The development of microsurgery has been dependent on experimental animals. Microsurgery could be a very valuable technique to improve experimental models of liver diseases. Microdissection and microsutures are the tw...The development of microsurgery has been dependent on experimental animals. Microsurgery could be a very valuable technique to improve experimental models of liver diseases. Microdissection and microsutures are the two main microsurgical techniques that can be considered for classifying the experimental models developed for liver research in the rat. Partial portal vein ligation, extrahepatic cholestasis and hepatectomies are all models based on microdissection. On the other hand, in portacaval shunts, orthotopic liver transplantation and partial heterotopic liver transplantation, the microsuture techniques stand out. By reducing surgical complications, these microsurgical techniques allow for improving the resulting experimental models. If good experimental models for liver research are successfully developed, the results obtained from their study might be particularly useful in patients with liver disease. Therefore experimental liver microsurgery could be an invaluable way to translate laboratory data on liver research into new clinical diagnostic and therapeutic strategies.展开更多
Brentano in 1870s was the first to introduce intentionality to mean “conscious of”. At the end of the 1960s, a version of this view was developed by analytic American philosophy to construct a theory of meaningful l...Brentano in 1870s was the first to introduce intentionality to mean “conscious of”. At the end of the 1960s, a version of this view was developed by analytic American philosophy to construct a theory of meaningful language. That led Dennett to claim that intentionality was mainly a feature of sentence, not mental states. In contrast, Searle in 1990s rejected the Brentanian thesis and explained intentionality by a biological naturalism. Thereafter, radical eliminativists such as Churchland claimed that all philosophical arguments merited replacement by neuroscientific knowledge. Unfortunately, very few neurophysiological studies attempted to scientifically tackle the problem raised by intentionality. The issue now emerging is a new conception of intentionality based on phenomenological, neurobiological and quantum theories, such as: 1) the notion of “intentional arc” proposed in the philosophy of Merleau-Ponty;2) the neurobiological and quantum model of Freeman, in which self-organizing pathways are accompanied by quantum transitions in controlling intentionality in brain;3) the recent hypothesis that some visuo-motor neurons would be involved in controlling these self-organized pathways;4) the quantum models of Vitiello and Globus, in which a thermofield (dissipative) system governs the dynamic dialog of dual quantum modes between environment and brain. Based on this conception of mind-world interactions, it implicitly appears that intentionality might be a fundamental force which draws us irreversibly towards the future. An alternative hypothesis based on this promising proposal is argued.展开更多
Motivation: Bipolar disorder (BD) and schizophrenia (SZ) has a difficult diagnosis, so the main objective of this article is to propose the use of Artificial Neural Networks (ANNs) to classify (diagnose) groups of pat...Motivation: Bipolar disorder (BD) and schizophrenia (SZ) has a difficult diagnosis, so the main objective of this article is to propose the use of Artificial Neural Networks (ANNs) to classify (diagnose) groups of patients with BD or SZ from a control group using sociodemographic and biochemical variables. Methods: Artificial neural networks are used as classifying tool. The data from this study were obtained from the array collection from Stanley Neuropathology Consortium databank. Inflammatory markers and characteristics of the sampled population were the inputs variables. Results: Our findings suggest that an artificial neural network could be trained with more than 90% accuracy, aiming the classification and diagnosis of bipolar, schizophrenia and control healthy group. Conclusion: Trained ANNs could be used to improve diagnosis in Schizophrenia and Bipolar disorders.展开更多
BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bo...BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.展开更多
Mental time travel(MTT)refers to the ability to mentally re-experience the past and preexperience the future.Here we briefly review impairments in MTT,its underlying cognitive and neural mechanisms,and ways to improve...Mental time travel(MTT)refers to the ability to mentally re-experience the past and preexperience the future.Here we briefly review impairments in MTT,its underlying cognitive and neural mechanisms,and ways to improve MTT in psychiatric patients.Future research directions on MTT are discussed.展开更多
Mental time travel(MTT)is the ability to project oneself to the past or future through mental simulation.Moreover,MTT can involve self-related or other-related information.This study aimed to compare MTT in individual...Mental time travel(MTT)is the ability to project oneself to the past or future through mental simulation.Moreover,MTT can involve self-related or other-related information.This study aimed to compare MTT in individuals with high levels of schizotypy and that in their counterparts with low levels of schizotypy.Participants with high(n=37)and low(n=37)levels of schizotypy completed an MTT task with four conditions[2(Condition:self vs.other)×2(Time orientation:past vs.future)].They were required to recall past events that had happened to themselves or to a non-intimate person,and to imagine possible future events that might happen to themselves or to a non-intimate person,related to cue words.Outcome measures included specificity,vividness,sense of experience,emotional valence,emotional intensity,proportion of first-person visual perspective in events,and difficulty in event generation.A 2(Group:high vs.low levels of schizotypy)×2(Condition)×2(Time orientation)mixed analysis of variance was conducted on each index.Results showed that self-related MTT was more specific than other-related MTT in low levels of schizotypy participants but not in high levels of schizotypy participants.Participants with a high level of schizotypy reported fewer specific events,and reported events with lower vividness and positive emotion than did those with a low level of schizotypy.Self-related MTT showed higher levels of phenomenological characteristics than did other-related MTT.In conclusion,individuals with a high level of schizotypy have altered MTT,and cannot benefit from the self-advantage effect on the specificity of MTT.展开更多
Faces and their aesthetic appreciation are a core element of social interaction.Although studies have been made on facial processing when looking at faces with different perspectives,a direct comparison of faces in th...Faces and their aesthetic appreciation are a core element of social interaction.Although studies have been made on facial processing when looking at faces with different perspectives,a direct comparison of faces in the left to the right perspective is missing.Portraits in classical Western art indicate a preference of the left compared to the right perspective,but the neural underpinnings of such an asymmetry still have to be clarified.Using functional magnetic resonance imaging,the current study focuses on the processing of three-quarter faces seen with different perspectives.Seventeen participants were asked to passively look at photographs of six male and six female faces with a neutral expression;the photographs were taken from the left,right,and frontal perspectives while keeping their focus on the eyes.The results showed that specific brain areas were involved in processing the three-quarter faces in either symmetric or asymmetric ways.Viewing left and right three-quarter faces resulted in two mirror-like activations in the striate cortex corresponding to the symmetric layout of the left and right perspectives.Viewing the left face resulted additionally in an enhanced activation also in the left extrastriate cortex.The right perspective of male faces elicited a lower activation compared to other perspectives in face-selective areas of the brain.Our findings suggest that the preference of the left three-quarter face emerges already in the early visual pathway presumably prior to facial identification,emotional processing,and aesthetic appreciation.Our observations may have general importance in disentangling different neural components and processing stages in the spatiotemporal characteristics of artistic expressions.展开更多
Neurodegenerative diseases such as Alzheimer’s disease(AD),Parkinson’s disease(PD),Amyotrophic lateral sclerosis(ALS)and retinal degeneration have been studied extensively and varying molecular mechanisms have been ...Neurodegenerative diseases such as Alzheimer’s disease(AD),Parkinson’s disease(PD),Amyotrophic lateral sclerosis(ALS)and retinal degeneration have been studied extensively and varying molecular mechanisms have been proposed for onset of such diseases.Although genetic analysis of these diseases has also been described,yet the mechanisms governing the extent of vulnerability to such diseases remains unresolved.Recent studies have,therefore,focused on the role of environmental exposure in progression of such diseases especially in the context of prenatal and postnatal life,explaining how molecular mechanisms mediate epigenetic changes leading to degenerative diseases.This review summarizes both the animal and human studies describing various environmental stimuli to which an individual or an animal is exposed during in-utero and postnatal period and mechanisms that promote neurodegeneration.The SNPs mediating gene environment interaction are also described.Further,preventive and therapeutic strategies are suggested for effective intervention.展开更多
The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule(MT)-mediated axonal transport system.This mechanistically regulated system delivers cargo...The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule(MT)-mediated axonal transport system.This mechanistically regulated system delivers cargos(proteins,mRNAs and organelles such as mitochondria)back and forth from the soma to the synapse.Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde(from the soma to the synapse)and retrograde(from the synapse to the soma)commute of the cargos,respectively.Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications(PTMs)ofα-andβ-tubulin heterodimers,core components constructing the MTs.Occurring within the lumen of MTs,K40 acetylation ofα-tubulin viaα-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible,which in turn promotes their lifespan.The movement of various motor proteins,including kinesin-1(responsible for axonal mitochondrial commute),is enhanced by this PTM,and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions,including Alzheimer’s disease and Parkinson’s disease(PD).PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels.Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question,our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD.The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored.Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it.展开更多
Cancer stem cell （CSC） theory suggests a cell-lineage structure in tumor cells in which CSCs are capable of giving rise to the other non-stem cancer cells （NSCCs） but not vice versa. However, an alternative scenar...Cancer stem cell （CSC） theory suggests a cell-lineage structure in tumor cells in which CSCs are capable of giving rise to the other non-stem cancer cells （NSCCs） but not vice versa. However, an alternative scenario of bidirectional interconversions between CSCs and NSCCs was proposed very recently. Here we present a general population model of cancer cells by integrating conventional cell divisions with direct conversions between different cell states, namely, not only can CSCs differentiate into NSCCs by asymmetric cell division, NSCCs can also dedifferentiate into CSCs by cell state conversion. Our theoretical model is validated when applying the model to recent experimental data. It is also found that the transient increase in CSCs proportion initiated from the purified NSCCs subpopulation cannot be well predicted by the conventional CSC model where the conversion from NSCCs to CSCs is forbidden, implying that the cell state conversion is required especially for the transient dynamics. The theoretical analysis also gives the condition such that our general model can be equivalently reduced into a simple Markov chain with only cell state transitions keeping the same cell proportion dynamics.展开更多
Background Alzheimer’s disease(AD)is associated with metabolic abnormalities linked to critical elements of neurodegeneration.We recently administered combined metabolic activators(CMA)to the AD rat model and observe...Background Alzheimer’s disease(AD)is associated with metabolic abnormalities linked to critical elements of neurodegeneration.We recently administered combined metabolic activators(CMA)to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals.CMA promotes mitochondrial fatty acid uptake from the cytosol,facilitates fatty acid oxidation in the mitochondria,and alleviates oxidative stress.Methods Here,we designed a randomised,double-blinded,placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients.One-dose CMA included 12.35 g L-serine(61.75%),1 g nicotinamide riboside(5%),2.55 g N-acetyl-L-cysteine(12.75%),and 3.73 g L-carnitine tartrate(18.65%).AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84.The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms.The secondary aim of this study was to evaluate the safety and tolerability of CMA.A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.Results We showed a significant decrease of AD Assessment Scale-cognitive subscale(ADAS-Cog)score on day 84 vs day 0(P=0.00001,29%improvement)in the CMA group.Moreover,there was a significant decline(P=0.0073)in ADAS-Cog scores(improvement of cognitive functions)in the CMA compared to the placebo group in patients with higher ADAS-Cog scores.Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis.Moreover,the plasma levels of proteins and metabolites associated with NAD+and glutathione metabolism were significantly improved after CMA treatment.Conclusion Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics,metabolomics,proteomics and imaging analysis.展开更多
The aim of the present paper was to check for the presence of cerebrovascular dystroglycan in vertebrates,because dystroglycan,which is localized in the vascular astroglial end-feet,has a pivotal function in glio-vasc...The aim of the present paper was to check for the presence of cerebrovascular dystroglycan in vertebrates,because dystroglycan,which is localized in the vascular astroglial end-feet,has a pivotal function in glio-vascular connections.In mammalian brains,the immunoreactivity ofβ-dystroglycan subunit delineates the vessels.The results of the present study demonstrate similar patterns in other vertebrates,except for anurans and the teleost groups Ostariophysi and Euteleostei.In this study,we investigated 1 or 2 representative species of the main groups of Chondrichthyes,teleost and non-teleost ray-finned fishes,urodeles,anurans,and reptiles.We also investigated 5 mammalian and 3 bird species.Animals were obtained from breeders or fishermen.The presence ofβ-dystroglycan was investigated immunohistochemically in free-floating sections.Pre-embedding electron microscopical immunohistochemistry on Heterodontus japonicus shark brains demonstrated that in Elasmobranchii,β-dystroglycan is also localized in the perivascular glial end-feet despite the different construction of their blood-brain barrier.The results indicated that the cerebrovascularβ-dystroglycan immunoreactivity disappeared separately in anurans,and in teleosts,in the latter group before its division to Ostariophysi and Euteleostei.Immunohistochemistry in muscles and western blots from brain homogenates,however,detected the presence ofβ-dystroglycan,even in anurans and all teleosts.A possible explanation is that in the glial end-feet,β-dystroglycan is masked in these animals,or disappeared during adaptation to the freshwater habitat.展开更多
基金Supported by grants from the Mutua Madrile a Foundation, No. FMM Ref.no AP 69772009the National Department of Science and Innovation, No. MICINN, Ref. no PSIC2010-19348, in part
文摘The development of microsurgery has been dependent on experimental animals. Microsurgery could be a very valuable technique to improve experimental models of liver diseases. Microdissection and microsutures are the two main microsurgical techniques that can be considered for classifying the experimental models developed for liver research in the rat. Partial portal vein ligation, extrahepatic cholestasis and hepatectomies are all models based on microdissection. On the other hand, in portacaval shunts, orthotopic liver transplantation and partial heterotopic liver transplantation, the microsuture techniques stand out. By reducing surgical complications, these microsurgical techniques allow for improving the resulting experimental models. If good experimental models for liver research are successfully developed, the results obtained from their study might be particularly useful in patients with liver disease. Therefore experimental liver microsurgery could be an invaluable way to translate laboratory data on liver research into new clinical diagnostic and therapeutic strategies.
文摘Brentano in 1870s was the first to introduce intentionality to mean “conscious of”. At the end of the 1960s, a version of this view was developed by analytic American philosophy to construct a theory of meaningful language. That led Dennett to claim that intentionality was mainly a feature of sentence, not mental states. In contrast, Searle in 1990s rejected the Brentanian thesis and explained intentionality by a biological naturalism. Thereafter, radical eliminativists such as Churchland claimed that all philosophical arguments merited replacement by neuroscientific knowledge. Unfortunately, very few neurophysiological studies attempted to scientifically tackle the problem raised by intentionality. The issue now emerging is a new conception of intentionality based on phenomenological, neurobiological and quantum theories, such as: 1) the notion of “intentional arc” proposed in the philosophy of Merleau-Ponty;2) the neurobiological and quantum model of Freeman, in which self-organizing pathways are accompanied by quantum transitions in controlling intentionality in brain;3) the recent hypothesis that some visuo-motor neurons would be involved in controlling these self-organized pathways;4) the quantum models of Vitiello and Globus, in which a thermofield (dissipative) system governs the dynamic dialog of dual quantum modes between environment and brain. Based on this conception of mind-world interactions, it implicitly appears that intentionality might be a fundamental force which draws us irreversibly towards the future. An alternative hypothesis based on this promising proposal is argued.
文摘Motivation: Bipolar disorder (BD) and schizophrenia (SZ) has a difficult diagnosis, so the main objective of this article is to propose the use of Artificial Neural Networks (ANNs) to classify (diagnose) groups of patients with BD or SZ from a control group using sociodemographic and biochemical variables. Methods: Artificial neural networks are used as classifying tool. The data from this study were obtained from the array collection from Stanley Neuropathology Consortium databank. Inflammatory markers and characteristics of the sampled population were the inputs variables. Results: Our findings suggest that an artificial neural network could be trained with more than 90% accuracy, aiming the classification and diagnosis of bipolar, schizophrenia and control healthy group. Conclusion: Trained ANNs could be used to improve diagnosis in Schizophrenia and Bipolar disorders.
基金results in part from collaboration and network activities promoted under the frame of the international network GENIEUR (Genes in Irritable Bowel Syndrome Research Network Europe),which has been funded by the COST program (BM1106, www.GENIEUR.eu)currently supported by the European Society of Neurogastroenterology and Motility (ESNM, www.ESNM.eu)
文摘BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.
基金National Natural Science Foundation of China,Grant/Award Number:32071062Philip KH Wong Foundation。
文摘Mental time travel(MTT)refers to the ability to mentally re-experience the past and preexperience the future.Here we briefly review impairments in MTT,its underlying cognitive and neural mechanisms,and ways to improve MTT in psychiatric patients.Future research directions on MTT are discussed.
基金National Natural Science Foundation of China,Grant/Award Number:32071062Philip KH Wong Foundation,Grant/Award Number:na。
文摘Mental time travel(MTT)is the ability to project oneself to the past or future through mental simulation.Moreover,MTT can involve self-related or other-related information.This study aimed to compare MTT in individuals with high levels of schizotypy and that in their counterparts with low levels of schizotypy.Participants with high(n=37)and low(n=37)levels of schizotypy completed an MTT task with four conditions[2(Condition:self vs.other)×2(Time orientation:past vs.future)].They were required to recall past events that had happened to themselves or to a non-intimate person,and to imagine possible future events that might happen to themselves or to a non-intimate person,related to cue words.Outcome measures included specificity,vividness,sense of experience,emotional valence,emotional intensity,proportion of first-person visual perspective in events,and difficulty in event generation.A 2(Group:high vs.low levels of schizotypy)×2(Condition)×2(Time orientation)mixed analysis of variance was conducted on each index.Results showed that self-related MTT was more specific than other-related MTT in low levels of schizotypy participants but not in high levels of schizotypy participants.Participants with a high level of schizotypy reported fewer specific events,and reported events with lower vividness and positive emotion than did those with a low level of schizotypy.Self-related MTT showed higher levels of phenomenological characteristics than did other-related MTT.In conclusion,individuals with a high level of schizotypy have altered MTT,and cannot benefit from the self-advantage effect on the specificity of MTT.
基金Hanns-Seidel FoundationNational Natural Science Foundation of China,Grant/Award Numbers:31371018,31771213Parmenides Foundation。
文摘Faces and their aesthetic appreciation are a core element of social interaction.Although studies have been made on facial processing when looking at faces with different perspectives,a direct comparison of faces in the left to the right perspective is missing.Portraits in classical Western art indicate a preference of the left compared to the right perspective,but the neural underpinnings of such an asymmetry still have to be clarified.Using functional magnetic resonance imaging,the current study focuses on the processing of three-quarter faces seen with different perspectives.Seventeen participants were asked to passively look at photographs of six male and six female faces with a neutral expression;the photographs were taken from the left,right,and frontal perspectives while keeping their focus on the eyes.The results showed that specific brain areas were involved in processing the three-quarter faces in either symmetric or asymmetric ways.Viewing left and right three-quarter faces resulted in two mirror-like activations in the striate cortex corresponding to the symmetric layout of the left and right perspectives.Viewing the left face resulted additionally in an enhanced activation also in the left extrastriate cortex.The right perspective of male faces elicited a lower activation compared to other perspectives in face-selective areas of the brain.Our findings suggest that the preference of the left three-quarter face emerges already in the early visual pathway presumably prior to facial identification,emotional processing,and aesthetic appreciation.Our observations may have general importance in disentangling different neural components and processing stages in the spatiotemporal characteristics of artistic expressions.
基金This work was supported by grants from Alzheimer's Association and National Institute on Aging/NH to DKL.We sincerely thank the assistance of Bryan Maloney.
文摘Neurodegenerative diseases such as Alzheimer’s disease(AD),Parkinson’s disease(PD),Amyotrophic lateral sclerosis(ALS)and retinal degeneration have been studied extensively and varying molecular mechanisms have been proposed for onset of such diseases.Although genetic analysis of these diseases has also been described,yet the mechanisms governing the extent of vulnerability to such diseases remains unresolved.Recent studies have,therefore,focused on the role of environmental exposure in progression of such diseases especially in the context of prenatal and postnatal life,explaining how molecular mechanisms mediate epigenetic changes leading to degenerative diseases.This review summarizes both the animal and human studies describing various environmental stimuli to which an individual or an animal is exposed during in-utero and postnatal period and mechanisms that promote neurodegeneration.The SNPs mediating gene environment interaction are also described.Further,preventive and therapeutic strategies are suggested for effective intervention.
文摘The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule(MT)-mediated axonal transport system.This mechanistically regulated system delivers cargos(proteins,mRNAs and organelles such as mitochondria)back and forth from the soma to the synapse.Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde(from the soma to the synapse)and retrograde(from the synapse to the soma)commute of the cargos,respectively.Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications(PTMs)ofα-andβ-tubulin heterodimers,core components constructing the MTs.Occurring within the lumen of MTs,K40 acetylation ofα-tubulin viaα-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible,which in turn promotes their lifespan.The movement of various motor proteins,including kinesin-1(responsible for axonal mitochondrial commute),is enhanced by this PTM,and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions,including Alzheimer’s disease and Parkinson’s disease(PD).PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels.Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question,our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD.The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored.Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it.
文摘Cancer stem cell （CSC） theory suggests a cell-lineage structure in tumor cells in which CSCs are capable of giving rise to the other non-stem cancer cells （NSCCs） but not vice versa. However, an alternative scenario of bidirectional interconversions between CSCs and NSCCs was proposed very recently. Here we present a general population model of cancer cells by integrating conventional cell divisions with direct conversions between different cell states, namely, not only can CSCs differentiate into NSCCs by asymmetric cell division, NSCCs can also dedifferentiate into CSCs by cell state conversion. Our theoretical model is validated when applying the model to recent experimental data. It is also found that the transient increase in CSCs proportion initiated from the purified NSCCs subpopulation cannot be well predicted by the conventional CSC model where the conversion from NSCCs to CSCs is forbidden, implying that the cell state conversion is required especially for the transient dynamics. The theoretical analysis also gives the condition such that our general model can be equivalently reduced into a simple Markov chain with only cell state transitions keeping the same cell proportion dynamics.
基金funding provided by Royal Institute of Technology.This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation(72110).
文摘Background Alzheimer’s disease(AD)is associated with metabolic abnormalities linked to critical elements of neurodegeneration.We recently administered combined metabolic activators(CMA)to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals.CMA promotes mitochondrial fatty acid uptake from the cytosol,facilitates fatty acid oxidation in the mitochondria,and alleviates oxidative stress.Methods Here,we designed a randomised,double-blinded,placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients.One-dose CMA included 12.35 g L-serine(61.75%),1 g nicotinamide riboside(5%),2.55 g N-acetyl-L-cysteine(12.75%),and 3.73 g L-carnitine tartrate(18.65%).AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84.The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms.The secondary aim of this study was to evaluate the safety and tolerability of CMA.A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.Results We showed a significant decrease of AD Assessment Scale-cognitive subscale(ADAS-Cog)score on day 84 vs day 0(P=0.00001,29%improvement)in the CMA group.Moreover,there was a significant decline(P=0.0073)in ADAS-Cog scores(improvement of cognitive functions)in the CMA compared to the placebo group in patients with higher ADAS-Cog scores.Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis.Moreover,the plasma levels of proteins and metabolites associated with NAD+and glutathione metabolism were significantly improved after CMA treatment.Conclusion Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics,metabolomics,proteomics and imaging analysis.
文摘The aim of the present paper was to check for the presence of cerebrovascular dystroglycan in vertebrates,because dystroglycan,which is localized in the vascular astroglial end-feet,has a pivotal function in glio-vascular connections.In mammalian brains,the immunoreactivity ofβ-dystroglycan subunit delineates the vessels.The results of the present study demonstrate similar patterns in other vertebrates,except for anurans and the teleost groups Ostariophysi and Euteleostei.In this study,we investigated 1 or 2 representative species of the main groups of Chondrichthyes,teleost and non-teleost ray-finned fishes,urodeles,anurans,and reptiles.We also investigated 5 mammalian and 3 bird species.Animals were obtained from breeders or fishermen.The presence ofβ-dystroglycan was investigated immunohistochemically in free-floating sections.Pre-embedding electron microscopical immunohistochemistry on Heterodontus japonicus shark brains demonstrated that in Elasmobranchii,β-dystroglycan is also localized in the perivascular glial end-feet despite the different construction of their blood-brain barrier.The results indicated that the cerebrovascularβ-dystroglycan immunoreactivity disappeared separately in anurans,and in teleosts,in the latter group before its division to Ostariophysi and Euteleostei.Immunohistochemistry in muscles and western blots from brain homogenates,however,detected the presence ofβ-dystroglycan,even in anurans and all teleosts.A possible explanation is that in the glial end-feet,β-dystroglycan is masked in these animals,or disappeared during adaptation to the freshwater habitat.
