Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have ...Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have shown success in late-stage clinical trials for Tau-associated neurodegenerative disorders. The most commonly prescribed treatments are symptomatic treatments such as cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers that were approved for use in Alzheimer's disease. As diagnostic screening can detect disorders at earlier time points, the field needs pre-symptomatic treatments that can prevent, or significantly delay the progression of these disorders(Koychev et al., 2019). These approaches may be different from late-stage treatments that may help to ameliorate symptoms and slow progression once symptoms have become more advanced should early diagnostic screening fail. This mini-review will highlight five key avenues of academic and industrial research for identifying therapeutic strategies to treat Tau-associated neurodegenerative disorders. These avenues include investigating(1) the broad class of chemicals termed “small molecules”;(2) adaptive immunity through both passive and active antibody treatments;(3) innate immunity with an emphasis on microglial modulation;(4) synaptic compartments with the view that Tau-associated neurodegenerative disorders are synaptopathies. Although this mini-review will focus on Alzheimer's disease due to its prevalence, it will also argue the need to target other tauopathies, as through understanding Alzheimer's disease as a Tau-associated neurodegenerative disorder, we may be able to generalize treatment options. For this reason, added detail linking back specifically to Tau protein as a direct therapeutic target will be added to each topic.展开更多
Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of ly...Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of lysosome-related organelles（LROs） whose formation is regulated by HPS protein associated complexes such as BLOC（biogenesis of lysosome-related organelles complex）-1,-2,-3, AP-3（adaptor protein complex-3） and HOPS（homotypic fusion and protein sorting complex）. Von Willebrand factor（VWF） is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin（DDAVP） stimulation in HPS1（BLOC-3 subunit）, HPS6（BLOC-2 subunit）, and HPS9（BLOC-1 subunit）deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.展开更多
Amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD)are both devastating neurodegenerative conditions.Despite affecting different regions of the nervous system(FTD affecting primarily the frontal and tem...Amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD)are both devastating neurodegenerative conditions.Despite affecting different regions of the nervous system(FTD affecting primarily the frontal and temporal lobes,whilst ALS presents with motor neuron loss),there is significant overlap between these conditions in terms of genetics,pathology,and disease mechanisms,and they are therefore often grouped as a spectrum of symptoms under the heading FTD/ALS(Abramzon et al.,2020).Significantly,there is currently no cure for ALS or FTD.However,recent mechanistic insight points to a novel pathway to target for potential therapeutic intervention.展开更多
It is well recognized that cell death plays an important role during the maturation of the nervous system as well as in many neurological diseases. Apoptosis has been shown to be important particulary during embryogen...It is well recognized that cell death plays an important role during the maturation of the nervous system as well as in many neurological diseases. Apoptosis has been shown to be important particulary during embryogenesis as a means to eliminating unwanted neurons. Severed axons have also been shown to degenerate in an organized fashion termed Wallerian degeneration. Excitotoxic death is another form of cell death in the nervous system which is induced by high concentrations of neurotransmitters such as glutamate. It is not known whether the same molecular mechanisms underlie these different forms of cell death in the nervous system. The Bax-/-Bak-/- double knock-out mouse provides an ideal system to展开更多
Context: Human Natural Killer T cells are T lymphocytes that express an invariant αβ T cells receptors and NK cells receptors. They regulate innate and adaptive immune response but are susceptible to HIV-1 infection...Context: Human Natural Killer T cells are T lymphocytes that express an invariant αβ T cells receptors and NK cells receptors. They regulate innate and adaptive immune response but are susceptible to HIV-1 infection. Objective: We compare the frequency and the activity of NKT cells in HIV-1 and HIV-2 infected individuals with CD4+ counts greater than 500/mm3 using flow cytometry after overnight stimulation with phytohemagglutinin (PHA). Results: The frequency of NKT cells was similar between both groups and also to sero-negative control subjects. There were also no significant differences in the proportions of total NKT cells and the CD4+ NKT subset that secreted interferon gamma (IFN-γ) after polyclonal stimulation. However, there was a significantly higher frequency of IFN-γ﹣ CD4+ NKT cells in HIV-1-infected compared with HIV-2 infected subjects (p = 0.043). Conclusion: These data suggest there is no relationship between the functional activity of NKT cell subsets and the total NKT cell population in HIV infection. The expansion of IFN-γ﹣ CD4+ NKT cells in HIV-1 infection may serve as target for viral infection and may eventually result in their depletion during chronic infection.展开更多
Context: The functional activity of NK cells depends on the balance between the engagement of activating and inhibitory receptors on the cell surface with their ligands, which enables them to kill infected cells. Obje...Context: The functional activity of NK cells depends on the balance between the engagement of activating and inhibitory receptors on the cell surface with their ligands, which enables them to kill infected cells. Objectives: The aim of this study was to evaluate and compare expressions of selected activating and inhibitory receptors on stimulated NK cells in HIV-1 and HIV-2 infections. Methods: PBMCs were analysed for activating (NKp30, NKp44, NKp46) and inhibitory (CD158a, CD158b, p70) receptor expressions in 30 HIV-1, 30 HIV-2 and 30 HIV uninfected healthy control (HC) subjects by flow cytometry after stimulating with K562 cells. Results: There was an expression of other receptors following an already in vitro engagement of NK cells with K562 cells. Higher expression of the activating receptors, NKp44 (p = 0.029) and NKp46 (p = 0.032) on NK cells from HIV-2 compared to HIV-1 infected individuals but similar NKp30 expression (p = 0.980). The levels of expression of inhibitory receptor CD158a were similar between HIV-1 and HIV-2 infected subjects (p = 0.309) but there was significant up-regulation of inhibitory receptors p70 (p = 0.010) and CD158b (p = 0.05) in HIV-1 compared to HIV-2 subjects. Conclusion: Despite the in vitro engagement of NK cells with stimulating K562 cells, our data showed differential expressions of other selected activating and inhibitory receptors in HIV-1 and HIV-2 infected subjects.展开更多
A number of cytokines are secreted during HIV infection that enhances both innate and adaptive immune responses. Interferon-α/β/γ, IL-12, IL-15 and IL-18 have been found to contribute to the development, maturation...A number of cytokines are secreted during HIV infection that enhances both innate and adaptive immune responses. Interferon-α/β/γ, IL-12, IL-15 and IL-18 have been found to contribute to the development, maturation, differentiation and function of NK and other immune cells. The levels of IFN-α/β/γ, IL-12, IL-15 and IL-18 were compared in the plasma of 90 HIV-1 infected and 90 HIV-2 infected subjects by ELISA or Cytometric Beads Array assays. The HIV-infected subjects were stratified according to CD4<sup>+</sup> T cell counts into three groups: >500, 200 - 500 and <200 cells/ul, with 30 subjects in each group. Cytokine levels were also determined in the plasma of 50 HIV uninfected blood bank donors. Among the cytokines tested, IFN-α was found to be significantly increased in HIV-2 infected compared to HIV-1 infected subjects at high CD4<sup>+</sup> T cell counts (p = 0.001). The levels of IFN-β were seen to differ between the two infections in patients from the category of medium CD4<sup>+</sup> T cell counts: this was significantly increased in HIV-2 infected patients (p < 0.001) as well as compared to uninfected controls (p = 0.001). The levels of IFN-γ were similar at all the CD4<sup>+</sup> T cell categories except for an increase in HIV-2 infected patients at low CD4<sup>+</sup> T cell counts (p = 0.02). The levels of these cytokines were similar in all HIV-1 subjects. Also, the level of IL-12p70 was similar between the two infections but significantly higher in HIV-2 at low compared to medium CD4<sup>+</sup> T cells categories (p = 0.047). Similar to IFN-γ and IL-12p70, the levels of both IL-18 and IL-15 were found to be significantly higher in HIV-2 infected patients compared to HIV-1 at low CD4<sup>+</sup> T cell counts (p < 0.05). These data show that there is variability in the levels of innate cytokines at different stages of HIV infection but the finding of increased IFN-α in HIV-2 infected asymptomatic subjects is consistent with the high innate NK responses previously noted at this stage of infection.展开更多
Dear Editor,An outbreak of an unknown infectious pneumonia has recently occurred in Wuhan,China.1 The pathogen of the disease was quickly identified as a novel coronavirus(SARS-CoV-2,severe acute respiratory syndrome ...Dear Editor,An outbreak of an unknown infectious pneumonia has recently occurred in Wuhan,China.1 The pathogen of the disease was quickly identified as a novel coronavirus(SARS-CoV-2,severe acute respiratory syndrome coronavirus 2),and the disease was named coronavirus disease-19(COVID-19).2 The virus has so far caused 78,959 confirmed cases and 2791 deaths in China according to the reports of government.COVID-19 has been spreading in many countries such as Japan,Korea,Singapore,Iran,and Italia.展开更多
Seeing is believing! Cryo-electron microscopy （cryo-EM） has greatly expanded the limit of human vision. The Nobel Prize in Chemistry 2017 was awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for thei...Seeing is believing! Cryo-electron microscopy （cryo-EM） has greatly expanded the limit of human vision. The Nobel Prize in Chemistry 2017 was awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for their development of cryo-EM. This method has revolutionized the structural study of biomolecules in the past few years. Now, scientists can routinely visualize many different kinds of biological ma- chineries with unprecedented details.展开更多
The use of optogenetic and chemogenetic approaches to control cellular activities with high temporal,spatial and cell-type specific resolution has profoundly transformed the field of neuroscience.In addition to enabli...The use of optogenetic and chemogenetic approaches to control cellular activities with high temporal,spatial and cell-type specific resolution has profoundly transformed the field of neuroscience.In addition to enabling the manipulation of neuronal excitability,there is a great need for targeting intracellular signalling proteins and secondary messengers precisely。展开更多
Background:Hypoxic-ischemic encephalopathy(HIE)is a devastating condition affecting around 8.5 in 1000 newborns globally.Therapeutic hypothermia(TH)can reduce mortality and,to a limited extent,disability after HIE.Nev...Background:Hypoxic-ischemic encephalopathy(HIE)is a devastating condition affecting around 8.5 in 1000 newborns globally.Therapeutic hypothermia(TH)can reduce mortality and,to a limited extent,disability after HIE.Nevertheless,there is a need for new and effective treatment strategies.Cell-based treatments using mononuclear cells(MNCs),which can be sourced from umbilical cord blood,are currently being investigated.Despite promising preclinical results,there is currently no strong indicator for the clinical efficacy of the approach.This analysis aimed to provide potential explanations for this discrepancy.Methods:A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.Preclinical and clinical studies were retrieved from PubMed,Web of Science,Scopus,and clinicaltrials.gov using a predefined search strategy.A total of 17 preclinical and 7 clinical studies were included.We analyzed overall MNC efficacy in preclinical trials,the methodological quality of preclinical trials,and relevant design features in preclinical versus clinical trials.Results:There was evidence for MNC therapeutic efficacy in preclinical models of HIE.The methodological quality of preclinical studies was not optimal,and statistical design quality was particularly poor.However,methodological quality was above the standard in other fields.There were significant differences in preclinical versus clinical study design including the use of TH as a baseline treatment(only in clinical studies)and much higher MNC doses being applied in preclinical studies.Conclusions:Based on the analyzed data,it is unlikely that therapeutic effect size is massively overestimated in preclinical studies.It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of the efficacy of MNC treatments in HIE.Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment.展开更多
基金the MRC Laboratory of Molecular Biology (to MR)。
文摘Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have shown success in late-stage clinical trials for Tau-associated neurodegenerative disorders. The most commonly prescribed treatments are symptomatic treatments such as cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers that were approved for use in Alzheimer's disease. As diagnostic screening can detect disorders at earlier time points, the field needs pre-symptomatic treatments that can prevent, or significantly delay the progression of these disorders(Koychev et al., 2019). These approaches may be different from late-stage treatments that may help to ameliorate symptoms and slow progression once symptoms have become more advanced should early diagnostic screening fail. This mini-review will highlight five key avenues of academic and industrial research for identifying therapeutic strategies to treat Tau-associated neurodegenerative disorders. These avenues include investigating(1) the broad class of chemicals termed “small molecules”;(2) adaptive immunity through both passive and active antibody treatments;(3) innate immunity with an emphasis on microglial modulation;(4) synaptic compartments with the view that Tau-associated neurodegenerative disorders are synaptopathies. Although this mini-review will focus on Alzheimer's disease due to its prevalence, it will also argue the need to target other tauopathies, as through understanding Alzheimer's disease as a Tau-associated neurodegenerative disorder, we may be able to generalize treatment options. For this reason, added detail linking back specifically to Tau protein as a direct therapeutic target will be added to each topic.
基金partially supported by the grants from the National Natural Science Foundation of China(Nos.91539204 and 31230046)the Ministry of Science and Technology of China(No.2013CB530605)(to W.L.)from MRC of UK(MC-UU-12018/2,to D.C.)
文摘Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of lysosome-related organelles（LROs） whose formation is regulated by HPS protein associated complexes such as BLOC（biogenesis of lysosome-related organelles complex）-1,-2,-3, AP-3（adaptor protein complex-3） and HOPS（homotypic fusion and protein sorting complex）. Von Willebrand factor（VWF） is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin（DDAVP） stimulation in HPS1（BLOC-3 subunit）, HPS6（BLOC-2 subunit）, and HPS9（BLOC-1 subunit）deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.
基金MRC LMB.EC acknowledges funding from Alzheimer's Research UK(PPG2018B-017)the UK Dementia Research Institute which receives its funding from DRI Ltd.funded by the UK Medical Research Council,Alzheimer's Society,Alzheimer's Research UK。
文摘Amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD)are both devastating neurodegenerative conditions.Despite affecting different regions of the nervous system(FTD affecting primarily the frontal and temporal lobes,whilst ALS presents with motor neuron loss),there is significant overlap between these conditions in terms of genetics,pathology,and disease mechanisms,and they are therefore often grouped as a spectrum of symptoms under the heading FTD/ALS(Abramzon et al.,2020).Significantly,there is currently no cure for ALS or FTD.However,recent mechanistic insight points to a novel pathway to target for potential therapeutic intervention.
文摘It is well recognized that cell death plays an important role during the maturation of the nervous system as well as in many neurological diseases. Apoptosis has been shown to be important particulary during embryogenesis as a means to eliminating unwanted neurons. Severed axons have also been shown to degenerate in an organized fashion termed Wallerian degeneration. Excitotoxic death is another form of cell death in the nervous system which is induced by high concentrations of neurotransmitters such as glutamate. It is not known whether the same molecular mechanisms underlie these different forms of cell death in the nervous system. The Bax-/-Bak-/- double knock-out mouse provides an ideal system to
文摘Context: Human Natural Killer T cells are T lymphocytes that express an invariant αβ T cells receptors and NK cells receptors. They regulate innate and adaptive immune response but are susceptible to HIV-1 infection. Objective: We compare the frequency and the activity of NKT cells in HIV-1 and HIV-2 infected individuals with CD4+ counts greater than 500/mm3 using flow cytometry after overnight stimulation with phytohemagglutinin (PHA). Results: The frequency of NKT cells was similar between both groups and also to sero-negative control subjects. There were also no significant differences in the proportions of total NKT cells and the CD4+ NKT subset that secreted interferon gamma (IFN-γ) after polyclonal stimulation. However, there was a significantly higher frequency of IFN-γ﹣ CD4+ NKT cells in HIV-1-infected compared with HIV-2 infected subjects (p = 0.043). Conclusion: These data suggest there is no relationship between the functional activity of NKT cell subsets and the total NKT cell population in HIV infection. The expansion of IFN-γ﹣ CD4+ NKT cells in HIV-1 infection may serve as target for viral infection and may eventually result in their depletion during chronic infection.
文摘Context: The functional activity of NK cells depends on the balance between the engagement of activating and inhibitory receptors on the cell surface with their ligands, which enables them to kill infected cells. Objectives: The aim of this study was to evaluate and compare expressions of selected activating and inhibitory receptors on stimulated NK cells in HIV-1 and HIV-2 infections. Methods: PBMCs were analysed for activating (NKp30, NKp44, NKp46) and inhibitory (CD158a, CD158b, p70) receptor expressions in 30 HIV-1, 30 HIV-2 and 30 HIV uninfected healthy control (HC) subjects by flow cytometry after stimulating with K562 cells. Results: There was an expression of other receptors following an already in vitro engagement of NK cells with K562 cells. Higher expression of the activating receptors, NKp44 (p = 0.029) and NKp46 (p = 0.032) on NK cells from HIV-2 compared to HIV-1 infected individuals but similar NKp30 expression (p = 0.980). The levels of expression of inhibitory receptor CD158a were similar between HIV-1 and HIV-2 infected subjects (p = 0.309) but there was significant up-regulation of inhibitory receptors p70 (p = 0.010) and CD158b (p = 0.05) in HIV-1 compared to HIV-2 subjects. Conclusion: Despite the in vitro engagement of NK cells with stimulating K562 cells, our data showed differential expressions of other selected activating and inhibitory receptors in HIV-1 and HIV-2 infected subjects.
文摘A number of cytokines are secreted during HIV infection that enhances both innate and adaptive immune responses. Interferon-α/β/γ, IL-12, IL-15 and IL-18 have been found to contribute to the development, maturation, differentiation and function of NK and other immune cells. The levels of IFN-α/β/γ, IL-12, IL-15 and IL-18 were compared in the plasma of 90 HIV-1 infected and 90 HIV-2 infected subjects by ELISA or Cytometric Beads Array assays. The HIV-infected subjects were stratified according to CD4<sup>+</sup> T cell counts into three groups: >500, 200 - 500 and <200 cells/ul, with 30 subjects in each group. Cytokine levels were also determined in the plasma of 50 HIV uninfected blood bank donors. Among the cytokines tested, IFN-α was found to be significantly increased in HIV-2 infected compared to HIV-1 infected subjects at high CD4<sup>+</sup> T cell counts (p = 0.001). The levels of IFN-β were seen to differ between the two infections in patients from the category of medium CD4<sup>+</sup> T cell counts: this was significantly increased in HIV-2 infected patients (p < 0.001) as well as compared to uninfected controls (p = 0.001). The levels of IFN-γ were similar at all the CD4<sup>+</sup> T cell categories except for an increase in HIV-2 infected patients at low CD4<sup>+</sup> T cell counts (p = 0.02). The levels of these cytokines were similar in all HIV-1 subjects. Also, the level of IL-12p70 was similar between the two infections but significantly higher in HIV-2 at low compared to medium CD4<sup>+</sup> T cells categories (p = 0.047). Similar to IFN-γ and IL-12p70, the levels of both IL-18 and IL-15 were found to be significantly higher in HIV-2 infected patients compared to HIV-1 at low CD4<sup>+</sup> T cell counts (p < 0.05). These data show that there is variability in the levels of innate cytokines at different stages of HIV infection but the finding of increased IFN-α in HIV-2 infected asymptomatic subjects is consistent with the high innate NK responses previously noted at this stage of infection.
文摘Dear Editor,An outbreak of an unknown infectious pneumonia has recently occurred in Wuhan,China.1 The pathogen of the disease was quickly identified as a novel coronavirus(SARS-CoV-2,severe acute respiratory syndrome coronavirus 2),and the disease was named coronavirus disease-19(COVID-19).2 The virus has so far caused 78,959 confirmed cases and 2791 deaths in China according to the reports of government.COVID-19 has been spreading in many countries such as Japan,Korea,Singapore,Iran,and Italia.
文摘Seeing is believing! Cryo-electron microscopy （cryo-EM） has greatly expanded the limit of human vision. The Nobel Prize in Chemistry 2017 was awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for their development of cryo-EM. This method has revolutionized the structural study of biomolecules in the past few years. Now, scientists can routinely visualize many different kinds of biological ma- chineries with unprecedented details.
文摘The use of optogenetic and chemogenetic approaches to control cellular activities with high temporal,spatial and cell-type specific resolution has profoundly transformed the field of neuroscience.In addition to enabling the manipulation of neuronal excitability,there is a great need for targeting intracellular signalling proteins and secondary messengers precisely。
基金Academy of Medical Sciences(Newton Advanced Fellowship),Grant/Award Number:NAF\R11\1010。
文摘Background:Hypoxic-ischemic encephalopathy(HIE)is a devastating condition affecting around 8.5 in 1000 newborns globally.Therapeutic hypothermia(TH)can reduce mortality and,to a limited extent,disability after HIE.Nevertheless,there is a need for new and effective treatment strategies.Cell-based treatments using mononuclear cells(MNCs),which can be sourced from umbilical cord blood,are currently being investigated.Despite promising preclinical results,there is currently no strong indicator for the clinical efficacy of the approach.This analysis aimed to provide potential explanations for this discrepancy.Methods:A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.Preclinical and clinical studies were retrieved from PubMed,Web of Science,Scopus,and clinicaltrials.gov using a predefined search strategy.A total of 17 preclinical and 7 clinical studies were included.We analyzed overall MNC efficacy in preclinical trials,the methodological quality of preclinical trials,and relevant design features in preclinical versus clinical trials.Results:There was evidence for MNC therapeutic efficacy in preclinical models of HIE.The methodological quality of preclinical studies was not optimal,and statistical design quality was particularly poor.However,methodological quality was above the standard in other fields.There were significant differences in preclinical versus clinical study design including the use of TH as a baseline treatment(only in clinical studies)and much higher MNC doses being applied in preclinical studies.Conclusions:Based on the analyzed data,it is unlikely that therapeutic effect size is massively overestimated in preclinical studies.It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of the efficacy of MNC treatments in HIE.Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment.
