OMARIA which is used to treat malaria in Odisa province, India, was investigated in Africa. The in-vitro anti-malarial activity of OMARIA was tested on P. falciparum strains FCB (chloroquine-resistant) and 3D7 (chloro...OMARIA which is used to treat malaria in Odisa province, India, was investigated in Africa. The in-vitro anti-malarial activity of OMARIA was tested on P. falciparum strains FCB (chloroquine-resistant) and 3D7 (chloroquine-sensitive) and on fresh clinical isolates from Gabon, using the DELI method. Host cell toxicity was analysed with the MTT test. Interesting activity was observed. Inhibition concentrations (IC50) were 20.6 ± 5.2 μg/ml and 14.1 ± 4.3μg/ml respectively on FCB and 3D7 strains. On clinical isolates, the mean of IC50 was 10.65 ± 4.8μg/ml. OMARIA is highly potent against all field isolates tested by us (Gabon includes Pfmdr1 N86). Lethal dose on Vero cells being 165 ± 10.7μg/ml indicate a selective index of 13 for FCB, i.e., non-toxic. Data substantiates scientific rationale for use of OMARIA. This information and such understanding can be used in searching African phyto parables (for use in Africa with similar results as in India) and in new drug design. With Indian assistance, Punica granatum can also be cultivated in Central Africa, and OMARIA can be made, with an aim to Fight Malaria at Home.展开更多
Transketolase, the most critical enzyme of the non-oxidative branch of the pentose phosphate pathway, has been reported as a novel target in Plasmodium falciparum as it has least homology with the human host. Homology...Transketolase, the most critical enzyme of the non-oxidative branch of the pentose phosphate pathway, has been reported as a novel target in Plasmodium falciparum as it has least homology with the human host. Homology model of P. falciparum transketolase (PfTk) was constructed using the crystal structure of S. cervisiae transketolase as a template, and used for the identification and prioritization of potential compounds targeted against Plasmodium falciparum transketolase. The docking studies with fructose-6-phosphate and thiamine pyrophosphate showed that His31, Asp473, Ser388, Arg361 and His465 formed hydrogen bonds with fructose-6-phosphate while pyrimidine ring of coenzyme interacted with conserved residues of protein viz., Leu121, Glu415, Gly119. The major interacting residues involved in binding of oxythiamine pyrophosphate were similar to cofactor binding site of PfTk. An integrated pharmacophore, co-factor ThDP and substrate fructose-6-pho- sphate, based virtual screening of a small mo- lecule database retrieved eight and thirteen compounds respectively. When screened for their activity against P. falciparum transketolase, one compound in case of ThDP and three compounds in case of fructose-6-phosphate based screening were found active against PfTk. Identification of these novel and chemically diverse inhibitors provides initial leads for optimization of more potent and efficacious drug candidates to treat malarial infection.展开更多
Objective:To evaluate the antimalarial activity of noscapine against Plasmodium falciparum 3D7 strain(Pf3D7),its clinical isolate(Pf140/SS),and Plasmodium berghei ANKA(PbA).Methods:Using ring-stage survival assay,phen...Objective:To evaluate the antimalarial activity of noscapine against Plasmodium falciparum 3D7 strain(Pf3D7),its clinical isolate(Pf140/SS),and Plasmodium berghei ANKA(PbA).Methods:Using ring-stage survival assay,phenotypic assessments,and SYBR-green-based fluorescence assay,the antimalarial activities of noscapine were assessed compared with dihydroartemisinin(DHA)in in vivo and in vitro studies.In addition,hemolysis and cytotoxicity tests were carried out to evaluate its safety.RT-PCR assay was also conducted to determine the effect of noscapine on papain-like cysteine protease Plasmodium falciparum falcipain-2(PfFP-2).Results:The antimalarial efficacy of noscapine against Pf3D7 and Pf140/SS was comparable to DHA,with IC50 values of(7.68±0.88)and(5.57±0.74)nM/mL,respectively,and>95%inhibition of PbA infected rats.Noscapine also showed a safe profile,as evidenced by low hemolysis and cytotoxicity even at high concentrations.Moreover,PfFP-2 expression was significantly inhibited in both noscapine-treated Pf3D7 and Pf140/SS(P<0.01).Conclusions:Noscapine has antimalarial properties comparable to standard antimalarial DHA with better safety profiles,which may be further explored as a therapeutic candidate for the treatment of malaria.展开更多
Background:Andrographis paniculata has been widely reported as an herbal plant for malaria treatment.The increasing rate of resistance to recommended antimalarial drugs has justified the need for a continuous search f...Background:Andrographis paniculata has been widely reported as an herbal plant for malaria treatment.The increasing rate of resistance to recommended antimalarial drugs has justified the need for a continuous search for new and more potent drugs that target all stages of the Plasmodium falciparum life cycle from natural plant sources.This study aimed to determine the antiplasmodial effect of phytocompounds derived from A.paniculata on the stages of plasmodium falciparum.Methods:Phytocompounds from A.paniculata were identified by Gas Chromatography-Mass Spectrophotometry(GCMS)analysis.The phytocompounds were screened for their druggability using Lipinski’s rule of five and subjected to Absorption,Distribution,Metabolism,Excretion,Toxicity(ADMET)and druglikeness analysis.The phytocompounds were docked against some validated drug targets at different stages of Plasmodium falciparum(hepatic,asexual,sexual,and vector targets)using PyRx software to analyze the inhibitory potential and protein-ligand interaction.Thereafter,the stability and flexibility of the best complexes were assessed through molecular dynamics simulations at 50ns using WebGRO.Result:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl exhibited a higher binding affinity and better stability throughout the simulation period with P.falciparum dihydrofolate reductase-thymidylate synthase and Plasmodium falciparum M1 alanyl aminopeptidase for asexual blood stage and gametocyte stage of Plasmodium falciparum,respectively than the existing drugs.Meanwhile,N-Ethyl-3-methoxy-4-methylphenethylamine was also found to have a higher binding affinity and more stability throughout the simulation period with P.falciparum purine nucleoside phosphorylase and Plasmodium falciparum gametocyte surface protein for Hepatic schizonts stage of Plasmodium falciparum and gametocyte transmission blocking stage,respectively,than the existing drugs.Conclusion:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl and N-Ethyl-3-methoxy-4 methylphenethylamine from A.paniculata are predicted as an antimalarial drug candidate.Thus,it is recommended that in vitro and in vivo bioassays be conducted on these hit compounds to validate these predictions.展开更多
随着分布式清洁能源发电技术的发展,传统电力用户逐渐转变为电能产消者,并可采用合作联盟形式参与电力P2P(peer to peer)交易,促进分布式清洁能源就地消纳。该文通过从源端和传输端分别核算碳减排量的方法,构建一类考虑经济效益和环境...随着分布式清洁能源发电技术的发展,传统电力用户逐渐转变为电能产消者,并可采用合作联盟形式参与电力P2P(peer to peer)交易,促进分布式清洁能源就地消纳。该文通过从源端和传输端分别核算碳减排量的方法,构建一类考虑经济效益和环境效益的社会福利函数,研究分布式电能产消者通过合作联盟形式实现社会福利最大化的途径。设计一种依据产消者对联盟社会福利贡献值分配合作剩余的机制,激励产消者合作的积极性以维持联盟的稳定。算例分析表明:相较于P2G(peer-to-grid)交易和非合作P2P交易,产消者以合作联盟方式参与电力P2P交易的社会福利分别提升了62.62%、33.79%。因此,以市场化的方式组建合作联盟参与电力P2P交易并合理分配利益,可挖掘分布式清洁能源就地消纳的潜力,促进能源消费的绿色低碳转型。展开更多
目前电磁时间反演(electromagnetic time reversal,EMTR)多应用在单一线路故障定位,且现有判据在高阻抗接地情况下效果不理想。针对上述问题,基于EMTR故障定位原理和均匀传输线理论推导了传播过程中线路故障信号与测量信号的传递函数,...目前电磁时间反演(electromagnetic time reversal,EMTR)多应用在单一线路故障定位,且现有判据在高阻抗接地情况下效果不理想。针对上述问题,基于EMTR故障定位原理和均匀传输线理论推导了传播过程中线路故障信号与测量信号的传递函数,根据传递函数的相关性提出了P范数判据。利用ATP-EMTP搭建10 kV配电网线路,对比了2范数与P范数判据在复杂配电网中的定位性能,并验证了所提判据在混合配电网线路的适用性。最后,分析了配电网发生低阻抗及高阻抗接地故障下P范数判据的鲁棒性。仿真结果表明,该方法在过渡电阻高达3 kΩ的情况下能准确定位,且定位精度高,受噪声、故障类型和采样频率的影响小。展开更多
1958—1999年,在广东省佛山市南海区西樵镇一带发现了众多记录了史前人类活动的石器地点,石器中包括双肩石器和细石器。迄今为止,“西樵山遗址”被认定是4—7 ka B P的大型新石器时期采石场和加工场。2011—2022年,笔者经多次地质遗迹...1958—1999年,在广东省佛山市南海区西樵镇一带发现了众多记录了史前人类活动的石器地点,石器中包括双肩石器和细石器。迄今为止,“西樵山遗址”被认定是4—7 ka B P的大型新石器时期采石场和加工场。2011—2022年,笔者经多次地质遗迹和地质环境调查,在西樵山东南麓富贤村北面发现了良好的第四纪地层剖面。地质探槽剖面测量和地质年代学研究表明:富贤地点存在2套原始沉积地层:上部为第四纪全新世沼泽相地层,AMS14C校正年龄为5052—5409 a B P;下部为第四纪晚更新世冲积-洪积相地层,AMS14C校正年龄为38420—40502 a B P,OSL (光释光)年龄为41.977—43.796 ka B P;在晚更新世地层中发现2层含旧石器层,下部A1层主要石器类型有较大型刮削器、尖刃器、舌型刃器及小型石片工具,如各类刮削器、锯齿刃器、凹缺器、石刀、使用石片、石核等,包括带铤斧型小石刀;上部A2层明显出现更多石刀类型且常常附带修背和修铤工作,其中一件用于生产细小长石片的原始楔形石核引人关注。据平均沉积速率计算,下部A1石器层年龄为46.511—47.325 ka B P,上部A2石器层年龄为41.977—42.167 ka B P;距今大于5 ka的全新世沉积物中的石制品数量虽少,但器物类型仍具有明显继承性与发展性特点。本文的发现更新并延伸了西樵山国家地质公园和“西樵山文化”的内涵,首次突破了珠江三角洲地区有确切年代的晚更新世旧石器遗存的纪录,追踪到大约40—50 ka现代人在华南沿海的足迹,揭示了同期石器工业的面貌及其文化内涵的发展特征和演变。研究表明,在MIS3间冰段相对湿热时期以及MIS2相对干冷阶段,富贤地点的古人类面临环境变化的挑战而开启了新的生计模式,这对于揭示现代人对全球和区域环境变化的响应与适应的科学问题具有重要意义。展开更多
文摘OMARIA which is used to treat malaria in Odisa province, India, was investigated in Africa. The in-vitro anti-malarial activity of OMARIA was tested on P. falciparum strains FCB (chloroquine-resistant) and 3D7 (chloroquine-sensitive) and on fresh clinical isolates from Gabon, using the DELI method. Host cell toxicity was analysed with the MTT test. Interesting activity was observed. Inhibition concentrations (IC50) were 20.6 ± 5.2 μg/ml and 14.1 ± 4.3μg/ml respectively on FCB and 3D7 strains. On clinical isolates, the mean of IC50 was 10.65 ± 4.8μg/ml. OMARIA is highly potent against all field isolates tested by us (Gabon includes Pfmdr1 N86). Lethal dose on Vero cells being 165 ± 10.7μg/ml indicate a selective index of 13 for FCB, i.e., non-toxic. Data substantiates scientific rationale for use of OMARIA. This information and such understanding can be used in searching African phyto parables (for use in Africa with similar results as in India) and in new drug design. With Indian assistance, Punica granatum can also be cultivated in Central Africa, and OMARIA can be made, with an aim to Fight Malaria at Home.
文摘Transketolase, the most critical enzyme of the non-oxidative branch of the pentose phosphate pathway, has been reported as a novel target in Plasmodium falciparum as it has least homology with the human host. Homology model of P. falciparum transketolase (PfTk) was constructed using the crystal structure of S. cervisiae transketolase as a template, and used for the identification and prioritization of potential compounds targeted against Plasmodium falciparum transketolase. The docking studies with fructose-6-phosphate and thiamine pyrophosphate showed that His31, Asp473, Ser388, Arg361 and His465 formed hydrogen bonds with fructose-6-phosphate while pyrimidine ring of coenzyme interacted with conserved residues of protein viz., Leu121, Glu415, Gly119. The major interacting residues involved in binding of oxythiamine pyrophosphate were similar to cofactor binding site of PfTk. An integrated pharmacophore, co-factor ThDP and substrate fructose-6-pho- sphate, based virtual screening of a small mo- lecule database retrieved eight and thirteen compounds respectively. When screened for their activity against P. falciparum transketolase, one compound in case of ThDP and three compounds in case of fructose-6-phosphate based screening were found active against PfTk. Identification of these novel and chemically diverse inhibitors provides initial leads for optimization of more potent and efficacious drug candidates to treat malarial infection.
文摘Objective:To evaluate the antimalarial activity of noscapine against Plasmodium falciparum 3D7 strain(Pf3D7),its clinical isolate(Pf140/SS),and Plasmodium berghei ANKA(PbA).Methods:Using ring-stage survival assay,phenotypic assessments,and SYBR-green-based fluorescence assay,the antimalarial activities of noscapine were assessed compared with dihydroartemisinin(DHA)in in vivo and in vitro studies.In addition,hemolysis and cytotoxicity tests were carried out to evaluate its safety.RT-PCR assay was also conducted to determine the effect of noscapine on papain-like cysteine protease Plasmodium falciparum falcipain-2(PfFP-2).Results:The antimalarial efficacy of noscapine against Pf3D7 and Pf140/SS was comparable to DHA,with IC50 values of(7.68±0.88)and(5.57±0.74)nM/mL,respectively,and>95%inhibition of PbA infected rats.Noscapine also showed a safe profile,as evidenced by low hemolysis and cytotoxicity even at high concentrations.Moreover,PfFP-2 expression was significantly inhibited in both noscapine-treated Pf3D7 and Pf140/SS(P<0.01).Conclusions:Noscapine has antimalarial properties comparable to standard antimalarial DHA with better safety profiles,which may be further explored as a therapeutic candidate for the treatment of malaria.
文摘Background:Andrographis paniculata has been widely reported as an herbal plant for malaria treatment.The increasing rate of resistance to recommended antimalarial drugs has justified the need for a continuous search for new and more potent drugs that target all stages of the Plasmodium falciparum life cycle from natural plant sources.This study aimed to determine the antiplasmodial effect of phytocompounds derived from A.paniculata on the stages of plasmodium falciparum.Methods:Phytocompounds from A.paniculata were identified by Gas Chromatography-Mass Spectrophotometry(GCMS)analysis.The phytocompounds were screened for their druggability using Lipinski’s rule of five and subjected to Absorption,Distribution,Metabolism,Excretion,Toxicity(ADMET)and druglikeness analysis.The phytocompounds were docked against some validated drug targets at different stages of Plasmodium falciparum(hepatic,asexual,sexual,and vector targets)using PyRx software to analyze the inhibitory potential and protein-ligand interaction.Thereafter,the stability and flexibility of the best complexes were assessed through molecular dynamics simulations at 50ns using WebGRO.Result:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl exhibited a higher binding affinity and better stability throughout the simulation period with P.falciparum dihydrofolate reductase-thymidylate synthase and Plasmodium falciparum M1 alanyl aminopeptidase for asexual blood stage and gametocyte stage of Plasmodium falciparum,respectively than the existing drugs.Meanwhile,N-Ethyl-3-methoxy-4-methylphenethylamine was also found to have a higher binding affinity and more stability throughout the simulation period with P.falciparum purine nucleoside phosphorylase and Plasmodium falciparum gametocyte surface protein for Hepatic schizonts stage of Plasmodium falciparum and gametocyte transmission blocking stage,respectively,than the existing drugs.Conclusion:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl and N-Ethyl-3-methoxy-4 methylphenethylamine from A.paniculata are predicted as an antimalarial drug candidate.Thus,it is recommended that in vitro and in vivo bioassays be conducted on these hit compounds to validate these predictions.
文摘随着分布式清洁能源发电技术的发展,传统电力用户逐渐转变为电能产消者,并可采用合作联盟形式参与电力P2P(peer to peer)交易,促进分布式清洁能源就地消纳。该文通过从源端和传输端分别核算碳减排量的方法,构建一类考虑经济效益和环境效益的社会福利函数,研究分布式电能产消者通过合作联盟形式实现社会福利最大化的途径。设计一种依据产消者对联盟社会福利贡献值分配合作剩余的机制,激励产消者合作的积极性以维持联盟的稳定。算例分析表明:相较于P2G(peer-to-grid)交易和非合作P2P交易,产消者以合作联盟方式参与电力P2P交易的社会福利分别提升了62.62%、33.79%。因此,以市场化的方式组建合作联盟参与电力P2P交易并合理分配利益,可挖掘分布式清洁能源就地消纳的潜力,促进能源消费的绿色低碳转型。
文摘目前电磁时间反演(electromagnetic time reversal,EMTR)多应用在单一线路故障定位,且现有判据在高阻抗接地情况下效果不理想。针对上述问题,基于EMTR故障定位原理和均匀传输线理论推导了传播过程中线路故障信号与测量信号的传递函数,根据传递函数的相关性提出了P范数判据。利用ATP-EMTP搭建10 kV配电网线路,对比了2范数与P范数判据在复杂配电网中的定位性能,并验证了所提判据在混合配电网线路的适用性。最后,分析了配电网发生低阻抗及高阻抗接地故障下P范数判据的鲁棒性。仿真结果表明,该方法在过渡电阻高达3 kΩ的情况下能准确定位,且定位精度高,受噪声、故障类型和采样频率的影响小。
文摘1958—1999年,在广东省佛山市南海区西樵镇一带发现了众多记录了史前人类活动的石器地点,石器中包括双肩石器和细石器。迄今为止,“西樵山遗址”被认定是4—7 ka B P的大型新石器时期采石场和加工场。2011—2022年,笔者经多次地质遗迹和地质环境调查,在西樵山东南麓富贤村北面发现了良好的第四纪地层剖面。地质探槽剖面测量和地质年代学研究表明:富贤地点存在2套原始沉积地层:上部为第四纪全新世沼泽相地层,AMS14C校正年龄为5052—5409 a B P;下部为第四纪晚更新世冲积-洪积相地层,AMS14C校正年龄为38420—40502 a B P,OSL (光释光)年龄为41.977—43.796 ka B P;在晚更新世地层中发现2层含旧石器层,下部A1层主要石器类型有较大型刮削器、尖刃器、舌型刃器及小型石片工具,如各类刮削器、锯齿刃器、凹缺器、石刀、使用石片、石核等,包括带铤斧型小石刀;上部A2层明显出现更多石刀类型且常常附带修背和修铤工作,其中一件用于生产细小长石片的原始楔形石核引人关注。据平均沉积速率计算,下部A1石器层年龄为46.511—47.325 ka B P,上部A2石器层年龄为41.977—42.167 ka B P;距今大于5 ka的全新世沉积物中的石制品数量虽少,但器物类型仍具有明显继承性与发展性特点。本文的发现更新并延伸了西樵山国家地质公园和“西樵山文化”的内涵,首次突破了珠江三角洲地区有确切年代的晚更新世旧石器遗存的纪录,追踪到大约40—50 ka现代人在华南沿海的足迹,揭示了同期石器工业的面貌及其文化内涵的发展特征和演变。研究表明,在MIS3间冰段相对湿热时期以及MIS2相对干冷阶段,富贤地点的古人类面临环境变化的挑战而开启了新的生计模式,这对于揭示现代人对全球和区域环境变化的响应与适应的科学问题具有重要意义。
