Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynth...Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.展开更多
The analysis of the filamentary structure of the cosmo as well as that of the internal structure of the polar ice suggests the development of models based on three-dimensional(3D)point processes.A point process,regard...The analysis of the filamentary structure of the cosmo as well as that of the internal structure of the polar ice suggests the development of models based on three-dimensional(3D)point processes.A point process,regarded as a random measure,can be expressed as a sum of Delta Dirac measures concentrated at some random points.The integration with respect to the point process leads the continuous wavelet transform of the process itself.As possible mother wavelets,we propose the application of the Mexican hat and the Morlet wavelet in order to implement the scale-angle energy density of the process,depending on the dilation parameter and on the three angles which define the direction in the Euclidean space.Such indicator proves to be a sensitive detector of any variation in the direction and it can be successfully implemented to study the isotropy or the filamentary structure in 3D point patterns.展开更多
Aicardi–Goutières syndrome(AGS)is a rare genetic disease caused by mutations in nine genes that are all involved in nucleic acid metabolism or sensing.1,2 The three RNASEH2 subunits represent the most frequently...Aicardi–Goutières syndrome(AGS)is a rare genetic disease caused by mutations in nine genes that are all involved in nucleic acid metabolism or sensing.1,2 The three RNASEH2 subunits represent the most frequently mutated genes in AGS patients,1,3 and mutations in RNASEH2 subunits lead to the accumulation of endogenous RNA:DNA hybrids that may trigger an interferon-α-mediated immune response4 through the activation of pattern recognition receptors(PRRs).5 PRRs perform surveillance on extracellular,endosomal,and cytosolic compartments to identify signs of infection:endogenous nucleic acids that are inappropriately cleared may enter and accumulate in the cytoplasm,driving inflammation and autoimmune diseases.6 This accumulation may be the cause of the clinical autoimmune phenotype of AGS patients carrying RNASEH2 mutations.A proven effective cure for AGS has not been discovered,and targeting these two pathways may lead to a treatment that improves patients’immunological symptoms.Hydroxychloroquine(HCQ)interferes with normal antigen processing and presentation and is widely used in the clinical treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.7 HCQ is also a well-known inhibitor of autophagy that prevents the degradation of autolysosomes.This drug inhibits acidification and maturation of endosomes and increases the pH in lysosomes,resulting in the inhibition of their main functions,such as downstream cell signaling through TLRs.7 Therefore,the aim of our work was to investigate whether HCQ is able to modulate the abnormal inflammatory response driven by RNA:DNA hybrids.展开更多
文摘Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.
文摘The analysis of the filamentary structure of the cosmo as well as that of the internal structure of the polar ice suggests the development of models based on three-dimensional(3D)point processes.A point process,regarded as a random measure,can be expressed as a sum of Delta Dirac measures concentrated at some random points.The integration with respect to the point process leads the continuous wavelet transform of the process itself.As possible mother wavelets,we propose the application of the Mexican hat and the Morlet wavelet in order to implement the scale-angle energy density of the process,depending on the dilation parameter and on the three angles which define the direction in the Euclidean space.Such indicator proves to be a sensitive detector of any variation in the direction and it can be successfully implemented to study the isotropy or the filamentary structure in 3D point patterns.
基金supported by grants from the Italian Ministry of Health RC 2018-2019 to IRCCS Mondino Foundation,Pavia,Italy.
文摘Aicardi–Goutières syndrome(AGS)is a rare genetic disease caused by mutations in nine genes that are all involved in nucleic acid metabolism or sensing.1,2 The three RNASEH2 subunits represent the most frequently mutated genes in AGS patients,1,3 and mutations in RNASEH2 subunits lead to the accumulation of endogenous RNA:DNA hybrids that may trigger an interferon-α-mediated immune response4 through the activation of pattern recognition receptors(PRRs).5 PRRs perform surveillance on extracellular,endosomal,and cytosolic compartments to identify signs of infection:endogenous nucleic acids that are inappropriately cleared may enter and accumulate in the cytoplasm,driving inflammation and autoimmune diseases.6 This accumulation may be the cause of the clinical autoimmune phenotype of AGS patients carrying RNASEH2 mutations.A proven effective cure for AGS has not been discovered,and targeting these two pathways may lead to a treatment that improves patients’immunological symptoms.Hydroxychloroquine(HCQ)interferes with normal antigen processing and presentation and is widely used in the clinical treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.7 HCQ is also a well-known inhibitor of autophagy that prevents the degradation of autolysosomes.This drug inhibits acidification and maturation of endosomes and increases the pH in lysosomes,resulting in the inhibition of their main functions,such as downstream cell signaling through TLRs.7 Therefore,the aim of our work was to investigate whether HCQ is able to modulate the abnormal inflammatory response driven by RNA:DNA hybrids.
