Objective:To investigate the antimalarial potential of kolaviron(KV),a biflavonoid fraction from Garcinia kola seeds,against Plasmodium berghei(P.berghei)infection in Swiss albino mice.Methods:The study consists of se...Objective:To investigate the antimalarial potential of kolaviron(KV),a biflavonoid fraction from Garcinia kola seeds,against Plasmodium berghei(P.berghei)infection in Swiss albino mice.Methods:The study consists of seven groups of ten mice each.Groups I,II and III were normal mice that received com oil.KV1 and chloroquine(CQ),respectively.Groups IV,V,ⅥandⅦwere infected mice that received corn oil.CQ,KYI and KV2.respectively.CQ.KY1 and KV2were given at 10-,100-and 200-mg/kg daily,respectively for three consecutive days.Results:Administration of KV1 and KV2 significantly(P<0.05)suppressed P.berghei-infection in the mice by 85%and 90%.respectively,while CQ produced 87%suppression relative to untreated infected group after the fifth day of treatment.Also,KV2 significantly(P<0.05)increased the mean survival time of the infected mice by 175%.The biflavonoid prevented a drastic reduction in HCV from day4 of treatment,indicating its efficacy in ameliorating anaemia.Significant(P<0.05)oxidative stress assessed by the elevation of serum and hepatic malondialdehydewere observed in unlrealed P.berghei-infected mice.Specifically,senum and hepatic malondialdehyde levels increased by93%and 78%,resjiectively in the unlrealed infecled mice.Furlhennore,antioxidant indices,viz;superoxide dismutase.catalase,glutathione-s-transferasc.glualhione peroxidase and reduced gluathione decreased significantly(P<0.05)in the tissues of untreated P.berghei-infected mice.KV significantly(P<0.05)ameliorated the P.berghei-induced decrease in antioxidant status of the infected mice.Conclusions:This study shows that kolaviron,especially at 200 mg/kg,has high antimalarial activities in P.berghei-infected mice,in addition to its known antioxidant properties.展开更多
Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an i...Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an indispensable role, however, its mechanism of action(MoA) is not fully understood.Methods: We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling(ABPP) and mass spectrometry-coupled cellular thermal shift assay(MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays.Results: We developed a novel clickable, photo-affinity chloroquine analog probe(CQP) which retains the antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photocrosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods.Conclusions: We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ antimalarial targets by a parallel usage of labeled(ABPP)and label-free(MS-CETSA) methods.展开更多
Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades,any anti-malarial drug can able to eradicate completely till now.Many anti-malarial substances...Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades,any anti-malarial drug can able to eradicate completely till now.Many anti-malarial substances are practically ineffectual because of their physicochemical limitations,cytotoxicity,chemical instability and degradation,and limited activities against intracellular parasites.Taking into consideration,the amount of research is going to conduct in the field of nanoparticle based drug delivery systems,lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug application for the opening out of novel chemotherapeutics in laboratory research,which may show the way to better use with age-old antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.展开更多
Objective:To investigate the possibility of increased antimalarial activity of Icacina senegalensis A.Juss(Icacinaceae)upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice.Methods:Chl...Objective:To investigate the possibility of increased antimalarial activity of Icacina senegalensis A.Juss(Icacinaceae)upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice.Methods:Chloroquine sensitive ANKA clones of Plasmodium berghei were used to develop experimental models based on intraperitoneal injection of 10^(7)parasitized erythrocytes in phosphate buffer saline(pH 7.2)and subsequent development of parasitemia.The models were employed to investigate prophylactic and curative anti-malarial activities of tuber and tuberleaf methanol extracts of the plant at selected dosages(25,50 and 100 mg/kg body weight).Chloroquine with a curative dosage of 10 mg/kg body weight was used as positive control in both studies.Results:Tuber and tuber-leaf extracts produced a dose-dependent chemosuppression of the parasites,with higher activity and mean survival time exhibited by the combined extract.Conclusions:Anti-plasmodia activity has been discovered in methanol extract of Icacina senegalensis tuber extract.The observed optimization of the antimalarial actions of the plant upon a combination of its leaf and tuber opens a new area of medicinal plant research.展开更多
Objective:To compare the two methods of rapid diagnostic tests(RDTs)and microscopy in the diagnosis of malaria.Methods:RDTs and microscopy were carried out to diagnose malaria. Percentage malaria parasitaemia was calc...Objective:To compare the two methods of rapid diagnostic tests(RDTs)and microscopy in the diagnosis of malaria.Methods:RDTs and microscopy were carried out to diagnose malaria. Percentage malaria parasitaemia was calculated on thin films and all non-acute cases of plasmodiasis with less than 0.001%malaria parasitaemia were regarded as negative.Results were simply presented as percentage positive of the total number of patients under study.The results of RDTs were compared to those of microscopy while those of RDTs based on antigen were compared to those of RDTs based on antibody.Patients' follow-up was made for all cases.Results: All the 200 patients under present study tested positive to RDTs based on malaria antibodies(serum)method(100%).128 out of 200 tested positive to RDTs based on malaria antigen(whole blood)method(64%),while 118 out of 200 patients under present study tested positive to visual microscopy of Lieshman and diluted Giemsa(59%).All patients that tested positive to microscopy also tested positive to RDTs based on antigen.All patients on the second day of follow-up were non-febrile and had antimalaria drugs.Conclusions;We conclude based on the present study that the RDTs based on malaria antigen(whole blood)method is as specific as the traditional microscopy and even appears more sensitive than microscopy.The RDTs based on antibody(serum)method is unspecific thus it should not be encouraged.It is most likely that Africa being an endemic region,formation of certain levels of malaria antibody may not be uncommon.The present study also supports the opinion that a good number of febrile cases is not due to malaria. We support WHO's report on cost effectiveness of RDTs but,recommend that only the antigen based method should possibly,be adopted in Africa and other malaria endemic regions of the world.展开更多
Objective:To evaluate the effect of short term artemether administration on some blood parameters in adult male Wistar rats.Methods:Sixty five albino rats with body weight of 190-220 g were used for the four-phased st...Objective:To evaluate the effect of short term artemether administration on some blood parameters in adult male Wistar rats.Methods:Sixty five albino rats with body weight of 190-220 g were used for the four-phased study. The animals were randomly divided into five groups. The first-four groups of 15 rats were further divided into 3 subgroups of 5 rats. The drug was administered orally at sub-optimal, therapeutic, and high doses of 25, 50 and 75 mg/kg bw,respectively to the rats for 1 day, 2 days and 3 days. Blood samples were collected by cardio-puncture from the rats for hematology at the end of each phase. The last group served as control,and they were given waterad libitum.Results:Artemether caused significant reduction(P<0.05)of the hematological profile of the animals in a dose dependent manner. Discontinuation of the drug use however showed gradual recovery of the depressed indices of the blood parameters.Conclusions:The results suggest that artemether can induce reversible changes in hematological profiles of rats by extension man. This can probably aggravate anemia when artemether is administered to malaria patients. Hence, the study supports the use of the drug with cautione specially in patients prone to anemic tendencies.展开更多
The widespread use of artemisinin(ART)and its derivatives has significantly reduced the global burden of malaria;however,malaria still poses a serious threat to global health.Although significant progress has been ach...The widespread use of artemisinin(ART)and its derivatives has significantly reduced the global burden of malaria;however,malaria still poses a serious threat to global health.Although significant progress has been achieved in elucidating the antimalarial mechanisms of ART,the most crucial target proteins and pathways of ART remain unknown.Knowledge on the exact antimalarial mechanisms of ART is urgently needed,as signs of emerging ART resistance have been observed in some regions of the world.Here,we used a combined strategy involving mass spectrometry-coupled cellular thermal shift assay(MS-CETSA)and transcriptomics profiling to identify a group of putative antimalarial targets of ART.We then conducted a series of validation experiments on five prospective protein targets,demonstrating that ART may function against malaria parasites by interfering with redox homeostasis,lipid metabolism,and protein synthesis processes.Taken together,this study provides fresh perspectives on the antimalarial mechanisms of ART and identifies several crucial proteins involved in parasite survival that can be targeted to combat malaria.展开更多
Leaf and stem essential oils of Lonchocarpus cyanescens Benth., (Fabaceae) were obtained by hydro-distillation, using all-glass apparatus adapted to British Pharmacopeia specifications with yields of 0.03% and 0.17% r...Leaf and stem essential oils of Lonchocarpus cyanescens Benth., (Fabaceae) were obtained by hydro-distillation, using all-glass apparatus adapted to British Pharmacopeia specifications with yields of 0.03% and 0.17% respectively. The oils were investigated by GC and GC-MS analyses. Results show seven compounds were responsible for 90.4% of leaf;eleven compounds responsible for 97.6% of stem volatile oils. Phytol (62.5%) and hexadecanoic acid (12.4%) dominate the leaf oil;octadecenoic (24.1%) and hexadecanoic acids (17.2%) are predominant in the stem oil. Phytochemical screening of stem, leaf, and root methanol extracts of Lonchocarpus cyanescens reveal presence of following seven classes of metabolites: saponin, tannin, steroid, terpenoid, cardiac glycosides, phlobatannins and flavonoids. Partitioning of methanol extract from dried leaf of it with ethylacetate gave fraction, which was chromatographed using gradient elution. TLC with high Rf was used in monitoring elution. Two white crystalline solids eluted at 5% and 10% ethylethanoate in hexane, were re-crystallized and characterized. They were subjected to Infra-Red spectra, mass spectrometry (ESI technique), 1H and 13C-NMR analyses, which confirmed they are triterpenoids. Above mentioned metabolites may be responsible for literature acclaimed bio-activities L. cyanescens display [anti-inflammatory, anti-arthritic, anti-microbial effects]. This paper presents details of above results which are new in literature.展开更多
Effects of amodiaquine, artesunate and artesunate amodiaquine combination on open field novelty-induced behaviors and spatial memory in healthy mice were studied. Forty mice were used in the open field and fifty each ...Effects of amodiaquine, artesunate and artesunate amodiaquine combination on open field novelty-induced behaviors and spatial memory in healthy mice were studied. Forty mice were used in the open field and fifty each in the radial arm maze and Y maze;mice were assigned into four or five groups of ten each, Group A served as control (distilled water), Groups B, C and D received artesunate (4 mg/kg), amodiaquine (10 mg/kg) and artesunate-amodiaquine combination (4 mg/kg and10 mg/kg) respectively, while Group E animals (for the cognition tests) were given scopolamine (2 mg/kg). Drugs and vehicle were administered orally for three days. Results were analysed by one way analysis of variance followed by a posthoc test. Results showed that artesunate and amodiaquine either in combination or administered singly caused a significant increase in open field novelty-induced horizontal locomotion and rearing. Grooming in the open field showed increments in the artesunate alone and artesunate amodiaquine groups while significant reductions in spatial memory were also seen in the cognition models used.展开更多
文摘Objective:To investigate the antimalarial potential of kolaviron(KV),a biflavonoid fraction from Garcinia kola seeds,against Plasmodium berghei(P.berghei)infection in Swiss albino mice.Methods:The study consists of seven groups of ten mice each.Groups I,II and III were normal mice that received com oil.KV1 and chloroquine(CQ),respectively.Groups IV,V,ⅥandⅦwere infected mice that received corn oil.CQ,KYI and KV2.respectively.CQ.KY1 and KV2were given at 10-,100-and 200-mg/kg daily,respectively for three consecutive days.Results:Administration of KV1 and KV2 significantly(P<0.05)suppressed P.berghei-infection in the mice by 85%and 90%.respectively,while CQ produced 87%suppression relative to untreated infected group after the fifth day of treatment.Also,KV2 significantly(P<0.05)increased the mean survival time of the infected mice by 175%.The biflavonoid prevented a drastic reduction in HCV from day4 of treatment,indicating its efficacy in ameliorating anaemia.Significant(P<0.05)oxidative stress assessed by the elevation of serum and hepatic malondialdehydewere observed in unlrealed P.berghei-infected mice.Specifically,senum and hepatic malondialdehyde levels increased by93%and 78%,resjiectively in the unlrealed infecled mice.Furlhennore,antioxidant indices,viz;superoxide dismutase.catalase,glutathione-s-transferasc.glualhione peroxidase and reduced gluathione decreased significantly(P<0.05)in the tissues of untreated P.berghei-infected mice.KV significantly(P<0.05)ameliorated the P.berghei-induced decrease in antioxidant status of the infected mice.Conclusions:This study shows that kolaviron,especially at 200 mg/kg,has high antimalarial activities in P.berghei-infected mice,in addition to its known antioxidant properties.
基金suppor ted by the National Key Research and Development Program of China(2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202002)+2 种基金the National Natural Science Foundation of China(82074098,82003814)the CACMS Innovation Fund(CI2021A05101)the Fundamental Research Funds for the Central public welfare research institutes(ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-ND-010,ZZ15-ND-10 and ZZ14-FL-002)。
文摘Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an indispensable role, however, its mechanism of action(MoA) is not fully understood.Methods: We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling(ABPP) and mass spectrometry-coupled cellular thermal shift assay(MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays.Results: We developed a novel clickable, photo-affinity chloroquine analog probe(CQP) which retains the antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photocrosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods.Conclusions: We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ antimalarial targets by a parallel usage of labeled(ABPP)and label-free(MS-CETSA) methods.
文摘Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop antimalarial drug for decades,any anti-malarial drug can able to eradicate completely till now.Many anti-malarial substances are practically ineffectual because of their physicochemical limitations,cytotoxicity,chemical instability and degradation,and limited activities against intracellular parasites.Taking into consideration,the amount of research is going to conduct in the field of nanoparticle based drug delivery systems,lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug application for the opening out of novel chemotherapeutics in laboratory research,which may show the way to better use with age-old antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.
文摘Objective:To investigate the possibility of increased antimalarial activity of Icacina senegalensis A.Juss(Icacinaceae)upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice.Methods:Chloroquine sensitive ANKA clones of Plasmodium berghei were used to develop experimental models based on intraperitoneal injection of 10^(7)parasitized erythrocytes in phosphate buffer saline(pH 7.2)and subsequent development of parasitemia.The models were employed to investigate prophylactic and curative anti-malarial activities of tuber and tuberleaf methanol extracts of the plant at selected dosages(25,50 and 100 mg/kg body weight).Chloroquine with a curative dosage of 10 mg/kg body weight was used as positive control in both studies.Results:Tuber and tuber-leaf extracts produced a dose-dependent chemosuppression of the parasites,with higher activity and mean survival time exhibited by the combined extract.Conclusions:Anti-plasmodia activity has been discovered in methanol extract of Icacina senegalensis tuber extract.The observed optimization of the antimalarial actions of the plant upon a combination of its leaf and tuber opens a new area of medicinal plant research.
文摘Objective:To compare the two methods of rapid diagnostic tests(RDTs)and microscopy in the diagnosis of malaria.Methods:RDTs and microscopy were carried out to diagnose malaria. Percentage malaria parasitaemia was calculated on thin films and all non-acute cases of plasmodiasis with less than 0.001%malaria parasitaemia were regarded as negative.Results were simply presented as percentage positive of the total number of patients under study.The results of RDTs were compared to those of microscopy while those of RDTs based on antigen were compared to those of RDTs based on antibody.Patients' follow-up was made for all cases.Results: All the 200 patients under present study tested positive to RDTs based on malaria antibodies(serum)method(100%).128 out of 200 tested positive to RDTs based on malaria antigen(whole blood)method(64%),while 118 out of 200 patients under present study tested positive to visual microscopy of Lieshman and diluted Giemsa(59%).All patients that tested positive to microscopy also tested positive to RDTs based on antigen.All patients on the second day of follow-up were non-febrile and had antimalaria drugs.Conclusions;We conclude based on the present study that the RDTs based on malaria antigen(whole blood)method is as specific as the traditional microscopy and even appears more sensitive than microscopy.The RDTs based on antibody(serum)method is unspecific thus it should not be encouraged.It is most likely that Africa being an endemic region,formation of certain levels of malaria antibody may not be uncommon.The present study also supports the opinion that a good number of febrile cases is not due to malaria. We support WHO's report on cost effectiveness of RDTs but,recommend that only the antigen based method should possibly,be adopted in Africa and other malaria endemic regions of the world.
文摘Objective:To evaluate the effect of short term artemether administration on some blood parameters in adult male Wistar rats.Methods:Sixty five albino rats with body weight of 190-220 g were used for the four-phased study. The animals were randomly divided into five groups. The first-four groups of 15 rats were further divided into 3 subgroups of 5 rats. The drug was administered orally at sub-optimal, therapeutic, and high doses of 25, 50 and 75 mg/kg bw,respectively to the rats for 1 day, 2 days and 3 days. Blood samples were collected by cardio-puncture from the rats for hematology at the end of each phase. The last group served as control,and they were given waterad libitum.Results:Artemether caused significant reduction(P<0.05)of the hematological profile of the animals in a dose dependent manner. Discontinuation of the drug use however showed gradual recovery of the depressed indices of the blood parameters.Conclusions:The results suggest that artemether can induce reversible changes in hematological profiles of rats by extension man. This can probably aggravate anemia when artemether is administered to malaria patients. Hence, the study supports the use of the drug with cautione specially in patients prone to anemic tendencies.
基金supported by grants from the National Key Research and Development Program of China(2020YFA0908000 and 2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese-Medicine(ZYYCXTD-C-202002)+8 种基金the National Natural Science Foundation of China(82141001,82274182,82074098,82003814,and 82173914)the China Academy of Chinese Medical Sciences(CACMS)Innovation Fund(CI2021A05104 and CI2021A05101)the Distinguished Expert Project of Sichuan Province Tianfu Scholar(CW202002)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(CI2021B014)the China Postdoctoral Science Foundation(2022M721541)the Establishment of Sino-Austria‘‘Belt and Road”Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research(2020YFE0205100)the Excellent Scientific and Technological Innovation Training Program of Shenzhen(RCYX20210706092040048)the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-YQ-050,ZZ14-ND-010,and ZZ15-ND-10)the Introduce Innovative Team Projects of Jinan(202228029)。
文摘The widespread use of artemisinin(ART)and its derivatives has significantly reduced the global burden of malaria;however,malaria still poses a serious threat to global health.Although significant progress has been achieved in elucidating the antimalarial mechanisms of ART,the most crucial target proteins and pathways of ART remain unknown.Knowledge on the exact antimalarial mechanisms of ART is urgently needed,as signs of emerging ART resistance have been observed in some regions of the world.Here,we used a combined strategy involving mass spectrometry-coupled cellular thermal shift assay(MS-CETSA)and transcriptomics profiling to identify a group of putative antimalarial targets of ART.We then conducted a series of validation experiments on five prospective protein targets,demonstrating that ART may function against malaria parasites by interfering with redox homeostasis,lipid metabolism,and protein synthesis processes.Taken together,this study provides fresh perspectives on the antimalarial mechanisms of ART and identifies several crucial proteins involved in parasite survival that can be targeted to combat malaria.
文摘Leaf and stem essential oils of Lonchocarpus cyanescens Benth., (Fabaceae) were obtained by hydro-distillation, using all-glass apparatus adapted to British Pharmacopeia specifications with yields of 0.03% and 0.17% respectively. The oils were investigated by GC and GC-MS analyses. Results show seven compounds were responsible for 90.4% of leaf;eleven compounds responsible for 97.6% of stem volatile oils. Phytol (62.5%) and hexadecanoic acid (12.4%) dominate the leaf oil;octadecenoic (24.1%) and hexadecanoic acids (17.2%) are predominant in the stem oil. Phytochemical screening of stem, leaf, and root methanol extracts of Lonchocarpus cyanescens reveal presence of following seven classes of metabolites: saponin, tannin, steroid, terpenoid, cardiac glycosides, phlobatannins and flavonoids. Partitioning of methanol extract from dried leaf of it with ethylacetate gave fraction, which was chromatographed using gradient elution. TLC with high Rf was used in monitoring elution. Two white crystalline solids eluted at 5% and 10% ethylethanoate in hexane, were re-crystallized and characterized. They were subjected to Infra-Red spectra, mass spectrometry (ESI technique), 1H and 13C-NMR analyses, which confirmed they are triterpenoids. Above mentioned metabolites may be responsible for literature acclaimed bio-activities L. cyanescens display [anti-inflammatory, anti-arthritic, anti-microbial effects]. This paper presents details of above results which are new in literature.
文摘Effects of amodiaquine, artesunate and artesunate amodiaquine combination on open field novelty-induced behaviors and spatial memory in healthy mice were studied. Forty mice were used in the open field and fifty each in the radial arm maze and Y maze;mice were assigned into four or five groups of ten each, Group A served as control (distilled water), Groups B, C and D received artesunate (4 mg/kg), amodiaquine (10 mg/kg) and artesunate-amodiaquine combination (4 mg/kg and10 mg/kg) respectively, while Group E animals (for the cognition tests) were given scopolamine (2 mg/kg). Drugs and vehicle were administered orally for three days. Results were analysed by one way analysis of variance followed by a posthoc test. Results showed that artesunate and amodiaquine either in combination or administered singly caused a significant increase in open field novelty-induced horizontal locomotion and rearing. Grooming in the open field showed increments in the artesunate alone and artesunate amodiaquine groups while significant reductions in spatial memory were also seen in the cognition models used.
