Background:In Nigeria,malaria is a leading cause of hospital admission and death.The country accounts for highest malaria cases and deaths globally.About 25% of all malaria cases and deaths in the world occurs in Nige...Background:In Nigeria,malaria is a leading cause of hospital admission and death.The country accounts for highest malaria cases and deaths globally.About 25% of all malaria cases and deaths in the world occurs in Nigeria.In 2010,malaria was reported to account for 60% of all outpatient visits and responsible for 30% of all hospital admission of children under the age of five years leaving in Nigeria.Objective:The goal of this research work was to investigate the possible role of the state of protein nutrition,kidney and liver functions of the under 5 years children with P.falciparum malaria;the assessment of these biochemical parameters as possible indicator of P.falciparum infection in the studied subjects and the effect of home-based oral chloroquine treatment in these children leaving in Jos metropolis.Method:Total of 93 children within the age range of 1 to 59 months and leaving in Jos North,Central Nigeria were recruited for this cross-sectional study.Malaria parasite identification was done using microscopic examination of Leishman-stained thick and thin blood films while the complete blood count was carried out using Beckman Coulter Analyzer.Results:The serum albumin concentration of(37.63±0.82 g/L)obtained in the malaria-free children was higher than concentration of(34.07±1.90 g/L)obtained in the chloroquine treated children with malaria,but not different from those obtained in the untreated uncomplicated malaria(37.35±1.19 g/L)and untreated severe malaria(37.43±1.02 g/L)groups.The Serum globulin concentration of 35.09±1.95 g/L,obtained in the untreated simple malaria group was higher than 30.18±1.30 g/L in the control group,34.57±2.59 g/L in the untreated severe malaria group and chloroquine treated malaria with 30.71±2.38 g/L,respectively.Conclusion:This study suggests that the biochemical parameters of serum creatinine,serum albumin,total protein,and globulin,serum alkaline phosphatase,serum alanine aminotransferase and serum aspartate aminotransferase are not sensitive indicators of P.falciparum infection in studied children with malaria.It also demonstrated that involvement of liver and kidney or impairment of their functions could be ruled out in the pathogenesis of malaria in this group of children.These results further shows that there was no significant effect of first-line treatment with oral chloroquine on the studied biochemical parameters in the study population.展开更多
Objective:Avidly phagocytosed hemozoin(malarial pigment) alters several functions of human monocytes and stimulates generation of several cytokines.Recently,we showed that phagocytosis of hemozoin by human monocytes i...Objective:Avidly phagocytosed hemozoin(malarial pigment) alters several functions of human monocytes and stimulates generation of several cytokines.Recently,we showed that phagocytosis of hemozoin by human monocytes increases expression and activity of matrix metalloproteinase-9,a proteolytic enzyme available in specific gelatinase granules,which contain several enzymes including lysozyme.Present work investigated active lysozyme release after phagocytosis of hemozoin and its dependence on production of tumor necrosis factor alpha. Methods:After phagocytosis of hemozoin,hemozoin-containing trophozoites or control meals(opsonized nonparasitized red blood cells and latex particles),monocyte supematants were monitored for 2 hours,in presence of blocking anti-human tumor necrosis factor alpha antibodies or recombinant human tumor necrosis factor alpha cytokine in selected experiments.Lysozyme release was evaluated by a specific spectrometric assay measuring lysozyme activity after coincubation of cell supematants with suspensions of Mycrococcus Lysodeikticus,while levels of soluble tumor necrosis factor alpha were analyzed by specific enzyme-linked immunodsorbent assay. Results:Levels of lysozyme activity and soluble tumor necrosis factor alpha protein were increased in hemozoin in-or trophozoites-laden monocytes supematants.Phagocytosis per se(control meals) also increased lysozyme release,but levels were significantly lower than those obtained after phagocytosis of hemozoin or trophozoites. Interestingly,all effects on lysozyme release observed after phagocytosis were abrogated by blocking anti-human tumor necrosis factor alpha antibodies,while they were mimicked by recombinant human tumor necrosis factor alpha cytokine.Conclusions:Present work shows that phagocytosis of hemozoin promotes monocyte degranulation and enhances active lysozyme release.The effect requires tumor necrosis factor alpha mediation.展开更多
Malaria is an infectious and communicable disease,caused by one or more species of Plasmodium parasites.There are five species of parasites responsible for malaria in humans,of which two,Plasmodium Falciparum and Plas...Malaria is an infectious and communicable disease,caused by one or more species of Plasmodium parasites.There are five species of parasites responsible for malaria in humans,of which two,Plasmodium Falciparum and Plasmodium Vivax,are the most dangerous.In Djibouti,the two species of Plasmodium are present in different proportions in the infected population:77%of P.Falciparum and 33%of P.Vivax.In this study we present a new mathematical model describing the temporal dynamics of Plasmodium Falciparum and Plasmodium Vivax co-infection.We focus briefly on the well posedness of this model and on the calculation of the basic reproductive numbers for the infections with each Plasmodium species that help us understand the long-term dynamics of this model(i.e.,existence and stability of various eqiuilibria).Then we use computational approaches to:(a)identify model parameters using real data on malaria infections in Djibouti;(b)illustrate the influence of different estimated parameters on the basic reproduction numbers;(c)perform global sensitivity and uncertainty analysis for the impact of various model parameters on the transient dynamics of infectious mosquitoes and infected humans,for infections with each of the Plasmodium species.The originality of this research stems from employing the FAST method and the LHS method to identify the key factors influencing the progression of the disease within the population of Djibouti.In addition,sensitivity analysis identified the most influential parameter for Falciparium and Vivax reproduction rates.Finally,the uncertainty analysis enabled us to understand the variability of certain parameters on the infected compartments.展开更多
Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.展开更多
TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal...TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.展开更多
Atomic-scale doping strategies and structure design play pivotal roles in tailoring the electronic structure and physicochemical property of electromagnetic wave absorption(EMWA)materials.However,the relationship betw...Atomic-scale doping strategies and structure design play pivotal roles in tailoring the electronic structure and physicochemical property of electromagnetic wave absorption(EMWA)materials.However,the relationship between configuration and electromagnetic(EM)loss mechanism has remained elusive.Herein,drawing inspiration from the DNA transcription process,we report the successful synthesis of novel in situ Mn/N co-doped helical carbon nanotubes with ultrabroad EMWA capability.Theoretical calculation and EM simulation confirm that the orbital coupling and spin polarization of the Mn–N4–C configuration,along with cross polarization generated by the helical structure,endow the helical converters with enhanced EM loss.As a result,HMC-8 demonstrates outstanding EMWA performance,achieving a minimum reflection loss of−63.13 dB at an ultralow thickness of 1.29 mm.Through precise tuning of the graphite domain size,HMC-7 achieves an effective absorption bandwidth(EAB)of 6.08 GHz at 2.02 mm thickness.Furthermore,constructing macroscale gradient metamaterials enables an ultrabroadband EAB of 12.16 GHz at a thickness of only 5.00 mm,with the maximum radar cross section reduction value reaching 36.4 dB m2.This innovative approach not only advances the understanding of metal–nonmetal co-doping but also realizes broadband EMWA,thus contributing to the development of EMWA mechanisms and applications.展开更多
Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may de...Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.展开更多
文摘Background:In Nigeria,malaria is a leading cause of hospital admission and death.The country accounts for highest malaria cases and deaths globally.About 25% of all malaria cases and deaths in the world occurs in Nigeria.In 2010,malaria was reported to account for 60% of all outpatient visits and responsible for 30% of all hospital admission of children under the age of five years leaving in Nigeria.Objective:The goal of this research work was to investigate the possible role of the state of protein nutrition,kidney and liver functions of the under 5 years children with P.falciparum malaria;the assessment of these biochemical parameters as possible indicator of P.falciparum infection in the studied subjects and the effect of home-based oral chloroquine treatment in these children leaving in Jos metropolis.Method:Total of 93 children within the age range of 1 to 59 months and leaving in Jos North,Central Nigeria were recruited for this cross-sectional study.Malaria parasite identification was done using microscopic examination of Leishman-stained thick and thin blood films while the complete blood count was carried out using Beckman Coulter Analyzer.Results:The serum albumin concentration of(37.63±0.82 g/L)obtained in the malaria-free children was higher than concentration of(34.07±1.90 g/L)obtained in the chloroquine treated children with malaria,but not different from those obtained in the untreated uncomplicated malaria(37.35±1.19 g/L)and untreated severe malaria(37.43±1.02 g/L)groups.The Serum globulin concentration of 35.09±1.95 g/L,obtained in the untreated simple malaria group was higher than 30.18±1.30 g/L in the control group,34.57±2.59 g/L in the untreated severe malaria group and chloroquine treated malaria with 30.71±2.38 g/L,respectively.Conclusion:This study suggests that the biochemical parameters of serum creatinine,serum albumin,total protein,and globulin,serum alkaline phosphatase,serum alanine aminotransferase and serum aspartate aminotransferase are not sensitive indicators of P.falciparum infection in studied children with malaria.It also demonstrated that involvement of liver and kidney or impairment of their functions could be ruled out in the pathogenesis of malaria in this group of children.These results further shows that there was no significant effect of first-line treatment with oral chloroquine on the studied biochemical parameters in the study population.
基金supported in the context of the Italian Malaria Network by grants from Compagnia di San Paolo-IMIthe University of Torino Intramural FundsRegione Piemonte,Ricerca Sanitaria Finalizzata 2007 to PA
文摘Objective:Avidly phagocytosed hemozoin(malarial pigment) alters several functions of human monocytes and stimulates generation of several cytokines.Recently,we showed that phagocytosis of hemozoin by human monocytes increases expression and activity of matrix metalloproteinase-9,a proteolytic enzyme available in specific gelatinase granules,which contain several enzymes including lysozyme.Present work investigated active lysozyme release after phagocytosis of hemozoin and its dependence on production of tumor necrosis factor alpha. Methods:After phagocytosis of hemozoin,hemozoin-containing trophozoites or control meals(opsonized nonparasitized red blood cells and latex particles),monocyte supematants were monitored for 2 hours,in presence of blocking anti-human tumor necrosis factor alpha antibodies or recombinant human tumor necrosis factor alpha cytokine in selected experiments.Lysozyme release was evaluated by a specific spectrometric assay measuring lysozyme activity after coincubation of cell supematants with suspensions of Mycrococcus Lysodeikticus,while levels of soluble tumor necrosis factor alpha were analyzed by specific enzyme-linked immunodsorbent assay. Results:Levels of lysozyme activity and soluble tumor necrosis factor alpha protein were increased in hemozoin in-or trophozoites-laden monocytes supematants.Phagocytosis per se(control meals) also increased lysozyme release,but levels were significantly lower than those obtained after phagocytosis of hemozoin or trophozoites. Interestingly,all effects on lysozyme release observed after phagocytosis were abrogated by blocking anti-human tumor necrosis factor alpha antibodies,while they were mimicked by recombinant human tumor necrosis factor alpha cytokine.Conclusions:Present work shows that phagocytosis of hemozoin promotes monocyte degranulation and enhances active lysozyme release.The effect requires tumor necrosis factor alpha mediation.
基金funded by CEALT(Centre d’Excellence Africain en Logistique et Transport)of the University of DjiboutiCEALT for their financial supportsupport from the MODCOV19 platform of the National Institute of Mathematical Sciences and their Interactions,(CNRS).
文摘Malaria is an infectious and communicable disease,caused by one or more species of Plasmodium parasites.There are five species of parasites responsible for malaria in humans,of which two,Plasmodium Falciparum and Plasmodium Vivax,are the most dangerous.In Djibouti,the two species of Plasmodium are present in different proportions in the infected population:77%of P.Falciparum and 33%of P.Vivax.In this study we present a new mathematical model describing the temporal dynamics of Plasmodium Falciparum and Plasmodium Vivax co-infection.We focus briefly on the well posedness of this model and on the calculation of the basic reproductive numbers for the infections with each Plasmodium species that help us understand the long-term dynamics of this model(i.e.,existence and stability of various eqiuilibria).Then we use computational approaches to:(a)identify model parameters using real data on malaria infections in Djibouti;(b)illustrate the influence of different estimated parameters on the basic reproduction numbers;(c)perform global sensitivity and uncertainty analysis for the impact of various model parameters on the transient dynamics of infectious mosquitoes and infected humans,for infections with each of the Plasmodium species.The originality of this research stems from employing the FAST method and the LHS method to identify the key factors influencing the progression of the disease within the population of Djibouti.In addition,sensitivity analysis identified the most influential parameter for Falciparium and Vivax reproduction rates.Finally,the uncertainty analysis enabled us to understand the variability of certain parameters on the infected compartments.
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
基金supported by the Koeln Fortune Program/Faculty of Medicine,University of Cologne,the Alzheimer Forschung Initiative e.V.(grant#22039,to HZ)open-access funding from the DFG/GRC issued to the University of CologneAlzheimer Forschung Initiative e.V.for Open Access Publishing(a publication grant#P2401,to MAAK)。
文摘TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.
基金supported by the National Natural Science Foundation of China(22265021)the Aeronautical Science Foundation of China(2020Z056056003)Jiangxi Provincial Natural Science Foundation(20232BAB212004).
文摘Atomic-scale doping strategies and structure design play pivotal roles in tailoring the electronic structure and physicochemical property of electromagnetic wave absorption(EMWA)materials.However,the relationship between configuration and electromagnetic(EM)loss mechanism has remained elusive.Herein,drawing inspiration from the DNA transcription process,we report the successful synthesis of novel in situ Mn/N co-doped helical carbon nanotubes with ultrabroad EMWA capability.Theoretical calculation and EM simulation confirm that the orbital coupling and spin polarization of the Mn–N4–C configuration,along with cross polarization generated by the helical structure,endow the helical converters with enhanced EM loss.As a result,HMC-8 demonstrates outstanding EMWA performance,achieving a minimum reflection loss of−63.13 dB at an ultralow thickness of 1.29 mm.Through precise tuning of the graphite domain size,HMC-7 achieves an effective absorption bandwidth(EAB)of 6.08 GHz at 2.02 mm thickness.Furthermore,constructing macroscale gradient metamaterials enables an ultrabroadband EAB of 12.16 GHz at a thickness of only 5.00 mm,with the maximum radar cross section reduction value reaching 36.4 dB m2.This innovative approach not only advances the understanding of metal–nonmetal co-doping but also realizes broadband EMWA,thus contributing to the development of EMWA mechanisms and applications.
基金supported by the Natural Science Foundation of Guangdong Province,Nos.2019A1515010649(to WC),2022A1515012044(to JS)the China Postdoctoral Science Foundation,No.2018M633091(to JS).
文摘Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.
