.The stability of the PNC can be found to be greatly enhanced compared to the Pt/C(PC)catalyst,and p-aminophenol selectivity is greatly enhanced,showing excellent catalytic performance.
基金the National Key Research and Development Program of China(Grant No.2022YFB3504800)the National Natural Science Foundation of China(Grant Nos.61901142,52003256,and 51902037)the Natural Science Foundation of Shanxi Province,China(Grant No.201901D211259)。
文摘Magneto-dielectric properties of Co_(2)Z ferrite materials are tuned via Gd doping for applications in high-frequency antennas and filters in the present work.Ba_(3)Co_(2)Fe_(24-x)Gd_(x)O_(41)(x=0.00,0.05,0.10,0.15,and 0.20)materials are successfully prepared by using solid-state method at 925℃for 4 h with 2.5-wt%Bi_(2)O_(3)sintering aids.The content of Gd^(3+)ion can affect micromorphology,grain size,bulk density,and magneto-dielectric properties of the ferrite.With Gd^(3+)ion content increasing,saturation magnetization(Ms)first increases and then decreases.The maximum value of Ms is 44.86 emu/g at x=0.15.Additionally,sites occupied by Gd^(3+)ions can change magnetic anisotropy constant of the ferrite.Magnetocrystalline anisotropy constant(K_1)is derived from initial magnetization curve,and found to be related to spin-orbit coupling and intersublattice interactions between metal ions.The real part of magnetic permeability(μ′)and real part of dielectric permittivity(ε′)are measured in a frequency range of 10 MHz-1 GHz.When x=0.15,material has excellent magneto-dielectric properties(μ′≈12.2 andε′≈17.61),low magnetic loss(tanδμ≈0.03 at 500 MHz),and dielectric loss(tanδε≈0.04 at 500 MHz).The results show that Gd-doped Co_(2)Z ferrite has broad application prospects in multilayer filters and high-frequency antennas.
基金National Key R&D program of China,Grant/Award Number:2021YFC2500700The National Natural Science Foundation of China+1 种基金Grant/Award Number:81730078The Chinese Academy of Medical Sciences Initiative for Innovative Medicine,Grant/Award Number:2021-I2M-1-049。
文摘Background:The expression of pyruvate kinase muscle 2(PKM2)is augmented in macrophages of patients with atherosclerotic coronary artery disease.The role of PKM2 in atherosclerosis is to be determined.Methods:Global and myeloid cell-specific PKM2 knock-in mice with ApoE^(-/-)background(ApoE^(-/-),PKM2^(KI/KI)and Lyz2-cre,ApoE^(-/-),and PKM2^(flox/flox))were produced to evaluate the clinical significance of PKM2 in atherosclerosis development.Wild-type and PKM2 knock-in macrophages were isolated to assess the function of PKM2 in macrophage phagocytosis.Atherosclerotic mice were treated with PKM2 inhibitor shikonin(SKN)to evaluate the therapeutic potential of PKM2 suppression in atherosclerosis.Results:Oxidized low-density lipoprotein(oxLDL)upregulated PKM2 in macrophages.PKM2 in return promoted the uptake of oxLDL by macrophages.Overexpressed PKM2 accelerated atherosclerosis in mice.SKN blocked the progress of mouse atherosclerosis.Conclusions:PKM2 accelerates macrophage phagocytosis and atherosclerosis.Targeting PKM2 is a potential therapy for atherosclerosis.
基金supported by the National Natural Science Foundation of China for the Youth,No.30800338,30801211the National Natural Science Foundation of China,No.30872721
文摘Our previous studies have revealed that amyloidβ(Aβ)-binding alcohol dehydrogenase (ABAD) decoy peptide antagonizes Aβ42-induced neurotoxicity. However, whether it improves oxidative stress injury remains unclear. In this study, a recombinant adenovirus constitutively secreting and expressing Aβ-ABAD decoy peptide (rAAV/ABAD-DP-6His) was successfully constructed. Our results showed that rAAV/ABAD-DP-6His increased superoxide dismutase activity in hydro-gen peroxide-induced oxidative stress-mediated injury of PC12 cells. Moreover, rAAV/ABAD-DP-6His decreased malondialdehyde content, intracellular Ca2+concentration, and the level of reactive oxygen species. rAAV/ABAD-DP-6His maintained the stability of the mitochondrial membrane potential. In addition, the ATP level remained constant, and apoptosis was reduced. Overall, the results indicate that rAAV/ABAD-DP-6His generates the fusion peptide, Aβ-ABAD decoy peptide, which effectively protects PC12 cells from oxidative stress injury induced by hy-drogen peroxide, thus exerting neuroprotective effects.
基金supported by the National Key Research and Development Program of China (Grant No. 2017YFE0109900)the National Natural Science Foundation of China (Grant Nos. 82025034 and 81973392)+5 种基金the Shenzhen Science and Technology Program (Grant No. KQTD20190929174023858)the Natural Science Foundation of Guangdong (Grant No. 2017A030311018)the 111 project (Grant No. B16047)the Key Laboratory Foundation of Guangdong Province (Grant No. 2017B030314030)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (Grant No. 2017BT01Y093)the National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, Grant No. 2017B090903004)。
文摘Lipotoxicity, caused by intracellular lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in cancer development and therapy. Previously, carnitine palmitoyltransferase 1C(CPT1C), a mitochondrial enzyme that catalyzes carnitinylation of fatty acids, was found to be a critical regulator of cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1,MDA-MB-231, HCT-116 and A549 cancer cells was conducted after siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in fatty acid, diacylglycerol, triacylglycerol, oxidative lipids, cardiolipin, phosphatidylglycerol, phosphatidylcholine/phosphatidylethanolamine ratio and sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis.Histological and biochemical analyses revealed higher lipid accumulation and increased malondialdehyde and reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene m RNAs indicated mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of tumor lipotoxicity and senescence.
基金supported by grants from the National Key Research and Development Program of China(2016YFC1102800)the Natural Science Foundation of China(81870741,21774045,and 81920108012)Program for JLU Science and Technology Innovative Research Team(2017TD-11)。
文摘Nanomaterial-based drug sustainable release systems have been tentatively applied to bone regeneration.They,however,still face disadvantages of high toxicity,low biocompatibility,and low drug-load capacity.In view of the low toxicity and high biocompatibility of polymer nanomaterials and the excellent load capacity of hollow nanomaterials with high specific surface area,we evaluated the hollow polydopamine nanoparticles(HPDA NPs),in order to find an optimal system to effectively deliver the osteogenic drugs to improve treatment of bone defect.Data demonstrated that the HPDA NPs synthesized herein could efficiently load four types of osteogenic drugs and the drugs can effectively release from the HPDA NPs for a relatively longer time in vitro and in vivo with low toxicity and high biocompatibility.Results of qRT-PCR,ALP,and alizarin red S staining showed that drugs released from the HPDA NPs could promote osteogenic differentiation and proliferation of rat bone marrow mesenchymal stem cells(rBMSCs)in vitro.Image data from micro-CT and H&E staining showed that all four osteogenic drugs released from the HPDA NPs effectively promoted bone regeneration in the defect of tooth extraction fossa in vivo,especially tacrolimus.These results suggest that the HPDA NPs,the biodegradable hollow polymer nanoparticles with high drug load rate and sustainable release ability,have good prospect to treat the bone defect in future clinical practice.
文摘<div style="text-align:justify;"> In this paper, we study the error estimates for direct discontinuous Galerkin methods based on the upwind-biased fluxes. We use a newly global projection to obtain the optimal error estimates. The numerical experiments imply that <em>L</em><sup>2 </sup>norms error estimates can reach to order <em>k</em> + 1 by using time discretization methods. </div>
基金the National Key Research and Development Program of China(Grant No.2018YFE0115500)the National Natural Science Foundation of China(Grant Nos.51902037 and 62005033)+2 种基金the Open Foundation of State Key Laboratory of Electronic Thin Films and Integrated Devices(Grant No.KFJJ201912)the Science and Technology Project Affiliated to the Education Department of Chongqing Municipality(Grant No.KJQN201900615)the Nature Science Foundation of Chongqing(Grant No.cstc2019jcyjmsxm X0696)。
文摘The combined effects of Sm^(3+)substitution together with the addition of 3 wt%Bi_(2)O_(3)endow Mg Cd ferrites with excellent magnetic permeability and dielectric permittivity.Various concentrations of Sm^(3+)(x=0,0.03,0.06,0.09,0.12and 0.15)were employed to modify the permeability(μ)and permittivity(ε)of the Mg Cd ferrites.X-ray diffraction,scanning electron microscopy(SEM),vibrating sample magnetometry and vector network analysis techniques were used to characterize the samples.The measurement results reveal that the ferrites processed a saturation magnetization of up to 36.8 emu/g and coercivity of up to 29.2 Oe via the conventional solid-state reaction method.The surface morphology SEM confirms that with increasing Sm^(3+)concentration,the grain shape changes from a polygon to a circle.Moreover,the dielectric permittivity can reach a value of 23.The excellent properties obtained in Sm^(3+)-substituted Mg ferrites suggest that they could be promising candidates for modern high-frequency antenna substrates or multilayer devices.
基金Sponsored by the National Basic Research Program of China(973 Program)(Grant No.2012CB723303)
文摘The capacity is impacted badly by pedestrians' violation behavior at signal intersections. In order to quantify the impact,the time-headway and the vehicular speed from start-up to reach the stable saturation flow with and without pedestrian traffic are used as the direct measurements. Using the statistical analysis,the timeheadway of saturation flow is mainly affected by the position of pedestrians and the degree of pedestrians 'influence is classified into four levels. Then the speed-time profile for the vehicular acceleration at each level is fitted by Curve Fitting Software. Based on the effect to the time-headway and acceleration time,the model of capacity influenced by pedestrians is established and the influence is quantified, which enriches the fundamental theory of traffic engineering. The result shows that the vehicular capacity can be decreased by 14%at the worst case( level I). The conclusions obtained in this paper are valuable for better management of the signal intersection.
文摘Heavily congested intersections in metropolitan areas in China are facing unique problems due to high travel demand and a high degree of traffic law violations. Based on a study conducted by the authors of this paper, 93% of left-turn vehicles turning left in these areas were slowed in order to avoid conflict with pedestrians. Intertwined pedestrian and vehicular flows can significantly reduce the capacity of exclusive left-turn lane group through reducing saturation flow rate, which increases the congestion at intersections. This paper investigates how the saturation flow rate of exclusive left-turn lane group is affected by the characteristics of pedestrian flow. By analyzing the imagery data collected by video cameras installed at intersections, the research team is able to obtain the characteristics of both vehicular and pedestrian flows, such as speed and spatial locations. The average operating speed at the saturation flow rate with and without pedestrian traffic is used as a direct measurement to evaluate the effect of pedestrians. Based on the statistical analysis, the paper concludes that saturation flow rate is mainly affected by the position of pedestrian in the crosswalk (inside or outside of left-turn vehicle’s trajectory), and the distance between the vehicle and pedestrians. In general, when the distance is less than four meters, the smaller the distance between vehicle and pedestrians, the larger the impact. However, there is no significant impact when the distance is larger than four meters. To accurately quantify the effect, the degree of pedestrian-vehicle impact is defined in four levels. The results show that the difference in the saturation flow rate between the best and the worst level could be 15.7%, which clearly indicates how important it is to enforce pedestrian crossing behavior.
文摘Speed-flow relationship is the fundamental for the traffic simulation and traffic volume forecast. Traditional quadratic polynomial model can’t reflect the saturate flow at signal intersections. In order to determine the speed-flow relationship at signal intersections, the speed and time-headway of vehicles at two signal intersections were investigated and the accuracy of software used to get the speed was tested. After vehicle starting-up from queuing, the time-headway reduces gradually with the increase of speed. The relationship of power exponential function between speed and time-headway is formulated. Traffic volume can be calculated by the vehicle time-headway. Then the speed-flow relationship was developed and an S-shaped curve model was built in this paper. In the S-shaped curve model, traffic flow approaches to the saturate when the speed doesn’t increase. Thus, S-shaped curve model is better to describe the speed-flow relationship at signal intersection. The results can provide a reference to determine the parameters in traffic simulation and for the study of level of service of intersections.
基金This work was supported by Basic Science Center Program of the National Natural Science Foundation of China for"Multiscale Problems in Nonlinear Mechanics"(Grant No.11988102)the National Natural Science Foundation of China(Grant Nos.12102439,92252203,and 91952301)the China Postdoctoral Science Foundation(Grant No.2021M703290)。
基金supported in part by the National Cancer Institute[R01CA225958,R01253230]National Institute of General Medical Sciences[R35GM140835]+3 种基金National Institutes of Health(USA)supported by grants from the Chinese National Key Research and Development Program(2017YFE0109900,China)supported by a scholarship from the Chinese Scholarship Council(No.201806380133,China)the Molecular Pharmacology,Flow Cytometry,and Mouse Biology Shared Resources funded by the UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute(P30CA093373),National Institutes of Health。
文摘During the development of therapeutic microRNAs(miRNAs or miRs),it is essential to define their pharmacological actions.Rather,miRNA research and therapy mainly use miRNA mimics synthesized in vitro.After experimental screening of unique recombinant miRNAs produced in vivo,three lead antiproliferative miRNAs against human NSCLC cells,miR-22-3p,miR-9-5p,and miR-218-5p,were revealed to target folate metabolism by bioinformatic analyses.Recombinant miR-22-3p,miR-9-5p,and miR-218-5p were shown to regulate key folate metabolic enzymes to inhibit folate metabolism and subsequently alter amino acid metabolome in NSCLC A549 and H1975 cells.Isotope tracing studies further confirmed the disruption of one-carbon transfer from serine to folate metabolites by all three miRNAs,inhibition of glucose uptake by miR-22-3p,and reduction of serine biosynthesis from glucose by miR-9-5p and-218-5p in NSCLC cells.With greater activities to interrupt NSCLC cell respiration,glycolysis,and colony formation than miR-9-5p and-218-5p,recombinant miR-22-3p was effective to reduce tumor growth in two NSCLC patient-derived xenograft mouse models without causing any toxicity.These results establish a common antifolate mechanism and differential actions on glucose uptake and metabolism for three lead anticancer miRNAs as well as antitumor efficacy for miR-22-3p nanomedicine,which shall provide insight into developing antimetabolite RNA therapies.
基金supported by the National Program on Key Research Project of China(2020YFC0842600)the National Natural Science Foundation of China(82041038,81871651,and 81991491)+1 种基金the Major Science and Technology Program of Fujian Province(2020YZ014001)the Natural Science Foundation of Fujian Province(2021J02006)。
基金supported by the National Natural Science Foundation of China(41101003,41230743,41328001,and 41371082)National Natural Science Awards of China(2009) to Yafeng Shi,Zhijiu Cui,Jijun Li,Benxing Zheng,and Shangzhe Zhou(Z104-2-05)
文摘The onset of Quaternary glaciations is a critical event in the climate and tectonic history of the Tibetan Plateau.The Shishapangma Glaciation,defined based on the till deposit from the northern slopes of Mt.Shishapangma,has been identified as the oldest glaciation on the Tibetan Plateau.However,the timing of this glaciation has not been constrained.We measured^(10)Be and^(26)Al concentrations of a set of boulders on top of this till and simulated their complex exposure-burial histories.The simulated results indicate that the formation age of this till is likely around 835.2±241.0 ka,representing the minimum timing of glacial onset on the Tibetan Plateau.The Shishapangma Glaciation is apparently much younger than the glacial onset in many other areas of the world,such as Europe and North America,and was likely driven by the coupled effect between tectonic uplift and climate cooling during the early–middle Pleistocene transition.
基金supported by the National Natural Science Foundation of China(Grants 81603185,81973392,and 82025034)the Natural Science Foundation of Guangdong Province(Grant 2020A1515011452,China)+1 种基金the National Key Research and Development Project(Grant 2017YFE0109900,China)the Sanming Project of Medicine in Shenzhen(SZSM201406007 and SZSM201606088,China)
文摘Acetaminophen(APAP)overdose is the leading cause of drug-induced liver injury,and its prognosis depends on the balance between hepatocyte death and regeneration.Sirtuin 6(SIRT6)has been reported to protect against oxidative stress-associated DNA damage.But whether SIRT6 regulates APAPinduced hepatotoxicity remains unclear.In this study,the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment,respectively.Sirt6 knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress,inhibited cell viability and proliferation,and downregulated CCNA1,CCND1 and CKD4 protein levels.Sirt6 knockdown signifi-cantly prevented APAP-induced NRF2 activation,reduced the transcriptional activities of GSTm andNQO1 and the m RNA levels of Nrf2,Ho-1,Gsta and Gstm.Furthermore,SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation(Co-IP)assay.Additionally,the protective effect of P53 against APAP-induced hepatocytes injury was Sirt6-dependent.The Sirt6 m RNA was significantly down-regulated in P53à/àmice.P53 activated the transcriptional activity of SIRT6 and exerted interaction with SIRT6.Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation,and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.
基金This work was supported by grants from the National Science and Technology Major Project of Infectious Diseases(No.2017ZX10304402-002-003)the National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2018ZX09711003-005-003)+2 种基金the Science and Technology Project of Fujian Province(2020YZ014001)the Science and Technology Project of Xiamen City(3502Z2020YJ01)the CAMS Innovation Fund for Medical Sciences(No.2019RU022).
文摘Epidemiological studies of the COVID-19 patients have suggested the male bias in outcomes of lung illness.To experimentally demonstrate the epidemiological results,we performed animal studies to infect male and female Syrian hamsters with SARS-CoV-2.Remarkably,high viral titer in nasal washings was detectable in male hamsters who presented symptoms of weight loss,weakness,piloerection,hunched back and abdominal respiration,as well as severe pneumonia,pulmonary edema,consolidation,and fibrosis.In contrast with the males,the female hamsters showed much lower shedding viral titers,moderate symptoms,and relatively mild lung pathogenesis.The obvious differences in the susceptibility to SARS-CoV-2 and severity of lung pathogenesis between male and female hamsters provided experimental evidence that SARS-CoV-2 infection and the severity of COVID-19 are associated with gender.
基金This work was supported in part by the National Natural Science Foundation of China (Grant Nos. 61502412, 61379066, and 61402395), Natural Science Foundation of the Jiangsu Province (BK20150459, BK20151314, and BK20140492), Natural Science Foundation of the Jiangsu Higher Education Institutions (15KJB520036), United States NSF grants (IIS-0534699, IIS-0713109, CNS-1017701), Microsoft Research New Faculty Fellowship, and the Research Innovation Program for Graduate Student in Jiangsu Province (KYLX16 1390).
文摘A main focus of machine learning research has been improving the generalization accuracy and efficiency of prediction models. However, what emerges as missing in many applications is actionability, i.e., the ability to turn prediction results into actions. Existing effort in deriving such actionable knowledge is few and limited to simple action models while in many real applications those models are often more complex and harder to extract an optimal solution. In this paper, we propose a novel approach that achieves actionability by combining learning with planning, two core areas of AI. In particular, we propose a framework to extract actionable knowledge from random forest, one of the most widely used and best off-the-shelf classifiers. We formulate the actionability problem to a sub-optimal action planning (SOAP) problem, which is to find a plan to alter certain features of a given input so that the random forest would yield a desirable output, while minimizing the total costs of actions. Technically, the SOAP problem is formulated in the SAS+ planning formalism, and solved using a Max-SAT based ap- proach. Our experimental results demonstrate the effectiveness and efficiency of the proposed approach on a personal credit dataset and other benchmarks. Our work represents a new application of automated planning on an emerging and challenging machine learning paradigm.